CZ453499A3 - Quaternary ammonium compounds functioning as tachykinin antagonists - Google Patents

Abstract

The compounds of formula I wherein the substituents have specific meanings. These compounds are antagonists tachykinin.

Description

Technical field

The invention relates to quaternary ammonium compounds. In particular, the invention relates to 1- (2-acylimidazol-1-ylalkyl) quinuclidinium salts and to a process for their preparation, intermediates used in their preparation, compositions containing them and the use of these salts.

The compounds of the invention are tachykinin antagonists, including NKA (neurokinin A), NKB (neurokinin B) and Substance P acting on human neurokinin-1 (NKJ, neurokinin-2 (NK ₂ ) and neurokinin-3 (NK ₃ ) receptors).

These compounds are particularly useful as dual NK _X and NK ₂ receptors, and can therefore be used for treating inflammatory diseases such as arthritis, psoriasis, asthma or inflammatory bowel disease, disorders of the central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, gastrointestinal tract (GI) disorders such as bowel disease, irritable bowel syndrome, gastro-esophageal reflux, inability to maintain stool, colitis or Crohn's disease, a disease caused by Helicobacter pylori or other urease-positive gram-negative bacteria, disorders urogenital tract such as incontinence, impotence, hyperreflexia or cystitis, pulmonary disorders such as chronic obstructive airway disease, allergies such as eczema, contact dermatitis, atopic dermatitis, urticaria, eczematoid dermatitis or rhinitis such as hypersensitivity disorders over oral diseases, such as cancer, or disorders involving ligamentous growth, vasospastic diseases, such as angiogenesis, angina or Reynaud's disease, fibrosis, or disease

Collagen such as atherosclerosis, scleroderma or eosinophilic fascioliasis, reflux sympathetic dystrophy such as shoulder / hand syndrome, addictive disorders such as alcoholism , somatic disorders associated with stress, peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, herpetic neuralgia or postherpetic neuralgia, neuropathological disorders such as Alzheimer's disease or multiple sclerosis, disorders of increased or decreased immunity such as systemic lupus erythematosus, rheumatic diseases such as fibrosis, vomiting, cough, acute or chronic pain, migraine, eye diseases such as corneal proliferation, flu or colds.

BACKGROUND OF THE INVENTION

EP-A-680 962 and EP-A-0 739 891 disclose heterocyclic compounds which are non-peptide NKA antagonists and are useful for the treatment of diseases such as asthma. EP-A-0 591 040 discloses quaternary compounds with tachykinin antagonist activity.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

where

R is phenyl, C 3 -C 7 cycloalkyl or heteroaryl, each of which is optionally

Condensed with a benzene ring or C 3 -C 7 cycloalkyl ring and optionally substituted, including in the benzene or C 3 -C 7 cycloalkyl ring condensed moiety , 1 to 3 substituents each independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, phenoxy, alkanoyl; C 2 -C 4, halogen, C 1 -C 4 alkoxycarbonyl, C 3 -C 7 cycloalkyl, -S (O) _m C 1 -C 4 alkyl, cyano, -NR ² R ³ , -S (O) _m NR ² R ³ , -NR ⁴ C 1-4 alkanoyl in the alkanoyl moiety and -CONR ² R ³ , or R is 2,3-dihydro-benzo [b] furanyl or chromanyl ,

R ¹ is hydrogen or an alkyl group having 1 to 6 carbon atoms,

R ² and R ³ are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl or taken together to form C 4 -C 6 alkylene,

R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

W is a direct bond, a methylene group or an ethylene group,

X is an unbranched alkylene group 2 to 4 atoms carbon, Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or

C 3 -C 7 cycloalkyl, each of which is optionally substituted with 1 to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy carbon atoms,

-4 C 1 -C 4 fluoroalkoxy, halogen atom and cyano,

Ar is phenyl, naphthyl, benzyl, thienyl, benzo [b] thienyl or indolyl, each of which is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl. C 4 -C 4 alkoxy, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, halogen and cyano, or Ar is 1,3-benzodioxolane-4 or 5-yl or 1,4-benzodioxane-5- or 6- yl, m is 0, 1 or 2,

Z ^A is a pharmaceutically acceptable anion, and a heteroaryl group used in defining R is a thienyl or a five or six membered ring heteroaryl group containing 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatoms and 1 oxygen or sulfur heteroatom, with the proviso that when W is a direct bond and R is an optionally fused and optionally substituted heteroaryl group, the heteroaryl group being bound by a ring carbon atom to the carbonyl group.

In the above definitions, a halogen atom is fluorine, chlorine, bromine or iodine, and alkyl and alkoxy groups have three or more carbon atoms, alkanoyl groups have four carbon atoms, and alkylene groups having two or more carbon atoms (except where indicated) they may have unbranched or branched chains.

Z ^A is a pharmaceutically acceptable anion such as chloride, bromide, nitrate, methanesulfonate, para-toluenesulfonate, benzenesulfonate, hydrogensulfate or sulfate.

Preferably, Z ^{A is} chloride or methanesulfonate.

Most preferably, Z ^{A is a} methanesulfonate.

The compound of formula I contains one or more asymmetric carbon atoms and therefore exists in two or more

-5stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of formula I and mixtures thereof.

Separation of diastereoisomers may be accomplished by conventional means, for example, fractional crystallization, chromatography, or HPLC of a stereoisomeric mixture of a compound of Formula I or a suitable salt or derivative thereof. A single enantiomer of a compound of Formula I can also be prepared from the corresponding optically pure intermediate or by resolution, such as HPLC of the corresponding racemate using a suitable chiral carrier or by fractional crystallization of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid.

Preferably, R is phenyl, which is optionally fused with a benzene ring or a C 3 -C 7 cycloalkyl group and optionally substituted, including in the fused portion with a benzene ring or a C 3 -C 7 cycloalkyl group, 1, 2 or 3 substituents each independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, phenoxy and halogen, or R 2 1,3-dihydrobenzo [b] furanyl.

Even more preferably, R is phenyl which is optionally fused with a benzene ring or a C 3 -C 7 cycloalkyl group and optionally substituted, including in the fused part with a benzene ring or a C 3 -C 7 cycloalkyl group, 1, 2 or 3 substituents each independently selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluorine and chlorine, or R is

2,3-dihydrobenzo [b] furanyl.

Even more preferably, R is phenyl, naphthyl or tetrahydronaphthyl, each of which is optionally

9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 or 9 substituted with 1, 2 or 3 substituents each independently selected from ethyl, trifluoromethyl, trifluoromethoxy, chlorine or R is methyl, methoxy, isopropoxy, phenoxy,

2,3-dihydrobenzo [b] furanyl.

Still more preferably, R is phenyl, 3,5-dimethylphenyl,

2,3-dimethylphenyl, 2-trifluoromethoxyphenyl, 2-methoxy-3-methylphenyl, 2,3-dihydrobenzo [b] furan-7-yl, naphth-2-yl, 4-fluoro-3-trifluoromethylphenyl, 1,2,3, 4-tetrahydronaphth-5-yl,

1,2,3,4-Tetrahydronaphth-6-yl, 5-chloro-2-methoxyphenyl,

2-methoxyphenyl, 2-trifluoromethylphenyl, 2-isopropoxyphenyl,

2-ethylphenyl, 2-phenoxyphenyl or 3,5-bis (trifluoromethyl) phenyl.

Most preferably, R is 2,3-dimethylphenyl, naphth-2-yl, 1,2,3,4-tetrahydronaphth-5-yl or 2-methoxyphenyl.

Preferably R ¹ is hydrogen.

Preferably W is a direct bond or methylene.

Most preferably, W is a direct bond.

Preferably X is 1,2-ethylene.

Preferably, Y is phenyl, naphthyl or cyclohexyl, each optionally substituted with 1, 2 or 3 C 1 -C 4 alkyl substituents.

Even more preferably, Y is phenyl, 3,5-dimethylphenyl, cyclohexyl or naphth-2-yl.

Most preferably, Y is phenyl.

Preferably, Ar is phenyl, optionally substituted with 1, 2 or halogen atoms.

Even more preferably, Ar is phenyl substituted with 1 or 2 chlorine atoms.

Most preferably, Ar is 3,4-dichlorophenyl.

Preferred examples of compounds of formula I are compounds of formula IA 9 9 9 9 9 9 9

9 9 9 99

-1 4 9 9 9 9 9 9 9 9 ································

where

1) RW- is 3,5-dimethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

2) RW- is 2,3-dimethylphenyl ₍ Y is phenyl and Z ^A is CH ₃ SO ₃ -,

3) RW- is 2-trifluoromethoxyphenyl, Y is phenyl and Z ^A is

CH ₃ SO ₃ -,

4) RW- is 2-methoxy-3-methylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

5) RW- is 2,3-dihydrobenzo [b] furan-7-yl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

6) RW- is naphth-2-yl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

7) RW- is 4-fluoro-3-trifluoromethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

8) RW- is 1,2,3,4-tetrahydronaphth-5-yl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

9) RW- is 1,2,3,4-tetrahydronaphth-6-yl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

10) RW- is 5-chloro-2-methoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

11) RW- is 2-methoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

12) RW- is 2-trifluoromethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

13) RW- is 2-isopropoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

14) RW- is 2-ethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

15) RW- is 2-phenoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

16) RW- is benzyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -,

-8Φ · «φφφ

17) RW- is 3,5-bis (trifluoromethyl) phenyl, Y is phenyl and Z ^A is cr,

18) RW- is 2-methoxyphenyl, Y is cyclohexyl and Z ^A is CH ₃ SO ₃ -,

19) R-W- is 4-fluoro-3-trifluoromethylphenyl, Y is cyclohexyl and

Z ^A is CH ₃ SO ₃ -,

20) RW- is 2-methoxyphenyl, Y is 3,5-dimethylphenyl and Z ^A is

CH ₃ SO ₃ -, or

21) RW- is 2-methoxyphenyl, Y is naphth-2-yl and Z ^A is CH ₃ SO ₃ -, or an alternative pharmaceutically acceptable salt of any anion (see Z ^A ).

Particularly preferred examples of compounds of formula I include 4-phenyl-1- (3 (S) - [3,4-dichlorophenyl] -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl)) imidazol-1-yl] butyl) quinuclidinium methanesulfonate and 4-phenyl-1- (3 (R) - [3,4-dichlorophenyl] -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) (imidazol-1-yl) butyl) quinuclidinium methanesulfonate.

All compounds of formula I can be prepared by reacting a compound of formula II

R-W. .O

N — CH3 — C — X— (Z or Z ¹ ) (II)

Ar wherein R, R ¹ , Ar, W and X are as defined above for compounds of Formula I, Z is a suitable leaving group capable of forming a pharmaceutically acceptable anion (Z ^A ) and Z ¹ is a suitable leaving group, with a compound of Formula III 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 · 9 9 9 9 9 9 9 9 9 _Λ ·· 9 9 9 9 9 9 9 _ Q _ «·· · · 9 9 9 · ·· 9 9 where Y is meaning above for a compound of formula I, followed by either (a) when Z ¹ is a suitable leaving group, exchange for a pharmaceutically acceptable anion (Z ^A ), or (b) optionally, when Z ^A is a pharmaceutically acceptable anion, another pharmaceutically acceptable anion.

Preferred examples for Z include C1 -C4 alkanesulfonyloxy, benzenesulfonyloxy, para-toluenesulfonyloxy, chloro, bromo and iodo.

An example of Z ¹ is trifluoromethanesulfonyloxy.

Preferably the leaving group in the compound of formula II forms a pharmaceutically acceptable anion (Z / Z ^A ), for example a methanesulfonyloxy / methanesulfonate, and therefore an anion exchange at the end of the process is not necessary.

It is possible to exchange pharmaceutically acceptable anions (see Z ^A ) in the processing procedure, for example the methanesulfonate can be exchanged for chloride by treating the isolated compound or the crude mixture with an aqueous hydrochloric acid solution.

The reaction of the compounds of formulas II and III is generally carried out in a suitable solvent, for example acetonitrile, at elevated temperature, preferably at boiling point.

The starting compounds of formula II can be prepared according to Scheme 1.

-10 · ♦ © * * * * * * * * * *

Scheme 1

(or, when R ¹ is C 1 -C ₆ alkyl)

1) base (eg sodium hydride)

2) L '- _{A C -C alkyl)

R ¹

NC-C- (C 1 -C 6 alkylene)

Ar (VII) reduction (eg diisobutylaluminum hydride)

R ¹

OHC-C _(Ci-C3 alkylene)

Ar (Vlil) reduction (eg sodium borohydride)

-11 · ♦ ··· · · «V * 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 99 99 9 1 · · ·

HO-CH ₂ -C (C C ^ alkylene), Ar (IX)

CH 3 SO 2 Cl, acid acceptor (eg NEt _} )

CH ₃ SO ₂ O-CH ₂ -C _(Ci-C3 alkylene)

Ar (X) imidazole; another acid acceptor (eg K ₂ CO ₃ )

R ¹

N ^ N— \ = J

CH ₂ -C- (C 1 -C 4 alkylene) (XI)

Ar aqueous mineral acid (eg 5N HCl)

N> ^X

R

CH2-C- (C1-C6 alkylene) Ar

-CHO (XII) reduction (e.g. NaBH ₄ ) \ = 7

CH ₂ -C-X-OH (XIII)

Ar

-12

9

9 • · # 99 9 t <t 9 9 9 ·

9 9 9

9 9 9. 9 ·

R-W-COCI, acid acceptor (eg triethylamine)

R = Wn / 0

N ^ N-CH

R O

I II

-c — X — O — C — W-R

AND

Ar (XIV) aqueous sodium hydroxide with methanol or 1,4-dioxane

R H = ^X N-CH, = JI

R ¹

AND

C — X — OH

AND

Ar (XV) functional group interconversion

R-v \ r .o

R ¹ hr _'N-CH2 \ = J

C — X— (Z or Z ¹ )

Ar (II)

99 9 r ?.

9999 99 99 • 9

9 9 9 99

9 9 9 9 9

9 9 9 9 9 9

Wherein R, R ¹ , Ar, W, X, Z and Z ¹ have the meanings given above for the compound of formula II and L and I? leaving groups such as chloro, bromo, iodo, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and para-toluenesulfonyloxy are suitable.

Suitable reaction conditions, reagents and solvents for carrying out any of the steps in Scheme 1 are known to those skilled in the art with respect to the preparations herein.

Regarding the last step in the reaction sequence, a compound of formula XV can be converted to a compound of formula II using conventional conditions. For example, an alcohol of formula XV can be converted to a compound of formula II wherein Z is methanesulfonyl by treatment with methanesulfonyl chloride, triethylamine and dichloromethane and a compound of formula II wherein Z ¹ is trifluoromethanesulfonyloxy can be prepared by reacting an alcohol of formula XV with trifluoromethanesulfonic anhydride. in the presence of a suitable acid acceptor and in a suitable solvent, for example dichloromethane.

Compounds of formula XII can also be prepared according to Scheme 2.

• 99 9 9 9 9 9 9 9 9 9 9

9 · 999 99 9 • 9 9 9 9 9 999 99

-14Schema 2

ArCH, CN » ^wn

1) base (eg lithium diisopropylamide)

2) ^J L - _(Ci-C3 alkylene) -CH = _{CH2 (XV} |)

NC <JJH (C _r C alkylene) -CH = CH ₂ Ar (or. Where R is C ¹ -C ₆ alkyl)

1) base (eg sodium hydride)

2) L - (C _r C _alkyl)

R ¹

NC-c- (C 1 -C ₃ alkylene) -CH = CH ₂

Ar (XVII) (XVIII) (XIX) reduction (eg diisobutylaluminum hydridein)

OHC-C _(Ci-C3 alkylene) -CH = CH ₂

Ar (XX)

-15444 • ·

4444 44 44

4 4 4 4

4444 4 44 4 • 4444 44 4

4 4 4 4 4 5

444 * 4 ·· reduction (eg NaBHj '

R ^{1 2}

HO-CH-C- _{(Ci-C 3} alkylene) CH ₂ --CH = ^(xx 0

Ar

CH 3 SO 3 Cl, acid acceptor (eg NEt ₃ )

R ¹

CH ₂ SO ₂ O - CH ₂ C- (C 1 -C 6 alkylene) —CH = CH ₂ (XXH)

Ar imidazole, resp. another acid acceptor (eg K ₂ CO 3)

N ^ N \ J = -CH ₂ -C- (C _r C alkylene) Ar-CH = CH ₂ (XXIII)

1) formation of the hydrochloride salt

2) OsO ₄ (catalyst), NaIO ₄

R ¹ / '«· v = /

-CH;

-C _(Ci-C3 alkylene) -CHO (XII)

Ar

-16 • 99 99999 9 9 9 9 9 9 9

9 9 9 999 999

Wherein R ¹ and Ar have the meanings given above for the compound of formula XII and L ² and L ³ are suitable leaving groups, for example those mentioned above for L and L ¹ .

Suitable reaction conditions, reagents and solvents for carrying out any of the steps in Scheme 2 are known to those skilled in the art with respect to the preparations herein.

Compounds of formula XV can also be prepared according to Scheme 3.

Scheme 3

ArCH ₂ CN

1) base (eg sodium hydride)

(2) L / -X-O-P (XXIV)

NC — CH — X — O — P (XXV)

Ar (or. Where R ¹ is 0 _χ -0 _C6 alkyl), l) of a base (e.g. sodium hydride) in 2) LA _(Ci-C6 alkyl)

R ¹

NC-C-X-O-X (XXVI)

Ar reduction (eg diisobutylaluminum hydride)

R ¹

OHC-C — X — O — P (XXVII)

Ar

-17 * ΒΒ · · • • • · · ·

* · * * * * * * *

Β Β Β Β

ΒΒ ΒΒ reduction (eg NaBH ₄ )

R ¹

HO - CH ₂ -C-X-O - P (XXVIII)

Ar

MeSO ₂ CI, acid acceptor (eg NEt ₃ )

R ¹

MeSO ₂ O - CH ₃ - C - X - O - P Ar (XXIX) imidazole; another acid acceptor (eg K ₂ CO ₃ )

N ^ N = J

R ¹

CH ₂ -C-X-P

Ar (XXX)

R-W-COCI, acid acceptor (eg triethylamine)

R ¹

ÉT N— \ = J ch ₂ C — X — o — p (XXXI)

Ar

-18 ···

9 99 99 99

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

999 99 99 cleavage of protecting group

R ¹

N ^X N - CH ₂ -C — X — OH (XV)

Ar wherein R, R ¹ , Ar, W and X have the meanings given above for the compound of the general formula XV, L 1 and L ⁵ are suitable leaving groups, for example the groups mentioned above for L and L ¹ and P are a suitable protecting group.

Examples of suitable protecting groups (P) together with methods for their removal can be found in Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, Second Edition, Wiley-Interscience. A preferred example of P is tetrahydropyran-2-yl, which can be removed using Amberlyst 15 (trademark) ion exchange resin or methanol saturated with hydrogen chloride gas.

Suitable reaction conditions, reagents and solvents for carrying out any of the steps in Scheme 3 are known to those skilled in the art with respect to the preparations herein.

Compounds of formula XXXI can also be prepared by reacting a compound of formula XXIX with a compound of formula XXXII

(XXXII) ** ** ** XXX XXX XXX XXX XXX

-19 ·· · <

• · · · · · · · · · · · · · · · · · ·

Wherein R and W are as defined above for the compound of formula XXXI, optionally in the presence of another acid acceptor, for example potassium carbonate.

Compounds of formula XXXII can be prepared according to Scheme 4.

Scheme 4 (= n-butyllithium) 2) CICH ₂ OC ₂ H _S

1) base (eg n-butyllithium)

2) (CH3SiCl

3) R-W-COCl

aqueous hydrochloric acid / ethanol

(XXXII)

«» «» »9 9 999 99 99 99 9 • 9 9 9 9 9 9 • * • 9 9 9 9 9 9 9 9 • · 9 • 9 9 9 9 9 99 9 9 99 999 • 9 99

wherein R and W are as defined above for the compound of formula XXXII.

Compounds of formula III may be prepared by a method similar to that described in Chem. Ber., 108, 3475 (1975).

Alternatively, compounds of formula III wherein Y is cyclohexyl optionally substituted as mentioned above for Y in a compound of formula I may be prepared by catalytic hydrogenation of a compound of formula IIIA (IIIA) wherein Y is phenyl optionally substituted as described above for Y. The reduction can be carried out under a hydrogen atmosphere using a suitable catalyst such as rhodium on alumina and in a suitable solvent such as acetic acid.

Compounds of formula (IIIA) can be prepared in a similar manner as described in Chem. Ber., 108, 3475 (1975) and J. Org. Chem., 22, 1484 (1957).

Compounds of formula III can also be prepared according to Scheme 5.

· 99 99 99 99 99 99 99 9 99 9 9 9 9 9 9 9 »»

Scheme 5

Y-MgBr, Grignard reaction

CN

CO ₂ Et (XXXIV)

N

AND

CH ₂ Ph

1) aqueous potassium hydroxide, ethanol, microwaves

2) re-esterification

(XXXV)

LIAIHx

(XXXVI)

p-toluenesulfonyl chloride, pyridine

CH ₃ (XXXVIII) catalytic hydrogenation (eg palladium on carbon)

N (III) wherein Y is as defined above for a compound of formula

III.

• ······························· 4 4 4 ·

-23 ·· ··· · 4 · 44 · 4 4 44 · ·

Suitable reaction conditions, reagents and solvents for carrying out any of the steps in Scheme 5 are known to those skilled in the art with respect to the preparations herein.

All of the above reactions and the preparation of the novel starting materials used in the foregoing processes are conventional, and the appropriate reagents and reaction conditions for carrying out or preparing them, as well as procedures for isolating the desired products, are well known to those skilled in the art. .

The affinity of the compounds of Formula I for the human NK _X receptor can be determined in vitro by determining their ability to inhibit [ ³ H] -substance P binding to membranes prepared from a human IM9 cell line by expressing the human NK _X receptor using a modification of the method described in S. McLean et al., J. Pharm. Exp. Ther., 267. 472-479 (1993), in which whole cells were used.

The affinity of the compounds of formula I for the human NK ₂ receptor can be determined in vitro by determining their ability to compete with [ ³ H] -NKA (neurokinin A) for binding to membranes prepared from Chinese hamster ovary cells by expressing the cloned human NK ₂ receptor . In this method, cell membranes are prepared from Chinese hamster ovary by the method described above, where the membranes are used in place of IM9 cells. Membranes are incubated (90 minutes, 25 ° C) with [ ³ H] -NKA and with varying concentrations of test compound. Non-specific binding is determined in the presence of 10 μΜ NKA.

The potency of the NK _X receptor antagonist of the compounds of formula I can be determined in vitro by testing their ability to antagonize the contractile effects of substance P in epithelium-deprived guinea pig tracheal strips. Tissues can be prepared from guinea pigs (350-600 g) killed by stunning and bleeding. The excised trachea is cleared of connective tissue and opened longitudinally on the opposite side of the tracheal bundle of muscle. The epithelial layer can then be removed by internal friction

Fl • surface trachea with cotton wool lint. Strips of approximately four cartilage bundles are cut and mounted under tension with 1 g in an organ bath containing Krebs solution (composition: NaCl 118 mM, KCl 4.6 mM, NaHCO ₃ 25 mM, KH ₂ PO ₄ 1.4 mM, MgSO ₄ 1) 2 mM, CaCl ₂ 2.5 mM, glucose 11 mM) at 37 ° C and 95% O ₂ and 5% CO ₂ . The potential effect of substance P on the NK ₂ receptor population found in this tissue can be prevented by adding selective NK ₂ receptor antagonists ± SR-48986 (1 μΜ) to the Krebs buffer solution. Indomethacin (3 μΜ) is also added to remove the effect of endogenous prostanoids. Changes in tissue tension in response to the cumulative addition of substance P agonists are measured isometrically. The efficacy of the compounds of formula I can be evaluated from the dose-induced shift in substance P using standard Schild analysis after 30 minutes of incubation of the compound with tissue.

The epithelium-depleted guinea pig tracheal strip preparation can also be used to evaluate the in vitro potency of NK ₂ receptor antagonists of compounds of formula I using the selective NK ₂ receptor [β-Ala ⁸ ] NKA agonist (4.10) as a contractile agent. Strips are prepared for these studies and placed in an organ bath as described above using Krebs solution of the following composition: NaCl 118 mM, KCl 4.6 mM, NaHCO 3 25 mM, KH 2 PO 4 1.4 mM, MgSO 4 1.2 mM, CaCl2 2.5 mM, glucose 11 mM, indomethacin 3 μΜ. The potency of the compounds can be evaluated from the magnitude of the shift induced by [β-Ala ⁸ ] NKA (4.10 ₎ in a dose-dependent manner using standard Schild analysis after 30 minutes of incubation of the compound with the tissue.

Compounds of formula I may be tested for potency of NK ₃ receptor antagonists in vitro by testing their ability to antagonize the contractile effects of selective guinea pig ileum ₃ receptor agonists using the method of Maggi et al., Br. J. Pharmacol., 101, 996-1000 (1990).

-25 • ···················································· '· · · · · · ···· · · · · ···

For use in humans, the compounds of Formula I may be administered alone, but are generally administered in admixture with a pharmaceutical carrier having regard to the intended route of administration and standard pharmaceutical practice.

For example, they can be administered orally or sublingually in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules either alone or in admixture with excipients, or in the form of infusions, solutions or suspensions containing flavoring or coloring agents.

They may be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are preferably used in the form of a sterile aqueous solution which may contain other substances, for example, sufficient salts or glucose to render the solution isotonic with blood.

For oral and parenteral administration to human patients, the daily dosage level of the compounds of Formula I is from 0.01 to 20 mg / kg (in single or divided doses).

Thus, tablets or capsules contain from 1 mg to 1.0 g of the active compound for administration in one or two or more doses as desired. In any case, the actual dose will be determined by the physician to be most appropriate for the individual patient, and this dose will vary according to the patient's age, weight and response. The above dosages are exemplary for average cases. Of course, there may be instances where lower or higher dosage ranges are used and are within the scope of the invention.

The compounds of Formula I may also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry inhalation powder or aerosol spray in a pressurized container or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrogen-containing fluorines such as , 1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane

-26 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99

9,999,999

9999 99999 99 (HFA 227EA [Trade Mark]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dose may be delivered by means of a valve delivering a specified amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound, for example using a mixture of ethanol and a propellant as solvent, which may additionally contain a lubricant, for example sorbitan trioleate. Capsules and cartridges (formed, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of Formula I and a suitable powder base such as lactose or starch.

The aerosol formulations are preferably arranged such that each delivered dose or aerosol puff delivered to a patient contains 20 pg to 1000 pg of a compound of formula I. The total daily dose of aerosol is in the range of 20 pg to 20 mg, and can be administered in a single dose. or usually multiple times in divided doses during the day.

Alternatively, the compounds of formula (I) may be administered in the form of suppositories or pessaries or may be administered topically in the form of a lotion, solution, cream, ointment or powder. For example, they may be incorporated into a cream containing an aqueous emulsion of polyethylene glycols or liquid paraffin or may be incorporated at a concentration of from 1 to 10% by weight into an ointment containing a white wax or white soft paraffin base together with stabilizers and preservatives as desired. The compounds of formula I can also be applied transdermally by application to the skin.

It should be noted that references to treatments include therapeutic, soothing, or prophylactic treatments.

Thus, the present invention further relates to:

(1) A pharmaceutical composition comprising a compound of formula I together with a pharmaceutically acceptable diluent or carrier.

• · · · ·

Or a medicament thereof for (2) The compounds of formula (I) or a pharmaceutically acceptable mixture thereof for use as a medicament.

(3) Use of a compound of formula I of a pharmaceutically acceptable composition for the preparation of a medicament for the treatment of diseases resulting from an antagonistic effect on tachykinin receptors or a combination of tachykinin receptors.

(4) The use as in (3), wherein the antagonistic effect acts on human NK ₁ and NK ₂ receptors of tachykinin.

(5) The use as in (3) or (4), wherein the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, central nervous system (CNS) disorders such as anxiety, depression, dementia or psychosis gastrointestinal disorders (GI) such as functional bowel disorder, irritable bowel syndrome, gastro-esophageal reflux, stool failure, colitis or Crohn's disease, diseases caused by Helicobacter pylori or other urease-positive gram-negative bacteria, urogenital tract disorders such as is incontinence, hyperreflexia or cystitis, pulmonary disorders such as chronic obstructive airway disease, allergies such as eczema, contact dermatitis, atopic dermatitis or rhinitis, hypersensitivity disorders such as poisoning, peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia , painful neuropathy, burns, herpetic neuralgia or post herpetic neuralgia, vomiting, cough, migraine or acute or chronic pain.

(6) A method of treating a human disease resulting from an antagonistic effect on tachykinin receptors or a combination of tachykinin receptors, comprising treating said people with an effective amount of a compound of Formula I or a pharmaceutically acceptable composition comprising the compound.

(7) The method as under paragraph (6), wherein the antagonistic effect exerted on the human _X and NK NK ₂ tachykinin receptors.

• 4

-28 • 4,444 44 • 4 4 4 4 · 444 4 44

4 444 44

444 peripheral neuralgia, (8) The method of (6) or (7), wherein 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, gastro-intestinal tract disorder (GI) such as bowel function disorder, irritable bowel syndrome, gastro-esophageal reflux, inability to maintain stool, colitis or Crohn's disease, a disease caused by Helicobacter pylori or other urease-positive gram-negative bacteria, urogenital tract disorders such as incontinence, hyperreflexia or cystitis, pulmonary disorders such as chronic obstructive airway disease, allergies such as eczema, contact dermatitis, atopic dermatitis or rhinitis, hypersensitivity disorders such as poisoning such as diabetic pain neuropathy, herpetic neuralgia or postherpetic neuralgia, vomiting relief, cough, migraine or acute or chronic pain.

(9) Compounds of formulas II, XI, XII, XIII, XIV, XV, XXIII, XXX or XXXI.

The following examples illustrate the preparation of compounds of Formula I.

neuropathy, causalgia, neuropathy, burns,

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-phenyl-1- (3- [3,4-dichlorophenyl] -4- [2- (3,5-dimethylbenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate • 9

9

9 9 99 *

Χ _χ Me

O O

1-methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylbenzoyl) imidazol-1-yl] -butane (0.71 g) (see Preparation 74) and 4-phenylquinuclidine ( 0.32 g) (see J. Org. Chem., 22, 1484, (1957)) was dissolved in acetonitrile (10 mL) and the mixture was heated under reflux for 4 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in dichloromethane and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel, eluting with a solvent gradient of 95: 5 to 85:15, by volume, dichloromethane / methanol to give Ta, which is then triturated with and dried at temperature to give the 4-phenyl-1-product as a white foam. diethyl ether, filter the rooms under reduced pressure,

- (3- [3,4-dichlorophenyl] -4- [2- (3,5-dimethylbenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate (0.71 g) as a white solid.

NMR (CDCl 3): δ = 7.62 (2H, s), 7.16-7.41 (10H, m), 7.11 (1H, s), 4.66-4.86 (2H, m) 3.52-3.81 (7H, m), 3.32-3.47 (1H, m), 2.91-3.08 (1H, m), 2.82 (3H, s), 2 22-2.50 (14H, m) ppm. Found: C 61.53, H 6.17, N 6.03, calculated for C ₃₆ H ₄₁ Cl ₂ N ₃ O ₄ S: C 61.70, H 6.18, N 5.99%.

-301 * 9 · 9 9 9 ·· 9 9 * · • 9 9 9 9 9 · · 9 9 · 9 · 9 99 «• 9 9 9 9 9 ·

999 98 »9

Examples 2 to 16

Compounds summarized in the following table (Table 1) having the general formula

were prepared in a similar manner to Example 1 using the appropriate mesylate (see Preparations 75-84 and 86-90) and 4-phenylquinuclidine as starting materials.

Table 1

ex. in C. Eastern substance prepar. C. R-W- analytical data 2 75 Me ^X H-NMR (CDC1 _3): 5 = 7.03 to 7.41 (13H, m), 4.80 to 4.97 (2H, m), 3.59 to 3.84 (7H, m) 3.38-3.50 (1H, m), 2.97-3.10 (1H, m), 2.84 (3H, s), 2.40-2.59 (2H, m), 2.232, 34 (9H, m), 2.09 (3H, s) ppm. Nal: C 61.70, H 6.01, N 6.00, for C ₃₆ H ₄₁ Cl ₂ N ₃ O ₄ S. 1.00 mol of H ₂ O calcd; C 61.70, H 6.18, N 6.00%. 3 76 ¹ H-NMR (CDCl ₃ ): δ = 7.21-7.59 (13H, m), 7.11 (1H, s), 4.89 (1H, dd), 4.75 (1H, dd) 3.55-3.85 (7H, m), 3.30-3.42 (1H, m), 2.99-3.11 (1H, m), 2.84 (3H, s), 2 21-2.62 (8H, m) ppm. Nal: C 55.35, H 4.86, N 5.48, for C ₃₅ H ₃₆ Cl ₂ F ₃ N ₃ O ₅ S. 0.4 mol CH ₂ Cl ₂ calcd: C 55.03, H 4.93, N 5.43%.

• ·

-31 • ··· 9 99 9999 99

9,999 · 99 *

9 9 9 999 9 9 9 9 · · 9 9 999 99 9

9,999 · 9999

999 9 99

4 77 Me Me @ 1 H-NMR (CDCl3): .delta. = 7.21-7.46 (10H, m), 7.01-7.16 (3H, m), 4.72-4.92 (2H, m), 3 , 52-3.85 (1H, m), 3.32-3.49 (1H, m), 3.00-3.12 (1H, m), 2.82 (3H, S), 2.42 -2.56 (2H, m), 2.20-2.38 (9H, m) ppm. Nal: C 59.25, H 5.86, N 5.67 for C ₃₆ H ₄₁ Cl ₂ N ₃ O ₅ S. 0.5 mol H ₂ 0.0.3 mol CH ₂ Cl ₂ calcd: C 59.29, H 5.84, N 5.71%. 5 78 H-NMR _(CDCl3): 5 = 7.6 0 (lH, d), 7217.42 (10H, m), 7.09 (1H, s), 6.89 (1H, t), 4.82 (1H, dd), 4.57-4.71 (3H, m), 3.58-3.84 (7H, m), 3.41-3.52 (1H, m), 3.22 (2H) t, 3.02-3.14 (1H, m), 2.81 (3H, s), 2.20-2.55 (8H, m) ppm. Nal: C 60.32, H 5.66, N 5.88 for C ₃₆ H ₃₉ Cl ₂ N ₃ O ₅ S. 0.3 mol CH ₂ Cl ₂ calcd: C 60.38, H 5.53, N 5.82%. 6 79 ^X H-NMR _(CDCl3): 5 = 8.79 (1H, s), 8.11 (lH, d), 8.00 (lH, d), 7.89 (2H, t), 7.51 -7.64 (2H, m), 7.48 (1H, s), 7.197.40 (9H, m), 4.71-4.90 (2H, m), 3.593.80 (7H, m), 3.03-3.51 (1H, m), 2.993.09 (1H, m), 2.88 (3H, s), 2.42-2.55 (2H, m), 2.22-2, 38 (6 H, m) ppm. Nal: C 64.08, H 5.68, N 5.90 for C ₃₈ H ₃₉ Cl ₂ N ₃ O ₄ S. 0.5 mol H ₂ O calc: C 63.95, H 5.65, N 5 , 79%. 7 80 Λ ¹ H-NMR (CDC1 _3): 5 = 8.41 to 8.52 (2H, m), 7.51 (1H, s), 7.11-7.42 (10H, m), 4,72- 4.89 (2H, m), 3.60-3.89 (7H, m), 3.31-3.46 (1H, m), 2.97-3.09 (1H, m), 2, 85 (3H, s), 2.42-2.59 (2H, m), 2.212.39 (6H, m) ppm. Nal: C 56.15, H 4.88, N 5.77 for C ₃₅ H ₃₅ Cl ₂ F ₄ N ₃ O ₄ S. 0.5 mol H ₂ O calc: C 56.08, H 4.84, N 5.61%. 8 81 ¹ H-NMR _(CDCl3): 5 = 7.05-7.44 (13H, m), 4,8 0-4,94 (2H, m), 3.61 to 3.89 (7H, m) 3.38-3.71 (1H, m), 3.01-3.12 (1H, m), 2.76 -2.91 (5H, m), 2.22-2.69 (10H, m), 1.63-1.86 (4H, m) ppm. Nal: C 64.11, H 6.30 N 6.00 for C ₃₈ H ₄₃ Cl ₂ N ₃ O ₄ S calc: C 64.40, H 6.12, N 5.93%.

• · · · · • · · • ·· • ···· • • ·· 4 » • ·· 9 • · • • ··· • • • 9 • • · • • • • • ♦ • • · · · • · • ·· 9 9 * ·

9 82 / 9 ¹ H-NMR (CDC1 _3): δ = 7.78-7.86 (2H, m), 7.21-7.40 (9H, m), 7.11-7.16 (2H, m) 4.80 (1H, dd), 4.68 (1H, dd), 3.603.85 (7H, m), 3.37-3.49 (1H, m), 3.023, 11 (1H, m), 2 79-2.90 (7H, m), 2.402.51 (2H, m), 2.22-2.36 (6H, m), 1.82 (4H, broad s) ppm. Nal: C 63.90, H 6.25, N 6.05 for C ₃₈ H ₄₃ Cl ₂ N ₃ O ₄ S. 0.25 mol H ₂ 0 calc: C 63.99, H 6.15, N 5.89%. 10 83 X ¹ H-NMR (CDCl ₃ ): δ = 7.24-7.46 (HH, m), 7.08 (1H, s), 6.91 (1H, d), 4.89 (1H, dd) 4.72 (1H, dd), 3.64-3.88 (10H, m), 3.15-3.46 (1H, m), 3.07-3.17 (1H, m), 2 88 (3H, s), 2.46-2.56 (2H, m), 2.26-2.40 (6H, m) ppm. 11 84 1 H-NMR (CDCl ₃ ): δ = 6. 94-7.49 (14H, m), 4.90 (1H, dd), 4.70 (1H, dd), 3.613.84 (10H, m) 3.36-3.49 (1H, m), 3.09-3.20 (1H, m), 2.82 (3H, s), 2.222.59 (8H, m) ppm. Nal: C 58.80, H 5.68, N 5.88 for C ₃₅ H ₃₉ Cl ₂ N ₃ O ₅ S. 0.5 mol H ₂ O calc: C 58.87, H 5.38, N 6.06%. 12 86 70 ¹ H-NMR (CDCl ₃ ): δ = 7.72 (1H, d), 7.557.66 (2H, m), 7.20-7.49 (10H, m), 7.09 (1H, s) 4.94 (1H, dd), 4.72 (1H, dd), 3.60-3.85 (7H, m), 3.30-3.42 (1H, m), 3.05-3 18 (1H, m), 2.86 (3H, s), 2.362.59 (2H, m), 2.21-2.32 (6H, m) ppm. Nal: C 57.41, H 5.13, N 5.79 for C ₃₅ H ₃₆ Cl ₂ F ₃ N ₃ O ₄ S. 0.5 mol H ₂ O calc: C 57.46, H 5.10, N, 5.74%. 13 87 / 0 ¹ H-NMR _(CDCl3): δ = 7.20-7.46 (10H, m), 6.91 to 7.10 (4H, m), 4.83 (lH, dd), 4,43- 4.68 (2H, m), 3.66-3.90 (7H, m), 3.32-3.48 (1H, m), 3.15-3.31 (1H, m), 2, 42-2.58 (2H, m), 2.22-2.36 (6H, m), 1.11-1.21 (6H, m) ppm. Nal: C 61.88, H 5.97, N 6.11 for C ₃₇ H ₄₃ Cl ₂ N ₃ O _with S. 0.25 mol H ₂ O calc: C 61.96, H 6.11, N 5 , 86%.

• ΒΒΒΒ ΒΒ · ·· ♦ * ·· · · Β Β ΒΒΒΒ

Β Β · ΒΒΒ · Β Β «

ΒΒ · Β Β ΒΒΒΒΒ Β

ΒΒ ΒΒ ΒΒΒΒΒ

ΒΒΒ · ΒΒ ΒΒΒ ΒΒ ΒΒ

14 88 ‘70 ¹ H-NMR (CDC1 _3): δ = 7.15-7.41 (13H, m), 7.06 (lH, s), 4.80 to 4.91 (2H, m), _# 3593.86 ( 7H, m), 3.34-3.49 (1H, m), 3.003.12 (1H, m), 2.83 (3H, s), 2.40-2.66 (4H, m), 2 21-2.35 (6H, m); 1.15 (3H, t) ppm. Nal: C 62.45, H 6.11, N 6.13 for C ₃₆ H ₄₁ Cl ₂ N ₃ O ₄ S. 0.2 mol CH ₂ Cl ₂ calcd: C 62.14, H 5.96, N 6.01%. 15 Dec 89 70 ¹ H-NMR (CDCl ₃ ): δ = 6.83-7.53 (19H, m), 4.79 (1H, dd), 4.55 (1H, dd), 3.433.72 (7H, m) 3.03-3.30 (2H, m), 2.81 (3H, s), 2.09-2.49 (8H, m) ppm. Nal: C 63.02, H 5.55, N 5.72 for C ₄₀ H ₄₁ Cl ₂ N ₃ O ₅ S. 0.2 5 mol of CH ₂ Cl ₂ calcd: C 62.95, H 5.45, N 5.47%. 16 90 ¹ H-NMR (CDC1 _3): δ = 7.08-7.40 (15H, m), 4.74 (lH, dd), 4.61 (lH, dd), 4.46 (1H, d) 4.29 (1H, d), 3.4 8-3.71 (7H, m), 3.14-3.28 (1H, m), 2.88-3.04 (1H, m), 2.79 (3H, s), 2.15-2.39 (8H, m) ppm. Nal: C 61.41, H 5.68, N 6.19 for C ₃₅ H ₃₉ Cl ₂ N ₃ O ₄ S. 0.2 mol CH ₂ Cl ₂ calcd: C 61.66, H 5.79, N 6.13%.

Example 17

4-Phenyl-1- (3- [3,4-dichlorophenyl] -4- {2- [3,5-bis (trifluoromethyl) benzoyl] imidazol-1-yl} butyl) quinuclidinium chloride

• · ·· · ·· 9 · » 9 « · • • • * 9 • 9 • · • t ··· • • • • • • · • • • • • • 9 ··· 9 • 9 999 • 9 99

1-methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- {2- [3,5-bis (trifluoromethyl) benzoyl] imidazol-1-yl} butane (0.7 g) (see Preparation 85) and 4 -phenylquinuclidine (0.32 g) (see J. Org. Chem., 22, 1484, (1957)) was dissolved in acetonitrile (10 mL) and the mixture was heated under reflux for 18 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in dichloromethane and washed twice with 2N aqueous hydrochloric acid. The organic phase was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 95: 5 to 90:10, v / v, dichloromethane and methanol to give 4-phenyl -1- (3- [3,4-dichlorophenyl] -4- {2- [3,5-bis (trifluoromethyl) benzoyl] imidazol-1-yl} butyl) quinuclidinium chloride (0.37 g) as a white foam.

¹ H-NMR (CDCl ₃ ): δ = 8.69 (2H, s), 8.04 (1H, s), 7.54 (1H, s),

7.14-7.41 (9H, m), 4.76-4.96 (2H, m), 3.70-3.98 (7H, m), 3.803.93 (1H, m), 3, 10-3.21 (1 H, m), 2.49-2.62 (2 H, m), 2.23-2.40 (6 H, m) ppm.

Found: C 56.34, H 4.53, N 5.55 for C ₃₅ H ₃₂ Cl ₃ F ₆ N ₃ 0.1.00 mol H ₂ O calculated: C 56.12, H 4.58, N 5.61 %.

Example 18

4-phenyl-1- (3 (S) - [3,4-dichlorophenyl] -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate

• FFFF FF • · · · • · ·· F F · • F • F • • F • * • • FFF • • • • F • · • • F • • F F FFF F FF FFF • F FF

1-Methanesulfonyloxy-3 (S) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butane (0.82 g) (see Preparation 105) and 4-phenylquinuclidine (0.35 g) (see J. Org. Chem., 22, 1484, (1957)) are dissolved in acetonitrile (10 mL) and the mixture is heated to reflux for 3 hours. for 4 hours and then allowed to stand overnight at room temperature. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluting with a solvent gradient of 9: 1 to 8: 2, v / v, dichloromethane and methanol to give the product as a white foam. This was dissolved in dichloromethane, filtered and the solvent was removed from the filtrate to give 4-phenyl-1- (3 (S) - [3,4-dichlorophenyl] -4- [2- (1,2,3, 4-tetrahydro-5-naphthoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate (0.7 g) as a white powder.

1 H-NMR (CDCl ₃ ): δ = 7.05-7.44 (13H, m), 4.80-4.94 (2H, m), 3.61-3.89 (7H, m), 3 , 38-3.71 (1H, m), 3.01-3.12 (1H, m), 2.76-2.91 (5H, m), 2.22-2.69 (10H, m) , 1.63-1.86 (4H, m) ppm. Found: C 63.81, H 6.20, N 5.99 for C ₃₈ H ₄₃ Cl ₂ N ₃ O ₄ calculated: C 64.40, H 6.12, N 5.93%.

Example 19

4-phenyl-1- (3 (R) - [3,4-dichlorophenyl] -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate

Me

α α

O

α α

-36 • · ♦♦♦ 99 ·

9 9 · 9 9999

9 9 9 9 9 9 9 9

9,999,9999 9

99 9 9999

999 99 99 99 99

This compound was prepared in analogy to Example 18 using 1-methanesulfonyloxy-3 (R) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazole-1. 1-yl] butane (see Preparation 106) and 4-phenylquinuclidine (0.36 g) (see J. Org. Chem., 22, 1484 (1957)) as starting materials.

¹ H-NMR (CDCl 3): δ = 7.05-7.44 (13H, m), 4.80-4.94 (2H, m), 3.61-3.89 (7H, m), 3 , 38-3.71 (1H, m), 3.01-3.12 (1H, m), 2.76-2.91 (5H, m), 2.22-2.69 (10H, m) , 1.63-1.86 (4H, m) ppm. Found: C 62.69, H 6.07, N 5.87 for C ₃₈ H ₄₃ Cl ₂ N ₃ O ₄ S. 1.00 mol H ₂ O: Calculated: C 62.80, H 6.25, N 5.78%.

Example 20

4-Cyclohexyl-1- (3- [3,4-dichlorophenyl] -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate

1-methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butane (0.59 g) (see Preparation 84) and 4-cyclohexylquinuclidine (0.27 g) g) (see Preparation 1) was dissolved in acetonitrile (8 mL) and heated to reflux for 3.5 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in dichloromethane and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel, eluting with a solvent gradient

-37 · 9 · 9 9 9 9 9 9 9 9 9 9 • 9 9

9 · 9 9 9 9

999 99 99

95: 5 to 85:15, v / v, dichloromethane and methanol to give 4-cyclohexyl-1- (3- [3,4-dichlorophenyl] -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate (0.69 g) as a white foam.

¹ H-NMR (CDCl ₃ ): δ = 7.21-7.49 (6H, m), 6.94-7.08 (3H, m), 4.87 (1H, dd), 4.71 ( 1H, dd), 3.77 (3H, s), 3.33-3.70 (8H, m),

2.91-3.06 (1H, m), 2.83 (3H, s), 2.30-2.49 (2H, m), 1.60-1.89 (11H, m), O, 80-1.28 (6 H, m) ppm.

Found: C 56.76, H 6.31, N 5.63 for C ₃₅ H ₄₅ Cl ₂ N ₃ O ₅ S. 0.5 mol of CH ₂ Cl ₂ .0.5 mol of H ₂ O calculated: C 56.64, H 6.38, N 5.66%.

Example 21

4-Cyclohexyl-1- (3- [3,4-dichlorophenyl] -4- [2- (3-trifluoromethyl-4-fluorobenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate

1-methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- [2- (3-trifluoromethyl-4-fluorobenzoyl) imidazol-1-yl] butane (0.77 g) (see Preparation 80) and 4-cyclohexylquinuclidine (0.31 g) (see Preparation 1) was dissolved in acetonitrile (10 mL) and heated to reflux for 5 hours. The solvent was removed under reduced pressure, the resulting residue was dissolved in dichloromethane and

• · · · · • 9 ···· • 9 99 • · 9 9 9 9 9 9 9 9 9 9 • 9 9 9 * • 9 9 9 9 • · 9 • 9 9 9 9 9 9 94 9 9 9 • 9 · 9 9 99

the solvent was removed under reduced pressure. The residue is chromatographed on silica gel eluting with a solvent gradient of 95: 5 to 80:20, v / v, dichloromethane and methanol to give 4-cyclohexyl-1- (3- [3,4-dichlorophenyl] -4- [2- (3- trifluoromethyl-4-fluorobenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate (0.69 g) as a white foam.

¹ H-NMR (CDCl ₃ ): δ = 8.42-8.50 (2H, m), 7.55 (1H, s), 7.22-7.32 (3H, m), 7.11- 7.20 (2H, m), 4.80-4.85 (2H, m), 3.34-3.76 (8H,

m), 2.90-2.98 (1H, m), 2.85 (3H, s), 2.30-2.50 (2H, m),

1.75-1.81 (6H, m), 1.61-1.72 (5H, m), 1.02-1.27 (4H, m),

0.81-0.95 (2 H, m) ppm.

Found: C 56.14, H 5.62, N 5.70 for C ₃₅ H ₄₁ Cl ₂ F ₄ N ₃ O ₄ S calculated: C 56.30, H 5.53, N 5.63%.

Example 22

4- (3,5-dimethylphenyl) -1- (3- [3,4-dichlorophenyl] -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate

1-methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butane (0.55 g) (see Preparation 84) and 4- (3,5- dimethylphenyl) quinuclidine (0.28 g) (see Preparation 12) was dissolved in acetonitrile (10 mL) and heated to reflux for 2.5 hours. Remove the solvent

-39 99 99 99 9 9 9 9

9 9 9 9 9 under reduced pressure, the resulting residue was dissolved in dichloromethane and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel eluting with a solvent gradient of 95: 5 to 90:10, v / v, dichloromethane and methanol to give 4- (3,5-dimethylphenyl) -1- (3- [3,4-dichlorophenyl] -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate (0.69 g) as a white foam.

1 H-NMR (CDCl ₃ ): δ = 7.28-7.48 (5H, m), 7.23 (1H, d), 6.92-7.07 (3H, m), 6.88 ( 1H, s), 6.82 (2H, s), 4.89 (1H, dd), 4.71 (1H, dd), 3.53-3.80 (10H, m), 3.34-3 47 (1H, m); 3.01-3.12 (1H, m);

2.82 (3H, s), 2.42-2.51 (2H, m), 2.20-2.34 (12H, m) ppm.

Example 23

4- (2-naphthyl) -1- (3- [3,4-dichlorophenyl] -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate

1-methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- [2- (2-methoxybenzoyl] imidazol-1-yl] butane (0.55 g) (see Preparation 84) and 4- (2-naphthyl) Quinuclidine (0.31 g) (see Preparation 7) was dissolved in acetonitrile (10 mL) and heated to reflux for 2.5 hours. The solvent was removed under reduced pressure, the resulting residue was dissolved in dichloromethane and evaporated. ···

The solvent is removed under reduced pressure. The residue is chromatographed on silica gel eluting with a solvent gradient of 95: 5 to 85:15, v / v, dichloromethane and methanol to give 4- (2-naphthyl) -1- (3- [3,4-dichlorophenyl] -4- [2]. (2-methoxybenzoyl) imidazol-1-yl] butyl) quinuclidinium methanesulfonate (0.65 g) as a white foam.

¹ H-NMR (CDC1 _3): δ = 7.71-7.86 (3H, m), 7.62 (1H, s), 7.23-7.51 (8H, m), 7.17 ( 1H, s), 6.92-7.07 (3H, m), 4.89 (1H, dd), 4.70 (1H, dd), 3.61-3.86 (10H, m), 3 34-3.66 (1H, m), 3.03-3.16 (1H, m), 2.84 (3H, s), 2.30-2.55 (8H, m) ppm.

• · · · ·

The following preparations describe the preparation of certain starting materials used in the synthesis of the compounds in the preceding examples.

Preparation 1

4-Cyclohexylquinuclidine

4-Phenylquinuclidine (5 g) (see J. Org. Chem., 22, 1484, (1957)) was dissolved in glacial acetic acid (25 ml), 50% w / w added. rhodium on alumina (2 g) and the mixture was hydrogenated for 5 days at 50 psi. The mixture was filtered through a short Arbacel column (trademark) and the column was washed with methanol. The filtrate was collected and the solvent was removed under reduced pressure to give a residue which was dissolved in water. The pH was adjusted to > 10 by addition of 0.88 aqueous ammonia solution. The aqueous mixture was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4-cyclohexylquinuclidine (4.7 g) as a light pink solids.

@ 1 H-NMR (CDCl3): .delta. = 2.75-2.96 (6H, m), 1.60-1.85 (5H, m),

1.06-1.45 (9H, m); 1.80-1.98 (3H, m) ppm.

Preparation 2

Ethyl 2- (1-benzylpiperidin-4-ylidene) -2-cyanoacetate

N-benzylpiperidin-4-one (25 g), ethyl cyanoacetate (16.4 g), glacial acetic acid (6 mL) and ammonium acetate (2.54 g) were heated in toluene (200 mL) with water removal using Dean- Stark equipment for 90 minutes. The mixture was cooled, additional toluene (100 mL) was added and the solution was washed successively with water (100 mL) and brine (100 mL) until a red oily product precipitated. The phases are separated and the oily product is dissolved in dichloromethane. The toluene and dichloromethane solutions were combined and the solvents were removed under reduced pressure to give a residue. This residue was dissolved in dichloromethane and washed sequentially with water and saturated aqueous sodium bicarbonate solution, and then the solvent was removed under reduced pressure. The crude product is chromatographed on silica gel eluting with 98: 2, v / v, dichloromethane and methanol to give the title compound (30.8 g) as an oil.

1 H-NMR (CDCl ₃ ): δ = 7.24-7.34 (5H, m), 4.22-4.32 (2H, q), 3.54 (2H, s), 3.12-3 16 (2H, m), 2.79 (2H, d), 2.66 (2H, d), 2.56 (2H, d), 1.32 (3H, t) ppm.

Preparation 3

Ethyl 2-cyano-2- (1-benzyl-4- (2-naphthyl) piperidin-4-yl) ethanoate

2-Bromo-naphthalene (26 g) was dissolved in anhydrous diethyl ether (100 ml) and one fifth of this solution was added to a vigorously stirred mixture of magnesium shavings (3.3 g) and 2-3 iodine crystals under nitrogen. Slight heating initiates the formation of the Grignard reagent, since it is difficult to maintain spontaneous boiling. The remaining 2-bromonaphthalene solution was added in 4 portions, allowing to boil off after each addition, and the mixture was finally heated to reflux for 1 hour, whereupon two dark organic phases formed. The mixture was cooled in an ice bath and anhydrous tetrahydrofuran (50 mL) was added followed by the dropwise addition of a solution of ethyl 2- (1-benzylpiperidin-4-ylidene) -2-cyanoacetate (12 g) (see Preparation 2) in tetrahydrofuran (100 mL). The single-phase mixture was stirred at 0 ° C for 30 minutes and then allowed to stand overnight at room temperature. The mixture was then poured into saturated aqueous ammonium chloride solution (450 mL) and extracted twice with diethyl ether. The organic extracts were combined and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 4: 0 to 4: 1, v / v, dichloromethane and diethyl ether to give the title compound (5.9). (g) in the form of an oil.

• ·

-44 ^X H-NMR (CDC1 _3): δ = 7.72 to 7.90 (4H, τη), 7.46-7.57 (3H, τη)

7.20-7.38 (5Η, m), 3.85 (2Η, q), 3.71 (1Η, s), 3.37 (2H, s),

2.60-2.80 (4H, m), 2.15-2.40 (4H, m), 0.80 (3H, t) ppm.

Preparation 4

Ethyl 2- (1-benzyl-4- (2-naphthyl) piperidin-4-yl) ethanoate

A solution of potassium hydroxide (10 g) in water (30 mL) was added to a solution of ethyl 2-cyano-2- (1-benzyl-4- (2-naphthyl) piperidin-4-yl) ethanoate (5.9 g) (see Preparation 3) in ethanol (40 mL) to give a suspension which is stirred at room temperature overnight and then heated on a steam bath until a clear solution is formed. This solution is divided into two microwave containers and microwaved at 690 kPa at 100% intensity for 5 hours. The solutions were then combined, the solvent was removed under reduced pressure and the residue azeotroped four times with toluene to remove any residual water. The residue was dissolved in ethanol (250 mL), cooled in an ice bath, and saturated with hydrogen chloride gas until a precipitate formed. The mixture was allowed to stand at room temperature for 3 days, filtered and the solvent was removed from the filtrate under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 98: 2 to 96: 4, v / v, dichloromethane and methanol. to give the hydrochloride of the title compound. The hydrochloride salt is partitioned between dichloromethane and

-45 4 4 4 4 4 4 4 4 4 44 44 saturated aqueous sodium carbonate, the organic phase is separated, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound (3.6 g) as an oil.

H-NMR (CDC1 _3): 6 = 7.70-7.85 (4H, m), 7.40-7.52 (3H, m), 7.20-7.32 (5H, m), 3 2.78 (2H, q), 3.41 (2H, s), 2.58-2.70 (4H, m), 2.30-2.50 (4H, m), 2.10-2.20 (2H, m), 0.84 (3H, t) ppm.

Preparation 5

4- (2-naphthyl) -4- (2-hydroxyethyl) -N-benzylpiperidine

Ethyl 2- (1-benzyl-4- (2-naphthyl) piperidin-4-yl) ethanoate (5.8 g) (see Preparation 4) was dissolved in anhydrous diethyl ether (100 mL), cooled from an ice bath. and lithium aluminum hydride (0.57 g) was added portionwise. The mixture was stirred at room temperature for 30 minutes, then water (0.8 ml) was carefully added followed by 2 N aqueous sodium hydroxide solution (0.8 ml) and then water (1.6 ml) again. The mixture was stirred for 20 minutes 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 again removed under reduced pressure to give 4- (2-naphthyl) -4- ( 2-hydroxyethyl) -N-benzylpiperidine (2.2 g) as a white solid.

• · · · · · · · · · · · · · · · · · · ·

The granular precipitate is triturated with dichloromethane and filtered. The filtrate was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a second crop of 4- (2-naphthyl) -4- (2-hydroxyethyl) -N-benzylpiperidine (2.7 g) in white solid.

@ 1 H-NMR (CDCl3): .delta. = 7.75-7.86 (3H, m), 7.70 (1H, s), 7.43-7.50 (3H, m), 7.20-7 35 (5H, m), 3.35-3.45 (4H, m), 2.60-2.70 (2H,

m), 2.25-2.40 (4H, m), 1.92-2.04 (4H, m), 0.90 (1H, broad s) ppm.

Preparation 6

4- (2-naphthyl) -N-benzylquinuclidinium-4-methylphenyl sulfonate

4- (2-naphthyl) -4- (2-hydroxyethyl) -N-benzylpiperidine (4.9 g) (see Preparation 5) was dissolved in pyridine (30 mL) and cooled in an ice bath, then 4 methyl methylsulfonyl chloride (3.0 g). The mixture was left at 0 ° C for 16 hours and then the solvent was removed under reduced pressure. The residue is suspended in 10% w / w. aqueous potassium carbonate solution (120 mL) and extracted with toluene (2 x 130 mL). The combined organic phases were washed with 10% w / w. aqueous potassium carbonate solution, dried over anhydrous potassium carbonate for 10 minutes and filtered.

-47 • ·· ·

The filtrate was collected and the volume was reduced to ~ 60 mL under reduced pressure to give a suspension. This was then heated at 90 ° C for 6 hours, allowed to stand at room temperature overnight, and the resulting precipitate was filtered off. The precipitate was washed sequentially with toluene and diethyl ether and dried to give 4- (2-naphthyl) -N-benzylquinuclidinium-4-methylphenylsulfonate (3.5 g) as a white solid.

δ-NMR (CDCl ₃ ): δ = 7.90 (2H, d), 7.78 (3H, m), 7.30-7.65 (9H,

m), 7.16 (2H, d), 4.89 (2H, s), 3.80-3.95 (6H, m), 2.31 (3H,

s), 2.13-2.29 (6H, m) ppm.

Preparation 7

4- (2-naphthyl) quinuclidine

4- (2-naphthyl) -N-benzylquinuclidinium-4-methylphenylsulfonate (3.5 g) (see Preparation 6) was dissolved in methanol (35 ml), 10% w / w added. palladium on carbon (0.5 g) and the mixture was hydrogenated for 40 hours at 50 psi. The mixture was then filtered through a short Arbacel column (trademark) and the solvent was removed from the filtrate under reduced pressure to give a residue. This was partitioned between diethyl ether 1 N aqueous sodium hydroxide solution. The two phases were separated and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined and the solvent was removed under reduced pressure. The resulting residue was washed sequentially with 0.88 sodium chloride and then quenched

Dissolve in ethyl acetate and dry the solution with aqueous ammonia solution and dry over anhydrous sodium sulfate. The solvent was again removed under reduced pressure to give 4- (2-naphthyl) quinuclidine (1.56 g) as a solid.

¹ H-NMR (CDCl ₃ ): δ = 7.80 (3H, d), 7.63 (1H, s), 7.40-7.52 (3H,

m), 3.00-3.15 (6H, m), 1.82-1.96 (6H, m) ppm.

Preparation 8

Ethyl 2-cyano-2- (1-benzyl-4- (3,5-dimethylphenyl) piperidin-4-yl) ethanoate

Dissolve 1,3-dimethyl-5-bromobenzene (15.6 g) in anhydrous diethyl ether (60 mL) and add to a vigorously stirred mixture of magnesium shavings (2.2 g) and 2-3 iodine crystals under a nitrogen atmosphere. A slight heating is applied to initiate the formation of the Girgnard reagent, and once the spontaneous boiling has dropped, the mixture is refluxed for an additional 30 minutes. The mixture was cooled in an ice bath and a solution of ethyl 2- (1-benzylpiperidin-4-ylidene) -2-cyanoacetate (8.0 g) (see Preparation 2) in anhydrous tetrahydrofuran (80 mL) was added over 20 minutes. The mixture was stirred at 0 ° C for 15 minutes, then allowed to stand at room temperature for 3 days. The mixture was then poured into a saturated aqueous ammonium chloride solution (300 mL) and extracted twice with diethyl ether. Organic ··· ·

-49 ·· ·· ··· · · · · · · · · · ·

9 9 9

The 99 extracts were combined and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 3: 0 to 3: 1, v / v, dichloromethane and diethyl ether to afford the title compound (4, (G) in the form of an oil.

¹ H-NMR (CDCl ₃ ): δ = 7.20-7.35 (5H, m), 6.91 (3H, s), 3.94 (2H,

q), 3.61 (1H, s), 3.40 (2H, s), 2.40-2.70 (4H, m), 2.30 (6H,

s), 2.10-2.22 (4H, m), 1.00 (3H, t) ppm.

Preparation 9

Ethyl 2- (1-benzyl-4- (3,5-dimethylphenyl) piperidin-4-yl) ethanoate

A solution of potassium hydroxide (3.4 g) in water (20 ml) was added to a solution of ethyl 2-cyano-2- (1-benzyl-4- (3,5-dimethylphenyl) piperidin-4-yl) ethanoate (4). 7 g) (see Preparation 8) in ethanol (24 ml) and the mixture was microwaved at 345 kPa at 100% intensity for 2.5 hours. The solvent was removed under reduced pressure and the residue azeotroped with toluene to remove any residual water. The residue was dissolved in ethanol (100 mL), cooled in an ice bath, and saturated with hydrogen chloride gas. The mixture was allowed to stand at room temperature overnight, then re-saturated with hydrogen chloride gas and allowed to stand for an additional 24 hours. The solution is filtered and the solvent is removed from the filtrate under reduced pressure to give a residue which is dissolved in

-50444 4

4 * 44 • 4

4 «44

4 4 ·

4 4 ·

4 4 4

4 4 ·

44 saturated aqueous sodium carbonate solution and extracted twice with dichloromethane. 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 eluting with a solvent gradient of 97: 3 to 90:10, v / v, dichloromethane and methanol to give the title compound. title compound (2.0 g) as an oil.

@ 1 H-NMR (CDCl3): .delta. = 7.20-7.35 (5H, m), 6.90 (2H, s), 6.82 (1H,

s), 3.80-3.90 (2H, q), 3.43 (2H, s), 2.50-2.63 (4H, m),

2.20-2.40 (10H, m), 1.92-2.08 (2H, m), 0.95-1.03 (3H, t) ppm.

Preparation 10

4- (3,5-dimethylphenyl) -4- (2-hydroxyethyl) -N-benzylpiperidine

Ethyl 2- (1-benzyl-4- (3,5-dimethylphenyl) piperidin-4-yl) ethanoate (2.0 g) (see Preparation 9) was dissolved in anhydrous diethyl ether (50 mL), cooled in a bath. Lithium aluminum hydride (0.21 g) was added portionwise with ice. The mixture was stirred at room temperature for 45 minutes, water (0.3 mL) was carefully added, followed by 2 N aqueous sodium hydroxide solution (0.3 mL) followed by water (0.6 mL). The mixture was stirred for 20 minutes and the resulting granular precipitate was removed by filtration and washed with diethyl ether. 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 re-evaporated.

Removal of the product under reduced pressure affords 4- (3,5-dimethylphenyl) -4- (-). 2-hydroxyethyl) -N-benzylpiperidine (1.67 g) as an oil.

@ ¹ H-NMR (CDCl3): .delta. = 7.20-7.35 (5H, m), 6.90 (2H, s), 6.83 (1H, s), 3.32-3.43 (4H) m), 2.54-2.64 (2H, m), 2.13-2.37 (11H, m), 1.80-1.90 (4H, m) ppm.

Preparation 11

4- (3,5-dimethylphenyl) -N-benzylquinuclidinium-4-methylphenyl sulfonate

4- (3,5-Dimethylphenyl) -4- (2-hydroxyethyl) -N-benzylpiperidine (1.6 g) (see Preparation 10) was dissolved in pyridine (10 mL), cooled in an ice bath, and stirred for 10 min. 4-Methylphenylsulfonyl chloride (1.0 g) was added in 4 portions. The mixture was left at 0 ° C for 16 hours, then the solvent was removed under reduced pressure. The residue is suspended in 10% w / w. aqueous potassium carbonate solution (30 mL) and extracted with toluene (50 mL). The organic phase is washed with 10% w / w. aqueous potassium carbonate solution, dried over anhydrous potassium carbonate and filtered. The filtrate was collected and the volume was reduced to 1212 mL under reduced pressure to give a suspension which was then heated to 90 ° C for 3 hours, allowed to cool to room temperature and volume.

Reduce to ~ 5 ml when the product starts to precipitate out of solution. -52 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Diethyl ether (30 mL) was added, the precipitate was filtered off, washed with diethyl ether and dried to give 4- (3,5-dimethylphenyl) -N-benzylquinuclidinium-4-methylphenylsulfonate (1.59 g) as a white solid. .

1 H-NMR (CDC1 _3): δ = 7.96 (2H, d), 7.58 (2H, d), 7,30-7,40 (3H, m), 7, 16 (2H, d), 6.96 (1H, s), 6.75 (2H, s), 4.86 (2H, d), 3,72-3 82 (6H, m), 2.34 (3H, s), 2.25 (6H, s), 2.05-2.12 (6H,

m) ppm.

Preparation 12

4- (3,5-dimethylphenyl) quinuclidine

4- (3,5-dimethylphenyl) -N-benzylquinuclidinium-4-methylphenylsulfonate (1.4 g) (see Preparation 11) was dissolved in methanol (14 mL), 10% w / w added. palladium on carbon (0.2 g) and the mixture is hydrogenated for 40 hours at 50 psi. The mixture was then filtered through a short Arbacel column (trademark) and the solvent was removed under reduced pressure to give a residue. This was partitioned between diethyl ether and 1 N aqueous sodium hydroxide solution. The two phases were separated and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined and the solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was washed with brine and then dried over anhydrous sodium sulfate. The solvent was again removed under reduced pressure to give 4- (3,5-dimethylphenyl) quinuclidine (0.59 g) as a white solid.

@ 1 H-NMR (CDCl3): .delta. = 6.89 (2H, s), 6.83 (1H, s), 2.95-3.05 (6H,

m), 2.33 (6H, s), 1.70-1.81 (6H, m) ppm.

Preparation 13

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

Sodium hydride (60% w / w dispersion in mineral oil) (4.73 g) was suspended in tetrahydrofuran (70 mL) under nitrogen and the mixture was cooled in an ice bath. A solution of 3,4-dichlorophenylacetonitrile (20 g) in tetrahydrofuran (80 mL) was added dropwise over 35 minutes, allowed to warm to room temperature and then allowed to stir 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 under reflux 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 gel using 80:20, v / v, ethyl acetate and hexane as eluent to give the product as an orange mobile oil. This oil was dissolved in methanol, cooled in ice and the precipitate formed.

4444

-544 · 4

4 ·

4 4 4 ·

4 4

4 4

444

44

4 4 4

4 4 4

4 4 4 4

44 was filtered, washed with methanol and dried under reduced pressure to give 2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propanenitrile (15.8 g) as a white solid.

¹ H-NMR (CDCl ₃ ): 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 14

2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propan-1-al

2- (3,4-Dichlorophenyl) -3- (1,3-dioxolan-2-yl) propanenitrile (64 g) (see Preparation 13) was suspended in anhydrous toluene (500 mL) and cooled under a nitrogen atmosphere to - 70 ° C. Diisobutylaluminum hydride (200 mL of a 1.5 M solution in toluene) was added over 50 minutes, during which time a clear solution was formed. The mixture was stirred at -70 ° C for an additional 30 minutes and then allowed to warm slowly to -20 ° C. Water (24 mL) was carefully added (exothermic) and the mixture was poured into a 15% (w / w) aqueous citric acid solution (1800 mL). Toluene (100 mL) was added and the mixture was stirred vigorously for 1 hour. The resulting emulsion was filtered through a short Arbacel column (trademark) to give two clear phases which were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propane- 1-a1 as a yellow oil (53.5 g).

• 9999 99 9999 99 99 • 9 9 • • 9 • « 9 9 * 9 • « 9 9 9 • • 9 9 • 9 • 9 9 9 9 9 9 99 9 · 99 999 9 · 99

¹ H-NMR (CDCl 3): δ = 9.90 (1H, s), 7.10-7.50 (3H, m), 4.89 (1H, t), 3.70-4.00 (5H) m, 1.45-1.55 (1H, t), 2.20-2.10 (1H, m) ppm.

Preparation 15

2- (3,4-Dichloro-phenyl) -3- (1,3-dioxolan-2-yl) -propan-1-ol

To an ice-cooled solution of 2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propan-1-al (53.5 g) (see Preparation 14) in ethanol (40 mL) over 40 min. 300 ml) was added in two portions sodium borohydride (5 g). The mixture was stirred for an additional 30 minutes and then the solvent was removed under reduced pressure to give a residue. This was suspended in water (200 mL), cooled to 0 ° C and acidified (pH <6) with glacial acetic acid. Dichloromethane was added and the aqueous phase was basified (pH > 8) by addition of solid sodium carbonate. An additional amount of dichloromethane (200 mL) was added and the organic and aqueous phases were separated. The aqueous phase was further extracted with dichloromethane (200 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 2- (3,4-dichloro99).

-56 in the form

9999

9 *

Phenyl) -3- (1,3-dioxolan-2-yl) propan-1-ol (54.6 g) yellow oil.

9 9

9 · · · ·

9 9 ^X H-NMR (CDC1 _3): δ = 7.30-7.45 (2H, m), 7.09 (1H, dd), 4.79 (1H,

t), 3.70-4.00 (6H, m), 2.97-3.08 (1H, m), 1.96-2.09 (3H, m) ppm.

Preparation 16

1-Methanesulfonyloxy-2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propane

Methanesulfonyl chloride (5.5 g) was added over 10 minutes to an ice-cooled solution of 2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propan-1-ol (12 g) (see Preparation 15) and triethylamine (5.7 g) in dichloromethane (100 mL). The mixture was stirred for 30 minutes before additional dichloromethane (50 mL) was added. The solution was then washed sequentially with water (3 x 50 mL) and brine (50 mL), then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 1-methanesulfonyloxy-2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propane as a yellow oil (15.6 g), which solidified on standing.

1 H-NMR (CDCl ₃ ): δ = 7.41 (1H, d), 7.34 (1H, d), 7.10 (1H, dd), 4.75 (1H, t), 4.26 -4.43 (2H, m), 3.90-4.00 (2H, m), 3.80-3.87 (2H, m), 3.30 (1H, m), 2.90 (3H) s), 2.00-2.10 (2H, m) ppm.

-57Preparation 17

1- (Imidazol-1-yl) -2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propane

MeOjS

1-Methanesulfonyloxy-2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propane (15.5 g) (see Preparation 16) and the imidazole (9 g) was dissolved in anhydrous acetonitrile (100 mL) and the mixture was heated to boiling for 90 hours. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (100 ml) and the solvent was removed again under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and washed with enough aqueous sodium carbonate solution to bring the pH of the aqueous phase to 14. The two phases were separated and the aqueous phase was extracted with dichloromethane (100 mL). The organic phases were then combined and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel, eluting with a solvent gradient of 99: 1 to 95: 5, by volume, dichloromethane and methanol, to give 1- (imidazole-1). -yl) -2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propane (11.1 g) as an orange oil.

¹ H-NMR (CDCl ₃ ): δ = 6.95-7.40 (4H, m), 6.85 (1H, dd), 6.69 (1H, s), 4.69 (1H, m) 4.15-4.25 (1H, m), 3.70-4.10 (5H, m), 3.15-3.25 (1H, m), 1.90-2.10 (2H, m) ppm.

Preparation 18 • ·

-58 · · fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl f fl ·· flfl flfl

3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-al

To an ice-cooled solution of 1- (imidazol-1-yl) -2- (3,4-dichlorophenyl) -3- (1,3-dioxolan-2-yl) propane (11 g) (see Preparation 17) in tetrahydrofuran ( 100 ml) was added a 5 N aqueous hydrochloric acid solution. The mixture was allowed to warm slowly to room temperature and then allowed to stand for 24 hours. Tetrahydrofuran was removed under reduced pressure and the acidic phase was extracted with dichloromethane (2 x 100 mL). The organic phases were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 97.5: 2.5 to 95: 5, v / v, dichloromethane and methanol to afford

3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-al (4.4 g) as a viscous oil.

¹ H-NMR (CDClj) δ = 9.70 (1H, s) , 7.38 (1H, d), 7.20-7.30 (2H, m), 7, 01 (1H, s), 6.89 (1 H, dd) , 6.71 (1H, s), 4.00-4.22 (2H, m), 3, 60 (1H, m), 2.72-2.92 (2H, m) ppm

Preparation 19

3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol

-59 • ·····························································

Sodium borohydride (0.52 g) was added over three minutes to an ice-cooled solution of 3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-alu (3.3 g). (see Preparation 18) in ethanol (25 mL). The mixture was stirred for an additional hour and then the solvent was removed under reduced pressure to give a residue. The residue was then suspended in water (50 mL), cooled to 0 ° C, and the mixture was first acidified to pH 1 with 2N aqueous hydrochloric acid and then basified to pH 14 by addition of solid sodium carbonate, then extracted with ethyl acetate (3 mL). 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol (2.84). (g) in the form of a cream solid.

¹ H-NMR (CDCl ₃ ): δ = 7.35 (1H, d), 7.15-7.30 (2H, m), 6.95 (1H, s), 6.89 (1H, d) 6.70 (1H, s), 4.00-4.25 (2H, m), 3.60-3.70 (1H, m), 3.40-3.50 (1H, m), 3 15-3.30 (1H, m), 2.10 (1H, broad s), 1.75-2.00 (2H, m) ppm.

Preparation 20

4-Cyano-4- (3,4-dichlorophenyl) but-1-ene

-60 • ···· * * 9999 ·· ·>

9 9 9999 9 99 9 99 99 ······

99 9 9999

999 99 99 99 99

Dissolve 3,4-dichlorophenylacetonitrile (80 g) in anhydrous tetrahydrofuran (800 mL) under nitrogen, cool to -70 ° C and add lithium diisopropylamide (320 mL of a 1.5 M solution in cyclohexane). The mixture was stirred at -70 ° C for 30 minutes, allyl bromide (63 g) was added over 15 minutes, and the mixture was stirred for an additional 30 minutes. A 2 N aqueous hydrochloric acid solution (600 mL) was then added and the mixture was extracted twice with diethyl ether. The organic extracts were combined and the solvent was removed under reduced pressure. The resulting residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a red mobile oil. This was chromatographed on silica gel eluting with 4: 1, v / v, hexane and dichloromethane to give 4-cyano-4- (3,4-dichlorophenyl) -but-1-ene as an oil.

1 H-NMR (CDCl ₃ ): δ = 7.40-7.51 (2H, m), 7.14-7.21 (1H, m),

5.70-5.95 (1H, m), 5.13-5.27 (2H, m), 3.84 (1H, t), 2.56-2.70 (2H, m) ppm.

Preparation 21

4- (3,4-dichlorophenyl) -4-formylbut-1-ene

4-Cyano-4- (3,4-dichlorophenyl) but-1-ene (13 g) (see Preparation 20) was dissolved in anhydrous toluene (100 mL) and cooled to -70 ° C under a nitrogen atmosphere. Diisobutylaluminum hydride (50 mL of a 1.5 M solution in toluene) was added over 30 minutes, the mixture was stirred at -70 ° C for an additional 30 minutes and then allowed to warm slowly to -10 ° C. Water (6 ml) was carefully added (exothermic reaction), then the mixture was poured into a 15% (w / w) aqueous citric acid solution (500 ml), then additional toluene (300 ml) was added and stirred vigorously for 30 minutes. The two phases were separated, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4- (3,4-dichlorophenyl) -4-formylbut-1-ene as an oil. (14 g).

^Χ Η-ΝΜΗ (CDCl 3): δ = 9.68 (1H, s), 7.48 (1H, d), 7.31 (1H, s),

7.03 (1H, d), 5.61-5.77 (1H, m), 4.94-5.13 (2H, m), 3.56-3.65 (1H, m), 2, 77-2.91 (1 H, m), 2.40-2.54 (1 H, m) ppm.

Preparation 22

4- (3,4-dichlorophenyl) -5-hydroxypent-1-ene

Cl

Cl

-62 • 9 9 4 9 9 4 9999

9 9 9 4 9 • 4 · 9 4 4 9

9 9 9 9 • 99 * 99 94

Sodium borohydride (2.2 g) was added in four portions to an ice-cooled solution of 4- (3,4-dichlorophenyl) -4-formylbut-1-ene (13 g) (see Preparation 21) in ethanol (100 ml) over 10 minutes. ml). After stirring for an additional 30 minutes, the solvent was removed under reduced pressure to give a residue. This was suspended in water (50 mL), cooled to 0 ° C and acidified (pH <6) with a 2 N aqueous acid solution

The mixture was extracted three times with dichloromethane, combined and the solvent was removed. Dichloromethane (200 mL) was then added, the mixture was stirred and filtered, and the solvent was removed from the filtrate under reduced pressure to give an oil. This oil was chromatographed on silica gel eluting with dichloromethane to give 4- (3,4-dichlorophenyl) -5-hydroxypent-1-ene (7 g) as an orange oil.

¹ H-NMR (CDCl ₃ ): δ = 7.24-7.45 (2H, m), 7.06 (1H, dd), 5.61-5.75 (1H, m), 4.96- 5.10 (2H, m), 3.70-3.90 (2H, m), 2.80-2.91 (1H, m), 2.30-2.55 (2H, m), 1, 32 (1 H, t) ppm.

Preparation 23

4- (3,4-dichlorophenyl) -5- (methanesulfonyloxy) pent-1-ene hydrochloride. organic phase of reduced pressure.

To an ice-cooled solution of 4- (3,4-dichlorophenyl) -5-hydroxypent-1-ene (4.3 g) (see Preparation 22) and triethylamine (2.5 g) in dichloromethane (50 mL) was added over 10 minutes add a solution

-63 • ···· · fc · ** ** · »9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 ** 99

9 9 9 9 9

9 9 9 9 9 99 9 · 99 methanesulfonyl chloride (2.3 g) in dichloromethane (10 ml). The mixture was stirred for an additional 30 minutes, then washed successively with water (3 x 25 mL) and brine (25 mL), and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 4- (3,4-dichlorophenyl) -5- (methanesulfonyloxy) pent-1-ene (5.4 g) as an oil.

¹ H-NMR (CDCl 3): δ = 7.42 (1H, d), 7.30 (1H, s), 7.04 (1H, dd), 5.56-5.72 (1H, m), 5 01-5.10 (2H, m); 4.22-4.39 (2H, m) ppm.

(and his

3.05-3.05 (1 H, m), 2.88 (3H, s), 2.33-2.60 (2 H, m)

Preparation 24

- (3,4-dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene hydrochloride salt

4- (3,4-dichlorophenyl) -5- (methanesulfonyloxy) pent-1-ene (5.4 g) (see Preparation 23) and imidazole (3.6 g) were dissolved in anhydrous acetonitrile (40 ml) and the mixture was heated to reflux for 100 hours. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane and

se

The residual solvent was removed under reduced pressure, dissolved in dichloromethane (100 ml) and washed with sufficient aqueous sodium carbonate solution until the aqueous phase reached pH 14. The two phases were separated and the aqueous phase was extracted with dichloromethane (100 ml). The organic phases were combined and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 100: 0 to 98: 2, v / v, dichloromethane and methanol to afford 4- (3,4-dichloro). -64 • 99 99 99 9999 9 · 99 »9 9 9 * 9 · * 9 ♦ • 9 9 9999 9 9 9 9

9,999,999 9 9 9 9,999,999 9

99 »· 99999 99 99 phenyl) -5- (imidazol-1-yl) pent-1-ene (3.45 g) as an orange oil.

¹ H-NMR (CDCl 3): δ = 7.35 (1H, d), 7.15-7.30 (2H, m), 6.99 (1H,

s), 6.84 (1H, d), 6.69 (1H, s), 5.55-5.70 (1H, m), 5.07 (2H, d), 3.95-4.22 (2H, m), 2.95-3.10 (1H, m), 2.32-2.45 (2H, m) ppm.

The hydrochloride salt is prepared by dissolving the free base in dichloromethane, treating the solution with hydrogen chloride gas, and removing the solvent under reduced pressure to give 4- (3,4-dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene hydrochloride in the form of foam.

Preparation 25 (Alternative to Preparation 18)

3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-al

4- (3,4-dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene hydrochloride (3.6 g) (see Preparation 24) was dissolved in a mixture of acetonitrile (50 mL) and water (20 mL). ml) and osmium tetroxide (4 ml of a 0.05 M solution in toluene) was added. The mixture was stirred for 30 minutes, sodium periodate (5.3 g) was added and stirring was continued for 2 hours. An additional portion of acetonitrile (20 mL) was added and stirring was continued for 16 hours, after which the organic solvent was removed under reduced pressure to give an aqueous suspension. This was basified to pH > 7 by addition of solid sodium carbonate. The mixture is then extracted with dichloromethane, the organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure to remove the solvent.

-65 · t t t t t t • • • • • • • • • • • • • • 65 • 65 65 65 65 65 65 65 65 This gives a dark oil which is chromatographed on silica gel, eluting with a solvent gradient of 98: 2 to 92.5: 7.5, v / v, dichloromethane and methanol, to give 3- (3,4-dichlorophenyl) -4- (imidazole-1-). yl) butan-1-al (2.28 g) as a colorless viscous oil.

NMR (CDCl 3): δ = 9.70 (1H , s) 7.38 (1 H, d), 7,20-7,30 (2H, m), 7, 01 (1 H, s), 6.89 (1 H, dd), 6.71 (1 H, s), 4.00-4.22 (2H, m), 3, 60 (1H, m), 2.72-2.92 (2H, m) ppm.

Preparation 26

2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butanenitrile

To a mixture of sodium hydride (60% w / w dispersion in mineral oil) (19.24 g) and anhydrous tetrahydrofuran (450 mL) under a nitrogen atmosphere at 0 ° C was added dropwise a solution of 3,4- dichlorophenylacetonitrile (89.5 g) in anhydrous tetrahydrofuran (450 mL). After an additional 30 minutes, a solution of 2- (2-bromoethoxy) tetrahydropyran (100 g) in anhydrous tetrahydrofuran (100 mL) was added. The mixture was allowed to warm to room temperature and then stirred for 14 hours. 30% w / w is added. aqueous ammonium chloride solution (500 mL) and the mixture was extracted with diethyl ether (2 x 400 mL). The organic extracts were combined, washed with water (2 x 400 mL), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel, eluting with a solvent gradient of 1: 9 to 1: 1, by volume, diethyl ether and hexane, to give 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-66). · * 9 f f f f f f • • • • • • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

-2-yloxy) butanenitrile diastereoisomers.

¹ H-NMR (CDCl ₃ ) (mixture 2 7.20-7.25 (1H, m),

2.80-2.95 (2H, (51 g) as an oil and as a mixture of diastereoisomers): δ 4.50-4.60 (1H, m),

2.40-2.65 (2 H, m),

= 7.25-7.50 (2H, m) 4.00-4.10 (1H, m), 2,05-2,30 (2H, m),

1.50-1.90 (6H, m) ppm

Preparation 27

2- (3,4-dichlorophenyl) -4-tetrahydropyran-2-yloxy) butan-1-al

2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butanenitrile (20.2 g) (see Preparation 26) was dissolved in anhydrous toluene (300 mL) and cooled to -78 ° C in nitrogen atmosphere. Diisobutylaluminum hydride (85.6 mL of a 1.0 M solution in toluene) was then added dropwise. The mixture was stirred at -78 ° C for 1.5 hours and then allowed to warm slowly to -40 ° C. Water (100 mL) and saturated aqueous ammonium chloride solution (50 mL) were carefully added (exothermic) and the mixture was allowed to warm to 10 ° C, then additional water (100 mL) and saturated aqueous ammonium chloride solution (50 mL) were added. ). 10% w / w was added. aqueous Rochelle's salt (sodium potassium tartrate-tetrahydrate) solution (400 mL) and the mixture was extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the crude product. This was chromatographed on silica gel

Eluting with a 98: 2 by volume mixture of dichloromethane and methanol to give 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) -67-9; butan-1-al (17.02 g) as a yellow oil and as a mixture of diastereoisomers.

¹ H-NMR (CDCl ₃ ) (mixture of two diastereoisomers): δ = 9.70 (1H, s)

7.44 (1H, d), 7.32 (1H, m), 7.06 (1H, m), 4.55 (0.5H, t), 4.46 (0.5H, t), 3 20-3.90 (6H, m), 2.35-2.50 (1H, m), 1.45-2.00 (6H, m) ppm.

Preparation 28

- (3,4-Dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butan-1-ol

Sodium borohydride (2.03 g) was added portionwise to a solution of 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butan-1-alu (17.02 g) (see Preparation 27) in Of 2-propanol (250 mL). The mixture was stirred at room temperature overnight and glacial acetic acid (4 mL) was added carefully followed by water (2 mL). The solvent was removed under reduced pressure to give a residue which was dissolved in dichloromethane and washed sequentially with water, dilute aqueous sodium bicarbonate solution and brine. The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel eluting with 1: 1 v / v ethyl acetate / hexane to give 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butan-1-ol (14.7 g). ) as a colorless oil and as a mixture of diastereoisomers.

«4 ··» · »» »» »4

4 9 9 9 9 9 4 · 4 * · 4 · · 9 «i 9 9 4 • 4 9 9» 9 9 9 »_gg_ 4 ··. ¹ H-NMR (CDCl ₃ ) (mixture of two diastereoisomers): δ = 7.30-7.40 (2H, m), 7.09 (1H, d), 4.55 (0.5H, t), 4.46 (0.5H, t), 3.24-3.82 (6H, m), 2.90-3.00 (1H, m), 1.45-2 10 (9H, m) ppm.

Preparation 29 1-Methanesulfonyloxy-2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane

Methanesulfonyl chloride (2.4 mL) was added dropwise to an ice-cooled solution of 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butan-1-ol (8.13 g) (see Preparation 28). and triethylamine (5.32 mL) in dichloromethane (100 mL) under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0 ° C and then for 90 minutes at room temperature, then washed twice with water. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the crude product. This was chromatographed on silica gel eluting with 95: 5, v / v, dichloromethane and diethyl ether to give 1-methanesulfonyloxy-2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane (8.85 g) in the form of a yellow oil and as a mixture of diastereoisomers.

¹ H-NMR (CDCl ₃ ) (mixture of two diastereoisomers): δ = 7.42 (1H, d),

7.32 (1H, dd), 7.09 (1H, m), 4.30-4.50 (3H, m), 3.20-3.80 (5H, m), 2.89 (3H, m) s), 2.05-2.15 (1H, m), 1.50-1.95 (7H, m) ppm.

-699 9900 99 9900 99 99

9 ··· ♦ ♦ ·

9 9 9999 9 9 9 9 · 9 9 9

9 9 9 9 9

9999 99999 »

Preparation 30

1- (Imidazol-1-yl) -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane

1-methanesulfonyloxy-2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane (10 g) (see Preparation 29), imidazole (2.07 g) and potassium carbonate (7.65 g) Dissolve in anhydrous acetonitrile (50 mL) and heat to reflux under nitrogen for 3 days. The organic solvent was then removed under reduced pressure and the resulting aqueous suspension was partitioned between dichloromethane and water. The organic phase was separated, washed successively with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product is chromatographed on silica gel, eluting with 95: 5, v / v, dichloromethane / methanol to give 1- (imidazol-1-yl) -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy). butane (3 g) as an oil and as a mixture of diastereoisomers.

¹ H-NMR (CDCl ₃ ) (mixture of two diastereoisomers): δ = 7.35 (1H, d),

7.18-7.28 (2H, m), 6.99 (1H, s), 6.88 (1H, m), 6.69 (1H, s),

4.49 (0.5H, t), 4.40 (0.5H, t), 4.00-4.25 (2H, m), 3.10-3.85 (5H, m), 1, 45-2.10 (8 H, m) ppm.

Preparation 31

3- (3,4-Dichlorophenyl) -4- [2- (3,5-dimethylbenzoyl) imidazol-1-yl] butyl 3,4-dimethylbenzoate

-7045 4 4

4 4 »444

4 4 4

444 4 44

4 · 44

4 4 4 4 4 4 4 4 4 4 4

3,5-dimethylbenzoyl chloride (1.33 g) was added dropwise to a suspension of 3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol (0.75 g) (see preparation) 19) and triethylamine (1.1 g) in anhydrous acetonitrile (15 mL) and the solution was stirred at room temperature for 120 hours. The mixture was then treated with water (30 ml) and dichloromethane (50 ml), the organic phase was separated and washed successively with water and brine. The solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 100: 0 to 99: 1, v / v, dichloromethane and methanol to give 3- (3,4-dichlorophenyl) -4- [ 2- (3,5-dimethylbenzoyl) imidazol-1-yl] butyl 3,5-dimethylbenzoate (0.94 g) as a yellow foam.

1 H-NMR (CDCl 3): δ = 7.69 (2H, s) 7.49 (2H, s), 7.10 -7.27 (5H, m) 6.92 (1 H, dd) , 6.81 (1H, s) 4.76 (1H, dd), 4.51 (1H, dd), 4.10-4.30 (2 H, m) , 3.32 (1H, m) 2.35 (6H, s), 2.29 (6H, s),

2.19 (2 H, m) ppm.

Preparation 32

2,3-dihydrobenzo [b] furan-7-enoic acid • 71-

· ♦ · ·

999 · ♦ · 9 9 ·

Ν, Ν, Ν, N'-tetramethylethylenediamine (38 mL) was dissolved in hexane (300 mL), cooled in an ice bath, and n-butyllithium (100 mL of a 2.5 M solution in hexane) was added. The mixture was stirred at 0 ° C for 15 minutes, then 2,3-dihydrobenzo [b] furan (30 g) was added dropwise over 30 minutes. The mixture was allowed to warm to room temperature over 30 minutes, stirred at room temperature for an additional 4 hours, poured into excess solid carbon dioxide and allowed to stand for 3 days, during which time the solvent was evaporated. The residue was partitioned between ethyl acetate (1 L) and 4 N 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 then triturated with diethyl ether to give 2,3-dihydro [b] furan-7-enoic acid as a white solid (21 g).

¹ H-NMR (CDCl 3): δ = 7.75 (1H, d), 7.31 (1H, d), 6.88 (1H, t),

4.69 (2H, t), 3.20 (2H, t) ppm.

Preparation 33

1,2,3,4-tetrahydro-5-naphthoic acid

-72 • 999 * 99 99 * 9 99 99 * 9 9 · 9 * 9 * • 9 9 9999 9 99

9,999 9 ♦ 9 9 9 9 9

99 9 9999

999 «99999 99

To a solution of 1-naphthoic acid (33.4 g) in glacial acetic acid (150 mL) was added 10% w / w. palladium on carbon (10 g), and the mixture is hydrogenated at 50 psi and 85 ° C for 4 days. The warm mixture was filtered through a short Arbacel column (trademark) and the column was washed with glacial acetic acid (150 mL). Water (1.5 L) was added to the filtrate and the resulting precipitate was filtered off and washed with water. The precipitate was dissolved in dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give an oil which was recrystallized from ethyl acetate to give 1,2,3,4-tetrahydro-5-naphthoic acid ( 2.94 g) as a white solid (m.p. 148-150 ° C).

1 H-NMR (CDCl ₃ ): δ = 7.85 (1H, d), 7.28 (1H, d), 7.16 (1H, m), 3.15 (2H, broad s), 2, 84 (2H, broad s), 1.72-1.90 (4H, m) ppm.

Preparation 34

1,2,3,4-tetrahydro-6-naphthoic acid.

1,2,3,4-tetrahydro-6-naphthaldehyde (2.0 g) was suspended in 0.5 M aqueous sodium hydroxide solution (125 ml), stirred vigorously and 70% w / w added. solution of tert-butyl hydroperoxide in water (10.3 mL). The mixture was heated to about 70 ° C for 4 hours and then allowed to stand at room temperature for 3 days. An additional amount of 70% w / w was added. of a solution of tert-butyl hydroperoxide in water (10 mL) and the mixture was heated to about 70 ° C for an additional 24 hours. The mixture was cooled, diethyl ether (100 mL) was added and the phases separated. The aqueous phase was acidified to pH 1 with 2 N aqueous hydrochloric acid

• · ♦ ·· 9 »· 9 9 * • 999 · • • · • • • 9 • · • 9 9 9 999 • 9 9 9 9 9 9 9 • • 9 9 · 999 9 99 9 9 · • · «9

extract with diethyl ether (2 x 100 mL). The organic phases ^with P ° it »dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica using a gradient of 1: 1 to 1: 0, by volume, diethyl ether and pentane to give is obtained

1,2,3,4-tetrahydro-6-naphthoic acid (0.62 g) as a white solid.

¹ H-NMR (CDCl ₃ ): δ = 7.78-7.86 (2H, m), 7.14 (1H, d), 2.78-2.87 (4H, broad s), 1.79 -1.88 (4H, broad s) ppm.

Preparation 35

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

2,3-dihydrobenzo [b] furan-7-enoic acid (3 g) (see Preparation 32) was suspended in anhydrous dichloromethane (30 mL) and oxalyl chloride (3.5 g) was added followed by dimethylformamide (3 drops) . The mixture was stirred at room temperature for 2.5 hours, the solvent was removed 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 yield

2,3-dihydrobenzo [b] furan-7-oyl chloride as a pink solid (3.3 g).

Preparation 36

1,2,3,4-tetrahydro-5-naphthoyl chloride

-4 • ♦ ·

• 9 • 9

999 9 • 9,999 • ·

999

9 ·

999 ·· • 9 9 9 • 9 9 9 • 9 9

9 9 9

99

This compound was prepared analogously to the procedure used in Preparation 35 using 1,2,3,4-tetrahydro-5-naphthoic acid (see Preparation 33) as starting material.

Preparation 37

1,2,3,4-tetrahydro-6-naphthoyl chloride

This compound was prepared analogously to the procedure used in Preparation 35 using 1,2,3,4-tetrahydro-6-naphthoic acid (see Preparation 34) as the starting material.

Preparations 38 to 46

Compounds of the following preparations summarized in Table 2 of the general formula

• 8 «·· 9 · 9 99 9 9 9999 9 99 9 9 9 9 · 9 • 9 • 9 • 99 9 9 • • • 9 9 9 9 • 9 9 9 9 • 99 9 99 999 9 · 99

was prepared in a similar manner to Preparation 31 using 3- (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol (see Preparation 19) and the appropriate acid chloride as starting materials.

Table 2

event. * / C. default chloride acid R-W- analytical data 38 2,3-dimethyl benzoyl chloride M « ¹ H-NMR (CDC1 _3): δ = 7.47 (1H, d), 7.33 (lH, d), 7.22-7.29 (3H, m), 6,96- 7.15 ( 5H, m), 6.82 (1H, s), 4.83 (1H, dd), 4.64 (1H, dd), 4.27-4.36 (1H, m), 4.09-4 20 (1H, m), 3.32-3.44 (1H, m), 2.41 (3H, s), 2.31 (6H, s), 2.15-2.25 (2H, m) ), 2.15 (3H, s) ppm 39 2-tri- fluoromethoxybenzoyl chloride YES ¹ H-NMR (CDC1 _3): 5 = 7.82 (lH, d), 7.20 -7.65 (9H, m), 7.10 (1H, s), 6.93 (lH, dd) 6.79 (1H, s), 4.86 (1H, dd), 4.53 (1H, dd), 4.30-4.42 (1H, m), 4.12-4.28 (1H m, 3.28-3.42 (1H, m), 2.10-2.30 (2H, m) ppm

-Ί6 flfl fl fll fl fl fll fl fl fll fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl Fl

40 2- methoxy3-methylbenzoyl chloride Mt Me 1 H-NMR (CDCl 3): δ = 7.48 (1H, d), 7.24 -7.36 (4H, m), 7.18 (1H, d), 6.95- 7.09 (4H, m), 6.80 (1H, s), 4.86 (1H, dd), 4.56 (1H, dd), 4.27-4.36 (1H, m), 4.10-4.22 (1H, m), 3.76 (3H, s), 3.66 (3H, s), 3.31-3.43 (1H, m), 2.30 (3H, s), 2.28 (3H, s), 2.08- 2.18 (2 H, m) ppm 41 viz prpr. No 35 ¹ H-NMR (CDCl 3): δ = 7.58 (1H, d), 7.50 (1H, d), 7.20-7.36 (4H, m), 7.08 (1H, s), 6.98 (1H, d), 6.72-6.90 (3H, m), 4.50-4.81 (6H, m), 4.27-4.38 (1H, m), 4, 03-4.15 (1H, m), 3.35-3.49 (1H, m), 3.05-3.28 (4H, m), 2.04-2.23) 2H, m) ppm 42 (note: 2- naphthoyl- @ ¹ H-NMR (CDCl3): .delta. = 8.82 (1H, s), 8.46 (and)) chloride .E (1H, S), 8.15 (1H, d), 7.74-7.99 (8H, m), 7.43-7.64 (4H, m), 7.26 (1H, S), 7.17 (1H, S), 6.98 (1H, d), 6.86 (1H, s), 4.89 (1H, dd), 4.58 (1H, dd), 4.39-4.48 (1H, m), 4.25- 4.30 (1H, m), 3.42-3.52 (1H, m), 2.20-2.38 (2 H, m) ppm 43 3-tri- @ ¹ H-NMR (CDCl3): .delta. = 8.49-8.62 (2H, (note: fluor- CF 1 * (b) methyl-4- A- ^f m), 8.20 (1H, d), 8.04-8.09 (1H, m), fluor- benzoyl- chloride 7.12-7.32 (5H, m), 6.90 (1H, d), 6.82 (1H, s), 4.81 (1H, dd), 4.26- 4.51 (3H, m), 3.29-3.40 (1H, m), 2.20-2.29 (2 H, m) ppm

4 <4 3 4 5 4 9 4 9 9 9 4 4

4 44 44 49 49 99

-ΊΊ-

44 (note) viz prpr. No 36 S6 ¹ H-NMR _(CDCl3): 6 = 7.50 (lH, d), 6.95 to 7.38 (10H, m), 4.83 (1H, dd), 4.63 (lH, m) 4.30-4.35 (1H, m), 4.08-4.16 (1H, m), 3.30-3.40 (1H, m), 3.00 (2H, broad s), 2.63-2.84 (6H, m), 2.10-2.25 (2H, m), 1.67-1.83 (8H, m) ppm 45 (note (c)) viz prpr. No 37 ¹ H-NMR (CDC1 _3): 6 = 7.79 to 7.88 (2H, m), 7.52-7.62 (2H, m), 7.01 to 7.34 (5H, m) 6.90 (1H, dd), 6.79 (1H, s), 4.76 (1H, dd), 4.51 (1H, dd), 4.10-4.32 (2H, m), 3 27-3.40 (1H, m), 2.68-2.91 (8H, m), 2.11-2.26 (2H, m), 1.72-1.91 (8H, m) ppm 46 2- methoxy- 5-chloro- benzoyl- chloride Me @ 1 H-NMR (CDCl3): .delta. = 7.62 (1H, s), 7.32-7.43 (4 H, m), 7.24 (1H, s), 7.07 (1H, s), 7.02 (1H, dd), 6.90 (2H, t), 6.77 (1H, s), 4.87 (1H, dd), 4.49 (1H, dd), 4.30-4.35 (1H, m), 4.11-4.20 (1H, m), 3.86 (3H, s), 3.72 (3H, s), 3.32-3.41 (1H, m), 2.10-2.25 (2 H, m) ppm

Comment:

(a) chromatographed on silica gel eluting with a solvent gradient of 1: 2 to 1: 0, v / v, ethyl acetate and pentane; (b) chromatographed on silica gel eluting with diethyl ether; , ethyl acetate and pentane.

Preparation 47

-78 ··· • · «• · ··· * * 9 9 * 9 9

3- (3,4-dichlorophenyl) -4- (2- (3,5-dimethylbenzoyl) imidazol-1-yl) butan-1-ol

3- (3,4-Dichlorophenyl) -4- (2- (3,5-dimethylbenzoyl) imidazol-1-yl] butyl 3,5-dimethylbenzoate (0.93 g) (see Preparation 31) was dissolved in methanol (10 mL) and 2 N aqueous sodium hydroxide solution (2 mL) was added, a thick gum formed, additional methanol (50 mL) was added, and the resulting suspension was stirred at room temperature overnight. and the residue was partitioned between dichloromethane (50 mL) and water (10 mL) The organic phase was separated, washed with brine and the solvent was removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 99 : 1-95: 5, v / v, dichloromethane and methanol to give 3- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylbenzoyl) imidazol-1-yl] butan-1-ol ( 0.67 g) in the form of a foam.

1 H-NMR (CDCl 3): δ = 7.70 (2H, s), 7.10-7.32 (4H, m), 6.89 (1H, d), 6.72 (1H, s), 4 83 (1H, dd), 4.40 (1H, dd), 3.70-3.80 (1H,

m), 3.50-3.80 (1H, m), 3.28-3.40 (1H, m), 2.40 (6H, s), 1.85-2.07 (3H, m) ppm.

Preparations 48 to 53

• · * ·· ·· in * 99 ·· · • • • 9 9 • · • · • • ·· * 9 9 • * <· • • 9 9 9 • · ·· »· 999 99 99

Compounds of the following preparations summarized in Table 3 of the general formula

were prepared in a similar manner to Preparation 47 using the appropriate starting materials (see Preparations 38-41, 44 and 46).

Table 3

prpr. C. Eastern substance prepar. C. R-W- analytical data 48 38 Me 1 H-NMR (CDCl ₃ ): δ = 7.31 (1H, d), 7.107.28 (4H, m), 7.06 (1H, s), 6.92 (1H, dd), 6.75 ( 1H, s), 4.90 (1H, dd), 4.50 (1H, dd), 4.70-7.81 (1H, m), 3.503.64 (1H, m), 3.30-3 43 (1H, m), 2.29 (3H, s), 2.18 (3H, S), 1.90-2.05 (2H, m), 1.80 (1H, t) ppm 49 39 '70 ¹ H-NMR (CDC1 _3): δ = 7.20-7.64 (6H, m), 7.09 (lH, s), 6.91 (H, d), 6.72 (1H, s) 4.96 (1H, dd), 4.39 (1H, dd), 3.693.83 (1H, m), 3.51-3.67 (1H, m), 3.283.41 (1H, m), 1.87-2.08 (2 H, m), 1.74 (1 H, t) ppm

····

-80 ·· · · · · · · · · · · · · · · · · · · · · · · · ·

9 9

9 9 9

9 9 ·· 99

50 40 Me AND Ύ Me H-NMR (CDC1 _3): 5 = 7.18-7.3 7 (4H, m), 7.05-7.10 (2H, m), 6.93 (lH, dd), 6.72 ( 1H, s), 4.92 (1H, dd), 4.42 (1H, dd), 3.75 (1H, m), 3.70 (3H, s), 3.50-3.62 (1H) , m), 3.31-3.45 (1H, m), 2.32 (3H, s), 1.86-2.02 (3H, m) ppm 51 41 r b @ ¹ H-NMR (CDCl3) .delta. = 7.64 (1H, d), 7.117.38 (3H, m), 7.06 (1H, s), 6.85-6.96 (2H, m) 6.67 (1H, s), 4.89 (1H, dd), 4.60-4.75 (2H, m), 4.35 (1H, dd), 3.63-3.75 (1H) , m), 3.49-3.61 (1H, m), 3.18-3.41 (3H, m), 1.84-2.06 (2H, m), 1.72 (1H, t) ) ppm 52 44 56 ¹ H-NMR (CDCl 3): δ = 7.10-7.3 δ (5H, m), 7.06 (1H, s), 6.92 (1H, dd), 6.74 (1H, s) 4.90 (1H, dd), 4.50 (1H, dd), 3.703.82 (1H, m), 3.53-3.64 (1H, m), 3.30-3.42 (1H , m), 2.70-2.86 (4H, m), 1.70-2.04 (6H, m), 1.70-2.04 (6H, m) ppm 53 46 Me X @ 1 H-NMR (CDCl3): .delta. = 7.30-7.42 (3H, m), 7.19 (1H, s), 7.03 (1H, s), 6.92 (2H, t), 6.69 (1H, S), 4.91 (1H, dd), 4.35 (1H) (dd), 3.50-3.80 (4H, m), 3.503.63 (1H, m), 3.29-3.40 (1H, m), 1.892.0l (2H, m), 1.72 (1 H, t) ppm

Preparation 54

3- (3,4-dichlorophenyl) -4- [2- (2-naphthoyl) imidazol-1-yl] butan-1-ol

Cl

-813- (3,4-dichlorophenyl) -4- [2- (2-naphthoyl) imidazol-1-yl] butyl 2-naphthoate (1.25 g) (see Preparation 42) was dissolved in 1,4-dioxane ( 15 ml), 1 N aqueous sodium hydroxide solution (4 ml) was added and the mixture was stirred at room temperature overnight. The dioxane was then removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed successively with 1 N aqueous sodium hydroxide solution, water and brine and the solvent was removed to give the product under reduced pressure, which was chromatographed on silica gel eluting with a solvent gradient of 99: 1 to 95: 5, v / v , dichloromethane and methanol to give 3- (3,4-dichlorophenyl) -4- [2- (2-naphthoyl) imidazol-1-yl] butan-1-ol (0.8 g) as a gum.

¹ H-NMR (CDCl ₃ ): δ = 8.82 (1H, s), 8.16 (1H, d), 7.99 (1H, d),

7.89 (2H, t), 7.50-7.63 (2 H, m), 7, 26 (1 H, d), 7.16 (1H, (d) 6.90 (1 H, dd), 6.76 (1 H, s) , 4.90 (1H, dd) 4.43 (1H, dd) 3,69-3,83 (1H, m), 3.51-3.68 (1H, m), 3.32-3.45 (1H, (m) 1,86-2,08 (3H, m) ppm.

Preparation 55 to 56

Compounds of the following preparations summarized in Table 4 of the general formula

were prepared in a similar manner to Preparation 54 using the appropriate starting materials (see Preparations 43 and 45).

-82Table 4

prpr. C. Eastern substance prepar. C. R-W- analytical data 55 (note (a)) 43 Λ ¹ H-NMR (CDCl ₃ ): δ = 8.49-8.62 (2H, m), 7.23-7.32 (2H, m), 7.11 (2H, s), 6.86 ( 1H, d), 6.80 (1H, s), 4.85 (1H, dd), 4.47 (1H, dd), 3.70-3.81 (1H, m), 3.52-3 63 (1H, m), 3.29-3.39 (1H, m), 1.89-2.09 (2H, m), 1.71 (1H, broad s) ppm 56 45 @ ¹ H-NMR (CDCl3): .delta. = 7.81-7.91 (2H, m), 7.05-7.32 (4H, m), 6.88 (1H, dd), 6.71 (1H) 4.75 (1H, dd), 4.37 (1H, dd), 3.69-3.80 (1H, m), 3.51-3.66 (1H, m), 3, 07-3.42 (m, m), 2.70-2.92 (4H, m), 1.76-2.05 (6H, m) ppm

Note (a) Chromatograph on silica gel eluting with a solvent gradient of 1: 0 to 0: 1, by volume, diethyl ether and ethyl acetate

Preparation 57

1- [2- (2-methoxybenzoyl) imidazol-1-yl] -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane

Cl

Φ φ φ φ φ φ φ φ φ φ φ φ φ

-83φφ φφ φφφφφ φφφφ φφφφφ φφ φφ

1- (imidazol-1-yl) -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane (0.86 g) (see Preparation 30) and triethylamine (1.3 mL) were added. Dissolve under nitrogen in acetonitrile (15 mL), cool the solution in an ice bath and add 2-methoxybenzoyl chloride (1.4 mL) dropwise. The mixture was allowed to warm slowly to room temperature and then stirred for 2 days. The acetonitrile was removed under reduced pressure and the residue was dissolved in dichloromethane (20 mL) and washed successively with water and brine. The organic phase was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with 97: 3, v / v, dichloromethane and methanol to afford 1- [2- (2- methoxybenzoyl) imidazol-1-yl] -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane (1.1 g) as an oil and as a mixture of diastereoisomers.

¹ H-NMR (CDCl ₃ ) (mixture of two diastereoisomers): δ = 6.76-7.52 (9H,

m), 4.10-4.90 (3H, m), 3.11-3.90 (8H, m), 1.45-2.25 (6H, m),

1.26 (1H, t), 1.06 (1H, t) ppm.

Preparations 58 to 62

Compounds of the following preparations summarized in Table 5 of the general formula

were prepared in a similar manner to Preparation 57 using the appropriate starting materials.

-84Table 5

prpr. C. default chloride acid R-W- analytical data 58 3,5-bis (trifluoromethyl) benzoyl chloride Ά, ¹ H-NMR (CDCl ₃ ) (mixture of two diastereoisomers): δ = 8.71 (2H, d), 8.06 (1H, s), 7.13-7.32 (3H, m), 6.98 (1H, d), 6.85-6.95 (1H, m), 4.40-4.80 (3H, m), 3.60-3.85 (2H, m), 3.20-3 50 (3H, m); 1.43-2.18 (8H, m) ppm 59 2-tri- fluoromethyl benzoyl chloride X ¹ H-NMR (CDCl 3) (mixture of two diastereoisomers): δ = 7.75 (1H, dd), 7.60 (2H, m), 7.43 (2H, m), 7.24 (1H, t) 7.09 (1H, s), 6.97 (1H, m), 6.86 (1H, d), 4.80-4.90 (1H, m), 4.40-4.64 (2H , m), 3.55-3.83 (2H, m), 3.20-3.50 (3H, m), 1.90-2.18 (2H, m), 1.43-1.86 (6H, m) ppm 60 2-iso- propoxy- benzoyl- chloride Me ^^ Me X ¹ H-NMR (CDCl 3) (mixture of two diastereoisomers): δ = 6.75-7.58 (9H, m), 4.38-4.91 (4H, m), 3.203.80 (5H, m), 1.15-2.13 (14H, m) ppm ťfí 2-ethylbenzoyl chloride X ¹ H-NMR (CDCl 3) (mixture of two diastereoisomers): δ = 6.87-7.43 (9H, m), 4.40-4.83 (3H, m), 3.203.82 (5H, m), 2.62-2.75 (2H, m), 1.10-2.10 (11H, m) ppm 62 2- phenoxy- benzoyl- chlordi 9 X ¹ H-NMR (CDCl 3) (mixture of two diastereoisomers): δ = 6.90-7.52 (12H, m), 6.84 (1H, d), 6.67 (1H, d), 4.69- 4.80 (1H, m), 4.29-4.48 (2H, m), 3.12-3.79 (5H, m), 1.41-2.08 (8H, m) ppm

Preparation 63

1-ethoxymethylimidazole

-854 ········ 4444 44 44

4 · · · · ·

4,444 · 444 «

4,444 4 · 4 4 4 ·

44 4444

444 · 4 4 4 · 4 44 · 4

^ '^ ΝΗ \ = J

-> · \ = J

OEt

Imidazole (20 g) was dissolved in tetrahydrofuran (700 mL) in a nitrogen atmosphere, cooled to -70 ° C and n-butyllithium (117.5 mL of a 2.5 M solution in hexane) was added dropwise over 15 minutes. The mixture was allowed to warm to -20 ° C and stirred at -20 ° C for 30 minutes, then chloromethyl ethyl ether (30.5 g) was added dropwise. The mixture was allowed to warm to room temperature and stirring was continued for an additional hour. The solvent was removed under reduced pressure to give a residue which was triturated with dichloromethane and filtered through a short column of Arbacel (trademark). The solvent was removed from the filtrate under reduced pressure to give a mobile oil which was distilled under reduced pressure (71 Pa) to give 1-ethoxymethylimidazole (20.8 g) as an oil.

¹ H-NMR (CDCl 3): δ = 7.61 (1H, s), 7.09 (2H, d), 5.29 (2H, s),

3.49 (2H, q), 1.21 (3H, t) ppm.

Preparation 64 1-Ethoxymethyl-2-phenacetylimidazole

g) (see Preparation 63) tetrahydrofuran (400

1-ethoxymethylimidazole (11.98 dissolved in nitrogen per ml), 99

Cool to -70 ° C and add n-butyllithium (40 mL of a 2.5 M solution in hexane) dropwise over 5 minutes. The mixture was stirred at -70 ° C for 1 hour and chlorotrimethylsilane (10.83 g) was added dropwise. The mixture was stirred at -70 ° C for 1 hour, then allowed to warm to room temperature and stirred for an additional 3 hours. Phenacetyl chloride (14.68 g) was added and stirring was continued for 18 hours, after which time the solvent was removed under reduced pressure. The resulting residue was dissolved in dichloromethane and washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate. The solvent was removed from the organic phase under reduced pressure. The crude product was chromatographed eluting with 95: 5 (v / v) dichloromethane to give 1-ethoxymethyl-2-phenacetylimidazole (8.23 g) as an oil.

^X ~ H-NMR (CDCl₃) δ = 7.19-7.39 (7H, m), 5.72 (2H, s), 4.43 (2H,

s), 3.48 (2H, q), 1.14 (3H, t) ppm.

methanol silica gel,

Preparation 65

2-Phenacetylimidazole

ξ_j OEt

Dissolve 1-ethoxymethyl-2-phenylacetylimidazole (8.23 g) (see Preparation 64) in ethanol (200 mL), add 2 N aqueous hydrochloric acid solution (200 mL) and heat the resulting suspension to reflux for 2 hours. for 30 minutes. An additional amount of ethanol (50 mL) was added to give a solid

• <<

• 9 9 9 9 1

I · · · · · ·

The residual suspended material dissolves and the mixture is refluxed for an additional 6 hours, then allowed to stand at room temperature overnight. The organic solvent was removed under reduced pressure and the resulting aqueous suspension was basified to pH 9 by addition of saturated aqueous sodium bicarbonate solution. The mixture was then extracted (three times) with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 2-phenacetylimidazole (6.29 g) as a yellow solid.

¹ H-NMR (CDC1 _3): δ = 7.19-7.39 (7H, m), 4.40 (2H, s) ppm.

Preparation 66

1- [2-Phenacetylimidazol-1-yl] -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane

1-methanesulfonyloxy-2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane (0.57 g) (see Preparation 29) and 2-phenacetylimidazole (0.27 g) (See Preparation 65) Dissolve in acetonitrile (20 mL). Potassium carbonate (0.41 g) was added and the mixture was heated to reflux in an atmosphere

-88 © 9 9 9 9 99 9999 99 99 • 9 9 9 9 9 9

9 99999 999 »

9,999,999 99 ·

9 · · ·

9999 99 999 9 · ·· nitrogen for 18 hours. The mixture was cooled, the solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue is then chromatographed on silica gel, eluting with 99: 1, v / v, dichloromethane and methanol, to give 1- [2-phenacetylimidazol-1-yl] -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2). -yloxy) butane (0.23 g) as an oil and as a mixture of diastereoisomers.

¹ H-NMR (CDCl ₃ ) (mixture of two diastereoisomers): δ = 7.22-7.38 (6H,

m), 7.05-7.12 (2H, m), 6.71-6.84 (2H, m), 4.64-4.76 (1H, m),

4.28-4.50 (4H, m), 3.10-3.79 (5H, m), 1.42-2.05 (8H, m) ppm.

Preparation 67

3- (3,4-Dichlorophenyl) -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butan-1-ol

1- [2- (2-Methoxybenzoyl) imidazol-1-yl] -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane (1.1 g) (see Preparation 57) was dissolved in methanol (20 ml, Amberlyst 15 (trade mark) ion exchange resin (0.11 g) was added and the mixture was stirred at room temperature for 5 days. The resin was removed by filtration through a short Arbacel column (commercial grade).

-89 ·· «· ·· ······ 9 9 • · • 9 9 9 9 · 9 9

9 9 99 99 99 99

9 9 9 9 9

9 9 9 9 9 9

9 9 9 · 9 9 9 9 9 mark) and the solvent is removed from the filtrate under reduced pressure to give a residue. This was chromatographed on silica gel, eluting with a 97: 3, v / v mixture of dichloromethane and methanol to give 3- (3,4-dichlorophenyl) -4- [2- (2-methoxybenzoyl) imidazol-1-yl] butan-1- ol (0.31 g) as a white foam. ¹ H-NMR (CDCl 3): δ = 7.19-7.48 (4H, m), 6.91-7.06 (4H, m), 6.67 (1H, s), 4.93 (1H , dd), 4.36 (1H, dd), 3.52-3.80 (2H, m), 3.80 (3H, s), 3.30-3.41 (1H, m), 1, 90-2.03 (2H, m), 1.72 (1H, broad s) ppm.

Preparation 68

3- (3,4-dichlorophenyl) -4- [2- [3,5-bis (trifluoromethyl) benzoyl] imidazol-1-yl] butan-1-ol

3- (3,4-dichlorophenyl) -4- [2- [3,5-bis (trifluoromethyl) benzoyl] imidazol-1-yl] butan-1-ol was prepared analogously to the compound of Preparation 67 using the compound of Preparation 58 as starting materials.

¹ H-NMR (CDCl 3): δ = 8.76 (2H, s), 8.08 (1H, s), 7.30 (1H, d),

7.19 (2H, d), 6.85-6.92 (2H, m), 4.88 (1H, dd), 4.50 (1H, dd), 3.71-3.81 (1H, m), 3.51-3.63 (1H, m), 3.30-3.42 (1H, m), 1.90-2.10 (2H, m), 1.71 (1H, t) ppm.

-90Preparation 69

3- (3,4-dichlorophenyl) -4- [2- (2-trifluoromethylbenzoyl) imidazol-1-yl] butan-1-ol

1- [2- (2-Trifluoromethylbenzoyl) imidazol-1-yl] -2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butane (0.68 g) (see Preparation 59) dissolves in methanol (15 ml), which was previously saturated with hydrogen chloride gas, and allowed to stand for 4 hours. The solvent was then removed under reduced pressure to give a residue which was partitioned between dichloromethane and saturated aqueous sodium bicarbonate (maintaining the pH of the aqueous layer at 8-9). The organic phase was separated and the aqueous phase was extracted (twice) with dichloromethane. The organic phases are then combined, dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure to give 3- (3,4-dichlorophenyl) -4- [2- (2-trifluoromethylbenzoyl) imidazol-1-yl] butane 1-ol (0.41 g) as a white foam.

^X H-NMR (CDC1 _3): δ = 7.77 (1H, d), 7.54-7.69 (2 H, m), 7.47 (1H, m), 7.32 (1 H, d), 7.22 (1H, d), 7.07 (1H, s), 6.91 (1H, dd), 6.74 (1 H, S, 4.98 (1H, dd), 4.42 (1H, dd), 3.70-3.81 (1H, m), 3,52-3,67 (LH, m), 3.28 · -3.41 (1H, m), 1.90-2.09 (2H, m), 1.77

(1H, broad s) ppm.

• · ♦ · · • · · • · 99 • ··· • • 99 9 9 9 9 99 9 9 • • • • • · • • • • 9 9 9 • · · 9 ·· 9 9 · 9 9 9 9

Preparations 70 to 73

The compounds of the following Preparations summarized in Table 6, of the general formula

was prepared in a similar manner to Preparation 69 using the appropriate tetrahydropyranyl protected starting materials (see Preparations 60-62 and 66).

Table 6

prpr. in C. Eastern substance prepar. C. R-W- analytical data 70 (note (a)) 60 Xj @ ¹ H-NMR (CDCl3): .delta. = 7.31-7.46 (3H, m), 7.24 (1H, d), 6.91-7.04 (4H, m), 6.85 (1H) S, 4.95 (1H, dd), 4.55 (1H, q), 4.30 (1H, dd), 3.71-3.83 (1H, m), 3.52-3, 66 (1H, m), 3.31-3.44 (1H, m), 1.90-2.05 (2H, m), 1.22 (6H, d) ppm

-92 • 99 · • 9,999

Μ · • 9 9 9 9 9 9

99

71 (note (a)) 61 30 ¹ H-NMR (CDCl ₃ ): δ = 7.19-7.47 (6H, m), 7.09 (1H, s), 6.91 (1H, dd), 6.76 (1H, S) 4.91 (1H, dd), 4.51 (1H, dd), 3.71-3.84 (1H, m), 3.52-3.66 (1H, m), 3.30-3 44 (1H, m), 2.70 (2H, q), 1.90-2.09 (2H, m), 1.86 (1H, broad s), 1.24 (3H, t) ppm 72 62 9 X ¹ H-NMR (CDC1 _3): δ = 6.90 to 7.59 (12H, m), 6.79 (lH, dd), 6.56 (lH, s), 4.86 (1H, dd) 4.17 (1H, dd), 3.62-3.76 (1H, m), 3.48-3.59 (1H, m), 3.15-3.27 (1H, m), 1 82-1.95 (2H, m), 1.76 (1H, broad t) ppm 73 66 Ό ¹ H-NMR (CDC1 _3): 5 = 7.22-7.38 (6H, m), 7.04-7.10 (2H, m), 6.76 (lH, dd), 6.64 ( 1H, s), 4.81 (1H, dd), 4.40 (2H, dd), 4.21 (1H, dd), 3.60-3.70 (1H, m), 3.44-3 55 (1H, m), 3.10-3.21 (1H, m), 1.80-1.91 (2H, m), 1.67 (1H, t) ppm

Note (a) the product is purified by chromatography on silica gel, eluting with a 98: 2 mixture by volume, dichloromethane and methanol

Preparation 74 1-Methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylbenzoyl) imidazol-1-yl] butane

Cl

Cl

-93 · ♦ »·

9 · · • • • •

Φ «· 1 · · · ·

9 9 <

9 99

3- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylbenzoyl) imidazol-1-yl] butan-1-ol (0.63 g) (see Preparation 47) and triethylamine (0.20 g) was dissolved in dichloromethane (12 ml), cooled in an ice bath and methanesulfonyl chloride (0.19 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 dried over sodium chloride over anhydrous sulfate under reduced pressure.

(30 mL). The organic phase with sodium and solvent was removed. The residue was dissolved in acetonitrile and the solvent was removed under reduced pressure to give 1-methanesulfonyloxy-3- (3,4-dichlorophenyl) -4- [2- (3,5-dimethylbenzoyl) Imidazol-1-yl] butane (0.72 g) as an oil.

¹ H-NMR (CDCl 3): δ = 7.68 (2H, s), 7.10-7.32 (4H, m), 6.91 (1H, dd), 6.83 (1H, s), 4.73 (1H, dd), 4.53 (1H, dd), 4.15-4.24 (1H, m), 4.00-4.10 (1H, m), 3.26-3, 36 (1H, m), 2.92 (3H, s), 2.40 (6H, s), 2.05-2.28 (2H, m) ppm.

Preparations 75 to 90

Compounds of the following preparations summarized in Table 7 of the general formula

About me

X 10 is prepared in a similar manner to Preparation 74 using the appropriate alcohol as starting material (see Preparations 48-56 and 67-73).

-944 «·· 4» 4444 44 44

443 4 · 44

44444 «444

4 · 4 44444 *

44 44 4444 44 44 44 44

Table 7

prpr. C. Eastern substance prepar. in C. R-W- analytical data 75 48 ¹ H-NMR (CDC1 _3): 5 = 7.3 8 (H, d), 7217.29 (2H, m), 7.15 (2H, d), 7.09 (1H, s), 6 98 (1H, d), 6.84 (1H, s), 4.82 (1H, dd), 4.65 (1H, dd), 4.20-4.28 (1H, m), 4.02 -4.11 (1H, m), 3.303.43 (1H, m), 2.96 (3H, s), 2.31 (3H, s), 2.08-2.28 (2H, m), 2.19 (3H, s) ppm 76 49 ¹ H-NMR (CDC1 _3): 5 = 7.50-7.60 (2H, m), 7.31-7.44 (3H, m), 7.26 (lH, dd), 7.10 ( 1H, s), 6.95 (1H, dd), 6.79 (1H, s), 4.89 (1H, dd), 4.48 (1H, dd), 4.20-4.28 (1H , m), 4.03-4.11 (1H, m), 3.28-3.39 (1H, m), 2.05-2.30 (2H, m), 1.98 (3H, s) ) ppm 77 50 Me Me / 0 ^X H-NMR _(CDCl3): 5 = 7.17-7.41 (4H, m), 6.96-7.11 (3H, m), 6.80 (lH, s), 4.86 ( 1H, dd), 4.52 (1H, dd), 4.20-4.29 (1H, m), 4.02-4.11 (1H, m), 3.70 (3H, s), 3 30-3.44 (1H, m), 2.95 (3H, s), 2.31 (3H, s), 2.05-2.29 (2H, m) ppm 78 51 ¹ H-NMR (CDC1 _3): 5 = 7.64 (lH, d), 7207.39 (3H, m), 7.09 (1H, s), 6.86 -6.99 (2H, m) 6.72 (1H, s), 4.63-4.85 (3H, m), 4.45 (1H, dd), 4.12-4.23 (1H, m), 4.00-4 09 (1H, m), 3.20-3.40 (3H, m), 2.93 (3H, s), 2.02-2.18 (2H, m) ppm 79 54 ^X H-NMR (CDC1 _3): 5 = 8.81 (1H, s), 8.14 (lH, d), 8.00 (lH, d), 7.89 (2H, t), 7.50 -7.64 (2H, m), 7.18-7.31 (3H, m), 6.95 (1H, d), 6.86 (1H, s), 4.82 (1H, dd), 4.56 (1H, dd), 4.02-4.29 (2H, m), 3.31-3.43 (1H, m), 2.94 (3H, s), 2.06-2 32 (2H, m) ppm

-95 «Ι ·« 99 »9 © 9 9 9 9 9« 9 9 * 99 * 9 9 9

99 9 9999

99 99 99 99 *

80 55 ¹ H-NMR (CDC1 _3): 5 = 8.44 to 8.58 (2H, m), 7.25 -7.35 (2H, m), 7.17 (2H, s), 6.90 ( 2H, m), 4.75 (1H, dd), 4.59 (1H, dd), 4.21-4.30 (1H, m), 4.03-4.11 (1H, m), 3 27-3.39 (1H, m), 2.98 (3H, s), 2.08-2.33 (2H, m) ppm 81 52 Coll ¹ H-NMR (CDC1 _3): 5 = 7.37 (lH, d), 7057.31 (5H, m), 6.99 (lH, dd), 6.84 (1H, s), 4.80 (1H, dd), 4.65 (1H, dd), 4.05-4.30 (2H, m), 3.30-3.40 (1H, m), 2.97 (3H, s), 2.65-2.85 (4H, m), 2.10-2.30 (2H, m), 1.70-1.85 (4H, m) ppm 82 56 / 9 ¹ H-NMR (CDCl 3): δ = 7.79-7.89 (2H, m), 7.10-7.35 (4H, m), 6.91 (1H, dd), 6.81 (1H , s), 4.72 (1H, dd), 4.51 (1H, dd), 4.17-4.27 (1H, m), 4.00-4.10 (1H, m), 3, 06-3.39 (1H, m), 2.792.99 (7H, m), 2.03-2.29 (2H, m), 1.75-1.77 (4H, m) ppm 83 53 ! Me íxx ¹ H-NMR (CDC1 _3): 5 = 7.31-7.42 (3H, m), 7.21 (H, d), 7.07 (1H, s), 6.99 (1H, dd) 6.91 (1H, d), 6.75 (1H, s), 4.83 (1H, dd), 4.48 (1H, dd), 4.16-4.28 (1H, m), 4.02-4.11 (1H, m), 3.75 (3H, s), 3.28-3.39 (1H, m), 2.92 (3H, s), 2.02-2, 28 (2 H, m) ppm 84 67 Mc ío ¹ H-NMR (CDC1 _3): 5 = 7.35-7.50 (3H, m), 7.24 (lH, d), 6.95-7.07 (4H, m), 6.72 ( 1H, S), 4.89 (1H, dd), 4.49 (1H, dd), 4.19-4.28 (1H, m), 4.05-4.14 (1H, m), 3 79 (3H, s), 3.30-3.41 (1H, m), 2.94 (3H, s), 2.06-2.29 (2H, m) ppm 85 68 Λ, ¹ H-NMR (CDC1 _3): 5 = 8.79 (2H, s), 8.07 (lH, s), 7.32 (lH, d), 7.20 (2H, d), 6.91 (2H, d), 4.80 (1H, dd), 4.61 (1H, dd), 4.20-4.29 (1H, m), 4.04-4.12 (1H, m), 3.27-3.40 (1H, m), 2.93 (3H, s), 2.08-2.30 (2H, m) ppm

9

-9699 99 * 9

9 • 999 • 9 * 9

9 9 · · 9 9 9 9 9 · · 9 9 9 9 99

86 69 ¹ H-NMR (CDCl 3): δ = 7.76 (1H, d), 7.587.68 (2H, m), 7.49 (1H, d), 7.39 (1H, d), 7.26 (1H) , d), 7.10 (1H, s), 6.95 (1H, dd), 6.80 (1H, s), 4.91 (1H, dd), 4.50 (1H, dd), 4 22-4.30 (1H, m), 4.05-4.15 (1H, m), 3.30-3.41 (1H, m), 2.98 (3H, s), 2.07 -2.30 (2H, m) ppm 1 87 70 Mc O ¹ H-NMR (CDC1 _3): 5 = 7.32-7.46 (3H, m), 7.24 (1H, s), 6.92-7.07 (4H, m), 6.71 ( 1H, s), 4.87 (1H, dd), 4.40-4.56 (2H, m), 4.18-4.27 (1H, m), 4.044, 11 (1H, m), 3 30-3.42 (1H, m), 2.94 (3H, s), 2.07-2.27 (2H, m), 1.21 (6H, d) ppm 88 71 and ^* H NMR (CDC1 _3): δ = 7.21-7.45 (6H, m), 7.08 (1H, s), 7.96 (lH, dd), 6.85 (1H, s) 4.82 (1H, dd), 4.63 (1H, dd), 4.20-4.30 (1H, m), 4.03-4.11 (1H, m), 3.30-3 42 (1H, m), 2.94 (3H, s), 2.68 (2H, q), 2.06-2.31 (2H, m), 1.21 (3H, t) ppm 89 72 9 0 ¹ H-NMR (CDCl ₃ ): δ = 6.90-7.59 (12H, m), 6.83 (1H, dd), 6.63 (1H, s), 4.80 (1H, dd) 3.96-4.32 (3H, m), 3.153.25 (1H, m), 2.90 (3H, s), 2.00-2.21 (2H, m) ppm 90 73 ^ 0 ^X H-NMR (CDCl): 6 = 7.22 to 7.3 7 (6H, m), 7.10 (2H, dd), 6.8 l (lH, dd), 6.70 (1H, S) 4.76 (1H, dd), 4.25-4.50 (3H, m), 4.10-4.18 (1H, m), 3,914.03 (1H, m), 3.10-3 21 (1H, m), 2.89 (3H, s), 1.94-2.05 (2H, m) ppm

Preparation 91

4 (S) - (3,4-Dichloro-phenyl) -5-hydroxypent-1-ene

4 (S) -benzyl-3- (2 (3) - (3,4-dichlorophenyl) pent-4-en-1-oyl) oxazolidin-2-one (30.32 g) Chemistry Letters, 2,319, tetrahydrofuran (400 mL), (see Bioorganic and Medicinal (1993)) was dissolved in anhydrous, cooled in an ice bath, and lithium aluminum hydride (5.7 g) was carefully added in two portions (exothermic reaction). The mixture was stirred at 0 ° C for minutes and then stirred at room temperature for 1 hour, then cooled to 0 ° C. Water (6 mL) was carefully added, followed by 2 N aqueous sodium hydroxide (6 mL) followed by water (12 mL). The mixture was stirred vigorously for 40 minutes and the resulting precipitate was removed by filtration and washed with diethyl ether. The filtrate was collected and the organic and aqueous phases separated. The solvent was then removed from the organic phase under reduced pressure to give a yellow oil which was chromatographed on silica gel eluting with a solvent gradient of 4: 1 to 4: 0, v / v, dichloromethane and hexane to afford 4 (S) - (3, 4). 4-dichlorophenyl) -5-hydroxypent-1-ene (11.74 g) as an oil.

1 H-NMR (CDCl 3): δ = 7.24-7.45 (2H, m), 7.06 (1H, dd), 5.61-5.75 (1H, m), 4.96-5, 10 (2H, m), 3.70-3.90 (2H, m), 2.80-2.91 (1H,

m), 2.30-2.55 (2H, m), 1.32 (1H, t) ppm.

Preparation 92

4 (R) - (3,4-Dichlorophenyl) -5-hydroxypent-1-ene mp

-98 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

This compound is prepared analogously to the method used to prepare the compound of Preparation 91 using the appropriate starting material (see Bioorganic and Medicinal Chemistry Letters, 2, 319, (1993)).

¹ H-NMR (CDCl 3): δ = 7.24-7.45 (2H, m), 7.06 (1H, dd), 5.61-5.75 (1H, m), 4.96-5 10 (2H, m), 3.70-3.90 (2H, m), 2.80-2.91 (1H, m), 2.30-2.55 (2H, m), 1.32 (1 H, t) ppm.

Preparation 93

4 (S) - (3,4-dichlorophenyl) -5- (methanesulfonyloxy) pent-1-ene

To an ice-cooled solution of 4 (S) - (3,4-dichlorophenyl) -5-hydroxypent-1-ene (6.0 g) (see Preparation 91) and triethylamine (3.48 g) in dichloromethane (100 mL) was added. Methanesulfonyl chloride (3.55 g) was added dropwise and the mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue was partitioned between diethyl ether and water. The two phases were separated and the aqueous layer was further extracted with diethyl ether. The organic phases are then combined and washed successively with water, dilute aqueous citric acid solution, sodium chloride solution, saturated aqueous sodium hydrogencarbonate solution and sodium chloride solution, and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 4 (S) - (3,4-dichlorophenyl) -5- (methanesulfonyloxy) pent-1-ene (8.25 g) as an oil. ¹ H-NMR (CDCl ₃ ): δ = 7.42 (1H, d), 7.30 (1H, s), 7.04 (1H, dd), 5.56-5.72 (1H, m) 5.01-5.10 (2H, m), 4.22-4.39 (2H, m), 3.05-3.15 (1H, m), 2.88 (3H, s), 2 33-2.60 (2 H, m) ppm.

Preparation 94

4 (R) - (3,4-dichlorophenyl) -5- (methanesulfonyloxy) pent-1-ene

This compound was prepared in an analogous manner to the preparation of compound 93 using 4 (R) - (3,4-dichlorophenyl) -5-hydroxy-pent-1-ene (see Preparation 92) as starting material.

¹ H-NMR (CDCl 3): δ = 7.42 (1H, d), 7.30 (1H, s), 7.04 (1H, dd), 5.56-5.72 (1H, m), 5.01-5.10 (2H, m), 4.22-4.39 (2H, m), 3.05-3.15 (1H, m), 2.88 (3H, s), 2, 33-2.60 (2 H, m) ppm.

Preparation

4 (S) - (3,4-Dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene

-100-

4 (S) - (3,4-Dichlorophenyl) -5-methanesulfonyloxy) pent-1-ene (8.25 g) (see Preparation 93) and imidazole (5.3 g) were dissolved in anhydrous acetonitrile (80 mL). and the mixture was heated at reflux for 6 days. The solvent was removed under reduced pressure to give a residue which was partitioned between diethyl ether and saturated aqueous sodium bicarbonate solution (pH of the aqueous phase was maintained > 7). The phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic extracts were then washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel with a solvent gradient of 98: 2 to 95: 5, v / v, dichloromethane and methanol to give the title compound. There was thus obtained 4 (S) - (3,4-dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene (4.78 g) as an oil.

¹ H-NMR (CDCl 3): δ = 7.35 (1H, d), 7.15-7.30 (2H, m), 6.99 (1H,

s), 6.84 (1H, d), 6.69 (1H, s), 5.55-5.70 (1H, m), 5.07 (2H, d), 3.95-4.22 (2H, m), 2.95-3.10 (1H, m), 2.32-2.45 (2H, m) ppm.

Preparation 96

4 (R) - (3,4-Dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene

-101 ·· ·· · · · · ·

This compound was prepared analogously to the method of Preparation 95 using 4 (R) - (3,4-dichlorophenyl) -5- (methanesulfonyloxy) pent-1-ene (see Preparation 94) as starting material.

¹ H-NMR (CDCl ₃ ): δ = 7.35 (1H, d), 7.15-7.30 (2H, m), 6.99 (1H,

s), 6.84 (1H, d), 6.69 (1H, s), 5.55-5.70 (1H, m), 5.07 (2H,

d), 3.95-4.22 (2H, m), 2.95-3.10 (1H, m), 2.32-2.45 (2H, m) ppm.

Preparation 97

3 (S) - (3,4-Dichlorophenyl) -4- (imidazol-1-yl) butan-1-al

4 (S) - (3,4-Dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene (4.75 g) (see Preparation 95) was dissolved in a mixture of acetonitrile (75 mL), water ( 13 ml) and 1 N aqueous hydrochloric acid solution (17 ml). Osmium tetroxide (3.4 ml of a 0.05 M solution in toluene) was added and the mixture was stirred for 20 minutes. Sodium periodate (5.3 g) was then added along with an additional amount of acetonitrile (30 mL) and stirring was continued overnight. Water (about 100 mL) was added and the acetonitrile was removed under reduced pressure to give an aqueous suspension which was made alkaline to give a residue.

-102pH> 7 by adding solid sodium carbonate. The mixture was then extracted (three times) with ethyl acetate, and the combined organic extracts were washed successively with water and brine, then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 3 (S) - (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-al (4.3 g) as an oil.

¹ H-NMR (CDCl 3) Δ = 9.70 (1H, s), , 7.38 (1H, d), 7,20-7,30 (2H, m), 7.01 (1H, s), 6.89 (1 H, dd), 6.71 (1H, s), 4.00-4.22 (2H, m), 3.60 (1H, m), 2.72-2.92 (2H, m) ppm

Preparation 98

3 (R) - (3,4-Dichlorophenyl) -4- (imidazol-1-yl) butan-1-al

This compound was prepared analogously to the method of Preparation 97 using 4 (R) - (3,4-dichlorophenyl) -5- (imidazol-1-yl) pent-1-ene (see Preparation 96) as starting material.

¹ H-NMR (CDCl 3): δ = 9.70 (1H, s), 7.38 (1H, d), 7.20-7.30 (2H, m), 7.01 (1H, s), 6.89 (1H, dd), 6.71 (1H, s), 4.00-4.22 (2H, m), 3.60 (1H, m), 2.72-2.92 (2H, m) ppm.

Preparation 99 (S) - (3,4-Dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol ···

-103-

To an ice-cooled solution of 3 (S) - (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-alu (4.3 g) (see Preparation 97) in ethanol (40 mL) was carefully added. Add sodium borohydride (0.68 g) and stir at room temperature for 1 hour, then remove the solvent under reduced pressure to give a residue. This residue was suspended in water (30 mL), cooled in an ice bath, and the mixture was first acidified to pH 1 with 2 N aqueous hydrochloric acid and then basified to pH 14 by addition of 2 N aqueous sodium hydroxide. The resulting suspension was filtered and the residue washed with water, dried and then recrystallized from acetonitrile to give 3 (S) - (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol ( 1.37 g) as a creamy solid.

@ ¹ H-NMR (CDCl3): .delta. = 7.35 (1H, d), 7.15-7.30 (2H, m), 6.95 (1H, s), 6.89 (1H, d), 6.70 (1H, s), 4.00-4.25 (2H, m), 3.60-3.70 (1H, m), 3.40-3.50 (1H, m), 3, 15-3.30 (1H, m), 2.10 (1H, broad s), 1.75-2.00 (2H, m) ppm.

Preparation 100 (R) - (3,4-Dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol

Cl

Cl • 9 • ·

-104II »

This compound was prepared analogously to the method of Preparation 99 using 3 (R) - (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-alu (see Preparation 98) as starting material.

¹ H-NMR (CDCl 3): δ = 7.35 (1H, d), 7.15-7.30 (2H, m), 6.95 (1H,

s), 6.89 (1H, d), 6.70 (1H, s), 4.00-4.25 (2H, m), 3.60-3.70 (1H, m), 3.40 -3.50 (1H, m), 3.15-3.30 (1H, m), 2.10 (1H, broad s), 1.75-2.00 (2H, m) ppm.

Preparation 101 (S) - (3,4-Dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butyl-1,2,3,4- tetrahydro-5-naphthoate

1,2,3,4-tetrahydro-5-naphtholychloride (1.70 g) (see Preparation 36) is added dropwise to a suspension of 3 (S) - (3,4-dichlorophenyl) -4- (imidazole-1- yl) butan-1-ol (0.90 g) (see Preparation 99) and triethylamine (1.45 g) in anhydrous acetonitrile (15 mL) and the solution was stirred at room temperature for 4 days. The solvent was then removed under reduced pressure to give a residue which was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The organic phases are combined, washed successively with water and brine, 4 *

-105 dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 2: 1 to 0: 1, v / v, pentane and ethyl acetate to give 3 (S) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butyl-1,2,3,4-tetrahydro-5-naphthoate ( 1.38 g) as a gum.

¹ H-NMR (CDCl ₃ ): δ = 7.50 (1H, d), 6.95-7.38 (10H, m), 4.83 (1H, dd), 4.63 (1H, m) 4.30-4.35 (1H, m), 4.08-4.16 (1H, m), 3.30-3.40 (1H, m), 3.00 (2H, broad s), 2.63-2.84 (6 H, m),

2.10-2.25 (2H, m), 1.67-1.83 (8H, m) ppm.

Preparation 102 (R) - (3,4-Dichlorophenyl) -4- (2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl) butyl-1,2,3,4- tetrahydro-5-naphthoate

This compound was prepared analogously to the method used to prepare the compound of Preparation 101 using 3 (R) - (3,4-dichlorophenyl) -4- (imidazol-1-yl) butan-1-ol (see Preparation 100) as the starting material. substances.

¹ H-NMR (CDCl 3): δ = 7.50 (1H, d), 6.95-7.38 (10H, m), 4.83 (1H, dd), 4.63 (1H, m), 4.30-4.35 (1 H, m), 4.08-4.16 (1 H, m),

-106. 1

3.30-3.40 (1H, m), 3.00 (2H, broad s),

2.10-2.25 (2H, m), 1.67-1.83 (8H, m) ppm.

2.63-2.84 (6 H, m),

Preparation 103

3 (S) - (3,4-Dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butan-1-ol

3 (S) - (3,4-Dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butyl-1,2,3,4-tetrahydro The -5-naphthoate (1.38 g) (see Preparation 101) was dissolved in methanol (40 mL), 1 N aqueous sodium hydroxide solution (5 mL) was added and the resulting mixture was stirred at room temperature overnight. The methanol was then removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 3 (S) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butan-1-ol (0.82 g) as a gum.

¹ H-NMR (CDCl ₃ ): δ = 7.10-7.35 (5H, m), 7.06 (1H, s), 6.92 (1H, dd), 6.74 (1H, s) 4.90 (1H, dd), 4.50 (1H, dd), 3.70-3.82

-1072.70-2.86 (4H, 9 * (1H, m), 3.53-3.64 (1H, m), 3.30-3.42 (1H) , m),

m), 1.70-2.04 (6H, tn) ppm.

Preparation 104

3 (R) - (3,4-Dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butan-1-ol

This compound was prepared in an analogous manner to that used in Preparation 103 using 3 (R) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-). naphthoyl) imidazol-1-yl] butyl 1,2,3,4-tetrahydro-5-naphthoate (see Preparation 102) as starting material.

1 H-NMR (CDCl 3): δ = 7.10-7.35 (5H, m), 7.06 (1H, s), 6.92 (1H, dd), 6.74 (1H, s), 4 90 (1H, dd), 4.50 (1H, dd), 3.70-3.82 (1H, m), 3.53-3.64 (1H, m), 3.30-3.42 (1H, m), 2.70-2.86 (4H,

m), 1.70-2.04 (6H, m) ppm.

-108Preparation 105

1-Methanesulfonyloxy-3 (S) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butane

3 (S) - (3,4-Dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butan-1-ol (0.68 g) (see Preparation 103) and triethylamine (0.22 g) were dissolved in dichloromethane (15 mL), cooled in an ice bath, and methanesulfonyl chloride (0.22 g) was added. After stirring for 4 hours, the solvent was removed under reduced pressure to give a residue which was partitioned between ethyl acetate and water. The organic phase was separated and washed with a saturated aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1-methanesulfonyloxy-3 (S) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazole-1. -yl] butane (0.82 g) as an oil.

^X H-NMR (CDC1 _3): 8 = 7.37 (1H, d), 7.05-7.31 (5H, m), 6.99 (1H, dd), 6.84 (1H, s) 4.80 (1H, dd), 4.65 (1H, dd), 4.05-4.30 (2H, m), 3.30-3.40 (1H, m), 2.97 (3H) , s), 2.65-2.85 (4H, m),

2.10-2.30 (2H, m), 1.70-1.85 (4H, m) ppm.

-109 • F 9 · F F • FF *

Preparation 106 1-Methanesulfonyloxy-3 (R) - (3,4-dichlorophenyl) -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazol-1-yl] butane

This compound was prepared in an analogous manner to that used in Preparation 105 using 3 (R) - (3,4-dichlorophenyl) -4- (2- (1,2,3,4-tetrahydro-5-). naphthoyl) imidazol-1-yl] butan-1-ol (see Preparation 104) as starting material.

1 H-NMR (CDCl 3): δ = 7.37 (1H, d), 7.05-7.31 (5H, m), 6.99 (1H, dd), 6.84 (1H, s), 4 80 (1H, dd), 4.65 (1H, dd), 4.05-4.30 (2H, m), 3.30-3.40 (1H, m), 2.97 (3H, s) 2.65-2.85 (4H, m),

2.10-2.30 (2H, m), 1.70-1.85 (4H, m) ppm.

Pharmacological data

The affinities of the following compounds of the examples for human NK ₁ and NK ₂ receptors were determined by the methods described in the description on page 23 and the results are summarized in the table below.

-110 • φ φ «· · · φ · · · · · φ φ φ φ φ φ» »» »» »» »» »» »»

example no. binding NK _X (IC ₅₀ ) NK ₂ binding (IC ₅₀ ) Example 2 0.6 nM 4 nM Example 5 8 nM 11 nM Example 6 9 nM 96 nM Example 18 123 nM 3 nM Example 19 2 nM 24 nM

These data indicate that the compounds are dual NK _X and NK ₂ receptors.

Claims (33)

PATENT CLAIMS 7777- 913 · A compound of formula I Y Ar (I) where R is phenyl, C 3 -C 7 cycloalkyl or heteroaryl, each optionally fused with a benzene ring or C 3 -C 7 cycloalkyl ring and optionally substituted, including in the benzene ring or cycloalkyl ring fused moiety (C až-C uhlíku), (C až-C substitu) substituents each independently selected from C skupiny-C alky alkyl, (C až-C fluor) fluoroalkyl, (C až-C alko) alkoxy, (C až-C fluor) fluoroalkoxy , phenoxy, (C 2 -C 4) alkanoyl, halogen, (C 1 -C 4) alkoxycarbonyl, (C 3 -C 7) cycloalkyl, -S (O) C 1 -C 4 alkyl , cyano, -NR ² R ^3, -S (O) _m NR ² R ^3, -NR ⁴ alkanoyl having 1-4 carbon atoms in the alkanoyl part, and -CONR ² R ^3, or R is 2,3-dihydrobenzo [ (b) furanyl or chromanyl; R ¹ is hydrogen or C 1 -C 6 alkyl, R ² and R ³ are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl or taken together to form C 4 -C 6 alkylene, -112 · · t. < »4 · 4 ► ♦ ·« » 49 94 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, W is a direct bond, a methylene group or an ethylene group, X is a branched alkylene group having 2 to 4 carbon atoms, Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C 3 -C 7 cycloalkyl, each of which is optionally substituted with 1 to 3 substituents each independently selected from C 1 -C 4 alkyl, fluoroalkyl (C 1 -C 4), (C 1 -C 4) alkoxy, (C 1 -C 4) fluoroalkoxy, halogen, and cyano, Ar is phenyl, naphthyl, benzyl, thienyl, benzo [b] thienyl or indolyl, each of which is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl. C 4 -C 4 alkoxy, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, halogen and cyano, or Ar is 1,3-benzodioxolane-4 or 5-yl or 1,4-benzodioxane-5- or 6- yl, m is 0, 1 or 2, Z ^A is a pharmaceutically acceptable anion, and a heteroaryl group used in defining R is a thienyl or a five or six membered ring heteroaryl group containing either 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatoms and 1 oxygen or sulfur heteroatom, with the proviso that when W is a direct bond and R is an optionally fused and optionally substituted heteroaryl group, the heteroaryl group is bound by a ring carbon atom to the carbonyl group. 113- • »44 4 44 4444 44 44 44 · • • • ♦ • 4 4 9 9 * • ·· · • • « ♦ 4 • · • • • 4 • • 4 ·· · · 44 • * » • 4 4 4 A compound according to claim 1, wherein R is phenyl, which is optionally fused with a benzene ring or a C 3 -C 7 cycloalkyl ring and optionally substituted, including in the fused portion with a benzene ring or a C 3 -C 7 cycloalkyl ring , 1, 2 or 3 substituents each independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, phenoxy and C 1 -C 4 -alkyl; or R is 2,3-dihydrobenzo [b] furanyl. A compound according to claim 1 or 2, wherein R is phenyl, which is optionally fused with a benzene ring or a C 3 -C 7 cycloalkyl ring and optionally substituted, including in the fused portion with a benzene ring or a 3 to 7 cycloalkyl ring carbon atoms, 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo [b] furanyl. A compound according to claim 1, 2 or 3 wherein R is phenyl, naphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy , phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo [b] furanyl. A compound according to any one of claims 1 to 4, wherein R is phenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2-trifluoromethoxyphenyl, 2-methoxy-3-methylphenyl, 2,3-dihydrobenzo [b] furan- 7-yl, naphth-2-yl, 4-fluoro-3-trifluoromethylphenyl, -114- 9 ♦ ·· 9 • · 9999 99 99 tl · • 9 (B) 9 ♦ 9 9 • t (B) 9 999 (B) (B) • • • · (B) 9 9 (B) (B) (B) (B) ♦ · · · 99 9 99 9 B 99 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, 5-chloro-2-methoxyphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-isopropoxyphenyl, 2-ethylphenyl, 2-phenoxyphenyl or 3,5-bis (trifluoromethyl) phenyl. A compound according to any one of claims 1 to 5, wherein R is 2,3-dimethylphenyl, naphth-2-yl, 1,2,3,4-tetrahydronaphth-5-yl or 2-methoxyphenyl. A compound according to any one of claims 1 to 6, wherein R ¹ is hydrogen. A compound according to any one of claims 1 to 7, wherein W is a direct bond or methylene. A compound according to any one of claims 1 to 8, wherein W is a direct bond. A compound according to any one of claims 1 to 9, wherein X is 1,2-ethylene. A compound according to any one of claims 1 to 10, wherein Y is phenyl, naphthyl or cyclohexyl, each of which is optionally substituted with 1, 2 or 3 alkyl substituents of 1 to 4 carbon atoms. A compound according to any one of claims 1 to 11, wherein Y is phenyl, 3,5-dimethylphenyl, cyclohexyl or naphth-2-yl. A compound according to any one of claims 1 to 12, wherein Y is phenyl. 9 ·· »9999 9 9 • 999 .UR ·· · * · · · 9 9 9 99 99 A compound according to any one of claims 1 to 13, wherein Ar is phenyl, optionally substituted with 1, 2 or 3 halogen substituents. A compound according to any one of claims 1 to 14, wherein Ar is phenyl substituted with 1 or 2 chloro substituents. A compound according to any one of claims 1 to 15, wherein Ar is 3,4-dichlorophenyl. A compound according to any one of claims 1 to 16, wherein Z ^A is chloride, bromide, nitrate, methanesulfonate, para-toluenesulfonate, benzenesulfonate, hydrogensulfate or sulfate. A compound according to any one of claims 1 to 17, wherein Z ^A is chloride or methanesulfonate. A compound according to any one of claims 1 to 18, wherein Z ^A is a methanesulfonate. The compound of claim 1, wherein R ¹ is hydrogen, X is -CH ₂ CH ₂ - and Ar is 3,4-dichlorophenyl, and wherein RW- is 3,5-dimethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2,3-dimethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-trifluoromethoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-methoxy-3-methylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2,3-dihydrobenzo [b] furan-7-yl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is naphth-2-yl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 4-fluoro-3-trifluoromethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 1,2,3,4-tetrahydronaphth-5-yl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, -116φφφφ φ φ φ · · · · · · Φ φ · • »» RW- is 1,2,3,4-tetrahydronaphth-6-yl, Υ is phenyl and Ζ ^Α is CH ₃ SO ₃ -, RW- is 5-chloro-2-methoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-methoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-trifluoromethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-isopropoxyphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-ethylphenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-phenoxy phenyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is benzyl, Y is phenyl and Z ^A is CH ₃ SO ₃ -, RW- is 3,5-bis (trifluoromethyl) phenyl, Y is phenyl and Z ^A is Cl ', RW- is 2-methoxyphenyl, Y is cyclohexyl and Z ^A is CH ₃ SO ₃ -, RW- is 4-fluoro-3-trifluoromethylphenyl, Y is cyclohexyl and Z ^A is CH ₃ SO ₃ -, RW- is 2-methoxyphenyl, Y is 3,5-dimethylphenyl, and Z ^A is CH ₃ SO ₃ -, or RW- is 2-methoxyphenyl, Y is naphth-2-yl and Z ^A is CH ₃ SO ₃ -, or wherein Z ^A is an alternative pharmaceutically acceptable anion. The compound of claim 1 which is 4-phenyl-1- (3 (S) - [3,4-dichlorophenyl] -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazole) -l-yl] butyl) quinuclidinium methanesulfonate or 4-phenyl-1- (3 (R) - [3,4-dichlorophenyl] -4- [2- (1,2,3,4-tetrahydro-5-naphthoyl) imidazole (1-yl) butyl) quinuclidinium methanesulfonate. A process for the preparation of a compound of the formula I as defined in claim 1, wherein R, R ¹ , W, X, Y, Ar and Z ^A are as defined in claim 1, characterized in that the compound of the formula I is reacted. II R-W N-CH2-C-X- (Z or ZJ) Ar ** wherein R, R ¹ , Ar, W and X are as defined above for the compound of formula I in this claim, Z is a leaving group capable of forming a pharmaceutically acceptable anion (Z ^A and Z ¹ is a leaving group, with a compound of formula III (III) wherein Y is as defined above for a compound of formula I, followed by either (a) when Z ¹ is a leaving group, exchange for a pharmaceutically acceptable anion (Z ^A ), or (b) optionally, when Z ^A is a pharmaceutically acceptable anion, in exchange for another pharmaceutically acceptable anion. The method of claim 22 wherein Z is C 1 -C 4 alkanesulfonyloxy, benzenesulfonyloxy, para-toluenesulfonyloxy, chloro, bromo, or iodo, and Z ¹ is trifluoromethanesulfonyloxy. 24. The method according to claim 22, characterized in that Z is a methanesulphonyl sulfonyloxy and Z ^A is methanesulphonate. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 21, together with a pharmaceutically acceptable diluent or carrier. A compound of formula I, or a pharmaceutically acceptable composition thereof, as claimed in claims 1 to 21 and 25, for use as a medicament. -118- 9 * 99 9 9 999 · ·· 9 » • 9 9 9 • 9 • • • 9 9 9 • 9 999 9 9 9 • • 9 9 9 9 9 9 9 • 9 9 9 · 9 9 9 • 99 9 9 9 9 Use of a compound of formula I or a pharmaceutically acceptable composition thereof as claimed in claims 1 to 21 and 25 for the preparation of a medicament for the treatment of diseases resulting from a tachykinin receptor antagonist effect or a combination of tachykinin receptors. 28. Use according to claim 27, wherein the antagonistic effect exerted on the human _X and NK NK ₂ tachykinin receptors. Use according to claim 27 or 28, wherein the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, central nervous system (CNS) disorders such as anxiety, depression, dementia or psychosis, gastrointestinal disorders (GI) such as functional bowel disorder, irritable bowel syndrome, gastro-esophageal reflux, stool failure, colitis or Crohn's disease, diseases caused by Helicobacter pylori or other urease-positive gram-negative bacteria, urogenital tract disorders such as incontinence, hyperreflexia or cystitis , pulmonary disorders such as chronic obstructive airway disease, allergies such as eczema, contact dermatitis, atopic dermatitis or rhinitis, hypersensitivity disorders such as poisoning, peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, herpetic neuralgia or postherpeti neuralgia, vomiting, cough, migraine or acute or chronic pain. 30. A method for the treatment of human diseases resulting from an antagonistic effect on tachykinin receptors or a combination of tachykinin receptors, characterized in that they are treated with an effective amount of a compound of formula I or a pharmaceutically acceptable -119- • · »· · < »» * • • * • • • • • » • • • ·· • • • • « • · • • • • • • • ttt · * · ··· ·· • * a composition comprising the compound as claimed in claims 1 to 21 and 25. 31. The method according to claim 30, characterized in that the antagonistic effect exerted on the human NK, and NK ₂ tachykinin receptors. The method of claim 30 or 31, wherein 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, a disorder gastro-intestinal tract (GI) such as intestinal disorder, irritable bowel syndrome, gastro-esophageal reflux, inability to maintain stool, colitis or Crohn's disease, a disease caused by Helicobacter pylori or other urease-positive gram-negative bacteria, urogenital tract disorders such as incontinence, hyperreflexia or cystitis, pulmonary disorders such as chronic obstructive airway disease, allergies such as eczema, contact dermatitis, atopic dermatitis or rhinitis, hypersensitivity disorders such as poisoning, peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, herpet ne neuralgia or postherpetic neuralgia, vomiting, cough, migraine or acute or chronic pain. Compounds of formulas II, XI, XII, XIII, XIV, XV, XXIII, XXX, or XXXI R-W X) N ^ N-CH ^ —C — X— (Z or ζη l = J I Ar (II) -120R ¹ ·· • 4 4 4 · <♦ · 1 • »4 449 9 · · 4 4 · 4 9 9 4 4 ·· * · ··« · 4 9 4 44 9 4 9 4 4 4 49 N ^ N \ = J 'CH ₂ -c-alkylene) Ar n (XI) R ¹ CH ₂ -C- (C 1 -C 6 alkylene) Ar CHO (XII) R ¹ Ν '^ ΝU7 CH ₂ -CX-OH (XIII) Ar R-W O N ^ N-CFL = J R O I II -c — X — O — c — W-R Ar (XIV) R-W. \ = J N-CH, C-X-OH Ar (XV) -121- • 4 * 44 4 4 • • 4 4 • 4 ·· 4 4 4 and 4 4 • • • • * · 4 4 444 4 • • 4 φ • 4 4 4 • • • 4 4 • 4 4 4 4 · 4 4 · • · • 4 N ^ NW CH ₂ -C ^(C i -C ₃ alkylene) CH = CH ₂ (XXIII) Ar R ¹ N ^ N — CH, C — X — O — p (XXX) \ = y I Ar where R, R ¹ , the outgoing anion (Z ^A ), R — W O X τ N ^X N - CH ₂ CXOP (XXXI) Ar W, X and Ar are as defined in claim 1, Z is a group capable of forming a pharmaceutically acceptable Z ¹ is a leaving group, and P is a protecting group.