Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-11
2003-07-08
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S292000, C549S293000, C549S294000
Reexamination Certificate
active
06589984
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel benzofuryl-&agr;-pyrone derivatives and to medicines containing them as active ingredients. More specifically, the invention relates to novel benzofuryl-&agr;-pyrone derivatives and to lipid metabolism enhancers, arteriosclerosis prophylactic agents, arteriosclerosis treatment agents, triglyceride biosynthesis inhibitors, blood triglyceride lowering agents or blood HDL elevating agents containing them as active ingredients.
BACKGROUND ART
Blood cholesterol and triglycerides (TG) themselves are generally insoluble in blood, and they exist as lipoproteins by binding with apolipoproteins. In the body, triglycerides are biosynthesized primarily in the liver from acetyl CoA as the starting substance which is produced from sugars, etc., by 6 different enzymes and one enzyme group (acetyl CoA carboxylase, the fatty acid synthase group, fatty acyl CoA synthase, glycerophosphoric acid acyl transferase, lysophosphatidic acid acyl transferase, phosphatidic acid phosphatase and diacylglycerol acyl transferase), and are secreted from the liver into the blood as lipoproteins.
The condition of a higher-than-normal cholesterol and/or triglyceride blood level is known as hyperlipidemia. The condition termed hyperlipidemia is classified into 6 types based on the lipoproteins in the blood, according to the Fredrickson classification (WHO classification). Types I, IV and V are characterized by increased triglycerides only, type IIa by increased cholesterol, and types IIb and III by increases in both (“Sogo Rinsho”, 43, 871(1994)). This means that present hyperlipidemia drugs (that lower only cholesterol or that lower both cholesterol and triglycerides) cannot always be appropriately applied for all hyperlipidemia cases. In particular, type IV accounts for 40 to 50% of male hyperlipidemia patients (“Rinsho to Kenkyu”, 69, 318(1992)). Most secondary onset forms accompanying diabetes are also type IV (“Sogo Rinsho”, 43, 878(1994)).
Hypertriglyceridemia is a condition in which blood triglyceride levels are increased, and in the past few years it has been receiving attention among clinical physicians and pharmaceutical manufacturers as a risk factor in arteriosclerosis and ischemic diseases.
Because most attention in the field of hyperlipidemia, which includes hypertriglyceridemia, has been focused on cholesterol alone, which is directly implicated in arteriosclerosis, few drugs have been developed with the aim of lowering triglycerides, and treatment of hypertriglyceridemia has been limited to the use of clofibrate-based hypolipidemic drugs or nicotinic acid preparations as the existing hypolipidemic drugs. Because these must be used in high doses and many action sites have been reported, there are concerns about a number of related side-effects (The Lipid, 5, 65 to 72(1994)). It would therefore be highly desirable to find a new type of drug that has a triglyceride-lowering effect at low doses, exhibits few side-effects and has a clear action mechanism.
Hypertriglyceridemia occurs as a result of various causes, including genetic background and, as mentioned above, secondary onset accompanying diabetes, etc. (“Sogo Rinsho”, 43, 878(1994)); more specifically, it is attributed to:
A. accelerated triglyceride synthesis (secretion) in the liver, and
B. delayed decomposition of synthesized triglycerides (present in the blood as lipoproteins) by lipoprotein lipase (LPL) (“Rinsho to Kenkyu”, 69, 340(1992)). In particular, for hypertriglyceridemia accompanying diabetes, A. is said to be the cause of non-insulin-dependent diabetes mellitus (NIDDM), while B. is said to be the cause of insulin-dependent diabetes mellitus (IDDM) (“Rinsho to Kenkyu”, 69, 379(1992)). Consequently, the action mechanism of therapeutic agents for hypertriglyceridemia is believed to be inhibition of triglyceride synthesis (secretion) in the liver and/or accelerated decomposition of synthesized triglycerides (present in the blood as lipoproteins) by lipoprotein lipase (LPL).
In the prior art there have been known &agr;-pyrone derivatives with substitution of a heteroaromatic ring at the C-6 position, for example, in WO 9635664, WO 9514013, WO 9514014, EP 588137, U.S. Pat. No. 4,668,803, FR 2665445, Japanese Unexamined Patent Publication SHO No. 49-5976, Japanese Unexamined Patent Publication No. 8-503216, Japanese Unexamined Patent Publication No. 9-505291, Japanese Unexamined Patent Publication No. 9-505293, Japanese Unexamined Patent Publication No. 9-505294, Japanese, Unexamined Patent Publication No. 9-505295, or for example, in Tetrahedron Letters, 37, 6461 (1996), J. Chem. Research (S), 86 (1994), Chem. Pharm. Bull., 32, 1665 (1984), Chem. Ber., 100, 658 (1967) and J. Org. Chem., 54, 3985 (1989).
However, no explanation or suggestion has been published regarding a triglyceride biosynthesis inhibiting effect, blood triglyceride lowering effect or blood HDL elevating effect for any of these &agr;-pyrone derivatives of the prior art.
Of the prior art publications, WO 9635664 and EP 588137 describe compounds with a structural feature wherein phenyl is a substituent at the C-3 position of the &agr;-pyrone ring, but no description or suggestion is given regarding the use of an alkyl group instead of a phenyl group as the substituent at the C-3 position of the &agr;-pyrone ring.
Similarly, U.S. Pat. No. 4,668,803 among the prior art publications describes &agr;-pyrone derivatives wherein the substituent at the C-3 position is an acyl group of 2 to 11 carbons or a phenyl group, but no description or suggestion is given regarding the use of an alkyl group instead of an acyl group of 2 to 11 carbons or a phenyl group as the substituent at the C-3 position of the &agr;-pyrone ring.
Also, FR 2665445 among the prior art publications describes &agr;-pyrone derivatives with —S(O)
n
—R
1
as a substituent at the C-4 position, wherein n is 1 or 2 and R
1
represents an alkyl group of 1 to 6 carbons, a benzyl group or a phenyl group. However, no description or suggestion is given regarding the use of OH, OCOR or OSO
2
R instead of —S(O)
n
—R
1
as the substituent at the C-4 position of the &agr;-pyrone ring.
Likewise, Japanese Unexamined Patent Publication No. 49-5976 among the prior art publications describes &agr;-pyrone derivatives with hydrogen, a lower alkyl group or phenyl as a substituent at the C-4 position, but no description or suggestion is given regarding the use of OH, OCOR or OSO
2
R instead of hydrogen, a lower alkyl group or phenyl as the substituent at the C-4 position of the &agr;-pyrone ring.
Likewise, Chem. Ber., 100, 658 (1967) among the prior art publications describes &agr;-pyrone derivatives with hydrogen, methyl or ethyl as a substituent at the C-4 position, but no description or suggestion is given regarding the use of OH, OCOR or OSO
2
R instead of hydrogen, methyl or ethyl as the substituent at the C-4 position of the &agr;-pyrone ring.
Likewise, J. Chem. Research (S), 86(1994) among the prior art publications describes &agr;-pyrone derivatives with an SMe group as a substituent at the C-4 position, but no description or suggestion is given regarding the use of OH, OCOR or OSO
2
R instead of an SMe group as the substituent at the C-4 position of the &agr;-pyrone ring.
In addition, Tetrahedron Letters, 37, 6461 (1996), Chem. Pharm. Bull., 32, 1665 (1984) and J. Org. Chem., 54, 3985 (1989) among the prior art publications describe &agr;-pyrone derivatives with a pyridyl group substituent at the C-6 position, but no description or suggestion is given regarding the use of a benzofuryl group instead of a pyridyl group as the substituent at the C-6 position of the &agr;-pyrone ring.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide benzofuryl-&agr;-pyrone derivatives, and especially novel benzofuryl-&agr;-pyrone derivatives having a benzofuryl group as a substituent at the C-6 position of the &agr;-pyrone ring.
It is another object of the invention to provide lipid metabolism enhancers, arteriosclerosis prophylactic agents or arteriosclerosis
Hamada Masa
Ida Tomohide
Imai Hiroshi
Kitai Kazuo
Kosugi Tomomi
Solola Taofiq
Teijin Limited
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