(19)
(11)EP 1 960 353 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
12.03.2014 Bulletin 2014/11

(21)Application number: 06827406.7

(22)Date of filing:  02.11.2006
(51)International Patent Classification (IPC): 
C07C 405/00(2006.01)
C07D 333/04(2006.01)
C07D 209/08(2006.01)
A61K 31/559(2006.01)
A61P 27/06(2006.01)
(86)International application number:
PCT/US2006/042861
(87)International publication number:
WO 2007/056087 (18.05.2007 Gazette  2007/20)

(54)

PROSTAGLANDINS AND ANALOGUES AS AGENTS FOR LOWERING INTRAOCULAR PRESSURE

PROSTAGLANDINE UND ANALOGA ALS MITTEL ZUR ABSENKUNG DES AUGENINNENDRUCKS

PROSTAGLANDINES ET ANALOGUES UTILISES EN TANT QU'AGENTS POUR ABAISSER LA PRESSION INTRAOCULAIRE


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

(30)Priority: 03.11.2005 US 733117 P

(43)Date of publication of application:
27.08.2008 Bulletin 2008/35

(60)Divisional application:
13166783.4 / 2628725

(73)Proprietor: ALLERGAN, INC.
Irvine CA 92612 (US)

(72)Inventor:
  • BURK, Robert, M.
    Laguna Beach, CA 92651 (US)

(74)Representative: HOFFMANN EITLE 
Patent- und Rechtsanwälte Arabellastrasse 4
81925 München
81925 München (DE)


(56)References cited: : 
US-A- 6 124 344
US-B1- 6 476 064
  
     
    Remarks:
    The file contains technical information submitted after the application was filed and not included in this specification
     
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    Background of the Invention


    1. Field of the Invention



    [0001] The present invention relates to [1α,2β,3α,5α]-1-(5-(cis-2-heptenoic acid))-2-(3α-hydroxy or lower alkyloxy-5-thienylpentyl)-3,5-dihydroxy cyclopentane 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



    [0002] 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.

    [0003] 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.

    [0004] 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.

    [0005] 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.

    [0006] 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.

    [0007] 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:



    [0008] 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).

    [0009] 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 PGF and its prodrugs, e.g., its 1-isopropyl ester, in humans.

    [0010] 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



    [0011] The present invention concerns certain compounds for use in a method of treating ocular hypertension in a mammal having ocular hypertension, said compounds being selected from the group consisting of compounds represented by the following formula:

    wherein R1 is H or methyl;

    R is substituted thienyl comprising two chloro radicals or substituted thienyl comprising a chloro radical and a methyl radical and X is selected from the group consisting of

    wherein R2 is H or methyl and R3 is selected from the group consisting of 2-butyl-4-hydroxy, methoxy, 2-hydroxyethyl, and 2-[2-(5-hydroxyindolyl)]-ethyl.



    [0012] Preferably, when said thienyl is substituted with two chloro radicals, R2 is H and R3 is 2-hydroxyethyl, or when said thienyl is substituted with one chloro radical and one methyl radical, R2 is H and R3 is 2-[2-(5-hydroxyindolyl)]-ethyl.

    [0013] Most preferably said compound is selected from the group consisting of the following compounds.





    [0014] The compounds are very selective FP agonists.

    [0015] Preferably R is substituted with two or more, e.g. 3, of said radicals.

    [0016] These compounds effectively lower intraocular pressure while having lower hyperemia.

    [0017] 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.

    [0018] 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.



    [0019] 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



    [0020] 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.

    [0021] 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.

    [0022] For the two most preferred compounds shown above, the in-vitro activity is as follows:
    Table 1
    FUNCTIONAL_HFP FUNCTIONAL_HTP FEFP_EP4_RATIO
    10.0000 300.0000 0.0030
    FUNCTIONAL_HEP1 FUNCTIONAL_HIP GPEP1
    98.0000 50000.0000  
    FUNCTIONAL_HEP2 FUNCNONAL_HDP GPEP3
    50000.0000 50000.0000  
    FUNCTIONAL_HEP3A FEFP_OHL RTTPVASC
    50000.0000 0.2000  
    FUNCTIONAL_HEP4 RBEPVASC_EP4 HTPPLAT
    50000.0000 80.0000  
         
    FUNCTIONAL_HFP FUNCTIONAL_HTP FEFP_EP4_RATIO
    8.5000 1140.0000  
    FUNCTIONAL_HEP1 FUNCTIONAL_HIP GPEP1
    187.0000 50000.0000  
    FUNCTIONAL_HEP2 FUNCTIONAL_HDP GPEP3
    50000.0000 50000.0000  
    FUNCTIONAL_HEP3A FEFP_OHL RTTPVASC
    50000.0000 9.3000  
    FUNCTIONAL_HEP4 RBEPVASC_EP4 HTPPLAT
    50000.0000    


    [0023] 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 0.0001 and 5% (w/v), preferably 0.001 to 1.0% (w/v) in liquid formulations.

    [0024] For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. 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.

    [0025] 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.

    [0026] 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.

    [0027] 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.

    [0028] In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

    [0029] Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.

    [0030] The ingredients are usually used in the following amounts:
    IngredientAmount (% w/v)
    active ingredient about 0.001-5
    preservative 0-0.10
    vehicle 0-40
    tonicity adjustor 1-10
    buffer 0.01-10
    pH adjustor q.s. pH 4.5-7.5
    antioxidant as needed
    surfactant as needed
    purified water as needed to make 100%


    [0031] 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.

    [0032] 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 0.5 and 15 ml solution.

    [0033] 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.

    [0034] 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.


    Claims

    1. A compound selected from the group consisting of compounds represented by the following formula:

    wherein R1 is H or methyl;

    R is substituted thienyl comprising two chloro radicals or substituted thienyl comprising one chloro radical and one methyl radical; and

    X is selected from the group consisting of

    wherein R2 is H or methyl and R3 is selected from the group consisting of 2-butyl-4-hydroxy, methoxy, 2-hydroxyethyl and 2-[2-(5-hydroxyindolyl)]-ethyl, for use in a method of treating ocular hypertension in a mammal.


     
    2. The compound of claim 1, wherein R is substituted thienyl comprising two chloro radicals, R2 is H and R3 is 2-hydroxyethyl.
     
    3. The compound of claim 1, wherein R is substituted thienyl comprising one chloro radical and one methyl radical, R2 is H and R3 is 2-[2-(5-hydroxyindolyl)]-ethyl.
     
    4. An ophthalmic solution comprising a compound as defined in any one of claims 1 to 3.
     
    5. A pharmaceutical product comprising a container adapted to dispense its contents in a metered form and the ophthalmic solution of claim 4.
     
    6. A compound selected from the group consisting of

    and


     


    Ansprüche

    1. Verbindung, ausgewählt aus der Gruppe, bestehend aus Verbindungen, die durch die folgende Formel dargestellt sind:

    wobei R1 H oder Methyl ist;

    R ein substituiertes Thienyl mit zwei Chlorradikalen oder ein substituiertes Thienyl mit einem Chlorradikal und einem Methylradikal ist; und

    X ausgewählt ist aus der Gruppe, bestehend aus

    wobei R2 H oder Methyl ist und R3 ausgewählt ist aus der Gruppe, bestehend aus 2-Butyl-4-hydroxy, Methoxy, 2-Hydroxyethyl und 2-[2-Hydroxyindolyl)]-ethyl, zur Verwendung in einem Verfahren zur Behandlung von okulärer Hypertension in einem Säugetier.


     
    2. Verbindung gemäß Anspruch 1, wobei R ein substituiertes Thienyl mit zwei Chlorradikalen ist, R2 H ist und R3 2-Hydroxyethyl ist.
     
    3. Verbindung gemäß Anspruch 1, wobei R ein substituiertes Thienyl mit einem Chlorradikal und einem Methylradikal ist, R2 H ist und R3 2-[2-(5-Hydroxyindolyl)]-ethyl ist.
     
    4. Augenlösung, umfassend eine Verbindung, wie in einem der Ansprüche 1 bis 3 definiert.
     
    5. Pharmazeutisches Produkt, welches einen Behälter, der seinen Inhalt in dosierter Form abgibt, und die Augenlösung gemäß Anspruch 4 umfasst.
     
    6. Verbindung, ausgewählt aus der Gruppe, bestehend aus

    und


     


    Revendications

    1. Composé choisi dans le groupe constitué de composés représentés par la formule suivante :

    dans laquelle R1 représente H ou un groupe méthyle ;

    R représente un groupe thiényle substitué comprenant deux radicaux chloro ou un groupe thiényle substitué comprenant un radical chloro et un radical méthyle ; et

    X est choisi dans le groupe constitué de

    où R2 représente H ou un groupe méthyle et R3 est choisi dans le groupe constitué des groupes 2-butyl-4-hydroxy, méthoxy, 2-hydroxyéthyle et 2-[2-(5-hydroxyindolyl)]-éthyle,

    pour une utilisation dans un procédé de traitement de l'hypertension oculaire chez un mammifere.
     
    2. Composé selon la revendication 1, dans lequel R représente un groupe thiényle substitué comprenant deux radicaux chloro, R2 représente H et R3 représente un groupe 2-hydroxyéthyle.
     
    3. Composé selon la revendication 1, dans lequel R représente un groupe thiényle substitué comprenant un radical chloro et un radical méthyle, R2 représente H et R3 représente un groupe 2-[2-(5-hydroxyindolyl)]-éthyle.
     
    4. Solution ophtalmique comprenant un composé tel que défini dans l'une quelconque des revendications 1 à 3.
     
    5. Produit pharmaceutique comprenant un récipient adapté pour distribuer son contenu sous une forme calibrée et la solution ophtalmique selon la revendication 4.
     
    6. Composé choisi dans le groupe constitué de

    et


     






    Cited references

    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description