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US4494547A
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2H-isoindolediones, their synthesis and use as radiosensitizers
Assignee: North Carolina Central University
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Filing: 1981-03-30
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Granted: 1985-01-22
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Expires: 2001-03-30
Abstract
Abstract Isoindoledione compounds of the formula: <IMAGE> wherein: R1 and R3 each separately is phenyl, substituted phenyl, alkyl of 1 to 4 carbons, -CHO, -CH2OR6, -CO2R6, -COR6, hydrogen, or together with R2 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R2 is phenyl, substituted phenyl, -CH2OR6, -CH2CH2OR6, alkyl of 1 to 4 carbons or with either R1 or R3 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R4 and R5 which may be the same or different each separately is hydrogen, alkyl of 1 to 4 carbons, -OR6, -CO2R6, -COR6, -CHO, -CH2OR6 or together R4 and R5 is a butadiene radical which forms a benzene ring; R6 is hydrogen or alkyl of 1 to 4 carbons; provided that R1 and R3 are not both phenyl and that when R4 and R5 are both hydrogen, R1, R2 and R3 are not all methyl. The compounds are useful as radio-sensitizers in the therapeutic radiation of cancerous tissues.
Inventors
- 👤 John A. Myers
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 21:25
CPC Classifications
C; C07; C07D; C07D209/00; C07D209/56; C07D209/58; C07D209/62; C07D209/02; C07D209/44
Claims Analysis
Total Claims: 22
Claim 1
Independent Claim
210 words
An isoindoledione compound of the formula: ##STR13## wherein: R 1 and R 3 each separately is phenyl, substituted phenyl, alkyl of 1 to 4 carbons, --CHO, --CH 2 OR 6 , --CO 2 R 6 , --COR 6 , hydrogen, or together with R 2 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 2 is phenyl, substituted phenyl, --CH 2 OR 6 , --CH 2 CH 2 OR 6 , alkyl of 1 to 4 carbons or with either R 1 or R 3 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 4 and R 5 which may be the same or different each separately is hydrogen, alkyl of 1 to 4 carbons, --OR 6 , --CO 2 R 6 , --COR 6 , --CHO, --CH 2 OR 6 or together R 4 and R 5 is a butadiene radical which forms a benzene ring; R 6 is hydrogen or alkyl of 1 to 4 carbons; provided that R 1 and R 3 are not both phenyl and that when R 4 and R 5 are both hydrogen, R 1 , R 2 and R 3 are not all methyl.
Claim 2
Dependent Claim
210 words
An isoindoledione compound of the formula: ##STR13## wherein: R 1 and R 3 each separately is phenyl, substituted phenyl, alkyl of 1 to 4 carbons, --CHO, --CH 2 OR 6 , --CO 2 R 6 , --COR 6 , hydrogen, or together with R 2 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 2 is phenyl, substituted phenyl, --CH 2 OR 6 , --CH 2 CH 2 OR 6 , alkyl of 1 to 4 carbons or with either R 1 or R 3 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 4 and R 5 which may be the same or different each separately is hydrogen, alkyl of 1 to 4 carbons, --OR 6 , --CO 2 R 6 , --COR 6 , --CHO, --CH 2 OR 6 or together R 4 and R 5 is a butadiene radical which forms a benzene ring; R 6 is hydrogen or alkyl of 1 to 4 carbons; provided that R 1 and R 3 are not both phenyl and that when R 4 and R 5 are both hydrogen, R 1 , R 2 and R 3 are not all methyl.
Claim 3
Dependent Claim
62 words
An isoindoledione compound according to claim 1 wherein R 1 and R 3 are selected from phenyl, alkyl of 1 to 4 carbons, and together with R 2 , R 1 or R 3 forms a cyclic ring; R 4 and R 5 which may be the same or different are selected from hydrogen, alkyl of 1 to 4 carbons, and methoxy.
Claim 4
Dependent Claim
36 words
A compound according to claim 1 selected from the group consisting of: 1,2-dimethyl-3-phenyl-2H-benz[f]isoindole-4,9-dione; 1-phenyl-2,3-trimethylene-2H-benz[f]isoindole-4,9-dione; 1,2,5-trimethyl-3-phenyl-2H-isoindole-4,7-dione; 1,2,6-trimethyl-3-phenyl-2H-isoindole-4,7-dione; 5-methoxy-1,2,6-trimethyl-3-phenyl-2H-isoindole-4,7-dione; 6-methoxy-1,2,5-trimethyl-3-phenyl-2H-isoindole-4,7-dione; 5-methyl-1-phenyl-2,3-trimethylene-2H-isoindole-4,7-dione; 6-methyl-1-phenyl-2,3-trimethylene-2H-isoindole-4,7-dione; 5-methoxy-6-methyl-3-phenyl-1,2-trimethylene-2H-isoindole-4,7-dione; 6-methoxy-5-methyl-3-phenyl-1,2-trimethylene-2H-isoindole-4,7-dione; 1-methyl-2,3-trimethylene-2H-benz[f]isoindole-4,9-dione; 2-methyl-1-phenyl-2H-benz[f]isoindole-4,9-dione; 2,5-dimethyl-1-phenyl-2H-isoindole-4,7-dione; 2,6-dimethyl-1-phenyl-2H-isoindole-4,7-dione; 1,5-dimethyl-2,3-trimethylene-2H-isoindole-4,7-dione; 1,6-dimethyl-2,3-trimethylene-2H-isoindole-4,7-dione; 1-carboethoxy-5-methyl-2,3-trimethylene-2H-isoindole-4,7-dione; 1-carboethoxy-6-methyl-2,3-trimethylene-2H-isoindole-4,7-dione; 1-carboethoxy-2,5-dimethyl-3-phenyl-2H-isoindole-4,7-dione; 1-carboethoxy-2,6-dimethyl-3-phenyl-2H-isoindole-4,7-dione; 5-methyl-1,2-trimethylene-2H-isoindole-4,7-dione; 6-methyl-1,2-trimethylene-2H-isoindole-4,7-dione; and 1,2,3,5-tetramethyl-2H-isoindole-4,7-dione.
Claim 5
Independent Claim
277 words
A method for the preparation of 2H-isoindolediones by the 1,3-dipolar addition of oxazolium-5-oxides to 1,4-quinones which comprises the steps of: (a) generating, at a temperature of from about 20° to about 80° C. in the presence of a non-polar aprotic solvent and a dehydration agent, an oxazolium 5-oxide of the formula: ##STR14## from an N-acyl amino acid of the formula ##STR15## (b) reacting the oxazolium 5-oxide obtained in step (a) with a 1,4-quinone of the formula ##STR16## in the presence of a non-polar aprotic solvent for a period of time sufficient to produce a product of the formula ##STR17## wherein: R 1 and R 3 each separately is phenyl, substituted phenyl, alkyl of 1 to 4 carbons, --CHO, --CH 2 OR 6 , --CO 2 R 6 , --COR 6 , hydrogen, or together with R 2 are a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 2 is phenyl, substituted phenyl, --CH 2 OR 6 , --CH 2 CH 2 OR 6 , alkyl of 1 to 4 carbons or with either R 1 or R 3 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 4 and R 5 which may be the same or different is hydrogen, alkyl of 1 to 4 carbons, --OR 6 , --CO 2 R 6 , --COR 6 , --CHO, --CH 2 OR 6 or together R 4 and R 5 are a butadiene radical which form a benzene ring; R 6 is hydrogen or alkyl of 1 to 4 carbons; and (c) separating and recovering the product from the solvent solution.
Claim 6
Independent Claim
277 words
A method for the preparation of 2H-isoindolediones by the 1,3-dipolar addition of oxazolium-5-oxides to 1,4-quinones which comprises the steps of: (a) generating, at a temperature of from about 20° to about 80° C. in the presence of a non-polar aprotic solvent and a dehydration agent, an oxazolium 5-oxide of the formula: ##STR14## from an N-acyl amino acid of the formula ##STR15## (b) reacting the oxazolium 5-oxide obtained in step (a) with a 1,4-quinone of the formula ##STR16## in the presence of a non-polar aprotic solvent for a period of time sufficient to produce a product of the formula ##STR17## wherein: R 1 and R 3 each separately is phenyl, substituted phenyl, alkyl of 1 to 4 carbons, --CHO, --CH 2 OR 6 , --CO 2 R 6 , --COR 6 , hydrogen, or together with R 2 are a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 2 is phenyl, substituted phenyl, --CH 2 OR 6 , --CH 2 CH 2 OR 6 , alkyl of 1 to 4 carbons or with either R 1 or R 3 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 4 and R 5 which may be the same or different is hydrogen, alkyl of 1 to 4 carbons, --OR 6 , --CO 2 R 6 , --COR 6 , --CHO, --CH 2 OR 6 or together R 4 and R 5 are a butadiene radical which form a benzene ring; R 6 is hydrogen or alkyl of 1 to 4 carbons; and (c) separating and recovering the product from the solvent solution.
Claim 7
Dependent Claim
14 words
The method of claim 4 wherein the dehydration agent is acetic anhydride or dicyclohexylcarbodiimide.
Claim 8
Dependent Claim
22 words
The method of claim 4 wherein step (b) is carried out at a temperature ranging from about 20° to about 55° C.
Claim 9
Dependent Claim
19 words
The method of claim 4 or 5 wherein steps (a) and (b) are carried out in an inert atmosphere.
Claim 10
Dependent Claim
30 words
The method of claim 5 wherein said agent is acetic anhydride and prior to step (b) the reaction solution is neutralized by the addition of sodium carbonate and sodium sulfate.
Claim 11
Dependent Claim
41 words
The method of claim 4 wherein R 1 and R 2 each separately is selected from the group consisting of phenyl, methyl R 3 is methyl or phenyl; R 4 is hydrogen, or methoxy; and R 5 is hydrogen, or methyl.
Claim 12
Dependent Claim
20 words
The method of claim 4 wherein said 1,4-quinone is selected from the group consisting of 1,4-benzoquinone; 1,4-naphthoquinone; 2-methyl-1,4-benzoquinone and 2-methyl-3-methoxy-1,4-benzoquinone.
Claim 13
Dependent Claim
22 words
The method of claim 4 or 10 wherein said oxazolium 5-oxide is selected from the group consisting of 3-methyl-2,4-diphenyloxazolium-5-oxide; 2,3-dimethyl-4-phenyloxazolium-5-oxide and 2-phenyl-3,4-trimethyleneoxazolium-5-oxide.
Claim 14
Dependent Claim
198 words
A radiosensitizing composition for use in the radiotherapeutic treatment of cancerous tissues which comprises as an active ingredient an isoindoledione compound of the formula ##STR18## wherein: R 1 and R 3 each separately is phenyl, substituted phenyl, alkyl of 1 to 4 carbons, --CHO, --CH 2 OR 6 , --CO 2 R 6 , --COR 6 , hydrogen, or together with R 2 are a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 2 is phenyl, substituted phenyl, --CH 2 OR 6 , --CH 2 CH 2 OR 6 , alkyl of 1 to 4 carbons or with either R 1 or R 3 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 4 and R 5 which may be the same or different is hydrogen, alkyl of 1 to 4 carbons, --OR 6 , --CO 2 R 6 , --COR 6 , --CHO, --CH 2 OR 6 or together R 4 and R 5 are a butadiene radical which form a benzene ring; R 6 is hydrogen or alkyl of 1 to 4 carbons; together with a pharmaceutically acceptable carrier.
Claim 15
Dependent Claim
198 words
A radiosensitizing composition for use in the radiotherapeutic treatment of cancerous tissues which comprises as an active ingredient an isoindoledione compound of the formula ##STR18## wherein: R 1 and R 3 each separately is phenyl, substituted phenyl, alkyl of 1 to 4 carbons, --CHO, --CH 2 OR 6 , --CO 2 R 6 , --COR 6 , hydrogen, or together with R 2 are a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 2 is phenyl, substituted phenyl, --CH 2 OR 6 , --CH 2 CH 2 OR 6 , alkyl of 1 to 4 carbons or with either R 1 or R 3 is a divalent alkyl or alkenyl group of 3 to 5 carbons which form a cyclic ring; R 4 and R 5 which may be the same or different is hydrogen, alkyl of 1 to 4 carbons, --OR 6 , --CO 2 R 6 , --COR 6 , --CHO, --CH 2 OR 6 or together R 4 and R 5 are a butadiene radical which form a benzene ring; R 6 is hydrogen or alkyl of 1 to 4 carbons; together with a pharmaceutically acceptable carrier.
Claim 16
Dependent Claim
24 words
An injectable composition according to claim 12, wherein said carrier is selected from the group consisting of sterile buffered saline solution and sterile water.
Claim 17
Dependent Claim
15 words
The composition of claim 12 in the form of a tablet, capsule, syrup or elixir.
Claim 18
Dependent Claim
54 words
A method for the radiotherapeutic treatment of cancerous tissues in mammals which comprises: (a) administering to said mammal, in an amount effective to enhance subsequent radiation of cancerous tissue, a radiosensitizing composition as claimed in claim 12; and (b) subsequently exposing the cancerous tissue to radiation whereby enhanced radiation of the tissue is achieved.
Claim 19
Dependent Claim
29 words
The method of claim 13 wherein the amount of said composition administered ranges from about 0.1 to 0.8 mg of active ingredient per kg body weight of the mammal.
Claim 20
Dependent Claim
21 words
The method of claim 16 wherein the amount of said composition administered is about 0.4 mg per kg of body weight.
Claim 21
Dependent Claim
11 words
The method of claim 12 wherein said radiation is gamma radiation.
Claim 22
Dependent Claim
22 words
The method of claim 12 wherein the time between steps (a) and (b) is from between about 15 to about 60 minutes.
References Cited (Backward Citations)
US4066650A
Cited
US4241060A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1988-01-22 | 1988-07-23 | 1989-01-22 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1992-01-22 | 1992-07-23 | 1993-01-22 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1996-01-22 | 1996-07-23 | 1997-01-22 | $7700.00 | Window Closed / Lapsed |