Claims
- 1. A compound of formula (I) wherein:A is a benzoxazole or benzothiazole, optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkanoyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4 alkoxylC1-6 alkyl, C1-6 alkylaminoC1-6 alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6 alkynyloxy, di-[(C1-6)alkyl]amino, C2-6 alkanoylamino, N—C1-6 alkylcarbamoyl, C1-6 alkoxylcarbonyl, halogeno, nitro, cyano, amino trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, linked to the nitrogen via a ring carbon atom in one ring and to the group B by a ring carbon atom in the second ring; B is a linking group connecting group A to group D selected from acetamido, —C(RcRd)—C(O)—NRe—, where Rc, Rd and Re are each independently selected from hydrogen and C1-2 alkyl, and —O—CH2—C(O)—NH—; C is phenyl optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4 alkoxylC1-6 alkyl, C1-6 alkylaminoC1-6 alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6 alkynyloxy, di-[(C1-6)alkyl]amino, C2-6 alkanoylamino, N—C1-6 alkylcarbarnoyl, C1-6 alkoxylcarbonyl, phenoxy, cyano, nitro, amino, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, linked to NR1 through a ring carbon atom; D is phenyl optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4 alkoxylC1-6 alkyl, C1-6 alkylamninoC1-6 alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6 alkynyloxy, di-[(C2-6)alkyl]amino, C1-6 alkanoylamino, N—C1-6 alkylcarbamoyl, C1-6 alkoxylcarbonyl, phenoxy, cyano, nitro, amino, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl; R1 is hydrogen, C1-5 alkyl, C1-3 alkanoyl or C1-3 alkoxycarbonyl; R2 to R5 are each independently selected from hydrogen, C1-6 alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with C1-6 alkyl, C1-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4 alkylC1-6 alkyoxyl, C1-6 alkylaminoC1-6 alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra, and —CONRaRb, where Ra and Rb are independently selected from hydrogen and C1-6 alkyl or two of R2 to R5 can be taken together to form a 3 to 7 membered ring; R6 is an acidic functional group; r and s are each independently 0 or 1 with the proviso that r and s cannot both be 0; or a pharmaceutically acceptable salt or in vivo hydrolysable protected acidic functional group thereof.
- 2. A compound according to claim 1 whereinA is benzoxazolyl.
- 3. A compound of formula (II) whereinR1 is hydrogen, C1-5 alkyl, C1-3 alkanoyl or C1-3 alkoxycarbonyl; R2 to R5 are each independently selected from hydrogen, C1-6 alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4alkylC1-6alkyoxyl, C1-6alkylaminoC1-6alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra, and —CONRaRb, where Ra and Rb are independently selected from hydrogen and C1-6 alkyl or two of R2 to R5 can be taken together to form a 3 to 7 membered ring; each R7 is independently selected from C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4alkoxylC1-6alkyl, C1-6alkylaminoC1-6alkyl, cyano, nitro, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra, and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, or two adjacent substituents can be taken together to form a 5-7 membered ring; R8 to R14 are independently selected from hydrogen, C1-4 alkyl, C1-4 alkanoyl, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-4 alkoxy, C1-6 alkylamino, C1-4alkoxylC1-6alkyl, C1-6 alkylaminoC1-6alkyl, halogeno, nitro, cyano, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra, and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl; m is zero or an integer from 1 to 5; and r and s are each independently 0 or 1 with the proviso that r and s cannot both be 0; or a pharmaceutically acceptable salt or in vivo hydrolysable protected acidic functional group thereof.
- 4. A compound according to claim 3 whereinR2 and R3 are independently selected from hydrogen or C1-6 alkyl; R1, R4 and R5 are each hydrogen; R7 is independently selected from halogeno and C1-6 alkyl; R8, R9 to R11 and R14 are each hydrogen; R10 is hydrogen or methoxy; R12 is C1-6 alkoxy, halogeno or hydrogen; s is zero, m is zero, 1 or 2, and r is 1, or a pharmaceutically acceptable salt or in vivo hydrolysable protected acidic functional group thereof.
- 5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or an in vivo hydrolysable protected acidic functional group thereof in association with a pharmaceutically acceptable diluent or carrier.
- 6. A method for inhibiting the interaction between VCAM-1 and/or fibronectin and the intergrin receptor VLA-4 warm-blooded mammals in need of such treatment which comprises administering to said warm-blooded mammals an effective amount of a compound according to any one of of claims 1 to 4 or a pharmaceutically acceptable salt or an in vivo hydrolysable protected acidic functional group thereof.
- 7. A method according to claim 6 for treating multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease, psoriasis, atherosclerosis, transplant rejection, inflammatory bowel disease, insulin-dependent diabetes and glomerulonephritis.
- 8. A process for preparing a compound of formula (I), a pharmaceutically acceptable salt or an in vivo hydrolysable protected acidic functional goup thereof, wherein:A is a benzoxazole or benzothiazole, optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkanoyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4 alkoxylC1-6 alkyl, C1-6 alkylaminoC1-6 alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6 alkynyloxy, di-[(C1-6)alkyl]amino, C2-6 alkanoylamino, N—C1-6 alkylcarbamoyl, C1-6 alkoxylcarbonyl, halogeno, nitro, cyano, amino trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, linked to the nitrogen via a ring carbon atom in one ring and to the group B by a ring carbon atom in the second ring; B is selected from acetamido, —C(RcRd)—C(O)—NRe—, where Rc, Rd and Re are each independently selected from hydrogen and C1-2 alkyl, and —O—CH2—C(O)—NH—; C is phenyl optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4 alkoxylC1-6 alkyl, C1-6 alkylaminoC1-6 alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6 alkynyloxy, di-[(C1-6)alkyl]amino, C2-6 alkanoylamino, N—C1-6 alkylcarbamoyl, C1-6 alkoxylcarbonyl, phenoxy, cyano, nitro, amino, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, linked to NR1 thrqough a ring carbon atom; D is phenyl optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4 alkoxylC1-6 alkyl, C1-6 alkylaminoC1-6 alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6 alkynyloxy, di-[(C2-6)alkyl]amino, C1-6 alkanoylamino, N—C1-6 alkylcarbamoyl, C1-6 alkoxylcarbonyl, phenoxy, cyano, nitro, amino, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra and —CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl; R1 is hydrogen, C1-5 alkyl, C1-3 alkanoyl or C1-3 alkoxycarbonyl; R2 to R5 are each independently selected from hydrogen, C1-6 alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with C1-6 alkyl, C1-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4 alkylC1-6 alkyoxyl, C1-6 alkylaminoC1-6 alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra, and —CONRaRb, where Ra and Rb are independently selected from hydrogen and C1-6 alkyl or two of R2 to R5 can be taken together to form a 3 to 7 membered ring; R6 is an acidic functional group; r and s are each independently 0 or 1 with the proviso that r and s cannot both be 0; or a pharmaceutically acceptable salt or in vivo hydrolysable protected acidic functional group thereof,which process comprises coupling together, via the formation of an amide bond, a compound of formula (III) where L is a leaving group,and an amine containing group D, where any functional group is optionally protected;and thereafter, if necessary:a) removing any protecting group; and b) forming a pharmaceutically acceptable salt or in vivo hydrolysable protected acidic functional group.
Priority Claims (2)
Number |
Date |
Country |
Kind |
9815971 |
Jul 1998 |
GB |
|
9815973 |
Jul 1998 |
GB |
|
Parent Case Info
This application is the national phase of international application PCT/GB99/02342 filed Jul. 20, 1999 which designated the U.S., and that international application was published under PCT Article 21 (2) in English.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/GB99/02342 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO00/05224 |
2/3/2000 |
WO |
A |
Foreign Referenced Citations (6)
Number |
Date |
Country |
WO 9622966 |
Aug 1996 |
WO |
9703094 |
Jan 1997 |
WO |
WO 9708145 |
Mar 1997 |
WO |
WO 9736862 |
Oct 1997 |
WO |
9804247 |
Feb 1998 |
WO |
WO 9924398 |
May 1999 |
WO |
Non-Patent Literature Citations (1)
Entry |
Bundgaard, Hans, 1985, Design of Prodrugs, Elsvier, p. 1. |