US4596676A
Expired / Lapsed
US
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Bifunctional ester derivatives of 4-desacetyl indole-dihydroindole alkaloids
Assignee: Lilly Industries Ltd
•
Filing: 1984-03-26
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Granted: 1986-06-24
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Expires: 2004-03-26
Abstract
Abstract Bifunctional ester derivatives at C-4 carbon of dimeric indole-dihydroindole alkaloids; e.g., VLB 4-hemisuccinate.
Inventors
- 👤 George J. Cullinan
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 22:49
CPC Classifications
C; C07; C07D; C07D519/00; C07D519/04; A; A61; A61P; A61P35/00; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55; Y10; Y10S; Y10S530/00; Y10S530/81; Y10S530/812; Y10S530/815; Y10S530/816
Claims Analysis
Total Claims: 24
Claim 1
Independent Claim
182 words
A compound for the formula: R--O--CO--X--CO--Z wherein R is a dimeric indole-dihydroindole radical ##STR7## wherein R 2 is H, CH 3 or CHO; when R 4 and R 5 are taken singly, R 5 is H, and one of R 3 and R 4 is ethyl and the other is H or OH; when R 4 and R 5 are taken together with the carbons to which they are attached, they form an oxirane ring in which R 3 is ethyl; and R 7 is COOC 1-3 alkyl or CO--R 9 , wherein R 9 is NH 2 , NH--C 1-3 alkyl, NH--CH 2 CH 2 Cl, 1-pyrrolidyl, 1-piperidinyl, or NH--CH 2 CH 2 YCH 3 wherein Y is S or O; X is C 1-4 straight chain alkylene, C 2-8 branched chain alkylene, C 2-4 alkenylene, C 3-4 alkynylene, C 3-6 cycloalkylene, phenylene, hydroxysubstituted C 1-4 alkylene or a direct bond, Z is OH, O--C 1-3 alkyl, Cl, Br, N 3 , NH 2 , NH--NH 2 , or a carboxy protecting group (Z 2 ), and acid addition salts thereof.
Claim 2
Dependent Claim
182 words
A compound for the formula: R--O--CO--X--CO--Z wherein R is a dimeric indole-dihydroindole radical ##STR7## wherein R 2 is H, CH 3 or CHO; when R 4 and R 5 are taken singly, R 5 is H, and one of R 3 and R 4 is ethyl and the other is H or OH; when R 4 and R 5 are taken together with the carbons to which they are attached, they form an oxirane ring in which R 3 is ethyl; and R 7 is COOC 1-3 alkyl or CO--R 9 , wherein R 9 is NH 2 , NH--C 1-3 alkyl, NH--CH 2 CH 2 Cl, 1-pyrrolidyl, 1-piperidinyl, or NH--CH 2 CH 2 YCH 3 wherein Y is S or O; X is C 1-4 straight chain alkylene, C 2-8 branched chain alkylene, C 2-4 alkenylene, C 3-4 alkynylene, C 3-6 cycloalkylene, phenylene, hydroxysubstituted C 1-4 alkylene or a direct bond, Z is OH, O--C 1-3 alkyl, Cl, Br, N 3 , NH 2 , NH--NH 2 , or a carboxy protecting group (Z 2 ), and acid addition salts thereof.
Claim 3
Dependent Claim
17 words
A compound according to claim 1 in which Z is OH, NH 2 or OC 1-3 alkyl.
Claim 4
Dependent Claim
11 words
A compound according to claim 2 in which Z is methoxy.
Claim 5
Dependent Claim
11 words
A compound according to claim 2 in which Z is OH.
Claim 6
Dependent Claim
186 words
A compound of the formula R--O--CO--X--CO--Z wherein R is a dimeric indole-dihydroindole radical ##STR8## wherein R 2 is H, CH 3 or CHO; when R 4 and R 5 are taken singly, R 5 is H, and one of R 3 and R 4 is ethyl and the other is H or OH; when R 4 and R 5 are taken together with the carbons to which they are attached, they form an oxirane ring in which case R 3 is ethyl; and R 7 is COOC 1-3 alkyl or CO--R 9 , wherein R 9 is NH 2 , NH--C 1-3 alkyl, NH--CH 2 CH 2 Cl, 1-pyrrolidyl, 1-piperidinyl or NH--CH 2 CH 2 YCH 3 wherein Y is S or O; X is C 1-4 straight chain alkylene, C 2-8 branched chain alkylene, hydroxy substituted C 1-4 alkylene, C 2-4 alkenylene, C 3-4 alkynylene, C 3-6 cycloalkylene, phenylene or a direct bond; Z is OH, OC 1-3 alkyl, NH 2 , NHNH 2 , Z 1 or Z 2 wherein Z 1 is an acylating group and Z 2 is a carboxy protecting group.
Claim 7
Dependent Claim
186 words
A compound of the formula R--O--CO--X--CO--Z wherein R is a dimeric indole-dihydroindole radical ##STR8## wherein R 2 is H, CH 3 or CHO; when R 4 and R 5 are taken singly, R 5 is H, and one of R 3 and R 4 is ethyl and the other is H or OH; when R 4 and R 5 are taken together with the carbons to which they are attached, they form an oxirane ring in which case R 3 is ethyl; and R 7 is COOC 1-3 alkyl or CO--R 9 , wherein R 9 is NH 2 , NH--C 1-3 alkyl, NH--CH 2 CH 2 Cl, 1-pyrrolidyl, 1-piperidinyl or NH--CH 2 CH 2 YCH 3 wherein Y is S or O; X is C 1-4 straight chain alkylene, C 2-8 branched chain alkylene, hydroxy substituted C 1-4 alkylene, C 2-4 alkenylene, C 3-4 alkynylene, C 3-6 cycloalkylene, phenylene or a direct bond; Z is OH, OC 1-3 alkyl, NH 2 , NHNH 2 , Z 1 or Z 2 wherein Z 1 is an acylating group and Z 2 is a carboxy protecting group.
Claim 8
Dependent Claim
23 words
A compound according to claim 5 in which Z 1 is Br, Cl, N 3 , succinimidoxy, phthalimidoxy, benzotriazolyloxy, methanesulfonyloxy, tosyloxy or benzenesulfonyloxy.
Claim 9
Dependent Claim
41 words
A compound according to claim 5 in which Z 2 is CCl 3 CH 2 --O, CBr 3 CH 2 O, CH 2 ICH 2 O, benzyloxy, methylbenzyloxy, t-butyloxy, allyloxy, methoxybenzloxy, nitrobenzyloxy, phenacyloxy, nitrophenacyloxy, methoxyphenacyloxy, methylphenacyloxy, diphenylmethyloxy, trityloxy, (triphenylmethyloxy), or trimethylsilyloxy.
Claim 10
Dependent Claim
15 words
A compound according to claim 5 in which X is C 1-4 straight chain alkylene.
Claim 11
Dependent Claim
13 words
A compound according to claim 5 in which X is C 2-4 alkenylene.
Claim 12
Dependent Claim
15 words
A compound according to claim 8 in which X is CH 2 --CH 2 .
Claim 13
Dependent Claim
11 words
A compound according to claim 5, said compound being VLB 4-hemisuccinate.
Claim 14
Dependent Claim
11 words
A compound according to claim 5, said compound being VLB 4-hemimaleate.
Claim 15
Dependent Claim
11 words
A compound according to claim 5, said compound being vindesine 4-hemisuccinate.
Claim 16
Dependent Claim
11 words
A compound according to claim 5, said compound being vincristine 4-hemisuccinate.
Claim 17
Dependent Claim
159 words
A compound of the formula R.sup.11 --O--CO--XCO--Z wherein R 11 is a dimeric indole-dihydroindole radical of the formula ##STR9## wherein R 2 is H, CH 3 or CHO; when R 4 and R 5 are taken singly, R 5 is H, and one of R 3 and R 4 is ethyl and the other is H or OH; when R 4 and R 5 are taken together with the carbons to which they are attached, they form an oxirane ring in which case R 3 is ethyl; and R 10 is H or Z 2 ; X is C 1-4 straight chain alkylene, C 2-8 branched chain alkylene, hydroxy substituted C 1-4 alkylene, C 2-4 alkenylene, C 3-4 alkynylene, C 3-6 cycloalkylene, phenylene or a direct bond; Z is OH, OC 1-3 alkyl, NH 2 , NHNH 2 , Z 1 or Z 2 wherein Z 1 is an acylating group and Z 2 is a carboxy protecting group.
Claim 18
Dependent Claim
159 words
A compound of the formula R.sup.11 --O--CO--XCO--Z wherein R 11 is a dimeric indole-dihydroindole radical of the formula ##STR9## wherein R 2 is H, CH 3 or CHO; when R 4 and R 5 are taken singly, R 5 is H, and one of R 3 and R 4 is ethyl and the other is H or OH; when R 4 and R 5 are taken together with the carbons to which they are attached, they form an oxirane ring in which case R 3 is ethyl; and R 10 is H or Z 2 ; X is C 1-4 straight chain alkylene, C 2-8 branched chain alkylene, hydroxy substituted C 1-4 alkylene, C 2-4 alkenylene, C 3-4 alkynylene, C 3-6 cycloalkylene, phenylene or a direct bond; Z is OH, OC 1-3 alkyl, NH 2 , NHNH 2 , Z 1 or Z 2 wherein Z 1 is an acylating group and Z 2 is a carboxy protecting group.
Claim 19
Dependent Claim
22 words
A compound according to claim 15 in which Z is Br, Cl, N 3 , succinimidoxy, phthalimidoxy, benzotriazolyloxy, methanesulfonyloxy, tosyloxy or benzenesulfonyloxy.
Claim 20
Dependent Claim
41 words
A compound according to claim 15 in which Z 2 is CCl 3 CH 2 --O, CBr 3 CH 2 O, CH 2 ICH 2 O, benzyloxy, methylbenzyloxy, t-butyloxy, allyloxy, methoxybenzloxy, nitrobenzyloxy, phenacyloxy, nitrophenacyloxy, methoxyphenacyloxy, methylphenacyloxy, diphenylmethyloxy, trityloxy, (triphenylmethyloxy), or trimethylsilyloxy.
Claim 21
Dependent Claim
15 words
A compound according to claim 15 in which X is C 1-4 straight chain alkylene.
Claim 22
Dependent Claim
13 words
A compound according to claim 15 in which X is C 2-4 alkenylene.
Claim 23
Dependent Claim
15 words
A compound according to claim 18 in which X is CH 2 CH 2 .
Claim 24
Dependent Claim
12 words
A compound according to claim 15, said compound being vinblastinoic acid 4-hemisucinate.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1989-06-23 | 1989-12-23 | 1990-06-24 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1993-06-23 | 1993-12-23 | 1994-06-24 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1997-06-23 | 1997-12-23 | 1998-06-24 | $7700.00 | Window Closed / Lapsed |