Substituted tetrahydroisoquinolines
The invention is directed to physiologically active compounds of formula (I): wherein: R 1 represents optionally substituted aryl, optionally substituted heteroaryl, R 3 NH—Ar 1 —L 2 — or R 3 —NH—C(═O)—NH—Ar 2 —L 2 —; R 3 represents aryl or heteroaryl; Ar 1 represents a saturated, partially saturated or fully unsaturated 8- to 10-membered bicyclic ring system containing at least one heteroatom selected from O, S or N; Ar 2 represents aryldiyl or heteroaryldiyl; L 1 represents a linkage, such as an alkylene linkage; L 2 represents an alkylene chain linkage; R 2 represents hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy; and Y is carboxy or an acid bioisostere; but excluding compounds where an oxygen, nitrogen or sulfur atom is attached directly to a carbon carbon multiple bond of an alkenylene or alkynylene residue; and the corresponding N-oxides and ester prodrugs thereof, and the pharmaceutically acceptable salts and solvates of such compounds, and the N-oxides and ester prodrugs thereof. Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).
1. A compound of formula (I):
wherein:
R 1 represents R 3 NH—Ar 1 —L 2 ;
R 2 represents hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
R 3 represents optionally substituted aryl;
R 5 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
Ar 1 represents a fully unsaturated 8- to 10-membered bicyclic ring system containing at least one heteroatom selected from O, S or N, optionally substituted by one or more aryl group substituents;
L 1 represents R 5 ;
L 2 represents an alkylene chain;
Y is carboxy;
and the corresponding N-oxides and ester prodrugs thereof, and the pharmaceutically acceptable salts and solvates of such compounds, and the N-oxides and ester prodrugs thereof.
2. A compound according to claim 1 in which: L 2 is a straight or branched C 1-6 alkylene chain; and
Ar 1 is an 8- to 10-membered bicyclic system
in which (i) ring
is a 5- or 6-membered optionally substituted heterocycle, (ii) ring
is a 5- or 6-membered optionally substituted heterocycle or an optionally substituted benzene ring, and (iii) the two rings are joined together by a carbon-carbon linkage or a carbon-nitrogen linkage.
3. A compound according to claim 2 in which
is a 5-membered optionally substituted heterocycle, ring
is an optionally substituted benzene ring, and the two rings are joined together by a carbon-carbon linkage.
4. A compound according to claim 2 in which
is an optionally substituted benzoxazolyl or an optionally substituted benzimidazolyl, each in which the benzene ring contains the optional substituents.
5. A compound according to claim 2 in which ring
is a benzene ring optionally substituted by one of C 1-4 alkyl, C 1-4 alkoxy, amino, halogen, hydroxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, nitro or trifluoromethyl.
6. A compound according to claim 2 in which R 3 represents a 2-substituted phenyl.
7. A compound according to claim 6 in which R 3 represents 2-methylphenyl.
8. A compound according to claim 1 of formula (Ia):
in which R 2 , R 3 , L 1 , L 2 and Y are as defined in claim 1 , X is O or NR 18 , where R 18 is hydrogen or C 1-4 alkyl, and R 17 is hydrogen or an aryl group substituent, and the corresponding N-oxides and ester prodrugs thereof, and the pharmaceutically acceptable salts and solvates of such compounds, and the N-oxides and ester prodrugs thereof.
9. A compound according to claim 8 in which R 17 represents hydrogen, halo, C 1-4 alkyl, or C 1-4 alkoxy.
10. A compound according to claim 8 in which L 2 represents a straight or branched C 1-6 alkylene chain.
11. A compound according to claim 8 in which the group
is attached at the ring 6 position or at the ring 5 or 6 position when X is NR 18 and R 18 is C 1-4 alkyl.
12. A compound according to claim 8 in which the group -L 1 -Y is attached at position 6 or 7 of the tetrahydroisoquinoline ring.
13. A compound according to claim 1 in which L 1 represents a C 1-4 alkylene linkage optionally substituted by C 1-4 alkyl, aryl, heteroaryl.
14. A compound according to claim 13 in which the C 1-4 alkylene linkage is an ethylene linkage.
15. A compound according to claim 14 in which L 1 represents a group
where R 14 is hydrogen or C 1-4 alkyl and R 15 represents hydrogen or C 1-4 alkyl; or where R 14 is hydrogen and R 15 represents aryl, heteroaryl.
16. A compound according to claim 14 in which L 1 represents a group
where R 14 is hydrogen or C 1-4 alkyl and R 16 represents C 1-4 alkyl; or where R 14 is hydrogen and R 16 represents aryl or, heteroaryl.
17. A compound according to claim 1 selected from:
3-{((4-methyl-2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl}-butanoic acid;
3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl}-butanoic acid;
3-phenyl-3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl}-propanoic acid;
3-cyclohexyl-3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl}-propanoic acid;
3-(pyrid-4-yl)-3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl}-propanoic acid;
3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl}-but-2-enoic acid;
3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl-1,2,3,4-tetrahydro-isoquinolin-8-yl}-butanoic acid; acid;
3-phenyl-3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl}-propanoic acid;
3-{(2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl}-butanoic acid;
3-(pyrid-4-yl)-3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl}-propanoic acid, enantiomer A;
3-(pyrid-4-yl)-3-{((2-o-tolylamino-benzoxazol-6-yl)-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl}-propanoic acid, enantiomer B;
and the corresponding N-oxides and ester prodrugs thereof, and the pharmaceutically acceptable salts and solvates of such compounds, and the N-oxides and ester prodrugs thereof.
18. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a corresponding N-oxide or ester prodrug thereof, or a pharmaceutically acceptable salt or solvate of such a compound, or an N-oxide or ester prodrug thereof, in association with a pharmaceutically acceptable carrier or excipient.
19. A method for the treatment of a patient suffering from, or subject to, asthma comprising administering to said patient an effective amount of a compound according to claim 1 or a corresponding N-oxide or ester prodrug thereof, or a pharmaceutically acceptable salt or solvate of such a compound, or an N-oxide or ester prodrug thereof.
20. A method for the treatment of a patient suffering from, or subject to, an inflammatory bowl disease or a joint inflammation comprising administering to said patient an effective amount of a compound according to claim 1 or a corresponding N-oxide or ester prodrug thereof, or a pharmaceutically acceptable salt or solvate of such a compound, or an N-oxide or ester prodrug thereof.
21. A method for the treatment of a patient suffering from, or subject to, asthma comprising administering to said patient an effective amount of a composition according to claim 18 .
22. A method for the treatment of a patient suffering from, or subject to, an inflammatory bowl disease or a joint inflammation comprising administering to said patient an effective amount of a composition according to claim 18 .