1,3,8-triaza-spiro[4.5]decan-4-one derivatives as neurokinin receptor antagonists

专利摘要:
The present invention relates to compounds of formula (I) and their pharmaceutically acceptable acid addition salts: Formula I Where R 1 is — (CH 2 ) m -non-aromatic heterocyclyl group optionally substituted by hydrogen, lower alkyl, lower alkenyl, phenyl, or lower alkyl, or lower alkyl, lower alkoxy, halogen, CF 3 , benzyl And-(CH 2 ) m -heteroaryl optionally substituted by one or two substituents selected from the group consisting of cyano, or-(CH 2 ) m -C (O) -NRR ',-(CH 2 ) m- C (O) -lower alkyl,-(CH 2 ) m -C (O) -O-lower alkyl,-(CH 2 ) m -O-lower alkyl,-(CH 2 ) m -CH [C ( O) -O-lower alkyl] 2 ,-(CH 2 ) m -CH (OH) -CH 2- (O) -phenyl,-(CH 2 ) m -CH (CF 3 ) OH,-(CH 2 ) m- OH,-(CH 2 ) m -CN,-(CH 2 ) m -NRR ',-(CH 2 ) m -cycloalkyl or-(CH 2 ) m -CHF 2 ; R 2 is hydrogen, lower alkyl, halogen or lower alkoxy; R 3 is lower alkyl, lower alkoxy, halogen or CF 3 ; R and R 'are the same or different and are hydrogen or lower alkyl; X is> N-,> C = or> CH-; X 1 / X 2 may be independently of each other hydrogen, hydroxy or lower alkoxy or wherein X 1 / X 2 together may be an oxo group; Y 1 / Y 2 may be independently of each other hydrogen, lower alkyl, — (CH 2 ) m -phenyl or the Y 1 / Y 2 together may be an oxo group; Z is a bond, -CH 2 -or -C (O)-; m is 0, 1, 2, 3 or 4; n is 2 or 3 n 'is 0, 1 or 2. The aforementioned compounds exhibit good affinity for the NK 1 receptor.
公开号:KR20030016283A
申请号:KR1020027016671
申请日:2001-06-01
公开日:2003-02-26
发明作者:갈레이구이도；고델티에리；괴르글러아니크；호프만토스텐；콜체브스키자빈；로에베르스테판
申请人:에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

1,3,8-triaza-spiro [4.5] decan-4-one derivative as a neurokinin receptor antagonist {1,3,8-TRIAZA-SPIRO [4.5] DECAN-4-ONE DERIVATIVES AS NEUROKININ RECEPTOR ANTAGONISTS}
[15] Compounds of formula I and salts thereof represent useful therapeutic treatments. Surprisingly, the compounds of the present invention have been found to be antagonists of neurokinin 1 (NK-1, substance P) receptors. Substance P is a natural undecapeptide belonging to the tachykinin class of peptides, also referred to as tachykinin due to their immediate contractile action in extravascular smooth muscle. Receptors for substance P belong to the subclass of G protein bound receptors.
[16] Neuropeptide receptors for substance P (NK-1) are widely distributed throughout the mammalian nervous system (particularly the brain and spinal ganglia), the circulatory system and surrounding tissues (particularly the duodenum and jejunum) and are involved in regulating various biological processes. The central and peripheral action of mammalian tachykinin substance P is associated with a variety of inflammatory symptoms, including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease, as well as mediating and recurrent central nervous system (CNS) diseases such as Parkinson's disease ( Adjustment of Parkinson's disease (see Neurosci. Res., 1996, 7, 187-214) and anxiety (see Can. J. Phys., 1997, 75, 612-621); Related. Pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, weakening of morphine withdrawal, cardiovascular changes, edema, edema caused by thermal damage, chronic inflammatory diseases such as rheumatoid arthritis, For the usefulness of takinin receptor antagonists for asthma / bronchial hyperreactivity, and other respiratory diseases including allergic rhinitis, inflammatory diseases of the intestine, including ulcerative colitis and Crohn's disease, eye damage and inflammatory diseases of the eye See, for example, "Tachykinin Receptor and Tachykinin Receptor Antagonists", J. Auton. Pharmacol., 13, 23-93, 1993.
[17] The utility of neurokinin 1 receptor antagonists in the treatment of certain types of incontinence is further described in "Neuropeptides, 32 (1), 1-49, (1998)" and "Eur. J. Pharmacol., 383 (3). ), 297-303 (1999) ".
[18] In addition, neurochitin 1 receptor antagonists have been developed to treat many physiological diseases associated with excessive or unbalanced tachykinin, in particular substance P. Examples of symptoms involving substance P include diseases of the central nervous system, such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO WO). 95/23798).
[19] Neurokinin-1 receptor antagonists are further useful for the treatment of motor diseases and the treatment of induced vomiting.
[20] In addition, The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 discloses the reduction of cisplatin-induced vomiting by selective neurokinin-1 receptor antagonists.
[21] In addition, U. S. Patent No. 5,972, 938 discloses a method for the treatment of mental and mental disorders or psychoimmune diseases by administration of tachykinin receptors such as NK-1 receptor antagonists.
[22] NK1 receptor antagonists have been reported to have a useful effect in the treatment of traumatic brain injury ("Nurokinin 1 (NK-1) receptor antagonists improve the neurological consequences of traumatic brain injury" (author: AJ Nimmo) ), CJ Bennett, X. Hu, I. Cernak, and R. Vink) from La Grande Mote, France, from October 17-20, 2000 See oral presentation by Professor Nimmo at the International Takkinin Conference 2000 held).
[1] The present invention relates to compounds of formula (I) and their pharmaceutically acceptable acid addition salts:
[2]
[3] Where
[4] R ¹ is — (CH ₂ ) _m -non-aromatic heterocyclyl group optionally substituted by hydrogen, lower alkyl, lower alkenyl, phenyl, or lower alkyl, or lower alkyl, lower alkoxy, halogen, CF ₃ , benzyl And-(CH ₂ ) _m -heteroaryl optionally substituted by one or two substituents selected from the group consisting of cyano, or-(CH ₂ ) _m -C (O) -NRR ',-(CH ₂ ) _m- C (O) -lower alkyl,-(CH ₂ ) _m -C (O) -O-lower alkyl,-(CH ₂ ) _m -O-lower alkyl,-(CH ₂ ) _m -CH [C ( O) -O-lower alkyl] ₂ ,-(CH ₂ ) _m -CH (OH) -CH _2- (O) -phenyl,-(CH ₂ ) _m -CH (CF ₃ ) OH,-(CH ₂ ) _m- OH,-(CH ₂ ) _m -CN,-(CH ₂ ) _m -NRR ',-(CH ₂ ) _m -cycloalkyl or-(CH ₂ ) _m -CHF ₂ ;
[5] R ² is hydrogen, lower alkyl, halogen or lower alkoxy;
[6] R ³ is lower alkyl, lower alkoxy, halogen or CF ₃ ;
[7] R and R 'are the same or different and are hydrogen or lower alkyl;
[8] X is> N-,> C = or> CH-;
[9] X ¹ / X ² may be independently of each other hydrogen, hydroxy or lower alkoxy or wherein X ¹ / X ² together may be an oxo group;
[10] Y ¹ / Y ² may be independently of each other hydrogen, lower alkyl, — (CH ₂ ) _m -phenyl or the Y ¹ / Y ² together may be an oxo group;
[11] Z is a bond, -CH ₂ -or -C (O)-;
[12] m is 0, 1, 2, 3 or 4;
[13] n is 2 or 3
[14] n 'is 0, 1 or 2.
[23] It is an object of the present invention to provide compounds of formula (I), pharmaceutically acceptable salts and enantiomer forms thereof, methods of preparing the compounds described above, medicaments and preparations thereof containing the same, and diseases, in particular of the aforementioned kind The use of the aforementioned compounds in the control or prevention of a disease or disorder, or the manufacture of a corresponding medicament.
[24] The compounds of formula I can also be used in their prodrug form. Examples are esters, N-oxides, phosphate esters, glycoamide esters and glyceride conjugates. Prodrugs can double the advantages of the compounds of the present invention in terms of adsorption capacity, pharmacokinetics on distribution and migration to the brain.
[25] The most preferable indications for applying the present invention include diseases of the central nervous system, and for example, treating or preventing certain depressive diseases or vomiting by administering NK-1 receptor antagonists. Major depressive episodes are defined as signs of depressed mood during most of the night and day, loss of interest or joy in all areas, or almost inactivity for more than two weeks.
[26] The following definitions of general terms used herein apply regardless of whether the terms are used alone or in combination.
[27] As used herein, the term "lower alkyl" refers to a straight or branched chain saturated alkyl group of 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl and t- Butyl etc. are mentioned. Preferred lower alkyl groups are groups of 1 to 4 carbon atoms.
[28] As used herein, the term "lower alkenyl" refers to a straight or branched chain unsaturated alkyl group having 2 to 7 carbon atoms, for example ethenyl, propenyl, isopropenyl, n-butenyl, i-part Tenyl, t-butenyl and the like. Preferred lower alkyl groups are groups of 2 to 4 carbon atoms.
[29] The term "lower alkoxy" refers to a group in which an alkyl moiety is the same as defined above and is bonded to an oxygen atom.
[30] The term "halogen" means chlorine, iodine, fluorine and bromine.
[31] The term "cycloalkyl" is a saturated carbocyclic group of 3 to 6 carbon atoms.
[32] The term "nonaromatic heterocyclyl" refers to, for example, pyrrolidinyl, 5-oxo-pyrrolidinyl, 2-oxo-oxazolidinyl, piperidyl, piperazinyl, morpholinyl, imidazolidinyl Or pyrazolidinyl. Preferred groups are pyrrolidinyl, 5-oxo-pyrrolidinyl, 2-oxa-oxazolidinyl, piperidinyl, piperazinyl or morpholinyl.
[33] The term "heteroaryl" refers to, for example, pyridinyl, 1,3,5-triazinyl, pyrimidinyl, quinoxalinyl, pyrazinyl, isoxazolyl, benzoimidazolyl, 1,2,4-oxa Diazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl. Preferred groups are pyridinyl, 1,3,5-triazinyl, pyrimidinyl, quinoxalinyl, pyrazinyl, imidazolyl, thiazolyl, isoxazolyl, benzoimidazolyl, 1,2,4-oxadia Zolyl, furyl or thiethyl.
[34] The term "pharmaceutically acceptable acid addition salts" refers to inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid and p- Salts with toluenesulfonic acid or the like.
[35] Preferred are all compounds in which R ³ is trifluoromethyl and n is 2.
[36] Preferred are compounds wherein X is> N-, X ¹ / X ² together form an oxo group, and Y ¹ / Y ² are both hydrogen, for example the following compounds can be exemplified:
[37] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl) -1-phenyl-1,3, 8-triaza-spiro [4.5] decan-4-one,
[38] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl ) -1,3,8-triaza-spiro [4.5] decan-4-one,
[39] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-pyridin-3-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- On,
[40] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-isopropylamino-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane- 4-on,
[41] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-4-one,
[42] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyridin-4-yl-1,3,8-triaza-spiro [4.5] decan-4-one,
[43] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-methyl-1,3,8-triaza-spiro [4.5] decan-4-one,
[44] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (3-dimethylamino-propyl) -1,3,8-triaza-spiro [4.5 ] Decane-4-one,
[45] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-pyridin-4-yl-1,3,8-triaza-spiro [4.5] decane- 4-on, and
[46] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one.
[47] Preference is given to compounds in which X is> N-, X ¹ / X ² together form an oxo group, one of Y ¹ / Y ² is hydrogen and the other is not hydrogen.
[48] Examples of such compounds include the following compounds:
[49] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one,
[50] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one,
[51] (rac) -2-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one,
[52] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-phenyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one,
[53] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-3-pyridin-3-yl-methyl-1,3,8-triaza-spiro [ 4.5] decane-4-one,
[54] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2,3-dimethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one,
[55] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-3- (2-pyrrolidin-1-yl-ethyl) -1,3,8 -Triaza-spiro [4.5] decan-4-one,
[56] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-propyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one,
[57] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2,3-dimethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- On,
[58] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-piperazin-1-yl-ethyl) -1-o-tolyl-1,3, 8-triaza-spiro [4.5] -4-one,
[59] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3 , 8-triaza-spiro [4.5] decan-4-one,
[60] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-piperidin-2-yl-ethyl) -1-o-tolyl-1,3 , 8-triaza-spiro [4.5] decan-4-one,
[61] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-methoxy-ethyl) -2-methyl-1-o-tolyl-1,3,8-triaza Spiro [4.5] decan-4-one,
[62] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-morpholin-4-yl-ethyl) -1-o-tolyl-1,3, 8-triaza-spiro [4.5] decan-4-one, and
[63] (rac) -8- (3,5-dichloro-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] detan-4-one.
[64] Preferred are compounds wherein X is> N- and X ¹ / X ² and Y ¹ / Y ² both form an oxo group, for example the following compounds:
[65] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione,
[66] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-pyridin-3-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2, 4-dione,
[67] 3- (1H-Benzoimidazol-2-yl-methyl) -8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-2,4-dione,
[68] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-methyl-thiazol-4-yl-methyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione,
[69] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-2-yl-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-2,4- Dion,
[70] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-2-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2, 4-dione, and
[71] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-thiophen-2-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2 , 4-dione.
[72] Preferred are compounds wherein X is> C =, for example the following compounds:
[73] 8- (3,5-bis-trifluoromethyl-benzoyl) -2- (2-pyrrolidin-1-yl-ethyl) -4-o-tolyl-2,8-diaza-spiro [4.5] Deck-3-en-1-one, and
[74] 8- (3,5-bis-trifluoromethyl-benzoyl) -2- (3-dimethylamino-propyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-ene -1-one.
[75] Preferred are compounds wherein X is> CH-, for example the following compounds:
[76] (rac) -8- (3,5-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] decan-1-one.
[77] Compounds of the invention of formula (I) and their pharmaceutically acceptable salts are known in the art, for example
[78] (a) reacting a compound of formula II with a compound of formula III to provide a compound of formula I:
[79]
[80]
[81] Formula I
[82]
[83] [Wherein L is a leaving group comprising a halogen such as chlorine and the other substituents are the same as defined above]; or
[84] (b) reacting a compound of formula I-1 with a compound of formula IV in the presence of sodium hydride or potassium carbonate and CuCl to provide a compound of formula I
[85]
[86] LR ¹
[87] Formula I
[88]
[89] [Wherein L in formula IV is a leaving group containing chlorine, other substituents are the same as defined above, R ¹ is not-(CH ₂ ) _m -OH and X ¹ / X ² is not hydroxy .]; or
[90] (c) reacting the compound of formula I-1 with formula V to provide a compound of formula I-2
[91] Formula I-1
[92]
[93]
[94]
[95] [Wherein TBDMS is a t-butyldimethylsilyl group and the substituents are the same as defined above]; or
[96] (d) activating a compound of formula (I-2) as a mesylate and then reacting with an amine of formula (RR'NH, wherein R and R 'are as defined above) to provide a compound of formula (I-3) step
[97] Formula I-2
[98]
[99]
[100] [Wherein the substituents are the same as defined above]; or
[101] (e) reacting a compound of formula I-1 with a compound of formula VI to provide a compound of formula I-4
[102] Formula I-1
[103]
[104]
[105]
[106] [Wherein R ⁴ is lower alkyl and the other substituents are as defined above]; or
[107] (f) reacting a compound of formula (I-1) with a compound of formula (VII) to provide a compound of formula (I)
[108] Formula I-1
[109]
[110]
[111] Formula I
[112]
[113] [Wherein R ¹ is phenyl or heteroaryl optionally substituted as defined above and the other substituents are as defined above]; or
[114] (g) closing the compound of formula VIII to provide a compound of formula I-5
[115]
[116]
[117] [Wherein the substituents are the same as defined above]; or
[118] (h) a compound of formula (I-6) Reacting with a compound of to provide a compound of formula I-7
[119]
[120]
[121] [Wherein the substituents are the same as defined above]; or
[122] (i) reacting a compound of formula XIV with hydrogen on Pd / C and then reacting with (CF ₃ ) ₂ C ₆ H ₃ COCl to provide a compound of formula I-12
[123]
[124]
[125] [Wherein the substituents are the same as defined above]; or
[126] (j) changing at least one of the substituents R ¹ to R ³ within the ranges defined above and optionally converting the obtained compound into a pharmaceutically acceptable acid addition salt. Can be.
[127] Salt formation is known and carried out at room temperature according to methods familiar to those skilled in the art. Salts with inorganic acids as well as salts with organic acids are also contemplated. Hydrochloride, hydrobromide, sulfate, nitrate, citrate, acetate, maleate, succinate, methane-sulfonate, p-toluenesulfonate and the like are examples of such salts.
[128] Schemes 1-17 below describe in more detail the preparation of compounds of formula (I). Starting materials are known compounds and can be prepared according to methods known in the art.
[129] In the schemes, the following abbreviations are used:
[130] NMP: 1-methyl-2-pyrrolidinone;
[131] DME: ethylene glycol dimethyl ether;
[132] TBDMS: tert-butyldimethylsilane;
[133] DMF: Dimethylformamide.
[134] THF: tetrahydrofuran
[135] TMSCN: trimethylsilyl cyanide
[136] DIBAH: diisobutylaluminum hydride
[137]
[138] Where
[139] L is a leaving group containing a halogen such as chlorine,
[140] The other substituents are the same as defined above.
[141] A solution of the compound of formula II, for example 3,5-bis (trifluoromethyl) benzoyl chloride in dichloromethane, is a mixture of the compound of formula III, for example 1-phenyl-1,3,8- To triaza-spiro [4.5] decan-4-one and triethylamine. The reaction is carried out at room temperature. The compounds of Examples 1 to 3 were prepared according to Scheme 1.
[142]
[143] Where
[144] Substituents are the same as defined above.
[145] The reaction is carried out in the presence of sodium hydride and / or N-methyl-2-pyrrolidone (NMP) / 1,2-dimethoxyethane. To the suspension is added a compound of formula I-1 and then a compound of formula IV, for example 4- (2-chloroethyl) morpholine, 3- (chloromethyl) pyridine, 2-chloro-4,6-dimeth Oxy-1,3,5-triazine, 1- (2-chloroethyl) piperidine, 1- (2-chloroethyl) pyrrolidine, 2-bromoacetamide, 2-chloro-N, N- Dimethylacetamide, methyl bromoacetate, bromomethyl methyl ether, dimethyl bromomalonate, phenylglycidyl ether, 2,4,6-trichloropyrimidine, 2-chloro-5- (trifluoromethyl) Pyridine, 3-bromo-1,1,1-trifluoro-2-propanol, 2-picolichloride, 4-chloromethylpyridine, 2,4-dichloropyrimidine, methyliodide, 1-benzyl- (2-Chloromethyl) -imidazole, 5-chloromethyl-2-oxazolidinone, 1-chloro-2-dimethylaminoethane, 1- (2-chloroethyl) pyrrolidine, 4-chloromethyl-2- Methylthiazole, 4,6-dichloropyridine, 2,3,5-trichloropyridine 2-chloro-4- (trifluoromethyl) -pyrimidine, 2-chloro-pyridine, 2-chloro-N, N-dimethylacetamide, 3-dimethylaminopropylchloride, 4- (chloromethyl) 3, 5-dimethylisoxazole or 2,4-dichloro-6-methylpyrimidine is added.
[146] Examples 4 to 21, 25 to 47, 70 to 82, 86, 87 and 134 describe examples according to Scheme 2 in more detail.
[147]
[148] Where
[149] Substituents are the same as defined above.
[150] The reaction is carried out using compounds of formula (I-1) and compounds of formula (V), for example (3-bromopropoxy) -tert-butyldimethylsilane, under the conditions described in Scheme 2. The intermediate TBDMS-ether is cleaved in a solution of HCl and ethanol.
[151] Examples 22-24 describe examples according to Scheme 3.
[152]
[153] Where
[154] Substituents are the same as defined above.
[155] A solution of the compound of formula I-2 and triethylamine in dichloromethane is added to a cooled solution of methanesulfonyl chloride in dichloromethane or DMF, followed by addition of sodium bicarbonate and an amine of formula RR'NH to Obtain the compound.
[156] Examples 48-58 describe examples according to Scheme 4.
[157]
[158] Where
[159] R ⁴ is lower alkyl,
[160] Substituents are the same as defined above.
[161] According to the scheme, a compound of formula VI is added to the mixture of compound of formula I-1, cesium fluoride and tetraethoxysilane, for example ethyl acrylate. The reaction is carried out at room temperature.
[162] In Examples 59 and 60 it is prepared as described in Scheme 5.
[163]
[164] Where
[165] Substituents are the same as defined above.
[166] The reaction was carried out in the presence of potassium carbonate, CuCl and tris [2- (2-methoxyethoxy) -ethyl] -amine in a mixture of the compound of formula (I-1) and a solution of the compound of formula (IV) (e.g. 4 in xylene , 6-dichloropyrimidine).
[167] Example 61 describes an example according to Scheme 6.
[168]
[169] Where
[170] Substituents are the same as defined above.
[171] A mixture of the compound of formula I-1, boronic acid of formula VII, copper acetate and triethylamine in dichloromethane is stirred at room temperature. Chromatography on silica gel affords the desired compound of formula (I).
[172] Examples 62, 83, and 84 describe the procedure of Scheme 7 in more detail.
[173]
[174] Where
[175] Substituents are the same as defined above.
[176] A mixture of the compound of formula VIII, formic acid and acetic anhydride is stirred at room temperature to give an intermediate N-formyl derivative, which is treated with formic acid and acetic acid to give an intermediate amide. The amide is dissolved in triethyl orthoformate and boiled. After evaporation, the solid is dissolved in methanol and sodium borohydride is added at room temperature. The desired product is obtained by chromatography on silica gel.
[177] Examples 63-68 and 85 describe the procedure according to Scheme 8 in more detail.
[178]
[179] Where
[180] Substituents are the same as defined above.
[181] Ethylenediamine-trimethylaluminum complex is added to a solution of the compound of formula I-6 in toluene. The reaction is carried out at about 120 ° C.
[182] Example 69 describes an example according to Scheme 9.
[183]
[184] Where
[185] Substituents are the same as defined above.
[186] A solution of the compound of formula IX in dichloromethane is added to the solution of 4-piperidone trifluoroacetate and triethylamine with cooling. The reaction is carried out at room temperature.
[187] Example A describes the process in more detail.
[188]
[189] Where
[190] Substituents are the same as defined above.
[191] To a solution of the compound of formula XI in acetic acid is added cooling the compound of formula XII (eg 3-chloroaniline) and TMSCN.
[192] In Examples B, C, D, E, F, G and H, prepared according to Scheme 11.
[193]
[194] Where
[195] Substituents are the same as defined above.
[196] According to Scheme 12, a mixture of formula (R ² ) _{n '} -C ₆ H ₄ -Z-NH ₂ in a solution of 1-benzyl-piperidin-4-one (Formula XI-1) in acetic acid, for example Aniline and TMSCN are added. To the solution of intermediate amino nitrile in formic acid is added acetic anhydride while cooling, and the resulting foam is dissolved in formic acid and acetic acid. The intermediate was circulated by boiling in triethylorthoformate and subsequently treated with Grignard reagent such as methylmagnesium bromide. The intermediate is treated with hydrogen in methanol and palladium on charcoal. In the last step, the obtained solution is treated with 3,5-bis-trifluoromethyl benzoylchloride to give a compound of formula I-8.
[197] Examples 91-109, 112, 114-120, and 132 describe the process according to Scheme 12 in more detail.
[198]
[199] Where
[200] Substituents are the same as defined above.
[201] Formula (R ²⁾ To a solution of the compound of formula XI-1 in acetic acid _{n '-C 6} H ₄ Compounds of -Z-NH _2, for example, the addition of aniline, and TMSCN. Then chlorosulfonyl isocyanate is added to the solution of intermediate amino nitrile. The solid is suspended in hydrochloric acid and refluxed. The intermediate is treated with hydrogen and palladium on charcoal. In the last step, treatment with (CF ₃ ) ₂ C ₆ H ₃ COCl affords compounds of formula (I-9).
[202] Examples 110, 111 and 113 describe in more detail the example according to Scheme 13.
[203]
[204] Where
[205] Substituents are the same as defined above.
[206] The piperidine To a solution of 4-one (Formula ^{XI-1) (R 2)} n '-C 6 H 4 Compounds of -Z-NH _2, for example aniline, and TMSCN added - 1-benzyl-acetic acid . To the solution of the obtained intermediate amino nitrile in dichloromethane is added chlorosulfonyl isocyanate. The white solid obtained is suspended in HCl and reduced. It is then reduced using diisobutyl aluminum hydride. Intermediate n-benzyl protected spirpiperidine is treated with hydrogen and palladium on charcoal. After stirring under hydrogen atmosphere at room temperature, (CF ₃ ) ₂ C ₆ H ₃ COCl is added to afford the compound of formula I-10.
[207] Examples 129 and 130 describe examples according to Scheme 14.
[208]
[209] Where
[210] Substituents are the same as defined above.
[211] Piperidine-4-one _{^{(R 2) n '-C 6}} H 4 Compounds of -Z-NH _2, for example o- toluidine, and TMSCN To a solution of (Formula XI-1) - 1- benzyl-acetic acid Add. The solution of intermediate amino nitrile obtained is dissolved in PtO ₂ acetic acid and the reaction mixture is hydrogenated at room temperature. To the solution of the obtained intermediate in dichloromethane and triethylamine is added trichloromethyl chloroformate at about -20 ° C. The obtained intermediate N-benzyl protected spirpiperidine is treated with hydrogen and palladium on charcoal. After stirring under hydrogen atmosphere at room temperature, (CF ₃ ) ₂ C ₆ H ₃ COCl is added to afford the compound of formula I-11.
[212] In Example 131, it is prepared according to Scheme 15.
[213]
[214] Where
[215] Substituents are the same as defined above.
[216] Benzyl cyanide and N-benzyl-4-piperidone (Formula XI-1) are added to the sodium ethoxide solution and the reaction is carried out at 85 ° C. for 3 hours. Work up with concentrated hydrochloric acid to afford the intermediate (1-benzyl-piperidin-4-ylidene) -phenyl-acetonitrile, which is treated with potassium cyanide. The obtained intermediate N-benzyl protected spirpiperidine is treated with hydrogen and palladium on charcoal. After stirring under hydrogen atmosphere at room temperature, (CF ₃ ) ₂ C ₆ H ₃ COCl is added to afford the compound of formula I-12.
[217] In Example 156, it is prepared according to Scheme 16.
[218]
[219] Where
[220] Substituents are the same as defined above.
[221] Benzyl cyanide and N-benzyl-4-piperidone (Formula XI-1) are added to the sodium ethoxide solution and the reaction is carried out at 85 ° C. for 3 hours. Work up with concentrated hydrochloric acid to afford the intermediate (1-benzyl-piperidin-4-ylidene) -phenyl-acetonitrile, which is treated with potassium cyanide. Excess diisobutylaluminum hydride is used to reduce one carbonyl group and is removed using acetic acid. The obtained intermediate N-benzyl protected spirpiperidine is treated with hydrogen and palladium on charcoal. After stirring under hydrogen atmosphere at room temperature, (CF ₃ ) ₂ C ₆ H ₃ COCl is added to afford the compound of formula I-13.
[222] In Example 161, it is prepared according to Scheme 17.
[223] As mentioned above, the compounds of formula (I) and their pharmaceutically useful addition salts have useful pharmacological properties. The compounds of the present invention are antagonists of neurokinin 1 (NK-1, substance P).
[224] Compounds of the present invention were studied according to the tests presented below.
[225] In the affinity of test compounds for the NK ₁ receptor, and infection with the human NK ₁ receptor (count Ricky (Semliki) using a virus expression system) ^[3 H] substance P (final concentration 0.6nM) to the radiolabeled CHO cell Evaluation at human NK ₁ receptor. Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%), Leupeptin (8 μg / ml), MnCl ₂ (3 mM) and phosphoramidone (2 μM). The binding assay consisted of 250 μl of membrane suspension (1.25 × 10 ⁵ cells / assay tubes), 0.125 μl of buffer of substituents and 125 μl of [ ³ H] substance P. Substitution curves were determined with compounds of at least 7 concentrations. The assay tube was incubated at room temperature for 60 minutes and then the contents of the tube were washed with 2 ml of HEPES buffer (50 mM, pH 7.4) twice with GF / C filter pre-soaked for 60 minutes with PEI (0.3%). Filtration quickly under vacuum. Radioactivity retained on the filter was measured by scintillation countering. All assays were performed three times in two or more separate experiments.
[226] Affinity for the NK ₁ receptor, expressed as pKi, ranges from 6.5 to 8.8 for the compounds exemplified. Examples of such compounds are as follows.
[227] Example pKi 6 8.66 26 7.47 39 7.03 45 8.29 58 8.08 70 8.37 91 8.12 137 8.34 170 7.96 176 8.12
[228] The compounds of formula (I) as well as their pharmaceutically useful acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, it may also be administered in the form of rectal administration (eg suppositories) or parenteral administration (eg injection solutions).
[229] The compounds of formula (I) and their pharmaceutically useful acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the manufacture of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as excipients for tablets, dragees and hard gelatin capsules.
[230] Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like.
[231] Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like.
[232] Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.
[233] Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
[234] Moreover, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts of varying osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically useful substances.
[235] The dosage can vary widely and can be tailored to the requirements of the individual in each particular case. In general, for oral administration, it is suitable to administer the compound of formula I in a daily dosage of about 10 to 1000 mg per person, although in some cases the upper limit may be exceeded.
[236] The invention is illustrated by the following examples, which are not intended to limit the invention. All temperatures are in degrees Celsius.
[237] Example 1
[238] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[239] A solution of 3,5-bis (trifluoromethyl) benzoyl chloride (2.3 mL, 13 mmol) in dichloromethane (50 mL) was added at room temperature to 1-phenyl-1,3,8-tri in dichloromethane (250 mL). To a mixture of aza-spiro [4.5] decan-4-one (2.9 g, 13 mmol) and triethylamine (3.5 mL, 25 mmol) was added with stirring. Stir for 2 hours. Water (150 mL) was added, the phases were separated and the aqueous phase was extracted twice with dichloromethane (100 mL). The organic phase was decanted, washed with brine (200 mL), dried over Na ₂ SO ₄ and the solvent was evaporated. Purification by silica gel chromatography (ethyl acetate / n-hexane 1: 1) afforded the desired product (5.3 g, 89%) (mp 251 ° C, MS: m / e = 472.1 (M + H ⁺ )).
[240] Example 2
[241] 1-phenyl-8- (3,4,5-trimethoxy-benzoyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[242] Using the title compound (MS) according to the method of Example 1 using 3,4,5-trimethoxybenzoyl chloride and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one m / e = 426.4 (M + H ⁺ )).
[243] Example 3
[244] 8- (3-Fluoro-5-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[245] According to the method of Example 1, using 3-fluoro-5- (trifluoromethyl) benzoyl chloride and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one The title compound (MS: m / e = 422.3 (M + H ⁺ )) was prepared.
[246] Example 4
[247] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-morpholin-4-yl-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane -4-on
[248] Sodium hydride (34 mg, 60%) is suspended in N-methyl-2-pyrrolidone (2 mL) and 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3 , 8-triaza-spiro [4.5] decan-4-one (200 mg) was added with stirring. After stirring for 5 minutes at room temperature, 4- (2-chloroethyl) morpholine hydrochloride (79 mg) was added. The mixture was heated to 100 ° C. and maintained for 1 hour. After cooling, saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was decanted, dried over Na ₂ SO ₄ and the solvent was evaporated. Purification by silica gel chromatography (ethyl acetate) gave the desired product (180 mg, 73%) (MS: m / e = 585.1 (M + H ⁺ )).
[249] Example 5
[250] 8- (3,5-bis-trifluoro-benzoyl) -1-phenyl-3-pyridin-3-yl-methyl-1,3,8-triaza-spiro [4.5] decan-4-one
[251] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using the 3- (chloromethyl) pyridine hydrochloride, the title compound (MS: m / e = 563.3 (M + H ⁺ )) was prepared according to the method of Example 4.
[252] Example 6
[253] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl) -1-phenyl-1,3, 8-triaza-spiro [4.5] decan-4-one
[254] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 611.0 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-chloro-4,6-dimethoxy-1,3,5-triazine. It was.
[255] Example 7
[256] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3- (2-piperidin-1-yl-ethyl) -1,3,8-triaza-spiro [4.5] Decan-on
[257] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and 1- (2-chloroethyl) piperi Using the Dean hydrochloride, the title compound (MS: m / e = 583.2 (M + H ⁺ )) was prepared according to the method of Example 4.
[258] Example 8
[259] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3- (2-pyrrolidin-1-yl-ethyl) -1,3,8-triaza-spiro [4.5] Decan-4-one
[260] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and 1- (2-chloroethyl) pyrroli Using the Dean hydrochloride, the title compound (MS: m / e = 569.2 (M + H ⁺ )) was prepared according to the method of Example 4.
[261] Example 9
[262] 2- [8- (3,5-bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -acetamide
[263] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using the 2-bromoacetamide, the title compound (MS: m / e = 529.2 (M + H ⁺ )) was prepared according to the method of Example 4.
[264] Example 10
[265] 2- [8- (3,5-bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -N, N-dimethyl-acetamide
[266] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 557.2 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-chloro-N, N-dimethylacetamide.
[267] Example 11
[268] [8- (3,5-Bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -acetic acid methyl ester
[269] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using methyl bromoacetate, the title compound (MS: m / e = 544.2 (M + H ⁺ )) was prepared according to the method of Example 4.
[270] Example 12
[271] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-methoxymethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[272] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 516.2 (M + H ⁺ )) was prepared according to the method of Example 4 using bromomethyl methylether.
[273] Example 13
[274] 2- [8- (3,5-Bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -malonic acid Dimethyl ester
[275] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using dimethyl bromomalonate, the title compound (MS: m / e = 602.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[276] Example 14
[277] (R, S) -8- (3,5-Trifluoromethyl-benzoyl) -3- (2-hydroxy-3-phenoxy-propyl) -1-phenyl-1,3,8-triaza- Spiro [4.5] decan-4-one
[278] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using phenylglycidylether, the title compound (MS: m / e = 622.1 (M + H ⁺ )) was prepared according to the method of Example 4.
[279] Example 15
[280] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dichloro-pyrimidin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5 ] Decane-4-one
[281] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,4,6-trichloropyrimidine, the title compound (MS: m / e = 618.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[282] Example 16
[283] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3- (5-trifluoromethyl-pyridin-2-yl) -1,3,8-triaza-spiro [4.5 ] Decane-4-one
[284] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 617.1 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-chloro-5- (trifluoromethyl) pyridine.
[285] Example 17
[286] (R, S) -8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3- (3,3,3-trifluoro-2-hydroxy-propyl) -1, 3,8-triaza-spiro [4,5] decan-4-one
[287] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4,5] decan-4-one and 3-bromo-1,1 The title compound (MS: m / e = 584.0 (M + H ⁺ )) was prepared according to the method of Example 4 using, 1-trifluoro-2-propanol.
[288] Example 18
[289] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyridin-2-yl-methyl-1,3,8-triaza-spiro [4.5] decan-4-one
[290] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 563.3 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-picolichloride hydrochloride.
[291] Example 19
[292] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyridin-4-yl-methyl-1,3,8-triaza-spiro [4.5] decan-4-one
[293] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 563.3 (M + H ⁺ )) was prepared according to the method of Example 4 using 4-chloromethylpyridine hydrochloride.
[294] Example 20
[295] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4-chloro-pyrimidin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane -4-on
[296] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,4-dichloropyrimidine, the title compound (MS: m / e = 584.1 (M + H ⁺ )) was prepared according to the method of Example 4.
[297] Example 21
[298] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4-chloro-6-methyl-pyrimidin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[299] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,4-dichloro-6-methylpyrimidine, the title compound (MS: m / e = 598.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[300] Example 22
[301] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxy-propyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[302] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using (3-bromopropoxy) -t-butyldimethylsilane, the title compound (MS: m / e = 530.2 (M + H ⁺ )) was prepared according to the method of Example 4. Intermediate TBDMS-ether was partitioned using HCl in ethanol (3% concentrate).
[303] Example 23
[304] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4 -On
[305] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and (3-bromoethoxy)- Using t-butyldimethylsilane, the title compound (MS: m / e = 530.2 (M + H ⁺ )) was prepared according to the method of Example 4. Intermediate TBDMS-ether was partitioned using HCl in ethanol (3% concentrate).
[306] Example 24
[307] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[308] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using the 2-chloroethoxytrimethylsilane, the title compound (MS: m / e = 516.2 (M + H ⁺ )) was prepared according to the method of Example 4. Intermediate TMS-ethers were partitioned using silica gel chromatography.
[309] Example 25
[310] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyrimidin-2-yl-1,3,8-triaza-spiro [4.5] decan-4-one
[311] Carried out using 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and 2-chloropyrimidine The title compound (MS: m / e = 550.1 (M + H ⁺ )) was prepared according to the method of Example 4.
[312] Example 26
[313] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3,5-dichloro-pyridin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] Decan-4-one
[314] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,3,5-trichloropyridine, the title compound (MS: m / e = 617.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[315] Example 27
[316] 2- [8- (3,5-bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -6- Methyl-nicotinonitrile
[317] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 588.2 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-chloro-3-cyanopyridine.
[318] Example 28
[319] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -1-phenyl-1,3,8-triaza Spiro [4.5] decan-4-one
[320] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,3-dichloro-5- (trifluoromethyl) pyridine, the title compound (MS: m / e = 651.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[321] Example 29
[322] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (5-ethyl-pyrimidin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane -4-on
[323] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 578.0 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-chloro-5-ethylpyrimidine.
[324] Example 30
[325] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3- (4-trifluoromethyl-pyrimidin-2-yl) -1,3,8-triaza-spiro [ 4.5] decane-4-one
[326] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 618.1 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-chloro-4- (trifluoromethyl) pyrimidine.
[327] Example 31
[328] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-chloro-pyrazin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane- 4-on
[329] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,3-dichloropyrazine, the title compound (MS: m / e = 584.1 (M + H ⁺ )) was prepared according to the method of Example 4.
[330] Example 32
[331] [8- (3,5-Bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -acetic acid ethyl ester
[332] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using the ethyl bromoacetate, the title compound (MS: m / e = 558.2 (M + H ⁺ )) was prepared according to the method of Example 4.
[333] Example 33
[334] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-chloro-quinoxalin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane -4-on
[335] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,3-dichloroquinoxaline, the title compound (MS: m / e = 634.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[336] Example 34
[337] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (6-chloro-pyrazin-2-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane- 4-on
[338] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and Using 2,6-dichloropyrazine, the title compound (MS: m / e = 584.1 (M + H ⁺ )) was prepared according to the method of Example 4.
[339] Example 35
[340] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyrazin-2-yl-1,3,8-triaza-spiro [4.5] decan-4-one
[341] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 550.1 (M + H ⁺ )) was prepared according to the method of Example 4 using 2-chloropyrazine.
[342] Example 36
[343] [8- (3,5-Bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -acetonitrile
[344] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and The title compound (MS: m / e = 510.1 (M + H ⁺ )) was prepared according to the method of Example 4 using bromoacetonitrile.
[345] Example 37
[346] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy-pyrimidin-2-yl) -1-phenyl-1,3,8-triaza-spiro [ 4.5] decane-4-one
[347] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and 2-chloro-4,6-dimethok Using cipyrimidine, the title compound (MS: m / e = 610.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[348] Example 38
[349] (S) -8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3- (4,4,4-trifluoro-3-hydroxy-butyl) -1.3,8- Triaza-spiro [4.5] decane-4-one
[350] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one in 1,2-dimethoxyethane as a solvent and According to the method of Example 4 using toluene-4-sulfonic acid (S) -4,4,4-trifluoro-3-hydroxy-butyl ester, the title compound (MS: m / e = 598.0 ( M + H ⁺ )).
[351] Example 39
[352] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (3,4-dichloro-phenyl) -3- (4,6-dimethoxy- [1,3,5] triazine-2 -Yl) -1,3,8-triaza-spiro [4.5] decan-4-one
[353] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (3,4-dichloro-phenyl) -1,3,8-triaza-spiro [in solvent 1,2-dimethoxyethane] 4.5], according to the method of Example 4 using decan-4-one and 2-chloro-4,6-dimethoxy-1,3,5-triazine, the title compound (MS: m / e = 679.0 ( M + H ⁺ )).
[354] Example 40
[355] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (3-chloro-phenyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl ) -1,3,8-triaza-spiro [4.5] decan-4-one
[356] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (3-chloro-phenyl) -1,3,8-triaza-spiro [4.5] in solvent 1,2-dimethoxyethane Using decan-4-one and 2-chloro-4,6-dimethoxy-1,3,5-triazine, the title compound (MS: m / e = 645.1 (M < + > H ⁺ )) was prepared.
[357] Example 41
[358] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl) -1-o-tolyl-1, 3,8-triaza-spiro [4.5] decan-4-one
[359] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- in solvent 1,2-dimethoxyethane The title compound (MS: m / e = 625.1 (M + H ⁺ )) according to the method of Example 4 using one and 2-chloro-4,6-dimethoxy-1,3,5-triazine Was prepared.
[360] Example 42
[361] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl ) -1,3,8-triaza-spiro [4.5] decan-4-one
[362] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] in solvent 1,2-dimethoxyethane Using decan-4-one and 2-chloro-4,6-dimethoxy-1,3,5-triazine, the title compound (MS: m / e = 645.0 (M + H ⁺ )) was prepared.
[363] Example 43
[364] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (4-chloro-phenyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl ) -1,3,8-triaza-spiro [4.5] decan-4-one
[365] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-4-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decane in solvent 1,2-dimethoxyethane The title compound (MS: m / e = 645.1 (M + H) according to the method of Example 4 using 4-one and 2-chloro-4,6-dimethoxy-1,3,5-triazine ⁺ )) Was prepared.
[366] Example 44
[367] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-pyridin-3-yl-methyl-1,3,8-triaza-spiro [4.5] Decan-4-one
[368] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] in solvent 1,2-dimethoxyethane Using decan-4-one and 3- (chloromethyl) pyridine hydrochloride, the title compound (MS: m / e = 597.0 (M + H ⁺ )) was prepared according to the method of Example 4.
[369] Example 45
[370] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-pyridin-3-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- On
[371] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- in solvent 1,2-dimethoxyethane The title compound (MS: m / e = 577.0 (M + H ⁺ )) was prepared according to the method of Example 4 using one and 3- (chloromethyl) pyridine hydrochloride.
[372] Example 46
[373] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-methoxy-phenyl) -3-pyridin-3-yl-methyl-1,3,8-triaza-spiro [4.5 ] Decane-4-one
[374] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-methoxy-phenyl) -1,3,8-triaza-spiro [4.5 in solvent 1,2-dimethoxyethane ] Decan-4-one and 3- (chloromethyl) pyridine hydrochloride to give the title compound (MS: m / e = 592.1 (M + H ⁺ )) according to the method of Example 4.
[375] Example 47
[376] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl) -1- (2-methoxy- Phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[377] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-methoxy-phenyl) -1,3,8-triaza-spiro [4.5 in solvent 1,2-dimethoxyethane ] Decan-4-one and 2-chloro-4,6-dimethoxy-1,3,5-triazine, according to the method of Example 4 the title compound (MS: m / e = 640.2 (M ⁺ )) Was prepared.
[378] Example 48
[379] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-imidazol-1-yl-propyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane -4-on
[380] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxy-propyl) -1-phenyl-1,3,8-triaza-spiro [in dichloromethane (2 mL) [ 4.5] decane-4-one (128 mg, 0.25 mmol) and triethylamine (35 μl, 0.27 mmol) were cooled to 0 ° C. A solution of methanesulfonyl chloride (19 μl, 0.25 mmol) in dichloromethane (0.5 mL) was added and the mixture was stirred at 0 ° C. for 4 h. Sodium bicarbonate (saturated solution, 2.5 mL) was added, the phases were separated and the organic phase was dried over Na ₂ SO ₄ and the solvent was evaporated. Silica gel chromatography (ethyl acetate / n-hexane 1: 1) gave intermediate mesylate. The mesylate was dissolved in dimethylformamide (6 mL), sodium bicarbonate (70 mg, 0.74 mmol) and imidazole (26 mg, 0.37 mmol) were added and the mixture was stirred at 80 ° C. for 2 days. After filtration and evaporation of the solvent, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ / MeOH 9: 1) to give the desired product (23 mg, 16%) (MS: m / e = 580.1 (M + H ^+). )) Was obtained.
[381] Example 49
[382] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-isopropylamino-propyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane-4- On
[383] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxy-propyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one And using isopropylamine, the title compound (MS: m / e = 571.1 (M + H ⁺ )) was prepared according to the method of Example 48.
[384] Example 50
[385] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- [3- (4-methyl-piperazin-1-yl) -propyl] -1-phenyl-1,3,8-triaza Spiro [4.5] decan-4-one
[386] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxy-propyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one And using 1-methylpiperazine, the title compound (MS: m / e = 612.2 (M + H ⁺ )) was prepared according to the method of Example 48.
[387] Example 51
[388] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-propyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[389] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxy-propyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one And using dimethylamine to prepare the title compound (MS: m / e = 557.2 (M + H ⁺ )) according to the method of Example 48.
[390] Example 52
[391] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-imidazol-1-yl-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane -4-on
[392] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one And using imidazole, the title compound (MS: m / e = 566.2 (M + H ⁺ )) was prepared according to the method of Example 49.
[393] Example 53
[394] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-isopropylamino-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane-4- On
[395] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one And using isopropylamine, the title compound (MS: m / e = 557.2 (M + H ⁺ )) was prepared according to the method of Example 48.
[396] Example 54
[397] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- [2- (4-methyl-piperazin-1-yl) -ethyl] -1-phenyl-1,3,8-triaza Spiro [4.5] decan-4-one
[398] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one And using 1-methylpiperazine, the title compound (MS: m / e = 598.1 (M + H ⁺ )) was prepared according to the method of Example 48.
[399] Example 55
[400] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-dimethylamino-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[401] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one And using dimethylamine to prepare the title compound (MS: m / e = 543.2 (M + H ⁺ )) according to the method of Example 48.
[402] Example 56
[403] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-dimethylamino-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4 -On
[404] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one And using dimethylamine to prepare the title compound (MS: m / e = 557.2 (M + H ⁺ )) according to the method of Example 48.
[405] Example 57
[406] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-isopropylamino-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane- 4-on
[407] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4 Using the -one and isopropylamine, the title compound (MS: m / e = 571.1 (M + H ⁺ )) was prepared according to the method of Example 48.
[408] Example 58
[409] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-4-one
[410] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4 Using the -one and pyrrolidine, the title compound (MS: m / e = 583.2 (M + H ⁺ )) was prepared according to the method of Example 48.
[411] Example 59
[412] 3- [8- (3,5-Bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -ethyl propionate ester
[413] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (1.0 g, 2.1 in THF (10 mL)) mmol), cesium fluoride (32 mg, 0.21 mmol) and tetraethoxysilane (475 μl, 2.1 mmol) were added ethyl acrylate (254 μl, 2.3 mmol). The mixture was stirred at rt for 1 day. The solvent was evaporated and the residue was purified by silica gel chromatography (ethyl acetate / n-hexane 1: 2) to afford the desired product (0.9 g, 75%) (MS: m / e = 572.1 (M + H ⁺ )). Obtained.
[414] Example 60
[415] 3- [8- (3,5-Bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] dec-3-yl] -methyl propionate ester
[416] Example 59, using 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and methyl acrylate The title compound (MS: m / e = 558.2 (M + H ⁺ )) was prepared according to the method of.
[417] Example 61
[418] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (6-chloro-pyrimidin-4-yl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane -4-on
[419] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (0.1 g, 0.21) in xylene (5 mL) mmol), potassium carbonate (59 mg, 0.42 mmol), CuCl (2 mg, 0.021 mmol), tris [2- (2-methoxyethoxy) -ethyl] -amine (1.5 μl) and 4,6-dichloropyrimidine ( 32 mg, 0.21 mmol) was stirred and boiled for 18 hours. The mixture was cooled and washed with water and washed again with ammonia in water (10%) and water. The solvent was evaporated and the residue was purified by silica gel chromatography (ethyl acetate / n-hexane 1: 2) to afford the desired product (29 mg, 24%) (mp212-214 ° C.) (MS: m / e = 584.1 (M +). H ⁺ )).
[420] Example 62
[421] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyridin-4-yl-1,3,8-triaza-spiro [4.5] decan-4-one
[422] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (0.1 g, in dichloromethane (2 mL) 0.21 mmol), 4-pyridylboronic acid (52 mg, 0.42 mmol), cupric acetate (58 mg, 0.32 mmol) and triethylamine (60 μL, 0.42 mmol) were stirred at room temperature for 2 days. Purification by silica gel chromatography (ethyl acetate) gave the desired product (26 mg, 21%) (MS: m / e = 549.1 (M + H ⁺ )).
[423] Example 63
[424] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (3-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[425] Solution of 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (3-chloro-phenylamino) -piperidine-4-carbonitrile (6.2 g, 13 mmol) in formic acid (80 mL) To this was added cooled acetic anhydride (80 ml). Stir at room temperature for 2 hours. The solvent was evaporated to yield 7.2 g of white foam, which was used for the next step without further purification.
[426] The solid was dissolved in formic acid (74 mL) and acetic acid (7.4 mL) was added. The solution was stirred overnight at room temperature. The solvent was evaporated and saturated sodium bicarbonate solution (150 mL) was added, then the mixture was extracted with ethyl acetate. The organic phase was decanted and dried over Na ₂ SO ₄ and the solvent was evaporated. The residue was white foam (7.5 g) and used for the next step without further purification.
[427] The solid was dissolved in triethyl orthoformate (320 mL) and boiled for a week. After cooling, the solvent was evaporated to give 8.5 g of brown foam which was used for the next step without further purification.
[428] The solid was dissolved in methanol (300 mL) and sodium borohydride (1.03 g, 27 mmol) was added to the solution, and then the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 1 hour. After cooling the solvent was evaporated and the residue was dissolved in dichloromethane (250 mL) and washed with ice ammonia (12%). The phases were separated and the aqueous phase was extracted with dichloromethane and then the organic phase was decanted and dried over MgSO ₄ . Evaporation gave 8.1 g of a light brown residue. Purification by silica gel chromatography (dichloromethane / methanol 50: 1) gave the desired product (2.7 g, 41%) (mp 235-236 ° C., MS: m / e = 506.2 (M + H ⁺ )).
[429] Example 64
[430] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (4-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[431] The title compound according to the method of Example 63 using 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (4-chloro-phenylamino) -piperidine-4-carbonitrile (mp 233-235 ° C., MS: m / e = 506.2 (M + H ⁺ )).
[432] Example 65
[433] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (3,4-dichloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[434] According to the method of Example 63 using 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (3,4-dichloro-phenylamino) -piperidine-4-carbonitrile The title compound (mp 220-222 ° C., MS: m / e = 540.1 (M + H ⁺ )) was prepared.
[435] Example 66
[436] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[437] The title compound (mp 164-), according to the method of Example 63, using 1- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolylamino-piperidine-4-carbonitrile. 168 ° C., MS: m / e = 486.3 (M + H ⁺ )).
[438] Example 67
[439] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[440] The title compound, according to the method of Example 63, using 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (2-chloro-phenylamino) -piperidine-4-carbonitrile (mp 157-159 ° C., MS: m / e = 506.2 (M + H ⁺ )) was prepared.
[441] Example 68
[442] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-methoxy-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[443] The title above, according to the method of Example 63, using 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (2-methoxy-phenylamino) -piperidine-4-carbonitrile Compound (MS: m / e = 502.2 (M + H ⁺ )) was prepared.
[444] Example 69
[445] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (4.5-dihydro-1H-imidazol-2-yl-methyl) -1-phenyl-1,3,8-triaza- Spiro [4.5] decan-4-one
[446] Ethylenediamine-trimethylaluminum complex (0.8 mmol) was dissolved in [8- (3,5-bis-trifluoromethyl-benzoyl) -4-oxo-1-phenyl-1,3,8-tri in toluene (1.5 mL). To a solution of aza-spiro [4.5] dec-3-yl] -acetonitrile (0.2 g, 0.4 mmol) was added and heated at 120 ° C. for 18 hours. Purification by silica gel chromatography (dichloromethane / methanol 9: 1) gave the desired product (14 mg, 6%) (MS: m / e = 554.2 (M + H ⁺ )).
[447] Example 70
[448] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-methyl-1,3,8-triaza-spiro [4.5] decan-4-one
[449] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one (253 mg) Suspension in, 2-dimethoxyethane (3 mL) and sodium hydride (24 mg, 60%) were added with stirring at room temperature. After 15 minutes, methyliodide (78 mg) was added and stirred overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic phase was decanted, dried over Na ₂ SO ₄ and the solvent was evaporated. Purification by silica gel chromatography (hexane / ethyl acetate = 1: 1) afforded the desired product (152 mg, 59%) (MS: m / e = 520.1 (M + H ⁺ )).
[450] Example 71
[451] 3- (1-benzyl-1H-imidazol-2-ylmethyl) -8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8 -Triaza-spiro [4.5] decan-4-one
[452] 8- (3,5-Bistrifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one (253 mg) Suspended in 2-dimethoxyethane (3 mL) and sodium hydride (24 mg, 60%) was added with stirring at room temperature. After 15 minutes, 1-benzyl- (2-chloromethyl) -imidazole (121 mg) was added and stirred at 80 ° C. overnight. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was decanted and dried over Na ₂ SO ₄ and the solvent was evaporated. Purification by silica gel chromatography (hexane / ethyl acetate = 1: 1) gave the desired product (215 mg, 64%) (MS: m / e = 676.0 (M + H ⁺ )).
[453] Example 72
[454] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (2-oxo-oxazolidin-5-ylmethyl) -1,3,8- Triaza-spiro [4.5] decane-4-one
[455] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 5-chloromethyl Using the 2-oxazolidinone the title compound (MS: m / e = 604.9 (M + H ⁺ )) was prepared according to the method of Example 71.
[456] Example 73
[457] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (2-dimethylamino-ethyl) -1,3,8-triaza-spiro [4.5 ] Decane-4-one
[458] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 1-chloro- The title compound (MS: m / e = 577.0 (M + H ⁺ )) was prepared according to the method of Example 71 using 2-dimethylaminoethane hydrochloride.
[459] Example 74
[460] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (2-pyrrolidin-1-yl-ethyl) -1,3,8-tri Aza-spiro [4.5] decane-4-one
[461] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 1- (2 Using -chloroethyl) -pyrrolidine hydrochloride, the title compound (MS: m / e = 603.0 (M + H ⁺ )) was obtained according to the method of Example 71.
[462] Example 75
[463] 8- (3,5, -bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (2-methyl-thiazol-4-ylmethyl) -1,3,8- Triaza-spiro [4.5] decane-4-one
[464] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 4-chloromethyl Using 2-methylthiazole hydrochloride, the title compound (MS: m / e = 617.0 (M + H ⁺ )) was obtained according to the method of Example 71.
[465] Example 76
[466] 8- (3,5, -bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (6-chloro-pyrimidin-4-yl) -1,3,8-tri Aza-spiro [4.5] decane-4-one
[467] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 4,6- Using dichloropyrimidine, the title compound (MS: m / e = 618.0 (M + H ⁺ )) was obtained according to the method of Example 71.
[468] Example 77
[469] 8- (3,5, -bis-trifluoro-benzoyl) -1- (2-chloro-phenyl) -3- (3,5-dichloro-pyridin-2-yl) -1,3,8-tri Aza-spiro- [4.5] decan-4-ones
[470] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 2,3, Using 5-trichloropyridine, the title compound (MS: m / e = 652.9 (M + H ⁺ )) was obtained according to the method of Example 71.
[471] Example 78
[472] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (4-trifluoromethyl-pyrimidin-2-yl) -1,3,8 -Triaza-spiro [4.5] decan-4-one
[473] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 2-chloro- Using 4- (trifluoromethyl) -pyrimidine, the title compound (MS: m / e = 651.9 (M + H ⁺ )) was obtained following the method of Example 71.
[474] Example 79
[475] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-pyrimidin-2-yl-1,3,8-triaza-spiro [4.5] decane -4-on
[476] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 2-chloro- Using pyrimidine, the title compound (MS: m / e = 584.0 (M + H ⁺ )) was obtained according to the method of Example 71.
[477] Example 80
[478] 2- [8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -4-oxo-1,3,8-triaza-spiro [4.5] deck-3 -Yl] -N, N-dimethyl-acetamide
[479] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 2-chloro- Using N, N-dimethylacetamide, the title compound (MS: m / e = 591.0 (M + H ⁺ )) was obtained according to the method of Example 71.
[480] Example 81
[481] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (3-dimethylamino-propyl) -1,3,8-triaza-spiro [4.5 ] Decane-4-one
[482] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 3-dimethylamino Using propylchloride hydrochloride, the title compound (MS: m / e = 591.1 (M + H ⁺ )) was obtained according to the method of Example 71.
[483] Example 82
[484] 8- (3,5, -bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (3,5-dimethyl-isoxazol-4-yl-methyl) -1,3 , 8-triaza-spiro [4.5] decan-4-one
[485] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 4- (chloro Using methyl) -3,5, -dimethylisoxazole, the title compound (MS: m / e = 615.1 (M + H ⁺ )) was obtained according to the method of Example 71.
[486] Example 83
[487] 8- (3,5, -bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-pyridin-3-yl-1,3,8-triaza-spiro [4.5] decane -4-on
[488] Dichloromethane (5 mL) to 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decane-4 -One (253 mg) was dissolved and 3-pyridineboronic acid (246 mg), triethylamine (101 mg) and copper (II) -acetate (136 mg) were added. The mixture was stirred at rt overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2: 1) to afford the desired compound (120 mg, 41%) (MS: m / e = 583.0 (M + H ⁺ )). Obtained.
[489] Example 84
[490] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-pyridin-4-yl-1,3,8-triaza-spiro [4.5] decane- 4-on
[491] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 4-pyrimidine Using boronic acid, the title compound (MS: m / e = 583.0 (M + H ⁺ )) was obtained according to the method of Example 83.
[492] Example 85
[493] 1-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[494] The title compound (MS: m / e) according to the method of Example 63 using 4-benzylamino-1- (3,5-bis-trifluoromethyl-benzoyl) -piperidine-4-carbonitrile = 486.3 (M + H ⁺ )).
[495] Example 86
[496] 1-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -3-methyl-1,3,8-triaza-spiro [4.5] decan-4-one
[497] 1-benzyl-8- (3,5, -bis-trifluoromethyl-benzoyl) -1,3,8-triaza-spiro [4.5] decan-4-one and methyliodide The title compound (MS: m / e = 500.3 (M + H ⁺ )) was obtained according to the method of Example 71.
[498] Example 87
[499] 1-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-pyrrolidin-1-yl-ethyl) -1,3,8-triaza-spiro [4.5] Decan-4-one hydrochloride
[500] 1-benzyl-8- (3,5, -bis-trifluoromethyl-benzoyl) -1,3,8-triaza-spiro [4.5] decan-4-one and 1- (2-chloroethyl)- Using pyrrolidine, the title compound (MS: m / e = 583.2 (M + H ⁺ )) was obtained according to the method of Example 71.
[501] Example 88
[502] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-benzyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[503] Dissolve 1-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1,3,8-triaza-spiro [4.5] decan-4-one (292 mg) in methanol (5 mL) And Pd / C (10%, 78 mg) was added. After stirring for 30 minutes at room temperature and hydrogen atmosphere (1 bar), the mixture was filtered through celite and the solvent was evaporated.
[504] The residue was dissolved in 1,2-dichloroethane (5 mL) and 2-chlorobenzaldehyde (71 mg), acetic acid (300 mg) and sodium triacetoxyborohydride (148 mg) were added. The reaction mixture was stirred at rt overnight. Water was added and the organic phase was separated and dried. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (160 mg, 62%) (MS: m / e = 520.1 (M + H ⁺ )).
[505] Example 89
[506] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (3-chloro-benzoyl) -3-methyl-1,3,8-triaza-spiro [4.5] decan-4-one
[507] 1-benzyl-8- (3,5, -bis-trifluoromethyl-benzoyl) -3-methyl-1,3,8-triaza-spiro [4.5] decan-4-one and 3-chlorobenzaldehyde Using this, the title compound (MS: m / e = 534.2 (M + H ⁺ )) was obtained according to the method of Example 88.
[508] Example 90
[509] 1-benzoyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1,3,8-triaza-spiro [4.5] decan-4-one
[510] Dissolve 1-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1,3,8-triaza-spiro [4.5] decan-4-one (50 mg) in methanol (2 mL). And Pd / C (10%, 13 mg) was added. After stirring for 30 minutes at room temperature and hydrogen atmosphere (1 bar), the mixture was filtered through celite and the solvent was evaporated.
[511] The residue was dissolved in dichloroethane (2 mL), triethylamine (22 mg) was added and the compound was cooled to 0 ° C. Benzoylchloride (14 mg) was added and the mixture was stirred at this temperature for 1 hour. Water was added and the organic layer was separated and dried. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (30 mg, 60%) (MS: m / e = 500.2 (M + H ⁺ )).
[512] Example 91
[513] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[514] To a solution of 1-benzyl-piperidin-4-one (18.9 g, 100 mmol) in acetic acid (150 mL) was added aniline (10.2 g, 110 mg) and trimethylsilyl cyanide (12.5 mL, 100 mmol). The suspension was stirred at rt for 22 h. The reaction mixture was then added to ice water (350 mL) and ammonia until pH 9 was added. The reaction mixture was then extracted with dichloromethane, decanted organic phase, washed with brine and dried over MgSO ₄ . The solvent was evaporated and the residue was crystallized with diethyl ether to give intermediate amino nitrile (19.2 g, 66%).
[515] To a solution of the intermediate amino nitrile (16.0 g, 55 mmol) in formic acid (210 mL) was added cooled acetic anhydride (210 mL). Stir at room temperature for 2.5 hours. The solvent was evaporated to give a white foam which was used for the next step without further purification.
[516] The foam was dissolved in formic acid (210 mL) and acetic acid (21 mL) was added. The solution was stirred overnight at room temperature. The solvent was evaporated and saturated sodium bicarbonate solution (300 mL) was added and the mixture was extracted with dichloromethane. The organic layer was decanted and dried over Na ₂ SO ₄ and the solvent was evaporated. The residue was white foam (18.2 g) which was used for the next step without further purification.
[517] The solid was dissolved in triethyl orthoformate (500 mL) and boiled for 1 week. After cooling, the solvent was evaporated to give 18.5 g of brown foam, which was used in the next step without further purification.
[518] The brown foam (7.68g, 24mmol) was dissolved in THF (80ml) and added slowly to methylmagnesium bromide (24ml, 3M in diethylether, 72mmol) at room temperature and then stirred at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate. The organic phase was decanted and dried over MgSO ₄ . Evaporation gave 7.64 g of a light brown residue. Purification by silica gel chromatography (hexane, ethyl acetate, triethyl amine 40: 20: 1) gave intermediate n-benzyl protected piperidine (3.7 g, 46%).
[519] The intermediate (3.7 g, 11 mmol) was dissolved in methanol (125 mL) and Pd / C (10%, 1.25 g) was added. After stirring overnight at hydrogen atmosphere (1 bar) and at room temperature, the mixture was filtered and the solvent was evaporated.
[520] The residue was dissolved in dichloromethane (200 mL), triethyl amine (2.1 mL, 15 mmol) and 3,5-bistrifluoromethyl benzoyl chloride (1.8 mL, 10 mmol) were added and the mixture was stirred at rt overnight. It was. Water was added and the organic layer was separated and dried. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane, ethyl acetate, triethyl amine 20: 10: 1) to give the desired product (4.17 g, 86%) (MS: m / e = 486.3 (M + H). ⁺ )) Was obtained.
[521] Example 92
[522] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-phenethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[523] Using 1-benzyl-piperidin-4-one, aniline and phenethyl magnesium chloride, the title compound (MS: m / e = 576.0 (M + H ⁺ )) was prepared according to the method of Example 91. .
[524] Example 93
[525] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-isopropyl-1-phenyl-1,3,8-triaza-spiro [4.5] -decan-4-one
[526] Using 1-benzyl-piperidin-4-one, aniline and isopropyl magnesium chloride, the title compound (MS: m / e = 514.3 (M + H ⁺ )) was obtained according to the method of Example 91 above. It was.
[527] Example 94
[528] (rac) -2-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[529] Using 1-benzyl-piperidin-4-one, aniline and benzyl magnesium chloride, the title compound (MS: m / e = 562.2 (M + H ⁺ )) was obtained according to the method of Example 91 above. .
[530] Example 95
[531] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -1,2-diphenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[532] Using 1-benzyl-piperidin-4-one, aniline and phenyl magnesium chloride, the title compound (MS: m / e = 548.1 (M + H ⁺ )) was obtained according to the method of Example 91 above. .
[533] Example 96
[534] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[535] The title compound (MS: m / e = 500.2 (M + H ⁺ )) according to the method of Example 91 above using 1-benzyl-piperidin-4-one, 1-methyl aniline and methyl magnesium bromide Obtained.
[536] Example 97
[537] (rac) -2-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[538] The title compound (MS: m / e = 576.0 (M + H ⁺ )) according to the method of Example 91 above using 1-benzyl-piperidin-4-one, 1-methyl aniline and benzyl magnesium chloride Obtained.
[539] Example 98
[540] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-phenyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[541] The title compound (MS: m / e = 562.3 (M + H ⁺ )) according to the method of Example 91 above using 1-benzyl-piperidin-4-one, 1-methyl aniline and phenyl magnesium chloride Obtained.
[542] Example 99
[543] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-3-pyridin-3-yl-methyl-1,3,8-triaza-spiro [ 4.5] decane-4-one
[544] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (200 mg, 0.41 mmol) was dissolved in dimethyl formamide (10 mL) and sodium hydride (40 mg, 60% in mineral oil, 1 mmol) and 3-chloromethyl pyridinium chloride (82 mg, 5 mmol) were added and stirred overnight at room temperature. Water (30 mL) was added and the reaction mixture was extracted with ethyl acetate. The organic phase was decanted and dried over MgSO ₄ and the solvent was evaporated. The residue was purified by silica gel chromatography (ethyl acetate) to give the desired product (219 mg, 93%) (MS: m / e = 577.0 (M + H ⁺ )).
[545] Example 100
[546] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2,3-dimethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[547] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one 1-benzyl Using the piperidin-4-one and methyl iodide, the title compound (MS: m / e = 500.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[548] Example 101
[549] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-3- (2-pyrrolidin-1-yl-ethyl) -1,3,8 -Triaza-spiro [4.5] decan-4-one
[550] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one 1-benzyl Using the piperidin-4-one and 1- (2-chloroethyl) pyrrolidine, the title compound (MS: m / e = 583.2 (M + H ⁺ )) was obtained according to the method of Example 99. Prepared.
[551] Example 102
[552] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-methyl-thiazol-4-yl-methyl) -1-phenyl-1,3, 8-triaza-spiro [4.5] decan-4-one
[553] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one 1-benzyl Prepare the title compound (MS: m / e = 597.0 (M + H ⁺ )) according to the method of Example 99 using piperidin-4-one and 4-chloromethyl-2-methylthiazole It was.
[554] Example 103
[555] (rac) -8- (3.5-bis-trifluoromethyl-benzoyl) -3-cyclopropylmethyl-2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-4- On
[556] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one 1-benzyl The title compound (MS: m / e = 540.3 (M + H ⁺ )) was prepared according to the method of Example 99 using piperidin-4-one and cyclopropylmethyl bromide.
[557] Example 104
[558] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-propyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one
[559] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one 1-benzyl The title compound (MS: m / e = 571.1 (M + H ⁺ )) was prepared according to the method of Example 99 using piperidin-4-one and 3-dimethylamino-1-propyl chloride .
[560] Example 105
[561] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2,3-dimethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- On
[562] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and methyl yo Using the amide, the title compound (MS: m / e = 571.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[563] Example 106
[564] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3 , 8-triaza-spiro [4.5] decan-4-one
[565] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using 1- (2-chloroethyl) -pyrrolidine, the title compound (MS: m / e = 597.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[566] Example 107
[567] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-piperidin-1-yl-ethyl) -1-o-tolyl-1,3 , 8-triaza-spiro [4.5] decan-4-one
[568] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using 1- (2-chloroethyl) -piperidine, the title compound (MS: m / e = 610.3 (M + H ⁺ )) was prepared according to the method of Example 99.
[569] Example 108
[570] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-piperazin-1-yl-ethyl) -1-o-tolyl-1,3, 8-triaza-spiro [4.5] decan-4-one
[571] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using 1- (2-chloroethyl) -piperazine, the title compound (MS: m / e = 626.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[572] Example 109
[573] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-3-pyridin-4-yl-1,3,8-triaza-spiro [4.5] Decan-4-one
[574] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one and pyridine- Using the 4-boronic acid, the title compound (MS: m / e = 563.2 (M + H ⁺ )) was prepared according to the method of Example 63.
[575] Example 110
[576] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione
[577] To a solution of 1-benzyl-piperidin-4-one (18,9 g, 100 mmol) in acetic acid (150 mL) was added aniline (10.2 g, 110 mmol) and trimethylsilyl cyanide (12.5 mL, 100 mmol) at 0 ° C. It was. The suspension was stirred at rt for 22 h. The reaction mixture was then added to ice water (350 mL) and ammonia was added until pH 9. The mixture was then extracted with dichloromethane, decanted organic phase, washed with brine and dried over MgSO ₄ . The solvent was evaporated and the residue was crystallized with diethyl ether to give intermediate amino nitrile (19.2 g, 66%).
[578] To a solution of intermediate amino nitrile (5.0 g, 17.2 mmol) in dichloromethane (50 mL) was added chlorosulfonyl isocyanate (1.65 mL, 19 mmol). Stir at room temperature for 1 hour. The solvent was evaporated to give a white solid which was used in the next step without further purification.
[579] The white solid was suspended in 1N hydrochloric acid (50 mL) and refluxed for 2 hours. The pH was adjusted to exactly 7 by addition of 15% sodium hydroxide solution, then the mixture was extracted with dichloromethane. The organic phase was decanted and dried over MgSO ₄ . Evaporation gave 5.4 g of solid residue. Purification by silica gel chromatography (hexane, ethyl acetate 1: 1) afforded the intermediate n-benzyl protected spirpiperidine (2.6 g, 45%).
[580] The intermediate (500 mg, 1.5 mmol) was dissolved in methanol (30 mL) and Pd / C (10%, 100 mg) and 5 drops of concentrated hydrochloric acid were added. After stirring overnight at hydrogen atmosphere (1 bar) and at room temperature, the mixture was filtered and the solvent evaporated.
[581] The residue was dissolved in dichloromethane (20 mL), triethylamine (0.63 mL, 4.5 mmol) and 3,5-bistrifluoromethyl benzoyl chloride (0.27 mL, 1.5 mmol) were added and the mixture was allowed to stand overnight at room temperature. Stirred at. Water was added and the organic layer was separated and dried. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane, ethyl acetate 1: 1) to afford the desired product (414 mg, 57%) (MS: m / e = 486.3 (M + H ⁺ )). .
[582] Example 111
[583] 8- (3,5-bis-trifluoro-benzoyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione
[584] Using 1-benzyl-piperidin-4-one and o-toluidine, the title compound (MS: m / e = 498.3 (M + H ⁺ )) was prepared according to the method of Example 110.
[585] Example 112
[586] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyridin-3-yl-methyl-1,3,8-triaza-spiro [4.5] decane-2,4- Dion
[587] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 3- (hydroxymethyl)- Using pyridine, the title compound (MS: m / e = 577.0 (M + H ⁺ )) was prepared according to the method of Example 121.
[588] Example 113
[589] 8- (3,5-bis-trifluoromethyl-benzoyl) -1,3-diphenyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione
[590] The title compound (MS: m / e = 562.2 (M + H ⁺ )) was prepared according to the method of Example 110 using 1-benzyl-piperidin-4-one, aniline and phenyl isocyanate.
[591] Example 114
[592] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-pyridin-3-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2, 4-dion
[593] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 3- (hydroxymethyl Using) -pyridine, the title compound (MS: m / e = 591.1 (M + H ⁺ )) was prepared according to the method of Example 121.
[594] Example 115
[595] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-2,4-dione
[596] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 1- (2-chloro Using the ethyl) -pyrrolidine, the title compound (MS: m / e = 597.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[597] Example 116
[598] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3,5-dimethyl-isoxazol-4-yl-methyl) -1-o-tolyl-1,3,8-triaza Spiro [4.5] decan-2,4-dione
[599] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 4- (chloromethyl) The title compound (MS: m / e = 609.0 (M + H ⁺ )) was prepared according to the method of Example 99 using -3,5-dimethylisoxazole.
[600] Example 117
[601] 3- (1H-Benzoimidazol-2-yl-methyl) -8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-2,4-dione
[602] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 2- (chloromethyl) Using benzimidazole, the title compound (MS: m / e = 630.0 (M + H ⁺ )) was prepared according to the method of Example 99.
[603] Example 118
[604] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-methyl-thiazol-4-yl-methyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione
[605] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 4-chloromethyl-2 Using -methylthiazole, the title compound (MS: m / e = 611.0 (M + H ⁺ )) was prepared according to the method of Example 99.
[606] Example 119
[607] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- [1,2,4] oxadiazol-3-yl-methyl-1-o-tolyl-1,3,8-triaza Spiro [4.5] decan-2,4-dione
[608] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 3- (chloromethyl) Using the -1,2,4-oxadiazole, the title compound (MS: m / e = 581.2 (M ⁺ )) was prepared according to the method of Example 99.
[609] Example 120
[610] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-oxo-oxazolidin-5-yl-methyl) -1-o-tolyl-1,3,8-triaza- Spiro [4.5] decane-2,4-dione
[611] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 5-chloromethyl-2 Using the oxazolidinone the title compound (MS: m / e = 599.0 (M ⁺ )) was prepared according to the method of Example 99.
[612] Example 121
[613] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-2-yl-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-2,4- Dion
[614] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione (200 mg, 0.41 mmol) Dissolved in oxane (10 mL) and triphenylphosphine (145 mg, 0.54 mmol), perfuryl alcohol (53.1 mg, 0.54 mmol) and diethylazodicarboxylate (40% in toluene, 0.54 mmol) were added sequentially Stir overnight at room temperature. The solvent was evaporated and the residue was purified by silica gel chromatography (dichloromethane) to give the desired product (143 mg, 61%) (MS: m / e = 566.1 (M + H ⁺ )).
[615] Example 122
[616] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-3-yl-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-2,4- Dion
[617] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro- [4.5] decane-2,4-dione and 3-furan methanol , The title compound (MS: m / e = 566.1 (M ⁺ )) was prepared according to the method of Example 121.
[618] Example 123
[619] (S) -8- (3,5-bis-trifluoromethyl-benzoyl) -3- (5-oxo-pyrrolidin-2-yl-methyl) -1-phenyl-1,3,8-tri Aza-spiro [4.5] decane-2,4-dione
[620] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-1,3,8-triaza-spiro- [4.5] decane-2,4-dione and (S) -5- ( Using hydroxymethyl) -2-pyrrolidinone, the title compound (MS: m / e = 583.1 (M ⁺ )) was prepared according to the method of Example 121.
[621] Example 124
[622] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (5-methyl-isoxazol-3-yl-methyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione
[623] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 5-methylisoxazole Using 3-methanol, the title compound (MS: m / e = 595.0 (M ⁺ )) was prepared according to the method of Example 121.
[624] Example 125
[625] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-3-yl-ethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2, 4-dion
[626] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 3-furan-methanol Using this, the title compound (MS: m / e = 580.1 (M ⁺ )) was prepared according to the method of Example 121.
[627] Example 126
[628] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-2-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2, 4-dion
[629] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and perfuryl alcohol , According to the method of Example 121, to prepare the title compound (MS: m / e = 580.0 (M ⁺ )).
[630] Example 127
[631] 8- (3,5-bis-trifluoro-benzoyl) -3-thiophen-2-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2, 4-dion
[632] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and 2-thiophene methanol Using the title compound according to the method of Example 121 (MS: m / e = 596.0 (M ⁺ )) to prepare.
[633] Example 128
[634] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-morpholin-4-yl-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5 ] Decane-2,4-dione
[635] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione and N- (2-hydr Using oxyethyl) morpholine, the title compound (MS: m / e = 613.1 (M ⁺ )) was prepared according to the method of Example 121.
[636] Example 129
[637] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-hydroxy-1,3-diphenyl-1,3,8-triaza-spiro [4.5] decan-2-one
[638] To a solution of 1-benzyl-piperidin-4-one (18.9 g, 100 mmol) in acetic acid (150 mL) was added aniline (10.2 g, 110 mmol) and trimethylsilyl cyanide (12.5 mL, 100 mmol) at 0 ° C. . The suspension was stirred at rt for 22 h. The reaction mixture was then added to ice water (350 mL) and ammonia was added until pH 9. The mixture was extracted with dichloromethane and then the organic phase was decanted, washed with brine and dried over MgSO ₄ . The solvent was evaporated and the residue was crystallized with diethyl ether to give intermediate amino nitrile (19.2 g, 66%).
[639] To a solution of this intermediate amino nitrile (5.0 g, 17.2 mmol) in dichloromethane (50 mL) was added phenyl isocyanate (2.20 mL, 20 mmol). Stirred at room temperature for 1 hour. The solvent was evaporated to give a white solid which was used in the next step without further purification.
[640] The white solid was suspended in 1N hydrochloric acid (50 mL) and refluxed for 2 hours. After adjusting the pH to exactly 7 by adding 15% sodium hydroxide solution, the mixture is extracted with dichloromethane. The organic phase was decanted, dried over MgSO ₄ and evaporated. Purification by silica gel chromatography (hexane, ethyl acetate 1: 1) afforded n-benzyl protected spirpiperidine (5.54 g, 78%).
[641] The n-benzyl protected spirpiperidine (4.0 g, 9.7 mmol) was dissolved in tetrahydrofuran (50 mL) and diisobutyl aluminum hydride (24 mL, 1M in THF) was added at 0 ° C. The reaction mixture was stirred at rt overnight and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane, ethyl acetate, triethylamine 40: 10: 1) to give a reduced intermediate (874 mg, 22%).
[642] The intermediate (870 mg, 2,1 mmol) was dissolved in methanol (30 mL) and Pd / C (10%, 200 mg) and 5 drops of concentrated hydrochloric acid were added. After stirring overnight under hydrogen atmosphere (1 bar) and room temperature, the mixture was filtered and the solvent was evaporated.
[643] The residue was dissolved in dichloromethane (20 mL), triethylamine (1.2 mL, 8.5 mmol) and 3,5-bistrifluoromethyl benzoyl chloride (0.42 mL, 2.3 mmol) were added and the mixture was at room temperature. Stir overnight. Water was added and the organic layer was separated and dried. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane, ethyl acetate 1: 1) to afford the desired product (497 mg, 42%) (MS: m / e = 564.1 (M + H ⁺ )).
[644] Example 130
[645] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-methoxy-1,3-diphenyl-1,3,8-triaza-spiro [4.5] decan-2-one
[646] The title compound (MS: m / e = 578.0 (M ⁺ )) was obtained as a byproduct of Example 129.
[647] Example 131
[648] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one
[649] To a solution of 1-benzyl-piperidin-4-one (37.8 g, 200 mmol) in acetic acid (300 mL) o-toluidine (23.8 mg, 200 mmol) and trimethylsilyl cyanide (25.0 mL, 200 mmol) at 0 ° C. Added. The suspension was stirred for 22 hours at room temperature. The reaction mixture was then added to ice water (500 mL) and ammonia was added until pH 9 was reached. The mixture was extracted with dichloromethane and the organic phase was decanted, washed with brine and dried over MgSO ₄ . The solvent was evaporated and the residue was crystallized with diethyl ether to give intermediate amino nitrile (46.2 g, 75%).
[650] The intermediate amino nitrile (29.5 g, 96 mmol) was dissolved in acetic acid (200 mL), PtO ₂ (1,3 g, 5.7 mmol) was added and the reaction mixture was hydrogenated at 2.7 bar and room temperature for 3 days. Acetic acid was evaporated and treated with saturated sodium bicarbonate solution until the residue was at pH 9. The mixture was then extracted with dichloromethane. The organic layer was decanted and dried over MgSO ₄ . Evaporation gave 21.2 g (71%) of oil.
[651] To a solution of intermediate triamine (3.2 g, 10.2 mmol) in dichloromethane (330 mL) and triethylamine (2.9 mL, 20.5 mmol), trichloromethyl chloroformate (0.446 mL, 3.6 mmol) in dichloromethane (30 mL) ) Was added at -20 ° C. The reaction mixture was then stirred at rt overnight. Water (50 mL) was added and the mixture was extracted with dichloromethane. The organic phase was decanted and dried over MgSO ₄ . Evaporation and purification by silica gel chromatography (dichloromethane / methanol 99: 1) yielded the intermediate N-benzyl protected spirpiperidine (1.4 g, 41%).
[652] The intermediate N-benzyl protected spirpiperidine (3.05 g, 9.1 mmol) was dissolved in methanol (120 mL) and Pd / C (10%, 610 mg) and 20 drops of concentrated hydrochloric acid were added. After stirring overnight under hydrogen atmosphere (1 bar) and room temperature, the mixture was filtered and the solvent was evaporated.
[653] The residue was dissolved in dichloromethane (100 mL), triethylamine (3.73 mL, 26.6 mmol) and 3,5-bistrifluoromethyl benzoyl chloride (2.45 mL, 8.9 mmol) were added, then the mixture Was stirred at rt overnight. Water was added and the organic layer was separated and dried. The solvent was evaporated and recrystallized with dichloromethane to afford the desired product of white crystals (3.29 g, 76%) (MS: m / e = 486.3 (M + H ⁺ )).
[654] Example 132
[655] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-2-one
[656] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one and 1- (2-chloroethyl) Using pyrrolidine, the title compound (MS: m / e = 583.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[657] Example 133
[658] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[659] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- in solvent 1,2-dimethoxyethane Using the warm and iodomethane, the title compound (MS: m / e = 500.2 (M + H ⁺ )) was prepared according to the method of Example 4.
[660] Example 134
[661] 8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-methyl-thiazol-4-yl-methyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[662] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- in solvent 1,2-dimethoxyethane The title compound (MS: m / e = 597.0 (M + H ⁺ )) was prepared according to the method of Example 4 using one and 4-chloromethyl-2-methyl-thiazole.
[663] Example 135
[664] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decane-2,4-dione
[665] 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (2-chloro-phenylamino) -piperidine-4-carbonitrile (5.0 g, 10.5 mmol) in dichloromethane (50 mL) To the solution of chlorosulfonyl isocyanate (1 mL, 11.5 mmol) was added. Stir at room temperature for 1 hour. The solvent was evaporated to give a white foam which was used for the next step without further purification.
[666] The white foam was suspended in 1N hydrochloric acid (50 mL) and refluxed for 2 hours. The suspension obtained was filtered to yield 5.4 g of a solid residue. Purification by silica gel chromatography (hexane, ethyl acetate 2: 1) and recrystallization from ethyl acetate / n-hexane to give the desired product (2.9 g, 53%) (mp 153-154 ° C.) (MS: m / e = 520.1 (M + H ⁺ ) was obtained.
[667] Example 136
[668] Rac-8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3-phenyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- On
[669] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using the 4-phenylboronic acid, the title compound (MS: m / e = 576.0 (M + H ⁺ )) was prepared according to the method of Example 62.
[670] Example 137
[671] rac-8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-methoxy-ethyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[672] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and The title compound (MS: m / e = 542.2 (M + H ⁺ )) was prepared according to the method of Example 99 using 2-chloroethyl-methyl ether.
[673] Example 138
[674] Rac-8- (3,5-bis-trifluoromethyl-benzoyl) -3-cyclopropylmethyl-2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane- 4-on
[675] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using cyclopropyl methyl bromide, the title compound (MS: m / e = 554.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[676] Example 139
[677] Rac-8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2,2-difluoro-ethyl) -2-methyl-1-o-tolyl-1,3,8-tri Aza-spiro [4.5] decane-4-one
[678] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using 2,2-difluoroethyl bromide, the title compound (MS: m / e = 564.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[679] Example 140
[680] Rac-8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (3-methyl-but-2-enyl) -1-o-tolyl-1,3,8-tri Aza-spiro [4.5] decane-4-one
[681] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using 1-bromo-3-methyl-2-butene, the title compound (MS: m / e = 568.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[682] Example 141
[683] Rac-8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-morpholin-4-yl-ethyl) -1-o-tolyl-1,3,8- Triaza-spiro [4.5] decane-4-one
[684] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and Using the 4- (chloroethyl) morpholine, the title compound (MS: m / e = 613.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[685] Example 142
[686] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (1-methyl-1H-imidazol-2-yl-methyl) -1-o-tolyl-1,3,8-triaza Spiro [4.5] decan-4-one
[687] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one and 2-chloromethyl-1-methyl Using -1H-imidazole, the title compound (MS: m / e = 580.3 (M + H ⁺ )) was prepared according to the method of Example 99.
[688] Example 143
[689] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (1-methyl-1H-imidazol-2-ylmethyl) -1,3,8 -Triaza-spiro [4.5] decan-2,4-dione
[690] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decane-2,4-dione and 1- Using methylimidazole-2-methanol, the title compound (MS: m / e = 614.1 (M + H ⁺ )) was prepared according to the method of Example 121.
[691] Example 144
[692] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (1,5-dimethyl-1H-pyrazol-3-ylmethyl) -1,3 , 8-triaza-spiro [4.5] decan-2,4, -dione
[693] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decane-2,4-dione and 1, Using the 5-dimethylpyrazole-3-methanol, the title compound (MS: m / e = 627.1 (M ⁺ )) was prepared according to the method of Example 121.
[694] Example 145
[695] 8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (1,5-dimethyl-1H-pyrazol-3-ylmethyl) -1,3 , 8-triaza-spiro [4.5] decane-2,4-dione
[696] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-propyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2 The title compound (MS: m / e = 585.1 (M ⁺ )) was prepared according to the method of Example 121 using, 4-dione and 3-dimethylamino-1-propyl chloride.
[697] Example 146
[698] (rac) -8- (3,5-dimethoxy-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[699] According to the method of Example 91, using 1-benzyl-piperidin-4-one, 1-methyl aniline, methyl magnesium bromide and 3,5-dimethoxy benzoyl chloride, the title compound (MS: m / e = 424.5 (M + H ⁺ )).
[700] Example 147
[701] (rac) -8- (3,5-dichloro-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[702] The title compound (MS: m / e = 432.4) according to the method of Example 91 using 1-benzyl-piperidin-4-one, 1-methyl aniline, methyl magnesium bromide and 3,5-dichloro benzoyl chloride (M + H ⁺ )) was prepared.
[703] Example 148
[704] (rac) -8- (3-fluoro-5-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[705] According to the method of Example 91 using 1-benzyl-piperidin-4-one, 1-methyl aniline, methyl magnesium bromide and 3-fluoro-5-trifluoromethyl-benzoyl chloride, the title compound ( MS: m / e = 450.4 (M + H ⁺ )).
[706] Example 149
[707] (rac) -8- (3,5-difluoro-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one
[708] Using the 1-benzyl-piperidin-4-one, 1-methyl aniline, methyl magnesium bromide and 3,5-difluoro-benzoyl chloride, the title compound (MS: m / e = 400.5 (M + H ⁺ )).
[709] Example 150
[710] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-cyclopropylmethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one
[711] Using 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one and cyclopropyl methyl bromide, The title compound (Ms: m / e = 540.4 (M + H ⁺ )) was prepared according to the method of Example 99.
[712] Example 151
[713] 8- (3,5-bis-trifluoromethyl-benzoyl) -3-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one
[714] Using 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one and methyl iodide, The title compound (MS: m / e = 500.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[715] Example 152
[716] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-morpholin-4-yl-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5 ] Decane-2-one
[717] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one and 4- (chloroethyl) morpholine Using the method of Example 99 to prepare the title compound (MS: m / e = 599.1 (M + H ⁺ )).
[718] Example 153
[719] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-methoxy-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2 -On
[720] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one and 2-chloromethyl methyl ether Thus, the title compound (MS: m / e = 544.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[721] Example 154
[722] 8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-propyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2 -On
[723] 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one and 3-dimethylamino-1-propyl Using chloride, the title compound (MS: m / e = 571.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[724] Example 155
[725] 3-acetyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one
[726] Example using 8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-2-one and acetyl chloride The title compound (MS: m / e = 528.1 (M + H ⁺ )) was prepared according to the method of 99.
[727] Example 156
[728] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione
[729] Benzyl cyanide (113g, 1.05mol) and N-benzyl-4-piperidone (90g, 0.48mol) were added to a room temperature of sodium ethoxide solution (prepared by slowly adding Na 22g (0.96mol) to 800ml of anhydrous ethanol) Was added. The reaction mixture was stirred at 85 ° C. for 3 hours and the solvent was evaporated. The residue was added to a mixture of ice (1 Kg) and concentrated hydrochloric acid (200 mL). Then it was adjusted to pH 9 by addition of solid sodium hydroxide and the reaction mixture was extracted three times with ethyl acetate (500 ml each). The organic phase was decanted and dried over MgSO ₄ . The solvent was evaporated and purified by silica gel chromatography (hexane, ethyl acetate, triethyl amine 80: 20: 1) to give (1-benzyl-piperidine-4-yridine) -phenyl-acetonitrile (135 g) as yellow crystals. , 97%) was obtained.
[730] To a solution of this intermediate (1-benzyl-piperidine-4-yridine) -phenyl-acetonitrile (135 g, 0.47 mol) in ethanol (400 mL) potassium cyanide (30 g, 0.47 mol) in water (80 mL) ) Was added. Stir overnight at 90 ° C. The solvent was evaporated. The residue was added to 2N hydrochloric acid (300 mL) and adjusted to pH 1-2 by addition of concentrated hydrochloric acid (50 mL). The reaction mixture was stirred at reflux overnight. After cooling to room temperature, solid sodium carbonate was added until pH 8-9 and the mixture was extracted three times with methyl chloride (300 ml each). The organic phase was decanted, dried over MgSO ₄ and evaporated. The crude product was suspended in ethyl acetate (300 mL) and kept at room temperature overnight. The crystals were filtered and dried to yield 106 g (68%) of intermediate (rac) -8-benzyl-4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione.
[731] The intermediate (rac) -8-benzyl-4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione (4.0 g, 12 mmol) was dissolved in methanol (100 mL) and concentrated hydrochloric acid ( 1 ml) and Pd / C (10%, 0.60 g) were added. After stirring overnight under hydrogen atmosphere (1 bar) and room temperature, the mixture was filtered and the solvent was evaporated.
[732] The residue was dissolved in dichloromethane (100 mL), triethylamine (5.5 mL, 40 mmol) and 3,5-bistrifluoromethyl benzoyl chloride (2.7 mL, 15 mmol) were added and the mixture was stirred at rt overnight. It was. Water was added and the organic layer was separated and dried. The solvent was evaporated and the residue was purified by silica gel flash chromatography (hexane, ethyl acetate, triethyl amine 30: 10: 1) to give the desired product (3.44 g, 59%) (MS: m / e = 485.3 (M +). H ⁺ )).
[733] Example 157
[734] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione
[735] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione and methyl iodide Using this, the title compound (MS: m / e = 499.2 (M + H ⁺ )) was prepared according to the method of Example 121.
[736] Example 158
[737] (rac) -8- (3,5-bistrifluoromethyl-benzoyl) -2- (2-morpholin-4-yl-ethyl) -4-phenyl-2,8-diaza-spiro [4.5] Decan-1,3-dione
[738] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione and N- (2-hydro Using oxyethyl) -morpholine, the title compound (MS: m / e = 598.1 (M + H ⁺ )) was prepared according to the method of Example 121.
[739] Example 159
[740] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2- (2-pyrrolidin-1-yl-ethyl) -2,8-diaza-spiro [ 4.5] decane-1,3-dione
[741] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione and 1- (2-hydro Using oxyethyl) -pyrrolidine, the title compound (MS: m / e = 582.2 (M + H ⁺ )) was prepared according to the method of Example 121.
[742] Example 160
[743] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2- (3-dimethylamino-propyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1 , 3-dione
[744] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione and 3-dimethylamino-1 Using the propanol, the title compound MS: m / e = 570.2 (M + H ⁺ )) was prepared according to the method of Example 121.
[745] Example 161
[746] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one
[747] (rac) -8-benzyl-4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione (10.0 g, 30 mmol, the synthesis described in Example 156) was dissolved in toluene (200 mL). Dissolved in. Diisobutyl aluminum hydride (220 mL, 1 M in THF, 220 mmol) was slowly added while cooling with an ice bath so that the reaction temperature did not exceed 10 ° C. The reaction mixture was stirred for 2 days at room temperature. A mixture of methanol (6 mL) and water (6 mL) was added at room temperature. The resulting gel was filtered through decalite and washed with methylene chloride. The filtrate was evaporated to afford 8-benzyl-3-hydroxy-4-phenyl-2,8-diaza-spiro [4.5] decan-1-one (8.0 g, 80%) as a mixture of diastereomers. .
[748] The intermediate 8-benzyl-3-hydroxy-4-phenyl-2,8-diaza-spiro [4.5] decan-1-one (8.0 g, 23.8 mmol) was dissolved in cold acetic acid (50 mL) and 1.5 h. Reflux for a while. The reaction mixture was poured into ice water (500 mL) and adjusted to pH 8-9 by the addition of solid sodium hydroxide. The mixture was extracted three times with ethyl acetate (300 ml each). The organic phase was decanted, dried over magnesium sulfate and evaporated. The crude product was recrystallized from methylene chloride to give white crystals 8-benzyl-4-phenyl-2,8-diaza-spiro [4.5] dec-3-en-1-one (2.64 g, 35%). .
[749] The intermediate 8-benzyl-4-phenyl-2,8-diaza-spiro [4.5] dec-3-en-1-one (3.7 g, 11.6 mmol) was dissolved in methanol (100 mL) and concentrated hydrochloric acid (1 ML) and Pd / C (10%, 0.60 g) were added. After stirring overnight under hydrogen atmosphere (1 bar) and room temperature, the mixture was filtered and the solvent was evaporated.
[750] The residue was dissolved in dichloromethane (100 mL), triethyl amine (8.1 mL, 58 mmol) and 3,5-bistrifluoromethyl benzoyl chloride (2.65 mL, 15 mmol) were added and the mixture was then allowed to come to room temperature. Stir overnight. Water was added and the organic layer was separated and dried. The solvent was evaporated and the residue was purified by silica gel flash chromatography (methylene chloride / methanol 98: 2) to give the desired product (4.65 g, 85%) (MS: m / e = 471.2 (M + H ⁺ )). It was.
[751] Example 162
[752] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-4-phenyl-2,8-diaza-spiro [4.5] decan-1-one
[753] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one and methyl iodide, The title compound (MS: m / e = 485.3 (M + H ⁺ )) was prepared according to the method of Example 99.
[754] Example 163
[755] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2- (2-pyrrolidin-1-yl-ethyl) -2,8-diaza-spiro [ 4.5] decane-1-one
[756] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one and 1- (2-chloroethyl) Using pyrrolidine, the title compound (MS: m / e = 568.3 (M + H ⁺ )) was prepared according to the method of Example 99.
[757] Example 164
[758] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2- (2-methoxy-ethyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1 -On
[759] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one and 2-chloroethyl-methyl-ether Using the method of Example 99 to prepare the title compound (MS: m / e = 529.2 (M + H ⁺ )).
[760] Example 165
[761] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2- (2-morpholin-4-yl-ethyl) -4-phenyl-2,8-diaza-spiro [4.5 ] Decane-1-one
[762] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one and 4- (2-chloroethyl) Using the morpholine, the title compound (MS: m / e = 584.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[763] Example 166
[764] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2- (3-dimethylamino-propyl) -4-phenyl-2,8-diaza-spiro [4.5] decane-1 -On
[765] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one and 3-dimethylamino-1-propyl Using chloride, the title compound (MS: m / e = 556.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[766] Example 167
[767] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2-pyridin-3-yl-methyl-2,8-diaza-spiro [4.5] decane-1- On
[768] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-phenyl-2,8-diaza-spiro [4.5] decan-1-one and 3- (chloromethyl) pyridine Using the method of Example 99 to prepare the title compound (MS: m / e = 562.3 (M + H ⁺ )).
[769] Example 168
[770] (rac)-(3,5-bis-trifluoromethyl-phenyl)-(2-methyl-4-phenyl-2,8-diaza-spiro [4.5] dec-8-yl) -methanone
[771] (rac) -8-benzyl-4-phenyl-2,8-diaza-spiro [4.5] decane-1,3-dione (3.0 g, 9.0 mmol, the synthesis described in Example 156) was dried with anhydrous tetrahydrofuran (50 mL) and triphenylphosphine (3.1 g, 11.7 mmol), methanol (0.374 g, 11.7 mmol) and diethylazodicarboxylate (5.35 mL, 40% in toluene, 11.7 mmol) were added sequentially. Then, stirred overnight at room temperature. The solvent was evaporated and the residue was purified by silica gel chromatography (dichloromethane / methanol / triethyl amine 98: 1: 1) to give (rac) -8-benzyl-2-methyl-4-phenyl-2,8-diaza. Spiro [4.5] decane-1,3-dione (2.57 g, 82%) was obtained.
[772] Lithium aluminum hydride (1.39 g, 37 mmol) was dissolved in tetrahydrofuran (20 mL) and the intermediate (rac) -8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro [4.5] Deccan-1,3-dione (2.55 g, 7.32 mmol, dissolved in 20 mL of anhydrous tetrahydrofuran) was added slowly. The reaction mixture was stirred at rt for 2 h. Water (1.4 mL), sodium hydroxide (15% in water, 1.5 mL) and water (4.2 mL) were added dropwise. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash chromatography (hexane / ethyl acetate / triethyl amine 30: 20.1) to give intermediate (rac) -8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro [4.5]. Deccan (1.40 g, 60%) was obtained.
[773] The intermediate (rac) -8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro [4.5] decane (1.29 g, 2.51 mmol) was dissolved in methanol (50 mL) and concentrated hydrochloric acid (0.3 ML) and Pd / C (10%, 0.214 g) were added. After stirring overnight under hydrogen atmosphere (1 bar) and room temperature, the mixture was filtered and the solvent was evaporated.
[774] The residue was dissolved in dichloromethane (50 mL), triethyl amine (2.04 mL, 20 mmol) and 3.5-bistrifluoromethyl benzoyl chloride (0.95 mL, 5.2 mmol) were added and the reaction mixture was stirred at rt overnight. It was. Water was added and the organic layer was separated and dried. The solvent was evaporated and the residue was purified by silica gel flash chromatography (hexane / Ethilangate / triethyl amine 10: 20: 1) to give the desired product (1.18 g, 62%) (MS: m / e = 471.2 (M). + H ⁺ )).
[775] Example 169
[776] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en-1-one
[777] The title compound (MS: m / e = 483.1 (M + H ⁺ )) was prepared according to the method of Examples 156 and 161 using o-tolyl cyanide and N-benzyl-4-piperidone. Reduction of double bonds with hydrogen was unsuccessful and a 2.8-diaza-spiro [4.5] deck-3-en-1-one core was obtained instead of a 2.8-diaza-spiro [4.5] decan-1-one core. .
[778] Example 170
[779] 8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-4-o-tolyl-2,8-diaza-spiro [4,5] dec-3-en-1-one
[780] Using 8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en-1-one and methyl iodide To obtain the title compound (MS: m / e = 497.1 (M + H ⁺ )) according to the method of Example 99.
[781] Example 171
[782] 8- (3,5-bis-trifluoromethyl-benzoyl) -2-cyclopropylmethyl-4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en-1-one
[783] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4,5] dec-3-en-1-one and cyclopropyl methyl bromide Using the above, the title compound (MS: m / e = 537.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[784] Example 172
[785] 8- (3,5-bis-trifluoromethyl-benzoyl) -2- (2-pyrrolidin-1-yl-ethyl) -4-o-tolyl-2,8-diaza-spiro [4, 5] deck-3-en-1-one
[786] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en-1-one and 1- (2-chloro Using the ethyl) -pyrrolidine, the title compound (MS: m / e = 580.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[787] Example 173
[788] 8- (3,5-bis-trifluoromethyl-benzoyl) -2- (2-morpholin-4-yl-ethyl) -4-o-tolyl-2,8-diaza-spiro [4.5] deck -3-en-1-one
[789] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en-1-one and 1- (2-chloro Using the ethyl) -morpholine, the title compound (MS: m / e = 596.1 (M + H ⁺ )) was prepared according to the method of Example 99.
[790] Example 174
[791] 8- (3,5-bis-trifluoromethyl-benzoyl) -2- (3-dimethylamino-propyl) -4-o-tolyl-2,8-diaza-spiro [4,5] deck-3 -En-1-one
[792] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en-1-one and 3-dimethylamino-1 Using -propyl chloride, the title compound (MS: m / e = 568.2 (M + H ⁺ )) was prepared according to the method of Example 99.
[793] Example 175
[794] 8- (3,5-Bis-trifluoromethyl-benzoyl) -2-pyridin-3-yl-methyl-4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-ene- 1-on
[795] 8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-en-1-one and 3-chloromethyl pyridine Using the method of Example 99 to prepare the title compound (MS: m / e = 574.1 (M + H ⁺ )).
[796] Example 176
[797] (rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] decan-1-one
[798] Using o-tolyl cyanide and N-benzyl-4-piperidone, the title compound (MS: m / e = 485.3 (M + H ⁺ )) was prepared according to the methods of Examples 156 and 161. Reduction with hydrogen was performed for 3 days to reduce the double bonds.
[799] Example A
[800] 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one
[801] A solution of 3,5-bis-trifluoromethyl-benzoyl chloride (17.4 g, 63 mmol) in dichloromethane (30 mL) was cooled to a temperature not exceeding 20 ° C., 4-piperidone trifluoroacetate (13.4 g). , 63 mmol) and triethylamine (22 mL, 158 mmol). Stir at room temperature for 2 hours. Water was added and the phases were separated and the aqueous phase was extracted with dichloromethane. The organic phase was decanted and dried over MgSO ₄ and the solvent was evaporated. Purification by silica gel chromatography (ethyl acetate / n-hexane 1: 1) gave the desired product (20.2 g, 94%) (mp 155-157 ° C.) (MS: m / e = 339.1 (M ⁺ )). .
[802] Example B
[803] 1- (3,5-Bis-trifluoromethyl-benzoyl) -4- (3-chloro-phenylamino) -piperidine-4-carbonitrile
[804] To a solution of 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one (5.1 g, 15 mmol) in acetic acid (20 mL) while cooling to a temperature not exceeding 20 ° C. 3 -Chloroaniline (1.7 mL, 16.5 mmol) and trimethylsilylcyanide (1.9 mL, 15 mmol) were added. The suspension was stirred at rt for 6 h. The reaction mixture was then added to ice water (350 mL) and ammonia (55 mL, 25%) was added to the reaction compound and stirred for 15 minutes. The mixture was extracted with dichloromethane and then the organic phase was decanted, washed with brine and dried over MgSO ₄ . The solvent was evaporated and the residue was crystallized with ethyl acetate to give the desired product (5.3 g, 74%) (mp 205-207 ° C) (MS: m / e = 476.1 (M + H ⁺ )).
[805] Example C
[806] 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (4-chloro-phenylamino) -piperidine-4-carbonitrile
[807] The title compound (mp 176-180 ° C.) according to the method of Example B using 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one and 4-chloroaniline. (MS: m / e = 474.1 (M ⁻ H)) were prepared.
[808] Example D
[809] 1- (3,5-bis-trifluoromethyl-benzoyl) -4- (3,4-dichloro-phenylamino) -piperidine-4-carbonitrile
[810] The title compound (mp 195-197) according to the method of Example B using 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one and 3,4-dichloroaniline. C) (MS: m / e = 512.1 (M + H ⁺ ) were prepared.
[811] Example E
[812] 1- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolylamino-piperidine-4-carbonitrile
[813] The title compound (mp 141-142 ° C.) according to the method of Example B using 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one and 2-methylaniline. (MS: m / e = 456.3 (M + H ⁺ )) was prepared.
[814] Example F
[815] 1- (3,5-Bis-trifluoromethyl-benzoyl) -4- (2-chloro-phenylamino) -piperidine-4-carbonitrile
[816] According to the method of Example B, using 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one and 2-chloroaniline, the title compound (MS: m / e = 474.1 (MH ⁻ )) was prepared.
[817] Example G
[818] 1- (3,5-Bis-trifluoromethyl-benzoyl) -4- (2-methoxy-phenylamino) -piperidine-4-carbonitrile
[819] Using the 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one and o-anisidine, the title compound (MS: m / e = 472.2 (M + H ⁺ )) was prepared.
[820] Example H
[821] 4-benzylamino-1- (3,5-bis-trifluoromethyl-benzoyl) -piperidine-4-carbonitrile
[822] Using the 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one and benzylamine, the title compound (MS: m / e = 456.3 ( M + H ⁺ )).
[823] MS m / e (%): 586 (M + H ⁺ , 100).
[824] Example AA
[825] The tablet of the following composition is manufactured by a conventional method.
[826] mg / tablet Active substance5 Lactose45 Corn starch15 Microcrystalline cellulose34 Magnesium stearateOneTablet weight 100
[827] Example BB
[828] A capsule of the following composition is prepared.
[829] mg / capsules Active substance10 Lactose155 Corn starch30 talc5Capsule Fill Weight 200
[830] The active substance, lactose and corn starch are first mixed in a mixer and then placed in a grinder. The mixture is placed back into the mixer and mixed well by the addition of talc. The mixture is filled into hard gelatin capsules using a machine.
[831] Example CC
[832] Suppositories of the following compositions are prepared.
[833] mg / suppositories Active substance15 Suppository mass12851300 total
[834] The suppositories are melted in a glass or steel vessel and mixed well, then cooled to 45 ° C. Finely pulverized active material is added and stirred until completely dispersed. The mixture is poured into suppository molds of suitable size and cooled, then the suppositories are removed from the molds and individually packaged in wax paper or metal foil.

权利要求:
Claims (19)
[1" claim-type="Currently amended] A compound of formula (I) and pharmaceutically acceptable acid addition salts thereof:
Formula I

Where
R ¹ is — (CH ₂ ) _m -non-aromatic heterocyclyl group optionally substituted by hydrogen, lower alkyl, lower alkenyl, phenyl, or lower alkyl, or lower alkyl, lower alkoxy, halogen, CF ₃ , benzyl And-(CH ₂ ) _m -heteroaryl optionally substituted by one or two substituents selected from the group consisting of cyano, or-(CH ₂ ) _m -C (O) -NRR ',-(CH ₂ ) _m- C (O) -lower alkyl,-(CH ₂ ) _m -C (O) -O-lower alkyl,-(CH ₂ ) _m -O-lower alkyl,-(CH ₂ ) _m -CH [C ( O) -O-lower alkyl] ₂ ,-(CH ₂ ) _m -CH (OH) -CH _2- (O) -phenyl,-(CH ₂ ) _m -CH (CF ₃ ) OH,-(CH ₂ ) _m- OH,-(CH ₂ ) _m -CN,-(CH ₂ ) _m -NRR ',-(CH ₂ ) _m -cycloalkyl or-(CH ₂ ) _m -CHF;
R ² is hydrogen, lower alkyl, halogen or lower alkoxy;
R ³ is lower alkyl, lower alkoxy, halogen or CF ₃ ;
R and R 'are the same or different and are hydrogen or lower alkyl;
X is> N-,> C = or> CH-;
X ¹ / X ² may independently of each other be hydrogen, hydroxy or lower alkoxy or wherein X ¹ / X ² together may be an oxo group;
Y ¹ / Y ² may be independently of each other hydrogen, lower alkyl, — (CH ₂ ) _m -phenyl or the Y ¹ / Y ² together may be an oxo group;
Z is a bond, -CH ₂ -or -C (O)-;
m is 0, 1, 2, 3 or 4;
n is 2 or 3
n 'is 0, 1 or 2.
[2" claim-type="Currently amended] The method of claim 1,
R ³ is trifluoromethyl and n is 2.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
X is> N-, X ¹ / X ² together is an oxo group and Y ¹ / Y ² are both hydrogen.
[4" claim-type="Currently amended] The method of claim 3, wherein
8- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl) -1-phenyl-1,3, 8-triaza-spiro [4.5] decan-4-one,
8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl ) -1,3,8-triaza-spiro [4.5] decan-4-one,
8- (3,5-bis-trifluoromethyl-benzoyl) -3-pyridin-3-ylmethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one ,
8- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-isopropylamino-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane- 4-on,
8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-4-one,
8- (3,5-bis-trifluoromethyl-benzoyl) -1-phenyl-3-pyridin-4-yl-1,3,8-triaza-spiro [4.5] decan-4-one,
8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-methyl-1,3,8-triaza-spiro [4.5] decan-4-one,
8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3- (3-dimethylamino-propyl) -1,3,8-triaza-spiro [4.5 ] Decane-4-one,
8- (3,5-bis-trifluoromethyl-benzoyl) -1- (2-chloro-phenyl) -3-pyridin-4-yl-1,3,8-triaza-spiro [4.5] decane- 4-on, or
8- (3,5-bis-trifluoromethyl-benzoyl) -3-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one.
[5" claim-type="Currently amended] The method according to claim 1 or 2,
X is> N-, X ¹ / X ² together is an oxo group, ^one of Y ¹ / Y ² is hydrogen and the other is different from hydrogen.
[6" claim-type="Currently amended] The method of claim 5,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one,
(rac) -2-benzyl-8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-phenyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-3-pyridin-3-ylmethyl-1,3,8-triaza-spiro [4.5 ] Decane-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2,3-dimethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-1-phenyl-3- (2-pyrrolidin-1-yl-ethyl) -1,3,8 -Triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-propyl) -2-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2,3-dimethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-4- On,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-piperazin-1-ethyl) -1-o-tolyl-1,3,8- Triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-pyrrolidin-1-yl-ethyl) -1-o-tolyl-1,3 , 8-triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-piperidin-1-yl-ethyl) -1-o-tolyl-1,3 , 8-triaza-spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-methoxy-ethyl) -2-methyl-1-o-tolyl-1,3,8-triaza Spiro [4.5] decan-4-one,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -2-methyl-3- (2-morpholin-4-yl-ethyl) -1-o-tolyl-1,3, 8-triaza-spiro [4.5] decan-4-one, or
(rac) -8- (3,5-dichloro-benzoyl) -2-methyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decan-4-one.
[7" claim-type="Currently amended] The method according to claim 1 or 2,
X is> N- and X ¹ / X ² and Y ¹ / Y ² are oxo groups.
[8" claim-type="Currently amended] The method of claim 7, wherein
8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione,
8- (3,5-bis-trifluoromethyl-benzoyl) -3-pyridin-3-ylmethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4 Dion,
3- (1H-Benzoimidazol-2-ylmethyl) -8- (3,5-bis-trifluoromethyl-benzoyl) -1-o-tolyl-1,3,8-triaza-spiro [4.5 ] Decane-2,4-dione,
8- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-methyl-thiazol-4-ylmethyl) -1-o-tolyl-1,3,8-triaza-spiro [ 4.5] decane-2,4-dione,
8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-2-ylmethyl-1-phenyl-1,3,8-triaza-spiro [4.5] decane-2,4-dione ,
8- (3,5-bis-trifluoromethyl-benzoyl) -3-furan-2-ylmethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2,4 Dion, or
8- (3,5-bis-trifluoromethyl-benzoyl) -3-thiophen-2-ylmethyl-1-o-tolyl-1,3,8-triaza-spiro [4.5] decane-2, Compound that is 4-dione.
[9" claim-type="Currently amended] The method according to claim 1 or 2,
X is> C =.
[10" claim-type="Currently amended] The method of claim 9,
8- (3,5-bis-trifluoromethyl-benzoyl) -2- (2-pyrrolidin-1-yl-ethyl) -4-o-tolyl-2,8-diaza-spiro [4.5] Deck-3-en-1-one or
8- (3,5-bis-trifluoromethyl-benzoyl) -2- (3-dimethylamino-propyl) -4-o-tolyl-2,8-diaza-spiro [4.5] dec-3-ene 1-one compound.
[11" claim-type="Currently amended] The method according to claim 1 or 2,
X is> CH-.
[12" claim-type="Currently amended] The method of claim 11,
(rac) -8- (3,5-bis-trifluoromethyl-benzoyl) -4-o-tolyl-2,8-diaza-spiro [4.5] decan-1-one.
[13" claim-type="Currently amended] A medicament containing at least one compound according to any one of claims 1 to 12 and a pharmaceutically acceptable excipient.
[14" claim-type="Currently amended] The method of claim 13,
Agents for treating diseases associated with NK-1 receptor antagonists.
[15" claim-type="Currently amended] A process for preparing a compound of formula (I) as defined in claim 1 comprising the following steps (a) to (j):
(a) reacting a compound of formula II with a compound of formula III to provide a compound of formula I
Formula II

Formula III

Formula I

[Wherein L is a leaving group comprising a halogen such as chlorine and the other substituents are the same as defined above]; or
(b) reacting a compound of formula I-1 with a compound of formula IV in the presence of sodium carbonate or potassium carbonate and CuCl to provide a compound of formula I
Formula I-1

Formula IV
LR ¹
Formula I

[Wherein L is a leaving group comprising chlorine and the other substituents are as defined above, R ¹ is not — (CH ₂ ) _m —OH and X ¹ / X ² is not hydroxy; or
(c) reacting the compound of formula I-1 with a compound of formula V to provide a compound of formula I-2
Formula I-1

Formula V

Formula I-2

[Wherein TBDMS is a t-butyldimethylsilyl group and the substituents are the same as defined above]; or
(d) activating the compound of formula (I-2) as a mesylate and then reacting with an amine of formula RR'NH, wherein R and R 'are as defined above to provide a compound of formula
Formula I-2

Formula I-3

[Wherein the substituents are the same as defined above]; or
(e) reacting a compound of formula I-1 with a compound of formula VI to provide a compound of formula I-4
Formula I-1

Formula VI

Formula I-4

[Wherein R ⁴ is lower alkyl and the other substituents are as defined above]; or
(f) reacting a compound of formula (I-1) with a compound of formula (VII) to provide a compound of formula (I)
Formula I-1

Formula VII

Formula I

[Wherein R ¹ is phenyl or heteroaryl optionally substituted as defined above and the other substituents are as defined above]; or
(g) closing the compound of formula VIII to provide a compound of formula I-5
Formula VIII

Formula I-5

[Wherein the substituents are the same as defined above]; or
(h) a compound of formula (I-6) Reacting with a compound of to provide a compound of formula I-7
Formula I-6

Formula I-7

[Wherein the substituents are the same as defined above]; or
(i) reacting a compound of formula XIV with hydrogen on Pd / C and then reacting with (CF ₃ ) ₂ C ₆ H ₃ COCl to provide a compound of formula I-12
Formula XIV

Formula I-12

[Wherein the substituents are the same as defined above]; or
(j) changing one or more of the substituents R ¹ to R ³ within the ranges defined above and optionally converting the obtained compound into a pharmaceutically acceptable acid addition salt.
[16" claim-type="Currently amended] A compound according to any one of claims 1 to 12 prepared by the process according to claim 15 or a method equivalent thereto.
[17" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 12 for treating a disease.
[18" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament containing at least one compound according to claim 1 for the treatment of a disease associated with an NK-1 receptor antagonist.
[19" claim-type="Currently amended] The invention described above.

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同族专利:

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公开号 | 公开日

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JP2003535863A|2003-12-02|

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AU2001267513B2|2006-03-16|

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DE60131971T2|2008-12-04|

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WO2001094346A1|2001-12-13|

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CA2411716C|2010-06-22|

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KR100518198B1|2005-10-04|

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ZA200209488B|2004-02-23|

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AU6751301A|2001-12-17|

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US20020006932A1|2002-01-17|

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ES2296761T3|2008-05-01|

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UY26754A1|2001-12-28|

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BR0111538A|2003-07-01|

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DE60131971D1|2008-01-31|

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CN1261433C|2006-06-28|

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AT381565T|2008-01-15|

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PE20020298A1|2002-04-17|

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EP1292596B1|2007-12-19|

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CA2411716A1|2001-12-13|

---

EP1292596A1|2003-03-19|

---

JP4245348B2|2009-03-25|

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CN1436188A|2003-08-13|

---

US6482829B2|2002-11-19|

---

MXPA02012001A|2003-04-22|

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AR028683A1|2003-05-21|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-06-08|Priority to EP00112285

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2000-06-08|Priority to EP00112285.2

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2001-06-01|Application filed by 에프. 호프만-라 로슈 아게

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2001-06-01|Priority to PCT/EP2001/006305

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2003-02-26|Publication of KR20030016283A

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2005-10-04|Application granted

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2005-10-04|Publication of KR100518198B1

优先权:

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申请号 | 申请日 | 专利标题

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EP00112285|2000-06-08|

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EP00112285.2|2000-06-08|

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PCT/EP2001/006305|WO2001094346A1|2000-06-08|2001-06-01|1,3,8-TRIAZA-SPIRO'4,5!DECAN-4-ONE DERIVATIVES AS NEUROKININ RECEPTOR ANTAGONISTS|