1,2,4-thiadiazolium derivatives as melanocortin receptor modulators

• US 7,319,107 B2
• Filed: 11/04/2002
• Issued: 01/15/2008
• Est. Priority Date: 11/08/2001
• Status: Expired due to Fees

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Johnson & Johnson Consumer Companies Incorporated (Johnson & Johnson)
• Inventors: Reitz, Allen B., Lee, Daniel H., Zhao, Boyu, Pan, Kevin, Fitzpatrick, Louis J., Smith-Swintosky, Virginia L., Eisinger, Magdalena, Plata-Salaman, Carlos
• Primary Examiner(s): SHAMEEM, GOLAM M
• Application Number:
  US10/287,096
• Publication Number:
  US 20030162819A1
• Time in Patent Office: 1,898 Days
• Field of Search: 548/190, 548/193, 548/128, 514/370, 514/361
• US Class Current: 514/361
• CPC Class Codes: A61K 8/49 containing heterocyclic compounds
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/10 Anti-acne agents
• 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 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/16 Otologicals
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: A61Q 19/007 Preparations for dry skin
• CPC Class Codes: A61Q 5/006 Antidandruff preparations
• CPC Class Codes: C07D 285/08 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• CPC Class Codes: C07D 333/16 : by oxygen atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 9/4018 : Esters of cycloaliphatic acids

Abstract

The present invention is directed to novel 1,2,4-thiadiazol-2-ium derivatives useful as agonists or antagonists of the melanocortin receptor. More particularly, the compounds of the present invention are useful for the treatment of metabolic, CNS and dermatological disorders such as obesity, impaired oral glucose tolerance, elevated blood glucose levels, type II diabetes, Syndrome X, diabetic retinopathy, spinal cord injury, nerve injury, acute neurodegenerative disorders, chronic neurodegenerative disorders, plexopathies, male erectile dysfunction, dry eyes, acne, dry skin, aged skin, seborrheic dermatitis, rosacea, excessive ear wax, meibomian gland disorder, pseudofolliculitis, yeast infections, dandruff, hidradenitis suppurativa, ocular rosacea and eccrine gland disorder.

Claims

1. A compound of the formula (I)

2. A compound as in claim 1 wherein

R¹ is aryl;

wherein aryl group is substituted with one to two substituents independently selected from halogen, alkyl and alkoxy;

R² is aryl;

wherein the aryl group is substituted with one to two substituents independently selected from alkyl and alkoxy;

R³ is hydrogen; and

R⁴ is aryl;

wherein the aryl is optionally substituted with one to two substituents independently selected from halogen, alkyl and alkoxy.

3. A compound as in claim 2 wherein

R¹ is selected from the group consisting of 2-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl and 4-methoxyphenyl,

R² is selected from the group consisting of 4-methylphenyl, 2-methoxyphenyl and 4-methoxyphenyl;

R³ is hydrogen; and

R⁴ is selected from the group consisting of phenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 4-methoxybenzyl, 2,6-difluorophenyl, 3,5-difluorophenyl, and 2-chloro-6-methylphenyl.

4. A compound as in claim 3, selected from the group consisting of

2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-[1 ,2,4]-thiadiazol-2-ium;

2-(2-methoxyphenyl)-3-(2-methoxyphenyl )-5-(2-methoxyphenylamino)-[1 ,2,4]-thiadiazol-2-ium; and

2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-(4-tolylamino)-[1 ,2,4]-thiadiazol-2ium.

5. The compound of claim 4 selected from 2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-[1 ,2,4]thiadiazol-2-ium.

6. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

7. A method of making a pharmaceutical composition comprising mixing a compound of claim 1 with a pharmaceutically acceptable carrier.

8. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 8 wherein the pharmaceutical composition is a topical formulation.

12. The pharmaceutical composition of claim 9 wherein the pharmaceutical composition is a topical formulation.

13. The pharmaceutical composition of claim 10 wherein the pharmaceutical composition is a topical formulation.

14. The pharmaceutical composition of claim 11 wherein the topical formulation additionally contains one or more of the following components comedolytic/keratolytic agents, antimicrobial agents, steroidal anti-inflammatory agents and non-steroidal anti-inflammatory agents.

15. The pharmaceutical composition of claim 14 wherein the comedolytic/keratolytic agent is selected from the group consisting of retinoids, salicyclic acid, glycolic acid and cetyl betaine.

16. The pharmaceutical composition of claim 15 wherein the antimicrobial agents is selected from the group consisting of benzoyl peroxide, erythromycin, tetracycline, clindamycin and azelaic acid.

17. The compound of claim 1 wherein X⁻

is selected from the group consisting of bromide, chloride and iodide.

18. The compound of claim 2 wherein X⁻

is selected from the group consisting of bromide, chloride and iodide.

19. The compound of claim 3 wherein X⁻

is selected from the group consisting of bromide, chloride and iodide.

20. The compound of claim 4 wherein X⁻

is selected from the group consisting of bromide, chloride and iodide.

21. The compound of claim 4 wherein X⁻

is bromide.

22. 2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-[1,2,4]thiadiazol-2-ium bromide.

23. A pharmaceutical composition comprising a compound as claimed in claim 22 and a pharmaceutically acceptable carrier.

24. A method of making a pharmaceutical composition comprising mixing a compound of claim 22 with a pharmaceutically acceptable carrier.

25. A pharmaceutical composition made by mixing a compound of claim 22 and a pharmaceutically acceptable carrier.