Treatment of conditions of abnormally increased intraocular pressure by administration of phosphonylmethoxyalkyl nucleoside analogs and related nucleoside analogs

• US 5,869,468 A
• Filed: 05/12/1995
• Issued: 02/09/1999
• Est. Priority Date: 04/04/1994
• Status: Expired due to Fees

• Current Assignee: William R. Freeman
• Original Assignee: William R. Freeman
• Inventors: Freeman, William R.
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US08/440,447
• Time in Patent Office: 1,369 Days
• Field of Search: 514/81, 514/913
• US Class Current: 514/81
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics

Abstract

Methods for treatment of conditions of abnormally increased intraocular pressure, particularly those caused by glaucoma, by administration of phosphonylmethoxyalkyl nucleoside analogs are provided. Compositions formulated and packaged for intraocular administration for use in the methods are also provided. Administration of the compound may be by intravitreal injection, aqueous humor injection, injection into the external layers of the eye, such as subconjunctival injection or subtenon injection, or may be, when penetrating derivatives are used, by topical application to the eye. The degree of reduction in pressure is dosage-dependent, and significant reduction in pressure is obtained. A single injection can produce prolonged, and perhaps permanent, lowering of the intraocular pressure.

Claims

1. A method for reducing intraocular pressure, comprising administering to the eye an effective amount of a compound of formula I or pharmaceutically acceptable salts or acids thereof:

##STR7## wherein;

R¹ and R² are (i) or (ii) as follows;

(i) R¹ is CH₂ (CH₂)_n, CH₂ CH(OH)(CH₂)_n, CH₂ CH(CH₂)_n,(OH), CH₂ OCH(R⁷), CH₂ OCH(R⁷)(CH₂)_p, CH₂ OCH(R⁷)(CH₂)_p O or O(CH₂)_p CH(R⁷)O;

R² is OH or O(CH₂)_r H;

R⁷ is H, OH or (CH₂)_r OH;

n is 0-6;

r is 1-6;

p is 0-3; and

m is 0 to 3;

or

(ii) R¹, R², n, m, r and p are defined as in (i), and R¹ and R² are linked to form a cyclic ester group;

B is a purine of formula (II);

##STR8## and is selected from the group consisting of purin-3-yl, purin-7-yl and purin-9-yl; and

R³, R⁴ and R⁶ are independently selected from NH₂, alkylamino, aminoalkyl, hydroxyalkyl, hydrazino, H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, hydroxylamino and CH_3-q (hal)_q in which g is 1-3 and hal is a halide; and

the amount is effective for lowering intraocular pressure.

3. The method of claim 1, wherein:

R¹ is CH₂ CH(OH)(CH₂)_n, CH₂ CH(CH₂)_n (OH), CH₂ OCH(R⁷), CH₂ OCH(R⁷)(CH₂)_p, CH₂ OCH(R⁷)(CH₂)_p O or O(CH₂)_p CH(R⁷)O;

R² is OH or O(CH₂)_r H;

R⁷ is OH or (CH₂)_r OH, preferably (CH₂)OH;

n is 0-6, preferably 0-3;

r is 1-6, preferably 1-3, more preferably 1;

p is 0-3; and

m is 0 to 3.

4. The method of claim 1, wherein the compound has formula (III):

##STR11## wherein R¹ and R² are selected from (i) or (ii);

(i) R¹ is ##STR12## or (ii) R¹ and R², which are as defined in (i), are linked to form a cyclic ester group.

5. The method of claim 1, wherein n is 1-3, p is 0 or 1, r is 1 and m is 0 or 1.

6. The method of claim 1, wherein R³ and R⁴ are each independently selected from H, NH₂, CH₃, CH₃ CH₂, CF₃, dimethylamino, halide, and OH, and R⁶ is H or halide.

7. The method of claim 1, wherein B is selected from among guanin-9-yl, guanin-7-yl, guanin-3-yl, adenin-9-yl, adenin-7-yl, adenin-3-yl, hypoxanthin-9-yl, hypoxanthin-7-yl, hypoxanthin-3-yl, 2-methyladenin-9-yl, 2-methyladenin-7-yl, 2-methyladenin-3-yl, 2-methylthio-adenin-9-yl, 2-methylthioadenin-7-yl, 2-methylthioadenin-3-yl, 2-aminoadenin-9-yl, 2-aminoadenin-7-yl, 2-aminoadenin-3-yl, 2-aminopurin-9-yl, 2-aminopurin-7-yl, 2-aminopurin-3-yl, N⁶ -dimethyladenin-9-yl, N⁶ -dimethyladenin-7-yl, N⁶ -dimethyladenin-3-yl, 8-bromoadenin-9-yl, 8-bromoadenin-7-yl, 8-bromoadenin-3-yl, 8-hydroxyadenin-9-yl, 8-hydroxyadenin-7-yl, 8-hydroxyadenin-3-yl, 6-hydroxylaminopurin-9-yl, 6-hydroxylaminopurin-7-yl, 6-hydroxylaminopurin-3-yl, 6-hydrazinopurin-9-yl, 6-hydrazinopurin-7-yl, 6-hydrazinopurin-3-yl, 6-thiopurin-9-yl, 6-thiopurin-7-yl, 6-thiopurin-3-yl, purin-9-yl, purin-7-yl, purin-3-yl, xanthin-9-yl, xanthin-7-yl, and xanthin-3-yl.

8. The method of claim 4, wherein B is selected from the group consisting of thymin-1-yl,! 5-fluorouracil-1-yl, guanin-9-yl, guanin-7-yl, adenin-3-yl, hypoxanthin-9-yl, 2-methyladenin-9-yl, 2-methylthioadenin-9-yl, 2-aminoadenin-9-yl, 2-aminopurin-9-yl, N⁶ -dimethyladenin-9-yl, 8-bromoadenin-9-yl, 8-hydroxyadenin-9-yl, 6-hydroxylaminopurin-9-yl, 6-hydrazinopurin-9-yl, 6-thiopurin-9-yl, purin-9-yl, and xanthin-9-yl.

10. The method of claim 1, wherein the compound is selected from among 9-(s)-(2-phosphonylmethoxy-3-hydroxy-propyl)adenine (HPMPA), 9-(2-phosphonylmethoxyethyl)adenine (PMEA), (2-phosphonylmethoxyethyl)guanine (PMEG), 9-(s)-3-hydroxy-2-phosphonylmethoxypropylguanine ((S)-HPMPG) (2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), and 9-(s)-2-phosphonylmethoxypropyladenine ((S)-PMPA).

11. The method of claim 1, wherein the compound is 9-(s)-(2-phosphonylmethoxy-3-hydroxy-propyl) adenine(HPMPA), and the amount delivered by a single dosage of the medicament is greater than about 40 μ

g up to about 500 μ

g.

12. The method of claim 1, wherein the compound is in a composition formulated for intravitreal administration.

13. The method of claim 1, wherein the compound is in a composition formulated for administration by aqueous humor injection, by injection into the external layers of the eye, or topically, whereby contact with the vitreous cavity is effected.

14. The method of claim 1, wherein the compound is in a composition formulated for intraocular administration.

15. The method of claim 1, wherein the compound is 9-(s)-(2-phosphonylmethoxy-3-hydroxy-propyl)adenine (HPMPA).

16. The method of claim 1, wherein the compound is 9-(cyclic(s)-3-hydroxy-2-phosphonylmethoxypropyl)adenine (cHPMPA).

17. The method of claim 1, wherein the amount is about 20 μ

g up to about 100 μ

g.

18. The method of claim 1, wherein the compound is administered intravitreally.

19. The method of claim 1, wherein the compound is administered by aqueous humor injection, by injection into the external layers of the eye, or topically, whereby contact with the vitreous cavity is effected.

20. The method of claim 1, wherein the initial intraocular pressure has damaged the optic nerve or reduced the visual field;

and the method further comprises, monitoring intraocular pressure after the injection, and then, when the pressure stabilizes, injecting another effective amount of the compound; and

repeating the monitoring and injecting step a plurality of times until intraocular pressure is at a level whereby further damage to the optic nerve or loss of visual field does not occur.

21. The method of claim 1, wherein the amount administered is effective for lowering intraocular pressure to about 90% of its initial value.

22. The method of claim 1, wherein the compound is PMEG.

23. The method of claim 1, wherein R⁷ is CH₂ OH.

25. The method of claim 1, wherein each of m, n and p is independently 0 or 1.

26. The method of claim 1, wherein the amount of the compound is about 1 μ

g to about 1000 μ

g.

28. The method of claim 1, wherein the compound is HPMPA.

29. The method of claim 22, wherein the composition is encapsulated in a liposome.

30. The method of claim 1, wherein:

R¹ is CH₂ CH(OH)(CH₂)_n, CH₂ CH(CH₂)_n (OH), CH₂ OCH(R⁷), CH₂ OCH(R⁷)(CH₂)_p, CH₂ OCH(R⁷)(CH₂)_p O or O(CH₂)_p CH(R⁷)O;

R² is OH or O(CH₂)_r H;

R⁷ is OH or (CH₂)_r OH;

n is 0-6;

r is 1-6;

p is 0-3; and

m is 0 to 3.

31. The method of claim 4, wherein B is selected from the group consisting of guanin-9-yl, guanin-7-yl, adenin-3-yl, hypoxanthin-9-yl, 2-methyladenin-9-yl, 2-methylthioadenin-9-yl, 2-aminoadenin-9-yl, 2-aminopurin-9-yl, N⁶ -dimethyladenin-9-yl, 8-bromoadenin-9-yl, 8-hydroxyadenin-9-yl, 6-hydroxylaminopurin-9-yl, 6-hydrazinopurin-9-yl, 6-thiopurin-9-yl, purin-9-yl, and xanthin-9-yl.

32. The method of claim 1, wherein the compound is 9-(s)-(2-phosphonylmethyoxy-3-hydroxy-propyl) adenine (HPMPA), and the amount delivered by a single dosage of the medicament is greater than about 40 μ

g up to about 500 μ

g.

33. The method of claim 1, wherein the compound is 9-(cyclic(s)-3-hydroxy-2-phosphonylmethoxypropyl) adenine (cHPMPA).

34. The method of claim 1, wherein the amount is greater than about 20 μ

g up to about 100 μ

g.

35. The method of claim 1, wherein the compound is 9-(s)-3-hydroxy-2-phosphonylmethoxypropylguanine ((S)-HPMPG).

36. The method of claim 1, wherein:

R¹ and R² are selected from (i) only, and

R¹ is CH₂ CH(OH)(CH₂)_n, CH₂ CH(CH₂)_n (OH), CH₂ OCH(R⁷), CH₂ OCH(R⁷)(CH₂)_p, CH₂ OCH(R⁷)(CH₂)_p O or O(CH₂)_p CH(R⁷)O;

R² is OH or O(CH₂)_r H;

R⁷ is H, OH or (CH₂)_r OH;

n is 1-6;

r is 1-6;

p is 0-3; and

m is 0 to 3.

37. The method of claim 1, wherein the composition is packaged in a container for delivery of between about 0.50 ml and 0.150 ml and comprises a concentration of the compound of about 10 μ

g/0.100 ml up to about 100 μ

g/0.100 ml.

38. The method of claim 1, wherein the concentration of the compound is about 10 μ

g to about 50 μ

g per 0.100 ml of the composition.

39. The method of claim 4, wherein B is selected from the group consisting of guanin-9-yl, guanin-7-yl, guanin-3-yl, adenin-9-yl, adenin-7-yl, adenin-3-yl, hypoxanthin-9-yl, hypoxanthin-7-yl, hypoxanthin-3-yl, 2-methyladenin-9-yl, 2-methyladenin-7-yl, 2-methyladenin-3-yl, 2-methylthioadenin-9-yl, 2-methylthioadenin-7-yl, 2-methylthioadenin-3-yl, 2-aminoadenin-9-yl, 2-aminoadenin-7-yl, 2-amino-adenin-3-yl, 2-aminopurin-9-yl, 2-aminopurin-7-yl, 2-aminopurin-3-yl, N⁶ -dimethyladenin-9-yl, N⁶ -dimethyladenin-7-yl, N⁶ -dimethyladenin-3-yl, 8-bromoadenin-9-yl, 8-bromoadenin-7-yl, 8-bromoadenin-3-yl, 8-hydroxyadenin-9-yl, 8-hydroxyadenin-7-yl, 8-hydroxyadenin-3-yl, 6-hydroxylaminopurin-9-yl, 6-hydroxylaminopurin-7-yl, 6-hydroxylaminopurin-3-yl, 6-hydrazinopurin-9-yl, 6-hydrazinopurin-7-yl, 6-hydrazinopurin-3-yl, 6-thiopurin-9-yl, 6-thiopurin-7-yl, 6-thiopurin-3-yl, purin-9-yl, purin-7-yl, purin-3-yl, xanthin-9-yl, xanthin-7-yl, and xanthin-3-yl.

40. The method of claim 1, wherein the composition is encapsulated in a liposome.

2. A method for reducing intraocular pressure, comprising administering to the eye an effective amount of a compound or pharmaceutically acceptable salts of acids thereof, wherein the compound is selected from the group consisting of ##STR9## wherein:

R⁷ is H, OH, or (CH₂)_r OH;

r is 1-6;

B is a purine of formula (II);

##STR10## and is selected from the group consisting of purin-3-yl, purin-7-yl and purin-9-yl;

R³, R⁴ and R⁵ are independently selected from NH₂, alkylamino, aminoalkyl, hydroxyalkyl, hydrazino, H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, hydroxylamino and CH_3-q (hal)_q in which q is 1-3 and hal is a halide; and

the amount is effective for lowering intraocular pressure.

9. The method of claim 2, wherein B is selected from the group consisting of adeninyl and guaninyl.

24. The method of claim 2, wherein R⁷ is CH₂ OH.

27. The method of claim 2, wherein the compound is selected from the group consisting of compounds having the formula:

##STR13##