Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1995-04-05
1996-07-02
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562501, 562503, 562504, 562506, 560 56, 560119, 556441, C07C 6206, C07C 6974, C07C17700, C07F 704
Patent
active
055324088
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 PCT of JP93/01407 filed Oct. 1, 1993.
TECHNICAL FIELD
The present invention relates to .alpha.-chain-modified isocarbacyclins and a process for the production thereof. More specifically, it relates to a process for positionally selective production of .alpha.-chain-modified isocarbacyclins having oxygen atoms in the 6,9.alpha.-positions of prostaglandin I.sub.2 replaced with methine group (--CH.dbd.) and having an optionally substituted phenylene group in the .alpha.-chain from 2,6,7-trisubstituted-3-methy-lenebicyclo[3.3.0]-oct as starting materials, and .alpha.-chain-modified isocarbacyclins that can be produced by the above process.
TECHNICAL BACKGROUND
Prostacyclin is a topical hormone produced mainly in the inner wall of the arterial blood vessel of a living body, and is an important factor which adjusts the cellular functions of a living body with its strong physiological activities such as platelet aggregation inhibition activity and vasodilation activity. Attempts have been made to provide this directly as a drug (Clinical Pharmacology of Prostacyclin, Raven Press, N.Y. 1981).
However, natural prostacyclin has an extremely easily hydrolyzable enol ether bond in its molecule so that it is easily hydrolyzed under neutral or acidic conditions to be deactivated. Natural prostacyclin, therefore, cannot be said to be a desirable compound as a drug due to its chemical instability. Under the circumstances, studies have been and are being diligently made of chemically stable synthetic prostacyclin derivatives having physiological activities similar to those of natural prostacyclin.
JP-A-57-54180 and EP 0 045842B1 corresponding thereto disclose prostacylins of the following formula, ##STR1## wherein R.sup.1 is a H, a pharmaceutically acceptable cation or an alcohol residue, R.sup.2 is H or CH.sub.3, A is --CH.sub.2 CH.sub.2 --, (trans)--CH.dbd.CH-- or --C.tbd.C-- and B is an alkyl group represented by ##STR2## (each of R.sup.3 and R.sup.4 is H, CH.sub.3 or C.sub.2 H.sub.5) or a cyclohexyl group, those of prostacyclin on the aggregation of platelet and blood pressure but that these prostacyclins have higher stability than prostacyclin.
JP-A-3-7275 and EP 0 389162A1 corresponding thereto disclose prostacyclins of the following formula, ##STR3## wherein R.sub.1 is H, a pharmaceutically acceptable cation or an ester residue and R.sub.2 is a C.sub.1-12 linear alkyl group or the like, it is disclosed that these prostacyclins have excellent stability in a living body.
JP-A-2-57548 discloses prostacyclins of the following formula, ##STR4## wherein R.sub.1 is --COOR.sub.2 . . . , R.sub.2 is H or a pharmaceutically acceptable cation, A is --(CH.sub.2).sub.n -- (n=an integer of 1 to 3), --CH=CHCH.sub.2 --, --CH.sub.2 CH.dbd.CH-- or --CH.sub.2 OCH.sub.2 -- and B is, for example, ##STR5## (R.sub.8 is H, C.sub.1-12 acyl or the like, R.sub.9 is H or C.sub.1-4 alkyl and R.sub.13 is C.sub.5-10 branched alkyl or the like), the inhibition of platelet aggregation and the reduction of blood pressure,
Further, it is known that prostacyclin derivatives having the oxygen atoms in the 6,9-.alpha.positions of prostacyclin replaced with methine group, i.e., 9(O)-methanoprostacyclin (carbacyclin) is a prostacyclin derivative which satisfies chemical stability (see Prostacyclin, I. R. Vane and S. Bergstrom. Eds. Raven Press, N.Y., pages 31 to 34), and this derivative is expected to be applied as a drug.
U.S. Pat. No. 4,306,076 discloses carbacyclins of the following formula, ##STR6## wherein g is 0, 1, 2 or 3, n is 1 or 2, L.sub.1 is .alpha.-R.sub.3,.beta.-R.sub.4 ; .alpha.-R.sub.4,.beta.-R.sub.3 or a mixture of these (each of R.sub.3 and R.sub.4 is H, CH.sub.3 or F), M.sub.1 is .alpha.-OH,.beta.-R.sub.5 or .alpha.-R.sub.5,.beta.-OH (R.sub.5 is H or CH.sub.3), R.sub.7 is --C.sub.m H.sub.2m --CH.sub.3 (m is an integer of 1 to 5) or the like, Y.sub.1 is trans--CH.dbd.CH--, cis--CH.dbd.CH--, --CH.sub.2 CH.sub.2 -- or --C.tbd.C--, X.sub.1 is --COOR.sub.1 (R.sub.1 is H, C.sub.1-12 alkyl or the like), R.sub.8 i
REFERENCES:
Lautens, M. et al J.ACS 1995 117 1954-1964.
Fujii Takao
Koga Masahiro
Masegi Tsukio
Tanaka Toshio
Killos Paul J.
Teijin Limited
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