A derivative of imidazole, pharmaceutical composition and methods of inhibiting farnesyltransferase and prenyltransferase and inhibit the growth of tumors

 

The invention relates to new imidazole derivative of formula I and IIorwhere 1, m, r, s, and t = 0 or 1; n = 1 or 2; provided that when 1 and m = 0, n = 2 Y - SO2or CH2; Z - CR12, NR32SO; NR13, NR36CO., OCONR15, SO2NR14; R1selected from the group consisting of hydrogen, alkyl, or aralkyl, the symbola single or double bond, R7, R8selected from the group consisting of hydrogen, aryl, - CN, halogen, and U-R44group, where U = O and R44and R11selected from the group consisting of hydrogen, alkyl, aralkyl, aryl; R32selected from the group consisting of hydrogen, lower alkyl, unsubstituted or substituted phenyl, and tanila; R9, R10, R12, R13, R14, R15, R36, R57and R58represent hydrogen or lower alkyl; one of R, S and T is CH2or CH(CH2)pQ, where Q denotes NR57R58; where p = 0,1 or 2; provided that when Y is - SO2, R11cannot be hydrogen; its enantiomers, diastereoisomers, pharmaceutically acceptable salt and solvate. The invention relates also to pharmaceutical compositions n the Oia growth of tumors. The technical result - obtaining new imidazole derivatives having inhibitory activity against farnesyltransferase and prenyltransferase, and applicable to inhibit the growth of cancerous tumors. 6 C. and 8 C.p. f-crystals, 1 table.

Table T%

Claims

1. Derived imidazole of the formula I or IIorwhere l, m, r, s, and t = 0 or 1;
n= 1 or 2; provided that when 1 and m= 0, n= 2;
Y - SO2or CH2;
Z - CR12, NR32SO2, NR13, NR36CO., OCONR15, SO2NR14;
R1selected from the group consisting of hydrogen, alkyl, or aralkyl;
the symbola single or double bond,
R7, R8selected from the group consisting of hydrogen, aryl, - CN, Galaga, and U-R44group, where U= O and R44and R11selected from the group consisting of hydrogen, alkyl, aralkyl, aryl;
R32selected from the group consisting of hydrogen, lower alkyl, unsubstituted or substituted phenyl, and tanila;
R9, R10, R12, R13, R14, R15, R36, R57and R58represent hydrogen or nission> where p= 0,1 or 2;
provided that when Y is - SO2, R11cannot be hydrogen;
its enantiomers, diastereoisomers, pharmaceutically acceptable salt and solvate.

2. A derivative of imidazole under item 1, wherein 1, m, r, s, and t = 0 or 1; n = 1 or 2; Y denotes SO2or Y is absent; Z represents CR12, NR13, SO2NR14, CONR15, NR32SO2, NR36CO or Z is absent.

3. A derivative of imidazole under item 2 of the formula I, wherein l, r, s, and t = 0; m = 1; n = 1 or 2; Y denotes SO2or Y is absent; and Z represents CR12, SO2NR14, CONR15NR32SO2, NR36CO or Z is absent.

4. A derivative of imidazole under item 2 of the formula II, wherein r, s, m, t = 0; 1 = 1; n = 1 or 2; Y denotes SO2or Y is absent; and Z represents CR12, NR13, SO2NR14, CONR15or Z is absent.

5. A derivative of imidazole under item 3 or 4, wherein R7, R8denote halogen, cyano or U-R44where U represents O, R44denotes hydrogen, alkyl, aralkyl.

6. A derivative of imidazole under item 1, wherein the salt is a salt of an organic or inorganic acid.

7. A derivative of imidazole under item 6, distinguish what you hydroxyethanesulfonic acid, sulfuric acid, acetic acid, triperoxonane acid, maleic acid, benzosulfimide acid, toluensulfonate acid, nitric acid, phosphoric acid, boric acid, tartaric acid, citric acid, succinic acid, benzoic acid, ascorbic acid or salicylic acid.

8. A derivative of imidazole under item 1, which is a
N-[6-bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -1-naphthalenesulfonate, dihydrochloride;
N-[6-bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -1-naphthaleneboronic, dihydrochloride;
N-[6-bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-(phenylmethyl)methanesulfonamide, dihydrochloride;
N-[6-bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -benzosulfimide, dihydrochloride;
N-[6-bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-(phenylmethyl)ndimethylacetamide, dihydrochloride;
N-[6-bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(4-methoxyphenyl)methyl] methanesulfonamide, monohydrochloride;
N-[6-bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(4-were)methyl)] methanesulfonamide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-eliminator-4-ylmethyl)-3-chinoline] -N-[(2-were)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-(phenylethyl) benzosulfimide, monohydrochloride;
2,3,4,5-tetrahydro-5-[(1H-imidazol-4-ylmethyl)amino] -2-(1-naphthylmethyl)-8-methoxy-1H-2-benzazepine, dihydrochloride;
2,3,4,5-tetrahydro-5-[(1H-imidazol-4-ylmethyl)amino] -2-(1-naphthylmethyl sulfonyl)-8-phenyl-1H-2-benzazepine, dihydrochloride;
2,3,4,5-tetrahydro-5-[(1H-imidazol-4-ylmethyl)amino] -2-(1-naphthylmethyl)-8-phenyl-1H-2-benzazepine, dihydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(2-ethoxyphenyl)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-(phenylmethyl)benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(2,3-acid)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(3, 5dimethylphenyl)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(1-naphthalenyl)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(2-thiophene)methyl)] benzosulfimide, monohydrochloride;
N-[6-qi is lore;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(3-thiophene)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(3-chlorophenyl)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(2-forfinal)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-[(3-pyridyl)methyl)] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-[[1-(methyl)-1H-imidazol-5-yl] methyl] -3-chinoline] -N-(phenylmethyl)benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-[[1-(methyl)-1H-imidazol-5-yl] methyl] -3-chinoline] -N-[(3-thiophenemethyl] benzosulfimide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-chinoline] -N-(phenylmethyl)methanesulfonamide, monohydrochloride;
N-[6-cyan-1,2,3,4-tetrahydro-1-[[1-(methyl)-1H-imidazol-5-yl] methyl] -3-chinoline] -N-(phenylmethyl)methanesulfonamide, monohydrochloride;
(R)-N-[6-cyan-1,2,3,4-tetrahydro-1-[[1-(methyl)-1H-imidazol-5-yl] methyl] -3-chinoline] -N-(phenylmethyl)benzosulfimide, monohydrochloride;
(R, E)-8-cyan-2,3,4,5-tetrahydro-3-(phenylmethyl)-2-(phenylsulfonyl)-5-[[1H-imidazol-4-yl] methylene] -1H-2-benzazepin, monohidrato effective for inhibiting farnesyltransferase number of connection p. 1.

10. Method of inhibiting prenyltransferase, which is the introduction to the mammal is effective for inhibiting prenyltransferase number of connections on p. 1.

11. The method of suppressing the growth of tumors, which consists in the introduction to the mammal effective to suppress tumor growth in the number of connections on p. 1.

12. Pharmaceutical composition having the ability to inhibit farnesyltransferase and containing a carrier and a therapeutically effective amount of the compounds under item 1.

13. The pharmaceutical composition according to p. 12, containing additional anti-cancer and cytotoxic agents.

14. The method of suppressing the growth of tumors, which consists in the introduction to the mammal effective to suppress tumor amount of a composition under item 12 or 13.

 

Same patents:

The invention relates to new substituted beendocumented formula (I) and their pharmaceutically acceptable salts, where R1denotes hydrogen and R2denotes methyl, or R1denotes methyl and R2denotes hydrogen, or R1represents hydroxymethyl and R2denotes methyl

The invention relates to a method for producing derivatives of imidazole of formula A, where R1represents a substituted heterocycle, R4is phenyl, optionally substituted, R2represents the алкилN3, -(CR10R20)nOR9further as stated in the description

The invention relates to a new 2-{4-[4-(4,5-dichloro-2-Mei-1-yl)butyl]-1-piperazinil}-5-torpedinidae formula I (see

The invention relates to novel azole compounds having antifungal activity, their preparation and application

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to a new polymorphic and hydrated forms of the dihydrochloride of Lesopitron(2-[4-[4-(chloropyrazole-1-yl)butyl] -1-piperazinil] pyrimidine] ), which have effect on the Central nervous system, showing, in particular, anxiolytic, sedative and antidepressant action, and pharmaceutical compositions based on these forms of Lesopitron

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to new indole derivative of the formula I

< / BR>
where R1- H, halogen, CN; R2and R3the same or different is H, C1-C4alkyl, halogen; R4- H, C1-C4alkyl; And means cyanoaniline, aminosulphonylphenyl, aminopyridine, aminopyrimidine, halogenopyrimidines or cianciarulo group, provided that if all R1, R2and R3- N, when both R2and R3- N or when ring A - aminosulphonylphenyl group and both R1and R2the halogen atoms is excluded; and, in addition, when the ring a represents cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom

The invention relates to new derivatives of arylpiperazines General formula I, where X Is O or S1- C1-C4alkoxy, CF3, R2- C1-C6alkyl, saturated WITH3-C6cycloalkyl; heteroseksualci of 3-6 ring atoms, heteroatom of which is O, S or N, optionally N-substituted WITH1-C6by alkyl; phenyl, optionally substituted by F, Cl, Br, NH2CH3CF3or OCH3; 5-6-membered heteroaryl, the heteroatom of which is O, S or N, possibly substituted, or condensed heteroaromatic system containing 9 atoms

Arylalkylamine // 2201923
The invention relates to arylalkylamines formula I, where B - A, OA, NH2, CF3, aromatic heterocycle selected from pyridine, pyrazine and pyrimidine; Q is absent or denotes alkylene with 1-6 carbon atoms; R1and R2independently from each other represent OR5where R5- Or cycloalkyl with 3-7 carbon atoms; And the alkyl with 1-10 carbon atoms, and their physiologically acceptable salts

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient
Up!