RU2226526C2 - Azabicycles modulating inhibition of cellular adhesion, pharmaceutical composition based on thereof and method for treatment - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy. SUBSTANCE: invention relates to compound of the formula (I):

wherein R¹ represents: (i) R³-Z³- or: (ii) R³-L³-Ar¹-L⁴-Z³-; R² represents hydrogen atom; R³ represents alkyl, aryl optionally substituted with one or two substituents taken among halogen atom and C_1-4-alkyl, arylalkyl; R⁵ represents hydrogen atom; R⁷ and R^7a represent hydrogen atom; R⁸ represents hydrogen atom; R⁹ represents alkyl optionally substituted with halogen atom, aryl, heteroaryl comprising up to 2 heteroatoms taken among nitrogen and oxygen atoms, or alkyl substituted with aryl or heteroaryl; A¹ represents unsubstituted C_1-3-alkylene bond with linear chain; Ar¹ represents arylene that can be substituted optionally with C_1-4-alkoxy-group or heteroaryldiyl comprising up to 2 heteroatoms taken among nitrogen and oxygen atoms; L¹ represents alkylene bond that is substituted optionally with

; L³ represents -NR⁵-C(=Z)-NR⁵-, -Z-, -NR⁵-, -NR⁵-C(= O)-O-, or O- C(=O)-NR⁵- L⁴ represents alkylene bond; Z represents oxygen atom; Z¹ represents C(R⁷)(R^7a); Z³ represents C(=O) or SO₂; Y represents carboxy-group under condition that when R¹ represents R³ or R³-C(=O) then R³ can't represent alkyl; or its corresponding N-oxide or ester that can be converted to the primary molecule in vivo by metabolism, or pharmaceutically acceptable salt of such compound, or its N-oxide, or its ester. Invention relates also to pharmaceutical composition eliciting inhibitory effect on cellular adhesion and comprising effective amount of compound of the formula (I) and pharmaceutically acceptable carrier or excipient. Invention relates also to the application of compound of the general formula (I):

wherein R¹ represents R³ or R³--C(=O) wherein R³ represents alkyl;

, Z, Z¹, Z³ and Y are given above; or its corresponding N-oxide or ester that can be converted to the primary molecule in vivo by metabolism; or pharmaceutically acceptable salt of such compound or its N-oxide or ester used for preparing a medicinal agent used for treatment of patient suffering with states or subjected for states that can be relieved by administration of inhibitor of α4β1-mediated cellular adhesion. Invention relates also to method for treatment of patient suffering with states or subjected for states that can be relieved by administration of inhibitor of α4β1-mediated cellular adhesion involving administration to the indicated patient the effective dose of compound of the formula (I). Invention provides preparing new compounds eliciting inhibitory effect on cellular adhesion. EFFECT: improved treatment method, valuable medicinal properties of compounds. 65 cl, 3 tbl, 40 ex

Description

Description text in facsimile form (see graphic part).

Claims (65)

1. The compound of formula (I):

where R ¹ represents (i) R ³ -Z ³ -or (ii) R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -; R ² is hydrogen; R ³ is alkyl; aryl optionally substituted with one or two substituents from halogen and C _1-4 alkyl; arylalkyl; R ⁵ is hydrogen; R ⁷ and R ^7a are hydrogen; R ⁸ is hydrogen; R ⁹ is alkyl; optionally halogen-substituted aryl; heteroaryl containing up to 2 heteroatoms selected from nitrogen and oxygen atoms, or alkyl substituted with an aryl, heteroaryl or acid functional group; A ¹ represents an unsubstituted C _1-3 alkylene bond with a linear chain; Ar ¹ is arylene, which may optionally be substituted with C _1-4 alkoxy; or heteroaryldiyl containing up to 2 heteroatoms selected from nitrogen and oxygen atoms; L ¹ represents an alkylene bond which is substituted with —N (R ⁸ ) —C (═O) —R ⁹ ; -N (R ⁸ ) -C (= O) -OR ⁹ ; -N (R ⁸ ) -SO ₂ -R ⁹ ; L ³ represents —NR ⁵ —C (= Z) —NR ⁵ -; -Z-; -NR ⁵ -; —NR ⁵ —C (= O) —O— or —OC (= O) —NR ⁵ -; L ⁴ represents an alkylene bond; Z is an oxygen atom; Z ¹ represents C (R ⁷ ) (R ^7a ); Z ³ represents C (= O) or SO ₂ ; Y carboxy; with the proviso that when R ¹ represents R ³ or R ³ -C (= O), then R ³ cannot represent alkyl; or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its, N-oxide, or its ester. 2. The compound according to claim 1, in which R ¹ represents a group R ³ -Z ³ -, where Z ³ represents (C = O) and R ³ is aryl, optionally substituted with one or two substituents from halogen and C _1-4 - alkyl, or arylalkyl. 3. The compound according to claim 2, in which R ³ is phenyl or phenyl substituted with one or two substituents from halogen and C _1-4 alkyl. 4. The compound according to claim 2, in which R ³ is benzyl, optionally substituted on the phenyl ring by one or two halogen substituents. 5. The compound according to claim 2, in which R ³ - 2-chlorophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl or 2,6-difluorophenyl. 6. The compound according to claim 1, in which R ¹ represents a group R ³ -L ³ -Ar ^l -L ⁴ -Z ³ in which Z ³ represents C (= O); Ar ¹ is optionally substituted phenylene or heteroaryldiyl; L ³ represents a bond —NH — C (═O) —NH— and R ³ is an optionally substituted aryl. 7. The compound according to claim 6, in which L ⁴ is methylene; Ar ¹ is optionally substituted p-phenyl; and R ³ is optionally substituted phenyl. 8. The compound according to claim 7, in which Ar ¹ is p-phenylene or p-phenylene substituted at the 3-position of C _1-4 alkoxy, and R ³ is phenyl substituted at the 2-position of C _1-4 alkyl . 9. The compound according to claim 1, in which R ¹ represents a group R ³ -L ³ -Ar ¹ - L ⁴ -Z ³ , in which Z ³ represents C (= O); L ⁴ is a straight or branched C _1-6 alkylene chain; Ar ¹ is an optionally substituted 8-10 membered bicyclic system

in which the ring

represents a 5- or 6-membered heterocyclic ring; ring

represents a 5- or 6-membered heterocycle or two rings are joined together by a carbon-carbon bond or a carbon-nitrogen bond; L ³ represents NH and R ³ is optionally substituted aryl. 10. The compound according to claim 9, in which L ⁴ is methylene and Ar ¹ is optionally substituted benzoxazolyl or optionally substituted benzimidazolyl. 11. The compound of claim 10, in which R ³ is phenyl substituted in the 2nd position with C _1-4 alkyl or halogen. 12. The compound according to any preceding paragraph, in which A ¹ is methylene. 13. The compound according to any preceding paragraph, in which A ¹ is ethylene. 14. The compound according to any preceding paragraph, in which L ¹ is ethylene or propylene, each of which is optionally substituted with -N (R ⁸ ) -C (= O) -R ⁹ ; -N (R ⁸ ) -C (= O) -OR ⁹ ; —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 15. The compound according to claim 1, in which L ¹ represents a group

where R ⁵ is hydrogen and R ¹⁵ is hydrogen or lower alkyl or where R ⁵ is hydrogen and R ¹⁵ is —N (R ⁸ ) —C (═O) —R ⁹ ; -N (R ⁸ ) -C (= O) -OR ⁹ ; —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 16. The compound according to clause 15, in which L ¹ represents the group

where R ¹⁵ is hydrogen, lower alkyl, -N (R ⁸ ) -C (= O) -R ⁹ ; —N (R ⁸ ) —C (= O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 17. The compound according to claim 1, in which L ¹ represents a group

where R ⁵ is hydrogen or lower alkyl and R ^15a is lower alkyl or where R ⁵ is hydrogen and R ^15a is —N (R ⁸ ) —C (═O) —R ⁹ ; —N (R ⁸ ) —C (= O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 18. The compound according to 17, in which L ¹ represents a group

where R ^15a represents —N (R ⁸ ) —C (═O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (wherein R ⁸ and R ⁹ are as defined in claim 1). 19. The compound according to 17, in which L ¹ represents a group

where R ^15a represents —N (R ⁸ ) —C (═O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (wherein R ⁸ and R ⁹ are as defined in claim 1). 20. The compound according to claim 1, having the formula (Ia)

in which R ² , R ³ , A ¹ , Ar ¹ , L ⁴ , Y and Z ¹ have the meanings indicated in any suitable preceding paragraph, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 21. The compound according to claim 1, having the formula (Ib)

in which R ² , R ³ , A ¹ , L ² , Y and Z ¹ have the meanings indicated in any suitable preceding paragraph; X represents NR ⁵ or O; Z ⁴ represents NR ⁵ or O (where R ⁵ has the meanings indicated in any suitable preceding paragraph); R is hydrogen or aryl group substituent, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 22. The compound according to claim 1, having the formula (Id)

where R ³ , A ¹ , R ² , L ¹ , Y and Z ¹ have the meanings indicated in any suitable preceding paragraph, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 23. The compound according to claim 20, in which R ³ is phenyl substituted in the 2nd position with C _1-4 alkyl. 24. The compound according to any one of claims 20 and 23, wherein Ar ¹ is p-phenylene or p-phenylene substituted at the 3-position of C _1-4 alkoxy. 25. The compound according to item 21, in which R ³ is phenyl substituted in the 2nd position with C _1-4 alkyl or halogen. 26. The compound according to item 21 or 25, in which Z ⁴ represents NH. 27. The compound according to any one of paragraphs.21, 25 and 26, in which R is hydrogen or C _1-4 alkoxy. 28. The compound according to any one of paragraphs.20, 21, 23-27, in which L ⁴ represents a straight or branched C _1-4 alkylene chain. 29. The compound of claim 28, wherein L ⁴ is methylene. 30. The compound of claim 22, wherein R ³ is phenyl or phenyl substituted with one or two substituents from halogen or C _1-4 alkyl. 31. The compound of claim 22, wherein R ³ is benzyl optionally substituted on the phenyl ring with one or two substituents from halogen or methoxy. 32. The compound according to item 22, in which R ³ - 2-chlorophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl or 2,6-difluorophenyl. 33. The compound according to any one of paragraphs.20-32, in which A ¹ is methylene. 34. The compound according to any one of paragraphs.20-32, in which A ¹ is ethylene. 35. The compound according to any one of claims 20-34, wherein L ¹ is ethylene or propylene, each of which is optionally substituted with —N (R ⁸ ) —C (= O) —R ⁹ ; -N (R ⁸ ) -C (= O) -OR ⁹ ; —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 36. The compound according to any one of paragraphs.20-34, in which L ¹ represents a group

where R ⁵ is hydrogen or lower alkyl and R ¹⁵ is hydrogen or lower alkyl or where R ⁵ is hydrogen and R ¹⁵ is —N (R ⁸ ) —C (═O) —R ⁹ ; —N (R ⁸ ) —C (= O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 37. The compound according to clause 36, in which L ¹ represents a group

where R ¹⁵ is hydrogen, lower alkyl, -N (R ⁸ ) -C (= O) -R ⁹ ; —N (R ⁸ ) —C (= O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 38. The compound according to any one of paragraphs.20-34, in which L ¹ represents a group

where R ⁵ is hydrogen or lower alkyl and R ^15a is lower alkyl or R ⁵ is hydrogen, and R ^15a is —N (R ⁸ ) —C (═O) —R ⁹ ; —N (R ⁸ ) —C (= O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (where R ⁸ , R ⁹ are as defined in claim 1). 39. The compound of claim 38, wherein L ¹ represents a group

where R ^15a represents —N (R ⁸ ) —C (═O) —R ⁹ or | —N (R ⁸ ) —SO ₂ —R ⁹ (wherein R ⁸ and R ⁹ are as defined in claim 1). 40. The compound according to 38, in which L ¹ represents a group

where R ^15a represents —N (R ⁸ ) —C (═O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ (wherein R ⁸ and R ⁹ are as defined in claim 1). 41. The compound of formula (Ia) according to claim 20, in which R ³ is 2-substituted phenyl; A ¹ is methylene or ethylene; Ar ¹ is optionally substituted m- or p-phenylene or optionally substituted p-pyridinediyl; L ¹ represents

[where R ¹⁵ represents hydrogen, —N (R ⁸ ) —C (═O) —R ⁹ ; -N (R ⁸ ) -C (= O) -OR ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ; L ⁴ represents a straight or branched C ₁ alkylene chain, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 42. The compound of formula (Ia) according to claim 20, where R ³ is 2-substituted phenyl; A ¹ is methylene or ethylene; Ar ¹ is optionally substituted m- or p-phenylene or optionally substituted p-pyridinediyl; L ¹ represents

[where R ^15a represents —N (R ⁸ ) —C (═O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ; L ⁴ - unbranched or branched C _1-6 alkylene chain, or its corresponding N-oxide or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 43. The compound of formula (Ib) according to item 21, where R is methoxy; R ³ is optionally substituted aryl, A ¹ is methylene or ethylene; L ¹ represents a group

[where R ¹⁵ is hydrogen, lower alkyl, —N (R ⁸ ) —C (═O) —R ⁹ ; —N (R ⁸ ) —C (═O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ]; L ⁴ represents a straight or branched C _1-4 alkylene chain; X represents O; Z ⁴ represents NH; and group

attached at position 6 of the ring, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 44. The compound of formula (Ib) according to item 21, where R is hydrogen or methoxy; R ² is hydrogen; R ³ is optionally substituted aryl; A ¹ is methylene or ethylene; L ¹ represents a group

[where R ^15a represents —N (R ⁸ ) —C (═O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ]; L ⁴ represents a straight or branched C _1-4 alkylene chain; X represents O; Z ⁴ represents NH; and group

attached at position 6 of the ring, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 45. The compound of formula (Ib) according to item 21, where R ³ is optionally substituted aryl; A ¹ is methylene or ethylene; L ¹ represents a group

[where R ¹⁵ is hydrogen, lower alkyl, —N (R ⁸ ) —C (═O) —R ⁹ ; —N (R ⁸ ) —C (═O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ]; L ⁴ represents a straight or branched C _1-4 alkylene chain; X represents NR ⁵ ; Z ⁴ represents NH; and group

attached at position 5 or 6 of the ring, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 46. The compound of formula (Ib) according to item 21, where R ³ is optionally substituted aryl; A ¹ is methylene or ethylene; L ¹ represents a group

[where R ^15a represents —N (R ⁸ ) —C (═O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ]; L ⁴ represents a straight or branched C _1-4 alkylene chain; X represents NR ⁵ ; Y is carboxy; Z ¹ represents CH ₂ ; Z ⁴ represents NH; and group

attached at position 5 or 6 of the ring, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 47. The compound of formula (Id) according to claim 22, wherein R ³ is optionally substituted phenyl or benzyl; A ¹ is methylene or ethylene; L ¹ represents a group

[where R ¹⁵ is hydrogen, methyl, —N (R ⁸ ) —C (= O) —R ⁹ ; —N (R ⁸ ) —C (= O) —OR ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ], or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 48. The compound of formula (Id) according to item 22, where R ³ is optionally substituted phenyl or benzyl, A ¹ is methylene or ethylene, L ¹ represents a group

[where R ^15a - represents —N (R ⁸ ) —C (═O) —R ⁹ or —N (R ⁸ ) —SO ₂ —R ⁹ ], or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester. 49. The compound according to any one of paragraphs 42, 44, 46 and 48, where L ¹ represents a group

50. The compound according to any one of paragraphs 43, 45 and 47, where L ¹ represents a group

51. The compound of claim 50, wherein R ¹⁵ is hydrogen. 52. The compound of claim 50, wherein R ¹⁵ is lower alkyl. 53. The compound of claim 50, wherein R ¹⁵ is —N (R ⁸ ) —C (═O) —R ⁹ , where R ⁸ is hydrogen and R ⁹ is lower alkyl, aryl, heteroaryl, or substituted carboxy alkyl. 54. The compound of claim 50, wherein R ¹⁵ is —N (R ⁸ ) —C (═O) —R ⁹ where R ⁸ is hydrogen and R ⁹ is lower alkyl. 55. The compound of claim 50, wherein R ¹⁵ is —N (R ⁸ ) —SO ₂ —R ⁹ where R ⁸ is hydrogen and R ⁹ is lower alkyl, aryl, or heteroaryl. 56. The compound of claim 50, wherein R ¹⁵ is —H,

—CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ CH _3, or —CH ₂ CH ₂ C ₂ CH ₃ . 57. The compound of claim 49, wherein R ^15a is —N (R ⁸ ) —C (═O) —R ⁹ , where R ⁸ is hydrogen and R ⁹ is lower alkyl. 58. The compound of claim 49, wherein R ^15a is —N (R ⁸ ) —C (═O) —R ⁹ , where R ⁸ is hydrogen and R ⁹ is 2-chlorophenyl. 59. The compound of claim 49, wherein R ^15a is —N (R ⁸ ) —C (═O) —R ⁹ wherein R ⁸ is hydrogen and R ^{9 is} selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-dimethylpyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin-3-yl, 3,5-dimethylisoxazol-4-yl and 4-trifluoromethylpyrimidin-5-yl. 60. The compound according to claim 1, selected from 3- (1 - {[3-Methoxy-4- (3- [2-methylphenyl] ureido) phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) propionic acid, 3- (1 - {[3-Methoxy-4- (3-o-tolylurenedo) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) butyric acid; 3- (1 - {[3-Methoxy-4- (3-o-tolylureido) phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) butyric acid; 3- (1 - {[3-Methoxy-4- (3-o-tolylureido) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) pentanedioic acid, 3- (1 - {[3-Methoxy-4- (3-o-tolylureido) phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) pentanedioic acid; 4- [2-Carboxy-1- (1 - {[3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) ethylcarbamoyl] - butyric acid; N- [2-Carboxy-1- (1 - {[3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) ethyl] succinamic acids; 3- (1 - {[3-Methoxy-4- (3-o-tolylureido] phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -3 - [(5-methylisoxazol-3- carbonyl) amino] propionic acid; 2- (2-Chloro-6-methylbenzoylamino) -3- [1- (2,6-dichlorobenzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] propionic acid; 2- (2,6-Dichlorobenzoylamino) -3- [1-2,6-dichlorobenzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] propionic acid; 3- (1 - {[3-Methoxy-4- (3-o-tolylureido) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) -3-phenylpropionic acid; 3- (1 - {[3-Methoxy-4- (3-o-tolylureido) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) pentanoic acid and their corresponding N-oxides or esters, which can be converted in vivo by metabolism into a primary molecule, or pharmaceutically acceptable salts of such compounds, or their N-oxides, or their esters. 61. The compound according to claim 1, or its corresponding N-oxide, or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or its ester for use in the treatment of a patient suffering from conditions or susceptible to conditions that can be alleviated by the administration of an inhibitor of α4β1-mediated cell adhesion. 62. A pharmaceutical composition having an inhibitory effect on cell adhesion, comprising an effective amount of a compound of formula (I)

where R ¹ represents (i) R ³ -Z ³ - or (ii) R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -; R ³ is alkyl; aryl substituted with one or two substituents from halogen and C _1-4 alkyl; arylalkyl; or R ¹ represents R ³ where R ³ is alkyl; R ² , R ⁵ , R ⁷ , R ^7a , R ⁸ , R ⁹ , A ¹ , Ar ¹ , L ¹ , L ³ , L ⁴ , Z, Z ¹ , Z ³ and Y are defined in claim 1, or its corresponding N-oxide or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide or ester, and a pharmaceutically acceptable carrier or excipient. 63. The composition according to p. 62 for use in the treatment of a patient suffering from conditions or susceptible to conditions that can be alleviated by the introduction of an inhibitor of α4β1-mediated cell adhesion. 64. The use of the compounds of General formula 1

where R ¹ represents R ³ or R ³ -C (= O), where R ³ is alkyl; R ² , R ⁵ , R ⁷ , R ^7a , R ⁸ , R ⁹ , A ¹ , Ar ¹ , L ¹ , L ³ , L ⁴ , Z, Z ¹ , Z ³ and Y are defined in claim 1, or its corresponding N-oxide or ester, which can be converted in vivo by metabolism to a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide, or ester for the manufacture of a medicament for the treatment of a patient suffering from conditions or prone to conditions that can be alleviated by the administration of an inhibitor of α4β1-mediated cell adhesion. 65. A method of treating a patient suffering from conditions or susceptible to conditions that can be alleviated by the administration of an α4β1-mediated cell adhesion inhibitor, comprising administering to said patient an effective amount of a compound of formula (1)

where R ¹ represents (i) R ³ -Z ³ - or (ii) R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -; R ³ is alkyl; aryl substituted with one or two substituents from halogen and C _1-4 alkyl; arylalkyl; or R ¹ represents R ³ where R ³ is alkyl; R ² , R ⁵ , R ⁷ , R ^7a , R ⁸ , R ⁹ , A ¹ , Ar ¹ , L ¹ , L ³ , L ⁴ , Z, Z ¹ , Z ³ and Y are defined in claim 1, or its corresponding N-oxide or ester, which can be converted in vivo by metabolism into a primary molecule, or a pharmaceutically acceptable salt of such a compound, or its N-oxide or ester. Priority on points and signs: 3- (1 - {[3-Methoxy-4- (3- [2-methylphenyl] uredo) phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) propionic acid according to claim 60 - 08/26/1998. claims 1-67, except for 3- (1 - {[3-Methoxy-4- (3- [2-methylphenyl] -uredo) phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl ) propionic acid - 08/26/1999.

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