Claims for Patent: 5,422,368

Summary for Patent: 5,422,368

Title:	Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
Abstract:	The invention relates to ophthalmological compositions for topical treatment of glaucoma or ocular hypertension comprising an effective intraocular pressure reducing amount of a prostaglandin derivative of PGA, PGB, PGD, PGE or PGF, in which the omega chain contains a ring structure, in an ophthalmologically compatible carrier. The invention further relates to the preparation of said compositions and their use for treatment of glaucoma or ocular hypertension.
Inventor(s):	Johan W. Stjernschantz, Bahram Resul
Assignee:	Pfizer Health AB
Application Number:	US07/986,943
Patent Claims:	1. A therapeutic composition for topical treatment of ocular hypertension or glaucoma containing a prostaglandin PGA, PGB, PGE or PGF in an amount sufficient to reduce intraocular pressure without causing substantial ocular irritation, and an ophthalmologically compatible vehicle, in which the alpha chain of the prostaglandin comprises a chain of 6 to 10 carbon atoms, which is either(a) saturated or (b) unsaturated having one or more double bonds, allene bonds, or a triple bond,the alpha chain being (c) unsubstituted or (d) substituted with one or more substituents selected from the group of alkyl groups, alicyclic rings, aromatic rings or heteroaromatic rings,and in which the omega chain of the prostaglandin has the formula C.sub.13 --B--C.sub.14 --D.sub.15-24 --R.sub.2 wherein C is a carbon atom (the number according to standard prostaglandin nomenclature being indicated by the subscript); B is a single bond, a double bond, or a triple bond; D represents a sub-chain of 1-10 carbon atoms with substituents on each carbon atom that are selected from the group consisting of a hydrogen atom, an alkyl group, an oxo group and a hydroxyl group, and R2 is (e) an aromatic ring structure which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting of C1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, a phenyl group, or(f) an aromatic heterocyclic group having 5-6 ring atoms, or (g) a cycloalkane or a cycloalkene with 3-7 carbon atoms in the ring, which is (1) unsubstituted or (2) has at least one substituent selected from the group consisting of lower alkyl groups with 1-5 carbon atoms. 2. A composition according to claim 1 in which, in the omega chain of the prostaglandin, R2 is an aromatic ring structure which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, or a phenyl group. 3. A composition according to claim 1 in which, in the omega chain of the prostaglandin, R2 is a phenyl group which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, or a phenyl group. 4. A composition according to claim 1 in which, in the omega chain of the prostaglandin R2 is a phenyl group. 5. A composition according to claim 1 in which, in the omega chain of the prostaglandin PGA, PGB, PGE, or PGF, the D sub-chain contains 2-8 carbon atoms. 6. A composition according to claim 1 in which, in the omega chain of the prostaglandin, the D sub-chain contains 2-5 carbon atoms. 7. A composition according to claim 6 in which the prostaglandin is a PGF2α. 8. A composition according to claim 7 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 9. A composition according to claim 1 in which, in the omega chain of the prostaglandin, the D sub-chain contains 3 carbon atoms. 10. A composition according to claim 1 in which the prostaglandin is a PGA2, PGB2, PGE2 or PGF2. 11. A composition according to claim 1 in which, in the omega chain of the prostaglandin,B is a single or double bond, D is a carbon chain with 2-5 carbon atoms, in which C15 is substituted with an oxo or hydroxyl substitutent, and C16 -C19 are unsubstituted or substituted with lower alkyl substituents, and R2 is a phenyl ring which is unsubstituted or substituted with one or more substituent selected from the group consisting of alkyl or alkoxy groups. 12. A composition according to claim 1 in which the prostaglandin is a PGE. 13. A composition according to claim 1 in which the prostaglandin is a PGF. 14. A composition according to claim 1 in which the prostaglandin is a PGF2. 15. A composition according to claim 1 in which, in the omega chain of the prostaglandin,B is a single or double bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 16. A composition according to claim 1 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 17. A composition according to claim 1 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms, in which C15 is substituted with an oxo group, an (R)--OH group, or an (S)--OH group; and R2 is a phenyl group. 18. A composition according to claim 1 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms, in which C15 is substituted with an oxo group; and R2 is a phenyl group. 19. A composition according to claim 1 in which the prostaglandin is an isopropyl ester. 20. A composition according to claim 1 in which the prostaglandin is an ester of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α. 21. A composition according to claim 1 in which the prostaglandin is an alkyl ester of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α, having 1-10 carbon atoms in the alkyl group. 22. A composition according to claim 1 in which the prostaglandin is 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α isopropyl ester. 23. A composition according to claim 1 in which the prostaglandin is 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α. 24. A method of treating glaucoma or ocular hypertension by topical application of the therapeutic composition of claim 1. 25. The method of claim 23 in which the composition of claim 1 is applied once or twice a day. 26. The method of claim 23 wherein the composition applied contains from about 0.1 μg to about 30 μg of the prostaglandin. 27. The method of claim 23 wherein the composition applied contains about 1.0 μg to about 10 μg of the prostaglandin. 28. The method of claim 23 wherein the composition is applied twice a day, containing about 1.0 μg to about 10 μg of prostaglandin in a volume of about 10 to about 50 μL of composition. 29. A therapeutic composition for topical treatment of ocular hypertension or glaucoma containing a prostaglandin PGA, PGB, PGE or PGF in an amount sufficient to reduce intraocular pressure without causing substantial ocular irritation, and an ophthalmologically compatible vehicle, in which the alpha chain of the prostaglandin comprises a chain of 6 to 10 carbon atoms, which is either(a) saturated or (b) unsaturated having one or more non-cummulated double bonds, or a triple bond,the alpha chain being (c) unsubstituted or (d) substituted with one or more substituents selected from the group of alkyl groups, alicyclic rings, aromatic rings or heteroaromatic rings,and in which the omega chain of the prostaglandin has the formula C.sub.13 --B--C.sub.14 --D.sub.15-24 --R.sub.2 wherein C is a carbon atom (the number according to standard prostaglandin nomenclature being indicated by the subscript); B is a single bond, a double bond, or a triple bond; D represents a sub-chain of 1-10 carbon atoms and 1-2 heteroatoms selected from the group oxygen, sulfur, and nitrogen, with substituents on each carbon atom that are selected from the group consisting of a hydrogen atom, an alkyl group, an oxo group and a hydroxyl group, and R2 is (e) an aromatic ring structure which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, a phenyl group, or(f) an aromatic heterocyclic group having 5-6 ring atoms, or (g) a cycloalkane or a cycloalkene with 3-7 carbon atoms in the ring, which is (1) unsubstituted or (2) has at least one substituent selected from the group consisting of lower alkyl groups with 1-5 carbon atoms. 30. A composition according to claim 28 in which, in the omega chain of the prostaglandin, R2 is an aromatic ring structure which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, or a phenyl group. 31. A composition according to claim 28 in which, in the omega chain of the prostaglandin, R2 is a phenyl group which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, or a phenyl group. 32. A composition according to claim 28 in which, in the omega chain of the prostaglandin R2 is a cycloalkane or a cycloalkene with 3-7 carbon atoms in the ring, which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting of lower alkyl groups with 1-5 carbon atoms. 33. A composition according to claim 28 in which, in the omega chain of the prostaglandin PGA, PGB, PGE, or PGF, the D sub-chain contains 2-8 carbon atoms. 34. A composition according to claim 28 in which, in the omega chain of the prostaglandin, the D sub-chain contains 2-5 carbon atoms. 35. A composition according to claim 33 in which the prostaglandin is a PGF2α. 36. A composition according to claim 34 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 37. A composition according to claim 28 in which, in the omega chain of the prostaglandin, the D sub-chain contains 3 carbon atoms. 38. A composition according to claim 28 in which the prostaglandin is a PGA2, PGB2, PGE2 or PGF2. 39. A composition according to claim 28 in which, in the omega chain of the prostaglandin,B is a single or double bond, D is a carbon chain with 2-5 carbon atoms, in which C15 is substituted with an oxo or hydroxyl substitutent, and C16 -C19 are unsubstituted or substituted with lower alkyl substituents, and R2 is a phenyl ring which is unsubstituted or substituted with one or more subsitutent selected from the group consisting of alkyl or alkoxy groups. 40. A composition according to claim 28 in which the prostaglandin is a PGE. 41. A composition according to claim 28 in which the prostaglandin is a PGF. 42. A composition according to claim 28 in which the prostaglandin is a PGF2. 43. A composition according to claim 28 in which, in the omega chain of the prostaglandin,B is a single or double bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 44. A composition according to claim 28 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 45. A composition according to claim 28 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms, in which C15 is substituted with an oxo group, an (R)--OH group, or an (S)--OH group; and R2 is a phenyl group. 46. A composition according to claim 28 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms, in which C15 is substituted with an oxo group; and R2 is a phenyl group. 47. A composition according to claim 28 in which the prostaglandin is an isopropyl ester. 48. A composition according to claim 28 in which the prostaglandin is an ester of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α. 49. A composition according to claim 28 in which the prostaglandin is an alkyl ester of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α, having 1-10 carbon atoms in the alkyl group. 50. A composition according to claim 28 in which the prostaglandin is 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α isopropyl ester. 51. A composition according to claim 28 in which the prostaglandin is 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α. 52. A method of treating glaucoma or ocular hypertension by topical application of the therapeutic composition of claim 28. 53. The method of claim 51 in which the composition of claim 49 is applied once or twice a day. 54. The method of claim 51 wherein the composition applied contains from about 0.1 μg to about 30 μg of the prostaglandin. 55. The method of claim 51 wherein the composition applied contains about 1.0 μg to about 10 μg of the prostaglandin. 56. The method of claim 51 wherein the composition is applied twice a day, containing about 1.0 μg to about 10 μg of prostaglandin in a volume of about 10 to about 50 μL of composition. 57. A therapeutic composition for topical treatment of ocular hypertension or glaucoma containing a prostaglandin PGD in an amount sufficient to reduce intraocular pressure without causing substantial ocular irritation, and an ophthalmologically compatible vehicle, in which the alpha chain of the prostaglandin comprises a chain of 6 to 10 carbon atoms, which is either(a) saturated or (b) unsaturated having one or more double bonds, allene bonds, or a triple bond,the alpha chain being (c) unsubstituted or (d) substituted with one or more substituents selected from the group of alkyl groups, alicyclic rings, aromatic rings or heteroaromatic rings,and in which the omega chain of the prostaglandin has the formula C.sub.13 --B--C.sub.14 --D.sub.15-24 --R.sub.2 wherein C is a carbon atom (the number according to standard prostaglandin nomenclature being indicated by the subscript); B is a single bond, a double bond, or a triple bond; D represents a sub-chain of 1-10 carbon atoms with substituents on each carbon atom that are selected from the group consisting of a hydrogen atom, an alkyl group, an oxo group and a hydroxyl group, and R2 is (e) an aromatic ring structure which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, a phenyl group, or (f) an aromatic heterocyclic group having 5-6 ring atoms. 58. A composition according to claim 56 in which, in the omega chain of the prostaglandin, R2 is an aromatic ring structure which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, or a phenyl group. 59. A composition according to claim 56 in which, in the omega chain of the prostaglandin, R2 is a phenyl group which is(1) unsubstituted or (2) has at least one substituent selected from the group consisting ofC1 -C5 alkyl groups, C1 -C4 alkoxy groups, trifluoromethyl groups, C1 -C3 aliphatic acylamino groups, nitro groups, halogen atoms, or a phenyl group. 60. A composition according to claim 58 in which, in the omega chain of the prostaglandin the group R2 is thiazol, imidazole, pyrrolidine, thiophene or oxazole. 61. A composition according to claim 56 in which, in the omega chain of the prostaglandin PGD, the D sub-chain contains 2-8 carbon atoms. 62. A composition according to claim 56 in which, in the omega chain of the prostaglandin, the D sub-chain contains 2-5 carbon atoms. 63. A composition according to claim 61 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 64. A composition according to claim 56 in which, in the omega chain of the prostaglandin, the D sub-chain contains 3 carbon atoms. 65. A composition according to claim 56 in which, in the omega chain of the prostaglandin,B is a single or double bond, D is a carbon chain with 2-5 carbon atoms, in which C15 is substituted with an oxo or hydroxyl substitutent, and C16 -C19 are unsubstituted or substituted with lower alkyl substituents, and R2 is a phenyl ring which is unsubstituted or substituted with one or more subsitutent selected from the group consisting of alkyl or alkoxy groups. 66. A composition according to claim 56 in which, in the omega chain of the prostaglandin,B is a single or double bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 67. A composition according to claim 56 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms; and R2 is a phenyl group. 68. A composition according to claim 56 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms, in which C15 is substituted with an oxo group, an (R)--OH group or an (S)--OH group; and R2 is a phenyl group. 69. A composition according to claim 56 in which, in the omega chain of the prostaglandin,B is a single bond; D is a chain of 3 carbon atoms, in which C15 is a carbonyl group; and R2 is a phenyl group. 70. A composition according to claim 56 in which the prostaglandin is an isopropyl ester. 71. A method of treating glaucoma or ocular hypertension by topical application of the therapeutic composition of claim 56. 72. The method of claim 71 in which the composition of claim 56 is applied once or twice a day. 73. The method of claim 71 wherein the composition applied contains from about 0.1 μg to about 30 μg of the prostaglandin. 74. The method of claim 71 wherein the composition applied contains about 1.0 μg to about 10 μg of the prostaglandin. 75. The method of claim 71 wherein the composition is applied twice a day, containing about 1.0 μg to about 10 μg of prostaglandin in a volume of about 10 to about 50 μL of composition. 76. A composition according to claim 28 in which the D sub-chain contains 3 carbon atoms and the R2 group of the prostaglandin is located at position 17. 77. A composition according to claim 25 in which the D sub-chain contains 3 carbon atoms and the R2 group of the prostaglandin is located at position 17. 78. A composition according to claim 26 in which the D sub-chain contains 3 carbon atoms and the R2 group of the prostaglandin is located at position 17. 79. A method of treating glaucoma or ocular hypertension by topical application of the therapeutic composition of claim 76. 80. A method of treating glaucoma or ocular hypertension by topical application of the therapeutic composition of claim 77. 81. A method of treating glaucoma or ocular hypertension by topical application of the therapeutic composition of claim 78. 82. A composition according to claim 44 comprising a 13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor-PGF2α alkyl ester having 1-10 carbon atoms in the alkyl group. 83. A composition according to claim 36 comprising a 13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor-PGF2α alkyl ester having 1-10 carbon atoms in the alkyl group. 84. A composition according to claim 38 comprising a 13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor-PGF2α alkyl ester having 1-10 carbon atoms in the alkyl group. 85. A method of treating glaucoma or ocular hyptertension by topical application of the therapeutic composition of claim 81. 86. A method of treating glaucoma or ocular hyptertension by topical application of the therapeutic composition of claim 82. 87. A method of treating glaucoma or ocular hyptertension by topical application of the therapeutic composition of claim 83.