Combinations of statins and estrogenic agents

Details Combinations of statins and estrogenic agents Combinations of statins and estrogenic agents

2001-06-29

2002-10-15

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S323000, C514S339000, C514S451000

Reexamination Certificate

active

06465454

ABSTRACT:

This invention relates to methods of using substituted indole compounds in the combination with statins for the treatment, prevention, inhibition or alleviation of cardiovascular disease, and related pharmaceutical compositions and kits.
BACKGROUND OF THE INVENTION
EP 0 802 183 A1 and U.S. Pat. No. 5,780,497 describe substituted indole compounds of the formulae below:
as well as their use as estrogenic agents, including the treatment of bone loss, cardiovascular disease, maladies associated with or resulting from the proliferation or abnormal development of endometrial or endometrial-like tissues, and disease states or syndromes associated with estrogen deficiency.
EP 0 802 184 A1, published Oct. 22, 1997, describes comparable uses for substituted indole compounds of the formulae below.
Analogous indole compounds having the general structures:
are described in U.S. Pat. No. 5,880,137 (Miller et al.).
DESCRIPTION OF THE INVENTION
This invention comprises methods of treating, preventing, alleviating or inhibiting cardiovascular disease, including coronary artery disease, and for lowering blood cholesterol levels in a mammal, preferably in a human, the methods comprising administering to a mammal in need thereof a pharmaceutically effective combination of:
a) a pharmaceutically effective amount of a statin compound, such as, but not limited to, Cervistatin, Fluvastatin, Atorvastatin, Simvastatin, Pravastatin or Lovastatin, or a pharmaceutically acceptable salt of these statin compounds; and
b) a pharmaceutically effective amount of a substituted indole compound of the formulae I or II, below:
wherein Z is a moiety selected from the group of:
wherein:
R
1
is selected from H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
(straight chain or branched or cyclic) alkyl ethers thereof, benzyloxy, or halogens; or C
1
-C
4
halogenated ethers including trifluoromethyl ether and trichloromethyl ether.
R
2
, R
3
, R
5
, and R
6
are independently selected from H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
alkyl ethers (straight chain or branched or cyclic) thereof, halogens, or C
1
-C
4
halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, C
1
-C
6
alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R
1
is H, R
2
is not OH;
R
4
is selected from H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
alkyl ethers (straight chain or branched or cyclic) thereof, benzyloxy, halogens, or C
1
-C
4
halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, C
1
-C
6
alkyl (straight chain or branched), or trifluoromethyl;
X is selected from H, C
1
-C
6
alkyl, cyano, nitro, trifluoromethyl, halogen;
n is 1, 2 or 3;
Y is selected from:
a) the moiety:
 wherein R
7
and R
8
are independently selected from the group of H, C
1
-C
6
alkyl, or phenyl optionally substituted by CN, C
1
-C
6
alkyl (straight chain or branched), C
1
-C
6
alkoxy (straight chain or branched), halogen, —OH, —CF
3
, or —OCF
3
;
b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)-, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl;
c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)-, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl;
d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)-, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl; or
e) a bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)-, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
) alkyl;
and the pharmaceutically acceptable salts thereof.
The more preferred substituted indole compounds of this invention are those having the general structures I or II, above, wherein:
R
1
is selected from H, OH or the C
1
-C
12
esters or alkyl ethers thereof, benzyloxy, or halogen;
R
2
, R
3
, R
5
, and R
6
are independently selected from H, OH or the C
1
-C
12
esters or alkyl ethers thereof, halogen, cyano, C
1
-C
6
alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when R
1
is H, R
2
is not OH;
R
4
is selected from H, OH or the C
1
-C
12
esters or alkyl ethers thereof, benzyloxy, halogen, cyano, C
1
-C
6
alkyl, or trihalomethyl;
X is selected from H, C
1
-C
6
alkyl, cyano, nitro, trifluoromethyl, halogen;
Y is the moiety
R
7
and R
8
are selected independently from H, C
1
-C
6
alkyl, or combined by —(CH
2
)
p
—, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H, —CN, —CONH(C
1
-C
4
), —NH
3
, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, —NHSO
2
(C
1
-C
4
), —NHCO(C
1
-C
4
), and —NO
3
; and the pharmaceutically acceptable salts thereof.
The rings formed by a concatenated R
7
and R
8
, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
The most preferred substituted indole compounds of the present invention are those having the structural formulas I or II, above, wherein R
1
is OH; R
2
-R
6
are as defined above; X is selected from the group of Cl, NO
2
, CN, CF
3
, or CH
3
; and Y is the moiety
and R
7
and R
8
are concatenated together as —(CH
2
)
r
—, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trih

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