Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-31
2002-08-13
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S155000
Reexamination Certificate
active
06432978
ABSTRACT:
This application is a 371 application of PCT/JP99/06738 filed Dec. 1, 1999.
TECHNICAL FIELD
This invention relates to SF2809-I substance, SF2809-II substance, SF2809-III substance, SF2809-IV substance, SF2809-V substance and SF2809-VI substance or salts thereof, which are novel compounds having a chymase-inhibiting activity. This invention also relates to a process for the preparation of the SF2809-I substance to the SF2809-VI substance. Further, this invention relates to a pharmaceutical composition which contains as an active ingredient SF2809-I, -II, -III, -IV, -V or -VI substance or a pharmaceutically acceptable salt thereof, as well as to a chymase-inhibitor. Furthermore, this invention includes strain SF2809 as a novel microorganism having a characteristic that it is capable of producing the SF2809-I substance to the SF2809-VI substance as above-mentioned.
BACKGROUND ART
An enzyme, chymase, is a chymotripsin-like serine proteinase which is mainly stored in the secretory granules of mast cell and is secreted in tissues of heart, blood vessel, skin and others. As one of the main actions of chymase, there is an action that chymase produces angiotensin II from angiotensin I as substrate.
It has hitherto been thought that the production of angiotensin II is affected basically by the action of angiotensin-converting enzyme (ACE). Recently, however, in the course of study for the elucidation of the production system of angiotensin II in local tissues, it has newly been suggested that there exists a system of production of angiotensin II by a serine proteinase which is different from the angiotensin-converting enzyme. Specifically, it has been clarified that in the left ventricle of human heart, more than 80% of the production of angiotensin II are brought about by serine proteinase [Urata et al., Circ. Res., Vol. 66, pp.883-890 (1990)]. The serine proteinase present in the left ventricle of human heart has been determined for the nucleotide sequence of its encoding gene and thus is identified as a chymase with a molecular weight of about 30,000 [Urata et al, J. Biol. Chem., Vol. 266, pp.17173-17179 (1991)].
It is known in the art that, in the progress of restenosis induced after angiopathy or in cardiomyopathy, there occurs an increase in the chymase activity in the heart. Therefore, a chymase-inhibitor is expected to be useful as a therapeutic agent or a prophylactic agent for hypercardia, cardiac incompetence or arteriosclerosis. It is also known that chymase can promote the degranulation of mast cell, and thus a chymase-inhibitor is also expected to be useful as an anti-inflammatory agent and an antiallergic agent, too.
In addition to the above-mentioned facts, it is also known that chymase has further actions on the production of endothelin and collagenase, and the metabolisms of various physiologically active peptides such as bradykinin, Substance P, neurotensin, somatostatin, VIP, LH-RH, &agr;-MSH and the like, as well as restrictive decomposition of extracellular matrixes such as collagen, fibronectin, vitronectin and the like; decomposition of blood coagulation factors such as thrombin and the like; rise in the secretion reactions of airway mucosa secreting glands; and acceleration in the foam cell-formation of macrophage, and others. Therefore, chymase-inhibitors are also expected to be useful in therapy of asthma, rheumatism, thrombosis or bronchitis, and so on.
PCT Application Publications WO93/25574, WO95/27053 and WO95/27055 disclose some chymase-inhibitors of peptide type among the compounds having the chymase-inhibiting activities. While, chymase-inhibitors of the non-peptide type are disclosed in PCT Application Publication WO96/04248 and European Patent Application First Publication No. 713876. Further, a chymase-inhibitor made of a microbial product is disclosed in Japanese Patent Application Kokai Hei-10-101666.
Hitherto, some compounds having the chymase-inhibiting activity were found. Among of them, however, there was presented no such substance having the chymase-inhibiting activity which has actually been utilized in clinics as a therapeutic drug for treating the above-mentioned diseases. Thus, there is a keen demand to find out such a novel substance which has the chymase-inhibiting activity and which may be useful in clinics.
An object of this invention is to provide a novel compound having an excellent enzyme-inhibiting activity against chymase.
Another object of this invention is to provide a process for the preparation of such a novel compound having a chymase-inhibiting activity. Further objects of this invention are to provide a novel pharmaceutical composition having a chymase-inhibiting activity which is useful as medicine, and also to provide a chymase-inhibitor.
DISCLOSURE OF THE INVENTION
We, the inventors of this invention, have carried out extensive investigations in order to achieve the above-mentioned objects of this invention. As a part of our investigations, we have conducted the screening of microbial metabolites which have a chymase-inhibiting activity. In the course of our research, we cultivated a strain of a family Micromonosporaceae, which is a new microorganism as isolated from a soil sample collected at Hachijo Island, Tokyo, and which is designated as strain SF2809 by us. As a result, we have now found that the resulting culture of strain SF2809 inhibits a human chymase. As a result of further investigations, we have succeeded in isolating and purifying six active compounds having the human chymase-inhibiting activity, from the culture of strain SF2809. We have further found that these six active compounds have such chemical structures as represented by the under-mentioned formulae (I) to (IV), respectively. And, we have confirmed that each of these six active compounds as obtained is a novel compound. Then, we designated these substances as SF2809-I substance, SF2809-II substance, SF2809-III substance, SF2809-IV substance, SF2809-V substance and SF2809-VI substance, respectively. Furthermore, we have confirmed that all and each of the SF2809-I substance of formula (I), SF2809-II substance of formula (II), SF2809-III substance of formula (III), SF2809-IV substance of formula (IV), SF2809-V substance of formula (V) and SF2809-VI substance of formula (VI) as given hereinunder, exhibits an activity inhibitory to a human chymase. Further, these SF2809-I substance to SF2809-VI substance are recognized as a class of compounds which can collectively be represented by the under-mentioned general formula (VII). This invention has been completed on the basis of these findings.
According to a first aspect of this invention, therefore, there is provided a compound which is SF2809-I substance, SF2809-II substance, SF2809-III substance, SF2809-IV substance, SF2809-V substance or SF2809-VI substance each represented by the following general formula (VII)
wherein R
1
is a hydrogen atom, phenyl group or p-hydroxy-phenyl group, and R
2
is acetylamino group —NHCOCH
3
or hydroxyl group; and wherein R
1
is hydrogen atom and R
2
is acetylamino group for SF2809-I substance; R
1
is p-hydroxyphenyl group and R
2
is acetylamino group for SF2809-II substance; R
1
is hydrogen atom and R
2
is hydroxyl group for SF2809-III substance; R
1
is p-hydroxyphenyl group and R
2
is hydroxyl group for SF2809-IV substance; R
1
is phenyl group and R
2
is acetylamino group for SF2809-V substance; R
1
is phenyl group and R
2
is hydroxyl group for SF2809-VI substance, or a pharmaceutically acceptable salt thereof.
As a first example of the compound according to the first aspect of this invention, there is provided SF2809-I substance represented by the following formula (I)
or a pharmaceutically acceptable salt thereof.
As a second example of the compound according to the first aspect of this invention, there is provided SF2809-II substance represented by the following formula (II)
or a pharmaceutically acceptable salt thereof.
As a third example of the compound according to the first aspect of this invention, there is provided SF2809-
Gyobu Yasuhiro
Harada Toshiaki
Kamimura Takashi
Kawamura Takashi
Moriyama Chieko
Davis Zinna Northington
Larson & Taylor PLC
Meiji Seika Kaisha Ltd.
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