Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1984-09-27
1988-04-05
Gerstl, Robert
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
544173, 544391, 546108, 546225, 548200, 548540, 549417, 549422, 549466, 556441, 560 56, 562466, 562501, 564172, 564188, C07C17700
Patent
active
047360585
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to prostacyclins and a process for the production thereof. More particularly, this invention relates to novel prostacyclins obtained by substituting oxygen atoms at 6- and 9-positions of prostaglandin I.sub.1 with methine groups --HC.dbd. and a process for the production thereof.
BACKGROUND ART
Natural prostaglandin is a local hormone which is produced in vivo mainly by the inner walls of arteries and biologically it works as an importent factor to control the cell function in a living body because of its strong physiological activities such as platalet aggregation inhibiting activity and vasodilating activity. Attempts have, therefore, been made to use it directly as pharmaceuticals (P. J. Lewis, J. O. Grady et al., "Clinical Pharmacology of Prostacyclin", Raven Press, N.Y., 1981). However, since natural prostacyclin has an enol ether bond, which is apt to be appreciably hydrolyzed, in its molecule, its action is readily paralysed under the neutral or acidic conditions, and accordingly it can not be a desirable compound to be used as medicine because of its chemical unstableness. To resolve such defect of natural prostacyclin, efforts have been directed to the development of chemically stable synthetic prostacyclin derivatives which have the same physiological activities as natural prostacyclin in Japan and abroad.
Especially, 6,9-(0)-methanoprostacyclin (Carbacyclin), which is a compound obtained by substituting the oxygen atom at the 6,9-positions or prostacyclin with a methylene group, is known as one of prostacyclins which are able to satisfy the chemical stableness to perfection (J. R. Vane et al., "Prostacyclin", pp. 31-41, Raven Press, N.Y., 1979) and is expected to work effectively as medicines. However, this 6,9(0)-methanoprostacyclin can not necessarily be regarded as a desirable compound in that it is inferior to natural prostacyclin in biological activity and it is not enough specific in action-selectivity. Beside this, nitroprostacyclin, a derivative obtained by substituting the oxygen atoms at the 6,9-positions with --N.dbd. group, is known as another type of stable prostacyclin and it is said that its biological activity is equal to that of natural prostacyclin (G. L. Bundy et al., Tetrahedron Letter, 1371 (1978) and W. Bartman et al., Tetrahedron Letter, 23, 3647 (1982)).
DISCLOSURE OF THE INVENTION
Having noticed the chemical structures of the chemically stable prostacyclin derivatives mentioned above, the inventors of the present invention have newly synthesized a prostacyclin derivative in which the oxygen atoms at the 6,9-positions are substituted with methine groups, --CH.dbd., found that this type of prostacyclin derivative is chemically stable, excellent in action-selectivity, and useful as medicine, thus achieving this invention. This invention is to provide novel prostacyclins expressed by the following formula (I) ##STR2## wherein a symbol between the 2-position and 3-position indicates single bond or double bond between the 2-position and 3-position; G indicates --CO.sub.2 R.sup.5 or --CONR.sup.6 R.sup.7, in which R.sup.5 is a hydrogen atom, C.sub.1 -C.sub.10 alkyl group, substituted or unsubstituted alicyclic group, substituted or unsubstituted phenyl (C.sub.1 -C.sub.2) alkyl group, tri(C.sub.1 -C.sub.7) hydrocarbon-silyl group, or one equivalent of cation, R.sup.6 and R.sup.7 are identical or different and each represents a hydrogen atom or C.sub.1 -C.sub.10 alkyl group, or R.sup.6 and R.sup.7 are substituted or unsubstituted five to six-membered rings which may join together with a nitrogen atom to which they are linked and further contain a hetero atom; R.sup.1 indicates a hydrogen atom or methyl group; R.sup.2 indicates an unsubstituted C.sub.3 -C.sub.8 alkyl group, substituted or unsubstituted alicyclic group, or substituted C.sub.1 -C.sub.5 alkyl group substituted by a substituent selected from phenyl, phenoxy, and C.sub.5 -C.sub.6 cycloalkyl, which substituent may be substituted; and R.sup.3 and R.sup.4 are inde
REFERENCES:
Koyama et al, Chem. Pharm. Bull., 32, 2866 (1984).
Sodoka et al, Chem. Letters, 579, (1984).
Torisawa et al, Chem. Letters, 1069 (1984).
Ogawa et al, Tet. Letters, 25, 1067 (1984).
Ikegami Shiro
Kurozumi Seizi
Gerstl Robert
Teijin Limited
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