HRP970451A2 - Quaternary ammonium compounds - Google Patents

Description

This invention relates to quaternary ammonium compounds. More specifically, the invention relates to C3-C7 cycloalkyl-substituted quaternary ammonium compounds and processes for preparing such derivatives, intermediates used in these processes, compositions containing these derivatives and the use of these derivatives.

The presented compounds are tachykinin antagonists, including NKA (neurokinin A), NKB (neurokinin B), and substance P, which act on human neurokinin-1 (NK1), neurokinin-2 (NK2), and neurokinin-3 (NK3) receptors.

These compounds are particularly useful as antagonists of the double NK1 and NK2 receptors, so they can be used to treat an inflammatory disease, such as arthritis, psoriasis, asthma or inflammatory bowel disease; some central nervous system (CNS) disorder, such as anxiety, depression, dementia or psychosis; any gastrointestinal (GI) disorder, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, irritable bowel syndrome, colitis, or Crohn's disease; some disease caused by Helicobacter pylori or some other urease-positive Gram-negative bacteria; urogenital tract disorder, such as uncontrolled discharge, impotence, hyperreflexia or cystitis; a pulmonary disorder, such as chronic obstructive airways disease; allergy, such as eczema, contact dermatitis, hereditary allergic dermatitis, urticaria, eczematous dermatitis or rhinitis; a hypersensitivity disorder, such as hypersensitivity to poison ivy; a proliferative disorder, such as cancer or a disorder associated with fibroblast proliferation, a vasospasmatic disease, such as angiogenesis, angina or Reynauld's disease; fibrotic or collagenous disease, such as atherosclerosis, scleroderma, or eosinophilic fluke infection of the liver; reflux sympathetic dystrophy, such as shoulder/hand syndrome, addiction disease, such as alcoholism; somatic disorder related to stress; peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burn, herpetic neuralgia or post-herpetic neuralgia; a neuropathological disorder, such as Alzheimer's disease or multiple sclerosis; a disorder associated with enhancing immunity or suppressing immunity, such as systemic lupus erythematosus; rheumatic disease, such as fibrositis, vomiting, cough, acute or chronic pain; migraine; an eye disease, such as proliferative retinopathy, the flu or a cold.

EP-A-0591040 describes quaternary ammonium compounds optionally substituted with phenyl or benzyl, which act as tachykinin antagonists.

EP-A-0714891 describes, inter alia, cyclohexylpiperidine and cyclohexylpiperazine derivatives as tachykinin receptor antagonists.

The presented invention provides a compound of the formula:

[image]

where R is phenyl, C3-C7 cycloalkyl or heteroalkyl, both of which may be optionally benzo-fused or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused part, with 1 to 3 substituents of each of which is independently selected from C1-C4 alkyl, fluoro(C1-C4) alkyl, C1-C4 alkoxy, fluoro(C1-C4) alkoxy, C2-C4 alkanoyl, halo, C1-C4 alkoxycarbonyl, C3-C7 cycloalkyl, - S(O)p(C1-C4 alkyl), cyano, -NR7R8, -S(O)pNR7R8, -NR7(C1-C4 alkanoyl) and -CONR7R8, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl ;

R 1 and R 2 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent C 2 -C 6 alkylene;

R 3 and R 4 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent unbranched C 1 -C 4 alkylene;

R5 is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which is substituted with 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4) alkyl, C1-C4 alkoxy, halo and cyano, or R5 is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl.

R6 is C3-C7 cycloalkyl optionally substituted with 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, fluoro(C1-C4) alkyl and fluoro(C1-C4) alkoxy;

R 7 and R 8 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent C 2 -C 6 alkylene;

T is carbonyl;

Y is unbranched C2-C4 alkylene;

ZA is a pharmaceutically acceptable anion;

m is 0 or 1;

n is 1 or 2;

p is 0, 1 or 2; And

"heteroaryl", as used in the definition of R, means thienyl, or a 5- or 6-membered ring heteroaryl group containing either 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatoms and 1 oxygen or sulfur heteroatom, provided that when m is 0, and R is optionally fused and optionally substituted heteroaryl, this aryl is bound by one carbon atom from the ring to T.

In the preceding definitions, "halo" means fluorine, chlorine, bromine or iodine, and alkyl and alkoxy groups having three or more carbon atoms, alkanoyl groups having four carbon atoms and alkylene groups having two or more carbon atoms (except where expressly provided said) can be with a straight or forked string.

It is preferred that R is phenyl, optionally benzo- or C3-C7 cycloalkyl-fused, and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused part, with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, fluoro(C1-C4)alkyl in C1-C4 alkoxy, or R is 2,3-dihydrobenzo[b]furanyl. It is more preferred that R is phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl, each of which is optionally substituted with 1 to 3 substituents independently selected from methyl, fluoro, bromo, trifluoromethyl, methoxy and ethoxy, or R is 2,3 -dihydrobenzo[b]furanyl.

Examples of R include phenyl, 2,3-dimethylphenyl, 3,5-dimethylphenyl, 3,5-dibromophenyl, 4-fluoro-3-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 3,5-dimethoxy-4-methylphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, naphth-1-yl, 1,2, 3,4-tetrahydro-naphth-5-yl and 2,3-dihydrobenzo[b]furan-7-yl.

R is preferably 3,5-bis(trifluoromethyl)phenyl or 3,5-dimethylphenyl.

Preferably, R1 and R2 are H.

It is preferred that either R 3 is C 1 -C 4 alkyl and R 4 is H, or that R 3 and R 4 , taken together, represent C 2 -C 3 alkylene.

More preferably, either R 3 is methyl and R 4 is H, or R 3 and R 4 taken together represent 1,2-ethylene or 1,3-propylene.

It is preferred that either R 3 is methyl and R 4 is H, or that R 3 and R 4 taken together represent 1,2-ethylene.

R5 is preferably phenyl optionally substituted with 1, 2 or 3 halo substituents.

R5 is, more preferably, phenyl optionally substituted with 1, 2 or 3 chloro substituents.

R5 is preferably 3,4-dichlorophenyl.

R 6 is preferably cyclohexyl substituted as defined above for R 6 for a compound of formula (I).

It is preferred that R 6 is cyclohexyl.

Preferably, Y is 1,2-ethylene.

ZA is some pharmaceutically acceptable anion, such as chloride, bromide, nitrate, methanesulfonate, para-toluenesulfonate, benzenesulfonate, hydrogen sulfate or sulfate.

Preferably, ZA is chloride or methanesulfonate.

Preferably, m is 0.

Preferably, n is 2.

Recommended examples of compounds of formula (I) are:

(i) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-phenylacetylpiperidin-3-yl]ethyl)quinuclidinium methanesulfonate;

(ii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium methanesulfonate;

(iii) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methylphenylacetamido]butyl)quinuclidinium chloride;

(iv) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-dimethylbenzamido]butyl)quinuclidinium methanesulfonate;

(v) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)phenyl-acetoamido]butyl)quinuclidinium chloride;

(vi) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium methanesulfonate;

(vii) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-1-(3,5-dimethylbenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(viii) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methylnaphthalene-1-carboxyamido]butyl)quinuclidinium methanesulfonate;

(ix) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-dimethylphenylacetamido]butyl)quinuclidinium methanesulfonate;

(x) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-4-fluoro-3-trifluoromethylbenzamido]butyl)quinuclidinium methanesulfonate;

(xi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-bis[trifluoromethyl]phenylacetyl)piperidin-3-yl]ethyl)quinuclidinium methanesulfonate;

(xii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-bis[trifluoromethyl]benzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(xiii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethylphenylacetyl)pyrrolidin-3-yl]ethyl)quinuclidinium methanesulfonate;

(xiv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,4-dimethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(xv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethoxy-4-methylbenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(xvi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(2,3-dihydrobenzo[b]furan-7-carbonyl)pyrrolidin-3-yl]ethyl) quinuclidinium chloride ;

(xvii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(2,3-dimethylbenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(xviii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methylnaphthalene-1-actamido]butyl)quinuclidinium methanesulfonate;

(xix) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-3,5-dibromobanza-mido]butyl)quinuclidinium methanesulfonate;

(xx) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-1,2,3,4-tetrahydronaphthalene-5-carboxamido]butyl)quinuclidinium methanesulfonate;

(xxi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoro-methyl)benzamido]butyl)-1-azoniabicyclo[2 ,2,1]heptane methanesulfonate;

(xxii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(xxiii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,4,5-triethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(xxiv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(4-fluoro-3-trifluoromethyl-benzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride;

(xxv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethyl-4-methoxy-benzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; and

(xxvi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium chloride;

and their alternatives, pharmaceutical salts (re ZA) and individual (R)- and (S)-stereomers of any of them.

One compound of formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. The presented invention includes individual stereoisomers of compounds of formula (I) and their mixtures.

Separation of diastereomers can be accomplished by conventional techniques, for example fractional crystallization, chromatography or H.P.L.C. stereoisomeric mixtures of one compound of formula (I) or one of its suitable salts or derivatives. A single enantiomer of one of the compounds of formula (I) may also be prepared from a suitable optically pure intermediate or by resolving, for example by H.P.L.C., the corresponding racemate, using a suitable chiral support or by fractional crystallization of the diastereoisomeric salts formed by reacting the corresponding racemate with a suitable optically active acid .

Examples of recommended individual stereoisomers include:

(i) 4-cyclohexyl-1-(2-[3(S)-(3,4-dichlorophenyl)-1-phenylacetylpiperidin-3-yl]ethyl)quinuclidinium methanesulfonate;

(ii) 4-cyclohexyl-1-(2-[3(S)-(3,4-dichlorophenyl)-1-(3,5-bis[trifluoromethyl]-phenylacetyl)piperidin-3-yl]ethyl)quinuclidinium methanesulfonate ;

(iii) 4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)phenylacetamido]butyl)quinuclidinium chloride;

(iv) 4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium methanesulfonate;

(v) 4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-4-fluoro-3-trifluoromethylbenzamido]butyl)quinuclidinium methanesulfonate;

(vi) 4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)-1-azoniabicyclo[2,2 ,1]heptane methanesulfonate;

(vii) 4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium;

and their alternative pharmaceutically acceptable salts (re ZA).

All compounds of the formula (I) can be prepared by reacting one compound of the formula:

[image]

wherein R, R1, R2, R3, R4, R5, T, Y and m are as previously defined for a compound of formula (I), Z is a suitable leaving group capable of forming a pharmaceutically acceptable anion (ZA), and Z1 is one suitable leaving group with one compound of the formula:

[image]

where R 6 and n are as previously defined for the compound of formula (I), wherein said process is followed by: a) when Z 1 is a suitable leaving group, substitution for a pharmaceutically acceptable anion (ZA); or b), optionally, if ZA is one pharmaceutically acceptable anion, substitute for another pharmaceutically acceptable anion.

Preferred examples of Z are C1-C4 alkanesulfonyloxy, benzenesulfonyloxy, para-toluenesulfonyloxy, chlorine, bromine and iodine.

One example of Z1 is trifluoromethanesulfonyloxy.

Preferably, the leaving group in the compound of formula (II) forms one pharmaceutically acceptable anion (Z/ZA), for example methanesulfonyloxy/methanesulfonate, so that replacement of the anion at the end of the process is unnecessary.

It is possible to replace pharmaceutically acceptable anions (re ZA) during the work-up procedure, for example, methanesulfonate can be replaced by chloride by treatment of the isolated compound or the crude reaction mixture diluted with aqueous hydrochloric acid.

The reaction of compounds (II) and (III) is usually carried out in a suitable solvent, for example acetonitrile, at an elevated temperature, preferably at their reflux temperature.

Starting materials of formula (II) can be prepared by the following procedures:

a) Starting materials of formula (II) when R 3 and R 4 are both independently selected from H and C 1 -C 6 alkyl, and R, R 1 , R 2 , R 5 , T, Y, Z, Z 1 and m are as previously defined for a compound of the formula (II), can be prepared as shown in scheme 1:

[image]

where R, R1, R2, R3, R4, R5, Y, Z, Z1 and m are as previously defined for this Scheme 1, P is a suitable protecting group and X and XA are suitable leaving groups.

Examples of suitable protecting groups (P) can be found in "Protective Groups in Organic Synthesis", T.W. Grrene and P.G.M. Wuts, Second Edition, Wiley-Interscience. A preferred example for P is tetrahydropyranyl.

Examples of suitable leaving groups for X include chloro, bromo, iodo, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and para-toluenesulfonyloxy.

Examples of suitable leaving groups for XA are chloro and bromo.

In one typical procedure, a nitrile of formula (III) is treated with a suitable base, for example sodium hydride, in a suitable solvent, for example tetrahydrofuran, and then alkylated with a compound of formula (IV). The prepared nitrile of formula (V) is reduced to the amine of formula (VI) using conventional conditions, for example catalytic hydrogenation. Deprotection of the amine of formula (VI) can be accomplished using the conditions described in the aforementioned Greene publication. If a compound of formula (II) wherein R 1 is C 2 -C 6 is desired, the amine of formula (VII) is subjected to reductive amination using an aldehyde of the formula (C 1 -C 5 alkyl)CHO, a suitable reducing agent, for example BH 3 S(CH 3 ) 2 , and a suitable solvent, for example tetrahydrofuran. When a compound of formula (II) where R3 is methyl is desired, the amine of formula (VII) is first treated with formic anhydride of acetic acid and the product is then reduced using a suitable reducing agent, for example BH3S(CH3)2. A compound of formula (VIII) (which, when R 3 is H, corresponds to a compound of formula VII) can then be acylated with at least two mole equivalents of a compound of formula (IX), preferably in the presence of a suitable acid acceptor, for example triethylamine, and using a suitable solvent, for example dichloromethane. Hydrolysis of compound (X) under suitable conditions, for example aqueous sodium hydroxide in methanol, gives the alcohol of formula (XI). Alternatively, a compound of formula (VIII) may be converted directly to a compound of formula (XI) using approximately one mole equivalent of one compound of formula (IX) under the specified acylation conditions. A compound of formula (XI) can be converted to a compound of formula (IIA) using conventional conditions. Thus, for example, an alcohol of formula (XI) can be converted into a compound of formula (IIA), when Z is methanesulfonyloxy, by treatment with methanesulfonyl chloride, triethylamine and dichloromethane, and a compound of formula (IIA) where Z1 is trifluoromethanesulfonyloxy can be prepared by treatment of an alcohol of formula ( XI) with trifluoromethanesulfonic anhydride, possibly in the presence of a suitable acid acceptor, and in a suitable solvent, for example dichloromethane.

b) Starting materials of formula (II) when R3 and R4, taken together, represent C1-C4 straight chain alkylene, and R, R1, R2, R5, T, Y, Z, Z1 and m are as previously defined for a compound of formula ( II), can be prepared as shown in scheme 2.

[image]

[image]

where R, R1, R2, R5, Y, Z, Z1 and m are as previously defined for this Scheme 2, X1 and X2 are both suitable leaving groups, such as one of those previously defined for X, and X4 is a suitable leaving group, such as chloro or bromo.

In one typical procedure, a nitrile of formula (XII) is treated with a suitable base, for example sodium hydride or lithium hexamethyldisilazide, in a suitable solvent, for example tetrahydrofuran, and then alkylated with a compound of formula (XIII). The resulting nitrile of formula (XIV) is either further alkylated with a compound of formula (XV) under conditions similar to those of the previous step, or is treated with an acrylate of formula (XVA) in the presence of a suitable base, for example sodium methoxide, and in a suitable solvent, at example methanol. The reductive cyclization of formula (XVI) is carried out under a hydrogen atmosphere using a suitable catalyst, for example platinum (II) oxide, in the presence of a suitable solvent, for example acetic acid. It is also possible to convert the compound of formula (XVI) into the compound of formula (XVII) by hydrolysis of the compound of formula (XVI) using, for example, an aqueous solution of sodium hydroxide, followed by reductive cyclization of the corresponding carboxylic acid obtained under the conditions described above for the compound of formula (XVI). The lactam of formula (XVII) is then reduced to the cyclic amine of formula (XXII) under standard conditions, for example lithium aluminum hydride/tetrahydrofuran. Acylation of a compound of formula (XXII) with a compound of formula (XXIII), optionally in the presence of a suitable acid acceptor, for example triethylamine, and in a suitable solvent, for example dichloromethane, gives a compound of formula (XXIV). Acylation can also be performed by conventional condensation of the compound of formula (XXII) with a suitable carboxylic acid. This compound can be deprotected under conventional conditions, such as those described in the aforementioned Greene publication, for example using aqueous hydrochloric acid/tetrahydrofuran. The resulting aldehyde of formula (XXV) can be reduced to the alcohol of formula (XXVI) under standard conditions, for example sodium borohydride/ethanol. This alcohol can be converted to a compound of formula (IIC) using conditions similar to those previously described for converting a compound of formula (XI) to a compound of formula (IIA).

c) Starting materials of formula (II), where Y is ethylene, R3 and R4, taken together, represent ethylene, and R, R1, R2, R5, T, Y, Z, Z1 and m are as previously defined for one compound of the formula ( II), can be prepared, as shown in Scheme 3.

[image]

wherein R, R1, R2, R5, T, Y, Z, Z1 and m are as previously defined for this Scheme 3, X5 is a suitable leaving group, such as one previously described for X, and X6 is a suitable leaving group , such as chloro or bromo.

In one typical procedure, a nitrile of formula (XII) is alkylated with a compound of formula (XXVII) using a suitable base, for example sodium hexamethyldisilazide, and in a suitable solvent, for example tetrahydrofuran. Reduction of a compound of formula (XXVIII) using a suitable reducing agent, for example sodium borohydride/cobalt (II) chloride, and in a suitable solvent, for example ethanol, followed by in situ intramolecular cyclization of the intermediate amine gives the lactam of formula (XXIX). Reduction of the ester group in this lactam, using a suitable reducing agent, for example lithium aluminum hydride, and in a suitable solvent, for example tetrahydrofuran, gives an alcohol of formula (XXX) which can be reduced to a pyrrolidine of formula (XXXI) using a suitable reducing agent, for example diborane , and in a suitable solvent, for example tetrahydrofuran. Acylation of this pyrrolidine (possibly as addition acid salts, for example hydrochloride) with a compound of formula (XXXII), preferably in the presence of a suitable acid acceptor, for example triethylamine, and in a suitable solvent, for example dichloromethane, gives a compound of formula (XXXIII) which can hydrolyze to a compound of formula (XXXIV) using conventional conditions, for example aqueous sodium hydroxide in methanol or ethanol. A compound of formula (XXXIV) can be converted to a compound of formula (IID) using conventional conditions, such as those previously used to convert a compound of formula (XI) to a compound of formula (IIA).

d) Starting materials of formula (II), where R3 and R4 are both independently selected from H and C1-C6 alkyl, and R, R1, R2, R5, T, Y, Z, Z1 and m are as previously defined for one compound of formula (II), can be prepared as shown in scheme 4.

[image]

wherein R, R1, R2, R3, R4, R5, T, Y, Z, Z1 and m are as previously defined for this Scheme 4, and X1 and XA are as previously defined in procedures a) and b).

Reactions can be performed using similar procedures, as those described for analogous transformations in previous procedures a) - c).

Starting materials of formula (III) can be prepared by the following procedures.

i) Compounds of formula (III) where n is 2 can be prepared by methods similar to those described in Chem.Ber., 108, 3475 (1975).

Alternatively, compounds of formula (III), where n is 2, and R6 is cyclohexyl optionally substituted as previously given in the definition of R6 for some of the compounds of formula (I), can be prepared by catalytic hydrogenation of one compound of formula:

[image]

where Ar is phenyl optionally substituted as stated earlier in the aforementioned definition for R6. The reduction can be carried out in a hydrogen atmosphere using a suitable catalyst, for example rhodium on silica, and in a suitable solvent, for example acetic acid. Compounds of formula (XXXV) can be prepared by procedures such as those described in Chem.Ber., 108, 3475 (1975) and in J. Org. Chem., 22, 1484 (1957).

ii) Compounds of formula (III) where n is 1 and R 6 is cyclohexyl optionally substituted as previously given in the definition of R 6 for some of the compounds of formula (I), may be prepared conventionally as shown in Scheme 5.

[image]

where Ar 1 is phenyl optionally substituted as set forth above in the aforementioned definition for R6 for Scheme 5, R 6A is cyclohexyl optionally substituted as set forth above in the aforementioned definition for R6 for Scheme 5. "Ph" is phenyl and "Ts" is para- toluenesulfonyl oxy. Starting materials of formula (XXXVI) can be prepared by conventional procedures.

All the aforementioned reactions and preparations of new starting materials used in the previous procedures are conventional, and the appropriate reagents and reaction conditions for their execution or preparation, as well as the procedures for isolating the desired products, are known to experts who can refer to known solutions from the literature and examples and preparations from this application.

The affinity of compounds of formula (I) for the human NK1 receptor can be determined in vitro by determining their ability to inhibit the binding of [3H]-Substance P to membranes prepared from the human IM9 cell line expressing the human NK1 receptor using a modification of the procedure described in the article by S. McLean , et al., J. Pharm. Exp. Ther., 267, 472-9 (1993), where whole cells were used.

The affinity of compounds of formula (I) for the human NK2 receptor can be determined in vitro by determining their ability to compete with [3H]-NKA (neurokinin A) for binding to membranes prepared from Chinese hamster ovary cells expressing the cloned human NK2 receptor. Membranes are incubated (90 min, 25 °C) with [3H]-NKA and with the full range of concentrations of the tested compound. Non-specific binding is determined in the presence of 10 µM NKA.

The NK1 receptor antagonist activity of the compounds of formula (I) can be determined in vitro by examining their ability to antagonize the spasm action induced by Substance P in deepithelialized strips of guinea pig trachea. Tissue can be prepared from guinea pigs (350 - 600 g) killed by stunning and exsanguination. The cut trachea is cleaned of connective tissue and opened longitudinally, opposite the strip of tracheal muscle. The upper layer of tissue can be removed by rubbing the inner surface of the trachea with a piece of cotton wool. Strips approximately 4 strips of cartilage are cut and placed under a tension of 1 g in an organic bath containing Krebs solution (composition: NaCl 118 mM, KCl 4.6 mM, NaHCO3 25 mM, KH2PO4 1.4 mM, MgSO4 1.2 mM, CaCl2 2.5 mM, glucose 11 mM) at 37 °C and gassed with 95% O2 / 5% CO2. A possible effect of Substance P on the NK2 receptor population found in this tissue can be prevented by including the selective NK2 receptor antagonist ±SR-48,968 (1 µM) in the Krebs stock solution. In addition, indomethacin (3 µM) is added to eliminate the influence of endogenous prostanoids. Changes in tissue tension in response to the cumulative addition of the Substance P agonist are recorded isometrically. The potency of a compound of formula (I) can be estimated by the magnitude of the shift induced in the dose response curve of Substance P, using a standard Schild assay, after 30 minutes of incubation of the compound with the tissue.

A strip preparation of deepithelialized guinea pig trachea can also be used to evaluate the NK2 receptor antagonist activity of a compound of formula (I) in vitro using the selective [ß-Ala8]NKA(4-10) NK2 receptor agonist as an inducing agent. For these studies, strips were prepared and placed in organic baths as described above, using a Krebs solution of the following composition: NaCl 118 mM, KCl 4.6 mM, NaHCO3 25 mM, KH2PO4 1.4 mM, MgSO4 1.2 mM, CaCl2 2.5 mM, glucose 11 mM, indomethacin 3 µM. The potency of a compound of formula (I) can be assessed by the magnitude of the shift induced in the dose response curve of [ß-Ala8]NKA(4-10), using a standard Schild assay, after 30 minutes of incubation of the compound with the tissue.

Compounds of formula (I) can be screened for NK3 receptor antagonist activity in vitro by examining their ability to antagonize the spasm-inducing activity of the selective NK3 receptor agonist, senkid, in the guinea pig ileum using the procedure of Maggi, et al., Br.J.Pharmacol ., 101, 966 - 1000 (1990).

For use in humans, the compounds of formula (I) may be administered alone, but will usually be administered in admixture with some pharmaceutical carrier selected in accordance with the intended route of administration and standard pharmaceutical practice.

Thus, for example, they can be administered orally or under the tongue in the form of tablets containing additives, such as starch or lactose, or in capsules or granules, either alone or mixed with neutral additives, or in the form of elixirs, solutions or suspensions that contain flavoring or coloring agents.

They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution that may contain other substances, for example enough salt or glucose to make the solution isotonic with blood.

For oral and parenteral administration to human patients, the daily dosage level of the compounds of formula (I) will be from 0.01 to 20 mg/kg (in single or divided doses), preferably from 0.1 to 5 mg/kg.

Thus, the tablets or capsules of the compounds will contain from 1 mg to 0.5 g of the active compound for administration one or two or more each time, but as needed. In any case, the doctor will determine the actual dose that will be most suitable for the individual patient, and it will change depending on the age, body weight and response of the specific patient. There may, of course, be special cases when higher or lower doses will be determined, and they are within the scope of this invention.

The compounds of formula (I) can also be administered through the nose (sniffing) or inhalation (inhalation), and are usually given in the form of a dry powder for inhalation or in the form of an aerosol jet from a pressurized box, or from a nebulizer, using a suitable means for spraying, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, some hydrofluoroalkane, such as 1,1,1,2-tetrafluoroethane (HFA 134A™) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA™ ), carbon dioxide or other suitable gas. In the case of pressurized aerosols, the dosage unit can be determined by fitting a valve that releases a measured quantity. A pressure can or nebulizer may contain a solution or suspension of the active compound, for example using a mixture of ethanol and a dispersing agent as a solvent, which may additionally contain a lubricant, for example sorbitan trioleate. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or pressurized inhaler may be formulated to contain a powder mixture consisting of a compound of formula (I) and some suitable powder base, such as lactose or starch.

Preferably, the aerosol formulations are designed such that each metered dose or "push" of the aerosol contains from 20 µg to 1000 µg of a compound of formula (I) for administration to a patient. The total daily dose with a single aerosol will be in the range of 20 µg to 20 mg, which may be given as a single dose or, more commonly, in smaller doses throughout the day.

Alternatively, the compounds of formula (I) can be administered in the form of suppositories or vaginates, or they can be administered locally, topically, in the form of a liquid for external use, solution, cream, ointment or powder for sprinkling. So, for example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin, or they can be incorporated, in a concentration of 1 to 10 wt.%, into an ointment consisting of white wax or a base of white of soft paraffin, together with stabilizers and preservatives, as needed. The compounds of formula (I) can also be administered through the skin using patches.

It goes without saying that calling for treatment implies prophylactic use as well as alleviation of the established symptoms of the disease.

In this way, the invention further ensures:

(i) a pharmaceutical composition containing a compound of formula (I) together with a pharmaceutically acceptable solvent or carrier;

(ii) a compound of formula (I) or a pharmaceutically acceptable composition thereof, which is used as a medication;

(iii) application of one compound of formula (I), or its pharmaceutically acceptable composition, for the production of medication for the treatment of diseases by causing an antagonistic effect on one tachykinin receptor or on a combination of tachykinin receptors;

(iv) use as under (iii) when the antagonistic activity is directed at human NK1 and NK2 tachykinin receptors;

(v) administration as under (iii) or (v) when the disease is an inflammatory disease, such as arthritis, psoriasis, asthma or inflammatory bowel disease, some central nervous system (CNS) disorder, such as agitation, depression, dementia or psychosis, some gastrointestinal (GI) disorder, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, uncontrolled bowel movements, colitis or Crohn's disease, some disease caused by Helicobacter pylori or some other urease-positive Gram-negative bacteria , urogenital tract disorder, such as uncontrolled discharge, hyperreflexia or cystitis, pulmonary disorder, such as chronic obstructive airways disease, allergy, such as eczema, contact dermatitis, hereditary allergic dermatitis or rhinitis, hypersensitivity disorder, such as hypersensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy self, burn, herpetic neuralgia or post-herpetic neuralgia, vomiting, cough, migraine, acute or chronic pain;

(vi) a method for treating a human for the treatment of a disease by producing an antagonistic effect on one tachykinin receptor or on a combination of tachykinin receptors, comprising treating that human with an effective amount of a compound of formula (I) or a pharmaceutically acceptable composition thereof;

(vii) a method as under (vi) when the antagonistic activity is directed at human NK1 and NK2 tachykinin receptors; and

(viii) procedure as under (vi) or (vii) when the disease is an inflammatory disease, such as arthritis, psoriasis, asthma or inflammatory bowel disease, some central nervous system (CNS) disorder, such as agitation, depression, dementia or psychosis, some gastrointestinal (GI) disorder, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, uncontrolled bowel movements, colitis or Crohn's disease, some disease caused by Helicobacter pylori or some other urease-positive Gram-negative bacteria , urogenital tract disorder, such as uncontrolled discharge, hyperreflexia or cystitis, pulmonary disorder, such as chronic obstructive airways disease, allergy, such as eczema, contact dermatitis, hereditary allergic dermatitis or rhinitis, hypersensitivity disorder, such as hypersensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neur opathy, burn, herpetic neuralgia or post-herpetic neuralgia, vomiting, cough, migraine, acute or chronic pain.

The following examples illustrate the preparation of compounds of formula (I).

Example 1

4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-phenylacetylpiperidin-3-yl]ethyl)quinuclidinium methanesulfonate

[image]

The compound of preparation 8 (0.47 g) and 4-cyclohexylquinuclidine (0.2 g) (see preparation 20) were dissolved in acetonitrile (10 ml) and heated at reflux temperature for 8 hours. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in dichloromethane, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica with a solvent gradient of 95:5, varying up to 93:7, by volume, dichloromethane:methanol, to afford the title compound (0.64 g) as a white foam.

1H-NMR (CDCl3): δ = 7.16-7.48 (8H, m), 4.31 (1H, d), 3.69-3.91 (3H, m), 3.26-3, 42 (7H, m), 3.02-3.22 (2H, m), 2.80-2.90 (2H, m), 2.00-2.30 (4H, m), 1.50- 1.90 (15H, m), 1.03-1.23 (4H, m), 0.80-0.95 (2H, m) ppm.

Found: C, 64.44; H, 7.69; N, 4.62. C35H48Cl2N2O4S. 0.2 mol of water requirement C, 64.64; H, 7.35; N, 4.31%.

Example 2

4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium methanesulfonate

[image]

The compound of preparation 13 (0.7 g) and 4-cyclohexylquinuclidine (0.3 g) (see preparation 20) were dissolved in acetonitrile (10 ml) and heated at reflux temperature for 18 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica with a solvent gradient of 98:2, varying up to 90:10, by volume, dichloromethane:methanol, to give a white foam which was dissolved in dichloromethane and filtered. The solvent was removed under reduced pressure and the product was triturated with diethyl ether to give the title compound (0.55 g) as a white solid.

1H-NMR (CDCl3): δ = 7.20-7.50 (3H, m), 6.74-6.82 (2H, m), 3.80-4.10 (11H, m), 3, 30-3.57 (9H, m), 2.75 (3H, s), 2.58 (2H, m), 2.22 (2H, m), 1.60-1.85 (12H, m) , 1.05-1.25 (4H, m), 0.87 (2H, m) ppm.

Found: C, 59.06; H, 7.29; N, 3.82. C 36 H 50 Cl 2 N 2 O 7 S requires C, 59.58; H, 6.95; N, 3.86%.

Example 3

4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methylphenylacetamido]butyl)quinuclidinium chloride

[image]

The compound of preparation 16 (0.4 g) and 4-cyclohexylquinuclidine (0.26 g) (see preparation 20) were dissolved in acetonitrile (10 ml) and heated at reflux temperature for 20 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 ml) and washed with 2N aqueous hydrochloric acid (3 x 25 ml). The organic phase was separated, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica with a solvent gradient of 95:5, varying up to 90:10, by volume, dichloromethane:methanol, to afford the title compound (0.21 g) as a white foam.

1H-NMR (CDCl3): δ = 7.11-7.40 (8H, m), 3.85-4.01 (2H, m), 3.30-3.75 (9H, m), 3, 19 (1H, m), 2.98 (3H, s), 2.90 (1H, m), 1.40-2.20 (13H, m), 1.05-1.26 (4H, m) , 0.80-0.95 (2H, m) ppm.

Example 4

4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-3,5-dimethylbenzamido]-butyl)quinuclidinium methanesulfonate

[image]

The title compound was prepared in an analogous manner to the compound from example 3 using the compound of preparation 17 i

4-cyclohexylquinuclidine (see preparation 20) as starting materials, but without treatment with hydrochloric acid in the finishing procedure.

1H-NMR (CDCl3): δ = 7.25-7.50 (3H, m), 6.99 (1H, s), 6.81 (2H, s), 3.85-4.02 (2H, m), 3.35-3.69 (8H, m), 2.81 (6H, s), 2.29-2.35 (7H, s), 2.10 (1H, m), 1.60 -1.90 (12H, m), 1.05-1.25 (4H, m), 0.80-0.95 (2H, m) ppm.

Found: C, 60.90; H, 7.39; N, 4.15. C34H48Cl2N2O4S. 0.5 mol of water. 0.17 mol dichloromethane requirement C, 60.80; H, 7.36; N, 4.15%.

Example 5

4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)phenylacetamido]butyl)quinuclidinium chloride

[image]

The compound of preparation 19 (2.5 g) and 4-cyclohexylquinuclidine (1.0 g) (see preparation 20) were dissolved in acetonitrile (20 ml) and heated at reflux temperature for 18 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 ml) and washed with 2N aqueous hydrochloric acid (3 x 25 ml) and then with brine. The organic phase was separated, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica with a solvent gradient of 95:5, varying up to 93:7, by volume, dichloromethane:methanol, to afford the title compound (0.64 g) as a white foam.

1H-NMR (CDCl3): δ = 7.75 (3H, s), 7.41 (1H, d), 7.31 (1H, s), 7.16 (1H, dd), 4.00-4 .15 (3H, m), 3.80 (1H, d), 3.60-3.70 (3H, m), 3.36-3.50 (3H, m), 3.21 (1H, m ), 3.16 (3H, s), 2.85 (1H, m), 2.39 (1H, m), 2.02 (1H, m), 1.60-1.90 (12H, m) , 1.05-1.27 (4H, m), 0.82-0.98 (2H, m) ppm.

Found: C, 56.39; H, 5.96; N, 3.74. C34H41Cl3F6N2OS. 0.5 mol of water requirement C, 56.47; H, 5.72; N, 3.87%.

[image] - 50.2° (c = 1 mg/ml in ethanol).

Example 6

4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium methanesulfonate

[image]

The compound of preparation 22 (0.58 g) and 4-cyclohexylquinuclidine (0.24 g) (see preparation 20) were dissolved in acetonitrile (8 ml) and heated at reflux temperature for 18 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane before removal of the solvent under reduced pressure. The crude product was chromatographed on silica with a solvent gradient of 95:5, varying up to 85:5, by volume, methanol:dichloromethane, to afford the title compound (0.65 g) as a white foam.

1H-NMR (CDCl3): δ = 7.89 (1H, s), 7.80 (2H, s), 7.46 (2H, m), 7.30 (1H, m), 4.11 (2H , m), 3.30-3.65 (8H, m), 2.95 (3H, s), 2.78 (3H, s), 2.70 (1H, m), 2.47 (1H, m), 2.00 (1H, m), 1.60-1.90 (11H, m), 1.05-1.25 (4H, m), 0.80-0.95 (2H, m) ppm.

Found: C, 53.10; H, 5.64; N, 3.33. C34H42Cl2F6N2O4S. 0.1 mol dichloromethane requirement C, 53.32; H, 5.54; N, 3.64%.

[image] - 20.2° (c = 1 mg/ml in methanol).

Example 7

4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethylbenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride

[image]

The title compound was prepared in an analogous manner to the compound from Example 3 using the compound of preparation 24 and 4-cyclohexylquinuclidine (see preparation 20) as starting materials.

1H-NMR (CDCl3): δ = 7.20-7.50 (3H, m), 7.0-7.10 (3H, m), 3.40-4.05 (10H, m), 2, 50-2.90 (2H, m), 2.15-2.40 (8H, s), 1.50-1.90 (13H, m), 1.00-1.25 (4H, m), 0.70-0.90 (2H, m) ppm.

Found: C, 63.91; H, 7.64; N, 4.39. C34H45Cl3N2O. 0.33 mol dichloromethane. 0.66 mol of water requirement C, 63.99; H, 7.35; N, 4.35%.

Examples 8 and 9

The compounds of the following examples given in Table 1 have the general formula:

[image]

The compounds were prepared by the same procedure as in example 1, using the corresponding mesylates (methanesulfonates) and 4-cyclohexylquinuclidine (see preparation 20) as starting materials.

Table 1

[image]

Examples 10 - 16

The compounds of the following examples given in Table 2 have the general formula:

[image]

The compounds were prepared by the same procedure as in example 6, using the corresponding mesylates (methanesulfonates) and 4-cyclohexylquinuclidine (see preparation 20) as starting materials.

Table 2

[image] [image]

Example 17

4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)-benzamido]butyl)-1-azoniabicyclo[2,2,1 ]heptane methanesulfonate

[image]

The title compound was prepared in an analogous manner to the compound described in Example 6, using compounds of preparations 30 and 22 as starting materials.

1H-NMR (CDCl3): δ = 7.90 (1H, s), 7.80 (2H, s), 7.46 (2H, d), 7.30 (1H, m), 4.30 (1H , m), 4.11 (1H, m), 3.95 (1H, m), 3.25-3.70 (8H, m), 3.05 (1H, m), 2.95 (3H, s), 2.80 (3H, s), 2.50 (1H, m), 2.00-2.20 (3H, m), 1.50-1.90 (6H, m), 1.00 -1.30 (6H, m) ppm.

Found: C, 52.45; H, 5.53; N, 3.69. C33H40Cl2F6N2O4S. 0.1 mol dichloromethane requirement C, 52.72; H, 5.37; N, 3.71%.

Example 18

4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethylphenylacetyl)-pyrrolidin-3-yl]ethyl)quinuclidinium methanesulfonate

[image]

The title compound was prepared according to a procedure similar to that described in Example 2, using the compound of preparation 72 i

4-cyclohexylquinuclidine (see preparation 20) as starting materials.

1H-NMR (CDCl3): δ = 7.11-7.43 (4H, m), 6.84 (2H, s), 3.32-3.75 (13H, m), 2.78 (3H, m), 2.60-2.75 (1H, m), 2.26 (6H, s), 2.08 (2H, m), 1.58-1.80 (13H, m), 1.15 (4H, m), 0.88 (2H, m) ppm.

Found: C, 63.56; H, 7.86; N, 4.06. C 36 H 50 Cl 2 N 2 O 3 S requires C, 63.80; H, 7.44; N, 4.13%.

Examples 19 - 27

The compounds of the following examples given in Table 3 have the general formula:

[image]

were prepared by a similar procedure as those from example 3 using 4-cyclohexylquinuclidine (see preparation 20) and the corresponding methanesulfonates (mesylates) as starting materials.

Table 3

[image] [image]

Example 28

4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis-(trifluoromethanol)benzamido]butyl)quinuclidinium chloride

[image]

4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium methanesulfonate (1.5 g) ( see example 6) was dissolved in dichloromethane (25 ml) and washed three times with 2N aqueous hydrochloric acid solution (25 ml) and then with brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound (1.04 g) as a white foam.

1H-NMR (CDCl3): δ = 7.89 (1H, s), 7.66 (2H, s), 7.30-7.50 (3H, m), 4.19-4.31 (1H, m), 3.40-4.00 (9H, m), 2.87 (3H, s), 2.32-2.49 (1H, m), 2.09-2.25 (1H, m) , 1.60-1.90 (12H, m), 0.80-1.33 (6H, m) ppm.

Found: C, 54.82; H, 5.85; N, 3.82. C33H39Cl3F6N2O. 1.0 mol of water requirement C, 55.20; H, 5.76; N, 3.90%.

The following preparations illustrate the syntheses of certain starting materials used in the previous examples.

Preparation 1

2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propanenitrile

[image]

Sodium hydride (60 wt.% dispersion in mineral oil) (4.73 g) was suspended in tetrahydrofuran (70 ml) under a nitrogen atmosphere, and the mixture was cooled in an ice bath. A solution of 3,4-fichlorophenylacetonitrile (20 g) in tetrahydrofuran (80 ml) was added dropwise over 35 minutes. The mixture was allowed to warm to room temperature and stirred for 16 hours. 2-bromomethyl-1,3-dioxolane (19.71 g) and tetra-n-butylammonium iodide (2 g) were added, and the resulting mixture was heated at reflux temperature for 4 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine. The organic solvents were removed under reduced pressure to give a brown oil which was chromatographed on silica using 80:20, by volume, ethyl acetate:hexane as eluent to give the product as an orange liquid oil. The product was then dissolved in methanol, cooled in ice and a precipitate formed which was filtered, washed with methanol and dried under reduced pressure to give the title compound (15.8 g) as a white solid.

1H-NMR (CDCl3): δ = 7.40-7.50 (2H, m), 7.20-7.25 (1H, dd), 4.95 (1H, dd), 3.82-4, 05 (5H, m), 2.30-2.40 (1H, m), 2.05-2.15 (1H, m) ppm.

Preparation 2

Methyl 4-cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl)pentanoate

[image]

The compound of preparation 1 (0.5 g) and methyl acrylate (1.77 ml) were dissolved in methanol (15 ml) and a 5 wt.% solution of sodium methoxide in methanol (1.05 ml) was added. The mixture was heated at 40-50 °C for 8 hours before the next addition of a 5 wt% solution of sodium methoxide in methanol (0.5 ml). The heating at 40 - 50 °C was extended for the next 15 hours, an additional amount of methyl acrylate (1.77 ml) was added, and the heating was continued for the next 4 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water twice. The organic layer was separated and dried over anhydrous magnesium sulfate before removing the solvent under reduced pressure to give an oil which crystallized on standing. The solid product was triturated with diethyl ether, filtered and dried to give the title compound as a white solid.

1H-NMR (CDCl3): δ = 7.53 (1H, s), 7.48 (1H, d), 7.30 (1H, dd), 4.80 (1H, dd), 3.75-4 .00 (4H, m), 3.65 (3H, s), 2.40-2.60 (2H, m), 2.05-2.34 (4H, m) ppm.

Preparation 3

5-(3,4-dichlorophenyl)-5-(1,3-dioxan-2-ylmethyl)-2(1H)-piperidinone

[image]

The compound of preparation 2 (3.91 g) was dissolved in glacial acetic acid (60 ml), and platinum (II) oxide (0.35 g) was added. The mixture was hydrogenated for 18 hours at 414 kPa (60 psi). The mixture was filtered through a short column of Arbacel™ filters, and the filtrate was concentrated under reduced pressure to a thick oil. It was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the solvent was removed under reduced pressure until a white precipitate began to form. The precipitate was filtered and dried overnight under reduced pressure to give the title compound (3.01 g) as a white solid.

1H-NMR (CDCl3): δ = 7.41 (2H, m), 7.19 (1H, dd), 6.2 (1H, s), 4.35 (1H, dd), 3.80-3 .95 (4H, m), 3.65-3.75 (2H, m), 3.49 (1H, d), 2.35-2.42 (1H, m), 2.05-2.20 (3H, m), 1.85-1.92 (1H, m) ppm.

LRMS: m/z = 330 (m)+.

Preparation 4

3-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-ylmethyl)piperidine

[image]

The compound of preparation 3 (12 g) was added in parts to a solution of lithium aluminum hydride in anhydrous tetrahydrofuran (76 ml of a 1M solution in tetrahydrofuran), and the mixture was stirred for 18 hours at room temperature and in a nitrogen atmosphere. Water (2.88 ml) was carefully added over 20 minutes, the mixture was stirred for the next 15 minutes, then 2N aqueous sodium hydroxide solution (2.88 ml) was added, followed by water (8.6 ml). The mixture was stirred for 1 hour and partitioned between diethyl ether and saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica, eluting with a solvent gradient of 95:5 to 90:10, by volume, dichloromethane:methanol, to give the title product (8 g) as a yellow oil.

1H-NMR (CDCl3): δ = 7.48 (1H, s), 7.39 (1H, d), 7.22 (1H, dd), 4.35 (1H, t), 3.86 (2H , m), 3.68 (2H, m), 3.30 (1H, d), 2.96 (1H, d), 2.79 (2H, m), 2.10 (1H, m), 1 .95 (2H, m), 1.80-1.85 (1H, m), 1.40-1.65 (2H, m) ppm.

LRMS: m/z = 316 (m)+.

Preparation 5

3-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-ylmethyl)-1-phenylacetylpiperidin

[image]

The compound of preparation 4 (0.75 g) and triethylamine (0.49 ml) were dissolved in dichloromethane (20 ml), the solution was cooled in an ice bath, and phenacetyl chloride (0.38 ml) was added dropwise. The mixture was stirred for 1.5 hours at room temperature and dichloromethane (25 ml) was added. The solution was washed with water, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica, washed with 2% by volume methanol in dichloromethane, to give the title compound as a colorless oil.

1H-NMR (CDCl3): δ = 7.49 (1H, s), 7.25-7.39 (2H, m), 7.10-7.15 (3H, m), 7.02 (2H, m), 4.83 (1H, d), 4.40 (1H, t), 3.80-3.95 (2H, m), 3.65-3.70 (4H, m), 3.58 (1H, m), 3.00-3.16 (2H, m), 2.15 (1H, m), 1.60-1.85 (3H, m), 1.39 (1H, m), 1.10 (1H, m) ppm.

LRMS: m.z = 434 (m)+.

Preparation 6

3-(3,4-dichlorophenyl)-3-(formylmethyl)-1-phenylacetylpiperidine

[image]

The compound of preparation 5 (0.75 g) was dissolved in tetrahydrofuran (8 ml), cooled in an ice bath, and a 5N aqueous solution of hydrochloric acid (14 ml) was carefully added. The resulting mixture was stirred for 18 hours at room temperature, then the solvent was removed under reduced pressure to obtain a residue. The residue was dissolved in dichloromethane, washed with water, and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.66 g) as a pale yellow oil.

1H-NMR (CDCl3): δ = 9.45 (1H, s), 7.10-7.49 (8H, m), 4.23 (1H, d), 3.60-3.38 (3H, m), 3.30-3.50 (2H, m), 2.50-2.66 (2H, q), 2.15 (1H, m), 1.90 (1H, m), 1.40 (1H, m), 1.30 (1H, m) ppm.

LRMS: m/z = 390 (m)+.

Preparation 7

3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)-1-phenylacetylpiperidine

[image]

Sodium borohydrate (0.097 g) was added to a solution of the compound of preparation 6 (0.66 g) in ethanol (15 mmol), and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was acidified to pH 1 by adding 2N aqueous hydrochloric acid and then alkalized to pH 7 by adding solid sodium carbonate. The organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica with 2.5 vol% methanol in dichloromethane to give the title compound (0.4 g) as a colorless oil.

1H-NMR (CDCl3): δ = 7.05-7.43 (8H, m), 4.27 (1H, d), 3.30-3.82 (7H, m), 2.01 (1H, m), 1.63-1.89 (4H, m), 1.40 (1H, m), 1.20 (1H, m) ppm.

LRMS: m/z = 392 (m)+.

Preparation 8

3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)-1-phenylacetylpiperidine

[image]

The compound of preparation 7 (0.4 g) and triethylamine (0.18 ml) were dissolved in dichloromethane (10 ml), cooled in an ice bath, and methanesulfonyl chloride (0.09 ml) was added. The mixture was stirred for 1 hour at room temperature, dichloromethane (10 ml) was added and the mixture was washed twice with water. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile, and the solvent was removed again under reduced pressure to give the title compound (0.47 g) as an oil.

1H-NMR (CDCl3): δ = 7.05-7.43 (8H, m), 4.30 (1H, d), 4.00 (1H, m), 3.90 (1H, m), 3 .70 (2H, m), 3.30-3.50 (3H, m), 2.91 (3H, s), 2.09 (1H, m), 2.00 (2H, m), 1, 80 (1H, m), 1.42 (1H, m), 1.21 (1H, m) ppm.

Preparation 9

4-(3,4-dichlorophenyl)-4-(2-hydroxyethyl)-2(1H)-pyrrolidinone

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4-(3,4-dichlorophenyl)-4-ethoxycarbonylmethyl-2(1H)-pyrrolidinone (4.8 g) (see WO 94/26735) was dissolved in anhydrous tetrahydrofuran (50 ml) and added over 30 minutes to a suspension of lithium aluminum hydride (0.6 g) in anhydrous tetrahydrofuran (10 ml) under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature, the next amount of lithium aluminum hydride (0.3 g) was added, and stirring was continued for the next 2.5 hours. Water (1.1 ml), then 2N aqueous sodium hydroxide solution (1.1 ml), then water (2.2 ml) and tetrahydrofuran (100 ml) were carefully added. The mixture was stirred for 30 minutes, and the resulting suspension was filtered through a short column of Arbacel™ filter aid. The filtrate was collected and the solvent was removed under reduced pressure to give a residue which was dissolved in dichloromethane and the solvent was again removed under reduced pressure. The crude product was chromatographed on silica, eluted with a solvent gradient from 96:4 to 90:10, by volume, dichloromethane:methanol, to give the title compound (3.15 g) as a resin.

1H-NMR (CDCl3): δ = 7.42 (1H, d), 7.29 (1H, s), 7.03 (1H, d), 6.04 (1H, s), 3.74 (1H , d), 3.63 (1H, d), 3.45-3.60 (2H, m), 2.71 (2H, s), 2.03-2.12 (2H, m), 1, 57 (1H, t) ppm.

Preparation 10

3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine hydrochloride

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A solution of diborane (1M solution in tetrahydrofuran; 300 ml) was added to the compound of Preparation 9 (2.5 g) and the mixture was heated for 18 hours at reflux temperature under a nitrogen atmosphere. The solution was cooled and carefully added to a 6N aqueous solution of hydrochloric acid (60 ml) previously cooled in an ice bath. The mixture was stirred for 10 minutes at 0 °C, and the pH was adjusted to pH 14 by careful addition of sodium hydroxide beads. Water (50 ml) was added and the phases were separated. The precipitate appeared in the lower aqueous phase. The organic layer was separated by decantation, and the aqueous layer was extracted with tetrahydrofuran. The organic phases were combined and the solvent was removed under reduced pressure. The crude product was dissolved in diethyl ether and filtered. Diethyl ether, saturated with hydrogen chloride gas, was added to the filtrate and a cloudy solution was formed. The solution was extracted twice with water (30 ml, 10 ml), the aqueous extracts were combined, and the water was removed under reduced pressure. The product was dried under reduced pressure in the presence of phosphorus pentoxide to give the title compound (2.2 g) as a white foam.

1H-NMR (d6-DMSO): δ = 7.63 (1H, d), 7.58 (1H, s), 7.33 (1H, d), 3.00-3.50 (6H, m) , 2.26 (2H, m), 1.89 (2H, m) ppm.

Preparation 11

3,4,5-trimethoxybenzoyl chloride

3,4,5-trimethoxybenzoic acid (15 g) was suspended in dichloromethane (150 ml), then oxalyl chloride (13.5 g) was added, followed by catalytic dimethylformamide (3 drops). The mixture was stirred for 2.5 hours at room temperature, then dimethylformamide (2 drops) was added again and stirring was continued for another hour. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane and the solvent was removed under reduced pressure to give 3,4,5-trimethoxybenzoyl chloride (16.4 g) as a white solid.

Preparation 12

3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidine

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The compound of preparation 10 (2.2 g) and triethylamine (4 g) were dissolved in dichloromethane (60 ml), the solution was cooled in an ice bath, and a solution of 3,4,5-trimethoxybenzoyl chloride (4.8 g) was added (see preparation 11) in dichloromethane (40 ml). The mixture was stirred for 15 minutes at 0 °C and then for 30 minutes at room temperature before the addition of dichloromethane (100 ml). The solution was washed successively with water (2 × 50 ml) and saline (50 ml). The solvent was removed from the organic layer under reduced pressure. The resulting residue was dissolved in ethanol (100 ml), a 2N aqueous solution of sodium hydroxide (15 ml) was added, and the mixture was stirred for 1 hour at room temperature.

Ethanol was removed under reduced pressure to give a residue which was dissolved in dichloromethane and washed, respectively, with water, 1N aqueous sodium hydroxide solution and brine. The organic layers were collected and the solvent was removed under reduced pressure. The crude product was chromatographed on silica, washed with 98:2:0.1, by volume, dichloromethane : methanol : 0.88 aqueous ammonia solution, to give the title compound (2.53 g) as a white foam.

1H-NMR (CDCl3): δ = 7.00-7.50 (3H, m), 6.71 (2H, d), 3.30-4.10 (16H, m), 1.85-2, 35 (4H, m) ppm.

Preparation 13

3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidine

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The compound of preparation 12 (0.6 g) and triethylamine (0.17 g) were dissolved in dichloromethane (10 ml), cooled in an ice bath, and methanesulfonyl chloride (0.16 g) was added. The mixture was stirred for 100 minutes, dichloromethane (20 ml) was added, and the solution was washed successively with water (× 2) and brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile and the solvent was removed under reduced pressure to give the title compound (0.74 g) as an oil.

1H-NMR (CDCl3): δ = 6.99-7.50 (3H, m), 6.72 (2H, d), 3.42-4.07 (15H, m), 2.83 (1, 5H, s), 2.94 (1.5H, s), 2.06-2.40 (4H, m) ppm.

Preparation 14

3-(3,4-dichlorophenyl)-4-(N-methylphenylacetamido)butan-1-ol

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3-(3,4-dichlorophenyl)-4-(N-methylamino)butan-1-ol (2 g) (see EP-A-0474561) and triethylamine (0.9 g) were dissolved in dichloromethane (20 ml) , the solution was cooled in an ice bath, and a solution of phenylacetyl chloride (1.25 g) in dichloromethane (5 ml) was added dropwise over 10 minutes. The mixture was stirred at room temperature for 90 minutes, then dichloromethane (25 ml) was added. The solution was washed sequentially with 2N aqueous hydrochloric acid (20 ml) and brine (20 ml). The dichloromethane was removed under reduced pressure and the crude product was chromatographed on silica, eluted with 98:2:0.1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution, to give the title compound (1.35 g ) in the form of resin.

1H-NMR (CDCl3): δ = 7.21-7.33 (5H, m), 7.09 (2H, d), 6.99 (1H, dd), 3.79 (1H, dd), 3 .62 (2H, s), 3.38-3.53 (3H, m), 3.15 (1H, m), 2.72 (3H, s), 1.60-1.90 (3H, m ) ppm.

Preparation 15

3-(3,4-dichlorophenyl)-4-(N-methyl-3,5-dimethylbenzamido)butan-1-ol

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3-(3,4-dichlorophenyl)-4-(N-methylamino)butan-1-ol (see EP-A-0474561) (0.75g) and triethylamine (1.2g) were dissolved in dichloromethane (20 ml ), the solution was cooled in an ice bath and a solution of 3,5-dimethylbenzoyl chloride (1.5 g) was added dropwise. The mixture was stirred for 18 hours at room temperature, then dichloromethane (50 ml) was added. The solution was washed with water (3 x 50 ml) and the solvent was removed under reduced pressure. The resulting residue was dissolved in methanol (25 ml), a 2N aqueous solution of sodium hydroxide (6 ml) was added, and the mixture was stirred for 18 hours at room temperature. The methanol was removed under reduced pressure, water (20 ml) was added, and the solution was extracted with dichloromethane (2x25 ml). The organic phases were combined and the solvent was removed under reduced pressure. The crude product was chromatographed on silica, eluted with 3.4 volume % methanol in dichloromethane, to give the title compound (0.68 g) as a foam.

1H-NMR (CDCl3): δ = 6.7-7.45 (6H, m), 2.60-4.00 (8H, m), 2.31 (6H, s), 1.75-2.09 ( 2H, m) ppm.

Preparation 16

3-(3,4-dichloromethyl)-1-methanesulfonyloxy-4-(N-methylphenylacetamido)butane

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Compound 14 (1.35 g) and tertylamine (0.56 g) were dissolved in dichloromethane (15 ml), cooled in an ice bath, and methanesulfonyl chloride (0.50 g) was added. The mixture was stirred for 30 minutes, dichloromethane (35 ml) was added, and the solution was washed successively with water (2 x 30 ml) and brine (30 ml). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile and the solvent was removed under reduced pressure to give the title compound (1.75 g) as an oil.

1H-NMR (CDCl3): δ = 7.15-7.35 (5H, m), 7.09 (2H, d), 7.01 (1H, dd), 4.15 (1H, m), 3 .96 (1H, m), 3.72 (1H, dd), 3.62 (2H, s), 3.54 (1H, m), 3.14 (1H, m), 2.93 (3H, s), 2.77 (3H, s), 2.12 (1H, m), 1.95 (1H, m) ppm.

Preparation 17

3-(3,4-dichlorophenyl)-1-methanesulfonyloxy-4-(N-methyl-3,5-dimethylbenzamido)butane

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The title compound was prepared in an analogous manner to the compound of preparation 16 using the compound of preparation 15 as starting material.

1H-NMR (CDCl3): δ = 7.05-7.46 (3H, m), 7.00 (1H, s), 6.73 (2H, s), 3.80-4.30 (3H, m), 3.05-3.65 (3H, m), 2.94 (3H, s), 2.71 (2H, s), 2.20-2.38 (7H, m), 2.05 (1H, m) ppm.

Preparation 18

3(S)-(3,4-dichlorophenyl)-4-(N-methyl-3,5-bis(trifluoromethyl)phenylacetamido)butan-1-ol

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3(S)-(3,4-dichlorophenyl)-4-(N-methylamino)butan-1-ol (2.5 g) (see EP-A-0474561) and tertylamine (6 g) were dissolved in dichloromethane ( 50 ml), the solution was cooled in an ice bath, and a solution of 3,5-bis(trifluoromeryl)-phenylacetyl chloride (9.2 g) in dichloromethane (20 ml) was added dropwise over 15 minutes. The mixture was stirred for 1 hour at room temperature, then dichloromethane (100 ml) was added. The solution was washed sequentially with water (50 ml), 2N aqueous hydrochloric acid (2 x 50 ml) and water (50 ml) before removing the dichloromethane under reduced pressure. The obtained residue was dissolved in ethanol (75 ml), 2N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred for 18 hours at room temperature. Ethanol was removed under reduced pressure, water (50 ml) was added, and the solution was extracted with dichloromethane (2 x 50 ml). The organic phases were combined and the solvent was removed under reduced pressure. The crude product was chromatographed on silica, eluting with 96:4:0.25, by volume, dichloromethane: methanol: 0.88 aqueous ammonia solution, to give the title compound (4.3 g) as a yellow resin.

1H-NMR (CDCl3): δ = 7.25-7.78 (5H, m), 7.03 (1H, d), 3.89 (1H, dd), 3.33-3.71 (5H, m), 3.20 (1H, m), 2.88 (0.5H, s), 2.84 (2.5H, s), 1.70-1.90 (2H, m), 1.57 (1H, m) ppm (mixture of amide rotamers 1:5).

LRMS: m/z = 502 (m)+.

Preparation 19

3(S)-(3,4-dichlorophenyl)-1-methanesulfonyloxy-4-(N-methyl-3,5-bis(trifluoromethyl)phenylacetamido)butane

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The compound of preparation 18 (2.2 g) and triethylamine (0.65 g) was dissolved in dichloromethane (20 ml), cooled in an ice bath, and methanesulfonyl chloride (0.55 g) was added. The mixture was stirred for 30 minutes, dichloromethane (50 ml) was added, and the solution was washed successively with water (× 3) and brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile and the solvent was removed under reduced pressure to give the title compound (2.5 g) as an oil.

1H-NMR (CDCl3): δ = 7.79 (1H, s), 7.67 (2H, s), 7.39 (1H, d), 7.29 (1H, d), 7.06 (1H , dd), 4.18 (1H, m), 3.99 (1H, m), 3.87 (1H, dd), 3.71 (2H, s), 3.41 (1H, m), 3 .19 (1H, m), 2.93 (3H, s), 2.89 (3H, s), 2.12 (1H, m), 1.95 (1H, m) ppm.

Preparation 20

4-cyclohexylquinuclidine

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4-phenylquinuclidine (5 g, see J. Org. Chem., 1957, 22, 1484) was dissolved in glacial acetic acid (25 ml), 5% rhodium on aluminum oxide (2 g) was added, and the mixture was hydrogenated for 5 days at 345 kPa. The mixture was filtered through a short column of Arbacel™ filter aid, and the residue was washed with methanol. The filtrate was collected and the solvent was removed under reduced pressure. The obtained residue was dissolved in water, and the pH was adjusted to >10 by adding 0.88 aqueous ammonia solution. The aqueous mixture was extracted with ethyl acetate (×3), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4-cyclohexyquiniclidine (4.7 g) as pale pink solid.

1H-NMR (CDCl3): δ = 2.75-2.86 (6H, m), 1.60-1.85 (5H, m), 1.06-1.45 (9H, m), 180- 1.98 (3H, m) ppm.

Preparation 21

3(S)-(3,4-dichlorophenyl)-4-(N-methyl-3,5-bis[trifluoromethyl]-benzamido)butan-1-ol

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(3S)-3-(3,4-dichlorophenyl)-4-(N-methylamino)butan-1-ol (0.7 g) (see EP-A-0474561) and triethylamine (1.1 g) were dissolved in dichloromethane (20 ml), the solution was cooled in an ice bath, and a solution of 3,5-bis(trifluoromethyl)-benzoyl chloride was added dropwise. The mixture was stirred for 18 hours at room temperature and dichloromethane (30 ml) was added. The solution was washed with water (3 × 50 ml) and the solvent was removed under reduced pressure. The resulting residue was dissolved in methanol (30 ml), 2N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was heated on a steam bath for 30 minutes. Methanol was removed under reduced pressure, water (20 ml) was added, and the solution was extracted with diethyl ether (50 ml). The organic phase was collected and washed with 2N aqueous sodium hydroxide solution (2 x 20 ml). The organic phase was collected and the solvent was removed under reduced pressure to give a residue which was dissolved in dichloromethane and the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel, washed with 2.5 volume % methanol in dichloromethane, to obtain the title compound as a foam.

1H-NMR (CDCl3): δ = 7.88 (1H, s), 7.59 (2H, s), 7.35-7.45 (2H, m), 7.19 (1H, m), 3 .00-3.95 (5H, m), 2.71 (3H, s), 1.80-2.05 (2H, m), 1.61 (1H, s) ppm.

Preparation 22

3(S)-(3,4-dichlorophenyl)-1-methanesulfonyloxy-4-(N-methyl-3,5-bis[trifluoromethyl]benzamido)butane

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The title compound was prepared in an analogous manner to the compound of preparation 19, using the compound of preparation 21 as starting material.

1H-NMR (CDCl3): δ = 7.90 (1H, s), 7.61 (2H, s), 7.35-7.48 (2H, m), 7.19 (1H, m), 4 .26 (1H, m), 3.60-4.10 (3H, m), 3.37 (1H, m), 2.95 (3H, s), 2.78 (3H, s), 2, 25 (1H, m), 2.05 (1H, m) ppm.

Preparation 23

3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)-1-(3,5-dimethylbenzoyl)pyrrolidine

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The title compound was prepared in an analogous manner to the compound of preparation 12, using the compound of preparation 10 and 3,5-dimerylbenzoyl as starting materials.

1H-NMR (CDCl 3 ): δ = 6.95-7.50 (6H, m), 3.30-4.05 (7H, m), 1.83-2.40 (10H, m) ppm.

Preparation 24

3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)-1-(3,5-dimethylbenzoyl)pyrrolidine

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The title compound was prepared in an analogous manner to the compound of preparation 13, using the compound of preparation 23 as starting material.

1H-NMR (CDCl3): δ = 6.99-7.50 (6H, m), 3.37-4.06 (6H, m), 2.92 (1.5H, s), 2.80 ( 1.5H, s), 2.05-2.40 (10H, m) ppm.

Preparation 25

1-benzyl-4-carbamoyl-4-phenylpiperidine

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1-Benzyl-4-cyano-4-phenylpiperidine hydrochloride (10 g) was carefully added to concentrated sulfuric acid (50 ml) (cooled in an ice bath) over 15 minutes, and the resulting solution was allowed to stand at room temperature for 20 hours. The solution was poured into ice (200 g) and the aqueous mixture was washed (pH >10) by adding 0.880 aqueous ammonia solution and then extracted with ethyl acetate (3 x 100 ml).

The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel, eluted with 5:95, by volume, methanol : ethyl acetate, to give the title compound (8 ,6 g) in the form of oil.

1H-NMR (CDCl3): δ = 7.20-7.42 (10H, m), 5.15 (2H, s), 3.48 (2H, s), 2.35-2.65 (6H, m), 2.05-2.15 (2H, m) ppm.

LRMS m/z = 295 (M+1)+.

Preparation 26

1-benzyl-4-methoxycarbonyl-4-phenylpiperidine

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The compound of preparation 25 (7 g) was dissolved in methanol (150 ml) and the solution was saturated with hydrogen chloride gas. The mixture was left to stand for 7 hours at room temperature. Methanol (150 ml) was then added and a continuous stream of hydrogen chloride gas was blown through the solution while it was heated at reflux temperature for the next 3 hours. The mixture was cooled and allowed to stand for 16 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in water, washed (pH >10) by adding solid sodium carbonate and extracted with ethyl acetate (× 3). The organic phases were combined and the solvent was removed under reduced pressure to give the crude product which was chromatographed on silica gel, eluting with ethyl acetate to give the title compound (2.9 g) as a white solid.

1H-NMR (CDCl3): δ = 7.19-7.40 (10H, m), 3.63 (3H, s), 3.47 (2H, s), 2.80 (2H, m), 2 .55 (2H, m), 2.20 (2H, m), 2.00 (2H, m) ppm.

Preparation 27

1-benzyl-4-dihydromethyl-4-phenylpiperidine

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The compound of preparation 26 (2.7 g) was dissolved in anhydrous diethyl ether (50 ml) and lithium aluminum hydride (0.33 g) was added in 4 portions over 2 minutes. The mixture was stirred for 30 minutes at room temperature, water (0.4 ml) was carefully added, then 2N aqueous sodium hydroxide solution (0.4 ml), then water again (0.8 ml). The mixture was stirred and the resulting granular precipitate was removed by filtration. The solvent was removed from the filtrate under reduced pressure to give a solid which was dissolved in dichloromethane, dried over anhydrous sodium sulfate and the solvent was removed again under reduced pressure to give the title compound (2.4 g) as a white solid .

1H-NMR (CDCl3): δ = 7.20-7.40 (10H, m), 3.60 (2H, d), 3.42 (2H, s), 2.60 (2H, m), 2 .10-2.32 (4H, m), 1.90-2.00 (2H, m) ppm.

Preparation 28

1-benzyl-4-phenyl-1-azoniabicyclo[2,2,1]heptane-4-methylphenylsulfonate

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The compound of preparation 27 (2.3 g) was dissolved in pyridine (20 ml) and cooled in an ice bath before the addition of 4-methylphenyl sulfonyl chloride (1.7 g). The mixture was allowed to stand at 0 °C for 16 h before removing the solvent under reduced pressure. The residue was suspended in 10% aqueous sodium carbonate solution (40 ml) and extracted with toluene (3 x 50 ml). The combined organic phases were stirred for 10 minutes with anhydrous potassium carbonate and filtered. The filtrate was collected and the volume reduced to about 40 ml by evaporation under reduced pressure. The solution was then heated for 7 hours at 90 °C, allowed to stand at room temperature for 16 hours, and the precipitate obtained was filtered. The precipitate was washed with diethyl ether and dried to give the title compound (2.75 g) as a white solid.

1H-NMR (CDCl3): δ = 7.84 (2H, d), 7.60 (2H, d), 7.10-7.40 (10H, m), 5.11 (2H, s), 4 .05-4.15 (2H, m), 3.92 (2H, s), 3.60-3.70 (2H, m), 2.30-2.42 (5H, m), 2.05 -2.15 (2H, m) ppm.

Preparation 29

4-phenyl-1-azabicyclo[2,2,1]heptane

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The compound of preparation 28 (2.7 g) was dissolved in methanol (20 ml). 10 wt.% palladium on carbon (0.3 g) was added and the mixture was hydrogenated for 18 hours at 207 kPa (30 psi). The following amount of 10 wt.% palladium on carbon (0.2 g) was added, and the mixture was hydrogenated for the next 14 hours. The mixture was then filtered through a short column of filter aid (Arbacel™). The solvent was removed from the filtrate under reduced pressure to give a residue which was dissolved in diethyl ether. The solvent was again removed under reduced pressure. The residue was dissolved in diethyl ether (50 ml), washed with 1N aqueous sodium hydroxide solution (25 ml), and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, the solvent removed under reduced pressure, the residue dissolved in ethyl acetate, and the solvent removed again under reduced pressure to give the title compound (0.91 g) as a white solid.

1H-NMR (CDCl3): δ = 7.18-7.38 (5H, m), 3.05-3.18 (2H, m), 2.68-2.00 (4H, m), 1, 80-1.90 (2H, m), 1.60-1.70 (2H, m) ppm.

LRMS m/z = 174 (m+1)+.

Preparation 30

4-cyclohexyl-1-azabicyclo[2,2,1]heptane

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4-phenyl-1-azabicyclo[2,2,1]heptane (0.62 g) (see preparation 29) was dissolved in glacial acetic acid, 5 wt.% rhodium on aluminum oxide (0.1 g) was added, and is a mixture hydrogenated for 7 days at 345 kPa (50 psi). 5 wt.% rhodium on alumina (0.05 g) was added, and the mixture was hydrogenated at 345 kPa (50 psi) for the next 2 days. The mixture was filtered through a short column of filter aid (Arbacel™), and the residue was washed with methanol. The filtrate was collected and the solvent was removed under reduced pressure to give a residue. It was dissolved in water and the pH was adjusted to >10 by adding 0.88 aqueous ammonia solution. The aqueous mixture was extracted with ethyl acetate (× 3), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to give 4-cyclohexyl-1-azabicyclo[2,2,1]heptane. (0.57 g) as an oil.

1H-NMR (CDCl3): δ = 2.82-2.98 (2H, m), 2.50-2.68 (2H, m), 2.23 (2H, s), 1.02-1, 80 (15H, m) ppm.

Preparation 31

(4S)-4-cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl)pentan-1-oic acid

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To a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.69 L) at 5 °C, under a nitrogen atmosphere, a solution of 3,4-dichlorophenylacetonitrile (750 g) in tetrahydrofuran (750 ml) was added dropwise over 45 minutes. The reaction mixture was stirred for 2 hours, cooled again to 5 °C, and a solution of 2-bromomethyl-1,3-dioxolane (782 g) in tetrahydrofuran (780 ml) was added dropwise over 50 minutes. Tetra-n-butylammonium iodide (75 g) was then added in portions, and the mixture was allowed to warm to room temperature, and then stirred for 14 hours. The reaction mixture was then cooled to 5 °C, and a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.89 l) was added dropwise. The reaction mixture was stirred for 5 hours at room temperature. The solution was then cooled to 5 °C and a solution of ethyl 3-bromopropanoate (840.5 g) in tetrahydrofuran was added dropwise over 50 minutes. The reaction mixture was stirred for 14 hours. The reaction mixture was cooled to 5 °C and 1.5 M aqueous sodium hydroxide solution was added (enough to contain 225 g of sodium hydroxide) and the mixture was stirred for 14 hours. Water (5 L) was added and the mixture was extracted with ethyl acetate (2 x 3 L). The combined organic extracts were washed with water (2 × 3 l). The aqueous phases were combined, acidified to pH 1 using 5N aqueous hydrochloric acid, and then extracted with ethyl acetate (2 × 3 l). The combined organic extracts were concentrated under reduced pressure to a concentration of approximately 3 l/g based on the theoretical yield of the product. The described experimental procedure was repeated once more in an identical volume.

(S)-(-)-α-methyl-benzylamine (1.13 kg) was added to the combined organic solutions of both reactions, and the mixture was stirred for 14 hours. The thick suspension was then stirred with cooling in an ice bath for 2 hours, filtered, the solid washed with ethyl acetate (2 x 1 l) and dried under reduced pressure at 35 °C to obtain 1.85 kg of material. Part of this material (1.34 kg) was dissolved in a mixture of 2-butanone (2 l) and water (503 ml) and heated to reflux temperature. The next amount of 2-butanone (4.7 L) was added and the solution was allowed to cool slightly to room temperature overnight. The obtained solid material was filtered, washed with 2-butanone (2 × 1 l) and dried under reduced pressure at 35 °C for 10 hours, to obtain 563 g of material (93.8% e.e. according to HPLC analysis).

Subsequent recrystallization from 2-butanone/water gave (S)-(-)-α-methylbenzylamine salt (4S)-4-cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolane-2 -yl)pentan-1-oic acid at 99.8% e.e. A 5N aqueous solution of hydrochloric acid was added to a mixed solution of this salt in ethyl acetate and water until pH 1 was reached. The mixture was stirred for 30 minutes, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, and the solvent was removed under reduced pressure to give (4S)-4-cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl) pentan-1-oic acid.

1H-NMR (CDCl3): δ = 9.90 (1H, no.s), 7.25-7.55 (3H, m), 4.75-4.85 (1H, m), 3.70- 4.00 (4H, m), 2.40-2.65 (2H, m), 2.05-2.35 (4H, m) ppm.

Preparation 32

(5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2(1H)-piperidinone

[image]

Solutions of (4S)-4-cyano-4-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl)pentan-1-oic acid (13.5 g) (see preparation 31) in platinum oxide (1.21 g) was added to glacial acetic acid (130 ml), and the mixture was hydrogenated at 414 kPa (60 psi) at room temperature for 17 hours. The catalyst was removed by filtration and the next portion of platinum oxide (1.21 g) was added. The mixture was then hydrogenated for the next 48 hours at 414 kPa (60 psi) at room temperature. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (80 ml) and washed with saturated aqueous sodium bicarbonate (2 x 75 ml). The organic phase was separated, and the solvent was removed under reduced pressure. The resulting solid was stirred in a solution of hexane (20 ml) and ethyl acetate (20 ml) for 2 hours at 0 °C and then filtered to give the title compound (8.15 g) as a white solid.

1H-NMR (CDCl3): δ = 7.20-7.45 (3H, m), 6.15 (1H, no.s), 4.35-4.40 (1H, m), 3.80- 3.90 (3H, m), 3.65-3.77 (2H, m), 3.45-3.55 (1H, m), 2.35-2.40 (1H, m), 2, 00-2.25 (4H, m), 1.85-1.95 (1H, m) ppm.

Preparation 33

(3S)-3-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-ylmethyl)piperidine

[image]

The title compound was prepared by a similar procedure to that of preparation 4 using the compound of preparation 32 as starting material.

1H-NMR: Identical to that of compound preparation 4.

Preparation 34

(3S)-3-(3,4-dichlorophenyl)-3-(1,3-dixolan-2-ylmethyl)-1-phenylacetylpiperidin

[image]

The title compound was prepared by an analogous procedure to the compound of preparation 5, using the compound of preparation 32 as starting material.

1H-NMR: Identical to that of compound preparation 5.

Preparation 35

(3S)-1-(3,5-bis[trifluoromethyl]phenylacetyl)-3-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-ylmethyl)piperidine

[image]

The compound of preparation 33 (1.42 g), 3,5-bis(trifluoromethyl)phenylacetic acid (1.11 g) and 4-methylmorpholine N-oxide (1.34 ml) were dissolved in dichloromethane (15 ml), so 1-hydroxybezotriazole monohydrate (0.62 g) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.86 g). The mixture was stirred at room temperature for 18 hours, after which the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed successively with 2N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The organic phases were separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel, eluting with 2 volume % methanol in dichloromethane, to obtain the title compound (2.07 g) as a colorless oil.

1H-NMR (CDCl3): δ = 7.75 (2H, m), 7.61 (2H, s), 7.50 (1H, s), 7.32 (1H, m), 4.80 (1H , d), 4.35 (1H, m), 3.50-3.90 (7H, m), 3.10-3.30 (2H, m), 2.29 (1H, m), 1, 80-2.10 (3H, m), 1.61 (1H, m) 1.40 (1H, m) ppm.

LRMS m/z = 570 (m)+.

Preparations 36 - 37

The compounds of the following examples given in Table 4 have the general formula:

[image]

The compounds were prepared by a similar procedure to that of preparation 6, using the appropriate 1,3-dioxolanyl protected starting materials.

Table 4

[image]

Preparations 38 - 39

The compounds of the following examples given in table 5 have the general formula:

[image]

The compounds were prepared in a manner similar to that of preparation compound 7, using the appropriate aldehyde starting materials.

Table 5

[image]

Preparations 40 - 41

The compounds of the following examples given in Table 6 have the general formula:

[image]

The compounds were prepared by a similar procedure to compound 8, using the appropriate alcoholic starting materials.

Table 6

[image]

Preparation 42

1,2,3,4-tetrahydronaphth-5-oyl chloride

[image]

1,2,3,4-tetrahydronaphth-5-alynecarboxylic acid (1.4 g) (see Org. Prep. & Proc. Int., 1973, 285) was suspended in anhydrous dichloromethane (10 ml) and oxalyl was added chloride (1.6 g) and then dimethylformamide (1 drop). The mixture was stirred for 1 hour at room temperature before removing the solvent under reduced pressure. The resulting residue was dissolved in dichloromethane, and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane and the solvent was removed under reduced pressure to give the title compound as an oil (1.5 g).

Preparations 43 - 49

The compounds of the following examples given in Table 7 have the general formula:

[image]

The compounds were prepared by a procedure similar to that of preparation 15 using either (R/S)- or (S)-3-(3,4-dichlorophenyl)-4-(N-methylamino)butan-1-ol and the appropriate chloroanhydride starting materials.

Table 7

[image]

Preparations 50 - 56

The compounds of the following examples given in Table 8 have the general formula:

[image]

The compounds were prepared by a similar procedure to compound 19, using the appropriate alcoholic starting material.

Table 8

[image]

Preparation 57

2,3-Dihydrobenzo[b]furan-7-carboxylic acid

[image]

N,N,N',N'-tetramethylethylenediamine (38 ml) was dissolved in hexane (300 ml), cooled in an ice bath, and n-butyllithium (100 ml of a 2.5M solution in hexane) was added. The mixture was stirred for 15 minutes at 0 °C, after which 2,3-dihydrobenzo[b]furan (30 g) was added dropwise over 30 minutes. The mixture was allowed to warm to room temperature for 30 minutes, stirred at room temperature for 4 hours, poured onto an excess of solid carbon dioxide and allowed to stand for 3 days, during which time the solvent evaporated. The residue was partitioned between ethyl acetate (1 l) and 4N aqueous hydrochloric acid solution (240 ml), the layers were separated and the aqueous layer was extracted with ethyl acetate (500 ml). The organic extracts were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give 2,3-dihydrobenzo[b]furan-7-carboxylic acid as a white solid (21 g).

1H-NMR (CDCl3): δ = 7.75 (1H, d), 7.31 (1H, d), 6.88 (1H, t), 4.69 (2H, t), 3.20 (2H , t) ppm.

Preparation 58

2,3-dihydrobenzo[b]furan-7-oyl chloride

[image]

The title compound was prepared from 2,3-dihydrobenzo[b]furan-7-carboxylic acid (see preparation 57) according to the procedure described for preparation 11.

Preparation 59

3,5-dimethoxy-4-methylbenzoyl chloride

[image]

The title compound was prepared from 3,5-dimethoxy-4-methylbenzoic acid according to the procedure described for preparation 11.

Preparation 60

3,4,5-triethoxybenzoyl chloride

[image]

The title compound was prepared from 3,4,5-triethoxybenzoic acid according to the procedure described for preparation 11.

Preparation 61

3,5-dimethyl-4-methoxybenzoyl chloride

[image]

The title compound was prepared from 3,5-dimethyl-4-methoxybenzoic acid according to the procedure described for preparation 11.

Preparations 62 - 71

The compounds of the following examples given in Table 9 have the general formula:

[image]

The compounds were prepared in a similar manner to preparation 12, using 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine hydrochloride (see preparation 10) and the corresponding chloroanhydrides as starting materials.

Table 9

[image]

Preparations 72 - 81

The compounds of the following examples given in table 10 have the general formula:

[image]

The compounds were prepared by a procedure similar to that of preparation 13, using the appropriate alcohol as starting material.

Table 10

[image]

COMPARATIVE PHARMACOLOGICAL DATA

Antagonistic action on the NK1 and NK2 receptors of a selection of compounds from the previous examples, compounds from example 1 in EP-A-0591040, racemic mixtures of compounds from examples 4 and 10 from EP-A-0591040 and compounds from example 31 from EP-A-0714891 determined by the procedures described on pages 17 and 18.

The results are shown in Tables A and B. A value of "6.0" represents very weak action. A difference of one. log. of units corresponds to a tenfold difference in action.

Table A

[image] [image]

Table B

[image]

Claims (27)

1. Compound formula: [image] characterized in that R is phenyl, C3-C7 cycloalkyl or heteroalkyl, both of which may be optionally benzo-fused or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused part, with 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4) alkyl, C1-C4 alkoxy, fluoro(C1-C4) alkoxy, C2-C4 alkanoyl, halo, C1-C4 alkoxycarbonyl, C3-C7 cycloalkyl, -S(O)p(C1-C4 alkyl), cyano, -NR7R8, -S(O)pNR7R8, -NR7(C1-C4 alkanoyl) and -CONR7R8, or R is 2,3-dihydrobenzo[b] furanil or chromanil; R 1 and R 2 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent C 2 -C 6 alkylene; R 3 and R 4 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent unbranched C 1 -C 4 alkylene; R5 is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which is substituted with 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4) alkyl, C1-C4 alkoxy, halo and cyano, or R5 is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl. R6 is C3-C7 cycloalkyl optionally substituted with 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, fluoro(C1-C4) alkyl and fluoro(C1-C4) alkoxy; R 7 and R 8 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent C 2 -C 6 alkylene; T is carbonyl; Y is unbranched C2-C4 alkylene; ZA is a pharmaceutically acceptable anion; m is 0 or 1; n is 1 or 2; p is 0, 1 or 2; And "heteroaryl", as used in the definition of R, means thienyl, or a 5- or 6-membered ring heteroaryl group containing either 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatoms and 1 oxygen or sulfur heteroatom, provided that when m is 0, and R is optionally fused and optionally substituted heteroaryl, this aryl is bound by one carbon atom from the ring to T. 2. Compound according to claim 1, characterized in that R is phenyl, optionally benzo- or C3-C7 cycloalkyl-fused, and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused part, with 1 to 3 substituents chosen independently from C1-C4 alkyl, halo, fluoro(C1-C4)alkyl to C1-C4 alkoxy, or R is 2,3-dihydrobenzo[b]furanyl. 3. A compound according to claim 1 or 2, characterized in that R is phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl, each of which is optionally substituted by 1 to 3 substituents independently selected from methyl, fluorine, bromine, trifluoromethyl, methoxy and ethoxy, or R is 2,3-dihydrobenzo[b]furanyl. 4. A compound according to any of the preceding claims, characterized in that R is 3,5-bis(trifluoromethyl)phenyl or 3,5-dimethylphenyl. 5. A compound according to any of the preceding claims, characterized in that R1 and R2 are H. 6. A compound according to any of the preceding claims, characterized in that either R3 is C1-C4 alkyl and R4 is H, or R3 and R4, taken together, represent C2-C3 alkylene. 7. A compound according to any of the preceding claims, characterized in that R3 is methyl and R4 is H, or R3 and R4, taken together, represent 1,2-ethylene or 1,3-propylene. 8. A compound according to any of the preceding claims, characterized in that R5 is phenyl, optionally substituted with 1, 2 or 3 halo substituents. 9. A compound according to any one of the preceding claims, characterized in that R5 is 3,4-dichlorophenyl. 10. A compound according to any of the preceding claims, characterized in that R6 is cyclohexyl substituted with 1 to 3 substituents, each of which is independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, fluoro(C1-C4) alkyl and fluoro(C 1 -C 4 ) alkoxy. 11. A compound according to any of the preceding claims, characterized in that R6 is cyclohexyl. 12. A compound according to any one of the preceding claims, characterized in that Y is 1,2-ethylene. 13. A compound according to any of the preceding claims, characterized in that ZA is chloride or methanesulfonate. 14. A compound according to any one of the preceding claims, characterized in that m is 0. 15. A compound according to any of the preceding claims, characterized in that n is 2. 16. Compound according to claim 1, characterized in that it is selected from the group comprising: (i) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-phenylacetylpiperidin-3-yl]ethyl)quinuclidinium methanesulfonate; (ii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium methanesulfonate; (iii) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methylphenylacetamido]butyl)quinuclidinium chloride; (iv) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-dimethylbenzamido]butyl)quinuclidinium methanesulfonate; (v) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)phenyl-acetoamido]butyl)quinuclidinium chloride; (vi) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium methanesulfonate; (vii) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-1-(3,5-dimethylbenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (viii) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methylnaphthalene-1-carboxyamido]butyl)quinuclidinium methanesulfonate; (ix) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-3,5-dimethylphenylacetamido]butyl)quinuclidinium methanesulfonate; (x) 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[N-methyl-4-fluoro-3-trifluoromethylbenzamido]butyl)quinuclidinium methanesulfonate; (xi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-bis[trifluoromethyl]phenylacetyl)piperidin-3-yl]ethyl)quinuclidinium methanesulfonate; (xii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-bis[trifluoromethyl]benzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (xiii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethylphenylacetyl)pyrrolidin-3-yl]ethyl)quinuclidinium methanesulfonate; (xiv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,4-dimethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (xv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethoxy-4-methylbenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (xvi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(2,3-dihydrobenzo[b]furan-7-carbonyl)pyrrolidin-3-yl]ethyl) quinuclidinium chloride ; (xvii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(2,3-dimethylbenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (xviii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methylnaphthalene-1-actamido]butyl)quinuclidinium methanesulfonate; (xix) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-3,5-dibromobanza-mido]butyl)quinuclidinium methanesulfonate; (xx) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-1,2,3,4-tetrahydronaphthalene-5-carboxamido]butyl)quinuclidinium methanesulfonate; (xxi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoro-methyl)benzamido]butyl)-1-azoniabicyclo[2 ,2,1]heptane methanesulfonate; (xxii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (xxiii) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,4,5-triethoxybenzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (xxiv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(4-fluoro-3-trifluoromethyl-benzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; (xxv) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl)-1-(3,5-dimethyl-4-methoxy-benzoyl)pyrrolidin-3-yl]ethyl)quinuclidinium chloride; and (xxvi) 4-cyclohexyl-1-(2-[3-(3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium chloride; and their alternatives, pharmaceutical salts (re ZA) and individual (R)- and (S)-stereomers of any of them. 17. Compound according to claim 1, characterized in that it is selected from the group comprising: (i) 4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl)quinuclidinium methanesulfonate; and (ii) 4-cyclohexyl-1-(3(S)-[3,4-dichlorophenyl]-4-[N-methyl-3,5-bis(trifluoromethyl)benzamido]butyl) quinuclidinium chloride. 18. Pharmaceutical composition, characterized in that it contains one compound of formula (I) according to any of the preceding claims, together with some pharmaceutically acceptable solvent or carrier. 19. A compound of formula (I) or a pharmaceutically acceptable composition thereof, according to any one of claims 1 to 17 and 18, characterized in that it is used as a medication. 20. Application of the compound of formula (I), or some of its pharmaceutically acceptable compositions, according to any one of claims 1 to 17 and 18, characterized in that it is used for the production of a medication for the treatment of a disease by producing an antagonistic effect on a tachykinin receptor or on a combination tachykinin receptors. 21. Application according to claim 20, characterized in that it is an antagonistic effect on human NK1 and NK2 tachykinin receptors. 22. Use according to claim 20 or 21, characterized in that the disease is an inflammatory disease, such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder, such as anxiety, depression, dementia or psychosis , some gastrointestinal (GI) disorder, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, uncontrolled bowel movements, colitis or Crohn's disease, some disease caused by Helicobacter pylori or some other urease-positive Gram-negative bacteria, urogenital tract disorder, such as uncontrolled discharge, hyperreflexia or cystitis, pulmonary disorder, such as chronic obstructive airways disease, allergy, such as eczema, contact dermatitis, hereditary allergic dermatitis or rhinitis, hypersensitivity disorder, such as hypersensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia a, painful neuropathy, burn, herpetic neuralgia or post-herpetic neuralgia, vomiting, cough, migraine, acute or chronic pain. 23. A method for treating a human from a disease by producing an antagonistic effect on one tachykinin receptor or on a combination of tachykinin receptors, characterized in that it comprises the treatment of that human with an effective amount of one compound of formula (I) or a pharmaceutically acceptable composition thereof, according to any of the requirements 1 to 17 and 18. 24. The method according to claim 23, characterized in that the antagonistic action is directed at human NK1 and NK2 tachykinin receptors. 25. The method as in claim 23 or 24, characterized in that the disease is an inflammatory disease, such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder, such as anxiety, depression, dementia or psychosis, some gastrointestinal (GI) disorder, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflux, uncontrolled bowel movements, colitis or Crohn's disease, some disease caused by Helicobacter pylori or some other urease-positive Gram-negative bacteria , urogenital tract disorder, such as uncontrolled discharge, hyperreflexia or cystitis, pulmonary disorder, such as chronic obstructive airways disease, allergy, such as eczema, contact dermatitis, hereditary allergic dermatitis or rhinitis, hypersensitivity disorder, such as hypersensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causal gia, painful neuropathy, burn, herpetic neuralgia or post-herpetic neuralgia, vomiting, cough, migraine, acute or chronic pain. 26. Process for preparing a compound of the formula (I) according to claim 1, which includes the reaction of one compound of the formula: [image] wherein R, R1, R2, R3, R4, R5, T, Y and m are as previously defined for the compound of formula (I), Z is a suitable leaving group capable of forming a pharmaceutically acceptable anion (ZA), and Z1 is one suitable leaving group, with one compound of the formula: [image] where R 6 and n are as previously defined for the compound of formula (I), wherein said process is followed by: a) when Z 1 is a suitable leaving group, substitution for a pharmaceutically acceptable anion (ZA); or b) optionally, if ZA is one pharmaceutically acceptable anion, substitute for another pharmaceutically acceptable anion. 27. Compound formula: [image] characterized in that R is phenyl, C3-C7 cycloalkyl or heteroalkyl, both of which may be optionally benzo-fused or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused part, with 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4) alkyl, C1-C4 alkoxy, fluoro(C1-C4) alkoxy, C2-C4 alkanoyl, halo, C1-C4 alkoxycarbonyl, C3-C7 cycloalkyl, -S(O)p(C1-C4 alkyl), cyano, -NR7R8, -S(O)pNR7R8, -NR7(C1-C4 alkanoyl) and -CONR7R8, or R is 2,3-dihydrobenzo[b] furanil or chromanil; R 1 and R 2 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent C 2 -C 6 alkylene; R 3 and R 4 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent unbranched C 1 -C 4 alkylene; R5 is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which is substituted with 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4) alkyl, C1-C4 alkoxy, halo and cyano, or R5 is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl. R 6 is C 3 -C 7 cycloalkyl optionally substituted with 1 to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, fluoro(C 1 -C 4 )alkyl and fluoro(C 1 -C 4 )alkoxy; R 7 and R 8 are each independently selected from H and C 1 -C 6 alkyl or, taken together, represent C 2 -C 6 alkylene; T is carbonyl; Y is unbranched C2-C4 alkylene; ZA is a pharmaceutically acceptable anion; m is 0 or 1; n is 1 or 2; p is 0, 1 or 2; And "heteroaryl", as used in the definition for R, means thienyl, or a 5- or 6-membered ring heteroaryl group containing either 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatoms and 1 oxygen or sulfur heteroatom.