US2011015371A1PendingUtilityA1
Inhibitors of interleukin-1 beta converting enzyme
Est. expiryJun 17, 2014(expired)· nominal 20-yr term from priority
Inventors:Guy BemisJulian M. C. GolecDavid J. LaufferMichael D. MullicanMark A. MurckoDavid J. Livingston
C07K 5/0202C07K 5/06052C07D 243/08A61K 38/00C07D 243/12C07D 263/56C07K 5/0812C07D 487/04C07D 413/04
58
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Claims
Abstract
The present invention relates to novel classes of compounds which are inhibitors of interleukin-1β converting enzyme. The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against interleukin-1 mediated diseases, including inflammatory diseases, autoimmune diseases and neurodegenerative diseases. This invention also relates to methods for inhibiting ICE activity and methods for treating interleukin-1 mediated diseases using the compounds and compositions of this invention.
Claims
exact text as granted — not AI-modified1 - 18 . (canceled)
19 . An ICE inhibitor comprising:
(a) a scaffold of formula I:
wherein:
each X is independently C or N;
Z is CO or SO 2 ;
W 1 is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;
W 2 is a straight chain comprising 3-5 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;
each bond labeled r is independently a single or a double bond;
H is a first hydrogen bonding moiety and Z is a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide —NH— group of Arg-341, the carbonyl oxygen of Ser-339 and the amide —NH— group of Ser-339;
(b) a first and a second moderately hydrophobic moiety, said moieties each being covalently bound to said scaffold and each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P′ binding pocket; and
(c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being covalently bound to said scaffold and being capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of ICE.
20 - 48 . (canceled)
49 . A compound represented by the formula:
wherein:
X 1 is CH or N;
g is 0 or 1;
each J is independently selected from the group consisting of —H, —OH, and —F, provided that when a first and second J are bound to a C and said first J is —OH, said second J is —H;
m is 0, 1, or 2;
T is —Ar 3 , —OH, —CF 3 , —CO—CO 2 H, —CO 2 H or any bioisosteric replacement for —CO 2 H;
R 1 is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q 1 , at any nitrogen by R 5 , or at any atom by ═O, —OH, —CO 2 H, or halogen, and in which any saturated ring may optionally be unsaturated at one or two bonds:
R 20 is selected from the group consisting of:
and
wherein each ring C is independently chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R 3 is: —CN, —CH═CH—R 9 , —CH═N—O—R 9 , —CO—R 13 , or
each R 4 is independently selected from the group consisting of: —H, —Ar 1 , —R 9 , -T 1 -R 9 , and —(CH 2 ) 1,2,3 -T 1 -R 9 ,
each T 1 is independently selected from the group consisting of: —CH═CH—, —O—, —S—, —SO—, —SO 2 —, —NR 10 —, —NR 10 —CO—, —CO—, —O—CO—, —CO—O—, —CO—NR 10 —, —O—CO—NR 10 —, —NR 10 —CO—O—, —NR 10 —CO—NR 10 —, —SO 2 —NR 10 —, —NR 10 —SO 2 —, and —NR 10 —SO 2 —NR 10 —;
each R 5 is independently selected from the group consisting of: —H, —Ar 1 , —CO—Ar 1 , —SO 2 —Ar 1 , —R 9 , —CO—R 9 , —CO—O—R 9 , —SO 2 —R 9 ,
R 6 and R 7 taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—,
or R 7 is —H and R 6 is —H, —Ar 1 , —R 9 , or —(CH 2 ) 1,2,3 -T 1 -R 9 ,
each R 9 is a C 1-6 straight or branched alkyl group optionally singly or multiply substituted by —OH, —F, or ═O and optionally substituted with one or two Ar 1 groups;
each R 10 is independently selected from the group consisting of —H or a C 1-6 straight or branched alkyl group;
each R 13 is independently selected from the group consisting of —Ar 2 and —R 4 ,
each Ar 1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from —O—, —S—, —SO—, —SO 2 —, ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by ═O, —OH, perfluoro C 1-3 alkyl, or -Q 1 ;
each Ar 2 is independently selected from the following group, in which any ring may optionally be substituted by -Q 1 :
Ar 3 is a cyclic group selected from the set consisting of a phenyl ring, a 5-membered heteroaromatic ring, and a 6-membered heteroaromatic ring, said heteroaromatic rings comprising 1-3 heteroatom groups selected from —O—, —S—, —SO 7 , —SO 2 —, ═N—, and —NH—, said cyclic group optionally being singly or multiply substituted with ═O, —OH, halogen, perfluoro C 1-3 alkyl, or —CO 2 H;
each Q 1 is independently selected from the group consisting of —Ar 1 , —R 9 , -T 1 -R 9 , and —(CH 2 ) 1,2,3 -T 1 -R 9 ,
provided that when —Ar 1 is substituted with a Q 1 group which comprises one or more additional —Ar 1 groups, said additional —Ar 1 groups are not substituted with Q 1 ;
each X is independently selected from the group consisting of ═N—, and ═CH—;
each X 2 is independently selected from the group consisting of —O—, —CH 2 —, —NH—, —S—, —SO—, and —SO 2 —;
each X 3 is independently selected from the group consisting of —CH 2 —, —S—, —SO—, and —SO 2 —;
each X 4 is independently selected from the group consisting of —CH 2 — and —NH—;
each X 5 is independently selected from the group consisting of
X 6 is CH or N, provided that when X 6 is N in the R 1 group labeled (o) and X 5 is CH and
X 2 is CH 2 the ring of the R 1 group labeled (o) must be substituted by Q1 or benzofused;
each Y is independently selected from the group consisting of —O— and —S—;
each Z is independently CO or SO 2 ,
each a is independently 0 or 1,
each c is independently 1 or 2,
each d is independently 0, 1, or 2, and
each e is independently 0, 1, 2, or 3.
50 - 51 . (canceled)
52 . The compound according to claim 49 or 80 , wherein R 1 is:
53 . The compound according to claim 49 or 80 , wherein R 1 is:
54 . (canceled)
55 . The compound according to claim 49 or 80 , wherein R 1 is:
56 . The compound according to claim 49 or 80 , wherein R 1 is:
57 . The compound according to claim 49 or 80 , wherein R 1 is:
58 . The compound according to claim 49 or 80 , wherein R 1 is:
59 . The compound according to claim 49 or 80 , wherein R 1 is:
60 . (canceled)
61 . The compound according to claim 49 or 80 , wherein R 1 is:
62 . (canceled)
63 . The compound according to claim 49 or 80 , wherein R 1 is:
64 . The compound according to claim 49 or 80 , wherein R 1 is:
65 . The compound according to claim 49 or 80 , wherein R 1 is:
66 . The compound according to claim 49 or 80 , wherein R 1 is:
67 . The compound according to claim 49 or 80 , wherein R 1 is:
68 . The compound according to claim 49 or 80 , wherein R 1 is:
69 . The compound according to claim 49 or 80 , wherein R 1 is:
70 . The compound according to claim 49 or 80 , wherein R 1 is:
71 - 79 . (canceled)
80 . A compound represented by the formula:
wherein:
X 1 is —CH;
g is 0 or 1;
each J is independently selected from the group consisting of —H, —OH, and —F, provided that when a first and second J are bound to a C and said first J is —OH, said second J is —H;
m is 0, 1, or 2;
T is —OH, —CO—CO 2 H, —CO 2 H, or any bioisosteric replacement for —CO 2 H;
R 1 is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q 1 , at any nitrogen by R 5 , or at any atom by ═O, —OH, —CO 2 H, or halogen; any saturated ring may optionally be unsaturated at one or two bonds; and wherein R 1 (e) and R 1 (y) are optionally benzofused;
R 20 is selected from the group consisting of:
wherein each ring C is independently chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;
R 3 is: —CN, —CH═CH—R 9 , —CH═N—O—R 9 , —(CH 2 ) 1-3 -T 1 -R 9 , —CJ 2 -R 9 , —CO—R 13 , or
each R 4 is independently selected from the group consisting of: —H, —Ar 1 , —R 9 , -T 1 -R 9 , and —CH 2 ) 1,2,3 -T 1 -R 9 ;
each T 1 is independently selected from the group consisting of: —CH═CH—, —O—, —S—, —SO—, —SO 2 —, —NR 10 —CO—, —CO—, —O—CO—, —CO—NR 10 —, —NR 1 o-CO—NR 10 —, —NR 1 o-SO 2 —, and —NR 10 —SO 2 —NR 10 —;
each R 5 is independently selected from the group consisting of: —H, —Ar 1 , —CO—Ar 1 , —SO 2 —Ar 1 , —CO—NH 2 , —SO 2 —NH 2 , —R 9 , —CO—R 9 , —SO 2 —R 9 ,
R 6 and R 7 taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;
or R 7 is —H and R 6 is —H, —Ar 1 , —R 9 , —(CH 2 ) 1,2,3 -T 1 -R 9 , or an α-amino acid side chain residue;
each R 9 is a C 1-6 straight or branched alkyl group optionally singly or multiply substituted by —OH, —F, or ═O and optionally substituted with one or two Ar 1 groups;
each R 10 is independently selected from the group consisting of —H or a C 1-6 straight or branched alkyl group;
each R 13 is independently selected from the group consisting of —Ar 2 , —R 4 and
each Ar 1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from —O—, —S—, —SO—, —SO 2 —, ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3 alkyl,
each Ar 2 is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by -Q 1 and -Q2:
each Q 1 is independently selected from the group consisting of —Ar 1 , —O—Ar 1 , —R 9 , -T 1 -R 9 , and —(CH 2 ) 1,2,3 -T 1 -R 9 ;
each Q2 is independently selected from the group consisting of —OH, —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, —CF 3 , and
provided that when —Ar 1 is substituted with a Q 1 group which comprises one or more additional —Ar 1 groups, said additional —Ar 1 groups are not substituted with Q 1 ;
each X is independently selected from the group consisting of ═N—, and ═CH—;
each X 2 is independently selected from the group consisting of —O—, —CH 2 —, —NH—, —S—, —SO—, and —SO 2 —;
each X 3 is independently selected from the group consisting of —CH 2 —, —S—, —SO—, and —SO 2 —;
each X 4 is independently selected from the group consisting of —CH 2 — and —NH—;
each X 5 is independently selected from the group consisting of
X 6 is
each Y is independently selected from the group consisting of —O—, —S—, and —NH;
each Z is independently CO or SO 2 ;
each a is independently 0 or 1;
each c is independently 1 or 2;
each d is independently 0, 1, or 2; and
each e is independently 0, 1, 2, or 3;
provided that when
R 1 is (f),
R 6 is an α-amino acid side chain residue, and
R 7 is —H,
then (aa1) and (aa2) must be substituted with Q 1 ;
also provided that when
R 1 is (o),
g is 0,
J is —H,
m is 1,
R 6 is an α-amino acid side chain residue,
R 7 is —H,
X 2 is —CH 2 —,
and
R 3 is
or —CO—R 13 , when
R 13 is: —CH 2 —O—CO—Ar 1 , —CH 2 —S—CO—Ar 1 , —CH 2 —O—Ar 1 , —CH 2 —S—Ar 1 , or —R 4 when —R 4 is —H;
then the ring of the R 1 (o) group must be substituted with Q 1 or benzofused; and
provided that when
R 1 is (w),
g is 0,
J is —H,
m is 1,
T is —CO 2 H,
X 2 is O,
R 5 is benzyloxycarbonyl, and
ring C is benzo,
then R 3 cannot be —CO—R 13 when:
R 13 is —CH 2 —O—Ar 1 and
Ar 1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl wherein the phenyl is optionally substituted with a chlorine atom;
or when
R 13 is —CH 2 —O—CO—Ar 1 , wherein
Ar 1 is 2,6-dichlorophenyl.
81 - 124 . (canceled)Join the waitlist — get patent alerts
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