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WO2006137658A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO2006137658A1
WO2006137658A1 PCT/KR2006/002325 KR2006002325W WO2006137658A1 WO 2006137658 A1 WO2006137658 A1 WO 2006137658A1 KR 2006002325 W KR2006002325 W KR 2006002325W WO 2006137658 A1 WO2006137658 A1 WO 2006137658A1
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WIPO (PCT)
Prior art keywords
thiazol
pyrimidin
fluorophenyl
amine
piperidin
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PCT/KR2006/002325
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English (en)
Inventor
In Young Choi
Kwangjun Lee
Kyungjae Lee
Myeong Yun Chae
Hosoon Kim
Hwan Mook Kim
Song-Kyu Park
Kiho Lee
Sang Bae Han
Original Assignee
Dongbu Hitek Co., Ltd.
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Publication of WO2006137658A1 publication Critical patent/WO2006137658A1/fr

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    • 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
    • A61K31/41—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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to new substituted 1,3- thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppresion and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same.
  • TNF-ot tumor necrosis factor- ⁇
  • IL-I interleukin-1
  • Such substances are produced by a variety of cells, such as monocyte or macrophage, in response to the inflammation and the other cell stress. It has been known that the cytokines play a key role in the immune response or the inflammatory response if they exist with an optimal dose, whereas, they may be related to various inflammatory diseases if they are produced excessively.
  • the proinflammatory cytokines are regulated by p-38 MAP kinase that is one of the mitogen-activated protein (MAP) kinases (Seiji Miwatashi et al., J. Med. Chem. 48, 5966-5979, 2005).
  • MAP mitogen-activated protein
  • the protein kinase (PK) includes a Ser/Thr kinase that participates in the activation of its substrate by phosphorylation as an enzyme that participates in a variety of cell responses for the extra cellular signal (B. Stein et al., Ann. Rep. Med. Chem., 31, 289-298, 1996).
  • the MAPK of such PKs is activated in itself by a variety of signals including growth factor, cytokine, UV irradiation and stress inducer in general.
  • the p38 MAP kinase also known as a cycling sequence binding protein (CSBP) and a reacting kinase (RK)
  • CSBP cycling sequence binding protein
  • RK reacting kinase
  • LPS lipopolysaccarides
  • the p38 MAP kinase is considered as it plays a role in the cell response to the inflammatory stimuli, such as accumulation of leukocytes, activation of macrophages/monocytes, tissue resorption, pyrexia, acute phase reaction and neutrophilia.
  • Diseases associated with p38 MAP kinase include cancer, platelet aggregation induced by thrombin, immunodeficiency disease, autoimmune disease, necrocytosis, allergy, osteoporosis, degenerative disease, etc.
  • the p38 MAP kinase was activated in the cell stimulated by stress (e.g., LPS process, UV, isomycin or osmotic shock) and cytokines, such as TNF- ⁇ , IL-I, etc. Accordingly, if it would blockade the production of cytokines of TNF- ⁇ , 11-1, etc., it is possible to inhibit the activation of p38 MAP kinase.
  • stress e.g., LPS process, UV, isomycin or osmotic shock
  • cytokines such as TNF- ⁇ , IL-I, etc. Accordingly, if it would blockade the production of cytokines of TNF- ⁇ , 11-1, etc., it is possible to inhibit the activation of p38 MAP kinase.
  • Tumor necrosis factor- ⁇ is a cytokine produced mainly by activated monocyte and macrophage and is a strong proinflammatory mediator. Excessive or non-regulated production of TNF- ⁇ is associated with a variety diseases such as: rheumatic arthritis, rheumatoid spondylitis, osteoarthritis and other arthritis diseases; sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS) , cerebral malaria, chronic pulmonary inflammatory disease, silicosis, osseous resorption disease, reperfusion injury, graft versus host reaction, allograft rejection; myalgia and febricity due to infection, e.g., secondary cachexia due to influenza infection and secondary cachexia due to acquired immune deficiency syndrome (AIDS) , AIDS, AIDS-related complex (ARC) , keloid formation, wounded tissue formation, Crohn's disease, ulcerative colitis
  • AIDS acquired
  • IL-I Interleukin-1 is a cytokine produced mainly by activated monocyte and macrophage and is a strong proinflammatory mediator, like TNF- ⁇ . Moreover, it has been established that the numeric value of IL-I is increased also by the excessive or non-regulated production of TNF- ⁇ . Accordingly, TNF- ⁇ inhibitor reduces the numeric value of IL-I (European Cytokine Network 6, 225, 1995) and improves symptoms of disease due to the non-regulated synthesis of IL-I.
  • a variety of diseases exacerbated or induced by the excessive of non-regulated synthesis of IL-I include rheumatic arthritis, rheumatoid spondylitis, osteoarthritis, gout, traumatic arthritis, rubella arthritis, acute synovitis, sepsis, septic shock, endotoxin shock, gram- negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS) , cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, osseous absorption disease, ischemic reperfusion injury, arteriosclerosis, traumatic brain injury, multiple sclerosis, graft versus host reaction, allograft rejection; myalgia and febricity due to infection, e.g., secondary cachexia due to infection or malignant tumor, secondary cachexia due to acquired immune deficiency syndrome (AIDS), AIDS, AIDS-related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colonitis
  • IL-I regulates various biological activities such as activation of T-helper cell, heat induction, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis and inhibition of plasma iron concentration (Rev. Infect. Disease, 6, 51(1984)).
  • virus sensitive to TNF inhibition e.g., HIV-I, HIV-2 and HIV-3
  • IL-I virus sensitive to TNF inhibition
  • 11-1 and TNF all induce the synthesis of collagenase to cause tissue destruction in joint ultimately (Lymphokine Cytokine Res. (11): 253-256, (1992)) and (Clin. Exp. Immunol. 989: 244-250, 1992).
  • IL- ⁇ IL-6 is another inflammatory cytokine associated with a variety of symptoms including inflammation.
  • IL-6 is a growth factor in various oncological diseases including multiple myeloma and related plasma cell dyscrasia.
  • IL-6 Diseases related to the excessive or non-regulated production of IL-6 include neurological disorders, such as AIDS dementia complex (ADC), Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus (SLE) , CNS trauma, and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15:307); and numerous diseases such as multiple myeloma, rheumatic arthritis, psoriasis and postmenopausal osteoporosis (Simpson, et al . , Protein Sci. 6, 929, 1997).
  • IL-8 IL-8 is a characterized chemotactic factor produced by- several cells such as monocyte, fibroblast, endothelial cell and keratinocyte.
  • the production of IL-8 induced by IL-I, TNF- ⁇ or lipopolysaccarides (LPS) in the endothelial cell releases histamine from basophile of normal and atopic subjects and further contributes to the induction of lysosomal enzyme release from neutrophil and the increase in vascular endothelial cell adhesion.
  • LPS lipopolysaccarides
  • IL-8 diseases mediated mainly by neutrophil, such as cerebral paralysis and myocardial infarction; heat injury, adult respiratory distress syndrome (ARDS) , multiple organ injury after trauma, acute glomerulonephritis, dermatosis accompanied by acute inflammatory disease, acute purulent meningitis, or other central nervous system (CNS) disorders, hemodialysis, granulocyte transfusion-related syndrome, necrotizing enterocolitis (NEC), etc.
  • neutrophil such as cerebral paralysis and myocardial infarction
  • ARDS adult respiratory distress syndrome
  • CNS central nervous system
  • hemodialysis hemodialysis
  • granulocyte transfusion-related syndrome necrotizing enterocolitis
  • GM-CSF graft versus host disease
  • IFN-Y is associated with collagen deposition that is one of the major histopathological characteristics of graft versus host disease (GVHD) and induces the activation of most peripheral T-cells prior to the progression of malfunctions of the central nervous system (CNS) in the diseases such as multiple sclerosis and AIDS dementia complex (ADC) (Martino et al., 1998, Ann Neurol. 43, 430) .
  • GVHD graft versus host disease
  • ADC AIDS dementia complex
  • Cyclooxygenase is generally classified into a constitutive expression of cyclooxygenase (COX-I) and an inducible expression of cyclooxygenase (COX-2) . It has been established that the expression of COX-2 is increased by cytokines. Accordingly, it is expected that a cytokine inhibitor may inhibit the expression of COX-2 (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 4888).
  • the COX inhibitor like non-steroidal anti-inflammatory drug (NSAID) well known as a drug that inhibits the cytokines such as IL-I and the like, will show efficacies for various diseases being under medical treatment.
  • NSAID non-steroidal anti-inflammatory drug
  • Anti-inflammatory agents of the initial stage served as tools to elucidate the role of p38 MAP kinase were pyridinyl imidazoles.
  • the first one is the bicyclic pyridinyl imidazole SKF-86002 developed by Lee, J. C. et al (Lee, J. C. et al., Int. J. Immunopharmacol . 10, 835-843, 1992). Since then, the structure-activity relationship
  • the new aryl-pyridinyl-heterocycle compounds were synthesized by replacing the imidazole pharmacophore with other heteroaryl pharmacophore.
  • the aryl-pyridinyl-heterocycle complexes include SB-242235 prepared by GlaxoSmithKline Inc., and RWJ-67657 provided by RW Johnson Pharmaceutical Research Institute (Badger, A. M. et . al., Arthritis Rheum. 43. 175-183, 2000; Wadsworth, S. A. et . al., J. Pharmacol. Exp. Ther. 291, 680- 687, 1999) .
  • Cirillo et al. prepared the non-aryl-pyridinyl compounds including triazanapthalenones, A/,W -diary1 ureas, -V,N-diaryl ureas, benzophenones, pyrazoleketones, indole amides, diamides, quinazolinones, pyrimido [4, 5-d] pyrimidinones and pyridyl- amino-quinazolines (Cirillo, P. F. et . al., Curr. Top. Med. Chem. 2, 1021-1035, 2002) .
  • non-aryl-pyridinyl compounds include VX-745 of Vertex Pharmaceutical Inc. classified as triazanapthalenones and BIRB-796 of Boehringer Ingelheim Pharmaceutical Inc. related to N,N r -diaryl ureas (Regan, J. et . al . , J. Med. Chem. 45, 2994-3008, 2002).
  • GlaxoSmithKline WO/2002/059083
  • Merck WO/2002/058695
  • the inventors of the present invention having executing researches aiming at selecting thiazole compounds as a pharmacophore to develop effective compounds that are useful in treating diseases mediated by proinflammatory cytokines such as TNF- ⁇ and IL-I and have excellent inhibitory activities of the proinflammatory cytokines, have confirmed that substituted 1,3-thiazole derivatives shows excellent immunosuppression or inflammation inhibitory activity, thus completing the present invention.
  • Still another object of the present invention is to provide a process for the preparation of the substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof and intermediate compounds or pharmaceutically acceptable salts thereof.
  • Still another object of the present invention is to provide a pharmaceutical composition comprising the substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof.
  • the present invention provides new substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activities, intermediate compounds or pharmaceutically acceptable salts thereof, a method for the preparation thereof and, further, a pharmaceutical composition comprising the substituted 1,3- thiazole derivatives or pharmaceutically acceptable salts thereof.
  • New substituted 1,3-thiazole derivatives of the present invention having excellent TNF- ⁇ inhibitory activity and inflammation inhibitory activity can be effectively used for preventing and treating TNF- ⁇ related diseases.
  • Fig. 1 is photographs of colons in a vehicle treatment group extracted by sacrificing rats having ulcers induced by TNBS (2, 4, ⁇ -trinitrobenzenesulfonic acid solution) that is an inflammatory intestinal disease induced substance
  • Fig. 2 is photographs of colons in a treatment group extracted by sacrificing rats having ulcers induced by TNBS, which is an inflammatory intestinal disease induced substance, and treated with prednisolone; and
  • Fig. 3 is photographs of colons extracted by sacrificing rats having ulcers induced by TNBS, which is an inflammatory intestinal disease induced substance, and treated with the compounds of Example 334 in accordance with the present invention. [Best Mode]
  • the present invention provides new substituted 1,3- thiazole derivatives expressed by Formula 1 below or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activities:
  • Z denotes CH or N
  • Rl denotes a halogen atom, a haloalkyl of C 1 -C 4 , an alkyl of Ci ⁇ C4 or alkoxy of Ci-C 4 ;
  • R2 denotes H, a halogen atom, an alkyl of C 1 -C 4 , -NH-R4, an alkyl-S (O) n -phenyl of Ci-C 4 ,
  • X denotes CH, C-OH or N
  • Y denotes CH 2 , an alkyl of CH-Ci-C 4 , NH, an alkyl of N-Ci-C 4 , an alkyl of amino-Ci ⁇ C 4 of N-Ci-C 4 , an alkyl of N-CO-Ci-C 4 , a cycloalkyl of N-CO-C 3 -C 8 , an aryl of N-CO-C 5 -C 8 , an alkyl of amino-Ci ⁇ C 4 of N-CO-Ci-C 4 or an alkoxy of N-Co-N-Ci-C 4 ;
  • R3 denotes a halogen atom, -NH-R4, -NH-C0-R5, -N-(CO- R5) 2 or an alkyl of -S(O) n -Ci-C 4 ;
  • R4 denotes H, an alkyl of Ci-C 4 , a cycloalkyl of C 3 -C 8 , a cycloalkylalkyl of C 3 -C 8 , an aryl of C 5 -C 8 , CH(Ci-C 4 alkyl) - phenyl or amine;
  • R5 denotes an alkyl of Ci-C 4 , a cycloalkyl of C 3 -C 8 , an aryl of C 5 -C 8 or an alkoxy of Ci-C 4 ; m is 1 or 2; and n is 0, 1 or 2.
  • Z is CH or N;
  • Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 ;
  • R2 is H, Cl, ethyl, amino, NHNH 2 , methylamino, 6,N- dimethylnicotinilamino, 4- methylsulfanylphenyl, 4- methanesulfinylphenyl, 4-methanesulfonylphenyl, piperidin-1- yl, 4-methyl-piperidin-l-yl, piperidin-4-yl, N-methyl piperidin-4-yl, N-ethyl- piperidin-4-yl, N-isopropyl- piperidin-4-yl, N-cyclopropylmethyl-piperidin-4-yl, N- dimethylaminoethyl- piperidin-4-yl, N-methylcarbonyl- piperidin-4-yl, N-cyclopropylcarbonyl-piperidin-4-yl, N- dimethylaminomethylcarbonyl-piperidin-4-yl, N- phenylcarbonyl-pipe
  • Rl denotes a halogen atom, a haloalkyl of Ci-C 4 , an alkyl of Ci-C 4 or alkoxy of Ci-C 4 ; and Hal denotes F, Cl or I.
  • Rl denotes a halogen atom, a haloalkyl of Ci-C 4 , an alkyl of Ci-C 4 or alkoxy of Ci-C 4 ; and Hal denotes F, Cl or I.
  • Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 ; and Hal is Cl.
  • the substituted 1,3-thiazol derivatives expressed by Formula 1 above and the intermediate compounds expressed by Formula 2 above can be used in the form of pharmaceutically acceptable salts, i.e., metal salts, salts of organic bases, salts of inorganic acids, salts of organic acids, salts of basic or acidic amino acids, etc.
  • metal salts are exemplified by alkali metal salts such as sodium salt, potassium salt, etc.; alkaline-earth metal salts such as calcium salt, magnesium salt, barium salt, etc.; and aluminum salts.
  • Suitable salts of organic bases are salts of trimethylamine, triethylamine, pyridine, picoline, 2,6- lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N- dibenzylethylenediamine, etc.
  • Appropriate salts of inorganic acids are salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Appropriate salts of organic acids are salts of formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Suitable salts of basic amino acids are salts of arginine, lysine, ornithine and the like.
  • Appropriate salts of acidic amino acids are salts of aspartic acid, glutamic acid and the like.
  • inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline-earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.) and organic salts such as aluminum salt; and if the compounds have basic functional groups therein, such salts include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like) and salts of organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like) . Furthermore, the present invention provides a process formic acid, acetic acid, trifluoroacetic acid, phthal
  • step (1) (2) preparing a compound (V) by halogenating the compound (IV) obtained in step (1);
  • Rl, R2 and R4 are the same as defined in Formula 1; Hal' denotes a halogen atom; and L denotes a leaving group.
  • Compounds II, IE, VI and Vl may be used as they are if available commercially or be prepared according to the well- known method as it is or the similar process thereto.
  • Compound IV is prepared by treating compound II with base and reacting with compound HI.
  • Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of base to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound II, preferably, about 1.0 to 1.2 mol.
  • the "base” to be applied hereto includes, for example, alkyllithium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 60 ° C, desirably, in the range from -78 ° C to the room temperature.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 3 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound V is prepared by treating compound IV with halogen or metal halide. This reaction may be carried out under the presence of a base or a basic salt, if necessary.
  • Hal or Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of halogen or metal halide to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound IV, preferably, about 1.0 to 2.0 mol.
  • the "halogen” includes bromine, chloride, iodine and the like.
  • the "metal halide” includes copper halides such as copper ( II ) bromide, copper ( 13 ) chloride and the like.
  • the amount of base to be applied hereto is about 1.0 to 10.0 mol for 1.0 mol of compound IV, preferably, about 1.0 to 3.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.; aromatic amines such as pyridine, lutidine, etc.; and tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N, N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc .
  • reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound VII is prepared by reacting compound V with thioamide compound VI. This reaction may be carried out under the presence of a base, if necessary.
  • Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of thioamide compound VI to be applied hereto is about 0.5 to 6.0 mol for 1.0 mol of compound V, preferably, about 0.8 to 3.0 mol.
  • the amount of base to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of compound V, preferably, about 1.0 to 10.0 mol.
  • the "base” to be applied hereto includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.; aromatic amines such as pyridine, lutidine, etc. ; and tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
  • basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.
  • aromatic amines such as pyridine, lutidine, etc.
  • tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyr
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, amide, nitrile or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -5 to 200 ° C, desirably, in the range from 5 to 150 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 30 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound I -a is prepared by reacting compound VI with amide compound Vi. This reaction may be carried out under the presence of a base, if necessary.
  • the amount of amide compound Vl to be applied hereto is about 0.8 to 30.0 mol for 1.0 mol of compound VH, preferably, about 1.0 to 10.0 mol.
  • the amount of base to be applied hereto is about 0.8 to 30.0 mol for 1.0 mol of compound VH, preferably, about 1.0 to 10.0 mol.
  • the “base” includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 200 ° C, desirably, in the range from the room temperature to 170 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound I -a is deprotected using acid or base.
  • the amount of acid or base to be applied hereto is about 0.1 to 50.0 mol for 1.0 mol of compound I -a, preferably, about 1.0 to 20.0 mol.
  • the “acid” to be applied hereto includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; Lewis acids such as boron trichloride, boron tribromide, trimethylsilyl halide, etc.; use of thiol or sulfide with Lewis acids; and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, etc.
  • the “base” to be applied hereto includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide, etc.; and organic salts such as triethylamine, imidazole, formamidine, etc.
  • metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.
  • basic salts such as sodium carbonate, potassium carbonate, etc.
  • metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide, etc.
  • organic salts such as triethylamine, imidazole, formamidine, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent alcohol, ether, aromatic hydrocarbon, halogenated hydrocarbon, aliphatic hydrocarbon, sulfoxide or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about 0 to 200 ° C, desirably, in the range from 20 to 120 ° C.
  • Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the deprotected compound of compound I -a can be methylated. This reaction may be carried out under the presence of a base, if necessary.
  • the amount of methylation agent to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 5.0 mol.
  • the "methylation agent” includes, for example, methyl halide, dimethylsulfate, reductive amination using formamide, etc.
  • the amount of base to be applied hereto is about 1.0 to 5.0 mol for 1.0 mol of the corresponding deprotected compound of compound I -a, preferably, about 1.0 to 2.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, etc. ; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; and organic salts such as triethylamine, imidazole, formamidine, etc.
  • the methylated compound of compound I -a is prepared by reacting the deprotected compound of compound I -a with formaldehyde using a reducing agent under the presence of an alcohol solvent via the reductive amination.
  • the amount of formaldehyde to be applied hereto is about 1.0 to 10.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 3.0 mol.
  • the reducing agent sodiumborohydride NaBH 4 , sodiumcyanoborohydride NaBH 3 CN or sodiumtriacetoxyborohydride NaB(OAc) 3 H is used.
  • the amount of the reducing agent to be applied hereto is about 1.0 mol to 10.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 3.0 mol.
  • Reaction temperature is about -20 to 100 ° C, desirably, in the range of 0 ° C to the room temperature.
  • Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound X is prepared from compound IX via the process described in the references (Synthesis, 877-882, 1996, or Journal of Organic Chemistry, 61: 4810-4811, 1996) .
  • the amount of base to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound X, preferably, about 2.0 to 2.5 mol.
  • Compound X II is prepared by halogenating compound X I obtained in the above step in the same manner as step (2) of Scheme 1 above .
  • Hal denotes a halogen atom such as chlorine, bromine and iodine.
  • Thioamide compound VI may be used as it is if available commercially or be prepared according to the well-known method as it is or the similar process thereto.
  • Compound XIV is prepared by deprotecting compound XlH using acid or base.
  • Compound I -b is prepared by reacting compound XIV with acylation agent XV under the presence of a base.
  • the amount of acylation agent XV to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound XIV, preferably, about 1.0 to 3.0 mol.
  • the amount of base to be applied hereto is about 0.1 to 3.0 mol for 1.0 mol of compound XIV, preferably, about 0.3 to 1.2 mol.
  • the “base” includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 100 ° C, desirably, in the range from -78 to 70 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 20 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 3 below comprises the steps of: (1) treating a compound (XVI) with a base and reacting the base-treated compound with a compound (HI) to prepare a compound ( XVH) ;
  • Compound XVI may be prepared via the process described in the references such as Bioorganic & Medicinal Chemistry Letters, 13 (3) : 347-350, 2003; Organic Letters, 4(6): 979-981, 2002; or Zhurnal Organicheskoi Khimii, 12 (10) : 2063-6, 1976.
  • Compound XVH is prepared by reacting compound XVI with compound IH in the same manner as step (1) of Scheme 1 above.
  • Compound XVl may be prepared by halogenating compound XVK obtained in the above step in the same manner as step (2) of Scheme 1 above.
  • Rl is the same as defined in Formula 2; R2 is the same as defined in Formula 1; and Hal denotes Cl.
  • the base to be used in the chlorination of above (a) includes, besides LDA, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium bis (triraethylsilyl) amide and the like.
  • methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4- (trifluoromethyl) benzenesulfonyl chloride, sulfuryl chloride, etc. may be used, besides trifluoromethanesulfonyl .
  • the amount of chlorination agent to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound XVII, preferably, about 1.0 to 2.0 mol.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 150 ° C, desirably, in the range from -78 ° C to the room temperature.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the amount of TBAB applied thereto is about 0.01 to 5.0 mol for 1.0 raol of compound XVE, preferably, about 0.05 to 0.5 raol.
  • the amount of TMSCI to be used is about 0.1 to 8.0 mol for 1.0 mol of compound XVI, preferably, about 1.0 to 5.0 mol .
  • the amount of DMSO to be used is about 0.1 to 8.0 mol for 1.0 mol of compound XVH, preferably, about 1.0 to 5.0 mol .
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 50 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound XIX is prepared by reacting compound XVI obtained in the above step with thioamide compound VI in the same manner as step (3) of Scheme 1. According to International Publication No.
  • compound XIX is prepared in the yield of 24% by reacting compound XVl, of which Rl is 4-F and Hal is bromine, with thioamide compound VI, of which R2 is N-ethoxycarbonyl-piperydin-4-yl .
  • the yield of compound XIX is very low as about 7%.
  • Compound X X is prepared by treating compound XIX with organic peroxy acid.
  • the amount of organic peroxy acid to be applied hereto is about 0.8 to 10.0 mol for 1.0 mol of compound XIX, preferably, about 1.0 to 3.0 mol.
  • the "organic peroxy acid” includes, for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc.
  • reaction temperature is generally about -20 to 130 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • compound X X is prepared by treating compound XlX with hydrogen peroxide or alkyl hydroperoxide under the presence of base, acid or metal oxide.
  • the amount of hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to 10.0 mol for 1.0 mol of .compound
  • alkyl hydroperoxide includes, for example, tert- butyl hydroperoxide, cumene hydroperoxide, etc.
  • the amount of base, acid or metal oxide to be used is about 0.1 mol to 30.0 mol for 1.0 mol of compound XK, preferably, about 0.8 to 5.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc.
  • the “acid” includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc.; and organic acids such as formic acid, acetic acid, etc.
  • the "metal oxide” includes, for example, vanadium oxide (V 2 O 5 ) , osmium tetroxide (OSO4) , tungsten oxide (WO 3 ) , selenium dioxide (SeO 2 ), chrome oxide (CrO 3 ), etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • an inert solvent there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 130 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the deprotected compound of compound I -c can be methylated in the same manner as the methylation of Scheme 1.
  • the process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 4 below comprises the steps of: (1) preparing a compound (XXII) by reacting a compound ( XVHI) with a thiourea compound (XXI);
  • step (2) (2) preparing a compound (X XIH) by halogenating the compound (XXII) obtained in step (1) ;
  • Compound XXHI is prepared by halogenating compound X X ⁇ with tert-butyl nitrite and metal halide (Sandmeyer reaction) .
  • the halogenation reaction may be a general one.
  • Hal denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of tert-butyl nitrite to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound XXII, preferably, about 1.0 to 2.0 mol.
  • the amount of metal halide to be used is about 1.0 to 8.0 mol for 1.0 mol of compound XXII, preferably, about 1.0 to 2.0 mol.
  • the "metal halide” includes copper halides such as copper ( II ) bromide, copper ( II ) chloride and the like.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 100°C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound XXV is prepared by reacting compound XXIH with compound XXIV. This reaction may be carried out under the presence of a base, if necessary.
  • Compound XXIV may be used as it is if available commercially or be prepared according to the well-known method as it is or the similar process thereto.
  • the amount of compound XXIV to be used is about 0.8 to 30.0 mol for 1.0 mol of compound XXHI, preferably, about 1.0 to 10.0 mol.
  • the amount of base to be used is about 0.8 to 30.0 mol for 1.0 mol of compound XXIII, preferably, about 1.0 to 10.0 mol.
  • the “base” includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyridine, N, N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • reaction temperature is generally about -78 to 200 ° C, desirably, in the range from the room temperature to 170 "C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compounds XXVI and XXVE may be prepared according to steps (4) and (5) of Scheme 3, respectively.
  • compound XXV if Y is NH, compound X XVI may be prepared by protecting NH of compound XXV, and compounds X X IX and XXX may be prepared according to steps (4) and (5) of Scheme 3, respectively.
  • the deprotected compound may be methylated in the same manner as the methylation of Scheme 1.
  • Rl, R4 and Y are the same as defined in Formula 1; and Hal denotes a halogen atom.
  • Compound XXXVI is prepared by treating compound XXXIV with a base and reacting the base-treated compound with compound XXXV, if Y is an alkyl of N-C 1 --C 4 in compound XXXV.
  • compound X X XVII is prepared by deprotecting compound X X XVI, obtained in step (4) above, in the same manner as the deprotection of Scheme 1.
  • the amount of base to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXIV, preferably, about 1.0 to 1.2 mol.
  • the “base” includes, for example, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 60 ° C, desirably, in the range from -78 °C to the room temperature.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 3 hours.
  • step (3) treating the compound (XXXX) obtained in step (2) with base, ZnCl 2 and reacting the base-treated compound with Pd (PPh 3 ) 4 and a compound (XXXXI).
  • a basic framework of Formula 1 may be prepared via Negishi type coupling reaction.
  • Compound XXXXI may be prepared via the process described in the reference (Tetrahedron, 45(3): 993, 1989).
  • Compound XIX is prepared treating compound XXXX with base, ZnCl 2 , and reacting the base-treated compound with Pd (PPh 3 ) 4 and compound XXXXI.
  • the amount of base to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol .
  • the amount of ZnCl 2 to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol .
  • the amount of Pd(PPh 3 ) 4 to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol.
  • the "base” includes, for example, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
  • reaction temperature is generally about -78 to 200 ° C, desirably, in the range from -78 to 100 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Thioamide compound VI is prepared according to Scheme 7 below.
  • R2 is the same as defined in Formula 1.
  • Thioamide compound VI may be prepared by treating compound XXXXII with hydrogen sulfide.
  • the amount of hydrogen sulfide to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of compound XXXXII.
  • the amount of base to be used is about 1.0 to 30.0 mol for 1.0 mol of compound X X X II , preferably, about 1.0 to 10.0 mol.
  • the “base” includes, for example, aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine, etc.; and ammonia. It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, aromatic amine or a mixture of more than two of them may be used, for example.
  • aromatic amines such as pyridine, lutidine, etc.
  • tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexy
  • Reaction temperature is generally about -20 to 80 ° C, desirably, in the range from - 10 to 30 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 30 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound VI may be prepared by treating compound X X X X II with diethyl dithiophosphate under the presence of an acid.
  • the amount of diethyl dithiophosphate to be used is about 1.0 to 10.0 mol for 1.0 mol of compound XXXXII, preferably, about 1.0 to 3.0 mol.
  • the amount of acid to be used is about 1.0 to 30.0 mol for 1 . 0 mol of compound X X X II , preferably, about 1 . 0 to
  • the “acid” includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc. ; and organic acids such as formic acid, acetic acid, etc.
  • reaction temperature is generally about -20 to 100 ° C, desirably, in the range from 0 to 50 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound VI may be prepared by treating compound XXXXIII with phosphorus pentasulfide or Lawesson' s reagent under the presence of a base.
  • the amount of phosphorus pentasulfide or Lawesson' s reagent to be used is about 1.0 to 10.0 mol for 1.0 mol of compound XXXXIII, preferably, about 0.5 to 3.0 mol.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours.
  • Reaction temperature is generally about 0 to 150 ° C, desirably, in the range from the room temperature to 120 ° C.
  • the product (VI) may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound I (including compounds I -a, I -b and I -c) is an acylamino compound
  • compound I is prepared by applying the corresponding amine compound directly to the well-known acylation reaction.
  • the compound, in which R2 is an acylamino having any substitution groups in compounds I is prepared by reacting the corresponding 2-thiazolamine compound with an acylation agent under the presence of any bases or acids.
  • the amount of acylation agent to be used is about 1.0 to 5.0 rtiol for 1.0 mol of the corresponding 2-thiazolamine, preferably, about 1.0 to 2.0 mol.
  • the "acylation agent” includes, for example, carboxylic acid corresponding to the target acyl group or its reactive derivative (e.g., acid halide, acid anhydride, ester, etc. ) .
  • the amount of base or acid to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of the corresponding 2- thiazolamine, preferably, about 1.0 to 2.0 mol.
  • the “base” includes, for example, triethylamine, pyridine, 4-dimethylaminopyridine, etc.
  • the “acid” includes, for example, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • an inert solvent there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, amide, nitrile, sulfoxide, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound I (including compounds I -a, I - b and I -c) is a sulfonyl or sulfinyl compound
  • compound I is prepared by applying the corresponding sulfide compound directly to the well-known oxidation reaction.
  • the compound, in which R2 is a methanesulfonylphenyl or methanesulfinylphenyl having any substitution groups in compounds I is prepared by treating the corresponding 2-methylsulfanyl thiazol compound with an organic peroxy acid.
  • the amount of organic peroxy acid to be used is about 0.8 to 10.0 mol for 1.0 mol of the corresponding 2- methylsulfanyl thiazol compound, preferably, about 1.0 to 3.0 mol .
  • the "organic peroxy acid” includes, for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc. It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 130 "C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • compound I is prepared by treating 2- methylsulfanyl thiazol compound with hydrogen peroxide or alkyl hydroperoxide under the presence of base, acid or metal oxide.
  • the amount hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to 10.0 mol for 1.0 mol of the 2- methylsulfanyl thiazol compound, preferably, 1.0 to 3.0 mol.
  • alkyl hydroperoxide includes, for example, The “alkyl hydroperoxide” includes, for example, tert-butyl hydroperoxide, cumene hydroperoxide, etc.
  • the amount of base, acid or metal oxide to be used is about 0.1 mol to 30.0 mol for 1.0 mol of compound XIX, preferably, about 0.8 to 5.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc.
  • the “acid” includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc. ; and organic acids such as formic acid, acetic acid, etc.
  • the "metal oxide” includes, for example, vanadium oxide (V 2 O 5 ) , osmium tetroxide (OSO 4 ) , tungsten oxide (WO 3 ) , selenium dioxide (SeO 2 ) , chrome oxide (CrO 3 ) , etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • an inert solvent there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 130 °C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the starting material has amino, carboxy or hydroxy as substitution group, it is possible to introduce the protective group commonly used in peptide chemistry, etc. into such groups and to prepare a target compound by removing the protective group used, if necessary.
  • the protective group for amino to be used includes, for example, formyl or Ci ⁇ C 6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) phenylcarbonyl, Ci-C ⁇ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C 7 ⁇ Cio aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.), trityl, phthaloyl, etc., which may have a substitution group, respectively.
  • formyl or Ci ⁇ C 6 alkyl-carbonyl e.g., acetyl, propionyl, etc.
  • phenylcarbonyl Ci-C ⁇ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.)
  • phenyloxycarbonyl C 7
  • substitution group includes, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C 6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, etc., and the number of the substitution groups is 1 to 3.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • Ci-C 6 alkyl-carbonyl e.g., acetyl, propionyl, valeryl, etc.
  • nitro etc.
  • the protective group for carboxy to be used includes, for example, Ci-C 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc., which may have a substitution group, respectively.
  • Ci-C 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.
  • phenyl, trityl, silyl, etc. which may have a substitution group, respectively.
  • substitution group may include, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C 6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, Ci-C 6 alkyl (e.g., methyl, ethyl, propyl, tert-butyl, etc.), C 6 -Ci O aryl (e.g., phenyl, naphthyl, etc.) and the like, and the number of the substitution groups is 1 to 3.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • Ci-C 6 alkyl-carbonyl e.g., acetyl, propionyl, valeryl, etc.
  • nitro Ci-C 6 alkyl (e.g., methyl, ethyl, propyl,
  • the protective group for hydroxy to be used may include, for example, Ci-C 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C 7 -Cn aralkyl (e.g., benzyl, etc.), formyl, Ci-C 6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), phenyloxycarbonyl, C 7 -Cn aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, silyl, etc., which may have a substitution group, respectively.
  • Ci-C 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc
  • substitution group may include, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C 6 alkyl (e.g., methyl, ethyl, tert-butyl, etc.), C 7 -Cn aralkyl (e.g., benzyl, etc.), C 6 -CiO aryl (e.g., phenyl, naphthyl, etc.), nitro, etc., and the number of the substitution groups is 1 to 3.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • Ci-C 6 alkyl e.g., methyl, ethyl, tert-butyl, etc.
  • C 7 -Cn aralkyl e.g., benzyl, etc.
  • C 6 -CiO aryl e.g., phenyl
  • the protective groups may be removed according to the well-known method as it is or the similar process thereto, for example, the methods of treating or reducing with acid, base, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc., may be used.
  • compound I may be synthesized by carrying out the well-known deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, carbon chain extension and substitution group exchange reactions solely or in association with at least two of them.
  • these reactions those disclosed in the reference (Shinjikkenkagakukoza 14, Vo. 15, 1997, Maruzen Press) are used.
  • a target product is prepared in the form of glass via the above reactions, the product can be converted into salts according to an ordinary method, whereas, if a target product is prepared as a salt, it can be converted into the form of glass or other salts according to an ordinary method.
  • Compound ( I ) prepared like that may be isolated and purified readily from the resulting solution via the well- known methods such as concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.
  • compound I is in the form of racemates thereof, they can be resolved into S- or R- enantiomers via any optical resolutions.
  • compound I may be hydrated or dehydrated.
  • Compound I may be labeled with isotopes (e.g., 3 H, 14 C, 35 S, etc.) .
  • Prodrug of compound I is referred to such compounds that are converted into compound I by enzymes, gastric acids, etc. under physiological conditions, that is, the prodrug includes compounds converted into compound I via enzymatic oxidation, reduction, hydrolysis, etc. and compounds converted into compound I via hydrolysis by gastric acids, etc.
  • the prodrug of compound I includes: compounds that the amino group of compound I is changed into acyl, alkyl, or phosphoryl group (e.g., compounds that the amino group of compound I is changed into eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-l, 3-dioxolen-4- yl) methoxycarbonyl, tetrahydrofuranyl, pyrrolidinyl, pivaloyloxymethyl or tert-butyl group) ; compounds that the hydroxy group of compound I is changed into acyl, alkyl, phosphoryl or boryl group (e.g., compounds that the hydroxy group of compound I is changed into acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl group) ; compounds that the carboxyl group of compound I is changed into ester or
  • the prodrugs of compound I may be the compounds that are converted into compound I under the physiological conditions disclosed in the reference (Iyakuhin no kaihatsu, Hirokawashoten, pressed in 1990, Vol. 7, Melecular Design: 163-198) .
  • the present invention provides a pharmaceutical composition comprising substituted 1,3- thiazol derivatives or pharmaceutically acceptable salts for preventing and treating TNF- ⁇ related diseases.
  • the compound of the present invention shows a very low toxicity in a concentration of 3 ⁇ M, whereas, shows a noticeable toxicity in a concentration of 10 ⁇ M for the human breast cancer cell line, MDA-MB-231, the human lung cancer cell line, A549, the human renal cancer cell line, ACHN, the human gastric cancer cell line, SUN216, and the human hepatoma cell line, SUN709, and exhibits little toxicity for the murine macrophage-derived cell line, RAW264.7.
  • the compound of the present invention strongly inhibits the production of TNF- ⁇ by the human macrophage-derived cancer cell line, THP-I cell, the murine macrophage-derived cancer cell line, RAW264.7, the murine marrow cell-derived macrophage and macrophages in vivo.
  • the compound of the present invention inhibits the inflammatory reactions in vivo.
  • the compound of the present invention having excellent TNF- ⁇ inhibitory activity and inflammation inhibitory activity can be effectively used as a safe drug based on such activities.
  • the pharmaceutical composition comprising compound I of the present invention can be applied to mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.) as an agent for the prevention or treatment of a variety of TNF- ⁇ related diseases such as arthritides (e.g., rheumatic arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis, etc.), toxemias (e.g., sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, etc.), inflammatory intestinal diseases (e.g., Crohn's disease, ulcerative colonitis, etc.), inflammatory pulmonary diseases (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc.), cachexias (e.g., cachexia due to infection, cancer cachexia, cachexia due to infection
  • composition comprising compound I of the present invention having a low toxicity can be administrated as it is, or by mixing compound I with pharmaceutically acceptable carriers according to the well-known methods generally used in preparing pharmaceutical formulations, safely by oral and parenteral (e.g., local, rectal or intravenous, etc.) administrations.
  • pharmaceutical formulations include tablets (e.g., sugar coating tablet, film coating tablet, etc.), powders, granules, capsules (including soft capsules) , solutions, injections, suppositories, sustained-release forms, etc.
  • the content of compound I in accordance with the present invention may be within 0.01 to 100 weight% based on the total weight of the preparation.
  • the pharmaceutically acceptable carrier that may be used in preparing the formulations in accordance with the present invention includes various organics or carrier-free as pharmaceutical materials, for example, excipients, lubricants, bonding agents and disintergrants in solid preparations, and solvents, solubilizers, suspending agents, isotonic agents, buffering agents and soothing agents in liquid preparations.
  • optimum quantity of additives such as general preservatives, oxidation inhibitors, colorants, sweeteners, absorbents, humectants, etc., may be appropriately used, if necessary.
  • the excipient includes, for example, lactose, sucrose,
  • the lubricant includes, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.
  • the bonding agent includes, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, gelatin, methyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.
  • the solvent include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame seed oil, corn oil, olive oil, etc.
  • the solubilizer includes, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
  • the suspending agent includes surfactants, such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc., and hydrophilic polymers, such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, etc.
  • surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose
  • the isotonic agent includes, for example, glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol, etc.
  • the buffering agent includes buffer solutions such as phosphate, acetate, carbonate, citrate, etc.
  • the soothing agent includes, for example, benzyl alcohol, etc.
  • the preservative includes, for example, p- hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
  • the oxidation inhibitor includes, for example, sulfate, ascorbic acid, ⁇ -tocopherol, etc.
  • room temperature indicates the temperatures generally in the range from 10 ° C to 35 ° C;
  • % denotes the percentage by weight, unless otherwise indicated; and
  • yield represents mol/mol% .
  • Example 5 4 - [ 4 - ( 4 -fluorophenyl ) -2 - ( 4 - methyl su If any lphenyl) thiazol-5-yl]pyridin-2-ylamine (5) Trifluoroacetic acid (20 mL) was added to ⁇ 4- [4- (4- Fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5- yl]pyridin-2-yl ⁇ carbaraic acid tert-butyl ester (1.12 g, 2.23 mmol) and the mixture was stirred at room temperature for 1 hour.
  • Examples 33 to 38 In the same process as Example 32 , compounds 33 to 38 were synthesized. The structure and 1 H-NMR data of them were shown in the following Table 3.
  • Example 39 4- [4- (4-fluorophenyl) -2-piperidin-l- ylthiazol-5- ⁇ l] -2-methylsulfanylpyrimidine (39)
  • Example 63 4- [4- (4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl]piperazine-l- carboxylic acid tert-butyl ester (63) 4- [4- (4-Fluorophenyl) -2-piperazin-l-yl-thiazol-5-yl] - 2-methylsulfanylpyrimidine (1.95 g, 5.03 mmol) , di-tert- butyl dicarbonate (1.1 g, 5.03 mmol), and triethylamine (0.51 g, 5.03 mmol) were dissolved in tetrahydrofurane (70 mL) and the mixture was stirred at room temperature for 1 hour.
  • Example 122 ⁇ 4- [2-amino-4- (3-chlorophenyl) thiazol-5- yl]pyrimidin-2-yl ⁇ cycloh ⁇ xylamine (122)
  • Examples 123 to 277 In the same process as Example 122, compounds 123 to 277 were synthesized. The structure and 1 H-NMR data of them were shown in the following Table 8. [Table 8]
  • Example 306 4- [5- (2-cyclopropylaminopyrimidin-4-yl) - 4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester (306)
  • a solution of cyclopropyl- ⁇ 4- [4- (4- fluorophenyl) thiazol-5-yl] pyrimidin- 2-yl ⁇ amine 150 rag, 0.48 mmol) in anhydrous tetrahydrofurane 4 mL) was cooled to - 40 ° C and a 1.6M n-butyllithium-hexane solution 0.6 mL, 0.96 ramol) was added thereto dropwise while stirring.
  • Example 334 cydopropyl- ⁇ 4- [4- (4 -fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl]p ⁇ rimidin-2-yl ⁇ amine (334)
  • Example 369 cyclopropyl- ⁇ 4- [4- (4-fluorophenyl) -2- piperazin-l-yl-thiazol-5-yl]pyrimidin-2-yl ⁇ amine (369)
  • Trifluoroacetic acid (5 mL) was added to a solution of 4- [5- (2-Cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester (352 mg, 0.67 ramol) in methylene chloride (5 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated sodium bicarbonate was added to the residue and the mixture was extracted with methylene chloride. The extract was washed with water, dried over MgSCU and the solvent was evaporated to give the title compound (254 mg, 0.60 mmol, yield 89%). The structure and 1 H-NMR data of compound 369 were shown in the following Table 12.
  • Example 428 4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] -2- methylsulfanylpyrimidine (428)
  • Example 485 compound 486 was synthesized using 2-iodopropane instead of iodoethane.
  • the structure and 1 H-NMR data of compound 486 were shown in the following Table 14.
  • compound 492 was synthesized using l- ⁇ 4- [5- (2-cyclopropylaminopyrimidin-4- yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-l-yl ⁇ -2- dimethylaminoethanone instead of cyclopropyl- ⁇ 4- [5- (2- cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2- yl] piperidin-1-yl ⁇ methanone .
  • the structure and 1 H-NMR data of compound 492 were shown in the following Table 15.
  • Example 499 N- ⁇ 4- [4- (4-Fluorophenyl) -2- (4- methanesulfinylphenyl) thiazol-5-yl]pyridin-2-yl ⁇ propionamide 499)
  • a solution of N- ⁇ 4- [4- (4-fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl ⁇ propionamide 300 mg, 0.66 mmol
  • methylenechloride 100 mL
  • 65% ra-chloroperoxybenzoic acid 212 mg, 0.80 mmol
  • Example 500 N- ⁇ 4- [4- (4-Fluorophenyl) -2- (4- methanesulfonylphenyl) thiazol-5-yl]pyridin-2-yl ⁇ propionamide (500)
  • Example 501 N- ⁇ 4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl]pyrimidin-2-yl ⁇ propionamide (501)
  • a solution of 4- [4- (4-fluorophenyl) -5- (2- propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester (56 mg, 0.12 mmol) in chloroform(3 mL) was admixed with iodotrimethylsilane (140 mg, 0.52 mmol) and the mixture was stirred at 60 ° C for 5 hours.
  • Example 504 N- [4- (3-chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6,N- dimethylnicotinamide (504)
  • a solution of 6-methylnicotinic acid (310 mg, 4.44 mmol) in benzene (5 mL) was cooled to 0 " C and a solution of oxalyl chloride (378 mL, 4.44 mmol) in benzene (2 mL) was added thereto while stirring. After completion of addition, N,N-dimethylformamide (25 mL) was added thereto.
  • the reaction mixture was admixed with 4- (3-Chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine (1.03 g, 3.07 mmol) and 4- (dimethylamino) pyridine (126 mg, 1.03 mmol) and the mixture was stirred at 80 ° C for overnight.
  • the reaction mixture was cooled to room temperature, saturated sodium bicarbonate (200 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO 4 and the solvent was evaporated.
  • the reaction mixture was admixed with ⁇ 4- [4- (3-chlorophenyl) -2- methylaminothiazol-5-yl]pyrimidine-2-yl ⁇ - (1- (S) - phenylethyl) amine (300 mg, 0.71 mmol) and 4- (dimethylamino) pyridine (28 mg, 0.23 mmol) and the mixture was stirred at 80 ° C for overnight.
  • the reaction mixture was cooled to room temperature, saturated sodium bicarbonate (100 mL) was added, and extracted with ethyl acetate. The extract was washed with water, dried over MgSU 4 and the solvent was evaporated.
  • Example 507 2-chloro-l- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone (507) (Compound of Formula 2)
  • a solution of 1- (4-fluorophenyl) -2- (2-methylthio-4- pyrimidyl) ethanone (131 mg, 0.5 itimol) in anhydrous tetrahydrofurane (3 mL) was cooled to -78 ° C and a 1.8M lithium diisopropylamide-hexane solution (306 mL, 0.55 mmol) was added thereto dropwise while stirring.
  • Trimethylchlorosilane (11.7 g, 107.5 ramol) was added to a solution of tetrabutylammoniumbromide (2 g, 10.7 mmol) in tetrahydrofurane (650 mL) and the mixture was stirred for 30min. The mixture cooled to 0 ° C , 1- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone (9.4 g, 35.8 mmol) and dimethylsulfoxide (2.9 g, 37.6 mmol) were added thereto, and stirred at room temperature for 2 hours.
  • Cell lines used in the present experiment were the human breast cancer cell line, MDA-MB-231, the human lung cancer cell line, A549, the human renal cancer cell line, ACHN, the human gastric cancer cell line, SUN216, and the human hepatoma cell line, SUN709, which were purchased from American Type Culture Collection.
  • Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS) . Cells were added in a 96-well plate in an appropriate concentration (IXlO 6 cells/ml) and cultured under the conditions of 5%, CO 2 and 37 ° C. After 24 hours, the compounds prepared in Examples 115, 126, 334 and 429 were added in concentrations of 1-10 ⁇ M thereto. After adding such samples, the culturing further proceeded for 48 hours. Then, 5% trichloroacetic acid was added thereto to fix the cells on the bottom of the culture vessel. Proteins of the fixed cells were dyed with a sulforhodamine B (SRB) solution to measure absorbance at 595 nm. With the increase of living cells the level of absorbance also increased and the results were shown as rates of living cells to the control group (100%) in Tables 19 to 23 below.
  • SRB sulforhodamine B
  • the compounds in accordance with Examples 115, 126, 334 and 429 of the present invention showed very low toxicities in a concentration of 3 ⁇ M, whereas, showed noticeable toxicities in a concentration of 10 ⁇ M.
  • MTT [3- (4, 5-dimethylthiazolyl-2) -2, 5- diphenyltetrazolium bromide] has been widely used in measuring the number of living cells, since it is a colorless reagent, whereas, changed into colored formazan when it is decomposed by living cells.
  • the cell line applied to the present experiment was the murine macrophage-derived cancer cell line, RAW264.7, purchased from American Type Culture Collection. Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). RAW264.7 cells were added in a 96-well plate in an appropriate concentration (IXlO 6 cells/ml) and cultured under the conditions of 5%, CO2 and 37 ° C. After 24 hours, the compounds prepared in Examples 115, 126, 334 and 429 were added in concentrations of 1-10 ⁇ M thereto. After adding such samples, the culturing further proceeded for 24 hours. Then, the MTT was added thereto and, after the lapse of 4 hours, the amount of formazan produced by living cells was measured at 595 nm. The results were shown as rates to the control group (100%l in Table 24 below.
  • the compounds in accordance with Examples 115 and 126 of the present invention showed little toxicities up to the concentration of 10 ⁇ M, whereas, the compounds of Examples 334 and 429 exhibited low toxicities in the concentration of 10 ⁇ M.
  • the concentrations of the compounds in accordance with the present invention were less than 1 ⁇ M in order to identify the effects of immunosuppression in such concentrations that there is no cell toxicity.
  • TNF- ⁇ production inhibitory effects of the compounds in accordance with the present invention on the human macrophage-derived cancer cell line, THP-I cells was carried out.
  • the cell line applied to the present experiment was the human macrophage-derived cancer cell line, THP-I cells, purchased from American Type Culture Collection.
  • TNF- ⁇ was induced by using lipopolysaccharide (final concentration: 1 mg/ml) (Sigma, USA) and the compounds prepared in Examples 115, 126, 334 and 429 were added thereto in concentrations of 0.0003-1 ⁇ M. After 24 hours, the culture solutions were collected and the amount of TNF- ⁇ existing in the cell culture solutions were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) . The results were depicted in Table 25 below.
  • Example 429 As shown in Table 24 above, it was seen that the compounds in accordance with Examples 115, 126, 334 and 429 of the present invention inhibited the production of TNF- ⁇ of THP-I cells concentration-dependently. Particularly, the compound of Example 429 showed the most excellent inhibitory effect with 0.28 nM of 50% inhibitory concentration (IC 50 ) and the compounds of Examples 334, 126 and 115 exhibited 1 nM, 1.5 nm, and 0.48 nm of 50% inhibitory concentration (IC50), respectively.
  • IC 50 50% inhibitory concentration
  • TNF- ⁇ induced by LPS in the experimental groups were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) , based on the amount of 100% TNF- ⁇ induced by treating only LPS existing in the cell culture solution. The results were depicted in Tables 26 to 30 below.

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Abstract

La présente invention concerne de nouveaux dérivés thiazole 1,3 substitués ou des pharmaceutiquement acceptables de ces derniers qui présentent une activité d'inhibition de l'immunosuppression et de l'inflammation, des composés intermédiaires ou des sels pharmaceutiquement acceptables de ces composés intermédiaires, un procédé de préparation de ces derniers et une composition pharmaceutique comprenant ces composés. Le composé selon la présente invention qui présente une excellente activité d'inhibition du TNF-α et une excellente activité d'inhibition de l'inflammation peut être utilisé efficacement dans la prévention et le traitement des maladies liées au TNF-α.
PCT/KR2006/002325 2005-06-20 2006-06-16 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 WO2006137658A1 (fr)

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FR2921063A1 (fr) * 2007-09-13 2009-03-20 Sod Conseils Rech Applic Ligands des recepteurs cannabinoides
WO2009046416A1 (fr) * 2007-10-05 2009-04-09 Targegen Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinases jak
WO2010064769A1 (fr) * 2008-12-05 2010-06-10 한국화학연구원 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
EP2198710A1 (fr) 2008-12-19 2010-06-23 Bayer CropScience AG Utilisation de 5-pyridine-4yl-(1,3)thiazoles destinés à lutter contre les champignons phytopathogènes
US8133900B2 (en) 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
US8138199B2 (en) 2005-11-01 2012-03-20 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
JP2012527461A (ja) * 2009-05-19 2012-11-08 ダウ アグロサイエンシィズ エルエルシー 真菌を防除するための化合物および方法
WO2013018735A1 (fr) 2011-07-29 2013-02-07 大正製薬株式会社 Composé d'amidine ou sel de celui-ci
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WO2013050437A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyridinylpyrazole et hétérocyclylpyrimidinylpyrazole utilisés comme fongicides
US8604042B2 (en) 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
WO2014172639A1 (fr) * 2013-04-19 2014-10-23 Ruga Corporation Inhibiteurs des kinases raf
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064894A1 (fr) * 1999-04-23 2000-11-02 Takeda Chemical Industries, Ltd. Composes 5-pyridyle-1,3-azole, leur procede de fabrication et leur utilisation
WO2001010865A1 (fr) * 1999-08-06 2001-02-15 Takeda Chemical Industries, Ltd. INHIBITEURS DE p38MAP KINASE
WO2001030778A1 (fr) * 1999-10-27 2001-05-03 Novartis Ag Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique
WO2001074811A2 (fr) * 2000-03-30 2001-10-11 Takeda Chemical Industries, Ltd. Composes de 1,3-thiazole substitues, production et utilisation desdits composes
WO2002100433A1 (fr) * 2001-06-11 2002-12-19 Takeda Chemical Industries, Ltd. Compositions medicinales

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040097555A1 (en) * 2000-12-26 2004-05-20 Shinegori Ohkawa Concomitant drugs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064894A1 (fr) * 1999-04-23 2000-11-02 Takeda Chemical Industries, Ltd. Composes 5-pyridyle-1,3-azole, leur procede de fabrication et leur utilisation
WO2001010865A1 (fr) * 1999-08-06 2001-02-15 Takeda Chemical Industries, Ltd. INHIBITEURS DE p38MAP KINASE
WO2001030778A1 (fr) * 1999-10-27 2001-05-03 Novartis Ag Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique
WO2001074811A2 (fr) * 2000-03-30 2001-10-11 Takeda Chemical Industries, Ltd. Composes de 1,3-thiazole substitues, production et utilisation desdits composes
WO2002100433A1 (fr) * 2001-06-11 2002-12-19 Takeda Chemical Industries, Ltd. Compositions medicinales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
REVESZ L. ET AL: "Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, 2004, pages 3595 - 3599, XP003005381 *
RUPERT K.C. ET AL.: "Imidazopyrimidines, Potent inhibition of p38 MAP kinase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 13, 2003, pages 347 - 350, XP008075204 *

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US8133900B2 (en) 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
WO2008090382A1 (fr) * 2007-01-25 2008-07-31 The University Of Sheffield Dérivés de thiazole et d'oxazole s'utilisant dans le traitement de maladies à prions, du cancer et de troubles du système nerveux central, et dans la régulation de cellules souches
WO2008134693A1 (fr) * 2007-04-30 2008-11-06 Abbott Laboratories Inhibiteurs d'enzyme diacylglycérol o-acyltransférase de type 1
US8901152B2 (en) 2007-04-30 2014-12-02 Abbvie Inc. Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme
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US8242139B2 (en) 2007-04-30 2012-08-14 Abbott Laboratories Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme
EP2452937A1 (fr) * 2007-04-30 2012-05-16 Abbott Laboratories Inhibiteurs de l'enzyme diacylglycérol o-acyltransférase de type 1
WO2008140262A3 (fr) * 2007-05-14 2008-12-31 Seoul Nat Univ Ind Foundation Utilisation d'un tensioactif biologique en tant qu'agent anti-inflammatoire et solution de conservation de tissus
WO2009071753A1 (fr) * 2007-09-13 2009-06-11 Ipsen Pharma S.A.S. Derives de 4-phenyl-l, 3-thiazoles et de 4-phenyl-l, 3-oxazoles comme ligands des recepteurs cannabinoides
FR2921063A1 (fr) * 2007-09-13 2009-03-20 Sod Conseils Rech Applic Ligands des recepteurs cannabinoides
WO2009046416A1 (fr) * 2007-10-05 2009-04-09 Targegen Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinases jak
KR101051077B1 (ko) 2008-12-05 2011-07-21 한국화학연구원 2-피페라지노-4,5-이중치환-1,3-티아졸 유도체, 그의 제조방법 및 그를 유효성분으로 함유하는 ｓｐｃ 수용체 활성으로 유발되는 염증관련질환 치료제
WO2010064769A1 (fr) * 2008-12-05 2010-06-10 한국화학연구원 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
EP2198710A1 (fr) 2008-12-19 2010-06-23 Bayer CropScience AG Utilisation de 5-pyridine-4yl-(1,3)thiazoles destinés à lutter contre les champignons phytopathogènes
US9198426B2 (en) 2008-12-19 2015-12-01 Bayer Intellectual Property Gmbh Use of 5 pyridin-4-yl-1,3-thiazoles for controlling phytopathogenic fungi
JP2012527461A (ja) * 2009-05-19 2012-11-08 ダウ アグロサイエンシィズ エルエルシー 真菌を防除するための化合物および方法
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis
WO2013018735A1 (fr) 2011-07-29 2013-02-07 大正製薬株式会社 Composé d'amidine ou sel de celui-ci
WO2013041468A1 (fr) 2011-09-23 2013-03-28 F. Hoffmann-La Roche Ag Dérivés d'acide benzoïque en tant qu'inhibiteurs d'eif4e
WO2013050437A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyridinylpyrazole et hétérocyclylpyrimidinylpyrazole utilisés comme fongicides
WO2014172639A1 (fr) * 2013-04-19 2014-10-23 Ruga Corporation Inhibiteurs des kinases raf

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