Boron-containing small molecules

• US 8,722,917 B2
• Filed: 01/23/2012
• Issued: 05/13/2014
• Est. Priority Date: 02/16/2005
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Baker, Stephen J., Akama, Tsutomu, Alley, Michael Richard Kevin, Benkovic, Stephen J., Hernandez, Vincent S., Hold, Karin M., Mao, Weimin, Maples, Kirk, Plattner, Jacob J., Rock, Fernando, Sanders, Virginia, Stemphoski, Aaron M., Yiannikouros, George Petros, Zagar, Siead, Zhang, Yong-Kang, Zhou, Huchen, Dipierro, Michael, Kennedy, Isaac, Likhotvorik, Igor
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US13/356,488
• Publication Number:
  US 20120289686A1
• Time in Patent Office: 841 Days
• Field of Search: 534/558, 549/213, 558/294, 558/298, 562/7
• US Class Current: 558/294
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0012 Galenical forms characterised by the site of application
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to compounds useful for treating fungal infections, more specifically topical treatment of onychomycosis and/or cutaneous fungal infections. This invention is directed to compounds that are active against fungi and have properties that allow the compound, when placed in contact with a patient, to reach the particular part of the skin, nail, hair, claw or hoof infected by the fungus. In particular the present compounds have physiochemical properties that facilitate penetration of the nail plate.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, having a structure according to the following formula:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said R¹ and R² are each members independently selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl

and wherein R¹ and R², together with the atoms to which they are joined, can optionally form a member selected from substituted or unsubstituted dioxaborolane, substituted or unsubstituted dioxaborinane and substituted or unsubstituted dioxaborepane.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein said R¹ and R², together with the atoms to which they are joined, form a member selected from dioxaborolane, substituted or unsubstituted tetramethyldioxaborolane, substituted or unsubstituted phenyldioxaborolane, dioxaborinane, dimethyldioxaborinane and dioxaborepane.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z1 is

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said R^3a is H and R^4a is a member selected from methyl, ethyl, propyl, butyl, phenyl, benzyl and cyano.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^10a is a member selected from the group consisting of fluoro, chloro, and bromo.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to the following formula:

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is a member selected from

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said R¹ and R² are each members independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said R¹ and said R² are each members independently selected from H, methyl, isopropyl, and phenyl.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said R¹ and said R² are methyl.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said R¹ and said R² are isopropyl.

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said R¹ and said R² are H.

31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to the following formula:

32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is a member selected from

9. A compound, or a pharmaceutically acceptable salt thereof, having a structure according to the formula:

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said R¹ and R² are each members independently selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstitutcd isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl

and wherein R¹ and R², together with the atoms to which they are joined, can optionally form a member selected from substituted or unsubstituted dioxaborolane, substituted or unsubstituted dioxaborinane and substituted or unsubstituted dioxaborepane.

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said R¹ and R², together with the atoms to which they are joined, form a member selected from dioxaborolane, substituted or unsubstituted tetramethyldioxaborolane, substituted or unsubstituted phenyldioxaborolane, dioxaborinane, dimethyldioxaborinane and dioxaborepane.

12. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said X is a member selected from triflate, chloro, bromo, iodo, substituted or unsubstituted sulfonic esters, substituted or unsubstituted acyloxy groups, and substituted or unsubstituted diazo.

13. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said R^3a is H and R^4a is a member selected from methyl, ethyl, propyl, butyl, phenyl, benzyl and cyano.

14. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R^9a is H, R^11a is H, R^12a is H, R^10a is a member selected from the group consisting of halogen, cyano, nitro, substituted or unsubstituted methoxy, substituted or unsubstituted methyl, substituted or unsubstituted ethoxy, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyloxy, substituted or unsubstituted phenyl methoxy, substituted or unsubstituted thiophenyloxy, substituted or unsubstituted pyridinyloxy, substituted or unsubstituted pyrimidinyloxy, substituted or unsubstituted benzylfuran, substituted or unsubstituted methylthio, substituted or unsubstituted mercaptomethyl, substituted or unsubstituted mercaptoalkyl, substituted or unsubstituted phenylthio, substituted or unsubstituted thiophenylthio, substituted or unsubstituted phenyl methylthio, substituted or unsubstituted pyridinylthio, substituted or unsubstituted pyrimidinylthio, substituted or unsubstituted benzylthiofuranyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted benzylsulfonyl, substituted or unsubstituted phenylmethylsulfonyl, substituted or unsubstituted thiophenylsulfonyl, substituted or unsubstituted pyridinylsulfonyl, substituted or unsubstituted pyrimidinylsulfonyl, substituted or unsubstituted sulfonamidyl, substituted or unsubstituted phenylsulfinyl, substituted or unsubstituted benzylsulfinyl, substituted or unsubstituted phenylmethylsulfinyl, substituted or unsubstituted thiophenylsulfinyl, substituted or unsubstituted pyridinylsulfinyl, substituted or unsubstituted pyrimidinylsulfinyl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted trifluoromethylamino, substituted or unsubstituted aminomethyl, substituted or unsubstituted alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted benzylamino, substituted or unsubstituted phenylamino, substituted or unsubstituted thiophenylamino, substituted or unsubstituted pyridinylamino, substituted or unsubstituted pyrimidinylamino, substituted or unsubstituted indolyl, substituted or unsubstituted morpholino, substituted or unsubstituted alkylamido, substituted or unsubstituted arylamido, substituted or unsubstituted ureido, substituted or unsubstituted carbamoyl, and substituted or unsubstituted piperizinyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R^10a is a member selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxylmethyl, trifluoromethyl, methoxy, trifluoromethyoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3-(butylcarbonyl)phenylmethoxy, 1H-tetrazol-5-yl, 1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethyl-, 1-ethoxycarbonyl-, carboxymethoxy-, thiophen-2-yl, thiophen-2-ylthio-, thiophen-3-yl, thiophen-3-ylthio, 4-fluorophenylthio, butylcarbonylphenylmethoxy, butylcarbonylphenylmethyl, butylcarbonylmethyl, 1-(piperidin-1-yl)carbonyl)methyl, 1-(piperidin-1-yl)carbonyl)methoxy, 1-(piperidin-2-yl)carbonyl)methoxy, 1-(piperidin-3-yl)carbonyl)methoxy, 1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methoxy, 1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methyl, 1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl, 1-4-(pyrimidin-2-yl)piperazin-1-yl, 1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl), 1-(4-(pyridin-2-yl)piperazin-1-yl)carbonylmethyl, (1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl)-methoxy), 1-(4-(pyridin-2-yl)piperazin-1-yl, 1H-indol-1-yl, morpholino-, morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido, phenylcarbamoyl, acetamido, 3-(phenylthio)-1H-indol-1-yl, 3-(2-cyanoethylthio)-1H-indol-1-yl, benzylamino, 5-methoxy-3-(phenylthio)-1H-indol-1-yl, 5-methoxy-3-(2-cyanoethylthio)-1H-indol-1-yl)), 5-chloro-1H-indol-1-yl, 5-chloro-3-(2-cyanoethylthio)-1H-indol-1-yl)), dibenzylamino, benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1-yl)), 4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phenyl, 4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio, 4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, and 4-fluorobenzyloxy.

16. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said compound is a member selected from

17. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said compound is a member selected from:

18. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said compound is a member selected from:

19. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said R¹ and said R² are each members independently selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl.

20. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said R¹ and said R² are each members independently selected from R¹ and R², together with the atoms to which they are joined, can optionally form a member selected from substituted or unsubstituted dioxaborolane, substituted or unsubstituted dioxaborinane, substituted or unsubstituted dioxaborepane.

21. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said X is a sulfonic ester group which is selected from the group consisting of substituted or unsubstituted mesylate, substituted or unsubstituted tosylate, substituted or unsubstituted brosylate and substituted or unsubstituted nosylate.

22. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said X is an acyloxy group which is substituted or unsubstituted acetoxy or substituted or unsubstituted trifluoroacetoxy.

23. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said X is selected from the group consisting of bromo, iodo, mesylate and diazo.

24. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said X is bromo or iodo.

25. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said compound is