Heterocyclic boronic acid compounds

• US 8,415,295 B2
• Filed: 01/22/2010
• Issued: 04/09/2013
• Est. Priority Date: 11/12/2003
• Status: Active Grant

• Current Assignee: Sino-Med International Alliance Inc.
• Original Assignee: Phenomix Corporation
• Inventors: Campbell, David Alan, Winn, David T., Betancort, Juan Manuel
• Primary Examiner(s): Heyer, Dennis
• Application Number:
  US12/692,276
• Publication Number:
  US 20100120661A1
• Time in Patent Office: 1,173 Days
• Field of Search: None
• US Class Current: 514/3
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 5/00 : Drugs for disorders of the endocrine system
• 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 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds

Abstract

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH_2; S; O; CF₂ or C(CH₃)₂; Z is H; halogen; hydroxyl; (C_1-6)alkoxy; (C_1-12)alkyl; (C_3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CrⁱRⁱⁱ, R¹, R¹, R³, R⁴ and R⁵ are as described herein. Methods for preparing these compounds, and methods for treating diabetes, especially Type II diabetes, and other related diseases are described using the compounds of formula I in pharmaceutical compositions which contain these compounds. Pharmaceutical compositions which contain combinations of these compounds with other antidiabetic agents are also described herein.

Claims

1. A method for inhibiting dipeptidyl peptidase-IV comprising contacting dipeptidyl peptidase-IV with an effective amount of a compound of formula (I):

2. A method according to claim 1, wherein the dipeptidyl peptidase-IV is within a mammal in need of treatment for a malcondition that can be regulated or normalized via inhibition of dipeptidyl peptidase-IV and the contacting step comprises administering to the mammal a therapeutically effective amount of the compound.

3. The method of claim 1 further comprising administering a therapeutically effective amount of a second medicament selected from the group consisting of a second medicament that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal tract, enhances the effect of endogenous peptides or proteins that affect glycemic control, or provides a replacement for endogenous peptides, proteins that affect glycemic control, or any combination thereof.

4. A method according to claim 3 wherein one or more second medicaments are administered and are selected from the group consisting of

a) Other dipeptidyl peptidase-IV inhibitors;

b) Insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase-1B inhibitors;

c) Insulin or insulin mimetics;

d) Sulfonylureas or other insulin secretagogues;

e) α

-glucosidase inhibitors;

f) glucagons receptor agonists;

g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;

h) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;

i) GIP, GIP mimetics, and GIP receptor agonists;

j) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

k) Cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα

agonists, (v) PPARα

/γ

dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA;

cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;

l) PPARδ

agonists;

m) Anti-obesity compounds;

n) An ileal bile acid transporter inhibitor;

o) Anti-inflammatory agents;

p) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; and

q) EPO, EPO mimetics, and EPO receptor agonists.

5. The method of claim 1, wherein R¹ and R² are each hydroxyl.

6. The method of claim 1 wherein R¹ and R² are each hydroxyl that independently or together bear a boronic acid protecting group formed from (+) -pinanediol;

pinacol;

1,2-dicyclohexyl-ethanediol;

1,2-ethanediol;

2,2-diethanolamine;

1,3-propanediol;

2,3-butanediol, diisopropyl tartrate;

1,4-butanediol;

diisopropylethanediol;

(S,S,)-5,6-decanediol;

1,1,2-triphenyl-1,2-ethanediol;

(2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol;

methanol;

ethanol;

isopropanol;

catechol;

or 1-butanol;

or wherein R¹ and R² independently or together are a group capable of being hydrolyzed to form a boronic acid group —

B(OH)₂ in an aqueous solution at physiological pH or in biological fluids.

7. The method of claim 1 wherein X is CH₂;

the ring containing X is saturated;

R¹ and R² are each hydroxyl, R³ and R⁴ are hydrogen; and

R⁵ is a group of Set I.

8. The method of claim 1 wherein X is CH₂;

the ring containing X is saturated;

R¹ and R² are each hydroxyl, R³ and R⁴ are hydrogen; and

R⁵ is a group of Set II.

9. The method of claim 1 wherein X is CH₂;

the ring containing X is saturated;

R¹ and R² are hydroxyl, R³ and R⁴ are hydrogen; and

R⁵ is a group of formula

10. The method of of claim 8 wherein R^x is hydrogen, R²⁰ is hydrogen, t is 0, and u is 1.

11. The method of 1 wherein the compound of formula (I) is

12. The method of 1 wherein the compound of formula (I) is