Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-01
2001-01-23
Badio, Barbara (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255030, C514S383000, C514S396000, C514S406000, C544S177000, C544S396000, C548S262200, C548S373100, C548S572000
Reexamination Certificate
active
06177427
ABSTRACT:
This invention is directed to the use of non-steroidal glucocorticoid antagonists for treating glaucoma and ocular hypertension.
BACKGROUND OF THE INVENTION
Current glaucoma therapy involves treating an important risk factor for the disease, that is, elevated intraocular pressure (IOP). For example, beta-blockers and carbonic anhydrase inhibitors lower IOP by decreasing aqueous humor production. It would be advantageous to control IOP without decreasing aqueous humor production as the aqueous humor is the fluid that nourishes the anterior parts of the eye that are devoid of blood vessels, such as, the cornea and the lens.
SUMMARY OF THE INVENTION
Non-steroidal glucocorticoid antagonists (NSGAs) and their pharmaceutical formulations are useful for treating glaucoma and ocular hypertension. The invention is also directed to methods for controlling glaucoma and ocular hypertension using NSGAs, some of which are novel.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Glaucomatous damage to vision is usually due to elevated IOP in a pressure sensitive eye. In glaucoma the trabecular meshwork (TM) of the eye is damaged causing increased aqueous humor outflow resistance resulting in elevated IOP. Glucocorticoids have been associated with the development of ocular hypertension and primary open angle glaucoma (Kass, et al.,
Corticosteroid
-
induced glaucoma,
In Ritch, R., Shields, M. B., Krupin, T. (eds.), The Glaucomas, The C. V. Mosby Company, St. Louis, Mo., pp. 1161-1168 (1989); DeSantis, et al.,
Dexamethasone
-
induction of ocular hypertension in the primate,
ARVO Abstracts. Invest. Ophthalmol. Vis. Sci. 31 (Suppl.): 99 (1990); Knepper, et al.,
Intraocular pressure and glycosaminoglycan distribution in the rabbit eye: effect of age and dexamethasone,
Exp. Eye Res. 27: 567-575 (1978); Francois, et al.,
Ultrastructural and morphometric study of corticosteroid glaucoma in rabbits,
Ophthalmic Res. 16: 168-178 (1984); Lorenzetti, O. J.,
Effects of corticosteroids on ocular dynamics in rabbits,
J. Pharmacol. Exp. Therap. 175: 763-772 (1970); and Zhan, et al.,
Steroid glaucoma: corticosteroid
-
induced ocular hypertension in cats,
Exp. Eye Res. 54: 211-218 (1992)). Glaucoma patients have also been reported to have higher levels of the endogenous glucocorticoid, cortisol (Rozsival, et al.,
Aqueous humour and plasma cortisol levels in glaucoma and cataract patients,
Current Eye Research 1: 391-396 (1981); Ray, et al.,
Plasma cortisol in glaucoma,
Ann. Ophthalmol. 9: 1151-1154 (1977); and Schwartz,
Increased plasma free cortisol in ocular hypertension and open angle glaucoma,
Arch. Ophthalmol. 105: 1060-1065 (1987)).
It is known that trabecular meshwork cells have glucocorticoid receptors and that glucocorticoid binding with these receptors causes a change in trabecular as meshwork cell gene expression. Known manifestations of this change include a reorganization of the cytoskeleton (Wilson, et al.,
Dexamethasone induced ultrastructural changes in cultured human trabecular meshwork cells,
Cur. Eye Res. 12: 783-793 (1993) and Clark, et al.,
Glucocorticoid
-
induced formation of cross-linked actions networks in cultured human trabecular meshwork cells,
Invest. Ophthalmol. Vis. Sci. 35: 281-294 (1994)) and increased deposition of the extracellular matrix material in trabecular meshwork cells. As a result, the trabecular meshwork becomes “clogged” and unable to perform one of its most critical functions, that is, serving as a gateway for aqueous humor flow from the anterior chamber of the eye. When the aqueous humor flow out of the eye via the trabecular meshwork is diminished, the intraocular pressure of the eye rises. If this state of elevated intraocular pressure is maintained or frequently occurs, the optic nerve head can be damaged resulting in the loss of visual field. Loss of visual field is the hallmark symptom associated with glaucoma.
Endogenous glucocorticoids may be responsible for producing the changes in the trabecular meshwork that lead to ocular hypertension and glaucoma. It is believed that non-steroidal glucocorticoid antagonists bind to the glucocorticoid receptor in trabecular meshwork cells, and thereby prevent binding of endogenous glucocorticoids to the glucocorticoid receptor. They may also displace endogenous glucocorticoids which are bound to glucocorticoid receptors. Use of the compounds of the present invention is advantageous over existing therapies in that the compounds function at the disease site, that is, at the trabecular meshwork cell level, rather than indirectly addressing elevated intraocular pressure by suppressing aqueous humor formation.
Ketoconazole and clotrimazole are known glucocorticoid antagonists. (Loose, et al.,
Ketoconazole Binds to Glucocorticoid Receptors and Exhibits Glucocorticoid Antagonist Activity in Cultured Cells,
J. Clin. Invest. 72: 404-408 (1983)). They are not known to be useful in treating or controlling glaucoma.
Non-steroidal glucocorticoid antagonists which are particularly useful in treating glaucoma or ocular hypertension have the following structure:
WHEREIN:
n=0,1,2;
X=CH or N;
R1=H, F, Cl, Br, R2, OR2, N(R2)
2
, COOH, CONH
2
, CONHR2, CON(R2)
2
, CH
2
N(CH
2
CH
2
)O;
R2=C
1
-C
6
alkyl;
Y=N-imidazolyl, N-pyrrolidinyl, N-(2-hydroxymethyl)pyrrolidinyl, N-triazolyl, N-pyrazolyl each optionally substituted with CH
3
, SH or S—C(4—Cl—C
6
H
4
)
3
; OH, O(CH
2
)
2
N(CH
2
CH
2
)
2
O, O(CH
2
)
2
N(CH
2
CH
2
)
2
N(CH
2
)
2
OH;
and all pharmaceutically acceptable salts and esters.
Most preferred compounds include the following specific compounds:
Names of Compounds:
1 Clotrimazole
2 N-(Triphenylmethyl)imidazole
3 N-([2-Fluoro-9-phenyl]fluorenyl)imidazole
4 N-([2-Pyridyl]diphenylmethyl)imidazole
5 N-(2-[4,4′,4″-Trichlorotrityl]oxyethyl)morpholine
6 1-(2[4,4′,4″-Trichlorotrityl]oxyethyl)-4-(2-hydroxyethyl)piperazine dimaleate
7 N-([4,4′,4″]-Trichlorotrityl)imidazole
8 9-(3-Mercapto-1,2,4-trazolyl)-9-phenyl-2,7-difluorofluorenone
9 1-(2-Chlorotrityl)-3,5-dimethylpyrazole
10 4-(Morpholinomethyl)-A-(2-pyridyl)benzhydrol
11 5-(5-Methoxy-2-(N-methylcarbamoyl)phenyl)dibenzosuberol
12 N-(2-Chlorotrityl)-L-prolinol acetate
13 1-(2-Chlorotrityl)-2-methylimidazole
14 1-(2-Chlorotrityl)-1,2,4-triazole
15 1, S-Bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol
16 N-((2,6-dichloro-3-methylphenyl)diphenyl)methylimidazole
17 Ketoconazole
Topical formulations contain about 0.05 to 5 wt. % of a non-steroidal glucocorticoid antagonist. Systemic formulations contain about 10 to 1000 mg.
The formulations can be administered systemically or topically, preferably topically, one to four times daily according to the discretion of a skilled clinician.
The following examples are not meant to be limiting.
REFERENCES:
patent: 3321366 (1967-05-01), Mussell et al.
patent: 3657445 (1972-04-01), Buchel et al.
patent: 3897438 (1975-07-01), Draber et al.
patent: 5234634 (1993-08-01), Janoff et al.
Loose et al., “Ketoconazole binds to glucocorticoid receptors and exhibits glucocrticoid antagonist activity in cultured cells.” J. Clin. Invest., vol. 72, pp. 404-408, 1983.
Lorenzetti, “Effects of corticosteroids on ocular dynamics in rabbits.” J. Pharm. Exp. Ther., vol. 175(3), pp. 763-772, 1970.
Zhan et al., “Steoid glaucoma: Corticosteroid-induced ocular hypertension in cats.” Exp. Eye Res., vol. 54, pp. 211-218, 1992.
Kass, et al., Corticosteroid-induced glaucoma, In Ritch, R., Shields, M.B., Krupin, T. (eds.), The Glaucomas, The C. V. Mosby Company, St. Louis, MO, pp. 1161-1168 (1989).
DeSantis, et al., Dexamethasone-induction of ocular hypertension in the primate, ARVO Abstracts. Invest. Ophthalmol. Vis. Sci. 31(Suppl.):99 (1990).
Knepper, et al., Intracular pressure and glycosaminoglycan distribution in the rabbit eye: effect of age and dexamethasone, Exp. Eye Res. 27:567-575 (1978).
Francois, et al., Ultrasonic and morphometric study of corticosteroid glaucoma in rabbits, Ophthalmic Res. 16:168-178 (1984).
Lorenzet
Clark Abbot F.
Conrow Raymond E.
Alcon Laboratories Inc.
Badio Barbara
Yeager Sally
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