HMG-CoA reductase inhibitors and method

Details HMG-CoA reductase inhibitors and method HMG-CoA reductase inhibitors and method

2001-12-04

2003-09-16

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...

C546S093000, C546S101000, C546S111000

Reexamination Certificate

active

06620821

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns (1) certain inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) that include a pyridine containing nucleus attached by means of a linker to an HMG-binding domain sidechain, (2) pharmaceutical compositions containing such compounds and (3) a method of lowering blood serum cholesterol levels and modulating blood serum lipids employing such pharmaceutical compositions.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,686,433 to Robl discloses the structure:
wherein:
Am is a binding domain sidechain;
X is a linker;
R
1
and R
2
are the same or different and are each independently selected from:
(i) hydrogen,
(ii) alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) aralkyl,
(vi) aralkoxy,
(vii) alkenyl,
(viii) cycloalkenyl, and
(ix) heterocyclo (e.g., thienyl, benzodioxolyl);
R
3
is selected from:
(i) hydrogen,
(ii) lower alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) alkoxy,
(vi) aralkyl,
(vii) aralkoxy,
(viii) alkenyl,
(ix) cycloalkenyl,
(x) halo-substituted alkyl,
(xi) adamantyl, and
(xii) heterocyclo (e.g., thienyl, benzodioxolyl);
R
4
is selected from:
(i) hydrogen,
(ii) lower alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) alkoxy,
(vi) aralkyl,
(vii) aralkoxy,
(viii) alkenyl,
(ix) cycloalkenyl,
(x) adamantyl,
(xi) halogen,
(xii) halo-substituted alkyl (e.g., trifluoromethyl), and
(xiii) heterocyclo (e.g., thienyl, benzodioxolyl);
or R
3
and R
4
taken together can be:
but when A
m
is:
or a &dgr; lactone thereof, R
3
and R
4
cannot be (CH═CH)
2
;
R
6
is hydrogen or lower alkyl;
R
8
is hydrogen, lower alkyl, alkali metal, or alkaline earth metal;
n is 0 or 1;
p is 3, 4 or 5;
q is 0, 1, 2, or 3; and
r is 0, 1, 2, or 3.
In preferred embodiments (Am) is an HMG-binding domain sidechain having a dihydroxy or a phosphinic acid function.
The phosphinic (or phosphonic when X is CH
2
—O—) acid HMG-binding domain sidechain (A
1
) is:
wherein R
5
and R
7
are independently selected from hydrogen, lower alkyl, alkali metal ion and alkaline earth metal ion; and R
6
is hydrogen or lower alkyl.
The dihydroxy acid binding domain sidechain (A
2
is:
wherein R
6
is hydrogen or lower alkyl, R
8
is hydrogen or lower alkyl in free acid form or in the form of a physiologically acceptable and hydrolyzable ester or &dgr; lactone thereof (i.e., when Am is:
In addition, R
8
can be alkali metal ion or alkaline earth metal ion.
A suitable linker (X) is —(CH
2
)
a
—, —CH═CH—, —C≡C—, —CH
2
O—, wherein O is linked to the phosphorous atom or the aromatic anchor when Am is A
1
, and wherein O is linked to the aromatic anchor when Am is A
2
, and wherein “a” is 1, 2, or 3.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided certain pyridine-containing compounds that are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit the enzyme 3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase).
In particular, in its broadest chemical compound aspect, the present invention provides compounds of the formula I:
wherein
Z is
n is 0 or 1;
x is 0, 1, 2, 3 or 4;
y is 0, 1, 2, 3 or 4, provided that at least one of x and y is other then o;
and optionally one or more carbons of (CH
2
)
x
and/or (CH
2
)
y
may form part of a 3 to 7 membered spirocyclic ring;
R
1
and R
2
are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
R
3
is H or lower alkyl;
R
4
is H, halogen, CF
3
, hydroxy, alkyl, alkoxy, carboxyl, carboxylalkyl-, aminoalkyl, amino, alkanoylamino, aroylamino, cyano, alkoxyCON(R
10
)—, R
11
R
12
NCO—, R
11
R
12
NCO
2
—, R
13
SO
2
N(R
10
)—, R
11
R
12
NSO
2
N(R
10
)—, R
13
OCO
2
— or R
13
OCO—;
R
13
is alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl,
R
11
and R
12
, and R
10
are the same or different and are independently selected from H, alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl; or R
11
and R
12
may be taken together with the nitrogen to which they are attached to form a stable 3 to 8 membered heterocyclic ring which, where applicable, includes a total of 1 to 3 heteroatoms in the ring, which heteroatoms may be N, O or S;
R
7
is H or lower alkyl; and
represents a single bond or a double bond (which may be cis or trans);
and including pharmaceutically acceptable salts thereof when R
3
is H, esters thereof, prodrug esters thereof, and all stereoisomers thereof.
Preferably, the Z group will be in form of a free acid, a physiologically acceptable and hydrolyzable ester or &dgr; lactone thereof, or an alkali metal salt, alkaline earth metal salt or an amino acid salt.
Preferred are compounds of formula I of the invention wherein
R
1
and R
2
are independently selected from alkyl, cycloalkyl and aryl;
R
4
is H, alkyl, or halogen;
x is 2 or 3;
y is o; and
n is o.
More preferred are compounds of formula I of the invention wherein R
1
is aryl (especially substituted aryl as defined hereinafter);
R
2
is alkyl or cycloalkyl;
R
4
is H;
x is 3;
y is o;
n is o; and
is a double bond.
Still more preferred are compounds of formula I of the invention wherein
R
1
is substituted aryl, preferably 4-fluorophenyl, 4-fluoro-3-methylphenyl or 3,5-dimethylphenyl;
R
2
is alkyl or cycloalkyl, preferably isopropyl, t-butyl or cyclopropyl;
R
4
is H;
x is 3;
y is o;
n is o;
is a double bond, preferably “trans”; and
Z is
or an alkali metal salt thereof, alkaline earth metal salt or an amino acid salt.
Most preferred compounds of formula I of the invention will have the structure IA: IA
or an alkali or alkaline earth metal (such as Na, K or Ca) salt thereof, or amino acid salt (such as arginine), wherein R
5
and R
6
are the same or different and independently selected from H, halogen and/or alkyl (preferably 4-fluoro, 4-fluoro-3-methyl or 3,5-dimethyl); and
R
2
is alkyl or cycloalkyl, preferably isopropyl, t-butyl or cyclopropyl.
In another aspect, the present invention provides pharmaceutical compositions, useful as hypolipidemic or hypocholesterolemic agents, or hypotriglyceridemic agents, or anti-Alzheimer's agents, or anti-osteoporosis agents as well as other uses as described herein, comprising a hypolipidemic or hypocholesterolemic or hypotriglyceridemic or anti-Alzheimer's disease or anti-osteoporosis amount, or other therapeutically effective amount (depending upon use) of a compound of formula I in accordance with this invention, in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of inhibiting cholesterol biosynthesis or lowering blood serum cholesterol levels and/or modulating blood serum cholesterol levels such as lowering LDL cholesterol and/or increasing HDL cholesterol, or treating dyslipidemia, mixed dyslipidemia, hyperlipidemia, hypercholesterolemia, hypo &agr;-lipoproteinemia, LDL Pattern B, LDL Pattern A, hyperlipoproteinemia or hypertriglyceridemia, and other aberrations of apolipoprotein B metabolism, or reducing levels of Lp(a), or treating or preventing other cholesterol-related diseases, or treating or preventing or reversing progression of atherosclerosis, or preventing or treating Alzheimer's disease, or preventing or treating osteoporosis and/or osteopenia, or reducing inflammatory markers such as C-reactive protein, or preventing or treating low grade vascular inflammation, or preventing or treating stroke, or preventing or treating dementia, or preventing and treating coronary heart disease (including primary and secondary prevention of myocardial infarction), or preventing or treating stable and unstable angina, or primary prevention of coronary events, or secondary prevention of cardiovascular events, or preventing or treating peripheral vascular disease, preventing or treating peripheral arterial disease, or pre

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