US2003096833A1PendingUtilityA1
Substituted ideno[1,2-c]isoquinoline derivatives and methods of use thereof
Priority: Aug 31, 2001Filed: Aug 31, 2001Published: May 22, 2003
Est. expiryAug 31, 2021(expired)· nominal 20-yr term from priority
A61P 3/10A61P 9/10A61P 39/06A61P 43/00A61P 9/00A61P 37/06A61P 35/00A61P 31/00A61P 27/02A61P 29/00A61P 25/28A61P 25/16A61P 1/02A61K 31/4741A61P 1/04C07D 471/04A61K 31/473A61K 31/4743C07D 495/04A61P 19/02A61K 31/4745A61K 31/435C07D 491/04A61P 11/00C07D 221/18Y02A50/30
50
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Claims
Abstract
The invention provides a novel class of substituted indeno[1,2-c]isoquinoline derivatives. Pharmaceutical compositions and methods of making and using the compounds, are also described.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I
wherein:
R 5 is O, N or S;
R6 is H or straight chain alkyl;
X is CO, CH 2 , CH-Halo, CH(CH 2 ) n OH, aryl-C—OH, O, NH, S or CH—NR 11 R 12 , wherein R 11 and R 12 are, independently, H, C 1 -C 9 alkyl, or NR 1 , R 12 , taken together, form an optionally-substituted heterocycle and
wherein n is zero or a positive integer;
R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R10 are, independently, hydrogen, halo, alkylhalo, hydroxy, alkoxy, C 1 -C 10 straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl group, C 3 -C 8 carbocyclic, aryl, alkylamino, amino, carboxy, ester, arylalkyl, nitro, or A-B;
wherein A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, O, CO, OCO, CONH, NH, CH 2 , S or CS; and
B is C 1 -C 10 straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl group, heterocycle, C 3 -C 8 carbocycle, aryl, amino, aminoalkyl, aminodialkyl, heterocyclic amine, alkylheterocycle, arylamido, carboxy, ester, arylalkyl, or NZ 1 Z 2 .
2 The compound of claim 1 wherein R 5 is O, and R 6 is H.
3 The compound of claim 2 wherein R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 are independently H, methyl, ethyl, halo, nitro, hydroxy, methoxy, ethoxy, amino or substituted amino, or A-B.
4 The compound of claim 3 , wherein either R 8 or R 9 is A-B.
5 The compound of claim 4 wherein R 1 , R 2 , R 3 , R 4 , R 7 , and R 10 are H.
6 The compound of claim 2 , wherein R 9 is A-B.
7 The compound of claim 3 , wherein R 9 is A-B.
8 The compound of claim 5 , wherein R 9 is A-B and R 8 is H.
9 The compound of claim 4 , wherein A is —SO 2 —, —SO 2 NH— or —NHCO—.
10 The compound of claim 5 , wherein A is —SO 2 —, SO 2 NH— or —NHCO—.
11 The compound of claim 6 , wherein A is —SO 2 —, —SO 2 NH— or —NHCO—.
12 The compound of claim 7 , wherein A is —SO 2 —, —SO 2 NH— or —NHCO—.
13 The compound of claim 8 , wherein A is —SO 2 —, —SO 2 NH— or —NHCO—.
14 The compound of claim 2 , wherein R 9 is AB and B is an optionally substituted C 1 -C 4 straight or branched chain alkyl, heterocycle, C 3 -C 8 carbocyclic, aryl, alkylamino, alkylhydroxy, or alkylheterocycle.
15 The compound of claim 3 , wherein A is SO 2 and B is NZ 1 Z 2 , and Z 1 and Z 2 are, independently, H, or C1-C5 alkyl, optionally substituted with halo, OH or NZ 3 Z 4 , wherein Z 3 and Z 4 are, independently, H, C1-C5 alkyl, optionally substituted with halo, OH or amino, or wherein Z 1 and Z 2 , taken together, NZ 1 Z 2 form a heterocyclic amine.
16 The compound of claim 15 , wherein Z1 and Z2 are —(CH 2 ) n D; wherein n is 1-5, D is H, hydroxy, heterocyclic amine or NZ 3 Z 4 ; wherein Z 3 and Z 4 are, independently, H, methyl, or ethyl.
17 The compound of claim 15 , wherein B is a heterocycle, and is optionally substituted with methyl, ethyl, or alkylhydroxy.
18 The compound of claim 15 , wherein Z 1 is H and Z 2 is —(CH 2 ) n NZ 3 Z 4 ; wherein n is 2 or 3, and Z 3 and Z 4 are, independently, methyl or ethyl, or, taken together, NZ 3 Z 4 forms a heterocyclic amine.
19 The compound of claim 13 , wherein X is CH 2 , A is SO 2 and B is NZ 1 Z 2 ; wherein Z 1 and Z 2 are, independently, H, C1-C5 alkyl optionally substituted with halo, OH or NZ 3 Z 4 ; wherein Z 3 and Z 4 are, independently, H, C1-C5 alkyl, optionally substituted with halo, OH or amino; or wherein Z 1 and Z 2 , taken together, form a heterocyclic amine.
20 The compound of claim 19 , wherein Z 1 and Z 2 are —(CH 2 ) n D, wherein n is 1-5, D is H, hydroxy, a heterocyclic amine or NZ 3 Z 4 , wherein Z 3 and Z 4 are, independently, H, methyl, or ethyl.
21 The compound of claim 15 , wherein B is a heterocycle, optionally substituted with methyl, ethyl, or alkylhydroxy.
22 The compound of claim 15 , wherein Z 1 is H and Z 2 is —CH 2 ) n NZ 3 Z 4 , wherein n is 2 or 3, and Z 3 and Z 4 are, independently, methyl or ethyl, or, taken together, NZ 3 Z 4 form a heterocyclic amine.
23 The compound of claim 2 wherein X is CO, CHOH, CHBr, CH 2 or CH—NR 11 R 12 wherein R 11 and R 12 are H, C 1 -C 9 alkyl, or NR 11 R 12 , taken together, form an optionally substituted heterocycle.
24 The compound of claim 4 wherein X is CO, CHOH, CHBr, CH 2 or CH—NR 11 R 12 wherein R 11 and R 12 are H, C 1 -C 9 alkyl, or NR 11 R 12 , taken together, form an optionally substituted heterocycle.
25 The compound of claim 6 wherein X is CO, CHOH, CHBr, CH 2 or CH—NR 11 R 12 wherein R 11 and R 12 are H, C 1 -C 9 alkyl, or NR 11 R 12 , taken together, form an optionally substituted heterocycle.
26 The compound of claim 7 wherein X is CO, CHOH, CHBr, CH 2 or CH—NR 11 R 12 wherein R 11 and R 12 are H, C 1 -C 9 alkyl, or NR 11 R 12 , taken together, form an optionally substituted heterocycle.
27 The compound of claim 8 wherein X is CO, CHOH, CHBr, CH 2 or CH—NR 11 R 12 wherein R 11 and R 12 are H, C 1 -C 9 alkyl, or NR 11 R 12 , taken together, form an optionally substituted heterocycle.
28 The compound of claim 4 wherein X is CO, CHOH, CHBr, or CH 2 .
29 The compound of claim 4 wherein X is CH 2 .
30 The compound of claim 6 wherein X is CO, CHOH, CHBr, or CH 2 .
31 The compound of claim 6 wherein X is CH 2 .
32 The compound of claim 7 wherein X is CO, CHOH, CHBr, or CH 2 .
33 The compound of claim 7 wherein X is CH 2 .
34 The compound of claim 8 wherein X is CO, CHOH, CHBr, or CH 2 .
35 The compound of claim 8 wherein X is CH 2 .
36 The compound of claim 11 wherein X is CO, CHOH, CHBr, or CH 2 .
37 The compound of claim 11 wherein X is CH 2 .
38 The compound of claim 12 wherein X is CO, CHOH, CHBr, or CH 2 .
39 The compound of claim 12 wherein X is CH 2 .
40 The compound of claim 15 wherein X is CO, CHOH, CHBr, or CH 2 .
41 The compound of claim 15 wherein X is CH 2 .
42 The compound of claim 16 wherein X is CO, CHOH, CHBr, or CH 2 .
43 The compound of claim 16 wherein X is CH 2 .
44 The compound of claim 17 wherein X is CO, CHOH, CHBr, or CH 2 .
45 The compound of claim 17 wherein X is CH 2 .
46 The compound of claim 18 wherein X is CO, CHOH, CHBr, or CH 2 .
47 The compound of claim 18 wherein X is CH 2 .
48 A compound of Formula II
wherein:
R 1 , R 4 , R 7 , and R 10 are hydrogen;
R 2 and R 3 are hydrogen, halo, alkylhalo, hydroxy, alkoxy, C 1 -C 3 straight or branched chain alkyl, nitro, amino, amido, carboxy, or ester;
R 8 and R 9 are either hydrogen or A-B;
wherein A is —SO 2 —, —SO 2 NH—, or —NHCO;
B is an optionally substituted C 1 -C 3 straight or branched chain alkyl, heterocycle, amino, aminoalkyl, aminodialkyl, or heterocyclic amine, or NZ 1 Z 2 .
49 . The compound of claim 48 , wherein A is SO 2 and B is NZ 1 Z 2 .
50 . The compound of claim 49 , wherein Z 1 and Z 2 are, independently, H, or C1-C3 alkyl, optionally substituted with OH or NZ 3 Z 4 , or, taken together, NZ 1 Z 2 form a heterocyclic amine.
51 . The compound of claim 50 , wherein Z 3 and Z 4 are, independently, H or C1-C3 alkyl optionally substituted with OH or amino, or, taken together, NZ 3 Z 4 form an optionally substituted heterocyclic amine.
52 . The compound of claim 51 , the heterocyclic amine is selected from the group consisting of piperidine, piperazine, morpholine, N-alkylated or alkylcarbonylated piperazines, pyrrolidine, and imidazole.
53 . The compound of claim 52 , wherein either NZ 1 Z 2 or NZ 3 Z 4 is a heterocycle substituted with alkyl, alkylhydroxy or alkylamino.
54 . A method of inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound of claim 1 or claim 48 in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell.
55 . A method of treating or preventing local or systemic inflammation in a subject, the method comprising administering the compound of claim 1 or claim 48 in an amount sufficient to inhibit inflammation in said subject.
56 . The method of claim 55 , wherein said subject is a human subject.
57 . The method of claim 55 , wherein administering is systemic.
58 . The method of claim 55 , wherein administering is topical.
59 . The method of claim 55 , where said local inflammatory condition is caused by an inflammatory disorder of a joint, an inflammatory bowel disease, an inflammatory lung disorder, an inflammatory disease of the central nervous system, or an inflammatory disease of the eye.
60 . The method of claim 55 , wherein said systemic inflammatory condition is caused by a condition selected from the group consisting of gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock, and systemic inflammation and chemotherapeutic shock.
61 . A method of treating or preventing reperfusion injury in a subject, the method comprising administering the compound of claim 1 or claim 48 in an amount sufficient to inhibit reperfusion injury in said subject.
62 . The method of claim 61 , wherein said compound is administered prophylactically.
63 . The method of claim 61 , wherein said compound is administered therapeutically.
64 . The method of claim 61 , wherein said reperfusion injury is myocardial infarction.
65 . The method of claim 61 , wherein said reperfusion injury is stroke.
66 . The method of claim 61 , wherein said subject is a human subject.
67 . The method of claim 61 , wherein administering is systemic.
68 . The method of claim 61 , wherein administering is topical.
69 . A method of treating or preventing diabetes or diabetic complications in a subject, the method comprising administering the compound of claim 1 or claim 48 in an amount sufficient to inhibit inflammation in said subject.
70 . A method of treating or preventing the rejection of transplanted organs in a subject, the method comprising administering the compound of claim 1 or claim 48 in an amount sufficient to inhibit inflammation in said subject.Join the waitlist — get patent alerts
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