US5137877A
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Bifunctional linking compounds, conjugates and methods for their production
Assignee: Bristol Myers Squibb Co
•
Filing: 1990-05-14
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Granted: 1992-08-11
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Expires: 2010-05-14
Abstract
Abstract The present invention provides novel N-substituted hydrazine bifunctional compounds, novel N-subhstituted hydrazone derivatives of a cytotoxic reagent incorporating the bifunctional compounds, novel conjugates containing at least one cytotoxic reagent molecule reacted with the bifunctional compound and bound to a molecule reactive with a target cell population, methods for their production, and pharmaceutical compositions and methods for delivering cytotoxic reagents to a target population of cells. The hydrazone bonds of the conjugates of the invention permit the release of free cytotoxic reagent from the conjugates in the acidic external or internal environment of the target cells. The bifunctional compounds, derivatives, conjugates and methods of the invention are useful in antibody-or ligand-mediated drug delivery systems for the perferential killing of a target cell population to treat diseases such as cancers, infections and autoimmune disorders.
Inventors
- 👤 Takushi Kaneko
- 👤 David Willner
- 👤 Ivo Monkovic
- 👤 Robert S. Greenfield
- 👤 Gary R. Braslawsky
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 01:14
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/20; C07H15/24; C07H15/252; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/62; A61K47/65; A61K47/68; A61K47/6801; A61K47/6803; A61K47/6807; A61K47/6809; A61K47/6889; A61P; A61P35/00; C07C; C07C323/00; C07C323/23; C07C323/39; C07C323/43; C07C323/44; C07D; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/62; C07D213/70; C07D213/71
Claims Analysis
Total Claims: 38
Claim 1
Independent Claim
31 words
A bifunctional N-substituted hydrazine compound having the formula: ps H.sub.2 NNHCONH(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR7## wherein X is H, NO 2 or halogen.
Claim 2
Dependent Claim
31 words
A bifunctional N-substituted hydrazine compound having the formula: ps H.sub.2 NNHCONH(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR7## wherein X is H, NO 2 or halogen.
Claim 3
Dependent Claim
1 words
N-[2-[(2-pyridinyl)dithio]ethyl]hydrazinecarboxamide.
Claim 4
Dependent Claim
1 words
N-[2-[(2-pyridinyl)dithio]ethyl]hydrazinecarboxamide.
Claim 5
Dependent Claim
30 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNHCONHNHCONH(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR8## wherein X is h, NO 2 or halogen.
Claim 6
Dependent Claim
30 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNHCONHNHCONH(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR8## wherein X is h, NO 2 or halogen.
Claim 7
Dependent Claim
2 words
2-[[[2-[(2-pyridinyl)dithio]ethyl]amino]carbonyl]carbonic dihydrazide.
Claim 8
Dependent Claim
2 words
2-[[[2-[(2-pyridinyl)dithio]ethyl]amino]carbonyl]carbonic dihydrazide.
Claim 9
Dependent Claim
37 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNHCSNH(CH.sub.2).sub.m CH═CH(CH.sub.2).sub.n SSR.sup.8 wherein m, n are integers from 1 to 10, which are the same or different; and ##STR9## wherein X is H, NO 2 or halogen.
Claim 10
Dependent Claim
37 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNHCSNH(CH.sub.2).sub.m CH═CH(CH.sub.2).sub.n SSR.sup.8 wherein m, n are integers from 1 to 10, which are the same or different; and ##STR9## wherein X is H, NO 2 or halogen.
Claim 11
Dependent Claim
1 words
N-4-[(2-pyridinyl)dithio-2-butenyl]hydrazinecarbothioamide.
Claim 12
Dependent Claim
1 words
N-4-[(2-pyridinyl)dithio-2-butenyl]hydrazinecarbothioamide.
Claim 13
Dependent Claim
30 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNHCOO(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR10## wherein X is H, NO 2 or halogen.
Claim 14
Dependent Claim
30 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNHCOO(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR10## wherein X is H, NO 2 or halogen.
Claim 15
Dependent Claim
2 words
2[(2-pyridinyl)dithio]ethyl hydrazinecarboxylate.
Claim 16
Dependent Claim
2 words
2[(2-pyridinyl)dithio]ethyl hydrazinecarboxylate.
Claim 17
Dependent Claim
34 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNH-Ar-CONH(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR11## wherein X is H, NO 2 or halogen and Ar is ##STR12##
Claim 18
Dependent Claim
34 words
A N-substituted hydrazine bifunctional compound having the formula: H.sub.2 NNH-Ar-CONH(CH.sub.2).sub.n SSR.sup.8 wherein n is an integer from 1 to 10; and ##STR11## wherein X is H, NO 2 or halogen and Ar is ##STR12##
Claim 19
Dependent Claim
1 words
N-[2-[(2-pyridinyl)dithio)ethyl]-4-hydrazinobenzamide.
Claim 20
Dependent Claim
1 words
N-[2-[(2-pyridinyl)dithio)ethyl]-4-hydrazinobenzamide.
Claim 21
Dependent Claim
19 words
An anthracycline derivative prepared by reacting the compound of claim 1, 3, 5, 7 or 9 with an anthracycline.
Claim 22
Dependent Claim
27 words
The anthracycline derivative of claim 11 wherein said anthracycline is selected from the group consisting of adriamycin, daunomycin, detorubicin, carminomycin, idarubicin, epirubicin, esorubicin, 4'-THP-adriamycin, AD-32 and 3'-deamino-3'-(3-cyano-4-morpholinyl)-doxorubicin.
Claim 23
Dependent Claim
4 words
Adriamycin 13-N-[2-[(2-pyridinyl)dithio]ethyl]hydrazinecarboxamide semicarbazone hydrochloride.
Claim 24
Dependent Claim
4 words
Adriamycin 13-N-[2-[(2-pyridinyl)dithio]ethyl]hydrazinecarboxamide semicarbazone hydrochloride.
Claim 25
Dependent Claim
6 words
Adriamycin 13-2-[[[2-[(2-pyridinyl)dithio]ethyl]amino] carbonyl]carbonic dihydrazide carbazone hydrochloride.
Claim 26
Dependent Claim
6 words
Adriamycin 13-2-[[[2-[(2-pyridinyl)dithio]ethyl]amino] carbonyl]carbonic dihydrazide carbazone hydrochloride.
Claim 27
Dependent Claim
4 words
Adriamycin 13-N-4-[(2-pyridinyl)dithio]-2-butenylhydrazinecarbothioamide thiosemicarbazone hydrochloride.
Claim 28
Dependent Claim
4 words
Adriamycin 13-N-4-[(2-pyridinyl)dithio]-2-butenylhydrazinecarbothioamide thiosemicarbazone hydrochloride.
Claim 29
Dependent Claim
5 words
Adriamycin 13-2-[(2-pyridinyl)dithio]ethyl hydrazinecarboxylate carboxylatehydrazone hydrochloride.
Claim 30
Dependent Claim
5 words
Adriamycin 13-2-[(2-pyridinyl)dithio]ethyl hydrazinecarboxylate carboxylatehydrazone hydrochloride.
Claim 31
Dependent Claim
4 words
Adriamycin 13-N-[2-[(2-pyridinyldithio)ethyl]-4-hydrazinobenzamide arylhydrazone hydrochloride.
Claim 32
Dependent Claim
4 words
Adriamycin 13-N-[2-[(2-pyridinyldithio)ethyl]-4-hydrazinobenzamide arylhydrazone hydrochloride.
Claim 33
Dependent Claim
194 words
An anthracycline derivative having the formula: ##STR13## wherein: R 1 is NHCONH(CH 2 ) n SSR 8 ; NHCONHNHCONH(CH 2 ) n SSR 8 ; NHCSNH(CH 2 ) m CH═CH(CH 2 ) n SSR 8 ; NHCOO(CH 2 ) n SSR 8 ; NH--Ar--CONH(CH 2 ) n SSR 8 ; NCONH(CH 2 ) n S--H; NHCONHNHCONH(CH 2 ) n S--H;NHCSNH(CH 2 ) m CH═CH(CH 2 ) n S--H; HNCOO(CH 2 ) n S--H or NH--Ar--CONH(CH 2 ) n S--H wherein m, n are integers from 1 to 10, which are the same or different; ##STR14## wherein X is H, NO 2 or halogen and Ar is ##STR15## R 2 is CH 3 , HC 2 OH, CH 2 OCO(CH 2 ) 3 CH 3 , or CH 2 OCOCH(OC 2 H 5 ) 2 ; R 3 is OCH 3 , OH or hydrogen; R 4 is NH 2 , NHCOCF 3 , 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R 5 is OH, O-THP or hydrogen; and R 6 is OH or hydrogen, provided that R 6 is not OH when R 5 is OH or O-THP.
Claim 34
Dependent Claim
194 words
An anthracycline derivative having the formula: ##STR13## wherein: R 1 is NHCONH(CH 2 ) n SSR 8 ; NHCONHNHCONH(CH 2 ) n SSR 8 ; NHCSNH(CH 2 ) m CH═CH(CH 2 ) n SSR 8 ; NHCOO(CH 2 ) n SSR 8 ; NH--Ar--CONH(CH 2 ) n SSR 8 ; NCONH(CH 2 ) n S--H; NHCONHNHCONH(CH 2 ) n S--H;NHCSNH(CH 2 ) m CH═CH(CH 2 ) n S--H; HNCOO(CH 2 ) n S--H or NH--Ar--CONH(CH 2 ) n S--H wherein m, n are integers from 1 to 10, which are the same or different; ##STR14## wherein X is H, NO 2 or halogen and Ar is ##STR15## R 2 is CH 3 , HC 2 OH, CH 2 OCO(CH 2 ) 3 CH 3 , or CH 2 OCOCH(OC 2 H 5 ) 2 ; R 3 is OCH 3 , OH or hydrogen; R 4 is NH 2 , NHCOCF 3 , 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperdinyl, benzyl amine, dibenzyl amine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R 5 is OH, O-THP or hydrogen; and R 6 is OH or hydrogen, provided that R 6 is not OH when R 5 is OH or O-THP.
Claim 35
Dependent Claim
215 words
An anthracycline derivative having the formula: ##STR16## wherein: R 1 is NHCONH(CH 2 ) n SSR 8 ; NHCONHNHCONH(CH 2 ) n SSR 8 ; NCHSNH(CH 2 ) m CH═CH(CH 2 ) n SSR 8 ; NHCOO(CH 2 ) n SSR 8 ; NH-Ar-CONH(CH 2 ) n SSR 8 ; NCONH(CH 2 ) n S--H; NHCONHNHCONH(CH 2 ) n S--H; NNHCSNH(CH 2 ) m CH═CH(CH 2 ) n S--H; NHCOO(CH 2 ) n S--H or NH-Ar-CONH(CH 2 ) n S--H wherein m, n are integers from 1 to 10, which are the same or different; ##STR17## wherein X is H, NO 2 or halogen and Ar is ##STR18## R 2 is CH 3 , CH 2 OH, CH 2 OCO(CH 2 ) 3 CH 3 , or CH 2 OCOCH(OC 2 H 5 ) 2 ; R 3 is OCH 3 , OH or hydrogen; R 4 and R 7 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R 4 , R 7 and N together form a 4-7 membered ring, wherein said ring may be optionally substituted; R 5 is OH, O-THP or hydrogen; and R 6 is OH or hydrogen, provided that R 6 is not OH when R 5 is OH or O-THP.
Claim 36
Dependent Claim
215 words
An anthracycline derivative having the formula: ##STR16## wherein: R 1 is NHCONH(CH 2 ) n SSR 8 ; NHCONHNHCONH(CH 2 ) n SSR 8 ; NCHSNH(CH 2 ) m CH═CH(CH 2 ) n SSR 8 ; NHCOO(CH 2 ) n SSR 8 ; NH-Ar-CONH(CH 2 ) n SSR 8 ; NCONH(CH 2 ) n S--H; NHCONHNHCONH(CH 2 ) n S--H; NNHCSNH(CH 2 ) m CH═CH(CH 2 ) n S--H; NHCOO(CH 2 ) n S--H or NH-Ar-CONH(CH 2 ) n S--H wherein m, n are integers from 1 to 10, which are the same or different; ##STR17## wherein X is H, NO 2 or halogen and Ar is ##STR18## R 2 is CH 3 , CH 2 OH, CH 2 OCO(CH 2 ) 3 CH 3 , or CH 2 OCOCH(OC 2 H 5 ) 2 ; R 3 is OCH 3 , OH or hydrogen; R 4 and R 7 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R 4 , R 7 and N together form a 4-7 membered ring, wherein said ring may be optionally substituted; R 5 is OH, O-THP or hydrogen; and R 6 is OH or hydrogen, provided that R 6 is not OH when R 5 is OH or O-THP.
Claim 37
Dependent Claim
23 words
A conjugate comprising the anthracycline derivative of claim 18 or 19 conjugated to at least one molecule reactive with a target cell population.
Claim 38
Dependent Claim
30 words
A pharmaceutically acceptable composition useful in the treatment of disease which comprises a pharmaceutically effective amount of at least one conjugate according to claim 20 and a pharmaceutically acceptable carrier.
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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) | 1995-08-11 | 1996-02-10 | 1996-08-11 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1999-08-11 | 2000-02-10 | 2000-08-11 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2003-08-11 | 2004-02-10 | 2004-08-11 | $7700.00 | Window Closed / Lapsed |