Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-18
2003-03-25
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S211050, C514S211090, C514S211110, C540S488000, C540S490000, C540S547000, C540S548000, C540S552000
Reexamination Certificate
active
06537987
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to squalene synthetase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat hypercholesterolemia, hypertriglyceridemia, atherosclerosis, fungal infections, acne and Alzheimer's disease in mammals, including humans.
Plasma cholesterol levels have been positively correlated with the incidence of clinical events associated with coronary heart disease (CHD). Thus, pharmacological interventions that reduce cholesterol levels in mammals have a beneficial effect on CHD. In particular, decreased plasma low density lipoprotein (LDL) cholesterol levels are associated with decreased atherosclerosis and a decreased risk of CHD, and hypolipidemic agents used in either monotherapy or combination therapy are effective at reducing plasma LDL cholesterol levels and the subsequent risk of CHD.
Cholesterol metabolism in mammals involves a series of pathways including cholesterol absorption in the small intestine, cholesterol biosynthesis in numerous tissues (primarily the liver and small intestine), bile acid biosynthesis in the liver and reabsorption in the small intestine, synthesis of cholesterol-containing plasma lipoproteins by the liver and intestine, catabolism of the cholesterol-containing plasma lipoproteins by the liver and extrahepatic tissues and secretion of cholesterol and bile acids by the liver.
Cholesterol synthesis occurs in multiple tissues, but principally in the liver and the intestine. It is a multistep process starting from acetyl-coenzyme A catalyzed by a series of enzymes including hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, HMG-CoA synthase, squalene synthetase, squalene epoxidase, squalene cyclase and lanosterol demethylase. Inhibition of catalysis by these enzymes or blocking HMG-CoA reductase gene expression is recognized as an effective means to reduce cholesterol biosynthesis (thus inhibitors thereof are referred to as cholesterol synthesis inhibitors) and can lead to a reduction in cholesterol levels. For example, there are known HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin) that are used for the treatment of hypercholesterolemia.
Recently adopted National Cholesterol Education Program guidelines recommend aggressive lipid-lowering therapy for patients with pre-existing cardiovascular disease or for those with multiple factors that place them at increased risk.
The term squalene synthetase inhibitor refers to compounds that inhibit the condensation of 2 molecules of famesylpyrophosphate to form squalene, a reaction that is catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1969; 15: 393-454 and Meth. Enzymol. 1985; 110:359-373 and references contained therein). A summary of squalene synthetase inhibitors has been compiled (Curr. Op. Ther. Patents (1993) 8614). European patent publication 0 567 026 A1 discloses certain 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their use in the treatment of hypercholesterolemia and as fungicides. European patent publication 0 645 378 A1 discloses certain condensed seven- or eight-membered heterocycles as squalene synthetase inhibitors and their use in treatment and prevention of hypercholesterolemia and fungal infections. European patent publication 0 645 377 A1 discloses certain benzoxazepine derivatives as squalene synthetase inhibitors useful for the treatment of hypercholesterolemia or coronary sclerosis. European patent publication 0 611 749 A1 discloses certain substituted amic acid derivatives useful for treatment of arteriosclerosis. European patent publication 0705607 A2 discloses certain condensed seven- or eight-membered heterocyclic compounds useful as antihypertriglyceridemic agents. PCT Publication WO 96/09827 discloses certain combinations of cholesterol absorption inhibitors and cholesterol synthesis inhibitors including benzoxazepin derivatives and benzothiazepinone derivatives. European patent publication 0710725 A1 discloses a process for producing certain optically active compounds, including benzoxazepine compounds, having plasma cholesterol and triglyceride lowering activities.
Thus, although there are a variety of hypercholesterolemia therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.
SUMMARY OF THE INVENTION
This invention is directed to cholesterol synthesis inhibitor compounds of FORMULA I useful for the treatment of hypercholesterolemia, hypertriglyceridemia, atherosclerosis, fungal infections, Alzheimer's disease and acne.
The compounds of this invention have the Formula I
or the pharmaceutically acceptable cationic and anionic salts, prodrugs or stereoisomers thereof wherein
X is oxy, thio, —S(O)— or —S(O)
2
—;
Y is carbonyl or methylene;
R
1
and R
2
are each independently hydrogen, halo, hydroxyl, trifluoromethyl, (C
1
-C
4
)alkyl, fluorinated (C
1
-C
4
)alkyl having from 1 to 9 fluorines, (C
1
-C
4
)alkoxy, fluorinated (C
1
-C
4
)alkoxy having from 1 to 9 fluorines, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulfinyl, (C
1
-C
4
)alkylsulfonyl, phenyl, amino, mono-N- or di-N,N-(C
1
-C
4
)alkylamino, carboxyl, (C
1
-C
4
)alkoxycarbonyl, carbamoyl, mono-N- or di-N,N-(C
1
-C
4
)alkylcarbamoyl, (C
1
-C
4
)alkanoylamino, fluorinated (C
1
-C
4
)alkanoylamino having from 1 to 9 fluorines, (C
1
-C
4
)alkylsulfonylamino or fluorinated (C
1
-C
4
)alkylsulfonylamino having from 1 to 9 fluorines, (C
1
-C
4
)alkanoyl, (C
1
-C
6
)alkanoyl(C
1
-C
6
)alkyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl or isothiazolyl wherein said preceding heterocycles are carbon linked or wherein R
1
and R
2
can be taken together to form a five, six or seven membered carbocyclic ring or can be taken together to form methylenedioxyl, ethylenedioxyl or propylenedioxyl and such rings formed by taking R
1
and R
2
together are fused at the 7 and 8 positions;
R
3
, R
9
and R
10
are each independently hydrogen, halo, hydroxyl, trifluoromethyl, (C
1
-C
4
)alkyl, fluorinated (C
1
-C
4
)alkyl having from 1 to 9 fluorines, (C
1
-C
4
)alkoxy, fluorinated (C
1
-C
4
)alkoxy having from 1 to 9 fluorines, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulfinyl, (C
1
-C
4
)alkylsulfonyl, phenyl, amino, mono-N- or di-N,N-(C
1
-C
4
)alkylamino, carboxyl, (C
1
-C
4
)alkoxycarbonyl, carbamoyl, mono-N- or di-N,N-(C
1
-C
4
)alkylcarbamoyl, (C
1
-C
4
)alkanoylamino, fluorinated (C
1
-C
4
)alkanoylamino having from 1 to 9 fluorines, (C
1
-C
4
)alkylsulfonylamino or fluorinated (C
1
-C
4
)alkylsulfonylamino having from 1 to 9 fluorines, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyl(C
1
-C
6
)alkyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl or isothiazolyl wherein said preceding heterocycles are carbon linked or wherein R
3
and R
9
can be taken together to form a five, six or seven membered carbocyclic ring or can be taken together to form methylenedioxyl, ethylenedioxyl or propylenedioxyl and such rings formed by taking R
3
and R
9
together are fused at the 2′ and 3′ or 3′ and 4′ positions;
R
4
is (C
1
-C?)alkyl, (C
1
-C
7
)alkenyl or (C
3
-C
4
)cycloalkylmethyl or said (C
1
-C
7
)alkyl, (C
1
-C
7
)alkenyl or (C
3
-C
4
)cycloalkylmethyl is optionally mono-, di-, or tri-substituted wherein the substituents are independently chosen from hydroxyl, oxo, (C
1
-C
4
)alkyl, amino, carboxy, thiol, (C
1
-C
4
)alkoxy, fluorinated (C
1
-C
4
)alkoxy having from 1 to 9 fluorines, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulfinyl, (C
1
-C
4
)alkylsulfonyl, mono-N- or di-N,N-(C
1
-C
4
)alkylamino, mono-N- or di-N,N-(C
1
-C
4
)alkylaminocarbonyl, mono-N-or di-N,N(C
1
-C
4
)alkylaminosulfonyl; or
R
4
is (C
1
-C
7
)alkyl substituted with 1 to 15 fluorines or (C
3
-C
4
)cycloalkylmethyl substituted with 1 to 9 fluorines; or
R
4
is het(C
1
-C
6
)alkyl wherein het is a 4-7 member saturated or unsaturated heterocycle containing independently one to three O, N or S atoms and said het is
Hamanaka Ernest S.
Hayward Cheryl M.
Benson Gregg C.
Coleman Brenda
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
LandOfFree
4,1-benzoxazepines or 4,1-benzothiazepines and their use as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 4,1-benzoxazepines or 4,1-benzothiazepines and their use as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 4,1-benzoxazepines or 4,1-benzothiazepines and their use as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3069253