Cycloalkyl guanidine F;F;-ATPase inhibitors and therapeutic uses thereof

• US 9,169,199 B2
• Filed: 12/08/2011
• Issued: 10/27/2015
• Est. Priority Date: 12/08/2010
• Status: Expired due to Fees

• Current Assignee: Lycera Corporation
• Original Assignee: Lycera Corporation
• Inventors: Hurd, Alexander R., Taylor, Clarke B., Toogood, Peter L., Van Huis, Chad A.
• Primary Examiner(s): Carter, Kendra D
• Application Number:
  US13/992,253
• Publication Number:
  US 20130331392A1
• Time in Patent Office: 1,419 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 279/22 Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
• CPC Class Codes: C07C 309/04 containing only one sulfo group
• CPC Class Codes: C07C 311/07 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07D 203/22 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 239/28 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/32 One oxygen, sulfur or nitrogen atom
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/195 Radicals derived from nitrogen analogues of carboxylic acids
• CPC Class Codes: C07D 295/205 Radicals derived from carbonic acid
• CPC Class Codes: C07D 295/30 non-acylated
• CPC Class Codes: C07D 307/22 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/66 : Nitrogen atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention provides cycloalkyl guanidine compounds that inhibit F₁F₀-ATPase, and methods of using cyclalkyl guanidine compounds as therapeutic agents in therapy, such as treating an immune disorder, inflammatory condition, or cancer.

Claims

1. A compound represented by Formula I:

2. The compound of claim 1, wherein A is cycloalkylene, that in addition to R³, is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, —

N(R⁵)CO₂R⁶, —

N(R⁵)C(O)R⁶, —

N(R⁷)(R⁸), —

OR⁵, and —

C(O)R⁵.

3. The compound of claim 1, wherein A is cyclobutylene, cyclopentylene, or cyclohexylene, each of which is, in addition to R³, optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxyl, and —

N(R⁷)(R⁸).

4. The compound of claim 1, wherein A is cyclohexylene.

5. The compound of claim 1, wherein R¹ represents independently for each occurrence halogen, haloalkyl, alkyl, or C₁-C₆alkoxy.

6. The compound of claim 1, wherein R¹ represents independently for each occurrence chloro, fluoro, or trifluoromethyl.

7. The compound of claim 1, wherein R² is hydrogen.

8. The compound of claim 1, wherein R³ is —

N(R⁵)CO₂R⁶, —

N(R⁵)C(O)R⁶, —

N(R⁵)C(O)N(R⁷)(R⁸), —

N(R⁵)SO₂R⁶, or —

N(R⁷)(R⁸).

9. The compound of claim 1, wherein R³ is —

N(R⁵)CO₂R⁶.

10. The compound of claim 1, wherein R³ is —

N(R⁵)C(O)R⁶.

11. The compound of claim 1, wherein R⁴ is aryl or aralkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, and C₁-C₆alkoxy.

12. The compound of claim 1, wherein R⁴ is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, and C₁-C₆alkoxy.

13. The compound of claim 1, wherein R⁴ is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.

14. The compound of claim 1, wherein R⁴ is benzyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of chloro, fluoro, trifluoromethyl, cyclopropyl, and (C₁-C₄)alkyl.

15. The compound of claim 1, wherein R⁵ represents independently for each occurrence hydrogen or (C₁-C₄)alkyl.

16. The compound of claim 1, wherein R⁶ represents independently for each occurrence (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, or haloalkyl.

17. The compound of claim 1, wherein n is 1 or 2.

18. The compound of claim 1, wherein said compound is represented by Formula 1-A1:

19. The compound of claim 18, wherein R¹ and R² are chloro or fluoro.

20. The compound of claim 18, wherein R³ is —

N(R⁵)CO₂R⁶;

R⁵ is hydrogen or methyl; and

R⁶ is methyl, ethyl, propyl or butyl.

21. The compound of claim 20, wherein R⁴ is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.

23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

24. A method of treating a disorder selected from the group consisting of psoriasis, lupus, B cell lymphoma and leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 in order to ameliorate a symptom of the disorder.

25. A method of inhibiting a F₁F₀-ATPase, comprising exposing a F₁F₀-ATPase to a compound of claim 1.

22. A compound listed in one of the following Tables, or a pharmaceutically acceptable salt or hydrate of said compound: