Patent ID: 6451796
Filing Date: 2002-09-17
Classification: A61K,C07D

Abstract:
A method of treating disorders mediated by cellular adhesion comprising administering an effective amount of a composition comprising fused pyrazine derivatives of the formula (I): wherein R1 and R2 each, independently, is (i) hydrogen, (ii) C1-8 alkyl, (iii) C1-8 alkoxy, (iv) C1-8 alkylthio, (v) Cyc1, (vi) nitrile, (vii) formyl, (viii) â€”COOR14, in which R14 is hydrogen or C1-8 alkyl, (ix) â€”CONR15R16, in which R15 and R16 each, independently, is hydrogen, C1-8 or phenyl, (x) C1-8 alkyl or C2-8 alkenyl substituted by 1 or 2 of hydroxy, C1-4 alkoxy, phenoxy, halogen atom, nitrile, C2-5 acyl, â€”COOR14, â€”CONR15R16, or â€”NR17R18, in which R17 and R18 each, independently, is hydrogen, C1-8 alkyl or acetyl, (xi) C1-8 alkyl, C1-8 alkoxy or C1-8 alkylthio substituted by Cyc1, or R1 and R2, taken together with carbon atoms which are attached to each of them, is in which Cyc1 is C3-15 mono-, bi- or tri-carbocyolic ring or 5-18 membered mono-, bi- or tri-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur, the above carbocyclic ring or heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen atom, (v) nitrile, (vi) hydroxy, (vii) benzyloxy, (viii) â€”NR101R102, in which R101 and R102 each, independently, is hydrogen or C1-8 alkyl (ix) â€”COOR103, in which R103 is hydrogen or C1-8 alkyl, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenyloxy, (xiv) C1-8 alkyl or C1-8 alkoxy substituted by phenyl, phenyloxy, hydroxy, â€”NR101R102 or â€”COOR103, is C3-7 mono-carbocyclic ring or 3-7 membered mono-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur;R3 is 1) hydrogen, 2) C1-8 alkyl, 3) C2-8 alkenyl, 4) C1-8 alkoxy, 5) C1-8 alkylthio, 6) halogen atom, 7) nitro, 8) cyano, 9) hydroxy, 10) formyl, 11) C2-5 acyl, 12) â€”NR4R5, in which R4 and R5 each, independently, is hydrogen, C1-8 alkyl or acetyl, 13) â€”COOR6, in which R6 is hydrogen or C1-8 alkyl, 14) â€”CONR19R20, in which R19 and R20 each, independently, is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by hydroxy, 5-7 membered mono-heterocyclic ring containing 1-2 of nitrogen(s), or 1 of nitrogen and 1 of oxygen, or R19 and R20, taken together is &boxH;CHâ€”NR21R22, in which R21 and R22 each, independently, is hydrogen or C1-4 alkyl, 15) trihalomethyl, 16) trihalomethoxy, 17) phenyl, 18) phenyloxy, 19) phenylthio, or 20) C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio or C1-8 alkylamino substituted by phenyl, or 21) C1-8 alkyl or C2-8 alkenyl substtuted ny 1 or 2 of hydroxy, C1 -4 alkoxy, phenoxy, halogen atom, nitrile, C2-5 acyl, â€”COOR6â€”CONR19R20 or â€”NR4R5; n is 0 or 1-5; J is Câ€”CF3 E is a single bond, C1-4 alkylene, oxygen atom, sulfur atom, â€”SOâ€”, â€”SO2â€”, C1-4 alkylene-Mâ€”, with the proviso that alkylene bond to ring and M is bond to G; M is oxygen atom, sulfur atom, â€”SOâ€”, â€”SO2â€”; G is 1) C1-8 alkyl, 2) C2-8 alkenyl, 3) C2-8 alkynyl, 4) Cyc3, or 5) C1-8 alkyl substituted by â€”OR8, â€”SR8, â€”NR9R10, â€”COR11 or Cyc3, with the proviso that (i) one carbon atom in C1-8 alkyl, which is a component atom of cycloalkyl, may represent 3-7 membered cycloalkyl, or (ii) neighboring two carbon atom in C1-8 alkyl, which are component atoms of cycloalkyl, may represent 3-7 membered cycloalkyl; in which Cyc3 is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur, the above carbocyclic ring or heterocyclic ring may be substituted by one or more of (i) C1 -8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen atom, (v) nitrile, (vi) hydroxy, (vii) benzyloxy, (viii) â€”NR301R302, in which R301 and R302 each, independently, is hydrogen or C1-8 alkyl, (ix) â€”COOR303, in which R303 is hydrogen or C1-8 alkyl, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenyloxy, (xiv) C1-8 alkyl or C1-8 alkoxy substituted by phenyl, phenyloxy, hydroxy, â€”NR301R302 or â€”COOR303, R8 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C1-8 alkyl substituted by phenyl or C1-8 alkoxy, or â€”Sâ€”(C1-8 alkylene)-OR23, in which R23 is hydrogen or C1-8 alkyl; with the proviso that (i) one carbon atom in C1-8 alkylene, which is a component atom of cycloalkyl, may represent 3-7 membered cycloalkyl , or (ii) neighboring two carbon atom in C1-8 alkylene, which are component atoms of cycloalkyl, may represent 3-7 membered cycloalkyl; R9 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C1-8 alkyl substituted by phenyl or C1-8 alkoxy; R10 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C1-8 alkyl substituted by phenyl, or C2-5 acyl; R11 is (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) hydroxy, (iv) C1-8 alkyl or C1-8 alkoxy substituted by phenyl, or (v) â€”NR12R13, in which R12 and R13 each, independently, is hydrogen, C1-8 alkyl or C1-8 alkyl substituted by phenyl;  is a single bond or a double bond; with the proviso that the compounds in which R2 is C1-8 alkyl, E is a single bond or C1-4 alkylene and G is C1-8 alkyl are excluded;or non-toxic acid thereof as active ingredient.