Novel Morpholine Derivatives, Method for the Production Thereof and Pharmaceutical Preparations Cont

专利摘要:
The present invention relates to a salt, solvate and / or hydrate thereof with a compound of formula (I), an inorganic or organic acid thereof, which inhibits the strong affinity and strong selectivity of substance P for the human NK 1 receptor. The present invention also relates to a process for the preparation of the above derivatives, intermediate compounds of the formulas IV, VI and VIII used for its preparation, pharmaceutical compositions containing said derivatives, and pharmaceutical compositions for the treatment of all diseases in which the substance P and / or human NK 1 receptor are associated To the use thereof for the manufacture of medicaments.
公开号:KR20010108381A
申请号:KR1020017012121
申请日:2000-03-21
公开日:2001-12-07
发明作者:장 필립 두코우스；사비 에몽드-알；패트릭 구욀르；빈센조 프로이토
申请人:고든 라이트；사노피-신델라보；
IPC主号:

专利说明:

TECHNICAL FIELD [0001] The present invention relates to a novel morpholine derivative, a preparation method thereof, and a pharmaceutical preparation containing the same.
[3] Recently, much research has been conducted on tachykinins and their receptors. Tachycinin is distributed throughout the central nervous system and peripheral nervous system. Tachykinin receptors are recognized and classified into three types, NK ₁ , NK ₂ and NK ₃ . The substance P (SP) is the endogenous ligand of the NK ₁ receptor, the neurokinin A (NK _A ) is the endogenous ligand of the NK ₂ receptor and the neurokinin B (NK _B ) is the endogenous ligand of the NK ₃ receptor.
[4] The NK ₁ , NK ₂ and NK ₃ receptors have been proven to be of various types.
[5] Seed. a. Maggie et al. (CA Maggi et al., J. Autonomic Pharmacol., 1993, 13 , 23-93) and di. Review of LEGOLI et al. (D. Regoli et al., Pharmacol. Rev., 1994, 46 , 551-599) discusses tachykinin receptors and their antagonists and describes their application in pharmacological research and human therapy .
[6] Many patents and patent applications describe compounds that are active at the tachykinin receptor. Thus, International Patent Publication No. WO96 / 23787 relates to compounds of formula (A)
[7]
[8] In the above formula, particularly
[9] A is a radical -O-CH ₂ -CH ₂ divalent - may represent,
[10] Am, m, Ar ₁ and T have different values.
[11] The patent application EP-A-0 776 893 relates to a compound of formula (B)
[12]
[13] In this formula,
[14] DE is the radical -O-CH ₂ -CH ₂ divalent - may represent,
[15] L, G, E, A, B, R _a and R _b have different values.
[1] The present invention relates to a novel morpholine derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient.
[2] The present invention more specifically, other Kiki the pathological condition associated with ningye, such as: pain (L. Urban et al, TINS, 1994, 17, 432-438; L. Seguin et al, Pain, 1995, 61.. (See SH Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, New Jersey), gastrointestinal tract disorders .. P. Holzer and U. Holzer- Petsche, Pharmacol Ther, 1997, 73, 173-217 and references 219-263), respiratory disorders (J. Mizrahi et al, Pharmacology, 1982, 25, 39-50;. C . Advenier et et al, Eur Respir J., 1997, 10, 1892-1906;.... C. Advenier and X. Emonds-Alt, Pulmonary Phamacol, 1996, referenced 9, 329-333), urinary disorders (SH Buck, 1994, The Tachykinin receptors, Humana Press, Totowa, New Jersey; CA Maggi, Progress in Neurobiology, 1995, see 45, 1-98), neurological disorders, and neurological and mental disorders (CA Maggi et al, J. Autonomic . Pharmacol., 1993, 13 , 23-93; M. Otsukaand K. Yoshioka, Physiol. Re v. 1993, 73 , 229-308).
[16] A novel compound which has strong affinity and strong selectivity for the human NK ₁ receptor of substance P and which is an antagonist of said receptor has been disclosed in accordance with the present invention.
[17] In addition, the compounds according to the invention have good bioavailability of the drug when the compound is administered orally.
[18] These compounds are substance P and NK ₁ receptor is any condition associated with, in particular, respiratory, gastrointestinal, urinary, immune system, useful for the treatment of cardiovascular and treated with pain in diseases of the central nervous system, migraine, inflammation, nausea and vomiting, and skin diseases Can be used to make medicines.
[19] Accordingly, one aspect of the present invention relates to compounds of formula (I), salts, solvates and / or hydrates thereof with inorganic or organic acids thereof.
[20]
[21] In this formula,
[22] Ar is a halogen atom, mono- or disubstituted phenyl, or (C ₁ -C ₃₎ represents an alkyl,
[23] X is group, Lt; / RTI >
[24] R ₁ represents a chlorine atom, a bromine atom, (C ₁ -C ₃ ) alkyl or trifluoromethyl,
[25] R ₂ represents (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl or -CR ₄ R ₅ CONR ₆ R ₇ group,
[26] R ₃ represents a -CR ₄ R ₅ CONR ₆ R ₇ group,
[27] R ₄ and R ₅ represent the same radical selected from methyl, ethyl, n-propyl or n-butyl or together with the carbon atoms to which they are attached form a (C ₃ -C ₆ )
[28] R ₆ and R ₇ each independently represent hydrogen or (C ₁ -C ₃ ) alkyl or, together with the nitrogen atom to which they are bonded, represent a group selected from 1-azetidinyl, 1-pyrrolidinyl, -Morpholinyl, 4-thiomorpholinyl or perhydro-1-azepinyl. The term " heterocyclic "
[29] Compounds of formula (I) according to the present invention include both pure optical isomers and mixtures thereof in any ratio.
[30] Salts of the compounds of formula (I) may be formed. The salts are formed with inorganic or organic acids which are capable of suitable isolation or crystallization of the compounds of formula I, for example salts with picric or oxalic acids or with optically active acids such as mandelic or camphorsulphonic acid, Such as hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, oxalate, maleate, fumarate, succinate , 2-naphthalenesulfonate, gluconate, citrate, benzenesulfonate or para-toluenesulfonate.
[31] The halogen atom means a chlorine, bromine, fluorine or iodine atom.
[32] In the present specification, the alkyl group is linear or branched.
[33] According to the present invention, compounds of formula I wherein Ar is 3,4-dichlorophenyl are preferred.
[34] According to the present invention, preferred compounds of formula I are those, wherein Ar is 3,4-dichlorophenyl.
[35] According to the present invention, preferred compounds of formula I are compounds wherein the substituent R < ₁ > is a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl.
[36] According to the present invention, preferred compounds of formula I are those wherein X is Group [wherein, R ₂ is (C ₁ -C ₆₎ alkyl or (C ₃ -C ₆₎ cycloalkyl-alkyl] are those compounds. Particularly preferred compounds are those wherein R ₂ represents cyclopentyl or cyclohexyl.
[37] According to the present invention, preferred compounds of formula I are those wherein X is (Wherein R ₂ is -CR ₄ R ₅ CONR ₆ R ₇ ).
[38] In such cases, preferred compounds are those wherein R ₄ and R ₅ each represent methyl or, together with the carbon atoms to which they are attached, form cyclopropyl or cyclohexyl. In particular, also preferred compounds are those wherein R ₆ and R ₇ are similar and are hydrogen or methyl.
[39] According to the present invention, preferred compounds of formula I are those wherein X is (Wherein R ₃ is a group -CR ₄ R ₅ CONR ₆ R ₇ ).
[40] In such cases, preferred compounds are those in which R ₄ and R ₅ each represent methyl, or together with the carbon atoms to which they are attached form cyclohexyl. In particular, also preferred compounds are those wherein R ₆ and R ₇ are similar and are hydrogen or methyl.
[41] According to the present invention, preferred compounds are those of formula (I '), salts, solvates and / or hydrates thereof with inorganic or organic acids thereof.
[42]
[43] In this formula,
[44] R ' ₁ represents a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl,
[45] R ' ₂ represents cyclopentyl or cyclohexyl.
[46] According to the present invention, preferred compounds are the compounds of formula I ", salts, solvates and / or hydrates thereof with inorganic or organic acids thereof.
[47]
[48] In this formula,
[49] R ' ₁ represents a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl,
[50] R ' ₄ and R' ₅ each represent methyl or together with the carbon atoms to which they are attached form a cyclohexyl or cyclopropyl,
[51] R ' ₆ and R' ₇ are similar and represent hydrogen or methyl.
[52] According to the present invention, preferred compounds are the compounds of formula I " ', salts, solvates and / or hydrates thereof with inorganic or organic acids thereof.
[53]
[54] In this formula,
[55] R ' ₁ represents a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl,
[56] R ' ₄ and R' ₅ each represent methyl or together with the carbon atoms to which they are attached form cyclohexyl or cyclopropyl,
[57] R ' ₆ and R' ₇ are similar and represent hydrogen or methyl.
[58] According to the present invention, preferred compounds are compounds of formula I, I ', I "and I"' in optically pure form.
[59] The following compounds, salts, solvates and / or hydrates thereof are more particularly preferred:
[60] 2- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylphenyl) -acetyl] morpholine , (-) isomer,
[61] 2- (3,4-dichlorophenyl) -4- [2- (3,5-dichlorophenyl) -acetyl] morpholine , (+) Isomer,
[62] 2- (3,4-dichlorophenyl) -4- [2- [3,5-bis (trifluoromethyl) phenyl] ] -Acetyl] morpholine, (+) isomer,
[63] 2- (3,4-Dichlorophenyl) -4- [2- (3, 5-dihydroxyphenyl) 5-dimethylphenyl) acetyl] morpholine, (-) isomer,
[64] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) - diethylphenyl] acetyl] morpholine, (-) isomer,
[65] 2- [3,4-dichlorophenyl) -4- [2- [3,5-bis ((4-fluorobenzyl) piperidin- Trifluoromethyl) -phenyl] acetyl] morpholine, (+) isomer,
[66] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) piperazin- Dimethyl phenyl) acetyl] morpholine, (-) isomer,
[67] 2- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylphenyl) piperazin-1- Acetyl] morpholine, (-) isomer,
[68] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) piperazin- Diethylphenyl) acetyl] morpholine, (-) isomer,
[69] Yl] ethyl] -2- (3,4-dichlorophenyl) -4- [2- (4-methylpiperazin- (3,5-diethylphenyl) acetyl] morpholine, (-) isomer,
[70] 2- (3,4-dichlorophenyl) -4- [2- (3,5-diethylphenyl) acetyl] morpholine , (-) isomer,
[71] Yl] ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylphenyl) piperazin-1- ) Acetyl] morpholine, (-) isomer,
[72] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) piperazin- Bis (trifluoromethyl) phenyl] acetyl] morpholine, (+) isomer,
[73] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) -Dichlorophenyl) acetyl] morpholine, (+) isomer,
[74] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) -Bis (trifluoromethyl) phenyl] acetyl] morpholine, (+) isomer,
[75] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) piperazin- Diisopropylphenyl) acetyl] morpholine, (-) isomer.
[76] According to another aspect,
[77] 1a) treating a compound of formula < RTI ID = 0.0 > (II) < / RTI > with a functional derivative of an acid of formula (III)
[78] 2a) optionally, when E represents a protecting group, it is removed by the action of an acid or a base to give an alcohol of formula IVa (E = H)
[79] 3a) Treatment of an alcohol of formula IVa (E = H) obtained in step 1a) or step 2a) with a compound of formula V to give a compound of formula VI,
[80] 4a) reacting a compound of formula (VI) with a compound of formula (VII)
[81] 5a) optionally, converting the compound thus obtained into a salt with an inorganic or organic acid, a salt, solvate and / or hydrate thereof.
[82]
[83]
[84]
[85] (E = H)
[86] Y-SO ₂ -Cl
[87]
[88]
[89] In this formula,
[90] Ar, R < ₁ > and X are as defined for a compound of formula (I)
[91] E represents hydrogen or an O-protecting group,
[92] Y represents a methyl, phenyl, tolyl or trifluoromethyl group.
[93] When E represents an O-protecting group, it is selected from conventional O-protecting groups known to those skilled in the art, such as 2-tetrahydropyranyl, benzoyl or (C ₁ -C ₄ ) alkylcarbonyl .
[94] In step 1a), the functional derivative of the acid III used is an activated ester such as one of the functional derivatives which react with the acid itself or with an amine, for example anhydride, mixed anhydride, acid chloride or para-nitrophenyl ester.
[95] When the acid of formula (III) itself is used, the process can be carried out using coupling agents used in the field of peptide chemistry, such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris (dimethylamino) In the presence of a base such as, for example, triethylamine or N, N-diisopropylethylamine in an inert solvent such as dichloromethane or N, N-dimethylformamide in the presence of hexafluorophosphate at 0 ° C To room temperature.
[96] When an acid chloride is used, the reaction is carried out in an inert solvent such as dichloromethane or benzene in the presence of a base such as triethylamine or N-methylmorpholine at -60 DEG C to room temperature.
[97] The thus obtained compound of formula IV is optionally deprotected in step 2a) according to methods known to those skilled in the art. For example, when E is a 2-tetrahydropyranyl group, the deprotection can be carried out using hydrochloric acid in a solvent such as ether, methanol or a mixture of these solvents, or using pyridinium p-toluenesulfonate in a solvent such as methanol , Or by acid hydrolysis using Amberlyst in a solvent such as methanol. The reaction is carried out at a temperature from room temperature to the reflux temperature of the solvent. When E is a benzoyl group or a (C ₁ -C ₄ ) alkylcarbonyl group, the deprotection may be carried out in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, water, methanol, In an inert solvent such as tetrahydrofuran, dioxane, tetrahydrofuran, dioxane, tetrahydrofuran, dioxane, or a mixture of these solvents.
[98] In step 3a) the reaction of an alcohol of formula IVa (E = H) with a sulfonyl chloride of formula V is carried out in the presence of a base such as triethylamine, pyridine, N, N-diisopropylethylamine or N-methylmorpholine Under an inert solvent such as dichloromethane, benzene or toluene at a temperature of from -20 占 폚 to the reflux temperature of the solvent.
[99] The thus obtained compound of formula (VI) is reacted with a compound of formula (VII) in step (4a). This reaction is carried out in the presence or absence of a base in an inert solvent such as N, N-dimethylformamide, acetonitrile, methylene chloride, toluene or isopropanol. If a base is used, the base can be obtained from an organic base such as, for example, triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an alkali metal carbonate such as, for example, potassium carbonate, sodium carbonate or sodium bicarbonate Or bicarbonate. In the absence of a base, the reaction is carried out in the presence of an excess of an alkali metal iodide such as, for example, potassium iodide or sodium iodide, using a compound of formula VII. This reaction is carried out at room temperature to 100 ° C.
[100] According to a variant of the invention,
[101] 1b) is carried out as in step 1a) and optionally step 2a)
[102] 2b) Oxidation of the thus obtained compound of formula IVa (E = H) to give a compound of formula VIII,
[103] 3b) After reacting the compound of formula (VIII) with a compound of formula (VII) in the presence of an acid, the intermediate iminium salt formed is reduced with a reducing agent,
[104] 4b) optionally converting the thus obtained compound into one of the salts with inorganic or organic acids.
[105]
[106] According to a variant of the invention, in step 2b), the alcohol of formula IVa (E = H) is oxidized to give the aldehyde of formula VIII. The oxidation reaction is carried out, for example, using oxalyl chloride, dimethylsulfoxide and triethylamine in a solvent such as dichloromethane at -78 ° C to room temperature.
[107] Next, in step 3b), the compound of formula (VII) is reacted with an aldehyde of formula (VIII) in the presence of an acid such as acetic acid, for example, in an inert solvent such as methanol or dichloromethane to give, for example, sodium cyanoborohydra Id or sodium triacetoxyborohydride, or catalytically reducing intermediate imines that are catalytically reduced using hydrogen and palladium on carbon or Raney (R) nickel catalysts in situ .
[108] According to another variant,
[109] 1c) protecting the nitrogen atom of the compound of formula (II) with an N-protecting group to give a compound of the formula (XXXV)
[110] 2c) optionally, when E represents a protecting group, it is removed by the action of an acid or base to give an alcohol of formula XXXVa (E = H)
[111] 3c) Treatment of an alcohol of formula XXXVa (E = H) obtained in step 1c) or step 2c) with a compound of formula V to give a compound of formula XXXVI,
[112] 4c) reacting a compound of formula (XXXVI) with a compound of formula (VII)
[113] 5c) Removal of the N-protecting group in the compound of formula (XXXVII) to give a compound of formula (XXXVIII)
[114] 6c) treating a compound of formula XXXVIII with a functional group derivative in the acid of formula III < RTI ID = 0.0 >
[115] 7c) optionally converting the thus obtained compound into one of the salts with inorganic or organic acids.
[116]
[117]
[118] (V)
[119] Y-SO ₂ -Cl
[120]
[121] (VII)
[122]
[123]
[124]
[125] (III)
[126]
[127] In this formula,
[128] Ar, R < ₁ > and X are as defined for a compound of formula (I)
[129] E represents hydrogen or an O-protecting group,
[130] Pr represents an N-protecting group,
[131] Y represents a methyl, phenyl, tolyl or trifluoromethyl group.
[132] Finally, compounds of formula I according to the invention are obtained.
[133] The compounds of formula (I) thus obtained are isolated in the free base form or in the form of a salt according to conventional techniques.
[134] When the compound of formula (I) is obtained in the free base form, the salt formation is obtained by treatment with an acid selected in an organic solvent. For example, the free base, dissolved in an ether such as diethyl ether or in an alcohol such as 2-propanol alcohol, or in acetone or dichloromethane, or in ethyl acetate, is treated with a solution of the selected acid in one of the solvents, Lt; / RTI > to give the corresponding salt.
[135] Thus, for example, there can be mentioned, for example, hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, oxalate, maleate, succinate, fumarate, , Benzenesulfonate, para-toluenesulfonate, gluconate, citrate or isethionate.
[136] At the end of the reaction, the compound of formula I can be isolated in the form of one of its salts, for example in the form of a hydrochloride or oxalate, in which case the salt is reacted with sodium hydroxide or triethylamine The free base can be prepared by neutralization with the same inorganic or organic base or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
[137] A compound of formula II wherein E represents hydrogen or an O-protecting group is prepared according to the following schemes 1 and 2. In Schemes 1 and 2, Pr ₁ and Pr ₂ represent an O-protecting group as defined above for E, in particular Pr ₁ represents an O-protecting group which is hydrolyzable in an acidic solute, Pr ₂ represents a hydrolyzable group in a basic solute Lt; / RTI >
[138]
[139]
[140]
[141] In step a1 of Scheme 1, the synthesis of the cyanohydrin XXXX from the aldehyde XXXIX is carried out as described in Organic Synthesis; Wiley, New York, 1932; Collect. Vol. 1, Or in a variant of this process which utilizes the action of sodium metabisulfite and potassium cyanide in aqueous solution.
[142] In step b1 , the hydroxyl group of compound XXXX is protected by methods known to those skilled in the art.
[143] The thus obtained compound of formula (IX) is treated in step c1 with a strong base such as lithium diisopropylamide, tert-butoxide potassium or sodium hydroxide to obtain a carbanion and a compound of the formula Hal- (CH ₂ ) ₂ -O -Pr _{2 wherein} Hal is halogen, preferably bromine or chlorine, to give a compound of formula X. The reaction is carried out at -70 to + 60 ° C in the presence of an ether (for example tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane) or an amide (for example N, N-dimethylformamide) or an aromatic hydrocarbon For example toluene or xylene).
[144] The nitrile derivative of formula X is reduced in step d1 to give the primary amine of formula XI. The reduction can be carried out in the presence of a catalyst such as Raney nickel Raney in ethanol mixed with aqueous ammonia in the presence of a catalyst such as lithium aluminum hydride or lithium aluminum hydride in a solvent such as toluene, hexane, petroleum ether, xylene or tetrahydrofuran, Diisobutylaluminum hydroxide, a reducing agent such as boron hydroxide in THF. The reaction is carried out at 0 캜 to 70 캜.
[145] In step e1, the compound to a tertiary amine of formula XI (for example, triethylamine, N- methylmorpholine or pyridine) with a compound of formula Hal-CO-CH ₂ -Hal under such salt present (Hal is halogen, Preferably chlorine or bromine, to give a compound of formula XII. The reaction is carried out at -70 ° C to room temperature in a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), an ether (for example tetrahydrofuran or dioxane) or an amide (for example N, N - < / RTI > dimethylformamide) in an inert solvent.
[146] The O-protecting group Pr < ₁ > is removed from the compound of formula (XII) by acid hydrolysis according to the method described above in step f1 .
[147] Or, an O- protecting group Pr ₁ by acid hydrolysis in step g1 removed from compounds of formula XI and, thus, a compound formula XIII obtained in step h1 according to the method described in step e1 Hal-CO-CH ₂ -Hal Lt; / RTI >
[148] The thus obtained compound of formula (XIV) is cyclized in the presence of a salt to give a compound of formula (XV). When a compound of the formula XV (wherein E represents the protecting group Pr ₂ ) is obtained, a base such as an alkali metal carbonate (for example potassium carbonate) or an alkali metal hydroxide (for example, sodium hydroxide) or a tertiary butoxide potassium In an inert solvent such as an aromatic hydrocarbon (e.g. xylene or toluene) or an amide (e.g. N, N-dimethylformamide) or an ether (e.g. tetrahydrofuran) at a temperature of from -30 캜 to the reflux temperature of the solvent Is used in the solvent (step i1 ). When a compound of the formula XV (wherein E represents hydrogen) is obtained, a base such as an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide) is reacted with an alkanol (for example, 2- Propanol) or an amide (for example, N, N-dimethylformamide) or a mixture of the solvents (step j1 ).
[149] Optionally, compounds of formula XV, wherein E represents O-protecting group Pr ₂ , are prepared in step k1 according to methods known to those skilled in the art.
[150] In step a2 of Scheme 2, a compound of formula XV (wherein E represents hydrogen or an O-protecting group) obtained according to Scheme 1 is reduced. This reduction can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene at room temperature to the reflux temperature of the solvent in the presence of lithium hydroxide, diisobutylaluminum hydroxide, sodium borohydride, Is carried out with a reducing agent such as boric acid hydroxide. The desired compound of formula II is thus obtained. In particular, when E in the compound of formula (XV) represents a benzoyl group, a mixture of a compound of formula II (wherein E is H) and a compound of formula II (wherein E is benzoyl) is obtained during the reaction. This compound is separated according to conventional techniques, such as, for example, chromatography.
[151] Compounds of formula (III) are either commercially available or can be prepared according to known methods.
[152] For example, a compound of formula (III) is prepared according to scheme (3) below.
[153]
[154] Steps a3 and b3 of scheme 3 are described in J. Med . Am. Chem. Soc., 1941, 63 , 3280-3282.
[155] In step c3 , the ester of formula XIX is prepared from an acid of formula XVIII according to methods known to those skilled in the art.
[156] The thus obtained ester XIX is reduced in accordance with the method known to a person skilled in the art with an alcohol of the formula XX in step d3 .
[157] Steps e3 and f3 are described in J. Med. Med. Chem., 1973, 16 , 684-687.
[158] The thus obtained phenylacetonitrile derivative of the formula (XXII) can be prepared by the method of J. Org. Chem., 1968, 33 , 4288] or EP-A-0 714 891.
[159] Bromo derivatives of formula (XVI) are known or described in J. Org. Chem., 1971, 36 (1), 193-196) or [J. Am. Chem. Soc., 1941, 63 , 3280-3282).
[160] X is Compounds of formula (VII) wherein R <_2> is (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) cycloalkyl are commercially available [J. Org. Chem., 1957, 22 , 713] or [J. Med. Chem., 1992, 35 , 2688-2696.
[161] X is (Wherein R &lt; ₂ &gt; is a group -CR ₄ R ₅ CONR ₆ R ₇ ) is prepared according to Scheme 4 below.
[162]
[163] In step a4 of Scheme 4, compound 1 is reacted with a ketone of formula XXIII in the presence of 2-hydroxyisobutyronitrile in accordance with the method described in Eur. J. Med. Chem., 1990, 25 , 609-615.
[164] The nitrile derivative of formula XXIV thus obtained is hydrolyzed in step b4 according to methods known to those skilled in the art to give the acid derivative of formula XXV.
[165] The acid XXV is reacted in step c4 according to the customary procedure for the coupling of an amine of formula XXVI with a peptide coupling to give the derivative XXVIII.
[166] Alternatively, by hydrolysis according to methods known in the nitrile derivative of the formula XXIV to give the carboxamide derivative of general formula XXVII in step d4, and by deprotection in a conventional manner in this derivative optionally e4 R ₆ = R ₇ = H. &Lt; / RTI &gt;
[167] In step f4, respectively, in the presence a strong base a compound of formula XXVII (C ₁ -C ₃₎ alkyl halide, or a continuous two kinds of (C ₁ -C ₃₎ alkyl halide or of the formula Hal-R ₆ -R ₇ -Hal Thus by reaction with a dihalide conventional alkylation method, each R ₆ is (C ₁ -C _3), or denotes an alkyl halide R ₇ = H, R ₆ and R ₇ are each independently (C ₁ -C ₃₎ alkyl Or forms a heterocycle with the nitrogen atom to which they are attached to form a compound of formula XXVIII.
[168] The thus obtained compound of the formula (XXVIII) is deprotected according to a known method in step g4 to obtain the compound of the formula (VII).
[169] X is _{CH-CR 4 R 5 CONR 6} R 7 group of the compound (VII) is prepared according to the following Scheme 5.
[170]
[171] In step a5 of Scheme 5, compound 2 is treated with a straight chain (C ₁ -C ₄ ) alkyl halide or a dihalide of formula Hal (CH ₂ ) _m -Hal wherein m = 2-5 and Hal is a halogen atom, and hydrogenated in the presence of a strong base such as sodium or sodium amide, N, N- dimethyl formamide, or in an inert solvent such as dichloromethane, it is reacted according to the conventional alkylation methods from 0 ℃ to room temperature, R ₄ and R ₅ are each (C ₁ -C ₄ ) alkyl, or together with the carbon atoms to which they are attached form a (C ₃ -C ₆ ) cycloalkyl.
[172] The thus obtained nitrile derivative XXIX is hydrolyzed in step b5 according to methods known to those skilled in the art to give the carboxamide derivative XXX. Optionally, in step c5 the pyridine ring is hydrogenated according to conventional methods in the presence of a catalyst such as platinum oxide to give compounds of formula VII wherein R &lt; ₆ &gt; and R &lt; ₇ &gt;
[173] In step d5, after the alkylation reaction of a compound of formula XXX according to the above-described conventional method, by reducing a compound of the obtained this way the formula XXXI by conventional catalytic hydrogenation R _6, and (or) R ₇ is other than hydrogen (VII) &Lt; / RTI &gt;
[174] X is Lt; RTI ID = 0.0 &gt; (VII) &lt; / RTI &gt;
[175]
[176] In step a6 of Scheme 6, compound 3 is reacted with an appropriate organolithium or organomagnesium derivative such as, for example, methyllithium, ethylmagnesium chloride, propylmagnesium chloride or pentane-1,5-di (magnesium chloride) 625 509 to give the alcohol of formula XXXII.
[177] The thus obtained alcohol XXXII is oxidized to the acid of formula XXXIII according to the method described in Helvetica Chimica Acta, 1972, 55 , (7), 2439, in step b6 .
[178] Acid XXXIII is reacted in accordance with the usual methods of peptide coupling with an amine of formula XXVI in step c6 to give compound XXXIV.
[179] Compound XXXIV is deprotected according to a known method in step d6 to obtain the desired compound VII.
[180] Compound 3 is prepared by reacting ethyl isonipecotate with benzyl bromide in the presence of a base according to a conventional alkylation method.
[181] It is essential to protect reactive or sensitive functional groups, such as amines, hydroxyls or carboxyl groups, present in any molecule involved, during any one step to produce a compound of formula (I) or an intermediate compound of formula (II), Or may be preferred. This protection is described in Organic Chemistry, JFW McOmie, ed. Plenum Press, 1973, Organic Synthesis, TW Greene et PGM Wutts, Ed. John Wiley and Sons, 1991 or Kocienski PJ, 1994, Georg Thieme Verlag). &Lt; / RTI &gt; Removal of the protecting group may be carried out at a later appropriate stage using methods known to those skilled in the art without affecting the rest of the appropriate molecule.
[182] Compounds of formula IV in pure enantiomeric or racemic forms are novel and form part of the present invention.
[183] Compounds of formula (IV) wherein E is hydrogen are preferred.
[184] Compounds of formula IV are prepared according to the invention in step 1a of the process.
[185] Compounds of formula VI in pure enantiomeric or racemic forms are novel and form part of the present invention.
[186] Compounds of formula (VI) are prepared according to the invention in step 3a of the process.
[187] Compounds of formula VIII in pure enantiomeric or racemic form are novel and form part of the present invention.
[188] Compounds of formula VIII are prepared according to the invention in step 2b of the process.
[189] The resolution of the racemic mixture in the compounds of formula (I) enables the separation of the enantiomers.
[190] However, it is preferred to carry out the resolution of racemic mixtures from intermediates which are useful in the preparation of compounds of formula (I) or which are useful in the preparation of compounds of formula (II) (E = H) or alternatively of formula (II). In particular, the resolution of the racemic mixture in the compound of formula XIII below is carried out.
[191]
[192] (+) - or (-) - tartaric acid, or (+) - or (-), when the resolution of the racemate is carried out in an intermediate compound of formula XIII or II -10-camphorsulfonic acid. &Lt; / RTI &gt; The diastereoisomer is then isolated by conventional methods such as crystallization or chromatography and the salt is advantageously obtained, followed by the pure optical enantiomer.
[193] The compounds of formula (I) also include those wherein at least one hydrogen or carbon atom is replaced by its radioactive isotope, such as thiolium, or carbon-14. Such labeled compounds are useful in biological studies as receptor ligands in research studies of metabolism or pharmacokinetics.
[194] The compounds according to the invention have undergone biochemical tests.
[195] The affinity of the compound for the tachykinin receptor was evaluated in vitro by several biochemical tests using radioligand.
[196] 1) binding of human lymphocyte cells to the NK ₁ receptor of [ ¹²⁵ I] BH-SP (substance P labeled with iodine-125 using a Bolton-Hunter reagent (DG Payan et al., J Immunol., 1984, 133 , 3260-3265).
[197] 2) Binding to human NK ₂ cloned receptors expressed by CHO cells of [ ¹²⁵ I] His-NK ₄ (Y. Takeda et al., J. Neurochem., 1992, 59 , 740-745).
[198] 3) binding of [ ¹²⁵ I] His [MePhe ⁷ ] NK _B to human NK ₃ cloned receptors expressed by rat cortex, guinea pig cerebral cortex and germillus rat cortical NK ₃ receptors, and CHO cells (Buell et al., FEBS Letters, 1992, 299 , 90-95).
[199] Exams are x. According to the method of Eons-Alt et al. (X. Emonds-Alt et al., Eur. J. Pharmacol., 1993, 250 , 403-413, Life Sci., 1995, 56 , PL 27-32) .
[200] The compounds according to the invention strongly inhibit the binding of substance P to the NK ₁ receptor of human IM9 lymphocyte cells. The inhibition constant Ki for human lymphocyte cell receptors is on the order of 10 ^-11 M.
[201] Inhibition constant Ki is the degree of 10 ^-8 and the inhibitory constant Ki for the human NK ₃ receptor Cloning of the human NK ₂ receptor is cloned into a greater than 10 ^-7 M.
[202] The compounds of formula I are potent and selective antagonists of substance P against the human NK ₁ receptor.
[203] Thus, the compounds of formula I were also evaluated in vivo in animal models.
[204] Local application of an agent specific for the NK ₁ receptor, such as [Sar ⁹ , Met (O ₂ ) ¹¹ ] substance P, to the guinea pig rhabdomyosus enhances secretion of acetylcholine. Such secretion is inhibited by oral or intraperitoneal administration of a compound according to the invention. This test is called Al. Steinberg et al., J. Neurochemistry, 1995, 65 , 2543-2548).
[205] This result shows that the compound of formula I is orally active and that this compound traverses the blood-fluid interface and can block the action specific to the NK ₁ receptor in the central nervous system.
[206] The compounds of formula (I) Were assessed by bronchial stenosis test of guinea pig according to the method described by Emmons-Alt et al. (X. Emonds-Alt et al., European Journal of Pharmacology, 1993, 250 , 403-413). Intravenously administered compounds of formula I strongly antagonize bronchial stenosis induced by intravenous administration of guinea pig to guinea pig under the experimental conditions of this compound.
[207] The in vivo pharmacological activity of the compounds of formula (I) Were evaluated in dog hypotensive models according to the method described by Emons-Alt et al. (X. Emonds-Alt et al., Eur. J. Pharmacol., 1993, 250 , 403-413). Intravenously administered compounds of formula I strongly inhibit hypotension induced by intravenous administration of [Sar ⁹ , Met (O ₂ ) ¹¹ ] Substance P to anesthetized dogs under the experimental conditions of this compound.
[208] This result shows that the compound of formula I blocks the action specific to the NK ₁ receptor in the peripheral nervous system.
[209] The compounds of the present invention are particularly active ingredients of pharmaceutical compositions whose toxicity is comparable to their use as medicaments.
[210] The compound of formula (I) may be used in an amount of 0.01 to 100 mg, preferably 0.1 to 50 mg / kg, per kg body weight of the mammal to be treated per day. In the case of humans, the dosage may preferably range from 0.1 to 4000 mg, more particularly from 0.5 to 1000 mg per day depending on the age or type of treatment: the prevention or treatment of the individual being treated.
[211] For its use as a medicament, the compounds of formula I are generally administered in dosage units. The dosage unit is preferably formulated as a pharmaceutical composition in which the active ingredient is mixed with one or more pharmaceutical excipients.
[212] Accordingly, another aspect of the present invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or hydrate thereof.
[213] In the pharmaceutical compositions of the present invention for oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous, transdermal, topical or rectal administration, the active ingredient is administered to an animal or human in unit dosage form admixed with a conventional pharmaceutical carrier Lt; / RTI &gt; Suitable unit forms of administration include, but are not limited to, oral-route forms such as tablets, gelcapsules, powders, granules and oral solutions or suspensions, sublingual and oral dosage forms, aerosols, topical dosage forms, implants, , Intranasal or intravenous administration forms, and rectal administration forms.
[214] When the solid preparation is prepared in the form of tablets or gel capsules, diluents such as lactose, microcrystalline cellulose, starch, dicalcium phosphate, binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose For example, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethyl-cellulose, flow agents such as silica or talc, and lubricants such as magnesium stearate, stearic acid, glyceryl A mixture of pharmaceutical excipients which may consist of tribehenate or sodium stearyl fumarate is added to the micronized or non-micronised active ingredient.
[215] Wetting agents or surfactants, such as sodium lauryl sulfate, polysorbate 80 or poloxamer 188, may be added to the formulation.
[216] Tablets may be prepared by a variety of techniques, direct tabletting, dry granulation, wet granulation, and heat-melting.
[217] The tablets may be uncoated, sugar-coated (e. G., With sugar) or coated with various polymers or other suitable materials.
[218] Tablets may be subjected to rapid release, delayed release, or sustained release, either by preparing a polymer matrix or by using a particular filmed polymer.
[219] The gel capsules may be soft or hard, and may be coated with a film or the like, so that they can have rapid, sustained or delayed activity (for example, by enteric coated form).
[220] They are not only solid formulated as described above for tablets, but may also be liquid or semi-solid preparations.
[221] Syrup or elixir formulations may contain a sweetening agent, preferably a non-calorie sweetening agent, methylparaben and propylparaben as preservatives, a flavoring agent and a suitable colorant, together with the active ingredient.
[222] Water-dispersible powders or granules may contain the active ingredient as a dispersant, wetting or suspending agent, for example, as a mixture of polyvinylpyrrolidone and a sweetener or flavor enhancer.
[223] For rectal administration, suppositories which are made with a binder which melts at rectal temperature, for example cocoa butter or polyethylene glycol, are used.
[224] Aqueous suspensions, isotonic saline solutions or sterile, injectable solutions containing pharmacologically compatible dispersants and / or solubilizers, for example propylene glycol, are used for parenteral, intranasal or intravenous administration.
[225] Thus, in order to prepare an aqueous solution which can be injected intravenously, a co-solvent such as an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as polysorbate 80 Or Poloxamer 188 may be used. The active ingredient may be dissolved in triglycerides or glycerol esters to produce injectable oily solutions for intramuscular administration.
[226] Creams, ointments, gels, eye drops and sprays can be used for topical administration.
[227] Patches and spray formulations in the form of multiple laminates or reservoirs in which the active ingredient may be present in the alcohol solution may be used for transdermal administration.
[228] For example, aerosols containing sorbitan trioleate or oleic acid and trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane, freon alternate or any other biologically compatible propellant gas may be administered by inhalation It is used for. A powdered system containing only the active ingredient alone or together with an excipient may also be used.
[229] The active ingredient may also be used in the form of a complex with a cyclodextrin, for example, -, - or -Cyclodextrin or 2-hydroxypropyl- -Cyclodextrin.
[230] The active ingredient may also optionally be formulated in the form of microcapsules or microspheres with one or more supports or additives.
[231] Among the sustained release forms useful in the case of chronic treatment, implants can be used. The compounds may be prepared in the form of oily suspensions or in the form of microsphere suspensions in isotonic media.
[232] In each dosage unit, the active ingredient of the formula I is present in an amount appropriate for the anticipated daily dose. Generally, each dosage unit will contain from 0.1 to 1000 mg of dosage unit, depending on the anticipated dosage and the mode of administration of the drip agent such as, for example, tablets, gel capsules, sachets, ampoules, syrups, , Preferably 0.5 to 250 mg of the active ingredient, and the number of times should be 1 to 4 times per day.
[233] This dose is an example of an average situation, and there may be special cases where lower or higher dosages are appropriate, which also form part of the present invention. According to conventional practice, The amount is determined by the physician according to the mode of administration, the age, weight and response of the patient.
[234] Another aspect of the invention relates to the use of a compound of formula I, a pharmaceutically acceptable salt, solvate and / or hydrate thereof for the manufacture of a medicament for the treatment of any disease associated with substance P and human NK ₁ receptor .
[235] Another aspect of the present invention is the use of a compound of formula I, its pharmaceutically acceptable salts, solvates and / or hydrates for the treatment of diseases of the respiratory, gastrointestinal, urinary, immunological or cardiovascular and central nervous system, Inflammation, nausea and vomiting, and for the treatment of skin diseases.
[236] By way of example and not limitation, the compounds of formula I are useful in the following.
[237] Particularly arthritic pain caused by osteoarthritis, rheumatoid arthritis or psoriatic arthritis, neurogenic pain such as post-herpetic neuralgia, trigeminal neuralgia, arthritic pain, , Neuropathies induced by interstitial or interstitial neuralgia, fibroma, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, laryngealgia, facial neuralgia or acute neuralgia, Such as chronic or acute migraine, temporomandibular pain, maxillary sinus pain, facial neuralgia or toothache, pain suffered by cancer patients, pain of visceral pain, gastrointestinal pain, pain caused by compression of the nerves, Pain caused by dysmenorrhea, menstrual cramps, or retinitis, musculoskeletal pain, spinal stenosis, escape di Pain associated with ankylosing spondylitis, pain associated with ankylosing spondylitis, pain associated with gout, burns, pain associated with scarring or eczematous dermatoses, thalamic pain caused by sciatica or sciatica Inflammatory diseases of the gastrointestinal tract such as Crohn &apos; s disease, Crohn &apos; s disease, Crohn &apos; s disease, Crohn &apos; s disease, Inflammatory and secretory consequences caused by disorders caused by ulcerative colitis, pancreatitis, gastritis, enteritis, non-steroidal anti-inflammatory agents, for example bacterial infection by Clostridium difficile , Diseases such as herpes and eczema, inflammatory bladder diseases such as cystitis and incontinence, eye inflammation such as conjunctivitis and eczema As an anti-inflammatory agent for the treatment of dermatitis, retinopathy, tooth inflammation such as gingivitis and dermatomyositis, in particular for the treatment of allergic diseases of the skin such as dermatitis, contact dermatitis, atopic dermatitis and respiratory diseases such as rhinitis , Diseases of the central nervous system, in particular psychosis such as schizophrenia, manic and dementia, cognitive disorders such as Alzheimer's disease, anxiety, AIDS-related dementia, diabetic neuropathy, depression, Parkinson's disease, Related disorders, neuropathic disorders such as peak disease or Creutzfeldt-Jakob syndrome, panic disorder, phobias or dyslipidemia, as well as psychotic disorders, sleep disorders, 24-hour rhythm disorders, mood disorders and epilepsy, Down syndrome, Huntington's chorea, For the treatment of stress-related disorders, for the treatment of inflammatory and autoimmune processes of the central nervous system, for example, the transmembrane modification of blood-flow gating during AIDS-related infection, Relaxing and antispasmodic agents may be used for the treatment of cancer or carcinoidosis by drugs such as drugs used in chemotherapy in the case of acute or delayed anticipated nausea and vomiting, Metabolic or infectious disorders caused by ingestion of poison, such as radiation therapy during irradiation, such as caused by gastritis, or by toxins produced during bacterial or viral gastrointestinal infections, during pregnancy, Migraine headache, migraine headache, migraine headache, migraine headache, migraine headache, migraine headache, headache, dizziness or Meniere's disease, postoperative disease, dialysis or prostaglandin induced gastrointestinal atresia, Of gastric acid overeating, overeating of food or beverage during gastroesophageal reflux, by ingestion of an opioid analgesic such as morphine For the treatment of gastrointestinal disorders such as irritable bladder syndrome, gastroesophageal reflux disease, gastroesophageal reflux disease, gastroesophageal reflux disease, gastroesophageal reflux disease, Treatment of skin diseases such as psoriasis, pruritus and burns, especially sunburn, in the treatment of gastric ulcer and duodenal ulcer, esophageal ulcer, diarrhea, hyperalgesia, lymphoma, gastritis, gastroesophageal reflux, For the treatment of diseases of the cardiovascular system such as hypertension, vascular appearance of the migraine head, head and neck, thrombosis, angina pectoris, vasoconstriction, circulatory diseases caused by vasodilation, Raynaud's disease, fibrosis, collagen diseases and atherosclerosis, For the treatment of small cell lung cancer, breast cancer, brain tumors and adenocarcinomas of comparative genital organs in an adjunctive treatment for preventing metastasis, dehydration diseases such as multiple sclerosis or proximal The present invention relates to the use of the compounds of formula I in the treatment of epidermolysis sclerosis, in the treatment of immune system diseases associated with the suppression or stimulation of immune cells, such as rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, In the treatment, for example in the treatment of systemic lupus erythematosus, as an anorexia inducer, in the treatment of models, lighter diseases, hemorrhoids, in the treatment of eye diseases such as glaucoma, intrahepatic hypertension, In the treatment, the treatment or prevention of cerebral ischemic lesions caused by epileptic seizures, cranial injuries, spinal cord injuries, vascular seizures or occlusion, especially in the treatment of heart rate diabetes and heart failure caused by pain or stress, And for the prevention or eradication of dermatitis, erythema or pruritus, for the treatment of neurogenic skin disorders such as hypotonia, For the treatment of syndrome, ulcers and H. pyrrolidone (Helicobacter pylori) or a urease-positive gram-for the treatment of all diseases caused by the negative bacteria, for the treatment of a or angiogenesis symptoms caused by angiogenic disorders, eye And / or palbbral tubs and / or eyes or palvbral are useful as anti-inflammatory agents in the treatment of sensations.
[238] The present invention also encompasses a method of treating the condition at a dose as described above.
[239] The pharmaceutical compositions according to the present invention may also contain other active substances useful for the treatment of diseases or disorders such as those mentioned above, such as bronchodilators, antiinflammatory agents, antihistamines, antiinflammatory agents, anti-topical agents and chemotherapeutic agents .
[240] The following preparations and examples illustrate the present invention without being limited thereto.
[241] The following abbreviations are used in the preparations and examples.
[242] DMF: Dimethylformamide
[243] DMSO: dimethylsulfoxide
[244] DCM: dichloromethane
[245] THF: tetrahydrofuran
[246] Hydrochloric ether: A saturated solution of hydrochloric acid in ether
[247] BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
[248] m.p .: melting point
[249] RT: room temperature
[250] b.p .: boiling point
[251] Silica H: 60H silica gel sold by Merck (Darmstadt).
[252] Proton nuclear magnetic resonance ( ¹ H NMR) spectra were recorded at 200 MHz in DMSO-d ₆ using the DMSO-d ₆ peak as a standard. Chemical shifts δ are reported in parts per million (ppm). The observation signal is expressed as follows.
[253] s: single, se: broad single, t: triple, qd: quadrature, m: undissolved mixture mt: multiple.
[254] Production Examples 1.1 and 1.2
[255] 2- (3,4-dichlorophenyl) -morpholine, (-) isomer (Preparation 1.1) and 2- (3,4-dichlorophenyl) 2-hydroxyethyl) morpholine, (-) isomer (Preparation 1.2).
[256] Preparation 1.1: &lt; RTI ID = 0.0 &gt; E = ; Ar =
[257] Preparation 1.2: Formula II: E = H; Ar =
[258] A) 2- (3,4-Dichlorophenyl) -2-hydroxyacetonitrile.
[259] A mixture of 70 g of 3,4-dichlorobenzaldehyde and 90 g of Na ₂ S ₂ O _{5 in} 300 ml of water was left to stir at room temperature overnight. The reaction mixture was cooled to 0 C and a solution of 52 g KCN in 100 ml water was added dropwise, and the mixture was left stirring while the temperature was brought to room temperature. After the reaction mixture was extracted with ether and the organic phase was washed with water, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. 76 g of the desired product were obtained and this product was used as follows.
[260] B) 2- (3,4-Dichlorophenyl) -2- (tetrahydropyran-2-yloxy) acetonitrile.
[261] A solution of 76 g of the compound obtained in the above step and 0.25 g of p-toluenesulfonic acid monohydrate in 300 ml of DCM was cooled to 0 C and a solution of 39 g of 3,4-dihydro-2H-pyran in 50 ml of DCM was added dropwise, The mixture was allowed to stand while stirring while the temperature was kept at room temperature. After saturation the reaction mixture is washed with a NaHCO ₃ solution and water successively, and the organic phase dried with Na ₂ SO _4, the solvent was evaporated in vacuo. After crystallization from pentane (mp = 61 ° C) at 0 ° C, 33 g of the desired product were obtained.
[262] C) 4- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) butanenitrile.
[263] 56 ml of a 2M solution of lithium diisopropylphenylamide in THF was cooled to -60 DEG C and a solution of 32 g of the compound obtained in the above step in 50 ml of THF was added dropwise, and then the mixture was left to stir at -60 DEG C for 1 hour. A solution of 25.4 g of 2-bromoethyl benzoate in 50 ml of THF was added dropwise at -60 &lt; 0 &gt; C and the mixture was left under stirring while the temperature was brought to room temperature. The reaction mixture was concentrated in vacuo and the residue was extracted with ether, the organic phase was washed sequentially with water and a buffer solution (pH 4) and the solvent was evaporated and dried in Na ₂ SO ₄ under vacuum. The residue was chromatographed on silica eluting with a toluene / AcOEt (100/5; v / v) mixture. 34 g of the desired product were obtained and this product was used as follows.
[264] D) 4- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2- (tetrahydropyran-2-yloxy) butylamine.
[265] A mixture of 34 g of the compound obtained in the above step and 10 ml of Raney (registered trademark Raney) nickel in 400 ml of EtOH and 40 ml of a concentrated aqueous ammonia solution was hydrogenated at room temperature under atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated in vacuo. After lifting it out of the water and the residue extracted with ether, washed with saturated NaCl solution and the organic phase dried by evaporation of the solvent under vacuum with Na ₂ SO _4. The residue was chromatographed on silica-H eluting with a (100/1; v / v) to (100/3; v / v) DCM / MeOH mixture. 16 g of the desired product were obtained and this product was used as follows.
[266] E) 4- (Benzoyloxy) -2- (3,4-dichlorophenyl) -2-hydroxybutylamine hydrochloride.
[267] A solution saturated with HCl gas in ether was added to a solution of 12 g of the compound obtained in the above step in 50 ml of MeOH at room temperature to pH 1 and then the mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM to remove water from the formed precipitate and washed with ether. After recrystallization from 2-propanol, 3.4 g of the desired product were obtained (m.p. = 200-204 [deg.] C).
[268] F) 4- (benzoyloxy) -2- (3,4-dichlorophenyl) -2-hydroxybutylamine, (-) isomer.
[269] A solution of 56.2 g of (1S) - (+) - 10-camphorsulfonic acid in 660 ml of 2-propanol was heated under reflux and then a solution of 78 g of the compound obtained in the above step, in free base form in 660 ml of 2- And the mixture was left to stir while the temperature was brought to room temperature. The water was removed from the crystals formed and the crystals were washed with 2-propanol, washed with ether and dried under vacuum. 115 g of camphorsulfonic acid salt was obtained. The salt thus obtained was recrystallized from 3000 ml of 2-propanol, stirred at room temperature overnight, washed with water and then washed and dried to give 100 g of camphorsulfonic acid salt. The thus obtained salt was recrystallized again in 3000 ml of EtOH, the water was removed, washed and the crystals formed were dried to give 32 g of camphorsulfonic acid salt.
[270] = -17.3 [deg.] (C = 1; MeOH).
[271] 30 g of the salt thus obtained was taken up in 10% Na ₂ CO ₃ solution and extracted with AcOEt. The organic phase was washed with water to neutralize the pH, then dried with Na ₂ CO ₄ and the solvent was evaporated under vacuum. After drying at 60 &lt; 0 &gt; C under vacuum, 17.72 g of the desired product are obtained (mp = 101 [deg.] C).
[272] = -49.1 [deg.] (C = 1; MeOH).
[273] G) N- (2-chloroacetyl) -4- (benzoyloxy) -2- (3,4-dichlorophenyl) -2-hydroxybutylamine, (-) isomer.
[274] A solution of 11.76 g of the compound obtained in the above step and 3.33 g of triethylamine in 150 ml of DCM was cooled to 0 &lt; 0 &gt; C and a solution of 3.75 g of chloroacetyl chloride was added dropwise, and the mixture was left under stirring for 5 minutes. The reaction mixture was concentrated in vacuo and the residue extracted with AcOEt, then the organic phase was washed sequentially with water, buffer solution (pH = 2) and saturated NaCl solution and the solvent was evaporated in vacuo. After crystallization in an ether iso / pentane mixture, 14 g of the desired product were obtained (m.p. = 72-74 [deg.] C).
[275] = -28 (c = 1; MeOH).
[276] H) 6- [2- (Benzoyloxy) ethyl] -6- (3,4-dichlorophenyl) morpholin-3-one, (-) isomer.
[277] A solution of 13.5 g of the compound obtained in the above step in 400 ml of THF was cooled to -30 占 and 7.02 g of potassium tert-butoxide was added in portions and the mixture was left to stir at -30 占 폚 for 20 minutes. The reaction mixture was concentrated in the cold under vacuum and, after extraction of the residue with AcOEt, the buffer and the organic phase solution (pH = 2), water and saturated NaCl solution washed sequentially and the solvent was evaporated and dried in Na ₂ SO ₄ vacuo . Crystallization in an ether iso / pentane mixture gave 11.87 g of the desired product (mp = 134-137 [deg.] C).
[278] = -4.9 [deg.] (C = 1; MeOH).
[279] I) 2- (3,4-dichlorophenyl) morpholine, (-) isomer (Preparation 1.1) and 2- (3,4-dichlorophenyl) (2-hydroxyethyl) morpholine, (-) isomer (Preparation 1.2).
[280] A solution of 19.5 g of the compound obtained in the above step in 100 ml of THF was added dropwise to 250 ml of a IM borane solution in THF at room temperature and then the mixture was heated under reflux for 3 hours. 120 ml of boiling MeOH was added dropwise and reflux was continued for 30 minutes. The reaction mixture was cooled on an ice bath and 50 ml of a hydrochloric ether solution was added and the mixture was left stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was taken up in 10% Na ₂ CO ₃ solution and extracted with AcOEt, then the organic phase was washed with water and dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was chromatographed on silica H gel gradient eluting with a (100/3; v / v) to (100/5; v / v) DCM / MeOH mixture. The following two compounds were isolated.
[281] - Minimum Polarity: The compound of Preparation 1.1
[282] m = 10.4 g, in oil form.
[283] = -17 [deg.] (C = 0.5; MeOH).
[284] - Maximum polarity: The compound of Preparation 1.2
[285] m = 5.3 g, in oil form.
[286] = -20 [deg.] (C = 0.5; MeOH).
[287] Production Example 2.1
[288] 3,5-Dichlorophenylacetic acid
[289] (III): R &_lt; ₁ &gt; = Cl.
[290] A) 3,5-Dichlorobenzyl chloride.
[291] A solution of 12.5 g of thionyl chloride in 20 ml of chloroform was added dropwise to a solution of 14.5 g of 3,5-dichlorobenzyl alcohol in 150 ml of chloroform at room temperature, then the mixture was heated at 40 to 50 ° C for 8 hours and stirred at room temperature overnight . The mixture was concentrated in vacuo to give 16 g of the desired product, which was used as follows.
[292] B) 3,5-Dichlorophenylacetonitrile.
[293] A solution of 6.5 g of potassium cyanide in 50 ml of water was added to a solution of 16 g of the compound obtained in the above step in 50 ml of EtOH and the mixture was heated under reflux for 4 hours. After the mixture is concentrated under vacuum and lifting it out of the water and the residue extracted with ether, washed the organic phase with water and evaporation of the solvent and dried by Na ₂ SO ₄ under vacuum. The residue was chromatographed on silica H, eluting sequentially with a mixture of heptane / toluene (50/50; v / v) and toluene. 7 g of the desired product were obtained and the product was used as follows.
[294] C) 3,5-Dichlorophenylacetic acid.
[295] A solution of 8.4 g of KOH in 10 ml of water was added to a solution of 7 g of the compound obtained in the above step in 50 ml of EtOH and the mixture was heated under reflux for 5 hours. The mixture was concentrated in vacuo, the residue was taken up in water and the aqueous phase was washed with ether, the aqueous phase was acidified to pH 1 by addition of concentrated HCl and the mixture was left stirring at room temperature overnight. The crystalline product formed was drained, washed with water and then dried under vacuum at 60 &lt; 0 &gt; C. 7 g of the desired product were obtained (m.p. = 112-114.5 [deg.] C).
[296] Production Example 2.2
[297] 3,5-diethylphenylacetic acid
[298] (III): R ₁ = CH ₂ CH ₃ .
[299] A) 3,5-diethyl bromobenzene.
[300] A mixture of 20 g of 4-bromo-2,6-diethylaniline, 160 ml of acetic acid, 100 ml of concentrated HCl solution, 30 ml of water and 100 ml of EtOH was cooled to -5 DEG C and then a solution of 6.6 g of sodium nitrate in 25 ml of water was added dropwise The mixture was left to stir at room temperature for 30 minutes. The reaction mixture was poured onto 170 ml of 50% H ₃ PO ₂ cooled to 0 ° C and the mixture was left to stir at 0 ° C for 2 hours and then left to stir at room temperature for 48 hours. After the reaction mixture was extracted with ether, the organic phase was washed with water, 1N NaOH solution and water successively, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The residue was chromatographed on silica gel eluting with cyclohexane. 18 g of the desired product were obtained.
[301] B) 3,5-Diethylbenzonitrile.
[302] A mixture of 24.7 g of the compound obtained in the above step and 12 g of copper (I) cyanide in 70 ml of DMF was heated under reflux for 15 hours. After cooling to room temperature, the reaction mixture was poured onto 50 ml of water and allowed to stir at room temperature until gum was formed. The mixture was cooled on an ice bath, 150 ml of ethylenediamine was added, and the mixture was left to stir at room temperature for 2 hours. After the mixture was extracted with AcOEt and the organic phase was washed with water, dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. The residue was chromatographed on silica gel eluting with cyclohexane / AcOEt (95/5; v / v). 12 g of the desired product was obtained.
[303] C) 3,5-Diethylbenzoic acid.
[304] A solution of 22 g of KOH in 15 ml of water is added to a solution of 12 g of the compound obtained in the above step in 60 ml of EtOH and the mixture is heated under reflux for 24 hours. The reaction mixture was concentrated in vacuo, the residue was extracted with water, and the aqueous phase was washed with ether. The aqueous phase was acidified to pH 2 by addition of concentrated HCl, the precipitate formed was washed with water, and then dried under vacuum. 13 g of the desired product were obtained.
[305] D) 3,5-Diethylbenzoic acid methyl ester.
[306] A mixture of 13 g of the compound obtained in the above step and 10 drops of H ₂ SO ₄ in 90 ml of MeOH was heated under reflux for 48 hours. The reaction mixture was concentrated in vacuo and the residue was taken up in water, neutralized with 10% NaHCO ₃ solution, extracted with water, and the organic phase was washed sequentially with 10% NaHCO ₃ solution and water, dried over Na ₂ SO ₄ , Was evaporated in vacuo. 12 g of the desired product was obtained.
[307] E) 3,5-diethylbenzyl alcohol.
[308] A suspension of 2.5 g of lithium aluminum hydride in 50 ml of THF was cooled to 0 &lt; 0 &gt; C and 12 g of the compound obtained in the above step in 50 ml of THF was added dropwise, and the mixture was left to stir for 30 minutes. 2.5 ml of water, 25 ml of 4N NaOH and 7.5 ml of water were sequentially added to the reaction mixture, followed by hydrolysis. The inorganic salts were filtered and the filtrate was concentrated in vacuo. 10.9 g of the desired product was obtained and used as follows.
[309] F) 3,5-Diethylbenzyl methanesulfonate.
[310] A solution of 8.4 g of methanesulfonyl chloride in 50 ml of DCM was added dropwise to a solution of 10.9 g of the compound obtained in the above step and 7.4 g of triethylamine in 100 ml of DCM at room temperature and then the mixture was left to stir for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was then lifting it out of the water, extracted with ether, the organic phase was washed with water and evaporation of the solvent and dried in Na ₂ SO ₄ under vacuum. 16 g of the desired product was obtained and used as follows.
[311] G) 3,5-Diethylphenylacetonitrile.
[312] A solution of 5.15 g of potassium cyanide in 20 ml of water was added to a solution of 16 g of the compound obtained in the above step in 100 ml of DMF and the mixture was heated at 80 占 폚 for 1 hour. The reaction mixture was concentrated in vacuo and the residue was then lifting it out of the water, extracted with ether, the organic phase was washed with water and evaporation of the solvent and dried in Na ₂ SO ₄ under vacuum. The residue was chromatographed on silica H gel eluting with DCM. 3 g of the desired product was obtained.
[313] H) 3,5-Diethylphenylacetic acid.
[314] A solution of 7.8 g of KOH in 10 ml of water was added to a solution of 3 g of the compound obtained in the above step in 50 ml of EtOH and the mixture was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue was taken up in water to wash the aqueous phase with ether, acidified to pH 1 by addition of concentrated HCl to the aqueous phase and the mixture was allowed to stir at room temperature overnight. The crystalline product formed was desiccated, washed with water and then dried under vacuum. 2.5 g of the desired product were obtained.
[315] Production Example 2.3
[316] 3,5-Diisopropylphenylacetic acid.
[317] (III): R &_lt; _{1 &}
[318] A) 4-Bromo-2,6-diisopropylamine.
[319] A solution of 17.7 g of 2,6-diisopropylamine in 50 ml of MeOH and 10 ml of acetic acid was cooled in an ice bath and a solution of 16 g of bromine in 50 ml of acetic acid was added dropwise while the temperature was kept below 15 ° C, And allowed to stand at room temperature with stirring for 2 hours. The reaction mixture was concentrated in vacuo and the residue was extracted with ether, washed several times with water the organic phase and evaporation of the solvents, followed by drying with Na ₂ SO ₄ under vacuum. 25 g of the desired product was obtained.
[320] B) 3,5-Diisopropylbromobenzene.
[321] A mixture of 25 g of the compound obtained in the above step, 120 ml of water and 35 ml of concentrated HCl solution in 180 ml of acetic acid is cooled to 0 C and a solution of 7.6 g of sodium nitrate in 30 ml of water is added dropwise while the temperature is kept below 5 ° C, The mixture was left to stir at -5 DEG C for 30 minutes. The reaction mixture was cooled to 0 ℃ 50% H ₃ PO ₂ was poured onto 75ml was allowed to stand while the mixture was allowed to stir overnight as the temperature is room temperature. After the reaction mixture was extracted with ether, the organic phase was washed with water, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The residue was chromatographed on silica gel eluting with cyclohexane. 16.2 g of the desired product were obtained.
[322] C) 3,5-Diisopropylbenzonitrile.
[323] A mixture of 6.95 g of copper (I) cyanide in 50 ml of DMF and 16.2 g of the compound obtained in the above step was heated under reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured onto 150 ml of water and left stirring for 30 minutes at room temperature. The mixture was cooled on an ice bath and 150 ml of ethylenediamine were added, and the mixture was left to stir at room temperature for 2 hours. After the mixture was extracted with AcOEt and the organic phase was washed with water, dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. The residue was chromatographed on silica gel eluting with a cyclohexane / AcOEt (100/5; v / v) mixture. 5.5 g of the desired product was obtained.
[324] D) 3,5-Diisopropylbenzoic acid.
[325] A solution of 6.7 g of KOH in 10 ml of water was added to a solution of 5.5 g of the compound obtained in the above step in 50 ml of EtOH and the mixture was heated under reflux for 18 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water, the aqueous phase was washed with ether, and the aqueous phase was acidified to pH 1 by addition of concentrated HCl. The precipitate formed was drained and washed with water and dried. 5.4 g of the desired product were obtained.
[326] E) 3,5-Diisopropylbenzoic acid ethyl ester.
[327] A mixture of 5.4 g of the compound obtained in the above step and 10 drops of H ₂ SO ₄ in 100 ml of EtOH was heated under reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue containing After taking in water, neutralized by adding a 10% NaHCO ₃ solution and extracted with ether, washed the organic phase with water, dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. 6 g of the desired product was obtained.
[328] F) 3,5-diisopropylbenzyl alcohol.
[329] A solution of 6 g of the compound obtained in the above step in 50 ml of THF was added dropwise to a suspension of 1 g of lithium aluminum hydride in 25 ml of THF at room temperature and then the mixture was left to stir for 30 minutes. To the reaction mixture, 1 ml of water, 1 ml of 4N NaOH and 3 ml of water were added successively and hydrolyzed. The inorganic salts were filtered and the filtrate was concentrated in vacuo. After extracting the residue with DCM and the organic phase was washed with water, dried over Na ₂ SO _4, dried and the solvent in vacuo. The residue was chromatographed on silica gel eluting with a cyclohexane / AcOEt (100/5; v / v) mixture. 4.4 g of the desired product was obtained.
[330] G) 3,5-Diisopropylbenzyl methanesulfonate.
[331] A solution of 2.88 g of methanesulfonyl chloride in 10 ml of DCM was added dropwise at room temperature to a solution of 2.5 g of triethylamine in 50 ml of DCM and 4.4 g of the compound obtained in the above step, and the mixture was left to stir for 30 minutes. After washing the reaction mixture with water, dry the organic phase with Na ₂ SO _4, the solvent was evaporated in vacuo. 6.2 g of the desired product were obtained.
[332] H) 3,5-Diisopropylphenylacetonitrile.
[333] A solution of 1.8 g of potassium cyanide in 10 ml of water was added to a solution of 6.2 g of the compound obtained in the above step in 40 ml of EtOH and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated in vacuo and then lifting it out of the water and the residue extracted with ether, the organic phase is washed with water, dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. The residue was chromatographed on silica gel eluting with a cyclohexane / AcOEt (100/5; v / v) mixture. 2.2 g of the desired product were obtained.
[334] I) 3,5-Diisopropylphenylacetic acid.
[335] A solution of 3.8 g of KOH in 10 ml of water was added to a solution of 2.2 g of the compound obtained in the above step in 40 ml of EtOH and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under vacuum and lifting it out of the residue of the water after washing Water with ether, addition of concentrated HCl in Water by acidification to pH 1, and the organic phase was washed by extraction with DCM with water and dried with Na ₂ SO _4, The solvent was evaporated in vacuo. 2 g of the desired product was obtained.
[336] Production example 3.1
[337] 2- (Piperidin-4-yl) isobutyramide hydrochloride.
[338] (VII)
[339] A) 2-Methyl-2- (pyridin-4-yl) propionitrile.
[340] A mixture of 3 g of pyridin-4-yl acetonitrile hydrochloride in 50 ml of DMF was cooled to 0 C and 2.6 g of 60% sodium hydroxide in oil was added in small portions and the mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was cooled on an ice bath and 6 g of methyl iodide was added dropwise, and then the mixture was left to stir at room temperature overnight. The reaction mixture was poured on water / ice mixture, extracted with ether, washed with saturated NaCl solution and the organic phase was dried with MgSO _4, filtered, and the solvent was evaporated in vacuo. The residue was chromatographed on silica-H gel, eluting sequentially with a mixture of DCM and DCM / MeOH (98/2; v / v). 2.39 g of the desired product in oil form was obtained and crystallized.
[341] B) 2- (Pyridin-4-yl) isobutyramide hydrochloride.
[342] A mixture of 2.39 g of the compound obtained in the above step and 10 ml of a concentrated H ₂ SO ₄ solution was heated at 100 ° C. for 15 minutes. The reaction mixture was cooled to room temperature and 50 g of ice was added, then the mixture was basified to pH 14 by adding concentrated NaOH solution and the inorganic salts were filtered. The filtrate was sequentially extracted with AcOEt and DCM, and all organic phases were combined, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo (mp = 134 ° C, base). The obtained product was dissolved in acetone, the mixture was acidified to pH 1 by adding hydrochloric ether, and the precipitate formed was drained. 2.9 g of the desired product was obtained.
[343] C) 2- (Piperidin-4-yl) isobutyramide hydrochloride.
[344] A compound 2.9g, PtO ₂ and the mixture of 1g MeOH 50ml obtained in the above step was hydrogenated under a pressure of 60 bar and 60 ℃ 3 days. The catalyst was filtered over Celite (Celite) and the filtrate was washed with MeOH and concentrated in vacuo. The residue was taken up in acetonitrile and the precipitate formed was taken off from water and washed successively with acetonitrile and ether. 2.5 g of the desired product were obtained (mp &gt; 260 &lt; 0 &gt; C).
[345] Production Example 3.2
[346] 2- (Piperazin-1-yl) isobutyramide dihydrochloride.
[347] (VII)
[348] A) 2- (4-Benzylpiperazin-1-yl) -2-methylpropionitrile.
[349] 4.5 ml of acetone, 20 g of anhydrous MgSO ₄ , ₁₀ g of N, N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile were mixed and the mixture was stirred vigorously at 45 ° C for 48 hours And heated. The reaction mixture was poured onto ice and allowed to stir for 30 minutes. The mixture was extracted with ether, washed several times with water the organic phase, dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. 13 g of the desired product were obtained.
[350] B) 2- (4-Benzylpiperazin-1-yl) isobutyramide dihydrochloride.
[351] A mixture of 13 g of the compound obtained in the above step and 130 ml of a 90% H ₂ SO ₄ solution was immediately heated at 110 ° C. for 30 minutes. After cooling to room temperature and pouring the reaction mixture onto ice, the mixture was basified to pH 10 by adding concentrated NH ₄ OH solution and the water was removed from the crystalline product formed. After dissolving the product in DCM and the organic phase was dried with MgSO _4, the solvent was evaporated in vacuo. The product was extracted from the hydrochloric ether and the water was removed from the formed precipitate. 9.5 g of the desired product was obtained.
[352] C) 2- (Piperazin-1-yl) isobutyramide dihydrochloride.
[353] A mixture of 0.18 g of 10% palladium on carbon in 30 ml of 95% EtOH and 1.3 g of the compound obtained in the above step was hydrogenated overnight at room temperature and at atmospheric pressure. The catalyst was filtered over Celite (R) and the filtrate was concentrated in vacuo. 0.6 g of the desired product was obtained.
[354] Production Example 3.3
[355] 1- (Piperazin-1-yl) cyclohexanecarboxamide dihydrochloride.
[356] VII, 2HCl: X =
[357] A) 1- (4-Benzylpiperazin-1-yl) cyclohexanecarbonitrile.
[358] 5.7 g of cyclohexanone, 20 g of anhydrous MgSO ₄ , ₁₀ g of N, N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile were mixed and the mixture was stirred vigorously at 45 ° C for 48 hours And heated with stirring. The reaction mixture was poured onto ice and allowed to stir for 30 minutes. The mixture was extracted with ether, washed several times with water the organic phase, dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. 15 g of the desired product was obtained.
[359] B) 1- (4-Benzylpiperazin-1-yl) cyclohexanecarboxamide dihydrochloride.
[360] This compound was prepared according to the procedure described in Step 3.2 of Preparation 3.2 with 15 g of the compound obtained in the above step and 50 ml of a 90% H ₂ SO ₄ solution. 5.5 g of the desired product was obtained.
[361] C) 1- (Piperazin-1-yl) cyclohexanecarboxamide dihydrochloride.
[362] This compound was prepared according to the procedure described in Preparation 3.2, Step C, from 0.3 g of 10% palladium on carbon in 30 ml of 95% EtOH and 2.3 g of the compound obtained in the above step. 1.6 g of the desired product was obtained.
[363] Production Example 3.4
[364] N, N-dimethyl-2- (piperazin-1-yl) isobutyramide diformate.
[365] (VII)
[366] A) N, N-dimethyl-2- (4-benzylpiperazin-1-yl) isobutyramide.
[367] 1.44 g of 60% sodium hydroxide in oil was added in portions over several times to a mixture of 2.6 g of the compound obtained in Step B of Preparation 3.2 (free base) in 50 ml of anhydrous THF. 1.3 ml of methyl iodide was added dropwise and the mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was poured into water, extracted with ether, the organic phase was dried with MgSO ₄ and the solvent evaporated under vacuum. 1.8 g of the desired product was obtained.
[368] B) N, N-Dimethyl-2- (piperazin-1-yl) isobutyramide diformate.
[369] 2 g of ammonium formate and 0.5 g of 5% palladium on carbon are added to a solution of 1.8 g of the compound obtained in the above step in 30 ml of MeOH and the mixture is left stirring for 4 hours at room temperature. The catalyst was filtered over Celite (R) and the filtrate was concentrated in vacuo. The residue was taken up in AcOEt and the water formed was removed from the filtrate which formed, washed with AcOEt and dried. 1.2 g of the desired product was obtained.
[370] Production Example 3.5
[371] 1- (Pyrrolidin-4-yl) cyclohexanecarboxamide hydrochloride.
[372] VII, HCl:
[373] A) 1- (Pyridin-4-yl) cyclohexanecarbonitrile.
[374] A mixture of 3 g of pyridin-4-yl acetonitrile hydrochloride in 50 ml of DMF was cooled to 0 C and 2.6 g of 60% sodium hydroxide in oil was added in small portions and the mixture was left stirring for 1 hour 30 minutes at room temperature. The reaction mixture was cooled on an ice bath and 2.7 ml of 1,5-dibromopentane was added dropwise, and then the mixture was left to stir at room temperature for 48 hours. The reaction mixture was poured onto saturated NH ₄ Cl solution and extracted with ether, then the organic phase was washed three times with water and dried over MgSO ₄ and the solvent was evaporated in vacuo. The residue was chromatographed on silica-gel, eluting sequentially with DCM and DCM / MeOH (98/2; v / v) mixture. 2.5 g of the desired product were obtained (mp = 79 &lt; 0 &gt; C).
[375] B) 1- (Pyridin-4-yl) cyclohexanecarboxamide hydrochloride.
[376] A mixture of 2.5 g of the compound obtained in the above step and 15 ml of concentrated H ₂ SO ₄ solution was heated at 100 ° C. for 15 minutes. The reaction mixture was cooled to room temperature and poured onto ice, followed by basification to pH 14 with concentrated NaOH solution, removing the water from the precipitate formed, washing with water and drying. The obtained product was dissolved in acetone and acidified to pH 1 by addition of hydrochloric ether, then left to stir at room temperature for 30 minutes, and water was removed from the formed precipitate. 3 g of the desired product were obtained [mp = 224 [deg.] C (dec.)].
[377] C) 1- (Piperidin-4-yl) cyclohexanecarboxamide hydrochloride.
[378] A compound 2.9g, PtO ₂ and the mixture of 0.5g 50ml MeOH obtained in the above step was hydrogenated under a pressure of 80 bar and 60 ℃ 3 days. The catalyst was filtered over Celite (R) and the filtrate was concentrated in vacuo. The residue was taken up in acetonitrile, left to stir at room temperature for 1 hour, and then the water was removed from the formed precipitate. 2.7 g of the expected product are obtained (mp = 235 [deg.] C).
[379] Production Example 3.6
[380] 1- (Piperidin-4-yl) cyclopropanecarboxamide hydrochloride.
[381] VII, HCl: X =
[382] A) 1- (Pyridin-4-yl) cyclopropanecarbonitrile.
[383] 3.5 g of pyridin-4-ylacetonitrile and 2.6 g of 1,2-dibromoethane were added sequentially to a mixture of 2.5 g of sodium amide in 80 ml of DCM and the mixture was left stirring at room temperature overnight. The reaction mixture was poured into water, extracted with AcOEt, the organic phase was washed with water and evaporation of the solvent and dried in Na ₂ SO ₄ under vacuum. The residue was chromatographed on silica gel with DCM and a DCM / MeOH mixture of (99/1; v / v) to (95/5; v / v). 2.5 g of the desired product were obtained.
[384] B) 1- (Pyridin-4-yl) cyclopropanecarboxamide hydrochloride.
[385] A mixture of 2.5 g of the compound obtained in the above step and 20 ml of a 96% H ₂ SO ₄ solution was immediately heated to 100 ° C and left to stir at 100 ° C for 1 hour. After cooling to room temperature and pouring the reaction mixture onto ice, the solution was neutralized to pH 7 with 20% NH ₄ OH solution, the precipitate formed was drained, washed with water and dried. The precipitate was dissolved in DCM and the mixture was acidified to pH 1 by the addition of hydrochloric ether, and then the water was removed from the precipitate formed. 1.8 g of the desired product was obtained.
[386] C) 1- (Piperidin-4-yl) cyclopropanecarboxamide hydrochloride.
[387] 50ml of MeOH 0.6g of PtO ₂ and the mixture of 1.8g of the compound obtained in the above step under a pressure of 100 bar and 80 ℃ was hydrogenated for 15 hours. The catalyst was filtered over Celite (R) and the filtrate was concentrated in vacuo to a volume of 5 ml and acetonitrile was added until crystallization. The water was removed and dried to give 1.7 g of the desired product.
[388] Production Example 3.7
[389] N, N-dimethyl-2- (piperidin-4-yl) isobutyramide hydrochloride.
[390] (VII), HCl: X =
[391] A) 1-Benzylpiperidine-4-carboxylic acid ethyl ester.
[392] 30 g of benzyl bromide was added dropwise to a mixture of 25 g of K ₂ CO _{3 and} 25 g of ethyl isonipecotate in 125 ml of DMF while maintaining the temperature of the reaction mixture at 25 to 30 ° C and the mixture was left to stir at room temperature for 1 hour. After the reaction mixture was poured into ice-cold water on the one liters extracted twice with ether, the organic phase was washed with water and dried with MgSO ₄ and the solvent was evaporated in vacuo. The oil thus obtained was distilled under reduced pressure. 2.92 g of the desired product are obtained (bp = 120-122 [deg.] C at 2.7 Pa).
[393] B) 2- (l-Benzylpiperidin-4-yl) propan-2-ol.
[394] A solution of 24.73 g of the compound obtained in the above step in 100 ml of benzene was added dropwise to 200 ml of a 1.5 M methyl lithium solution as a complex with lithium bromide in ether while dropwise maintaining the temperature of the solute at 25-30 &Lt; / RTI &gt; under reflux. The reaction mixture was cooled to room temperature and poured onto 400 ml of saturated NH ₄ Cl in water precooled on an ice bath. The mixture was extracted three times with ether, and collecting all organic phases were dried with MgSO _4, and concentrated the solvent under vacuum. The residue was dissolved in 100 ml of acetone and the mixture was cooled to 10 ° C, acidified to pH 1 with hydrochloric ether, and the precipitate formed was washed with a mixture of acetone / ether (50/50; v / v) . 24.5 g of the desired product in hydrochloride form was obtained (mp = 204 [deg.] C). After the NaOH solution was concentrated in from the hydrochloride to the free base extracted out with ether and dried over MgSO _4, the solvent was evaporated in vacuo. 21 g of the desired product were obtained (mp = 66 [deg.] C).
[395] C) 2- (l-Benzylpiperidin-4-yl) -2-methylpropionic acid.
[396] A mixture of 4.42 g of 30% fuming sulfuric acid in SO ₃ and 5.98 g of 95% sulfuric acid was cooled to 3 ° C and a solution of 2 g of the compound obtained in the above step in 1.55 g of 100% formic acid was added dropwise while keeping the temperature below 10 ° C. The mixture was allowed to stir at 3 - 5 [deg.] C for 2 hours and the temperature returned to room temperature before allowing the mixture to stand overnight at room temperature. The reaction mixture was poured onto ice, the concentrated NaOH solution and concentrated NH ₄ OH solution were added to adjust to pH 6.5, and extracted three times with DCM. The organic phases were combined and dried over MgSO ₄ and the solvent was concentrated in vacuo. The residue was taken up in acetone to remove water from the precipitate and dried. 1.22 g of the desired product were obtained (mp = 195 &lt; 0 &gt; C).
[397] D) N, N-Dimethyl-2- (1-benzylpiperidin-4-yl) isobutyramide hydrochloride.
[398] A mixture of 1.2 g of the compound obtained in the above step, 0.8 ml of triethylamine, 2.8 ml of a 2M dimethylamine solution in THF and 2.5 g of BOP in 20 ml of DCM was left stirring for 1 hour at room temperature. The reaction mixture was concentrated under vacuum and the organic phase is washed lifting it out of the residue in ether with water, 1N NaOH solution and successively with a saturated NaCl solution and dried with MgSO _4, and concentrated the solvent under vacuum. The residue was chromatographed on silica gel, gradient eluting sequentially with DCM and (99/1; v / v) to (95/5; v / v) DCM / MeOH mixture. The obtained product was dissolved in acetone, and the mixture was acidified to pH 1 by the addition of hydrochloric ether, and then the precipitate formed was drained and dried. 0.8 g of the desired product was obtained (mp = 229 &lt; 0 &gt; C).
[399] E) N, N-Dimethyl-2- (piperidin-4-yl) isobutyramide hydrochloride.
[400] A mixture of 0.2 g of 10% palladium on carbon in 20 ml of MeOH and 0.8 g of the compound obtained in the above step was hydrogenated at atmospheric pressure and room temperature overnight. The catalyst was filtered over Celite (R) and the filtrate was concentrated in vacuo. The residue was dissolved in acetonitrile, ether was added, the precipitate formed was drained and dried. 0.51 g of the desired product was obtained (m.p. = 258 [deg.] C).
[401] Production Example 3.8
[402] 2-Methyl-1- (morpholin-4-yl) -2- (piperidin-4-yl) propan-1-one hydrochloride.
[403] VII, HCl: X =
[404] A) 2- (1-Benzylpiperidin-4-yl) -2-methyl-1- (morpholin-4-yl) propan-1-one hydrochloride.
[405] A mixture of 1.2 ml of thionyl chloride in 20 ml of 1,2-dichloroethane and 1 g of the compound obtained in Step C of Preparation 3.7 was heated at 80 占 폚 for 3 hours. The reaction mixture is concentrated in vacuo and the acid chloride thus obtained is dissolved in 20 ml of DCM and the solution is added to a mixture of 1.6 ml of triethylamine and 0.7 g of morpholine in 20 ml of DCM precooled to 0 &Lt; / RTI &gt; for 24 hours. The reaction mixture was concentrated in vacuo and the residue was washed and extracted with ether, the organic phase was washed sequentially with 1N NaOH solution, with water, the solvent evaporated and dried in MgSO ₄ under vacuum. The obtained product was dissolved in acetone, and the mixture was acidified to pH 1 by the addition of hydrochloric ether, and then the precipitate formed was drained and dried. 0.7 g of the desired product was obtained.
[406] B) 2-Methyl-1- (morpholin-4-yl) -2- (piperidin-4-yl) propan-1-one hydrochloride.
[407] 0.7 g of the compound obtained in the above step, 0.7 g of ammonium formate and 0.2 g of 10% palladium-on-carbon in 10 ml of MeOH was left stirring at room temperature for 4 hours. The catalyst was filtered over Celite (R) and the filtrate was concentrated in vacuo. The residue was dissolved in acetonitrile, ether was added, and the precipitate formed was drained and dried. 0.46 g of the desired product was obtained (m.p. = 225 &lt; 0 &gt; C).
[408] Example 1
[409] 2- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylphenyl) acetyl] morpholine di Hydrochloride, monohydrate, (-) isomer.
[410] Formula I, 2HCl: X = ; R ₁ = -CH _3; Ar =
[411] A) 2- [2- (benzoyloxy) ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylphenyl) acetyl] morpholine, single isomer.
[412] A mixture of 2.2 g of the compound obtained in Preparation 1.1, 1.48 g of triethylamine and 0.96 g of 3,5-dimethylphenylacetic acid in 40 ml of DCM was cooled in an ice bath and 2.85 g of BOP was added, after which the mixture was cooled to room temperature Lt; / RTI &gt; for 3 hours. The reaction mixture was concentrated under vacuum, washed and extracted the residue with AcOEt, the organic phase was washed with water, 10% Na ₂ SO ₄ solution, water, and successively with a saturated NaCl solution and dried with Na ₂ SO ₄ and the solvent was evaporated in vacuo . The residue was chromatographed on silica H gel eluting with a DCM / MeOH (100 / 0.5; v / v) mixture. 2.4 g of the desired product in oil form was obtained.
[413] B) 2- (3,4-Dichlorophenyl) -2- (2-hydroxyethyl) -4- [2- (3,5-dimethylphenyl) acetyl] morpholine, single isomer.
[414] A mixture of 2.4 g of the compound obtained in the above step and 1.7 ml of 30% NaOH aqueous solution in 30 ml of MeOH was left to stir at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and was then lifting it out of the water and the residue extracted with AcOEt, the organic phase was washed with a saturated NaCl solution and water sequentially, and the solvent is evaporated and dried by Na ₂ SO ₄ under vacuum. 1.92 g of the desired product in oil form was obtained.
[415] C) 2- (3,4-Dichlorophenyl) -2- [2- (methanesulfonyloxy) ethyl] -4- [2- (3,5-dimethylphenyl) -acetyl] morpholine, single isomer.
[416] A solution of 1.92 g of the compound obtained in the above step and 0.94 ml of triethylamine in 30 ml of DCM was cooled in an ice bath and a solution of 0.57 g of methanesulfonyl chloride in 10 ml of DCM was added dropwise and the mixture was left under stirring for 5 minutes . The reaction mixture was concentrated in vacuo and was then lifting it out of the water and the residue extracted with AcOEt, the organic phase was washed with a saturated NaCl solution and water sequentially, and the solvent is evaporated and dried by Na ₂ SO ₄ under vacuum. 2.22 g of the desired product in oil form was obtained.
[417] D) 2- [2- (4-cyclohexylpiperazin-1-yl) ethyl] -2- (3,4- Morpholine dihydrochloride, monohydrate, (-) isomer.
[418] A mixture of 1.1 g of the compound obtained in the above step, 0.56 g of 1-cyclohexylpiperazine and 0.61 g of K ₂ CO _{3 in 2} ml of DMF was heated at 80 ° C for 3 hours. Was added to cool to room temperature and ice-water to the reaction mixture, and the mixture was extracted with AcOEt and the organic phase was washed sequentially with a saturated NaCl solution and water and dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. The residue was chromatographed on silica H gel eluting with a DCM / MeOH (100/3; v / v) mixture. The resulting product was dissolved in DCM and acidified to pH 1 by the addition of hydrochloric ether and then the mixture was concentrated in vacuo. After concentrating with a DCM / pentane mixture, 0.51 g of the desired product was obtained.
[419] = -28.7 [deg.] (C = 1, MeOH)
[420] ^& Lt; ¹ &gt; H NMR: [delta] (ppm): 0.7 to 2.45: m: 18H; 2.5 to 4.65: m: 19H; 6.4 to 7.8: m: 6H; 11.8: s: 2H.
[421] Example 2
[422] 2- (3,4-dichlorophenyl) -4- [2- (3,5-dichlorophenyl) acetyl] morpholine di Hydrochloride, hemihydrate, (+) isomer.
[423] Formula I, 2HCl: X = ; R ₁ = Cl; Ar =
[424] A) 2- [2- (benzoyloxy) ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-dichlorophenyl) acetyl] morpholine, single isomer.
[425] This compound was prepared according to the procedure described in step A of Example 1, 1.92 g of the compound obtained in Preparation 1.1, 1.27 g of triethylamine, 1.04 g of 3,5-dichlorophenylacetic acid, 35 ml of DCM and 2.46 g of BOP. 2.2 g of the desired product in oil form was obtained.
[426] B) 2- (3,4-Dichlorophenyl) -4- [2- (3,5-dichlorophenyl) acetyl] -2- (2-hydroxyethyl) morpholine, single isomer.
[427] This compound was prepared according to the procedure described in step B of Example 1, 2.2 g of the compound obtained in the above step, 1.5 ml of a 30% aqueous NaOH solution and 30 ml of MeOH. 1.8 g of the desired product in oil form was obtained.
[428] C) 2- (3,4-Dichlorophenyl) -4- [2- (3,5-dichlorophenyl) acetyl] -2- [2- (methanesulfonyloxy) ethyl] morpholine, single isomer.
[429] This compound was prepared according to the procedure described in step C of Example 1 from 1.8 g of the compound obtained in the above step, 0.59 g of triethylamine, 30 ml of DCM and 0.49 g of methanesulfonyl chloride in 10 ml of DCM. 2 g of the desired product in oil form was obtained.
[430] D) 2- [2- (4-cyclohexylpiperazin-1-yl) ethyl] -2- (3,4-dichlorophenyl) -4- [2- Folin dihydrochloride, semi-hydrate, (+) isomer.
[431] This compound was prepared according to the procedure described in step D of Example 1, 1 g of the compound obtained in the above step, 0.45 g of 1-cyclohexylpiperazine, 0.51 g of K ₂ CO ₃ and 2 ml of DMF. 0.54 g of the desired product was obtained.
[432] = + 1.2 (c = 1; MeOH)
[433] ¹ H NMR: (Ppm): 0.8 to 2.5: m: 12H; 2.55 to 4.4: m: 19H; 7.0 to 8.0: m: 6H; 11.6: s: 2H.
[434] Example 3
[435] 2- (3,4-dichlorophenyl) -4- [2- [3,5-bis (trifluoromethyl) phenyl] ] Acetyl] morpholine dihydrochloride, anhydride, (+) isomer.
[436] Formula I, 2HCl: X = ; R ₁ = CF _3; Ar =
[437] A) 2- (3,5-bis (trifluoromethyl) phenyl] acetyl] morpholine, single Isomer.
[438] This compound was prepared according to the procedure described in step A of Example 1, using 2.23g of the compound obtained in Preparation 1.1, 1.48g of triethylamine, 1.59g of 3,5-bis (trifluoromethyl) phenylacetic acid, 40ml of DCM, 2.85 g. 2.4 g of the desired product in oil form was obtained.
[439] B) 2- (3,4-Dichlorophenyl) -4- [2- [3,5-bis (trifluoromethyl) phenyl] acetyl] -2- (2-hydroxyethyl) morpholine, single isomer.
[440] This compound was prepared according to the procedure described in step B of Example 1, 2.4 g of the compound obtained in the above step, 1.4 ml of a 30% aqueous NaOH solution and 30 ml of MeOH. 2 g of the desired product in oil form was obtained.
[441] C) 2- (3,4-dichlorophenyl) -4- [2- [3,5-bis (trifluoromethyl) phenyl] acetyl] -2- [2- (methanesulfonyloxy) ethyl] , Single isomer.
[442] This compound was prepared according to the procedure described in step C of Example 1, 2 g of the compound obtained in the above step, 0.57 g of triethylamine, 30 ml of DCM and 0.47 g of methanesulfonyl chloride in 10 ml of DCM. 2.29 g of the desired product in oil form was obtained.
[443] D) 2- [2- (4-Cyclohexylpiperazin-1-yl) ethyl] -2- (3,4-dichlorophenyl) -4- [2- [3,5- ) Phenyl] acetyl] morpholine dihydrochloride, the semi-hydrate, (+) isomer.
[444] A mixture of 1 g of the compound obtained in the above step, 0.29 g of 1-cyclohexylpiperazine and 0.71 g of K ₂ CO ₃ was heated at 80 to 100 ° C for 2 hours. After pouring the cooled reaction mixture with water to room temperature and extracted with AcOEt, the organic phase was washed with water and dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo. The residue was chromatographed on silica-H gel by gradient elution with a (100/2; v / v) to (100/5; v / v) DCM / MeOH mixture. The resulting product was dissolved in DCM and acidified to pH 1 by the addition of hydrochloric ether and then the mixture was concentrated in vacuo. After concentration in a DCM / pentane mixture, 0.6 g of the desired product was obtained.
[445] = + 23.4 [deg.] (C = 0.5; MeOH)
[446] ^& Lt; ¹ &gt; H NMR: [delta] (ppm): 0.8-2.6: m: 12H; 2.6 to 4.3: m: 19H; 7.1 to 8.0: m: 6H; 11.8: m: 2H.
[447] Example 4
[448] 2- (3,4-Dichlorophenyl) -4- [2- (3, 5-dihydroxyphenyl) 5-dimethylphenyl) acetyl] morpholine hydrochloride, sesquihydrate, (-) isomer.
[449] Formula I, HCl: X = ; R ₁ = -CH _3; Ar =
[450] A) 2- (3,4-Dichlorophenyl) -2- (formylmethyl) -4- [2 - (3,5-dimethylphenyl) acetyl] morpholine, single isomer.
[451] A solution of 0.63 ml of oxalyl chloride in 20 ml of DCM was cooled to -60 <0> C under a nitrogen atmosphere, then a solution of 1.3 ml of DMSO in 20 ml of DCM was added dropwise and then a solution of 1.84 ml of DMSO in 20 ml of DCM and 1.84 ml of A solution of 2.55 g of the compound was added dropwise. The mixture was allowed to stir at -60 &lt; 0 &gt; C for 30 minutes and the temperature was brought to -50 &lt; 0 &gt; C, then 5.2 ml of triethylamine was added and the mixture was left stirring while the temperature was brought to room temperature. After washing the reaction mixture sequentially with 2N HCl solution, water and saturated NaHCO ₃ solution, dry the organic phase with MgSO _4, the solvent was evaporated in vacuo. 2.38 g of the desired product was obtained.
[452] B) 2- [2- [4- (1-Carbamoyl-1-methylethyl) piperidin- 1 -yl] ethyl] -2- (3,4- 3,5-dimethylphenyl) acetyl] morpholine hydrochloride, sesquihydrate, (-) isomer.
[453] 0.26 g of the compound obtained in Preparation Example 3.1 (free base), 0.74 g of sodium triacetoxyborohydride and 8 drops of acetic acid were added sequentially to a solution of 0.64 g of the compound obtained in the above step in 30 ml of DCM at room temperature and under a nitrogen atmosphere The mixture was allowed to stir at room temperature overnight. The reaction mixture was basified with saturated NaHCO ₃ solution to pH 8 and extracted with DCM, and the organic phase was washed three times with water and dried over MgSO ₄ and the solvent was evaporated in vacuo. The residue was chromatographed on silica-H gel gradient eluting with a (100/1; v / v) to (100/5; v / v) DCM / MeOH mixture. The resulting product was dissolved in DCM and acidified to pH 1 by the addition of hydrochloric ether, then the precipitate formed was drained and dried. 0.631 g of the desired product was obtained.
[454] = -23.8 [deg.] (C = 0.5; MeOH)
[455] &Lt; ¹ &gt; H NMR: [delta] (ppm): 0.8-1.2: se: 6H; 1.2 to 2.0: m: 6H; 2.0 to 4.8: m: 21H; 6.6 to 8.8: m: 8H; 10.2: se: 1H.
[456] Example 5
[457] 2- (3,4-Dichlorophenyl) -4- [2- (3, 5-dihydroxyphenyl) Diethylphenyl) acetyl] morpholine hydrochloride, hemihydrate, (-) isomer.
[458] Formula I, HCl: X = ; R ₁ = -CH ₂ CH _3; Ar =
[459] A) 2- [2- (benzoyloxy) ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-diethylphenyl) acetyl] morpholine, single isomer.
[460] A solution of 2.27 g of the compound obtained in Preparation 1.1 in 25 ml of DCM was cooled to 0 캜, 1.15 g of the compound obtained in Preparation 2.2, 0.72 g of triethylamine and 3.17 g of BOP were added and the mixture was stirred for 1 hour . The reaction mixture was extracted with DCM and the organic phase was washed sequentially with water, buffer (pH 2), water and 10% Na ₂ CO ₃ solution, then dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was chromatographed on silica-H gel, eluting sequentially with DCM and DCM / MeOH (100/1; v / v) mixture. 3.1 g of the desired product were obtained.
[461] B) 2- (3,4-Dichlorophenyl) -2- (2-hydroxyethyl) -4- [2- (3,5, diethylphenyl) acetyl] morpholine, single isomer.
[462] A mixture of 3.1 g of the compound obtained in the above step and 1.5 ml of 30% NaOH aqueous solution in 130 ml of MeOH was left to stir at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and the residue was purified by AcOEt / ether (50/50; v / v) and extracted with the mixture, washed three times with water and the organic phase was dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. The residue was chromatographed on silica-gel, eluting sequentially with DCM and DCM / MeOH (100/2; v / v) mixture. 2 g of the desired product was obtained.
[463] C) 2- (3,4-Dichlorophenyl) -2- (formylmethyl) -4- [2- (3,5-diethylphenyl) acetyl] morpholine, single isomer.
[464] This compound was prepared according to the procedure described in step A of Example 4 from 0.67 g of oxalyl chloride in 20 ml of DCM, 1.0 g of DMSO in 10 ml of DCM, 1.44 g of DMSO in 20 ml of DCM and 2.0 g of the compound obtained in the above step and triethylamine 2.9 g. 1.95 g of the desired product was obtained.
[465] D) 2- [2- [4- (1-Carbamoyl-1-methylethyl) piperidin- 1 -yl] ethyl] -2- 3,5-diethylphenyl) acetyl] morpholine hydrochloride, hemihydrate, (-) isomer.
[466] This compound was prepared according to the procedure described in step B of Preparation 4, from 0.58 g of the compound obtained in the above step in 50 ml of DCM, 0.23 g of the compound obtained in Preparation Example 3.1 (free base), 0.58 g of sodium triacetoxyborohydride and Acetic acid. 0.4 g of the desired product was obtained.
[467] = -23.4 [deg.] (C = 0.5; MeOH)
[468] ¹ H NMR: (Ppm): 0.6 to 1.8: m: 18H; 1.8 to 4.8: m: 19H; 6.4 to 8.0: m: 8H; 9.8 to 10.2: se: 1H.
[469] Example 6
[470] 2- [3,4-dichlorophenyl] -4- [2- [3,5-bis (trifluoromethyl) (Trifluoromethyl) phenyl] acetyl] morpholine hydrochloride, (+) isomer.
[471] Formula I, HCl: X = ; R ₁ = CF _3; Ar =
[472] A) 2- (3,4-Dichlorophenyl) -2- (formylmethyl) -4- [2- [3,5-bis (trifluoromethyl) phenyl] acetyl] morpholine, single isomer.
[473] This compound was prepared according to the procedure described in step A of Example 4 from 0.62 ml of oxalyl chloride in 15 ml of DCM, 1.26 g of DMSO in 15 ml of DCM, 1.81 g of DMSO in 15 ml of DCM and 3.15 g of the compound obtained in Step B of Example 3 and And 5.12 ml of triethylamine. 3.13 g of the desired product were obtained.
[474] B) 2- [2- [4- (1-Carbamoylcyclohexyl) piperidin- 1 -yl] ethyl] -2- (3,4- dichlorophenyl) -4- [ -Bis (trifluoromethyl) phenyl] acetyl] morpholine hydrochloride, (+) isomer.
[475] This compound was prepared according to the procedure described in step B of Preparation 4, from 0.5 g of the compound obtained in the above step in 20 ml of DCM, 0.198 g of the compound obtained in Preparation 3.5 (free base), 0.46 g of sodium triacetoxyborohydride and Acetic acid. 0.467 g of the desired product was obtained.
[476] = + 28.8 [deg.] (C = 0.5; MeOH)
[477] ¹ H NMR: (Ppm): 0.6 to 1.9: m: 12H; 1.9 to 4.5: m: 18H; 6.8 to 8.2: m: 8H; 9.8 to 10.4: 2s: 2H.
[478] Were carried out according to the processes described in the above Examples to prepare compounds according to the present invention summarized in Table I below.
[479] <Table I>
[480] (I)
[481]
[482] ExampleXR ₁ Salt, hydroxide NMR (c = 0.5; MeOH) 7 (a) CH ₃ 2HCl, 1.5H ₂ ONMR-27 ° 8 (b) -CH ₃ 2HCl, 1H ₂ ONMR-24.6˚ 9 (c) -CH ₂ CH ₃ 2HCl, 0.75H ₂ ONMR-24.2˚ 10 (d) -CH ₂ CH ₃ 2HCl, 0.5H ₂ ONMR-23.6 ° 11 (e) -CH ₂ CH ₃ 2HCl, 0.5H ₂ ONMR-25.2 占 (c = 0.25) 12 (f) -CH ₃ HCl, 2H ₂ ONMR-24.4 ° 13 (g) CF2HCl, 2H ₂ ONMR + 27.6 °
[483] a) This compound is prepared according to the procedure described in Step B of Example 4 from the compound obtained in Step A of Example 4 and the free base form of the compound obtained in Preparation 3.2.
[484] b) This compound is prepared according to the procedure described in Step B of Example 4 from the compound obtained in Step A of Example 4 and the free base form of the compound obtained in Preparation 3.3.
[485] c) This compound is prepared according to the procedure described in Step D of Example 5 from the compound obtained in Step C of Example 5 and the free base form of the compound obtained in Preparation 3.2.
[486] d) This compound is prepared according to the procedure described in Step D of Example 5 from the compound obtained in Step C of Example 5 and the free base form of the compound obtained in Preparation 3.4.
[487] e) This compound is prepared according to the procedure described in step D of Example 5 from the compound obtained in step C of Example 5 and 1-cyclohexylpiperazine.
[488] f) This compound is prepared according to the procedure described in Step B of Example 4 from the compound obtained in Step A of Example 4 and the free base form of the compound obtained in Preparation 3.6.
[489] g) This compound is prepared according to the procedure described in Step B of Example 4 from the compound obtained in Step A of Example 6 and the free base form of the compound obtained in Preparation 3.2.
[490] Example 7 : ¹ H NMR: (Ppm): 1.6: se: 6H; 2.0 to 2.4: m: 8H; 2.5 to 5.0: m: 18H; 6.6 to 8.0: m: 10H.
[491] Example 8 : ¹ H NMR: (Ppm): 0.8 to 2.4: m: 18H; 2.6 to 4.8: m: 18H; 6.4 to 8.2: m: 8H.
[492] Example 9 : ¹ H NMR: (Ppm): 0.8 to 1.2: 2t: 6H; 1.4: s: 6H; 2.0 to 5.0: m: 24H; 6.4 to 8.0: m: 6H.
[493] Example 10 : ¹ H NMR: (Ppm): 0.6 to 1.8: m: 12H; 2.0 to 4.8: m: 32H; 6.4 to 8.0: m: 6H; 10.6 to 11: se: 2H.
[494] Example 11 : ¹ H NMR: (Ppm): 0.9 to 2.7: m: 22H; 2.7 to 4.8: m: 19H; 6.4 to 7.8: m: 6H; 11.75: s: 1H.
[495] Example 12 : ¹ H NMR: (Ppm): 0.4 to 1.0: 2 mt: 4H; 1.3 to 2.5: m: 13H; 2.55 to 4.5: m: 14H; 6.4 to 7.8: m: 8H; 10.1: s: 1H.
[496] Example 13 : ¹ H NMR: (Ppm): 1.4: se: 6H; 2.15 to 4.4: m: 20H; 7.2 to 8.2: m: 8H.
[497] Example 14
[498] 2- (3,4-Dichlorophenyl) -4- [2- (3, 5-dihydroxyphenyl) 5-dichlorophenyl) acetyl] morpholine hydrochloride, semi-hydrate, (+) isomer.
[499] Formula I, HCl: X = ; R ₁ = Cl; Ar =
[500] A) 2- (3,4-Dichlorophenyl) -2- (formylmethyl) -4- [2- (3,5-dichlorophenyl) acetyl] morpholine, single isomer.
[501] This compound was prepared according to the procedure described in step A of Example 4 from 0.715 g of oxalyl chloride in 15 ml of DCM, 1.08 g of DMSO in 15 ml of DCM, 1.55 g of DMSO in 15 ml of DCM and 2.14 g of the compound obtained in Step 2 of Example 2 and And 2.89 g of triethylamine. 2.13 g of the desired product were obtained.
[502] B) 2- [2- [4- (1-Carbamoyl-1-methylethyl) piperidin- 1 -yl] ethyl] -2- (3,4- 3,5-dichlorophenyl) acetyl] morpholine hydrochloride, hemihydrate, (+) isomer.
[503] This compound was prepared according to the procedure described in step B of Preparation 4, from 0.47 g of the compound obtained in the above step in 20 ml of DCM, 0.21 g of the compound obtained in Preparation Example 3.1 (free base), 0.5 g of sodium triacetoxyborohydride and Acetic acid. 0.428 g of the desired product was obtained.
[504] = + 4.8 [deg.] (C = 0.5; MeOH)
[505] &Lt; ¹ &gt; H NMR: [delta] (ppm): 0.9: s: 6H; 1.3 to 2.5: m: 7H; 2.5 to 4.2: m: 14H; 6.6 to 7.8: m: 8H; 10.1: 2s: 1H.
[506] Example 15
[507] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- [3,3-dihydro- 5-bis (trifluoromethyl) phenyl] acetyl] morpholine hydrochloride, monohydrate, (+) isomer.
[508] Formula I, HCl: X = ; R ₁ = CF; Ar =
[509] 0.3 g of the compound obtained in Preparation Example 3.1 and 0.6 g of K ₂ CO _{3 in} 10 ml of acetonitrile was heated under reflux for 3 hours. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The product of Preparation 3.1 dissolved in the free base form is obtained in 20 ml of DCM, and 0.77 g of the compound obtained in Step A of Preparation Example 6, 0.62 g of sodium triacetoxyborohydride and 8 drops of acetic acid are added successively, Was left under stirring at room temperature and under a nitrogen atmosphere overnight. The reaction mixture was basified to pH 8 with 10% Na ₂ CO ₃ solution and extracted with DCM, the organic phase was washed with water three times, washed with saturated NaCl solution, dried over MgSO ₄ and the solvent was evaporated in vacuo . The residue was chromatographed on silica-H gel by gradient elution with DCM and DCM / MeOH (95/5; v / v) mixture. The resulting product was dissolved in AcOEt and acidified to pH 1 by the addition of hydrochloric ether, then the precipitate formed was drained and dried. 0.5 g of the desired product was obtained.
[510] = + 29 [deg.] (C = 0.5; MeOH)
[511] &Lt; ¹ &gt; H NMR: [delta] (ppm): 1.0: s: 6H; 1.4 to 2.5: m: 6H; 2.5 to 4.4: m: 15H; 6.8 to 7.2: 2s: 2H; 7.3 to 8.1: m: 6H; 9.7 to 10.15: 2s: 1H.
[512] Example 16
[513] Yl] ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) piperazin- -Diisopropylphenyl) acetyl] morpholine dihydrochloride, monohydrate, (-) isomer.
[514] Formula I, 2HCl: X = ; R ₁ = ; Ar =
[515] A) 2- (3,4-Dichlorophenyl) -2- (2-hydroxyethyl) -4- [2- (3,5-diisopropylphenyl) acetyl] morpholine, single isomer.
[516] A mixture of 1.78 g of the compound obtained in Preparation 1.2, 0.8 g of triethylamine and 1.4 g of 3,5-diisopropylphenylacetic acid in 40 ml of DCM was cooled to 0 占 폚, 2.85 g of BOP was added and the mixture was stirred for 30 minutes And left while stirring. The reaction mixture was concentrated in vacuo and after washing the organic phase and extract the residue in ether with water, sequential buffer (pH 2), water, 1N NaOH solution and water, dried over Na ₂ SO ₄ and evaporation of the solvent in vacuo . The residue was chromatographed on silica-gel, gradient elution with (100/1; v / v) to (100/3; v / v) DCM / MeOH mixture. 1.2 g of the desired product was obtained.
[517] B) 2- (3,4-Dichlorophenyl) -2- (formylmethyl) -4- [2- (3,5-diisopropylphenyl) acetyl] morpholine, single isomer.
[518] This compound was prepared according to the procedure described in step A of Example 4 from 0.4 g of oxalyl chloride in 20 ml of DCM, 0.6 g of DMSO in 10 ml of DCM, 0.8 g of DMSO in 20 ml of DCM, 1.2 g of the compound obtained in the above step and triethylamine 1.64 g. 1.1 g of the desired product was obtained.
[519] C) 2- [2- [4- (1-Carbamoyl-1-methylethyl) piperazin-1-yl] ethyl] -2- (3,4- , 5-diisopropylphenyl) acetyl] morpholine dihydrochloride, monohydrate, (-) isomer.
[520] This compound was prepared according to the procedure described in step B of Preparation 4, from 0.45 g of the compound obtained in the above step in 50 ml of DCM, 0.2 g of the compound obtained in Preparation 3.2 (free base), 0.4 g of sodium triacetoxyborohydride and Acetic acid. 0.3 g of the desired product was obtained.
[521] = -18.4 [deg.] (C = 0.25; MeOH)
[522] ^& Lt; ¹ &gt; H NMR: [delta] (ppm): 0.8-1.7: m: 18H; 2.2: mt: 2H; 2.5 to 4.7: m: 18H; 6.4 to 8.0: m: 8H.

权利要求:
Claims (30)
[1" claim-type="Currently amended] Compounds of formula (I), salts, solvates and / or hydrates thereof with inorganic or organic acids.
(I)

In this formula,
Ar is a halogen atom, mono- or disubstituted phenyl, or (C ₁ -C ₃₎ represents an alkyl,
X is group, Lt; / RTI &gt;
R ₁ represents a chlorine atom, a bromine atom, (C ₁ -C ₃ ) alkyl or trifluoromethyl,
R ₂ represents (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl or -CR ₄ R ₅ CONR ₆ R ₇ group,
R ₃ represents a -CR ₄ R ₅ CONR ₆ R ₇ group,
R ₄ and R ₅ represent the same radical selected from methyl, ethyl, n-propyl or n-butyl or together with the carbon atoms to which they are attached form a (C ₃ -C ₆ )
R ₆ and R ₇ each independently represent hydrogen or (C ₁ -C ₃ ) alkyl or, together with the nitrogen atom to which they are bonded, represent a group selected from 1-azetidinyl, 1-pyrrolidinyl, -Morpholinyl, 4-thiomorpholinyl or perhydro-1-azepinyl. The term &quot; heterocyclic &quot;
[2" claim-type="Currently amended] 2. The compound according to claim 1, wherein Ar is 3,4-dichlorophenyl.
[3" claim-type="Currently amended] The compound according to claim 1, wherein R &lt; ₁ &gt; is a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl.
[4" claim-type="Currently amended] The compound according to claim 1, wherein X is Group (wherein, R ₂ is (C ₁ -C ₆₎ alkyl or (C ₃ -C ₆₎ cycloalkyl-alkyl) compounds.
[5" claim-type="Currently amended] 5. The compound according to claim 4, wherein R &lt; ₂ &gt; is cyclopentyl or cyclohexyl.
[6" claim-type="Currently amended] The compound according to claim 1, wherein X is Group (wherein, R ₂ is -CR ₄ R ₅ CONR ₆ R ₇ group) of the compound.
[7" claim-type="Currently amended] 7. A compound according to claim 6 wherein R &lt; ₄ &gt; and R &lt; ₅ &gt; are each methyl or together with the carbon atoms to which they are attached form cyclohexyl.
[8" claim-type="Currently amended] The compound according to claim 6, wherein R ₆ and R ₇ are similar and are hydrogen or methyl.
[9" claim-type="Currently amended] The compound according to claim 1, wherein X is Wherein R ₃ is a -CR ₄ R ₅ CONR ₆ R ₇ group.
[10" claim-type="Currently amended] 10. The compound of claim 9 wherein R &lt; ₄ &gt; and R &lt; ₅ &gt; are each methyl or together with the carbon atoms to which they are attached form a cyclohexyl or cyclopropyl.
[11" claim-type="Currently amended] 10. The method of claim 9, wherein, R ₆ and R ₇ are similar and hydrogen or methyl.
[12" claim-type="Currently amended] The compound according to claim 1, which is a compound of formula (I '), a salt, solvate and / or hydrate thereof with an inorganic or organic acid.
<Formula I '

In this formula,
R ' ₁ represents a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl,
R ' ₂ represents cyclopentyl or cyclohexyl.
[13" claim-type="Currently amended] The compound according to claim 1, which is a salt, solvate and / or hydrate thereof with a compound of formula I &quot;
&Lt; RTI ID = 0.0 &gt;

In this formula,
R ' ₁ represents a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl,
R ' ₄ and R' ₅ each represent methyl or together with the carbon atoms to which they are attached form cyclohexyl,
R ' ₆ and R' ₇ are similar and represent hydrogen or methyl.
[14" claim-type="Currently amended] The compound according to claim 1, which is a salt, solvate and / or hydrate thereof with a compound of formula (I '' '), an inorganic or organic acid thereof.
&Lt; RTI ID = 0.0 &gt;

In this formula,
R ' ₁ represents a chlorine atom, methyl, ethyl, isopropyl or trifluoromethyl,
R ' ₄ and R' ₅ each represent methyl or together with the carbon atoms to which they are attached form cyclohexyl or cyclopropyl,
R ' ₆ and R' ₇ are similar and represent hydrogen or methyl.
[15" claim-type="Currently amended] 15. Compounds of formula I, I ', I "or I"' in any one of claims 1 to 14 in optically pure form.
[16" claim-type="Currently amended] 2- (3,4-dichlorophenyl) -4- [2- [3,5-bis (trifluoromethyl) phenyl] ] Acetyl] morpholine, (+) isomer, its salt, solvate and / or hydrate thereof.
[17" claim-type="Currently amended] 2- [3,4-dichlorophenyl) -4- [2- [3,5-bis ((4-fluorobenzyl) piperidin- Trifluoromethyl) phenyl] acetyl] morpholine, (+) isomer, its salt, solvate and / or hydrate thereof.
[18" claim-type="Currently amended] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- (3,5-difluorophenyl) piperazin- Bis (trifluoromethyl) phenyl] acetyl] morpholine, (+) isomer, its salt, solvate and / or hydrate thereof.
[19" claim-type="Currently amended] Ethyl] -2- (3,4-dichlorophenyl) -4- [2- [3,5-difluoro-4- -Bis (trifluoromethyl) phenyl] acetyl] morpholine, (+) isomer, its salt, solvate and / or hydrate thereof.
[20" claim-type="Currently amended] 1a) treating a compound of formula &lt; RTI ID = 0.0 &gt; (II) &lt; / RTI &gt; with a functional derivative of an acid of formula (III)
2a) optionally, when E represents a protecting group, it is removed by the action of an acid or base to give an alcohol of formula IVa (E = H)
3a) Treatment of an alcohol of formula IVa (E = H) obtained in step 1a) or step 2a) with a compound of formula V to give a compound of formula VI,
4a) reacting a compound of formula (VI) with a compound of formula (VII)
5a) optionally, converting the thus obtained compound into one of its salts with an inorganic or organic acid, or a salt, solvate and / or hydrate thereof according to claim 1.
&Lt;

(III)

(IV)

&Lt; Formula IVa >
(E = H)
(V)
Y-SO ₂ -Cl
&Lt; Formula (VI)

(VII)

In this formula,
Ar, R &lt; ₁ &gt; and X are as defined for a compound of formula (I)
E represents hydrogen or an O-protecting group,
Y represents a methyl, phenyl, tolyl or trifluoromethyl group.
[21" claim-type="Currently amended] 1b) treating a compound of formula &lt; RTI ID = 0.0 &gt; (II) &lt; / RTI &gt; with a functional derivative of an acid of formula (III)
Optionally, when E represents a protecting group, it is removed by the action of an acid or base to give an alcohol of formula IVa (E = H)
2b) Oxidation of the thus obtained compound of formula IVa (E = H) to give a compound of formula VIII,
3b) reacting the compound of formula (VIII) with a compound of formula (VII) in the presence of an acid, then reducing the intermediate iminium salt formed with a reducing agent,
4b) A process for the preparation of a compound of formula I according to claim 1, a salt, solvate and / or hydrate thereof, characterized in that the compound thus obtained is converted into one of its salts with an inorganic or organic acid.
&Lt;

(III)

(IV)

&Lt; Formula IVa >
(E = H)
&Lt; Formula (VIII)

(VII)

In this formula,
Ar, R &lt; ₁ &gt; and X are as defined for a compound of formula (I)
E represents hydrogen or an O-protecting group.
[22" claim-type="Currently amended] (IV) &lt; / RTI &gt; in pure enantiomeric or racemic form.
(IV)

In this formula,
Ar is a halogen atom, mono- or disubstituted phenyl, or (C ₁ -C ₃₎ represents an alkyl,
E represents hydrogen or an O-protecting group,
R ₁ represents a chlorine atom, a bromine atom, (C ₁ -C ₃ ) alkyl or trifluoromethyl.
[23" claim-type="Currently amended] 23. Compounds of formula (IV) according to claim 22, wherein E is hydrogen.
[24" claim-type="Currently amended] Compounds of formula VI, pure enantiomeric or racemic,
&Lt; Formula (VI)

In this formula,
Ar is a halogen atom, mono- or disubstituted phenyl, or (C ₁ -C ₃₎ represents an alkyl,
Y represents a methyl, phenyl, tolyl or trifluoromethyl group,
R ₁ represents a chlorine atom, a bromine atom, (C ₁ -C ₃ ) alkyl or trifluoromethyl.
[25" claim-type="Currently amended] Compounds of formula (VIII), either pure enantiomerically or racemic.
&Lt; Formula (VIII)

In this formula,
Ar is a halogen atom, mono- or disubstituted phenyl, or (C ₁ -C ₃₎ represents an alkyl,
R ₁ represents a chlorine atom, a bromine atom, (C ₁ -C ₃ ) alkyl or trifluoromethyl.
[26" claim-type="Currently amended] 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, a pharmaceutically acceptable salt, solvate and / or hydrate thereof as an active ingredient.
[27" claim-type="Currently amended] 27. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition comprises from 0.1 to 1000 mg of the active ingredient in combination with one or more pharmaceutical excipients.
[28" claim-type="Currently amended] Use of a compound of formula (I) according to claim 1, a pharmaceutically acceptable salt, solvate and / or hydrate thereof for the manufacture of a medicament for the treatment of any disease associated with substance P and a human NK ₁ receptor.
[29" claim-type="Currently amended] 29. The use according to claim 28 for the manufacture of a medicament for the treatment of diseases and pain of the respiratory, gastrointestinal, urinary, immune or cardiovascular or central nervous system, migraine, inflammation, nausea and vomiting, and skin diseases.
[30" claim-type="Currently amended] 30. The use according to claim 29 for the manufacture of a medicament for the treatment of obstructive chronic bronchitis, asthma, urinary incontinence, irritable bladder syndrome, Crohn's disease, ulcerative colitis, depression and anxiety.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US9969711B2|2018-05-15|NK1 antagonists

---

EP3164395B1|2019-03-27|Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators

---

AU2002333220B2|2008-02-07|Phenyl-piperazine derivatives as serotonin reuptake inhibitors

---

US7790753B2|2010-09-07|Derivatives of N-[phenyl|methyl]benzamide, preparation method thereof and application of same in therapeutics

---

DE69534164T2|2006-03-09|Tri-substituted phenyl derivatives use as pde iv hemmer

---

KR0179053B1|1999-03-20|Indole derivatives

---

US5770735A|1998-06-23|Polycyclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which they are present

---

US7208602B2|2007-04-24|Gamma secretase inhibitors

---

EP1680400B1|2007-06-06|Derivatives of n-[ phenyl|methyl]benzamide and n-[ |phenylmethyl]benzamide, preparation method thereof and application of same in therapeutics

---

RU2157807C2|2000-10-20|Substituted heterocyclic compounds, method of their synthesis and pharmaceutical composition

---

ES2286444T3|2007-12-01|Derivatives of n-phenyl | methylbenzamide, its preparation and its application in therapeutics.

---

JP2614408B2|1997-05-28|Acyclic ethylenediamine derivatives as substance P receptor antagonists

---

US7718666B2|2010-05-18|Pyrido [2,1-a] isoquinoline derivatives

---

JP4181622B2|2008-11-19|New compounds

---

US5656639A|1997-08-12|Heterocyclic compounds, method of preparing them and pharmaceutical compositions in which they are present

---

ES2229259T3|2005-04-16|Piperidine derivatives with taquiquinina antagonist activity.

---

JP2786480B2|1998-08-13|1-indolylalkyl-4- | piperazine

---

FI116621B|2006-01-13|Antagonist compounds selective against the human NK3 receptor, their preparation, pharmaceutical compositions containing them and their use as drugs and diagnostic agents

---

US8071651B2|2011-12-06|5-amino-4-hydroxy-7-|-8-methyl-nonamide derivatives and related compounds as renin inhibitors for the treatment of hypertension

---

DE69631390T2|2004-11-25|Substituted benzylamine piperidine compounds

---

JP3022951B2|2000-03-21|Aroyl-piperidine derivatives

---

JP4617292B2|2011-01-19|Preparation of arylalkyl carbamate derivatives and their therapeutic use

---

US5081246A|1992-01-14|Compound having vessel smooth muscle relaxation activity

---

JP2602635B2|1997-04-23|Oxazolidin-2-one derivatives

---

EP1874746B1|2015-11-18|Derivatives of 1-n-azacycloalkyl-3-phenoxypropane useful for the preparation of psychotropic medicaments

同族专利:

---

公开号 | 公开日

---

CZ300911B6|2009-09-09|

---

UY26079A1|2000-10-31|

---

AT275136T|2004-09-15|

---

HK1042092B|2005-04-22|

---

ME00057B|2010-10-10|

---

PT1165528E|2005-01-31|

---

CZ20013365A3|2002-01-16|

---

DE60013418D1|2004-10-07|

---

AU3301600A|2000-10-16|

---

YU68201A|2004-03-12|

---

WO2000058292A1|2000-10-05|

---

SI1165528T1|2005-02-28|

---

PE20001596A1|2001-04-01|

---

EE200100499A|2002-12-16|

---

CA2366829A1|2000-10-05|

---

NO20014632D0|2001-09-24|

---

RS50085B|2009-01-22|

---

TR200102639T2|2002-02-21|

---

UA73931C2|2002-01-15|

---

RU2222537C2|2004-01-27|

---

AU756855B2|2003-01-23|

---

CN1353698A|2002-06-12|

---

JP2002540195A|2002-11-26|

---

EE04525B1|2005-08-15|

---

NZ513674A|2003-05-30|

---

DK1165528T3|2005-01-10|

---

HK1042092A1|2005-04-22|

---

ZA200106981B|2002-10-24|

---

AR023139A1|2002-09-04|

---

FR2791346A1|2000-09-29|

---

IL145041D0|2002-06-30|

---

BG105923A|2002-05-31|

---

US6506750B1|2003-01-14|

---

IL145041A|2010-11-30|

---

KR100696340B1|2007-03-20|

---

HRP20010704B1|2005-04-30|

---

CN100422160C|2008-10-01|

---

BR0009281B1|2011-05-17|

---

TW534906B|2003-06-01|

---

CO5160340A1|2002-05-30|

---

EP1165528B1|2004-09-01|

---

IS6063A|2001-08-24|

---

IS2338B|2008-02-15|

---

PL351317A1|2003-04-07|

---

PL205318B1|2010-04-30|

---

JP3853155B2|2006-12-06|

---

NO321576B1|2006-06-06|

---

ID29871A|2001-10-18|

---

HU0201863A3|2003-03-28|

---

CA2366829C|2007-05-15|

---

BR0009281A|2002-01-22|

---

FR2791346B3|2001-04-27|

---

MXPA01009643A|2002-05-14|

---

SK286977B6|2009-08-06|

---

DE60013418T2|2005-09-22|

---

HU0201863A2|2002-12-28|

---

MEP12008A|2010-06-10|

---

HRP20010704A2|2002-08-31|

---

SK13462001A3|2002-05-09|

---

ES2226794T3|2005-04-01|

---

EP1165528A1|2002-01-02|

---

BG64623B1|2005-09-30|

---

NO20014632L|2001-11-26|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1999-03-25|Priority to FR99/03,854

---

1999-03-25|Priority to FR9903854A

---

2000-03-21|Application filed by 고든 라이트, 사노피-신델라보

---

2001-12-07|Publication of KR20010108381A

---

2007-03-20|Application granted

---

2007-03-20|Publication of KR100696340B1

优先权:

---

申请号 | 申请日 | 专利标题

---

FR99/03,854|1999-03-25|

---

FR9903854A|FR2791346B3|1999-03-25|1999-03-25|Novel morpholine derivatives, process for their preparation and pharmaceutical compositions containing them|