Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-04-18
2004-03-30
Nazario-Gonzalez, Porfirio (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S538000, C562S426000, C562S431000, C562S445000
Reexamination Certificate
active
06713514
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain 1,4-disubstituted phenyl derivatives that act as agonists to the PPAR-&ggr; receptor. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating Type II diabetes, or NIDDM. The interaction of certain 1,4-disubstituted phenyl derivatives of the invention with the nuclear receptor PPAR-&ggr; is described. This interaction results in the pharmacological activities of these compounds.
2. Description of the Related Art
Type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), is a common metabolic disorder which has no effective treatment. NIDDM occurs predominantly in adults and involves a subnormal or inadequate amount of circulating endogenous insulin. The two defects associated with NIDDM are tissue insensitivity to insulin and impaired pancreatic B-cell response to glucose. Both of these defects are further aggravated by increased hyperglycemia, and therefore many therapeutic maneuvers seek to reduce this condition.
The currently marketed oral agents for Type II diabetes fall into several classes (i) sulphonylureas (ii) biguanides, or (iii) thiazolidinedione (TZD) derivatives such as the recently approved insulin sensitizer Rezulin™, an agonist of the PPAR-&ggr; receptor. The sulfonyureas are an older class of drug which suffer serious drawbacks such as profound hypoglycemia and cardiovascular disease. At least three mechanisms of sulfonylurea action have been proposed: (1) release of insulin from B-cells, (2) reduction of serum glucagon levels, and (3) an extrapancreatic effect to potentiate the action of insulin on its targets. Examples of sulfonylureas are tolbutamide, tolazimide, acetohexamide, chloropropamide and second generation hyperglycemic agents such as glyburide, glipizide and glimepiride.
Biguanides, such as metformin, have also been around since the mid-1950s and are generally considered as anti-hyperglycemic agents with marginal effects on insulin responsiveness. Currently proposed mechanisms of action for biguanides include (1) direct stimulation of glycolysis in tissues, with increased glucose removal from blood; (2) reduced hepatic gluconeogenesis; (3) slowing of glucose absorption from the gastrointestinal tract; and (4) reduction of plasma glucagon levels. While biguanides do not cause hyperglycemia, there is a clear need for more effective drugs that provide glycemic control and promote insulin responsiveness.
TZD derivatives are a new class of oral antidiabetic drugs in which the primary mechanism appears to be increased target tissue sensitivity to insulin. Specifically, the TZD involves binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. This type of drug potentiates the action of insulin to increase glucose uptake and glucose oxidation in both muscle and adipose tissue, while reducing hepatic glucose output as well as lipid synthesis in muscle and fat cells. TZDs such as troglitazone (Rezulin™), ciglitazone, englitazone, rosiglitazone and pioglitazone are said to reduce hyperglycemia, hyperinsulinemia and hypertriglyceridemia in animal models.
The recently marketed TZD, Rezulin™, while effective, has a number of post-marketing safety problems including induction of liver enzymes (e.g. P450 3A4) and hepatotoxicity with significantly associated lethality. A newer TZD, rosiglitazone, suffers a poor pharmacokinetic profile in humans, which could limit its effectiveness in a larger population. Therefore, there is a clear need for more effective novel structures of PPAR-&ggr; agonists that provide glycemic control and promote insulin responsiveness.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I that interact with the nuclear receptor PPAR-&ggr;.
The invention provides pharmaceutical compositions comprising the compounds of Formula I. The invention also provides compounds useful in the treatment of Type II diabetes, or NIDDM. Accordingly, a broad embodiment of the invention is directed to compounds of general Formula I:
wherein:
Z is a 5 or 6 membered aryl or heteroaryl ring optionally substituted with up to three groups selected from lower alkyl, halogen or lower alkoxy;
n and m independently represent 0, 1 or 2;
A is CO
2
R
9
; or
A is
D, F and G are the same or different and represent hydrogen, NR
1
R
12
, OR
1
, CH
2
R
1
or SR
1
;
R
1
and R
12
are the same or different and represent hydrogen, lower alkyl, R
10
C═O,
R
10
SO
2
, or
cycloalkyl optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl, or
aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl;
R
10
is hydrogen or lower alkyl, or aryl, heteroaryl, arylalkyl or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl;
R
9
is H or lower alkyl;
X is N, O, CH
2
, S, SO or SO
2
;
R
4
is O, hydrogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyl, R
10
C═O or R
10
SO
2
;
Y is hydrogen, NR
1
R
12
, OR
1
, CH
2
R
1
, SR
1
, SOR
1
or SO
2
R
1
; and
R
5
, R
6
and R
8
, are the same or different and represent hydrogen, lower alkyl, R
10
C═O,
R
10
SO
2
, or
cycloalkyl optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl, or
aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where the ring portion of each is optionally substituted with one, two, three or four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, alkoxycarboxy, alkylcarboxy, hydroxy, lower alkyl, lower alkoxy, amino, or mono or dialkylamino where each alkyl portion is lower alkyl; or
R
5
and R
6
together with the carbon atom to which they are attached form a 5, 6, or 7 membered carbocyclic ring up to two of which members are optionally hetero atoms selected from oxygen, sulfur and nitrogen.
These compounds are highly selective agonists for the PPAR-&ggr; receptor or prodrugs of agonists for the PPAR-&ggr; receptor. These compounds are therefore useful in the treatment of Type II diabetes.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention can be described by the general Formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof.
In addition, the present invention also encompasses compounds of Formula II
wherein n, m, A, D, X, Y, R
4
, R
5
, R
6
and R
8
are as defined above for Formula I.
Preferred compounds of Formula II are where n is 1; m is 0; A is CO
2
R
9
; D is NR
1
R
12
; R
4
is O; X is N; Y is —S-aryl, —O-aryl or —CH
2
-aryl; R
9
is hydrogen or lower alkyl; R
8
is hydrogen or lower alkyl; R
12
is hydrogen; and R
1
is a substituted or unsubstituted aryl or arylalkyl.
“----” refers to a bond or nothing.
By “alkyl”, “lower alkyl”, and “C
1
-C
6
alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-
Cavallaro Cullen
Kolb Hartmuth C.
Kolla Laxma Reddy
McGeehan Gerard
Shi Zhi-Cai
Lexicon Pharmaceuticals, Inc.
McDonnell & Boehnen Hulbert & Berghoff
Nazario-Gonzalez Porfirio
Zucker Paul A.
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