Imidazole derivatives, their preparation and their use as medicaments

1. A compound of the formula

in racemic, enantiomeric form or any combinations of these forms wherein:

X is at least one H or halo;

Y is —O— or —S—;

A is H or (C 1 -C 6 )alkyl;

Z is selected from the group consisting of:

(C 1 -C 6 )alkyl optionally substituted by at least one halo;

aryl optionally substituted by at least one member selected from the group consisting of: halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, —(CH 2 ) n —NR 3 R 4 , (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkyl-thio,

(C 1 -C 6 )alkoxy optionally substituted by at least one halo, (C 1 -C 6 )alkoxy-carbonyl, phosphate, sulfate, glycoside and —NH—C(O)—CH(R A )—NR 5 R 6 ;

aryl-(C 1 -C 6 )alkyl;

heteroaryl;

Z 1 -Z′ 1 ;

—NR N —C(O)-Z′ 2 and

-Z 2 -Z′ 2 ;

Z 1 is selected from the group consisting of —O—, —C(O)—O—, —NR N —C(O)— and —C(O)—NR N —;

Z′ 1 is selected from the group consisting of (C 1 -C 10 )alkyl; aryl-(C 1 -C 6 )alkyl, the aryl of which is optionally substituted by at least one halo; and (C 1 -C 6 )alkyl substituted by at least one member selected from the group consisting of halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio and —NR 1 R 2 ;

R 1 and R 2 are, independently, H or (C 1 -C 6 )alkyl, or form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by (C 1 -C 6 )alkyl;

Z 2 is selected from the group consisting from —O—, —S—, —SO 2 —, —C(O)—, —C(O)—NR N — and —NR N —;

Z′ 2 is an aryl or heteroaryl, the aryl and heteroaryl being optionally substituted by at least one member selected from the group consisting of:

halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, (C 1 -C 6 )alkyl-thio, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkoxy optionally substituted by at least one halo, aryl-alkoxy, (C 1 -C 6 )alkoxy-carbonyl, phosphate, sulfate, glycoside, —(CH 2 ) n —NR 3 R 4 and —NH—C(O)—CH(R A )—NR 5 R 6 ;

R 3 and R 4 are, independently, selected from the group consisting of H or (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-carbonyl and (C 1 -C 6 )alkyl-sulfonyl, or R 3 and R 4 form together with the nitrogen atom to which they are attached, a heteroaryl or a heterocycloalkyl optionally substituted by (C 1 -C 6 )alkyl;

R 5 and R 6 are, independently, H or (C 1 -C 6 )alkyl;

R A is the residue of an amino acid of the formula NH 2 —CH(R A )—C(O)—OH;

R N is hydrogen or (C 1 -C 6 )alkyl;

n is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof except compounds in which A is hydrogen and Z is -3-CF 3 .

2. A compound of claim 1 , wherein

X is H or halo;

Y is —O— or —S—;

A is H or (C 1 -C 6 )alkyl;

Z is selected from the group consisting of:

(C 1 -C 6 )alkyl optionally substituted by at least one halo;

aryl optionally substituted by at least one member selected from the group consisting of: halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, and (C 1 -C 6 )alkoxy optionally substituted by at least one halo;

heteroaryl;

Z 1 -Z′ 1 ;

—NH—C(O)-Z′ 2 ; and

Z 2 -Z′ 2 ;

Z 1 is selected from the group consisting of —O—, —N—C(O)— and —C(O)—NH—;

Z′ 1 is selected from the group consisting of (C 4 -C 10 )alkyl; aryl-(C 1 -C 6 )alkyl, the aryl of which is optionally substituted by at least one halo and (C 1 -C 6 )alkyl substituted by at least one member selected from the group consisting of halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio and —NR 1 R 2 ;

R 1 and R 2 are, independently, H or (C 1 -C 6 )alkyl, or form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by (C 1 -C 6 )alkyl;

Z 2 is selected from the group consisting of —O—, —S—, —SO 2 —, —C(O)— or —C(O)—NH—;

Z′ 2 is aryl optionally substituted by at least one member selected from the group consisting of: halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, and (C 1 -C 6 )alkoxy optionally substituted by at least one halo; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein A is H and Y is —O—; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 wherein X is H; or a pharmaceutically acceptable salt thereof.

5. A compound of claim 4 , wherein

Z is at least one member, in meta and/or para position and selected from heteroaryl or Z 2 -Z′ 2 ;

Z 2 is selected from the group consisting of —O—, —S—, —SO 2 —, —C(O)— and —C(O)—NH—;

Z′ 2 is phenyl of naphthyl optionally substituted by at least one member selected from the group consisting of halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, and (C 1 -C 6 )alkoxy optionally substituted by at least one halo; or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 , Z is selected from the group consisting of:

heteroaryl;

Z 1 -Z′ 1 wherein

either Z 1 is selected from the group consisting of —O—, —NR N —C(O)— or —C(O)—NR N — and Z′ 1 benzyl;

or Z 1 is selected from the group consisting of —O—, —C(O)—O—, —NR N —C(O)— or —C(O)—NR N — and Z′ 1 is (C 1 -C 6 )alkyl substituted by at least one member selected from the group consisting of: halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio and —NR 1 R 2 ;

R 1 and R 2 are, independently, H or (C 1 -C 6 )alkyl, or form together with the nitrogen atom to which they are attached, a heterocycloalkyl;

Z 2 -Z′ 2 wherein

Z 2 is selected from the group consisting of —O—, —S—, —SO 2 —, —C(O)—, —C(O)—NR N — and —NR N —;

Z′ 2 is phenyl or phenyl substituted by at least one member selected from the group consisting of:

halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, (C 1 -C 6 )alkyl-thio, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkoxy optionally substituted by at least one halo, aryl-alkoxy, C 1 -C 6 )alkoxy-carbonyl, —(CH 2 ) n —NR 3 R 4 and —NH—C(O)—CH(R A )—NR 5 R 6 ;

R 3 and R 4 are, independently, selected from the group consisting of H or (C 1 -C 6 )alkyl and (C 1 -C 6 )alkyl-carbonyl;

R 5 and R 6 are, independently, H or (C 1 -C 6 )alkyl;

R A is the residue of an amino acid of the formula NH 2 —CH(R A )—C(O)—OH;

R N is hydrogen or (C 1 -C 6 )alkyl; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 , wherein Z is -Z 2 -Z′ 2 ; or a pharmaceutically acceptable salt thereof.

8. A compound of claim 7 , wherein Z is in meta and/or para position; or a pharmaceutically acceptable salt thereof.

9. A compound of claim 7 , wherein Z 2 is selected from the group consisting of —O—, —S—, —SO 2 — and —C(O)—; or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9 , wherein Z 2 is —O—; or a pharmaceutically acceptable salt thereof.

11. A compound of claim 7 , wherein Z 2 is —NR N —; or a pharmaceutically acceptable salt thereof.

12. A compound of claim 7 , wherein

Z′ 2 is phenyl or phenyl substituted by at least one member selected from the group consisting of:

halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, (C 1 -C 6 )alkyl-thio, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkoxy optionally substituted by at least one halo, benzyloxy, (C 1 -C 6 )alkoxy-carbonyl, phosphate, —(CH 2 ) n —NR 3 R 4 and —NH—C(O)—CH(R A )—NR 5 R 6 ;

R 3 and R 4 are, independently, selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-carbonyl and (C 1 -C 6 )alkyl-sulfonyl:

R N is hydrogen or (C 1 -C 6 )alkyl;

R 5 and R 6 are, independently, H or (C 1 -C 6 )alkyl; and

R A is the residue of an amino acid of the formula NH 2 —CH(R A )—C(O)—OH; or a pharmaceutically acceptable salt thereof.

13. A compound of claim 7 , wherein

Z′ 2 is phenyl substituted by at least one member selected from the group consisting of: halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkoxy, —(CH 2 ) n —NR 3 R 4 and —NH—C(O)—CH(R A )—NR 5 R 6 ;

R 3 and R 4 are, independently, selected from the group consisting of H, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkyl-carbonyl;

R 5 and R 6 are, independently, H or (C 1 -C 6 )alkyl; or a pharmaceutically acceptable salt thereof.

14. A compound of claim 13 wherein

Z′ 2 is phenyl substituted by at least two members selected from the group consisting of: fluoro, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkoxy, —NH 2 and

—NH—C(O)—CH(R A )—NR 5 R 6 ; R 5 and R 6 are, independently, H or (C 1 -C 6 )alkyl; or a pharmaceutically acceptable salt thereof.

15. A compound of claim 7 , wherein

Z′ 2 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl, purinyl, triazinyl, pyrrazolo-pyrimidinyl, quinoxalinyl and indolyl, each of these radicals being optionally substituted by at least one member selected from the group consisting of: halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl and —NH 2 ; or a pharmaceutically acceptable salt thereof.

16. A compound of claim 1 selected from the group consisting of:

4-[4-(4-fluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-(1,1′-biphenyl-4-yl)-2-[(phenylthio)methyl]-1H-imidazole;

4-(1,1′-biphenyl-4-yl)-2-(phenoxymethyl)-1H-imidazole;

4-[4-(4-fluorophenoxy)phenyl]-2-[(phenylthio)methyl]-1H-imidazole;

2-[(4-fluorophenoxy)methyl]-4-[4-(4-fluorophenoxy)phenyl]-1H-imidazole;

2-(phenoxymethyl)-4-[4-(phenylthio)phenyl]-1H-imidazole;

2-(phenoxymethyl)4-[4-phenylsulfonyl)phenyl]-1H-imidazole;

4-{4-[(2-fluorobenzyl)oxy]phenyl}-2-(phenoxymethyl)-1H-imidazole;

2-(phenoxymethyl)-4-(4-phenoxyphenyl)-1H -imidazole trifluoroacetate;

4-[4-(4-bromophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole trifluoroacetate;

4-[4-(1H-imidazol-1-yl)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-[4-(4-methoxyphenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-(4-hexylphenyl)-2-(phenoxymethyl)-1H-imidazole;

4-(4-butoxyphenyl)-2-(phenoxymethyl)-1H-imidazole;

4-[4-(4-nitrophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-(2-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}ethyl) morpholine;

1-(2-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}ethyl) piperidine hydrochloride;

N,N-dimethyl-N-(2-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}ethyl) amine hydrochloride;

4-[4-(2-methoxyethoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

2-(phenoxymethyl)-4-[4-(4,4,4-trifluorobutoxy)phenyl]-1H-imidazole;

4-[4-(4-fluorophenoxy)phenyl]-5-methyl-2-(phenoxymethyl)-1H-imidazole;

4-fluoro-N-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenyl}benzamide;

4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}benzonitrile;

ethyl 4-[2-(phenoxymethyl)-1H-imidazol-4-yl]benzoate;

ethyl 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}benzoate;

4-{4-[4-(methylthio)phenoxy]phenyl}-2-(phenoxymethyl)-1H-imidazole;

4-{4-[4-(methylsulfonyl)phenoxy]phenyl}-2-(phenoxymethyl)-1H-imidazole;

4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline hydrochloride;

{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenyl}phenyl methanone trifluoroacetate;

N-(4-fluorophenyl)-4-[2-(phenoxymethyl)-1H-imidazol-4-yl]benzamide trifluoroacetate;

4-[4-(3-nitrophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

3-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline hydrochloride;

4-{4-[4-(benzyloxy)phenoxy]phenyl}-2-(phenoxymethyl)-1H-imidazole;

4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}phenol;

4-[4-(3-fluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

N-(4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}phenyl) acetamide;

2-nitro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline trifluoroacetate;

N-methyl-N-(4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}phenyl) amine;

3-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}benzonitrile;

4-[4-(2-nitrophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

2-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline hydrochloride;

1-(4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}phenyl) methanamine hydrochloride;

1-(3-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}phenyl) methanamine hydrochloride;

4-[4-(3-bromophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline hydrochloride;

4-[4-(3-chlorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-[4-(3,5-difluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-(4-benzylphenyl)-2-(phenoxymethyl)-1H-imidazole;

4-[4-(3-methylphenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-[4-(2-chlorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole hydrochloride;

4-[4-(2-fluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-[4-(3,4-difluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

N 1 -(4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}phenyl) glycinamide hydrochloride;

4-[4-(2,5-difluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-[4-(2,4-difluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-[4-(2,3-difluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole;

4-[4-(2,6-difluorophenoxy)phenyl]-2-(phenoxymethyl)-1H-imidazole.

17. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula

wherein X and Y have the meaning of claim 1 with a base to form a compound of formula (II) in a salified form, then with the α-halogeno-ketone of the formula

in which Z and A have the meaning of claim 1 , in an inert solvent, then the keto-ester thus obtained is cyclized in the presence of an ammonium salt to produce the compound of claim 1 .

18. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula II-iii

wherein X and Y have the meaning of claim 1 , and an α-halogeno-ketone of the formula

in which Z and A are as defined in claim 1 by condensing under reflux in a polar inert solvent.

19. A pharmaceutical composition containing, as active ingredient, at least one compound of claim 1 with a pharmaceutically acceptable support.

20. A method of inhibiting tubulin polymerization in warm-blooded animals comprising administering to warm-blooded animals in need thereof of an amount of a compound of claim 1 sufficient to inhibit tubulin polymerization.

21. The method of claim 20 using a compound of the formula

in racemic, enantiomeric form or any combinations of these forms, wherein

X′ is H and halo;

Y is —O— or —S—;

A′ is H or (C 1 -C 6 )alkyl

Z′ is a member selected from the group consisting of:

(C 1 -C 6 )alkyl optionally substituted by at least one halo;

aryl optionally substituted by at least one halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally by at least one halo, —(CH 2 ) n —NR 3 R 4 , (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkyl-thio, (C 1 -C 6 )alkoxy optionally substituted by at least one halo, (C 1 -C 6 )alkoxy-carbonyl, phosphate, sulfate, glycoside and —NH—C(O)—CH(R A )—NR 5 R 6 ;

aryl-(C 1 -C 6 )alkyl;

heteroaryl;

-Z 1 -Z′ 1 ;

—NR N —C(O)-Z′ 2 ; and

-Z 2 -Z′ 2 ;

Z 1 is selected from the group consisting of —O—, —C(O)—O—, —NR N —C(O)— and —C(O)—NR N ;

Z′ 1 is selected from the group consisting of (C 1 -C 10 )alkyl; aryl-(C 1 -C 6 )alkyl, the aryl of which is optionally substituted by at least one halo; and (C 1 -C 6 )alkyl substituted by at least one member selected from the group consisting of halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio and —NR 1 R 2 ;

R 1 and R 2 are, independently, H or (C 1 -C 6 )alkyl, or form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by (C 1 -C 6 )alkyl;

Z 2 is selected from the group consisting from —O—, —S—, —SO 2 —, —C(O)—, —C(O)—NR N — and —NR N —;

Z′ 2 is aryl or heteroaryl, the aryl and heteroaryl being optionally substituted by at least one member selected from the group consisting of:

halo, nitro, cyano, hydroxy, (C 1 -C 6 )alkyl optionally substituted by at least one halo, (C 1 -C 6 )alkyl-thio, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkoxy optionally substituted by at least one halo, aryl-alkoxy, (C 1 -C 6 )alkoxy-carbonyl, phosphate, sulfate, glycoside, —(CH 2 ) n —NR 3 R 4 and —NH—C(O)—CH(R A )—NR 5 R 6 ;

R 3 and R 4 are, independently, selected from the group consisting of H or (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-carbonyl and (C 1 -C 6 )alkyl-sulfonyl, or R 3 and R 4 form together with the nitrogen atom to which they are attached, a heteroaryl or a heterocycloalkyl optionally substituted by (C 1 -C 6 )alkyl;

R 5 and R 6 are, independently, H or (C 1 -C 6 )alkyl;

R A is the residue of an amino acid of the formula NH 2 —CH(R A )—C(O)—OH;

R N is hydrogen or (C 1 -C 6 )alkyl;

n is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.