Methods of treating excessive intraocular pressure

Details Methods of treating excessive intraocular pressure Methods of treating excessive intraocular pressure

2001-06-29

2003-01-21

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S414000, C514S913000

Reexamination Certificate

active

06509332

ABSTRACT:

This invention relates to methods of using substituted indole compounds in the treatment, prevention, inhibition or alleviation of the problems associated with excessive intraocular pressure. More particularly, the present invention provides new used of substituted indole compounds in methods of lowering intraocular pressure in a mammal, preferably in a human.
BACKGROUND OF THE INVENTION
Intraocular pressure elevation in disease states such as glaucoma results from an imbalance between the normal production and outflow of aqueous humor. Excessive pressure increases resulting therefrom can lead to a breakdown of ocular tissues, including ocular nerve damage, and blindness.
PCT publication WO 98/02155 (Korsgaard et al.) teaches methods of using raloxifene in the lessening of intraocular pressure.
U.S. Pat. No. 5,948,804 (Jeon et al.) teaches the use of substituted indole compounds having the general structure:
in the treatment or lowering of intraocular pressure.
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 lessening intraocular pressure in a mammal, preferably in a human, the methods comprising administering to a mammal in need thereof a pharmaceutically effective amount of a 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 halogen; 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
-C4)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 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 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
an

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