Novel aminocyclohexane derivatives

专利摘要:
The present invention relates to a compound of formula (I) wherein U, V, W, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , m and n are as defined in the specification and claims; To salts and / or pharmaceutically acceptable esters. The compounds are used in diseases associated with 2,3-oxidosqualene-lanosterol cyclase such as hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal diseases, parasitic infections, cholelithiasis, tumors and / or hyperproliferative disorders. Treatment and / or prevention, and / or treatment and / or prevention of impaired glucose tolerance and diabetes.
公开号:KR20030048010A
申请号:KR10-2003-7002254
申请日:2001-08-08
公开日:2003-06-18
发明作者:악커만얀；아에비요하네스；블룸데니제；추콜로브스키알렉산더；뎀로브헨리에타；마에르키한스-페터；모랑올리비에；트루자르디레네；폰데르마르크엘리자베트；발바움자비네；벨러토마스
申请人:에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

Novel aminocyclohexane derivatives {NOVEL AMINOCYCLOHEXANE DERIVATIVES}
[17] The compounds of the present invention inhibit the 2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.) Required for the biosynthesis of cholesterol, ergosterol and other sterols. Causal risk factors that directly promote the expression of coronary and peripheral atherosclerosis include elevated low density lipoprotein cholesterol (LDL-C), low high density lipoprotein cholesterol (HDL-C), high blood pressure, smoking and diabetes. Other synergistic risk factors include elevated concentrations of triglyceride (TG) -rich lipoproteins, small, dense, low density lipoprotein particles, lipoproteins (a) (Lp (a)), and homocysteine. Predisposing risk factors indirectly affect atherosclerosis by altering the causative or condition risk factors. Predisposing risk factors are obesity, physical lethargy, family history of early CVD, and men. The strong association of high LDL-C levels in plasma with coronary heart disease (CHD) and the therapeutic benefits of lowering elevated LDL-C levels are now well documented (Gotto et al., Circulation 81, 1990). , 1721-1733; Stein et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113-156; Illingworth, Med. Clin. North. Am. 84, 2000, 23-42). Cholesterol-rich, often unstable atherosclerotic plaques cause blood vessel obstruction resulting in ischemia or infarction. Studies on primary prevention have shown that by lowering plasma LDL-C levels in plasma, the overall morbidity remains unchanged while the frequency of nonfatal seizures of CHD is reduced. CHD lethality and morbidity are reduced by lowering plasma LDL-C levels in patients with pre-established CHD (secondary intervention); Meta-analysis of other studies has shown that this decrease is proportional to the decrease in LDL-C (see Ross et al., Arch. Intern. Med. 159, 1999, 1793-1802). .
[18] The clinical benefit of cholesterol lowering is greater in patients with pre-established CHD than in humans with no symptoms of hypercholesterolemia. According to current guidelines, cholesterol lowering treatment is required for patients who have survived myocardial infarction or for patients with angina or other atherosclerotic disease, with a target LDL-C level of 100 mg / dl.
[19] Agents such as bile acid sequestrant, fibrate, nicotinic acid, probucol and statins, ie HMG-Co-A reductase inhibitors such as simvastatin and atorvastatin, are used in conventional standard therapies. Best statins effectively reduce plasma LDL-C by more than 40% and also reduce plasma triglycerides, a synergistic risk factor, but less effective. In contrast, fibrate effectively reduces plasma glycerides while LDL-C does not. The combination of statins and fibrate has proven to be very effective in lowering LDL-C and triglycerides (see Ellen and McPherson, J. Cardiol. 81, 1998, 60B-65B), but the safety of the combination is still It is controversial (see Shepherd, Eur. Heart J. 16, 1995, 5-13). Single drugs with mixed propyl combinations that are effective in lowering both LDL-C and triglycerides provide additional clinical benefit to asymptomatic and symptomatic patients.
[20] In humans, statins are resistant at standard doses, but at high doses, the reduction of non-sterol intermediates of cholesterol synthesis pathways such as isoprenoids and coenzyme Q may be associated with adverse clinical events (Davignon et al. , Can. J. Cardiol. 8, 1992, 843-864; Pederson and Tobert, Drug Safety 14, 1996, 11-24).
[21] This has prompted the search and development of compounds that inhibit cholesterol biosynthesis but which are distal to the synthesis of these important non-sterol intermediates. The microsomal enzyme 2,3-oxidosqualene: lanosterol cyclase (OSC) represents a unique target for cholesterol-lowering drugs (Morand et al., J. Lipid Res., 38, 1997, 373-390; Mark et al., J. Lipid Res. 37, 1996, 148-158). OSC is downstream of the farnesyl-pyrophosphate beyond the synthesis of isoprenoids and coenzyme Q. In hamsters, pharmacologically active administration of OSC inhibitors did not show adverse side effects, in contrast to statins, which reduce food intake and body weight and increase plasma bilirubin, liver weight and hepatic triglyceride content (Morand et al. , J. Lipid Res., 38, 1997, 373-390). The compounds described in European Patent Application No. 636367, which inhibit OSC and lower the total cholesterol of the plasma, belong to this substance.
[22] OSC inhibition does not trigger overexpression of indirect negative feedback regulatory mechanisms involved in the production of 24 (S), 25-epoxycholesterol (Peffley et al., Biochem. Pharmacol. 56, 1998, 439-449; Nelson et al. ., J. Biol. Chem. 256, 1981, 1067-1068; Spencer et al., J. Biol. Chem. 260, 1985, 13391-13394; Panini et al., J.Lipid Res. 27, 1986, 1190. -1204; Ness et al., Arch. Biochem. Biophys. 308, 1994, 420-425). This negative feedback control mechanism is fundamental to the concept of OSC inhibition, because (i) indirect down-regulation of HMGR synergistically enables the primary inhibitory effect, and (ii) the precursor monooxidose squalene in the liver. This is because it prevents the accumulation of large amounts. In addition, 24 (S), 25-epoxycholesterol has been found to be one of the most potent agonists of nuclear receptor LXR (Janowski et al., Proc. Natl. Acad. Sci. USA, 96, 1999, 266-271). ] Reference). Given that 24 (S), 25-epoxycholesterol is a by-product of OSC inhibition, the OSC inhibitors of the present invention are (i) cholesterol-7α-hydroxylase for increasing cholesterol consumption through the bile acid route, (ii) Stimulate reverse cholesterol transport and increase plasma HDL-C levels (Venkateswaran et al., J. Biol. Chem. 275, 2000, 14700-14707; Costet et al., J. Biol. Chem. See June 2000, in press; Ordovas, Nutr Rev 58, 2000, 76-79, Schmitz and Kaminsky, Front Biosci 6, 2001, D505-D514) to inhibit intestinal cholesterol absorption (Mangelsdorf, XIIth International Symposium on Atherosclerosis , Stockholm, June 2000). It is hypothesized that LXR-dependent pathways, such as the expression of latent ABC proteins, may also be indirectly activated. In addition, there is a hypothesis that cross-talk between fatty acid and cholesterol circulation mediated by liver LXR is possible (see Tobin et al., Mol. Endocrinol. 14,2000, 741-752).
[23] The compounds of formula (I) of the present invention inhibit OSC, thus inhibiting the biosynthesis of cholesterol, ergosterol and other sterols and reducing plasma cholesterol levels. Thus, the compounds can be used for the treatment and prevention of hypercholesterolemia, hyperlipidemia, atherosclerosis and common vascular diseases. In addition, the compounds can be used for the treatment and / or prevention of filamentous fungal diseases, parasitic infections, cholelithiasis, cholestatic liver disorders, tumors and hyperproliferative disorders such as hyperproliferative skin and vascular disorders. In addition, it has unexpectedly been found that the compounds of the present invention can also be used therapeutically to improve glucose tolerance for the treatment and / or prevention of related diseases such as diabetes. The compounds of the present invention also exhibit improved pharmaceutical properties compared to known compounds.
[1] The present invention relates to novel aminocyclohexanol derivatives, their preparation and their use as medicaments. In particular, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts and / or pharmaceutically acceptable esters thereof:
[2]
[3] Where
[4] U is O or a lone pair of electrons,
[5] V is O, S, -CH _2- , -CH = CH-, or -C≡C-,
[6] W is CO, COO, CONR ¹ , CSO, CSNR ¹ , SO ₂ , or SO ₂ NR ¹ ,
[7] m and n are independently from each other 0-7 and m + n is 0-7, when V is O or S, m is not 0,
[8] A ¹ is H, lower-alkyl, hydroxy-lower-alkyl, or lower-alkenyl,
[9] A ² is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, or lower-alkenyl, optionally substituted with R ² ,
[10] A ³ and A ⁴ are hydrogen or lower-alkyl, or
[11] A ¹ and A ² or A ¹ and A ³ are bonded to each other to form a ring and -A ¹ -A ² -or -A ¹ -A ³ -is lower-alkylene or lower-alke optionally substituted with R ² Nylene, wherein one -CH ₂ -group of -A ¹ -A ² -or -A ¹ -A ³ -can optionally be replaced with NR ³ , S, or O, or
[12] A ³ and A ⁴ are bonded to each other to form a ring together with the carbon atom to which they are attached and -A ³ -A ⁴ -is optionally-(CH ₂ ) _2-5 which may be monosubstituted or polysubstituted with lower-alkyl. -ego,
[13] A ⁵ is H, lower-alkyl, lower-alkenyl, or aryl-lower-alkyl,
[14] A ⁶ is lower-alkyl, cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, lower-alkoxy-carbonyl-lower-alkyl,
[15] R ² is hydroxy, hydroxy-lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl, N (R ⁴ , R ⁵ ), or thio-lower-alkoxy,
[16] R ¹ , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen or lower-alkyl.
[24] Unless otherwise indicated, the following definitions are presented to illustrate and define the meaning and scope of the various terms used to describe the invention.
[25] As used herein, the term "lower" means a group having 1 to 7, preferably 1 to 4 carbon atoms.
[26] The term "isolated electron pair" refers to an unbonded electron pair, especially an unpaired electron pair of nitrogen atoms, for example in an amine.
[27] The term "halogen" refers to fluorine, chlorine, bromine and iodine, with chlorine, bromine and iodine being preferred.
[28] The term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical having 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms. Alkyl groups can be substituted, for example, with halogen, CN, NO ₂ , carboxy and / or phenyl. Other, more preferred substituents are hydroxy, lower-alkoxy, NH ₂ , N (lower-alkyl) ₂ and / or lower-alkoxycarbonyl.
[29] The term "lower-alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. The term is also exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. Lower-alkyl groups may have a substitution pattern as described above in connection with the term "alkyl".
[30] The term "cycloalkyl" refers to a monovalent carbocyclic radical having 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. Cycloalkyl wherein one or more —CH ₂ — groups are substituted with O, S, NH or N (lower alkyl) is referred to as “heterocycloalkyl”.
[31] The term "alkoxy" refers to the group R'-O-, wherein R 'is alkyl. The term "lower-alkoxy" refers to the group R'-O-, wherein R 'is lower-alkyl. The term "thio-alkoxy" refers to the group R'-S-, wherein R 'is alkyl. The term "thio-lower-alkoxy" refers to the group R'-S-, wherein R 'is lower-alkyl.
[32] The term "alkenyl", alone or in combination with other groups, means a straight or branched hydrocarbon moiety comprising one olefin bond and having up to 20 carbon atoms, preferably up to 16 carbon atoms. The term "lower-alkenyl" refers to a straight or branched hydrocarbon residue, such as 2-propenyl, containing one olefin bond and having up to 7 carbon atoms, preferably up to 4 carbon atoms. Alkenyl or lower-alkenyl groups may have a substitution pattern as described above in connection with the term "alkyl".
[33] The term "alkylene" refers to a straight or branched divalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms. The term "lower-alkylene" refers to a straight or branched divalent saturated aliphatic hydrocarbon group having 1 to 7, preferably 2 to 4 carbon atoms. The alkylene or lower-alkylene group may have a substitution pattern as described above in connection with the term "alkyl".
[34] The term "alkenylene" refers to a straight or branched divalent hydrocarbon group containing one olefin bond and having up to 20 carbon atoms, preferably up to 16 carbon atoms. The term "lower-alkenylene" refers to a straight or branched divalent hydrocarbon group containing one olefin bond and having up to 7 carbon atoms, preferably up to 4 carbon atoms. Alkenylene or lower-alkenylene groups may have a substitution pattern as described above in connection with the term “alkyl”.
[35] The term "aryl" refers to lower-alkyl, lower-alkyl-di-oxo, halogen, hydroxy, cyano, CF ₃ , NH ₂ , N (lower-alkyl) ₂ , aminocarbonyl, carboxy, nitro, lower- Alkoxy, lower-alkylcarbonyl, lower-alkylcarbonyloxy, aryl, aryl oxy or lower-alkylcarbonyl-amino, preferably lower-alkyl, lower-alkyl-di-oxo, halogen, hydroxy, cyano Optionally substituted by CF ₃ , NH ₂ , N (lower-alkyl) ₂ , aminocarbonyl, carboxy, nitro, lower-alkoxy, lower-alkylcarbonyl, lower-alkylcarbonyloxy, aryl or aryloxy Or phenyl or naphthyl groups which may be polysubstituted. Preferred substituents are lower-alkyl, lower alkoxy, lower-alkyl-carbonyl, lower-alkoxycarbonyl, fluorine, chlorine, bromine, CN, CF ₃ , NO ₂ , NH ₂ and / or N (lower-alkyl) ₂ . More preferred substituents are fluorine, chlorine, bromine and CF ₃ .
[36] The term "heteroaryl" refers to an aromatic five or six membered ring, such as furyl, pyridyl, 1,2-, 1,3, which may include one, two or three atoms selected from nitrogen, oxygen and / or sulfur. And 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl. The term “heteroaryl” also refers to a bicyclic aromatic comprising two 5- or 6-membered rings in which one ring or both rings may contain one, two or three atoms selected from nitrogen, oxygen or sulfur. Groups such as indole or chinoline, or partially hydrogenated bicyclic aromatic groups such as indolinyl. Heteroaryl groups may have a substitution pattern as described above in connection with the term “aryl”.
[37] The term "pharmaceutically acceptable salts" refers to hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, salts with inorganic or organic acids such as p-toluenesulfonic acid and the like. Preferred salts are formate, hydrochloride and hydrobromide.
[38] The term "pharmaceutically acceptable ester" means that the hydroxy groups are inorganic or organic acids such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. It encompasses esters of compounds of formula (I) which are non-toxic to living organisms, converted to the corresponding esters.
[39] In particular, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts and / or pharmaceutically acceptable esters thereof:
[40] Formula I
[41]
[42] Where
[43] U is O or a lone pair of electrons,
[44] V is O, S, -CH _2- , -CH = CH-, or -C≡C-,
[45] W is CO, COO, CONR ¹ , CSO, CSNR ¹ , SO ₂ , or SO ₂ NR ¹ ,
[46] m and n are independently from each other 0-7 and m + n is 0-7, when V is O or S, m is not 0,
[47] A ¹ is H, lower-alkyl, hydroxy-lower-alkyl, or lower-alkenyl,
[48] A ² is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, or lower-alkenyl, optionally substituted with R ² ,
[49] A ³ and A ⁴ are hydrogen or lower-alkyl, or
[50] A ¹ and A ² or A ¹ and A ³ are bonded to each other to form a ring and -A ¹ -A ² -or -A ¹ -A ³ -is lower-alkylene or lower-alke optionally substituted with R ² Nylene, wherein one -CH ₂ -group of -A ¹ -A ² -or -A ¹ -A ³ -can optionally be replaced with NR ³ , S, or O, or
[51] A ³ and A ⁴ are bonded to each other to form a ring together with the carbon atom to which they are attached and -A ³ -A ⁴ -is optionally-(CH ₂ ) _2-5 which may be monosubstituted or polysubstituted with lower-alkyl. -ego,
[52] A ⁵ is H, lower-alkyl, lower-alkenyl, or aryl-lower-alkyl,
[53] A ⁶ is lower-alkyl, cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, lower-alkoxy-carbonyl-lower-alkyl,
[54] R ² is hydroxy, hydroxy-lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl, N (R ⁴ , R ⁵ ), or thio-lower-alkoxy,
[55] R ¹ , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen or lower-alkyl.
[56] In formula (I) as defined above, compounds in which A ³ and A ⁴ are bonded to each other and together with the carbon atoms to which they are attached do not form a ring are preferred. In such compounds,
[57] A ¹ is H, lower-alkyl, hydroxy-lower-alkyl, or lower-alkenyl,
[58] A ² is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, or lower-alkenyl, optionally substituted with R ² ,
[59] A ³ and A ⁴ are hydrogen or lower-alkyl, or
[60] A ¹ and A ² or A ¹ and A ³ are bonded to each other to form a ring and -A ¹ -A ² -or -A ¹ -A ³ -is lower-alkylene or lower-alke optionally substituted with R ² Nylene, wherein one -CH ₂ -group of -A ¹ -A ² -or -A ¹ -A ³ -can optionally be replaced with NR ³ , S, or O.
[61] Preference is given to compounds of the formula (I) and / or pharmaceutically acceptable salts thereof. Another preferred embodiment relates to compounds wherein U is an isolated electron pair in Formula I and further preferred embodiments relates to compounds wherein U is O in Formula I.
[62] A further preferred embodiment of the invention relates to the trans-form of a compound as defined above characterized by the formula
[63]
[64] Wherein U, V, W, m, n, A ¹ , A ² , A ³ , A ⁴ , A ⁵ and A ⁶ have the meanings given above.
[65] Particularly preferred are compounds in which V represents O, as are compounds in which V is -CH _2- . Also preferred are compounds wherein V represents -C = C-. In addition, compounds in which V represents -C≡C- also relate to preferred embodiments of the invention.
[66] Among the compounds of the invention, it is particularly individually preferred that W represents CO, COO, CONR ¹ , CSNR ¹ , SO ₂ or SO ₂ NR ¹ , R ¹ is hydrogen, and W represents COO or SO ₂ . Do.
[67] Preferred are compounds of the invention wherein n is 0, and so is n. Another preferred embodiment relates to compounds as defined above, wherein m is 1-6. Also preferred are compounds as defined above wherein m is 0 and V is -C = C- or -C≡C-.
[68] In compounds in which A ¹ represents lower-alkyl, the lower-alkyl group may be optionally substituted with fluorine. Another preferred compound of the invention is that A ¹ represents H, methyl, ethyl, isopropyl, 2-hydroxy-ethyl or 2-propenyl. Another group of preferred compounds of the invention represent lower-alkyl, cycloalkyl-lower-alky, or lower-alkenyl, wherein A ² is optionally substituted with R ² , wherein R ² is hydroxy, methoxy, or ethoxy Particular preference is given to compounds which are carbonyl and wherein A ² represents methyl, ethyl, 2-hydroxy-ethyl, 2-propenyl, propyl or isopropyl.
[69] In formula (I), A ¹ and A ² are bonded to each other to form a ring, and -A ¹ -A ² -is lower-alkylene or lower-alkenylene optionally substituted with R ² , -A ¹ -A ^2- One -CH ₂ -group of may optionally be replaced with NR ³ , S, or O, R ² and R ³ is also preferably a compound as defined above, A ¹ and A ² are bonded to each other to form a ring And -A ¹ -A ² -can be lower-alkylene or lower-alkenylene optionally substituted with R ² , wherein one -CH ₂ -group of -A ¹ -A ² -can be optionally replaced with O With R ² being hydroxy or 2-hydroxyethyl. Especially preferred are compounds as defined above. In compounds in which A ¹ and A ² are bonded to each other to form a ring, the ring is preferably a 4, 5 or 6 membered ring such as, for example, piperidinyl or pyrrolidinyl. Preferred compounds as defined above are those in which A ¹ and A ² are bonded to each other to form a ring and -A ¹ -A ² -is-(CH ₂ ) _5- . The compound thus comprises a piperidinyl group.
[70] A further preferred embodiment of the invention relates to compounds in which A ³ and / or A ⁴ in formula (I) represent hydrogen. Compounds in which A ³ and A ⁴ are bonded to each other to form a cyclopropyl ring with the carbon atoms to which they are attached and -A ³ -A ⁴ -is-(CH ₂ ) ₂ -represent another preferred embodiment of the invention . The _term- (CH ₂ ) _2-5 -denotes-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ ) ₄ -and-(CH ₂ ) ₅ -groups.
[71] Preference is furthermore given to compounds wherein in the formula (I) H ⁵ is optionally substituted with halogen, lower-alkyl, lower-alkenyl, or benzyl, it is particularly preferred that A ⁵ represents methyl or ethyl.
[72] In formula (I), A ⁶ is lower-alkyl, lower-alkoxy, lower-alkylcarbonyl, lower-alkoxycarbonyl, fluorine, chlorine, bromine, CN, CF ₃ , NO ₂ , or N (R ⁶ , R ⁷ ) ( Wherein R ⁶ and R ⁷ independently of one another are hydrogen or lower-alkyl, lower-alkyl, cycloalkyl, phenyl, naphthyl, phenyl-lower-alkyl, pyri, optionally substituted with one or more substituents selected from the group consisting of Compounds which are dill, indolyl, indolinyl, thienyl, thienyl-methylene, furyl-methylene, benzodioxyl, chinolyl, isoxazolyl, or imidazolyl are other preferred embodiments of the invention and A ⁶ is More preferred are compounds wherein phenyl is phenyl optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine and CF ₃ , wherein A ⁶ is 4-chloro-phenyl, 4-bromo-phenyl or 4-trifluoro Particular preference is given to compounds which are methyl-phenyl.
[73] Preferred compounds of formula (I) are selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:
[74] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-nitro-phenyl ester,
[75] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid naphthalen-2-yl ester,
[76] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid pentafluorophenylmethyl ester,
[77] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid benzyl ester,
[78] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid phenyl ester,
[79] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid p-tolyl ester,
[80] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[81] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester,
[82] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[83] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid hexyl ester,
[84] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-methoxy-phenyl ester,
[85] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid isobutyl ester,
[86] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[87] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[88] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[89] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[90] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester,
[91] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester,
[92] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[93] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[94] {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[95] {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid isobutyl ester,
[96] {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid phenyl ester,
[97] 4-({4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamoyloxy) -benzoic acid methyl ester,
[98] {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-methoxy-phenyl ester,
[99] {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid p-tolyl ester,
[100] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[101] Trans- [4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[102] Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[103] Trans- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[104] {4-trans- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester,
[105] {4-trans- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[106] Trans {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 2,4-difluoro-phenyl ester,
[107] {4- [trans-4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[108] [Trans-4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[109] (Trans-4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[110] [Trans-4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[111] Ethyl- [trans-4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 3,4-difluoro-phenyl ester,
[112] [Trans-4- (4-azetidin-1-yl-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[113] Methyl- [trans-4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -carbamic acid 3,4-difluoro-phenyl ester,
[114] Methyl- [trans-4- (4-pyrrolidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 3,4-difluoro-phenyl ester,
[115] (4- {trans-4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[116] Trans-5-chloro-thiophene-2-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[117] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4, N-dimethyl-benzenesulfonamide,
[118] Trans-naphthalene-2-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[119] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-methanesulfonamide,
[120] Trans-quinoline-8-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[121] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-C-phenyl-methanesulfonamide,
[122] Trans-3,5-dimethyl-isoxazole-4-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[123] Trans-naphthalene-1-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[124] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-methoxy-N-methyl-benzenesulfonamide,
[125] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[126] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-N-methyl-benzenesulfonamide,
[127] Trans-thiophene-2-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[128] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2-fluoro-N-methyl-benzenesulfonamide,
[129] Trans-1-methyl-1H-imidazole-4-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[130] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-tert-butyl-N-methyl-benzenesulfonamide,
[131] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-butoxy-N-methyl-benzenesulfonamide,
[132] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-chloro-N-methyl-benzenesulfonamide,
[133] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[134] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-bromo-N-methyl-benzenesulfonamide,
[135] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-nitro-benzenesulfonamide,
[136] Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide,
[137] Trans-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[138] Trans-4-bromo-N-methyl-N- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -benzenesulfonamide,
[139] Trans-N- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -4-bromo-N-methyl-benzenesulfonamide,
[140] Trans-4-bromo-N- {4- [6- (butyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[141] Trans-4-bromo-N-methyl-N- [4- (6-piperidin-1-yl-hexyloxy) -cyclohexyl] -benzenesulfonamide,
[142] Trans-4-bromo-N- {4- [6- (3,6-dihydro-2H-pyridin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl- benzenesulfonamide,
[143] Trans-4-bromo-N- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide,
[144] Trans-4-bromo-N- {4- [6- (3-hydroxy-pyrrolidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[145] Trans-4-bromo-N-methyl-N- {4- [6- (methyl-propyl-amino) -hexyloxy] -cyclohexyl} -benzenesulfonamide,
[146] Trans-4-bromo-N- [4- (6-diallylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
[147] Trans-4-bromo-N- {4- [6- (4-hydroxymethyl-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[148] Trans-4-bromo-N- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide,
[149] Trans-4-bromo-N-methyl-N- {4- [6- (4-methyl-piperidin-1-yl) -hexyloxy] -cyclohexyl} -benzenesulfonamide,
[150] Trans-4-bromo-N- {4- [6- (4-hydroxy-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[151] Trans-4-bromo-N- {4- [6- (cyclopropylmethyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[152] Trans-[(6- {4-[(4-bromo-benzenesulfonyl) -methyl-amino] -cyclohexyloxy} -hexyl) -methyl-amino] -acetic acid ethyl ester,
[153] Trans-N- [4- (6-allylamino-hexyloxy) -cyclohexyl] -4-bromo-N-methyl-benzenesulfonamide,
[154] Trans-4-bromo-N- {4- [6- (2-hydroxy-ethylamino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[155] Trans-4-bromo-N- [4- (6-ethylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
[156] Trans-N-methyl-N- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[157] Trans-N- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[158] Trans-N- {4- [6- (butyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[159] Trans-N-methyl-N- [4- (6-piperidin-1-yl-hexyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[160] Trans-N- {4- [6- (3,6-dihydro-2H-pyridin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide ,
[161] Trans-N- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[162] Trans-N- {4- [6- (3-hydroxy-pyrrolidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[163] Trans-N-methyl-N- {4- [6- (methyl-propyl-amino) -hexyloxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[164] Trans-N- [4- (6-diallylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[165] Trans-N- {4- [6- (4-hydroxymethyl-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[166] Trans-N- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[167] Trans-N- {4- [6- (4-hydroxy-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[168] Trans-N- {4- [6- (cyclopropylmethyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[169] Trans- [methyl- (6- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -hexyl) -amino] -acetic acid ethyl ester,
[170] Trans- [methyl- (6- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -hexyl) -amino] -acetic acid,
[171] Trans-N- [4- (6-allylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[172] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-chloro-N-methyl-benzenesulfonamide,
[173] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2,4-difluoro-N-methyl-benzenesulfonamide,
[174] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2-bromo-N-methyl- benzenesulfonamide,
[175] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-bromo-N-methyl-benzenesulfonamide,
[176] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2,4-dichloro-N-methyl-benzenesulfonamide,
[177] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-fluoro-N-methyl- benzenesulfonamide,
[178] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3,4-dichloro-N-methyl-benzenesulfonamide,
[179] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2-chloro-N-methyl-benzenesulfonamide,
[180] N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3,4-difluoro-N-methyl-benzenesulfonamide,
[181] Trans-N- [4- (3-allylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[182] Trans-N- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} N-methyl-4-trifluoromethyl-benzenesulfonamide,
[183] Trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxy} -cyclohexyl) N-methyl-4-trifluoromethyl-benzenesulfonamide,
[184] Trans-N- [4- (3-diethylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[185] Trans-N- (4- {3-[(2-hydroxy-ethyl) -methyl-amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[186] Trans-N- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -propoxy} -cyclohexyl) N-methyl-4-trifluoromethyl-benzenesulfonamide,
[187] Trans-N- {4- [3- (cyclopropylmethyl-methyl-amino) -propoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[188] Trans-N-methyl-N- [4- (3-pyrrolidin-1-yl-propoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[189] Trans-N- [4- (3-ethylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[190] Trans-N-methyl-N- [4- (3-morpholin-4-yl-propoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[191] Trans-N- {4- [3- (2-hydroxy-ethylamino) -propoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[192] Trans-N- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[193] Trans-N- {4- [3- (3,6-dihydro-2H-pyridin-1-yl) -propoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[194] Trans-N-methyl-N- {4- [3- (methyl-propyl-amino) -propoxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[195] Trans-N- [4- (4-allylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[196] N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl- benzenesulfonamide,
[197] Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[198] Trans-N- [4- (4-diethylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[199] Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[200] Trans-N- (4- {4-[(2-methoxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[201] Trans-N- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[202] Trans-N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[203] Trans-N- {4- [4- (cyclopropylmethyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[204] Trans-N- [4- (4-ethylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[205] Trans-N-methyl-N- [4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[206] Trans-N- {4- [4- (2-hydroxy-ethylamino) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[207] Trans-N- {4- [4- (3,6-dihydro-2H-pyridin-1-yl) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[208] Trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[209] Trans-N- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[210] Trans-N- (4- {3-[(2-methoxy-ethyl) -methyl-amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[211] N- {4-trans- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -4-chloro-N-methyl-benzenesulfonamide,
[212] N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-chloro-N-methyl-benzenesulfonamide,
[213] N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-bromo-N-methyl-benzenesulfonamide,
[214] N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-C-phenyl-methanesulfonamide,
[215] N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-fluoro-N-methyl-benzenesulfonamide,
[216] N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -2-fluoro-N-methyl- benzenesulfonamide,
[217] N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl- benzenesulfonamide,
[218] 5-Chloro-thiophene-2-sulfonic acid {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-amide,
[219] Trans-pyridine-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[220] Trans-1H-indole-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[221] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzamide,
[222] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-chloro-N-methyl-benzamide,
[223] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-N-methyl-benzamide,
[224] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-bromo-N-methyl-benzamide,
[225] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzamide,
[226] Trans-thiophene-3-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[227] Trans-5-bromo-thiophene-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[228] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-2-thiophen-3-yl-acetamide,
[229] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2- (2,4-difluoro-phenyl) -N-methyl-acetamide,
[230] Trans-5-fluoro-1H-indole-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[231] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2- (4-fluoro-phenyl) -N-methyl-acetamide,
[232] Trans-1H-indole-5-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide,
[233] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-chloro-N-methyl-benzamide,
[234] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-3, N-dimethyl-benzamide,
[235] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-nitro-benzamide,
[236] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4, N-dimethyl-benzamide,
[237] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-cyano-N-methyl-benzamide,
[238] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3, N-dimethyl-benzamide,
[239] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3,4-dimethoxy-N-methyl-benzamide,
[240] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-methoxy-N-methyl-benzamide,
[241] Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-N-methyl-3-nitro-benzamide,
[242] Trans-4-acetyl-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzamide,
[243] Trans-N- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzamide,
[244] Trans-N- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzamide,
[245] Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3-cyano-N-methyl-benzamide,
[246] Trans-N- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -4-bromo-N-methyl-benzamide,
[247] Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-bromo-N-methyl-benzamide,
[248] Trans-5-bromo-thiophene-2-carboxylic acid {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-amide,
[249] Trans-N- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -4-fluoro-N-methyl-benzamide,
[250] Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-fluoro-N-methyl-benzamide,
[251] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2,4-difluoro-phenyl) -1-methyl-urea,
[252] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2,4-dimethoxy-phenyl) -1-methyl-urea,
[253] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methyl-urea,
[254] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-methoxy-phenyl) -1-methyl-urea,
[255] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3-p-tolyl-urea,
[256] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-methoxy-2-methyl-phenyl) -1-methyl-urea,
[257] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2,4-dimethyl-phenyl) -1-methyl-urea,
[258] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (3,4,5-trimethoxy-phenyl) -urea,
[259] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (3,4-dimethyl-phenyl) -1-methyl-urea,
[260] Trans-3- (4-acetyl-phenyl) -1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-urea,
[261] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-chloro-phenyl) -1-methyl-urea,
[262] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3-phenyl-urea,
[263] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -urea,
[264] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (3,4-dichloro-phenyl) -1-methyl-urea,
[265] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methyl-urea,
[266] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3-naphthalen-2-yl-urea,
[267] Trans-{4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (4-nitro-phenyl) -urea,
[268] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-dimethylamino-phenyl) -1-methyl-urea,
[269] Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -1 methyl-3-p-tolyl-urea,
[270] Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methylurea,
[271] Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methylurea,
[272] Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-butyl-phenyl) -1-methylurea,
[273] Trans-1- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-3-p-tolyl-urea,
[274] Trans-1- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methylurea,
[275] Trans-1- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methylurea,
[276] Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -1-methyl-3-p-tolyl-urea,
[277] Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methyl-urea,
[278] Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methyl-urea,
[279] Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-butyl-phenyl) -1-methyl-urea,
[280] Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester,
[281] Trans-N- (4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl) -4-bromo-N-methyl-benzenesulfonamide,
[282] Trans-4-bromo-N- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
[283] Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide,
[284] Trans-N- (4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[285] Trans-N- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[286] Trans-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[287] Trans-4-bromo-N- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
[288] Trans-4-bromo-N- {4- [6- (isopropyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide,
[289] Trans-4-bromo-N-methyl-N- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -benzenesulfonamide,
[290] Trans-N- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[291] Trans-N- {4- [6- (isopropyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[292] Trans-N-methyl-N- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[293] Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide,
[294] Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[295] Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide,
[296] Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide,
[297] Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy}-(cyclohexyl) -N-propyl-benzenesulfonamide,
[298] Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-propyl-benzenesulfonamide,
[299] Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N- (2,4,5-trifluoro -Benzyl) -benzenesulfonamide,
[300] Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N- (2,4,5-trifluoro Rho-benzyl) -benzenesulfonamide,
[301] Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid 4-chloro-phenyl ester,
[302] Trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid 4-chloro-phenyl ester,
[303] Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -propyl-carbamic acid 4-chloro-phenyl ester,
[304] Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid 4- Chloro-phenyl esters,
[305] Trans-ethyl- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[306] Trans-benzyl- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[307] Trans- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester,
[308] Trans-allyl- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[309] Trans- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester ,
[310] Trans- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester,
[311] Trans- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -benzyl-carbamic acid benzyl ester,
[312] Trans- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester,
[313] Trans-ethyl- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[314] Trans-benzyl- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[315] Trans- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester,
[316] Trans-allyl- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[317] Trans- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester ,
[318] Trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[319] Trans-benzyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester,
[320] Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester,
[321] Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester ,
[322] Trans-ethyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[323] Trans-benzyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[324] Trans-methyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[325] Trans-allyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[326] Trans- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester,
[327] Trans-ethyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[328] Trans-benzyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[329] Trans-methyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[330] Trans-allyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[331] Trans- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester,
[332] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid benzyl ester,
[333] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -ethyl-carbamic acid benzyl ester,
[334] Trans-allyl- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -carbamic acid benzyl ester,
[335] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -benzyl-carbamic acid benzyl ester,
[336] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl}-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester,
[337] Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester,
[338] Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester,
[339] Trans-allyl- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[340] Trans-benzyl- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[341] Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester,
[342] Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester,
[343] Trans- (4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester,
[344] Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester,
[345] Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester,
[346] Trans-4-chloro-N-ethyl-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide,
[347] Trans-4-bromo-N-ethyl-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide,
[348] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[349] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[350] Trans- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[351] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[352] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[353] Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[354] Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[355] Trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[356] Trans- (4- {6- [ethyl- (2-methoxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[357] Trans- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[358] Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[359] Trans- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[360] Trans- (4- {5- [ethyl- (2-methoxy-ethyl) -amino] -pentyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[361] Trans- [4- (3-dimethylamino-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[362] Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[363] Trans-methyl- [4- (3-piperidin-1-yl-propoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[364] Trans-methyl- [4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[365] Trans-methyl- [4- (6-piperidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[366] Trans-methyl- [4- (5-piperidin-1-yl-pentyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[367] Trans- [4- (3-diethylamino-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[368] Trans- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[369] Trans- [4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[370] Trans- [4- (5-diethylamino-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[371] Trans-methyl- [4- (3-pyrrolidin-1-yl-propoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[372] Trans-methyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[373] Trans- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[374] Trans- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[375] Trans- (4- {5-[(2-hydroxy-ethyl) -methyl-amino] -pentyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[376] Trans-methyl- [4- (4-pyrrolidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[377] Trans-methyl- [4- (5-pyrrolidin-1-yl-pentyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[378] Trans- (4- {3-[(2-hydroxy-ethyl) -methyl-amino] -propoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[379] Trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester N-oxide,
[380] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[381] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[382] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[383] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-bromo-phenyl ester,
[384] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[385] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 3,4-difluoro-phenyl ester,
[386] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[387] Trans- {4- [3- (allyl-methyl-amino) -propoxymethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[388] Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxymethyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[389] Trans- [4- (3-azetidin-1-yl-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[390] Trans-methyl- [4- (3-piperidin-1-yl-propoxymethyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[391] Trans- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propoxymethyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[392] Trans- {4- [4- (allyl-methyl-amino) -butoxymethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[393] Trans- {4- [2- (allyl-methyl-amino) -ethoxymethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[394] Trans-N- {4- [3- (allyl-methyl-amino) -propoxymethyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[395] (Trans) -N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxymethyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide ,
[396] Trans-N- [4- (3-azetidin-1-yl-propoxymethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[397] Trans-N-methyl-N- [4- (3-piperidin-1-yl-propoxymethyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[398] (Trans) -N- [4- (2-dimethylamino-ethylsulfanylmethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[399] Trans-N- [4- (2-diethylamino-ethylsulfanylmethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[400] Trans-N- {4- [2- (allyl-methyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[401] Trans- [4- (2-diethylamino-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[402] Trans- {4- [2- (allyl-methyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[403] Trans- {4- [3- (allyl-methyl-amino) -propylsulfanylmethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[404] Trans- [4- (2-dimethylamino-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[405] Trans- (4- {2- [ethyl- (2-hydroxy-ethyl) -amino] -ethylsulfanylmethyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[406] Trans-methyl- {4- [2- (methyl-propyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[407] Trans- {4- [3- (allyl-methyl-amino) -prop-1-ynyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[408] Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[409] Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[410] Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -carbamic acid 3,4-difluoro-phenyl ester,
[411] Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-sulfame acid benzyl amide,
[412] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfame acid phenyl amide,
[413] Trans-4-[({4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfamoyloxy) -methyl] -benzoic acid methyl ester,
[414] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid butyl amide,
[415] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid phenethyl amide,
[416] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid furan-2-ylmethyl amide,
[417] Trans-({4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonylamino) -acetic acid ethyl ester,
[418] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid cyclopropyl amide,
[419] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid 2,2,2-trifluoro-ethyl amide,
[420] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfame acid benzo [1,3] dioxol-5-ylmethyl amide,
[421] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfame acid 4-fluorobenzyl amide,
[422] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfamic acid (4-chloro-phenyl) -amide,
[423] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (4-fluoro-phenyl) -amide,
[424] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfamic acid (4-bromo-phenyl) -amide,
[425] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (p-tolyl) -amide,
[426] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (3,4-difluoro-phenyl) -amide,
[427] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (4-trifluoromethyl-phenyl) -amide,
[428] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (3-fluoro-phenyl) -amide,
[429] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfamic acid (4-cyano-phenyl) -amide,
[430] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (2,4-difluoro-phenyl) -amide,
[431] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (4-methoxy-phenyl) -amide,
[432] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (2,5-difluoro-phenyl) -amide,
[433] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid benzyl amide,
[434] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide,
[435] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-chlorophenyl amide,
[436] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-bromophenyl amide,
[437] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-methylphenyl amide,
[438] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-trifluoromethylphenyl amide,
[439] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfameic acid p-cyanophenyl amide,
[440] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-methoxyphenyl amide,
[441] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluorophenyl amide,
[442] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid 3-fluorophenyl amide,
[443] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy-cyclohexyl} -methyl-sulfonic acid 2,4-difluorophenyl amide,
[444] Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid 2,5-difluorophenyl amide,
[445] Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide,
[446] Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluorophenyl amide,
[447] Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfonic acid 4-chlorophenyl amide,
[448] Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfameic acid benzyl amide,
[449] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide,
[450] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfonic acid 3-fluoro phenyl amide,
[451] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluoro phenyl amide,
[452] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfonic acid 4-chloro phenyl amide,
[453] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfameic acid benzylamide,
[454] Trans-({4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfamoylamino) -acetic acid ethyl ester,
[455] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide,
[456] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid 3-fluoro-phenyl amide,
[457] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluoro-phenyl amide,
[458] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid 4-chloro-phenyl amide,
[459] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid furan-2-ylmethyl amide,
[460] Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfameic acid benzyl amide,
[461] Trans-({4- (7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfamoyloxy) -acetic acid ethyl amide,
[462] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2-bromo-4-fluoro-phenyl) -1-methyl-thiourea,
[463] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-bromo-2-methyl-phenyl) -1-methyl-thiourea,
[464] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea,
[465] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-chloro-phenyl) -1-methyl-thiourea,
[466] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-methoxy-phenyl) -1-methyl-thiourea,
[467] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-cyano-phenyl) -1-methyl-thiourea,
[468] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (3-methyl-butyl) -thiourea,
[469] Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-sec-butyl-1-methyl-thiourea,
[470] Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea,
[471] Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-cyano-phenyl) -1-methyl-thiourea,
[472] Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -1-methyl-3- (3-methyl-butyl) -thiourea,
[473] Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea,
[474] Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-cyano-phenyl) -1-methyl-thiourea,
[475] Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -1-methyl-3- (3-methyl-butyl) -thiourea,
[476] Trans-1- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea,
[477] Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[478] Trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[479] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -carbamic acid benzyl ester,
[480] Trans-N- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[481] Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide, and
[482] Trans- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester.
[483] Other preferred compounds of formula I are those selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:
[484] Trans-N- [4- (3-allylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[485] Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
[486] Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
[487] Trans-N-ethyl-N- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide,
[488] Trans-N-ethyl-N- (4- {4-[(2-methoxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide,
[489] Trans-N-ethyl-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide,
[490] Trans-N-ethyl-N- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide,
[491] Trans-N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
[492] Trans-N- [4- (4-diethylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
[493] Trans-N- [4- (4-allylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
[494] Trans-N-ethyl-N- [4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[495] Trans-N-ethyl-N- {4- [4- (4-methyl-piperazin-1-yl) -butoxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[496] Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[497] Trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -carbamic acid benzyl ester,
[498] Trans-N- {4- [4- (2-hydroxy-ethylamino) -butyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[499] Trans-N- [4- (5-ethylamino-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[500] Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide N-oxide,
[501] Trans-N- (4- {5- [ethyl- (2-fluoro-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[502] Trans-4-bromo-N- [4- (2-diisopropylamino-ethoxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
[503] Trans-4-bromo-N-methyl-N- [4- (2-piperidin-1-yl-ethoxy) -cyclohexyl] -benzenesulfonamide,
[504] Trans-4-bromo-N- [4- (2-diethylamino-ethoxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
[505] Trans-4-bromo-N-methyl-N- [4- (2-morpholin-4-yl-ethoxy) -cyclohexyl] -benzenesulfonamide,
[506] Trans-4-bromo-N-methyl-N- [4- (2-pyrrolidin-1-yl-ethoxy) -cyclohexyl] -benzenesulfonamide,
[507] Trans-N- [4- (3-dimethylamino-3-methyl-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[508] Trans-N- {4- [2- (1-dimethylamino-cyclopropyl) -ethoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[509] Trans-N- [4- (5-diethylamino-5-methyl-hexyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[510] Trans-N- {4- [4- (1-diethylamino-cyclopropyl) -butyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[511] Trans-N- [4- (4-dimethylamino-pentyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[512] Trans-N- [4- (2-diethylamino-ethoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[513] Trans-N-methyl-N- [4- (2-piperidin-1-yl-ethoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[514] Trans-N- [4- (2-diisopropylamino-ethoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[515] Trans-N-methyl-N- [4- (2-pyrrolidin-1-yl-ethoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[516] Trans-N-methyl-N- [4- (2-morpholin-4-yl-ethoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[517] Trans-N-methyl-N- [4- (4-piperidin-1-yl-pentyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[518] Trans- [4- (3-dimethylamino-3-methyl-but-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester,
[519] Cis-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[520] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[521] Trans- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[522] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[523] Trans- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[524] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -methyl-carbamic acid 4-bromo-phenyl ester,
[525] Trans-methyl- {4- [4- (methyl-propyl-amino) -butyl] -cyclohexyl} -carbamic acid 4-bromo-phenyl ester,
[526] Trans- [4- (4-diethylamino-butyl) -cyclohexyl] -methyl-carbamic acid 4-bromo-phenyl ester,
[527] Trans- [4- (4-dimethylamino-butyl) -cyclohexyl] -methyl-carbamic acid 4-bromo-phenyl ester,
[528] Trans-methyl- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester,
[529] Trans-methyl- {4- [4- (4-methyl-piperazin-1-yl) -butyl] -cyclohexyl} -carbamic acid 4-bromo-phenyl ester,
[530] Trans-methyl- [4- (4-morpholin-4-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester,
[531] Trans-methyl- [4- (4-thiomorpholin-4-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester,
[532] Trans-methyl- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester,
[533] Trans- [4- (4-dimethylamino-butyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[534] Trans-methyl- [4- (4-thiomorpholin-4-yl-butyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester,
[535] Trans-methyl- {4- [4- (methyl-propyl-amino) -butyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester,
[536] Trans-N- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[537] Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[538] Trans-N-methyl-N- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[539] Trans-N- [4- (4-dimethylamino-butyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[540] Trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -butyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[541] Trans-N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[542] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 2,4-difluoro-phenyl ester,
[543] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 2,4-difluoro-phenyl ester,
[544] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[545] Trans-methyl- {4- [5- (methyl-propyl-amino) -pentyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[546] Trans- [4- (5-dimethylamino-pentyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[547] Trans-methyl- [4- (5-piperidin-1-yl-pentyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[548] Trans-methyl- {4- [5- (4-methyl-piperazin-1-yl) -pentyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[549] Trans- {4- [5- (cyclopropyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[550] Trans-N- [4- (5-diethylamino-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[551] Trans-N- (4- {5- [bis- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[552] (Cis) {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[553] Trans- {4- [5- (allylamino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[554] Trans-methyl- [4- (5-methylamino-pentyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester,
[555] Trans-N- [4- (5-allylamino-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[556] Trans-N- {4- [5- (2-hydroxy-1,1-dimethyl-ethylamino) -pentyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[557] Trans-N-methyl-N- [4- (5-methylamino-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[558] (Trans)-[4- (5-dimethylamino-pent-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[559] Trans-methyl- {4- [5- (methyl-propyl-amino) -pent-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[560] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pent-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[561] Trans-N- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides,
[562] Trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides,
[563] Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester,
[564] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid isobutyl ester,
[565] Trans- [4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester,
[566] Trans- [4- (4-azetidin-1-yl-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester,
[567] Trans-methyl- [4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -carbamic acid isobutyl ester,
[568] Trans-methyl- [4- (4-pyrrolidin-1-yl-butoxy) -cyclohexyl] -carbamic acid isobutyl ester,
[569] Trans- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid isobutyl ester,
[570] Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -carbamic acid isobutyl ester,
[571] Trans- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid isobutyl ester,
[572] Trans- {4- [4- (cyclopropylmethyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid isobutyl ester,
[573] Trans-N- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[574] Trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[575] Trans- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[576] Trans- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[577] Trans-methyl- [4- (3-piperidin-1-yl-prop-1-ynyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[578] Trans- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[579] Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester,
[580] Trans-methyl- [4- (3-piperidin-1-yl-prop-1-ynyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester,
[581] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 2,4-difluoro-phenyl ester,
[582] Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenyl ester,
[583] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 2,4-difluoro-phenyl ester,
[584] Trans-methyl- [4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -carbamic acid 2,4-difluoro-phenyl ester,
[585] Trans- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 2,4-difluoro-phenyl ester,
[586] Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxyl] -cyclohexyl} -carbamic acid 2,4-difluoro-phenyl ester,
[587] Trans-3,4-difluoro-N-methyl-N- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -benzenesulfonamide,
[588] Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -3,4-difluoro-N-methyl-benzenesulfonamide,
[589] Trans-2,4-difluoro-N-methyl-N- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -benzenesulfonamide,
[590] Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -2,4-difluoro-N-methyl-benzenesulfonamide,
[591] Trans-4-dimethylamino-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -3-fluoro-N-methyl-benzenesulfonamide,
[592] Trans-4-dimethylamino-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -2-fluoro-N-methyl-benzenesulfonamide,
[593] Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[594] Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[595] Trans- [4- (3-dimethylamino-propyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[596] Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[597] Trans- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[598] Trans-methyl- {4- [3- (methyl-propyl-amino) -propyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[599] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[600] Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pent-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide ,
[601] Trans-N-methyl-N- {4- [5- (methyl-propyl-amino) -pent-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[602] Trans-N- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[603] Trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[604] Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide ,
[605] Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-methoxy-phenyl ester,
[606] Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid p-tolyl ester,
[607] Trans- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[608] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester N-oxide,
[609] Trans-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[610] Trans-N- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[611] Trans-N- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides,
[612] Trans-methyl- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester,
[613] Trans- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[614] Trans- {4- [4- (allyl-methyl-amino) -but-1-ynyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[615] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[616] Trans-methyl- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[617] Trans- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[618] Trans- {4- [4- (allyl-methyl-amino) -but-1-ynyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[619] Trans- (1E) -N-methyl-N- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[620] Trans- (1E) -N- [4- (3-dimethylamino-propenyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[621] Trans- (1E) -N- {4- [3- (allyl-methyl-amino) -propenyl] -cyclohexyl} -N-methyl-4-trifluoromethyl- benzenesulfonamide,
[622] Trans- (1E) -N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propenyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides,
[623] Trans-N-methyl-4-nitro-N- [4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -benzenesulfonamide,
[624] Trans-N- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-nitro-benzenesulfonamide,
[625] Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamide,
[626] Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-4-nitro-benzenesulfonamide,
[627] Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-nitro-benzenesulfonamide,
[628] Trans-N- {4- [4- (4-hydroxy-piperidin-1-yl) -butoxy] -cyclohexyl} -N-methyl-4-nitro-benzenesulfonamide,
[629] Trans-methyl- {4- [3- (methyl-propyl-amino) -propyl] -cyclohexyl} -carbamic acid p-tolyl ester,
[630] Trans-4-amino-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -benzenesulfonamide,
[631] Trans-methyl- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester,
[632] Trans-methyl- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[633] Trans- (1E)-(4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propenyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[634] Trans- (1E)-(4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propenyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[635] Trans-4-chloro-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -benzamide,
[636] Trans-3- (4-chloro-phenyl) -1-methyl-1- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -urea,
[637] Trans-4-chloro-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-benzamide,
[638] Trans-3- (4-chloro-phenyl) -1- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -1-methyl Urea,
[639] Trans- [4- (3-dimethylamino-propenyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[640] Trans- [4- (3-dimethylamino-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester,
[641] Trans-methyl- [4- (3-piperidin-1-yl-propenyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[642] Trans-4-chloro-N-methyl-N- [4- (3-piperidin-1-yl-prop-1-ynyl) -cyclohexyl] -benzenesulfonamide,
[643] Trans-4-chloro-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -benzenesulfonamide,
[644] Trans-4-chloro-N- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -N-methyl-benzenesulfonamide,
[645] Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide,
[646] Trans-N- {4- [5- (2-hydroxy-ethylamino) -pentyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide, and
[647] Trans-N- [4- (5-ethylamino-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide.
[648] Particularly preferred compounds of formula (I) are those selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:
[649] Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[650] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[651] Trans-N- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[652] Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[653] Trans- {4- [2- (allyl-methyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[654] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[655] Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[656] Trans-N- [4- (3-allylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[657] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[658] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[659] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-bromo-phenyl ester,
[660] Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[661] Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
[662] Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester,
[663] Trans- {4- [3- (allyl-methyl-amino) -prop-1-ynyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
[664] Trans-N- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[665] Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester, and
[666] Trans- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester.
[667] Other particularly preferred compounds of formula I are those selected from the group consisting of the following compounds and their pharmaceutically acceptable salts:
[668] Trans-N- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
[669] Trans-methyl- [4- (5-piperidin-1-yl-pentyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
[670] Trans-methyl- [4- (5-methylamino-pentyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester,
[671] Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pent-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
[672] Trans-N-ethyl-N- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide,
[673] Trans- (1E) -N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propenyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides,
[674] Trans-4-bromo-N- [4- (2-diisopropylamino-ethoxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
[675] Trans-methyl- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester,
[676] Trans-N-methyl-N- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
[677] Trans-N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
[678] Trans-4-bromo-N-methyl-N- [4- (2-piperidin-1-yl-ethoxy) -cyclohexyl] -benzenesulfonamide,
[679] Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
[680] Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
[681] Trans- (1E) -N-methyl-N- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
[682] Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide ,
[683] Trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide, and
[684] Trans-N- {4- [2- (1-dimethylamino-cyclopropyl) -ethoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide.
[685] The compounds of formula (I) may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers or as racemates. The present invention encompasses all of these forms.
[686] It will be appreciated that the compounds of formula (I) in the present invention can provide derivatives that can be derivatized at the functional group and converted back to the parent compound in vivo.
[687] In addition, the present invention provides a compound of formula II is ClSO ₂ -A ⁶ , ClCOO-A ⁶ , ClCSO-A ⁶ , OCN-A ⁶ , SCN-A ⁶ , HOOC-A ⁶ , or ClSO ₂ NR ¹ -A ⁶ (A ⁶ has the meaning given above) and to a process for the preparation of a compound as described above, comprising reacting:
[688]
[689] Where
[690] A ⁵ has the meaning given above,
[691] Z is (A ¹ , A ² ,) NC (A ³ , A ⁴ )-(CH ₂ ) _m -V- (CH ₂ ) _n or HO- (CH ₂ ) _n , and A ¹ , A ² , A ³ , A ⁴ , V, m and n have the meanings given above.
[692] The invention also relates to a compound of formula (I) as defined above prepared according to the process as defined above.
[693] As noted above, the compounds of formula (I) of the present invention can be used to treat and / or prevent, and / or impair, diseases associated with OSC, such as hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal disease, parasitic infections and cholelithiasis. It can be used for the treatment and / or prevention of glucose tolerance, diabetes, tumors and / or hyperproliferative disorders, preferably for the treatment and / or prevention of hypercholesterolemia and hyperlipidemia. Hyperproliferative disorders include hyperproliferative skin and vascular disorders.
[694] Accordingly, the present invention relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant.
[695] The invention also provides for the treatment and / or prevention of therapeutically active substances, in particular diseases associated with OSC, such as hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular diseases, filamentous fungal diseases, parasitic infections, gallstones, tumors and / or hyperproliferative disorders. And / or compounds as defined above for use as therapeutically active substances for the treatment and / or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and / or prophylaxis of hypercholesterolemia and / or hyperlipidemia.
[696] In another embodiment, the present invention comprises administering to a human or animal a compound as defined above, hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal disease, parasitic infection, cholelithiasis, tumor and / or hyperproliferation Methods for the treatment and / or prevention of diseases associated with OSC, such as sexual disorders, and / or for the treatment and / or prevention of impaired glucose tolerance and diabetes, preferably for the treatment and / or prevention of hypercholesterolemia and / or hyperlipidemia. It is about.
[697] The invention also provides for the treatment and / or prevention and / or impairment of diseases associated with OSC such as hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal disease, parasitic infections, gallstones, tumors and / or hyperproliferative disorders. The use of a compound as defined above for the treatment and / or prevention of glucose tolerance and diabetes, preferably for the treatment and / or prevention of hypercholesterolemia and / or hyperlipidemia.
[698] The invention also provides for the treatment and / or prevention and / or impairment of diseases associated with OSC such as hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal disease, parasitic infections, gallstones, tumors and / or hyperproliferative disorders. The use of a compound as defined above for the preparation of a medicament for the treatment and / or prevention of glucose tolerance and diabetes, preferably for the treatment and / or prevention of hypercholesterolemia and / or hyperlipidemia. The medicament comprises a compound as defined above.
[699] Compounds of formula (I) may be prepared by the methods given in the following, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. Starting materials may be purchased commercially or may be prepared by methods analogous to those given in the examples or by methods known in the art.
[700]
[701]
[702]
[703]
[704]
[705]
[706]
[707]
[708] Scheme 1a:
[709] The preparation of starting materials for aminocyclohexyl derivatives in which V is O or S in Formula I is described in Scheme 1a.
[710] For compounds with n = 0, synthesis is converted to Z-derivatives or BOC derivatives (2), for example, by ZCl, Na ₂ CO ₃ , THF, H ₂ O or (BOC) ₂ O, iPrOH, CH ₂ Cl ₂ , respectively. Starting from trans-4-aminocyclohexanol (1) (step a). Reduction with lithium aluminum hydride yields trans-4-methylaminocyclohexanol, which is BOC-protected to yield compound (3), or as described later for compound (3) or (5) in Scheme 3. One of the methods is used to transfer directly into the desired A ⁶ W-derivative (4). If necessary, the aminocyclohexanol derivative can be treated with hexamethyldisilazane while refluxing before introducing the A ⁶ W-residue. Alternatively, the A ⁵ residue may be introduced via alkylation with sodium hydride and reactive alkyl or arylalkyl derivatives (step b). BOC-deprotection (TFA, CH ₂ Cl ₂ ) or Z-deprotection (hydrogenation) followed by A ⁶ W-derivatives yields compounds of formula (4).
[711] For n = 1, the starting material is (trans) -4-tert-butoxycarbonyl amino-cyclohexane-carboxylic acid (5). It is converted to derivative (6) by ester formation (eg carbonyl-di-dimidazole, methanol in THF) and direct alkylation with sodium hydride and reactive alkyl or arylalkyl derivatives (step d). Reduction with lithium aluminum hydride affords a protected alcohol (7).
[712] For n = 2, the starting material was trans-4-aminocyclohexyl acetic acid (Karpavichyus, KI; Palaima, AI; Knunyants, IL; BACCAT; Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.); EN; 29; 1980; 1689-1694; IASKA6; Izv.Akad.Nauk SSSR Ser.Khim .; RU; 10; 1980; 2374-2379 or TP Johnston et al. Journal of Medicinal Chemistry, 1977, Vol , No. 2, 279-290.], Which may be derived from 4-nitrophenylacetic acid, which may be converted to the corresponding alcohol according to the procedure for compounds (5) to (7).
[713] For n ≧ 3, the starting material is (trans) -4-tert-butoxycarbonyl amino-cyclohexane-carboxylic acid (5). Chain extension can be accomplished using methods known in the art or as described below:
[714] For C ₂ -extension: Unsaturated esters (8) were reacted with triethyl phosphono acetate, sodium methanolate in triethan phosphonate, sodium methanolate in ethanol following the corresponding aldehyde Swern oxidation To obtain. It is hydrogenated with 10% palladium on carbon in methanol and reduced with lithium aluminum hydride in THF to give a chain-extended alcohol (4). The above procedure is repeated to obtain C ₄ -extended alcohol (4).
[715] The Corey-Fuchs methodology can be used for C _(n-1) -extension in C ₂ : Thus, acid (5) is added N, O- with EDCI and HOBT in CH ₂ Cl ₂ at room temperature. Treatment with dimethyl-hydroxyl-amine-hydrochloride converts to Weinreb derivatives, which are reduced with lithium aluminum hydride to give the corresponding aldehyde 9 (step i). This aldehyde (9) can be treated with triphenylphosphine, tetrabromomethane and triethylamine in CH ₂ Cl ₂ at 0 ° C. to room temperature to give 2,2-dibromo-vinyl derivative (10). . Rearrange at -78 ° C with n-BuLi (about 1.6M in hexane) in THF and then react with formaldehyde (from -78 ° C to room temperature) to give propargyl alcohol (step l, the conditions described in the literature below). According to: Marshall, James A .; Bartley, Gary S .; Wallace, Eli M. Total Synthesis of the Pseudopterane (-)-Kallolide B, the Enantiomer of Natural (+)-Kallolide BJ Org. Chem. (1996 ), 61 (17), 5729-5735; and Baker, Raymond; Boyes, Alastair L .; Swain, Christopher J. Synthesis of talaromycins A, B, C, and EJ Chem. Soc., Perkin Trans. 1 (1990) , (5), 1415-21.]), From which a propanol derivative (4) can be obtained by hydrogenation at 10% Pd / C.
[716] For longer side chains, rearrangements are carried out using n-BuLi (about 1.6 M in hexane) in THF at −78 ° C. as above, followed by addition of a cosolvent such as DMPU and O-protected 1-bromo Reaction with alcohol (11) (step m; e.g. 1-bromo-n-tetrahydropyranyloxyalkane) affords O-protected compound (12). Compound (12) can be converted to an alkanol derivative by hydrogenation at 10% Pd / C, which is then deprotected to give derivative (4).
[717] If WA ⁶ is a protecting group, it can be degraded as described for derivative (3) and the final residue WA ⁶ can be introduced as described for the compound of Scheme 3.
[718] Scheme 1b:
[719] Scheme 1b describes the synthesis of pure trans-aldehyde building blocks (8). A ⁵ substituted 4-aminocyclohexanol (1) is converted to a Z-derivative or WA ⁶ derivative (2) (e.g. ZCl, Na ₂ CO ₃ , THF, H ₂ O or WA ⁶ -introduction, see Scheme 3) (Step a). Oxidation with TMPO (2,2,6,6-tetramethylpiperidine 1-oxyl, radical) and sodium hypochlorite yields ketone (3) (step b). (Witig) reaction with (methoxymethyl) triphenylphosphonium chloride (4) in THF and potassium t-butoxide as a base to give enolether (5) (step c), which was followed by 1N HCl in THF. Hydrolysis under reflux (step d). Crude aldehyde 6 (as cis / trans mixture) isomerizes via bisulfite-addition 7 (with disodium pyrophosphate in water / TBME, step e). The bisulfite adduct 7 can then be converted to pure trans-aldehyde 8 using aqueous Na ₂ CO ₃ in water / TBME (step f).
[720] Scheme 2:
[721] Scheme 2 shows the synthesis of aminothiol (4) used in the synthesis of mixtures with thioether spacers. Triphenylmethanethiol is deprotonated with NaH in DMA and reacted with α, ω-dihaloalkane in DMA (step a). Treatment with amine A ¹ A ² NH gives S-protected amine 3 (step b). Deprotection of thiol residues can be achieved by treatment with TFA / triisopropylsilane in CH ₂ Cl _{2 at} 0 ° C. to room temperature, and aminothiol 4 is obtained (step c).
[722] Scheme 3:
[723] The synthesis of ether derivatives of formula (I) is described in Scheme 3. For the preparation of n = 0 derivatives, as for example, α, ω- dihalo under phase transfer conditions, an amino-cyclohexanol (1) by treatment with an alkane, NaOH, nBu ₄ NHSO ₄ it is possible to obtain the bromide (2). If n> 0, the alcohol derivative (1) is treated with α, ω-dihaloalkane (C ₄ or higher alkane) at 0 ° C. to room temperature in the presence of NaH in DMF to give bromide (2). The method chosen for shorter alkanes is in situ production of haloalkanes-triplates (from corresponding haloalkanols to trifluoromethanesulfonic anhydride / 2,6-di-tert-butylpyridine in CH ₂ Cl ₂₎ . At 0 ° C). This haloalkane-triplate is then reacted with alcohol (1) with 2,6-di-tert-butylpyridine as a base at 60 ° C. in nitromethane to give bromide (2) (Belostotskii, Anatoly M. Hassner, Alfred.Synthetic methods.41.Etherification of hydroxysteroids via triflates.Follow the procedure of Tetrahedron Lett. (1994), 35 (28), 5075-6).
[724] The bromide 2 can be aminated with amine A ¹ A ² NH at reflux at room temperature in DMA or DMF or at room temperature in MeOH to afford the final amine 3 and optionally DBU can be added. A mixture of hydrogen peroxide urea adduct and phthalic anhydride can be used to convert the amine (3) to a salt or N-oxide (4) at room temperature in CH ₂ Cl ₂ .
[725] If A ⁶ W in bromide 2 is a protective moiety, it can be degraded by using TFA in CH ₂ Cl ₂ for BOC groups or hydrogenating to Pd / C in methanol / HCl for Z-groups. The resulting ammonium salt (not shown) can be treated according to one of the procedures described below to derive the appropriate A ⁶ W derivative, which is then refluxed at room temperature in DMA or DMF, optionally with DBU, or at room temperature in MeOH. Under reaction with excess amine A ¹ A ² NH to afford the final amine 3.
[726] Alternatively, alkylation of alcohol (1) to amine (5) by attaching a pre-associated fragment A ¹ A ² NC (A ³ A ⁴ ) (CH ₂ ) _m -OH which can be synthesized by known methods Conditions can be used to convert mesylate / halogenide of derivative (1) (step d). The amine 5 can be converted into its salt or N-oxide 6 as described above (step c).
[727] Finally, the substitution pattern for A ⁶ in the product 5 can be manipulated. For example, the acetyl group is hydrolyzed to NH ₂ . In addition, the substitution pattern of A ¹ or A ² can be changed by treating hydroxyethylamine with, for example, DAST.
[728] If A ⁶ W in (3) or (5) is a protective moiety, this is done using TFA in CH ₂ Cl ₂ for BOC-groups or Pd / C in methanol for Z-groups before salt or N-oxide formation. Can be decomposed by hydrogenation. The resulting amine (not shown) may be treated according to one of the following procedures to derive the appropriate A ⁶ W derivative (3 or 5).
[729] a) Sulfonamide: The amine is sulfonylated with Hunig's base and sulfonyl chloride in dioxane or CH ₂ Cl ₂ at room temperature overnight to give sulfonamide (3 or 5).
[730] b) Carbamate: The amine can be reacted with A ⁶ OCOCl / Hunig base in dioxane or CH ₂ Cl ₂ . Alternatively, chloroformate can be prepared in situ by treating A ⁶ OH with Cl ₃ COCl in the presence of quinoline and then reacting with an amine in the presence of Hunig's base.
[731] c) Thiocarbamate: The amine can be reacted with A ⁶ OCSCl in dioxane.
[732] d) Urea: The amine can be reacted with isocyanates at room temperature in dioxane.
[733] e) Thiourea: The amine can be reacted with isothiocyanate at room temperature in dioxane.
[734] f) amides: react amines with A ⁵ COCl / Wignig base, A ⁶ COOH / EDCI / DMAP (by forming the symmetric anhydride and then adding the starting amine at −10 ° C. to room temperature) in CH ₂ Cl ₂ ; Or alternatively react with A ⁶ COOH / EDCI / DMAP or A ⁶ COOH / Wignig base or NMM / EDCI / HOBT at room temperature in DMF, dioxane or CH ₂ Cl ₂ .
[735] g) sulfamide: The amine can be reacted with sulfamoyl chloride in the presence of excess triethylamine in dioxane to give sulfamide (3 or 5). Sulfamoyl chloride can be prepared by reacting from A ⁶ NH ₂ and chlorosulfonic acid at 0 ° C. to room temperature in CH ₂ Cl ₂ and then with PCl ₅ in toluene at 75 ° C. Alternatively, sulfamoyl chloride can be synthesized from 0 ° C. to 65 ° C. with A ⁶ NH ₂ and sulfuryl chloride in acetonitrile.
[736] Scheme 4:
[737] Scheme 4 depicts the synthesis of thio ether derivatives in which V is S in Formula (I). For compounds where n is zero, mesylation is performed under inversion (Mitsunobu conditions, step a). For compounds with n> 0, alcohol (1) may be mesylated with methanesulfonyl chloride in pyridine in the presence of DMAP at 0 ° C. to room temperature to give sulfonate (2) (step a). The sulfonate (2) is then thiolated with a corresponding A ¹ A ² aminoalkanethiol (similar to the method described in the context of Scheme 2) with NaH as the base in DMF to form a final compound (3 or 3 respectively). 5) is obtained (step b).
[738] Another approach for the synthesis of thioethers (3) that opens up the possibility of changing the A ¹ A ² amine end at the end is described in steps d to f. Sulfonate 2 is treated with potassium thioacetate in DMF at 100 ° C. to give thioacetate 7. Deprotection with 1N LiOH in ethanol and alkylation with haloalkanols affords alcohol (8). Alcohol 8 was treated with methanesulfonyl chloride in pyridine with methanesulfonyl chloride at 0 ° C. to room temperature to give mesylate / chloride, which was then aminated with the corresponding A ¹ A ² amine in the presence of NaI in DMA. The amine 3 can be obtained. If WA ⁶ is a protective group, it can be decomposed and converted to the desired WA ⁶ derivatives by employing one of the methods described for compounds (3) and (5) of Scheme 3.
[739] Finally, the substitution pattern for A ⁶ can be manipulated. For example, the acetyl group is hydrolyzed to NH ₂ . In addition, the substitution pattern of A ¹ or A ² can be changed by treating hydroxyethylamine with, for example, DAST.
[740] The amines (3 or 5) can optionally be converted to salts or N-oxides (4 or 6) (with hydrogen peroxide adduct and phthalic anhydride at room temperature in step c such as CH ₂ Cl ₂ ).
[741] Scheme 5:
[742] Scheme 5 describes the synthesis of C-like aminocyclohexane in which V in formula I is -CH _2- , -CH = CH- or -C≡C-. Synthesis starts from aldehyde (1) which can be derived from (trans) -4-tert-butoxycarbonyl amino-cyclohexane-carboxylic acid (Scheme 1a, see compound (9)) or the corresponding alcohol ( Start from Scheme 1a, compound (4). Side chain extension is performed by applying the Corey-Fuchs method. Aldehyde (1) is treated with triphenylphosphine, tetra-bromo-methane and triethylamine in CH ₂ Cl _{2 at} 0 ° C. to room temperature to give 2,2-dibromo-vinyl derivative (2). Rearrangement with n-BuLi (about 1.6 M in hexane) at -78 ° C in THF followed by reaction with formaldehyde (-78 ° C to room temperature; step b) yields propargyl alcohol (3) (Marshall, James A .; Bartley, Gary S .; Wallace, Eli M. Total Synthesis of the Pseudopterane (-)-Kallolide B, the Enantiomer of Natural (+)-Kallolide BJ Org. Chem. (1996), 61 (17), 5729-5735; and Baker, Raymond; Boyes, Alastair L .; Swain, Christopher J. Synthesis of talaromycins A, B, C, and EJ Chem. Soc., Perkin Trans. 1 (1990), (5), 1415- According to the conditions described in [21.]).
[743] For longer side chains, rearrangement of dibromoalkenes (2) with n-BuLi (about 1.6 M in hexane) at -78 ° C. in THF as above, followed by addition of a co-solvent such as DMPU and O- Reaction with protected 1-bromo-alcohol 4a (e.g. 1-bromo-n-tetrahydro-pyrananyloxyalkane) affords O-protected compound 3, which is 50 to It may be deprotected at 60 ° C. with the corresponding alkynol (3) derivative in the presence of a catalytic amount of pyridinium toluene-4-sulfonate (step c). Alternatively, the side chain extension of dibromoalkene 2 can be carried out with chloroalkaniodide 4b (m> 1) under the same conditions as above to obtain the chloride 5 directly. The chloride 5 is then converted via iodide 5 (Finkelstein reaction) to an amine 6 as described later.
[744] Alcohol (3) is mesylated with methanesulfonylchloride, pyridine and DMAP in CH ₂ Cl _{2 at} 0 ° C. to room temperature to give mesylate (5), which is excess in DMA or MeOH at room temperature or at 50 to 70 ° C. The corresponding amine NHA ¹ A ² can be used to convert to amine 6 (step e).
[745] If A ⁶ W is a protective moiety, it can be decomposed prior to salt or n-oxide formation by hydrogenation with TFA in CH ₂ Cl ₂ for BOC-groups or hydrogenated to Pd / C in methanol for Z-groups. have. The resulting amine (not shown) can be treated according to one of the procedures described for Scheme 3 to obtain the appropriate A ⁶ W derivative (6).
[746] Optionally an earlier step, such as the introduction of the desired A ⁶ W residue in the derivative (2) or O-protected derivative (3) or mesylate, chloride or iodide (2), is carried out to give NA ¹ in the final step e. Allows optimization of the A ² terminus.
[747] In order to obtain compound 6 wherein A ³ and / or A ⁴ is not H and m> 0, compound 2 can be reacted with compound 10 under the same conditions as described in step c. The building block 10 can be manufactured by a known method. For the introduction of (A ¹ , A ² ) NC (A ³ , A ⁴ )-, where A ³ and / or A ⁴ are not H and m = 0, a two-step procedure must be performed: first Rearranged to n-BuLi (about 1.6M in hexane) at -78 ° C in THF followed by reaction with the corresponding aldehyde (A ³ or A ⁴ -COH) or ketone (A ³ COA ⁴ , -78 ° C to room temperature) A ³ , A ⁴ substituted propargyl alcohol is obtained, which is transformed into phosphoester or chloride (not shown) and tetrakis (triphenylphosphine) palladium (for phosphoester) or Cu for chloride ( I) Reaction with the desired (A ¹ , A ² ) -amine in the presence of Cl / Cu bronze and Hunig base to give the desired A ³ , A ⁴ -substituted compound (6) (step h). (Bartlett, Paul A .; McQuaid, Loretta A. Total synthesis of (±) -methyl shikimate and (±) -3-phosphoshikimic acid. J. Am. Chem. Soc. (1984), 106 (25), 7854-60 and Cooper, Matthew A .; Lucas, Mathew A .; Taylor, Joanne M .; Ward, A. David; Williamson, Natalie M. A convenient method for the aromatic amino-Claisen rearrangement of N- (1,1 -disubstituted-allyl) anilines.Synthesis (2001), (4), 621-625.).
[748] Compounds in which V is -CH ₂ -or -CH = CH- can be hydrogenated compound (6) to Pt / C (obtained saturated analog (8)) or hydrogenated by other known methods (double bond analog (8)) ) Can be obtained. Alternatively, the alkyne group can already be reduced in a previous step, such as alcohol (3) (eg, V = trans-CH = CH- or Pt / C or PtO ₂ .H ₂ O with LAH-reduction for m = 0). Hydrogenation with V = CH ₂ CH _2- ), the resulting compound can be further modified into final compounds (8) and / or (9).
[749] Finally, the substitution pattern for A ⁶ can be engineered on amines 6 or 8: for example, by hydrolyzing acetyl groups to NH ₂ . In addition, the substitution pattern of A ¹ or A ² can be altered, for example, by treating hydroxyethylamine with DAST.
[750] The amines (6 or 8) can be converted to N-oxides (7 and 9) as described in step f or salts, respectively, using a mixture of hydrogen peroxide urea adduct and phthalic anhydride at room temperature in CH ₂ Cl ₂ .
[751] Scheme 6:
[752] The synthesis of C-analogs where V is -CH ₂ -or -CH = CH- is described in Scheme 6. Alcohol (1) (see Synthesis of Alcohol (4) in Scheme 1a) can be converted to aldehyde (2) via sone-oxidation. Alternatively, alcohol 1 may be tosylated (tosylchloride in pyridine) followed by treatment with NaCN (100 ° C. in DMF) and reduction with DIBALH (−78 ° C. to room temperature in THF) C 1 -extended aldehyde (2) To obtain. Horner-Emmons reaction with triethyl phosphono acetate, sodium methanolate in ethanol affords unsaturated ester (3) (step b). Ester (3) can be directly reduced to prepare unsaturated alcohol (4) (V is -CH = CH-, x = 1) or hydrogenated to 10% Pd / C in methanol and reduced to lithium aluminum hydride in THF and saturated Alcohol 4 (V is -CH _2- , x = 2) is obtained. The alcohol was mesylated with methane sulfonyl chloride, triethylamine in CH ₂ Cl ₂ to give mesylate (step d), which was treated with the desired amine A ¹ A ² NH to give the derivative (6). (Step e). As described in the previous scheme, where A ⁶ W is a protecting group (BOC or Z), it can be digested using the method shown in Scheme 3 and the appropriate A ⁶ W residues introduced.
[753] Finally, the substitution pattern for A ⁶ can be manipulated on amine 6: for example, by hydrolyzing acetyl groups to NH ₂ . In addition, the substitution pattern of A ¹ or A ² can be changed by treating hydroxyethylamine with DAST.
[754] The amine 6 can be converted to a salt or N-oxide 7 as described in step f using a mixture of hydrogen peroxide urea adduct and phthalic anhydride at room temperature in CH ₂ Cl ₂ .
[755] Alternatively, side chains can be introduced directly by treating the aldehyde 2 via a bitig-reaction to obtain bromide 5 (step g; aldehyde (2) and bitig salt (8) 2-methyl-2). Reflux in the presence of K ₂ CO ₃ or Cs ₂ CO ₃ in butanol). The bromide (5) can be converted directly to amine (6) or N-oxide (7) as above. If A ⁶ W is a protecting group (BOC or Z), it can be decomposed in steps (5) or (6) (ie, first the double bond is selectively hydrogenated to Pt / C in toluene and then HBr ( 33%) to decompose the Z-protection.) The method shown in Scheme 3 can be used to introduce the appropriate A ⁶ W residue.
[756] Scheme 7:
[757] Another method for introducing substituted side chains is described in Scheme 7. Belostotskii, Anatoly M .; Hassner, Alfred. Synthetic methods. 41. Etherification of hydroxysteroids via triflates. Tetrahedron Lett. (1994), 35 (28), 5075-6, the reaction is initiated by attaching the ω-hydroxycarboxylic acid ester via in situ generated triflate (step a). Alternatively, bromine (3) (synthesized according to Scheme 3) can be treated with acetocyanhydrin, for example in acetonitrile, followed by a Pinner reaction and hydrolysis of the imidate to give the corresponding ester. Can be prepared (step b).
[758] For V = CH = CH, ester (2), or a mixture thereof, is treated with the corresponding bitig reagent Ph ₃ P (CH ₂ ) _{m + 1} CO ₂ R / H from aldehyde (4) (synthesis described in Scheme 6). The corresponding acid can be prepared. For V = C, the Vitig product is hydrogenated under standard conditions to give saturated product (2).
[759] For V = CC, rearranged from dibromo derivative (5) (synthesized according to Scheme 5) to n-BuLi (about 1.6 M in hexane) at -78 ° C. in THF followed by chloroformate or dimethylcarbamoyl chloride. Reaction can lead to ester (2) or amide (6) (-78 ° C. to room temperature; step d). For longer side chains, rearrangement of dibromoalkenes (5) with n-BuLi (about 1.6 M in hexane) at -78 ° C. in THF is followed by addition of a cosolvent such as DMPU and a suitable protected 1-bro Reaction with the parent-alkylalcohol Br- (CH ₂ ) _m CH ₂ OH followed by oxidation gives compound (2) as an acid (step e).
[760] Saponification of ester (2) using standard conditions such as EtOH, MeOH or LiOH in THF followed by NHA ¹ A ² , EDCI, HOBT and Hunig base, NEt _{3 in} CH ₂ Cl ₂ , DMF, DMA or dioxane Treatment with a base, such as NMM, affords amide (6). Reaction of the amide (6) with methylmagnesium bromide, ZrCl ₄ in THF at low temperature (Stephen M. Denton, Anthony Wood, A Modified Bouveault Reaction for the Preparation of α, α-dimethylamines from Amides, Synlett 1999, 1 , 55-56.) By treatment with other Grignard reagents in the presence of ZrCl ₄ or Ti (OiPr) ₄ (V. Chalinski, A. de Meijere, A versatile New Preparation of Cyclopropylamines from acid dialkylamides, Angew (Chem. Int. Ed. Engl. 1996, 35, No4, 413-4.).) May be converted to amine (7) (A ³ , A ⁴ = Me).
[761] For A ¹ = Me, A ^{2 ′} = OME, the amide (3) can be treated with Grignard reagent A ³ MgX to give the corresponding ketone (8). The ketone (8) is treated with NHA ¹ A ² in the presence of tetraisopropyl ortho titanate to reduce alkylation, followed by reduction with NaCNBH ₃ in ethanol to give an amine (Rj Mattson, KM Pham, DJ Leuck, KA Cowen, JOC 1990,55,2552-4.].
[762] The amine 7 can be converted to a salt or N-oxide 9 using a mixture of hydrogen peroxide urea adduct and phthalic anhydride at room temperature in CH ₂ Cl ₂ .
[763] If A ⁶ W is a protective moiety, it can be decomposed by TFA in CH ₂ Cl ₂ for BOC-groups or hydrogenated to Pd / C in methanol for Z-groups prior to salt or N-oxide formation. . The resulting amine (not shown) may be treated according to one of the procedures described previously (Scheme 3) to induce the appropriate A ⁶ W derivative.
[764] Pure cis- or trans-aminocyclohexane derivatives can be separated from the mixture using HPLC or obtained using stereochemically defined starting materials.
[765] The following tests were performed to determine the activity of the compounds of formula (I) and salts thereof.
[766] Inhibition of Human Liver Microsome 2,3-Oxidosqualene-Lanosterol Cylase (OSC)
[767] Liver microsomes from healthy volunteers were prepared in sodium phosphate buffer, pH 7.4. OSC activity was also measured in the same buffer containing 1 mM EDTA and 1 mM dithiothreitol. Microsomes were diluted to 0.8 mg / ml protein in cold phosphate buffer. Dry [ ¹⁴ C] R, S-monooxidose squalene (MOS, 12.8 mCi / mmol) was diluted with ethanol to 20 nCi / μl and mixed with phosphate buffer-1% BSA (bovine serum albumin). Stock solutions of 1 mM test material in DMSO were diluted with phosphate buffer-1% BSA to the desired concentration. 40 μl of microsomes were mixed with 20 μl of solution of test material and the reaction was then initiated with 20 μl of [ ¹⁴ C] R, S-MOS solution. Final conditions contain 0.5% albumin, less than 0.1% DMSO and less than 2% ethanol in a total volume of 0.4 mg / ml microsomal protein and 30 μl of [ ¹⁴ C] R, S-MOS in phosphate buffer, pH 7.4, 80 μl It was.
[768] After 1 hour at 37 ° C, the reaction was added with 0.6 ml of 10% KOH-methanol containing 0.7 µg of non-radioactive MOS and 25 µg of lanosterol, 0.7 ml of water and 0.1 ml of hexane: ether (1: 1, v / v) as a carrier. Was stopped. After stirring, 1 ml of hexane: ether (1: 1, v / v) was added to each test tube, which was stirred again and centrifuged. The upper phase was transferred to a glass test tube, and the lower phase was extracted again with hexanes: ether and combined with the first extract. The entire extract was evaporated to dryness with nitrogen and the residue suspended in 50 μl of hexanes: ether and applied to a silica gel plate. Chromatographic separation was carried out in hexane: ether (1: 1, v / v) as eluent. Rf values for the MOS substrate and lanosterol product were 0.91 and 0.54, respectively. After drying, radioactive MOS and lanosterol were observed on silica gel plates. The ratio of MOS to lanosterol from radioactivity bands was determined to determine the reaction rate and OSC inhibition.
[769] On the one hand the test was performed at a constant test substance concentration of 100 nm and the percentage of OSC inhibition relative to the control was calculated. More preferred compounds of the invention exhibit an inhibition greater than 50%. In addition, the test was performed with different test substance concentrations and then the concentration required to reduce the IC ₅₀ value, ie the conversion of MOS to lanosterol, to 50% of the control value was calculated. Preferred compounds of the invention exhibit IC ₅₀ values between 1 nM and 10 μM, preferably between 1 and 100 nM.
[770] The compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations for intra enteral, extra enteral or topical administration. They are for example orally in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, for example rectally, in the form of suppositories, for example ex vivo, in the form of injection solutions or infusion solutions, or For example, in the form of ointments, creams or oils.
[771] The preparation of pharmaceutical formulations may be carried out by combining the compound of formula (I) and its pharmaceutically acceptable acid addition salts, optionally with other therapeutically valuable substances, in a manner familiar to those skilled in the art, to a suitable nontoxic inert therapeutically compatible solid or It may be carried out by bringing the herbal carrier form into a liquid carrier material and, if desired, with a conventional pharmaceutical adjuvant.
[772] Suitable carrier materials are inorganic carrier materials as well as organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carrier materials for soft gelatin capsules are, for example, vegetable oils, waxes, fats, and semisolid and liquid polyols (however, for soft gelatin capsules, no carrier is required depending on the nature of the active ingredient). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semisolid or solid polyols. Suitable carrier materials for topical preparations are glycerides, semisynthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
[773] Conventional stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor improving agents, osmotic pressure adjusting salts, buffer materials, solubilizers, colorants, masking agents and antioxidants are contemplated as pharmaceutical adjuvants.
[774] The dosage of the compound of formula (I) may vary depending on the condition to be eliminated, the age and the individual condition of the patient and the mode of administration, and of course is tailored to the individual needs of each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 50 mg to about 500 mg, is considered for the prevention and treatment of local and systemic infections caused by pathogens. Daily dosages of 1 to 1000 mg, preferably 10 to 100 mg, are convenient for adult patients for the treatment of lowering cholesterol and impaired glucose tolerance and diabetes. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
[775] The pharmaceutical preparations conveniently contain about 1 to 500 mg, preferably 10 to 100 mg of the compound of formula (I).
[776] The following examples are provided to illustrate the invention in more detail. However, they are not intended to limit the scope in any way.
[777] Abbreviation:
[778] AcOH = acetic acid, BOC = t-butyloxycarbonyl, CH ₂ Cl ₂ = dichloromethane, DAST = diethylamino-sulfurtrifluoride, DEAD = diethyl azodicarboxylate, DBU = 1,8-diazabi Cyclo [5.4.0] undec-7-ene (1,5-5), DIBALH = di-i-butylaluminum hydride, DMAP = 4-dimethylaminopyridine, DMPU = 1,3-dimethyl-3,4 , 5,6-tetrahydro-2 (1H) -pyrimidinone, EDCI = N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, EtOAC = ethyl acetate, EtOH = ethanol, Et ₂ O = diethyl ether, Et ₃ N = triethylamine, eq = equivalent, HOBT = 1-hydroxybenzo-triazole, Hunig base = iPr ₂ NEt = DIPEA = N-ethyldiisopropylamine, LAH = lithium Aluminum hydride, LDA = lithium diisopropylamide, LiBH ₄ = lithium borohydride, MeOH = methanol, NaI = sodium iodide, PdCl ₂ (dppf) = (1,1′-bis (diphenylphosphino) ferrocene) Dichloropalladium (II) .CH ₂ Cl ₂ (1: 1), Pd (Ph ₃ P ₄ ) tetrakis (triphenylphosphine) palladium, Red-Al = sodium bis (2-methoxyethoxy) aluminum hydride, TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl, Radical, TBDMSCl = t-butyldimethylsilyl chloride, TBME = t-butyl methyl ether, TFA = trifluoroacetic acid, THF = tetrahydrofuran, quant = quantitative.
[779] General mention
[780] All reactions were performed under argon.
[781] The final amine was purified by preparative HPLC [eg RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% to 95% acetonitrile] to obtain the corresponding amino formate and the corresponding used in the reaction. A mixture of halogenides was obtained. The ratio was not always determined and the purity of the final amino salt was greater than 80% after LC-MS.
[782] Example 1
[783] 1.1
[784] THF and 650 ml water, 150 ml of trans-4-amino-cyclohexanol. Hydrochloride 50 g (0.33 mol) and Na ₂ CO ₃ 77 g in suspension, 51.2 ml of benzyl chloroformate (0.726 mol, 2.2 equiv.) ( 0.363 mol, 1.1 equiv) was added at 5 ° C. over a period of 20 minutes. The reaction mixture was stirred at rt for 2 h, diluted with EtOAc and the phases separated. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. Trituration from hexanes gave 162.4 g (98%) of trans-4-hydroxy-cyclohexylcarbamic acid benzyl ester as white crystals. MS: similar to 249 (M) (Venuti, Michael C .; Jones, Gordon H .; Alvarez, Robert; Bruno, John J .; J.Med. Chem .; 30; 2; 1987; 303-318). ).
[785] 1.2
[786] A suspension of 117 g (0.47 mol) of trans-4-hydroxy-cyclohexylcarbamic acid benzyl ester in 1 L of THF was added to a suspension of 37.9 g (0.94 mol, 2.0 equivalents) of LAH in 1.3 L of THF over a period of 6 hours. Application was made via cannula while maintaining at 5-10 ° C. The reaction was refluxed overnight and a mixture of Na ₂ SO ₄ , silica gel and water (160 g, 50 g, 80 ml) was added and stirred for an additional 30 minutes, filtered and concentrated. The crude material was triturated with hexanes to give 27.9 g (46%) of trans-4-methylamino-cyclohexanol. The mother liquor was column chromatographed on silica gel to give 17.1 g (28%) of additional trans-4-methylamino-cyclohexanol as a white solid. MS: 129 (MH ⁺ ) (Venuti, Michael C .; Jones, Gordon H .; Alvarez, Robert; Bruno, John J .; J.Med. Chem .; 30; 2; 1987; 303-318) Similar to).
[787] 1.3
[788] 13.32 g (103 mmol) of trans-4-methylamino-cyclohexanol were dissolved in isopropanol and treated with 24.75 g (113.4 mmol) of di-tert-butyl-dicarbonate in CH ₂ Cl ₂ . The reaction mixture was stirred at rt overnight and concentrated to give 23.3 g (98%) of trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid tert-butyl ester as a white solid. MS: 229 (M ⁺ ).
[789] 1.4
[790] To a suspension of 2.0 g (8.7 mmol) of trans- (4-hydroxycyclohexyl) -methyl-carbamic acid tert-butyl ester in 56.5 ml (261 mmol, 30 equiv) of 1,4-dibromobutane 0.89 g (2.6 mmol, 0.3 equiv) of ammonium hydrogensulfate and 56 ml of 50% aqueous NaOH were added. The mixture was stirred at rt for 4 days, CH ₂ Cl ₂ was added and the layers were separated. The inorganic layer was extracted with CH ₂ Cl ₂ and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . Excess dibromide was removed in vacuo and the residue was purified by column chromatography with hexanes: EtOAc 4: 1 as eluent on silica gel to give trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl 2.4 g (76%) of carbamic acid tert-butyl ester were obtained as a light yellow oil. MS: 364 (MH <^+> , 1Br).
[791] 1.5
[792] To 1.7 g (4.7 mmol) of trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 22 ml of DMA, 1.34 ml (14 mmol, N-allylmethylamine) 3 equivalents) was added over a period of 10 minutes. The reaction was stirred at rt overnight, concentrated and the residue dissolved in CH ₂ Cl ₂ /5% aqueous NaHCO ₃ . The phases were separated and the inorganic phase was extracted with CH ₂ Cl ₂ , the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated to trans- (4- [4- (allyl-methyl-amino)- Butoxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester 1.5 g (92%) was obtained as a colorless oil. MS: 355 (MH ⁺ ).
[793] 1.6
[794] Similar to Examples 1.4 and 1.5, trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid tert-butyl ester was reacted with 1,3-dibromopropane to trans- [4- (3-bro Mo-propoxy) -cyclohexyl] -methyl-carbamic acid tert-butyl ester which is reacted with N-allylmethylamine to give trans- (4- [3- (allyl-methyl-amino) -propoxy]- Cyclohexyl) -methyl-carbamic acid tert-butyl ester was obtained as a colorless oil. MS: 341 (MH ⁺ ).
[795] 1.7
[796] Similar to Examples 1.4 and 1.5, trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid tert-butyl ester was reacted with 1,5-dibromopentane to trans- [4- (5-bro Mo-pentyloxy) -cyclohexyl] -methyl-carbamic acid tert-butyl ester which is reacted with N-allylmethylamine to give trans- (4- [5- (allyl-methyl-amino) -pentyloxy]- Cyclohexyl) -methyl-carbamic acid tert-butyl ester was obtained as a white oil. MS: 369 (MH ⁺ ).
[797] 1.8
[798] Similar to Examples 1.4 and 1.5, trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid tert-butyl ester was reacted with 1,6-dibromohexane to trans- [4- (6-bro Mo-hexyloxy) -cyclohexyl] -methyl-carbamic acid tert-butyl ester which is reacted with N-allylmethylamine to give trans- (4- [6- (allyl-methyl-amino) -hexyloxy ] -Cyclohexyl) -methyl-carbamic acid tert-butyl ester was obtained as a light brown oil. MS: 382 (M).
[799] 1.9
[800] Similar to Examples 1.4 and 1.5, trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid tert-butyl ester was reacted with 1,7-dibromoheptane to trans- [4- (7-bro Parent-heptyloxy) -cyclohexyl] -methyl-carbamic acid tert-butyl ester which is reacted with N-allylmethylamine to give trans- (4- [7- (allyl-methyl-amino) -heptyloxy]- Cyclohexyl) -methyl-carbamic acid tert-butyl ester was obtained as a colorless oil. MS: 397 (MH ⁺ ).
[801] 1.10
[802] 2.1 g (5.9 mmol) of trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester in 28 ml of CH ₂ Cl _{2 with} 6 ml of TFA Treated at 0 ° C. for 1 h, the mixture was concentrated in vacuo and dissolved in EtOAc and saturated aqueous NaHCO ₃ solution. The phases were separated and the inorganic phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and evaporated to trans- (4- [4- (allyl-methyl-amino) -butoxy] 1.38 g (91%) of -cyclohexyl) -methyl-amine were obtained as a yellow oil. MS: 255 (MH ⁺ ).
[803] 1.11
[804] Similar to Example 1.10, trans- (4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester was converted to trans- (4- [3- (Allyl-methyl-amino) -propoxy] -cyclohexyl) -methyl-amine was obtained as a yellow oil. MS: 241 (MH ⁺ ).
[805] 1.12
[806] Similar to Example 1.10, trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester was converted to trans- (4- [5- (Allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine was obtained as a yellow oil. MS: 269 (MH ⁺ ).
[807] 1.13
[808] Similar to Example 1.10, trans- (4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester was converted to trans- [4- [6 -(Allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine was obtained as a yellow oil. MS: 283 (MH ⁺ ).
[809] 1.14
[810] Similar to Example 1.10, trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-carbamic acid tert-butyl ester was converted to trans- (4- [7- (Allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine was obtained as a colorless oil. MS: 297 (MH ⁺ ).
[811] Example 2
[812] A solution of 0.153 mmol of free amine in 0.35 ml of dry dioxane was treated with 0.23 mmol of isocyanate in 0.54 ml of dry dioxane. The solution was left overnight at room temperature. The resulting reaction mixture was treated with 0.15 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. Urea was obtained as amino formate after evaporation. The following compounds were prepared from the corresponding amines and isocyanates:
[813] ExamplecompoundMSMH ⁺ AmineIsocyanate 2.1Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2,4-difluoro-phenyl) -1-methyl-urea438Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-difluoro-phenylisocyanate 2.2Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2,4-dimethoxy-phenyl) -1-methyl-urea462Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-dimethoxy-phenylisocyanate 2.3Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methyl-urea420Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amine4-fluorophenyl-isocyanate 2.4Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-methoxy-phenyl) -1-methyl-urea432Trans- [4- [6- (allyl-methyl-amino) -hexyloxy} -cyclohexyl] -methyl-amine4-methoxy-phenylisocyanate
[814] 2.5Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3-p-tolyl-urea416Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-methylphenyl-isocyanate 2.6Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-methoxy-2-methyl-phenyl) -1-methyl-urea446Trans- [4- [6- (allyl-methyl-amino) -hexyloxy} -cyclohexyl] -methyl-amine4-methoxy-2-methylphenyl-isocyanate 2.7Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2,4-dimethyl-phenyl) -1-methyl-urea430Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-dimethyl-phenylisocyanate 2.8Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (3,4,5-trimethoxy-phenyl) -urea492Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,4,5-trimethoxy-phenylisocyanate 2.9Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (3,4-dimethyl-phenyl) -1-methyl-urea430Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,4-dimethyl-phenylisocyanate 2.10Trans-3- (4-acetyl-phenyl) -1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-urea444Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-acetylphenyl-isocyanate 2.11Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-chloro-phenyl) -1-methyl-urea436 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-chlorophenyl-isocyanate
[815] 2.12Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3-phenyl-urea402Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminePhenyl isocyanate 2.13Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -urea470Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-trifluoro-methylisocyanate 2.14Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (3,4-dichloro-phenyl) -1-methyl-urea470 (2Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,4-dichloro-phenylisocyanate 2.15Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methyl-urea480 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-brominephenyl-isocyanate 2.16Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3-naphthalen-2-yl-urea452Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-naphthyl-isocyanate 2.17Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (4-nitro-phenyl) -urea447Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-nitrophenyl-isocyanate 2.18Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-dimethylamino-phenyl) -1-methyl-urea445Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-dimethyl-aminophenyl-isocyanate
[816] 2.19Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -1-methyl-3-p-tolyl-urea430Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-tololoyl-isocarbonate 2.20Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methylurea434Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-fluorophenyl-isocyanate 2.21Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methylurea494 (1 Br)Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-bromophenyl-isocyanate 2.22Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-butyl-phenyl) -1-methylurea472Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-butylphenyl-isocyanate 2.23Trans-1- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -1-methyl-3-p-tolyl-urea402Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-tololoyl-isocarbonate 2.24Trans-1- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methylurea406Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-fluorophenyl-isocyanate 2.25Trans-1- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methylurea466 (1 Br)Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-bromophenyl-isocyanate
[817] 2.26Trans-1- {4- (4- (4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -1-methyl-3-p-tolyl-urea388Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-tololoyl-isocarbonate 2.27Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-fluoro-phenyl) -1-methyl-urea392Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-fluorophenyl-isocyanate 2.28Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-bromo-phenyl) -1-methyl-urea452 (1 Br)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-bromophenyl-isocyanate 2.29Trans-1- {4- (4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-butyl-phenyl) -1-methyl-urea430Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-butylphenyl-isocyanate
[818] Example 3
[819] A solution of 0.153 mmol of amine in 0.35 ml of dry dioxane was treated with Hunig's base (using 2 equivalents or 4 equivalents with amine-dihydrochloride) and 0.2 mmol of chloroformate in 0.54 ml of dry dioxane. The solution was left at room temperature overnight and the resulting reaction mixture was treated with 0.15 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. It was. After evaporation carbamate was obtained as a mixture of amino hydrochloride and formate. The following compounds were prepared from the corresponding amines and chloroformates:
[820] ExamplecompoundMSMH ⁺ AmineChloroformate 3.1Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-nitro-phenyl ester448Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-nitrophenyl-chloroformate 3.2Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid naphthalen-2-yl ester453Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-naphthyl-chloroformate 3.3Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-carbamic acid pentafluorophenylmethyl ester507Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminePentafluorobenzylchloroformate 3.4Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid benzyl ester417Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineBenzyl-chloroformate
[821] 3.5Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid phenyl ester403Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminePhenyl-chloroformate 3.6Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid p-tolyl ester417Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminep-tolyl-chloroformate 3.7Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester481 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-bromophenyl-chloroformate 3.8Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester421Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-fluorophenyl-chloroformate 3.9Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester437 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-chlorophenyl-chloroformate 3.10Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid hexyl ester411Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-hexyl-chloroformate 3.11Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-methoxy-phenyl ester433Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-methoxy-phenyl-chloroformate
[822] 3.12Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid isobutyl ester383Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineIsobutyl-chloroformate 3.13Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester495 (1 Br)Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-bromophenyl-chloroformate 3.14Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester467 (1 Br)Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-bromophenyl-chloroformate 3.15Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester453 (1 Br)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-bromophenyl-chloroformate 3.16Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester435Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-fluorophenyl-chloroformate 3.17Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester407Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-fluorophenyl-chloroformate 3.18{4-Trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester409 (1Cl)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-chloro-phenyl chloroformate
[823] 3.19{4-Trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl] -methyl-carbamic acid isobutyl ester355Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amineIsobutyl chloroformate 3.20{4-Trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid phenyl ester375Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-aminePhenyl chloroformate 3.214-({4-Trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamoyloxy) -benzoic acid methyl ester433Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-methoxy-carbonyl-phenyl chloroformate 3.22{4-Trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-methoxy-phenyl ester405Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-methoxy-phenylchloroformate 3.23{4-Trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid p-tolyl ester389Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amineP-tolyl chloroformate 3.24{4-Trans- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-carbamic acid 4-fluoro-phenyl ester379Trans- (4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl) -methyl-amine4-fluoro-phenyl chloroformate 3.25{4-Trans- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester439 (1 Br)Trans- (4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl) -methyl-amine4-bromo-phenyl chloroformate
[824] Example 4
[825] A solution of 1.5 mmol of trichloromethyl-chloroformate (diphosgene) in 20 ml of CH ₂ Cl ₂ was treated with 3 mmol of appropriate substituted phenol and 3 mmol of quinoline at 0 ° C. and then stirred at room temperature for 3 hours. The reaction was then cooled (0 ° C.) and a solution of 1 mmol of amine and 3 mmol of pyridine in 3 ml of CH ₂ Cl ₂ was added followed by 1 mmol of DMAP. The mixture was stirred at rt overnight, treated with 0.15 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After evaporation carbamate was obtained as a mixture of amino hydrochloride and formate. The following compounds were prepared from the corresponding amines and chloroformates:
[826] ExampleproductMSMH ⁺ AmineIn-situ generated chloroformate 4.1Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester471Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-trifluoro-methyl-phenyl-chloroformate 4.2Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester457Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-trifluoro-phenyl-chloroformate 4.3Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester443Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-trifluoro-methyl-phenyl chloroformate 4.4Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 2,4-difluoro-phenyl ester439Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-difluoro-phenyl chloroformate
[827] Example 5
[828] A solution of 0.143 mmol of amine in 0.35 ml of dry dioxane was treated with Hunig base (0.46 mmol; 3 equiv) and 0.18 mmol of sulfonylchloride in 0.5 ml of dry dioxane. The solution was left overnight at room temperature. The resulting reaction mixture was treated with 0.15 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After evaporation, sulfonamide was obtained as a mixture of amino hydrochloride and formate. The following compounds were prepared from the corresponding amines and sulfonylchlorides:
[829] ExamplecompoundMSMH ⁺ AmineSulfonyl chloride 5.1Trans-5-chloro-thiophene-2-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide463 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine5-chloro-thiophene-2-sulfonylchloride 5.2Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -4, N-dimethyl-benzenesulfonamide437Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-tosylsulfonyl-chloride 5.3Trans-naphthalene-2-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide473Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-naphthyl-sulfonylchloride 5.4Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-methanesulfonamide361Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineMethanesulfonyl-chloride
[830] 5.5Trans-quinoline-8-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide474Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine8-quinoline-sulfonylchloride 5.6Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-C-phenyl-methanesulfonamide437Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineα-toluene-sulfonylchloride 5.7Trans-3,5-dimethyl-isoxazole-4-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide442Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,5-dimethyl-isoxazole-sulfonylchloride 5.8Trans-naphthalene-1-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide473Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine1-naphthyl-sulfonylchloride 5.9Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-methoxy-N-methyl-benzenesulfonamide453Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-methoxy-benzene-sulfonylchloride 5.10Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide423Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineBenzene-sulfonylchloride 5.11Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-N-methyl-benzenesulfonamide441Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-fluorobenzene-sulfonylchloride
[831] 5.12Trans-thiophene-2-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide429Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-thiophene-sulfonylchloride 5.13Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2-fluoro-N-methyl-benzenesulfonamide441Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-fluorobenzene-sulfonylchloride 5.14Trans-1-methyl-lH-imidazole-4-sulfonic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide427Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine1-methyl-imidazole-4-sulfonylchloride 5.15Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-tert-butyl-N-methyl-benzenesulfonamide479Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-tert.-Butyl-benzene-sulfonylchloride 5.16Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-butoxy-N-methyl-benzenesulfonamide495Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-butoxybenzene-sulfonylchloride 5.17Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-chloro-N-methyl-benzenesulfonamide457 (1Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-chlorobenzene-sulfonylchloride 5.18Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide491Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-trifluoro-methylbenzene-sulfonylchloride
[832] 5.19Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-bromo-N-methyl-benzenesulfonamide501 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-brombenzene-sulfonylchloride 5.20Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-nitro-benzenesulfonamide468Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-nitrobenzene-sulfonylchloride 5.21N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-chloro-N-methyl-benzenesulfonamide457 (1Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3-chloro-phenyl sulfonylchloride 5.22N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2,4-difluoro-N-methyl-benzenesulfonamide459Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-difluoro-phenyl-sulfonylchloride 5.23N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2-bromo-N-methyl- benzenesulfonamide501 (1Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-bromo-phenyl sulfonyl chloride 5.24N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-bromo-N-methyl-benzenesulfonamide501 (1Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3-bromo-phenyl sulfonylchloride 5.25N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2,4-dichloro-N-methyl-benzenesulfonamide491 (2Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-dichloro-phenyl-sulfonylchloride
[833] 5.26N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-fluoro-N-methyl- benzenesulfonamide441Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3-fluoro-phenylsulfonylchloride 5.27N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3,4-dichloro-N-methyl-benzenesulfonamide491 (2 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,4-dichloro-phenyl-sulfonylchloride 5.28N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2-chloro-N-methyl-benzenesulfonamide457 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-chloro-phenyl sulfonyl chloride 5.29N- {4-trans- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3,4-difluoro-N-methyl-benzenesulfonamide459Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,4-difluoro-phenyl-sulfonylchloride 5.30N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl- benzenesulfonamide463Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-trifluoromethyl-phenyl-sulfonylchloride 5.31N- {4-trans- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -4-chloro-N-methyl-benzenesulfonamide415 (1 Cl)Trans- (4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl) -methyl-amine4-chloro-phenyl-sulfonylchloride 5.32N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-chloro-N-methyl-benzenesulfonamide429 (1 Cl)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-chloro-phenyl-sulfonylchloride 5.33N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-bromo-N-methyl- benzenesulfonamide473 (1 Br)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-bromo-phenyl-sulfonylchloride
[834] 5.34N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-C-phenyl-methanesulfonamide409Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amineBenzyl-sulfonylchloride 5.35N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-fluoro-N-methyl- benzenesulfonamide413Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-fluoro-phenyl-sulfonylchloride 5.36N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -2-fluoro-N-methyl- benzenesulfonamide413Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine2-fluoro-phenyl-sulfonylchloride 5.37N- {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl- benzenesulfonamide395Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-aminePhenyl-sulfonylchloride 5.385-Chloro-thiophene-2-sulfonic acid {4-trans- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-amide436 (1 Cl)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine5-chloro-thiophene-2-sulfonylchloride
[835] Example 6
[836] A solution of 0.133 mmol of amine in 0.5 ml of dry DMF was sequentially added with 0.17 mmol (1.3 equiv) of acid, 0.266 mmol (2 equiv) of Hunig's base, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride) (EDCI) 0.266 mmol (2 equiv) and catalytic amount of hydroxybenzotriazole (HOBT) (about 0.02 mmol). The solution was left overnight at room temperature. The resulting reaction mixture was treated with 0.15 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After evaporation, the amide was obtained as a mixture of amino hydrochloride and formate. The following compounds were prepared from the corresponding amines and acids:
[837] ExamplecompoundMSMH ⁺ Aminemountain 6.1Trans-pyridine-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide388Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminePicolinic acid 6.2Trans-1H-indole-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide426Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine1H-indole-2-carboxylic acid 6.3Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzamide387Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineBenzoic acid 6.4Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-chloro-N-methyl-benzamide421 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-Chloro-benzoic acid
[838] 6.5Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-N-methyl-benzamide405Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-fluoro-benzoic acid 6.6Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-bromo-N-methyl-benzamide465 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amine4-Bromo-benzoic acid 6.7Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzamide455Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-Trifluoro-methyl-benzoic acid 6.8Trans-thiophene-3-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide393Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineThiophene-3-carboxylic acid 6.9Trans-5-bromo-thiophene-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide471 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine5-Bromo-thiophene-2-carboxylic acid 6.10Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-2-thiophen-3-yl-acetamide407Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-thiophen-3-yl-carboxylic acid 6.11Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2- (2,4-difluoro-phenyl) -N-methyl-acetamide437Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-difluoro-acetic acid
[839] 6.12Trans-5-fluoro-1H-indole-2-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide444Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine1H-indole-5-fluoro-2-carboxylic acid 6.13Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -2- (4-fluoro-phenyl) -N-methyl-acetamide419Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amine4-fluoro-phenylacetic acid 6.14Trans-1H-indole-5-carboxylic acid {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-amide426Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine1H-indole-5-carboxylic acid 6.15Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-chloro-N-methyl-benzamide421 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3-chlorobenzoic acid 6.16Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-3, N-dimethyl-benzamide419Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-Fluoro-3-methyl-benzoic acid 6.17Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-nitro-benzamide432Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-nitro-benzoic acid 6.18Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4, N-dimethyl-benzamide401Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminep-toluic acid
[840] 6.19Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-cyano-N-methyl-benzamide412Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3-cyano-benzoic acid 6.20Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3, N-dimethyl-benzamide401Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminem-toluic acid 6.21Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3,4-dimethoxy-N-methyl-benzamide447Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,4-dimethoxy-benzoic acid 6.22Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-methoxy-N-methyl-benzamide417Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-methoxy-benzoic acid 6.23Trans-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -4-fluoro-N-methyl-3-nitro-benzamide450Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-Fluoro-3-nitro-benzoic acid 6.24Trans-4-acetyl-N- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzamide429Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-acetyl-benzoic acid 6.25Trans-N- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzamide469Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-Trifluoro-methyl-benzoic acid
[841] 6.26Trans-N- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzamide441Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-Trifluoro-methyl-benzoic acid 6.27Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3-cyano-N-methyl-benzamide384Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine3-Cyano-phenyl-benzoic acid 6.28Trans-N- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -4-bromo-N-methyl-benzamide451 (1 Br)Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-Bromo-phenyl-benzoic acid 6.29Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-bromo-N-methyl-benzamide337 (1 Br)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-Bromo-phenyl-benzoic acid 6.30Trans-5-bromo-thiophene-2-carboxylic acid {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-amide443 (1 Br)Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine2-Bromo-thiophene5-carboxylic acid 6.31Trans-N- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -4-fluoro-N-methyl-benzamide391Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-Fluoro-phenyl-benzoic acid 6.32Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -4-fluoro-N-methyl-benzamide377Trans- (4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl) -methyl-amine4-Fluoro-phenyl-benzoic acid
[842] Example 7
[843] A solution of 0.133 mmol of amine was treated with 0.17 mmol (1.3 equiv) of isothiocyanate in 0.35 ml of dry dioxane. The solution was left at room temperature overnight, treated with 0.15 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After evaporation of the corresponding fractions, thiourea was obtained as amino formate. The following compounds were prepared from the corresponding amines and isothiocyanates:
[844] ExamplecompoundMSMH ⁺ AmineIsothiocyanate 7.1Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (2-bromo-4-fluoro-phenyl) -1-methyl-thiourea514 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2-bromo-4-fluoro-phenyl-isothiocyanate 7.2Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-bromo-2-methyl-phenyl) -1-methyl-thiourea510 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-Bromo-2-methyl-phenyl-isothiocyanate 7.3Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea486Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-trifluoro-methyl-phenyl-isothiocyanate 7.4Trans1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-chloro-phenyl) -1-methyl-thiourea452 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-chloro-phenyl-isothiocyanate 7.5Trans1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-methoxy-phenyl) -1-methyl-thiourea448Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-methoxy-phenyl-isothiocyanate
[845] 7.6Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3- (4-cyano-phenyl) -1-methyl-thiourea443Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-cyanophenyl-isothiocyanate 7.7Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -1-methyl-3- (3-methyl-butyl) -thiourea412Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3-methylbutyl-isothiocyanate 7.8Trans-1- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -3-sec-butyl-1-methyl-thiourea398Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminesec-butyl-isothiocyanate 7.9Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea458Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine1-isothiocyanato-4-trifluoro-methyl-benzene 7.10Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -3- (4-cyano-phenyl) -1-methyl-thiourea415Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine1-isothiocyanato-4-cyano-benzene 7.11Trans-1- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -1-methyl-3- (3-methyl-butyl) -thiourea384Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine1-isothiocyanato-3-methyl-butane 7.12Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea500Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine1-isothiocyanato-4-trifluoro-methyl-benzene
[846] 7.13Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -3- (4-cyano-phenyl) -1-methyl-thiourea457Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine1-isothiocyanato-4-cyano-benzene 7.14Trans-1- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -1-methyl-3- (3-methyl-butyl) -thiourea426Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine1-isothiocyanato-3-methyl-butane 7.15Trans-1- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -1-methyl-3- (4-trifluoromethyl-phenyl) -thiourea444Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine4-trifluoro-methyl-phenyl-isothiocyanate
[847] Example 8
[848] The amine (3 equiv) was dissolved in CH ₂ Cl ₂ (1 ml / mmol) and placed in an ice bath. A solution of chlorosulfonic acid (1 equiv) in CH ₂ Cl ₂ (0.5 ml / mmol) was added slowly ( 30 minutes). The reaction mixture was stirred at 0 ° C. for a further 30 minutes. The ice bath was then removed and stirring continued at room temperature for 1 hour. The precipitate was collected by filtration and dried under high vacuum. This salt was suspended in toluene (1 ml / mmol amine) and PCl ₅ (1 equiv) was added. The mixture was stirred at 75 ° C. for 2 h, cooled to rt and filtered. The solid residue was washed with toluene. The filtrate was evaporated and dried under high vacuum. Crude sulfamoyl chloride was used for the next step without further purification. The following sulfamoyl chlorides were prepared from the corresponding amines according to the above procedure:
[849] Benzylsulfamoyl chloride, phenylsulfamoyl chloride, 2,4-difluoro-phenylsulfamoyl chloride, 2,5-difluoro-phenylsulfamoyl chloride, 3,4-difluoro-phenylsulfamoyl chloride, 3 -Fluoro phenyl-sulfamoyl chloride, 4-fluoro-phenylsulfamoyl chloride, 4-chloro-phenylsulfamoyl chloride, 4-bromo-phenylsulfamoyl chloride, 4-methyl-phenylsulfamoyl chloride, 4-tri Fluoromethyl-phenylsulfamoyl chloride, 4-cyano-phenylsulfamoyl chloride, 4-methoxy-phenylsulfamoyl chloride, butylsulfamoyl chloride, phenethylsulfamoyl chloride, cyclopropylsulfamoyl chloride, 2,2, 2-trifluoroethylsulfamoyl chloride, 4-fluoro-benzylsulfamoyl chloride, furan-2-ylmethylsulfamoyl chloride, benzo [1,3] dioxol-5-ylmethylsulfamoyl chloride.
[850] Example 9
[851] Amine-hydrochloride (1 equiv) was dissolved in CH ₃ CN and placed in an ice bath. Sulfuryl chloride (3 equiv) was added slowly (20 min). The reaction mixture was stirred at room temperature for 15 minutes and at 65 ° C. for 20 hours. The solvent was evaporated and the residue dried under high vacuum. Crude sulfamoyl chloride was used for the next step without further purification. The following sulfamoyl chlorides were prepared from the corresponding amines according to the above procedure:
[852] Chlorosulfonylamino-acetic acid ethyl ester, 4- (chlorosulfonylamino-methyl) -benzoic acid methyl ester.
[853] Example 10
[854] A solution of 0.135 mmol of amine in 0.75 ml of dry dioxane was treated with 5 equivalents of triethylamine followed by a solution of 0.175 mmol (1.3 equiv) of sulfamoyl chloride in 0.25 ml of dry dioxane. The suspension was overnight at room temperature, treated with 0.15 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After evaporation of the corresponding fractions, sulfamide was obtained as a mixture of amino hydrochloride and formate. The following compounds were prepared from the corresponding amines and sulfamoylchlorides:
[855] ExamplecompoundMSMH ⁺ AmineSulfamoyl-chloride 10.1Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-sulfameic acid benzyl amide452Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineBenzyl-sulfamoylchloride 10.2Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide438Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminePhenyl-sulfamoylchloride 10.3Trans-4-[({4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamoyloxy) -methyl] -benzoic acid methyl ester510Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4- (Chloro-sulfonylamino-methyl) -benzoic acid methyl ester 10.4Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid butyl amide418Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineButyl-Sulfamoylchloride
[856] 10.5Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfame acid phenethyl amide466Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminePhenethyl-sulfamoylchloride 10.6Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid furan-2-ylmethyl amide442Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineFuran-2-yl-methyl-sulfamoylchloride 10.7Trans-({4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonylamino) -acetic acid ethyl ester448Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineChloro-sulfonylamino-acetic acid ethyl ester 10.8Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid cyclopropyl amide402Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineCyclopropyl-sulfamoylchloride 10.9Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid 2,2,2-trifluoro-ethylamide444Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,2,2-trifluoro-ethyl-sulfamoylchloride 10.10Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfame acid benzo [1,3] dioxol-5-ylmethyl amide496Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amineBenzo [1,3] dioxol-5-yl-methyl-sulfamoylchloride 10.11Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-sulfamic acid 4-fluorobenzyl amide470Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-fluoro-benzyl-sulfamoylchloride
[857] 10.12Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (4-chloro-phenyl) -amide472 (1 Cl)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-Chloro-phenyl-sulfamoylchloride 10.13Trans- {4-j6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (4-fluoro-phenyl) -amide456Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-fluoro-phenyl-sulfamoylchloride 10.14Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfamic acid (4-bromo-phenyl) -amide516 (1 Br)Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-Bromo-phenyl-sulfamoylchloride 10.15Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (p-tolyl) -amide452Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-aminep-tolyl-sulfamoylchloride 10.16Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (3,4-difluoro-phenyl) -amide474Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3,4-difluoro-phenyl-sulfamoylchloride 10.17Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfame acid (4-trifluoromethyl-phenyl) -amide506Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-trifluoro-methylphenyl-sulfamoylchloride 10.18Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (3-fluoro-phenyl) -amide456Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine3-fluoro-phenyl-sulfamoylchloride
[858] A
[859] 10.19Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfamic acid (4-cyano-phenyl) -amide463Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-cyano-phenyl-sulfamoylchloride 10.20Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (2,4-difluoro-phenyl) -amide474Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,4-difluoro-phenyl-sulfamoylchloride 10.21Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (4-methoxy-phenyl) -amide468Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine4-methoxy-phenyl-sulfamoylchloride 10.22Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-sulfonic acid (2,5-difluoro-phenyl) -amide474Trans- [4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl] -methyl-amine2,5-difluoro-phenyl-sulfamoylchloride 10.23Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfameic acid benzyl amide436M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amineBenzyl-sulfamoylchloride 10.24Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide422M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-aminePhenyl-sulfamoylchloride 10.25Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-chlorophenyl amide456 (1Cl) MH ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-Chloro-phenyl-sulfamoylchloride
[860] 10.26Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-bromophenyl amide500 (1 Br) MH ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-Bromo-phenyl-sulfamoylchloride 10.27Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-methylphenyl amide436M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-Methyl-phenyl-sulfamoylchloride 10.28Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-trifluoromethylphenyl amide490M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-trifluoro-methyl-phenyl-sulfamoylchloride 10.29Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-cyanophenyl amide447M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-cyano-phenyl-sulfamoylchloride 10.30Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid p-methoxyphenyl amide452M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine4-methoxy-phenyl-sulfamoylchloride 10.31Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluorophenyl amide458M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine3,4-difluoro-phenyl-sulfamoylchloride 10.32Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid 3-fluorophenyl amide440M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine3-fluoro-phenyl-sulfamoylchloride
[861] 10.33Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfonic acid 2,4-difluorophenyl amide458M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine2,4-difluoro-phenyl-sulfamoylchloride 10.34Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-sulfamic acid 2,5-difluorophenyl amide458M-H ^- Trans- (4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl) -methyl-amine2,5-difluoro-phenyl-sulfamoylchloride 10.35Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide396Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-aminePhenyl-sulfamoylchloride 10.36Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluorophenyl amide432Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine3,4-difluoro-phenyl-sulfamoylchloride 10.37Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfonic acid 4-chlorophenyl amide430 (1 Cl)Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine4-Chloro-phenyl-sulfamoylchloride 10.38Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-sulfameic acid benzyl amide410Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amineBenzyl-sulfamoylchloride 10.39Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfame acid phenyl amide410Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-aminePhenyl-sulfamoylchloride 10.40Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfonic acid 3-fluorophenyl amide428Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine3-fluoro-phenyl-sulfamoylchloride
[862] 10.41Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluoro phenyl amide446Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine3,4-difluoro-phenyl-sulfamoylchloride 10.42Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfonic acid 4-chlorophenyl amide444 (1 Cl)Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amine4-Chloro-phenyl-sulfamoylchloride 10.43Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfameic acid benzyl amide424Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amineBenzyl-sulfamoylchloride 10.44Trans-({4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-sulfamoylamino) -acetic acid ethyl ester420Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-amineChloro-sulfonylamino-acetic acid ethyl ester 10.45Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid phenyl amide452Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-aminePhenyl-sulfamoylchloride 10.46Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid 3-fluoro-phenyl amide470Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine3-fluoro-phenyl-sulfamoylchloride 10.47Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid 3,4-difluoro-phenyl amide488Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine3,4-difluoro-phenyl-sulfamoylchloride 10.48Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfonic acid 4-chloro-phenyl amide486 (1 Cl)Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amine4-Chloro-phenyl-sulfamoylchloride
[863] 10.49Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl- sulfamic acid furan-2-ylmethyl amide456Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amineFuran-2-yl-methyl-sulfamoylchloride 10.50Trans- {4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfameic acid benzyl amide466Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amineBenzyl sulfamoyl chloride 10.51Trans-({4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl} -methyl-sulfamoyloxy) -acetic acid ethyl amide462Trans- (4- [7- (allyl-methyl-amino) -heptyloxy] -cyclohexyl) -methyl-amineChlorosulfonyl-amino-acetic acid ethyl ester
[864] Example 11
[865] 11.1
[866] Trans-4-methylamino-cyclohexanol (suspended twice in toluene and evaporated to remove water under reduced pressure) 4.01 g (31 mmol) was suspended in 60 ml of hexamethyldisilazane and refluxed for 2.5 hours. The solution was evaporated under reduced pressure, dissolved in 80 ml of CH ₂ Cl ₂ and added to a cooled solution (0 ° C.) of 2.06 ml (17.05 mmol) of trichloromethylchloroformate (diphosgene) and 4.40 ml (34.10 mmol) of quinoline. It was. The reaction was stirred at 0 ° C. for 3 hours and evaporated. The residue and 8.47 g (65.1 mmol) of 3,4-difluorophenol were dissolved in 220 ml of THF, and washed with 3.25 g (74.4 mmol) of NaH (about 55% in oil) and 0.26 g (1.6 mmol) of KI at 0 ° C. Treated in portions. The reaction was stirred at rt overnight, cooled (0 ° C.) and 0.68 g (15.5 mmol) of NaH (about 55% in oil) were added and stirred at rt for 24 h. After adding 60 ml of water, the pH was adjusted to pH 2 (1 N HCl) and the reaction mixture was stirred for 1 hour. The reaction was partitioned between aqueous 1N NaOH / Et ₂ O (3 × 300 ml) and the organic phase was dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in 200 ml of THF / dioxane (1: 1). 34 ml of 1N NaOH was added at 0 ° C. and the mixture was stirred for 3 hours. The reaction was partitioned between water / Et ₂ O (3 × 300) and the organic phase was dried over Na ₂ SO ₄ and evaporated to afford crude trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid 3,4- 11.6 g of difluoro-phenyl ester were obtained.
[867] 11.2
[868] A solution of 11.6 g (containing 31 mmol) of crude trans- (4-hydroxycyclohexyl) -methyl-carbamic acid 3,4-difluoro-phenyl ester in 110 ml of 1,4-dibromobutane was dissolved in tetrabutyl Treated with 3.16 g (9.3 mmol) of ammonium hydrogen sulphate and 200 ml of aqueous 50% NaOH and stirred at room temperature for 2.5 days. The reaction was extracted (CH ₂ Cl ₂ 2 ×). The organic phase was dried over Na ₂ SO ₄ , evaporated and purified by flash silica gel column (first with hexane to remove dibromobutane and then with hexane / EtOAc 1: 1) trans- [4- (4 -Bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester was obtained 4.06 g (31%). MS: 420 (M, 1 Br).
[869] 11.3
[870] Similar to Examples 11.1 and 11.2, trans-4-methylamino-cyclohexanol was reacted with α, α, α-trifluoro-p-cresol followed by 1,4-dibromobutane to trans- [4- (4-Bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester was obtained. MS: 452 (MH <^+> , 1Br).
[871] 11.4
[872] To a solution of 16.1 g (124.7 mmol) of trans-4-methylamino-cyclohexanol in 40 ml of CH ₂ Cl ₂ , 18.3 ml (130.9 mmol, 1.05 equiv) of 4-chlorophenylchloroformate and 22.4 ml of Hunig's base ( 130.9 mmol, 1.05 equiv) was added at 0 ° C. The solution was stirred overnight at room temperature, diluted and washed with 1M HCl, saturated aqueous NaHCO ₃ solution. The organic phase was dried over MgSO ₄ . Column chromatography on silica gel with EtOAc: hexanes 1: 1 gave 32.2 g (91%) of trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester as a white solid. MS: 283 (M, 1 Cl).
[873] 11.5
[874] To 1.46 g (5.1 mmol) of trans- (4-hydroxycyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester suspended in 30 ml (190.4 mmol, 37 equiv) of 1,6-dibromhexane, tetra 0.53 g (1.5 mmol, 0.3 equiv) of butylammonium hydrogensulfate and 30 ml of 50% aqueous NaOH were added. The mixture was stirred at 50 ° C. for 1 day, CH ₂ Cl ₂ was added and the layers were separated. The inorganic layer was extracted with CH ₂ Cl ₂ and the combined organic layers were washed with brine and dried over MgSO ₄ . Excess dibromide was removed in vacuo and the residue was purified by column chromatography with hexanes: EtOAc 4: 1 as eluent on silica gel to give trans- [4- (6-bromo-hexyloxy) -cyclohexyl]- 2.04 g (89%) of methyl-carbamic acid 4-chloro-phenyl ester was obtained as a light yellow oil. MS: 446 (M, 1 Br, 1 Cl).
[875] 11.6
[876] Similar to Example 11.5, trans- (4-hydroxy-hexyl) -methyl-carbamic acid 4-chloro-phenyl ester was reacted with 1,4-dibromobutane to trans- [4- (4-bro Parent-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester was obtained as a yellowish oil. MS: 418 (M, 1 Br, 1 Cl).
[877] 11.7
[878] Similar to Example 11.5, trans- (4-hydroxycyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester was reacted with 1,5-dibromopentane to trans- [4- (5-bro Parent-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester was obtained as a yellow oil. MS: 433 (MH <^+> , 1Br, 1Cl).
[879] 11.8
[880] To a solution of 1.26 ml (14.1 mmol) of 3-bromo-1-propanol and 3.5 ml (15.3 mmol) of 2,6-di-tert-butylpyridine in 7 ml of CH ₂ Cl ₂ at 0 ° C., CH ₂ Cl ₂ A solution of 2.49 ml (14.8 mmol) of trifluoromethanesulfonic anhydride in 3.6 ml was added. After 2.5 hours at 0 ° C., the solution was evaporated, dissolved in 7 ml of nitromethane and 2.0 g of trans- (4-hydroxycyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester in 27 ml of nitromethane. mmol) and 3.23 ml (14.1 mmol) of 2,6-di-tert-butylpyridine. The reaction mixture was heated to 60 ° C. for 3.5 h and then diluted with EtOAc, washed with 1M HCl, saturated aqueous NaHCO ₃ and water, dried over MgSO ₄ and evaporated. Purification by flash-chromatography with hexanes / EtOAc 9: 1 on silica gel gave trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester as a yellow oil. Obtained as MS: 405 (MH <^+> , 1Br, 1Cl).
[881] 11.9
[882] To 3 g (23.2 mmol) of trans-4-methylamino-cyclohexanol in 120 ml of CH ₂ Cl ₂ was added 4.2 ml (24.4 mmol, 1.05 equiv) of N, N-diisopropylethylamine, followed by CH ₂ Cl ₂ 50 5.96 g (24.4 mmol, 1.05 equiv) of 4- (trifluoromethyl) -benzenesulfonyl chloride in ml was added. The mixture was stirred at rt overnight and the organic phase was extracted with 1M KHSO ₄ followed by 5% NaHCO ₃ and brine. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and evaporated. Column chromatography on hexane: EtOAc 1: 1 on silica gel yields 6.0 g (77%) of trans-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide in gray. Obtained as a white solid. MS: 338 (MH <^+> ).
[883] 11.10
[884] Similar to Example 11.9, trans-4-methylamino-cyclohexanol and 4-bromobenzenesulfonylchloride were reacted to trans-4-bromo-N- (4-hydroxy-cyclohexyl) -N- Methyl-benzenesulfonamide was obtained as a greyish white solid. MS: 348 (MH <^+> , 1Br).
[885] 11.11
[886] 6 g (17.8 mmol) of trans-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide was added to 100 ml (658 mmol, 37) of 1,6-dibromohexane. Equivalent) and 1.8 g (5.3 mmol, 0.3 equiv) of tetra-butylammonium hydrogensulfate and 100 ml of 50% aqueous NaOH were added. The reaction mixture was stirred at 50 ° C. for 2 days, CH ₂ Cl ₂ was added and the layers were separated. The inorganic phase was extracted with CH ₂ Cl ₂ and the combined inorganic phases were washed with brine, dried over Na ₂ SO ₄ and evaporated. Excess dibromide was removed in vacuo and the residue was purified by column chromatography on silica gel with hexanes: EtOAc 4: 1 to trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl]- 8.3 g (93%) of N-methyl-4-trifluoromethyl-benzenesulfonamide were obtained as a yellow oil. MS: 500 (MH <^+> , 1Br).
[887] 11.12
[888] Similar to Example 11.11, trans-4-bromo-N- (4-hydroxycyclohexyl) -N-methyl-benzenesulfonamide was reacted with 1,6-dibromohexane to trans-4-bromohexane. Parent-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide was obtained as a grayish white solid. MS: 510 (MH <^+> , 1Br).
[889] 11.13
[890] Similar to Example 11.11, trans-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and 1,3-dibrompropane were converted to trans-N- [4- (3-Bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was obtained as a grayish white semisolid. MS: 320 [MC ₃ H ₆ BrO].
[891] 11.14
[892] Similar to Example 11.11, trans-N- (4-hydroxy-cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and 1,4-dibrombutane were converted to trans-N- [4- (4-Bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was obtained as a light yellow semisolid. MS: 320 [MC ₄ H ₈ BrO].
[893] 11.15
[894] Similar to Example 11.5, trans- (4-hydroxycyclohexyl) -methyl-carbamic acid tert-butyl ester was reacted with 1,4-dibrombutane to trans- [4- (4-bromo-part Methoxy) -cyclohexyl] -methyl-carbamic acid tert-butyl ester was obtained as a yellowish oil. MS: 364 (MH <^+> , 1Br).
[895] 11.16
[896] 5.7 g (15.65 mmol) of trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid tert-butyl ester were treated with 20 ml of 4N HCl in dioxane at room temperature. After 18 hours at this temperature, t-butyl methylether was added to give 4.34 g (92%) of trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-amine hydrochloride after filtration. MS: 264 (MH <^+> , 1Br).
[897] 11.17
[898] A solution of 1.5 mmol of trichloromethyl-chloroformate (diphosgene) in 20 ml of CH ₂ Cl ₂ was treated with 3 mmol of 2,4-difluoro-phenol and 3 mmol of quinoline at 0 ° C., followed by 3 hours at room temperature. Stirred. The reaction was then cooled (0 ° C.) and extracted with [4- (4-bromo-butoxy) -cyclohexyl] -methyl-amine (aq. NaHCO ₃ / EtOAc in 3 ml of CH ₂ Cl ₂ trans- [4]. A solution of 1 mmol of-(4-bromo-butoxy) -cyclohexyl] -methyl-amine hydrochloride) and 2.5 mmol of pyridine was added. The reaction was stirred at rt overnight and evaporated to afford crude trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenyl ester, which was then It was used directly in the step. See Examples 12.39-12.44.
[899] 11.18
[900] Similar to Example 11.4, 2.1 equivalents of trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-amine hydrochloride and isobutyl chloroformate (N, N-diisopropylethylamine) Together) to give trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester, which was used directly in the next step. See Examples 12.45-12.54.
[901] 11.19
[902] Similar to Example 11.9, trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-amine hydrochloride and 3,4-difluoro-benzenesulfonyl chloride (N, N-di With 2.1 equivalents of isopropylethylamine) to give trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -3,4-difluoro-N-methyl-benzenesulfonamide And used directly in the next step. See Examples 12.55-12.56 and 12.65 and 12.66.
[903] 11.20
[904] Similar to Example 11.9, trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-amine hydrochloride and 2,4-difluoro-benzenesulfonyl chloride (N, N-di With 2.1 equivalents of isopropylethylamine) to give trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -2,4-difluoro-N-methyl-benzenesulfonamide This was used directly in the next step. See Examples 12.57-12.58 and 12.65 and 12.66.
[905] 11.21
[906] Similar to Example 11.9, trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-amine hydrochloride and 4-nitro-benzenesulfonyl chloride (N, N-diisopropylethylamine Together with 2.1 equivalents) to afford trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamide. MS: 451 (MH ⁺ ).
[907] 11.22
[908] Similar to Example 11.9, trans-N- (4-hydroxy-cyclohexyl) -4-tri was converted by trans-amino-cyclohexanol and 4- (trifluoromethyl) -benzenesulfonyl chloride. Fluoromethyl-benzenesulfonamide was obtained as a white solid. 176.2 ° C, MS 322 (M-H).
[909] 11.23
[910] To 4 g (12.4 mmol) of trans-N- (4-hydroxycyclohexyl) -4-trifluoromethyl-benzenesulfonamide in 20 ml of DMF, 5.1 g (37.1 mmol, 3.3 equiv) of K ₂ CO ₃ and ethyl 2.04 ml (27.2 mmol, 2.2 equiv) of bromide were added. The mixture was stirred at 35 ° C. overnight, concentrated in vacuo and dissolved in CH ₂ Cl ₂ and water. The phases were separated and the inorganic phase was extracted with CH ₂ Cl ₂ , the combined organic phases were washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by column chromatography on CH ₂ Cl ₂ / MeOH 95: 5 on silica gel to give trans-N-ethyl-N- (4-hydroxy-cyclohexyl) -4-trifluoromethyl-benzenesulfon 1.6 g (38%) of amide was obtained as a brown oil. MS: 351 (M).
[911] 11.23
[912] Similar to Example 11.11, trans-N-ethyl-N- (4-hydroxycyclohexyl) -4-trifluoromethyl-benzenesulfonamide and 1,4-dibromobutane were converted to trans-N -[4- (4-Bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide was obtained as a colorless oil. MS 470 (M-CH 3, 1 Br).
[913] Example 12
[914] A solution of 0.25 mmol (1 equiv) of bromide in 0.7 ml of dry DMA was treated with a solution of 0.5 mmol (2 equiv) of secondary amine in 0.15 ml of dry DMA at room temperature. After 16 hours, 2 equivalents of secondary amine was added back to the solution. The reaction mixture was left at room temperature overnight, treated with 0.2 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After evaporation, the tertiary amine was obtained as a mixture of amine hydrobromide and formate. The following compounds were prepared from the corresponding bromide and secondary amines:
[915] ExamplecompoundMSMH ⁺ BromideSecondary amine 12.1Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester461Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester2- (ethylamino) -ethanol 12.2Trans- [4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester445Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl esterDiethylamine 12.3Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester417Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl esterDimethylamine
[916] 12.4Trans- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester477Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl esterDiethanolamine 12.5Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester445Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl esterN-methylpropyl-amine 12.6{4- [trans-4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 3,4-difluoro-phenyl ester411Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester;Allylmethylamine 12.7[Trans-4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester385Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester33% 5.6M in dimethylamineEtOH 12.8(Trans-4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 3,4-difluoro-phenyl ester429Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenylesterEthyl- (2-hydroxy-ethyl) -amine 12.9[Trans-4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester413Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenylesterDiethylamine 12.10Methyl- [trans-4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 3,4-difluoro-phenyl ester425Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl esterPiperidine
[917] 12.11[Trans-4- (4-azetidin-1-yl-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl ester397Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl esterAzetidine 12.12Methyl- [trans-4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -carbamic acid 3,4-difluoro-phenyl ester427Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl esterMorpholine 12.13Methyl- [trans-4- (4-pyrrolidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 3,4-difluoro-phenyl ester411Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl esterPyrrolidine 12.14(4- {trans-4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 3,4-difluoro-phenyl ester443Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl esterEthyl- (2-methoxy-ethyl) -amine 12.15Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -carbamic acid 3,4-difluoro-phenyl ester413Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 3,4-difluoro-phenyl esterN-methylpropyl-amine
[918] The following compounds were further prepared according to the above procedure by reacting the corresponding 2 equivalents of amine with the corresponding equivalent of 1 bromide:
[919] ExamplecompoundMSMH ⁺ BromideSecondary amine 12.16Trans-N- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide481Trans-N- [4- (3-bromo-propoxy) -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamideN- (2-methoxy-ethyl) -ethylamine
[920] 12.17Trans-N- {4- [3- (3,6-dihydro-2H-pyridin-1-yl) -propoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide461Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide1,2,3,6-tetra-hydro-pyridine 12.18Trans-N-methyl-N- {4- [3- (methyl-propyl-amino) -propoxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide451Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-methylpropyl-amine 12.19Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxyl-cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide481Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide2- (ethylamino) -ethanol 12.20Trans-N- [4- (4-diethylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide465Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-diethylamine 12.21Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide437Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide33% 5.6M in dimethylamineEtOH 12.22Trans-N- (4- {4-[(2-methoxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide481Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN- (2-methoxy-ethyl) -methyl-amine 12.23Trans-N- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide467Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide2- (methylamino) -ethanol
[921] 12.24Trans-N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide497Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideDiethanolamine 12.25Trans-N- {4- [4- (cyclopropylmethyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide477Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideCyclopropyl-methyl-methyl-amine 12.26Trans-N-methyl-N- [4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide479Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideMorpholine 12.27Trans-N- {4- [4- (3,6-dihydro-2H-pyridin-1-yl) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide475Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide1,2,3,6-tetra-hydro-pyridine 12.28Trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide465Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-methylpropyl-amine 12.29Trans-N- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide495Trans-N- [4- (4-bromo-butoxy) -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamideN- (2-methoxy-ethyl) -ethylamine 12.30Trans-N- (4- {3-[(2-methoxy-ethyl) -methyl-amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide467Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN- (2-methoxy-ethyl) -methyl-amine
[922] 12.31Trans-N- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} N-methyl-4-trifluoromethyl-benzenesulfonamide449Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-methylallyl-amine 12.32Trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide467Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide2- (ethylamino) -ethanol 12.33Trans-N- [4- (3-diethylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide451Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-diethylamine 12.34Trans-N- (4- {3-[(2-hydroxy-ethyl) -methyl-amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide453Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide2- (methylamino) -ethanol 12.35Trans-N- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -propoxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide483Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideDiethanol-amine 12.36Trans-N- {4- [3- (cyclopropylmethyl-methyl-amino) -propoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide463Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideCyclopropyl-methyl-methyl-amine 12.37Trans-N-methyl-N- [4- (3-pyrrolidin-1-yl-propoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide449Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamidePyrrolidine
[923] 12.38Trans-N-methyl-N- [4- (3-morpholin-4-yl-propoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide465Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideMorpholine
[924] The following compounds were further prepared from the corresponding bromide and secondary amines:
[925] ExamplecompoundMSMH ⁺ BromideSecondary amine 12.39Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 2,4-difluoro-phenyl ester411Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenyl esterAllylmethylamine 12.40Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenyl ester385Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenylester33% 5.6M in dimethylamineEtOH 12.41Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 2,4-difluoro-phenyl ester429Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenylesterEthyl- (2-hydroxy-ethyl) -amine 12.42Trans-methyl- [4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -carbamic acid 2,4-difluoro-phenyl ester427Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenylesterMorpholine 12.43Trans- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 2,4-difluoro-phenyl ester443Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenylesterEthyl- (2-methoxy-ethyl) -amine
[926] 12.44Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -carbamic acid 2,4-difluoro-phenyl ester413Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 2,4-difluoro-phenyl esterN-methylpropylamine 12.45Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester329Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester33% 5.6M in dimethylamineEtOH 12.46Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid isobutyl ester373Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterEthyl- (2-hydroxy-ethyl) -amine 12.47Trans- [4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester357Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterDiethylamine 12.48Trans- [4- (4-azetidin-1-yl-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester341Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterAzetidine 12.49Trans-methyl- [4- (4-morpholin-4-yl-butoxy) -cyclohexyl] -carbamic acid isobutyl ester371Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterMorpholine 12.50Trans-methyl- [4- (4-pyrrolidin-1-yl-butoxy) -cyclohexyl] -carbamic acid isobutyl ester356Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterPyrrolidine 12.51Trans- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid isobutyl ester387Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterEthyl- (2-methoxy-ethyl) -amine
[927] 12.52Trans-methyl- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -carbamic acid isobutyl ester357Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterN-methylpropylamine 12.53Trans- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid isobutyl ester389Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl ester2- (hydroxy-ethyl) -amino-ethanol 12.54Trans- {4- [4- (cyclopropylmethyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid isobutyl ester369Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid isobutyl esterCyclopropylmethyl-methyl-amine 12.55Trans-3,4-difluoro-N-methyl-N- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -benzenesulfonamide433Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -3,4-difluoro-N-methyl-benzenesulfonamideN-methylpropylamine 12.56Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -3,4-difluoro-N-methyl-benzenesulfonamide449Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -3,4-difluoro-N-methyl-benzenesulfonamide2- (hydroxy-ethyl) -amino-ethanol 12.57Trans-2,4-difluoro-N-methyl-N- {4- [4- (methyl-propyl-amino) -butoxy] -cyclohexyl} -benzenesulfonamide433Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -2,4-difluoro-N-methyl-benzenesulfonamideN-methylpropylamine 12.58Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -2,4-difluoro-N-methyl-benzenesulfonamide449Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -2,4-difluoro-N-methyl-benzenesulfonamide2- (hydroxy-ethyl) -amino-ethanol
[928] 12.59Trans-N-methyl-4-nitro-N- [4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -benzenesulfonamide454Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamidePiperidine 12.60Trans-N- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-nitro-benzenesulfonamide472Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamideEthyl- (2-methoxy-ethyl) -amine 12.61Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamide414Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamide33% 5.6M in dimethylamineEtOH 12.62Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-methyl-4-nitro-benzenesulfonamide439Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamideAllylmethylamine 12.63Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-methyl-4-nitro-benzenesulfonamide458Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamide2- (hydroxy-ethyl) -amino-ethanol 12.64Trans-N- {4- [4- (4-hydroxy-piperidin-1-yl) -butoxy] -cyclohexyl} -N-methyl-4-nitro-benzenesulfonamide469 (M)Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-nitro-benzenesulfonamide4-hydroxypiperidine
[929] The following compounds were further prepared according to the above procedure by reacting the corresponding 2 equivalents of amine with the corresponding equivalent of 1 bromide:
[930] ExamplecompoundMSMH ⁺ BromideSecondary amine 12.65Trans-4-dimethylamino-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -3-fluoro-N-methyl-benzenesulfonamide430Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -3,4-difluoro-N-methyl-benzenesulfonamide33% 5.6M in dimethylamineEtOH 12.66Trans-4-dimethylamino-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -2-fluoro-N-methyl-benzenesulfonamide430Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -2,4-difluoro-N-methyl-benzenesulfonamide33% 5.6M in dimethylamineEtOH
[931] Example 13
[932] One equivalent of bromide was treated with three equivalents of amine in DMA (4-10 ml / mmol bromide) at room temperature until the starting material could no longer be detected by TLC. The solution was concentrated and the residue was redissolved in CH ₂ Cl ₂ /5% aqueous NaHCO ₃ . The phases were separated, the inorganic phase was extracted with CH ₂ Cl ₂ , the combined organic phases were washed with brine and dried over Na ₂ SO ₄ . The crude material was purified by flash chromatography. The following compounds were prepared from the corresponding bromide and amines:
[933] ExamplecompoundMSMH ⁺ BromideAmine 13.1Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester409 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterAllylmethylamine 13.2Trans- {4- [5- (allyl-methyl-amino) -pentyloxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester424 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterAllylmethylamine 13.3Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester411 (1 Cl)Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester33% 5.6M in dimethylamineEtOH 13.4Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester383 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester33% 5.6M in dimethylamineEtOH 13.5Trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester397 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester33% 5.6M in dimethylamineEtOH
[934] 13.6Trans- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester456 (1 Cl)Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2-ethylamino-ethanol 13.7Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester427 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2-ethylamino-ethanol 13.8Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester442 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2-ethylamino-ethanol 13.9Trans- (4- {6- [ethyl- (2-methoxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester470 (1 Cl)Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterN- (2-methoxyethyl) ethylamine 13.10Trans- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester442 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterN- (2-methoxyethyl) ethylamine 13.11Trans- {4- [3- (allyl-methyl-amino) -propoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester395 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterAllylmethylamine 13.12Trans- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester427 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterN- (2-methoxyethyl) ethylamine
[935] 13.13Trans- (4- {5- [ethyl- (2-methoxy-ethyl) -amino] -pentyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester456 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterN- (2-methoxyethyl) ethylamine 13.14Trans- [4- (3-dimethylamino-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester369 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester33% 5.6M in dimethylamineEtOH 13.15Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester413 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2-ethylamino-ethanol 13.16Trans-methyl- [4- (3-piperidin-1-yl-propoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester409 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPiperidine 13.17Trans-methyl- [4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester424 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPiperidine 13.18Trans-methyl- [4- (6-piperidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester452 (1 Cl)Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPiperidine 13.19Trans-methyl- [4- (5-piperidin-1-yl-pentyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester438 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPiperidine 13.20Trans- [4- (3-Diethylamino-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester397 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterDiethylamine
[936] 13.21Trans- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester440 (1 Cl)Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterDiethylamine 13.22Trans- [4- (4-diethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester411 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterDiethylamine 13.23Trans- [4- (5-Diethylamino-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester426 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterDiethylamine 13.24Trans-methyl- [4- (3-pyrrolidin-1-yl-propoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester395 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPyrrolidine 13.25Trans-methyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester436 (1 Cl) MH ^- Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPyrrolidine 13.26Trans- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester442 (1 Cl)Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2- (methylamino) -ethanol 13.27Trans- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester413 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2- (methylamino) -ethanol
[937] 13.28Trans- (4- {5-[(2-hydroxy-ethyl) -methyl-amino] -pentyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester427 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2- (methylamino) -ethanol 13.29Trans-methyl- [4- (4-pyrrolidin-1-yl-butoxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester409 (1 Cl)Trans- [4- (4-bromo-butoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPyrrolidine 13.30Trans-methyl- [4- (5-pyrrolidin-1-yl-pentyloxy) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester424 (1 Cl)Trans- [4- (5-Bromo-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPyrrolidine 13.31Trans- (4- {3-[(2-hydroxy-ethyl) -methyl-amino] -propoxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester399 (1 Cl)Trans- [4- (3-bromo-propoxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester2- (methylamino) -ethanol
[938] The following compounds were further prepared from the corresponding bromide and amines:
[939] ExamplecompoundMSMH ⁺ Extract 1Extract 2 13.32Trans-N- (4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl) -4-bromo-N-methyl-benzenesulfonamide501 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideN-allylmethyl-amine 13.33Trans-4-bromo-N- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide475 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide33% 5.6M in dimethylamineEtOH
[940] 13.34Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide519 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideN- (2-methoxy-ethyl) methyl-amine 13.35Trans-N- (4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide528Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-allylmethyl-amine 13.36Trans-N- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide465Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide33% 5.6M in dimethylamineEtOH 13.37Trans-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide509Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN- (2-methoxy-ethyl) methyl-amine 13.38Trans-4-bromo-N- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide503 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideDiethylamine 13.39Trans-4-bromo-N- {4- [6- (isopropyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide503 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideIsopropylmethyl-amine 13.40Trans-4-bromo-N-methyl-N- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -benzenesulfonamide501 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamidePyrrolidine
[941] 13.41Trans-N- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide493Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideDiethylamine 13.42Trans-N- {4- [6- (isopropyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide493Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideIsopropylmethyl-amine 13.43Trans-N-methyl-N- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide491Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamidePyrrolidine 13.44Trans-N- [4- (3-allylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide435Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-allylamine 13.45Trans-N- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -N-ethyl-4-trifluoromethyl-benzenesulfonamide477Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideN-allyl-methylamine 13.46Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide451Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideDimethylamine.
[942] 13.47Trans-N-ethyl-N- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide481Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideMethylaminoethanol 13.48Trans-N-ethyl-N- (4- {4-[(2-methoxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide495Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideN- (methoxyethyl) methylamine 13.49Trans-N-ethyl-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide495Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideEthylamino-ethanol 13.50Trans-N-ethyl-N- (4- {4- [ethyl- (2-methoxy-ethyl) -amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide509Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideN- (methoxyethyl) -ethylamine 13.51Trans-N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-ethyl-4-trifluoromethyl-benzenesulfonamide511Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideDiethanolamine 13.52Trans-N- [4- (4-diethylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide479Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideDiethylamine
[943] 13.53Trans-N- [4- (4-allylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide463Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamideAllylamine 13.54Trans-N-ethyl-N- [4- (4-piperidin-1-yl-butoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide491Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamidePiperidine 13.55Trans-N-ethyl-N- {4- [4- (4-methyl-piperazin-1-yl) -butoxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide506Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide1-methylpiperazine
[944] Example 14
[945] A solution of secondary amine (0.6 mmol; 3.5 equiv) in 0.7 ml of dry DMF was added to 0.17 mmol (1 equiv) of bromide and 1,8-diazabicyclo [5.4.0] undec-7-ene in 0.25 ml of dry DMF. 1,5-5) (DBU) was treated with 0.17 mmol (1 equiv). The reaction mixture was stirred at 50 ° C. overnight, then treated with 0.2 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. . After evaporation, the tertiary amine was obtained as a mixture of amine formate and hydrobromide. The following compounds can be prepared from the corresponding bromide and secondary amines:
[946] ExamplecompoundMSMH ⁺ BromideSecondary amine 14.1Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide519 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideN- (2-methoxy-ethyl) methyl-amine 14.2Trans-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide509Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN- (2-methoxy-ethyl) methyl-amine 14.3Trans-4-bromo-N-methyl-N- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -benzenesulfonamide517 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideMorpholine 14.4Trans-N- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -4-bromo-N-methyl-benzenesulfonamide487 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideTrimethylene-amine 14.5Trans-4-bromo-N- {4- [6- (butyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide517 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideN-methylbutyl-amine
[947] 14.6Trans-4-bromo-N-methyl-N- [4- (6-piperidin-1-yl-hexyloxy) -cyclohexyl] -benzenesulfonamide515 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamidePiperidine 14.7Trans-4-bromo-N- {4- [6- (3,6-dihydro-2H-pyridin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl- benzenesulfonamide513 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide1,2,3,6-tetra-hydro-pyridine 14.8Trans-4-bromo-N- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide519 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide2- (ethylamino) -ethanol 14.9Trans-4-bromo-N- {4- [6- (3-hydroxy-pyrrolidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide517 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide(R) -3-hydroxy-pyrrolidine 14.10Trans-4-bromo-N-methyl-N- {4- [6- (methyl-propyl-amino) -hexyloxy] -cyclohexyl} -benzenesulfonamide503 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideN-methylpropylamine 14.11Trans-4-bromo-N- [4- (6-diallylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide527 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideDiallylamine 14.12Trans-4-bromo-N- {4- [6- (4-hydroxymethyl-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide545 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide4-hydroxy-methyl-piperidine 14.13Trans-4-bromo-N- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide505 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide2-hydroxyethyl-methylamine
[948] 14.14Trans-4-bromo-N-methyl-N- {4- [6- (4-methyl-piperidin-1-yl) -hexyloxy] -cyclohexyl} -benzenesulfonamide529 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide4-methyl-piperidine 14.15Trans-4-bromo-N- {4- [6- (4-hydroxy-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide531 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide4-hydroxy-piperidine 14.16Trans-4-bromo-N- {4- [6- (cyclopropylmethyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide515 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideN-methyl-cyclopropane-methylamine 14.17Trans-[(6- {4-[(4-bromo-benzenesulfonyl) -methyl-amino] -cyclohexyloxy} -hexyl) -methyl-amino] -acetic acid ethyl ester547 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideSarcosine ethyl ester hydrochloride 14.18Trans-N-methyl-N- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide507Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamideMorpholine 14.19Trans-N- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide477Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideTrimethylene-amine 14.20Trans-N- {4- [6- (butyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide507Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-methylbutyl-amine
[949] 14.21Trans-N-methyl-N- [4- (6-piperidin-1-yl-hexyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide505Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamidePiperidine 14.22Trans-N- {4- [6- (3,6-dihydro-2H-pyridin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide503Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide1,2,3,6-tetra-hydro-pyridine 14.23Trans-N- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide509Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide2- (ethylamino) -ethanol 14.24Trans-N- {4- [6- (3-hydroxy-pyrrolidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide507Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide(R) -3-hydroxy-pyrrolidine 14.25Trans-N-methyl-N- {4- [6- (methyl-propyl-amino) -hexyloxy] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide493Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-methylpropylamine 14.26Trans-N- [4- (6-diallylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide517Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideDiallylamine 14.27Trans-N- {4- [6- (4-hydroxymethyl-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide535Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide4-hydroxy-methylpiperidine
[950] 14.28Trans-N- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide495Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide2-hydroxyethyl-methylamine 14.29Trans-N- {4- [6- (4-hydroxy-piperidin-1-yl) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide521Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide4-hydroxy-piperidine 14.30Trans-N- {4- [6- (cyclopropylmethyl-methyl-amino) -hexyloxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide505Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-methyl-cyclopropane-methylamine 14.31Trans- [methyl- (6- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -hexyl) -amino] -acetic acid ethyl ester537Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideSarcosine Ethyl Ester Hydrochloride
[951] Example 15
[952] A solution of 1.02 mmol (6 equivalents) of primary amine in 0.7 ml of dry DMF was added to 0.17 mmol (1 equivalent) of bromide and 1,8-diazabicyclo [5.4.0] undec-7-ene (1 equivalent) in 0.25 ml of dry DMF. , 5-5) (DBU) with 0.17 mmol (1 equiv). The reaction mixture was stirred at 50 ° C. overnight, then treated with 0.2 ml of formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. . After evaporation, secondary amines were obtained as a mixture of amine formate and hydrobromide. The following compounds were prepared from the corresponding bromide and amines:
[953] ExamplecompoundMSMH ⁺ BromideAmine 15.1Trans-N- [4- (6-allylamino-hexyloxy) -cyclohexyl] -4-bromo-N-methyl-benzenesulfonamide487 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideAllylamine 15.2Trans-4-bromo-N- {4- [6- (2-hydroxy-ethylamino) -hexyloxy] -cyclohexyl} -N-methyl-benzenesulfonamide491 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide2-ethanolamine 15.3Trans-4-bromo-N- [4- (6-ethylamino-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamide475 (1 Br)Trans-4-bromo-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-benzenesulfonamideEthylamine 15.4Trans-N- {4- [4- (2-hydroxy-ethylamino) -butoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide453Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideEthanolamine- 15.5Trans-N- [4- (4-ethylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide437Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-ethylamine
[954] 15.6Trans-N- {4- [3- (2-hydroxy-ethylamino) -propoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide439Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideEthanolamine 15.7Trans-N- [4- (3-ethylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide423Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-ethylamine 15.8Trans-N- [4- (6-allylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide477Trans-N- [4- (6-bromo-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideAllylamine 15.9Trans-N- [4- (3-allylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide435Trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideN-methylallyl-amine 15.10Trans-N- [4- (4-allylamino-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide449Trans-N- [4- (4-bromo-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideAllylamine
[955] Example 16
[956] 16.1
[957] To 10 g (40.1 mmol) of trans-4-hydroxy-cyclohexylcarbamic acid benzyl ester in 40 ml of DMF, 4.09 g (60.1 mmol, 1.5 equivalents) of imidazole and 20 65 g (44.1 mmol, 1.1 equivalents) of TBDMSCl in 20 ml of DMF. ) Was added at 0 ° C. The mixture was warmed to 50 ° C. and stirred at that temperature for 2 hours. A saturated solution of NaHCO ₃ was added and the mixture was concentrated and redissolved in ether / water. The phases were separated and the inorganic phase was extracted with ether. The combined organic phases were washed with brine, dried over Na ₂ S0 ₄ and concentrated. The crude product was purified on silica gel with hexanes: EtOAc 5: 1 as eluent to colorless 11.8 g (81%) of trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl] -carbamic acid benzyl ester Obtained as rubber. MS: 348 (M-CH ₃ ).
[958] 16.2
[959] To a suspension of 0.58 g (55% in mineral oil, 13 mmol, 1.2 equivalents) in sodium hydride in 20 ml of DMF, trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl]-in 10 ml of DMF A solution of 4.2 g (11 mmol) of carbamic acid benzyl ester was added slowly. The temperature was slowly raised to 50 ° C. and maintained at that temperature for 1 hour. 0.9 ml (14 mmol; 1.3 equiv) of iodomethane were added at room temperature and the mixture was stirred overnight. Additional 0.58 g of sodium hydride (55% in mineral oil, 13 mmol, 1.2 equiv) and 0.9 ml (14 mmol; 1.3 equiv) of iodomethane were added and the reaction mixture was stirred for 1 h. NH ₄ Cl aqueous solution was added and the inorganic phase was extracted with ether, washed with brine, dried over Na ₂ SO ₄ and evaporated to trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl] -methyl 3.1 g (72%) of carbamic acid benzyl ester were obtained.
[960] 16.3
[961] To a solution of 3.1 g (8 mmol) of trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester in 20 ml of THF, 10.3 ml of tetrabutylammonium fluoride in THF (1M, 10.3 mmol, 1.3 equiv) was added at 6 ° C. and the mixture was stirred at rt for 2 days. Water was added and the phases were separated and the inorganic phase was extracted with ether and EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and evaporated. Column chromatography on silica gel with gradient EtOAc: hexanes 1: 4-EtOAc gave 1.9 g (92%) of trans- (4-hydroxy-cyclohexyl) -methyl-carbamic acid benzyl ester as an orange oil. MS: 263 (M).
[962] 16.4
[963] Similar to Examples 16.2 and 16.3, from trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl] -carbamic acid benzyl ester and bromoethane, trans-ethyl- (4-hydroxy- Cyclohexyl) -carbamic acid benzyl ester was obtained as orange oil. MS: 277 (M).
[964] 16.5
[965] Similar to Examples 16.2 and 16.3, from trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl] -carbamic acid benzyl ester and allyl bromide, trans-allyl- (4-hydroxy-cyclo Hexyl) -carbamic acid benzyl ester was obtained as orange oil. MS: 289 (M).
[966] 16.6
[967] Similar to Examples 16.2 and 16.3, from trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl] -carbamic acid benzyl ester and benzyl bromide, trans-benzyl- (4-hydroxy-cyclo Hexyl) -carbamic acid benzyl ester was obtained as orange oil. MS: 340 (MH ⁺ ).
[968] 16.7
[969] Similar to Examples 16.2 and 16.3, from trans- [4- (tert-butyl-dimethyl-silanyloxy) -cyclohexyl] -carbamic acid benzyl ester and 2,4,5-trifluorobenzyl bromide, trans- (4-hydroxy-cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester was obtained as an orange oil. MS: 394 (MH <^+> ).
[970] 16.8
[971] To 1.9 g (7 mmol) of trans- (4-hydroxycyclohexyl) -methyl-carbamic acid benzyl ester suspended in 40.7 ml (267 mmol, 37 equiv) of 1,6-dibromohexane, tetrabutyl ammonium hydrogen 0.74 g (2.0 mmol, 0.3 equiv) of sulfate and 40 ml of 50% aqueous NaOH were added. The mixture was stirred at rt for 3 days, CH ₂ Cl ₂ was added and the layers were separated. The inorganic layer was extracted with CH ₂ Cl ₂ and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . Excess dibromide was removed in vacuo and the residue was purified by column chromatography with hexanes: EtOAc 4: 1 as eluent on silica gel to give trans- [4- (6-bromo-hexyloxy) -cyclohexyl]- 2.0 g (64%) of methyl-carbamic acid benzyl ester were obtained as a light yellow oil. MS: 425 (M, 1 Br).
[972] 16.9
[973] Similar to Example 16.8, trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester was converted into a light yellow liquid (MS: 439 (M, 1Br)). Obtained from ethyl- (4-hydroxy-cyclohexyl) -carbamic acid benzyl ester.
[974] 16.10
[975] Similar to Example 16.8, trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester was converted into a bright yellow liquid (MS: 451 (M, 1Br)). Obtained from allyl- (4-hydroxy-cyclohexyl) -carbamic acid benzyl ester.
[976] 16.11
[977] Similar to Example 16.8, trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester was converted into a light yellow liquid (MS: 501 (M, 1Br)). Obtained from benzyl- (4-hydroxy-cyclohexyl) -carbamic acid benzyl ester.
[978] 16.12
[979] Similar to Example 16.8, trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester was converted into a light yellow liquid ( MS: 555 (M, 1Br)) obtained from trans- (4-hydroxy-cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester.
[980] 16.13
[981] Similar to Example 16.8, trans- [4- (6-bromo-hexyloxy) -cyclo from trans- (4-hydroxy-cyclohexyl) -carbamic acid benzyl ester and 1,6-dibromohexane Hexyl] -carbamic acid benzyl ester was obtained as a white solid. MS: 412 (MH <^+> , 1Br).
[982] 16.14
[983] Similar to Example 16.8, trans- [4- (5-bromo-pentyloxy) -cyclohexyl from trans- (4-hydroxy-cyclohexyl) -carbamic acid benzyl ester and 1,5-dibromopentane ] -Carbamic acid benzyl ester was obtained as a white solid. MS: 398 (MH <^+> , 1Br).
[984] Example 17
[985] One equivalent of bromide was treated with three equivalents of each amine in DMF (1 ml / mmol bromide) at room temperature in the presence of one equivalent of diisopropylethylamine and a catalytic amount of NaI until the starting material could no longer be detected by HPLC. Formic acid was added and the crude was purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After evaporation the amine was obtained as a mixture of amine formate and hydrobromide. The following compounds were prepared from the corresponding bromide and amines:
[986] ExamplecompoundMSMH ⁺ BromideAmine 17.1Trans-ethyl- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester449Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester2- (ethylamino) -ethanol 17.2Trans-benzyl- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester511Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester2- (ethylamino) -ethanol 17.3Trans- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester435Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester2- (ethylamino) -ethanol 17.4Trans-allyl- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester461Trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester2- (ethylamino) -ethanol 17.5Trans- (4- {6- [ethyl- (2-hydroxy-ethyl) -amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester565Trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester2- (ethylamino) -ethanol
[987] 17.6Trans- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester417Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl esterAzetidine 17.7Trans- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -benzyl-carbamic acid benzyl ester479Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterAzetidine 17.8Trans- [4- (6-azetidin-1-yl-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester403Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl esterAzetidine 17.9Trans-ethyl- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester435Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester2- (methylamino) -ethanol 17.10Trans-benzyl- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester497-Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester2- (methylamino) -ethanol 17.11Trans- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester421Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester2- (methylamino) -ethanol 17.12Trans-allyl- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid benzyl ester447Trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester2- (methylamino) -ethanol
[988] 17.13Trans- (4- {6-[(2-hydroxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester551Trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester2- (methylamino) -ethanol 17.14Trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acidbenzyl ester449Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl esterN- (2-methoxy-ethyl) -methyl-amine 17.15Trans-benzyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acidbenzyl ester511Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterN- (2-methoxy-ethyl) -methyl-amine 17.16Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester435Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl esterN- (2-methoxy-ethyl) -methyl-amine 17.17Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester565Trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl esterN- (2-methoxy-ethyl) -methyl-amine 17.18Trans-ethyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester447Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl esterMorpholine 17.19Trans-benzyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester509Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterMorpholine
[989] 17.20Trans-methyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester433Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl esterMorpholine 17.21Trans-allyl- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester459Trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterMorpholine 17.22Trans- [4- (6-morpholin-4-yl-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester563Trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl esterMorpholine 17.23Trans-ethyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester431Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl esterPyrrolidine 17.24Trans-benzyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester493Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterPyrrolidine 17.25Trans-methyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester417Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl esterPyrrolidine 17.26Trans-allyl- [4- (6-pyrrolidin-1-yl-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester443Trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterPyrrolidine
[990] 17.27[4- (6-Pyrrolidin-1-yl-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester547Trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl esterPyrrolidine 17.28[4- (6-Dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester377Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl esterDimethylamine 17.29Trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -carbamic acid benzyl ester363Trans- [4- (5-bromo-pentyloxy) -cyclohexyl] -carbamic acid benzyl esterDimethylamine
[991] Example 18
[992] One equivalent of bromide (0.13 mmol bromide / Iml DMF) was treated with three equivalents of amine until the starting material could no longer be detected by HPLC in the presence of one equivalent of diisopropylethylamine and a catalytic amount of NaI. Formic acid was added and the crude was purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile]. After purification, the product was extracted with EtOAc and saturated NaHCO ₃ / H ₂ O to separate the free amine. The following compounds were prepared from the corresponding bromide and amines:
[993] ExamplecompoundMSMH ⁺ BromideAmine 18.1Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid benzyl ester417Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl esterN-allylmethyl-amine 18.2Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -ethyl-carbamic acid benzyl ester431Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl esterN-allylmethyl-amine 18.3Trans-allyl- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -carbamic acid benzyl ester443Trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterN-allylmethyl-amine 18.4Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -benzyl-carbamic acid benzyl ester493Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl esterN-allylmethyl-amine 18.5Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl}-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester547Trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl esterN-allylmethyl-amine
[994] 18.6Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester391Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester33% 5.6M in dimethylamineEtOH 18.7Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester405Trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester33% 5.6M in dimethylamineEtOH 18.8Trans-allyl- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester417Trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester33% 5.6M in dimethylamineEtOH 18.9Trans-benzyl- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester467Trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester33% 5.6M in dimethylamineEtOH 18.10Trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester521Trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl) -carbamic acid benzyl ester33% 5.6M in dimethylamineEtOH
[995] Example 19
[996] 19.1
[997] Similar to Example 17, trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester (MS: 435 ( MH ⁺ )) was obtained from trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -methyl-carbamic acid benzyl ester and N- (2-methoxyethyl) methylamine.
[998] 19.2
[999] 0.43 g (0.001 mmol) of trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid benzyl ester in 4 ml EtOAc Hydrogenate for 1 hour in the presence of 0.06 g of% Pd / C, remove the catalyst and evaporate the solvent before trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} 0.29 g (98%) of -cyclohexyl) -methyl-amine was obtained as a colorless oil. MS: 301 (MH ⁺ ).
[1000] 19.3
[1001] Similar to Examples 19.1 and 19.2, trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -amine (MS: 315 (MH ⁺ )) Was obtained from trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -ethyl-carbamic acid benzyl ester and N- (2-methoxyethyl) methylamine.
[1002] 19.4
[1003] Similar to Examples 19.1 and 19.2, trans-benzyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -amine (MS: 377 (MH) ⁺ )) Was obtained from trans-benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester and N- (2-methoxyethyl) methylamine.
[1004] 19.5
[1005] Similar to Examples 19.1 and 19.2, trans-4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexylamine (MS: 287 (MH ⁺ )) Obtained from -benzyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester and N- (2-methoxyethyl) methylamine (overnight hydrogenation).
[1006] 19.6
[1007] Similar to Examples 19.1 and 19.2, trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro Rho-benzyl) -amine (MS: 431 (MH ⁺ )) trans- [4- (6-bromo-hexyloxy) -cyclohexyl]-(2,4,5-trifluoro-benzyl)- Obtained from carbamic acid benzyl ester and N- (2-methoxyethyl) methylamine.
[1008] 19.7
[1009] Similar to Examples 19.1 and 19.2, trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -propyl-amine (MS: 329 (MH) ⁺ )) Was obtained from trans-allyl- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester and N- (2-methoxyethyl) methylamine.
[1010] Example 20
[1011] Starting material can no longer be detected by TLC at room temperature in the presence of 1.1 equivalents of diisopropylamine with sulfonylchloride (1.1 equivalents for each NH ₂ ) in dioxane (2-5 ml / mmol amine) Treatment was done until none. The solution was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ , brine and dried over Na ₂ SO ₄ . Flash chromatography or purification with preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile] and extracted with EtOAc and saturated NaHCO ₃ / H ₂ O. Free amine was obtained. The following compounds were prepared from the corresponding amines and sulfonylchlorides:
[1012] ExamplecompoundMSMH ⁺ AmineSulfonyl chloride 20.1Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-methyl-benzenesulfonamide475 (1Cl)Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-amine4-chlorobenzene-sulfonylchloride 20.2Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide461 (1Cl)Trans-4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexylamine4-chlorobenzene-sulfonylchloride 20.3Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide505 (1Br)Trans-4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexylamine4-bromobenzene-sulfonylchloride 20.4Trans-4-chloro-N-ethyl-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide489 (1Cl)Trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -amine4-chlorobenzene-sulfonylchloride
[1013] 20.5Trans-4-bromo-N-ethyl-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -benzenesulfonamide533 (1 Br)Trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -amine4-bromobenzene-sulfonylchloride 20.6Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-propyl-benzenesulfonamide503 (1 Cl)Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -propyl-amine4-chlorobenzene-sulfonylchloride 20.7Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N-propyl-benzenesulfonamide547 (1 Br)Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -propyl-amine4-bromobenzene-sulfonylchloride 20.8Trans-4-chloro-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N- (2,4,5-trifluoro -Benzyl) -benzenesulfonamide605 (1 Cl)Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -amine4-chlorobenzene-sulfonylchloride 20.9Trans-4-bromo-N- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -N- (2,4,5-trifluoro Rho-benzyl) -benzenesulfonamide649 (1 Br)Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy] -cyclohexyl)-(2,4,5-trifluoro-benzyl) -amine4-bromobenzene-sulfonylchloride
[1014] Example 21
[1015] Starting material can no longer be detected by TLC at room temperature in the presence of 1.1 equivalents of diisopropylamine with chloroformate (1.1 equivalents for each NH ₂ ) in dioxane (2-5 ml / mmol amine) Treatment was done until none. The solution was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ , brine and dried over Na ₂ SO ₄ . Flash chromatography or purification with preparative HPLC [RP-18, acetonitrile (0.1% HCOOH) / water (0.1% HCOOH), 10% -95% acetonitrile] and extracted with EtOAc and saturated NaHCO ₃ / H ₂ O. Free amine was obtained. The following compounds were prepared from the corresponding amines and chloroformates:
[1016] ExamplecompoundMSMH ⁺ AmineChloroformate 21.1Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester455 (1 Cl)Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyl-oxy} -cyclohexyl) -methyl-amine4-chlorophenyl-chloroformate 21.2Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid 4-chloro-phenyl ester441 (1 Cl)Trans-4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexylamine4-chlorophenyl-chloroformate 21.3Trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -carbamic acid 4-chloro-phenyl ester469 (1 Cl)Trans-ethyl- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -amine4-chlorophenyl-chloroformate 21.4Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl) -propyl-carbamic acid 4-chloro-phenyl ester483 (1 Cl)Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyl-oxy} -cyclohexyl) -propyl-amine4-chlorophenyl-chloroformate
[1017] 21.5Trans- (4- {6-[(2-methoxy-ethyl) -methyl-amino] -hexyloxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -carbamic acid 4- Chloro-phenyl ester585 (1 Cl)Trans- (4-6-[(2-methoxy-ethyl) -methyl-amino] -hexyl-oxy} -cyclohexyl)-(2,4,5-trifluoro-benzyl) -amine4-chlorophenyl-chloroformate
[1018] Example 22
[1019] 22.1
[1020] To 15.0 g (60 mmol) of trans-4-hydroxycyclohexylcarbamic acid benzyl ester suspended in 183 ml (1.2 mol, 20 equiv) of 1,6-dibromohexane, 6.1 g of tetrabutylammonium hydrogensulfate ( 18 mmol, 0.3 equiv) and 183 ml of 50% aqueous NaOH were added. The mixture was stirred at rt for 4 days, CH ₂ Cl ₂ was added and the layers were separated. The inorganic layer was extracted with CH ₂ Cl ₂ and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . Excess dibromide was removed in vacuo and the residue was purified by column chromatography with hexanes: EtOAc 1: 1 as eluent on silica gel to give trans- [4- (6-bromo-hexyloxy) -cyclohexyl]- 3.4 g (14%) of carbamic acid benzyl ester are obtained as a white solid (MS: 412 (MH ⁺ , 1Br)) and trans- (6-bromo-hexyl)-[4- (6-bromo-hexyljade 11.2 g (32%) of c) -cyclohexyl] -carbamic acid benzyl ester were obtained as a yellow oil (MS: 574 (MH ⁺ , 2Br)).
[1021] 22.2
[1022] Similar to Example 22.1, trans- [4- (5-bromo-pentyloxy) -cyclohexyl] -carbamic acid benzyl ester was converted to (MS: 398 (MH ⁺ , 1Br)) as a white solid. Obtained from oxy-cyclohexylcarbamic acid benzyl ester and 1,5-dibromopentane.
[1023] 22.3
[1024] 1.7 g (4.12 mmol) of trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester in DMA with 2.2 ml of 5.6 M (12.4 mmol, 3 equiv) dimethylamine in ethanol Treated. The solution is stirred at rt overnight, concentrated and the residue is redissolved in CH ₂ Cl ₂ /5% aqueous Na ₂ CO ₃ , the phases are separated and the inorganic phase is extracted with CH ₂ Cl ₂ , the combined organic phases are brine Washed, dried over Na ₂ S0 ₄ and concentrated. The crude product was purified by CH ₂ Cl ₂ : MeOH 9: 1 on silica gel to light 1.3 g (84%) of trans- [4- (6-dimethylamino-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester Obtained as a yellow solid. MS: 377 (MH ⁺ ).
[1025] 22.4
[1026] Similar to Example 22.3, trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -carbamic acid benzyl ester was converted to trans- [4- (as a light yellow solid (MS: 363 (MH ⁺ ))). 5-bromo-pentyloxy) -cyclohexyl] -carbamic acid benzyl ester and dimethylamine (33% 5.6 M in EtOH).
[1027] 22.5
[1028] Similar to Example 22.3, trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -carbamic acid benzyl ester was grayish white solid (MS: 403 (MH ⁺ ) ) Was obtained from trans- [4- (6-bromo-hexyloxy) -cyclohexyl] -carbamic acid benzyl ester and N-allylmethylamine.
[1029] Example 23
[1030] 23.1
[1031] 30 g (123.3 mmol) of BOC-trans-1,4-amino cyclo-hexane carboxylic acid and 22 g (135.6 mmol) of carbonyl-di-imidazole were dissolved in 300 ml of THF and stirred at room temperature for 30 minutes. 50 ml (1.23 mol) of methanol were added and the solution was refluxed for 3 hours. The solution was evaporated under reduced pressure, dissolved in ether and washed with 1N HCl and water. The ether-phase was concentrated in vacuo to afford 31.7 g of trans-4-tert-butoxy carbonylamino-cyclohexane carboxylic acid methyl ester. MS: 275.4 (M + NH ₄ ⁺ ).
[1032] 23.2
[1033] A solution of 1.52 g (40 mmol) of LAH in 7 ml of THF was refluxed and treated with a solution of 5.15 g (20 mmol) of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester in 35 ml of THF for 2.5 hours. It was. The solution was heated for 15 hours, cooled (0 ° C.) and hydrolyzed with 10 ml of water. The mixture was diluted with THF, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was dissolved in CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , filtered and evaporated to give 2.89 g (100%) of trans- (4-methylamino-cyclohexyl) -methanol. mp: 87-88 ° C .; MS: 143 (M).
[1034] 23.3
[1035] A solution of 1.00 g (7 mmol) of (trans)-(4-methylamino-cyclohexyl) -methanol in 20 ml of pyridine was added at 1.80 g (7.35 mmol) of 4- (trifluoromethyl) -benzenesulfonyl chloride at 0 ° C. Treated with. The reaction was stirred 40 min at 0 ° C and poured into ice-water. Acidify (25% HCl), extract (Et ₂ O, 3 ×) and evaporate the organic phase to dryness over Na ₂ SO _{4 and} then CH ₂ Cl ₂ / MeOH (99: 1-98: 2) on silica gel. Flash column chromatography to trans-4-trifluoromethyl-benzenesulphonic acid 4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexylmethyl ester (MS: 560 (MH ⁺ ) ) 0.71 g (18%) and trans-N- (4-hydroxymethyl-cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide (MS: 352 (MH ⁺ )) 0.68 g (28 %) Was obtained.
[1036] 23.4
[1037] 4.60 g (32.14 mmol) of trans- (4-methylamino-cyclohexyl) -methanol were suspended in 85 ml of hexamethyldisilazane and refluxed for 5 hours. The solution was evaporated under reduced pressure and dissolved in 50 ml of THF. 6.14 g (32.14 mmol) of 4-chlorophenylchloroformate were added slowly at 0 ° C. and stirred for 16 h at room temperature. 30 ml of H ₂ O was added and after 1 hour the solvent was evaporated. The residue was extracted with water / Et ₂ O (3 ×), the organic phase was washed with 10% NaCl, dried over Na ₂ SO _4, evaporated and flash-chromatographic on silica gel (hexane / EtOAc 4: 1 1: 1) 5.48 g (57%) of trans- (4-hydroxymethyl-cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester were obtained. MS: 298 (MH <^+> , 1Cl).
[1038] 23.5
[1039] A solution of 0.6 g (2.03 mmol) of trans- (4-hydroxymethyl-cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester in 15 ml of CH ₂ Cl ₂ was 0.17 ml (2.24) of methanesulfonylchloride at 0 ° C. mmol), pyridine 0.5 ml (6.1 mmol) and 0.25 g (2.03 mmol) DMAP. The reaction mixture was allowed to warm to rt overnight, water (2 ml) was added and the reaction mixture was stirred for 5 minutes. After extraction with aqueous 10% KHSO ₄ / Et ₂ O (3 ×), the organic phase is washed with aqueous saturated NaHCO ₃ (2 ×), aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to trans-methanesulphate. 0.74 g (96%) of phonic acid 4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl ester was obtained. mp: 134-135 ° C .; MS: 376 (MH <^+> , 1 Cl).
[1040] 23.6
[1041] (In accordance with the procedure of Belostotskii, Anatoly M .; Hassner, Alfred. Synthetic methods. 41. Etherification of Hydroxysteroids via triflates. Tetrahedron Lett. (1994), 35 (28), 5075-6.) CH ₂ Cl ₂ A solution of 0.175 ml (2 mmol) of 3-bromo-1-propanol and 0.48 ml of 2,6-di-tert-butylpyridine in 1 ml was treated with trifluoromethanesulfonic anhydride in 0.5 ml of CH ₂ Cl ₂ at 0 ° C. Treated with 0.35 ml (2.1 mmol) solution. After 2.5 hours at 0 ° C., the purple solution was evaporated, dissolved in 1 ml of nitromethane and trans-N- (4-hydroxymethyl-cyclohexyl) -N-methyl-4-trifluoromethyl in 3 ml of nitromethane. Treated with a solution of 0.375 g (1 mmol) of benzenesulfonamide and 0.45 ml (2 mmol) of 2,6-di-tert-butylpyridine (3 min). The reaction was heated for 3.5 h (60 ° C.) and then extracted with aqueous 10% KHSO ₄ / EtOAc (3 ×). The organic phase was washed with aqueous saturated NaHCO ₃ , aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated. Purification by flash-chromatography on silica gel (hexanes / EtOAc 9: 1) gave trans-N- [4- (3-bromo-propoxymethyl) -cyclohexyl] -N-methyl-4-trifluoro 0.3 g (64%) of methyl-benzenesulfonamide were obtained. MS: 452 (MF, 1 Br).
[1042] 23.7
[1043] Similar to Example 23.6, trans- [4- (3-bromo-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester (MS: 418 (MH ⁺ , 1Br, 1Cl)) Was obtained from trans- (4-hydroxymethyl-cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester and 3-bromo-1-propanol.
[1044] 23.8
[1045] Similar to Example 23.6, trans- [4- (2-bromo-ethoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester (MS: 404 (MH ⁺ , 1Br, 1Cl)) Was obtained from trans- (4-hydroxymethyl-cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester and 2-bromoethanol.
[1046] 23.9
[1047] A solution of 1.5 g (5.04 mmol) of trans- (4-hydroxymethyl-cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl in 30 ml of DMF was added to 1.19 ml (15.11 mmol) of 1,4-dibromobutane. Treated and treated in small portions with 0.28 g (5.79 mmol) of 55% NaH at 0 ° C. The reaction was stirred at rt for 16 h. The reaction was again treated with 1.19 ml (15.11 mmol) of 1,4-dibromobutane, in small portions with 0.28 g (5.79 mmol) of 55% NaH at 0 ° C. and stirred at room temperature for 3 days. The solution was then poured into cooled aqueous saturated NH ₄ Cl and extracted (Et ₂ O 3 ×). The organic phase was washed with water, dried over Na ₂ SO ₄ , evaporated and purified by flash silica gel column (first with hexane to remove dibromobutane and then with hexane / EtOAc 4: 1-1: 1). 0.59 g (27%) of trans- [4- (4-bromo-butoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester was obtained. MS: 432 (MH <^+> , 1Br, 1Cl).
[1048] 23.10
[1049] A solution of 69 mg (0.146 mmol) of trans-N- [4- (3-bromo-propoxymethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide in 0.8 ml of DMA was added to 0 ml. Treated with 0.028 ml (0.29 mmol) of N-allylmethylamine at &lt; 0 &gt; C and stirred at room temperature for 22 hours. The solution was cooled (0 ° C.) and treated again with 0.028 ml (0.29 mmol) of N-allylmethylamine. After 6 h at rt, the solution was concentrated and dissolved in aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ SO ₄ and evaporated. Flash column chromatography on silica gel with CH ₂ Cl ₂ / MeOH (95: 5) trans-N- {4- [3- (allyl-methyl-amino) -propoxymethyl] -cyclohexyl} -N-methyl 43 mg (64%) of 4-trifluoromethyl-benzenesulfonamide were obtained. MS: 463 (MH <^+> ).
[1050] 23.11
[1051] Similar to Example 23.10, trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxymethyl} -cyclohexyl) -N-methyl-4-trifluoro Methyl-benzenesulfonamide (MS: 481 (MH ⁺ )) was converted to trans-N- [4- (3-bromo-propoxymethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfon Obtained from amide and 2-ethylaminoethanol.
[1052] 23.12
[1053] Similar to Example 23.10, trans-N- [4- (3-azetidin-1-yl-propoxymethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide (MS: 449 (MH ⁺ )) was obtained from trans-N- [4- (3-bromo-propoxymethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide and trimethyleneimine .
[1054] 23.13
[1055] Similar to Example 23.10, trans-N-methyl-N- [4- (3-piperidin-1-yl-propoxymethyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide (MS : 477 (MH ⁺ )) was obtained from trans-N- [4- (3-bromo-propoxymethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide and piperidine It was.
[1056] 23.14
[1057] Similar to Example 23.10, trans- {4- [3- (allyl-methyl-amino) -propoxymethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester (MS: 409 (MH ⁺ , 1Cl)) was obtained from trans- [4- (3-bromo-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and N-allylmethylamine.
[1058] 23.15
[1059] Similar to Example 23.10, trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propoxymethyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester ( MS: 427 (MH ⁺ , 1Cl)) was obtained from trans- [4- (3-bromo-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and 2-ethylaminoethanol .
[1060] 23.16
[1061] Similar to Example 23.10, trans- [4- (3-azetidin-1-yl-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester (MS: 395 (MH ⁺ , 1Cl) )) Was obtained from trans- [4- (3-bromo-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and trimethyleneimine.
[1062] 23.17
[1063] Similar to Example 23.10, trans-methyl- [4- (3-piperidin-1-yl-propoxymethyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester (MS: 423 (MH ⁺ , 1Cl)) was obtained from trans- [4- (3-bromo-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and piperidine.
[1064] 23.18
[1065] Similar to Example 23.10, trans- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propoxymethyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester ( MS: 441 (MH ⁺ , 1 Cl)) trans- [4- (3-bromo-propoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and N- (2-methoxy Obtained from ethyl) ethylamine.
[1066] 23.19
[1067] Similar to Example 23.10, trans- {4- [4- (allyl-methyl-amino) -butoxymethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester (MS: 423 (MH ⁺ , 1Cl)) was obtained from trans- [4- (4-bromo-butoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and N-allylmethylamine.
[1068] 23.20
[1069] Similar to Example 23.10, trans- {4- [2- (allyl-methyl-amino) -ethoxymethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester (MS: 395 (MH ⁺ , 1Cl)) was obtained from trans- [4- (2-bromo-ethoxymethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and N-allylmethylamine.
[1070] Example 24
[1071] 24.1
[1072] 5.53 g (20 mmol) of triphenylmethanethiol in 50 ml of DMA were deprotonated with 0.87 g (20 mmol) of 55% NaH at 0 ° C. The reaction was stirred at room temperature for 30 minutes and added slowly (30 minutes) to a solution of 1.72 ml (20 mmol) of 1,2-dibromoethane in 50 ml of cooled (0 ° C.) DMA. The reaction mixture was stirred at rt for 6 h, cooled (0 ° C.) and treated with 3.83 ml (40 mmol) N-allylmethylamine. After 16 h at rt, the reaction was cooled (0 ° C.) and treated again with 3.83 ml (40 mmol) N-allylmethylamine. After 24 h at rt, the solution was concentrated and dissolved in aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ SO ₄ and evaporated. Flash column chromatography on silica gel with CH ₂ Cl ₂ / MeOH (99.5: 0.5-95: 5) gave 3.27 g (44%) of allyl-methyl- (2-tritylsulfanyl-ethyl) -amine. MS: 374 (MH <^+> ).
[1073] 24.2
[1074] A solution of 1.12 g (3 mmol) of allyl-methyl- (2-tritylsulfanyl-ethyl) -amine in 30 ml of CH ₂ Cl ₂ was treated with 8.7 ml of TFA at 0 ° C., followed by 6.15 ml (30) of triisopropylsilane. mmol). After 30 minutes at room temperature, the reaction mixture was evaporated, dissolved in toluene (3 ×) and evaporated. TFA-salt was precipitated from ether / pentane. The oil was dissolved in ether, washed with aqueous saturated NaHCO ₃ , aqueous 10% NaCl, dried over Na ₂ SO ₄ and carefully evaporated to give 0.366 g (93%) of 2- (allyl-methyl-amino) -ethanethiol. Obtained. MS: 132 (MH ⁺ ).
[1075] 24.3
[1076] Similar to Examples 24.1 and 24.2, N-allylmethylamine and 1,3-dibrompropane were converted to 3- (allyl-methyl-amino) -propane-1-thiol. MS: 145 (MH ⁺ ).
[1077] 24.4
[1078] 280 mg (0.5 mmol) of 2--4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexylmethyl ester in 4.5 ml of DMF and 2- A solution of 78 mg (0.55 mmol) of dimethylaminoethanethiol hydrochloride was treated with 48 mg (1.1 mmol) of 55% NaH at 0 ° C. and stirred at room temperature for 20 hours. After cooling (0 ° C.) and treatment with a catalytic amount of NaI followed by 78 mg (0.55 mmol) of 2-dimethylaminoethanethiol hydrochloride and 48 mg (1.1 mmol) of 55% NaH and the reaction mixture was stirred at room temperature for 18 hours. . The reaction was neutralized (aqueous 10% KHSO ₄ , at 0 ° C.) and poured into aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was washed with 10% NaCl aqueous solution, dried over Na ₂ SO ₄ and evaporated. Purification by flash column chromatography on CH ₂ Cl ₂ / MeOH (95: 5) on silica gel trans-N- [4- (2-dimethylamino-ethylsulfanylmethyl) -cyclohexyl] -N-methyl- 138 mg (63%) of 4-trifluoromethyl-benzenesulfonamide were obtained. MS: 439 (MH ⁺ ).
[1079] 24.5
[1080] Similar to Example 24.4, trans-4-trifluoromethyl-benzenesulfonic acid 4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexylmethyl ester and 2- (allyl- Methyl-amino) -ethanethiol to trans-N- {4- [2- (allyl-methyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide Switched to MS: 465 (MH ⁺ ).
[1081] 24.6
[1082] Similar to Example 24.4, trans-4-trifluoromethyl-benzenesulfonic acid 4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexylmethyl ester and 2-diethylamino Conversion of ethanethiol hydrochloride with excess NaH to trans-N- [4- (2-diethylamino-ethylsulfanylmethyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide I was. MS: 467 (MH ⁺ ).
[1083] 24.7
[1084] Similar to Example 24.4, trans-methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl ester and 2-diethylaminoethanethiol hydrochloride were added with excess NaH. Together trans- [4- (2-diethylamino-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester. MS: 413 (MH <^+> , 1Cl).
[1085] 24.8
[1086] Similar to Example 24.4, trans-methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl ester and 2- (allyl-methyl-amino) -ethanethiol -{4- [2- (allyl-methyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester. MS: 411 (MH <^+> , 1Cl).
[1087] 24.9
[1088] Similar to Example 24.4, trans-methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl ester and 3- (allyl-methyl-amino) -propane-1- Thiols were converted to trans- {4- [3- (allyl-methyl-amino) -propylsulfanylmethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester. MS: 425 (MH <^+> , 1Cl).
[1089] 24.10
[1090] Similar to Example 24.4, trans-methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl ester and 2- (dimethylamino) -ethane-1-thiol -[4- (2-dimethylamino-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester. MS: 385 (MH <^+> , 1Cl).
[1091] Example 25
[1092] 25.1
[1093] To 1.72 g (4.58 mmol) of trans-methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl ester in 17 ml of DMF, 0.78 g (6.86 mmol, 1.5) of potassium thioacetate Equivalent) and the mixture was heated to 100 ° C for 10 minutes. The mixture was concentrated in vacuo and the residue dissolved in saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was washed with brine, dried over Na ₂ SO ₄ and evaporated to 1.69 g of trans-thioacetic acid S- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl} ester. (Quantitative) was obtained. MS: 356 (MH <^+> ).
[1094] 25.2
[1095] 0.63 g (corresponding to 1.7 mmol) of crude trans-thioacetic acid S- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexylmethyl} ester in 20 ml of degassed (Ar) ethanol. The solution was treated with 5.1 ml of 1N LiOH and after 10 minutes with 0.5 ml (6.8 mmol) of 2-bromo-ethanol. The reaction mixture was stirred for 1.25 h, cooled (0 ° C.) and neutralized with aqueous 10% KHSO ₄ / Et ₂ O (3 ×). The organic phase was washed with aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated with toluene before trans- [4- (2-hydroxy-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro 0.67 g (quantitative) of the phenyl ester were obtained. MS: 358 (MH <^+> , 1Cl).
[1096] 25.3
[1097] A solution of 645 mg (corresponding to 1.65 mmol) of trans- [4- (2-hydroxy-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester in 12 ml of CH ₂ Cl ₂ was Treated with 0.14 ml (1.82 mmol) methanesulfonylchloride, 0.20 ml (2.45 mmol) pyridine and 202 mg (1.65 mmol) DMAP at &lt; RTI ID = 0.0 &gt; The reaction mixture was allowed to warm to rt overnight. Water (2 ml) was added and the reaction stirred for 5 minutes. After extraction with aqueous 10% KHSO ₄ / Et ₂ O (3 ×), the organic phase is washed with aqueous saturated NaHCO ₃ (2 ×), aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to trans- [4 650 mg (quantitative) of-(2-chloro-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester was obtained. MS: 376 (MH <^+> , 2Cl).
[1098] 25.4
[1099] A solution of 94 mg (0.25 mmol) of trans- [4- (2-chloro-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester in 1 ml of DMA was prepared with a catalytic amount of NaI and 2-ethyl Treated with 0.05 ml (0.5 mmol) aminoethanol and stirred for 16 hours at room temperature. The reaction mixture was stirred for 1 week while adding 0.05 ml (0.5 mmol) of 2-ethylaminoethanol twice daily. The solution was concentrated and the remaining oil was extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was washed with 10% aqueous NaCl solution, dried over Na ₂ SO _4, flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 95: 5), followed by trans- (4- {2- [ethyl- (2 40 mg (39%) of -hydroxy-ethyl) -amino] -ethylsulfanylmethyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester were obtained. MS: 429 (MH <^+> , 1Cl).
[1100] 25.5
[1101] Similar to Example 25.4, trans- [4- (2-chloro-ethylsulfanylmethyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and N-methylpropylamine were converted to trans-methyl- {4 -[2- (methyl-propyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester. MS: 429 (MH <^+> , 1Cl).
[1102] Example 26
[1103] 26.1
[1104] A solution of 20 g (82.2 mmol) of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid in 1.2 L of CH ₂ Cl ₂ was charged with 12.83 g (131.5 mmol) of N, O-dimethyl-hydroxylamine hydrochloride, Treated with 10.85 ml (98.6 mmol) of N-methylmorpholine and 18.91 g (98.64 mmol) of EDCI and 12.62 g (82.2 mmol) of HOBT at 0 ° C. The reaction mixture was stirred at rt for 2 h and extracted with aqueous 10% KHSO ₄ / Et ₂ O (3 ×). The organic phase was washed with aqueous saturated NaHCO ₃ , 10% NaCl and dried over Na ₂ SO _{4 to} give 24.25 g of trans- [4- (methoxy-methyl-carbamoyl) -cyclohexyl] -carbamic acid tert-butyl ester (quantitative ) Was obtained. mp: 130-140 ° C., slowly degrading; MS: 287 (MH ⁺ ).
[1105] 26.2
[1106] A solution of 24.18 g (82 mmol) of trans- [4- (methoxy-methyl-carbamoyl) -cyclohexyl] -carbamic acid tert-butyl ester in 80 ml of DMF was added to 5.37 g (123 mmol) of 55% NaH at 0 ° C. In small portions. The reaction was stirred at 0 ° C. for 1 h and then slowly (20 min) treated with 40.9 ml (656 mmol) of iodomethane and warmed to room temperature overnight. The reaction was cooled and neutralized with aqueous 10% KHSO ₄ and poured into water / Et ₂ O (3 ×). The organic phase was washed with aqueous 10% NaCl, dried over Na ₂ SO _4, evaporated and purified by flash silica gel column (CH ₂ Cl ₂ / EtOAc 9: 1-1: 1) to trans- [4- (methoxy 20.69 g (84%) of methyl-carbamoyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester was obtained. MS: 301 (MH ⁺ ).
[1107] 26.3
[1108] Cool a solution of 2.09 g (55 mmol) of LAH in 250 ml of THF (-50 ° C.) and trans- [4- (methoxy-methyl-carbamoyl) -cyclohexyl] -methyl-ca in 250 ml of THF for 25 minutes. Treated with a solution of 15.02 g (50 mmol) of chest acid tert-butyl ester. The reaction was heated for 3.5 hours to + 15 ℃, which was then cooled and hydrolyzed with a suspension of MgSO ₄ .7H ₂ O 15 g, 15 g of silica gel of ₄ 50 ml (-78 ℃) aqueous 10% KHSO. The cooling bath was removed, THF was added and the mixture was stirred for 30 minutes and filtered. After evaporation, the residue was dissolved in CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and evaporated to give 12.83 (quant.) Of trans- (4-formyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester. MS: 241 (M).
[1109] 26.4
[1110] A solution of 52.45 g (200 mmol) of triphenylphosphine in 200 ml of CH ₂ Cl ₂ was treated with 33.16 g (100 mmol) of tetrabromomethane (heated to reflux) and after 50 minutes 32.06 ml of triethylamine ( 230 mmol) (the reaction was heated to reflux and became dark purple). After cooling (0 ° C.) 12.83 g (50 mmol) of trans- (4-formyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester in 125 ml of CH ₂ Cl ₂ were added for 10 minutes. The solution was stirred for 16 h at room temperature, evaporated and filtered through silica gel (inactivated with hexanes / Et ₃ N) to hexane as eluent and then filtered to hexane / ether 4: 1-1: 1 to trans- [4 13.28 g (67%) of-(2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester were obtained. mp: 93-99 ° C., decomposition; MS: 396 (MH <^+> , 2Br).
[1111] 26.5
[1112] The following reactions are described in Marshall, James A .; Bartley, Gary S .; Wallace, Eli M. Total Synthesis of the Pseudopterane (-)-Kallolide B, the Enantiomer of Natural (+)-Kallolide BJ Org. Chem. (1996), 61 (17), 5729-5735 and Baker, Raymond; Boyes, Alastair L .; Swain, Christopher J. Synthesis of talaromycins A, B, C, and EJ Chem. Soc., Perkin Trans. 1 (1990), (5), 1415-21.). A solution of 993 mg (2.5 mmol) of trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 20 ml of THF was dissolved in BuLi (hexane) at -78 ° C. About 1.6 M) 3.28 ml (5.25 mmol). After 2 hours 790 mg (25 mmol) of paraformaldehyde were added at this temperature. The reaction mixture was allowed to warm to room temperature for 3 hours and extracted after 1 hour with water / ether (3 ×). The organic phase was washed with aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated. Purification by flash-chromatography on silica gel (hexane / EtOAc 4: 1) trans- [4- (3-hydroxy-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester 530 g (79%) were obtained. MS: 268 (MH <^+> ).
[1113] 26.6
[1114] A solution of 3.97 g (10 mmol) of trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 160 ml of THF was dissolved in BuLi (hexane) at -78 ° C. About 1.6 M) treated with 13.13 ml (21 mmol) and stirred for 2 hours. 11 ml of DMPU was added and after 10 minutes 4.60 g (20 mmol) of 1-bromo-3-tetrahydropyranyloxypropane in 15 ml of THF were added over a period of 20 minutes. The reaction mixture was warmed to rt for 16 h, cooled, poured into cooled aqueous saturated NH ₄ Cl and extracted (Et ₂ O 3 ×). The organic phase was washed with aqueous 10% NaCl, water, dried over Na ₂ S0 ₄ , evaporated and purified by flash silica gel column (hexane / EtOAc 98: 2-90:10) trans-methyl- {4- [ 1.61 g (42%) of 5- (tetrahydro-pyran-2-yloxy) -pent-1-ynyl] -cyclohexyl} -carbamic acid tert-butyl ester were obtained. MS: 378 (MH).
[1115] 26.7
[1116] A solution of 520 mg (1.95 mmol) of trans- [4- (3-hydroxy-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 14 ml of CH ₂ Cl ₂ was stirred at 0 ° C. 0.17 ml (2.14 mmol) of methanesulfonylchloride, 0.235 ml (2.92 mmol) of pyridine and 238 mg (1.95 mmol) of DMAP were treated. The reaction mixture was allowed to warm to room temperature overnight, water (2 ml) was added and the reaction stirred for 5 minutes. After extraction with aqueous 10% KHSO ₄ / Et ₂ O (3 ×), the organic phase is washed with aqueous saturated NaHCO ₃ (2 ×), aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to trans-methanesulfonic acid 435 mg (65%) of 3- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -prop-2-ynyl ester were obtained. MS: 345 (M).
[1117] 26.8
[1118] A solution of 420 mg (1.22 mmol) of trans-methanesulfonic acid 3- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -prop-2-ynyl ester in 4 ml of DMA at 0 ° C Treated with 0.234 ml (2.43 mmol) of N-allylmethylamine and stirred for 16 hours at room temperature. The solution was concentrated and the remaining oil was extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was washed with 10% aqueous NaCl solution, dried over Na ₂ SO ₄ and flash column chromatography on hexane / EtOAc (2: 1) on silica gel followed by trans- {4- [3- (allyl-methyl-amino) 355 mg (91%) of -prop-1-ynyl] -cyclohexyl} -methyl-carbamic acid tert-butyl ester were obtained. MS: 321 (MH <^+> ).
[1119] 26.9
[1120] Of 200 mg (0.62 mmol) of trans- {4- [3- (allyl-methyl-amino) -prop-1-ynyl] -cyclohexyl} -methyl-carbamic acid tert-butyl ester in 3.5 ml of CH ₂ Cl ₂ The solution was treated with 1.7 ml of TFA at 0 ° C. (for 20 minutes). After 30 minutes at this temperature, the reaction mixture was evaporated and treated with 1N NaOH / CH ₂ Cl ₂ (3 ×). The organic phase was dried over Na ₂ SO ₄ and evaporated to yield 147 mg (quantitative) of trans- {4- [3- (allyl-methyl-amino) -prop-1-ynyl] -cyclohexyl} -methyl-amine It was. MS: 221 (MH <^+> ).
[1121] 26.10
[1122] A solution of 66 mg (0.3 mmol) of trans- {4- [3- (allyl-methyl-amino) -prop-1-ynyl] -cyclohexyl} -methyl-amine in 0.3 ml of dioxane was charged with 0.103 ml of Hunig's base. (0.6 mmol; 2 equiv) and dropwise with a solution of 0.042 ml (0.27 mmol) of 4-chlorophenylchloroformate in 0.16 ml of dioxane (10 min). After 5 minutes at room temperature, the mixture was dissolved in aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ SO ₄ and evaporated. Flash column chromatography on silica gel with CH ₂ Cl ₂ / MeOH (99: 1-97: 3) trans- {4- [3- (allyl-methyl-amino) -prop-1-ynyl] -cyclohexyl } 68 mg (61%) of methyl-carbamic acid 4-chloro-phenyl ester were obtained. MS: 375 (MH <^+> , 1Cl).
[1123] 26.11
[1124] In a manner similar to that described in Example 26.5, trans- (4 from trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and dimethylcarbamoyl chloride -Dimethylcarbamoylethynyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester was obtained. mp: 115-117 ° C .; MS: 309 (MH <^+> ).
[1125] Example 27
[1126] 27.1
[1127] A solution of 975 mg (3.28 mmol) of trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 20 ml of CH ₂ Cl ₂ was added at 0 ° Treatment with ml (for 20 minutes). After 2 hours at room temperature, the reaction was evaporated, treated with aqueous saturated NaHCO ₃ (+ Na ₂ CO ₃ ) / Et ₂ O (3 ×), dried over Na ₂ SO ₄ and evaporated to trans- [4- (2 981 mg (87%) of, 2-dibromo-vinyl) -cyclohexyl] -methyl-amine were obtained. MS: 295 (M, 2 Br).
[1128] 27.2
[1129] Similar to Example 26.10 trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-amine and 4-chlorophenylchloroformate were converted to trans- [4- (2,2-di Bromo-vinyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester. MS: 449 (M, 2 Br, 1 Cl).
[1130] 27.3
[1131] Similar to Example 26.5, trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and BuLi (about 1.6 M in hexane) were paraformed. It was converted to trans- [4- (3-hydroxy-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester with aldehyde. MS: 321 (M, 1CI).
[1132] 27.4
[1133] Similar to Example 26.7, trans- [4- (3-hydroxy-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester and methanesulfonylchloride / pyridine were trans- Methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester. MS: 400 (MH <^+> , 1Cl).
[1134] 27.5
[1135] Similar to Example 26.8, trans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester and 2-ethylamino Ethanol was converted to trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester MS: 393 (MH <^+> , 1Cl).
[1136] Example 28
[1137] 28.1
[1138] Trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -methyl-ca in 5 ml of MeOH and 7 mg of Pt / C 10% A suspension of 65 mg (0.165 mmol) of chest acid 4-chloro-phenyl ester was hydrogenated (1 atm) for 16 hours. The reaction was filtered (Celite) and evaporated. Flash column chromatography on silica gel with CH ₂ Cl ₂ / MeOH (9: 1) trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl)- 21 mg (32%) of methyl-carbamic acid 4-chloro-phenyl ester were obtained. MS: 397 (MH <^+> , 1Cl).
[1139] 28.2
[1140] Similar to Example 28.1, trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4- Trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -N-methyl-4-trifluoro from trifluoromethyl-benzenesulfonamide Methyl-benzenesulfonamide was obtained. MS: 451 (MH ⁺ ).
[1141] 28.3
[1142] Similar to Example 28.1, trans-N- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4- Trans-N- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -N-methyl-4-trifluoro from trifluoromethyl-benzenesulfonamide Methyl-benzenesulfonamide was obtained. MS: 467 (MH ⁺ ).
[1143] Example 29
[1144] 29.1
[1145] 16.2 g (62.95 mmol) of 4-trans-4-tert-butoxy carbonylamino-cyclohexanecarboxylic acid methyl ester and 5.87 ml (94.43 mmol) of methyl iodide in 100 ml of DMF were added with NaH (in oil) under stirring and ice-cooling. 55%), 3.57 g (81.84 mmol). The solution was stirred at rt for 20 h and then treated with 1N HCl under ice-cooling. The reaction mixture was dissolved in ether and washed four times with water. The ether-phase was concentrated in vacuo to give 17.5 g of clear trans-4- (tert-butoxycarbonyl-methyl-amino) -cyclohexanecarboxylic acid methyl ester. MS: 201 (M-OC ₄ H ₉ ).
[1146] 29.2
[1147] 17.1 g (62.95 mmol) of trans-4- (tert-butoxycarbonyl-methyl-amino) -cyclohexanecarboxylic acid methyl ester dissolved in 150 ml of THF was treated with 2.74 g (126 mmol) of LiBH ₄ . The reaction mixture was stirred at reflux for 6 hours and then 200 ml of 1N HCl was added dropwise to the solution under ice-cooling. The mixture was dissolved in ether and washed with water. The solvent was evaporated under reduced pressure to give 16.2 g of trans- (4-hydroxymethyl-cyclo-hexyl) -methyl-carbamic acid tert-butyl ester.
[1148] 29.3
[1149] To a dry ice cooled solution of 8.94 ml (125.9 mmol) of DMSO in 150 ml of CH ₂ Cl ₂ was added 5.95 ml (69.24 mmol) of oxalylchloride. After 5 minutes at -78 ° C., a solution of 16.2 g (66.5 mmol) of trans- (4-hydroxymethyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester in 50 ml of CH ₂ Cl ₂ was slowly added. After 10 minutes 43.8 ml (314.75 mmol) Et ₃ N were added and the mixture was allowed to reach room temperature. The mixture was partitioned between Et ₂ O / 1N HCl and water. The solvent was evaporated under reduced pressure to give 16.12 g of clear (4-formyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester. MS: 241
[1150] 29.4
[1151] Ice-cooled to a solution of 13.71 g (56.8 mmol) of trans- (4-formyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester and 17.8 g (83.46 mmol) of triethyl-phosphono-acetate in 150 ml of ethanol. 6.0 g (110 mmol) of NaOMe were added thereto. The reaction mixture was stirred at rt for 20 h, then concentrated under reduced pressure and then extracted with Et ₂ O and water. The organic layer was evaporated to dryness and the crude product was purified by chromatography on silica gel with EtOAc / hexane 1: 4 and purified trans-3- [4- (tert-butoxy carbonyl methyl-amino) -cyclohexyl] -acrylic acid 8.4 g (56%, 4 steps) of ethyl-ester were obtained. MS: 238 (M-OtBu).
[1152] 29.5
[1153] A solution of 6 g (19.26 mmol) of trans-3- [4- (tert-butoxy carbonyl methyl-amino) -cyclohexyl] -acrylic acid ethyl-ester and 600 mg of Pd / C (10%) was H ₂ -atmosphere. Under 20 hours of stirring. After the solution was filtered, methanol was evaporated under reduced pressure to give 5.82 g of clear trans-3- [4- (tert-butoxycarbonyl methyl-amino) cyclohexyl] -propanoic acid ethyl-ester. To a solution of this ester in 60 ml of THF was added 917 mg (40 mmol) of LiBH ₄ . The solution was refluxed for 8 hours and then cooled to 0 ° C. in an ice-bath. At this temperature 1N HCl was slowly added dropwise to the reaction mixture to destroy excess LiBH ₄ . The reaction mixture was diluted with Et ₂ O and washed with water. The organic layer was evaporated to dryness to afford 3.39 g (73%) of clear trans- [4- (3-hydroxy-propyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester. MS: 271 (M).
[1154] 29.6
[1155] 1.4 ml (16.24 mmol) of oxalylchloride were added to a dry ice cooled solution (-78 ° C.) of 1.78 ml (25 mmol) of DMSO in 40 ml of CH ₂ Cl ₂ . 10 minutes later. While stirring at −78 ° C., 2.39 g (12.49 mmol) of trans- [4- (3-hydroxy-propyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester dissolved in 5 ml of CH ₂ Cl ₂ were added. It was. After 15 minutes, 8.7 ml (62.4 mmol) of Et ₃ N were added and the reaction mixture was allowed to reach room temperature. The mixture was diluted with Et ₂ O and then washed with 1N HCl and water. After evaporation of the solvent, crude trans-methyl- [4- (3-oxo-propyl) -cyclohexyl] -carbamic acid tert-butyl ester (3.24 g, 12.02 mmol) and 30% triethyl phosphono acetate in 30 ml of ethanol. ml (13.3 mmol) of solution were treated with 1.37 g (24.05 mmol) of NaOMe under ice-cooling. The solution was stirred at rt for 20 h and then concentrated in vacuo. The crude residue was dissolved in Et ₂ O and washed with water. The organic layer was concentrated in vacuo and the crude product was purified by chromatography on silica gel with EtOAc / hexane 1: 4 and purified trans-5- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] 2.46 g (58%, 2 steps) of pent-2-enoic acid ethyl ester were obtained. MS: 339 (M).
[1156] 29.7
[1157] 2.45 g (7.2 mmol) of trans-5- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -pent-2-enoic acid ethyl ester in 40 ml of MeOH and Pd / C (10%) 200 mg of the solution was stirred for 20 h under H ₂ -atmosphere. After filtration and evaporation of the methanol under vacuum, 2.39 g of 5- [4- (tert-butoxy carbonyl-methyl-amino) -cyclohexyl] -pentanoic acid ethyl ester could be separated. 2.05 g (6.0 mmol) of this ester and 470 mg (12 mmol) of LiAlH ₄ were stirred in 20 ml of THF for 5 hours at room temperature. 10 ml of EtOAc was added and brine was carefully added dropwise to the reaction mixture to destroy excess LiAlH ₄ . The solution was dissolved in ether and washed with 1N HCl and water. The organic phase was concentrated under reduced pressure to yield 1.75 g (97%) of clear trans- [4- (5-hydroxy pentyl) -cyclohexyl) -methyl-carbamic acid tert-butyl ester. MS: 300 (MH ⁺ ).
[1158] 29.8
[1159] 1.75 g (5.84 mmol) of trans- [4- (5-hydroxypentyl) -cyclohexyl) -methyl-carbamic acid tert-butyl ester in 20 ml of CH ₂ Cl ₂ and 0.5 ml (6.42 mmol) of methanesulfonyl chloride To the solution was added 1.56 ml (11.7 mmol) of Et ₃ N while cooling in an ice bath. The mixture was stirred at rt for 3 h. The reaction mixture was then partitioned between ether / 1N HCl and water. The ether-solution was concentrated in vacuo to yield 2.12 g (96%) of clear trans-methanesulfonic acid 5 [-4- (tert-butoxy carbonyl-methyl-amino) -cyclohexyl) -pentyl ester.
[1160] 29.9
[1161] 200 mg (0.53 mmol) of trans-methanesulfonic acid 5 [-4- (tert-butoxy carbonyl-methyl-amino) -cyclohexyl) -pentyl ester dissolved in 2 ml of CH ₂ Cl ₂ was treated with 2 ml of TFA It was. After stirring for 20 minutes at room temperature, the solution was concentrated in vacuo to yield 245 mg of pure trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentylester.trifluoroacetic acid salt. MS: 278 (MH ⁺ ).
[1162] 29.10
[1163] Trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester in 4 ml of dioxane. 245 mg (0.53 mmol) of trifluoroacetic acid salt and 143.5 mg (0.75 mmol) of 4-chlorophenyl chloroformate. To a solution of) was added 1.54 ml (3.12 mmol) of Hunig's base at room temperature. The mixture was stirred for 1 h and then extracted with EtOAc / 1N HCl and water. The organic phase was concentrated under reduced pressure and purified by chromatography on silica gel with EtOAc / hexane 1: 3 to give pure trans-methanesulfonic acid 5- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] 167 mg (73%, 2 steps) of -cyclohexyl} -pentyl ester were obtained. MS: 432 (MH <^+> , 1Cl).
[1164] 29.11
[1165] 160 mg (0.37 mmol) of trans-methanesulfonic acid 5- {4- (4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -pentyl ester in 3 ml of methanol and 0.21 ml of N-allylmethylamine The solution of was stirred at 60 ° C. overnight. The solution was concentrated in vacuo and the residue was then purified by chromatography on silica gel with 1N NH ₃ / methanol 1:10 to give pure trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl } 110 mg of methyl-carbamic acid 4-chloro-phenyl ester were obtained. MS: 407 (MH <^+> , 1Cl).
[1166] 29.12
[1167] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-trifluoromethyl-phenyl chloroformate , N-allylmethylamine gave trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester. MS: 441 (MH ⁺ ).
[1168] 29.13
[1169] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-trifluoromethyl-phenyl chloroformate , 2-ethylamino-ethanol to give trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl -Phenyl ester was obtained. MS: 459 (MH ⁺ ).
[1170] 29.14
[1171] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-bromophenyl chloroformate, N- Treatment with allylmethylamine gave trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester. MS: 451 (MH <^+> , 1Br).
[1172] 29.15
[1173] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-bromophenyl chloroformate, 2- Treatment with ethylamino-ethanol affords trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-bromo-phenyl ester It was. MS: 469 (MH <^+> , 1Br).
[1174] 29.16
[1175] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester-trifluoroacetic acid salt was reacted with 3,4-difluoro-phenyl chloroformate Then, treatment with N-allylmethylamine gave trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 3,4-difluoro-phenyl ester . MS: 409 (MH ⁺ ).
[1176] 29.17
[1177] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. A reaction of trifluoroacetic acid salt with 3,4-difluoro-phenyl chloroformate After treatment with 2-ethylamino-ethanol, trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 3,4-di A fluoro-phenyl ester was obtained. MS: 427 (MH ⁺ ).
[1178] 29.18
[1179] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. A reaction of trifluoroacetic acid salt with 4- (trifluoromethyl) benzenesulfonyl chloride After treatment with N-allylmethylamine, trans-N- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide Obtained. MS: 461 (MH ⁺ ).
[1180] 29.19
[1181] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. A reaction of trifluoroacetic acid salt with 4- (trifluoromethyl) benzenesulfonyl chloride Then, treated with 2-ethylamino-ethanol to trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-tri Fluoromethyl-benzenesulfonamide was obtained. MS: 479 (MH ⁺ ).
[1182] 29.20
[1183] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. A reaction of trifluoroacetic acid salt with 3,5-difluoro-phenyl chloroformate Then trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 3,5-difluoro-phenyl ester by treatment with N-allyl-N-methylamine Obtained. MS: 409 (MH ⁺ ).
[1184] 29.21
[1185] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester-trifluoroacetic acid salt was reacted with 3,5-difluoro-phenyl chloroformate After treatment with 2-ethylamino-ethanol, trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 3,5-di A fluoro-phenyl ester was obtained. MS: 427 (MH ⁺ ).
[1186] 29.22
[1187] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-chlorophenyl chloroformate, 2-ethyl Treatment with amino-ethanol yielded trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester. MS: 425 (MH <^+> , 1Cl).
[1188] 29.23
[1189] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-chlorophenyl chloroformate, methyl-propyl Treatment with -amine yielded trans-methyl- {4- [5- (methyl-propyl-amino) -pentyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester. MS: 409 (MH <^+> , 1Cl).
[1190] 29.24
[1191] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. The reaction of trifluoroacetic acid salt with 4-chlorophenyl chloroformate, followed by dimethylamine Treatment gave trans-methyl- {4- [5- (dimethylamino) -pentyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester. MS: 381 (MH <^+> , 1Cl).
[1192] 29.25
[1193] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-chlorophenyl chloroformate, piperidine Treatment with trans-methyl- [4- (5-piperidin-1-yl-pentyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester was obtained. MS: 421 (MH <^+> , 1Cl).
[1194] 29.26
[1195] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting trifluoroacetic acid salt with 4-chlorophenyl chloroformate, N-methyl Treatment with piperazine yielded trans-methyl- {4- [5- (4-methyl-piperazin-1-yl) -pentyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester. MS: 436 (MH <^+> , 1Cl).
[1196] 29.27
[1197] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting trifluoroacetic acid salt with 4-chlorophenyl chloroformate, N-methyl Treatment with -N-cyclopropyl-amine gave trans {4- [5- (cyclopropyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester. MS: 407 (MH <^+> , 1Cl).
[1198] 29.28
[1199] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-trifluoromethyl-phenyl sulfonylchloride And diethylamine gave trans N- [4- (5-diethylamino-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide. MS: 463 (MH <^+> ).
[1200] 29.29
[1201] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-trifluoromethyl-phenyl sulfonylchloride Treatment with 2- (2-hydroxy-ethylamino) -ethanol trans-N- (4- {5- [bis- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N- Methyl-4-trifluoromethyl-benzenesulfonamide was obtained. MS: 495 (MH <^+> ).
[1202] 29.30
[1203] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-trifluoromethyl-phenyl chloroformate Treatment with allylamine afforded trans- {4- [5- (allylamino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester. MS: 427 (MH ⁺ ).
[1204] 29.31
[1205] Similar to Examples 29.10 and 29.11, trans-methanesulfonic acid 5- (4-methyl amino-cyclohexyl) -pentyl ester. After reacting the trifluoroacetic acid salt with 4-trifluoromethyl-phenyl chloroformate And methylamine to give trans-methyl- [4- (5-methylamino-pentyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester. MS: 401 (MH ⁺ ).
[1206] 29.32
[1207] Similar to Example 29.11, trans-N- [from trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide and allylamine 4- (5-allylamino-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was prepared. MS: 447 (MH ⁺ ).
[1208] 29.33
[1209] Similar to Example 29.11, trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide and 2.amino-2-methyl- Trans-N- {4- [5- (2-hydroxy-1,1-dimethyl-ethylamino) -pentyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfon from 1-propanol Amide was prepared. MS: 479 (MH ⁺ ).
[1210] 29.34
[1211] Similar to Example 29.11, trans-N-methyl from trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide and methylamine -N- [4- (5-methylamino-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide was prepared. MS: 421 (MH <^+> ).
[1212] 29.35
[1213] Similar to Example 29.11, trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide and ethanolamine (6 equiv, in DMA Trans-N- {4- [4- (2-hydroxy-ethylamino) -butyl] -cyclohexyl} -N-methyl-4-trifluoromethyl- benzenesulfonamide was prepared. MS: 451 (MH ⁺ ).
[1214] 29.36
[1215] Similar to Example 29.11, trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide and ethylamine (6 equiv, in DMA ) Trans-N- [4- (5-ethylamino-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was prepared. MS: 435 (MH ⁺ ).
[1216] 29.37
[1217] Similar to Examples 29.4-29.9 and 29.12, (trans)-{4- [5- (allyl-methyl-amino from trans / cis- (4-formyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester ) -Pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester and (cis) {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-car Chest acid 4-trifluoromethyl-phenyl ester, MS: 441 (MH ⁺ ) was prepared, which was HPLC (ChiralpakAD, 20 um 5 × 50 cm von Daicel Chem.Industrie Ltd, eluent: 9.0 l n-heptane / 1.0 l isopropanol).
[1218] Example 30
[1219] 30.1
[1220] To a suspension of 1.39 g (4.4 mmol, 2.2 equiv) of hydrogen peroxide. Urea adduct in CH ₂ Cl ₂ , 338.5 mg (2.2 mmol, 1.1 equiv) of phthalic anhydride were added and stirred at room temperature for 15 minutes. 800 mg (2.01 mmol) of trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester in CH ₂ Cl ₂ were added and the mixture was stirred at room temperature for 2 hours. It was. 5% K ₂ CO ₃ aqueous solution was added and the inorganic phase was extracted with CH ₂ Cl ₂ . The organic phase was washed with water and brine and dried over MgSO ₄ . Column chromatography gave 525 mg (63%) of trans- [4- (5-dimethylamino-pentyloxy) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester N-oxide as a colorless oil. MS: 413 (MH <^+> , 1Cl).
[1221] 30.2
[1222] Similar to Example 30.1, from the trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester after precipitation (CH ₂ Cl ₂ / Et ₂ O) trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester N-oxide was obtained. MS: 457 (MH ⁺ ).
[1223] 30.3
[1224] Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide 400 mg (8.4 mmol) was suspended in toluene, evaporated (3 ×), redissolved in 1 ml of DMF and treated with 102.4 mg (1.5 mmol, 1.8 equiv) of imidazole. At 0 ° C. 176 mg (11.7 mmol, 1.4 equiv) of TBDMSCl in 2 ml of DMF were added and the reaction mixture was stirred at 50 ° C. for 1 hour. The solution was added to an aqueous solution of NaHCO ₃ and extracted with ether. The organic layer was washed with water and brine and dried over Na ₂ SO ₄ . Crude trans-N- [4- (5-{[2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -ethyl-amino} -pentyl) -cyclohexyl] -N-methyl-4-trifluoro 509 mg of rhomethyl-benzenesulfonamide were isolated as a light yellow oil.
[1225] 30.4
[1226] 175 mg (1.86 mmol) of H ₂ O ₂ -urea adduct suspended in 2 ml of CH ₂ Cl ₂ were treated with 137 mg (0.9 mmol) of phthalic anhydride. After stirring for 15 min at room temperature to this mixture was added crude trans-N- [4- (5-{[2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -ethyl- in 3 ml of CH ₂ Cl _2. Amino} -pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide 500 mg (8.4 mmol) were added and the solution was stirred at room temperature. The mixture was washed with an aqueous solution of NaHCO ₃ and the organic phase was washed with brine and dried over Na ₂ SO ₄ . Crude trans-N- [4- (5-{[2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -ethyl-amino} -pentyl) -cyclohexyl] -N-methyl-4-trifluoro 348 mg of rhomethyl-benzenesulfonamide N-oxide was isolated as a colorless oil.
[1227] 30.5
[1228] Trans-N- [4- (5-{[2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -ethyl-amino} -pentyl) -cyclohexyl] -N-methyl-4 in 8 ml THF To 335 mg (5.5 mmol) of -trifluoromethyl-benzenesulfonamide N-oxide 0.83 ml of 1M TBAF was added at 0 ° C. The solution was stirred at rt for 1 h and partitioned between EtOAc and an aqueous solution of Na ₂ CO ₃ . The organic phase was washed with brine and dried over Na ₂ SO ₄ . Column chromatography with CH ₂ Cl ₂ / MeOH 9: 1 trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl- 190 mg (44%, 3 steps) of 4-trifluoromethyl-benzenesulfonamide N-oxide were obtained as a colorless oil. MS: 495 (MH <^+> ).
[1229] Example 31
[1230] 31.1
[1231] Trans- [toluene-4-sulfonic acid 4- (tert-butoxycarbonyl-methyl-amino) -cyclohexylmethyl ester] (trans- (4-hydroxymethyl-cyclohexyl) -methyl-carbamic acid tert-butyl 5.85 g (14.71 mmol) and 1.45 g (29.43 mmol) sodium cyanide (synthesized from toluene sulfonyl chloride in ester and pyridine) were stirred for 48 h at 100 ° C. in 50 ml of DMF. The reaction mixture was partitioned between ether and water. After drying (Na ₂ SO ₄ ) and ether-phase concentrated in vacuo, 3.74 g of crude trans-[(4-cyanomethyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester] could be separated. This crude product (14.82 mmol) dissolved in 30 ml of THF was treated with 13.5 ml (16.18 mmol) of 1.2 M DIBALH-solution in toluene at −78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes and at room temperature for 15 minutes. Then 30 ml of 1N HCl was carefully added dropwise to the reaction mixture. The reaction mixture was dissolved in ether and washed with water. The ether-solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford 3.47 g (92%) of crude trans- [methyl- [4- (2-oxo-ethyl) -cyclohexyl] -carbamic acid tert-butyl ester] Step 2).
[1232] 31.2
[1233] Crude trans- [methyl- [4- (2-oxo-ethyl) -cyclohexyl] -carbamic acid tert-butyl ester] 3.47 g (13.58 mmol) and (triphenyl-l 5-phosphanilidene) -ethyl acetate 5.39 g (14.7 mmol) of the ester were stirred overnight in room temperature in 40 ml of CH ₂ Cl ₂ . The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel with EtOAc / hexane 1: 3 to give pure 4- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -but-2 1.57 g (36%) of enoic acid ethyl ester were obtained.
[1234] 31.3
[1235] 1.57 g (4.82 mmol) and Pd / C (10%) 200 mg of 4- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -but-2-enoic acid ethyl ester in 20 ml of MeOH The solution of was stirred for 3 h at room temperature under H ₂ -atmosphere. After filtration, the solution was concentrated to dryness under reduced pressure to give 1.58 g of clear trans-4- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -butyric acid ethyl ester. 1.58 g (4.82 mmol) of trans-4- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -butyric acid ethyl ester in 20 ml of THF were treated with 390 mg of LiAlH ₄ at room temperature. The solution was stirred at room temperature for 30 minutes and then excess LiAH ₄ was destroyed by dropwise addition of 10 ml of saturated brine under ice-cooling. The reaction mixture was partitioned between Et ₂ O / 1M HCl and H ₂ O. The ether-solution was concentrated in vacuo to yield 1.37 g (99%) of pure trans- [4- (4-hydroxy-butyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester.
[1236] 31.4
[1237] 1.37 g (4.8 mmol) of trans- [4- (4-hydroxy-butyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 15 ml of CH ₂ Cl ₂ and 0.95 ml of NEt ₃ are stirred and ice-cooled Ml (6.8 mmol) of methanesulfonyl chloride was added to the resulting solution. After stirring for 2 hours at room temperature, the reaction mixture was partitioned between Et ₂ O, 1M HCl and water. The ether-layers were concentrated in vacuo to afford 1.745 g of 4- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -butyl ester of clear trans-methanesulfonic acid, which was CH ₂ Cl ₂ 5 Treatment with 5 ml of trifluoro acetic acid in ml. The solution was stirred at room temperature for 30 minutes, then the solution was evaporated to dryness under reduced pressure to give 2.25 g (quantitative) of trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. It was.
[1238] 31.5
[1239] Trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester in 6 ml of CH ₂ Cl ₂ ; To a stirred solution of 590 mg (1.25 mmol) of compound with trifluoro-acetic acid and 0.644 ml of 4-ethylmorpholine was added 365 mg (1.91 mmol) of 4-chlorophenyl-chloroformate at room temperature. The reaction mixture was stirred at rt for 1 h and then partitioned between Et ₂ O, 1M HCl and water. After concentration of the ether-layer under reduced pressure, the residue was purified by chromatography on silica gel with EtOAc / hexane 1: 2 to give pure trans-methanesulfonic acid 4- {4-[(4-chloro-phenoxycarbonyl) 421 mg (81%) of -methyl-amino] -cyclohexyl} -butyl ester were obtained.
[1240] 31.6
[1241] 219 mg (0.524 mmol) of trans-methanesulfonic acid 4- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -butyl ester in 1 ml of MeOH and N-allyl methyl-amine 0.48 ml of the solution was stirred overnight at room temperature and for 2 hours under reflux. After the reaction mixture was concentrated in vacuo, the crude product was purified by chromatography on silica gel with EtOAc / H ₂ O / AcOH / acetone (6: 2: 1: 1) to give clear trans- {4- [4- ( 165 mg (80%) of allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester were obtained. MS: 393 (MH <^+> , 1Cl).
[1242] 31.7
[1243] Similar to Example 31.6, trans-methanesulfonic acid 4- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -butyl ester was treated with 2-ethylamino-ethanol Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester was obtained. MS: 411 (MH <^+> , 1Cl).
[1244] 31.8
[1245] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. Reaction of trifluoro-acetic acid with 4-trifluoromethyl-phenyl-chloroformate Then treated with N-allyl-N-methylamine to give trans- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester Obtained. MS: 427 (MH ⁺ ).
[1246] 31.9
[1247] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. Reaction of trifluoro-acetic acid with 4-trifluoromethyl-phenyl-chloroformate Then treated with 2-ethylamino-ethanol to trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoro Methyl-phenyl ester was obtained. MS: 445 (MH ⁺ ).
[1248] 31.10
[1249] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, N Treatment with -allyl-N-methylamine gave trans- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-bromo-phenyl ester. MS: 437 (MH <^+> , 1Br).
[1250] 31.11
[1251] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromo phenyl-chloroformate, 2 Treatment with ethylethyl-ethanol yields trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -methyl-carbamic acid 4-bromo-phenyl ester Obtained. MS: 455 (MH <^+> , 1Br).
[1252] 31.12
[1253] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, N Treatment with -methyl-propyl-amine gave trans-methyl- {4- [4- (methyl-propyl-amino) -butyl] -cyclohexyl} -carbamic acid 4-bromo-phenyl ester. MS: 439 (MH <^+> , 1Br).
[1254] 31.13
[1255] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, di Treatment with ethylamine gave trans-methyl- {4- [4- (diethylamino) -butyl] -cyclohexyl} -carbamic acid 4-bromo-phenyl ester. MS: 439 (MH <^+> , 1Br).
[1256] 31.14
[1257] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, dimethyl Treatment with amine gave trans-methyl- {4- [4- (dimethylamino) -butyl] -cyclohexyl} -carbamic acid 4-bromo-phenyl ester. MS: 411 (MH <^+> , 1Br).
[1258] 31.15
[1259] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, Treatment with ferridine gave trans-methyl- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester. MS: 451 (MH <^+> , 1Br).
[1260] 31.16
[1261] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, N Treatment with -methyl-piperazine gave trans-methyl- {4- [4- (4-methyl-piperazin-1-yl) -butyl] -cyclohexyl} -carbamic acid 4-bromo-phenyl ester . MS: 466 (MH <^+> , 1Br).
[1262] 31.17
[1263] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, Treatment with poline gave trans-methyl- [4- (4-morpholin-4-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester. MS: 453 (MH <^+> , 1Br).
[1264] 31.18
[1265] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. After reacting trifluoro-acetic acid with 4-bromophenyl-chloroformate, thio Treatment with morpholine gave trans-methyl- [4- (4-thiomorpholin-4-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester. MS: 469 (MH <^+> , 1Br).
[1266] 31.19
[1267] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. Reaction of trifluoro-acetic acid with 4-trifluoromethyl-phenyl-chloroformate Treatment with piperidine then yielded trans-methyl- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester. MS: 441 (MH ⁺ ).
[1268] 31.20
[1269] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. Reaction of trifluoro-acetic acid with 4-trifluoromethyl-phenyl-chloroformate Subsequent treatment with dimethylamine gave trans- [4- (4-dimethylamino-butyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester. MS: 401 (MH ⁺ ).
[1270] 31.21
[1271] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. Reaction of trifluoro-acetic acid with 4-trifluoromethyl-phenyl-chloroformate Then, treatment with thiomorpholine gave trans-methyl- [4- (4-thiomorpholin-4-yl-butyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester. MS: 459 (MH ⁺ ).
[1272] 31.22
[1273] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester. Reaction of trifluoro-acetic acid with 4-trifluoromethyl-phenyl-chloroformate Treatment with methyl-propyl-amine then yielded trans-methyl- {4- [4- (methyl-propyl-amino) -butyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester. MS: 429 (MH ⁺ ).
[1274] 31.23
[1275] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester was reacted with trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride. And then treated with N-allyl-N-methylamine to trans-N- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzene Sulfonamide was obtained. MS: 447 (MH ⁺ ).
[1276] 31.24
[1277] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester-trifluoro-acetic acid was reacted with 4-trifluoromethyl-phenyl-sulfonylchloride Then, treated with 2-ethylamino-ethanol to trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -N-methyl-4-tri Fluoromethyl-benzenesulfonamide was obtained. MS: 465 (MH ⁺ ).
[1278] 31.25
[1279] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester was reacted with trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride. After treatment with piperidine, trans-N-methyl-N- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide was obtained. . MS: 461 (MH ⁺ ).
[1280] 31.26
[1281] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester-trifluoro-acetic acid was reacted with 4-trifluoromethyl-phenyl-sulfonylchloride After treatment with dimethylamine, trans-N- [4- (4-dimethylamino-butyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was obtained. MS: 421 (MH ⁺ ).
[1282] 31.27
[1283] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester was reacted with trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride. Then treated with methyl-propyl-amine to give trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -butyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide Obtained. MS: 449 (MH ⁺ ).
[1284] 31.28
[1285] Similar to Examples 31.5 and 31.6, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -butyl ester was reacted with trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride. Then treated with 2- (2-hydroxy-ethylamino) -ethanol to give trans N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butyl} -cyclohexyl) -N -Methyl-4-trifluoromethyl-benzenesulfonamide was obtained. MS: 481 (MH ⁺ ).
[1286] Example 32
[1287] 32.1
[1288] A solution of 6.02 g (17.43 mmol) of trans-methanesulfonic acid 3- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -prop-2-ynyl ester in 95 ml of CH ₂ Cl ₂ Treated with 45 ml of TFA at 0 ° C. (for 20 minutes). After 30 minutes at this temperature, the reaction was evaporated and again evaporated with toluene (4 times) to give crude trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester. 8.17 g (quantitative) were obtained. MS: 245 (M).
[1289] 32.2
[1290] A solution of 1.41 g (corresponding to 3.0 mmol) of 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate in 20 ml of CH ₂ Cl ₂ was first brought to 0 ° C. Cooled and treated with 0.5 ml (3.6 mmol) of 4-chlorophenylchloroformate followed by 2.57 ml (15 mmol; 5 equiv) of Hunig's base (3 min). After 45 minutes at room temperature, the mixture was dissolved in aqueous 10% KHSO ₄ / Et ₂ O (3 ×). The organic phase was washed with aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to afford crude trans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl } 1.41 g (quantitative) of prop-2-ynyl ester were obtained. MS: 400 (MH <^+> , 1Cl). The crude product was used directly in the next step.
[1291] 32.3
[1292] Similar to Example 32.2, trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate and 4-trifluoromethylphenylchloroformate Phonic acid 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -prop-2-ynyl ester. MS: 434 (MH ⁺ ).
[1293] 32.4
[1294] Similar to Example 32.2, trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate and p-tolyl chloroformate were converted to trans-methanesulfonic acid 3- [4- (Methyl-p-tolyloxycarbonyl-amino) -cyclohexyl] -prop-2-ynyl ester. MS: 380 (MH <^+> ).
[1295] 32.5
[1296] Similar to Example 32.2, trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate and 4-methoxyphenyl chloroformate were converted to trans-methanesulfonic acid. 3- {4-[(4-methoxy-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester. MS: 396 (MH ⁺ ).
[1297] 32.6
[1298] Similar to Example 32.2, trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate and 4- (trifluoromethyl) benzenesulfonylchloride were transfected. Methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -prop-2-ynyl ester. MS: 454 (MH ⁺ ).
[1299] 32.7
[1300] Similar to Example 32.2, trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate and 4-acetamidophenylsulfonyl chloride were trans-methane Sulfonic acid 3- {4-[(4-acetylamino-benzenesulfonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester. MS: 443 (MH ⁺ ).
[1301] 32.8
[1302] Similar to Example 32.2, trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate and 4-chlorobenzoylchloride were converted to trans-methanesulfonic acid 3- { Converted to 4-[(4-chloro-benzoyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester. MS: 398 (MH <^+> , 1Cl).
[1303] 32.9
[1304] A solution of 1.38 g of trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate (corresponding to 3.0 mmol) in 7 ml of dioxane was first cooled to 8 ° C. , 0.69 g (4.5 mmol) of 4-chlorophenyl isocyanate followed by 1.2 ml (15 mmol; 5 equiv) of pyridine (3 min). After 45 minutes at room temperature, the mixture was dissolved in aqueous 10% KHSO ₄ / Et ₂ O (3 ×). The organic phase was washed with aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to afford crude trans-methanesulfonic acid 3- {4- [3- (4-chloro-phenyl) -1-methyl-ureido]- 1.22 g (quantitative) of cyclohexyl} -prop-2-ynyl ester were obtained. MS: 398 (MH <^+> , 1Cl). The crude product was used directly in the next step.
[1305] 32.10
[1306] Similar to Example 32.2, trans-methanesulfonic acid 3- (4-methylamino-cyclohexyl) -prop-2-ynyl ester trifluoroacetate and 4-chlorobenzenesulfonylchloride were converted to trans-methanesulfonic acid 3 -{4-[(4-chloro-benzenesulfonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester. MS: 420 (MH <^+> , 1Cl).
[1307] Example 33
[1308] 235 mg of trans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester in 2.5 ml of DMA (equivalent to 0.5 mmol) The solution of was cooled to 0 ° C., treated with 0.76 ml (1 mmol) of N-methylpropylamine and stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ S0 ₄ , filtered and evaporated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 98: 2) pure trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl } -153 mg (81%) of carbamic acid 4-chloro-phenyl ester were obtained. MS: 377 (MH <^+> , 1Cl).
[1309] The hydrochloride salt is optionally obtained after dissolving the amine in dioxane and adding 1 equivalent of 4N HCl (in dioxane). Lyophilisation to trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester; Compounds with HCl were obtained as white powder. MS: 377 (MH <^+> , 1Cl).
[1310] The following compounds were prepared from the corresponding mesylates and secondary amines (if the reaction did not complete after 16 hours, an additional 2 equivalents of amine was added. For dimethylamine (33% 5.6M in EtOH), 10 equivalents were added Was):
[1311] ExamplecompoundMSMH ⁺ MesylateSecondary amine 33.1Trans- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester349,10Trans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterDimethylamine, 33% 5.6M in EtOH 33.2Trans-methyl- [4- (3-piperidin-1-yl-prop-1-ynyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester389,1ClTrans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterPiperidine 33.3Trans- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester443Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -prop-2-ynyl esterDiethanolamine 33.4Trans- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester383Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -prop-2-ynyl esterDimethylamine, 33% 5.6M in EtOH 33.5Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester411Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -prop-2-ynyl esterN-methylpropyl-amine
[1312] 33.6Trans-methyl- [4- (3-piperidin-1-yl-prop-1-ynyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester423Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -prop-2-ynyl esterPiperidine
[1313] Example 34
[1314] 200 mg of trans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl ester in 4.3 ml of methanol (corresponding to 0.43 mmol) The solution of was cooled to 0 ° C., treated with 0.44 ml (1 mmol) of ethyl- (2-methoxy-ethyl) -amine and stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was haystacked with Na ₂ S0 ₄ , filtered and evaporated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 99: 1) yielded pure trans- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -prop-1- 144 mg (83%) of inyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester were obtained. MS: 407 (MH <^+> , 1Cl). The following compounds were prepared from the corresponding mesylates and secondary amines:
[1315] ExamplecompoundMSMH ⁺ MesylateSecondary amine 34.1Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid p-tolyl ester357Trans-methanesulfonic acid 3- [4- (methyl-p-tolyloxycarbonyl-amino) -cyclohexyl] -prop-2-ynyl esterN-methylpropyl-amine 34.2Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-methoxy-phenyl ester373Trans-methanesulfonic acid 3- {4-[(4-methoxy-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterN-methylpropyl-amine
[1316] 34.3Trans-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides447Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -prop-2-ynyl esterEthyl- (2-hydroxy-ethyl) -amine 34.4Trans-N- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides463Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -prop-2-ynyl esterDiethanolamine 34.5Trans-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide431Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -prop-2-ynyl esterN-methylpropyl-amine 34.6Trans-N- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide403Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -prop-2-ynyl esterDimethylamine, 33% 5.6M in EtOH 34.7Trans-N- (4- {3- [ethyl- (2-methoxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides461Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -prop-2-ynyl esterN- (2-methoxyethyl) ethylamine
[1317] 34.8Trans-N- [4- (methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -sulfamoyl) -phenyl] -acetamide431Trans-methanesulfonic acid 3- {4-[(4-acetylamino-benzenesulfonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterN-methylpropyl-amine 34.9Trans-4-chloro-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -benzamide361,1 ClTrans-methanesulfonic acid 3- {4-[(4-chloro-benzoyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterN-methylpropyl-amine 34.10Trans-4-chloro-N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -N-methyl-benzamide377,1 ClTrans-methanesulfonic acid 3- {4-[(4-chloro-benzoyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterEthyl- (2-hydroxy-ethyl) -amine 34.11Trans-3- (4-chloro-phenyl) -1-methyl-1- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl 1-urea376,10Trans-methanesulfonic acid 3- {4- [3- (4-chloro-phenyl) -1-methyl-ureido] -cyclohexyl 1-prop-2-ynyl esterN-methylpropyl-amine 34.12Trans-3- (4-chloro-phenyl) -1- (4-13- [ethyl- (2-hydroxy-ethyl) -amino] -prop-1-ynyl} -cyclohexyl) -1-methyl- Urea392,1 ClTrans-methanesulfonic acid 3- {4- [3- (4-chloro-phenyl) -1-methyl-ureido] -cyclohexyl} -prop-2-ynyl esterEthyl- (2-hydroxy-ethyl) -amine 34.13Trans-4-chloro-N-methyl-N- [4- (3-piperidin-1-yl-prop-1-ynyl) -cyclohexyl] -benzenesulfonamide409,1 ClTrans-methanesulfonic acid 3- {4-[(4-chloro-benzenesulfonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterPiperidine
[1318] 34.14Trans-4-chloro-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -benzenesulfonamide397,1C1Trans-methanesulfonic acid 3- {4-[(4-chloro-benzenesulfonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterN-methylpropyl-amine 34.15Trans-4-chloro-N- [4- (3-dimethylamino-prop-1-ynyl) -cyclohexyl] -N-methyl-benzenesulfonamide369,10Trans-methanesulfonic acid 3- {4-[(4-chloro-benzenesulfonyl) -methyl-amino] -cyclohexyl} -prop-2-ynyl esterDimethylamine, 33% 5.6M in EtOH
[1319] Example 35
[1320] Trans-N- [4- (methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -sulfamoyl) -phenyl] -acetamide in 4 ml of MeOH 44.3 A solution of mg (0.1 mmol) was treated with 0.37 ml (2 mmol) of sodium methylate (5.4 M in MeOH) and heated at 70 ° C. for 30 hours. The solvent was evaporated and the residue was extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ S0 ₄ , filtered and evaporated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 97: 3) pure trans-4-amino-N-methyl-N- {4- [3- (methyl-propyl-amino) -prop 31 mg (82%) of 1-ynyl] -cyclohexyl} -benzenesulfonamide were obtained. MS: 378 (MH ⁺ ).
[1321] Example 36
[1322] 36.1
[1323] 3.4 g (12.72 mmol) of trans- [4- (3-hydroxy-prop-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 125 ml of ethanol and 810 mg of PtO ₂ .H ₂ O The suspension of was hydrogenated for 7 hours (1 atm). The reaction was filtered (celite) and evaporated to yield 3.5 g (quantitative) of trans- [4- (3-hydroxy-propyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester. MS: 271 (MH ⁺ ).
[1324] 36.2
[1325] Trans-methanesulfonic acid from trans- [4- (3-hydroxy-propyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and 4-chlorophenylchloroformate similar to Examples 26.7, 32.1 and 32.2 3- {4-[(4-Chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -propyl ester was obtained. MS: 404 (MH <^+> , 1Cl).
[1326] 36.3
[1327] Trans-methane from trans- [4- (3-hydroxy-propyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and 4-trifluoromethylphenylchloroformate similar to Examples 26.7, 32.1 and 32.2 Sulfonic acid 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -propyl ester was obtained. MS: 438 (MH ⁺ ).
[1328] 36.4
[1329] Trans-methanesulfonic acid 3 from trans- [4- (3-hydroxy-propyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and p-tolyl chloroformate similar to Examples 26.7, 32.1 and 32.2 -[4- (Methyl-p-tolyloxycarbonyl-amino) -cyclohexyl] -propyl ester was obtained. MS: 384 (MH ⁺ ).
[1330] Example 37
[1331] Solution of 293 mg (corresponding to 0.5 mmol) of 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -propyl ester in 2.5 ml of DMA Was cooled to 0 ° C., treated with 0.195 ml (2 mmol) of ethyl- (2-hydroxy-ethyl) -amine and stirred overnight at room temperature. A catalytic amount of NaI and 0.195 ml (2 mmol) of ethyl- (2-hydroxy-ethyl) -amine were added and after 9 hours 0.88 ml (1 mmol) of ethyl- (2-hydroxy-ethyl) -amine were added. After 16 h the solvent was evaporated and the residue was extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ S0 ₄ , filtered and evaporated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1) yielded pure trans- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl 48 mg (22%) of 4-methyl-carbamic acid 4-trifluoromethyl-phenyl ester were obtained. MS: 431 (MH <^+> ). The following compounds were prepared analogously:
[1332] ExamplecompoundMSMH ⁺ MesylateSecondary amine 37.1Trans- (4- {3- [bis- (2-hydroxy-ethyl) -amino] -propyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenylester447Trans-methanesulfonic acid 3- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -propyl esterDiethanolamine
[1333] 37.2Trans- [4- (3-dimethylamino-propyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester353,10Trans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -propyl esterDimethylamine, 33% 5.6M in EtOH 37.3Trans-methyl- {4- [3- (methyl-propyl-amino) -propyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester381,1 ClTrans-methanesulfonic acid 3- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -propyl esterN-methylpropyl-amine 37.4Trans-methyl- {4- [3- (methyl-propyl-amino) -propyl] -cyclohexyl} -carbamic acid p-tolyl ester361Trans-methanesulfonic acid 3- [4- (methyl-p-tolyloxycarbonyl-amino) -cyclohexyl] -propyl esterN-methylpropyl-amine
[1334] Example 38
[1335] 38.1
[1336] Cool a suspension of 4.5 g (16.8 mmol) of trans- [4- (3-hydroxyprop-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 180 ml of Et ₂ O (0 C) was slowly treated with a solution of 13.46 ml (47.1 mmol) Red-Al (70% in toluene). The solution was stirred at rt for 2 h, cooled (0 ° C.) and treated again with 1.3 ml (4.7 mmol) of Red-Al (70% in toluene). After 2 hours at room temperature, the reaction was cooled (-50 ° C.) and hydrolyzed with a suspension of 3 g of MgSO ₄ .7H ₂ O, 3 g of silica gel in 4 ml of aqueous 10% KHSO ₄ . The cooling bath was removed, THF was added and the mixture was filtered. After evaporation, the residue was dissolved in CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and evaporated to trans- (1E)-[4- (3-hydroxy-propenyl) -cyclohexyl] -methyl-carbamic acid tert 3.59 g (quantitative) of the butyl ester were obtained. MS: 270 (MH ⁺ ).
[1337] 38.2
[1338] A solution of 4.37 g (16.35 mmol) of trans- (1E)-[4- (3-hydroxy-propenyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 120 ml of CH ₂ Cl ₂ was stirred at 0 It was treated with 1.4 ml (17.98 mmol) of methanesulfonylchloride, 1.97 ml (24.52 mmol) of pyridine and 2 g (16.35 mmol) of DMAP. The reaction mixture was stirred at rt for 3 h, water (5 ml) was added and the reaction stirred for 5 min. After extraction with aqueous 10% KHSO ₄ / Et ₂ O (3 ×), the organic phase is washed with aqueous saturated NaHCO ₃ (2 ×), aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to trans- (1E 3.51 g (75%) of)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester was obtained. mp: 42.5-43.9 ° C .; MS: 387 (MH <^+> , 1Cl).
[1339] 38.3
[1340] Similar to Examples 32.1 and 32.2, trans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and 4-chlorophenylchloroformate (1E)-[4- (3-Chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester was obtained. MS: 342 (MH <^+> , 2Cl).
[1341] 38.4
[1342] Similar to Examples 32.1 and 32.2, from trans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and 4-trifluoromethylphenylchloroformate Trans- (1E)-[4- (3-Chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester was obtained. MS: 376 (MH <^+> , 1Cl).
[1343] 38.5
[1344] Similar to Examples 32.1 and 32.2, trans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and 4- (trifluoromethyl) benzenesulfur Trans- (1E) -N- [4- (3-chloro-propenyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was obtained from polyvinylchloride. MS: 360 (M-Cl).
[1345] Example 39
[1346] A solution of 80 mg (0.23 mmol) of trans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester in 4.3 ml of methanol was added N-methylpropylamine. Treated with 0.24 ml (2.34 mmol) and stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ S0 ₄ , filtered and evaporated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 95: 5) trans- (1E) -methyl- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} 46 mg (52%) of carbamic acid 4-chloro-phenyl ester were obtained. MS: 379 (MH <^+> , 1Cl).
[1347] The following compounds were prepared from the corresponding chlorides and secondary amines (if the reaction did not complete after 16 hours, the reaction was heated under reflux for 2 hours):
[1348] ExamplecompoundMSMH ⁺ ChlorideSecondary amine 39.1Trans- (1E)-(4- {3- [ethyl- (2-methoxy-ethyl) -amino] -propenyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester409,1 ClTrans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterN- (2-methoxyethyl) ethylamine 39.2Trans- (1E)-(4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propenyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester395,10Trans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterEthyl- (2-hydroxy-ethyl) -amine 39.3Trans- (1E) -methyl- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester413Trans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl esterN-methylpropylamine 39.4Trans- (1E) -N-methyl-N- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide433Trans- (1E) -N- [4- (3-chloro-propenyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfon-amideN-methylpropyl-amine 39.5Trans- (1E) -N- [4- (3-dimethylamino-propenyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide405Trans- (1E) -N- [4- (3-chloro-propenyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfon-amideDimethylamine, 33% 5.6M in EtOH
[1349] 39.6Trans- (1E) -N- {4- [3- (allyl-methyl-amino) -propenyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide431Trans- (1E) -N- [4- (3-chloro-propenyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfon-amideN-allylmethylamine 39.7Trans- (1E) -N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propenyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides405Trans- (1E) -N- [4- (3-chloro-propenyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfon-amideEthyl- (2-hydroxy-ethyl) -amine 39.8Trans- (1E)-[4- (3-dimethylamino-propenyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester385Trans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl esterDimethylamine, 33% 5.6M in EtOH 39.9Trans- (1E)-[4- (3-dimethylamino-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester351,1 ClTrans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterDimethylamine, 33% 5.6M in EtOH 39.10Trans- (1E) -methyl- [4- (3-piperidin-1-yl-propenyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester391,1 ClTrans- (1E)-[4- (3-chloro-propenyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl esterPiperidine
[1350] Example 40
[1351] 40.1
[1352] A solution of 10.0 g (25.2 mmol) of trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 400 ml of THF was dissolved in BuLi (hexane) at -78 ° C. About 1.6 M) treated with 33.0 ml (68.3 mmol) and stirred for 2 hours, then 27.8 ml (230.4 mmol) of DMPU were added and after 10 minutes 2- (2-bromoethoxy) tetrahydro-2H- dissolved in 20 ml 19.0 ml (125.9 mmol) of piran were added dropwise for 20 minutes. The reaction was warmed to room temperature and stirred overnight (about 16 hours). An aqueous solution of saturated NH ₄ Cl was added and the mixture was extracted with ether (3 ×). The organic phase was washed with H ₂ O (2 ×), aqueous 10% NaCl, dried over Na ₂ SO ₄ , filtered and evaporated to flash column chromatography on silica gel (hexane / EtOAc 19: 1-3: 1 ) 3.5 g (38%) of trans-methyl- {4- [4- (tetrahydro-pyran-2-yloxy) -but-1-ynyl] -cyclohexyl} -carbamic acid tert-butyl ester were obtained. MS: 366 (MH ⁺ ).
[1353] 40.2
[1354] 3.45 g (9.44 mmol) of trans-methyl- {4- [4- (tetrahydro-pyran-2-yloxy) -but-1-ynyl] -cyclohexyl} -carbamic acid tert-butyl ester in 25 ml of MeOH and A solution of 0.7 g (2.83 mmol) of pyridiumdium toluene-4-sulfonate was stirred at 55 ° C. for 1.5 h. The reaction was partitioned between an aqueous solution of 10% KHSO ₄ / ether (3 ×). The organic phase was washed with aqueous saturated NaHCO ₃ , 10% NaCl, dried over Na ₂ SO ₄ and evaporated to trans- [4- (4-hydroxy-but-1-ynyl) -cyclohexyl] -methyl-carbamic acid 2.85 g (quant.) of tert-butyl ester were obtained. MS: 281 (M).
[1355] 40.3
[1356] A solution of 2.66 g (9.44 mmol) of trans- [4- (4-hydroxy-but-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 75 ml of CH ₂ Cl ₂ was methane at 0 ° C. Treated with 0.81 ml (10.38 mmol) of sulfonylchloride, 1.14 ml (14.16 mmol) of pyridine and 1.15 g (9.44 mmol) of DMAP. The reaction mixture was stirred at rt for 3 h, water (19 ml) was added and the reaction stirred for 5 min. After extraction with aqueous 10% KHSO ₄ / Et ₂ O (3 ×), the organic phase is washed with aqueous saturated NaHCO ₃ (2 ×), aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to trans-methanesulfonic acid 3.57 g (quantitative) of 4- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -but-3-ynyl ester were obtained. MS: 360 (MH ⁺ ).
[1357] 40.4
[1358] Similar to Example 32.1, trans-methanesulfonic acid 4- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -but-3-ynyl ester with TFA was applied to trans-methanesulfonic acid 4 -(4-methylamino-cyclohexyl) -but-3-ynyl ester trifluoroacetate. MS: 260 (MH ⁺ ).
[1359] 40.5
[1360] Similar to Example 32.2, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -but-3-ynyl ester trifluoroacetate and 4-chlorophenylchloroformate were converted to trans-methanesulfonic acid 4- {4-[(4-Chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -but-3-ynyl ester. MS: 414 (MH <^+> , 1Cl).
[1361] 40.6
[1362] Similar to Example 32.2, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -but-3-ynyl ester trifluoroacetate and 4-trifluoromethylphenylchloroformate were trans-methanesulfonic acid 4- {4- [Methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -but-3-ynyl ester was converted and used directly in the next reaction.
[1363] 40.7
[1364] Similar to Example 32.2, trans-methanesulfonic acid 4- (4-methylamino-cyclohexyl) -but-3-ynyl ester trifluoroacetate and 4- (trifluoromethyl) benzenesulfonylchloride were trans- Methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -but-3-ynyl ester. MS: 468 (MH ⁺ ).
[1365] Example 41
[1366] 400 mg of crude trans-methanesulfonic acid 4- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -but-3-ynyl ester in 4 ml of methanol (corresponding to 0.69 mmol) The solution of was treated with 1.23 ml (6.88 mmol) of dimethylamine (33% in EtOH, 5.6M) and stirred overnight at room temperature. The reaction was heated at 70 ° C. for 2 hours, cooled, evaporated and the residue extracted with aqueous saturated NaHCO ₃ / Et ₂ O (3 ×). The organic phase was dried over Na ₂ S0 ₄ , filtered and evaporated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 99: 1-9: 1) trans- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -methyl-ca 84 mg (34%) of chest acid 4-chloro-phenyl ester were obtained. MS: 363 (MH <^+> , 1Cl).
[1367] The following compounds were prepared from the corresponding mesylate and secondary amines (if the reaction did not complete after 16 hours, additional amine (10 equiv) and catalytic amount of NaI were added. Heated under reflux until the reaction was complete. In some cases DMA was used instead of MeOH as solvent):
[1368] ExamplecompoundMSMH ⁺ MesylateSecondary amine 41.1Trans- {4- [4- (allyl-methyl-amino) -but-1-ynyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester389,10Trans-methanesulfonic acid 4- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -but-3-ynyl esterN-allylmethylamine 41.2Trans-methyl- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester391,1C1Trans-methanesulfonic acid 4- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -but-3-ynyl esterN-methylpropyl-amine 41.3Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester407, ICITrans-methanesulfonic acid 4- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -but-3-ynyl esterEthyl- (2-hydroxy-ethyl) -amine 41.4Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester441Trans-methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -but-3-ynyl esterEthyl- (2-hydroxy-ethyl) -amine 41.5Trans- {4- [4- (allyl-methyl-amino) -but-1-ynyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenylester423Trans-methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -but-3-ynyl esterN-allylmethylamine
[1369] 41.6Trans- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester397Trans-methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -but-3-ynyl esterDimethylamine, 33% 5.6M in EtOH 41.7Trans-methyl- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -carbamic acid 4-trifluoromethyl-phenyl ester425Trans-methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-phenoxycarbonyl) -amino] -cyclohexyl} -but-3-ynyl esterN-methylpropyl-amine 41.8Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide461Trans-methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -but-3-ynyl esterEthyl- (2-hydroxy-ethyl) -amine 41.9Trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide445Trans-methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -but-3-ynyl esterN-methylpropyl-amine 41.10Trans-N- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide417Trans-methanesulfonic acid 4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -but-3-ynyl esterDimethylamine, 33% 5.6M in EtOH
[1370] Example 42
[1371] 42.1
[1372] Similar to Example 40.1, trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester and 1-chloro-3-iodopropane were trans- [ 4- (5-Chloro-pent-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester was used directly in the next step without purification.
[1373] 42.2
[1374] Similar to Example 32.1, trans- [4- (5-chloro-pent-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester was converted to trans- [4- (5-chloro-pent-1 -Ynyl) -cyclohexyl] -methyl-ammonium trifluoroacetate. The salt was dissolved in water and washed with Et ₂ O (3 ×) to purify the compound. The aqueous phase was adjusted to pH 8 (using aqueous saturated NaHCO ₃ ) and extracted with EtOAc (3 ×) to afford trans- [4- (5-chloro-pent-1-ynyl) -cyclohexyl] -methyl-amine. . MS: 314 (MH <^+> , 1Cl).
[1375] 42.3
[1376] Similar to Example 32.2, trans- [4- (5-chloro-pent-1-ynyl) -cyclohexyl] -methyl-amine and 4- (trifluoromethyl) benzenesulfonylchloride were converted to trans-N- [ 4- (5-chloro-pent-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide. MS: 356 (M- [SO ₂ + H]).
[1377] 42.4
[1378] 250 mg (0.59 mmol of trans-N- [4- (5-chloro-pent-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide in 10 ml of butan-2-one ) Was treated with 136 mg of NaI (0.91 mmol) and heated to 80 ° C. for 48 h. Evaporation gave 330 mg of crude trans-N- [4- (5-iodo-pent-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide which was then taken to the next step. Used directly. MS: 514 (MH ⁺ ).
[1379] Example 43
[1380] 43.1
[1381] Similar to Example 40.1, trans- [4- (2,2-dibromo-vinyl) -cyclohexyl] -methyl} -carbamic acid tert-butyl ester and 2- (3-bromopropoxy) tetrahydro Trans-methyl- {4- [5- (tetrahydro-pyran-2-yloxy) -pent-1-ynyl] -cyclohexyl} -carbamic acid tert-butyl ester was obtained from -2H-pyran. MS: 378 (M-H).
[1382] 43.2
[1383] Similar to Example 40.2, trans- [from trans-methyl- {4- [5- (tetrahydro-pyran-2-yloxy) -pent-1-ynyl] -cyclohexyl} -carbamic acid tert-butyl ester 4- (5-hydroxy-pent-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester was obtained. MS: 296 (MH ⁺ ).
[1384] 43.3
[1385] Similar to Example 40.3, trans-methanesulfonic acid 5- [4- (tert) from trans- [4- (5-hydroxy-pent-1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester -Butoxycarbonyl-methyl-amino) -cyclohexyl] -pent-4-ynyl ester was obtained. MS: 373 (M).
[1386] 43.4
[1387] Similar to Example 32.1, trans-methanesulfonic acid 5- (4 from trans-methanesulfonic acid 5- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -pent-4-ynyl ester -Methylamino-cyclohexyl) -pent-4-ynyl ester trifluoroacetate was obtained. MS: 274 (MH ⁺ ).
[1388] 43.5
[1389] Similar to Example 32.2, trans-methanesulfonic acid 5- (4-methylamino-cyclohexyl) -pent-4-ynyl ester trifluoroacetate and 4-chlorophenylchloroformate from trans-methanesulfonic acid 5- {4-[(4-Chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -pent-4-ynyl ester was obtained. MS: 428 (MH <^+> , 1Cl).
[1390] Example 44
[1391] Corresponds to 320 mg (0.59 mmol) of crude trans-N- [4- (5-iodo-pent-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml of MeOH ) Was treated with 0.6 ml (5.93 mmol) of N-methylpropylamine. The reaction was stirred at 65 ° C. overnight, partitioned between aqueous 1N NaOH / Et ₂ O (3 ×), and the organic phase was dried over Na ₂ SO ₄ and evaporated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ , then CH ₂ Cl ₂ / MeOH 95: 5-9: 1) trans-N-methyl-N- {4- [5- (methyl-propyl- 128 mg (47%, two or more steps) of amino) -pent-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide were obtained. MS: 459 (MH ⁺ ). The following compounds can be obtained similarly:
[1392] ExamplecompoundMSMH ⁺ Iodide or mesylateSecondary amine 44.1Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pent-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide475Trans-N- [4- (5-iodo-pent-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamideEthyl- (2-hydroxy-ethyl) -amine 44.2Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pent-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester421,1ClTrans-methanesulfonic acid 5- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -pent-4-ynyl esterEthyl- (2-hydroxy-ethyl) -amine 44.3Trans-methyl- {4- [5- (methyl-propyl-amino) -pent-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester405,10Trans-methanesulfonic acid 5- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -pent-4-ynyl esterN-methylpropylamine 44.4Trans- [4- (5-dimethylamino-pent-1-ynyl) -cyclohexyl] -methyl-carbamic acid 4-chloro-phenyl ester377,1C1Trans-methanesulfonic acid 5- {4-[(4-chloro-phenoxycarbonyl) -methyl-amino] -cyclohexyl} -pent-4-ynyl esterDimethylamine, 33% 5.6M in EtOH
[1393] Example 45
[1394] 45.1
[1395] Similar to Example 26.3, trans- (4-formyl-cyclohexyl) -carbamic acid tert-butyl from trans- [4- (methoxy-methyl-carbamoyl) -cyclohexyl] -carbamic acid tert-butyl ester An ester was obtained, which was used directly in the next reaction.
[1396] 45.2
[1397] A solution of 14.4 g (63.34 mmol) of trans- (4-formyl-cyclohexyl) -carbamic acid tert-butyl ester in 180 ml of 2-methyl-2-butanol was added to (4-bromobutyl) triphenylphosphonium bromide 36.5 g (76.32 mmol) and 82.8 g (254.2 mmol) cesium carbonate and heated at 65 ° C. for 7 h. The reaction was cooled (room temperature), diluted with hexanes / ETOAc (9: 1, 500 ml) and filtered. Purification by flash column chromatography on silica gel (hexane / EtOAc 9: 1) trans- (1E / Z)-[4- (5-bromo-pent-1-enyl) -cyclohexyl] -carbamic acid tert- 16.1 g (73%) of butyl ester were obtained. MS: 289 (M-butene, 1 Br).
[1398] 45.3
[1399] A solution of 14.0 g (40.4 mmol) of trans- (1E / Z)-[4- (5-bromo-pent-1-enyl) -cyclohexyl] -carbamic acid tert-butyl ester in 140 ml of EtOH was added with 7 ml of AcOH. And Pt / C 5% 1.4 g and hydrogenated with H ₂ (1 atm) for 1.5 hours. The reaction was filtered and evaporated (1 × toluene). The residue was dissolved in MeOH (105 ml) at room temperature and treated with 15.5 ml of water. After cooling (0 ° C.) and filtration, 7.43 g (53%) of trans- [4- (5-bromo-pentyl) -cyclohexyl] -carbamic acid tert-butyl ester were obtained. MS: 291 (M-butene, 1 Br).
[1400] 45.4
[1401] At 0 ° C., a solution of 4.4 g (12.63 mmol) of trans- [4- (5-bromo-pentyl) -cyclohexyl] -carbamic acid tert-butyl ester dissolved in 9 ml of MeOH was added with a solution of HBr in MeOH (0 ° C.). 4.7 ml (63.07 mmol) of acetylbromide was added dropwise to 35 ml of MeOH) and 40 ml) was added. The suspension was stirred at rt for 16 h, diluted with toluene and evaporated (2 ×). The residue was suspended in EtOAc (40 ml), cooled (-10 to -15 [deg.] C.) and filtered to afford 4.05 g (97%) of trans-4- (5-bromo-pentyl) -cyclohexylamine as hydrobromide salt. It was. MS: 248 (MH <^+> , 1Br).
[1402] 45.5
[1403] A solution of 1.0 g (3.04 mmol) of trans-4- (5-bromo-pentyl) -cyclohexylammonium bromide in 12 ml of CH ₂ Cl ₂ was first cooled to 0 ° C. and 4- (trifluoromethyl) benzenesul Treatment with 0.8 g (3.27 mmol) of polyvinylchloride followed by 1.2 ml (7.01 mmol; 2.3 equiv) of Hunig's base (30 min). After a total of 1.5 hours at 0 ° C., the mixture was dissolved in aqueous 10% KHSO ₄ / TBME (3 ×). The organic phase was washed with aqueous saturated NaHCO ₃ and aqueous 10% NaCl, dried over Na ₂ SO ₄ and evaporated to afford 1.38 g of crude product which was crystallized (CH ₂ Cl ₂ / hexanes) to give pure trans-N- [ 1.26 g (91%) of 4- (5-bromo-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide were obtained. MS: 454 (MH <^-> , 1Br).
[1404] Example 46
[1405] 46.1
[1406] A solution of 2.4 mg (5.26 mmol) of trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide in 36 ml of EtOH was dissolved in ethyl- (2-hydroxy 2.1 ml (21.53 mmol) of -ethyl) -amine, 1.8 g (21.43 mmol) of NaHCO ₃ were stirred and stirred at 90 ° C. overnight. The reaction was cooled, filtered, evaporated and the residue extracted with aqueous saturated NaHCO ₃ / EtOAc (3 ×). The organic phase was washed with aqueous 10% NaCl, dried (Na ₂ SO ₄ ), filtered and evaporated. Purified by flash column chromatography on silica gel (EtOAc / EtOH / NH ₃ 25% 98: 2: 1) trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino]- 1.96 g (80%) of pentyl} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide were obtained. MS: 463 (MH).
[1407] 46.2
[1408] Similar to Example 46.1, trans-N- {4- [5 from trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide and ethanolamine -(2-hydroxy-ethylamino) -pentyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide was obtained. MS: 437 (MH ⁺ ).
[1409] 46.3
[1410] Similar to Example 46.1 but without NaHCO ₃ for 19 hours at 60 ° C., trans-N- [4- (5-bromo-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide and 18 Trans-N- [4- (5-ethylamino-pentyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide was obtained from an equivalent of ethylamine (70% in water). MS: 421 (MH ⁺ ).
[1411] Example 47
[1412] 47.1
[1413] Cis-4-methylamino-cyclohexanol in 775 ml of EtOAc (Schut, Robert N. Analgesic 3- (Methylamino) -1,2,3,4-tetrahydrocarbazole from 4- (methylamino) cyclohexanone.Fr. (1968 ), 3 pp. FR 1515629 19680301) 100 g (774 mmol) of a well stirred solution was treated with 1.55 L of aqueous 1M NaHCO ₃ and 110 ml (774 mmol) of benzyl chloroformate (30 min, Tmax 30 ° C.). . After 2 hours the phases were separated at room temperature. The aqueous phase was extracted (EtOAc) and the organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated. Purification by chromatography on silica gel (hexane / EtOAc 2: 1) yielded 139 g (68%) of cis- (4-hydroxy-cyclohexyl) -methyl-carbamic acid benzyl ester. MS: 263 (M).
[1414] 47.2
[1415] A solution of 2.63 g (10 mmol) of cis- (4-hydroxy-cyclohexyl) -methyl-carbamic acid benzyl ester in 16 ml of CH ₂ Cl ₂ was added 0.24 g (2 mmol) of KBr and 0.28 g of NaHCO ₃ in 5 ml of water. (3.33 mmol) in solution. The suspension was cooled (0-5 ° C.) and 8 mg (0.05 mmol) of TEMPO followed by 5.7 ml (12.5 mmol) of NaOCl (13%, 2.18 M in water) was added for 20 minutes. After 1 h at this temperature, 8 mg (0.05 mmol) of TEMPO and then 2.85 ml (6.25 mmol) of NaOCl (13%, 2.18 M in water) were added. After 1 hour 5 ml of 1 M sodium thiosulfate solution was added. The aqueous phase is extracted with CH ₂ Cl ₂ (2 ×), the organic phase is dried (Na ₂ SO ₄ ), filtered and evaporated to 2.57 g (99) methyl- (4-oxo-cyclohexyl) -carbamic acid benzyl ester %) Was obtained. MS: 261 (M).
[1416] 47.3
[1417] A suspension of 749.88 g (2187.5 mmol) of (methoxymethyl) triphenylphosphonium chloride in 2.5 L of THF was cooled to −10 ° C. and deprotonated with 245.5 g (2187.5 mmol) of potassium t-butoxide. The dark red solution was stirred at 0-5 ° C. for 0.5 h, cooled to −20 ° C. and 457.32 g (261.33 mmol) of methyl- (4-oxo-cyclohexyl) -carbamic acid benzyl ester in 1.25 L of THF were subjected to a period of 1.25 h. Was added over. After 1.3 hours at room temperature, the reaction was treated with 1.75 L of aqueous 1M NaHCO ₃ and stirred for 45 minutes. The phases were separated and the aqueous phase was extracted with TBME (700 ml) and the organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was suspended in hexane (5 L), cooled (0 ° C.), filtered and evaporated to give 495.2 g (98%) of (4-methoxymethylene-cyclohexyl) -methyl-carbamic acid benzyl ester. MS: 289 (M).
[1418] 47.4
[1419] A solution of 495 g (1710.6 mmol) of (4-methoxymethylene-cyclohexyl) -methyl-carbamic acid benzyl ester in 1.7 L of THF was treated with 3.42 L of aqueous 1N HCl at room temperature and heated at reflux for 2 hours. The reaction was cooled to rt and extracted with TBME (1.7 and 0.9 L). The organic phase was washed with aqueous 1M NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and evaporated to afford crude (4-formyl-cyclohexyl) -methyl-carbamic acid benzyl ester (trans: cis about 70:30). 457.4 g (97%) was obtained.
[1420] A solution of 133.2 g (483.7 mmol) of crude (4-formyl-cyclohexyl) -methyl-carbamic acid benzyl ester in 330 ml of MeOH was treated with 24 ml of 1M NaOH and stirred at room temperature for 0.5 h, followed by 1.40 ml of acetic acid ( 24.2 mmol) was added and the mixture was evaporated to give 144.2 g of crude (4-formyl-cyclohexyl) -methyl-carbamic acid benzyl ester as an oil (trans: cis about 92: 8). A solution of 144.2 g of crude (4-formyl-cyclohexyl) methyl-carbamic acid benzyl ester in 670 ml of TBME was added to a solution of 184.0 g (968 mmol) of disodium pyrosulphite in 670 ml of water at room temperature. The reaction was stirred at rt for 16 h, filtered and washed (TBME 200 ml) to afford 147.2 g of sodium salt of [4- (benzyloxycarbonyl-methyl-amino) -cyclohexyl] -hydroxy-methanesulfonic acid It was. This compound was suspended in 250 ml TBME and 780 ml aqueous 1M Na ₂ CO ₃ and stirred at room temperature for 0.25 hours. The phases were separated and the aqueous phase was extracted with TBME (250 ml), the organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to trans- (4-formyl-cyclohexyl) -methyl-carbamic acid benzyl 98.9 g (72% over 2 steps) of ester (trans: cis 99.3: 0.7) were obtained. MS: 275 (M).
[1421] 47.5
[1422] A solution of 126.5 g (459.4 mmol) of trans- (4-formyl-cyclohexyl) -methyl-carbamic acid benzyl ester in 1.27 L of 2-methyl-2-butanol was dissolved in (4-bromobutyl) triphenylphosphonium bromide 263.6 g (551.3 mmol) and 254 g (1838 mmol) K ₂ C0 ₃ and heated at reflux for 3.5 h. The reaction was cooled (room temperature), filtered and evaporated. The residue was suspended in hexane (1.8 L, first at room temperature and then at 0 ° C.) and filtered. Purification by chromatography on silica gel (hexane / EtOAc 4: 1) trans- (1E / Z)-[4- (5-bromo-pent-1-enyl) -cyclohexyl] -methyl-carbamic acid benzyl 149.9 g (83%) of ester were obtained. MS: 293 (M, 1 Br).
[1423] 47.6
[1424] A solution of 38.61 g (97.9 mmol) of trans- (1E / Z)-[4- (5-bromo-pent-1-enyl) -cyclohexyl] -methyl-carbamic acid benzyl ester in 500 ml of toluene was dissolved in Pt / C. Treated with 4.5% of 5% and hydrogenated with H ₂ (1 atm) for 3 days. The reaction was filtered and evaporated to give 36.06 g (93%) of trans- [4- (5-bromo-pentyl) -cyclohexyl] -methyl-carbamic acid benzyl ester. MS: 396 (MH <^+> , 1Br).
[1425] 47.7
[1426] 22.55 g (56.89 mmol) of trans- [4- (5-bromo-pentyl) -cyclohexyl] -methyl-carbamic acid benzyl ester were dissolved in 100 ml of HBr (33% acetic acid) at room temperature. After 20 minutes, the reaction was evaporated, suspended in toluene (2 ×) and evaporated again. The suspension was dissolved in hexane and filtered to yield 17.49 g (90%) of trans- [4- (5-bromo-pentyl) -cyclohexyl] -methyl-amine hydrobromide. MS: 262 (MH <^+> , 1Br).
[1427] 47.8
[1428] Similar to 32.2, trans- [4- (5-bromo-pentyl) -cyclohexyl] -methyl-amine hydrobromide and 4-trifluoromethylphenylchloroformate were converted to trans- [4- (5-bromo- Pentyl) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester. MS: 450 (MH <^+> , 1Br).
[1429] 47.9
[1430] Similar to 32.2, trans- [4- (5-bromo-pentyl) -cyclohexyl] -methyl-amine hydrobromide and 4- (trifluoromethyl) benzenesulfonylchloride were converted to trans-N- [4- ( 5-Bromo-pentyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide. MS: 470 (MH <^+> , 1Br).
[1431] 47.10
[1432] Similar to Examples 47.5-7, 47.9 and 46.1, trans-N- (4- {5- [ethyl- (2-) from trans / cis- (4-formyl-cyclohexyl) -methyl-carbamic acid benzyl ester Hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and cis-N- (4- {5- [ethyl- (2-hydroxy- Ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide RO-72-5688 / 000 (MS: 479 (MH ⁺ )) was prepared, which gave HPLC ( ChiralpakAD, 20 um 5 × 50 cm von Daicel Chem. Industrie Ltd, eluent: 8.0 l n-heptane / 2.0 l ethanol und 0.1% CF ₃ COOH).
[1433] Example 48
[1434] Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl- in 6 ml of CH ₂ Cl ₂ To 500 mg (10.5 mmol) of benzenesulfonamide was added 0.2 ml (1.6 mmol) of DAST at -78 ° C. After 3.5 h at this temperature additional 0.2 ml (1.6 mmol) of DAST were added and the mixture was allowed to slowly warm to room temperature overnight. The solution was added to a cooled aqueous solution of Na ₂ CO ₃ and extracted with EtOAc. The organic phase was washed with brine and dried over Na ₂ SO ₄ . Column chromatography (CH ₂ Cl ₂ / MeOH 98: 2) trans-N- (4- {5- [ethyl- (2-fluoro-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl 125.4 mg (25%) of 4-trifluoromethyl-benzenesulfonamide were obtained as brown oil. MS: 481 (MH ⁺ ).
[1435] Example 49
[1436] 49.1
[1437] 344 mg of 2-diethylamino-ethylchloride.hydrochloride in 350 mg (1 mmol) of trans-4-bromo-N- (4-hydroxycyclohexyl) -N-methyl-benzenesulfonamide in 6 ml of toluene. (2.0 mmol) and a catalytic amount of Bu ₄ NHSO ₄ were added followed by 4 ml of 50% NaOH. The mixture was stirred at rt overnight, the phases were separated and the organic phase was dried over Na ₂ SO ₄ . Column chromatography on silica gel with CH ₂ Cl ₂ / MeOH 15: 1 to trans-4-bromo-N- [4- (2-diethylamino-ethoxy) -cyclohexyl] -N-methyl-benzenesulfon 380 mg (84%) of amide were obtained as a light yellow oil. MS: 447 (MH <^+> , 1Br).
[1438] 49.2
[1439] Similar to Example 49.1, trans-bromo-N- (4-hydroxycyclohexyl) -N-methyl-benzenesulfonamide and 1- (2-chloroethyl) -piperidine HCl were trans- 4-Bromo-N-methyl-N- [4- (2-piperidin-1-yl-ethoxy) -cyclohexyl] -benzenesulfonamide was prepared as a light yellow oil. MS: 459 (MH <^+> , 1Br).
[1440] 49.3
[1441] Similar to Example 49.1, Trans-4 from trans-4-bromo-N- (4-hydroxycyclohexyl) -N-methyl-benzenesulfonamide and 4- (2-chloroethyl) morpholine hydrochloride -Bromo-N-methyl-N- [4- (2-morpholin-4-yl-ethoxy) -cyclohexyl] -benzenesulfonamide was prepared as a colorless oil. MS: 461 (MH <^+> , 1Br).
[1442] 49.4
[1443] Similar to Example 49.1, trans-4-bromo-N- (4-hydroxycyclohexyl) -N-methyl-benzenesulfonamide and chlorethylpyrroline. Trans-4-bromo-N from hydrochloride -Methyl-N- [4- (2-pyrrolidin-1-yl-ethoxy) -cyclohexyl] -benzenesulfonamide was prepared as a colorless oil. MS: 445 (MH <^+> , 1Br).
[1444] 49.5
[1445] Similar to Example 49.1, trans-4-bromo-N- (4-hydroxycyclohexyl) -N-methyl-benzenesulfonamide and diisopropylaminoethylchloride. -N- [4- (2-diisopropylamino-ethoxy) -cyclohexyl] -N-methyl-benzenesulfonamide was prepared as a colorless oil. MS: 475 (MH <^+> , 1Br).
[1446] 49.6
[1447] Similar to Example 49.1, trans-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and diethylaminoethylchloride. 4- (2-Diethylamino-ethoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was prepared as a light yellow oil. MS: 437 (MH ⁺ ).
[1448] 49.7
[1449] Similar to Example 49.1, trans-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and 1- (2-chloroethyl) piperidine. Trans-N-methyl-N- [4- (2-piperidin-1-yl-ethoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide was prepared as a light yellow oil. MS: 449 (MH ⁺ ).
[1450] 49.8
[1451] Similar to Example 49.1, trans-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and diisopropylaminoethylchloride. [4- (2-Diisopropylamino-ethoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was prepared as a light yellow oil. MS: 465 (MH ⁺ ).
[1452] 49.9
[1453] Similar to Example 49.1, trans-N- (4-hydroxy-cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and chloroethylpyrrolidine. -N- [4- (2-pyrrolidin-1-yl-ethoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide was prepared as a light yellow oil. MS: 435 (MH ⁺ ).
[1454] 49.10
[1455] Similar to Example 49.1, trans-N- from 4-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide and 4-chloroethylmorpholine-hydrochloride Methyl-N- [4- (2-morpholin-4-yl-ethoxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide was prepared as a colorless oil. MS: 451 (MH ⁺ ).
[1456] Example 50
[1457] 50.1
[1458] (1,4-dioxa-spiro [4.5] dec-8-yl) -methyl-amine (eg, reductive amination: Avenell, Kim Y .; Boyfield, Izzy; Hadley, Michael S .; Johnson, Christopher N. ; Nash, David J .; Riley, Graham J .; Stemp, Geoffrey; BMCLE8; Bioorg.Med.Chem.Lett .; EN; 9; 18; 1999; 2715-2720.) 1.71 g (10 mmol) in 1M HCl Stir at 20 ml (20 mmol) for 1 hour. 2.12 g (20 mmol) of Na ₂ CO _{3 was added} at room temperature, followed by 2.4 g (11.0 mmol) of di-tert.butyldicarbonate in 20 ml of EtOAc. The solution was stirred at rt for 4 h, the phases were separated and the inorganic phase was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ and concentrated. Crystallization from methylcyclohexane gave 0.95 g (42%) of methyl- (4-oxo-cyclohexyl) -carbamic acid tert-butyl ester.
[1459] 50.2
[1460] 5 g (21.99 mmol) of methyl- (4-oxo-cyclohexyl) -carbamic acid tert-butyl ester and 12.68 g (28.59 mmol) of (4-carboxy-butyl) -triphenyl-phosphonium bromide are dispersed in 50 ml of DMF I was. A small portion of 2.49 g (57.2 mmol, 55%) of NaH was added and 50 ml of DMF was added to the slurry to dilute. The mixture was stirred at rt overnight, 10 ml of AcOH was added and the solvent was evaporated under reduced pressure. The residue was dissolved in ether and water and the inorganic layer was extracted with ether. The combined organic phases were dried and the crude was purified by column chromatography with ETOAc / hexanes to give 5.86 g of 5- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexylidene] -pentanoic acid ( 83%) was obtained.
[1461] 50.3
[1462] 5.0 g (16.1 mmol) of 5- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexylidene] -pentanoic acid in 50 ml of methanol was diluted with 0.94 ml (16.9 mmol, 1.05 equiv) of sodium methanolate. Hydrogenated at room temperature for 1 hour with 0.5 g of 10% Pd / C in the presence. After filtration and evaporation of the solvent, the residue was dissolved in ether and acidified with 1M HCl. The organic phase was extracted with water, dried over MgSO ₄ and evaporated to give 5.3 g (quantitative) of trans-5- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -pentanoic acid as a light yellow oil. Obtained. MS: (312 MH ⁺ ).
[1463] 50.4
[1464] To 1 g (3.19 mmol) of trans-5- [4- (tert-butoxycarbonyl-methyl-amino) -cyclohexyl] -pentanoic acid in 37 ml of CH ₂ Cl ₂ 0.5 ml (4.8 mmol, 1.5) of diethylamine Equivalent) and 0.53 ml (4.79 mmol, 1.5 equiv) of NMM were added. The solution was cooled to 0 ° C. and 795 mg (4.15 mmol, 1.3 equiv) of EDCI and 98 mg (6.4 mmol) of HOBT were added. The mixture was stirred at rt overnight and partitioned between saturated aqueous solutions of CH ₂ Cl ₂ and NaHCO ₃ . The organic phase was washed with KHSO ₄ and brine, dried over Na ₂ SO ₄ and evaporated. Column chromatography with EtOAc / hexanes 1: 1 gives 1.05 g (86%) of trans- [4- (4-diethylcarbamoyl-butyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester as a colorless liquid It was. MS: 369 (MH ⁺ ).
[1465] 50.5
[1466] 0.99 g (2.7 mmol) of trans- [4- (4-diethylcarbamoyl-butyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester in 5 ml of dioxane was charged with 7 ml of 4M HCl in dioxane at 0 ° C. Was added in. The solution was stirred at rt for 2 h, diluted with ether and the precipitated solid was separated. Trans-5- (4-methylamino-cyclohexyl) -pentanoic acid diethylamide. 0.83 g (quant.) Of hydrochloride was isolated as a white solid. mp. 122 ° C., MS: 269 (MH ⁺ ).
[1467] 50.6
[1468] Trans-5- (4-methylamino-cyclohexyl) -pentanoic acid diethylamide in 20 ml of CH ₂ Cl _2. 0.8 g (2.6 mmol) of hydrochloride was added 1.1 ml (6.3 mmol, 2.4 equiv) of Hunig's base, CH Treatment was performed with 706 mg (2.9 mmol, 1.1 equiv) and 32 mg (0.26 mmol, 0.1 equiv) of 4- (trifluoromethyl) benzenesulfonyl chloride in 10 ml of ₂ Cl ₂ . The solution was stirred at rt overnight. Additional 1.1 mg (6.3 mmol) of Hunig's base, 706 mg (2.9 mmol) of 4- (trifluoromethyl) benzenesulfonyl chloride in 10 ml of CH ₂ Cl ₂ were added and 32 mg (0.26 mmol) of DMAP were added for 3 hours. Stirring was continued. The mixture was partitioned between saturated aqueous solutions of CH ₂ Cl ₂ and NaHCO ₃ . The organic phase was washed with water, 1M KHSO ₄ and brine, dried over Na ₂ SO ₄ and evaporated. Column chromatography with EtOAc / hexanes 1: 1: 1.06 g of trans-5- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -pentanoic acid diethylamide %) Was obtained as a colorless oil. MS: 477 (MH ⁺ ).
[1469] 50.7
[1470] Zirconium (IV) in a solution of 200 mg (0.4 mmol) of trans-5- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -pentanoic acid diethylamide in THF 98 mg (4.2 mmol, 1 equiv) of chloride were added at −10 ° C. and the reaction mixture was stirred for an additional 30 minutes. 0.8 ml (25.2 mmol, 6 equiv) of 3M methylmagnesium bromide in THF was added at −10 ° C. and the mixture was slowly warmed to room temperature. After 2 hours the mixture was added to a mixture of 30% NaOH and CH ₂ Cl ₂ . The inorganic phase was extracted with CH ₂ Cl ₂ and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by ion exchange resin (Varian, SCX resin) to give trans-N- [4- (5-diethylamino-5-methyl-hexyl) -cyclohexyl] -N-methyl-4-trifluoromethyl- 133 mg (65%) of benzenesulfonamide were obtained as a colorless oil. MS: 491 (MH ⁺ ).
[1471] 50.8
[1472] Similar to Example 50.4, trans-N- from trans-5- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyl} -pentanoic acid diethylamide and ethylmagnesium bromide {4- [4- (1-Diethylamino-cyclopropyl) -butyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide was prepared as a yellow oil. MS: 489 (MH ⁺ ).
[1473] 50.9
[1474] Similar to Example 50.4, trans- [4- (3-dimethylamino-3-methyl-boot from trans- (4-dimethylcarbamoylethynyl-cyclohexyl) -methyl-carbamic acid tert-butyl ester and methyl magnesium bromide -1-ynyl) -cyclohexyl] -methyl-carbamic acid tert-butyl ester was prepared as a yellow oil. MS: 323 (MH <^+> ).
[1475] Example 51
[1476] 51.1
[1477] To a solution of 0.62 g (5.9 mmol) of methyl β-hydroxypropionate in 4.5 ml of CH ₂ Cl ₂ was added 1.4 ml (6.4 mmol, 2.4 equivalents) of 2,6-di-tert-butylpyridine, followed by trifluoro. 1.03 ml (6.2 mmol, 2.4 equiv) of methane sulfonic anhydride were added at 0 ° C. The solution stirred at this temperature for 2.5 hours was concentrated and the residue was dissolved in 5 ml of nitromethane. To this solution 1 g (2.96 mmol) of trans-N- (4-hydroxycyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide in 10 ml of nitromethane and 2,6-di-tert 1.3 ml (5.9 mmol, 2.0 equiv) of butylpyridine were added. The solution was stirred at 60 ° C. for 3 h and diluted with EtOAc and 1M KHSO ₄ . The inorganic phase was extracted with EtOAc, and the combined organic phases were washed with saturated aqueous solution of NaHCO ₃ , brine, dried over Na ₂ SO ₄ and evaporated. 1.2 g of trans-3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -methyl propionate by column chromatography on silica gel with EtOAc / hexanes 1: 3 (95%) was obtained as a light yellow oil. MS: 424 (MH ⁺ ).
[1478] 51.2
[1479] 1.14 g (2.7 mmol) of trans-3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -propionic acid methyl ester in 27 ml of THF was added 27 ml of 1 M LiOH. Treated at room temperature for 1 hour. To this was added 1M KHSO ₄ acidified and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ and evaporated to trans-3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -propionic acid 1.1 g (quantitative) was obtained as a colorless oil. MS: 408 (MH) ^- .
[1480] 51.3
[1481] 1.1 g (2.7 mmol) of trans-3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -propionic acid in 30 ml of CH ₂ Cl ₂ was dissolved in 2M of THF. Treated with 2 ml (4.0 mmol, 1.5 equiv) of dimethylamine and 0.44 ml (4.03 mmol, 1.5 equiv) of NMM. The solution was cooled to 0 ° C. and 670 mg (3.5 mmol, 1.3 equiv) of EDCI and 82 mg (5.4 mmol, 0.2 equiv) of HOBT were added. The mixture was stirred at rt overnight and partitioned between saturated aqueous solutions of CH ₂ Cl ₂ and NaHCO ₃ . The organic phase was washed with KHSO ₄ and brine, dried over Na ₂ SO ₄ and evaporated. Column chromatography with EtOAc, 1.06 g (90) of trans-N, N-dimethyl-3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -propionamide %) Was obtained as a white solid. mp 88 ° C., MS: 437 (MH ⁺ ).
[1482] 51.4
[1483] Similar to Example 50.4, trans-N, N-dimethyl-3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -propionamide and methylmagnesium From bromide, trans-N- [4- (3-dimethylamino-3-methyl-butoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide was prepared as a colorless oil. MS: 451 (MH ⁺ ).
[1484] 51.5
[1485] Similar to Example 50.4, trans-N, N-dimethyl-3- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -propionamide and ethylmagnesium Obtain trans-N- {4- [2- (1-dimethylamino-cyclopropyl) -ethoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide from bromide as light yellow oil It was. MS: 449 (MH ⁺ ).
[1486] Example 52
[1487] 52.1
[1488] To 1.0 g (2.18 mmol) of trans-N- [4- (3-bromo-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide in 10 ml of acetonitrile 5 0.29 ml (3.1 mmol) of acetocyanhydrin in ml and 0.37 ml (2.5 mmol) of 1,8-diazabicyclo- (5,4,0) -undec-7-ene in 5 ml of acetonitrile were added. The solution was stirred at rt overnight. An additional amount of acetocyanhydrin and 1,8-diazabicyclo- (5,4,0) -undec-7-ene was added and the solution was stirred at 50 ° C. for 6 hours. The mixture was concentrated and dissolved in water / ether. The organic phase was washed with brine, dried over Na ₂ SO ₄ and evaporated to trans-N- [4- (3-cyano-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzene 366 mg (41%) of sulfonamide were obtained as a light yellow oil. MS: 404 (M).
[1489] 52.2
[1490] 0.35 g (0.87 mmol) of trans-N- [4- (3-cyano-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml of ethanol was cooled with HCl gas. Treatment for 20 minutes at. The mixture was maintained at −20 ° C. for 48 hours and concentrated under reduced pressure to trans-4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -butyric 400 mg (quant.) Of methamic acid ethyl ester was obtained as a light brown oil. MS: 451 (MH ⁺ ).
[1491] 52.3
[1492] 400 mg (0.89 mmol) of trans-4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -butylimide acid ethyl ester were suspended in 10 ml of water. And heated at 100 ° C. for 2.5 h. EtOAc was added and the inorganic phase was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ and evaporated to trans-4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -butyric acid ethyl ester 355 mg (89%) was obtained as a yellow oil. MS: 452 (MH ⁺ ).
[1493] 52.4
[1494] 350 mg (0.78 mmol) of trans-4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -butyric acid ethyl ester in 3.5 ml of ethanol were added to 3.5 ml of 1 M LiOH. Treated at 60 ° C. for 2 hours. 2M HCl was added (pH 1-2), the mixture was extracted with CH ₂ Cl ₂ , the combined organic phases were washed with brine and dried over Na ₂ SO ₄ and evaporated to trans-4- {4- [methyl- 250 mg (76%) of (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -butyric acid were obtained as a grayish white solid. MS: 422 (MH ^-).
[1495] 52.5
[1496] 0.33 ml of NMM in 250 mg (0.59 mmol) of trans-4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -butyric acid in 7 ml of CH ₂ Cl ₂ (2.95 mmol), HOBT 18 mg (0.12 mmol, 0.2 equiv), 147 mg (0.77 mmol, 1.3 equiv) EDCI-hydrochloride and 127 mg (1.3 mmol, 2.2 equiv) N-methoxymethylamine hydro-chloride Treated. The mixture was stirred at rt for 3 h, acidified by addition of 1M KHSO ₄ and extracted with CH ₂ Cl ₂ . The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and evaporated to trans-N-methoxy-N-methyl-4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) 260 mg (94%) of -amino] -cyclohexyloxy} -butyramide were obtained as a light yellow oil. MS: 467 (MH ⁺ ).
[1497] 52.6
[1498] 260 mg of trans-N-methoxy-N-methyl-4- {4- [methyl- (4-trifluoromethyl-benzenesulfonyl) -amino] -cyclohexyloxy} -butyramide in 10 ml of THF To (0.56 mmol), 0.56 ml (1.67 mmol, 3 equiv) of 3M methylmagnesium bromide in THF was added at -78 ° C. The solution was slowly warmed to room temperature overnight, saturated aqueous solution of NH ₄ Cl was added and the mixture was stirred for 30 minutes. The phases were separated and the inorganic phase was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ and evaporated. 143 mg of trans-N-methyl-N- [4- (4-oxo-pentyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide on column silica column with EtOAc / hexane 1: 1 on silica gel (61%) was obtained as a white solid. MS: 422 (MH ⁺ ).
[1499] 52.7
[1500] 70 mg (0.17 mmol) of trans-N-methyl-N- [4- (4-oxo-pentyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide in 31 μM of dimethylamine (30% in ethanol , 0.17 mmol) and 61 μM (0.17 mmol) of tetraisopropyl ortho titanate. The solution was stirred at rt for 18 h, and additional 31 μM of dimethylamine (30% in ethanol, 0.17 mmol) and 61 μM (0.17 mmol) of tetraisopropyl ortho titanate were added and stirring continued for 2 hours. The mixture was diluted with 1.7 ml of ethanol and 7 mg (0.1 mmol) of NaCNBH ₃ were added and stirring continued overnight. 0.35 ml of water were added and the suspension was filtered and evaporated. The residue was purified by column chromatography with CH ₂ Cl ₂ / MeOH 9: 1 to trans-N- [4- (4-dimethylamino-pentyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl 13.2 mg (18%) of benzenesulfonamide were obtained as a colorless oil. MS: 451 (MH ⁺ ).
[1501] 52.8
[1502] Similar to Example 52.7, trans-N- from trans-N-methyl-N- [4- (4-oxo-pentyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide and pyrrolidine Methyl-N- [4- (4-piperidin-1-yl-pentyloxy) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide was prepared as a colorless oil. MS: 491 (MH ⁺ ).
[1503] Example A
[1504] Tablets containing the following ingredients can be prepared in a conventional manner:
[1505] ingredientRefined sugar Compound of formula (I)10.0-100.0 mg Lactose125.0 mg Corn starch75.0 mg talc4.0 mg Magnesium stearate1.0 mg
[1506] Example B
[1507] Capsules containing the following ingredients can be prepared in a conventional manner:
[1508] ingredientPer capsule Compound of formula (I)25.0 mg Lactose150.0 mg Corn starch20.0 mg talc5.0 mg
[1509] Example C
[1510] Injection solutions may have the following composition:
[1511] Compound of formula (I)3.0 mg gelatin150.0 mg phenol4.7 mg Water for injectionad 1.0 ml

权利要求:
Claims (41)
[1" claim-type="Currently amended] A compound of formula (I), pharmaceutically acceptable salts and / or pharmaceutically acceptable esters thereof:
Formula I

Where
U is O or a lone pair of electrons,
V is O, S, -CH _2- , -CH = CH-, or -C≡C-,
W is CO, COO, CONR ¹ , CSO, CSNR ¹ , SO ₂ , or SO ₂ NR ¹ ,
m and n are independently from each other 0-7 and m + n is 0-7, when V is O or S, m is not 0,
A ¹ is H, lower-alkyl, hydroxy-lower-alkyl, or lower-alkenyl,
A ² is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, or lower-alkenyl, optionally substituted with R ² ,
A ³ and A ⁴ are hydrogen or lower-alkyl, or
A ¹ and A ² or A ¹ and A ³ are bonded to each other to form a ring and -A ¹ -A ² -or -A ¹ -A ³ -is lower-alkylene or lower-alke optionally substituted with R ² Nylene, wherein one -CH ₂ -group of -A ¹ -A ² -or -A ¹ -A ³ -can optionally be replaced with NR ³ , S, or O, or
A ³ and A ⁴ are bonded to each other to form a ring together with the carbon atom to which they are attached and -A ³ -A ⁴ -is optionally-(CH ₂ ) _2-5 which may be monosubstituted or polysubstituted with lower-alkyl. -ego,
A ⁵ is H, lower-alkyl, lower-alkenyl, or aryl-lower-alkyl,
A ⁶ is lower-alkyl, cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, lower-alkoxy-carbonyl-lower-alkyl,
R ² is hydroxy, hydroxy-lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl, N (R ⁴ , R ⁵ ), or thio-lower-alkoxy,
R ¹ , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen or lower-alkyl.
[2" claim-type="Currently amended] The method of claim 1,
A compound in which A ³ and A ⁴ are bonded to each other to form a ring together with the carbon atom to which they are attached.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
A compound of formula la:
Formula Ia

Wherein U, V, W, m, n, A ¹ , A ² , A ³ , A ⁴ , A ⁵ and A ⁶ have the meanings given in claim 1 or 2.
[4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
A compound wherein U is an isolated electron pair.
[5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
V is O.
[6" claim-type="Currently amended] The method according to any one of claims 1 to 4,
V is -CH _2- .
[7" claim-type="Currently amended] The method according to any one of claims 1 to 4,
V is -C = C-.
[8" claim-type="Currently amended] The method according to any one of claims 1 to 4,
V is -C≡C-.
[9" claim-type="Currently amended] The method according to any one of claims 1 to 8,
W is CO, COO, CONR ¹ , CSNR ¹ , SO ₂ or SO ₂ NR ¹ and R ¹ is hydrogen.
[10" claim-type="Currently amended] The method according to any one of claims 1 to 9,
W is COO or SO ₂ .
[11" claim-type="Currently amended] The method according to any one of claims 1 to 10,
n is 0.
[12" claim-type="Currently amended] The method according to any one of claims 1 to 10,
n is 1;
[13" claim-type="Currently amended] The method according to any one of claims 1 to 12,
m is 1-6.
[14" claim-type="Currently amended] The method according to any one of claims 1 to 12,
m is 0 and V is -C = C- or -C≡C-.
[15" claim-type="Currently amended] The method according to any one of claims 1 to 14,
A ¹ is H, methyl, ethyl, isopropyl, 2-hydroxy-ethyl or 2-propenyl.
[16" claim-type="Currently amended] The method according to any one of claims 1 to 15,
A ² is optionally substituted with R ² a lower-alkyl, cycloalkyl-lower-alkyl or lower-alkenyl, R ² is hydroxy, methoxy or ethoxy carbonyl compounds.
[17" claim-type="Currently amended] The method according to any one of claims 1 to 16,
A ² is methyl, ethyl, 2-hydroxy-ethyl, 2-propenyl, propyl or isopropyl.
[18" claim-type="Currently amended] The method according to any one of claims 1 to 14,
A ¹ and A ² are joined to each other to form a ring, and -A ¹ -A ² -is lower-alkylene or lower-alkenylene optionally substituted with R ² , wherein one of -A ¹ -A ^2- The group —CH ₂ — may optionally be replaced with NR ³ , S or O, and R ² and R ³ are as defined in claim 1.
[19" claim-type="Currently amended] The method of claim 18,
A ¹ and A ² are joined to each other to form a ring, and -A ¹ -A ² -is lower-alkylene or lower-alkenylene optionally substituted with R ² , wherein one of -A ¹ -A ^2- And the —CH ₂ — group may be optionally replaced with O and R ² is hydroxy or 2-hydroxyethyl.
[20" claim-type="Currently amended] The method of claim 19,
A ¹ and A ² are bonded to each other to form a ring, and -A ¹ -A ² -is-(CH ₂ ) _5- .
[21" claim-type="Currently amended] The method according to any one of claims 1 to 20,
A ³ is hydrogen.
[22" claim-type="Currently amended] The method according to any one of claims 1 to 21,
A ⁴ is hydrogen.
[23" claim-type="Currently amended] The method according to any one of claims 1 to 19,
A ³ and A ⁴ are bonded to each other to form a cyclopropyl ring together with the carbon atom to which they are attached, wherein -A ³ -A ⁴ -is-(CH ₂ ) _2- .
[24" claim-type="Currently amended] The method according to any one of claims 1 to 23,
A ⁵ is H, lower-alkyl, lower-alkenyl, or benzyl optionally substituted with halogen.
[25" claim-type="Currently amended] The method according to any one of claims 1 to 24,
A ⁵ is methyl or ethyl.
[26" claim-type="Currently amended] The method according to any one of claims 1 to 25,
A ⁶ is lower-alkyl, lower-alkoxy, lower-alkylcarbonyl, lower-alkoxycarbonyl, fluorine, chlorine, bromine, CN, CF ₃ , NO ₂ , or N (R ⁶ , R ⁷ ), wherein R ⁶ and R ⁷ are independently of each other hydrogen or lower-alkyl) lower-alkyl, cycloalkyl, phenyl, naphthyl, phenyl-lower-alkyl, pyridyl, indole optionally substituted with one or more substituents selected from the group consisting of A compound that is reyl, indolinyl, thienyl, thienyl-methylene, furyl-methylene, benzodioxyl, chinolyl, isoxazolyl, or imidazolyl.
[27" claim-type="Currently amended] The method according to any one of claims 1 to 26,
A ⁶ is phenyl optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine and CF ₃ .
[28" claim-type="Currently amended] The method according to any one of claims 1 to 27,
A ⁶ is 4-chloro-phenyl, 4-bromo-phenyl or 4-trifluoromethyl-phenyl.
[29" claim-type="Currently amended] The method according to any one of claims 1 to 28,
Trans- {4- [6- (allyl-methyl-amino) -hexyloxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
Trans-N- [4- (6-diethylamino-hexyloxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
Trans- {4- [4- (allyl-methyl-amino) -butoxy] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
Trans- {4- [2- (allyl-methyl-amino) -ethylsulfanylmethyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
Trans- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
Trans-N- [4- (3-allylamino-propoxy) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -methyl-carbamic acid 4-bromo-phenyl ester,
Trans-N- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pentyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide,
Trans- [4- (4-dimethylamino-butoxy) -cyclohexyl] -methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
Trans- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl] -methyl-carbamic acid 4-bromo-phenyl ester,
Trans- {4- [3- (allyl-methyl-amino) -prop-1-ynyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester,
Trans-N- {4- [5- (allyl-methyl-amino) -pentyl] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide,
Trans- (4- {3- [ethyl- (2-hydroxyethyl) -amino] -propyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester, and
Trans- {4- [4- (allyl-methyl-amino) -butyl] -cyclohexyl} -methyl-carbamic acid 4-chloro-phenyl ester or a pharmaceutically acceptable salt thereof.
[30" claim-type="Currently amended] The method according to any one of claims 1 to 29,
Trans-N- [4- (4-dimethylamino-but-1-ynyl) -cyclohexyl] -N-methyl-4-trifluoromethyl-benzenesulfonamide,
Trans-methyl- [4- (5-piperidin-1-yl-pentyl) -cyclohexyl] -carbamic acid 4-chloro-phenyl ester,
Trans-methyl- [4- (5-methylamino-pentyl) -cyclohexyl] -carbamic acid 4-trifluoromethyl-phenyl ester,
Trans- (4- {5- [ethyl- (2-hydroxy-ethyl) -amino] -pent-1-ynyl} -cyclohexyl) -methyl-carbamic acid 4-chloro-phenyl ester,
Trans-N-ethyl-N- (4- {4-[(2-hydroxy-ethyl) -methyl-amino] -butoxy} -cyclohexyl) -4-trifluoromethyl-benzenesulfonamide,
Trans- (1E) -N- (4- {3- [ethyl- (2-hydroxy-ethyl) -amino] -propenyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfon amides,
Trans-4-bromo-N- [4- (2-diisopropylamino-ethoxy) -cyclohexyl] -N-methyl-benzenesulfonamide,
Trans-methyl- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -carbamic acid 4-bromo-phenyl ester,
Trans-N-methyl-N- [4- (4-piperidin-1-yl-butyl) -cyclohexyl] -4-trifluoromethyl-benzenesulfonamide,
Trans-N- (4- {4- [bis- (2-hydroxy-ethyl) -amino] -butoxy} -cyclohexyl) -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
Trans-4-bromo-N-methyl-N- [4- (2-piperidin-1-yl-ethoxy) -cyclohexyl] -benzenesulfonamide,
Trans-N- [4- (4-dimethylamino-butoxy) -cyclohexyl] -N-ethyl-4-trifluoromethyl-benzenesulfonamide,
Trans-methyl- {4- [3- (methyl-propyl-amino) -prop-1-ynyl] -cyclohexyl} -carbamic acid 4-chloro-phenyl ester,
Trans- (1E) -N-methyl-N- {4- [3- (methyl-propyl-amino) -propenyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide,
Trans-N- (4- {4- [ethyl- (2-hydroxy-ethyl) -amino] -but-1-ynyl} -cyclohexyl) -N-methyl-4-trifluoromethyl-benzenesulfonamide ,
Trans-N-methyl-N- {4- [4- (methyl-propyl-amino) -but-1-ynyl] -cyclohexyl} -4-trifluoromethyl-benzenesulfonamide, and
Trans-N- {4- [2- (1-dimethylamino-cyclopropyl) -ethoxy] -cyclohexyl} -N-methyl-4-trifluoromethyl-benzenesulfonamide or a compound thereof Pharmaceutically acceptable salts.
[31" claim-type="Currently amended] A compound of Formula II is represented by ClSO ₂ -A ⁶ , ClCOO-A ⁶ , ClCSO-A ⁶ , OCN-A ⁶ , SCN-A ⁶ , HOOC-A ⁶ , or ClSO ₂ NR ¹ -A ⁶ (A ⁶ is A process for preparing a compound according to claims 1 to 30, comprising reacting with the meaning given in claim 1).
Formula II

Where
A ⁵ has the meaning given in paragraph 1,
Z is (A ¹ , A ² ,) NC (A ³ , A ⁴ )-(CH ₂ ) _m -V- (CH ₂ ) _n or HO- (CH ₂ ) _n , and A ¹ , A ² , A ³ , A ⁴ , V, m and n have the meanings given in claim 1.
[32" claim-type="Currently amended] The method according to any one of claims 1 to 30,
A compound prepared by the method according to claim 31.
[33" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier and / or adjuvant.
[34" claim-type="Currently amended] The method according to any one of claims 1 to 30,
Compounds for use as therapeutically active substances.
[35" claim-type="Currently amended] The method according to any one of claims 1 to 30,
Compounds for use as therapeutically active substances for the treatment and / or prophylaxis of diseases associated with OSC.
[36" claim-type="Currently amended] 31. Hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal disease, parasitic infection, cholelithiasis, tumors and / or comprising administering a compound according to any one of claims 1 to 30 to a human or animal A method for treating and / or preventing a disease associated with OSC, such as a hyperproliferative disorder, and / or for treating and / or preventing impaired glucose tolerance and diabetes.
[37" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 30 for the treatment and / or prevention of diseases associated with OSC.
[38" claim-type="Currently amended] Treatment and / or prevention of diseases associated with OSC, such as hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal disease, parasitic infections, cholelithiasis, tumors and / or hyperproliferative disorders, and / or impaired glucose tolerance and diabetes Use of a compound according to any one of claims 1 to 30 for treatment and / or prophylaxis.
[39" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 30 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases associated with OSC.
[40" claim-type="Currently amended] Treatment and / or prevention of diseases associated with OSC, such as hypercholesterolemia, hyperlipidemia, atherosclerosis, vascular disease, filamentous fungal disease, parasitic infections, cholelithiasis, tumors and / or hyperproliferative disorders, and / or impaired glucose tolerance and diabetes Use of a compound according to any one of claims 1 to 30 for the manufacture of a medicament for treatment and / or prophylaxis.
[41" claim-type="Currently amended] Uses of such compounds as well as novel compounds, processes and methods as substantially described herein.

类似技术:

---

公开号 | 公开日 | 专利标题

---

CA2797011C|2018-10-02|Tranylcypromine derivatives as inhibitors of histone demethylase lsd1 and/or lsd2

---

CA2416685C|2008-10-07|Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids

---

US5236921A|1993-08-17|Arylalkylamines, process for preparing them and pharmaceutical compositions containing them

---

ES2262313T3|2006-11-16|Derivatives of bencenosulfonamine and its use as medicines.

---

DE60008369T2|2009-10-01|N-cyano-methyl-amide as a proteinase inhibitor

---

US7977387B2|2011-07-12|Aminobenzophenone compounds

---

US7148259B1|2006-12-12|Antibacterial agents

---

US7300936B2|2007-11-27|α-|acetamide derivatives as β-amyloid inhibitors

---

Ho et al.2001|Synthesis and structure–activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

---

EP1608374B1|2008-11-05|2-phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders

---

US6784173B2|2004-08-31|Aromatic dicarboxylic acid derivatives

---

DE60221569T2|2008-04-30|Acrylsulphonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological diseases

---

US6849649B2|2005-02-01|N-phenpropylcyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase

---

US7169928B2|2007-01-30|Non-imidazole alkylamines as histamine H3-receptor ligands and their therapeutic applications

---

RU2097371C1|1997-11-27|N-PHENYLALKYL-SUBSTITUTED DERIVATIVES OF α-AMINOCARBOXAMIDE, METHOD OF THEIR SYNTHESIS, PHARMACOLOGICALLY ACTIVE COMPOSITION ON THEIR BASE AND A METHOD OF DISEASE DEVELOPMENT PROPHYLAXIS

---

US7078438B2|2006-07-18|N-|-anthranilic acid hydroxamate esters

---

US7615557B2|2009-11-10|Tetrahydro-naphthalene and urea derivatives

---

US7906537B2|2011-03-15|Substituted p-diaminobenzene derivatives

---

ES2223454T3|2005-03-01|Oxamic acids and derivatives as ligandos of thyroid receptors.

---

US4629739A|1986-12-16|Substituted sulfonamidobenzamides and method of treating arrhythmias

---

US6509369B2|2003-01-21|Anti-inflammatory compounds

---

US6890956B2|2005-05-10|Cyclohexyl sulphones as gamma-secretase inhibitors

---

US6437147B1|2002-08-20|Imidazole compounds

---

US6316484B1|2001-11-13|Pentafluorobenzenesulfonamides and analogs

---

US7547731B2|2009-06-16|Formamide derivatives for the treatment of diseases

同族专利:

---

公开号 | 公开日

---

AU2001293744B2|2007-05-10|

---

HU0303105A2|2004-03-01|

---

BR0113408A|2003-06-17|

---

CN1468214A|2004-01-14|

---

ES2311547T3|2009-02-16|

---

MXPA03001269A|2003-06-09|

---

WO2002014267A1|2002-02-21|

---

JP2004506037A|2004-02-26|

---

PA8525101A1|2002-07-30|

---

NO20030657D0|2003-02-10|

---

EP1311475A1|2003-05-21|

---

RU2225393C1|2004-03-10|

---

AR030712A1|2003-09-03|

---

US6858651B2|2005-02-22|

---

US7335687B2|2008-02-26|

---

UY26891A1|2002-02-28|

---

KR100566175B1|2006-03-29|

---

HU0303105A3|2005-05-30|

---

US20020045777A1|2002-04-18|

---

PE20020367A1|2002-05-11|

---

CN100455566C|2009-01-28|

---

NZ523879A|2004-09-24|

---

CA2418744C|2010-04-20|

---

HRP20030086A2|2005-02-28|

---

AU9374401A|2002-02-25|

---

JP4244139B2|2009-03-25|

---

PL361783A1|2004-10-04|

---

NO20030657L|2003-02-13|

---

AT403646T|2008-08-15|

---

YU12003A|2006-05-25|

---

DE60135230D1|2008-09-18|

---

EP1311475B1|2008-08-06|

---

CZ2003451A3|2003-10-15|

---

IL154172D0|2003-07-31|

---

US20050176766A1|2005-08-11|

---

MA26941A1|2004-12-20|

---

CA2418744A1|2002-02-21|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
2000-08-16|Priority to EP00117611

---

2000-08-16|Priority to EP00117611.4

---

2001-06-19|Priority to EP01113646.2

---

2001-06-19|Priority to EP01113646

---

2001-08-08|Application filed by 에프. 호프만-라 로슈 아게

---

2001-08-08|Priority to PCT/EP2001/009174

---

2003-06-18|Publication of KR20030048010A

---

2006-03-29|Application granted

---

2006-03-29|Publication of KR100566175B1

优先权:

---

申请号 | 申请日 | 专利标题

---

EP00117611|2000-08-16|

---

EP00117611.4|2000-08-16|

---

EP01113646.2|2001-06-19|

---

EP01113646|2001-06-19|

---

PCT/EP2001/009174|WO2002014267A1|2000-08-16|2001-08-08|Novel aminocyclohexane derivatives|