US 2003/0166574 A1 · 1,3,4-Oxadiazoline derivatives and drugs containing these derivatives as active ingredient

Abstract

A 1,3,4-oxadiazoline derivative of formula (I) 1 , wherein W is oxygen, sulfer; 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., 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.

A 1,3,4-oxadiazoline derivative of formula (I)

377
, wherein W is oxygen or sulfur,
R is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA,
(iv) C1-8 alkyl substituted with a group selected from halogen, CycA, nitro, CF3 or cyano,
378
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 a group selected from halogen, nitro, CF3, cyano, CycA, NR18R19 or —NHC(O)-CycA;
R17 is hydrogen or C1-4 alkyl,
R18 and R19 are the same or different to represent hydrogen or C1-4 alkyl,
AA1 is
(i) a single bond, or
379
, 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) —NR23CONR21R22,
(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, —NR21R22, wherein all symbols are the same 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
380
AA1 and R may be taken together to form
381
, wherein
382
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,
383
, 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,
R4, 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, —NR41R1, 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
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 may be taken together to form
384
, 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, or
(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;
and, CycA is included in R, R1, R2, R4, R5, R7, R8, R16 maybe 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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1,3,4-Oxadiazoline derivatives and drugs containing these derivatives as active ingredient

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1,3,4-Oxadiazoline derivatives and drugs containing these derivatives as active ingredient

Life of this patent

Abstract

Claims17