US 2003/0153508 A1 · Nitrogen-containing 5-membered cyclic compounds and drugs containing these compounds as the active ingredient

Abstract

An N-containing five-membered ring compound of formula (I) 1 wherein all symbols are the same as described in the specification, and a non-toxic salt thereof. 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 systems 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 N-containing five-membered ring compound of formula (I)

1007
wherein R is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA,
(iv) C1-8 alkyl substituted with a group selected from halogen, CycA, nitro, CF3 and cyano,
1008
CycA is a mono-, bi- or tri-cyclic C3-15 carboring or a mono-, bi- or tri-cyclic 3-15 membered heteroring containing 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 or —NHC(O)-CycA;
R17, R18 and R19 are each independently, hydrogen or C1-4 alkyl,
AA1 is
(i) a single bond, or
1009
, 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) —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, —NR21PR22, 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,
R3is 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
1010
AA1 and R may be taken together to form
1011
, wherein
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,
1012
, 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) —NR41R42, (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 meanings as above, —OR43, wherein R43 is 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
6 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
1013
, 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) —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, 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,
q is an integer of 1-4,
1014
Z is a single bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, —O—, —S—, —CO—, —SO—, —SO2, —NR10—, or C1-6 alkylene whose one carbon atom is replaced by —O—, —S—, —CO—, —SO—, —SO2 or —NR10—,
R10 is hydrogen atom, C1-4 alkyl, phenyl, or C1-4 alkyl substituted with phenyl,
E is hydrogen atom, halogen atom, CF3, diphenyl (C1-4)alkyl, tri(C1-4 alkyl)silyl, C1-4 alkyl, —COOR18, —CONR19R20, —NR19R20, —G—(R35)r, —CH2—PO (OR36)2, or —CH(PO(OR36)2)2,
R18 is hydrogen atom, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R19 and R20 are each independently, hydrogen atom, C1-4 alkyl, phenyl, or C1-4 alkyl substituted with phenyl,
R19 and R20 are taken together with the nitrogen atom to which they are attached to form a 5-7 membered monocyclic heteroring containing 1-2 of nitrogen, 1 of nitrogen and oxygen atom or 1 of nitrogen or sulfur atom,
G is C3-10 mono- or bi-cyclic carboring or 5-18 membered mono-, bi- or tri-cyclic heteroring containing 1-3 of nitrogen, 1 of oxygen and/or 1 of sulfur,
r is an integer of 1-5,
R35 is (i) hydrogen, (ii) C1-8 alkyl, (iii) halogen, (iv) nitro, (v) CF3, (vi) cyano, (vii) —OR37, (viii) —NR37R38, (ix) —SR37, (x) —COOR37, (xi) —COR37, (xii) —CONR19R20, (xiii) C3-10 mono- or bi-cyclic carboring, (xiv) 5-18 mono-, bi- or tri-cyclic heteroring containing 1-3 of nitrogen, 1 of oxygen and/or 1 of sulfur, (xv) C1-8 alkyl substituted with C3-10 mono- or bi-cyclic carboring or 5-18 mono-, bi- or tri-cyclic heteroring containing 1-3 of nitrogen, 1 of oxygen and/or 1 of sulfur (above carboring or heteroring may be substituted with 1-5 of group selected from the following groups:
C1-8 alkyl, phenyl, C1-4 alkyl substituted with phenyl, halogen, nitro, CF3, cyano, tetrazole, —OR39, —NR39R40, —SR39, —COOR39 or —COR39,
R36 is hydrogen, C1-8 alkyl, cyano, phenyl, C1-8 alkyl substituted with phenyl or cyano, C1-4 alkyl substituted with 1-3 of halogen, R37 is hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R38 is hydrogen, C1-4 alkyl, phenyl, C1-4 alkyl substituted with phenyl, C2-5 acyl or COCF3,
R39 and R40 are each independently, hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
with proviso that (i) when Z is —SO—, E is not hydrogen,
1015
R7 and R8 are not C1alkyl substituted with —COR65;
(iii) CycA in R, R1, R2, R4, R5, R7, R8 and R16 are the same or different and CycA, CycB, CycC, CycD, CycE and CycF may each independently be substituted with 1-5 of R27:
R27 is
(1) C1-8 alkyl,
(2) halogen atom,
(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, (1) —SO2R15, (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,
R13and 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 have the same meanings as above, —OR13, wherein R13 has the same meaning as above, or C1-4 alkyl substituted with phenyl, or a non-toxic salt thereof.

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Nitrogen-containing 5-membered cyclic compounds and drugs containing these compounds as the active ingredient

Life of this patent

Nitrogen-containing 5-membered cyclic compounds and drugs containing these compounds as the active ingredient

Life of this patent

Abstract

Claims17