Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-31
2003-07-08
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...
C546S147000
Reexamination Certificate
active
06589963
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel heterocyclic compound and a pharmaceutically acceptable salt thereof, which have a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action or a PPAR (peroxisome proliferator-activated receptor)-activating action. The present invention also relates to a pharmaceutical composition comprising the above-mentioned novel heterocyclic compound or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a hypoglycemic agent, a hypolipidemic agent, an insulin resistance improver, a therapeutic agent of diabetes, an anti-diabetic complication agent (i.e., a therapeutic agent of diabetic complication), a glucose tolerance improver, an anti-atherosclerosis agent, an anti-obesity agent, an antiinflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated disease and an agent for the prophylaxis or treatment of syndrome X, all of which comprising the above-mentioned novel heterocyclic compound or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
As a therapeutic agent of diabetes, biguanide compounds having, as a main action, an inhibitory action on glucose absorption via the intestinal tract and on glucose release from the liver, sulfonylurea compounds having an accelerating action on insulin secretion as a main action, insulin and the like have been employed. However, biguanide compounds cause lactic acidosis, and sulfonylurea compounds sometimes cause serious hypoglycemia due to their strong hypoglycemic action. Therefore, a due care should be given when in use of these compounds. In recent years, there have been active researches and developments of a therapeutic agent of diabetes, which is free of these defects, with the consequence that various compounds having an insulin resistance-improving action have been found.
The insulin resistance is important as a cause of non-insulin dependent diabetes mellitus (NIDDM), along with decrease in the insulin secretion. Therefore, the development of a pharmaceutical agent that improves insulin resistance has been desired. Various thiazolidine compounds are known as the agent capable of improving the insulin resistance. As these compounds, for example, 5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]-2,4-thiazolidinedione (general name: troglitazone) is described in JP-B-2-31079, 5-[[4-[2-(5-ethyl-pyridin-2-yl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (general name: pioglitazone) is described in JP-B-5-66956, and 5-[[4-[2-[N-methyl-N-(pyridin-2-yl)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (general name: rosiglitazone) is described in JP-A-1-131169.
It is therefore an object of the present invention to provide a compound having a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action and a PPAR activating action, which has a structure completely different from that of conventional compounds, thereby to increase the diversity in and to broaden the range of selection from hypoglycemic agents, hypolipidemic agents, insulin resistance improvers, therapeutic agents of diabetes, therapeutic agents of diabetic complications, glucose tolerance improvers, anti-atherosclerosis agents, anti-obesity agents, antiinflammatory agents, agents for the prophylaxis or treatment of PPAR-mediated disease and agents for the prophylaxis or treatment of syndrome X.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies in an attempt to solve the above-mentione problems and found that a heterocyclic compound having a novel structure of the formula [I]
wherein
R
1
is hydrogen atom or lower alkyl,
R
2
is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent, heterocyclic alkyl optionally having a substituent or —COR
4
wherein R
4
is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent, alkenyl optionally having a substituent, arylalkyl optionally having a substituent or heterocyclic residue optionally having a substituent,
R
3
is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or >N—R
5
wherein R
5
is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent
and a pharmaceutically acceptable salt thereof have a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action and a PPAR activating action, which resulted in the completion of the invention.
Accordingly, the present invention relates to the following.
[1] A heterocyclic compound of the formula [I]
wherein
R
1
is hydrogen atom or lower alkyl,
R
2
is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent, heterocyclic alkyl optionally having a substituent or —COR
4
wherein R
4
is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent, alkenyl optionally having a substituent, arylalkyl optionally having a substituent or heterocyclic residue optionally having a substituent
R
3
is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or >N—R
5
wherein R
5
is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent (hereinafter to be referred to as
heterocyclic compound [I]), and a pharmaceutically acceptable salt thereof;
[2] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
R
1
is hydrogen atom or lower alkyl,
R
2
is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent or —COR
4
wherein R
4
is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent or arylalkyl optionally having a substituent,
R
3
is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or >N—R
5
wherein R
5
is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent, and a pharmaceutically acceptable salt thereof;
[3] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
R
1
is hydrogen atom or lower alkyl,
R
2
is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionally having a substituent, alkenyl, alkynyl, heterocyclic alkyl or —COR
4
wherein R
4
is alkyl, alkenyl or aryl,
R
3
is hydrogen atom or lower alkoxy,
A is a single bond or >N—R
5
wherein R
5
is lower alkyl,
B is lower alkylene, and
Y is aryl or an aromatic heterocyclic residue optionally having a substituent,
and a pharmaceutically acceptable salt thereof;
[4] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
R
1
is hydrogen atom or lower alkyl,
R
2
is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionally having a substituent or —COR
4
wherein R
4
is alkyl or aryl,
R
3
is hydrogen atom,
A is a single bond or >N—R
5
wherein R
5
is lower alkyl,
B is lower alkylene, and
Y is an aromatic heterocyclic residue optionally having a substituent,
and a pharmaceutically acceptable salt thereof;
[5] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
Y—A— is
wherein
R
A
is isopropyl or tert-butyl,
R
B
is isopropyl or tert-butyl,
R
C
is isoprop
Azukizawa Satoru
Kasai Masayasu
Kobayashi Hideo
Matsui Hiroshi
Shirahase Hiroaki
Davis Zinna Northington
Kyoto Pharmaceutical Industries, Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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