Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-12-10
2003-01-14
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C562S405000, C562S442000, C562S443000
Reexamination Certificate
active
06506797
ABSTRACT:
TECHNICAL FIELD
The present invention relates to substituted phenylpropanoic acid derivatives, effective for the therapy of abnormality of lipidmetabolism as agonists of human peroxisome proliferant-activated receptor (abbreviated as PPAR), in particular, as agonists for human PPAR&agr; isoform, their addition salts and their hydrates, processes for preparing them, and medicinal compositions containing these compounds.
BACKGROUND TECHNOLOGIES
The peroxisome proliferant-activated receptor (PPAR)'s are a ligand-dependent transcription factors that belong to nuclear receptor superfamily, such as steroid receptor, retinoid receptor, thyroid receptor, etc. Three isoforms (&agr; type, &bgr; (or &dgr;) type and &ggr; type) with different histological distribution have been identified hitherto in human and various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). Thereamong, the PPAR&agr; is distributed in the liver, kidney, etc., with high catabolic capacity for fatty acids and, in particular high expression is recognized in the liver, (Endo-crinology, 1995, 137, 354), positively or negatively controlling the expressions of genes relevant to the metabolism and the intracellular transport of fatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genes relevant to the metabolisms of cholesterol and neutral lipid. The PPAR&bgr; is expressed ubiquitously in the tissues or organisms, including nerve cells. At present, the physiological significance of PPAR&bgr; is unclear. The PPAR&ggr; is highly expressed in the adipocytes and involved the differentiation of adipocytes (J. Lipid Res., 1996, 37, 907). In this way, each isoform of PPAR play specific function in the particular organs and tissues.
Moreover, it is reported that a knock-out mouse of PPAR&agr; exhibits hypertriglyceridemia with ageing and becomes obesity mainly by increasing the white adipose tissues (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPAR&agr; and decreasing action of lipids (cholesterol and triglyceride) in blood is suggested strongly.
On the other hand, fibrates and statins are widely used so far as the therapeutic drugs for hyperlipidemia. However, the fibrates have only weak decreasing effect of cholesterol, while the statins have weak decreasing effect of free fatty acids and triglycerides. Moreover, with respect to the fibrates, various adverse effects such as gastrointestinal injury, anthema, headache, hepatic disorder, renal disorder and biliary calculus are reported. The reason is considered to be due to that the fibrates exhibit extensive pharmacological function, hence the development of a therapeutic drug for hyperlipidemia with specific mechanism is desired.
When considering the present situation of such conventional therapeutic drugs for hyperlipidemia, and the role on the adjusting mechanism of lipidmetabolism and the connection to the pathology of hyperlipidemia of transcription factor called PPAR&agr;, which has become clear until now, if a compound that binds directly to as a ligand of PPAR&agr;, in particular, human PPAR&agr; and is capable of activating human PPAR&agr; could be created, the medicinal use thereof would be expected as a compound that exhibits the decreasing effect of lipids (both of cholesterol and triglyceride) in blood due to very specific mechanism.
Prior arts
For compounds having an affinity to PPAR&agr; as ligands of PPAR&agr;, eicosanoids in HETE (hydroxyeicosatetraenoic acid) group produced via oxidation with cytochrome P-450, in particular, 8-HETE, 8-HEPE, etc. are reported in addition to LTB
4
being a metabolite of arachidonic acid (Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are unstable metabolically and chemically and cannot be offered as medicinal drugs.
On the other hand, as compounds with similar structure to the inventive substituted phenylpropanoic acid derivatives, a group of compounds shown below, etc. are reported.
As compounds with glucose-lowering action, in International Publication Number WO98/28254 (Nippon Chemiphar Co., Ltd.), compounds represented by a general formula (A)
(wherein A
1
denotes aryl group which may have substituent or hetero-cycle group, Y
2
denotes alkylene chain with carbon atoms of 1 to 5, X
4
denotes bond hand, oxygen atom or sulfur atom, W
1
denotes naphthalene ring which may have substituent, quinoline ring, indole ring, benzisoxazole ring or benzo[b]thiophene ring, R
4
denotes hydrogen atom or alkyl group with carbon atoms of 1 to 8, X
5
denotes oxygen atom or sulfur atom, and R
5
denotes alkyl group with carbon atoms of 1 to 8 which may have substituent, aralkyl group or aryl group), are reported. These compounds however have different structure from that of the inventive compounds in that carbonyl group or amide group is not contained in Y
2
and X
4
being connecting portions and that W
1
to bind to 3-position of propanoic acid is heterocycle, and it is also not described that these compounds have the binding activity to human PPAR&agr; and the transcription-activating function.
As propanoic acid derivatives with glucose-lowering action and lipid-decreasing effect, in International Publication Number WO98/07699 (Japan Tobacco Inc.), compounds represented by a general formula (B)
(wherein R denotes a substituent represented by D
1
or D
2
, R
1
denotes aromatic ring, cycloalkyl group or heteroaromatic ring, R
5
denotes alkyl group, R
4
denotes hydrogen atom or alkyl group, R
6
denotes hydrogen atom or it may be connected to R
9
to form double bond, R
7
denotes carboxyl group, acyl group, alkoxycarbonyl group which may have substituent, alkyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, NHR
8
group or OR
8
group, R
8
denotes acyl group which may have substituent or alkoxycarbonyl group, R
9
denotes hydrogen atom, alkyl group or alkoxycarbonyl group, and R
10
denotes hydrogen atom, amino group, alkoxy group, alkyl group, aryloxy group or aralkyloxy group), are reported. However, these compounds also have different structure from that of the inventive compounds in that substituents on benzene ring are of disubstituted form at 1-position and 4-position, and it is also not described that these compounds have the binding activity to human PPAR&agr; and the transcription-activating function.
As carboxylic acid derivatives with agonistic effect on leukotriene receptor, in Jpn. Kokai Tokkyo Koho JP 63-91354 (Yamanouchi Pharmaceutical Co., Ltd.), compounds represented by a general formula (C)
(wherein A denotes hydrogen atom or phenyl group, m denotes integer of 3 to 10, n denotes integer of 1 to 6, X denotes CONH group or NHCO group, and R denotes carboxy lower alkyl group or carboxy lower alkylcarbamoyl group (however, when A is phenyl group, R is carboxy lower alkylcarbamoyl lower alkyl group)), are reported. Among these compounds, however, propanoic acid derivatives have no substituent at 2-position and carbonyl groups exist in all of R group portions, hence the structure differs from that of the inventive compounds, and it is also not described that these compounds have the binding activity to human PPAR&agr; and the transcription-activating function.
As carboxylic acid derivatives with antagonism against fibrinogen receptor, in U.S. Pat. No. 5,227,490 (Merck & Co.,Inc.), compounds represented by a general formula (D)
(wherein R
1
denotes hydrogen atom, C
1-6
alkyl group, aryl C
4-10
alkyl group, aryl group, carboxyl group, C
1-6
alkoxy group, carboxy C
0-6
alkyl group, carboxy C
0-6
alkoxy group, hydroxy C
1-6
alkyl group, C
1-4
alkylsulfonyl C
0-6
alkyl group, C
0-4
alkylamino C
0-6
alkyl group, aryl C
0-10
alkylamino C
0-6
alkyl group, C
2-10
acylamino C
0-6
alkyl group, C
1-4
carboalkoxy C
0-6
alkyl group or halogen atom, R
2
s denote identically or differently hydrogen atoms, halogen atoms, hydroxyl groups, C
1-6
alkoxy groups, aryl C
0-4
alkyl groups, aryl C
0-6
alkoxy groups
Ide Tomohiro
Miyachi Hiroyuki
Murakami Koji
Nomura Masahiro
Takahashi Yukie
Kyorin Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Reyes Hector M.
Rotman Alan L.
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