US 4,288,371 AGrant
19-Hydroxy-19-methyl-6,7-didehydro-PGI.sub.1 Compounds
Issue Date:1981-09-08
•6 Claims
Abstract
The present invention provides novel 19-hydroxy-19-methyl-6,7-didehydro-PGI.sub.1 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 1265059
Filing Date:1980-03-03
Priority Date:1979-07-05
Art Unit:121
Classifications
IPC:
C07D307935
Field of Search:
260548346.22;346.73250
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-6,7-didehydro-PGI.sub.1 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. 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 L.sub.4 is (1) --(CH.sub.2).sub.n --, wherein n is one to 5, inclusive, or
(2) --(CH.sub.2).sub.p --CF.sub.2 --, wherein p is 2, 3, or 4, 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) --(p--PH)--CO--CH.sub.3,
(h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH.sub.3,
(i) --(p--Ph)--NH--CO--(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 (p--Ph)-- is phenylene and --(Ph) is 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,
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:
2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9.alpha.-epoxy-.DELTA..sup.6 -19-hydroxy-19-methyl-PGF.sub.1, and
2-Decarboxy-2-hydroxymethyl-9-deoxy-6.epsilon.,9.alpha.-epoxy-.DELTA..sup.6 -16,16-difluoro-19-hydroxy-19-methyl-PGF.sub.1.
Claims
I claim:
1. A prostacyclin-type compound of the formula ##STR2## wherein L.sub.4 is (1) --(CH.sub.2).sub.n --, wherein n is one to 5, inclusive, or (2) --(CH.sub.2).sub.p --CF.sub.2 --, wherein p is 2, 3, or 4, 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) --(p--Ph)--CO--CH.sub.3, (h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH.sub.3, (i) --(p--Ph)--NH--CO--(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 phenylene and --(Ph) is 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, 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 L.sub.4 is --(CH.sub.2).sub.3.
4. A compound according to claim 3, wherein Q is .alpha.-OH:.beta.-H, R.sub.2 is hydroxyl, and X is trans--CH.dbd.CH--.
5. 2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9.alpha.-epoxy-.DELTA..sup.6 -19-hydroxy-19-methyl-PGF.sub.1, a compound according to claim 4.
6. 2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9.alpha.-epoxy-.DELTA..sup.6 -16,16-difluoro-19-hydroxy-19-methyl-PGF.sub.1, a compound according to claim 4.
Non-Patent Literature (1)
- Johnson et al., J. Am. Chem. Soc., 100, 7690-7704, (1978).