Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-05
2004-10-19
Richter, Johann (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S470000
Reexamination Certificate
active
06806285
ABSTRACT:
The present invention is directed to novel substituted 3-(2-aminopropyl)-1H-indol-5-ols. These novel compounds are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
BACKGROUND OF THE INVENTION
The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are is considered to be a high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
It has been found that serotonergic compounds which possess agonist activity at 5-HT
2
receptors effectively lower and control normal and elevated IOP and are useful for treating glaucoma, see commonly owned co-pending application, PCT/US99/19888. Compounds that act as agonists at 5-HT
2
receptors are known and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Pat. No. 5,494,928 discloses certain 2-(indol-1-yl)-ethylamnine derivatives that are 5-HT
2c
agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders. U.S. Pat. No. 5,571,833 discloses typtamine derivatives that are 5-HT
2
agonist for the treatment of portal hypertension and migraine. U.S. Pat. No. 5,874,477 discloses a method for treating malaria using 5-HT
2A/2C
agonists. U.S. Pat. No. 5,902,815 discloses the use of 5-HT
2A
agonists to prevent adverse effects of NMDA receptor hypo-function. WO 98/31354A2 discloses 5-HT
2B
agonists for the treatment of depression and other CNS conditions. WO 00/12475 discloses indoline derivatives as 5-HT
2B
and 5-HT
2C
receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the treatment of obesity. WO00/35922 discloses certain pyrazino[1,2-a]quinoxaline derivates as 5-HT
2C
agonists for the treatment of obsessive-compulsive disorder, depression, eating disorders, and other disorders involving the CNS. Agonist response at the 5-HT
2A
receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT
2C
receptor possible [Psychopharmacology, Vol. 121:357, 1995].
A specific disclosure in co-pending application PCT/US99/19888 relates to certain substituted &agr;-methyltryptamines which are effective agents for lowering intraocular pressure in mammals (Table 1). However, when a phenolic moiety is included in this substitution, e.g. a hydroxyl group at indole ring position five such compounds can be particularly sensitive to oxidation reactions well known to occur with phenolic compounds in general, including hydroxytryptamines [
J. Phys. Chem
. 103, 8606 (1999),
Chem. Res. Toxicol
. 11, 639 (1998),
J. Org. Chem
. 52, 2817 (1987),
J. Pharm. Sci
. 77, 911 (198 9)], which are of particular relevance to the present application. Protection of such hydroxy substituted tryptamines from oxidation can be accomplished by derivatization of the aryl hydroxy group to provide a suitable ester, carbamate, or carbonate. Though the ester, carbamate, or carbonate derivatives do not themselves possess a high affinity for the above mentioned receptors, they do have utility in the treatment of glaucoma since suitably protected phenols can be cleaved in vivo either by chemical hydrolysis or through the action of tissue esterases, thereby delivering the desired therapeutic agent, that is, the desired hydroxytryptamine compound in the present case. The concept of utilizing such derivatized phenolic compounds as chemical delivery agents is well known in the art [
Drugs Pharm. Sci
. 53, 221 (1992),
Pharm. Res
., 168 (1984)].
TABLE 1
IOP Response in hypertensive cynomolgus monkeys.
Baseline
Percent IOP Reduction ± SEM
Dose,
IOP
Hours after dose
Example
&mgr;g
(mmHg)
1
3
6
&agr;-Methyl-
250
41.8
14.2 ± 4.39
25.8 ± 5.16
30.8 ± 7.72
serotonin
Serotonin
250
33.5
13.3 ± 5.31
18.0 ± 5.12
2.0 ± 7.39
SUMMARY OF THE INVENTION
The present invention is directed to new derivatives of 3-(2-aminopropyl)-1H-indol-5-ol which can be used to lower and control IOP associated with normal-tension glaucoma, ocular hypertension, and glaucoma in warm blooded animals, including man. The compounds are formulated in pharmaceutical compositions suitable for topical delivery to the eye.
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patent: WO 00/35922 (2000-06-01), None
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May Jesse A.
Zinke Paul W.
Alcon Inc.
Copeland Barry L.
Richter Johann
Sackey Ebenezer
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