Boronate ester compounds and pharmaceutical compositions thereof

• US 9,175,018 B2
• Filed: 08/01/2014
• Issued: 11/03/2015
• Est. Priority Date: 06/17/2008
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Elliott, Eric L., Ferdous, Abu J., Kaufman, Michael J., Komar, Sonja A., Mazaik, Debra L., Mccubbin, Quentin J., Nguyen, Phuong M., Palaniappan, Vaithianathan, Skwierczynski, Raymond D., Truong, Nobel T., Varga, Csanad M., Zawaneh, Peter N.
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US14/449,328
• Publication Number:
  US 20140343314A1
• Time in Patent Office: 459 Days
• Field of Search: 558/288
• US Class Current: 1/1
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/83 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 : Esters of boric acids
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N

Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Claims

1. A process for generating a compound of Formula (II)

2. The process of claim 1, wherein the reaction of step (1a) or step (3a) or both is conducted in the presence of a peptide coupling reagent.

3. The process of claim 2, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uronium reagent.

4. The process of claim 3, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and O-(1H-benzotriazol-1-yl)-N,N,N′

,N′

-tetramethyluronium tetrafluoroborate (TBTU).

5. The process of claim 1, further comprising converting the carboxylic acid moiety of compound (viia) to an activated ester or acid halide prior to the reaction of step (3a).

6. The process of claim 5, wherein said activated ester or acid halide is an O—

(N-hydroxysuccinnimide) ester.

7. The process of claim 1, wherein the reaction of step (1a) is conducted in the presence of a solvent.

8. The process of claim 7, wherein the solvent is tetrahydrofuran.

9. The process of claim 1, wherein the reaction of step (4) is conducted in the presence of an aqueous mineral acid.

10. The process of claim 9, wherein the mineral acid is hydrochloric acid.

11. The process of claim 1, wherein the reaction of step (4) is conducted in the presence of an organic boronic acid acceptor.

12. The process of claim 11, wherein the organic boronic acid acceptor is i-BuB(OH)₂.

13. The process of claim 1, wherein the reaction of step (5) is conducted in the presence of a solvent selected from the group consisting of ethyl acetate, methyl isobutyl ketone, acetone, acetonitrile, 2-methyltetrahydrofuran, anisole, isopropyl acetate, dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, toluene, heptane, methyl-cyclohexane, tert-butylmethyl ether, and any combination thereof.

14. The process of claim 1, wherein the reaction of step (5) is conducted in the presence of a catalyst, wherein the catalyst is an organic amine base.

15. The process of claim 14, wherein the catalyst is selected from the group consisting of triethylamine, triethylenediamine, pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine, di-tertbutylpyridine, N-methylmorpholine, N-methylpiperidine, tetramethylguanidine, diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicycle[4.3.0]non-5-ene, N,N′

diisopropylethylamine, or any combination thereof.

16. The process of claim 1, wherein step (5) further comprises cooling the solution.

17. The process of claim 16, wherein the cooling comprises cooling the solution uncontrolled until the internal temperature is about 25°

C.

18. The process of claim 16, wherein the cooling is conducted in the presence of a co-solvent.

19. The process of claim 18, wherein the co-solvent is selected from the group consisting of heptane, methylcyclohexane, toluene, tert-butylmethyl ether, ethyl acetate, or any combination thereof.

20. The process of claim 1, further comprising

(6) isolating the compound of Formula (II) as a crystalline solid.

21. The process of claim 1, wherein PG is a protecting group selected from the group consisting of an acyl protecting group and a urethane protecting group.

22. The process of claim 21, wherein PG is a protecting group selected from the group consisting of formyl, acetyl, succinyl, methoxysuccinyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc).

23. The process of claim 1, wherein LG is —

Cl.

24. The process of claim 1, wherein X⁻

is CF₃CO₂⁻

.

25. The process of claim 1, wherein R^c is selected from the group consisting of 2,5-dichlorophenyl.

26. The process of claim 1, wherein

A is 0;

R^a is C_1-6 aliphatic;

R^a1 is hydrogen, C_1-6 aliphatic, —

(CH₂)_m—

CH₂—

R^B, or —

(CH₂)_m—

CH(R^5a)—

OR^5b;

each of R^b1 and R^b2 independently is hydrogen, —

CO₂H, —

OH, or a substituted or unsubstituted aliphatic;

each of R^b3 and R^b4 independently is hydrogen, C_1-6 aliphatic, or —

(CH₂)_pCO₂H; and

p is 0 or 1.

27. The process of claim 1, wherein

A is 0;

R^D is 2,5-dichlorophenyl;

R^a is isobutyl;

R^a1 is hydrogen;

each R^b1 and R^b2 independently is hydrogen;

each R^b3 and R^b4 independently is —

(CH₂)_p—

CO₂H;

p is 0 or 1; and

n is 0 or 1.

28. The process of claim 1, wherein the alpha hydroxy carboxylic acid or a beta hydroxy carboxylic acid is citric acid.

29. The process of claim 1, wherein the compound of Formula (II) is 4-(R,S)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid.

30. The process of claim 1, wherein the compound of Formula (II) is 2,2′

-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid.

31. A process for generating a compound, Form-1,

32. The process of claim 31, wherein the reaction of step (1) is conducted in the presence of NaOH.

33. The process of claim 31, wherein the reaction of step (2) is conducted in the presence of TBTU.

34. The process of claim 31, wherein the reaction of step (2) is conducted in the presence of DIPEA.

35. The process of claim 31, wherein the reaction of step (3) is conducted in the presence of methanol and hexane.

36. The process of claim 31, wherein the reaction of step (4) is conducted in the presence of ethyl acetate.

37. The process of claim 31, wherein the reaction of step (4) comprises cooling the solution uncontrolled until the internal temperature is about 25°

C.

38. A process for generating a compound, Form-1,

39. The process of claim 38, wherein the reaction is conducted in the presence of ethyl acetate.

40. The process of claim 38, wherein the reaction further comprises cooling the solution uncontrolled until the internal temperature is about 25°

C.