Pyridone inhibitors of fatty acid binding protein and method

Details Pyridone inhibitors of fatty acid binding protein and method Pyridone inhibitors of fatty acid binding protein and method

2001-11-20

2003-12-30

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S350000, C514S340000, C514S336000, C514S335000, C514S334000, C514S333000, C514S332000, C546S298000, C546S296000, C546S290000, C546S268400, C546S268100, C546S261000, C546S256000, C546S302000, C546S303000

Reexamination Certificate

active

06670380

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to pyridones which are inhibitors of fatty acid binding protein (especially aP2) and to a method for treating diabetes, especially Type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, Syndrome X, diabetic complications, atherosclerosis and related diseases, and other chronic inflammatory and autoimmune/inflammatory diseases, employing such pyridones alone or in combination with one or more types of therapuetic agents. In addition, the compounds of the present invention act as inhibitors of aldose reductase and thus are useful in the treatment of diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy.
BACKGROUND OF THE INVENTION
Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that bind to fatty acids such as oleic acids which are important metabolic fuels and cellular regulators. Dysregulation of fatty acid metabolism in adipose tissue is a prominent feature of insulin resistance and the transition from obesity to non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes).
aP2 (adipocyte fatty binding protein), an abundant 14.6 KDa cytosolic protein in adipocytes, and one of a family of homologous intracellular fatty acid binding proteins (FABPs), is involved in the regulation of fatty acid trafficking in adipocytes and mediates fatty acid fluxes in adipose tissue. G. S. Hotamisligil et al, “Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein”, Science, Vol. 274, Nov. 22, 1996, pp. 1377-1379, report that aP2-deficient mice placed on a high fat diet for several weeks developed dietary obesity, but, unlike control-mice on a similar diet, did not develop insulin resistance or diabetes. Hotamisligil et al conclude “aP2 is central to the pathway that links obesity to insulin resistance” (Abstract, page 1377).
U.S. application Ser. No. 60/100,677, filed September 17, 1998, U.S. application Ser. No. 60/127,745 filed Apr. 5, 1999, and U.S. application Ser. No. 60/178,598 filed Jan. 28, 2000 disclose methods for treating diabetes employing an aP2 inhibitor.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, pyridone compounds are provided which have the structure of formula I
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein
A is selected from
—R
1
,
—(CR
3
R
4
)
n
—R
1
,
—(CR
3
R
4
)
m
R
5
(CR
6
R
7
)—R
1
, and
—(CR
3
R
4
)
n
(CR
6
R
7
)
p
—R
1
;
Q is selected from
—R
2
,
—(CR
3
R
4
)
n
R
2
,
—R
5
(CR
3
R
4
)
p
—R
2
,
—(CR
11
R
12
)
m
R
5
(CR
6
R
7
)
p
—R
2
,
—(CR
11
R
12
)
n
(CR
6
R
7
)
p
—R
2
,
—S(O)R
2
where R
2
is other than hydrogen, and
—S(O
2
)R
2
where R
2
is other than hydrogen;
R
1
and R
2
are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, cycloheteroalkyl and substituted cycloheteroalkyl;
R
3
and R
4
are the same or different and are independently selected from H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, arylcarbonyl, aryl and heteroaryl, halo, hydroxy, alkoxy and aryloxy;
or R
3
and R
4
together with the atom to which they are bonded may form a 3 to 9-membered saturated or unsaturated ring;
R
5
is a bond, O, NR
8
, S, SO, SO
2
, CO or CONH;
R
6
and R
7
are the same or different and are independently selected from H, alkyl, cycloalkyl, aryl, hydroxy, amino, halo, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, dialkylamino, arylamino, diarylamino, alkoxycarbonyl, alkylaminocarbonyl or alkylcarbonylamino;
R
8
is H, aryl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkyl or alkylcarbonyl;
R
9
is H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or a prodrug ester thereof;
R
10
is H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or a prodrug ester thereof;
R
11
and R
12
are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, cycloheteroalkyl and substituted cycloheteroalkyl;
X is selected from -Z, —(CR
3
R
4
)
n
-Z, —CH═CHZ, and -(cycloalkyl)-Z;
Z is —CO
2
R
9
, —CONHOH, —CONR
9
R
10
, —(CR
3
R
4
)
m
OH, tetrazole of the formula
or its tautomer; and when X is other than Z, Z is additionally selected from —SO
3
H, and —PO
3
R
9
R
10
,
n is an integer selected from 0 to 5;
m is an integer selected from 1 to 5; and
p is an integer selected from 0 to 4.
In addition, the present invention provides for novel intermediates useful in the synthesis of compounds of formula L Such intermediates have the structure of formula II
where A and Q are as defined above,
X* is -W, —(CR
3
R
4
)
n
-W, —CH═CHW, or -(cycloalkyl)-W; and
W is cyano, —C(O)Cl, or —C(O)H, and when W is other than X*, W is additionally selected from halogen, hydroxy, or alkenyl.
In addition, in accordance with the present invention, a method is provided for treating diabetes, especially Type II diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hypertriglyceridemia, atherosclerosis, inflammation, diabetic retinopathy, diabetic neuropathy and diabetic nephropathy wherein a therapeutically effective amount of a compound of structure I is administered to a human patient in need of treatment.
In addition, in accordance with the present invention, a method is provided for treating diabetes and related diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of structure I and another type antidiabetic agent is administered to a human patient in need of treatment.
In the above method of the invention, the compound of structure I will be employed in a weight ratio to another antidiabetic agent (depending upon its mode of operation) within the range from about 0.01:1 to about 100:1, preferably from about 0.1:1 to about 10:1.
Examples of X moieties include (but are not limited to)
Preferred compounds of formula I include compounds where
A is R
1
or (CR
3
R
4
)
n
—R
1
where n is 1 and R
3
and R
4
are the same or different and are selected from hydrogen, alkyl and substituted alkyl;
R
1
is aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl or cycloalkyl;
Q is R
2
or (CR
3
R
4
)
n
—R
2
where n is 1 and R
3
and R
4
are the same or different and are selected from hydrogen, alkyl and substituted alkyl;
R
2
is aryl, substituted aryl, cycloalkylalkyl, heteroaryl or substituted heteroaryl;
X is (CR
3
R
4
)
n
-Z where n is 0 or 1 and R
3
and R
4
are the same or different and are selected from hydrogen, hydroxy, alkyl and substituted alkyl; and
Z is CO
2
R
9
, CONH
2
, PO
3
H
2
, CONHOH, or tetrazole.
More preferred compounds of formula I include compounds where
A is R
1
;
R
1
is aryl (especially where aryl is phenyl), or substituted aryl (especially where substituted with one or more halogen, alkoxy or aryloxy);
Q is (CR
3
R
4
)
n
—R
2
where n is 1 and R
3
and R
4
are hydrogen
R
2
is aryl (especially where aryl is phenyl or napthyl), or substituted aryl (especially substituted with one or more halogen, alkyl, substituted alkyl alkoxy; arylalkoxy, or cyano);
X is —(CR
3
R
4
)
n
-Z where n is 0 or 1 and R
3
and R
4
are hydrogen; and
Z is CO
2
H, or tetrazole.
Most preferred compounds of formula I include compounds where
A is R
1
;
R
1
is substituted aryl (especially where aryl is phenyl and the substituents are selected from halogens);
Q is (CR
3
R
4
)
n
—R
2
where n is

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