Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-12-30
2002-09-17
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C502S503000
Reexamination Certificate
active
06452039
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel use of a prostanoic acid compound wherein the skeletal carbon atoms in &agr;-chain are increased as endothelin antagonist.
The antagonist according to the present invention is useful as a treating agent for a variety of diseases participated of endothelin.
BACKGROUND ART
Endothelin is an endogenous bioactive peptide composed of 21 amino acids, and three types of which, i.e., endothelin-1, endothelin-2, and endothelin-3 are known.
Endothelin is a bioactive substance for continuously constricting vascular or non-vascular smooth muscle in direct or indirect way (regulation of release of a variety of endogenous substances), and production of endothelin increases due to lesion of endothelium. Excessive production of endothelin is considered-to be a cause for diseases such as hypertension, pulmonary hypertension, Buerger disease, primary Raynaud syndrome, asthma, eyegrounds (amphiblestrodes, chorioidea, and the like) diseases, diabetes, arterial sclerosis, renal failure, cardiac infarction, angina pectoris, cerebrovascular contraction, and cerebral infarction. Furthermore, it is known that endothelin is an important mediator with respect to multiple organ failures, and diseases such as disseminated intravascular coagulation due to endotoxin shock and the like as well as renal lesion induced by cyclosporin and the like. Moreover, it is also known that an endothelin concentration in blood increases after organ transplantation such as liver transplant.
Prostanoic acid is a skeletal compound constituting a common structural feature of natural prostaglandins (PG) groups and is represented by the following structural formula:
Natural PG groups are classified based on the structural feature of five-membered ring into PGA group, PGB group, PGC group, PGD group, PGE group, PGF group, PGG group, PGH group, PGI group, and PGJ group; and further they are classified as follows on the basis of presence or absence of unsaturation and oxidation at their chain portions:
numerical subscript 1 . . . 13,14-unsaturated-15-OH
numerical subscript 2 . . . 5,6- and 13,14-di-unsaturated-15-OH
numerical subscript 3 . . . 5,6,13,14- and 17,-18-tri-unsaturated-15-OH
Moreover, the PGF group is classified into a (hydroxy group is in alpha-configuration) and &bgr; (hydroxy group is in beta-configuration) based on the configuration of hydroxy group at 9-position. In addition, a compound having oxo group in place of hydroxy group at 15-position is also known.
With respect to action of prostanoic acid compound on endothelin, it has been reported, for example, that PGE
2
inhibits renal endothelin inducible vasoconstriction in rat, and that prostacyclin (PGI
2
) moderates renal endothelin inducible vasoconstriction in dog.
However, any of these prostanoic acid compounds is the one wherein the basic carbon atoms in &agr;-chain are 7, and hence, they do not correspond to the prostanoic acid compound wherein the skeletal carbon atoms in &agr;-chain increase.
U.S. Pat. No. 3,974,195 and European Patent Application Laid-Open No. 0453127 (corresponding to Japanese Patent Kokai Hei 5-58992) describe a compound wherein the skeletal carbon atoms in &agr;-chain are increased by 2, but there is no description as to the action with respect to endothelin in these both publications.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide an endothelin antagonist useful for treating a variety of diseases and pathologies participated of endothelin.
The present inventor has eagerly studied with respect to biological activity of a prostanoic acid compound wherein the skeletal carbon atoms in &agr;-chain are increased. As a result, it has been surprisingly found that a prostanoic acid compound wherein the skeletal carbon atoms in &agr;-chain are increased has extremely strong antagonistic action as compared with that of a heretofore known prostanoic acid compound having 7 skeletal carbon atoms in &agr;-chain, so that the present invention has been completed.
More specifically, the present invention provides an endothelin antagonist comprising a prostanoic acid compound having 8 or more skeletal carbon atoms in &agr;-chain as an active ingredient.
As used herein, the term “a prostanoic acid compound having 8 or more skeletal carbon atoms in &agr;-chain” includes any of substituted compounds and derivatives of a compound wherein the skeletal carbon atoms in &agr;-chain of prostanoic acid are increased'so that the skeletal carbon atoms in &agr;-chain are 8 or more, irrespective of the structure of five-membered ring, the number of double bond on &agr;- or &ohgr;-chain, presence or absence of hydroxy group, oxo group, and the other substituents as well as any modification of chained portion.
Nomenclature of the prostanoic acid compounds herein uses the numbering system of the prostanoic acid represented in the formula (A) shown above.
While formula (A) shows a basic skeleton having twenty carbon atoms, the carbon atoms in the present invention are not limited thereto. Namely, the numbers of the carbons constituting the basic skeleton are assigned in such that number 1 is assigned to carboxylic acid, numbers 2 to 7 are given to the carbons on the &agr;-chain in accordance with the order directing to the five-membered ring, numbers 8 to 12 are assigned to the carbons of the five-membered ring, and numbers 13 to 20 are given to the carbons on the &ohgr;-chain, respectively. However, in the case where carbon atoms decrease on the &agr;-chain, numbers are successively deleted from the 2-position, while in the case where carbon atoms increase on the &agr;-chain, nomenclature is made in such that the 2-position is substituted by any substituent in place of the carboxyl group (1-position). Likewise, in case of decreasing carbon atoms on the &ohgr;-chain, the number of carbon atoms is successively deleted from 20-position, while in case of increasing carbon atoms on the &ohgr;-chain, nomenclature is made in such that the carbon atoms at 21- and thereafter positions are considered to be substituents. Further, with respect to steric configuration, it is in accordance with that involved in the above indicated basic skeleton unless otherwise specified.
For instance, while PGD, PGE, and PGF mean compounds each containing hydroxy group(s) at 9-position and/or 11-position, the present invention includes also compounds containing any other group(s) in place of hydroxy group(s) at 9-position and/or 11-position. In case of nomenclature of these compounds, it is made in the form of 9-dehydroxy-9-substituted compound or 11-dehydroxy-11-substituted compound. In case of containing hydrogen in place of hydroxyl group, it is simply named as 9(11)-dehydroxy compound.
As mentioned above, while nomenclature of prostanoic acid compound is made on the basis of prostanoic acid skeleton in the present invention, when the above described compound has the same partial structure as that of prostaglandins, there is a case where an abbreviation of PG is also utilized for simplicity. In such case, a PG compound having two increased skeletal carbon atoms in &agr;-chain, i.e., a PG compound having 9 skeletal carbon atoms in &agr;-chain is named as 2-decarboxy-2-(2-carboxyethyl)-PG compound. Likewise, a PG compound having 11 skeletal carbon atoms in &agr;-chain is named as 2-decarboxy-2-(4-carboxybutyl)-PG compound. Furthermore, a PG compound having two increased skeletal carbon atoms in &ohgr;-chain, i.e., a PG compound having 10 skeletal carbon atoms in &ohgr;-chain is named as 20-ethyl-PG compound. The naming may also be made based on IUPAC nomenclature. Examples of naming according to both the nomenclature are shown in the following Examples.
The prostanoic acid compounds used in the present invention are the ones wherein the skeletal carbon atoms in &agr;-chain may be 8 or more, preferably 8 to 13, more preferably 9 to 13, and particularly preferably 9 to 11. Accordingly, any of the following compounds may be used, and they are, for example, PG
1
compounds having double bonds at 13-14 positi
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