Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-02-05
2004-04-20
Fay, Zorreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C514S913000
Reexamination Certificate
active
06723748
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of cloprostenol and fluprostenol analogues for the treatment of glaucoma and ocular hypertension.
Cloprostenol and fluprostenol, both known compounds, are synthetic analogues of PGF
2&agr;
a naturally-occurring F-series prostaglandin (PG). Structures for PGF
2&agr;
,(I), cloprostenol (II), and fluprostenol (III), are shown below:
The chemical name for cloprostenol is 16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF
2&agr;
. Monograph No. 2397 (page 375) of
The Merck Index,
11th Edition (1989) is incorporated herein by reference to the extent that it describes the preparation and known pharmacological profiles of cloprostenol. Fluprostenol has 15 the chemical name 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor PGF
2&agr;
. Monograph No. 4121 (pages 656-657) of
The Merck Index,
11th Edition (1989) is incorporated herein by reference to the extent that it describes the preparation and known pharmacological profiles of fluprostenol. Cloprostenol and fluprostenol are 16-aryloxy PGs and, in addition to the substituted aromatic ring, differ from the natural product PGF
2&agr;
in that an oxygen atom is embedded within the lower (omega) chain. This oxygen interruption forms an ether functionality.
Naturally-occurring prostaglandins are known to lower intraocular pressure (IOP) after topical ocular instillation, but generally cause inflammation, as well as surface irritation characterized by conjunctival hyperemia and edema. Many synthetic prostaglandins have been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects which severely restrict clinical utility.
SUMMARY OF THE INVENTION
It has now been unexpectedly found that certain novel cloprostenol and fluprostenol analogues are useful in treating glaucoma and ocular hypertension. In particular, topical application of ophthalmic compositions comprising these novel cloprostenol and fluprostenol analogues result in significant IOP reduction.
DETAILED DESCRIPTION OF THE INVENTION
The compounds useful in the present invention have the following general formula:
wherein:
R
1
=H; C
1
-C
12
straight-chain or branched alkyl; C
1
-C
12
straight-chain or branched acyl; C
3
-C
8
cycloalkyl; or a cationic salt moiety;
R
2
, R
3
=H, or C
1
-C
5
straight-chain or branched alkyl; or R
2
and R
3
taken together may represent O;
X=O, S, or CH
2
;
represents any combination of a single bond, or a cis or frans double bond for the alpha (upper) chain; and a single bond or trans double bond for the omega (lower) chain;
R
9
=H, C
1
-C
10
straight-chain or branched alkyl, or C
1
-C
10
straight-chain or branched acyl;
R
11
=H, C
1
-C
10
straight-chain or branched alkyl, or C
1
-C
10
straight-chain or branched acyl;
Y=O; or H and OR
15
in either configuration wherein R
15
=H, C
1
-C
10
straight-chain or branched alkyl, or C
1
-C
10
straight-chain or branched acyl; and
Z=Cl or CF
3
;
with the proviso that when R
2
and R
3
taken together represent O, then R
1
≠C
1
-C
12
straight-chain or branched acyl; and when R
2
=R
3
=H, then R
1
≠a cationic salt moiety.
The term “acyl” represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and single bond to another carbon atom.
The term “acylamino” represents a group that is linked by an amino atom that is connected to a carbon atom has a double bond to an oxygen group and a single bond to a carbon atom or hydrogen atom.
The term “acyloxy” represents a group that is linked by an oxygen atom that is connected to a carbon that has a double bond to an oxygen atom and single bond to another carbon atom.
The term “alkenyl” includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon—carbon double bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkeny groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.
The term “alkoxy” represents an alkyl group attached through an oxygen linkage.
The term “alkyl” includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
The term “alkylamino” represents an alkyl group attached through a nitrogen linkage.
The term “alkynyl” includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon—carbon triple bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkynyl groups include, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 2-pentynyl.
The term “aryl” refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
The term “carbonyl” represents a group that has a carbon atom that has a double bond to an oxygen atom.
The term “carbonylalkoxy” represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to an alkoxy group.
The term “cationic salt moiety” includes alkali and alkaline earth metal salts as well as ammonium salts.
The term “carbonyloxyl” represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to a second oxygen atom.
The term “cycloalkyl” includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.
The term “dialkylamino” represents two alkyl groups attached through a nitrogen linkage.
The term “halogen” and “halo” represents fluoro, chloro, bromo, or iodo.
The term “heteroaryl” refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
The term “lower alkyl” represents alkyl groups containing one to six carbons (C
1
-C
6
).
Preferred compounds include: cloprostenol isopropyl ester (Table 1, compound 1A), fluprostenol isopropyl ester (compound 1B), 16-phenoxy-17,18,19,20-tetranor PGF
2&agr;
isopropyl ester (compound 2), 17-phenyl-18,19,20-trinor PGF
2&agr;
, isopropyl ester (compound 3), 13,14-dihydro-17-phenyl-18,19,20-trinor PGF
2&agr;
) isopropyl ester (compound 4), the 3-oxa form of cloprostenol isopropyl ester (Table 2, compound 5), 13,14-dihydrofluprostenol isopropyl ester (compound 6), cloprostenol-1-ol (compound 7), and 13,14-dihydrocloprostenol-1-ol pivaloate (compound 8).
TABLE 1
COMPOUND NAME
COMPOUND STRUCTURE
1A
Cloprostenol, isopropyl ester
1B
Fluprostenol, isopropyl ester
2
16-Phenoxy-17,18,19,20- tetranor PGF
2&agr;
, isopropyl ester
3
17-Phenyl-18,19,20-trinor PGF
2&agr;
, isopropyl ester
4
13,14-Dihydro-17-phenyl- 18,19,20-trinor PGF
2&agr;
, isopropyl ester
TABLE 2
COMPOUND NAME
COMPOUND STRUCTURE
5
3-oxacloprostenol isopropyl ester
6
13,14-dihydrofluprostenol isopropyl ester
7
cloprostenol-1-ol
8
13,14-dihydrocloprostenol-1-ol pivaloate
The compounds of formula (IV) are useful in lowering intraocular pressure and thus are useful in the treatment of glaucoma. Such comp
Bishop John E.
Klimko Peter G.
Sallee Verney L.
Zinke Paul W.
Alcon Manufacturing Ltd.
Copeland Barry L.
Fay Zorreh
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