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WO2010064769A1 - Dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole et son procédé de préparation, et agent thérapeutique le contenant en tant qu'ingrédient actif pour les maladies liées à une inflammation par l'activité du - Google Patents

Dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole et son procédé de préparation, et agent thérapeutique le contenant en tant qu'ingrédient actif pour les maladies liées à une inflammation par l'activité du Download PDF

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Publication number
WO2010064769A1
WO2010064769A1 PCT/KR2009/004058 KR2009004058W WO2010064769A1 WO 2010064769 A1 WO2010064769 A1 WO 2010064769A1 KR 2009004058 W KR2009004058 W KR 2009004058W WO 2010064769 A1 WO2010064769 A1 WO 2010064769A1
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WO
WIPO (PCT)
Prior art keywords
group
piperazino
formula
disubstituted
thiazole
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.)
Ceased
Application number
PCT/KR2009/004058
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English (en)
Korean (ko)
Inventor
공영대
이태호
전문국
황순희
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.)
Korea Research Institute of Chemical Technology KRICT
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Korea Research Institute of Chemical Technology KRICT
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Publication of WO2010064769A1 publication Critical patent/WO2010064769A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Sphingosylphosphorylcholine is a lysophosphatidic acid (LPA) with structurally similar spingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). lysophospholipid), which acts as an important signaling intermediate for immune functions such as cell proliferation, migration, and inflammatory responses.
  • SPC is known to be rarely present or detected in very low concentrations in normal people, but it is known to be increased thousands of times in the epidermis of atopic dermatitis patients.
  • SPCs also play an important role in abnormal keratinization that is characteristic of atopic diseases [Higuchi, J.
  • the present invention provides a 2-piperazino-4,5-disubstituted-1,3-thiazole derivative for the treatment of inflammation-related diseases represented by the following formula (1) and pharmaceutically acceptable salts thereof to provide.
  • the present invention is a derivative of the 2-piperazino-4,5-disubstituted-1,3-thiazole derivative represented by Formula 1, wherein Y is a C 1 to C 5 alkyl group, phenyl group or substituted phenyl group And optical isomers of 2-piperazino-4,5-disubstituted-1,3-thiazole derivatives separated by conventional separation methods.
  • the present invention contains a 2-piperazino-4,5-disubstituted-1,3-thiazole derivative represented by the formula (1) or an optical isomer thereof as an active ingredient in inflammation-related diseases caused by SPC receptor activity Its useful use is provided. That is, 2-piperazino-4,5-disubstituted-1,3-thiazole derivatives represented by Formula 1 or optical isomers thereof are useful as therapeutic agents for inflammatory diseases caused by SPC receptor activity by containing them as active ingredients. .
  • 2-piperazino-4,5-disubstituted-1,3-thiazole derivatives or optical isomers thereof represented by Formula 1 of the present invention contain them as active ingredients to inhibit scar formation after trauma and promote wound healing. It is useful as an external preparation for skin.
  • the present invention provides 2-piperazino-4,5-disubstituted-1,3-thiazole derivatives represented by the following formula (1).
  • R 1 and R 3 is a heteroaryl group, a phenyl group or substituted phenyl group
  • R 2 is an alkenyl group of C 1 ⁇ C 10 straight or branched chain, or cyclic alkyl group, C 2 ⁇ C 10 of, C 2 and one selected from ⁇ C 10 alkynyl group, a heteroaryl group, an arylalkyl group, the group consisting of amide with a heteroaryl group, a phenyl group or substituted phenyl group of the C 5 ⁇ C 10
  • X is piperacillin oscillator of 3 or A carbonyl group at position 5 (C ⁇ O) or hydrogen
  • Y is a C 1 to C 5 alkyl group, a phenyl group or a substituted phenyl group or hydrogen at positions 2 or 3 of the piperazine group, wherein X and Y are At the same time except hydrogen, in the above R 1 , R 2 , R 3 and Y, the substituted
  • R 1 and R 3 are heteroaryl groups, phenyl groups or substituted phenyl groups
  • R 2 is C 1 straight or branched chain of ⁇ C 5, or cyclic alkyl group, C 2 ⁇ C 5 alkenyl group, C 2 ⁇ C 5 of the alkynyl group, a heteroaryl group, an arylalkyl group, from the group consisting of amide with a phenyl group or a substituted phenyl group
  • Y is an alkyl group or hydrogen at C 1 -C 3 at position 2 or 3 of the piperazine group
  • the substituted phenyl group is a
  • the present invention provides a process for preparing 2-piperazino-4,5-disubstituted-1,3-thiazole derivatives represented by the formula (1).
  • the solvent used in the present invention uses an organic solvent having excellent swelling effect of Wang resin or Merrifield resin.
  • dichloromethane is used as the solvent.
  • the 2-piperazino-4,5-disubstituted-1,3-thiazole derivative compound of the present invention was inhibited by both ear edema and MPO activity as a result of the inflammatory reaction test induced by TPA, usually as an anti-inflammatory drug It suggests a comparable effect on the widely used hydrocortisone [ Table 4 ].
  • N- ⁇ 5-benzoyl-2- [4- (2) in the 2-piperazino-4,5-disubstituted-1,3-thiazole derivative represented by the general formula (1) of the present invention is useful as a therapeutic agent for inflammatory diseases caused by SPC receptor activity. .
  • Resin (2.00 g, 1.82 mmol) in the form of cyanocarbodiimidodithianate represented by the formula (2) was added to dimeformamide (DMF; 20 ml) and stirred at room temperature for 10 minutes, followed by 2-bromoacetophenone (PhCOCH). 2 Br; 1.08 g, 5.42 mmol) and triethylamine (Et 3 N; 0.77 mL, 5.52 mmol) were added thereto, followed by reaction at 80 ° C. for 3 hours. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with H 2 O, DMF, MeOH, DCM to obtain 4-amino-1,3-thiazole resin as a yellow solid represented by the formula (3-1).
  • 4-amino-1,3-thiazole resin (1.00 g, 0.90 mmol) represented by Chemical Formula 3-1 was added to acetonitrile (MeCN; 10 ml) and stirred for 10 minutes, followed by pivaloyl chloride ((CH 3 ) 3 CCOCl; 0.93 mL, 7.50 mmol) and pyridine (0.60 mL, 7.42 mmol) were added thereto, followed by reaction at room temperature for 6 hours. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with H 2 O, DMF, MeOH and DCM to obtain 4-N-pivaloyl-1,3-thiazole resin, which is a brown solid represented by Chemical Formula 4-1.
  • 4-N-pivaloyl-1,3-thiazole resin (1.00 g, 0.89 mmol) connected by a sulfanyl linker represented by Chemical Formula 4-1 was added to a dichloromethane (10 mL) solution, and stirred at room temperature for 10 minutes. Then, meta-chlorobenzoic acid (m-CPBA; 500 mg, 2.23 mmol) was added at room temperature, followed by reaction at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MeOH and DCM to obtain 4-N-pivaloyl-1,3-thiazole sulfonyl resin as a yellow solid represented by the formula (5-1).
  • m-CPBA meta-chlorobenzoic acid
  • Step 4 addition and desorption reaction of 4-N-pivaloyl-1,3-thiazole sulfonyl resin (5-1) with substituted piperazine compound (6-1)
  • SPC spinopolyphosphorylcholine
  • the compounds prepared in the examples of the present invention showed an antagonistic action on the selective cell proliferative response induced by SPC to the cell proliferation response. Since excessive cell division proliferation due to inflammatory reactions occurring during the wounding process when the trauma is wound, scars form, a substance that inhibits cell proliferation can be used to prevent the formation of unnecessary scars. At the same time, agents that enhance cell proliferation can be used to promote wound healing after trauma.
  • Examples 1-7 and 1-30 inhibited cell division proliferation response by SPC in a dose dependent manner. It is noteworthy that this effect has a chemical structure similar to that of SPC, and FTY720, a S1P agonist that shares some membrane receptors, did not inhibit SPC-induced cell proliferation. Therefore, the cell proliferation inhibiting action is due to the intrinsic structural activity of the compound of the present invention, and when the wound is wound, the inflammatory response that occurs during the wound healing process may inhibit excessive cell division and scarring. Can be.
  • the gasket was put up and the upper chamber was assembled.
  • Drug treated HUVEC cells were dispensed in 5 ⁇ 10 4 (56 ⁇ l volume) of the upper chamber and incubated for 8 hours in a 37 ° C. CO 2 incubator.
  • the membrane was separated, dyed with Diff-Quik dye (Sysmex Corporation), washed with deionized water, and glued to the slide glass with the shiny side facing down.
  • TPA Tetradecanoyl phorbol acetate
  • TPA-induced inflammation models have been widely used to test the mechanism of action of inflammatory responses and the efficacy of inhibitors (De Young LM et al., Agents and Actions , 1989, 26, 335-341).
  • TPA is a substance that causes an inflammatory response, and when applied to the ear of a subject, erythema and edema occur, and this inflammatory response can be measured by increasing activity of MPO (myeloperoxidase), an essential substance for bacterial attack of white blood cells.
  • MPO myeloperoxidase
  • mice 40 male 6-week-old ICR mice were prepared, and 20 ⁇ l of TPA solution (Sigma Aldrich Korea) dissolved in acetone at 125 ⁇ g / ml was applied to the left ear. After 1 hour of TPA application, 20 ⁇ l of acetone, 0.3% Example Compounds dissolved in acetone, or 0.3% hydrocortisone (Sigma Aldrich Korea) dissolved in acetone was applied to the TPA application site, and the same site 6 hours after TPA application. 20 ⁇ l was reapplied. At 24 hours after TPA application, the mice were euthanized by cervical dislocation, and the left ear was collected at a constant width to measure weight and MPO activity. Reaction inhibition rate was computed according to following formula (3) , and is shown in Table 4 .
  • the compounds of Examples 1-7 and 1-30 significantly inhibited the inflammatory response induced by TPA on both measures of ear edema and MPO activity, and its potency intensity was anti-inflammatory drug. It is comparable to hydrocortisone which is widely used as.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole présenté dans la formule chimique 1, et son procédé de préparation et son emploi qui est utile pour les maladies liées à une inflammation provoquées par l'activité du récepteur de la sphingosylphosphorylcholine (SPC), le contenant comme son ingrédient actif. Le dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole de la présente invention peut être utilisé avec profit comme agent thérapeutique pour les maladies liées à une inflammation, et est efficace pour la dermatite atopique causée par d'autres maladies, un prurit ou une infection cutanée causés par l'activité du récepteur de la SPC contenant ledit dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole ou un isomère optique isolé à partir de celui-ci comme ingrédient actif, les effets anti-inflammatoires ayant été constatés dans des expérimentations animales utilisant des cellules dermiques humaines et dans des essais sur animaux utilisant des souris, et son activité inhibitrice s'est avérée être supérieure aux dérivés de thiazole bien connus qui sont utilisés dans l'art antérieur pour les récepteurs de la SPC.
PCT/KR2009/004058 2008-12-05 2009-07-22 Dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole et son procédé de préparation, et agent thérapeutique le contenant en tant qu'ingrédient actif pour les maladies liées à une inflammation par l'activité du Ceased WO2010064769A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2008-0123618 2008-12-05
KR1020080123618A KR101051077B1 (ko) 2008-12-05 2008-12-05 2-피페라지노-4,5-이중치환-1,3-티아졸 유도체, 그의 제조방법 및 그를 유효성분으로 함유하는 ｓｐｃ 수용체 활성으로 유발되는 염증관련질환 치료제

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WO2010064769A1 true WO2010064769A1 (fr) 2010-06-10

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PCT/KR2009/004058 Ceased WO2010064769A1 (fr) 2008-12-05 2009-07-22 Dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole et son procédé de préparation, et agent thérapeutique le contenant en tant qu'ingrédient actif pour les maladies liées à une inflammation par l'activité du

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014087A1 (fr) * 2004-08-04 2006-02-09 Dong Wha Pharmaceutical. Ind. Co., Ltd. Dérivés de benzamidine nouveau, procédé de preparation correspondant et composition pharmaceutique les contenant
WO2006038734A1 (fr) * 2004-10-08 2006-04-13 Astellas Pharma Inc. Dérivés de la pyridazinone inhibiteurs de cytokines
WO2006137658A1 (fr) * 2005-06-20 2006-12-28 Dongbu Hitek Co., Ltd. Nouveaux derives thiazole 1,3 substitues ou sels pharmaceutiquement acceptables de ces derniers presentant une activite d'inhibition de l'immunosuppression ou de l'inflammation, composes intermediaires ou sels pharmaceutiquement acceptables de ces derniers, procede de preparation de ces derniers et compositions pharmaceutiq
WO2007028999A1 (fr) * 2005-09-09 2007-03-15 Argenta Discovery Limited Composés de thiazole et leur utilisation en tant qu'antagonistes de pgd2
WO2007104557A2 (fr) * 2006-03-15 2007-09-20 4Sc Ag Nouveaux inhibiteurs hétérocycliques de nf/kb
WO2007146066A2 (fr) * 2006-06-06 2007-12-21 Critical Therapeutics, Inc. Nouvelles pipérazines, compositions pharmaceutiques et procédés d'utilisation de celles-ci

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014087A1 (fr) * 2004-08-04 2006-02-09 Dong Wha Pharmaceutical. Ind. Co., Ltd. Dérivés de benzamidine nouveau, procédé de preparation correspondant et composition pharmaceutique les contenant
WO2006038734A1 (fr) * 2004-10-08 2006-04-13 Astellas Pharma Inc. Dérivés de la pyridazinone inhibiteurs de cytokines
WO2006137658A1 (fr) * 2005-06-20 2006-12-28 Dongbu Hitek Co., Ltd. Nouveaux derives thiazole 1,3 substitues ou sels pharmaceutiquement acceptables de ces derniers presentant une activite d'inhibition de l'immunosuppression ou de l'inflammation, composes intermediaires ou sels pharmaceutiquement acceptables de ces derniers, procede de preparation de ces derniers et compositions pharmaceutiq
WO2007028999A1 (fr) * 2005-09-09 2007-03-15 Argenta Discovery Limited Composés de thiazole et leur utilisation en tant qu'antagonistes de pgd2
WO2007104557A2 (fr) * 2006-03-15 2007-09-20 4Sc Ag Nouveaux inhibiteurs hétérocycliques de nf/kb
WO2007146066A2 (fr) * 2006-06-06 2007-12-21 Critical Therapeutics, Inc. Nouvelles pipérazines, compositions pharmaceutiques et procédés d'utilisation de celles-ci

Also Published As

Publication number Publication date
KR20100064952A (ko) 2010-06-15
KR101051077B1 (ko) 2011-07-21

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