Prostaglandins and analogues as agents for lowering intraocular pressure

The present invention relates to cyclopentane heptenoic acid-5-cis-2-(3ahydroxy or lower alkyloxy-5-thienylpentyl)-3, 5-dihydroxy, [la, 213, 3a, 50t] compounds lower alkyl, hydroxyl lower alkyl and indole lower alkyl amides and esters thereof as potent ocular hypotensives that are particularly suited for the management of glaucoma. 2. Description of Related Art Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive 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 pupilary 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 retinal 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 vis'on. Certain eicosanoids and their derivatives have been reported to possess ocular hypotensive activity, and have been recommended for use in glaucoma management. Eicosanoids and derivatives include numerous biologically important compounds such as prostaglandins and their derivatives. Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula: Various prostaglandin derivatives, e.g. latanoprost, travoprost, unoprostone isopropyl, etc. have been commercialized for lowering intraocular pressure and managing glaucoma. Recently, a prostamide, i.e. bimatoprost, has been marketed for treating increased eye pressure caused by open-angle glaucoma or ocular hypertension. Prostamides are structurally similar to prostaglandins but are biologically different. Prostamides, unlike prostaglandins, do not lower intraocular pressure by interaction with the prostaglandin receptor. (See U.S. Patent No. 5,352,708, which hereby is incorporated by reference in its entirety.) While prostaglandins and prostamides are effective in lowering intraocular pressure without significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been associated with the topical ocular use of such compounds, in particular PGF2c and its prodrugs, e.g., its 1-isopropyl ester, in humans. Thus, it would be desirable to discover a prostamide or prostaglandin compound which effectively lowers intraocular pressure while not causing excessive hyperemia. Summary of the Invention A first aspect of the invention provides a method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of a compound selected from the group consisting of compounds represented by the following formula: OII X wherein R l is H or methyl; R is selected from the group consisting of thienyl and substituted thienyl, wherein the substituent may be one or more radicals selected from the group consisting of fluoro, chloro, methyl and phenyl and X is selected from the group consisting of R 2 I N-R 3 wherein R 2 is H or methyl and R 3 comprises a substituted hydrocarbyl radical, including from 1 to 12 carbon atoms and at least one oxygen atom. A second aspect of the invention provides an ophthalmic solution comprising OI-I X J wherein R l is H or methyl; R is selected from the group consisting of thienyl and substituted thienyl, wherein the substituent may be one or more radicals selected from the group consisting of fluoro, ehloro, methyl and phenyl and X is selected from the group consisting of RECEIVED TI E 31. OCT, 9'03 N-R 3 wherein R 2 is H or methyl and R 3 comprises a substituted hydrocarbyl radical including from 1 to 12 carbon atoms and at least one oxygen atom. A third aspect of the invention provides a pharmaceutical product comprising a container adapted to dispense its contents in a metered form and the ophthalmic solution as defined in the second aspect. A fourth aspect of the invention provides a compound having the following formula: HO X R O wherein R l is H or methyl; R is thienyl optionally substituted with one or more substituents, wherein each substituent is independently fluoro, chloro, bromo, methyl or phenyl; and R2 I X is -NwR3, wherein R 2 is H or methyl and R 3 is a CH 2 ether or comprises a hydroxy indole. A fifth aspect of the invention provides a method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of a compound as defined in the fourth aspect. A sixth aspect of the invention provides use of a compound as defined in the first aspect, in the manufacture of a medicament for the treatment of ocular hypertension in a mammal. A seventh aspect of the invention provides use of a compound as defined in the fourth aspect, in the manufacture of a medicament for the treatment of ocular hypertension in a mammal. Disclosed herein is a method of treating ocular hypertension which comprises RECEIVED TIME 3".OCT. 9'03 administering to a mammal having ocular hypertension a therapeutically effective amount of a compound selected from the group consisting of compounds represented by the following formula: OH wherein R I is H or methyl; R is selected from the group consisting of thienyl and substituted thienyl, wherein the substituent may be one or more radicals selected from the group consisting of fluoro, chloro, bromo, methyl and phenyl and X is selected from the group consisting of R2 t N-R3 wherein R 2 is H or methyl and R 3 comprises a substituted hydrocarbyl radical, including from 1 to 12 carbon atoms and at least one oxygen atom, e.g. as an ether or a hydroxyl moiety, and, optionally, a nitrogen atom. That is R 3 may be an alkylhydroxy radical or an alkyl ether or a hydroxy indole radical. Thus, R 3 may be an alkyl or an aryl radical which includes an oxygen atom as a hydroxy, alkyloxy, oxo, oxa moiety, etc. Preferably, R 3 is selected from the group consisting of 2-butyl-4-hydroxy, methoxy, 2ethylhydroxy, and (2-ethyl)(5-hydroxy)indole. RECEIVED TIME 31.0CT, 9'03 Preferably, said thienyl is substituted with two chloro radicals, or two bromo radicals or one chloro and one methyl radical. More preferably, when said thienyl is substituted with two chloro radicals, is H and R 3 is 2-ethylhydroxy, or when said thienyl is substituted with two bromo radicals, R 2 is methyl and R 3 is methoxy, or when said thienyl is substituted with one chloro radical and one methyl radical, R 2 is H and R 3 is (2-ethyl) (5-hydroxy) indole. Most preferably said compound is selected from the group consisting of following compounds. Structure H H--Q I H H.---.-O CI,,,., LS" structure H--O I structure The compounds are very selective FP agonists. Preferably R is substituted with two or more, e.g. 3, of said radicals. These compounds effectively lower intraocular pressure while having lower hyperemia. In another aspect of the invention, a ophthalmic solution comprising one or more of the above compounds in combination with an ophthalmically-acceptable vehicle is contemplated. In a still further aspect, the present invention relates to a pharmaceutical product, comprising a container adapted to dispense its contents in a metered form; and an ophthalmic solution therein, as hereinabove defined. Finally, certain of the above compounds disclosed herein and utilized in the method of the present invention are novel and unobvious. Detailed Description of the Invention The above compounds of the present invention may be prepared by methods that are known in the art. For example, see U.S. Patents 5,834,498; 5,741,810 and 6,124,344 to Burk, which are hereby incorporated by reference. The compounds of the present invention were tested for in vitro activity as described in U.S. Patents 6,734,206 and 6,747,037 to Old et al which are incorporated by reference. For the most preferred compounds the in-vitro activity is as follows: Table 1 I :UNCTIONAL_HFP!FUNCTIONAl... HTP FEFP I=P 4 R TIO 10.0000 300.0000 0.0030 FUNCTIONAL_HEP1 F'UNCTI0NAL_HIP GPEP 1 . 98.0000 5000O.000O functional HEP 2 ' FUNCTIONAL HDP GPEP3 50000.0000 50000.0000 , L =UNCTI'ONA['_HEP 3 A RTTPVA'SC FEFP OHL ,: ........... ,s0ooo.oo0q 0.2000 HTPPLAT FUNCTIONAL HEP4 RBEPVASC_EP 4 .... 50000.0000 80.0000 i :UNCTIONAL_HFP FUNCTIONAL_HTP FEFP_EP4 RATIO 37.0000 374.0000 0.0480 ,,, ,,1 , ,, |, ,,,,,,,,, , .... FuNcTIONAL_HEP 1 FUNCTIONAL_HIP GPEP1 599.0000 50000.0000 FUNCTIONAL_HDP aP'EP 3 :UNCTIONAL_HEP 2 50000.0000 50000.0000 FUNCTIONAL HEP3A FEFP_OHL IRTTPvAsc 50000.0000 7,0000 -'UNGTIONAL._HEP4 F BEPVASC_EP 4 ITP'PLAT 500O0.00OO 147.0000 FUNCT 1 ON/ L HFP FUNCTIONAL_HTP FEFP_EP4_RA'TIO 8.5000 1140.0000 FUNCT1ONAL_HEP1;UNCTIONAL_HIP GPEP1 167.0000 50000.0000 FUNC ONAL_HEP 2 FUNCTI'O NAL_HD'P GPEP3 50000.0000 50000.0000 ':UNCTIONAL HEP3A iRTTPVAS'C FEFP_OHL 5o000.0000 9.aooo , i iFUNC:TIONAL_I'I EP4 RBEPVASC 'EP 4 HTPPLAT Ophthalmic solutions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations. For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a majorvehicle. The pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants. Preferred preservatives that may be used in the ophthalmic solutions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water. Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor. Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. In a similar vein, an present invention includes, but thiosulfate, acetylcysteine, butylated Other excipient components preparations are chelating agents. although other chelating agents may The ingredients are usually Ingredient active ingredient preservative vehicle tonicity adjustor buffer pH adjustor antioxidant surfactant purified water ophthalmically acceptable antioxidant for use in the is not limited to, sodium metabisulfite, sodium hydroxyanisole and butylated hydroxytoluene. which may be included in the ophthalmic The preferred chelating agent is edentate disodium, also be used in place or in conjunction with it. used in the following amounts: Amount (% w/v) about 0.001-5 0-0.10 0-40 1-10 0.01-10 q.s. pH 4.5-7.5 as needed as needed as needed to make 100% The actual dose of the active compounds of the present invention depends on the specific compound; the selection of the appropriate dose is well within the knowledge of the skilled artisan. The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate the application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. Certain of the compounds of this invention are useful in treating other diseases and conditions which are responsive to prostaglandin analogues, e.g. cardiovascular; e.g. acute myocardial infarction, vascular thrombosis, hypertension, pulmonary hypertension, ischemic heart disease, congestive heart failure, and angina pectoris; pulmonary-respiratory; gastrointestinal; reproductive and allergic diseases; osteoporosis and shock. The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or stop or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is krtown, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. RECEIVED TIME 31,0CT, 9'03