Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-08-25
2001-09-25
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S561000, C514S649000, C514S445000, C514S351000, C514S352000, C514S375000, C560S061000, C562S471000, C564S344000, C549S065000, C546S290000, C546S312000, C548S225000, C548S230000
Reexamination Certificate
active
06294580
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 agonist activity, to peroxisome proliferator-activated receptor gamma (PPAR-gamma) thereby enabling them to modulate the blood glucose levels in mammals.
The treatment of Type II or Non-insulin Dependent Diabetes Mellitus (NIDDM) remains unsatisfactory despite the widespread use of insulin, sulfonylureas (e.g. chlorpropamide, tolbutamide, tolazamide), and biguanides (e.g, phenformin, metformin) as oral hypoglycaemic agents. Treatment of NIDDM usually begins with a combination of diet and exercise, with progression to oral hypoglycaemics (e.g. sulfonylureas) and in more severe cases, insulin. Unfortunately the available hypoglycaemics suffer from a wide range of undesirable toxic effects which limits their usefulness in treatment of NIDDM. There is thus a clear need for the development of novel hypoglycaemic agents which may be less toxic or which suceed where others are ineffective.
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 NIDDM and also reduce lipid and insulin levels in these animal models. Recently, the thiazolidinedione troglitazone was shown to have these same beneficial effects in human patients suffering from impaired glucose tolerance, a metabolic condition that precedes the development of NIDDM, as in patients suffering from NIDDM (J. J. Nolan et. al.,
N. Eng. J. Med
. 1188-1193, 331 (1994)). While the mechanism of action is unclear, thiazolidinediones do not cause increases in insulin secretion or in the number or affinity of insulin receptor binding sites, suggesting that thiazolidinediones amplify post-receptor events in the insulin signaling cascade (J. R. Colca and D. R. Morton, “
Antihyperglycemic thiazolidinediones: ciglitazone and its analogs
,” in
New Antidiabetic Drugs
, C. J. Bailey and P. R. Flatt, eds., Smith-Gordon, New York, 255-261 (1990)).
Thiazolidinediones also induce the in vitro adipocyte differentiation of preadipocyte cell lines (A. Hiragun, et. al.
J. Cell. Physiol
. 124-130, 134 (1988); R. F. Kleitzen, et. al.,
Mol. Pharmacol
. 393-398, 41 (1992)). Treatment of pre-adipocyte cell lines with the thiazolidinedione pioglitazone results in increased expression of the adipocyte-specific genes aP2 and adipsin as well as the glucose transporter proteins GLUT-1 and GLUT-4, which suggests that the hypoglycaemic effects of thiazolidinediones seen in vivo may be mediated through adipose tissue.
Recently, an orphan member of the steroid/thyroid/retinoid receptor superfamily of ligand-activated transcription factors termed Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) has been discovered. PPAR-gamma is one of a subfamily of closely related PPARs encoded by independent genes (C. Dreyer, et. al.,
Cell
879-887, 68 (1992); A. Schmidt, et. al.,
Mol. Endocrinol
. 1634-1641, 6, (1992); Y. Zhu, et. al.,
J. Biol. Chem
. 26817-26820, 268 (1993); S. A. Kliewer et. al.,
Proc. Nat. Acad. Sci. USA
7355-7359, 91, (1994)). Three mammalian PPARs have been isolated and termed PPAR-alpha, PPAR-gamma, and NUC-1. These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H. Keller and W. Wahli,
Trends Endocrin. Met
. 291-296, 4 (1993)). It has now been reported that thiazolidinediones are potent and selective activators of PPAR-gamma and bind directly to the PPAR-gamma receptor (J. M. Lehmann et. al.,
J. Biol. Chem
. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones.
We have now discovered a novel group of compounds which bind to and activate the PPAR-gamma receptor. These compounds also show good blood-glucose lowering activity and are therefore of use in the treatment and/or prophylaxis of hyperglycaemia, dyslipidemia, and are of particular use in the treatment of Type II diabetes.
These compounds are also indicated to be of use for the treatment and/or prophylaxis of other diseases including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension and cardiovascular disease, especially atherosclerosis. In addition, these compounds are indicated to be useful for the regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa.
Accordingly, the present invention is directed to compounds having the formula (I):
wherein
A is selected from the group consisting of:
(i) phenyl, wherein said phenyl is optionally substituted by one or more of the following groups; halogen atoms, C
1-6
alkyl, C
1-3
alkoxy, C
1-3
fluoroalkoxy, nitrile, or —NR
7
R
8
where R
7
and R
8
are independently hydrogen or C
1-3
alkyl;
(ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and
(iii) a fused bicyclic ring
wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C;
B is selected from the group consisting of:
(iv) C
1-6
alkylene;
(v) —MC
1-6
alkylene or C
1-6
alkyleneMC
1-6
alkylene, wherein M is O, S, or —NR
2
wherein R
2
represents hydrogen or C
1-3
alkyl;
(vi) a 5- or 6-membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C
1-3
alkyl; and
(vii) Het-C
1-6
alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above;
Alk represents C
1-3
alkylene;
R
1
represents hydrogen or C
1-3
alkyl;
Z is selected from the group consisting of:
(viii) —(C
1-3
alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and
(ix) —NR
3
R
4
, wherein R
3
represents hydrogen or C
1-3
alkyl, and R
4
represents —Y—(C═O)—T—R
5
, or —Y—(CH(OH))—T—R
5
, wherein:
(a) Y represents a bond, C
1-6
alkylene, C
2-6
alkenylene, C
4-6
cycloalkylene or cycloalkenylene, a heterocyclic group as defined in point (vi) above, or phenyl optionally substituted by one or more C
1-3
alkyl groups and/or one or more halogen atoms;
(b) T represents a bond, C
1-3
alkyleneoxy, —O— or —N(R
6
)—, wherein R
6
represents hydrogen or C
1-3
alkyl;
(c) R
5
represents C
1-6
alkyl, C
4-6
cycloalkyl or cycloalkenyl, phenyl (optionally substituted by one or more of the following groups; halogen atoms, C
1-3
alkyl, C
1-3
alkoxy groups, C
0-3
alkyleneNR
9
R
10
(where each R
9
and R
10
is independently hydrogen, C
1-3
alkyl, —SO
2
C
1-3
alkyl, or —CO
2
C
1-3
alkyl, —SO
2
NHC
1-3
alkyl), C
0-3
alkyleneCO
2
H, C
0-3
alkyleneCO
2
C
1-3
alkyl, or —OCH
2
C(O)NH
2
), a 5- or 6-membered heterocyclic group as defined in point (ii) above, a bicylic fused ring
wherein ring D represents a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by (═O), which bicyclic ring is attached to T via a ring atom of ring D: or —C
1-6
alkyleneMR
11
M is O, S, or —NR
12
wherein R
12
and R
11
are independently hydrogen or C
1-3
alkyl,
or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate thereof.
Those skilled in the art will recognize that stereocenters exist in compounds of Formula (I). Accordingly, the present inv
Boswell Grady Evan
Brackeen Marcus
Cobb Jeffrey Edmond
Collins Jon Loren
Deaton David Norman
Brink Robert H.
Glaxo Wellcome Inc.
Lambkin Deborah C.
LandOfFree
Substituted 4-hydroxy-phenylalcanoic acid derivatives with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted 4-hydroxy-phenylalcanoic acid derivatives with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 4-hydroxy-phenylalcanoic acid derivatives with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2525486