The present invention provides ophthalmic compositions comprising non-hydrolyzable nucleoside di-or triphosphate analogues in which the a,ß- or ß,?-bridging-oxygen, respectively, is replaced with, e.g., a methylene or dihalomethylene group, such as 2MeS-adenosine-ß,?-CH2--5'-triphosphate and 2MeS-adenosine-ß,?-CCl25'-triphosphate. These compositions are useful for reducing intraocular pressure and thus for treatment of ocular hypertension and/or glaucoma.
CLAIMS An ophthalmic composition comprising a pharmaceutically acceptable and a compound of the general formula I: <img class="EMIRef" id="72861378-imgf000056-0001" /> or a diastereoisomer or mixture of diastereoisomers thereof, wherein Ri is H, halogen, -O-hydrocarbyl, -S-hydrocarbyl, -NR4R5, heteroaryl, hydrocarbyl optionally substituted by one or more groups each independently selected from halogen, -CN, -SCN, -NO<2>, -OR<4>, -SR4, -NR4R5 or heteroaryl, wherein R4 and R<5> each independently is H or hydrocarbyl, or R4 and R<5> together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring optionally containing 1-2 further heteroatoms selected from N, O, or S, wherein the additional nitrogen is optionally substituted by alkyl; R<2> and R<3> each independently is H or hydrocarbyl; Y each independently is H, -OH, or -NH<2>; Z<\>, Z<2> and Z<3> each independently is -O<">, -S<">, or -BH<3>" ; Wi and W<2> each independently is -O-, -NH-, or -C(XiX<2>)-, wherein X<\> and X<2> each independently is H or halogen, provided that at least one of W<] 5> if present, and W<2> is not -O-; n is 0 or 1 ; m is 3 or 4; and B<+> represents a pharmaceutically acceptable cation. 2. The composition of claim 1 , wherein R] is H, halogen, -O-hydrocarbyl, -S- hydrocarbyl, -NR4R5, heteroaryl, or hydrocarbyl; R and R<5> each independently is H or hydrocarbyl, or R4 and R<5> together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring optionally containing 1-2 further heteroatoms selected from N, O or S, wherein said hydrocarbyl each independently is (Ci-C<8>)alkyl, (C2-C<8>)alkenyl, (C2-C<8>)alkynyl, or (C<6>-Ci<4>)aryl; and said heteroaryl is a 5-6- membered monocyclic heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S. 3. The composition of claim 2, wherein said hydrocarbyl is (C]-C<6>)alkyl, preferably (C C4)alkyl, more preferably methyl or ethyl; (C2-C<6>)alkenyl, preferably (C<2>-C<4>)alkenyl; (C<2>-C<6>)alkynyl, preferably (C<2>-C<4>)alkynyl; or (C<6>-Ci<0>)aryl, preferably phenyl. 4. The composition of claim 1, wherein R<2> and R<3> each independently is H or hydrocarbyl selected from (C<r>C<8>)alkyl, (C<2>-C<8>)alkenyl, (C2-C<8>)alkynyl, or (C<6>- C<H>)aryl. 5. The composition of claim 4, wherein said hydrocarbyl each independently is (Ci-C<6>)alkyl, preferably (Ci-C<4>)alkyl, more preferably methyl or ethyl; (C<2>- C<6>)alkenyl, preferably (C<2>-C<4>)alkenyl; (C<2>-C<6>)alkynyl, preferably (C<2>-C )alkynyl; or (C<6>-C<10>)aryl, preferably phenyl. 6. The composition of claim 1, wherein Y each independently is -OH. 7. The composition of claim 1, wherein R<\> is H, halogen, -O-hydrocarbyl, -S- hydrocarbyl, -NR<4>R<5>, heteroaryl, or hydrocarbyl; R4 and R<5> each independently is H or hydrocarbyl, or R4 and R<5> together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring optionally containing 1-2 further heteroatoms selected from N, O or S; R2 and R<3> each independently is H or hydrocarbyl; and Y each independently is -OH, wherein said hydrocarbyl each independently is (C]-C<8>)alkyl, (C<2>-C<8>)alkenyl, (C2-C<8>)alkynyl, or (C<6>-Ci<4>)aryl; and said heteroaryl is a 5-6- membered monocyclic heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S. 8. The composition of claim 7, wherein said hydrocarbyl is (Ci-C<6>)alkyl, preferably (C]-C<4>)alkyl, more preferably methyl or ethyl; (C<2>-C<6>)alkenyl, preferably (C<2>-C<4>)alkenyl; (C<2>-C<6>)alkynyl, preferably (C<2>-C<4>)alkynyl; or (C<6>-C<10>)aryl, preferably phenyl. 9. The composition of claim 8, wherein R) is H, -O-hydrocarbyl, or -S- hydrocarbyl; R<2> and R<3> each independently is H or hydrocarbyl; Y each independently is -OH; and said hydrocarbyl each independently is methyl or ethyl. 10. The composition of claim 9, wherein Ri is H or -S-methyl; R<2> and R<3> are H; and Y each independently is -OH. 11. The composition of any one of claims 1 to 10, wherein W<b> if present, is -O-; W<2> is -C(X,X<2>)- or -NH-, preferably -C(XiX<2>)-; and Xi and X<2> each independently is H or a halogen selected from F, CI or Br, preferably CI. 12. The composition of claim 1 1, wherein Z<2>, if present, and Z<3> each independently is -O<">; and Zi is -O<"> or -BH<3>" . 13. The composition of claim 12, wherein n is 1 ; Y each independently is -OH; R<2> and R<3> are H; and (i) Ri is -SCH<3>; Z,, Z<2> and Z<3> are -O<">; W, is -O-; and W<2> is -CH<2>- (herein identified compound 1); (ii) R, is -SCH<3>; Z,, Z<2> and Z<3> are O<">; W[ is -O-; and W<2> is -CC1<2>- (herein identified compound 9); (iii) R, is H; Z, is -BH<3>" ; Z<2> and Z<3> are -O<">; W, is -O-; and W<2> is -CC1<2>-, characterized by being the isomer with a retention time (Rt) of 10.87 min when separated from a mixture of diastereoisomers using a semi- preparative reverse-phase Gemini 5u column (C-18 11 OA, 250 10 mm, 5 micron), and isocratic elution [100 mM triethylammonium acetate, pH 7: MeOH, 91 :9] with flow rate of 5 ml/min (herein identified compound 11B); or (iv) Ri is -SCH<3>; Z, is -BH<3>" ; Z<2> and Z<3> are -O<">; Wi is -O-; and W<2> is -CC1<2>- (herein identified compound 12); 14. The composition of claim 12, wherein n is 0; Y each independently is OH; Ri is -SCH<3>; R<2> and R<3> are H; Z<x> and Z<3> are -O<">; and W<2> is -CF<2>- or -CC1<2>- (herein identified compounds 13 and 14, respectively). 15. The composition of claim 13, comprising compound 1 or 9, preferably 9. 16. The composition of any one of claims 1 to 15, formulated as ophthalmic drops, emulsion, suspension, gel, ointment, or a membranous ocular eye patch. 17. The composition of claim 16, for reducing intraocular pressure. 18. The composition of claim 17, for prevention or treatment of intraocular hypertension and/or glaucoma. 19. The composition of claim 18, wherein the glaucoma is primary open angle glaucoma, normal pressure glaucoma, acute angle closure glaucoma, absolute glaucoma chronic glaucoma, congenital glaucoma, juvenile glaucoma, narrow angle glaucoma, chronic open angle glaucoma, or simplex glaucoma. 20. A compound of the general formula I, or a diastereoisomer or mixture of diastereoisomers thereof, for use in reducing intraocular pressure. 21. Use of a compound of the general formula I, or a diastereoisomer or mixture of diastereoisomers thereof, for the preparation of an ophthalmic composition. 22. A method for reducing intraocular pressure in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound of the general formula I, or a diastereomer or mixture of diastereoisomers thereof.