Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-11
2003-01-14
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S340000, C514S361000, C514S365000, C514S374000, C544S369000, C546S271400, C548S127000, C548S204000, C548S236000
Reexamination Certificate
active
06506757
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a carboxylic acid derivative and a peroxisome proliferator activated receptor regulator containing carboxylic acid derivative as active ingredient.
More particularly, the present invention relates to a peroxisome proliferator activated regulator containing a compound of formula (I)
(wherein all symbols are as hereinafter described), a non-toxic salt thereof and a hydrate thereof as active ingredient, a novel carboxylic acid derivative of formula (I), a non-toxic salt thereof, a hydrate thereof and a process for the preparation thereof.
BACKGROUND
Recently in the study of transcription factors concerned with genes expression in adipocytes differentiation, peroxisome proliferator activated receptor (abbreviated as PPAR hereinafter) has been focused. cDNAs of PPAR were cloned from various kinds of animals, and plural isoform genes were found, particularly in mammals three types of isoforms (&agr;, &dgr;, &ggr;) are known (see J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression,. 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol. Endocrinology., 6, 1634 (1992)). PPAR &ggr; isoform is predominantly expressed in adipose tissues, immune cells, adrenal gland, spleen, small intestine. PPAR &agr; isoform is mainly expressed in adipose tissue, liver, retina, and &dgr; isoform shows the expression with no tissue specificity, which is widely expressed (see Endocrinology., 137, 354 (1996)).
On the other hand, the following thiazolidine derivatives are known as agents for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and are hypoglycemic agents which are used for the improvement of hyperglycemia in the patients suffering from diabetes. They are also effective for the improvement of hyperinsulinemia, glucose tolerance and decrease of serum lipid and therefore they are thought to be considerably hopeful as agents for the treatment of insulin resistance.
One of the target proteins in the cells of these thiazolidine derivatives is exactly PPAR &ggr; and it is resolved that they enhance the transcription activity of PPAR &ggr; (see Endocrinology., 137, 4189 (1996); Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953 (1995)). Therefore, a PPAR activator (agonist) which enhances its transcription activity is thought to be hopeful as a hypoglycemic agent and/or a hypolipidemic agent. Furthermore, since a PPAR &ggr; agonist is known to promote the expression of PPAR &ggr; protein itself (Genes & Development., 10, 974 (1996)), an agent which increases the expression of PPAR &ggr; protein itself as well as PPAR &ggr; activating agent is also clinically useful.
Among all of nuclear receptors, PPAR &ggr; is related to adipocytes differentiation (see J. Biol. Chem., 272, 5637 (1997) and Cell., 83, 803 (1995)). It is known that thiazolidine derivatives which activate this receptor promote adipocytes differentiation. Recently it was reported that thiazolidine derivatives increase fat mass and cause man to gain weight and to become obese (see Lancet., 349, 952 (1997)). Therefore, it is also thought that antagonists which inhibit PPAR &ggr; activity and agents that decrease the expression of PPAR &ggr; protein itself are also clinically applicable. On the other hand, a compound that phosphorylates PPAR &ggr; protein and decreases its activity is reported (Science., 274, 2100 (1996)). This implies that an agent which does not bind on PPAR &ggr; protein as a ligand, but inhibits its activity is also clinically applicable.
From these, PPAR &ggr; activators (agonists) and PPAR &ggr; regulators for its expression that can increase the expression of the protein itself are expected to be useful as hypoglycemic agents, hypolipidemic agents, preventives and/or remedies for diseases associated with metabolic disorders (diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipidemia, atherosclerosis, hypertension, circulatory diseases, overeating, etc.
On the other hand, antagonists that inhibit the transcription activity of PPAR &ggr; or PPAR &ggr; regulators that inhibit the expression of the protein itself are expected to be useful as hypoglycemic agents, preventives and/or remedies for diseases associated with metabolic disorders (diabetes, obesity, syndrome X, etc.), hyperlipidemia, atherosclerosis, hypertension, overeating, etc.
The following fibrate compound (e.g. chlofibrate) is known as a hypolipidemic agent.
It is also resolved that one of the target proteins in the cells of fibrate compounds is PPAR &agr; (See Nature., 347, 645 (1990); J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598 (1993)). From these facts, PPAR &agr; regulators, which can be activated by fibrate compounds are thought to have a hypolipidemic effect, and so they are expected to be useful as preventives and/or remedies for hyperlipidemia etc.
Besides, it was recently reported that biological activation of PPAR &agr; linked anti-obese effect in the specification of WO 9736579. It was reported that the elevation of high density lipoprotein (HDL) cholesterol and the reduction of low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol and triglyceride were induced by PPAR &agr; activation (J. Lipid Res., 39, 17 (1998)). It was also reported that improvement of fatty acid composition in the blood, hypertension and insulin resistance by the treatment of bezafibrate (one of fibtrate compounds) (Diabetes., 46, 348 (1997)). Therefore, agonists that activate PPAR &agr; and PPAR &agr; regulators that promote expression of PPAR &agr; protein itself are useful as hypolipidemic agents and remedies for hyperlipidemia , and are expected to have HDL cholesterol-elevating effect, LDL cholesterol and/or VLDL cholesterol-lowering effect, inhibition on the progress of atherosclerosis and anti-obese effect. Therefore, they are thought to be hopeful agents for the treatment and/or prevention of diabetes as hypoglycemic agents, for the improvement of hypertension, for the relief from risk factor of syndrome X and for the prevention of occurrence of coronary heart diseases.
On the other hand, few reports are found on ligands that activate PPAR &dgr; significantly or on biological activities associated with PPAR &dgr;.
PPAR &dgr; is sometimes called PPAR &bgr;, or it is also called NUC1 in human. So far it was shown that in the specification of WO 9601430 hNUC1B (PPAR subtype whose structure is different from that of human NUC1 in one amino acid) inhibited the transcription activities of human PPAR &agr; and thyroid hormone receptor. Recently in the specification of WO 9728149, it was reported that compounds bound to PPAR &dgr; protein with high affinity activated PPAR &dgr; significantly (i.e. agonists) and they had HDL (high density lipoprotein) cholesterol-elevating activity. Therefore, agonists :that activate PPAR &dgr; are expected to have HDL cholesterol-elevating effect, and so they are expected to be useful for the inhibition on the progress of atherosclerosis and its treatment, as hypolipidemic agents and/or hypoglycemic agents, for the treatment of hyperlipidemia, as hypoglycemic agents, for the treatment of diabetes, for the relief from risk factor of syndrome X, and for the prevention of occurrence of coronary heart diseases.
The following PPAR regulators have been reported.
(1) For example, in the specification of WO 9728115, it is described that a compound of formula (A)
(wherein R
1A
is selected from hydrogen, C3~10 cycloalkyl, etc., R
2A
is selected from hydrogen, C5~10 aryl, C5~10 heteroaryl, etc., R
4A
is selected from R
2A
etc., (Z
A
—W
A
—) is Z
A
—CR
6A
R
7A
or Z
A
—CR
6A
R
7A
—R
8A
—, etc., R
8A
is selected from CR
6A
R
7A
, O, S(O)
pA
, etc., R
6A
and R
7A
are each independently, selected from hydrogen, C1~6 alkyl, etc., X
1A
and X
2A
are each independently, hydrogen, C1~15 alkyl, halogen, etc., Y
A
is selected from S(O)
pA
, —O—, etc., Y
1A
is selected from O, C, etc., Z
A
is selected from CO
2
R
3A
etc., tA and vA
Fukushima Daikichi
Nakayama Yoshisuke
Tajima Hisao
ONO Pharmaceutical Co., Ltd.
Rao Deepak R.
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