Vla-4 inhibitors
The present invention relates to a compound represented by the following formula (I): (wherein, W represents W A -A 1 -W B - (in which, W A is substituted or unsubstituted aryl, etc., A 1 is —NR 1 —, single bond, —C(O)—, etc., and W B is substituted or unsubstituted arylene, etc.), R is single bond, —NH—, —OCH 2 —, alkenylene, etc., X is —C(O)—, —CH 2 —, etc., and M is, for example, the following formula: (in which, R 11 , R 12 and R 13 each independently represents hydrogen, hydroxyl, amino, halogen, etc., R 14 is hydrogen or lower alkyl, Y represents —CH 2 —O—, etc., Z is substituted or unsubstituted arylene, etc., A 2 is single bond, etc, and R 10 is hydroxyl or lower alkoxy)), or salt thereof; and a medicament containing the same. This compound or salt thereof selectively inhibits binding of cell adhesion molecules to VLA-4 and exhibits high bioavailability so that it is useful as a preventive and/or remedy for inflammatory diseases, autoimmune diseases, metastasis, bronchial asthma, rhinostenosis, diabetes, and the like.
1. A compound represented by formula (I):
wherein W represents W A -A 1 -W B - in which,
W A represents a monovalent aryl group which may be substituted or a monovalent heterocyclic group which may be substituted,
A 1 represents —NR 1 —, a single bond, —C(O)—, —C(O)NR 1 —, a substituted or unsubstituted vinylene group, an ethynylene group, —CR 1a R 1b —O—, —CR 1a ═CR 1b —C(O)NR 1 or —CR 1a ═CR 1b —C(O)— (in which, R 1 represents a hydrogen atom or a lower alkyl group, and R 1a and R 1b each independently represents a hydrogen atom or a lower alkyl group), and
W B represents a divalent aryl group which may be substituted or a divalent heterocyclic group which may be substituted);
R represents a single bond, —NH—, —OCH 2 —, an alkenylene group or —(CH 2 ) n — (in which, n stands for 1 or 2);
X represents —C(O)—, —CH 2 — or —S(O) 2 —, and
M represents formula (iii)
(in which,
represents a divalent 5-membered heterocyclic group (in which the nitrogen atom is bonded to X and Q represents a carbon),
R 11 , R 12 and R 13 each independently represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a cyano group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a substituted or unsubstituted mono- or dialkylaminocarbonyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted mono- or dialkylamino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted alkylsulfonylamino group, a substituted or unsubstituted arylsulfonylamino group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted benzyloxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted cycloalkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted cycloalkylsulfonyl group, or a substituted or unsubstituted arylsulfonyl group, or R 11 and R 12 or R 12 and R 13 may be coupled to form, together with the atom constituting the heterocyclic group to which R 11 to R 13 are bonded, a 3 to 7-membered cyclic hydrocarbon or heterocycle (which may have, on the ring thereof, 1 to 3 substituents selected from a hydroxyl group, halogen atoms, an amino group, alkyl groups, alkoxy groups, aryl groups, aryloxy groups, alkylamino groups, a benzyloxy group and heteroaryl groups),
R 14 represents a hydrogen atom or a substituted or unsubstituted lower alkyl group,
Y represents a single bond, —C(O)—, —C(O)NH—, or a linear or branched divalent aliphatic C 1-12 hydrocarbon group which may have a C 3-6 spiro ring or may have one or more carbon atoms substituted with —O—, —S—, —S(O) 2 —, —C(O)— or —NY 1 — (in which, Y 1 represents a hydrogen atom or a lower alkyl group),
Z represents a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group or a substituted or unsubstituted cycloalkylene group,
A 2 represents a single bond, an alkenylene group, an alkynylene group, —(CH 2 ) t — or —O(CH 2 ) v — (in which, t stands for 1, 2 or 3 and v stands for 0, 1, 2 or 3), and
R 10 represents a hydroxyl or a lower alkoxy group or salt thereof.
2. A compound or salt according to claim 1 , wherein W represents formula (i):
W 1 -A 1 -W 2 - (i)
(wherein,
W 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted monovalent heterocyclic group,
A 1 represents —NR 1 —, a single bond, —C(O)—, —C(O)NR 1 —, a substituted or unsubstituted vinylene group, an ethynylene group, —CR 1a R 1b —O—, —CR 1a ═R 1b —C(O)NR 1 — or —CR 1a ═R 1b —C(O)— (in which, R 1 represents a hydrogen atom or a lower alkyl group, and R 1a and R 1b each independently represents a hydrogen atom or a lower alkyl group), and
W 2 represents a substituted or unsubstituted divalent bicyclic heterocyclic group).
3. The compound or salt according to claim 2 , wherein W 2 represents formula (i-a):
(wherein, the bonding on the left side is to A 1 , the bonding on the right side is to R, X 1 represents an oxygen or sulfur atom, and R 2 and R 3 each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group or an amino group, with the proviso that A 1 is not —NR 1 — when W 2 is (i-b) or (i-c)).
4. The compound or salt according to claim 2 , wherein W 2 is formula (i-b):
5. The compound or salt according to claim 2 , wherein W 2 is formula (i-c)
6. A compound or salt according to claim 1 , wherein A 1 represents a single bond, —NH, or —C(O)NH—.
7. A compound or salt according to claim 1 , wherein W 2 represents formula (iii-a) and the formula (iii-a) represents a pyrrolidine ring.
8. A compound or salt according to claim 1 , wherein Y represents —CH 2 O—, —CH 2 S—, —CH 2 S(O) 2 —, —(CH 2 ) 2 —, —CH═CH—, —C≡C— or —CH 2 NY 1 —.
9. A compound or salt according to claim 1 , wherein Y represents —CH 2 O—.
10. A compound or salt according to any one of claim 1 , wherein A 2 represents a single bond and R 10 represents a hydroxyl or lower alkoxy group.
11. A compound or salt according to claim 3 , wherein W 2 represents formula (i-a) and in the formula (i-a), X 1 represents an oxygen atom and the bonding on the right side is to R at the 6-position of benzoxazole.
12. The compound of claim 1 , wherein W represents formula (ii):
W 3 -A 1 -W 4 - (ii)
(wherein, W 3 represents a substituted or unsubstituted monovalent bicyclic heterocyclic group, A 1 represents —NR 1 —, a single bond, —C(O)—, —C(O)NR 1 —, a substituted or unsubstituted vinylene group, an ethynylene group, —CR 1a R 1b —O—, —CR 1a CR 1b ═C(O)NR 1 — or —CR 1a ═CR 1b —C(O)— (in which, R 1 represents a hydrogen atom or a lower alkyl group, and R 1a and R 1b each independently represents a hydrogen atom or a lower alkyl group), and W 4 represents a substituted or unsubstituted arylene group or a substituted or unsubstituted divalent monocyclic heterocyclic group).
13. The compound of claim 12 , wherein W 3 represents any one of the following formulas (ii-a) to (ii-j):
(in which, X 2 represents an oxygen or sulfur atom, R 4 and R 5 each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group or an amino group, R 6 and R 7 each independently represents a hydrogen atom or a lower alkyl group, and R 8 , R 9 , R 8a and R 9a each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group or an amino group, with the proviso that when W 3 represents (ii-c) or (ii-d), A 1 does not represents —NR 1 —).
14. A pharmaceutical composition comprising:
the compound of claim 1 or its salt, and
a pharmaceutically acceptable carrier.
15. The composition of claim 14 , further comprising at least one other drug selected from the group consisting of an anti-inflammatory, anti-arthritic, adrenocortical steroid, immunosuppressant, antipsoriatic, bronchodilator, bronchial asthma drug, and antidiabetic drug(s).
16. The composition of claim 14 in a form suitable for parenteral administration.
17. The composition of claim 14 in a form suitable for oral administration.
18. A method of treating a condition, wherein said condition is selected from the group consisting of bronchial asthma, allergic rhinitis, type-1 diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and allograft rejection upon transplantation which is associated with VLA-4 mediated cell adhesion, said method comprising administering to a subject in need thereof an effective amount of the compound according to claim 1 .
19. The method of claim 18 , wherein said condition is selected from the group consisting of bronchial asthma, allergic rhinitis type 1 diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and allograft rejection upon transplantation.
20. The method of claim 18 , wherein said effective amount ranges from 0.1 mg to 1,000 mg.
21. A method for making a pharmaceutical composition comprising admixing the compound or salt of claim 1 with at least one pharmaceutically acceptable carrier.