EP2242748A1 - Therapeutic disulfide compounds for treating pain and diabetes - Google Patents

Therapeutic disulfide compounds for treating pain and diabetes

Info

Publication number
EP2242748A1
EP2242748A1 EP09701462A EP09701462A EP2242748A1 EP 2242748 A1 EP2242748 A1 EP 2242748A1 EP 09701462 A EP09701462 A EP 09701462A EP 09701462 A EP09701462 A EP 09701462A EP 2242748 A1 EP2242748 A1 EP 2242748A1
Authority
EP
European Patent Office
Prior art keywords
pain
compound
diabetes
mammal
therapeutic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09701462A
Other languages
German (de)
French (fr)
Inventor
Gyorgy F. Ambrus
Mark P. Rubino
Todd M. Heidelbaugh
Phong X. Nguyen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
Original Assignee
Allergan Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Allergan Inc filed Critical Allergan Inc
Publication of EP2242748A1 publication Critical patent/EP2242748A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • 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.
  • These compounds may be administered to a mammal to treat symptoms of diabetes, including hyperglycemia, hyperlipidemia, decreased levels of blood insulin, and hypertriglyceridemia.
  • 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.
  • a dosage form such as pill, tablet, or capsule for oral administration, or a liquid for injection
  • a dosage form is prepared containing the compound, and the dosage form is administered to a mammal needing the treatment.
  • suitable dosage forms are known in the art.
  • U.S. Patent No. 7,141,597 describes suitable methods.
  • 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.
  • “treat,” “treating,” or “treatment” refers to the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition.
  • 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.
  • 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).
  • 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
  • [ll]Tautomers are isomers that are in rapid equilibrium with one another.
  • tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.
  • Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
  • alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
  • 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.
  • One embodiment is a compound represented by the structure:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

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.
EP09701462A 2008-01-11 2009-01-09 Therapeutic disulfide compounds for treating pain and diabetes Withdrawn EP2242748A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2045808P 2008-01-11 2008-01-11
PCT/US2009/030594 WO2009089448A1 (en) 2008-01-11 2009-01-09 Therapeutic disulfide compounds for treating pain and diabetes

Publications (1)

Publication Number Publication Date
EP2242748A1 true EP2242748A1 (en) 2010-10-27

Family

ID=40395099

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09701462A Withdrawn EP2242748A1 (en) 2008-01-11 2009-01-09 Therapeutic disulfide compounds for treating pain and diabetes

Country Status (2)

Country Link
EP (1) EP2242748A1 (en)
WO (1) WO2009089448A1 (en)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141597B2 (en) * 2003-09-12 2006-11-28 Allergan, Inc. Nonsedating α-2 agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009089448A1 *

Also Published As

Publication number Publication date
WO2009089448A1 (en) 2009-07-16

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