2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives for therapeutic agent of antiinflammatory disease, method thereof for preparation, therapeutic agent for antiinflammatory disease induced by SPC activity containing the same

• US 7,915,405 B2
• Filed: 09/30/2009
• Issued: 03/29/2011
• Est. Priority Date: 12/05/2008
• Status: Active Grant

• Current Assignee: Korea Research Institute of Chemical Technology
• Original Assignee: Korea Research Institute of Chemical Technology
• Inventors: Choi, Gildon, Hwang, Soon-Hee, Jeong, Dae Young, Cho, Heeyeong, Jeon, Moon-Kook, Lee, Taeho, Kong, Jae Yang, Gong, Young-Dae
• Primary Examiner(s): Saeed; Kamal A
• Assistant Examiner(s): GRAZIER, NYEEMAH A
• Application Number:
  US12/570,492
• Publication Number:
  US 20100145043A1
• Time in Patent Office: 545 Days
• Field of Search: None
• US Class Current: 544/82
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Disclosed herein are 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives, a preparation method thereof, and a therapeutic agent for treating inflammatory diseases induced by SPC, which contains the derivative as an active ingredient. The anti-inflammatory effect of the 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives was analyzed through a test employing human dermal cells and an animal test using mice and, as a result, it was found that the derivatives showed excellent inhibitory activity on SPC receptor compared to thiazole derivatives known in the prior art. Thus, the 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives or pharmaceutically acceptable salts thereof are useful as active ingredients in therapeutic agents for treating inflammatory diseases, such as inflammation, pruritus and skin infection, which appear in atopic dermatitis and other diseases induced by SPC activity.

wherein R¹, R², R³ and R⁴ are as defined in the specification.

Claims

1. A 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole compound represented by the following formula 1:

2. The 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole compound of claim 1, wherein

R¹ and R² are independently selected from the group consisting of a C₁-C₅ linear alkyl group and a C₃-C₁₀ branched alkyl group, or

R¹ and R² together with the nitrogen atom to which they are attached form a C₅-C₇ heterocyclic group containing one or more heteroatoms independently selected from the group consisting of N, S and O;

R³ is a carbonyl group substituted with at least one group selected from the group consisting of a C₁-C₅ linear alkyl group, a C₃-C₅ branched alkyl group, a C₃-C₆ cyclic alkyl group, a C₂-C₅ alkenyl group, a C₂-C₅ alkynyl group, a heteroaryl group, an arylalkyl group, a heteroaryl(C₅-C₁₀)alkyl group, and a phenyl or a substituted phenyl group; and

R⁴ is selected from the group consisting of piperidinyl, morpholino, 4-methoxybenzylamino, piperidin-1-yl-ethylamino, pyrrolidin-1-ylethylamino, 2-morpholinoethylamino, 2-morpholinopropylamino, 4-morpholinopiperidin-1-yl, 4-pyrrolidin-1-ylpiperidin-1-yl, 1,4′

-bipiperidin-1′

-yl, cyclopropylmethylamino, cyclohexylmethylamino, or

R⁴ is NR_aR_b wherein R_a and R_b are independently selected from the group consisting of a hydrogen, C₂-C₇ linear alkyl group, a C₃-C₇ branched alkyl group, a C₃-C₇ cyclic group, an aryl group, a heteroaryl group, an aryl(C₁-C₅)alkyl group a heteroaryl(C₁-C₅)alkyl group, or

R⁴ is a piperazinyl substituted with a group selected from the group consisting of C₁-C₇ linear alkyl group, a C₃-C₇ branched alkyl group, a C₃-C₇ cyclic group, a phenyl or substituted phenyl group, and a heteroaryl group,

wherein the substituted phenyl group in R³ and R⁴ represents a phenyl group substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, a C₁-C₅ alkyl group, and a C₁-C₅ alkoxy group.

3. A method for treating atopic dermatitis induced by excessive cellular division and proliferation caused by sphingosylphosphorylcholine (SPC), which contains a compound of claim 1, wherein the compound has an antagonistic effect on selective cell proliferation induced by SPC.

4. The method of claim 3, wherein the compound is selected from the group consisting of N-{5-(morpholine-4-carbonyl)-2-[2-(piperidin-1-yl)ethylamino]thiazol-4-yl}pivalamide, N-[2-(benzylamino)-5-(piperidine-1-carbonyl)thiazol-4-yl]pivalamide, and N-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-5-(piperidine-1-carbonyl)thiazol-4-yl}pivalamide.

5. A skin external agent for inhibiting post-traumatic scar formation and promoting wound healing, the agent containing a compound of claim 1.

6. A method for inhibiting chemotactic cell migration caused by SPC in a cell comprising administering to the cell an effective amount of a compound of claim 1 to inhibit the chemotactic migration or a pharmaceutically acceptable salt thereof as an active ingredient.

7. The method of claim 6, wherein the compound is N-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-5-(piperidin-1-carbonyl)thiazol-4-yl}pivalamide.