Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-28
2003-04-08
Tsang, Cecilia (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S365000, C514S374000, C514S396000, C546S256000, C548S204000, C548S236000, C548S341500
Reexamination Certificate
active
06545009
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a retinoid-related receptor function regulating agent comprising a 1,3-azole derivative or its salt, which is useful for treating or preventing diabetes, hyperlipidemia, impaired glucose tolerance, etc.
BACKGROUND ART
So far, 1,3-azole derivatives have been report in various references. For example, a compound having an anti-inflammatory effect (e.g., JP-A-4-154773, U.S. Pat. No. 5,342,851), a compound having a platelet aggregation-inhibiting effect (e.g., U.S. Pat. No. 5,342,851), a compound having an active oxygen-inhibiting effect (e.g., WO 9209586, Journal of Medicinal Chemistry, Vol.38, p. 353 1(1995), a compound having a thrombolytic effect (e.g., JP-B-49-32853) and a compound having a phospholipase IV-inhibiting effect (e.g., WO9808830) have been reported. Also, they have been reported as a liquid crystal composition (EP-A 439170) and a raw material compound for producing a vasopressin receptor ligand (WO9534540). Further, 1,3-azole carboxylic acid derivatives are described in Chemical Abstracts, vol.107, 23273h (1987), Chemical Abstracts, vol.113, 6239h (1990) and Chemical Abstracts, vol.120, 190974n (1994).
Some 1,3-azole derivatives are marketed as reagents by BIONET (Cornwall, England).
However, there has been no report that these compounds have a retinoid-related receptor function regulating effect, and exhibit excellent effects in treating or preventing diabetes, hyperlipidemia, impaired glucose tolerance, etc.
On the other hand, retinoid-related receptor function regulating agents are reported in JP-A-9-71566 (WO 9702244, EP838453), etc. However, there has been no report that these compounds exhibit excellent effects in treating or preventing hyperlipidemia, impaired glucose tolerance, etc.
Peroxisome proliferator-activated receptor gamma (PPAR&ggr;), a member of the intranuclear hormone receptor superfamily, which is typically exemplified by steroid hormone receptors and thyroid hormone receptors, plays an important role as a master regulator in the differentiation of adipose cells with its expression induced in the very early stage of adipose cell differentiation. PPAR&ggr; forms a dimer with the retinoid X receptor (RXR) by binding to a ligand, and binds to a responsive site of the target gene in the nucleus to directly control (activate) transcription efficiency. In recent years, it has been revealed that 15-deoxy-&Dgr;
12.14
prostaglandin J
2
, a metabolite of prostaglandin D
2
, serves as an endogenous ligand for PPAR&ggr;. Further it has been revealed that a class of insulin sensitivity enhancers, typically exemplified by thiazolidinedione derivatives, possess ligand activity for PPAR&ggr;, and that its potency is proportional to its hypoglycemic action or adipose cell differentiation-promoting action [Cell, vol. 83, p. 803 (1995): the Journal of Biological Chemistry, vol. 270, p. 12953 (1995); Journal of Medicinal Chemistry, vol. 39, p. 655 (1996)].
Many agents have been employed as agents for treating diabetes, hyperlipidemia, arteriosclerosis, etc. However, they are not satisfactory in terms of their therapeutic effects or reduced side effects, and the development of agents improved in these terms is strongly desired.
DISCLOSURE OF INVENTION
The inventors have discovered that a certain 1,3-azole derivative or its salt has an unexpectedly excellent PPAR ligand activity, and that it is useful as an agent for preventing or treating diabetes, hyperlipidemia, arteriosclerosis, etc. Based on these findings, the inventors made further investigations to complete the present invention.
Thus, the present invention relates to:
(1) a retinoid-related receptor function regulating agent comprising a 1,3-azole derivative represented by formula (I):
wherein R
1
is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R
2
is hydrogen or an optionally substituted hydrocarbon group; X is O, S or a group represented by the formula: —NR
4
— wherein R
4
is hydrogen or an optionally substituted alkyl group; A is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R
3
is a group represented by the formula: —OR
5
wherein R
5
is hydrogen or an optionally substituted hydrocarbon group, or —NR
6
R
7
wherein R
6
and R
7
are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R
6
and R
7
may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae:
are excluded, or its salt.
(2) a function regulating agent according to the above (1) wherein R
1
is an aromatic hydrocarbon group or an aromatic heterocyclic group which does not contain a nitrogen atom, each of which may be substituted.
(3) a function regulating agent according to the above (1) which is an agent for preventing or treating diabetes.
(4) a function regulating agent according to the above (1) which is a lipid metabolism-improving agent.
(5) a function regulating agent according to the above (1) which is an agent for preventing or treating hyperlipidemia.
(6) a function regulating agent according to the above (1) which is an agent for preventing or treating obesity.
(7) a function regulating agent according to the above. (1) which is an anti-obesity agent.
(8) a function regulating agent according to the above (1) which is an insulin sensitivity enhancer.
(9) a function regulating agent according to the above (1) which is an insulin resistance improving agent.
(10) a function regulating agent according to the above (1) which is an agent for preventing or treating impaired glucose tolerance.
(11) an oxazole derivative represented by formula (I-1):
wherein R
1
is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R
2
is hydrogen or an optionally substituted hydrocarbon group; A
1
is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R
3
is a group represented by the formula: —OR
5
wherein R
5
is hydrogen or an optionally substituted hydrocarbon group, or —NR
6
R
7
wherein R
6
and R
7
are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R
6
and R
7
may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formula:
wherein both R
8
s are NH
2
, OH, phenoxy, OCH
3
,
are excluded, or its salt.
(12) an oxazole derivative or its salt according to the above (11) wherein the formula is
(13) an oxazole derivative represented by formula (I-2):
wherein R
1
is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R
2
is hydrogen or an optionally substituted hydrocarbon group; A
1
is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R
3
is a group represented by the formula: —OR
5
wherein R
5
is hydrogen or an optionally substituted hydrocarbon group, or —NR
6
R
7
wherein R
6
and R
7
are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R
6
and R
7
may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae:
are excluded, or its salt.
(14) an oxazole derivative or its salt according to the above (13) wherein R
2
is hydrogen or an optionally substituted non-aromatic hydrocarbon group except for a non-aromatic hydrocarbon group which is substituted by an optionally esterified carboxyl group, and R
3
is a group represented by the formula: —OR
5
.
(15) an oxazole derivative represented by formula (I-3):
wherein R
1
is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R
2
is hydrogen or an optionally substituted hydrocarbon group; A
1
is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R
3
is a group represented by the formula: —OR
5
wherein R
5
is hydrogen or an optionally substituted hydrocarbon group, or —NR
6
R
7
whe
Kimura Hiroyuki
Momose Yu
Odaka Hiroyuki
Sakamoto Jun-ichi
Sugiyama Yasuo
Cha Mark
Ramesh Elaine
Sackey Ebenezer
Takeda Chemical Industries Ltd.
Tsang Cecilia
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