Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-06
2003-04-15
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S376100
Reexamination Certificate
active
06548529
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to heterocyclic containing biphenyls which are inhibitors of 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 heterocyclic containing biphenyls alone or in combination with one or more types of antidiabetic agents.
BACKGROUND OF THE INVENTION
Fatty acid binding proteins (FABPs) are small cytoplasmic proteins which 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 that “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. 60/100,677, filed Sep. 17, 1998 (attorney file LA24*) discloses a method for treating diabetes employing an aP2 inhibitor.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, heterocyclic containing biphenyl compounds are provided which have the structure
where R
1
and R
2
are the same or different and are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroarylalkyl, aralkyl, cycloheteroalkyl and cycloheteroalkylalkyl;
R
3
is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, haloalkyl, polyhaloalkyl, cyano, nitro, hydroxy, amino, alkanoyl, alkylthio, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylaminosulfonyl, alkylamino, dialkylamino, all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;
R
4
is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl, haloalkyl, polyhaloalkyl, cyano, nitro, hydroxy, amino, alkanoyl, aroyl, alkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylaminosulfonyl, arylaminosulfonyl, alkylamino, dialkylamino, all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, haloalkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, acyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, aminosulfinyl, aminosulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;
X is a bond or a linker group selected from (CH
2
)
n
, O(CH
2
)
n
, S(CH
2
)
n
, NHCO, CH═CH, cycloalkylene or N(R
5
) (CH
2
)
n
, (where n=0-5 and R
5
is H, alkyl, or alkanoyl);
Z is CO
2
H or tetrazole of the formula
or its tautomer; and
the group
represents a heterocyclic group (including heteroaryl and cycloheteroalkyl groups) preferably containing 5-members within the ring and containing preferably 1-3 heteroatoms within the ring, and which may further optionally include one or two substituents which are alkyl, alkenyl, hydroxyalkyl, keto, carboxyalkyl, carboxy, cycloalkyl, alkoxy, formyl, alkanoyl, alkoxyalkyl or alkoxycarboxyl;
with the provisos that (1) n≠o when Z is CO
2
H and X is O(CH
2
)
n
, S(CH
2
)
n
or N(R
5
) (CH
2
)
n
) and
(2) when
is
then X-Z may not be O-lower alkylene-CO
2
H or —O-lower alkylene-CO
2
alkyl when R
1
and R
2
are both aryl or substituted aryl and R
3
and R
4
are each hydrogen;
and including pharmaceutically acceptable salts thereof, and prodrug esters thereof, and all stereoisomers thereof.
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, Syndrome X, diabetic complications, atherosclerosis and other chronic inflammatory and autoimmune/inflammatory diseases, wherein a therapeutically effective amount of-a compound of structure I (which inhibits aP2) is administered to a human patient in need of treatment.
The term “chronic inflammatory and autoimmune/inflammatory diseases” referred to above includes inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, rheumatoid arthritis, chronic obstructive pulmonary disease, emphysema, systemic lupus erythematosis, and other disease states involving tissue injury-, necrosis-, and/or infection-induced imbalanced inflammation associated with macrophage and leukocyte over-stimulation and excessive or dysregulated release of cellular mediators.
In addition, in accordance with the present invention, a method is provided for treating chronic and autoimmune/inflammatory diseases including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, rheumatoid arthritis, chronic obstructive pulmonary disease, emphysema, systemic lupus erythematosis, and other disease states involving tissue injury-, necrosis-, and/or infection-induced imbalanced inflammation associated with macrophage and leukocyte over-stimulation and excessive or dysregulated release of cellular mediators, wherein a therap
Magnin David R.
Robl Jeffrey A.
Sulsky Richard B.
Bristol--Myers Squibb Company
Hermenau Ronald S.
Kilcoyne John
McKane Joseph K.
Rodney Burton
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