13-Thia prostaglandins for use in glaucoma therapy

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai

Reexamination Certificate

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C562S428000

Reexamination Certificate

active

06172109

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to the use of certain prostaglandin analogs for the treatment of glaucoma and ocular hypertension. As used herein, the terms “prostaglandin” and “PG” shall refer to prostaglandins and derivatives and analogs thereof, except as otherwise indicated by context.
Naturally-occurring prostaglandins, especially prostaglandins of the F series (such as PGF
2&agr;
), are known to lower intraocular pressure (IOP) after topical ocular instillation, but can cause conjunctival hyperemia and/or edema as well as inflammation. Many synthetic prostaglandins have been observed to lower intraocular pressure, but most such compounds also produce the aforementioned side effects which significantly limit their clinical utility.
Various attempts have been made to overcome these well-known side-effects. Some have synthesized or searched out derivatives of naturally-occurring prostaglandins in an attempt to design out selectively the side effects while maintaining the IOP-lowering effect. See, e.g., Bishop et al. (U.S. Pat. No. 5,510,383) Stjernschantz et al. (U.S. Pat. Nos. 5,422,368, 5,321,128, and 5,296,504), Woodward et al. (U.S. Pat. No. 5,093,329), Chan et al. (WO 92/08465 and U.S. Pat. No. 5,446,041). Others, including Ueno et al. (EP 330 511 A2) and Wheeler (EP 435 682 A2) have tried complexing prostaglandins with various cyclodextrins.
Certain sulfur containing prostaglandin derivatives are known in the art. Glutathione-prostaglandin conjugates and related compounds have been reported in the literature relating to the cytotoxicity of PGA and PGD. See e.g. Cagen, Fales and Pisano, J. Biological Chemistry 251, 6550-54 (1976); Cagen and Pisano, Biochimica et Biophysica Acta 573, 547-51 (1979); Honn and Marnett, Biochemical and Biophysical Research Comn. 129, 34-40 (1985); Atsmon et al., Cancer Res. 50, 1879-85 (1990); Parker and Ankel, Biochemical Pharmacology 43,1053-60 (1992); Ohno, et al., Eicosanoids 5, 81-85 (1992). However, the biological effects of these compounds, other than cytotoxicity or the lack thereof, have not been reported. Stjernschantz et al. (U.S. Pat. No. 5,516,796) disclose ring substituted thioprostaglandins and thioprostagiandin-like compounds for the treatment of glaucoma or ocular hypertension. 7-Thioprostaglandin derivatives may inhibit chemokine-induced cell migration (Kataoka et al. (WO97/01534)) and have been disclosed for the treatment of skin disease (see Hanahima et al. CA Selects: Prostaglandins, 125:185911p (1996)). Also, compounds which are derivatives of 13-thiaprostenoic acid have been reported to lower blood pressure (see, e.g., Radunz et al. (U.S. Pat. No. 4,309,441)).
SUMMARY OF THE INVENTION
It has now been discovered that certain 13 thia analogs of PGF
2&agr;
will lower or control IOP with no or significantly reduced side effects of conjunctival hyperemia and/or edema. An agent which exhibits comparable efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. While bound by no theories, the inventors believe that the 13-sulfur atom may act as a bioisostere of the 13,14-double bond of the normal prostaglandin omega chain. The present invention is believed to allow increased discrimination amongst the various PG receptors, which, in turn, allows a higher separation of desirable and undesirable activities, and therefore an improved therapeutic profile.
DETAILED DESCRIPTION OF THE INVENTION
The 13-thiaprostaglandins which are useful in the compositions of the present invention have the general formula (I):
wherein:
R
1
=CO
2
R, CONR
4
R
5
, CH
2
OR
6
, or CH
2
NR
7
R
8
; wherein:
R=H or cationic salt moiety, or CO
2
R=pharmaceutically acceptable ester moiety;
R
4
, R
5
=same or different=H or alkyl; R
6
=H, acyl, or alkyl;
R
7
, R
8
=same or different=H, acyl, or alkyl; with the proviso that if one of R
7
, R
8
=acyl then the other=H or alkyl;
n=0 or 2
R
2
, R
3
=same or different=H, alkyl, or acyl;
—=single or non-cumulated double bond;
B=H, and OH in either configuration, H and F in either configuration, double bonded O, or OCH
2
CH
2
O;
X=(CH
2
)
q
or (CH
2
)
q
O; where q=1-6; and
Y=C
1-6
alkyl group or phenyl ring optionally substitued with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkyl amino, or hydroxy; or
X-Y (CH
2
)
p
Y
1
; where p=0-6; and
wherein:
W=CH
2
, O, S(O)
m
, NR
9
, CH
2
CH
2
, CH═CH, CH
2
O, CH
2
S(O)
m
, CH═N, or CHNR
9
; where m=0-2. and R
9
=H, alkyl, or acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and
—=single or double bond.
As used herein, the term “pharmaceutically acceptable ester” means any ester that would be suitable for therapeutic administration to a patient by any convential means without significant deleterious health consequences; and “ophthalmically acceptable ester” means any pharmaceutically acceptable ester that would be suitable for ophthalmic application i.e. non-toxic and non-irritating. Preferred are alkyl esters. Most preferred are C
2
-C
4
alkyl esters and especially isopropyl esters.
Preferred compounds of the present invention are those of formula I wherein:
R
1
=CO
2
R; wherein R=alkyl;
R
2
, R
3
=H;
B=OH and H in either configuration;
X=CH
2
CH
2
or CH
2
O; and
Y=phenyl, optionally substitued with halo or trihalomethyl; or
X-Y=(CH
2
)
p
Y
1
; where p=0 and
wherein:
W=CH
2
, O, S(O)
m
, NR
9
, CH
2
CH
2
, CH═CH, CH
2
O, CH
2
S(O)
m
, CH═N, or CHNR
9
: where m=0-2. and R
9
=H, alkyl, or acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and
—=single or double bond.
Some of the above-mentioned prostaglandins are disclosed in U.S. Pat. No. 4,309,441 (Radunz et al.) and in German Patent No. 2,513,371 (Kraemer et al.). To the extent that such patents disclose the synthesis of the prostaglandin analogs of the present invention, they are incorporated by reference herein. Most preferred among the compounds that are generically or specifically disclosed in the art are:
II. (5Z)-(9S, 11R, 15S)-9, 11, 15-trihydroxy-16-m-chlorophenoxy-13-thia-17, 18, 19, 20-tetranor-5-prostenoic acid isopropyl ester; and
III. (5Z)-(9S, 11 R, 15S)9, 11, 15-trihydroxy-16-m-trifluoromethylphenoxy-13-thia-17, 18, 19, 20-tetranor-5-prostenoic acid isopropyl ester.
Others of the prostaglandins encompassed by the structure of formula (I) are believed to be novel. Specifically, those compounds possessing a cis double bond between carbons 4 and 5 in the &agr; chain are believed to be novel. These compounds are represented by formula (IA):
wherein all groups are as defined for formula (I). Most preferred among such cis &Dgr;
4
compounds is:
IV. (4Z)-(9S, 11R, 15S)9, 11,15-trihydroxy-16-m-trifluoromethylphenoxy-13-thia-17, 18, 19, 20-tetranor4-prostenoic acid isopropyl ester.
Also belielved to be novel are the 13-thia prostaglandins of formula (I) possessing a bicyclic ring at the terminus of the omega chain. Preferred among such bicyclic terminated compounds is:
V. (5Z)-(9S, 11R, 15S)-9, 11, 15-trihydroxy-15-(2-indanyl)-13-thia-17, 18, 19, 20-tetranor-5-prostenoic acid isopropyl ester.
The compounds of formula (I) can be prepared by generally employing the methods disclosed in the foregoing references either alone or in combination with other known methods (e.g. those disclosed in U.S. Pat. No. 4,152,527 (Hess et al.)). The syntheses described in Examples 1-3 below are representative of those which may be used to prepare compounds of the present invention. Those skilled in the art will appreciate the modifications to the syntheses of the following Examples 1-3 necessary to yield such compounds. Those skilled in the art will further appreciate that the compounds of the present invention may exist in racemic, non-race

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