Heterocyclic boronic acid compounds

• US 20070060547A1
• Filed: 11/12/2004
• Published: 03/15/2007
• Est. Priority Date: 11/12/2003
• Status: Active Grant

• Current Assignee: Sino-Med International Alliance Inc.
• Original Assignee: Phenomix Corporation
• Inventors: Winn, David, Campbell, David, Betancort, Juan
• Granted Patent: US 7,674,913 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• 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 CH₂; 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

1-178. -178. (canceled)

179. A compound of formula (I):

180. A compound of claim 179 wherein X is CH₂;

the ring containing X is saturated;

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

R⁵ is selected from i) a group of Set I or ii) a group of Set II wherein Y is CH₂. or iii) a nitrogen containing heterocycle.

181. A compound of claim 179 wherein X is CH₂;

the ring containing X is saturated;

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

R⁵ is

182. A compound of claim 179 of the formula (VI):

186. A compound of any of claims 179-185 wherein R¹ and R² independently or together are hydroxyl bearing the 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 a hydroxyl group in an aqueous solution at physiological pH or in biological fluids.

187. A pharmaceutical composition comprising a compound of any of claims 179-185 and a pharmaceutically acceptable carrier.

188. A method for inhibiting dipeptidyl peptidase-IV comprising contacting dipeptidyl peptidase-IV with an effective amount of a compound of any of claims 179-185.

189. The method of claim 188 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.

190. A method according to claim 189 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.

191. A pharmaceutical combination comprising a compound of any of claims 179-185;

and

a second medicament that increases insulin secretion, increases insulin sensitivity, reduces the uptake of sugar from the gastrointestinal track, enhances the effect of endogenous peptides or proteins that affect glycemic control, provides a replacement for endogenous peptides or proteins that affect glycemic control, or any combination thereof.

192. The pharmaceutical combination of claim 191, wherein the second medicament is glyburide, glipizide, nateglinide, repaglinide, metformin, pioglitazone, rosiglitazone, acarbose, miglitol, exenatide, insulin, metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR-HO39242, GW-409544, KRP297, AC2993, LY307161, NN2211, and LY315902 or any combination thereof.

193. The pharmaceutical combination of claim 191 wherein the second medicament is suitable for treatment of a diabetes-associated condition.

194. A method of preparing a compound of claim 179 comprising:

contacting a compound of Formula (XXX)

195. A method of preparing a compound of claim 179 or 183 having Formula XXI:

196. A compound of claim 181 wherein R⁵ is

197. A compound of claim 182 wherein R³ is methyl or ethyl.

198. A method according to claim 188, 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.

199. A method according to claim 198 wherein the malcondition is impaired glycemic control or the malcondition is diabetes.

200. A method for inhibiting dipeptidyl peptidase-IV according to claim 199 wherein the compound selectively inhibits dipeptidyl peptidase-IV over at least one other dipeptidyl peptidase.

201. A pharmaceutical combination according to claim 191 wherein the second medicament is an antidiabetic agent.

202. A pharmaceutical combination according to claim 201 wherein the weight ratio of the compound and the antidiabetic agent is from about 0.01:

1 to about 100;

1.

203. The pharmaceutical combination of claim 191 wherein the second medicament is suitable for treatment of a diabetes-associated condition and the compound is present in a weight ratio to the second medicament from about 0.01:

1 to about 100;

1.

204. A method according to claim 194 wherein L is a halo group or a sulfonate ester.

205. A method according to claim 204 wherein the halo group is chloride or bromide.

206. A method according to claim 195 wherein G is an (C_1-6)alkoxycarbonyl group or an aryloxycarbonyl group.

207. A method according to claim 206 wherein G is a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a 9-fluorenylmethoxycarbonyl group.

208. A pharmaceutical composition comprising a compound of claim 186 and a pharmaceutically acceptable carrier.

209. A method for inhibiting dipeptidyl peptidase-IV comprising contacting dipeptidyl peptidase-IV with an effective amount of a pharmaceutical composition of claim 208.

210. The method of claim 209 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.

183. A cyclic beta compound having formula IV:

184. A compound of claim 183,

wherein X is CH₂;

the ring containing X is saturated;

R¹ and R² are hydroxyl;

or wherein X is CH₂;

the ring containing X is saturated;

R¹ and R² are hydroxyl;

Y is CHR²⁵, R²⁵ is hydrogen; and

R²⁴ is selected from hydrogen;

or (C_1-12)alkyl, (C_2-12)alkenyl, (C_2-12)alkynyl, (C_3-12) cycloalkyl, or (C_3-12)cycloalkenyl;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R¹², and wherein the alkyl, alkenyl, and alkynyl portions include linear or branched chains and may include cyclic portions;

or phenyl optionally mono- or independently plurisubstituted with R¹²;

R¹¹(CH₂)_p—

;

a group of the formula;

(R¹³)₂CH(CH₂)_q—

;

or a group of the formula;

R²¹—

O—

(CH₂)_t—

;

or wherein X is CH₂;

the ring containing X is saturated;

R¹ and R² are hydroxyl;

R²⁴ is hydrogen;

Y is CHR²⁵ and R²⁵ is selected from hydrogen;

(C_1-12)alkyl, (C_2-12)alkenyl, (C_2-12)alkynyl, (C_3-12) cycloalkyl, or (C_3-12)cycloalkenyl;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R¹², and wherein the alkyl, alkenyl, and alkynyl portions include linear or branched chains and may include cyclic portions;

phenyl optionally mono- or independently plurisubstituted with R¹²;

R¹¹(CH₂)_p—

;

(R¹³)₂CH(CH₂)_q—

;

a group of the formula;

or a group of the formula

R²¹—

O—

(CH₂)_t—

;

or wherein X is CH₂;

the ring containing X is saturated;

R¹ and R² are hydroxyl;

R²⁴ is hydrogen;

Y is NR²⁶ and R²⁶ is selected from hydrogen;

(C_1-12)alkyl, (C_2-12)alkenyl, (C_2-12)alkynyl, (C_3-12) cycloalkyl, or (C_3-12)cycloalkenyl;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R¹², and wherein the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;

phenyl optionally mono- or independently plurisubstituted with R¹²;

R²⁷(CH₂)_p—

;


(R¹³)₂CH(CH₂)_q—

;

a group of the formula;

a group of the formula

R²¹—

O—

(CH₂)_tt—

.

185. The compound of claim 183 having Formula (V):