Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-06-14
2001-09-18
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C514S570000, C514S571000, C514S690000, C514S893000
Reexamination Certificate
active
06291521
ABSTRACT:
TECHNICAL FIELD
The present invention provides a novel use of 15-keto prostaglandins as an anti-portal hypertensive agent.
The agent of the present invention is useful for treatment of portal hypertension.
BACKGROUND ART
Portal hypertension is a disease state characterized by increased portal blood flow resistance and increased portal vein pressure due to occlusion or congestion of portal or hepatic venous system. Factors, which may contribute to the etiology of this state may be classified into pre sinusoidal and post sinusoidal conditions. The pre sinusoidal conditions include portal vein thrombosis, oriental schistosomiasis and Hodgkin's disease; and the post sinusoidal conditions include hepatocirrhosis, wedged hepatic venous occlusive disease and congestive heart disease.
The term “portal vein system” is a part of blood system wherein a vein or group of veins are branched to form a network of capillaries, and the capillaries then merge to form a vein or group of veins. In human beings, there are hepatic portal vein system and hypophyseal portal vein system, and in the hepatic portal vein system, splenic vein and superior and inferior mesenteric veins merge to form said system.
Prostaglandins (hereinafter, referred to as PG(s)) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or most other mammalian, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A):
On the other hand, some of synthetic analogues have a modified skeleton. The primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and named hereafter the existence or non-existence of an unsaturated bond or an oxidized group at the carbon chain moiety:
subscript 1: 13,14-unsaturated-15-OH
subscript 2: 5,6- and 13,14-diunsaturated-15-OH
subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position) into &agr; type (the hydroxyl group is of an &agr;-configuration) and &agr; type (the hydroxyl group is of a &bgr;-configuration).
In addition, some 15-keto (i.e. having an oxo group at position 15 in place of the hydroxy group) prostaglandins and 13,14-dihydro-15-keto-prostaglandins are known as substances naturally produced by enzymatic actions during metabolism of primary PGs. 15-keto PGs have been disclosed in, for example, EP-A-0281239 (corresponds to JP-A-104040/89), EP-A-0281480 (corresponds to JP-A-52753/89), EP-A0289349 (corresponds to JP-A-151552/89), and EP-A-0690049 (corresponds to JP-A-48665/96).
It is well known in the art that PG derivatives affect blood pressure. For example, PGE1, one of the primary PGs, has been known to have blood pressure decreasing activity, whereas 15-keto PGs have blood pressure increasing activity. However, the term “blood pressure” is generally used for “arterial blood pressure”, and therefore, the effect of PGs, which have some activity in “arterial blood pressure”, on pressure of portal vein system which consisting of venous vascular system is quite unpredictable.
As to the effects of PGs on portal vein pressure, PGE1 and PGE2, primary PGs, have been reported to have some effect. However, there are inconsistent evaluation among the reports such that increased, decreased and unchanged of the pressure due to the PGs were disclosed in the different reports. It has not been reported that how 15-keto-prostaglandin compounds affect portal vein pressure.
SUMMARY OF THE INVENTION
An object of the invention is to provide an anti-portal hypertensive agent useful for treatment to suppress increased portal vein pressure that occurs due to various factors and accomplished the present invention.
As a result of extensive studies about the biological properties of 15-keto-PG compounds, the present inventor has discovered that these compounds have anti-portal hypertensive activity.
That is, the present invention provides an anti-portal hypertensive agent comprising a PG compound as an active ingredient.
In the present invention, “15-keto-Prostagrandin compounds (hereinafter, referred as 15-keto-PG compounds)” include any of derivatives or substituted derivatives of a compound having an oxo group at 15-position of the prostanoic acid skeleton instead of the hydroxy group, irrespective to the configuration of the 5-memberd ring, or number of double bonds, presence or absence of a substituent or any other modification in the &agr; or &ohgr; chain.
Nomenclature of 15-keto-PG compounds 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 15-keto-PG compounds used in the present invention are not limited to those having the same number of carbon atoms. Carbon atoms in Formula (A) are numbered 2 to 7 on the &agr;-chain starting from the &agr;-carbon atom adjacent to the carboxylic carbon atom which is numbered 1 and towards the five-membered ring, 8 to 12 on the said ring starting from the carbon atom on which the &agr;-chain is attached, and 13 to 20 on the &ohgr;-chain starting from the carbon atom adjacent to the ring. When the number of carbon atoms is decreased in the &agr;-chain, the number is deleted in the order starting from position 2; and when the number of carbon atoms is increased in the &agr;-chain, compounds are named as substituted derivatives having respective substituents at position 1 in place of carboxy group (C-1). Similarly, when the number of carbon atoms is decreased in the &ohgr;-chain, the number is deleted in order starting from position 20; and when the number of carbon atoms is increased in the &ohgr;-chain, compounds are named as substituted derivatives having respective substituents at position 20. Stereochemistry of the compounds is the same as that of above formula (A) unless otherwise specified.
In general, PGDs, PGEs and PGFs represent a compound having hydroxy groups at positions 9 and/or 11, and in the present specification they also include PGs having substituents other than hydroxyl group at positions 9 and/or 11. Such compounds are referred to as 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PG compounds. In case of having hydrogen in place of hydroxy group, it is simply named as 9 or 11-dehydroxy compound.
As stated above, nomenclature of 15-keto-PG compounds is based upon the prostanoic acid skeleton. However, in case the compound has a similar partial construction as a prostaglandin, the abbreviation of “PG” may be used. Thus, a 15-keto-PG compound of which &ohgr;-chain is extended by two carbon atoms, that is, having 10 carbon atoms in the &ohgr;-chain is nominated as 15-keto-20-ethyl-PG. These compounds, however, can also be named according to the IUPAC naming system.
According to the IUPAC naming system, for example, 13,14-dihydro-15-keto-16R,S-fluoro-PGE
2
is (Z)-7-{(1R,2R,3R)-3-hydroxy-2-[(4R,S)-fluoro-3-oxo-1-octyl]-5-oxocyclopentyl}-hept-5-enoic acid; 13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE
2
methyl ester is methyl 7-{(1R,2S,3S)-3-methyl-2-[3-oxo-1-decyl]-5-oxocyclopentyl}-hept-5-enoate; and 13,14-dihydro-6,15-diketo-19-methyl-PGE
2
ethyl ester is ethyl 7-{(1R,2S,3S)-3-hydroxy-2-(7-methyl-3-oxo-1-octyl)-5-oxocyclopentyl}-6-oxo-heptanoate. 13,14-dihydro-15-keto-20-ethyl-PGF
2
&agr; isopropyl ester is isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydro-2-{3-oxo-1-decyl)-cyclopentyl]-hept-5-enoate; and 13,14-dihydro-15-keto-20-methyl-PGF
2
&agr; methyl ester is methyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{3-oxo-1-nonyl}-cyclopentyl]-hept-5-enonate.
The 15-keto-PG compounds used in the present invention may be any derivatives of PG insofar as they have an oxo group at position 15 in place of the hydroxy group, and may have a double bond between positions 13 and 14 (15-keto-PG type
Krass Frederick
R-Tech Ueno Ltd.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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