Boron-containing diacylhydrazines

• US 9,127,024 B2
• Filed: 03/14/2014
• Issued: 09/08/2015
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Intrexon Corporation
• Original Assignee: Intrexon Corporation
• Inventors: Hormann, Robert E., Shulman, Inna, Chellappan, Sheela K.
• Primary Examiner(s): Seaman, D M
• Application Number:
  US14/212,526
• Publication Number:
  US 20140274954A1
• Time in Patent Office: 543 Days
• Field of Search: 546/159
• US Class Current: 1/1
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/027 Organoboranes and organoborohydrides
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07F 7/0803 Compounds with Si-C or Si-Si linkages

Abstract

The present disclosure provides boron-containing diacylhydrazines having Formula I:

• • and the pharmaceutically acceptable salts and solvates thereof, wherein R¹, R², R³, R⁴, and R⁵ are defined as set forth in the specification. The present disclosure also provides the use of boron-containing diacylhydrazines is ecdysone receptor-based inducible gene expression systems. Thus, the present disclosure is useful for applications such as gene therapy, treatment of disease, large scale production of proteins and antibodies, cell-based screening assays, functional genomics, proteomics, metabolomics, and regulation of traits in transgenic organisms, where control of gene expression levels is desirable.

Claims

1. A compound having Formula I:

2. The compound of claim 1, wherein:

R⁴ is R⁴-1;

R⁵ is selected from the group consisting of R⁵-3, R⁵-4, and R⁵-5; and

R^10e is hydrogen,

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, wherein:

R⁴ is R⁴-2;

R⁵ is selected from the group consisting of R⁵-3, R⁵-4, and R⁵-5; and

R^10e is hydrogen,

or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1, wherein:

R⁴ is R⁴-5;

R⁵ is selected from the group consisting of R⁵-3, R⁵-4, and R⁵-5; and

R^10a is —

(CR^11aR^11b)_o—

B(R^12a)(R^12b),

or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1, wherein:

R⁴ is R⁴-5;

R⁵ is R⁵-3; and

R^10e is (CR^11cR^11d)_s—

B(R^12c)(R^12d),

or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 4 having Formula II:

7. The compound of claim 6, wherein o is 0 and R^10b and R^10c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy, or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 5, having Formula III:

9. The compound of claim 8, wherein s is 0 and R^10b, R^10c, and R^10d are independently selected from the group consisting of hydrogen, halogen, hydroxy, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy;

or

R^10b is selected from the group consisting of hydrogen, halogen, hydroxy, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; and

R^10c and R^10d taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group, or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 1 having Formula V:

11. The compound of claim 1 having Formula VI:

12. The compound of claim 10 or 11, wherein R^7a is selected from the group consisting of hydrogen, halogen, and alkyl, or a pharmaceutically acceptable salt or solvate thereof.

13. The compound of claim 12, wherein Z¹ is absent or —

O—

, or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of claim 12, wherein X¹ is —

O—

, or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 13, wherein Z¹ is absent, R^9a and R^9b are selected from the group consisting of hydrogen and methyl, and m is 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 1 having Formula VIII:

17. The compound of claim 16, wherein R^7c is selected from the group consisting of hydrogen, halogen, and alkyl;

Z² is absent;

X² is —

O—

;

R^9c and R^9d are selected from the group consisting of hydrogen and methyl; and

n is 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

18. The compound of claim 1, wherein:

R⁴ is selected from the group consisting of

19. The compound of claim 18, wherein

R^7a is selected from the group consisting of hydrogen, halogen, hydroxy, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy;

R^8a is selected from the group consisting of hydrogen and C_1-4 alkyl; and

R^6f is selected from the group consisting of hydrogen, C_1-4 alkyl, hydroxy, and —

NH₂,

or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of claim 1, wherein:

R¹ is optionally substituted C_1-6 alkyl;

R² is selected from the group consisting of hydrogen and optionally substituted C_1-6 alkyl; and

R³ is optionally substituted C_1-6 alkyl,

or a pharmaceutically acceptable salt or solvate thereof.

21. The compound of claim 20, wherein:

R¹ is selected from the group consisting of methyl, ethyl, n-propyl, and n-butyl; and

R² is selected from the group consisting of hydrogen and methyl,

or a pharmaceutically acceptable salt or solvate thereof.

22. The compound of claim 21, wherein R³ is selected from the group consisting of methyl and tert-butyl, or a pharmaceutically acceptable salt or solvate thereof.

23. The compound of claim 1, wherein R¹ is optionally substituted C_1-6 alkyl;

R² is hydrogen; and

R³ is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, and optionally substituted pyrimidinyl, or a pharmaceutically acceptable salt or solvate thereof.

24. The compound of claim 22, wherein R¹, R², and R³ are each methyl, or a pharmaceutically acceptable salt or solvate thereof.

25. The compound of claim 1 having Formula X

26. The compound of claim 1 having Formula XI

27. The compound of claim 25 or 26, wherein:

R⁴ is selected from the group consisting of;

28. The compound of claim 1 selected from the group consisting of:

29. A pharmaceutical composition comprising the compound of claim 1 or 28, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

30. A method of regulating gene expression of a gene of interest in an isolated host cell, the method comprising contacting said host cell with the compound of claim 1 or 28, or a pharmaceutically acceptable salt thereof.

31. A method of treating cancer in a subject, the method comprising administering to said subject the compound of claim 1 or 28, or a pharmaceutically acceptable salt or solvate thereof, wherein a host cell within said subject comprises a polynucleotide encoding a gene switch that comprises a ligand binding domain that binds said compound, and said gene switch comprises an ecdysone receptor ligand binding domain.

32. The method of claim 31, wherein said subject is human.

33. The method of claim 31, wherein said host cell further comprises a polynucleotide encoding a peptide, protein, or polypeptide whose expression is regulated by said gene switch.

34. The method of claim 33, wherein said polynucleotide encodes IL-12 or a subunit thereof.

35. A kit comprising the compound of claim 1 or 28, or a pharmaceutically acceptable salt or solvate thereof.

36. The method of claim 31, wherein said cancer is selected from the group consisting of breast cancer, lymphoma, pancreatic cancer, colon cancer, melanoma, glioma, non-small cell lung cancer, head or neck carcinoma, lung carcinoma, cervical carcinoma, renal cell carcinoma, mycosis fungoides, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Kaposi'"'"'s sarcoma, Hodgkin'"'"'s disease, and non-Hodgkin'"'"'s lymphoma.

37. The method of claim 36, wherein said cancer is selected from the group consisting of melanoma, colon cancer, lung cancer, breast cancer, leukemia, and pancreatic cancer.

38. The method of claim 31, wherein said cancer is selected from the group consisting of melanoma, colon cancer, lung cancer, breast cancer, leukemia, and pancreatic cancer, and said gene switch regulates the expression of a polynucleotide encoding IL-12 or a subunit thereof.