RU2000128033A

RU2000128033A - Heterocyclic derivatives of glycyl-beta-alanine as vitronectin antagonists

Info

Publication number: RU2000128033A
Application number: RU2000128033/04A
Authority: RU
Inventors: Низал Самьюэл ЧАНДРАКУМАР; Бипинчандра Нанубхай ДЕСАЙ; Балекудру Девадас; Рене ХАФФ; Иш К. КХАННА; Шашидхар Н. РАО; Джозеф Г. РИКО; Томас Э. РОДЖЕРС; Питер Г. РУМИНСКИ; Марк Эндрью РАССЕЛЛ; Йи ЮЙ; Алан Фрэнк ГАЗИКИ; Джеймз У. МАЛЕХА; Джули М. МИЯШИРО
Original assignee: Дж. Д. Серл Энд Ко.
Priority date: 1998-04-10
Filing date: 1999-04-09
Publication date: 2003-06-20

Claims

1. The compound of formula I

or a pharmaceutically acceptable salt of this compound,

Where

is a 5-8 membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, wherein X ^{1 is} selected from the group consisting of CH, CH ₂ , N, NH, O and S;

provided that

is not pyrrolidinyl when V is NH;

A represents a group of the formula

where Y ¹ selected from the group including NR ₂ , O and S;

R ^{2 is} selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, aryl, aryl substituted, single or multiple, by a C ₁ -C ₁₀ alkyl group, a halogen group, a hydroxy group, a haloalkyl group, a cyano group, a nitro group, a carboxy group, an amino group, an alkoxy group, an aryl group or an aryl group, which may be substituted, once or repeatedly, by a halogen group, a haloalkyl group, a C ₁ -C ₁₀ alkyl group, an alkoxy group, a cyano group, an alkylsulfonyl group, an alkylthio group, a nitro group, a carboxy group, an amino group, a hydroxy group, a sulfo group, a sulfonamide group, a a group, monocyclic heterocycles or fused monocyclic heterocycles; aryl, optionally substituted, single or multiple, by a halogen group, a haloalkyl group, a hydroxy group, a C ₁ -C ₁₀ alkyl group, an alkoxy group, a methylenedioxy group, an ethylenedioxy group, a cyano group, a nitro group, an alkylthio group, an alkylsulfonyl group, an sulfo group, a sulfonic group, sulfonic group, sulfonic group, a group, a fused aryl group, monocyclic heterocycles or a fused monocyclic heterocycle; monocyclic heterocycles and monocyclic heterocycles, optionally substituted, single or multiple, by a halogen group, a haloalkyl group, a C ₁ -C ₁₀ alkyl group, an alkoxy group, an amino group, a nitro group, a hydroxy group, a carboxy derivative, a cyano group, an alkylthiogrululfonic group, an alkylthiogrululfonic group, an alkylthiogrululfonic group, an alkylthiogrululfonic acid group, an aryl group or a fused aryl group,

or R ² together with R ⁷ forms a 4-12 membered heterocycle containing two nitrogen atoms, optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₁₀ alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halogen , phenyl, amino, carboxy or carboxylic acid ester, spirodioxolanes and condensed phenyl, or R ² together with R ⁷ forms a 4-12 membered, optionally unsaturated heterocycle containing one or more heteroatoms selected from the group consisting of O, N and S or R ² together with R ⁷ forms a 5-9 membered geteroaroma matic ring optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₁₀ alkyl, phenyl, alkoxy and hydroxy, or R ² together with R ⁷ forms a 5 membered heteroaromatic ring Bathing-condense with an aryl or heteroaryl ring ;

R ⁷ (when not together with R ² ) and R ⁸ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl, galoidalkilkarbonil, haloalkoxycarbonyl, alkylthiocarbonyl, ariltiokarbonil, atsiloksimetoksikarbonil, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally substituted by mono- or polysubstituted C ₁ -C ₁₀ alkyl, halogen, hydroxy, haloalkyl g uppoy, cyano, nitro, carboxy derivatives, amino, alkoxy, thio, alkylthio, sulfonyl group, an aryl group, an aralkyl group, an aryl group which may be substituted one or more times, halogen group, haloalkyl group, C ₁ -C ₁₀ alkyl group , alkoxy group, methylenedioxy group, ethylenedioxy group, alkylthio group, haloalkylthio group, thio group, hydroxy group, cyano group, nitro group, carboxy derivatives, aryloxy group, amido group, acyi amino, amino, alkylamino, dialkylamino, triftoralkokigruppoy, a trifluoromethyl group, a sulfonyl group, an alkylsulfonyl group, galoidalkilsulfonilnoy group, a sulfo group, a sulfonamide group, an aryl group, a condensed aryl group, monocyclic heterocycles, fused monocyclic heterocycles; aryl, optionally substituted, single or multiple, by a halogen group, a haloalkyl group, a C ₁ -C ₁₀ alkyl group, an alkoxy group, a methylenedioxy group, an ethylenedioxy group, an alkylthio group, a haloalkylthio group, a thio group, a hydroxy group, an amino group, an amino group, an amino group, an amino group, an amino group, an amino group, an amino group, an amino group , an alkylamino group, a dialkylamino group, a trifluoroalkoxy group, a trifluoromethylsulfonyl group, an alkylsulfonyl group, a sulfo group, a sulfonamide group Second, an aryl group, a condensed aryl group, monocyclic heterocycles, or fused monocyclic heterocycles; monocyclic heterocycles, monocyclic heterocycles, optionally substituted, single or multiple, by a halogen group, a haloalkyl group, a C ₁ -C ₁₀ alkyl group, an alkoxy group, an aryloxy group, an amino group, a nitro group, a hydroxy group, a carboxy derivative, a cyano group, an alkyl group, an alkyl group an aryl group; mono- and bicyclic heterocyclic alkyls, the group -SO ₂ R ¹⁰ where R ^{10 is} selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthiocyclo pu

where R has the above meaning;

or NR ⁷ together with R ⁸ form a 4-12 membered mono or bicyclic ring containing one nitrogen atom, optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₁₀ alkyl, carboxy derivatives, aryl or hydroxy, this ring optionally contains a heteroatom selected from the group consisting of O, N and S;

R ^{5 is} selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl and phenethyl; or

A denotes a group

where Y ^{2 is} selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl optionally substituted with aryl, which may also be optionally substituted, once or repeatedly, with a halogen group, a haloalkyl group, an alkyl group, a nitro group, a hydroxy group, an alkoxy group , an aryloxy group, an aryl group or a fused aryl group; an aryl optionally substituted, single or multiple, with a halo group, a haloalkyl group, a hydroxy group, an alkoxy group, an aryloxy group, an aryl group, a fused aryl group, a nitro group, a methylenedioxy group, an ethylenedioxy group or an alkyl group; alkynyl, alkenyl, —SR ⁹ and OR ⁹ groups, wherein R ^{9 is} selected from the group consisting of H, alkyl, aralkyl, aryl, alkenyl, and alkynyl; or R ⁹ together with R ⁷ forms a 4-12 membered atom containing one nitrogen atom and one sulfur atom or one oxygen atom, a heterocyclic ring optionally substituted with a C ₁ -C ₁₀ alkyl group, hydroxy group, keto group, phenyl group, carboxy group or carbonic ether an acid, or a fused phenyl group, or R ⁹ together with R ⁷ is thiazole, oxazole, benzoxazole or benzothiazole; and

R ⁵ and R ⁷ have the above meanings;

Y ² (when Y ² is carbon) together with R ⁷ forms a 4-12 membered ring containing one or two nitrogen atoms, optionally substituted with an alkyl group, an aryl group, a keto group or a hydroxy group;

A denotes a group

where R ² together with R ⁷ form a 5-8 membered heterocycle containing two nitrogen atoms, optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₁₀ alkyl, hydroxy, alkoxy, keto, phenyl and carboxy derivatives; and R ^{8 is} selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl or acyloxymethoxycarbonyl;

R ⁵ has the above meaning;

or R ² together with R ⁷ form a heteroaromatic ring, such as imidazole or pyrimidone;

A denotes a group

where R ² together with R ⁷ form a 5-8 membered heterocycle containing two nitrogen atoms, optionally substituted with a hydroxy group, a keto group, a phenyl group or an alkyl group;

R ^{8 is} selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkocarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl;

Z ¹ is one or more substituents selected from the group consisting of H, alkyl, hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl, carboxy derivatives, trihaloamides , acyl, aryl, condensed aryl, cycloalkyl, thio, monocyclic heterocycles, condensed monocyclic heterocycles and A, where A has the above meaning;

V is selected from the group consisting of —N- (R ⁶ ) -, where R ^{6 is} selected from the group consisting of H, C ₁ -C ₁₀ alkyl, cycloalkyl, aralkyl, aryl and monocyclic heterocycles, or R ⁶ together with Y forms 4- 12 membered ring containing one nitrogen atom;

Y, Y ³ , Z, and Z ^{3 are} independently selected from the group consisting of hydrogen, alkyl, aryl, and cycloalkyl; or Y together with Z form cycloalkyl; or Y ³ together with Z ³ form cycloalkyl;

n is an integer of 1, 2 or 3;

t is an integer of 0, 1 or 2;

p is an integer of 0, 1, 2 or 3;

R denotes a group XR ³ , where X is selected from the group consisting of O, S and NR ⁴ , wherein R ³ and R ^{4 are} independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, sugar , steroids, polyalkylethers, alkylamido, alkyl-N, N-dialkylamido, pivaloyloxymethyl, and in the case of the free acid, all pharmaceutically acceptable salts thereof;

R ^{1 is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxy derivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclic heterocycles optionally substituted with an alkyl group, halo group, haloalkyl group, cyano group, hydroxy group, aryl group , nitro group, alkoxy group, aryloxy group, alkylsulfonyl group, arylsulfonyl group, sulfonamide group, thio group, alkylthio group, carboxy derivatives, amino group, amido group; alkyl optionally substituted, single or multiple, by a halogen group, a haloalkyl group, a hydroxy group, an alkoxy group, an aryloxy group, a thio group, an alkylthio group, an alkynyl group, an alkenyl group, an alkyl group, an arylthio group, an alkyl sulfoxide group, an alkyl sulfonyl group, an alkyl sulfonoyl group, nitro group, amino group, alkylamino group, dialkylamino group, alkylsulfonamide group, arylsulfonamide group, acylamide group, as box derivatives, sulfonamide group, sulfo group, phosphonic acid derivatives, phosphinic acid derivatives, aryl group, arylthio group, aryl sulfoxide group or arylsulfonic group, all of which are optionally substituted on the aryl ring with a halogen group, an alkyl group, a haloalkyl group, a hydroxy group, a hydroxy carboxylic acid, nitro alkoxy group, aryloxy group, amino group, alkylamino group, dialkylamino group, amido group, aryl group, fused a yl group, monocyclic heterocycles; and fused monocyclic heterocycles, monocyclic heterocyclic thio group, monocyclic heterocyclic sulfoxide and monocyclic heterocyclic sulfone, which may optionally be substituted by a halogen group, haloalkyl group, nitro group, hydroxy group, alkoxy group, condensed aryl group or alkyl; alkylcarbonyl, galoidalkilkarbonil and arylcarbonyl, aryl optionally substituted at one or more positions halogen group, haloalkyl group, an alkyl group, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, galoidalkiltiogruppoy, thio, hydroxy, cyano, nitro, acyloxy, carboxy derivative, karboksialkoksigruppoy, amido group, acylamino group, amino group, alkylamino group, dialkylamino group, trifluoroalkoxy group, trifto a methylsulfonyl group, an alkylsulfonyl group, a sulfo group, a sulfonamide group, an aryl group, a condensed aryl group, monocyclic heterocycles and fused monocyclic heterocycles;

and group

where R ⁷ and R ⁸ have the above meanings, provided that taken together with nitrogen, R ⁷ and R ⁸ contain an amino acid;

R ^{11 is} selected from the group consisting of H, alkyl, aralkyl, alkenyl, alkynyl, haloalkyl and haloalkynyl, or R ¹¹ together with Y forms a 4-12 membered ring containing one nitrogen atom;

or a pharmaceutically acceptable salt of this compound.

2. The compound according to claim 1 of the formula

Where

denotes

or

where R ³² is H, alkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, wherein the alkyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl or alkylsulfonyl, carboxy and carboxy derivatives.

3. The compound according to claim 2, selected from the group comprising compounds

4. The compound according to claim 1 of the formula

denotes

5. The compound according to claim 4, selected from the group consisting of compounds

6. The compound according to claim 1 of the formula

denotes

7. The compound according to claim 6, selected from the group comprising compounds

8. The compound according to claim 1 of the formula

Where

denotes

or

9. The compound of claim 8 of the formula

10. The compound according to claim 1 of the formula

Where

denotes

11. The compound according to claim 10 of the formula

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 and a pharmaceutically acceptable carrier.

13. A method of treating diseases mediated by α _{vβ3 integrin} in mammals in need of such treatment, comprising administering a therapeutically effective amount of a compound according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

14. The method according to item 13, characterized in that it is used to treat tumor metastasis.