Combination therapy for lowering and controlling intraocular...

Details Combination therapy for lowering and controlling intraocular... Combination therapy for lowering and controlling intraocular...

1995-06-15

2001-01-09

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S172000, C514S173000, C514S176000, C514S180000, C514S182000, C514S913000

Reexamination Certificate

active

06172054

ABSTRACT:

The present invention relates generally to the field of ophthalmology. In particular, the invention relates to the treatment of glaucoma using a combination of an angiostatic agent which lowers intraocular pressure (IOP) and a second IOP lowering compound.
BACKGROUND OF THE INVENTION
Although the underlying causes of glaucoma are not understood at this time, glaucoma is characterized by damage to the optic nerve, accompanied by a decrease in the normal visual field. One early warning sign of possible glaucomatous visual field loss is elevated IOP.
There are angiostatic agents which are known to lower IOP, see, for example, U.S. Pat. Nos. 4,876,250 and 5,371,078. These compounds are very effective in controlling ocular hypertension, but they usually exhibit a slow onset of action; that is, it can take several weeks before an IOP lowering effect is seen.
Other known IOP controlling agents, such as miotics, sympathomemetics, beta-blockers, carbonic anhydrase inhibitors, and prostaglandins are immediately effective in lowering IOP.
The compositions of the present invention contain an angiostatic agent which provides effective, long duration control of IOP and a second IOP lowering compound to provide immediate control of a patient's elevated IOP. This combination is more effective in that a patient's IOP can be lowered and controlled with less IOP spiking. In addition, the effectiveness of the combination is at least additive because the angiostatic agents lower IOP via a different mechanism than any of the second IOP lowering compounds described in this invention.
SUMMARY OF THE INVENTION
The present invention is directed to compositions useful in the treatment of glaucoma and ocular hypertension. The compositions contain a combination of at least one angiostatic agent and at least one other compound which lowers IOP (“second agent”). The compositions are used to lower and control IOP by topical application to a patient's affected eye(s).
DETAILED DESCRIPTION OF THE INVENTION
The development of blood vessels for the purpose of sustaining viable tissue is known as angiogenesis or neovascularization. Agents which inhibit neovascularization are known by a variety of terms such as angiostatic, angiolytic, or angiotropic agents. In addition, it has been demonstrated that many angiostatic agents have significant IOP lowering activity, Clark et al., IOVS 35 (Suppl.): 1057, 1994. For purposes of this specification, the term “angiostatic agent” means compounds which inhibit new blood vessel formation as well as lower and/or control intraocular pressure associated with glaucoma or ocular hypertension.
Without intending to be bound by any theory, it is believed that angiostatic agents act to control intraocular pressure by inhibiting the accumulation or stimulating the dissolution of amorphous extracellular material in the trabecular meshwork of the eye. The presence of this amorphous extracellular material alters the integrity of the healthy trabecular meshwork and is a symptom associated with primary open angle glaucoma (POAG). It is not well understood why this amorphous extracellular material builds up in the trabecular meshwork of persons suffering from POAG. However, it has been found that the amorphous extracellular material is generally composed of glycosaminoglycans (GAGs) and basement membrane material; see, Ophthalmology, Vol.90, No.7 (July 1983);
Mayo Clin. Proc, Vol.
61, pp.59-67 (Jan.1986); and
Pediat. Neurosci.
Vol.12, pp.240-251 (1985-86). When these materials build up in the trabecular meshwork, the aqueous humor, normally present in the anterior chamber of the eye, cannot leave this chamber through its normal route (the trabecular meshwork) at its normal rate. Therefore, a normal volume of aqueous humor is produced by the ciliary processes of the eye and introduced into the anterior chamber, but its exit through the trabecular meshwork is abnormally slow. This results in a buildup of pressure in the eye, ocular hypertension, which can translate into pressure on the optic nerve. The ocular hypertension so generated can lead to blindness due to damage to the optic nerve.
It is believed that the angiostatic agents function in the trabecular meshwork in a similar manner as shown by Ingber, et al., wherein it was shown that angiostatic steroids caused dissolution of the basement membrane scaffolding using a chick embryo neovascularization model;
Endocrinology,
119, pp.1768-1775 (1986). It is believed that angiostatic agents prevent the accumulation, or promote the dissolution of, amorphous extracellular materials in the trabecular meshwork by inhibiting the formation of basement membrane materials and glycosaminoglycans. Thus, by preventing the development of these materials or promoting their dissolution, the normal integrity of the trabecular meshwork is retained and aqueous humor may flow through the trabecular meshwork at normal rates. As a result, the intraocular pressure of the eye is controlled.
Preferred angiostatic agents are represented by the following structures:
wherein R
1
is H, &bgr;—CH
3
or &bgr;—C
2
H
5
;
R
2
is F, C
9
-C
11
, double bond, C
9
-C
11
l epoxy, H or Cl;
R
3
is H, OR
26
, OC(═O)R
27
, halogen, C
9
-C
11
double bond, C
9
-Cl, epoxy, ═O, —OH, —O— alkyl(C
1
-C
12
), —OC(═O)alkyl(C
1
-C
12
), —OC(═O)ARYL, —OC(═O)N(R)
2
or —OC(═O)OR
7,
wherein ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (C
1
-C
4
)alkyl groups, or ARYL is —(CH
2
)
f
-phenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C
1
-C
3
), alkoxy(C
1
-C
3
), thioalkoxy-(C
1
-C
3
), Cl
3
C—, F
3
C—, —NH
2
and —NHCOCH
3
and R is hydrogen, alkyl (C
1
-C
4
), or phenyl and each R can be the same or different, and R
7
is ARYL as herein defined, or alkyl(C
1
-C
12
);
R
4
is H, CH
3
, Cl or F;
R
5
is H, OH, F, Cl, Br, CH
3
, phenyl, vinyl or allyl;
R
6
is H or CH
3
;
R
9
is CH
2
CH
2
OR
26
, CH
2
CH
2
OC(═O)R
27
, H, OH, CH
3
, F, ═CH
2
, CH
2
C(═O)OR
28
, OR
26
, O(C═O)R
27
or O(C═O)CH
2
(C═O)OR
26
R
10
is —C≡CH, —CH═CH
2
, halogen, CN, N
3
, OR
26
, OC(═O)R
27
, H, OH, CH
3
or R
10
forms a second bond between positions C-16 and C-17;
R
12
is H or forms a double bond with R
1
or R
14
;
R
13
is halogen, OR
26
, OC(═O)R
27
, NH
2
, NHR
26
, NHC(═O)R
27
, N(R
26
)
2
, NC(═O)R
27
, N
3
, H, —OH, ═O, —O—P(═O)(OH)
2
, or —O—C(═O)—(CH
2
)
t
COOH where t is an integer from 2 to 6;
R
14
is H or forms a double bond with R
12
;
R
15
is H, ═O or —OH;
and R
23
with R
10
forms a cyclic phosphate;
wherein R
9
and R
15
have the meaning defined above;
or wherein R
23
is —OH, O—C(═O)—R
11
, —OP(O)—(OH)
2
, or —O—C(═O)—(CH
2
)
t
COOH wherein t is an integer from 2 to 6; and R
11
is —Y—(CH
2
)
n
—X—(CH
2
)
m
—SO
3
H, —Y′—(CH
2
)
p
—X′—(CH
2
)
q
—NR
16
R
17
or —Z(CH
2
)
r
Q,
wherein Y is a bond or —O—; Y′ is a bond, —O—, or —S—; each of X and X′ is a bond, —CON(R
18
)—, —N(R
18
)CO—, —O—, —S—, —S(O)—, or —S(O
2
)—; R
18
is hydrogen or alkyl (C
1
-C
4
); each of R
16
and R
17
is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R
16
and R
17
taken together with the nitrogen atom to which each is attached forms a monocydic heterocycle selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkyl-piperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5;
Z is a bond or —O—; r is an integer of from 2 to 9; and Q is one of the following:
(1) —R
19
—CH
2
COOH wherein R
19
is —S—, —S(O)—, —S(O)
2
—, —SO
2
N(R
20
)—, or N(R
20
)SO
2
—; and R
20
is hydrogen or lower alkyl-(C
1
-C
4
); with the proviso that the total number of carbon atoms in R
20
and (CH
2
)
r
is not greater tha

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