JP4305668B2 - Drug for preventing or treating diseases associated with abnormal cytokine production or increased adhesion - Google Patents

Description

  The present invention relates to a drug for preventing or treating a disease associated with abnormal cytokine production or enhanced adhesion.

  As a number of cytokines were discovered as protein factors that suppress the expression of biological functions such as immune responses, inflammatory reactions, hematopoietic reactions, etc. in the living body, and their structures and actions are elucidated, the actions of the cytokines are not limited to the immune system, It has been revealed that it affects various functions of the living body and is closely related to the generation, differentiation, homeostasis and pathophysiology of the living body.

  Many cytokines such as TNF-α, IL-1β, IL-6, and IFN-γ are known, and it is also known to have various pharmacological actions.

  Among the above cytokines, TNF (Tumor Necrosis Factor) -α was discovered as an antitumor cytokine and expected as an anticancer agent, but thereafter it is identical to cachectin, a cachexia-inducing factor. It was found that IL-1 and other cytokine production stimulating action, fibroblast proliferation action, endotoxin shock induction action, endothelial cell leukocyte adhesion protein ICAM-1, ICAM-2 (Intercellular adhesion molecules) Have been reported to promote the adhesion of leukocytes to endothelial cells by increasing ELAM (Endothelial Leukocyte adhesion molecule-1), etc., the action of bone inflammation, the effect of arthritis such as cartilage destruction, etc. Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5].

  Furthermore, it is reported that the concentration of TNF in blood or cerebrospinal fluid increases in bacterial and parasitic infections [Non-patent Documents 6 and 7].

  Rheumatoid Arthritis (RA) also has TNF activity in synovial fluid and serum, and this activity has been reported to be TNF-α activity [Non-patent document 8, Non-patent document 9]. Non-patent document 10, Non-patent document 11, Non-patent document 12].

  In addition, it has been reported that TNF concentration is increasing in the middle of ARDS (Acute Respiratory Distress Syndrom) patients who are serious respiratory diseases [Non-patent Document 13], and fulminant viral hepatitis TNF is also involved in the conversion [Non-Patent Document 14].

  In addition, it has been reported that the concentration of TNF-α in the blood is high during myocardial ischemia such as acute myocardial infarction [Non-patent Document 15], suggesting the involvement of TNF-α in such pathological conditions. [Non-Patent Document 16]. More recently, it has been reported that TNF-α suppresses myocardial contractile force [Non-patent document 17, Non-patent document 18].

  However, chemotherapeutic agents that have satisfactory results for diseases such as rheumatoid arthritis, endotoxin shock and ARDS have not yet been developed, and steroids, anti-inflammatory agents, platelet aggregation inhibitors, antibiotics have not been developed yet. Substances are only applied symptomatically. In addition, as described above, it has been suggested that each of these diseases and TNF-α concentration increase and activity increase are closely related, and recently, TNF-α antibody and the like have been applied to the treatment of these diseases. Although these are still being tried, these have not yet yielded satisfactory results, and drugs with a new mechanism of action that can suppress the overproduction of TNF-α, particularly for the treatment of each of these diseases. Development is in the present situation demanded in the industry.

  IL-6 is known as a cytokine involved in differentiation, although activated B cells proliferate and differentiate into antibody-producing cells by antigen stimulation.

  The IL-6 not only plays an important role in the antibody production system of B cells, but also induces proliferation and differentiation in T cells, and acts on hepatocytes to induce acute phase protein synthesis. It is clear that it is an important factor not only for the immune system but also for the body defense system such as the hematopoietic system, nervous system, liver, etc., such as promoting the formation of multipotent colonies against hematopoietic cells.

  Diseases considered to involve IL-6 include a series of autoimmune diseases such as hypergammaglobulinemia, rheumatoid arthritis, systemic lupus erythematosus (SLE), monoclonal B cell abnormalities (myeloma, etc.), polyclonal B, etc. Examples include cell abnormalities, atrial myxoma, Castleman syndrome, primary glomerulonephritis, mesangial proliferative nephritis, cancer cachex, Rennert lymphoma, psoriasis, Kaposi sarcoma associated with AIDS, postmenopausal osteoporosis, etc. .

  IL-1β is known to have various physiological activities. Specific examples of such activities include tumor cell inhibitory action, cytokine production enhancing action from activated T cells, fibroblasts, synovial cells, and vascular endothelium. Cell proliferation, cell catabolism and heat generation, activated B cell differentiation, NK activity enhancement, neutrophil adhesion, inflammation, radiation damage prevention and the like.

  When the production of IL-1β is increased and it is in an excessively produced state, it may be a cause of various diseases. Examples include rheumatoid arthritis and various chronic inflammatory diseases.

  Various biological activities are known for IFN, and in fact, IFN is detected in tissues and blood in many diseases. Diseases considered to be strongly involved in the pathogenesis of IFN include viral infections, infections caused by microorganisms other than viruses, rheumatoid arthritis, collagen diseases such as SLE, type I allergy, uveitis, Behcet's disease, Examples include sarcoidosis, arteriosclerosis, diabetes, fulminant hepatitis, malignant tumor, Kawasaki disease, wound healing of skin / mucosa [Non-Patent Document 19].

  In addition, neutrophils exert a bactericidal action against foreign enemies that have invaded in the living body by migration reaction, phagocytosis, production of active oxygen, and release of lysosomal enzymes. However, it is known that neutrophils adhere to vascular endothelial cells and infiltrate into tissues at the time of ischemia / reperfusion or acute inflammation of each tissue, which is the origin of subsequent tissue damage.

  As described above, it is known that various cytokines become excessive due to abnormal production of cytokines and the like, causing various diseases. Prevention or treatment is desired.

  In addition, a drug that suppresses tissue damage caused by adhesion of neutrophil vascular endothelial cells is desired.

  General formula

[Wherein R ¹ represents a phenyl group which may have a lower alkoxy group as a substituent on the phenyl ring. R ² is a group

[Wherein R ³ is the same or different and is a carboxyl group, a lower alkoxy group, a lower alkyl group, a lower alkenyl group, a group — (A) ₁ —NR ⁴ R ⁵ (A represents a lower alkylene group; R ⁴ and R ⁵ is the same or different and represents a hydrogen atom or a lower alkyl group. L represents 0 or 1.), a hydroxyl group-substituted lower alkyl group, a lower alkoxy group-substituted lower alkoxy group, a lower alkoxy group-substituted lower alkoxycarbonyl group or A carboxyl group-substituted lower alkoxy group is shown. m shows the integer of 1-3. Or a heterocyclic residue having 1 to 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. On the heterocyclic ring, 1 to 3 groups selected from the group consisting of a carboxyl group and a lower alkoxy group may be substituted. ]
Some of the thiazole derivatives and salts thereof represented by general formulas are known compounds as described in, for example, Patent Document 1 and Patent Document 2, and such thiazole derivatives or salts thereof are active oxygen inhibitors. It is a well-known fact that it is useful as an agent.
JP-A-5-51318 JP-A-6-65222 Beutler, B., et al., Nature, 316, 552-554 (1985) Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986) Kurt-Jones, EA, et al., J. Immunol., 139, 2317-2324 (1987) Bevilacqua, MP, et al., Science, 241, 1160-1165 (1989) Akatu, K. & Suda, T., Medical Practice, 8 (9) 1393-1396 (1991) Mituyama, M., History of Medicine, 159 (8) 467-470 (1991) Nakao, M., History of Medicine, 159 (8) 471-474 (1991) Saxne, T., et al., Arthritis Rheum., 31, 1041 (1988) Chu, CQ, et al., Arthritis Rheum., 34, 1125-1132 (1991) Macnaul, KL, et al., J. Immunol., 145, 4154-4166 (1990) Brennan, FM, et al., J. Immunol., 22, 1907-1912 (1992) Brennan, FM, et al., Bri. J. Rheum., 31, 293-298 (1992) Millar, AB, et al., Nature, 324, 73 (1986) Muto, Y., et al., Lancet, ii, 72-74 (1986) Latini, R., et.al., J. Cardiovasc. Pharmacol., 23, 1-6 (1994) Lefer, AM, et.al., Science, 249, 61-64 (1990) Finkel, MS, et.al., Science, 257, 387-389 (1992) Pagani, DF, et.al., J.Clin.Invest., 90,389-398 (1992) History of Medicine, 174 (14), p1077,1995

  An object of the present invention is to provide an agent that suppresses abnormal production of cytokines that meets the above-mentioned needs of the industry or suppresses adhesion of neutrophil vascular endothelial cells, that is, a cytokine production inhibitor or an adhesion inhibitor. is there.

  As a result of further investigations on the pharmacological action of the thiazole derivatives represented by the general formula (1) and salts thereof, the present inventor has found that these thiazole derivatives and salts thereof have an action mechanism that meets the object of the present invention. It has been found that it can be a cytokine production inhibitor or an adhesion inhibitor. The present invention has been completed based on such findings.

  According to the present invention, there is provided a cytokine production inhibitor comprising at least one selected from the group consisting of a thiazole derivative represented by the above general formula (1) and a salt thereof.

  Moreover, according to this invention, the adhesion inhibitor characterized by containing the at least 1 sort (s) chosen from the group which consists of the thiazole derivative represented by the said General formula (1), and its salt is provided.

  In addition, according to the present invention, there is provided a TNF-α production inhibitor characterized by containing at least one selected from the group consisting of thiazole derivatives represented by the above general formula (1) and salts thereof. The

  Among the thiazole derivatives represented by the general formula (1), 6- [2- (3,4-diethoxyphenyl) thiazol-4-yl] pyridine-2-carboxylic acid is preferable.

  In the cytokine production inhibitor and adhesion inhibitor of the present invention, the thiazole derivative represented by the general formula (1) as an active ingredient and certain compounds among the salts thereof and the production method thereof are described in Patent Document 1 and It is described in Patent Document 2, and it is also known that the thiazole derivative is useful as an active oxygen inhibitor. However, the cytokine production inhibitory effect and adhesion inhibitory effect according to the present invention are not related to the active oxygen inhibitory action of the thiazole derivative, and of course cannot be predicted from the active oxygen inhibitory action.

  The cytokine production inhibitor or adhesion inhibitor of the present invention can be used in various diseases associated with abnormal production of cytokines, particularly abnormal production of TNF-α, IL-1β, IL-6, IFN-γ, etc. It is effective for diseases. In particular, various diseases such as chronic rheumatoid arthritis, endotoxin shock, accidental ingestion of gastric juice, ARDS, burns, asthma, etc. caused by toxic gas or sepsis, myocardial infarction in myocardial ischemia, acute stage of viral myocarditis, idiopathic As a preventive or therapeutic agent for chronic heart failure such as dilated cardiomyopathy and ischemic cardiomyopathy, from ischemia-reperfusion injury during coronary artery bypass surgery (CABG) and cardiopulmonary bypass, SIRS (systemic inflammatory response syndrome) Transition to organ failure (severe acute pancreatitis, DIC, etc.), liver failure after hepatectomy such as liver cancer, multiple organ failure resulting from severe acute pancreatitis, ulcerative colitis, inflammatory bowel diseases such as Crohn's disease A series of autoimmune diseases such as hypergammaglobulinemia, systemic lupus erythematosus (SLE), multiple sclerosis, suppression of cancer metastasis, suppression of rejection at the time of transplantation, monoclonal B cell abnormality (myeloma) ), Polyclonal B cell abnormalities, atrial myxoma, castorman syndrome, primary glomerulonephritis, mesangium proliferative nephritis, cancer cachex, rennert lymphoma, psoriasis, atopic dermatitis, kaposi sarcoma associated with AIDS, postmenopausal bone It can be suitably used as a prophylactic or therapeutic agent for inflammatory diseases such as osteoporosis, diabetes, sepsis, arteriosclerosis, vasculitis, and hepatitis.

The literature on indications is listed below.
(1) Transplant literature (a) Kojima, Y. et al., (1993) Cardiovasc. Surg., 1 , 577-582
(B) Yamataka, T et al., (1993) J. Pediatr. Surg., 28 , 1451-1457
(C) Stepkowshi, SM et al., (1994) J Immunol., 153 , 5336-5346.
(2) Literature on asthma (a) Ohkawara, Y. et al., (1995) Am J. Respir. Cell Mol. Biol., 12 , 4-12
(B) Chihara, J. et al., (1995) Immunol. Lett., 46 , 241-244
(C) Hakansson, L. et al., (1995) J. Allergy Clin. Immunol., 96 , 941-950.
(3) Literature on arteriosclerosis (a) Poston, RN et al., (1992) Am. J. Pathol., 140 , 665-673
(B) Ross, P., (1993) Nature, 362 , 801-809
(C) Li, H. et al., (1993) Arterioscler. & Thromb., 13 , 197-204
(D) Walpola, PL et al., (1995) Artherioscler. Thromb. Vasc. Biol., 15 , 2-10.
(4) Literature on cancer metastasis (a) Garofalo, A. et al., (1995) Cancer Res., 55 , 414-419
(B) Gardner, MJ et al., (1995) Cancer Lett., 91 , 229-234.
(5) Literature on diabetes (a) McLeod, DS et al., (1995) Am. J. Pathol, 147 , 642-653
(B) Schmidt, AM et al., (1995) J. Clin. Invest., 96 , 1395-1403
(C) Jakubowski, A. et al., (1995) J. Immunol., 155 , 938-946.
(6) Literature on multiple sclerosis (a) Dore-Duffy, P. et al., (1993) Adv. Exp. Med. Biol., 331 , 243-248
(B) Mizobuchi, M. and Iwasaki, Y., (1994) Nippon Rinsho, 52 , 2830-2836
(C) Cannella, B. and Raine, CS, (1995) Ann. Neurol., 37 , 424-435.
(7) Literature on multiple organ failure (a) Law, MM et al., (1994) J. Trauma., 37 , 100-109
(B) Anderson, JA et al, (1996) J. Clin. Invest., 97 , 1952-1959.
(8) Literature on atopic dermatitis (a) Meng, H. et al., (1995) J. Cell Physiol., 165 , 40-53
(B) Santamaria, LF et al., (1995) Int. Arch. Allergy Immunol., 107 , 359-362
(C) Wakita, H. et al., (1994) J. Cutan. Pathol., 21 , 33-39.
(9) Psoriasis literature (a) Groves, RW et al., (1993) J. Am. Acad. Dermatol., 29 , 67-72
(B) Uyemura, K., (1993) J. Invest. Dermatol., 101 , 701-705
(C) Lee, ML et al, (1994) Australas J. Dermatol., 35 , 65-70
(D) Wakita, H. and Takigawa, M., (1994) Arch. Dermatol., 130 , 457-463.
(10) Literature on rheumatoid arthritis (a) Hale, PL et al., (1993) Arthritis Rheum., 32 , 22-30
(B) Iigo Y. et al., (1991) J. Immunol., 147 , 4167-4171.
(11) Literature on acute respiratory distress syndrome (a) Tate, RM and Repine, JE, (1983) Am. Rev. Respir. Dis., 128 , 552-559
(B) Beutler, B., Milsark, IW and Cerami, AC, (1985) Science, 229 , 869-871
(C) Holman, RG and Maier, RV, (1988) Arch. Surg., 123 , 1491-1495
(D) Windsor, A. et al, (1993) J. Clin. Invest, 91 , 1459-1468
(E) van der Poll, T. and Lowry, SF, (1995) Prog. Surg. Basel. Karger, 20 , 18-32.
(12) Literature on ischemia-reperfusion injury (a) Yamazaki, T. et al., (1993) Am. J. Pathol., 143 , 410-418
(B) Vaage, J. and Valen, G., (1993) Acand. J. Thorac. Cardiovasc. Surg. Suppl., 41
(C) McMillen, MA et al, (1993) Am. J. Surg., 166 , 557-562
(D) Bevilacqua, MP et al (1994) Annu. Rev. Med., 45 , 361-378
(E) Panes, J. and Granger, DN, (1994) Dig. Dis., 12 , 232-241.
(13) Literature on inflammatory bowel disease (a) Mahida, YR et al., (1989) Gut, 30 , 835-838
(B) Nakamura, S. et al., (1993) Lab. Invest., 69 , 77-85
(C) Beil, WJ et al., (1995) J. Luekocyte Bio., 58 , 284-298
(D) Jones, SC et al., (1995) Gut, 36 , 724-730.
(14) Literature on SIRS (a) K.Mori, M.Ogawa, (1996) Molecular Medicine, 33 , 9,1080-1088
(B) Dinarello, CA et al., (1993) JAMA, 269 , 1829.

  More specifically, each group represented by the general formula (1) is as follows.

  Examples of the phenyl group that may have a lower alkoxy group as a substituent on the phenyl ring include phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4- Ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxy Phenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3-propoxy-4-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl, Such as 3-methoxy-4-ethoxyphenyl group Include a phenyl group which may have 1 to 3 straight-chain or branched alkoxy group having 1 to 6 carbon atoms as a substituent on the Le ring.

  Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups.

  Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. .

  Examples of the lower alkenyl group include linear or branched alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like. be able to.

The group-(A) ₁ -NR ⁴ R ⁵ (A represents a lower alkylene group. R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group. L represents 0 or 1). For example, amino, methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, methylpropylamino, aminomethyl, 2-aminoethyl , 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, ethylaminomethyl, propyl Aminomethyl, butylaminomethyl, pentylaminomethyl, hexylaminomethyl , Dimethylaminomethyl, 2-dimethylaminoethyl group such as ^{_{- (A) l -NR 4 R}} 5 (A is a hydrogen atom or .R ⁴ and R ⁵ represents an alkylene group having 1 to 6 carbon atoms the same or different A linear or branched alkyl group having 1 to 6 carbon atoms. L represents 0 or 1.).

  Examples of the hydroxyl group-substituted lower alkyl group include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1- 1 to 3 hydroxyl groups such as dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl and 2-methyl-3-hydroxypropyl Examples thereof include straight-chain or branched alkyl groups having 1 to 6 carbon atoms.

  Examples of the lower alkoxy group substituted lower alkoxy group include methoxymethoxy, 3-methoxypropoxy, ethoxymethoxy, 4-ethoxybutoxy, 6-propoxyhexyloxy, 5-isopropoxypentyloxy, 1,1-dimethyl-2-butoxyethoxy And an alkoxyalkoxy group in which the alkoxy moiety such as 2-methyl-3-tert-butoxypropoxy, 2-pentyloxyethoxy, hexyloxymethoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms. Can do.

  Examples of the lower alkoxycarbonyl group include straight chain or branched chain having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group and the like. A chain alkoxycarbonyl group can be exemplified.

  Examples of lower alkoxy group-substituted lower alkoxycarbonyl groups include methoxymethoxycarbonyl, 3-methoxypropoxycarbonyl, ethoxymethoxycarbonyl, 4-ethoxybutoxycarbonyl, 6-propoxyhexyloxycarbonyl, 5-isopropoxypentyloxycarbonyl, 1,1 A straight or branched chain in which an alkoxy moiety such as dimethyl-2-butoxyethoxycarbonyl, 2-methyl-3-tert-butoxypropoxycarbonyl, 2-pentyloxyethoxycarbonyl, hexyloxymethoxycarbonyl, etc. has 1 to 6 carbon atoms And an alkoxy-substituted alkoxycarbonyl group which is an alkoxy group.

  Examples of the carboxyl group-substituted lower alkoxy group include carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl. Examples thereof include a carboxyl group-substituted alkoxy group in which an alkoxy moiety such as 2-carboxyethoxy, 2-methyl-3-carboxypropoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms.

  Examples of the heterocyclic residue having 1 to 2 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridyl, 1,2,5,6-tetrahydropyridyl. , Thienyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, carbostyril, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinyl, indolyl, isoindolyl, Indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazolyl, acridinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl Pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydro [b] furyl, benzothienyl, phenoxathiinyl, phenoxazinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thiantenyl, 2-imidazolinyl, 2-pyrrolinyl, furyl Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyranyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H -1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl, 1 , 4-dithiaphthalenyl group, etc. It is possible.

  A hetero residue having 1 to 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, optionally substituted by 1 to 3 groups selected from the group consisting of a carboxyl group and a lower alkoxy group As, for example, 4-carboxy-2-furyl, 5-carboxy-2-furyl, 4-carboxy-2-pyridyl, 6-carboxy-2-pyridyl, 4-methoxy-5-carboxy-2-thiophenyl, 4- Examples thereof include carboxy-2-thiazole, 2-carboxy-4-pyridyl, 4-carboxy-2-pyrimidyl group and the like.

  Of the thiazole derivatives represented by the general formula (1) of the present invention, a compound having a basic group can easily form a salt with a normal pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid. And organic acids such as citric acid, succinic acid and benzoic acid.

  Moreover, the compound which has an acidic group among thiazole derivatives represented by General formula (1) of this invention can form a salt easily by making a pharmaceutically acceptable basic compound act. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

  The present invention naturally includes optical isomers.

  The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). In molding into a tablet form, various carriers well known in the art can be widely used as carriers. Examples thereof include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, Phosphorus, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. When forming into the form of a pill, those conventionally known in this field can be widely used as the carrier. Examples thereof include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar. Can be used. In molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods. When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used in this field as diluents when molded into these forms For example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. May be. Furthermore, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals can also be contained in a pharmaceutical formulation as needed.

  The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually preferably about 1 to 70% by weight in the preparation composition.

  The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it is administered by a method according to various preparation forms, patient age, sex and other conditions, disease degree, and the like. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal fluid such as glucose and amino acids, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it is administered intrarectally.

  The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, sex and other conditions, the degree of disease, etc. Usually, the amount of the active ingredient compound is about 0.2 per kg of body weight per day. It is good to be about ~ 200 mg.

  Reference examples, examples, pharmacological test results and formulation examples are listed below.

Reference example 1
0.19 ml of bromine was added dropwise to a solution of 8.8 ml of acetic acid in 0.88 g of 2-ethoxycarbonyl-3-acetyloxy-6-acetylpyridine, and the mixture was heated and stirred at 75 ° C. for 5 minutes. 0.77 g of 2-ethoxycarbonyl-3-hydroxy-6- (2-bromoacetyl) pyridine hydrobromide is obtained.

Reference example 2
2-methoxycarbonyl-5- (2-bromoacetyl) furan is obtained in the same manner as in Reference Example 1 using 2-methoxycarbonyl-5-acetylfuran as a starting material.

Reference example 3
29 g of 3,4-diethoxybenzonitrile and 23 g of thioacetamide are dissolved in 120 ml of 10% hydrochloric acid-dimethylformamide and heated at 90 ° C. for 3 hours. Further, after reacting at 130 ° C. for 5 hours, the solvent is distilled off, and the residue is washed twice with 100 ml of diethyl ether. Similarly, after washing with 100 ml of water, the crystals are collected by filtration and dried to obtain 21.7 g of 3,4-diethoxythiobenzamide.

Reference example 4
3-propoxy-4-methoxy-thiobenzamide is obtained in the same manner as in Reference Example 3 using 3-propoxy-4-methoxy-benzonitrile as a starting material.

Reference Example 5
After dissolving 877 mg of 2-methoxycarbonyl-5- (2-bromoacetyl) furan in 40 ml of methanol, 800 mg of 3-propoxy-4-methoxy-thiobenzamide is added and heated under reflux for 1 hour. The reaction mixture is concentrated to about 1/4, diethyl ether is added, and the mixture is left on an ice bath. The precipitated crystals are collected to give 1.05 g of 2- (3-propoxy-4-methoxyphenyl) -4- (5-methoxycarbonyl-2-furyl) thiazole as a brown powder.

  Melting point: 141.0-142.0 ° C.

Reference Examples 6 to 36
Using appropriate starting materials, the respective compounds shown in Tables 1 to 6 are obtained in the same manner as in the above Reference Example.

  The NMR spectrum of the compound obtained above is as follows.

NMR (1): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 1.86 (3H, d, J = 1.2 Hz), 1.98 (3H , D, J = 1.2 Hz), 3.81 (3H, s), 3.95 (3H, s), 4.12 (2H, q, J = 7.0 Hz), 4.22 (2H, q) , J = 7.0 Hz), 6.36 (1H, br-s), 6.92 (1H, d, J = 8.3 Hz), 7.37 (1H, s), 7.53 (1H, dd) , J = 2.0 Hz, J = 8.3 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.97 (1H, d, J = 2.3 Hz), 8.22 (1H, d, J = 2.3 Hz).

NMR (2): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.50 (3H, t, J = 7.0 Hz), 1.52 (3H, t, J = 7.0 Hz), 1.74-2.04 (3H, m), 2.86 (2H, t , J = 7.7 Hz), 3.58-3.72 (2H, m), 3.89 (3H, s), 3.96 (3H, s), 4.16 (2H, q, J = 7). .0Hz), 4.23 (2H, q, J = 7.0 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.40 (1H, s), 7.54 (1H, dd) , J = 2.1 Hz, J = 8.4 Hz), 7.60 (1H, d, J = 2.1 Hz), 8.02 (1H, d, J = 2.3 Hz), 8.23 (1H, d, J = 2.4 Hz).

NMR (3): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.52 (3H, t, J = 7.0 Hz), 3.53 (2H, d, J = 6.4 Hz), 3.86 (3H , S), 3.96 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 5.02-5.21 (2H, m), 5.91-6.19 (1H, m), 6.93 (1H, d, J = 8.4 Hz), 7.39 (1H, s), 7.53 (1H, dd) , J = 2.1 Hz, J = 8.4 Hz), 7.61 (1H, d, J = 2.1 Hz), 7.98 (1H, d, J = 2.4 Hz), 8.26 (1H, d, J = 2.4 Hz).

NMR (4): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.27 (6H, s), 1.50 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 2.61 (1H, br-s), 2.95 (2H, s), 3.89 (3H, s), 3.96 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 4.22 (2H, q, J = 7.0 Hz), 6.93 (1H, d, J = 8.3 Hz), 7.40 (1H, s), 7.54 (1H, dd, J = 2.1 Hz, J = 8.3 Hz) ), 7.59 (1H, d, J = 2.1 Hz), 8.00 (1H, d, J = 2.4 Hz), 8.31 (1H, d, J = 2.4 Hz).

NMR (5): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.29 (3H, d, J = 6.2 Hz), 1.49 (3H, t, J = 7.0 Hz), 1.52 (3H, t, J = 7.0 Hz), 2.08 (1H , Br-s), 2.75-3.05 (2H, m), 3.89 (3H, s), 3.97 (3H, s), 4.08-4.29 (1H, m), 4.16 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.40 (1H , S), 7.54 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.61 (1H, d, J = 2.1 Hz), 8.02 (1H, d, J = 2.3 Hz), 8.28 (1H, d, J = 2.3 Hz).

NMR (6): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.23 (3H, d, J = 6.2 Hz), 1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 1.71-1 .98 (3H, m), 2.86 (2H, t, J = 8.0 Hz), 3.69-3.86 (1H, m), 3.89 (3H, s), 3.96 (3H , S), 4.16 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 6.93 (1H, d, J = 8.4 Hz), 7 .40 (1H, s), 7.54 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.60 (1H, d, J = 2.1 Hz), 8.01 (1H, d, J = 2.3 Hz), 8.23 (1H, d, J = 2.3 Hz).

NMR (7): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 2.30 (6H, s), 3.56 (2H, s), 3. 88 (3H, s), 3.96 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 6.92 ( 1H, d, J = 8.4 Hz), 7.43 (1H, s), 7.54 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.61 (1H, d, J = 2.1 Hz), 8.15 (1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 2.4 Hz).

NMR (8): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 3.90 (3H, s), 3.96 (3H, s), 3. 99 (2H, s), 4.15 (2H, q, J = 7.0 Hz), 4.22 (2H, q, J = 7.0 Hz), 6.92 (1H, d, J = 8.3 Hz) ), 7.43 (1H, s), 7.53 (1H, dd, J = 2.1 Hz, J = 8.3 Hz), 7.59 (1H, d, J = 2.1 Hz), 8.14 (1H, d, J = 2.3 Hz), 8.29 (1H, d, J = 2.3 Hz).

NMR (9): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.19 (3H, s), 1.50 (3H, t, J = 7.0 Hz), 1.52 (3H, t, J = 7.0 Hz), 2.72 (1H, t, J = 6) .8 Hz), 2.91 (1H, d, J = 13.5 Hz), 3.01 (1 H, s), 3.07 (1 H, d, J = 13.5 Hz), 3.37 (2H, dd, J = 2.1 Hz, J = 6.8 Hz), 3.92 (1H, s), 3.97 (1H, s), 4.16 (2H, q, J = 7.0 Hz). 22 (2H, q, J = 7.0 Hz), 6.93 (1H, d, J = 8.3 Hz), 7.42 (1H, s), 7.54 (1H, dd, J = 2.1 Hz) , J = 8.3 Hz), 7.59 (1H, d, J = 2.1 Hz), 8.02 (1H, d, J = 2.3 Hz), 8.32 (1H, d, J = 2. 3 Hz).

NMR (10): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.50 (3H, t, J = 7.0 Hz), 1.52 (3H, t, J = 7.0 Hz), 1.58 (3H, d, J = 6.5 Hz), 2.32 (1H , D, J = 4.2 Hz), 3.91 (3H, s), 3.97 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 4.22 (2H, q , J = 7.0 Hz), 5.21-5.38 (1H, m), 6.92 (1H, d, J = 8.4 Hz), 7.43 (1H, s), 7.54 (1H) , Dd, J = 2.1 Hz, J = 8.4 Hz), 7.61 (1H, d, J = 2.1 Hz), 8.25 (1H, d, J = 2.2 Hz), 8.33 ( 1H, d, J = 2.2 Hz).

NMR (11): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.41-1.59 (9H, m), 1.94 (3H, dd, J = 1.6 Hz, J = 6.6 Hz), 6.22-6.51 (1H, m), 6.68 -6.85 (1H, m), 6.92 (1H, d, J = 8.4 Hz), 7.32 (1H, s), 7.41 (1H, d, J = 2.0 Hz), 7 .54 (1H, dd, J = 2.0 Hz, J = 8.4 Hz), 7.60 (2H, d, J = 2.0 Hz).

NMR (12): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 3.47 (2H , D, J = 6.4 Hz), 3.87 (1H, s), 4.16 (2H, q, J = 7.0 Hz), 4.19 (2H, q, J = 7.0 Hz), 4, .22 (2H, q, J = 7.0 Hz), 5.00-5.19 (2H, m), 5.91-6.15 (1H, m), 6.92 (1H, d, J = 8.4 Hz), 7.30 (1 H, s), 7.33 (1 H, d, J = 2.0 Hz), 7.44 (1 H, d, J = 2.0 Hz), 7.53 (1 H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.60 (1H, d, J = 2.1 Hz).

NMR (13): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.08 (3H, t, J = 7.5 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.82-2.05 (5H, m), 3.85 (3H, s ), 3.93 (3H, s), 4.11 (2H, t, J = 6.9 Hz), 4.19 (2H, q, J = 7.0 Hz), 6.22-6.51 (1H) , M), 6.65-6.83 (1H, m), 6.93 (1H, d, J = 8.3 Hz), 7.33 (1H, s), 7.41 (1H, d, J = 2.0 Hz), 7.55 (1H, dd, J = 2.0 Hz, J = 8.3 Hz), 7.60 (2H, d, J = 2.0 Hz).

NMR (14): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 1.78 (3H, s), 3.47 (2H, s), 3. 85 (3H, s), 3.96 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 4.69 ( 1H, s), 4.88 (1H, s), 6.92 (1H, d, J = 8.4 Hz), 7.39 (1H, s), 7.53 (1H, dd, J = 2. 1 Hz, J = 8.4 Hz), 7.61 (1H, d, J = 2.1 Hz), 7.96 (1H, d, J = 2.3 Hz), 8.28 (1H, d, J = 2) .3 Hz).

NMR (15): ¹ H-NMR (CDCl ₃ ) δ ppm;
0.95 (6H, d, J = 6.6 Hz), 1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 1.90-2 .14 (1H, m), 2.61 (2H, d, J = 7.3 Hz), 3.85 (3H, s), 3.96 (3H, s), 4.15 (2H, q, J = 7.0 Hz), 4.22 (2H, q, J = 7.0 Hz), 6.92 (1H, d, J = 8.3 Hz), 7.38 (1H, s), 7.55 (1H) , Dd, J = 2.1 Hz, J = 8.3 Hz), 7.60 (1H, d, J = 2.1 Hz), 7.93 (1H, d, J = 2.4 Hz), 8.23 ( 1H, d, J = 2.4 Hz).

NMR (16): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.01 (3H, t, J = 7.4 Hz), 1.44 (3H, t, J = 7.1 Hz), 1.49 (3H, t, J = 7.0 Hz), 1.51 (3H , T, J = 7.0 Hz), 1.71 (2H, sextet, J = 7.4 Hz), 2.72 (2H, t, J = 7.4 Hz), 3.87 (3H, s), 4 .16 (2H, q, J = 7.0 Hz), 4.22 (2H, q, J = 7.0 Hz), 4.43 (2H, q, J = 7.1 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.39 (1H, s), 7.53 (1H, dd, J = 2.1 Hz, J = 8.4 Hz), 7.62 (1H, d, J = 2) .1 Hz), 7.97 (1H, d, J = 2.3 Hz), 8.21 (1H, d, J = 2.3 Hz).

NMR (17): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 1.97 (3H, dd, J = 1.6 Hz, J = 6.5 Hz) 3.85 (3H, s), 3.96 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 6 .41 (1H, dq, J = 6.5 Hz, J = 15.9 Hz), 6.75 (1H, dd, J = 1.6 Hz, J = 15.9 Hz), 6.93 (1H, d, J = 8.3 Hz), 7.40 (1 H, s), 7.55 (1 H, dd, J = 2.1 Hz, J = 8.3 Hz), 7.60 (1 H, d, J = 2.1 Hz) 8.21 (2H, s).

NMR (18): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.49 (3H, t, J = 7.0 Hz), 1.51 (3H, t, J = 7.0 Hz), 3.87 (3H, s), 3.96 (3H, s), 4. 16 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 5.44 (1H, dd, J = 1.1 Hz, J = 11.1 Hz), 5 .92 (1H, dd, J = 1.1 Hz, J = 17.7 Hz), 6.93 (1H, d, J = 8.3 Hz), 7.09 (1H, dd, J = 11.1 Hz, J = 17.7 Hz), 7.42 (1 H, s), 7.54 (1 H, dd, J = 2.1 Hz, J = 8.3 Hz), 7.61 (1 H, d, J = 2.1 Hz) 8.28 (2H, br-s).

Example 1
Suspend 970 mg of 2- (3-propoxy-4-methoxyphenyl) -4- (5-methoxycarbonyl-2-furyl) thiazole in 30 ml of methanol, add 20 ml of dioxane and 5 ml of 5N aqueous sodium hydroxide, and heat to reflux for 3 hours. To do. The reaction mixture is concentrated under reduced pressure to about 1/10, water is added to the residue, and the mixture is washed with ethyl acetate. The aqueous layer is acidified with an appropriate amount of 5N hydrochloric acid and extracted with ethyl acetate. The organic layers are combined, washed with water and saturated brine, and then dried over magnesium sulfate. After distilling off the solvent, the residue is recrystallized with ethyl acetate to obtain 420 mg of 2- (3-propoxy-4-methoxyphenyl) -4- (5-carboxy-2-furyl) thiazole as a white powder.

Melting point: 191.0-192.0 ° C.
Examples 2-35
Using appropriate starting materials, the compounds described in Tables 7 to 12 are obtained in the same manner as in Example 1.

  The NMR spectrum of the compound obtained above is as follows.

NMR (1): ¹ H-NMR (CDCl ₃ ) δ ppm;
1.14 (3H, s), 1.35 (3H, s), 1.49 (3H, t, J = 7.0 Hz), 1.50 (3H, t, J = 7.0 Hz); 84 (3H, s), 4.15 (2H, q, J = 7.0 Hz), 4.21 (2H, q, J = 7.0 Hz), 4.96 (1H, s), 6.91 ( 1H, d, J = 8.3 Hz), 7.44 (1H, s), 7.52 (1H, dd, J = 2.1 Hz, J = 8.3 Hz), 7.58 (1H, d, J = 2.1 Hz), 8.37 (1H, d, J = 2.4 Hz), 8.55 (1H, d, J = 2.4 Hz).

NMR (2): ¹ H-NMR (DMSO-d ₆ ) δ ppm;
1.34 (3H, t, J = 6.8 Hz), 1.36 (3H, t, J = 6.8 Hz), 2.74 (3H, s), 2.76 (3H, s), 3. 86 (3H, s), 4.08 (2H, q, J = 6.8 Hz), 4.14 (2H, q, J = 6.8 Hz), 4.29-4.56 (2H, m), 7.06 (1H, d, J = 8.9 Hz), 7.35-7.72 (2H, m), 8.16 (1H, s), 8.39 (1H, d, J = 1.9 Hz) ), 8.67 (1H, d, J = 1.9 Hz), 10.95 (1H, br-s).

Pharmacological test 1 (adhesion inhibitory action 1)
A test compound is dissolved in 0.1 M sodium hydroxide, and 9 volumes of PBS (Dulbecco composition, manufactured by Takara) are added to prepare a 1 mM solution. Next, 0.1 mM sodium hydroxide / PBS (1: 9) was sequentially diluted to prepare 0.1 mM and 0.01 mM solutions, which were added to RPMI-1640 medium (10% FCS: fetal calf serum included). Prepare a 40-fold diluted one. Further, N-formylmethionyl leucylphenylalanine (fMLP) (2 mM dimethylformamide stock solution) is diluted with RPMI-1640 (10% FCS) to prepare a 0.25 mM solution.

  Neutrophils are purified from healthy human whole blood through dextran sedimentation, Ficoll-pack-density gradient centrifugation, and erythrocyte hemolysis, suspended in PBS (3 ml), and fluorescent labeling reagent (BCECF-AM: manufactured by Dojindo Laboratories) Add 50 μl and label at room temperature for 1 hour. The experiment is performed when human vascular endothelial cells (HUVEC: produced by Clontics) become confluent in a 24-well culture plate.

After removing the culture solution, 0.2 ml of RPMI-1640 (10% FCS) or test compound solution and 0.2 ml of fMLP solution were added, and finally 10 ⁶ fluorescently labeled neutrophils were added at 37 ° C. Let stand. Adherent and non-adherent neutrophils are collected and the fluorescence intensity is measured. The cell number is calculated from the standard line of neutrophil count and fluorescence intensity prepared separately, and the concentration (IC ₅₀ ) at which 50% inhibition is achieved is determined.

  The results are shown in Table 13.

Pharmacological test 2 (adhesion inhibitory action 2)
Effect of Vascular Endothelial Action on Expression of Adhesion Molecules ICAM-1 and VCAM-1 A test compound is dissolved in 0.1M sodium hydroxide, and 9 volumes of PBS (Dulbecco composition, manufactured by Takara) is added to prepare a 1 mM solution. . Next, prepare 300 μM, 100 μM, 30 μM, 10 μM, and 3 μM solutions by sequentially diluting with 0.1 M sodium hydroxide / PBS (1: 9), and dilute 10 times with RPMI-1640 (10% FCS). , 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM reaction solutions are prepared.

TNF-α (manufactured by R & D Systems, 10 μg / ml stock solution) is diluted with RPMI-1640 (10% FCS) to prepare a 6 ng / ml solution. Human aortic vascular endothelial cells (HAEC) and umbilical vein vascular endothelial cells (HUVEC) are cultured in a 96-well culture plate. When the cells become confluent, the culture solution is removed, and 50 μl of the various reaction solutions prepared above are added. Add 50 μl and 100 μl of the culture medium only to the positive and negative control wells, respectively. After standing at 37 ° C. for 30 minutes, 50 μl of the TNF-α solution is added to all wells except the negative control. After culturing at 37 ° C. for 24 hours, the culture solution is removed, 100 μl of paraformaldehyde (2% PBS solution) is added, and the mixture is fixed at room temperature for 10 minutes. After washing 6 times with physiological saline, block with 0.1% BSA / PBS for 1 hour at room temperature. After removing the blocking solution, 100 μl of a primary antibody solution (1000-fold diluted with 0.1% BSA / PBS) is added and reacted at 4 ° C. for 18 hours. After washing 5 times with physiological saline, 100 μl of a secondary antibody solution (diluted 1000-fold with 0.1% BSA / PBS) is added and reacted at room temperature for 2 hours. Next, after washing 5 times with physiological saline, 100 μl of peroxidase-labeled avidin (manufactured by DAKO, diluted 1000-fold with 0.1% BSA / PBS) is added and reacted at room temperature for 1 hour. After washing 5 times with physiological saline, 100 μl of OPD substrate solution is added, color is developed at 37 ° C., and the absorbance at 492/692 nm is measured. Determine the concentration (IC ₅₀ ) to inhibit 50%.

The compound of Example 2 was used as a test compound. The primary antibody and the secondary antibody are as follows.
Primary antibody:
Mouse anti-human ICAM-1 (Becton Dickinson)
Mouse anti-human VCAM-1 (Becton Dickinson)
Secondary antibody:
Rabbit anti-mouse immunoglobulin (manufactured by DAKO)
The results are shown in Table 14.

Pharmacological test 3 (TNF-α production inhibitory effect)
A test compound is dissolved in 0.1 M sodium hydroxide and 9 volumes of PBS (Dulbecco composition, manufactured by Takara) is added to prepare a 1 mM solution. Next, a 0.1 mM, 0.01 mM, 1 μM, 0.1 μM, and 0.01 μM solution is prepared by sequentially diluting with 0.1 M sodium hydroxide / PBS (1: 9).

A 50 μg / ml solution of lipopolysaccharide (LPS) is prepared with RPMI-1640 (10% FCS). Using a 24-well culture plate, add 1.35 ml of RPMI-1640 (10% FCS) to the LPS non-stimulated control well and 1.32 ml of RPMI-1640 (10% FCS) to the LPS-stimulated control well. Add 1.17 ml RPMI-1640 (10% FCS) and 0.15 ml test compound dilution to the test compound treated sample wells. Next, 0.15 ml of human whole blood is added to all wells and incubated at 37 ° C. for 30 minutes. Finally, 0.03 ml of LPS solution is added to all wells except LPS non-stimulated wells and incubated at 37 ° C. for 24 hours. The supernatant after low speed centrifugation is collected, and the amount of TNF-α produced is quantified with a commercially available ELISA kit. The concentration that suppresses 50% production (IC ₅₀ ) is determined.

  The results are shown in Table 15.

Pharmacological test 4 (IL-1 production inhibitory action)
In the same manner as in Pharmacological Test 3, the production amount of IL-1 is measured, and the concentration (IC ₅₀ ) at which it is inhibited by 50% is determined. When the compound of Example 2 was used as the test compound, the IC ₅₀ value was 80 μM.

Pharmacological test 5 (IL-6 production inhibitory effect)
The amount of IL-6 produced is measured in the same manner as in Pharmacological Test 3, and the concentration (IC ₅₀ ) at which it is inhibited by 50% is determined. When the compound of Example 2 was used as the test compound, the IC ₅₀ value was 100 μM or more.

Pharmacological test 6 (IFN-γ production inhibitory effect)
A test compound is dissolved in 0.1 M sodium hydroxide, and 9 volumes of PBS (Dulbecco composition, manufactured by Takara) is added to prepare a 1 mM solution. Next, a 0.1 mM, 0.01 mM, 1 μM, 0.1 μM, and 0.01 μM solution is prepared by sequentially diluting with 0.1 M sodium hydroxide / PBS (1: 9).

A 5 mg / ml solution of concanavalin A (Con A, manufactured by Seikagaku Corporation) is prepared with RPMI-1640 (10% FCS). Using 24-well culture plates, add 1.35 ml of RPMI-1640 (10% FCS) to ConA non-stimulated wells and 1.32 ml of RPMI-1640 (10% FCS) to ConA stimulated wells. Add 1.17 ml RPMI-1640 (10% FCS) and 0.15 ml test compound dilution to the other wells. Next, 0.15 ml of human whole blood is added to all wells and incubated at 37 ° C. for 30 minutes. Finally, 0.03 ml of ConA solution is added to all wells except for ConA non-stimulated wells, and incubated at 37 ° C. for 48 hours. The supernatant after low speed centrifugation is collected, and the amount of IFN-γ produced is quantified with a commercially available ELISA kit. The concentration that suppresses 50% production (IC ₅₀ ) is determined. When the compound of Example 2 was used as the test compound, the IC ₅₀ value was 5 μM.

Formulation Example 1
150 g of the compound of Example 1
Avicel (trade name, manufactured by Asahi Kasei) 40g
Corn starch 30g
Magnesium stearate 2g
Hydroxypropyl methylcellulose 10g
Polyethylene glycol-6000 3g
Castor oil 40g
Ethanol 40g
The active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and polished, and then tableted with a sugar-coated R10 mm kine. The obtained tablets are coated with a film coating agent comprising hydroxypropylmethylcellulose, polyethylene glycol-6000, castor oil and ethanol to produce film-coated tablets.

Formulation Example 2
150 g of the compound of Example 2
Citric acid 1.0g
Lactose 33.5g
Dicalcium phosphate 70.0g
Pluronic F-68 30.0g
Sodium lauryl sulfate 15.0g
Polyvinylpyrrolidone 15.0g
Polyethylene glycol (Carbowax 1500) 4.5g
Polyethylene glycol (Carbowax 6000) 45.0g
Cornstarch 30.0g
3.0g dry sodium stearate
Dry magnesium stearate 3.0g
Ethanol appropriate amount The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, pluronic F-68 and sodium lauryl sulfate are mixed.

  The above mixture is referred to as “No. Sieve with 60 screens and wet granulate with an alcoholic solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. Alcohol is added as necessary to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture was No. Pass through 10 screens, put in a tray and dry at 100 ° C. open for 12-14 hours. The dried particles were No. Sift through 16 screens, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compress to desired shape on tablet press.

  Treat the core with varnish, spray talc and prevent moisture absorption. An undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied to make the tablet completely round and smooth. Color coating is performed until the desired color is obtained. After drying, the coated tablet is polished to a uniform gloss tablet.

Formulation Example 3
Compound of Example 2 5 g
Polyethylene glycol (molecular weight: 4000) 0.3g
Sodium chloride 0.9g
0.4 g of polyoxyethylene-sorbitan monooleate
Sodium metabisulfite 0.1g
Methyl-paraben 0.18g
Propyl-paraben 0.02g
Distilled water for injection 10.0ml
The parabens, sodium metabisulfite and sodium chloride are dissolved in about half of the distilled water at 80 ° C. with stirring. The resulting solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the solution. Next, distilled water for injection is added to the solution to prepare a final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Claims (8)

A disease associated with abnormal cytokine production, comprising at least one selected from the group consisting of 6- [2- (3,4-diethoxyphenyl) thiazol-4-yl] pyridine-2-carboxylic acid and a salt thereof. A drug for preventing or treating,
Diseases associated with cytokine abnormal production, end-toxic shock, ARDS, burns, acute viral myocarditis, idiopathic dilated cardiomyopathy, shift to organ failure from SIRS (systemic inflammatory response syndrome), multiple organ failure , high γ gammopathy, inhibiting cancer metastasis, a sepsis or hepatitis drugs. Diseases associated with cytokine abnormal production, endotoxin shock, ARDS, SIRS transition to organ failure from (systemic inflammatory response syndrome), multiple organ failure, agent according to claim 1 which is sepsis or hepatitis. The drug according to claim 2, wherein the disease associated with abnormal cytokine production is ARDS. The drug according to claim 1, wherein the cytokine is TNF-α. Diseases associated with enhanced adhesive action, comprising at least one selected from the group consisting of 6- [2- (3,4-diethoxyphenyl) thiazol-4-yl] pyridine-2-carboxylic acid and salts thereof A drug for preventing or treating
Diseases associated with increased adhesion are uveitis , ARDS , multiple organ failure, hypergammaglobulinemia, systemic lupus erythematosus (SLE), multiple sclerosis, cancer metastasis suppression, cancer cachexia, psoriasis, atopic skin drug is a flame or sepsis. Diseases associated with enhanced adhesion effect, A RDS, multiple organ failure, systemic lupus erythematosus (SLE), multiple sclerosis, cancer cachexia, psoriasis, agent according to claim 5 is atopic dermatitis or sepsis . The drug according to claim 6 , wherein the disease associated with the enhanced adhesive action is ARDS. The drug according to claim 5 , wherein the disease associated with the enhanced adhesive action is uveitis.