WO2009089448A1

WO2009089448A1 - Therapeutic disulfide compounds for treating pain and diabetes

Info

Publication number: WO2009089448A1
Application number: PCT/US2009/030594
Authority: WO
Inventors: Gyorgy F. Ambrus; Mark P. Rubino; Todd M. Heidelbaugh; Phong X. Nguyen
Original assignee: Allergan, Inc.
Priority date: 2008-01-11
Filing date: 2009-01-09
Publication date: 2009-07-16
Also published as: EP2242748A1

Abstract

Disclosed herein are compounds represented by the formula: Therapeutic methods, compositions, and medicaments related thereto are also disclosed.

Description

THERAPEUTIC DISULFIDE COMPOUNDS FOR TREATING PAIN AND DIABETES

By Inventors

Gyorgy F. Ambrus, Mark P. Rubino, Todd M. Heidelbaugh, and

Phong X. Nguyen

CROSS-REFERENCE

[1] This application claims the priority to U.S. Provisional Application serial number 61/020,458, filed January 11, 2008, which is hereby incorporated by reference in its entirety.

[2] Disclosed herein are compounds represented by the formula:

[3] These compounds may be administered to a mammal to treat pain, including visceral pain, pain caused by irritable bowel syndrome, neuropathic pain, and pain caused by dyspepsia.

[4] These compounds may be administered to a mammal to treat symptoms of diabetes, including hyperglycemia, hyperlipidemia, decreased levels of blood insulin, and hypertriglyceridemia.

[5] Typically, a dosage form such as pill, tablet, or capsule for oral administration, or a liquid for injection, is prepared containing the compound, and the dosage form is administered to a mammal needing the treatment. Preparation of suitable dosage forms is known in the art. For example, U.S. Patent No. 7,141,597 describes suitable methods.

[6] The dose may vary depending upon the mammal being dosed and the particular condition being treated. A person of ordinary skill in the art can determine the dose appropriate for the situation. For example, for humans, a dose of from about 10 to about 100 mg, given twice a day is contemplated.

[7] For the purposes of this disclosure, "treat," "treating," or "treatment" refers to the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition. [8] Unless otherwise indicated, reference to a compound should be construed broadly to include compounds, pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of a depicted structural formula or chemical name. [9] A pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt. A salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).

[1O]A prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Prodrug preparation is well known in the art. For example, "Prodrugs and Drug Delivery Systems," which is a chapter in Richard

B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.

[ll]Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.

[12] For example, some tautomers of the compounds disclosed herein are depicted below.

[13] Unless stereochemistry is explicitly and unambiguously depicted, a structure is intended to include every possible stereoisomer, both pure or in any possible mixture.

[14] Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein. For example, alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.

[l5]Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species.

Examples might include solvates, hydrates, charge transfer complexes, and the like.

[16] One embodiment is a compound represented by the structure:

Procedure for the preparation of 2,2'-bis{4-ri-(2,3-dimethylphenyD- ethyli-lH-imidazolyl) disulfide (Compound 1).

1) MnO₂ activated (85%, ~2 equiv.) dioxane, rt, 2 d

2) Flash Chromat.

Intermediate A-1 Compound 1

A solution of (+)-4-(S*)-[l-(2,3-dimethyl-phenyl)-ethyl]-l,3-dihydro- inaidazole-2-thione Intermediate Al (prepared according to US 2005/0059721) (105 ing, 0.46 mmol) in dioxane (5 mL) was treated with manganese dioxide, MnO₃(IOO mg, 0.98 mmol, activated, -85%) for 48 h at rt. The reaction mixture was filtered through Celite and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 50% hexanes: ethyl acetate and repeated on a silica gel column with 70% hexane:tetrahydrofuran to give 58 mg of 2,2'-bis{4-[l-(2,3-dimethylphenyl)-ethyl]-lH-imidazolyl} disulfide (Compound 1). ¹H NMR (300 MHz, methanol-d⁴) 6.98 (s, 4H), 6.94 (s, 2H), 6.70 (s, 2H), 4.36 (q, J = 6.5 Hz, 2H), 2.26 (s, 6H), 2.21 (S, 6H), 1.51 (d, J = 7.0 Hz, 6H).

Claims

What is claimed is:

1. A compound represented by the formula:

2. The compound of claim 1 represented by the formula:

3. A method of treating pain comprising administering a therapeutically effective amount of the compound according to claim l to a mammal in need thereof.

4. The method of claim 3 wherein said pain is visceral pain.

5. The method of claim 3 wherein said pain is caused by irritable bowel syndrome.

6. The method of claim 3 wherein said pain is caused by dyspepsia.

7. The method of claim 3 wherein said pain is neuropathic pain.

8. A method of treating at least one symptom of diabetes in a mammal, the method comprising the step of administering to the mammal a therapeutically effective amount of the compound according to claim 1.

9. The method of claim 8 wherein the symptom comprises hyperglycemia.

10. The method of claim 8 wherein the symptom comprises hypertriglyeridemia .

11. The method of claim 8 wherein the symptom comprises decreased levels of blood insulin.

12. The method of claim 8 wherein the symptom comprises hyperlipidemia.