Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-22
2002-12-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S374000, C514S376000, C514S369000, C514S370000, C548S187000, C548S194000, C548S204000, C548S233000, C548S235000, C546S269700, C546S027000, C544S405000
Reexamination Certificate
active
06498174
ABSTRACT:
The present invention relates to certain novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it relates to compounds which exhibit activation, including dual agonist activity, to peroxisome proliferator-activated receptors gamma (PPAR&ggr;) and alpha (PPAR&agr;) thereby enabling them to modulate the blood glucose and lipid levels in mammals.
Treatment of type 2 diabetes mellitus usually begins with a combination of diet and exercise, with progression to oral hypoglycaemics (e.g. sulfonylureas) and in more severe cases, insulin. In the last decade a class of compounds known as thiazolidinediones (e.g. U.S. Pat. Nos. 5,089,514, 4,342,771, 4,367,234, 4,340,605, 5,306,726) have emerged as effective antidiabetic agents that enhance the insulin sensitivity of target tissues (skeletal muscle, liver, adipose) in animal models of type 2 diabetes mellitus and also reduce lipid and insulin levels in these animal models.
It has been reported that thiazolidinediones are potent and selective activators of PPAR&ggr; and bind directly to the PPAR&ggr; receptor (J. M. Lehmann et. al.,
J. Biol. Chem.
12953-12956, 270 (1995)), providing evidence that PPAR&ggr; is a possible target for the therapeutic actions of the thiazolidinediones.
PCT patent publication WO 97/31907 discloses certain novel compounds that bind to and activate PPAR&ggr;. These compounds are indicated to be useful for the treatment of type 2 diabetes mellitus and other diseases.
Activators of the nuclear receptor PPAR&ggr;, for example troglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E. Kelly et al.,
Curr. Opin. Endocrinol. Diabetes,
90-96, 5 (2), (1998); M. D. Johnson et al.,
Ann. Pharmacother.,
337-348, 32 (3), (1997); and M. Leutenegger et al.,
Curr. Ther. Res.,
403-416, 58 (7), (1997).
The mechanism for this triglyceride lowering effect appears to be predominantly increased clearance of very low density lipoproteins (VLDL) through induction of liporotein lipase (LPL) gene expression. See, for. example, B. Staels et al.,
Arterioscler. Thromb., Vasc. Biol.,
1756-1764, 17 (9), (1997).
Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10-15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and increase HDLc 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPAR&agr;. See, for example, B. Staels et al.,
Curr. Pharm. Des.,
1-14, 3 (1), (1997). Activation of PPAR&agr; results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion. In addition, PPAR&agr; activation decreases production of apoC-III. Reduction in apoC-III, an inhibitor of LPL activity, increases clearance of VLDL. See, for example, J. Auwerx et al.,
Atherosclerosis,
(Shannon, Irel.), S29-S37, 124 (Suppl), (1996).
In addition, a dual agonist of PPAR&agr; and PPAR&ggr; could be effective in reducing the dyslipidemia and hyperinsulinemia associated with impaired glucose tolerance (IGT) or metabolic syndrome and could be effective in patients with mixed hyperlipidemia. See, for example, U.S. Pat. Nos. 5,478,852.
PCT patent publication WO 98/05331 (Paterniti et al.) relates to methods for treating diabetes and cardiovascular disease using a PPAR&ggr; agonist in combination with a PPAR&agr; agonist, or a compound that activates both PPAR&ggr; and PPAR&agr;.
BRIEF DESCRIPTION
Briefly, in one aspect, the present invention provides compounds of formula (I), and tautomeric forms, pharmaceutically acceptable salts and solvates thereof,
wherein;
R
1
is hydrogen or C
1-3
alkyl;
R
2
is hydrogen, or C
1-8
alkyl optionally substituted by one or more halogens;
R
3
is C
1-6
alkyl, C
4-7
cycloalkyl or cycloalkenyl, —OC
1-6
alkyl, —NR′R′ (where each R′ is independently hydrogen or C
1-3
alkyl), a 5 or 6 membered heterocyclic group containing at least one oxygen, nitrogen, or sulfur ring atom (optionally substituted by one or more halogen, C
1-6
alkyl optionally substituted by one or more halogens, —OC
1-6
alkyl optionally substituted by one or more halogens, —CN, or —NO
2
), or phenyl (optionally substituted by one or more halogen, C
1-6
alkyl optionally substituted by one or more halogens, —OC
1-6
alkyl optionally substituted by one or more halogens, —CN, or —NO
2
);
R
4
is a 5 or 6 membered heterocyclic group containing at least one oxygen, nitrogen, or sulfur ring atom (optionally substituted by one or more halogen, C
1-6
alkyl optionally substituted by one or more halogens, —OC
1-6
alkyl optionally substituted by one or more halogens, —CN, or —NO
2
), or phenyl (optionally substituted by one or more halogen, C
1-6
alkyl optionally substituted by one or more halogens, —OC
1-6
alkyl optionally substituted by one or more halogens, —NR′R′ (as defined above), —CN, or —NO
2
);
R
5
is hydrogen, halogen, or C
1-3
alkyl optionally substituted by one or more halogens;
R
6
is hydrogen or C
1-3
alkyl;
X is O or S; and
n is 1, 2, or 3.
Preferably, the compounds of this invention activate both the hPPAR&ggr; and hPPAR&agr; receptors.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention. As used herein, “a compound of the invention” means a compound of formula (I) or a tautomeric form, pharmaceutically acceptable salt, or solvates thereof.
The invention further provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides a method for treatment or prevention of a hPPAR&ggr; and/or hPPAR&agr; mediated disease, risk factor, or condition, comprising administration of a therapeutically effective amount of a compound of this invention.
According to another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the is treatment or prevention of a hPPAR&ggr; and/or hPPAR&agr; mediated disease.
hPPAR&ggr; and/or hPPAR&agr; mediated diseases, risk factors, or conditions include hyperglycemia, dyslipidemia, type II diabetes mellitus including associated diabetic dyslipidemia, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, hyperlipidemia, hypercholesteremia, hypertension, cardiovascular disease, including atherosclerosis, regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the compounds of the present invention are useful in the treatment or prevention of hyperglycaemia, dyslipidemia, and type II diabetes mellitus including associated diabetic dyslipidemia.
DETAILED DESCRIPTION
Preferably, R
1
is hydrogen or methyl. Most preferably, R
1
is hydrogen.
Preferably, R
2
is C
1-8
alkyl optionally substituted by one or more halogens. Preferably, said halogen is fluorine. Most preferably, R
2
is straight-chain.
Preferably, R
3
is pyridine, pyrazine, thiophene, furan, thiazole, or phenyl (any of which may be optionally substituted by one or more halogen, C
1-6
alkyl optionally substituted by one or more halogens, —OC
1-6
alkyl optionally substituted by one or more halogens, —CN, or —NO
2
), or C
4-7
cycloalkyl. Most preferably, R
3
is phenyl (optionally substituted by one or more halogen, C
1-6
alkyl optionally substituted by one or more halogens, —OC
1-6
alkyl optionally substituted by one or more halogens, —CN, or —NO
2
).
Preferably R
4
is phenyl (optionally substituted by one or more halogen, C
1-6
alkyl optionally substituted by one or more halogens, or —OC
1-6
alkyl optionally substituted by one or more halogens). Preferably, said halogen is fluorine. Most preferably R
4
Collins Jon Loren
Dezube Milana
Oplinger Jeffrey Alan
Willson Timothy Mark
Brink Robert H.
Habte Kahsay
Shah Mukund J.
SmithKline Beecham Corporation
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