US 2003/0166573 A1 · Oxadiazole derivatives and drugs containing these derivatives as the active ingredient

Abstract

An oxadiazole derivative of formula (I) and a non-toxic salt thereof, 1 wherein R is hydrogen, alkyl, CycA, etc.; AA1 is a single bond, amino acid residue, etc.; AA2 is a single bond, amino acid residue, etc.; R7 and R8 are hydrogen, alkyl, etc.; R9 is hydrogen, alkyl, etc.; R10 is hydrogen, alkyl, etc.). 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 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),

1052
wherein R is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA,
(iv) C1-8 alkyl substituted with a group selected from halogen atom, CycA, nitro, CF3 and cyano,
1053
CycA is mono-, bi- or tri-cyclic C3-15 carboring or 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 a group selected from halogen, nitro, CF3, cyano, CycA, NR18R19 and —NHC(O)-CycA;
R17, R18 and R19 each independently are, hydrogen or C1-4 alkyl, AA1 is
(i) a single bond, or
1054
, 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)˜(8):
(1) —NR2 1R2 2,
(2) —OR2 3,
(3) —SR2 4,
(4) —COR2 5,
(5) —NR2 6CONR2 1R2 2,
(6) guanidino,
(7) CycA,
(8) —NR2 6SO2R2 1;
or
R1 and R2are 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, —NR21R22, wherein all symbols are the same meanings as above, —OR23 wherein R23 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
1055
AA1 and R may be taken together to form
1056
is a 5-12 membered mono- or bi-cyclic heteroring and the other symbols are the same meanings as above,
AA2 is
(i) a single bond,
1057
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)˜(h):
(a) —NR4 1R4 2, (b) —OR4 3, (c) —SR4 4, (d) —COR4 5, (e) —NR4 6CONR4 1R4 2, (f) guanidino, (g) CycA, (h) —NR4 6SO2R4 1;
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 is the same menaing as above, or C1-4 alkyl subbstituted 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
1058
, wherein CycE is a 4-18 membered mono- or bi-cyclic heteroring, CycF is a 5-8 membered monocyclic heteroring, and the other symbols are 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)˜(8);
(1) —NR61R62, (2) —OR63, (3) —SR64, (4) —COR65, (5) —NR66 CONR61R62, (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, R64 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,
1059
R10 is
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) CycA,
(iv) —COR71 or
(v) C1-8 alkyl substituted with 1-3 of group selected from CycA, guanidino, —COR71, —NR72R73, —OR74, cyano or —P(O)(OR78)2
, 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 R73are the same or different to represent hydrogen, C1-8 alkyl, CycA or C1-8 alkyl substituted with CycA,
R74 is
(1) hydrogen,
(2) C1-8 alkyl,
(3) CycA,
(4) —SiR7, R76R77, wherein R75, R76 and R77are 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;
and, CycA is included in R, R1, R2, R4, R5, R7, R8, R16 are the same or different and CycA, CycB, CycC, CycD, CycE and CycF, independently, may be substituted with 1-5 of R27:
R27 is
(1) C1-8 alkyl,
(2) halogen,
(3) —NR11R12,
(4) —OR13,
(5) a C5-10 mono-or bi-cyclic carboring,
(6) nitro,
(7) CF3,
(8) cyano,
(9) a 5-10 membered mono- or bi-cyclic heteroring
(10) —SR14,
(11) —COR15,
(12) oxo,
(13) —SO2R15,
(14) —OCF3 or
(15) C1-8 alkyl substituted with 1-5 of group selected from the following (a)˜(m):
(a) halogen, (b) —NR11R12, (c) —OR13, (d) a C5-10 mono- or bi-cyclic carboring, (e) nitro, (f) CF3, (g) cyano, (h) a 5-10 membered mono- or bi-cyclic heteroring, (j) —SR14, (k) —COR15, (l) —SO2R15, or (m) —OCF3
, wherein R11 and R12 are the same or different to represent hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R13 and R14 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl.
R15 is C1-4 alkyl, phenyl, —NR11R12, wherein all symbols are the same meanings as above, —OR13, wherein R13 is the same meaning as above, or C1-4 alkyl substituted with phenyl]
or a non-toxic salt thereof.

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Oxadiazole derivatives and drugs containing these derivatives as the active ingredient

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Oxadiazole derivatives and drugs containing these derivatives as the active ingredient

Life of this patent

Abstract

Claims22