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US4479966A
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6,9-Methano-PGI2 analogues
Assignee: Ono Pharmaceutical Co Ltd
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Filing: 1980-01-21
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Granted: 1984-10-30
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Expires: 2000-01-21
Abstract
Abstract Prostaglandin I 2 analogues of the formula: ##STR1## [wherein the symbol between the carbon atoms in positions 5 and 6 represents a single or double bond, Y represents ethylene or trans-vinylene, R 1 represents hydrogen, alkyl of 1 to 12 carbon atoms, aralkyl of 7 to 12 carbon atoms, cycloalkyl of 4 to 7 carbon atoms optionally substituted by alkyl of 1 to 4 carbon atoms, phenyl optionally substituted by chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms or phenyl, a --C m H 2m COOR 7 group (wherein m represents an integer of from 1 to 12 and R 7 represents alkyl of 1 to 4 carbon atoms), a --C n H 2n OR 8 group (wherein n represents an integer of from 2 to 12 and R 8 represents hydrogen or alkyl of 1 to 4 carbon atoms) or a ##STR2## group (wherein R 9 and R 10 each represent alkyl of 1 to 4 carbon atoms and n is as hereinbefore defined), R 2 represents hydrogen or a hydroxy-protecting group, R 3 represents hydrogen or a hydroxy-protecting group which is eliminated under acidic conditions, R 4 represents hydrogen, methyl or ethyl, R 5 represents a single bond or alkylene of 1 to 4 carbon atoms optionally substituted by a chlorine atom (provided that, when R 5 is alkylene substituted by chlorine, R 6 represents hydrogen or alkyl) R 6 represents hydrogen, alkyl or 1 to 8 carbon atoms, cycloalkyl of 4 to 7 carbon atoms optionally substituted by alkyl of 1 to 8 carbon atoms, or phenyl or phenoxy optionally substituted by cholrine, trifluoromethyl or alkyl of 1 to 4 carbon atoms, and when represents a double bond that bond is E, Z or a mixture thereof and when, represents a single bond, the absolute configuration of C 6 is R, S or a mixture thereof] and, when R 2 and R 3 represent hydrogen, cyclodextrin clathrates of such acids and esters and, when R 1 , R 2 and R 3 represent hydrogen, non-toxic salts thereof and, when R 1 represents ##STR3## in which n, R 9 and R 10 are as hereinbefore defined, non-toxic acid addition salts thereof, are new compounds, possessing prostaglandin-like activity.
Inventors
- 👤 Masaki Hayashi
- 👤 Yoshitaka Konishi
- 👤 Yoshinobu Arai
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-27 10:24
CPC Classifications
A; A61; A61K; A61K47/00; A61K47/50; A61K47/69; A61K47/6949; A61K47/6951; B; B82; B82Y; B82Y5/00; C; C07; C07C; C07C405/00; C07C405/005; C07C405/0075; C07C405/0083; C07C45/00; C07C45/61; C07C45/64; C07C45/65; C07C45/67; C07C45/673; C07C49/00; C07C49/385; C07C49/517; C07D; C07D309/00; C07D309/02; C07D309/08; C07D309/10; C07D309/12; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55
Claims Analysis
Total Claims: 41
Claim 1
Independent Claim
472 words
A prostaglandin I 2 analogue of the formula: ##STR50## wherein the symbol between the carbon atoms in positions 5 and 6 represents a single or double bond, Y represents ethylene or trans-vinylene, R 1 represents a hydrogen atom, a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, ar aralkyl group containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms unsubstituted or substituted by at least one straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, a phenyl group unsubstituted or substituted by at least one chlorine atom, trifluoromethyl group, alkyl group containing from 1 to 4 carbon atoms or phenyl group, a --C m H 2m COOR 7 group, wherein m represents an integer of from 1 to 12 and R 7 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, a --C n H 2n OR 8 group, wherein n represents an integer of from 2 to 12 and R 8 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, or a ##STR51## group, wherein R 9 and R 10 , which may be the same or different, each represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined, R 2 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under acidic or alkaline conditions selected from the group consisting of tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, 1-ethoxyethyl, (1-methoxy-1-methyl)ethyl, 1-methoxycyclohexyl, (1-methoxy-1-phenyl)ethyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, triphenylsilyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, p-phenylbenzoyl, and naphthyloyl, R 3 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under acidic conditions selected from the group consisting of tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, 1-ethoxyethyl, (1-methoxy-1-methyl)ethyl, 1-methoxy-cyclohexyl, (1-methoxy-1-phenyl)ethyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, and triphenylsilyl, R 4 represents a hydrogen atom or a methyl or ethyl group, R 6 represents a cycloalkyl group containing from 4 to 7 carbon atoms unsubstituted or substituted by at least one straight- or branched-chain alkyl group containing from 1 to 8 carbon atoms, the wavy line attached to the carbon in position 15 represents α- or β-configuration or a mixture thereof and when represents a double bond, the double bond between C 5 -C 6 is E, Z or a mixture thereof, and when represents a single bond, the absolute configuration of C 6 is R, S or a mixture thereof and, when R 2 and R 3 represent hydrogen atoms, cyclodextrin clathrates of such acids and esters and, when R 1 , R 2 and R 3 represent hydrogen atoms non-toxic salts thereof and, when R 1 represents a ##STR52## group in which n, R 9 and R 10 are as hereinbefore defined, non-toxic acid addition salts thereof.
Claim 2
Dependent Claim
472 words
A prostaglandin I 2 analogue of the formula: ##STR50## wherein the symbol between the carbon atoms in positions 5 and 6 represents a single or double bond, Y represents ethylene or trans-vinylene, R 1 represents a hydrogen atom, a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, ar aralkyl group containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms unsubstituted or substituted by at least one straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, a phenyl group unsubstituted or substituted by at least one chlorine atom, trifluoromethyl group, alkyl group containing from 1 to 4 carbon atoms or phenyl group, a --C m H 2m COOR 7 group, wherein m represents an integer of from 1 to 12 and R 7 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, a --C n H 2n OR 8 group, wherein n represents an integer of from 2 to 12 and R 8 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, or a ##STR51## group, wherein R 9 and R 10 , which may be the same or different, each represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined, R 2 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under acidic or alkaline conditions selected from the group consisting of tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, 1-ethoxyethyl, (1-methoxy-1-methyl)ethyl, 1-methoxycyclohexyl, (1-methoxy-1-phenyl)ethyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, triphenylsilyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, p-phenylbenzoyl, and naphthyloyl, R 3 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under acidic conditions selected from the group consisting of tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, 1-ethoxyethyl, (1-methoxy-1-methyl)ethyl, 1-methoxy-cyclohexyl, (1-methoxy-1-phenyl)ethyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, and triphenylsilyl, R 4 represents a hydrogen atom or a methyl or ethyl group, R 6 represents a cycloalkyl group containing from 4 to 7 carbon atoms unsubstituted or substituted by at least one straight- or branched-chain alkyl group containing from 1 to 8 carbon atoms, the wavy line attached to the carbon in position 15 represents α- or β-configuration or a mixture thereof and when represents a double bond, the double bond between C 5 -C 6 is E, Z or a mixture thereof, and when represents a single bond, the absolute configuration of C 6 is R, S or a mixture thereof and, when R 2 and R 3 represent hydrogen atoms, cyclodextrin clathrates of such acids and esters and, when R 1 , R 2 and R 3 represent hydrogen atoms non-toxic salts thereof and, when R 1 represents a ##STR52## group in which n, R 9 and R 10 are as hereinbefore defined, non-toxic acid addition salts thereof.
Claim 3
Dependent Claim
66 words
A compound of the general formula: ##STR53## wherein R 11 represents a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, R 12 represents a hydroxy-protecting group which is eliminated under acidic conditions selected from the group consisting of tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, 1-ethoxyethyl, (1-methoxy-1-methyl)ethyl, 1-methoxy-cyclohexyl, (1-methoxy-1-phenyl)ethyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, tribenzylsilyl and triphenylsilyl and the other symbols are as defined in claim 1.
Claim 4
Dependent Claim
54 words
A compound of the general formula: ##STR54## wherein R 14 represents a hydroxy-protecting group which is eliminated under alkaline conditions selected from the group consisting of acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, p-phenylbenzoyl, and naphthyloyl, R 11 is as defined in claim 2 and the other symbols are as defined in claim 1.
Claim 5
Dependent Claim
17 words
A prostaglandin analogue according to claim 1 wherein R 2 and R 3 both represent hydrogen atoms.
Claim 6
Dependent Claim
28 words
A prostaglandin analogue according to claim 1 wherein R 1 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 or 4 carbon atoms.
Claim 7
Dependent Claim
18 words
A prostaglandin analogue according to claim 1 wherein R 1 represents a hydrogen atom or a methyl group.
Claim 8
Dependent Claim
23 words
A prostaglandin analogue according to claim 1 wherein the symbol between the carbon atoms in positions 5 and 6 represents a double bond.
Claim 9
Dependent Claim
11 words
A prostaglandin analogue according to claim 1 wherein Y represents trans-vinylene.
Claim 10
Dependent Claim
29 words
A prostaglandin analogue according to claim 1 wherein the grouping --R 6 represents a cyclobutyl, cyclopentyl or cyclohexyl group unsubstituted or substituted by a methyl, ethyl or propyl group.
Claim 11
Dependent Claim
20 words
A prostaglandin analogue according to claim 1 wherein the grouping --R 6 represents 3-ethylcyclobutyl, cyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, cyclohexyl, or 4-methylcyclohexyl.
Claim 12
Dependent Claim
26 words
A prostaglandin analogue according to claim 1 wherein the hydroxy group or protected-hydroxy group attached to the C-15 carbon atom in formula II is in α-configuration.
Claim 13
Dependent Claim
17 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(3-ethylcyclobutyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester and cyclodextrin clathrates thereof.
Claim 14
Dependent Claim
17 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(4-methylcyclohexyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester and cyclodextrin clathrates thereof.
Claim 15
Dependent Claim
17 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester and cyclodextrin clathrates thereof.
Claim 16
Dependent Claim
17 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(3-ethylcyclopentyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester and cyclodextrin clathrates thereof.
Claim 17
Dependent Claim
17 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester and cyclodextrin clathrates thereof.
Claim 18
Dependent Claim
17 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester and cyclodextrin clathrates thereof.
Claim 19
Dependent Claim
18 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid and cyclodextrin clathrates and non-toxic salts thereof.
Claim 20
Dependent Claim
18 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid and cyclodextrin clathrates and non-toxic salts thereof.
Claim 21
Dependent Claim
18 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(3-ethylcyclopentyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid and cyclodextrin clathrates and non-toxic salts thereof.
Claim 22
Dependent Claim
18 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(3-ethylcyclobutyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid and cyclodextrin clathrates and non-toxic salts thereof.
Claim 23
Dependent Claim
18 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-(4-methylcyclohexyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid and cyclodextrin clathrates and non-toxic salts thereof.
Claim 24
Dependent Claim
18 words
A prostaglandin analogue according to claim 1 which is (5EZ,13E)-(9α,11α,15α)-6,9-methano-11,15-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid and cyclodextrin clathrates and non-toxic salts thereof.
Claim 25
Dependent Claim
12 words
A compound according to claim 2 which is (5EZ,13E)-(9α,11α,15αβ)-6,9-methano-11-(tetrahydropyran-2-yloxy)-15-hydroxy-15-(3-ethylcyclopentyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester.
Claim 26
Dependent Claim
12 words
A compound according to claim 2 which is (5EZ,13E)-(9α,11α,15αβ)-6,9-methano-11-(tetrahydropyran-2-yloxy)-15-hydroxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester.
Claim 27
Dependent Claim
12 words
A compound according to claim 2 which is (5EZ,13E)-(9α,11α,15αβ)-6,9-methano-11-(tetrahydropyran-2-yloxy)-15-hydroxy-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester.
Claim 28
Dependent Claim
26 words
A compound of the general formula: ##STR55## wherein R 11 is as defined in claim 2 and the other symbols are as defined in claim 1.
Claim 29
Dependent Claim
120 words
Pharmaceutical compositions useful in the treatment of hypertension, in the treatment of disorders of the peripheral circulation and in the prevention and treatment of cerebral thrombosis, myocardial infarction, and arteriosclerosis which comprise, as active ingredient, at least one prostaglandin analogue as claimed in claim 1, wherein R 2 and R 3 both represent hydrogen atoms, or cyclodextrin clathrate thereof or, when R 1 , R 2 and R 3 represent hydrogen atoms, non-toxic salt thereof, or when R 1 represents a ##STR56## group in which n, R 9 and R 10 are as defined in claim 1 and R 2 and R 3 represent hydrogen atoms, non-toxic acid addition salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
Claim 30
Dependent Claim
57 words
Pharmaceutical compositions according to claim 28 which comprise, as active ingredient, at least one prostaglandin analogue as claimed in any one of claims 12 to 15, 16, 18, 19 and 20 to 23, or cyclodextrin clathrate thereof, or non-toxic salt of a prostaglandin analogue as claimed in any one of claims 18, 19 and 20 to 23.
Claim 31
Dependent Claim
36 words
A prostaglandin analogue according to claim 1 which is a cyclodextrin clathrate of a prostaglandin analogue as claimed in any one of claims 4 to 11 wherein R 2 and R 3 both represent hydrogen atoms.
Claim 32
Dependent Claim
40 words
A prostaglandin analogue according to claim 1 which is a non-toxic salt of a prostaglandin analogue as claimed in any one of claims 4 to 11 wherein the symbols R 1 , R 2 and R 3 represent hydrogen atoms.
Claim 33
Dependent Claim
52 words
A prostaglandin analogue according to claim 1 which is a non-toxic acid addition salt of a prostaglandin analogue as claimed in any one of claims 1, 4 and 7 to 11 wherein R 1 represents a group ##STR57## in which n, R 9 and R 10 are as defined in claim 1.
Claim 34
Dependent Claim
63 words
A compound of the general formula: ##STR58## wherein R 21 and R 22 each represent a hydroxy-protecting group which is eliminated under acidic conditions selected from the group consisting of tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, 1-ethoxyethyl, (1-methoxy-1-methyl)ethyl, 1-methoxy-cyclohexyl, (1-methoxy-1-phenyl)ethyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, and triphenylsilyl and R 21 may also represent a hydrogen atom, and the other symbols are as defined in claim 1.
Claim 35
Dependent Claim
24 words
A prostaglandin analogue according to claim 1 wherein R 2 and R 3 both represent a hydroxy-protecting group which is eliminated under acidic conditions.
Claim 36
Dependent Claim
27 words
A prostaglandin analogue according to claim 1 wherein R 2 represents a hydroxy-protecting group which is eliminated under acidic conditions and R 3 represents a hydrogen atom.
Claim 37
Dependent Claim
30 words
A prostaglandin analogue according to claim 34 or 35 wherein the hydroxy-protecting group is a tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, 1-ethoxyethyl, (1-methoxy-1-methyl)ethyl, 1-methoxy-cyclohexyl, (1-methoxy-1-phenyl)ethyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, tribenzylsilyl or triphenylsilyl group.
Claim 38
Dependent Claim
17 words
A prostaglandin analogue according to claim 34 or 35 wherein the hydroxy-protecting group is the tetrahydropyran-2-yl group.
Claim 39
Dependent Claim
12 words
A compound according to claim 27 which is (5EZ,13E)-(9α,11α)-6,9-methano-11-hydroxy-15-oxo-15-(3-ethylcyclobutyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester.
Claim 40
Dependent Claim
12 words
A compound according to claim 27 which is (5EZ,13E)-(9α,11α)-6,9-methano-11-hydroxy-15-oxo-15-(4-methylcyclohexyl)-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester.
Claim 41
Dependent Claim
12 words
A compound according to claim 27 which is (5EZ,13E)-(9α,11α)-6,9-methano-11-hydroxy-15-oxo-15-cyclopentyl-16,17,18,19,20-pentanorprosta-5-13-dienoic acid methyl ester.
References Cited (Backward Citations)
GB2013001A
Cited
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-10-30 | 1988-04-30 | 1988-10-30 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-10-30 | 1992-04-30 | 1992-10-30 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-10-30 | 1996-04-30 | 1996-10-30 | $7700.00 | Window Closed / Lapsed |