Prodrugs of carbonic anhydrase inhibitors

• US 5,095,026 A
• Filed: 09/22/1989
• Issued: 03/10/1992
• Est. Priority Date: 02/04/1983
• Status: Expired due to Fees

• Current Assignee: University of Iowa Research Foundation
• Original Assignee: University of Iowa Research Foundation
• Inventors: Schoenwald, Ronald D., Barfknecht, Charles F.
• Primary Examiner(s): Griffin, Ronald W.
• Assistant Examiner(s): LEARY, LOUISE N
• Application Number:
  US07/410,982
• Time in Patent Office: 900 Days
• Field of Search: 536/1.1, 536/4.1, 514/367, 514/913, 424/80, 424/270, 424/321
• US Class Current: 514/367
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 277/80 to a nitrogen atom
• CPC Class Codes: C07H 15/18 Acyclic radicals, substituted by carbocyclic rings
• CPC Class Codes: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• CPC Class Codes: C07H 15/26 Acyclic or carbocyclic radicals, substituted by hetero rings
• CPC Class Codes: C07H 17/00 Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Prodrugs are prepared of the carbonic anhydrase inhibitors 2-benzothiazolesulfonamide, hydroxymethazolamide, and dichlorphenamide. The prodrugs link a water soluble compound to the pharmacologically active carbonic anhydrase inhibitor through an enzymatically or hydrolytically degradable bond.

Claims

1. Prodrugs of 2-benzothiazolesulfonamide carbonic anhydrase inhibitors (CAI) having the formula:

##STR4## wherein Z is a water soluble carrier, and A is a moiety which when attached to said 2-benzothiazolesulfonamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z.

2. The prodrugs of claim 1 wherein the water soluble carrier Z is selected from the group consisting of monosaccharides and 6-carboxylic acid derivatives of monosaccharides.

3. The prodrugs of claim 1 wherein A is selected from the group consisting of hydroxyethoxy, hydroxy, hydroxyacetamido, and amino.

4. The prodrugs of claim 1 wherein the enzymatically cleavable bond between Z and A is selected from the group consisting of ester, glycosidic, carbonate, carbamate, thiocarbamate, urea, and thiourea bonds.

5. The prodrug of claim 4 wherein Z is a monosaccharide and the linkage is glycosidic.

6. The prodrug of claim 4 wherein Z is 6-carboxylic acid and the linkage is esteratic.

7. Prodrugs of hydroxymethazolamide carbonic anhydrase inhibitors (CAI) having the formula:

##STR5## wherein n is from one to three, Z is a water soluble carrier, and A is a moiety which when attached to said hydroxymethazolamide which still retain CAI activity and which can also form an enzymatically cleavable bond with Z.

8. The prodrugs of claim 7 wherein the water soluble carrier Z is selected from the group consisting of monosaccharides and 6-carboxylic acid derivatives of monosaccharides.

9. The prodrugs of claim 7 wherein A is selected from the group consisting of hydroxyethoxy, hydroxy, hydroxyacetamido, and amino.

10. The prodrugs of claim 7 wherein the enzymatically cleavable bond between Z and A is selected from the group consisting of ester, glycosidic, carbonate, carbamate, thiocarbamate, urea, and thiourea bonds.

11. The prodrug of claim 10 wherein Z is a monosaccharide and the linkage is glycosidic.

12. The prodrug of claim 10 wherein Z is 6-carboxylic acid and the linkage is esteratic.

13. Prodrugs of dichlorphenamide carbonic anhydrase inhibitors (CAI) having the formula:

##STR6## wherein Z is a water soluble carrier, and A is a moiety which when attached to said dichlorphenamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z.

14. The prodrugs of claim 13 wherein the water soluble carrier Z is selected from the group consisting of monosaccharides and 6-carboxylic acid derivatives of monosaccharides.

15. The prodrugs of claim 13 wherein A is selected from the group consisting of hydroxyethoxy, hydroxy, hydroxyacetamido, and amino.

16. The prodrugs of claim 13 wherein the enzymatically cleavable bond between Z and A is selected from the group consisting of ester, glycosidic, carbonate, carbamate, thiocarbamate, urea, and thiourea bonds.

17. The prodrug of claim 16 wherein Z is a monosaccharide and the linkage is glycosidic.

18. The prodrug of claim 16 wherein Z is 6-carboxylic acid and the linkage is esteratic.

19. A method of reducing intraocular eye pressure, said method comprising:

(a) topically applying to the eye a small but therapeutically effective intraocular eye pressure reducing amount of a prodrug of 2-benzothiazolesulfonamide carbonic anhydrase inhibitor having the formula;

##STR7## wherein Z is a water soluble carrier, and A is a moiety which when attached to said 2-benzothiazolesulfonamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z.

20. A method of reducing intraocular eye pressure, said method comprising:

(a) topically applying to the eye a small but therapeutically effective intraocular eye pressure reducing amount of a prodrug of hydroxymethazolamide carbonic anhydrase inhibitor having the formula;

##STR8## wherein n is from one to three, Z is a water soluble carrier, and A is a moiety which when attached to said hydroxymethazolamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z.

21. A method of reducing intraocular eye pressure, said method comprising:

(a) topically applying to the eye a small but therapeutically effective intraocular eye pressure reducing amount of a prodrug of dichlorphenamide carbonic anhydrase inhibitor having the formula;

##STR9## wherein Z is a water soluble carrier, and A is a moiety which when attached to said dichlorphenamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z.

22. A topical composition for eye drop treatment, comprising:

a small but therapeutically effective intraocular eye pressure reducing amount of an analog of 2-benzothiazolesulfonamide carbonic anhydrase inhibitor of the formula;

##STR10## wherein Z is a water soluble carrier, and A is a moiety which when attached to said 2-benzothiazolesulfonamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z and an opthalmically acceptable carrier.

23. A topical composition for eye drop treatment, comprising:

a small but therapeutically effective intraocular eye pressure reducing amount of an analog of hyroxymethazolamide carbonic anhydrase inhibitor of the formula;

##STR11## wherein n is from one to three, Z is a water soluble carrier, and A is a moiety which when attached to said hydroxymethazolamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z and an opthalmically acceptable carrier.

24. A topical composition for eye drop treatment, comprising:

a small but therapeutically effective intraocular eye pressure reducing amount of an analog of dichlorphenamide carbonic anhydrase inhibitor of the formula;

##STR12## wherein Z is a water soluble carrier, and A is a moiety which when attached to said dichlorphenamide will still retain CAI activity and which can also form an enzymatically cleavable bond with Z and an opthalmically acceptable carrier.