US 2003/0191156 A1 · Beta3 adrenergic agonists

Abstract

The present invention relates to a β3 adrenergic receptor agonist of formula (I) or a pharmaceutical salt thereof, which is capable of increasing lipolysis and energy expenditure in cells and, therefore, is useful for treating Type II diabetes and/or obesity. The compound can also be used to lower triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to decrease gut motility. In addition, the compound can be used to reduced neurogenic inflammation or as an antidepressant agent. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for decreasing gut motility are also disclosed.

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Claims17

Dependent claims

A compound of formula I:

170
wherein:
A1, A2 and A3 are carbon or nitrogen provided that only one of A1, A2 and A3 can be nitrogen;
Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring;
R1, R1a and R1b are independently H, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, or SO2(C1-C6 alkyl);
R2 is H or C1-C6 alkyl;
R3 is H or C1-C6 alkyl;
R4 is H or C1-C6 alkyl;
or R3 and R4 combine with the carbon to which both are attached to form a C3-C6 cyclic ring;
or R4 and X1 combine with the carbon to which both are attached to form a C3-C8 cyclic ring;
or R4 combines with X1, the carbon to which both are attached, and the phenyl group to which X1 is attached to form:
171
wherein:
n and m are independently 0, 1, 2, or 3 provided that the sum of n+m is ≦4 and that R3 is H;
X is OCH2, SCH2 or a bond;
X1 is a bond or a C1-C5 divalent hydrocarbon moiety;
X2 is O, S, NH, NHSO2, SO2NH, CH2 or a bond;
and
X3 is optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring;
or a pharmaceutical salt thereof.

17 more elements

Dependencies are inferred from the claim text.

Description17,981 words

Summary10,655 words

#The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to β3 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.

#The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat either Type II diabetes or obesity.

#One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as β3 receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.

Detailed description7,326 words

#Representative Procedure 2: Amination of Epoxide

#A vial is charged with a solution of single amine of formula III (0.2M in ethanol or t-butanol, 90 micromolar) and a solution of a single epoxide of formula II (0.2M in dimethylsulfoxide, 80 micromolar). The vial is sealed and heated to 80° C. for 24-48 hours. The solution is cooled to room temperature, diluted with methanol, and passed over a cation exchange column, eluting the basic material with 1N methanolic ammonia.

#Representative Procedure 3: Amination of Epoxide

Facts

Application

10/311,112Filed 13 Dec 2002

Published

9 Oct 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07D 207/333
With substituted hydrocarbon radicals, directly attached to ring carbon atoms: radicals substituted by oxygen or sulfur atoms
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/0095
Galenical forms not covered by A61K9/02 - A61K9/7023: drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets…
A61K 9/08
Medicinal preparations characterised by special physical form: solutions

Timeline

13 Dec 2002Application filedUS 10/311,112
13 Dec 2002Assigned to Eli Lilly and Companyassignment of assignor's interest
9 Oct 2003Published
23 Jan 2018Assigned to Elanco US Inc.assignment of assignor's interest
3 Aug 2020Assigned to Goldman Sachs Bank USA, AS Collateral Agentsecurity interest
3 Dec 2025Assigned to Jpmorgan Chase Bank, N.A., AS Successor Collateral Agentassignment of security interest in patent rights, recorded on august 3, 2020, at reel/frame 053388/0967

Beta3 adrenergic agonists

Life of this patent

Beta3 adrenergic agonists

Life of this patent

Life of this patent

Abstract

Drawings

Drawings

Claims17

Description17,981 words

Drawings

Classification31 codes

Life of this patent

Description17,981 words