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US 2001/0041799 A1Published application
Diephenyl carbocyclic thioamide derivatives
AssigneeHoffmann-La Roche Inc.
InventorsKenneth G. Hull, Achytharao Sidduri, Jefferson W. Tilley
Life of this patent
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Abstract
It has been discovered that compounds of the formula: 1 and the pharmaceutically acceptable salts and esters thereof wherein X and Y are as defined below, inhibit the binding of VCAM-1 to VLA-4 and are useful in treating inflammation associated with chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis, (MS), asthma, and inflammatory bowel disease (I BD).
Claims85
A compound of the formula:
- 183
- wherein X is a group of the formula
- 184
- wherein:
- R15 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy;
- R16 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio;
- or
- X is a group of formula X-2
- 185
- wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N,O, and S, or
- Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
- R15 and R16 are as above;
- R30 is hydrogen or lower alkyl;
- and p is an integer from 0 to 1
- or X is a group of formula X-3
- 186
- wherein:
- R18 is aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl
- R19 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and
- R20 is substituted or unsubstituted lower alkanoyl or aroyl;
- and Y is a group of formula Y-1
- 187
- wherein:
- R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen, and
- R24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen;
- or Y-2 is a group of the formula:
- 188
- Het is a five or six membered heteroaromatic ring bonded via a carbon atom wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and R30 and R3, are independently hydrogen, lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of R30 and R31 is adjacent to the point of attachment;
- p is an integer of from 0 to 1;
- or Y is a group of formula Y-3
- 189
- wherein:
- R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R26-(CH2)e-, R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio , lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R26 is a group of formula —NR28R29,
- wherein
- R28 is H or lower alkyl,
- R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl, or R28 and R29 taken together form a 4, 5 or 6-membered saturated carbacyclic ring optionally containing one heteroatom selected from 0, S, and N;
- with the carbon atoms in the ring being unsubstituted or substituted by lower alkyl or halogen,
- Q is —(CH2)fO—, —(CH2)fS—, —(CH2)fN(R27)—, or —(CH2)f—,
- R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl,
- e is an integer from 0 to 4, and
- f is an integer from 0 to 3;
- and the dotted bond is optionally hydrogenated;
- and pharmaceutically acceptable salts and esters thereof.
40 more elements
A compound of claim I wherein X is a group of the formula X-3
- 216
- and Y is a group of the formula Y-3
- 217
- wherein R18, R19, R20, R25, and Q are as above and the dotted bond can be optionally hydrogenated.
1 more element
Dependencies are inferred from the claim text.