Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-11
2004-09-07
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S311000, C514S340000, C514S342000, C514S365000, C514S374000, C514S376000, C514S398000, C514S400000, C544S333000, C546S167000, C546S270400, C546S271400, C548S187000, C548S204000, C548S225000, C548S236000, C548S323500, C548S333500, C548S338100, C548S341500, C548S343500
Reexamination Certificate
active
06787552
ABSTRACT:
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority of Japanese International Application No. PCT/JP01/06836 filed Aug. 9, 2001 which claims the priority of Japanese International Application Nos. 2000-243596 filed Aug. 11, 2000 and 2000-402893 filed Dec. 28, 2000, the complete disclosures of which are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to an activator of peroxisome proliferator activated receptor &dgr;.
BACKGROUND OF THE INVENTION
The peroxisome is a small organ present in cells of animals and plants, and its matrix contains various enzymes such as catalase. The peroxisome proliferator is a substance inducing proliferation of the peroxisome. Various compounds such as fibrates, herbicides, and phthalic acid plasticizers are known to be able to induce proliferation of peroxisome.
Isseman, et al. have identified a nuclear receptor which is activated by the peroxisome proliferator and given a name of peroxisome proliferator activated receptor (PPAR).—Nature, 347, p645-650, 1990.
As PPAR, three subtypes such as PPAR&agr;, PPAR&ggr; and PPAR&dgr; have been identified until now.—Proc. Natl. Acad. Sci. USA, 91, p7335-7359, 1994.
The above-mentioned fibrates are a class of TG (triglyceride) lowering drugs that mediate their clinical effects through activation. Further, thiazolidine compounds (Troglitazone, Rosiglitazone, Pioglitazone) useful in the treatment of diabetes are also known as ligands of PPAR&ggr;.
As a pharmaceutical having PPAR&dgr; activating effect, there are known GW-2433 (Glaxo Wellcome), L-165041 (Merck), and YM-16638 (Yamanouchi Pharmaceutical each having the following formula:
WO 92/10468 describes that GW-2433 can be employable for prevention and treatment of atherosclerosis.
WO 97/28115 describes that L-165041 can be employable for treatment of diabetes and suppression of obesity.
WO 99/04815 describes that YM-1663B shows effects for reducing serum cholesterol and reducing LDL cholesterol.
Recently, JBC, 272(6), p3406-3410, 1997 and Cell, 99, p335-345, 1999 describe proposal for application of PPAR &dgr; ligand as an anti-cancer agent and an anti-inflammatory agent.
European Patent 558 062 describes the following compound A which has a structure similar to that of the general formula (II) [mentioned below] representing an oxazole derivative of the invention:
J. Immunol. Methods, 207(1), 23-31, 1997 describes a compound B having the following formula:
All of the oxazole derivatives identified by the compound A, compound B and the general formula (II) of the invention may be described as compounds of phenoxyacetic acid type. However, there are clear structural difference between the compounds A, B and the compound of the invention, that is, the compounds A, B have no substituents at the &agr;-site, while the compound of the invention is a compound of &agr;,&agr;-dialkylphenoxy type.
In addition, while the above-mentioned EP 558 062 teaches that the compound A is of value for treatment of hyperthrombinemia and as blood pressure depressant, no mention is given with respect to an effect as PPAR&dgr; ligand. Further, while the J. Immunol. Methods teaches the use of the compound B as blood pressure depressant, there is no concrete description to teach that the compound is effective as PPAR&dgr; ligand.
Recently, WO 01/40207 describes a substituted oxa(thia)zole derivative showing an agonist action for PPAR &agr;, and WO 01/16120 describes an oxa(thia)zole derivative substituted with a biaryl group which is employable as a PPAR controlling agent.
In comparison with the compounds of the invention, the compound of WO 01/40207 has C(═O)NH as X
1
and a bond as X
2
, and the compound of WO 01/16120 has a bond as X
1
and O, X or the like as X
2
. Accordingly, the structural difference is clear.
The present invention provides a compound having the below-mentioned general formula (I), an oxazole derivative having the below-mentioned general formula (II), and a thiazole derivative having the below-mentioned general formula (III), all of which has an action as activator of peroxisome proliferator activated receptor &dgr;.
DISCLOSURE OF THE INVENTION
The invention resides in a compound having the following general formula (I) or a salt thereof:
[wherein each of R
1
and R
2
independently is a hydrogen atom, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and a halogen atom substituent, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom and a 3-7 membered substituent, an arylalkyl group that has a C
6-10
aryl portion and C
1-4
alkyl portion and optionally has a substituent, or an aryl or heterocyclic group which optionally has a substituent; A is O, S, or NR
5
in which R
5
is H or C
1-8
alkyl; each of X
1
and X
2
independently is a bond (free valency), O, S (O)
p
in which p is an integer of 0 to 2, C(═O), C(═N—OR
6
) in which R
6
is H or C
1-8
alkyl; C(═O)NH, NHC(═O), SO
2
NH, NHSO
2
, CH(OR
7
) in which R
7
is H or C
1-8
alkyl, CH═CH, or C≡C; Y is an alkylene chain having 1-8 carbon atoms and optionally a substituent; Z is O or S; each of R
3
and R
4
independently is an alkyl group having 1-8 carbon atoms and optionally a substituent; and R
8
is a hydrogen atom or an alkyl group having 1-8 carbon atoms; provided that X
2
is neither O nor S(O)
p
when X
1
is a bond, while X
2
is not a bond when X
1
is C(═O)NH].
Further, the invention provides an oxazole derivative having the following formula (II) or a salt thereof:
[wherein each of R
11
and R
12
independently is an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and 1-3 halogen atom substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom and a 3-7 membered substituent, or a phenylalkyl group having C
1-4
alkyl portion, phenyl group, naphthyl group, pyridyl group, thienyl group, furyl group, quinolyl group, benzofuranyl group or benzothienyl group which optionally contains a substituent of halogen, hydroxyl, nitro, amino, C
1-8
alkyl, C
1-8
alkyl having 1-3 halogen substituents, C
1-8
alkoxy, C
1-8
alkoxy having 1-3 halogen substituents, phenyl, benzyl, phenyloxy, benzoyl or pyridyl; each of X
11
and X
12
independently is a bond, S(O)
q
in which q is an integer of 0 to 2, C(═O), C(═N—OR
16
) in which R
16
is H or C
1-8
alkyl; C(═O)NH, NHC(═O), SO
2
NH, NHSO
2
, CH(OR
17
) in which R
17
is H or C
1-8
alkyl, CH═CH, or C≡C; Y
1
is an alkylene chain having 1-8 carbon atoms and optionally a C
1-8
alkyl or C
1-8
alkoxy substituent; Z
1
is O or S; each of R
13
and R
14
independently is an alkyl group having 1-8 carbon atoms and optionally a halogen or C
1-8
alkoxy substituent; provided that X
12
is neither O nor S(O)
q
when X
11
is a bond, while X
12
is not a bond when X
11
is C(═O)NH].
Furthermore, the invention provides a thiazole derivative having the following formula (III) or a salt thereof:
[wherein each of R
21
and R
22
independently is an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and 1-3 halogen atom substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom and a 3-7 membered substituent, or a phenylalkyl group having C
1-4
alkyl portion, phenyl group, naphthyl group, pyridyl group, thienyl group, furyl group, quinolyl group, benzofuranyl group or benzothienyl group which optionally contains a substituent of halogen, hydroxyl, nitro, amino, C
1-8
alkyl, C
1-8
alkyl having 1-3 halogen substituents, C
1-8
alkoxy, C
1-8
alkoxy having 1-3 halogen substituents, phenyl, benzyl, phenyloxy, benzoyl or pyridyl; each of X
21
and X
22
independently is a bond, S(O)
r
in which r is an
Endo Tsuyoshi
Kanda Takashi
Kobayashi Kunio
Masui Seiichiro
Mochizuki Nobutaka
Nippon Chemiphar Co., Ltd.
Powers Fiona T.
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