Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-11
2002-04-30
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S181000, C548S184000
Reexamination Certificate
active
06380229
ABSTRACT:
TECHINICAL FIELD
The invention relates to novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or pharmaceutically acceptable salts or solvates thereof, which have excellent activities in a lowering blood triglyceride level and a cholesterol level, and are useful for prevention from and/or treatment of hyperlipidemia and related complications.
BACKGROUND ART
Many epidemiological studies have shown that hypercholesterolemia is a risk factor for coronary heart disease (CHD). Recently, hypertriglycemia is confirmed to be an independent risk factor for CHD. (J Jpn Atheroscler Soc, 25 (1-2), 1-34 (1997)—Guideline for Diagnosis and Treatment of Hyperlipidernias in Adults).
For the therapy of hypertriglycemia, dextran sulfate sodium, nicotinic acid derivatives, fibric acid derivatives (fibrates) have been used as the first choice. In particular bezafibrate is known to have more potent cholesterol lowering property as well as triglyceride lowering property than the earlier fibrates. And for hypercholesterolemia, HMG-CoA reductase inhibitors (e.g. pravastatin, simvastatin, etc., known as statins) are generally provided for clinical use.
When blood cholesterol level alone is elevated, HMG-CoA reductase inhibitors are employed. However, when both levels of blood cholesterol and triglyceride are elevated or the effect of hypolipidemic agent is not sufficient, some lipid lowering drugs are combined.
Thus, an aim of the present invention is to provide a novel class of potent hypolipidemic agents, which reduce more effectively a blood triglyceride level or both levels of blood triglycerides and cholesterol.
Some antidiabetic agents that are partially analogous to the compounds of the present invention have been found and developed, for example, troglitazone and pioglitazone. However, they are thiazolidin-2,4-dione derivatives, and according to the conference abstract of the 28th Meeting of the Japan Atherosclerosis Society, Osaka,. June, 1996, No.024, pioglitazone did not change total cholesterol and triglyceride levels in hyperlipidemic rabbits. Therefore, from a view of chemical and biological properties, the compounds of the present invention are considered to be different from those antidiabetic compounds.
DISCLOSURE OF INVENTION
This invention provides prophylactic or therapeutic agents for hyperlipidemia and related complications comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I or a pharmaceutically acceptable salt or solvate thereof as active ingredients:
wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C
1
-C
4
alkyl group, a haloalkyl group, a halogen atom or —OR
5
;
R
1
represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C
1
-C
4
alkylene or alkenylene group optionally substituted by a phenyl group, R
6
—X, X—R
6
, X—R
6
—X, R
6
—X—R
6
, —C(═O)—NR
7
— or —NR
7
—C(═O)—;
R
2
and R
3
are the same or different and each represents a hydrogen atom, a C
1
-C
4
alkyl group, —OR
8
or a halogen atom,
R
4
represents a hydrogen atom or a C
1
-C
4
alkyl group;
R
5
represents a hydrogen atom or a C
1
-C
4
alkyl group;
R
6
represents a straight or branched C
1
-C
4
alkylene or alkenylene group;
R
7
represents a hydrogen atom or a C
1
-C
4
alkyl group;
R
8
represents a hydrogen atom, a C
1
-C
4
alkyl group or an aralkyl group;
X represents an oxygen atom or a sulfur atom.
The present inventors have carried out various investigations to solve the above problem and found that the novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I have excellent blood triglyceride lowering and cholesterol lowering activities. Thus the present invention was successfully established.
BEST MODE FOR CARRYING OUT THE INVENTION
“Salts” refers to low toxic salts derived from sodium, potassium, ammonia or organic amines, for instance.
“C
1
-C
4
alkyl group” refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl, for instance.
“C
1
-C
4
alkoxy group” refers to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or tert-butoxy, for instance.
“halogen atom” refers to generally fluorine atom, chlorine atom, bromine atom or iodine atom. More preferably it is fluorine atom or chlorine atom.
“ring A” refers to a benzene ring, a benzodioxole ring, a benzofuran ring, a benzothiazole, a fluorene ring, an indan ring, an indoline ring or a pyridine ring, connecting with R
1
at any position, for instance.
Particularly preferred compounds represented by formula I are as follows:
2-(N-Cyanoimino)-5-[(E)-4-stylylbenzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(a-methylstylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(benzyloxymethyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(b-methylstylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(3-phenylpropoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-chlorophenoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenylthiobenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(2-fluorostylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(2,5-dimethylphenoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(2-phenylpropoxy)benzylidene]thiazolidin-4-one
2-(N-Cyanoimino)-5-(3-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-benzyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(5-chlorobenzofuran-2-yl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(4-methoxystylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(3-phenoxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(1,3-benzodioxol-5-ylmethoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-methylbenzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-chlorobenzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[3-methoxy-(E)-4-stylylbenzylidene]thiazolidin-4-one;,
2-(N-Cyanoimino)-5-(2-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenoxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[3-(benzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(benzylthio)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenethylbenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-[2-(4-chlorophenyl)ethoxy]benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[1-[(E)-4-(4-methoxystylyl)phenyl]ethylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-benzyloxy-2,5-dimethylbenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-3-stylylbenzylidene]thiazolidin-4-one;
The compounds of the present invention are novel compounds not described in any literature and can be prepared by the following methods as the example.
A 2-(N-cyanoimino)thiazolidin-4-one represented by formula II or the salts thereof are reacted with an aldehyde or ketone represented by formula III
wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C
1
-C
4
alkyl group, a haloalkyl group, a halogen atom or —OR
5
;
R
1
represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C
1
-C
4
alkylene or alkenylene group optionally substituted by a phenyl group, R
6
—X, X—R
6
, X—R
6
—X, R
6
—X—R
6
, —C(═O)—NR
7
— or —NR
7
—C(═O)—;
R
2
and R
3
are the same or different and each represents a hydrogen atom, a C
1
-C
4
alkyl group, —OR
8
or a halogen atom;
R
4
represents a hydrogen atom or a C
1
-C
4
alkyl group;
R
5
represents a hydrogen atom or a C
1
-C
4
alkyl group;
R
6
represents a straight or branched C
1
-C
4
alkylene or alkenylene group;
R
7
represents a hydrogen atom or a C
1
-C
4
alkyl group;
R
8
re
Ando Takashi
Ohde Hironori
Uegaki Yuko
Watanabe Mayumi
Yasusa Takuya
Fujimoto Co., Ltd.
Stockton Laura L.
Wenderoth , Lind & Ponack, L.L.P.
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