Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-07-27
2001-03-06
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06197821
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a new use of 15-keto-prostaglandin E compounds as an endothelin antagonist.
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, Raynaud disease, 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.
Prostaglandins (Prostaglandin is referred to as PG hereinafter) are a group of organic carboxylic acids contained in a tissue or an organ of human beings or mammals and having a wide range physiological activity. The PGs existing in nature have a prostanoic acid backbone represented by formula (A) as a general structure:
On the other hand some of synthetic analogs have a modified structure.
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-ti-unsaturated-15-OH
Moreover, the PGF group is classified into &agr;- (the hydroxy group is in an alpha-configuration) and &bgr;- (the hydroxy group is in a beta-configuration) based on the configuration of the hydroxy group at the 9-position.
It has been known that PGE
1
, PGE
2
and PGE
3
have an activity of vasodilation, blood depression, reduce of gastric juice, increase of intestine movement, uterine contraction, diuresis, bronchodilation and antiulcer. It has been also known that PGF
1
&agr;, PGF
2
&agr; and PGF
3
&agr; have an activity of hypertension, vasoconstriction, increase of intestine movement, uterine contraction, involution of corpus luteum and tracheo contraction.
Further, some of 15-keto-PGs (i.e., PGs having an oxo group instead of a hydroxyl group at the 15-position) and 13,14-dihydro-15-keto-PGs are compounds naturally produced by the enzymatic action during metabolism (Acta Physiologica Scandinavica, Vol. 66, 509(1966)). It was reported that 15-keto-PGF
2
a has an activity of antipregnancy. Further, it was known that 15-keto-PGE compounds could be used for the treatment of various kinds of diseases (EP Patent Application No. 0 284 180 A).
As an action against endothelin it has been known that PGE
2
inhibits vasoconstriction of a rat which is induced by the endothelin. This inventor has reported that prostanoic acid compounds whose hydrocarbon backbone is extended in &agr;-chain have a strong endothelin antagonistic activity (WO 97/47595) and a 15-keto-prostaglandin F compound expresses endothelin antagonistic activity by an eye-administration (Japanese Patent Application KOKAI No. Hei. 10-007574). It, however, has not been known that 15-keto-prostaglandin E compounds (excepting compounds having 8 or more carbon atoms in the &agr;-chain backbone) have an endothelin antagonistic effect.
The Most Preferable Embodiment for Working the Invention
The purpose of the invention is to provide an endothelin antagonist useful for the treatment of various kinds of disease and pathology participated of endothelin. Further the present invention relates to a treatment of disease caused by the excessive production of endothelin and a use of 15-keto-prostaglandin E compounds for manufacturing the endothelin antagonist.
As the result of research of biological activity of 15-keto-PGE compounds, it has been found that 15-keto-PGE compounds exhibit an extremely strong endothelin antagonistic effect. That is, the present invention provides an endothelin antagonist which comprises 15-keto-prostaglandin E compounds as an effective compound excepting prostanoic acids having 8 or more carbon atoms in the &agr;-chain.
As the endothelin antagonist of the present invention has an extremely strong endothelin antagonistic activity, it is effective for the treatment of various kinds of disease and pathology related to by the endothelin. The term “treatment” in the present specification includes any kinds of control of disease such as prevention, cure, decrudescence, reduction of symptom, quit of progression and the like.
In the present invention, “15-keto-prostaglandin E compounds” (referred to as 15-kto-PGE compounds hereinafter) include any substituention products or derivatives having an oxo group at the 15-position of the backbone of prostanoic acid instead of a hydroxyl group, irrespective to the number of double bond, presence or absence of a substituent or modification on the &agr;-chain or &ohgr;-chain (excepting compounds having 8 or more carbon atoms on the backbone of the &agr;-chain).
Nomenclature of 15-keto-PGE compounds in the present invention herein uses the numbering system of prostanoic acid represented in 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. 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 the 21-position 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.
Therefore, 15-keto-PGE compounds having 10 carbon atoms in the &ohgr;-chain is named as 15-keto-20-ethyl-PGE compounds (excepting compounds having 8 or more backbone carbon atoms in the &agr;-chain from the present invention).
The above Formula shows a specific configuration which is the most typical one, but any compounds, otherwise specifically illustrated, have this configuration in this specification.
PGEs generally mean prostanoic acids having an oxo group at the 9-position and a hydroxyl group at the 11-position, but in the present invention 15-keto-prostaglandin E compounds include a compound having another group at the 11-position instead of the hydroxyl group. In this case these compounds are named in the form of “11-dehydorxy-11-substituents”. The compounds having a hydrogen atom instead of the hydroxyl group at the 11-position are simply called as 11-dehydroxy compounds.
15-Keto-PGE compounds of the present invention include any PGE derivatives which have an oxo group at the 15-position instead of the hydroxyl group,
R-Tech Ueno Ltd.
Spivack Phyllis G.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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