US4386100A
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Spiro [imidazolidine 4,3'-indoline]2,2',5-triones, compositions and use
Assignee: Imperial Chemical Industries Ltd
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Filing: 1982-05-11
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Granted: 1983-05-31
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Expires: 2002-05-11
Abstract
Abstract The invention provides novel non-toxic biodegradable derivatives of the formula: <IMAGE> I wherein Ra is (1-12C)alkyl, phenyl, naphthylmethyl or cinnamyl, the aromatic rings of which optionally bear one or two halogeno substituents, or Ra is benzyl optionally bearing up to 3 substituents independently selected from halogeno, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, nitro, cyano and hydroxy; Rb and Rc are independently selected from hydrogen and non-toxic biodegradable protecting radicals, but are not both hydrogen; and benzene ring A optionally bears one substituent selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, nitro and hydroxy, or bears two substituents independently selected from halogeno, (1-4C)alkyl and nitro; pharmaceutical compositions thereof; and processes for their manufacture. The amides of formula I in which Rb=Rc=H are potent inhibitors of the enzyme aldose reductase. The derivatives of formula I provided by the invention are of use in vivo in the treatment or prophylaxis of certain complications of diabetes or galactosemia.
Inventors
- 👤 David R. Brittain
- 👤 Robin Wood
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-25 13:34
CPC Classifications
C; C07; C07D; C07D487/00; C07D487/02; C07D487/10; A; A61; A61P; A61P3/00; A61P3/08; A61P3/10; C07D209/00; C07D209/02; C07D209/04; C07D209/30; C07D209/32; C07D209/38; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804
Claims Analysis
Total Claims: 14
Claim 1
Independent Claim
114 words
A non-toxic biodegradable derivative of 1'-substituted-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, said derivative having the formula: ##STR9## wherein Ra is a (1-12 C)alkyl radical, a phenyl naphthylmethyl or cinnamyl radical, the aromatic rings of which optionally bear one or two halogeno radicals, or Ra is a benzyl radical optionally bearing one, two or three substituents independently selected from halogeno trifluoromethyl, (1-4 C)alkyl, (1-4 C)alkoxy, nitro, cyano and hydroxy radicals; Rb and Rc are independently selected from hydrogen and non-toxic biodegradable protecting radicals, but are not both hydrogen; and benzene ring A optionally bears one substituent selected from halogeno, (1-4 C)alkyl, (1-4 C)alkoxy, nitro and hydroxy radicals, or bears two substituents independently selected from halogeno, (1-4 C)alkyl and nitro radicals.
Claim 2
Dependent Claim
114 words
A non-toxic biodegradable derivative of 1'-substituted-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, said derivative having the formula: ##STR9## wherein Ra is a (1-12 C)alkyl radical, a phenyl naphthylmethyl or cinnamyl radical, the aromatic rings of which optionally bear one or two halogeno radicals, or Ra is a benzyl radical optionally bearing one, two or three substituents independently selected from halogeno trifluoromethyl, (1-4 C)alkyl, (1-4 C)alkoxy, nitro, cyano and hydroxy radicals; Rb and Rc are independently selected from hydrogen and non-toxic biodegradable protecting radicals, but are not both hydrogen; and benzene ring A optionally bears one substituent selected from halogeno, (1-4 C)alkyl, (1-4 C)alkoxy, nitro and hydroxy radicals, or bears two substituents independently selected from halogeno, (1-4 C)alkyl and nitro radicals.
Claim 3
Dependent Claim
111 words
A derivative as claimed in claim 1 wherein Ra is a methyl, ethyl, propyl, butyl, pentyl, hexyl, nonyl or decyl radical, a phenyl, naphthylmethyl or cinnamyl radical, the aromatic rings of which optionally bear one or two fluoro, chloro, bromo or iodo radicals, or Ra is a benzyl radical optionally bearing one, two or three substituents independently selected from fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, nitro, cyano and hydroxy radicals; and benzene ring A optionally bears one substituent selected from fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy, ethoxy, nitro and hydroxy radicals, or bears two substituents independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl and nitro radicals.
Claim 4
Dependent Claim
70 words
A derivative as claimed in claim 1 wherein Ra is a methyl, n-propyl, n-hexyl, n-nonyl, n-decyl, phenyl, cinnamyl, 3,4-dichlorocinnamyl, naphth-1-ylmethyl, naphth-2-ylmethyl, benzyl, 3,4-dichlorobenzyl, 4-bromo-2-fluorobenzyl, 4-methylbenzyl, 2-fluoro-4-iodobenzyl, 4-bromo-3-chlorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3,4-dimethoxybenzyl, 3-(trifluoromethyl)benzyl, 2-cyanobenzyl, 4-cyanobenzyl, 4-bromo-2-fluoro-5-nitrobenzyl, 4-nitrobenzyl, 4-bromo-3,5-dichlorobenzyl, 2,4-dichlorobenzyl, 4-hydroxybenzyl or 3,5-dichlorobenzyl radical; and benzene ring A is unsubstituted or bears 4'-chloro, 5'-fluoro, 5'-chloro, 5'-bromo, 5'-methyl, 5'-methoxy, 5'hydroxy, 5'-nitro, 6'-chloro, 7'-fluoro, 7'-chloro, 7'-methyl, 7'-ethyl, 5',6'-difluoro, 5',6'-dichloro, 4',5'-dichloro, 5',6'-dimethyl, 5'-bromo-7'-nitro or 5'-chloro-7'-methyl substituents.
Claim 5
Dependent Claim
35 words
A derivative as claimed in claim 1 wherein Ra is a 4-bromo-2-fluorobenzyl, 4-bromo-3-chlorobenzyl, 3,4-dichlorobenzyl or 2-fluoro-4-iodobenzyl radical; and benzene ring A is unsubstituted or bears a halogeno substituent located at position 5', 6' or 7'.
Claim 6
Dependent Claim
61 words
A derivative as claimed in claim 1 wherein Rb and Rc are independently selected from hydrogen, acyl and 1-(acyloxy)alkyl radicals, in which the acyl is an alkanoyl, optionally substituted aroyl, alkoxycarbonyl, optionally substituted aralkoxycarbonyl or an alkoxyoxalyl radical; and from N-alkylcarbamoyl, N,N-dialkylcarbamoyl, optionally substituted N-arylcarbamoyl, optionally substituted N-aralkylcarbamoyl and optionally substituted phthalidyl radicals; but Rb and Rc are not both hydrogen.
Claim 7
Dependent Claim
94 words
A derivative as claimed in claim 1 wherein Rb and Rc are independently selected from (2-12 C)alkanoyl, benzoyl [optionally bearing a halogeno, (1-4 C)alkyl or cyano substituent], (1-10 C)alkoxycarbonyl, benzyloxycarbonyl (optionally bearing a halogeno substituent), 1-[(2-20 C)alkanoyl]oxy-(1-6 C)alkyl, [(1-10 C)alkoxy]oxalyl, 1-(benzoyloxy)-(1-6 C)alkyl [optionally bearing a halogeno, (1-4 C)alkyl or cyano nuclear substitutent], 1-[(1-10 C)alkoxycarbonyloxy]-(1-6 C)alkyl, N-(1-6 C)alkylcarbamoyl, N,N-di-(1-6 C)alkylcarbamoyl, N-phenyl- or N-benzylcarbamoyl [optionally bearing a (1-4 C)alkyl or (1-4 C)alkoxy nuclear substituent], or a phthalidyl radical [optionally bearing a (1-4 C)alkyl, (1-4 C)alkoxy or halogeno substituent]; but Rb and Rc are not both hydrogen.
Claim 8
Dependent Claim
59 words
A derivative as claimed in claim 1 wherein Rb and Rc are independently selected from acetyl, pivaloyl, butyryl, stearoyl, benzoyl, methylbenzoyl, chlorobenzoyl, cyanobenzoyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, chlorobenzyloxycarbonyl, pivaloyloxymethyl, stearoyloxymethyl, 1-(pivaloyloxy)ethyl, methoxyoxalyl, ethoxyoxalyl, benzoyloxymethyl, (chlorobenzoyl)oxymethyl, (methylbenzoyl)oxymethyl, (methoxybenzoyl)oxymethyl, (cyanobenzoyl)oxymethyl, (ethoxycarbonyl)oxymethyl, 1-(ethoxycarbonyloxy)ethyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-phenylcarbamoyl, N-(methoxyphenyl)carbamoyl, N-benzylcarbamoyl, N-(methylbenzyl)carbamoyl, or a phthalidyl radical optionally bearing a fluoro, chloro, bromo, methyl or methoxy substituent.
Claim 9
Dependent Claim
57 words
A derivative as claimed in claim 1 wherein Ra is a benzyl radical bearing one or two halogeno radicals, Rb and Rc are independently selected from hydrogen and alkoxycarbonyl, aralkoxycarbonyl, alkoxyoxalyl and 1-[alkoxycarbonyloxy]alkyl radicals, but are not both hydrogen, and benzene ring A is unsubstituted or bears a halogeno substituent located at position 5', 6' or 7'.
Claim 10
Dependent Claim
52 words
A non-toxic biodegradable derivative as claimed in claim 1 which is a derivative of an aldose reductase inhibitor selected from: 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(4-bromo-2-fluorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(3,4-dichlorobenzyl)-5'-fluorospiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(4-bromo-3-chlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 5'-chloro-1'-(3,4-dichlorobenzyl)spiro[imidazolidine-4,3'-indoline]-2,2,',5-trione, 1'-(4-bromo-2-fluorobenzyl)-5'-chloro-spiro[imidazolidine-4,3'-indoline]-2,2,',5-trione, 5'-bromo-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(4-bromo-2-fluorobenzyl)-5'-fluoro-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, ' -(3,4-dichlorobenzyl)-5',6'-dichloro-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(3,4-dichlorobenzyl)-5',6'-difluoro-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione and 1'-(2-fluoro-4-iodobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione said derivative being one wherein one or both of the imidazolidine nitrogen atoms bears a non-toxic biodegradable protecting radical.
Claim 11
Dependent Claim
8 words
A compound selected from 1'-(3,4-dichlorobenzyl)-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(4-bromo-2-fluorobenzyl)-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione and 1'-(3,4-dichlorobenzyl)-7'-fluoro-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione.
Claim 12
Dependent Claim
8 words
A compound selected from 1'-(3,4-dichlorobenzyl)-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(4-bromo-2-fluorobenzyl)-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione and 1'-(3,4-dichlorobenzyl)-7'-fluoro-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione.
Claim 13
Dependent Claim
29 words
A pharmaceutical composition which comprises as active ingredient a non-toxic biodegradable derivative having the formula I as claimed in claim 1 together with a pharmaceutically acceptable diluent or carrier.
Claim 14
Dependent Claim
37 words
A method of inhibiting the enzyme aldose reductase which comprises administering to a warm-blooded animal requiring such treatment an aldose reductase inhibitory amount of a non-toxic biodegradable derivative having the formula I as claimed in claim 1.
References Cited (Backward Citations)
US4117230A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1986-05-30 | 1986-11-29 | 1987-05-31 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-05-30 | 1990-11-29 | 1991-05-31 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-05-30 | 1994-11-29 | 1995-05-31 | $7700.00 | Window Closed / Lapsed |