Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-26
2003-11-18
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...
C544S231000, C544S243000, C544S315000, C544S316000, C544S318000
Reexamination Certificate
active
06649622
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to tetrahydropyrimidones which are inhibitors of fatty acid binding protein (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 tetrahydropyrimidones alone 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).
DIALOG ALERT DBDR928 dated Jan. 2, 1997, Pharmaprojects No. 5149 (Knight-Ridder Information) discloses that a major drug company “is using virtual screening techniques to identify potential new antidiabetic compounds.” It is reported that “the company is screening using aP2, a protein related to adipocyte fatty acid binding protein.”
U.S. application Ser. No. 09/391,053, filed Sep. 7, 1999 and U.S. application Ser. No. 09/519,079 filed Mar. 6, 2000 disclose methods for treating diabetes employing an aP2 inhibitor.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, tetrahydropyrimidone compounds are provided which have the structure of formula I
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein
A and B are the same or different and are independently
—J,
—(CR
3
R
4
)
n
—J,
—R
5
(CR
3
R
4
)
p
—J,
—(CR
3
R
4
)
m
R
5
(CR
6
R
7
)
p
—J,
—(CR
3
R
4
)
n
(CR
6
R
7
)
p
—J,
—S(O)J where J is other than hydrogen,
—S(O
2
)J where J is other than hydrogen, and
—NH(CR
3
R
4
)
n
—J;
J is independently R
1
or R
2
;
R
1
and R
2
are independently 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 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 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, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a prodrug ester thereof;
R
10
is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a prodrug ester thereof;
R
11
is 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
12
and R
13
are the same or different and are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a pro drug ester thereof;
or R
12
and R
13
together with the nitrogen atom to which they are bonded together form an optionally substituted cycloheteroalkyl ring;
X is selected from —Z, —(CR
3
R
4
)
n
—Z, —O—(CR
3
R
4
)
p
—Z, —S—(CR
3
R
4
)
p
—Z, —NHC(═O)Z, —CH═CHZ, -(cycloalkylene)-Z, or —N(R
8
)(CR
3
R
4
)
n
—Z;
Y is H, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, hydroxy, —(CR
3
R
4
)
n
—CO
2
R
9
, —(CR
3
R
4
)
n
—CONR
12
R
13
, —NR
3
R
4
, aralkoxy, or heteroarylalkyl, provided that Y is other than hydroxy or NH
2
when X is —O(CR
3
R
4
)
p
—Z, —S(CR
3
R
4
)
p
—Z, —NHC(═O)Z, or —N(R
8
)(CR
3
R
4
)
n
—Z;
or X and Y, taken together with the atom to which they are joined, provide a group of the formula
Z is CO
2
R
9
, SO
3
H, PO
3
R
9
R
10
, CONHOH, CONR
12
R
13
, (CR
3
R
4
)
m
OH, or tetrazole of the formula
or its tautomer;
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 I. Such intermediates have the structure of formula II
where A and B are as defined above,
X* is W, —(CR
3
R
4
)
n
—W, —O(CR
3
R
4
)
n
—W, —S(CR
3
R
4
)
n
—W, —NHC(═O)W, —CH═CHW, -(cycloalkylene)-W, or —N(R
8
)(CR
3
R
4
)
n
—W;
Y is H, alkyl, alkenyl, aryl, aralkyl, heteroarylalkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, hydroxy, or NR
3
R
4
provided that Y is other than hydroxy or NH
2
when X is —O(CR
3
R
4
)
p
—W, —S(CR
3
R
4
)
p
—W, —NHC(═O)W, or —N(R
8
)(CR
3
R
4
)
n
—W;
W is cyano, halogen, hydroxy, alkenyl, C(O)Cl, or C(O)H.
or X* and Y, taken together with the atom to which they are joined, provide a group of the formula
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 inventi
Robl Jeffrey A.
Sulsky Richard
Bristol--Myers Squibb Company
Duncan, Jr. Sammy G.
McKenzie Thomas
O'Brien Maureen
Shah Mukund J.
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