Heterocycle derivatives as PPAR-gamma agonists

Details Heterocycle derivatives as PPAR-gamma agonists Heterocycle derivatives as PPAR-gamma agonists

2000-12-11

2002-10-08

Chang, Ceila (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C544S121000, C544S360000, C544S383000, C544S390000

Reexamination Certificate

active

06462046

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel compounds, pharmaceutical compositions containing them, to processes for their preparation and to the uses thereof. More particularly, this invention relates to compounds that exhibit agonist activity to peroxisome proliferator-activated receptor gamma enabeling them to be useful in modulation of blood glucose and the increase of insulin sensitivity in mammals
BACKGROUND OF THE INVENTION
Type II or Non-Insulin Dependent Diabetes Mellitus (NIDDM) involves abnormal glucose metabolism characterized by defects in three organ systems, namely, liver (increased glucose production by the liver due to increased levels of glucagon and free fatty acids as well as recycling of gluconeogenic precursors lactate and pyruvate), pancreas (impaired glucose-induced insulin secretion leading to fasting hyperglycemia) and peripheral target tissues such as the skeletal muscle (resistance to the action of insulin due to insulin receptor or post receptor defects).
The sulfonyl urea class of drugs exert their anti-hyperglycemic effects by stimulating the release of insulin from the &bgr; cells of the pancreas. These however have undesirable toxic effects such as fatigue of &bgr; cells with long term use, obesity and incidence of hypoglycemia. The biguanides act on insulin resistance by reduced glucose absorption, decreased glucuneogenesis, increased anorexia, enhance insulin binding to its receptor and increased glucose transport in fat and muscle. Thus the treatment of insulin resistance and/or suppression of increased hepatic glucose production in type II diabetes is an attractive area of drug development.
The thiazolidinedione class of drugs (troglitazone), was developed for its potent lipid-peroxide-lowering activity which improved hyperglycemia, hyperinsulinemia and hypertriglceridemia in the diabetic KK mice (a genetically insulin resistance model of type II diabetes). Troglitazone also increased glucose uptake in adipocytes thus increasing insulin sensitivity and responsiveness.
Three cell lines have been used to assess the effects of thiazolidinediones: NIH 3T3 mouse fibroblast that differentiates into insulin responsive adipocytes (fat cell model), HepG2, a human hepatoma cell line (liver cell model) and L6 rat myocytes (muscle cell model). In the first model the “glitazones” increase the differentiation into adipocytes and increase the expression of fat cell-specific genes like lipoprotein lipase, aP2, acyl CoA synthase and adipsin thereby contributing to the stimulation of triglyceride clearance. In the latter model and in fat cells the thiazolidinediones increase the expression of glucose transporter, GLUT4, thereby exerting an insulin-sensitizing effect by stimulating basal and insulin-stimulated glucose uptake. Recently, it has been demonstrated that the thiazolidinediones and prostanoids of the J2 series are ligands for the Peroxisome Proliferator Activated Receptors (members of the steroid/thyroid hormone receptor super family). Members of this family include the alpha, gamma and delta, of which the PPARg receptor has been shown to be preferentially expressed in preadipocytes and immune system. A general model for activation of PPARgamma by thiazolidinediones include a ligand induced conformational change leading to the displacement of a “corepressor” or allowing the binding of a coactivator thereby facilitating heterodimerization with another nuclear receptor RXR. The activated heterodimer interacts with specific DNA sequences “TGACCT-N-TGACCT” or PPREs (the Peroxisome Proliferator Response Elements) to activate transcription of thiazolidinedione responsive genes (such as lipoprotein lipase), either directly or by interacting with sites that overlap insulin responsive sequences (IRS) (such as in the glucokinase promoter). The PPREs have been identified in the promoters of a number of genes for proteins involved in the regulation of lipid metabolism suggesting that PPARgamma is an attractive therapeutic target for obesity and NIDDM.
SUMMARY OF THE INVENTION
The present invention relates to heterocycle derivatives which are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) selective agonists and such are useful in the modulation of blood glucose and the increase of insulin sensitivity in mammals. This activity of the piperazine derivatives of the invention make them particularly useful in the treatment of those conditions selected from the group consisting of diabetes, atherosclerosis, hyperglycemia, hyperlipidemia, obesity, syndrome X, insulin resistance, hypertension, heart failure and cardiovascular disease in mammals.
DESCRIPTION OF THE INVENTION
The present invention relates to the compounds of formula (I) below and its derivatives, pharmaceutically acceptable salts thereof, which are non-thiazolidinedione PPARgamma agonists so that they might surmount the problems associated with the known thiazolidinediones and thus offer an advantage as a therapeutic agent in treating diseases described above.
The present invention provides novel compounds of Formula (I) or pharmaceutical
acceptable salts thereof, wherein the broken line represents an optional double bond;
X is H, O, S;
A is —C(O)—, —S(O)m—;
B is O, S, NR
6
, wherein R
6
is H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl and C
2
-C
6
alkynyl and C
3
-C
6
cycloalkyl;
n is 0 or 1;
m is 1 or 2;
G is C
3
-C
10
cycloalkyl, C
4
-C
10
cycloalkenyl, saturated C
3
-C
10
heterocyclyl, C
3
-C
10
cycloalkyl-C
1
-C
3
alkyl, C
4
-C
10
cycloalkenyl-C
1
-C
3
alkyl, saturated C
3
-C
10
heterocyclyl-C
1
-C
3
alkyl, said cycloalkyl, cycloalkenyl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R
s
, wherein heterocyclyl contains 1 to 4 heteroatoms which may be nitrogen, sulfur or oxygen atom;
R
1
is hydrogen, hydroxy, thio, nitro, cyano, azido, amino, trifluoromethyl, trifluoromethoxy, C
1
-C
6
alkyl, C
1
-C
6
alkyloxy, C
1
-C
6
alkylthio, C
1
-C
6
alkylamino, C
1
-C
6
alkenyl, C
1
-C
6
alkenyloxy, C
1
-C
6
alkenylamino, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkyloxy, C
3
-C
8
cycloalkylamino, C
3
-C
8
cycloalkylthio, C
1
-C
6
alkylcarbonylamino, C
3
-C
8
cycloalkylcarbonylamino, C
5
-C
10
aryl, C
5
-C
10
heteroaryl or C
5
-C
10
saturated heteroaryl; said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of R
s
;
R
2
, R
3
, R
4
and R
5
independently are H, trifluoromethyl, C
5
-C
10
aryl, C
5
-C
10
heteroaryl, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, saturated C
5
-C
10
heteroaryl, C
5
-C
10
aryl-C
1
-C
10
alkyl, C
5
-C
10
heteroaryl-C
1
-C
10
alkyl, COR
7
, CO
2
R
7
, CONR
7
R
8
, SO
2
NR
7
R
8
, said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of R
s
;
R
7
and R
8
independently are H, hydroxy, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, C
5
-C
10
aryl, C
5
-C
10
heteroaryl, said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of R
s
;
R
s
represents a member selected from the group consisting of halo, cyano, nitro, trihalomethyl, carbamoyl, hydroxy, OCF
3
acyl, aryl, heteroaryl, S(O)R
8
, ═N(OR
8
), SO
2
R
8
, COOR
8
, —CONR
7
R
8
, —C
1
-C
6
alkylCONR
7
R
8
, C
1
-C
6
alkyloxy, aryloxy, arylC
1
-C
6
alkyloxy, thio, C
1
-C
6
alkylthio, arylthio, arylC
1
-C
6
alkylthio, NR
7
R
8
, C
1
-C
6
alkylamino, arylamino, arylC
1
-C
6
alkylamino, di(arylC
1
-C
6
alkyl)amino, C
1
-C
6
alkylcarbonyl, arylC
1
-C
6
alkylcarbonyl, C
1
-C
6
alkylcarboxy, arylC
1
-C
C
6
alkylcarboxy, —NR
7
CO
2
R
8
, —NR
7
CO
2
R
8
, —NR
7
SO
2
R
8
, —CONR
7
R
8
, —SO
2
NR
7
R
8
, —OCONR
7
R
8
, —C
1
-C
6
alkylaminoCONR
7
R
8
, arylC
1
-C
6
alkylcarbonylamino, tetrahydrofuryl, morpholinyl, piperazinyl, or a saturated or partial saturated cyclic 5,6 or 7 membered amine or lactam; said aryl, and heteroaryl optionally substituted with 1 to 3 groups of halo or C
1
-C
6
alkyl; wherein R
7
and R
8
are defined as above.
Definitions
As used herein, th

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