Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-06-18
2002-02-05
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S183000, C514S218000, C514S222200, C514S228800, C514S241000, C514S247000, C514S277000, C514S359000, C514S430000, C514S431000, C514S432000, C514S433000, C514S438000, C514S439000, C514S449000, C514S450000, C514S451000, C514S452000, C514S461000, C514S463000, C514S476000, C514S506000, C514S507000, C514S529000, C514S553000, C514S557000, C514S575000, C514S579000, C514S613000, C514S675000, C514S706000, C514S708000, C514S709000, C514S715000, C514S724000, C514S740000, C514S912000, C514S913000
Reexamination Certificate
active
06344485
ABSTRACT:
BACKGROUND OF INVENTION
This invention relates to the use of prostaglandin agonists to lower the intraocular pressure of mammals and thus treat glaucoma in mammals, including humans.
Ocular hypertensive agents are useful in the treatment of a number of various ocular hypertensive Conditions, such as post-surgical and post-laser trabecuclectomy ocular hyper-tensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma; are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed. and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior Synechia in iris bombe and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central rectinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical, &bgr;-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Prostaglandins were earlier regarded as potent ocular hypertensives, however, evidence accumulated in the last two decades shows that some prostaglandins are highly effective ocular hypotensive agents and are ideally suited for the long-term medical management of glaucoma (See, for example, Starr, M. S. Exp. Eye Res. 1971, 11, pp. 170-177; Bito, L. Z.
Bilogical Protection with Prostaglandins
Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and bito, L. Z.,
Applied Pharmacology in the Medical Treatment of Glaucomas
Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505). Such prostaglandins include PGF
2&agr;
PGF
1&agr;
PGE
2
and certain lipid-soluble esters, such as C
1
to C
5
alkyl esters, e.g. 1-isopropyl ester, of such compounds.
In the U.S. Pat. No. 4,599,353 certain prostaglandins, in particular PGE
2
and PGF
2&agr;
and the C
1
to C
5
alkyl esters of the latter compound, were reported to possess ocular hypotensive activity and were recommended for use in glaucoma management.
Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et al.,
Invest. Ophthalmol Vis. Sci.
28(suppl), 284 (1987)].
The compounds used in the methods herein were first claimed in PCT application No. PCT/IB 97/01417 filed on Nov. 10, 1997 which claims priority from a U.S. application filed on Dec. 20, 1996.
Although there are a variety of treatments for glaucoma there is a continuing need and a continuing search in this field of art for alternative glaucoma therapies.
SUMMARY OF THE INVENTION
This invention is directed to a method for reducing intraocular pressure in a mammal (including humans male or female) comprising administering to a mammal a therapeutically effective amount of a compound of Formula I or Formula IA or a pharmaceutically acceptable salt or prodrug thereof.
In one aspect the Formula I or Formula IA compound is applied locally.
A preferred dosage is about 0.001 to 100 mg/kg/day of the Formula I or Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof. An especially preferred dosage is about 0.01 to 10 mg/kg/day of the Formula I or Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
The Formula I compounds are herein described below as those compounds having the following Formula I:
or a pharmaceutically-acceptable salt or prodrug thereof wherein either (i):
B is N;
A is (C
1
-C
6
)alkylsulfonyl, (C
3
-C
7
)cycloalkylsulfonyl, (C
3
-C
7
)cycloalkyl(C
1
-C
6
)alkylsulfonyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C
1
-C
4
)alkyl or halo;
Q is
—(C
2
-C
6
)alkylene-W—(C
1
-C
3
)alkylene-,
—(C
3
-C
8
)alkylene-, said —(C
3
-C
8
)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C
1
-C
4
)alkyl,
—X—(C
1
-C
5
)alkylene-,
—(C
1
-C
5
)alkylene-X—,
—(C
1
-C
3
)alkylene-X—(C
1
-C
3
)alkylene-,
—(C
2
-C
4
)alkylene-W—X—(C
0
-C
3
)alkylene-,
—(C
0
-C
4
)alkylene-X—W—(C
1
-C
3
)alkylene-,
—(C
2
-C
5
)alkylene-W—X—W—(C
1
-C
3
)alkylene-, wherein the two occurrences of W are independent of each other,
—(C
1
-C
4
)alkylene-ethenylene-(C
1
-C
4
)alkylene-,
—(C
1
-C
4
)alkylene-ethenylene-(C
0
-C
2
)alkylene-X—(C
0
-C
5
)alkylene-,
—(C
1
-C
4
)alkylene-ethenylene-(C
0
-C
2
)alkylene-X—W—(C
1
-C
3
)alkylene-,
—(C
1
-C
4
)alkylene-ethynylene-(C
1
-C
4
)alkylene-, or
—(C
1
-C
4
)alkylene-ethynylene-X—(C
0
-C
3
)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N—(C
1
-C
4
)alkyleneaminosulfonyl-, sulfonylamino, N—(C
1
-C
4
)alkylenesulfonylamino, carboxamido, N—(C
1
-C
4
)alkylenecarboxamido, carboxamidooxy, N—(C
1
-C
4
)alkylenecarboxamidooxy, carbamoyl, -mono-N—(C
1
-C
4
)alkylenecarbamoyl, carbamoyloxy, or -mono-N—(C
1
-C
4
)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C
1
-C
3
)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C
1
-C
4
)alkoxy, or carbamoyl;
Z is carboxyl, (C
1
-C
6
)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C
1
-C
4
)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C
1
-C
8
)alkylene, thio(C
1
-C
4
)alkylene or oxy(C
1
-C
4
)alkylene, said (C
1
-C
8
)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is —Ar, —Ar
1
—V—Ar
2
, —Ar
1
—S—Ar
2
or —Ar
1
—O—Ar
2
wherein Ar, Ar
1
and Ar
2
are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar
1
and Ar
2
moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R
1
, R
2
and R
3
wherein R
1
, R
2
and R
3
are hydroxy, nitro, halo, (C
1
-C
6
)alkoxy, (C
1
-C
4
)alkoxy(C
1
-C
4
)alk
Cameron Kimberly O.
Lefker Bruce A.
Benson Gregg C.
Choi Frank
Dees Jose′ G.
Pfizer Inc.
Raymer Gregory P.
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