Patent ID: 6420427
Filing Date: 2002-07-16
Classification: A61P,C07B,C07C,C07D,C07F

Abstract:
An aminobutyric acid derivative of the formula (I): whereinR1 is â€”COOR10, â€”CONHOR10, â€”CONHNHR10, â€”(CH2)SR50 or â€”Yâ€”P(OR51)2; R10 is (i) hydrogen, (ii) C1-8 alkyl, (iii) phenyl, (iv) C1-8 alkyl substituted by phenyl or C1-8 alkoxy, or (v) oxycarbonyl substituted by phenyl, benzyl or C1-8 alkyl; n is 0-3; R50 is (i) hydrogen, (ii) C1-8 alkyl, (iii) â€”COR52, in which R52 is C1-8 alkyl or phenyl; or (iv) â€”SR53, in which R53 is hydrogen, C1-8 alkyl or phenyl; R51 is hydrogen, C1-8 alkyl or phenyl; Y is a single bond, â€”CH2â€” or â€”Oâ€”; R2, R3, R4, R5, R6 and R7 each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl (4) â€”OR11, (5) â€”SR11, (6) â€”NR12R13, (8) Cyc1, (9) C1-8 alkyl substituted by â€”OR11, â€”SR11, â€”NR12R13, â€”COR14, guanidino or Cyc1, or (10) C2-8 alkenyl substituted by â€”OR11, â€”SR11, â€”NR12R13, COR14, guanidino or Cyc1, or R3 and R4, taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R2 and R3, taken together is C2-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene, or R2 is 2-propynyl, and R3, R4, R5, R6 and R7 each, independently, is (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) â€”OR11, (5) â€”SR11, (6) â€”NR12R13, (8) Cyc1, (9) C1-8 alkyl substituted by â€”OR11, â€”SR11, â€”N12R13, â€”COR14, guanidino or Cyc1, or (10) C2-8 alkenyl substituted by â€”OR11, â€”SR11, â€”NR12R13, â€”COR14, guanidino or Cyc1, or R3 and R4, taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene; in which Cyc1 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atom, (vii) nitrile (viii) hydroxy, (ix) benzyloxy, (x) â€”NR101R102, in which R101 and R102 each, independently, is hydrogen or C1-8 alkyl, (xi) â€”COOR103, in which R103 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or nitrile, (xix) heterocyclic ring, (xx) keto, and (xxi) C1-8 alkoxy substituted by â€”CONR104R105, in which R104 and R105 each, independently, is hydrogen, C1-8 alkyl or phenyl; R11 is (i) hydrogen, (ii) C1-8 alkyl, (iii) Cyc1, or (iv) â€”COR18, or C1-8 alkyl substituted by â€”OR15, â€”SR15, â€”NR16R17, â€”COR18, guanidino or Cyc1; R15 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1 or C1-8 alkoxy; R16 is hydrogen or C1-8 alkyl; R17 is hydrogen, C1-8 alkyl or â€”COR19, in which R19 is C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1; R18 is hydroxy, C1-8 alkyl, C1-8 alkoxy or â€”NR20R21, in which R20 and R21, each independently, is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1; R12 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl, substituted by Cyc1; R13 is hydrogen, C1-8 alkyl, Cyc1, C1-8 alkyl substituted by Cyc1, or â€”COR22, in which R22 is C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1; R14 is hydroxy, C1-8 alkyl, C1-8 alkoxy, Cyc1, C1-8 alkyl substituted by Cyc1, or â€”NR23R24, in which R23 and R24, each independently, is (i) hydrogen, (ii) C1-8 alkyl, (iii) Cyc1 or (iv) C1-8 alkyl substituted by Cyc1 or hydroxy; (1) R8 is 1) hydrogen, 2) C1-8 alkyl, 3) C1-8 alkoxycarbonyl, 4) C1-8 alkyl substituted by â€”OR26, â€”SR26, â€”NR27R28 or â€”COR29, or 5) C1-8 alkoxycarbonyl substituted by Cyc2, and R9 is (2) R8 is R9 is 1) C1-8 alkyl, 2) C1-8 alkoxy, 3) C1-8 alkoxy substituted by Cyc2, 4) C1-8 alkyl substituted by â€”OR26, â€”SR26, â€”NR27R28, â€”COR29 or Cyc2 or 5) â€ƒin which Cyc2 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atom, (vii) nitrile (viii) hydroxy, (ix) benzyloxy, (x) â€”NR201R202, in which R201 and R202 each, independently, is hydrogen or C1-8 alkyl, (xi) â€”COOR203, in which R203 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or nitrile, (xix) heterocyclic ring, (xx) keto, and (xxi) C1-8 alkoxy substituted by â€”CONR204R205, in which R204 and R205 each, independently, is hydrogen, C1-8 alkyl or phenyl; R26 is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; R27 is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; R28 is hydrogen, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or â€”COR30, in which R30 is C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; R29 is hydroxy, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or â€”NR31R32, in which R31 and R32, each independently, is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2; â€ƒis carbocyclic ring or heterocyclic ring; R25 is â€”Eâ€”G; E is 1) a single bond, 2) â€”CONR33â€”, 3) â€”NR33COâ€”, 4) â€”COâ€”Oâ€”, 5) â€”Oâ€”COâ€”, 6) â€”NR33â€”COâ€”NR34â€”, 7) â€”COâ€”CH2â€”, 8) â€”COâ€”, 9) â€”Oâ€”COâ€”NR33â€”, 10) â€”NR33â€”COâ€”Oâ€”, 11) â€”Oâ€”COâ€”Oâ€”, 12) â€”CSâ€”NR33â€”, 13) â€”NR33â€”CSâ€”, 14) â€”CSâ€”Câ€”, 15) â€”Oâ€”CSâ€”, 16) â€”NR33â€”CSâ€”R34â€”, 17) â€”CSâ€”CH2â€”, 18) â€”CSâ€”, 19) â€”Oâ€”CSâ€”NR33â€”, 20) NR33 â€”CSâ€”Oâ€”, 21) â€”Oâ€”CSâ€”Oâ€”, 22) â€”CH2â€”CH2â€”, 23) â€”HC&boxH;CHâ€”, 24) â€”Câ‰¡Câ€”, 25) â€”SO2â€”NR33â€”, 26) â€”NR33â€”SO2â€”, 27) â€”SO2â€”CH2â€” or 28) â€”CH2â€”SO2â€”; R33 and R34, each independently, is hydrogen, C1-8 alkyl, Cyc3 or C1-8 alkyl substituted by Cyc3; Cyc 3 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atom, (vii) nitrile, (viii) hydroxy, (ix) benzyloxy, (x) â€”NR301R302, in which R301 and R302 each, independently, is hydrogen or C1-8 alkyl, (xi) â€”COOR303, in which R303 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or nitrile, (xix) heterocyclic ring, (xx) keto, and (xxi) C1-8 alkoxy substituted by â€”CONR304R305, in which R304 and R305 each, independently, is hydrogen, C1-8 alkyl or phenyl; G is 1) hydrogen, 2) C1-8 alkyl, 3) Cyc4, 4) â€”OR35, 5) â€”SR35, 6) halogen atom, 7) nitro, 8) nitrile, 9) â€”NR36R37, 10) â€”COR38, 11) C1-8 alkyl substituted by Cyc4, â€”OR35, â€”SR35, halogen atom, â€”NR36R37 or â€”COR38; in which Cyc4 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atom, (vii) nitrile (viii) hydroxy, (ix) benzyloxy, (x) â€”NR401R402, in which R401 and R402 each, independently, is hydrogen or C1-8 alkyl, (xi) â€”COOR403, in which R403 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or nitrile, (xix) heterocyclic ring, (xx) keto, and (xxi) C1-8 alkoxy substituted by â€”CONR404R405, in which R404 and R405 each, independently, is hydrogen, C1-8 alkyl or phenyl; R35 is hydrogen, C1-8 alkyl, C1-8 alkoxy, Cyc4 or C1-8 alkyl substituted by Cyc4; R36 is hydrogen, C1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4; R37 is hydrogen, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or â€”COR39, in which R39 is C1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4; R38 is hydroxy, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or â€”NR40OR41, in which R40 and R41, each independently, is hydrogen, C1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4; or â€”Eâ€”G taken together, is C1-4 alkylidene; p is 1-5; M is C1-8 alkylene; J is a single bond, an oxygen atom, a sulfur atom or â€”NR42â€”, in which R42 is hydrogen or C1-8 alkyl;  may be double bond, by releasing the hydrogens, when two of R2, R3, R4, R5, R6 and R7 that do not bond to the same carbon atom and bond to neighboring carbon atoms, are hydrogens, with the proviso that (1)  is not double bond when R3 and R4 taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene; (2) when one of R6 and R7 is hydrogen and the other is hydrogen or C1-8 alkyl, each R2, R3, R4, R5 and R6 is hydrogen, ring A in R9 is phenyl and E is a single bond, then G is 2) C1-8 alkyl, 3) Cyc4, 4) â€”OR35, 5) â€”SR35, 6) halogen atoms, 7) nitro, 8) nitrile, 9) â€”NR36R37, 10) â€”COR38, 11) C1-8 alkyl substituted by Cyc4, â€”OR35, â€”SR35, halogen atoms, â€”NR36R37 or â€”COR38, and (3) when one of R2 and R3 is hydrogen or C1-8 alkyl and the other is NR12R13 in which R12 is hydrogen and R3 is COR22, then R22 is C1-8 alkyl or C1-8 alkyl substituted by Cyc1; or non-toxic salts thereof.