US4525586A
Expired / Lapsed
US
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Composition and process
Assignee: Pharmacia and Upjohn Co
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Filing: 1983-09-19
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Granted: 1985-06-25
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Expires: 2003-09-19
Abstract
Abstract The present specification provides novel analogs of carbacyclin (CBA 2 ), 6a-carba-prostacyclin (6a-carba-PGI 2 ), which have pronounced prostacyclin-like pharmacological activity, e.g., as platelet anti-aggregatory agents. Specifically the novel chemical analogs of CBA 2 are those substituted by fluoro (C-5), alkyl (C-9), interphenylene (C-5), methano (C-6a,9), and an additional (olefinic) valence bond (C-6a,9). Further provided are benzindene analogs of CBA 2 and substituted forms thereof, i.e., 9-deoxy-2', 9-methano (or 2', 9-methano)-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGF 1 compounds. Also provided are a variety of novel chemical intermediates, e.g., substituted bicyclo[3.3.0]octane intermediates, and chemical process utilizing such intermediates which are useful in the preparation of the novel CBA 2 analogs.
Inventors
- 👤 Paul A. Aristoff
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-09 08:23
CPC Classifications
C; C07; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804; C07C; C07C405/00; C07C405/005; C07C405/0075; C07C405/0083; C07D; C07D309/00; C07D309/02; C07D309/08; C07D309/10; C07D309/12
Claims Analysis
Total Claims: 6
Claim 1
Independent Claim
588 words
A carbacyclin intermediate of formula VI or VII: wherein n is one or 2; wherein R 57 is (C 1 -C 4 )alkyl; wherein R 18 is hydrogen, hydroxy, hydroxymethyl, --OR 10 or --CH 2 OR 10 , wherein R 10 is an acid-hydrolyzable protective group; wherein R 32 is hydrogen or R 31 , wherein R 31 is selected from an acyl protective group, an acid hydrolyzable protective group, a silyl protective group and an arylmethyl hydroxy hydrogen replacing group; wherein X 1 is (1) --COOR 1 , wherein R 1 is (a) hydrogen, (b) (C 1 -C 12 )alkyl, (c) (C 3 -C 10 )cycloalkyl, (d) (C 7 -C 12 )aralkyl, (e) phenyl, optionally substituted with one, 2 or 3 chloro or (C 1 -C 3 )alkyl, (f) phenyl substituted in the para position by (i) --NH--CO--R 25 , (ii) --CO--R 26 , (iii) --O--CO--R 24 , or (iv) --CH═N--NH--CO--NH 2 wherein R 25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH 2 ; R 26 is methyl, phenyl, --NH 2 , or methoxy; and R 24 is phenyl or acetamidophenyl; inclusive, or (g) a pharmacologically acceptable cation; (2) --CH 2 OH, (3) --COL 4 , wherein L 4 is (a) amino of the formula --NR 21 R 22 , wherein R 21 and R 22 are (i) hydrogen, (ii) (C 1 -C 12 )alkyl, (iii) (C 3 -C 10 )cycloalkyl, (iv) (C 7 -C 12 )aralkyl, (v) phenyl, optionally substituted with one, 2 or 3 chloro or (C 1 -C 3 )alkyl, hydroxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (vi) (C 2 -C 5 )carboxyalkyl, (vii) (C 2 -C 5 )carbamoylalkyl, (viii) (C 2 -C 5 )cyanoalkyl, (ix) (C 3 -C 6 )acetylalkyl, (x) (C 7 -C 11 )benzoalkyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, (xii) (C 6 -C 9 )pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, or (C 1 -C 3 )alkyl, (xiii) (C 1 -C 4 )hydroxyalkyl, (xiv) (C 1 -C 4 )dihydroxyalkyl, (xv) (C 1 -C 4 )trihydroxyalkyl, with the further proviso that not more than one of R 21 and R 22 is other than hydrogen or alkyl, (b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (C 1 -C 12 )alkyl of one to 12 carbon atoms, inclusive, (c) carbonylamino of the formula --NR 23 COR 21 , wherein R 23 is hydrogen or (C 1 -C 4 )alkyl and R 21 is other than hydrogen, but otherwise as defined above, (d) sulfonylamino of the formula --NR 23 SO 2 R 21 , wherein R 21 and R 23 are as defined in (c), (4) --CH 2 NL 2 L 3 , wherein L 2 and L 3 are hydrogen or (C 1 -C 4 )-alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when X 1 is --CH 2 NL 2 L 3 , wherein Y 1 is trans--CH═CH--, cis--CH═CH--, CH 2 CH 2 --, or --C.tbd.C--; and wherein Z 2 is (1) --CH 2 --(CH 2 ) f --C(R 2 ) 2 , wherein R 2 is hydrogen or fluoro and f is zero, one, 2, or 3, or
Claim 2
Dependent Claim
588 words
A carbacyclin intermediate of formula VI or VII: wherein n is one or 2; wherein R 57 is (C 1 -C 4 )alkyl; wherein R 18 is hydrogen, hydroxy, hydroxymethyl, --OR 10 or --CH 2 OR 10 , wherein R 10 is an acid-hydrolyzable protective group; wherein R 32 is hydrogen or R 31 , wherein R 31 is selected from an acyl protective group, an acid hydrolyzable protective group, a silyl protective group and an arylmethyl hydroxy hydrogen replacing group; wherein X 1 is (1) --COOR 1 , wherein R 1 is (a) hydrogen, (b) (C 1 -C 12 )alkyl, (c) (C 3 -C 10 )cycloalkyl, (d) (C 7 -C 12 )aralkyl, (e) phenyl, optionally substituted with one, 2 or 3 chloro or (C 1 -C 3 )alkyl, (f) phenyl substituted in the para position by (i) --NH--CO--R 25 , (ii) --CO--R 26 , (iii) --O--CO--R 24 , or (iv) --CH═N--NH--CO--NH 2 wherein R 25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH 2 ; R 26 is methyl, phenyl, --NH 2 , or methoxy; and R 24 is phenyl or acetamidophenyl; inclusive, or (g) a pharmacologically acceptable cation; (2) --CH 2 OH, (3) --COL 4 , wherein L 4 is (a) amino of the formula --NR 21 R 22 , wherein R 21 and R 22 are (i) hydrogen, (ii) (C 1 -C 12 )alkyl, (iii) (C 3 -C 10 )cycloalkyl, (iv) (C 7 -C 12 )aralkyl, (v) phenyl, optionally substituted with one, 2 or 3 chloro or (C 1 -C 3 )alkyl, hydroxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (vi) (C 2 -C 5 )carboxyalkyl, (vii) (C 2 -C 5 )carbamoylalkyl, (viii) (C 2 -C 5 )cyanoalkyl, (ix) (C 3 -C 6 )acetylalkyl, (x) (C 7 -C 11 )benzoalkyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy, carboxy, (C 2 -C 5 )alkoxycarbonyl, or nitro, (xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, (xii) (C 6 -C 9 )pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C 1 -C 3 )alkyl, hydroxy, or (C 1 -C 3 )alkyl, (xiii) (C 1 -C 4 )hydroxyalkyl, (xiv) (C 1 -C 4 )dihydroxyalkyl, (xv) (C 1 -C 4 )trihydroxyalkyl, with the further proviso that not more than one of R 21 and R 22 is other than hydrogen or alkyl, (b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (C 1 -C 12 )alkyl of one to 12 carbon atoms, inclusive, (c) carbonylamino of the formula --NR 23 COR 21 , wherein R 23 is hydrogen or (C 1 -C 4 )alkyl and R 21 is other than hydrogen, but otherwise as defined above, (d) sulfonylamino of the formula --NR 23 SO 2 R 21 , wherein R 21 and R 23 are as defined in (c), (4) --CH 2 NL 2 L 3 , wherein L 2 and L 3 are hydrogen or (C 1 -C 4 )-alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when X 1 is --CH 2 NL 2 L 3 , wherein Y 1 is trans--CH═CH--, cis--CH═CH--, CH 2 CH 2 --, or --C.tbd.C--; and wherein Z 2 is (1) --CH 2 --(CH 2 ) f --C(R 2 ) 2 , wherein R 2 is hydrogen or fluoro and f is zero, one, 2, or 3, or
Claim 3
Dependent Claim
356 words
The carbacyclin intermediate of formula IV: ##STR2## wherein n is one or 2; wherein L 1 is α-R 3 :β-R 4 , α-R 4 :β-R 3 , or a mixture of α-R 3 :β-R 4 and α-R 4 :β-R 3 , wherein R 3 and R 4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R 3 and R 4 is fluoro only when the other is hydrogen or fluoro; wherein M 6 is α-OR 10 :β-R 5 or α-R 5 :β-OR 10 , wherein R 5 is hydrogen or methyl and R 10 is an acid hydrolyzable protective group; wherein R 27 is (1) --C m H 2 .sbsb.m --CH 3 , wherein m is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R 27 is phenoxy or substituted phenoxy, only when R 3 and R 4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis--CH═CH--CH 2 --CH 3 , (5) --(CH 2 ) 2 --CH(OR 10 )--CH 3 , wherein R 10 is as defined above, or (6) --(CH 2 ) 3 --CH═C(CH 3 ) 2 ; wherein --C(L 1 )--R 27 taken together is (1) (C 4 -C 7 )cycloalkyl optionally substituted by one to 3 (C 1 -C 5 )alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein R 18 is hydrogen, hydroxy, hydroxymethyl, --OR 10 or --CH 2 OR 10 , wherein R 10 is an acid-hydrolyzable protective group; wherein R 57 is (1) (C 1 -C 4 )alkyl, or (2) --CH 2 OH; and wherein Y 1 is trans--CH═CH--, cis--CH═CH--, --CH 2 CH 2 --, or --C.tbd.C--.
Claim 4
Dependent Claim
356 words
The carbacyclin intermediate of formula IV: ##STR2## wherein n is one or 2; wherein L 1 is α-R 3 :β-R 4 , α-R 4 :β-R 3 , or a mixture of α-R 3 :β-R 4 and α-R 4 :β-R 3 , wherein R 3 and R 4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R 3 and R 4 is fluoro only when the other is hydrogen or fluoro; wherein M 6 is α-OR 10 :β-R 5 or α-R 5 :β-OR 10 , wherein R 5 is hydrogen or methyl and R 10 is an acid hydrolyzable protective group; wherein R 27 is (1) --C m H 2 .sbsb.m --CH 3 , wherein m is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R 27 is phenoxy or substituted phenoxy, only when R 3 and R 4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis--CH═CH--CH 2 --CH 3 , (5) --(CH 2 ) 2 --CH(OR 10 )--CH 3 , wherein R 10 is as defined above, or (6) --(CH 2 ) 3 --CH═C(CH 3 ) 2 ; wherein --C(L 1 )--R 27 taken together is (1) (C 4 -C 7 )cycloalkyl optionally substituted by one to 3 (C 1 -C 5 )alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein R 18 is hydrogen, hydroxy, hydroxymethyl, --OR 10 or --CH 2 OR 10 , wherein R 10 is an acid-hydrolyzable protective group; wherein R 57 is (1) (C 1 -C 4 )alkyl, or (2) --CH 2 OH; and wherein Y 1 is trans--CH═CH--, cis--CH═CH--, --CH 2 CH 2 --, or --C.tbd.C--.
Claim 5
Dependent Claim
87 words
The carbacyclin intermediate of formula V: ##STR3## wherein n is one or 2; wherein R 57 is (1) (C 1 -C 4 )alkyl, or (2) --CH 2 OH; wherein R 18 is hydrogen, hydroxy, hydroxymethyl, --OR 10 or --CH 2 OR 10 , wherein R 10 is an acid-hydrolyzable protective group; and wherein R 32 is hydrogen or R 31 , wherein R 31 is selected from an acyl protective group, an acid hydrolyzable protective group, a silyl protective group and an arylmethyl hydroxy hydrogen replacing group.
Claim 6
Dependent Claim
87 words
The carbacyclin intermediate of formula V: ##STR3## wherein n is one or 2; wherein R 57 is (1) (C 1 -C 4 )alkyl, or (2) --CH 2 OH; wherein R 18 is hydrogen, hydroxy, hydroxymethyl, --OR 10 or --CH 2 OR 10 , wherein R 10 is an acid-hydrolyzable protective group; and wherein R 32 is hydrogen or R 31 , wherein R 31 is selected from an acyl protective group, an acid hydrolyzable protective group, a silyl protective group and an arylmethyl hydroxy hydrogen replacing group.
References Cited (Backward Citations)
DE2900352A1
Cited
GB2012265A
Cited
GB2013661A
Cited
GB2014143A
Cited
GB2017699A
Cited
US4180657A
Cited
US4192891A
Cited
US4225508A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1988-06-24 | 1988-12-24 | 1989-06-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1992-06-24 | 1992-12-24 | 1993-06-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1996-06-24 | 1996-12-24 | 1997-06-25 | $7700.00 | Window Closed / Lapsed |