RU2000113850A

RU2000113850A - SUBSTITUTED ANILIDES

Info

Publication number: RU2000113850A
Application number: RU2000113850/04A
Authority: RU
Inventors: Питер Чарльз Эстлз; Дэвид Эдвард КЛАРК; Алан Джон КОЛЛИЗ; Пол Джозеф Кокс; Пол Джозеф ИСТВУД; Нейл Виктор Харрис; Джастин Йеун Квай Лай; Эндрю Дэвид Морли; Барри Портер
Original assignee: Авентис Фарма Лимитед
Priority date: 1997-10-31
Filing date: 1998-11-02
Publication date: 2002-05-10

Claims

1. The compound of General formula I:

where R is hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy;
X ¹ , X ² and X ⁶ independently represent N or CR ¹⁰ and
one of X ³ , X ⁴ and X ⁵ is CR ¹¹ , and the others are independently N or CR ¹⁰
where R ¹⁰ is hydrogen, amino, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkyl-sulfinyl, lower alkylsulfonyl, nitro or trifluoromethyl;
R ¹¹ denotes a group-L ¹ -Ar ¹ -L ² -Y, in which:
L ¹ is —R ² —R ³ is a bridge, where R ² is a straight or branched C _1-6 alkylene chain, a straight or branched C _2-6 alkenylene chain or a straight or branched C _2-6 alkynylene, and R ³ is direct chemical bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, -C (= Z) -NR ⁴ - -NR ⁴ -C (= Z) -, -Z ¹ -, -C (= O) -, -C (= NOR ⁴ ) -, -NR ⁴ C (= Z) NR ⁴ -, -SO ₂ -NR ⁴ -, -NR ⁴ -SO ₂ -, -OC (= O) -, -С (= O) -O- , - NR ⁴ C (= O) -O- or -O-C (= O) -NR ⁴ - (where R ⁴ is a hydrogen atom or a lower alkyl group; Z is 0 or S; Z ¹ is O, S ( O) _n or NR ⁴ and n is zero or an integer number 1 or 2); excluding compounds in which the oxygen, nitrogen or sulfur atom in R ^{3 is} directly bonded to the carbon atom of the multiple bond in R ² ;
Ar ¹ is arylene or heteroaryldiyl;
L ² means:
(i) direct chemical (direct) bond;
(ii) a bridge of alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene, each of which is optionally substituted
(a) an acid functional group (or a corresponding protected derivative), R ⁵ , -ZH, -ZR ⁵ , -C (= O) -R ⁵ , -N (R ¹² ) -C (= O) -R ¹³ , - N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , —NY ¹ Y ^2, or - [C (= O) —N (R ⁶ ) —C ( R ⁴ ) (R ⁷ )] pC (= O) —NY ^l Y ² , or (b) alkyl substituted with an acid functional group (or a corresponding protected derivative), or —ZH, —ZR ⁵ , —C (= O) -NY ¹ Y ² or -HY ¹ Y ² ;
(iii) - [C (═O) —N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] p-bridge;
(iv) -z ² -r ⁹ bridge;
(v) -C (= O) -CH ₂ -C (= O) -bridge;
(vi) -R ⁹ -Z ² -R ⁹ bridge or
(vii) -C (R ⁴ ) (R ⁸ ) - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] p-bridge
where R ⁵ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylalkylalkyl;
R ⁶ is hydrogen, R ⁵ or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or —NY ¹ Y ² ;
each of R ⁷ and R ^{8 is} independently selected from hydrogen or a group comprising amino acid side chains and corresponding protected derivatives, from an acid functional group (or a corresponding protected derivative), R ⁵ ,
—ZR ⁵ , —C (= O) —R ⁵ or —C (= O) —NY ¹ Y ² , or alkyl substituted with an acidic functional group (or corresponding protected derivative) or substituted with R ⁵ , —ZR ⁵ , —HY ¹ Y ² , -NH-C (= O) -R ⁵ , -C (= O) -R ² -NH ₂ , -C (= O) -Ar ¹ NH ₂ , -C (= O) -R ² CO ₂ H or -C (= O) -NY ¹ Y ² ;
or R ⁶ and R ⁷ , or R ⁶ and R ^8, together with the atoms to which they are attached, form a 3-6 membered heterocycloalkyl ring;
R ⁹ is C _1-6 alkylene optionally substituted with R ⁵ ;
R ¹² is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R ¹³ is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted with aryl, an acid functional group (or a corresponding protected derivative), cycloalkyl, heteroaryl, heterocycloalkyl, -ZH, -ZR ⁵ , -C (= O) -NY ¹ Y ² or -NY ¹ Y ² ;
Y ¹ and Y ^{2 are} independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted with alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, —NY ¹ Y ² or one or more groups —CO ₂ R ¹² or —C (═O) —NY ¹ Y ² ; or the group —NY ¹ Y ² can form a 5-7 membered cyclic amine, which
(i) optionally, may be substituted with one or more substituents selected from: alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5, 6 or 7 membered cyclic acetal derivative), R ¹³ ;
(ii) may also contain an additional heteroatom selected from O, S, SO ₂ or NY ³ [where Y ³ is hydrogen, alkyl, aryl, arylalkyl, —C (= O) —R ¹⁴ , —C (= O) —OR ¹⁴ or —SO ₂ R ¹⁴ (where R ¹⁴ is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl) and
(iii) may also be condensed with additional rings of aryl, heteroaryl, heterocycloalkyl or cycloalkyl, to form a cyclic system of two or three rings;
Z ² is O, S (O) n, NR ⁴ , SONR ⁴ , C (= O) NR ⁴ or C (= O); a
p is zero or an integer from 1 to 4, and
Y is carboxy (or an acid bioisostere) or —C (═O) —NY ¹ Y ² ];
and corresponding N-oxides and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds, and their N-oxides and prodrugs;
excluding the following compounds: (2- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} thiazol-4-yl) -acetic acid, 2-phenylacetylamino-3- {4- [ 4- (3- (2-methylphenyl) ureido) benzyloxy] phenyl} propionic acid, 2-phenylacetylamino-3- (4- {2- [4- (3- (2-methylphenyl) ureido) phenyl] -ethoxy} -phenyl) -propionic acid, 2-benzylsulfonylamino-3- {4- [4- (3- (2-methylphenyl) ureido) -benzyloxy] phenyl} -propionic acid, (butane-1-sulfonylamino) - {2- [4- (3- (2-methylphenyl) -ureido) benzyl] benzofuran-6-yl} -acetic acid, 3- (benzyl aminocarbonyl) - (4- {2- [4- (3 - (2-methylphenyl) -ureido) phenyl] ethoxy} ben yl) -propionic acid and 2-benzyloxycarbonyl-amino-3- (5- {3- [4- (3- (2-methylphenyl) ureido) -phenyl] -propyl} -thiophene-2-yl) propionic acid;
and provided that L ¹ cannot denote C _1-6 alkylene-C (= O) -NH— or C _1-6 alkylene when Ar ¹ is optionally substituted phenylene, Y is —CO ₂ H, —CO ₃ H , —PO ₄ H ₂ or tetrazole, and L ² is
(i) a direct chemical bond,
(ii) a bridge of alkylene or alkenylene, each of which is optionally substituted
(a) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; or
(b) alkyl substituted with alkoxy, hydroxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl or —C (═O) —NH ₂ ,
(iii) - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] p-bridge, where R ⁴ is hydrogen or lower alkyl, R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted with alkoxy, hydroxy or alkylthio, R ⁷ represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted with al Kenyl, alkynyl, alkoxy, hydroxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl or carboxamide, and p is a unit,
(iv) -Z ² R ^{9 is a} bridge, where Z ² is O, S, NR ⁴ , SO ₂ NR ⁴ or C (= O) NR ⁴ and R ⁹ is C1-4 alkylene, optionally substituted with alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl, or
(v) -CH ₂ -Z ² R ⁹ -bridge, where Z ² is O, NR ⁴ or C (= O) NR ⁴ and R ⁹ is C _1-4 alkylene, optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl.

2. The compound of claim 1, wherein R ¹ is hydrogen.

3. The compound of claim 1 or 2, wherein X ¹ is CR ¹⁰ , where R ¹⁰ is lower alkyl or lower alkoxy.

4. The compound of claim 3, wherein X ¹ is CR ¹⁰ , where R ¹⁰ is methyl.

5. The compound according to any one of claims 1 to 4, wherein X ² is CR ¹⁰ , where R ¹⁰ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl.

6. The compound of claim 5, wherein R ¹⁰ is lower alkoxy.

7. The compound according to any one of the preceding paragraphs where X ³ and X ⁶ denote CH.

8. The compound according to any one of the preceding paragraphs, where one of X ⁴ and X ⁵ denotes CR ¹¹ and the other denotes CH.

9. The compound of claim 8, wherein in R ^{11 the} radical L ¹ is an R ² -R ³ bridge, and where R ² is a straight or branched C _1-6 alkylene chain and R ³ is —C (= O) —NR ⁴ , where R ⁴ is hydrogen or C _1-4 alkyl.

10. The compound of claim 8, wherein in R ^{11 the} radical L ¹ is —CH ₂ —C (═O) —NR ⁴ , where R ⁴ is hydrogen or methyl.

11. The compound according to any one of paragraphs. 8-10, where in the group R ¹¹ , the group Ar ¹ denotes unsubstituted p-phenylene.

12. The compound according to any one of paragraphs. 8-10, where in the group R ¹¹ , the group Ar ¹ denotes unsubstituted p-pyridinediyl.

13. The compound according to any one of paragraphs. 8-12, where in the R ¹¹ radical L ^{2 the} group denotes (a) a direct chemical bond, (b) an optionally substituted linear or branched alkylene bridge, (c) an unsubstituted linear or branched alkylene bridge, or (d.) -Z ² -R ^{9 is a} bridge.

14. The compound of claim 13, wherein L ² is a substituted linear or branched C _1-4 alkylene bridge.

15. The compound of claim 14, wherein L ² is a substituted ethylene bridge.

16. The compound of claim 14 or 15, wherein the alkylene substituent is selected from the group consisting of: lower alkyl aryl, heteroaryl, —N (R ¹² ) —C (= O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , —NY ¹ Y ^2, and - [C (= O — N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] pC ( = O) -NY ¹ Y ² .

17. The compound of claim 13, wherein L ² is a group

where R ⁴ is hydrogen or lower alkyl and R ¹⁵ is lower alkyl, or where R ⁴ is hydrogen and R ¹⁵ is aryl, heteroaryl, —N (R ¹² ) —C (= O) —R ¹³ , —N (R ¹² ) -C - (= O) -OR ¹³ , -N (R ¹² ) -SO ₂ -R ¹³ , -NY ¹ Y ² or - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] pC (= O) -NY ¹ Y ² .

18. The compound of claim 13, wherein L ² is a group

where R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ^13, or - NY ¹ Y ² .

19. The compound of claim 13, wherein L ² is a group

where R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ² —R ^13, or - NY ¹ Y ² .

20. The compound according to any one of paragraphs. 8-19, where: in the R ¹¹ radical, group Y represents a carboxy or acidic bioisostere.

21. The compound of claim 20, wherein Y is carboxy.

22. The compounds of claim 1, formula 1a:

where R ¹ , R ² , L ² , X ¹ , X ² , X ³ and Y take the values indicated in paragraph 1, Ar ¹ denotes arylene and -R ² -C (= O) -NH-Ar ¹ -L ² - attached to the ring at position 3 or 4, and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (1a) and their prodrugs.

23. The compound of claim 22, wherein R ¹ is hydrogen.

24. Connection PP. 22 and 23, where R ² denotes a linear or branched C _1-6 alkylene bridge.

25. The compound of claim 24, wherein R ² is methylene.

26. The compound according to any one of paragraphs. 22-25, where Ar ¹ is optionally substituted p-phenylene.

27. The compound of claim 26, wherein Ar ¹ is unsubstituted p-phenylene.

28. The compound according to any one of paragraphs. 22-27, where L ² denotes a substituted linear or branched C _1-4 alkylene bridge.

29. The compound of claim 28, wherein L ² is a substituted ethylene bridge.

30. The compound according to p. 27 or p. 29, where the alkylene substituent is selected from the group consisting of: lower alkyl, aryl, heteroaryl, —N (R ¹² ) —C (= O) —R ¹³ , —N (R ¹² ) -C - (= O) -OR ¹³ , -N (R ¹² ) -SO ₂ -R ¹³ , -NY ¹ Y ² or- [C (= O) -N (R ⁶ ) C (R ⁶ ) (R ⁷ )] pC (= O) -NY ¹ Y ² .

31. Connection PP. 21-27, where L ² denotes

a bridge where R is lower alkyl (e.g. methyl) and R ¹⁵ is lower alkyl (e.g. methyl), or R ⁴ is hydrogen and R ¹⁵ is aryl, heteroaryl, -N (R ¹² ) -C (= O ) -R ¹³ , -N (R ¹² ) -C - (= O) -OR ¹³ , -N (R ¹² ) -SO ₂ -R ¹³ , -NY ¹ Y ² or- [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] pC (= O) -NY ^l Y ² .

32. The compound of claim 31, wherein L ² is

a bridge where R ¹⁵ is —N (R ¹² ) —C (= O) —R ¹³ , —N (R ¹² ) —C - (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , -NY ¹ Y ² .

33. The compound of claim 31, wherein L ² is

34. The compound according to any one of paragraphs. 22-33, where X ¹ is CR ¹⁰ , where R ¹⁰ is lower alkyl or lower alkoxy.

35. The compound of claim 34, wherein R ¹⁰ is methyl.

36. The compound according to any one of paragraphs. 22-35, where X ² is CR ¹⁰ , where R ¹⁰ is lower alkyl or lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl.

37. The compound of claim 36, wherein R ¹⁰ is lower alkoxy.

38. The compound according to any one of paragraphs. 22-37, where X ³ is CH.

39. The compound according to any one of paragraphs. 22-38, where Y is carboxy.

40. The compound according to any one of paragraphs. 22-39, where the group —R 2 —C (═O) —NH — Ar ¹ —L ² —Y is attached to the ring at position 4.

41. The compound according to claim 1, which is selected from among the following compounds:
(R) -3-acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenyl] acetylamino} phenyl) propanoic acid;
(R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3- (3-carboxypropanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3-benzoylamino-3- (4- {3-methoxy-4- [3- (2-methyl-phenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3- [2- (2-methoxyethoxy) acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3 - [(5-methyl-isoxazole-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) - propanoic acid;
(R) -3 - [(thiophen-2-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3 - [(4-carboxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3- (4-carboxy-3, 3-dimethyl-butanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propane acid;
(R) -3- (benzoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;
(R) -3- (4-carboxybutanoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid
and corresponding N-oxides and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds, and their N-oxides and prodrugs.

42. (R) -3- (4-Carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid and the corresponding N-oxides and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds, and their N-oxides and prodrugs.

43. The compound of claim 1, wherein R ¹ is hydrogen, halogen, lower alkyl, or lower alkoxy; X ¹ , X ² and X ^{6 are} independently N or CR ¹⁰ and one of X ³ , X ⁴ and X ⁵ is CR ¹¹ and the others are independently N or CR ¹⁰ [where R ¹⁰ is hydrogen, halogen, lower alkyl, lower alkoxy, and R ¹¹ denotes a group-L ¹ -Ar ¹ -L ² -Y, in which L ¹ denotes -R ² -R ³ - a bridge, where R ² denotes a linear or branched C _1-6 alkylene chain, linear or branched A C _2-6 alkenylene chain or a linear or branched C _2-6 alkynylene chain, and R ³ is a direct chemical bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, -C (= Z) -NR ⁴ -, -NR ⁴ -C ( = Z) -, -Z ¹ -, -C (= O) -, C (= NOR ⁴ ) -, -NR ⁴ C (= Z) NR ⁴ -, -SO ₂ -NR ⁴ -, -NR ⁴ -SO ₂ -, -OC (= O) -, C (= O) -O-, - NR ⁴ C (= O) -O- or -OC (= O) -NR ⁴ - (where R ⁴ is a hydrogen atom or lower alkyl group; Z is 0 or S ; Z ¹ is O, S (O) _n or NR ⁴ and n is zero or an integer 1 or 2); excluding compounds in which the oxygen, nitrogen or sulfur atom in R ^{3 is} directly bonded to the carbon atom of the multiple bond in R ² , Ar ¹ is heteroaryldiyl, L ² is a direct chemical (direct) bond, a bridge of alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene, each of which is optionally substituted with an acid functional group (or a corresponding protected derivative), R ⁵ , -ZH, -ZR ⁵ , -C (= O) -R ⁵ , -NH-C (= O ) -R ⁵ - -NY ¹ Y ² or - [C (= O- (R ⁶ ) -C (R ⁴ ) (R ⁷ )] pC (= O) -NY ¹ Y ² , or (b) alkyl, s substituted by an acidic functional group (or the corresponding protected derivative), or —ZH, —ZR ⁵ , or — NY ¹ Y ² , [(C (= O) —N- (R ⁶ ) —C (R ⁴ ) (R ⁷ ) ] p-bridge, Z ² -R ⁹ -bridge, C (= O) -CH ₂ -C (= O) -bridge, R ⁹ -Z ² -R ⁹ bridge or C (R ⁴ ) (R ⁸ ) - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] p-bridge wherein R ⁵ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl, R ⁶ is hydrogen, R, or alkyl substituted by alkoxy, qi loalkilom, hydroxy, mercapto, alkylthio or -NY ¹ Y ^2, each of R ⁷ and R ⁸ are independently selected from hydrogen or a group consisting amino acid side chains and corresponding protected derivatives of acidic functional group (or corresponding protected derivative), R ⁵ , -ZR ⁵ , -C (= O) -R ⁵ or -C (= O) -NY ¹ Y ² , or alkyl substituted with an acid functional group (or a corresponding protected derivative) or substituted with R ⁵ , -ZR ⁵ , - NY ¹ Y ² , —NH — C (= O) —R ⁵ , - (= OR ² —NH ₂ , —C (= O) —Ar ¹ H ₂ , —C (= O) —CO ₂ H, or - C (= O) -NY ¹ Y ^2, or R ⁶ and R ^7, or R ⁶ and R ⁸ together with the atoms to which m they are attached form a 3-6-membered heterocycloalkyl ring, R ⁹ represents C _1-6 alkylene optionally substituted with R ^5, Y ¹ and Y ² are independently hydrogen, alkyl (optionally substituted by hydroxy, heterocycloalkyl, or one or more carboxy or -C (= 0) -NHR ⁴ groups), aryl, heteroaryl or heterocycloalkyl; or the group —NY ¹ Y — may form a 5-7 membered cyclic amine, which optionally may be substituted with one or more substituents selected from carboxamido, carboxy, hydroxy, oxo or alkyl, optionally substituted with carboxy or carboxamido, may also contain an additional heteroatom selected from O, S, SO ₂ or NH, and may also be fused to additional rings of aryl, heteroaryl, heterocycloalkyl or cycloalkyl to form a cyclic system of two or three cycles, Z ² is O, S (O) n, NR ⁴ , SONR ⁴ , C (= O) NR ⁴ or C (= O), and p is zero or an integer from 1 to 4}, and Y is carboxy (or acidic bioisoster) or -C (= O) -NY ¹ Y ² ], and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds, and prodrugs thereof.

44. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or the corresponding N-oxide, or a prodrug thereof; or a pharmaceutically acceptable salt or solvate of such a compound, or an N-oxide thereof, or a prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.

45. The compound of claim 1 or the corresponding N-oxide, or a prodrug thereof; or a pharmaceutically acceptable salt or solvate of such a compound, or an N-oxide thereof, or a prodrug thereof for use in the treatment of patients suffering from or susceptible to disease states that can be alleviated by the administration of an a4β1 mediated cell adhesion inhibitor.
46. The compound of claim 1 for the treatment of inflammatory diseases.

47. The compound of claim 1 for treating asthma.

48. The compound of claim 1 or the corresponding N-oxide, or prodrugs thereof; or pharmaceutically acceptable salts or solvates of such a compound, or its N-oxide, or their prodrugs as an active agent of the drug for the prevention and treatment of diseases whose symptoms can be improved by the administration of an a4β1-mediated cell adhesion inhibitor.

49. The compounds of claim 1 or the corresponding N-oxide, or prodrugs thereof; or pharmaceutically acceptable salts or solvates of such a compound, or its N-oxide, or prodrugs thereof as active agents of a preparation for treating asthma.

50. A method of treating patients, a person or animals suffering from or prone to diseases, the symptoms of which can be improved by the administration of an inhibitor of mediated cellular a4β1 adhesion, the method comprising administering to said patient an effective amount of a compound of claim 1 or the corresponding N-oxide, or their prodrugs; or a pharmaceutically acceptable salt or solvate of such a compound, or an N-oxide thereof, or a prodrug thereof.