Patent EA-004792-B1 (EA)
Title: Non-peptidyl inhibitors of vla-4 dependent cell binding useful in treating inflammatory, autoimmune and respiratory diseases
Inventor: DUPLANTIER ALLEN JACOB
IPC: C07D417/04
Filed: 1999-05-31
Abstract: 1. A compound of Formula (1.0.0): and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein: -A<1> is phenyl or pyridyl, each is optionally substituted with 0 to 2 R<10>; -B is a member independently selected from the group consisting of the following: -where the symbol "*" indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.14) to the moiety in Formula (1.0.0); and the symbol "->" indicates the point of attachment of the moiety represented by Formula (1.1.0) through (1.1.14) to the moiety "E" in Formula (1.0.0); -E is a single bond, -CH=CH- or a moiety of Formula (1.9.0): -where R<1>a is hydrogen when R<1> has the meaning of a mono-valent substituent; and R<1>a is a single bond when R<1> has the meaning of a di-valent substituent; -X in-O- or -S(=O)q-; -m is an integer independently selected from 0, 1 and 2; -n is an integer independently selected from 1 and 2; -p is an integer independently selected from 1 and 2, provided that p must be selected as 1 where B is selected as partial Formula (1.1.2), (1.1.6), (1.1.13) or (1.1.14); -q is an integer independently selected from 0 and 2; -R is independently selected from the group consisting of-tetrazolyl; -C(=O)OR<5>; -C(=O)(CH2)kC(=O)OR<5>; -C(=O)NH-S(=O)2R<5>; -where: -k is an integer independently selected from 0,1 and 2; -R<1> is independently selected from the group consisting of hydrogen or (C1-C6)alkyl; -R<2> and R<3> each is independently selected from the group consisting of hydrogen, (C1-C4)alkyl substituted with 0 to 1 R<13>; -R<2> or R<3> R is taken together with R<4> and the carbon and nitrogen atoms to which they are respectively attached to form a 5-membered saturated nitrogen-containing heterocycle; -R<4> is hydrogen; -R<5> is of hydrogen or (C1-C4)alkyl; -R<6> is hydrogen; -R<10> is independently selected from the group consisting of F, Cl, -OH, (C1-C4)alkyl or (C1-C4)alkoxy; and -R<13> is phenyl. 2. A compound according to Claim 1 wherein n is the integer 1 resulting in a methylene bridge. 3. A compound according to Claim 10 wherein said component and said methylene bridge attached thereto comprise a member selected from the group consisting of 3-methoxy-4-(N'-phenylurea)-phenylmethyl-; 4-(N'-phenylurea)-phenylmethyl-; 4-(N'-(2-methylphenyl)-urea)-phenylmethyl-; 4-(N'-(2-methoxyphenyl)-urea)-phenylmethyl-; 3-methoxy-4-(N'-(2-methylphenyl)-urea)-phenylmethyl-; 4-(N'-(2-pyridyl)-urea)-phenylmethyl-; 4-(N'-(2-fluorophenyl)-urea)-phenylmethyl-; 4-(N'-(2-chlorophenyl)-urea)-phenylmethyl-; 4-(N'-(2-chlorophenyl)-urea)-methoxyphenylmethyl-; 4-(N'-(4-iso-propylphenyl)-urea)-phenylmethyl-; and 4-(N'-(o-toluyl)-urea)-pyrid-5-ylmethyl-. 4. A compound according to Claim 1 wherein B is a member selected from the group consisting of partial Formulas (1.1.2) and (1.1.6): -where the symbol "*" and the symbol "->" are as previously defined; and wherein X is oxygen, sulfur or nitrogen. 5. A compound according to Claim 1 wherein one of R<2> and R<3> is hydrogen, and the other is iso-butyl. 6. A compound according to Claim 1 wherein R is COOH. 7. A compound according to Claim 1 wherein said compound is: 3-(3-iso-butyl-2-oxo-4-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-butyric acid; 3[3-(3-methyl-1-{2-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid; [2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-4,5-dihydro-oxazol-5-yl]-acetic acid; (3-benzyl-2-oxo-4-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid; 3-benzo[1,3]dioxol-5-yl-3-(3-iso-butyl-2-oxo-4-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid; 3-[5-(2-carboxy-ethyl)-3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-5-yl]-propionic acid; 3-[3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-4,5-dihydro-oxazol-5-yl]-propionic acid; [2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-propionic acid; 3-[3-(1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid; [3-(3-methyl-1-{2-[4-(3-pyridine-2-yl-ureido]-phenyl}-acetylamino)-thiazole-5-yl]-propionic acid; [2-(3-methyl-1-{2-[3-pyridine-2-yl-ureido]-phenyl}-acetylamino)-thiazol-5-yl]-propionic acid; 4-[3-(3-methyl-{2-[4-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-butyric acid; 3-[2-(3-methyl-{2-[4-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid; 3-(3-[3-methyl-1-(2-{4-[3-(4-methyl-pyridine-3-yl)-ureido]-phenyl}-butyl]-isoxazol-5-yl]-propionic acid; 3-{2-[1-(2-{4-[3-(2-chloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid; 3-{2-[1-(2-{4-[3-(2-methoxy-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid; 3-{2-[1-(2-{4-[3-(2-fluoro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid; 3-[3-(3-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-acrylic acid; 3-{2-[1-(2-{4-[3-(2,6-dichloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid; 3-{2-[1-(2-{4-[3-(2,6-dimethyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid; 3-{2-[1-(2-{4-[3-(2-chloro-6-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid; 3-[2-(3-methyl-1-{2-[4-(3-phenyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl}-propionic acid; N-hydroxy-3[2-(3-methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid; 3-{3-[1-(2-{4-[3-(2-chloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-isoxazol-5-yl}-propionic acid; 3-[2-(1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-but-3-enyl)-thiazol-5-yl]-propionic acid; 3-{3-[-(2-{4-[3-(2-chloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-isoxazol-5-yl}-3-oxo-propionic acid ethylic ether; 3-[2-(1-{2-[4-(3-o-Tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid; N-{1-[5-(3-methanesulfonylamino-3-oxo-propyl)-thiazol-2-yl]-3-methyl-butyl}-2-[4-(3-o-tolyl-ureido)-phenyl]-acetamide; 2-{4-[3-(2-chloro-phenyl)-ureido]-phenyl}-N-{1-[5-(3-methanesulfonylamino-3-oxo-propyl)-thiazol-2-yl]-3-methyl-butyl}-acetamide; 3-[2-({2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-methyl)-thiazol-5-yl]-propionic acid; 3-{2-[(2-{4-[3-(2-chloro-phenyl)-ureido]-phenyl}-acetylamino)-methyl]-thiazol-5-yl}-propionic acid; 3-[2-(1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid. 8. A pharmaceutical composition for preventing, inhibiting, suppressing or reducing cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4, comprising a compound of formula (1.0.0) as defined in Claim 1 together with a pharmaceutically acceptable carrier for said compound. 9. A pharmaceutical composition for treating asthma, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, host rejection following organ transplantation, atherosclerosis, and other diseases mediated by or associated with VLA-4. 10. A pharmaceutical composition according to Claim 8 additionally comprising one or more therapeutic agents. 11. A pharmaceutical composition according to Claim 8 wherein said one or more therapeutic agent or agents is or are selected from the group consisting essentially of anti-inflammatory corticosteroids; nonsteroidal anti-inflammatory agents; bronchodilators; antiasthmatic agents; immunosuppressant agents; immunostimulants; antimetabolites; antipsoriatics; and antidiabetics. 12. A pharmaceutical composition according to Claim 8 wherein said therapeutic agent is a member selected from the group consisting essentially of theophylline, sulfasalazine, aminosalicylates; cyclosporin, FK-506, rapamycin, clophosphamide, methotrexate, and the interferons.