WO2009041790A1 - Novel 2,4,5-trisubtituted-1,3-thiazole derivatives and pharmaceutically acceptable salt thereof, method for preparation, therapeutic agent for inflammatory disease induced by spc activity containing 2,4,5- trisubstituted-1,3-thiazole derivatives as an effective ingredient - Google Patents
Novel 2,4,5-trisubtituted-1,3-thiazole derivatives and pharmaceutically acceptable salt thereof, method for preparation, therapeutic agent for inflammatory disease induced by spc activity containing 2,4,5- trisubstituted-1,3-thiazole derivatives as an effective ingredient Download PDFInfo
- Publication number
- WO2009041790A1 WO2009041790A1 PCT/KR2008/005726 KR2008005726W WO2009041790A1 WO 2009041790 A1 WO2009041790 A1 WO 2009041790A1 KR 2008005726 W KR2008005726 W KR 2008005726W WO 2009041790 A1 WO2009041790 A1 WO 2009041790A1
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- WIPO (PCT)
- Prior art keywords
- chemical formula
- phenyl
- trisubstiuted
- substituted
- thiazole
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
Definitions
- Example embodiments of the present invention relate to a 2,4,5- trisubstiuted-thiazole derivative, a pharmaceutically acceptable salt thereof, a method for preparation thereof, and a therapeutic agent for inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the same as an effective ingredient, more particularly, to a 2,4,5-trisubstiuted-thiazole derivative as a novel compound exhibiting inhibition activity against SPC receptor, a pharmaceutically acceptable salt thereof, and pharmaceutical composition for treating inflammatory disease containing the derivative or the pharmaceutically acceptable salt thereof as an effective ingredient.
- SPC sphingosylphosphorylcholine
- SPC Sphingosylphosphorylcholine
- SlP structurally similar sphingosine-1-phosphate
- LPA lysophosphatidic acid
- SPC is produced from sphingomyelin, a component of the cell membrane, by the action of the enzyme sphingomyelin deacylase [Higuchi K, Biocheni. J., 2000, 350, 747-56].
- SPC is known to be deeply associated with growth and proliferation of various types of cells [Desai , Biochem. Biophys. Res. Comniun. , 1991, 181, 361-366], angiogenesis [Boguslawski , Biochem. Biophys. Res. Commun., 2000, 272, 603-609], apoptosis [Jeon ES, Biochem. Biophys. Acta., 2005, 1734(1); 25-33], and the like.
- a typical example of SPC-related diseases is atopic dermatitis.
- Atopic dermatitis results in reduced antibacterial activity due to decreased lipid content in the stratum corneum and reduced resistance to external stimulants because of reduced barrier capability. As a result, it causes inflammatory reactions and itching. Since the itching may lead to secondary infections, the hyperimmune response may result in a vicious cycle.
- SPC may be not only the direct cause of skin barrier function disorder characteristic of the atopic dermatitis, but also the cause of secondary inflammatory responses.
- the control of the production of SPC may lead to the development of a new therapeutic agent for skin inflammatory disease.
- the inventors of the present invention have researched to develop novel compounds that can be used as pharmaceutical composition for treating inflammatory disease. They designed and synthesized a 2,4,5-trisubstiuted- 1,3-thiazole derivative, which has not yet been reported to exhibit inhibition activity against SPC receptor. Through experiments using human- derived endothelial cells and mice, they confirmed that the 2,4,5- trisubstiuted-1,3-thiazole derivative has superior antiinflamatory effect and completed the present invention. [Disclosure] [Technical Problem]
- the present invention provides a 2,4,5-trisubstiuted-1,3- thiazole derivative prepared through an organic synthesis technique and a pharmaceutically acceptable salt thereof.
- the present invention provides a use of the 2,4,5- trisubstiuted-1,3-thiazole derivative or the pharmaceutically acceptable salt thereof as an effective ingredient of a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor.
- SPC sphingosylphosphorylcholine
- the present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof: [Chemical Formula 1]
- R is heteroaryl, phenyl or substituted phenyl, the substituted phenyl being substituted by 1-4 substituents selected from the group
- R is amide having
- the present invention further provides a method for preparation of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 using an organic synthesis technique.
- the present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the 2,4,5- trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
- SPC sphingosylphosphorylcholine
- the present invention further provides a pharmaceutical composition containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient for preventing scarring after injury and promoting wound healing.
- the present invention further provides a modulator of chemotaxis- mediated symptoms containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
- the present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative prepared using an organic synthesis technique and a pharmaceutically acceptable salt thereof, which exhibits superior inhibition activity against sphingosylphosphorylcholine (SPC) receptor in an animal model experiment using human-derived endothelial cells and mice.
- SPC sphingosylphosphorylcholine
- the present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of SPC receptor.
- the present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof:
- R is the same as defined above, and may be a substituent selected from the followings:
- R 2 is the same as defined above, and may be a substituent selected from the followings:
- R 3 is the same as defined above, and may be a substituent selected from the followings:
- R 1 may be selected from the group consisting of
- R 2 may be amide having C 1 -C 5
- arylalkyl C 5 -C 10 heteroarylalkyl , phenyl or substituted phenyl; and R 3 may be
- phenyl substituted by phenyl, C 1 -C 5 linear, branched or cyclic alkyl, or heteroarylamide, the phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C 1 -C 5 alkyl, C 1 -C 10 alkoxy and C 1 - C 10 haloalkyl .
- the present invention further provides a method for the preparation of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1.
- the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 of the present invention may be prepared by an organic synthesis technique, according to the following Scheme 1:
- R 1 , R 2 and R 3 are the same as defined above.
- the method for the preparation of the 2,4,5-trisubstiuted- 1,3-thiazole derivative represented by Chemical Formula 1 comprises: reacting methylcyanocarbonimidodithionate represented by Chemical Formula 2 with a 2-haloacetophenone derivative to synthesize a 4-amino-1,3- thiazole represented by Chemical Formula 3 in which the substituent R 1 is introduced; reacting the 4-amino group of the compound represented by Chemical Formula 3 with chlorocarboxylic acid to synthesize a 4-N-acyl-1,3-thiazole represented by Chemical Formula 4 in which the substituent R2 is introduced; oxidizing the sulfanyl group of the compound represented by Chemical Formula 4 with m-chloroperbenzoic acid (m-CPBA) to synthesize a 2-sulfonyl-4- N-acyl-1,3-thiazole represented by Chemical Formula 5; and reacting the compound represented by Chemical Formula 5 with a primary or secondary amine to synthesize the 2,4,5-tri
- dimethylformamide (DMF), acetone, methanol or ethanol is used as solvent.
- DMF may be used.
- the substituent R1 and a base may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy.
- the base may be N,N- diisopropylethylamine, triethylamine (Et3N), sodium methoxide (NaOMe), sodium ethoxide (NaOEt), or the like.
- the substituent R is the same as defined above, and may be an alkyl halide.
- acetonitrile MeCN
- dichloromethane CH2C12
- a base and the substituent R2 may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy.
- the base may be pyridine, triethylamine, or the like.
- the substituent R substituent is the same as defined above, and may be a chlorocarboxylic acid.
- dichloromethane is used as solvent.
- tn-CPBA or hydrogen peroxide may be used in an amount of about 4 equivalents, respectively. Preferably, they may be used in an amount of about 2.5 equivalents, respectively, considering economy.
- dioxane or dichloromethane is used, and the substituent R3 and a base are used for the addition reaction to obtain the wanted 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical
- the base and the substituent R 3 may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy.
- 3 base may be pyridine, triethylamine, or the like.
- the substituent R substituent is the same as defined above, and may be a primary or secondary amine.
- Structural analysis of the reaction intermediates represented by Chemical Formulas 3, 4 and 5 may be carried out by NMR or mass spectroscopy after separation and purification.
- the present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the 2,4,5- trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
- SPC sphingosylphosphorylcholine
- the pharmaceutical composition for treating inflammatory disease may comprise N- ⁇ 5-benzoyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]thiazoyl-4- yl ⁇ pivalamide (Compound No. 1-76, see Table 1 below) or N- ⁇ 5-benzoyl-2-[2- (piperidin-1-yl)ethylamido]thiazoyl-4-yl ⁇ -4-fluorobenzamide (Compound No. 1- 94, see Table 1) of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1, as an effective ingredient.
- the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention was confirmed to have an antagonistic effect in selective cell proliferation induced by SPC (see Table 2). Therefore, it may be effective for atopic dermatitis or other skin disease caused by excessive cell division and proliferation induced by SPC. Further, because excessive cell division and proliferation during wound healing may result in scars through inflammatory response, the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention, which inhibits the excessive cell division and proliferation, may be used to prevent unwanted scarring. In addition, it may be used to facilitate wound healing after injury.
- the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention reduced ear edema and inhibited MPO activity, comparable to hydrocortisone which is commonly used to treat inflammation (see Table 4). Accordingly, the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention may be effective in treating inflammation, itching, skin infections, etc. associated with atopic dermatitis or other disease, and may be useful as a pharmaceutical composition for preventing scarring after injury and promoting wound healing.
- the present invention provides a modulator of chemotaxis- mediated symptoms containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
- Chemotaxis is the phenomenon in which endothelial cells or immune cells are attracted by specific materials such as cytokines or chemokines. By this, immune cells move to inflamed area or endothelial cells migrate to result in angiogenesis.
- the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention was confirmed to be able to strongly inhibit the migration of endothelial cells or immune cells induced by SPC (see Table 3).
- a modulator of chemotaxis-mediated symptoms comprising the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an effective ingredient may inhibit angiogenesis caused by the migration of endothelial cells and may control the amplification of immune response to antigens from outside.
- the modulator of chemotaxis-mediated symptoms may comprise N- ⁇ 5- benzoyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]thiazoyl-4-yl ⁇ pivalamide (Compound No. 1-76) of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 as an effective ingredient.
- chemotaxis-mediated symptoms that can be controlled by the modulator of chemotaxis-mediated symptoms according to the present invention may include inflammation, itching and skin infection associated with atopic dermatitis or other disease.
- the pharmaceutically acceptable salt according to the present invention may be one that can be prepared by a method commonly used in the related art.
- a pharmaceutically acceptable acid salt may be prepared using an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium bisulfate, phosphoric acid, carbonic acid, etc.
- a metal salt may be prepared using an alkali metal ion such as sodium, potassium, etc., or other pharmaceutically acceptable salt may be prepared using an ammonium ion.
- a commonly used non-toxic pharmaceutically acceptable carrier, modifier or excipient may be added to the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition in oral or parenteral preparation forms common in the pharmaceutical field, e.g. tablet, capsule, troche, liquid, suspension, etc.
- the administration dose of the compound of the present invention may vary depending on the age, body weight and sex of the patient, administration route, physical conditions and severity of disease. For an adult patient weighing 70 kg, a usual dosage may be 0.01-1,000 mg/day. Depending on the physician' s or pharmacist' s decision, it may be administered once or several times a day at predetermined intervals.
- Step 1 Conversion of potassium (E)-methylcyanocarbonimidodithionate (Chemical Formula 2) to 4-amino-1,3-thiazole
- Step 4 Addition of amine to 2-sulfonyl-4-N-acetyl-1,3-thiazole (Chemical Formula 5-1)
- 2-Sulfonyl-4-N-acetyl-1,3-thiazole (50 mg, 0.15 mmol) represented by Chemical Formula 5-1 was dissolved in 5 mL of dioxane. After adding diethylamine (Et2NH; 0.031 mL, 0.30 mmol) and triethylamine (0.056 mL, 0.40 mmol), reaction was carried out at room temperature for 12 hours while stirring. Then, the reaction mixture was dissolved in 20 mL of EtOAc and washed with 20 mL of brine. After drying the organic layer using Na2S04, the reaction mixture was filtered and concentrated.
- Et2NH diethylamine
- EtOAc 0.031 mL, 0.30 mmol
- triethylamine 0.056 mL, 0.40 mmol
- IxIO 5 normally lxl0 4 ⁇ 10 6
- NIH 3T3 cells American Type Culture Collection
- Manassas, VA, USA were cultured on a culture plate. Then, they were cultured in an RPMI medium free of bovine serum for 24 hours until serum starvation. After treating with the compounds prepared in Examples or with FTY720 (fingolimod) , an agonist of sphingosine-1-phosphate (SlP), as control compound at concentrations of 0.001 ⁇ M, 0.01 ⁇ M, 0.1 ⁇ M and 1 ⁇ M, the cells were cultured for 30 minutes. Then, after adding SPC (Biomol , Plymouth Meeting, PA, USA) at a concentration of 7 ⁇ M, the cells were cultured for 24 hours at 37 ° C .
- SPC Biomol , Plymouth Meeting, PA, USA
- Proliferation rate (%) 100 (SPC treated group) - (SPC non - treated group)
- the compounds of the present invention prepared in Examples exhibited antagonistic effect against selective cell proliferation induced by SPC. Because inflammatory response due to excessive cell division and proliferation during wound healing after injury results in scars, the material which inhibits cell division and proliferation may be used to prevent unwanted scarring. And, the material which enhances cell division and proliferation may be used to promote wound healing after injury. Especially, the compounds of Examples 1-1 and 1-76 inhibited the cell division and proliferation induced by SPC in a dose-dependent manner. It is to be noted that FTY720, an agonist of SlP, which has a chemical structure similar to that of SPC and shares some of membrane receptors, did not inhibit the cell division and proliferation induced by SPC.
- the inhibition of cell division and proliferation is due to the inherent structural activity of the compound of the present invention, and the compound of the present invention may be used to prevent scarring caused by inflammatory response due to excessive cell division and proliferation during wound healing after injury.
- a 25 x 80 mm polycarbonate membrane (Neuro Probe, Inc.) having 8 ⁇ m pores was immersed in 0.01% gelatin, 0.1% acetic acid solution. After coating overnight, the membrane was allowed to be dried at room temperature.
- Human umbilical vein endothelial cells cultured in a complete EBM-2 medium containing 2% fetal bovine serum (FBS) were cultivated for 4 hours in a EBM-2 medium (Cambrex, Catalog No. CC-3121) without containing bovine serum until serum starvation, and harvested with trypsin/EDTA solution.
- the HUVECs were suspended in a EBM-2 medium containing 0.1% bovine serum albumin (BSA), transferred to a si Iicone-coated Eppendorf tube, and treated with the test compound of Example 1-78 at concentrations of 0, 0.1, 1 and 10 ⁇ g/mL, at 37°C for 30 minutes.
- BSA bovine serum albumin
- Example 1-76 strongly inhibited the chemotactic cell migration induced by SPC. This suggests that, by inhibiting the migration of endothelial cells or immune cells, the compound may control the process of angiogenesis in tumors or amplification of immune response to antigens from outside.
- TPA Tetradecanoyl phorbol acetate
- TPA myeloperoxidase
- Example 1-76 As seen from Table 4, the compound of Example 1-76 was superior in inhibiting ear edema caused by TPA-induced inflammatory response and MPO activity, comparable to hydrocortisone, which is commonly used as antiinflammatory drug. This result signifies that the compound of Example 1- 76 inhibited the infiltration of neutrophils at the inflammation area.
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Abstract
Provided are a 2,4,5-trisubstiuted-l,3-thiazole derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, a method for preparation thereof, and a use thereof as an effective ingredient in a therapeutic agent for inflammatory disease induced by sphingosylphosphorylcholine (SPC). The 2,4,5-trisubstiuted-l,3-thiazole derivative of the present invention has been confirmed to have superior inhibition activity against SPC receptor in an animal experiment using human-derived endothelial cells and mice. Thus, a pharmaceutical composition for treating inflammatory disease containing the 2,4,5-trisubstiuted-l,3-thiazole derivative or a pharmaceutically acceptable salt thereof as an effective ingredient may be useful for treating inflammation, itching or skin infection associated with atopic dermatitis or other disease induced by SPC receptor.
Description
[DESCRIPTION] [Invention Title]
NOVEL 2,4,5-TRISUBTITUTED-1,3-THIAZOLE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, METHOD FOR PREPARATION THERAPEUTIC AGENT FOR ANTIINFLAMMATORY DISEASE INDUCED BY SPC ACTIVITY CONTAINING 2,4,5- TRISUBSTITUTED-1,3-THIAZOLE DERIVATIVES AS AN EFFECTIVE INGREDIENT [Technical Field]
Example embodiments of the present invention relate to a 2,4,5- trisubstiuted-thiazole derivative, a pharmaceutically acceptable salt thereof, a method for preparation thereof, and a therapeutic agent for inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the same as an effective ingredient, more particularly, to a 2,4,5-trisubstiuted-thiazole derivative as a novel compound exhibiting inhibition activity against SPC receptor, a pharmaceutically acceptable salt thereof, and pharmaceutical composition for treating inflammatory disease containing the derivative or the pharmaceutically acceptable salt thereof as an effective ingredient. [Background Art]
Sphingosylphosphorylcholine (SPC) is the member of the Lysophospholipid family along with structurally similar sphingosine-1-phosphate (SlP) and lysophosphatidic acid (LPA). These materials act as important signaling mediators in immune actions, including cell proliferation, migration, inflammation, and the like.
SPC is produced from sphingomyelin, a component of the cell membrane, by the action of the enzyme sphingomyelin deacylase [Higuchi K, Biocheni. J., 2000, 350, 747-56]. SPC is known to be deeply associated with growth and proliferation of various types of cells [Desai , Biochem. Biophys. Res. Comniun. , 1991, 181, 361-366], angiogenesis [Boguslawski , Biochem. Biophys. Res. Commun., 2000, 272, 603-609], apoptosis [Jeon ES, Biochem. Biophys. Acta., 2005, 1734(1); 25-33], and the like.
A typical example of SPC-related diseases is atopic dermatitis. Atopic
dermatitis results in reduced antibacterial activity due to decreased lipid content in the stratum corneum and reduced resistance to external stimulants because of reduced barrier capability. As a result, it causes inflammatory reactions and itching. Since the itching may lead to secondary infections, the hyperimmune response may result in a vicious cycle.
While SPC exists hardly or at very low concentrations in healthy people, its concentration in the skin of atopic dermatitis patients increases thousands of times [Higuchi K, Biochem. J., 2000, 350, 747-756; Reiko Okamoto, Journal of Lipid Research, 2003, 44, 93-102]. It is the main cause of deficiency of intracellular lipids (ceramides) in the stratum corneum of atopic dermatitis patients [Junko Hara, J. invest. Dermatol., 2000, 115, 406- 413]. Further, SPC plays an important role in the abnormal cornification associated with the atopic disease [Higuchi, J. Lipid Res. , 2001, 42, 1562- 1570]. These researches suggest that SPC may be not only the direct cause of skin barrier function disorder characteristic of the atopic dermatitis, but also the cause of secondary inflammatory responses. Thus, the control of the production of SPC may lead to the development of a new therapeutic agent for skin inflammatory disease.
With regard to itching, which is a symptom of the atopic dermatitis afflicting the patient with pain and decreased quality of life, it was reported that LPA, which is structurally similar to SPC, induces itching [Hashimoto, Pharmacology, 2004, 72, 51-56]. Accordingly, it can be inferred that SPC may cause itching, too. Recently, it was shown that an intradermal injection of SPC may directly cause itching [WO 06/049451].
The inventors of the present invention have researched to develop novel compounds that can be used as pharmaceutical composition for treating inflammatory disease. They designed and synthesized a 2,4,5-trisubstiuted- 1,3-thiazole derivative, which has not yet been reported to exhibit inhibition activity against SPC receptor. Through experiments using human- derived endothelial cells and mice, they confirmed that the 2,4,5- trisubstiuted-1,3-thiazole derivative has superior antiinflamatory effect and
completed the present invention. [Disclosure] [Technical Problem]
In an aspect, the present invention provides a 2,4,5-trisubstiuted-1,3- thiazole derivative prepared through an organic synthesis technique and a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a use of the 2,4,5- trisubstiuted-1,3-thiazole derivative or the pharmaceutically acceptable salt thereof as an effective ingredient of a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor. [Technical Solution]
The present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof: [Chemical Formula 1]
wherein R is heteroaryl, phenyl or substituted phenyl, the substituted phenyl being substituted by 1-4 substituents selected from the group
2 consisting of halogen, nitro, C1-C5 alkyl and C1-C5 alkoxy; R is amide having
C1-C1o linear, branched or cyclic alkyl, C2-C10 alkenyl , C2-C10 alkynyl , heteroaryl, arylalkyl, C5-C10 heteroarylalkyl , phenyl or substituted phenyl, the substituted phenyl being substituted by 1-4 substituents selected from
3 the group consisting of halogen, nitro, C1-C5 alkyl and C1-C5 alkoxy; and R is
amine substituted by one or more C1-C10 linear, branched or cyclic alkyl, C1-C10
aryl , C1-C10 heteroaryl, C1-C10 arylalkyl or CrC10 heteroarylalkyl , or
piperazine
substituted by phenyl, C1-C10 linear, branched or cyclic alkyl , or heteroarylamide, the phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 haloalkyl.
The present invention further provides a method for preparation of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 using an organic synthesis technique.
The present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the 2,4,5- trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
The present invention further provides a pharmaceutical composition containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient for preventing scarring after injury and promoting wound healing.
The present invention further provides a modulator of chemotaxis- mediated symptoms containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
[Advantageous Effects]
The present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative prepared using an organic synthesis technique and a pharmaceutically acceptable salt thereof, which exhibits superior inhibition activity against sphingosylphosphorylcholine (SPC) receptor in an animal model experiment using human-derived endothelial cells and mice. The present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of SPC receptor. [Mode for Invention]
Hereinafter, the present invention will be described in more detail.
The present invention provides a 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
In Chemical Formula 1, R is the same as defined above, and may be a substituent selected from the followings:
R2 is the same as defined above, and may be a substituent selected from the followings:
R3 is the same as defined above, and may be a substituent selected from the followings:
heteroaryl, phenyl and substituted phenyl; R2 may be amide having C1-C5
linear, branched or cyclic alkyl , C2-C5 alkenyl , C2-C5 alkynyl, heteroaryl,
arylalkyl, C5-C10 heteroarylalkyl , phenyl or substituted phenyl; and R3 may be
amine substituted by one or more C1-C5 linear, branched or cyclic alkyl, C1-C5 aryl, C1-C5 heteroaryl, C1-C5 arylalkyl or C1-C5 heteroarylalkyl, or piperazine
substituted by phenyl, C1-C5 linear, branched or cyclic alkyl, or
heteroarylamide, the phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C1-C5 alkyl, C1-C10 alkoxy and C1- C10 haloalkyl .
The present invention further provides a method for the preparation of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1.
The 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 of the present invention may be prepared by an organic synthesis technique, according to the following Scheme 1:
[Scheme 1]
wherein R1 , R2 and R3 are the same as defined above.
In detail, the method for the preparation of the 2,4,5-trisubstiuted- 1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention comprises: reacting methylcyanocarbonimidodithionate represented by Chemical Formula 2 with a 2-haloacetophenone derivative to synthesize a 4-amino-1,3- thiazole represented by Chemical Formula 3 in which the substituent R1 is introduced; reacting the 4-amino group of the compound represented by Chemical Formula 3 with chlorocarboxylic acid to synthesize a 4-N-acyl-1,3-thiazole represented by Chemical Formula 4 in which the substituent R2 is introduced; oxidizing the sulfanyl group of the compound represented by Chemical Formula 4 with m-chloroperbenzoic acid (m-CPBA) to synthesize a 2-sulfonyl-4- N-acyl-1,3-thiazole represented by Chemical Formula 5; and reacting the compound represented by Chemical Formula 5 with a primary or secondary amine to synthesize the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1.
The reaction process, composition of the solvent system and reaction
condition in accordance with the present invention will be described in detail .
In the first step, dimethylformamide (DMF), acetone, methanol or ethanol is used as solvent. Preferably, DMF may be used. In this step, the substituent R1 and a base may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy. The base may be N,N- diisopropylethylamine, triethylamine (Et3N), sodium methoxide (NaOMe), sodium ethoxide (NaOEt), or the like. The substituent R is the same as defined above, and may be an alkyl halide.
In the second step, acetonitrile (MeCN) or dichloromethane (CH2C12) is used as solvent. In this step, a base and the substituent R2 may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy.
2
The base may be pyridine, triethylamine, or the like. The substituent R substituent is the same as defined above, and may be a chlorocarboxylic acid.
In the third step, dichloromethane is used as solvent. In this step, tn-CPBA or hydrogen peroxide may be used in an amount of about 4 equivalents, respectively. Preferably, they may be used in an amount of about 2.5 equivalents, respectively, considering economy.
In the fourth step, dioxane or dichloromethane is used, and the substituent R3 and a base are used for the addition reaction to obtain the wanted 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical
Formula 1. In this step, the base and the substituent R3 may be used in an amount of about 2 equivalents, respectively. Preferably, they may be used in an amount of about 1.5 equivalents, respectively, considering economy. The
3 base may be pyridine, triethylamine, or the like. The substituent R substituent is the same as defined above, and may be a primary or secondary amine.
In the preparation of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention, the progress of reaction of each step may be confirmed by TLC. Structural analysis of the reaction intermediates represented by Chemical Formulas 3, 4 and 5 may be carried out by NMR or mass spectroscopy after separation and purification.
The present invention further provides a pharmaceutical composition for treating inflammatory disease induced by activity of sphingosylphosphorylcholine (SPC) receptor containing the 2,4,5- trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
The pharmaceutical composition for treating inflammatory disease may comprise N-{5-benzoyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]thiazoyl-4- yl}pivalamide (Compound No. 1-76, see Table 1 below) or N-{5-benzoyl-2-[2- (piperidin-1-yl)ethylamido]thiazoyl-4-yl}-4-fluorobenzamide (Compound No. 1- 94, see Table 1) of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1, as an effective ingredient.
The 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention was confirmed to have an antagonistic effect in selective cell proliferation induced by SPC (see Table 2). Therefore, it may be effective for atopic dermatitis or other skin disease caused by excessive cell division and proliferation induced by SPC. Further, because excessive cell division and proliferation during wound healing may result in scars through inflammatory response, the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention, which inhibits the excessive cell division and proliferation, may be used to prevent unwanted scarring. In addition, it may be used to facilitate wound healing after injury.
Further, in tetradecanoylphorbol acetate (TPA)-induced inflammatory response test, the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention reduced ear edema and inhibited MPO activity, comparable to hydrocortisone which is commonly used to treat inflammation (see Table 4).
Accordingly, the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention may be effective in treating inflammation, itching, skin infections, etc. associated with atopic dermatitis or other disease, and may be useful as a pharmaceutical composition for preventing scarring after injury and promoting wound healing.
Further, the present invention provides a modulator of chemotaxis- mediated symptoms containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient.
Chemotaxis is the phenomenon in which endothelial cells or immune cells are attracted by specific materials such as cytokines or chemokines. By this, immune cells move to inflamed area or endothelial cells migrate to result in angiogenesis.
The 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention was confirmed to be able to strongly inhibit the migration of endothelial cells or immune cells induced by SPC (see Table 3).
Accordingly, a modulator of chemotaxis-mediated symptoms comprising the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an effective ingredient may inhibit angiogenesis caused by the migration of endothelial cells and may control the amplification of immune response to antigens from outside.
The modulator of chemotaxis-mediated symptoms may comprise N-{5- benzoyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]thiazoyl-4-yl}pivalamide (Compound No. 1-76) of the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 as an effective ingredient.
Specific examples of the chemotaxis-mediated symptoms that can be controlled by the modulator of chemotaxis-mediated symptoms according to the present invention may include inflammation, itching and skin infection associated with atopic dermatitis or other disease.
The pharmaceutically acceptable salt according to the present invention may be one that can be prepared by a method commonly used in the related art. For example, a pharmaceutically acceptable acid salt may be prepared using an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium bisulfate, phosphoric acid, carbonic acid, etc. or an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, acetylsalicylic acid (aspirin), etc., a metal salt may be prepared using an alkali metal ion such as sodium, potassium, etc., or other pharmaceutically acceptable salt may be prepared using an ammonium ion.
Further, a commonly used non-toxic pharmaceutically acceptable carrier, modifier or excipient may be added to the 2,4,5-trisubstiuted-1,3-thiazole derivative of the present invention or a pharmaceutically acceptable salt thereof to prepare a pharmaceutical composition in oral or parenteral preparation forms common in the pharmaceutical field, e.g. tablet, capsule, troche, liquid, suspension, etc.
The administration dose of the compound of the present invention may vary depending on the age, body weight and sex of the patient, administration route, physical conditions and severity of disease. For an adult patient weighing 70 kg, a usual dosage may be 0.01-1,000 mg/day. Depending on the physician' s or pharmacist' s decision, it may be administered once or several times a day at predetermined intervals.
Hereinafter, the present invention will be described in detail through examp1es .
However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited by them.
Example 1: Synthesis of 2,4,5-trisubstiuted-1,3-thiazole (Chemical Formula 1-1)
Step 1: Conversion of potassium (E)-methylcyanocarbonimidodithionate
(Chemical Formula 2) to 4-amino-1,3-thiazole
Potassium (E)-methylcyanocarbonimidodithionate (1.53 g, 8.98 mmol) represented by Chemical Formula 2 was dissolved in DMF (20 mL) . After adding 2-bromoacetophenone (PhCOCH2Br; 2.00 g, 10.0 mmol) and triethylamine (Et3N;
1.80 mL, 12.9 mmol), reaction was carried out at 80°C for 3 hours while stirring. Then, after cooling to room temperature, the reaction mixture was dissolved in 100 mL of EtOAc and washed with 100 mL of brine. After drying the organic layer using Na2SO4 the reaction mixture was filtered and concentrated. The concentrated reaction mixture was purified by recrystallization (hexane:EtOAc = 3:1) to obtain [4-amino-2- (methylthio)thiazole-5-yl] (phenyl)methanone (1.95 g, 77%) represented by Chemical Formula 3-1.
1H NMR (500 MHz, CDC13) δ 2.72 (s, 3H), 6.83 (br s, 2H), 7.44-7.52 (m, 3H),
7.75-7.77 (m, 2H); m/z ([M+l]+) 251.
Step 2: N-acetylation of 4-amino-1,3-thiazole (Chemical Formula 3-1)
4-Amino-1,3-thiazole (1.08 g, 4.31 mmol) represented by Chemical Formula 3-1 was dissolved in 10 mL of acetonitri Ie. After adding acetyl chloride (CH3C0C1; 0.53 mL, 7.50 mmol) and pyridine (0.60 mL, 7.42 mmol), reaction was carried out at room temperature for 6 hours while stirring. Then, the reaction mixture was dissolved in 50 mL of EtOAc and washed with 50
mL of brine. After drying the organic layer using Na2Sθ4, the reaction mixture was filtered and concentrated. The concentrated reaction mixture was purified by silica gel column chromatography (hexane÷EtOAc = 3:1) to obtain N-[5-benzoyl-2-(methylthio)thiazole-4-yl]acetamide (1.06 g, 84%) represented by Chemical Formula 4-1.
1H NMR (500 MHz, CDC13) δ 2.31 (s, 3H), 2.77 (s, 3H), 7.46-7.51 (m, 2H), 7.58
(m, 1H), 7.76-7.81 (m, 2H), 11.63 (s, IH); m/z ([M+1]+) 293.
Step 3: Oxidation of 4-N-acetyl-1,3-thiazole (Chemical Formula 4-1)
4-N-acetyl-1,3-thiazole (0.96 g, 3.28 mmol) represented by Chemical Formula 4-1 was dissolved in 10 mL of dichloromethane. After adding m- chloroperbenzoic acid (m-CPBA; 1.84 g, 8.21 mmol) at room temperature, reaction was carried out at room temperature for 12 hours while stirring. Then, the reaction mixture was dissolved in 50 mL of EtOAc and sequentially washed with 50 mL of saturated Na2S2O3 solution, 50 mL of saturated NaHCO3 solution and 50 mL of brine. After drying the organic layer using Na2SO4, the reaction mixture was filtered and concentrated. The concentrated reaction mixture was purified by silica gel column chromatography (hexane÷EtOAc = 2:1) to obtain N-[5-benzoyl-2-(methylsulfonyl)thiazole-4~yl]acetamide (1.01 g, 95%) represented by Chemical Formula 5-1.
1H NMR (500 MHz, CDC13) δ 2.33 (s, 3H), 3.43 (s, 3H), 7.53-7.67 (m, 3H),
7.84-7.86 (m, 2H), 10.89 (s, IH); m/z ([M+l]+) 325.
Step 4: Addition of amine to 2-sulfonyl-4-N-acetyl-1,3-thiazole (Chemical Formula 5-1)
2-Sulfonyl-4-N-acetyl-1,3-thiazole (50 mg, 0.15 mmol) represented by Chemical Formula 5-1 was dissolved in 5 mL of dioxane. After adding diethylamine (Et2NH; 0.031 mL, 0.30 mmol) and triethylamine (0.056 mL, 0.40 mmol), reaction was carried out at room temperature for 12 hours while stirring. Then, the reaction mixture was dissolved in 20 mL of EtOAc and washed with 20 mL of brine. After drying the organic layer using Na2S04, the reaction mixture was filtered and concentrated. The concentrated reaction mixture was purified by silica gel column chromatography (hexane÷EtOAc = 3:1) to obtain N-[5-benzoyl-2-(diethylamino)thiazole-4-yl]acetamide (41 mg, 87%) represented by Chemical Formula 1-1.
1H NMR (500 MHz, CDC13) δ 1.26-1.29 (m, 6H), 2.47 (s, 3H), 3.56 (m, 4H),
7.43-7.51 (m, 3H), 7.74-7.75 (m, 2H), 11.58 (s, IH); m/z ([M+l]+) 318.
Examples 2-150: Synthesis of 2,4,5-trisubstiuted-1,3-thiazole derivatives
2,4,5-Trisubstiuted-1,3-thiazole derivatives represented by Chemical Formula 1 were synthesized in the same manner as in Example 1, with the
1 2 3 substituents R , R and R being listed in Table 1. Analysis result for the synthesized 2,4,5-trisubstiuted-1,3-thiazole derivatives is also given in the table.
[Chemical Formula 1]
Experimental Example 1: Control of cell division and proliferation
Treatment of cells with SPC results in excessive cell division and proliferation, which may lead to pathological symptoms such as atopic dermatitis or other skin disease [Desai , Biochem. Biophys. Res. Commun., 1991, 181, 361-366], The effects of the compounds prepared in Examples on the cell division and proliferation induced by SPC was tested as follows.
IxIO5 (normally lxl04~106) NIH 3T3 cells (American Type Culture Collection,
Manassas, VA, USA) were cultured on a culture plate. Then, they were cultured in an RPMI medium free of bovine serum for 24 hours until serum starvation. After treating with the compounds prepared in Examples or with FTY720 (fingolimod) , an agonist of sphingosine-1-phosphate (SlP), as control compound at concentrations of 0.001 μM, 0.01 μM, 0.1 μM and 1 μM, the cells were cultured for 30 minutes. Then, after adding SPC (Biomol , Plymouth Meeting, PA, USA) at a concentration of 7 μM, the cells were cultured for 24 hours at 37°C . Cell proliferation was measured by [3H]-thymidine incorporated into DNA strands during cell division [Beales IL, Life Sci. , 2004, 75, 83-95]. Proliferation rate (%) was calculated by the following Equation 1, and the result is given in the following Table 2. [Equation 1]
(Test compound treated group) - (SPC non - treated group)
Proliferation rate (%) = 100 (SPC treated group) - (SPC non - treated group)
As seen from Table 2, the compounds of the present invention prepared
in Examples exhibited antagonistic effect against selective cell proliferation induced by SPC. Because inflammatory response due to excessive cell division and proliferation during wound healing after injury results in scars, the material which inhibits cell division and proliferation may be used to prevent unwanted scarring. And, the material which enhances cell division and proliferation may be used to promote wound healing after injury. Especially, the compounds of Examples 1-1 and 1-76 inhibited the cell division and proliferation induced by SPC in a dose-dependent manner. It is to be noted that FTY720, an agonist of SlP, which has a chemical structure similar to that of SPC and shares some of membrane receptors, did not inhibit the cell division and proliferation induced by SPC. Accordingly, it is conjectured that the inhibition of cell division and proliferation is due to the inherent structural activity of the compound of the present invention, and the compound of the present invention may be used to prevent scarring caused by inflammatory response due to excessive cell division and proliferation during wound healing after injury.
Experimental Example 2: Inhibition of chemotactic cell migration induced by SPC
Recently, it was reported that SPC plays an important role in chemotactic cell migration similarly to vascular endothelial growth factor (VEGF) [Boguslawski et al . , Biochem. Biophys. Res. Commun., 2000, 272, 603- 609]. Chemotaxis, the phenomenon in which cells are attracted by specific materials such as cytokines or chemokines, is critical to the migration of immune cells or endothelial cells. The effect of the compound prepared in Examples on the chemotactic migration of cells induced by SPC was tested by the Boyden chamber technique.
A 25 x 80 mm polycarbonate membrane (Neuro Probe, Inc.) having 8 μm pores was immersed in 0.01% gelatin, 0.1% acetic acid solution. After coating overnight, the membrane was allowed to be dried at room temperature.
Human umbilical vein endothelial cells (HUVECs) cultured in a complete
EBM-2 medium containing 2% fetal bovine serum (FBS) were cultivated for 4 hours in a EBM-2 medium (Cambrex, Catalog No. CC-3121) without containing bovine serum until serum starvation, and harvested with trypsin/EDTA solution. The HUVECs were suspended in a EBM-2 medium containing 0.1% bovine serum albumin (BSA), transferred to a si Iicone-coated Eppendorf tube, and treated with the test compound of Example 1-78 at concentrations of 0, 0.1, 1 and 10 μg/mL, at 37°C for 30 minutes. 27 μL of EBM-2 medium with or without containing 10 μM SPC was added to each well of the lower compartment of a Boyden chamber. The gelatin-coated membrane was placed so that a glossy surface faced downward. A gasket was placed thereon and the upper compartment was assembled. The HUVEC cells treated with the compound were transferred to the upper compartment, 5x104 (56 μL) each, and cultured for 8 hours at 37°C in a CO2 incubator. The membrane was separated, stained with a
Diff-Quik stain (Sysmex Corporation), washed with deionized water, and attached on a slide glass so that a glossy surface faced upward. The cells attached on the upper portion of the membrane were cautiously wiped out using KimWipes or a swab. Photographs were taken arbitrarily, 5 fields per each well (x 200), in order to count the cells. Inhibition rate (%) was calculated by the following Equation 2, and the result is given in the following Table 3. [Equation 2]
As seen from Table 3, the compound of Example 1-76 strongly inhibited the chemotactic cell migration induced by SPC. This suggests that, by inhibiting the migration of endothelial cells or immune cells, the compound
may control the process of angiogenesis in tumors or amplification of immune response to antigens from outside.
Experimental Example 3: Control of inflammatory response in mouse TPA- induced ear inflammation model
In order to confirm the inhibition effect against inflammatory response, experiment was carried out as follows using a Tetradecanoyl phorbol acetate (TPA)-induced inflammation model , as follows.
The TPA-induced inflammation model is widely used to test the mechanism of inflammatory response and the efficiency of inhibiting substance [De Young LM et al., Agents and Actions, 1989, 26, 335-341]. TPA is a potent tumor promoter resulting in inflammatory response. When applied on the ear of a subject, it results in erythema and edema. This inflammatory response can be measured by the increased activity of myeloperoxidase (MPO), which is essential when white blood cells attack bacteria.
Forty 6-week-old male ICR mice were prepared. TPA (Sigma Aldrich Korea) dissolved in acetone at 125 μg/mL was applied on the left ears of the mice, 20 μl per each. One hour later, acetone, 0.3% test compounds dissolved in acetone, or 0.3% hydrocortisone (Sigma Aldrich Korea) dissolved in acetone was applied on the TPA-applied area, 20 μi per each. 6 hours later, TPA was applied again on the same area, 20 μl per each. 24 hours later, the mice were euthanized by cervical dislocation, and the left ears were taken to measure weight and MPO activity. Inhibition rate (%) was calculated by the following Equation 3, and the result is given in the following Table 4. [Equation 3]
[Table 4]
( ): MPO inhibition rate
As seen from Table 4, the compound of Example 1-76 was superior in inhibiting ear edema caused by TPA-induced inflammatory response and MPO activity, comparable to hydrocortisone, which is commonly used as antiinflammatory drug. This result signifies that the compound of Example 1- 76 inhibited the infiltration of neutrophils at the inflammation area.
Preparation Example 1: Preparation of tablet (compression)
5.0 mg of the compound represented by Chemical Formula 1, as an effective ingredient, was sieved, mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate, and compressed into a tablet.
Preparation Example 2: Preparation of tablet (wet granulation)
5.0 mg of the compound represented by Chemical Formula 1, as an effective ingredient, was sieved, and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of Polysorbate 80 dissolved in pure water was added in an adequate amount and subjected to granulation. After drying and sieving, the granule was mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granule was compressed into a tablet.
Preparation Example 3: Preparation of powder and capsule
5.0 mg of the compound represented by Chemical Formula 1, as an
effective ingredient, was sieved, and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filled in a hard No. 5 gelatin capsule using an appropriate apparatus.
Preparation Example A'- Preparation of injection
100 mg of the compound represented by Chemical Formula 1, as an effective ingredient, was mixed with 180 mg of mannitol, 26 mg of Na2HPO4.
12H2O and 2,974 mg of distilled water to prepare an injection.
The invention has been described in detail with reference to example embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the present invention, the scope of which is defined in the accompanying claims and their equivalents. [Industrial Applicability]
As described above, the present invention
1) provides a 2,4,5-trisubstiuted-l,3-thiazole derivative and a pharmaceutically acceptable salt thereof through a solid-phase chemical synthesis technique,
2) elucidates superior inhibition activity of the 2,4,5-trisubstiuted- 1,3-thiazole derivative against sphingosylphosphorylcholine (SPC) receptor through an animal experiment using human-derived endothelial cells and mice, and
3) provides an inhibitor of SPC receptor and a pharmaceutical composition for treating inflammatory disease induced by SPC containing the 2,4,5-trisubstiuted-l,3-thiazole derivative as an effective ingredient, and a use thereof.
Claims
[CLAIMS] [Claim 1]
A 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1]
wherein R1 is heteroaryl, phenyl or substituted phenyl, the substituted phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C1-C5 alkyl and C1-C5 alkoxy; R2 is amide having
C1-C10 linear, branched or cyclic alkyl, C2-C10 alkenyl, C2-C10 alkynyl, heteroaryl, arylalkyl, C5-C10 heteroarylalkyl , phenyl or substituted phenyl, the substituted phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C1-C5 alkyl and C1-C5 alkoxy; and R3 is
amine substituted by one or more C1-C10 linear, branched or cyclic alkyl, C1-C10 aryl , C1-C10 heteroaryl, C1-C10 arylalkyl or C1-C10 heteroarylalkyl, or
piperazine substituted by phenyl, C1-C10 linear, branched or cyclic
alkyl, or heteroarylamide, the phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 haloalkyl.
[Claim 2]
The 2,4,5-trisubstiuted-1,3-thiazole derivative or the pharmaceutically acceptable salt thereof as set forth in claim 1, wherein, in Chemical Formula
1, R is selected from the group consisting of heteroaryl, phenyl and
zubstituted phenyl; R2 is amide having C1-C5 linear, branched or cyclic alkyl ,
C2-C5 alkenyl , C2-C5 alkynyl , heteroaryl , arylalkyl, C5-C10 heteroarylalkyl ,
3 phenyl or substituted phenyl; and R is amine substituted by one or more C1-C5
linear, branched or cyclic alkyl, C1-C5 aryl , C1-C5 heteroaryl, C1-C5 arylalkyl or C1-C5 heteroarylalkyl, or phenyl, C1-C5 linear, branched or cyclic alkyl, or
piperazine
substituted by phenyl or heteroarylamide, the phenyl being substituted by 1-4 substituents selected from the group consisting of halogen, nitro, C1-C5 alkyl, C1-C10 alkoxy and C1-C10 haloalkyl.
[Claim 3]
A method for the preparation of a 2,4,5-trisubstiuted-1,3-thiazole derivative comprising: reacting methylcyanocarbonimidodithionate represented by the following Chemical Formula 2 with a 2-haloacetophenone derivative to synthesize a 4- amino-1,3-thiazole represented by the following Chemical Formula 3 in which the substituent R1 is introduced; reacting the 4-amino group of the compound represented by Chemical
Formula 3 with chlorocarboxylic acid to synthesize a 4-N-acyl-1,3-thiazole represented by the following Chemical Formula 4 in which the substituent R2 is introduced; oxidizing the sulfanyl group of the compound represented by Chemical Formula 4 with m-chloroperbenzoic acid (m-CPBA) to synthesize a 2-sulfonyl-4- N-acyl-1,3-thiazole represented by the following Chemical Formula 5; and reacting the compound represented by Chemical Formula 5 with a primary or secondary amine to synthesize the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by the following Chemical Formula 1:
[Scheme 1]
[Claim 4]
A pharmaceutical composition for treating inflammatory disease induced by sphingosylphosphorylcholine (SPC) containing the 2,4,5-trisubstiuted-1,3- thiazole derivative represented by Chemical Formula 1 or the pharmaceutically acceptable salt thereof as set forth in claim 1 as an effective ingredient. [Claim 5]
The pharmaceutical composition for treating inflammatory disease induced by SPC as set forth in claim 3, wherein the 2,4,5-trisubstiuted-1,3- thiazole derivative represented by Chemical Formula 1 is N-{5-benzoyl-2-[4- (2-methoxyphenyl)piperazin-1-yl]thiazoyl-4-yl}pivalamide or N-{5-benzoyl-2- [2-(piperidin-1-yl)ethylamido]thiazoyl-4-yl}-4-fluorobenzamide. [Claim 6]
The pharmaceutical composition for treating inflammatory disease induced by SPC as set forth in claim 3, wherein the inflammatory disease is selected from the group consisting of inflammation, itching and skin infection associated with atopic dermatitis or other disease. [Claim 7]
A pharmaceutical composition for preventing scarring after injury and
promoting wound healing containing the 2,4,5-trisubstiuted-1,3-thiazole derivative represented by Chemical Formula 1 or the pharmaceutically acceptable salt thereof as set forth in claim 1 as an effective ingredient.
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| KR1020070097553A KR100903974B1 (en) | 2007-09-27 | 2007-09-27 | Novel 2,4,5-trisubtituted-1,3-thiazole derivatives and pharmaceutically acceptable salt thereof, method for preparation, therapeutic agent for antiinflammatory disease induced by spc activity containing 2,4,5-trisubstituted-1,3-thiazole derivatives as an effective ingredient |
| KR10-2007-0097553 | 2007-09-27 |
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| WO2009041790A1 true WO2009041790A1 (en) | 2009-04-02 |
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| WO2021214019A1 (en) | 2020-04-24 | 2021-10-28 | Bayer Aktiengesellschaft | Substituted aminothiazoles as dgkzeta inhibitors for immune activation |
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| KR101051078B1 (en) | 2008-12-05 | 2011-07-21 | 한국화학연구원 | 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives for the treatment of inflammation-related diseases, methods for their preparation and agents for the treatment of inflammation-related diseases caused by SPC receptor activity containing them as active ingredients |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006078287A2 (en) * | 2004-05-06 | 2006-07-27 | Plexxikon, Inc. | Pde4b inhibitors and uses therefor |
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2007
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| WO2006078287A2 (en) * | 2004-05-06 | 2006-07-27 | Plexxikon, Inc. | Pde4b inhibitors and uses therefor |
Non-Patent Citations (2)
| Title |
|---|
| HIRAI, KENTARO ET AL.: "Heterocyclic Cation System. 14. Synthesis of Thieno[3,2- e][1,4]diazepine, Thiazolo[4,5-e][1,4]diazepine, and s-Triazolo[3,4-c]thiazolo[4,5- e][1,4]diazepine derivatives.", J. ORG. CHEM., vol. 45, no. 2, 1980, pages 253 - 260 * |
| LEE, ILL YOUNG ET AL.: "Traceless solid-phase synthesis of2,4,5-trisubstituted thiazoles.", SYNLETT., vol. 16, 2005, pages 2483 - 2485 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021214019A1 (en) | 2020-04-24 | 2021-10-28 | Bayer Aktiengesellschaft | Substituted aminothiazoles as dgkzeta inhibitors for immune activation |
| WO2021214020A1 (en) | 2020-04-24 | 2021-10-28 | Bayer Aktiengesellschaft | Substituted aminothiazoles as dgkzeta inhibitors for immune activation |
| US11964953B2 (en) | 2020-04-24 | 2024-04-23 | Bayer Aktiengesellschaft | Substituted aminothiazoles as DGKzeta inhibitors for immune activation |
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| KR20090032372A (en) | 2009-04-01 |
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