US 4,267,114 AGrant
19-Hydroxy-19-Methyl-6,9.alpha.-Epoxymethano-PGF Compounds
Issue Date:1981-05-12
•6 Claims
Abstract
The present invention provides novel 19-hydroxy-19-methyl-6,9.alpha.-epoxy-methano-PGF compounds which are useful for pharmacological purposes, e.g., anti-asthmatic indications.
Metadata
Assignee
- The Upjohn Company
Inventor
- John C. Sih
Application Information
Application Number:US 1265091
Filing Date:1980-03-03
Priority Date:1979-07-05
Art Unit:126
Classifications
IPC:
C07D31102
Field of Search:
260542548345.2416;421;422;426252;253
Patent Drawings
This patent does not have any drawings.
Description
Background of the Invention
The present invention provides novel prostacyclin analogs. Particularly, the present invention relates to prostacyclin analogs substituted at the C-19 position by hydroxy.
Particularly, the present invention relates to 19-hydroxy-19-methyl-6,9.sub..alpha. -epoxymethano-PGF compounds. The novel prostacyclin analogs are useful for pharmacological purposes, e.g., as anti-asthmatic agents. The preparation and use of these compounds is incorporated here by reference from U.S. Ser. No. 054,720, filed 5 July 1979, now U.S. Pat. No. 4,225,507.
Prior Art
For background on prostacyclin, see for example R. A. Johnson, et al., Prostaglandins 12, 915-928 (1976) and R. A. Johnson, et al., J. Am. Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity, the references cited therein. For analogs of prostacyclin, see, for example, J. Fried, et al., Proc. Natl. Acad. Sci. U.S.A. 74, 2199-2203, K. C. Nicolaou, et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson, J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima, et al., Tetra. Letters, 1978, (1977), and K. Kojima, et al., Tetra. Letters, 1978, 3743-3746. Regarding the nomenclature for analogs of PGI.sub.2, see R. A. Johnson, et al., Prostaglandins, 15, 737-740 (1978).
Summary of the Invention
The present invention particularly provides a prostacyclin-type compound of the formula ##STR1## wherein A.sub.2 is --CH.sub.2 O-- with --CH.sub.2 bonded to the cyclopentane ring and E.sub.1 is --CH.sub.2 --;
wherein L.sub.1 is
(1) --(CH.sub.2).sub.n --, wherein n is one to 5, inclusive,
(2) --(CH.sub.2).sub.p --CF.sub.2 --, wherein p is 2, 3, or 4; or
(3) --CH.sub.2 --CH.dbd.CH--;
wherein M.sub.1 is ##STR2## wherein Q is oxo, .alpha.--H:.beta.--H, .alpha.--OH:.beta.--R.sub.4, or .alpha.--R.sub.4 :.beta.--OH, wherein R.sub.4 is hydrogen or alkyl of one to 4 carbon atoms, inclusive;
wherein R.sub.1 is
(1) --COOR.sub.3,
(2) --CH.sub.2 OH,
(3) --CH.sub.2 N(R.sub.7)(R.sub.8),
(4) --CO--N(R.sub.7)(R.sub.8),
(5) --CO--NH--SO.sub.2 --R.sub.15, or
(6) tetrazolyl,
wherein R.sub.3 is
(a) hydrogen,
(b) alkyl of one to 12 carbon atoms, inclusive,
(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,
(d) aralkyl of 7 to 12 carbon atoms, inclusive,
(e) phenyl,
(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive;
(g) --(Ph)--CO--CH.sub.3,
(h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH.sub.3,
(i) --(p--Ph)--NH--CO--(p--Ph),
(j) --(p--Ph)--NH--CO--CH.sub.3,
(k) --(p--Ph)--NH--CO--NH.sub.2,
(l) --(p--Ph)--CH.dbd.N--NH--CO--NH.sub.2,
(m) .beta.--naphthyl,
(n) --CH.sub.2 --CO--R.sub.16,
wherein --(Ph)-- is inter-phenylene and --(p--Ph) is inter-para-phenylene or para-phenyl;
wherein R.sub.16 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or
(o) a pharmacologically acceptable cation; wherein R.sub.7 and R.sub.8 are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different, and wherein R.sub.15 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive, in the alkoxy group
wherein R.sub.2 is hydrogen, hydroxyl, or hydroxymethyl,
wherein R.sub.5 and R.sub.6 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R.sub.5 and R.sub.6 is fluoro only when the other is hydrogen or fluoro, and
wherein X is
(1) trans--CH.dbd.CH--,
(2) cis--CH.dbd.CH--,
(3) --C.tbd.C--, or
(4) --CH.sub.2 CH.sub.2 --.
Description of the Preferred Embodiments
The present invention particularly relates to the following compounds:
(5Z)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9.alpha.-epoxymethano-.DELTA..su p.5,19-hydroxy-19-methyl-PGF.sub.1,
(5Z)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9.alpha.-epoxymethano-.DELTA..su p.5 -16,16-difluoro-19-hydroxy-19-methyl-PGF.sub.1,
2-Decarboxy-2-hydroxymethyl-9-deoxy-6.epsilon.,9.alpha.-epoxymethano-19-hyd roxy-19-methyl-PGF.sub.1, and
2-Decarboxy-2-hydroxymethyl-9-deoxy-6.epsilon.,9.alpha.-epoxymethano-16,16- difluoro-19-hydroxy-19-methyl-PGF.sub.1.
Claims
I claim:
1. A prostacyclin-type compound of the formula ##STR3## wherein A.sub.2 is --CH.sub.2 O-- with --CH.sub.2 bonded to the cyclopentane ring and E.sub.1 is --CH.sub.2 --; wherein L.sub.1 is (1) --(CH.sub.2).sub.n --, wherein n is one to 5, inclusive, (2) --(CH.sub.2).sub.p --CF.sub.2 --, wherein p is 2, 3, or 4; or (3) --CH.sub.2 --CH.dbd.CH--; wherein M.sub.1 is ##STR4## wherein Q is oxo, .alpha.--H:.beta.--H, .alpha.--OH:.beta.--R.sub.4, or .alpha.--R.sub.4 :.beta.--OH, wherein R.sub.4 is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R.sub.1 is (1) --COOR.sub.3, (2) --CH.sub.2 OH, (3) --CH.sub.2 N(R.sub.7)(R.sub.8), (4) --CO--N(R.sub.7)(R.sub.8), (5) --CO--NH--SO.sub.2 --R.sub.15, or (6) tetrazolyl, wherein R.sub.3 is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive; (g) --(Ph)--CO--CH.sub.3, (h) --(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH.sub.3, (i) --(p-Ph)--NH--CO--(p-Ph), (j) --(p-Ph)--NH--CO--CH.sub.3, (k) --(p-Ph)--NH--CO--NH.sub.2, (l) --(p-Ph)--CH.dbd.N--NH--CO--NH.sub.2, (m) .beta.--naphthyl, (n) --CH.sub.2 --CO--R.sub.16, wherein --(Ph)-- is inter-phenylene and --(p-Ph) is inter-para-phenylene or para-phenyl; wherein R.sub.16 is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or (o) a pharmacologically acceptable cation; wherein R.sub.7 and R.sub.8 are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different, and wherein R.sub.15 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive, in the alkoxy group wherein R.sub.2 is hydrogen, hydroxyl, or hydroxymethyl, wherein R.sub.5 and R.sub.6 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R.sub.5 and R.sub.6 is fluoro only when the other is hydrogen or fluoro, and wherein X is (1) trans--CH.dbd.CH--, (2) cis--CH.dbd.CH--, (3) --C.tbd.C--, or (4 ) --CH.sub.2 CH.sub.2 --.
2. A compound according to claim 1, wherein R.sub.1 is --CH.sub.2 OH.
3. A compound according to claim 2, wherein M.sub.1 is ##STR5## with bonds to A.sub.2 and L.sub.1 as shown.
4. A compound according to claim 3, wherein L.sub.1 is --(CH.sub.2).sub.2 -- Q is .alpha.--OH:.beta.--H, R.sub.2 is hydroxyl, and X is trans--CH.dbd.CH--.
5. A compound according to claim 2, wherein M.sub.1 is ##STR6##
6. A compound according to claim 5, wherein L.sub.1 is --(CH.sub.2).sub.2 --, Q is .alpha.--OH:.beta.--H, R.sub.2 is hydroxyl, and X is trans--CH.dbd.CH--.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US4123441 | 1978-10-01 | Johnson |