US 2004/0204368 A1 · Oxadiazole derivative compounds and drugs containing these compounds as the active ingredient

Abstract

An oxadiazole derivative of formula (I) and a non-toxic salt thereof, 1 wherein all symbols have the same meaning as described in the specification. The compound of formula (I) has an inhibitory activity against cysteine protease and therefore it is useful as an agent for the prophylaxis and/or treatment of inflammatory diseases, diseases induced by apoptosis, diseases induced by disorders of immune responses, autoimmune diseases, diseases induced by decomposition of proteins which compose organism, shock, circulatory system disorders, blood coagulation system(s) disorders, malignant tumors, acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC), parasitic diseases, nerve degeneration diseases, pulmonary disorders, bone resorption diseases, endocrinesthenia, etc.

An oxadiazole derivative of formula (I),

812
wherein R is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA,
(iv) C1-8 alkyl substituted with a group selected from halo, CycA, nitro, CF3 and cyano,
813
CycA is a mono-, bi- or tri-cyclic C3-15 carboring, or a mono-, bi- or tri-cyclic 3-15 membered heteroring comprising 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur,
R16 is
(1) C1-8 alkyl,
(2) C2-8 alkenyl,
(3) C2-8 alkynyl,
(4) CycA, or
(5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-5 of halogen, nitro, trifluoromethyl, cyano, CycA, NR18R19, —OR18, —NHC(O) —CycA and —NHC(O)O—(C1-8 alkyl),
R17, R18 and R19 are each independently, hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with C1-4 alkyl,
AA1 is
(i) a single bond, or
814
wherein R1 and R2 are the same or different to represent
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA or
(iv) C1-8 alkyl substituted with 1-5 of group selected from the following (1) to (8):
(1) —NR21R22,
(2)—OR23,
(3) —SR24,
(4) —COR25,
(5) —NR26CONR21R22,
(6) guanidino,
(7) CycA,
(8) NR26SO2R21;
or
R1 and R2 are taken together to form C2-8 alkylene wherein one carbon atom may be replaced by oxygen, sulfur or —NR20— and the alkylene may be substituted with —NR21R22 or —OR23,
R20 is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R21, R22, R23, R24 and R26 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R25 is C1-4 alkyl, phenyl, —NR2, R22 wherein all symbols have the same meaning as above, —OR23 wherein R13 is the same meaning as above, or C1-4 alkyl substituted with phenyl,
R3 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or
R3 is taken together with R1 to form C2-6 alkylene wherein one carbon atom may be replaced by oxygen, sulfur or —NR20— and the alkylene may be substituted with —NR21R22 or —OR23, or
when AA1 is
815
AA1 and R may be taken together to form
816
wherein
is a 5-12 membered mono- or bi-cyclic heteroring and the other symbols are the same meanings as above,
AA2 is
817
wherein R4 and R5 are the same or different to represent
(1) hydrogen,
(2) C1-8 alkyl,
(3) CycA or
(4) C1-8 alkyl substituted with 1-5 of group selected from the following (a) to (h):
(a) —NR_WR42,
(b) —OR43,
(c) —SR44,
(d) —COR45,
(e) —NR46CONR41R42,
(f) guanidino,
(g) CycA,
(h) —NR46SO2R41;
or
R4 and R5 are taken together to form C2-8 alkylene wherein one carbon atom may be replaced by oxygen, sulfur or —NR40— and the alkylene may be substituted with —NR41R42 or —OR43,
R40 is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R41, R42, R43, R44 and R46 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R45 is C1-4 alkyl, phenyl, —NR41R42 wherein all symbols are the same meaning as above, —OR43 wherein R43 has the same meaning as above, or C1-4 alkyl substituted with phenyl,
R6 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or
R6 is taken together with R4 to form C2-6 alkylene wherein one carbon atom may be replaced by oxygen, sulfur or —NR40— and the alkylene may be substituted with —NR41R42 or —OR43,
R48 is hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl or when AA1 is a single bond, R48 and R may be taken together to form C2-6 alkylene wherein one carbon atom may be replaced by oxygen, sulfur or —NR47 wherein R47 is hydrogen or C1-4 alkyl,
CycC is a 3-17 membered mono- or bi-cyclic heteroring,
CycD is a C3-14 mono- or bi-cyclic carboring or a 3-14 membered mono- or bi-cyclic heteroring, or
AA2 and AA1 are taken together to form,
818
wherein CycE is a 4-18 membered mono- or bi-cyclic heteroring, CycF is a 5-8 membered monocyclic heteroring, and the other symbols have the same meanings as above,
R7 and R8 are the same or different to represent
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA or
(iv) C1-8 alkyl substituted with 1-5 of group selected from the following (1) to (8);
(1) —NR61R62,
(2)—OR63,
(3) —SR64,
(4) —COR65,
(5) —NR66CONR61R62, (6) guanidino, (7) CycA, (8)—NR66SO2R61, or
R7 and R8 are taken together to form C2-8 alkylene wherein one carbon atom may be replaced by oxygen, sulfur or —NR60— and the alkylene may be substituted with —NR61R62 or OR63,
R60 is hydrogen, C1-4 alkyl, —COO-(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R61, R62, R63, R1 and R66 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl, R65 is C1-4 alkyl, phenyl, —NR61R62 wherein all symbols are the same meanings as above, —OR63 wherein R63 is the same meaning as above, or C1-4 alkyl substituted with phenyl,
R9 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or
R9 is taken together with R7 to form C2-6 alkylene wherein one carbon atom may be replaced by oxygen, sulfur or —NR60— and the alkylene may be substituted with —NR61R62 or —OR63,
819
wherein W is oxygen or sulfur,
R10 is
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) CycA,
(iv) —COR71, or
(v) C1-8 alkyl substituted with 1-3 of CycA, guanidino, —COR71, —NR72R73, —OR74, cyano, —P(O) (OR78)2 and —O—(C1-4 alkylene)-(C1-4 alkoxy)
wherein R71 is
(1) C1-4 alkyl,
(2) C1-4 alkoxy,
(3) CycA,
(4) —O-CycA,
(5) —NR72R73,
(6) C1-4 alkyl substituted with CycA,
(7) C1-4 alkoxy substituted with CycA or
(8) hydroxy,
R72 and R73 are the same or different to represent
(1) hydrogen,
(2) C1-8 alkyl,
(3) C1-8 alkoxy,
(4) C2-8 acyl,
(5) C2-8 alkoxycarbonyl,
(6) CycA,
(7) —C(O)CycA,
(8) —SO2CycA or
(9) C1-8 alkyl substituted with CycA, —C(O)CycA, —SO2CycA, C1-8 alkoxy, C2-8 acyl or C2-8 alkoxycarbonyl,
R74 is
(1) hydrogen,
(2) C1-8 alkyl,
(3) CycA,
(4) C1-8 alkyl substituted with —SiR75R71R77 wherein R75, R76 and R77 are the same or different to represent C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, or
(5) C1-8 alkyl substituted with CycA,
R78 is C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl;
wherein CycA in R, R1, R2, R4, R5, R7, R8, R16 may be the same or different and CycA, CycB, CycC, CycD, CycE and CycF may be independently substituted with 1-5 of R27;
R27 is
(1) C1-8 alkyl,
(2) halo,
(3) —NR1R12,
(4) —OR13,
(5)—SR14,
(6) CycG,
(7) nitro,
(8) cyano,
(9) oxo,
(10) —COR15,
(11)-SO2R5, or
(12) C1-8 alkyl substituted with 1-5 of the following (a) to (j):
(a) halo,
(b) —NR11R12,
(c) —OR13,
(d) —SR14,
(e) CycG,
(f) nitro,
(g) cyano,
(h) —COR15,
(j) —SO2R15;
wherein R11 and R12 are the same or different to represent hydrogen, C1-4 alkyl, C1-4 alkoxy, —C(O)O—(C1-4 alkyl), CycG, or C1-4 alkyl substituted with CycG,
R13 and R14 are the same or different to represent hydrogen, C1-4 alkyl, trifluoromethyl, CycG, or C1-4 alkyl substituted with CycG,
CycG is a 5-8 membered mono- or bi-cyclic carboring or a 5-8 membered mono- or bi-cyclic heteroring,
R15 is C1-4 alkyl, CycG, —NR11R12 wherein all symbols have the same meanings as above, —OR13 wherein R13 has the same meaning as above, or C1-4 alkyl substituted with CycG, —NR11R12 wherein all symbols have the same meanings as above or —OR13 wherein R13 has the same meaning as above, or
a non-toxic salt thereof.

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Oxadiazole derivative compounds and drugs containing these compounds as the active ingredient

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Oxadiazole derivative compounds and drugs containing these compounds as the active ingredient

Life of this patent

Abstract

Claims21