JP2013112674A - AGENT FOR SUPPRESSING OR ENHANCING OF EXPRESSION OF EACH mRNA, AND AGENT FOR PREVENTION AND/OR TREATMENT OF IMMUNE SYSTEM DISEASE - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an agent for treatment and/or prevention of an immune system disease.SOLUTION: The agent for suppressing expression of NFKBIL1, ITGAX, FCER1A, PHACTR1 and/or IRF5 mRNA and the agent for prevention and/or treatment of the immune system disease include a compound with a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient.

Description

  The present invention relates to NFKBIL1, ITGAX, FCER1A, PHACTR1, IRF5 mRNA expression inhibitor, TAT mRNA expression enhancer, and an agent for preventing and / or treating immune system diseases.

  Today, various therapeutic agents for immune system diseases have been developed, and development of therapeutic agents for immune system diseases that are more effective is desired.

  Cytoplasmic tyrosine aminotransferase (TAT) is a gene encoding the liver-specific enzyme TAT that catalyzes the conversion of tyrosine to p-hydroxyphenylpyruvate (GenBank accession number: NM_000353). Rat hepatocytes have been reported to be involved in autophagy (Non-patent Document 1). Therefore, enhanced gene expression is associated with bacterial infection, antigen presenting ability, canceration (Non-patent Document 2), myocardium. It is expected to be a therapeutic drug for diseases such as illness, aging, and cell death.

  NF-kappaB inhibitor-like protein 1 (NFKBIL1) is a gene encoding NFKBIL1 having a structure similar to that of the IKappaB family (GenBank accession number: NM_005007). It has been reported that polymorphisms of NFKBIL1 are seen in patients with rheumatism (Non-patent Document 3) and its involvement in allergic diseases (Non-patent Document 4). It is expected to have an effect on system diseases.

  Integrin alpha X (ITGAX) is a gene encoding integrin alpha X (GenBank accession number: NM_000887). Integrin αX forms a heterodimer and functions as a fibrinogen receptor, and is also known to be involved in monocyte accumulation and inflammation. A polymorphism of this gene has been discovered in patients with systemic lupus erythematosus (SLE), and it is known that this gene and SLE are closely related (Non-patent Documents 5 and 6). Modulation of ITGAX gene expression is expected to be effective as a therapeutic agent for SLE disease.

  IgE receptors play a central role in immediate hypersensitivity such as hay fever and asthma and allergic diseases that initiate an inflammatory response. The IgE receptor consists of three subunits, α, β, and γ, but FCER1A (Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide) is a gene that encodes the α subunit of the IgE receptor. (GenBank registration number: NM_002001). Therefore, modulating this gene expression can be expected to be effective as a rhinitis (Non-patent document 7), atopy (Non-patent document 8), or hay fever therapeutic agent.

  Phosphatase and actin regulator 1 (PHACTR1) is a gene encoding a Phosphatase and actin regulator 1 protein that inhibits protein phosphatase 1 (PP1) in a concentration-dependent manner (GenBank accession number: NM_030948, non-patent document 9). PHACTR1 is a protein obtained by cloning a sequence obtained from a hippocampal cDNA library, and has been shown to be highly expressed in adult hearts and fetal brains. Furthermore, it is distributed in the lung, kidney, pancreas, spleen, ovary and spinal cord, and expression in the liver and skeletal muscle has not been found (Non-patent Document 10). It has been reported that polymorphisms occur in the PHACTR1 gene in African-American asthma patients (Non-patent Document 11), and by modulating this gene expression, an effect as a therapeutic agent for asthma disease is expected. .

  Interferon regulatory factors (IRFs) are transcriptional regulators with helix-turn-helix DNA-binding motifs. Interferon regulatory factor 5 included in this IRF family has the function of mediating signal transduction induced by viruses and interferons. (IRF5) is a gene that induces the production of IFN-1 (GenBank accession number: NM_002200, Non-Patent Document 12). It also has the function of promoting the expression of proteins that control the cell cycle, apoptosis, signal transduction, early immune response, and the like. In addition, systemic lupus erythematosus (SLE) is a disease that develops due to genetic and environmental factors, but IFN-1 production and expression of genes that enhance IFN-1 are increased, and IFN-1 SNPs in Swedish SLE patients Many (single nucleotide polymorphism) have been observed. Tyrosine kinase-2 (TYK2) and IRF5 have also been shown to be closely related to SLE, and TYK2 binds to the IFN-1 receptor, and IRF5 regulates IFN-1 gene expression. This suggests that IFN-1 plays a central role in the development of SLE (Non-patent Document 13). In addition, IRF5 gene polymorphism has been found in patients with inflammatory bowel disease (IBD), and it has been reported that the polymorphism at the promoter position of IRF5 is closely related to IBD (Non-patent Document 14). It is known that type I diabetes (Non-Patent Document 15), IRF5 deficiency is also seen in RA patients (Non-Patent Documents 16 and 17), and is involved in autoimmune diseases such as Sjogren's syndrome (Non-Patent Document 18). It is known. Therefore, suppression of the expression of this gene is expected to have an effect as a preventive and / or therapeutic agent for autoimmune diseases.

  Cholesterol ester transfer protein (CETP (cholesteryl ester transfer protein)) is a very hydrophobic protein that transfers cholesterol ester from HDL cholesterol to LDL cholesterol and very low density lipoprotein (VLDL) cholesterol. By inhibiting it, it is possible to increase HDL cholesterol. For this reason, CETP inhibitors are dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper LDL, hypo HDL, hypercholesterolemia, hypertriglyceridemia Expected to be a therapeutic agent for diseases such as hypertension, familial hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension ing. As such compounds that inhibit CETP activity, for example, torcetrabib (patent document 3), anacetrapib (patent document 4), darcetrapib (patent document 5) and the like are known.

  On the other hand, it is known that CETP inhibitors are useful for suppressing the expression of NFKBIL1, ITGAX, FCER1A, PHACTR1 and IRF5 mRNA, enhancing the expression of TAT mRNA, and preventing and treating immune system diseases. Not.

Special Publication 2004-505637 International Publication No. 07/037299 International Publication No. 00/017164 International Publication No. 06/014357 International Publication No. 98/035937

J. Cell Biol., Sep; 111 (3): 941-53 (1990) Cell, 38: 523-534 (1984) Am. J. Hum. Genet., 72: 303-312 (2003) Immunogenetics., Jan; 57 (12): 893-903 (2006) New Eng. J. Med., 358: 900-909 (2008) Hum. Molec. Genet., 18: 2063-2070 (2009) J. Clin. Invest., 99: 901-914 (1997) Int. J. Immunogenet., 37 (2): 139 (2010,) Proc. Nat. Acad. Sci., 101: 7187-7192 (2004) DNA Res. 7: 347-355 (2000) J. Allergy Clin. Immunol., 121 (2, Suppl.): Abst 249 (2008) J. Biol. Chem., 276 (26): 23382 (2001) Am. J. Hum. Genet., 76: 528-537 (2005) Hum. Molec. Genet., 16: 3008-3016 (2007) J. Med. Genet., 44 (10): 670 (2007) Arthritis Rheum., 60 (1): 225 (2009) Arthritis Rheum., 58 (5): 1264 (2008) Genes. Immun., 10 (1): 68 (2009)

  An object of the present invention is to provide a preventive and / or therapeutic agent for immune system diseases. Another object of the present invention is to provide a preventive and / or therapeutic agent for immune system diseases by suppressing the expression of NFKBIL1, ITGAX, FCER1A, PHACTR1 and IRF5 mRNA, or by enhancing the expression of TAT mRNA.

  As a result of continuing intensive studies to achieve the above object, the inventors of the present invention are known as CETP inhibitors, compounds represented by the following general formula (I) or (II), or salts thereof, or These solvates have an excellent expression enhancing action on TAT mRNA, and also have an excellent expression suppressing action on NFKBIL1, ITGAX, FCER1A, PHACTR1 and IRF5 mRNA, and this substance is a TAT protein. It has been found that it has a production enhancing action and has a NFKBIL1, ITGAX, FCER1A, PHACTR1 and IRF5 protein production inhibitory action, and as a result, this substance is also useful for the prevention and treatment of immune system diseases. Was completed.

[In the formula (I), R ₁ represents a C _1-6 alkylthio C _1-6 alkyl group, a C _1-6 alkylsulfinyl C _1-6 alkyl group or a C _1-6 alkylsulfonyl C _1-6 alkyl group. ,
R ₂ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₃ represents a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₄ and R ₅ are the same or different from each other, and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, or a C _1-6 alkoxy group optionally substituted with a halogen atom. Or a cyano group,
R ₆ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may be substituted with a halogen atom;
In the formula (II), R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are the same or different from each other and are substituted with a hydrogen atom, a hydroxy group, a halogen atom or a halogen atom. It shows also a C _1-6 alkoxy group optionally substituted by also C _1-6 alkyl group or a halogen atom. ]

  That is, this invention relates to the invention shown below.

[1] An expression inhibitor of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient.
[2] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [1] The expression inhibitor according to [1].
[3] trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino ) Methyl] cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, or at least one compound thereof or a salt thereof, or a solvate thereof as an active ingredient The expression inhibitor as set forth in [1].
[4] (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl) )-[1,1′-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient, the expression suppression according to [1] Agent.

[5] A TAT mRNA expression enhancer comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient.
[6] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [5] The expression enhancer according to [5].
[7] trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino ) Methyl] cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, or at least one compound thereof or a salt thereof, or a solvate thereof as an active ingredient The expression enhancer according to [5].
[8] (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl) )-[1,1′-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient, the expression enhancement according to [5] Agent.

[9] A protein production inhibitor of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient.
[10] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [9] The protein production inhibitor according to [9].
[11] trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino ) Methyl] cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-y L} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, at least one compound or salt thereof, or a solvate thereof as an active ingredient The protein production inhibitor according to [9], comprising:
[12] (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl) )-[1,1′-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient, the protein production according to [9] Inhibitor.

[13] A TAT protein production enhancer comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient.
[14] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [13] The protein production enhancer according to [13].
[15] trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino ) Methyl] cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-y L} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, at least one compound or salt thereof, or a solvate thereof as an active ingredient The protein production enhancer according to [13], comprising:
[16] (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl) )-[1,1′-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient, the protein production according to [13] Enhancer.

[17] A preventive and / or therapeutic agent for immune system diseases comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient.
[18] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [17] The preventive and / or therapeutic agent for immune system diseases according to [17].
[19] trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino ) Methyl] cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-y L} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, at least one compound or salt thereof, or a solvate thereof as an active ingredient The preventive and / or therapeutic agent for immune system diseases according to [17], comprising:
[20] (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl) )-[1,1′-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient, the immune system according to [17] Disease prevention and / or treatment agent.
[21] The preventive and / or therapeutic agent according to [17], wherein the immune system disease is an allergic disease or an autoimmune disease.
[22] The preventive and / or therapeutic agent according to [17], wherein the immune system disease is hay fever, nasal allergy, airway hypersensitivity, systemic lupus erythematosus or rheumatoid arthritis.
[23] The preventive and / or therapeutic agent according to [22], wherein the nasal allergy is rhinitis.
[24] The prophylactic and / or therapeutic agent according to [22], wherein the airway hypersensitivity is asthma.

[25] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for suppressing the expression of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA.
[26] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [25] or a salt thereof, or a solvate thereof.
[27] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for enhancing expression of TAT mRNA.
[28] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [27] or a salt thereof, or a solvate thereof.
[29] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for suppressing protein production of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5.
[30] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [29] or a salt thereof, or a solvate thereof.
[31] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for enhancing TAT protein production.
[32] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. , [31] or a salt thereof, or a solvate thereof.
[33] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for the prevention and / or treatment of immune system diseases.
[34] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. , [33] or a salt thereof, or a solvate thereof.

[35] Use of a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for producing an expression inhibitor of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA.
[36] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [35] Use.
[37] Use of a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for the production of a TAT mRNA expression enhancer.
[38] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [37] Use.
[39] Use of a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof, for producing a protein production inhibitor of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5.
[40] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. , [39].
[41] Use of a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for the production of a protein production enhancer for TAT.
[42] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. , [41].
[43] Use of a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for the manufacture of an agent for preventing and / or treating an immune system disease.
[44] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [43] Use.

[45] A method for suppressing the expression of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[46] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [45] The expression suppression method according to [45].
[47] A method for enhancing expression of TAT mRNA, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[48] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [47] The method for enhancing expression.
[49] A method for inhibiting protein production of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[50] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [49] The method for inhibiting protein production according to [49].
[51] A method for enhancing protein production of TAT, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[52] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [51] The method for enhancing protein production according to [51].
[53] A method for preventing and / or treating an immune system disease, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[54] The compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is a compound represented by the formula (I) or (II) or a salt thereof, or a solvate thereof. [53] The method for preventing and / or treating an immune system disease according to [53].

  As a specific compound represented by the general formula (I) or (II), the compound (III) [trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ] Ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid] and (IV) [(4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)- [1,1′-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one] is more preferred.

  The CETP inhibitor has a strong expression enhancing action on TAT mRNA and is strongly expressed on NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA, as specifically disclosed in the Examples described later. Has an inhibitory effect. In addition, these compounds have TAT protein production enhancing action and have NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 protein production inhibitory action, so that they can be effectively used for prevention and / or treatment of immune system diseases. Can do.

It is a figure which shows the relative value of the TAT mRNA expression level of the cell which added the compound 2 or anacetrapib. It is a figure which shows the relative value of the IRF5 mRNA expression level of the cell which added the compound 2 or anacetrapib.

  The active ingredient of the medicament of the present invention is a compound having an activity of inhibiting CETP. Examples of such compounds include the compounds described in Patent Documents 3 to 5, the WO99 / 041237 pamphlet, the WO00 / 018721 pamphlet, the WO05 / 097805 pamphlet, the WO06 / 073973 pamphlet, and the WO08 / 079427 pamphlet. , WO08 / 129951 pamphlet, WO08 / 156718 pamphlet, WO09 / 007259 pamphlet, Bioorganic & Medicinal Chemistry Letters, 6, 1951-1954 (1996), Bioorganic & Medicinal Chemistry Letters, 15, 3611-3614 (2005), Bioorganic & Medicinal Chemistry Letters, 17, 2608-2613 (2007) and the like. Preferable examples include compounds represented by the general formula (I) or (II) or salts thereof, or solvates thereof, and anacetrapib.

  The compound represented by the general formula (I) is described in WO08 / 129951 pamphlet (Example 45), and can be produced by the method described in the document. Anacetrapib is described in the pamphlet of WO06 / 014357 (Example 73), and can be produced by the method described in the same document.

In the present specification, "C _1-6 alkylthio C _1-6 alkyl group, C _1-6 alkylsulfinyl C _1-6 alkyl group or a C _1-6 alkylsulfonyl C _1-6 alkyl group", "C _1-6 in “Alkyl” means linear or branched alkyl having 1 to 6 carbon atoms, preferably “C _1-3 alkyl”, more preferably “methyl or ethyl”. Examples of “C ₁ -C ₆ alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1 -Ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- Examples include dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl and the like.

In the present specification, examples of the “C ₁ -C ₆ alkylthio” of the “C _1-6 alkylthio C _1-6 alkyl group” include, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, 2-methylbutylthio, 1-ethylpropylthio, n-hexylthio, isohexylthio, 3-methylpentylthio, 2-methylpentyl Ruthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2, Examples include 3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio and the like.

In the present specification, examples of the “C ₁ -C ₆ alkylsulfinyl” of the “C _1-6 alkylsulfinyl C _1-6 alkyl group” include, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n- Butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, 2-methylbutylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, 3,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfin Nyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl and the like.

In this specification, the "C ₁ -C ₆ alkylsulfonyl" in the "C _1-6 alkylsulfonyl C _1-6 alkyl group", for example, methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n- Butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 2-methylbutylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl, 3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl, 1, Examples include 2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl and the like.

  In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.

In the present specification, the “C _1-6 alkyl group _optionally substituted with a halogen atom” means a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, isohexyl, Examples include trifluoromethyl, trichloromethyl, trifluoroethyl and the like. Preferably, it is “C _1-3 alkyl group _optionally substituted with a halogen atom”, more preferably “methyl or ethyl group optionally substituted with a halogen atom”.

In the present specification, the “C _1-6 alkoxy group which may be substituted with a halogen atom” means a linear or branched alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, trifluoromethoxy, trifluoroethoxy and the like. Preferably, it is “C _1-3 alkoxy group optionally substituted with a halogen atom”, more preferably “methoxy or ethoxy group optionally substituted with a halogen atom”.

  Examples of the compound represented by the general formula (I) or (II) include an optically pure isomer or any mixture of the above isomers, a racemate, any geometric isomer, or any mixture of geometric isomers, and the like. Any stereoisomer or any mixture thereof can be used.

  Examples of the stereoisomers of the compound represented by the general formula (I) include compounds represented by the following general formulas (I-1) and (I-2).

(In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as described above.)

  The compound represented by the general formula (I) or (II) includes all compounds which are metabolized in vivo and converted into the compound represented by the general formula (I) or (II), so-called prodrugs. The Examples of the group capable of forming a prodrug of the compound represented by the general formula (I) or (II) include, for example, “Progress in Medicine”, Life Science Medica, 1985, 5 Volumes, pages 2157-2161, and the groups described in Yodogawa Shoten 1990 "Pharmaceutical Development" Volume 7, Molecular Design pages 163-198.

Preferred compounds in the present invention include, for example,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (compound 1),
(S)-(-)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] Pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (compound 2),
(R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] Pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (compound 3), and (4S, 5R) -5- [3,5-bis (Trifluoromethyl) phenyl] -3-((4′-fluoro-5′-isopropyl-2′-methoxy-4- (trifluoromethyl)-[1,1′-biphenyl] -2-yl) methyl) -4-Methyloxazolidine-2-one (Compound 4)
The scope of the present invention is not limited to these compounds.

  Examples of the salt of the compound represented by formula (I) or (II) include acid addition salts and base addition salts, and are not particularly limited as long as they are pharmaceutically acceptable salts. For example, in the case of acid addition salts, acid addition salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, methanesulfonate And acid addition salts with organic acids such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. In addition, if it is a base addition salt, a base addition salt with a metal such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt; amine salt such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine; lysine, arginine And base addition salts with organic bases such as

  Examples of the solvent that forms a solvate of the compound represented by the general formula (I) or (II) or a salt thereof include water and physiologically acceptable organic solvents such as ethanol, hexane, and ethyl acetate. It can be mentioned, but is not limited to these. Examples of the active ingredient of the medicament of the present invention include, but are not limited to, hydrates and the like.

  The compound of general formula (I-1) (example: compound 2) or (I-2) (example: compound 3), which is an enantiomer of the compound represented by general formula (I) (example: compound 1), A method using a chiral column from a compound represented by the general formula (I) (example: compound 1) or a preferential crystallization method from a derivative of the compound represented by the general formula (I) (example: compound 1) After the fractionation, it can be produced by a method of inducing the compound of general formula (I-1) (example: compound 2) or (I-2) (example: compound 3).

  In the present specification, examples of the “immune system disease” include allergic diseases and autoimmune diseases.

  As used herein, the term “allergic disease” includes aspirin asthma, anaphylaxis, hay fever, airway hypersensitivity, asthma, nasal allergy, conjunctivitis, urticaria, atopy, and allergic diseases, metal allergy, drug hypersensitivity, Examples include mite allergy.

  As used herein, “autoimmune diseases” include Addison disease, Graves' disease, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, multiple sclerosis, optic neuromyelitis, encephalosclerosis, autoimmune lymphoproliferative syndrome , Type I diabetes, hemolytic anemia, and the like.

  The medicament containing the medicament of the present invention has a strong expression enhancing action on TAT mRNA, and has a strong expression suppressing action on NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA, and immune system It can be effectively used for prevention and / or treatment of diseases. As an immune system disease to which the compound of the general formula (I) or (II) can be applied, more preferable examples include allergic diseases and autoimmune diseases, and particularly preferable are nasal allergies such as hay fever and rhinitis. And airway hypersensitivity such as asthma, systemic lupus erythematosus, rheumatoid arthritis and the like.

  The medicament of the present invention contains the compound represented by the above general formula (I) or (II), or a salt thereof, or a solvate thereof as an active ingredient. Although the above-mentioned active ingredient itself may be administered as the medicament of the present invention, it can be preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art. Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. The pharmaceutical composition suitable for parenteral administration includes Examples include injections such as intravenous injections and intramuscular injections, drops, suppositories, inhalants, eye drops, nasal drops, transdermal absorbents, transmucosal absorbents, etc. It is not limited to.

  The above pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, binders, extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, Examples include, but are not limited to, flavoring agents, fragrances, coating agents, and diluents.

  The dosage of the pharmaceutical agent of the present invention is not particularly limited, and can be appropriately selected according to the type of disease, the purpose of prevention or treatment, the type of active ingredient, etc., and the patient's weight and age, symptoms, administration route, etc. It can be increased or decreased as appropriate according to various factors that should be normally considered. For example, in the case of oral administration, the weight of the compound represented by the compound according to the present invention per day for an adult can be used in the range of about 0.1 to 500 mg, but the dosage can be appropriately selected by those skilled in the art. However, the present invention is not limited to the above range.

EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform
¹ H-NMR: proton nuclear magnetic resonance

Production Example 1
Compound 1 used was prepared according to the method disclosed in Example 45 of WO 2008/129951. Moreover, what isolated the compound 1 by the fractionation using the chiral column of the following conditions was used for the compound 2 and the compound 3 which are both enantiomers of the compound 1.

Column: CHIRALCEL OD-H (4.6 × 250 mm)
Flow rate: 1.0 mL / min
Detector: UV 242nm
Temp. : 40 ° C
Mobile phase: Hexane / EtOH / TFA = 90/10 / 0.1
Retention time: (R)-(+)-form 21.3 min, (S)-(-)-form 23.7 min

Compound 2: (S)-(−)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid
¹ H-NMR (CDCl ₃ ) δ: 0.80-0.96 (7H, m), 1.38 (1 H.m), 1.47 (3H, d, J = 7.1 Hz), 1.65 -1.77 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.72 (1 H, m), 2.81-2.91 (3H, m), 3.08 (3H, s), 3.45 (2H, t, J = 5.4 Hz), 4.44 (2H, t, J = 5.4 Hz), 4.62 (1H, d, J = 17.1 Hz) , 4.86 (1H, d, J = 17.1 Hz), 6.21 (1 H, q, J = 7.1 Hz), 7.13 (1 H, d, J = 8.3 Hz), 7.19 ( 1H, s), 7.38 (1H, d, J = 8.3 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.15 (2H, s).
[Α] _D ²⁰ = −46.68 (c = 1.0, CHCl ₃ )

Compound 3: (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid
¹ H-NMR (CDCl ₃ ) δ: same as compound 2 [α] _D ²⁰ = + 48.92 (c = 1.0, CHCl ₃ )

Production Example 2: Production of substantially optically pure (S) compound 2 by the preferential crystallization method Substantially optically pure (S) by the preferential crystallization method carried out by the present inventors An outline of the production method of the body compound 2 is shown below as Scheme 1.
In addition, the absolute configuration of each compound was judged from the absolute configuration of (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane confirmed in Step 1.
In addition, (S) isomer compound 2 ((S) -trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} { The optical purity of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid) Determined by chiral HPLC analysis under the conditions described in 1.
Furthermore, 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane obtained in Step 1 and trans- {4-[({2-[({ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( The optical purity of ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester was determined by chiral HPLC analysis under the following conditions, respectively.

Conditions for chiral HPLC analysis of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane Column: CHIRALPAK AS-RH
Mobile phase: ethanol / water = 60/40
Flow rate: 0.5 mL / min
Column temperature: 25 ° C
Detection wavelength: 220 nm
Retention time: 1st peak / 21.8 min ((R) body), 2nd peak / 26.0 min ((S) body)

trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester chiral HPLC analytical condition column: CHIRALCEL OD-H
Mobile phase: hexane / ethanol = 80/20
Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Detection wavelength: 242 nm
Retention time: first peak / 11.3 min ((R) body), second peak / 13.0 min ((S) body)

Step 1: Preparation of (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (R) -1-Bromo-1- [3,5-bis (trifluoromethyl) Phenyl] ethane was produced by the following method 1- (a), and the absolute configuration thereof was confirmed as follows. That is, the obtained (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane was converted to (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethylamine. And comparing the sign of the measured value of specific rotation with a standard product of (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethylamine of known absolute configuration, which is commercially available Confirmed with.
In addition, (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane was also produced separately by the method 1- (b) below.

1- (a): Production of (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane, part 1
Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), and triphenylphosphine (6. 1 g, 23.2 mmol) was added and stirred for 30 minutes. To this was added a toluene solution (12.5 mL) of (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (1) (5.0 g, 19.4 mmol,> 99.5% ee). After dropwise addition at 0 ° C. over 10 minutes, the mixture was warmed to room temperature and stirred at the same temperature for 1 hour. N-Hexane (25 mL) was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The obtained residue was distilled under reduced pressure (56 ° C, 0.7 mmHg) to obtain 5.52 g of (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (2). Obtained as a colorless oil (yield: 88.6%).

Chiral HPLC analysis: optical purity> 99.5% ee (main peak: first peak), conversion ≧ 99%
[Α] _D ²⁵ +59.1 (c = 1.03, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 2.08 (3H, d, J = 7.1 Hz), 5.21 (1H, q, J = 7.1 Hz), 7.81 (1H, s), 7 .87 (2H, s)

Confirmation of absolute configuration of (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (R) -1-Bromo-1- [obtained in 1- (a) above 3,5-bis (trifluoromethyl) phenyl] ethane (2) (106 mg, 0.336 mmol, 99% ee) in N, N-dimethylformamide (1 mL) and sodium azide (64.4 mg, 0.990 mmol). ) And stirred at -18 to -15 ° C for 4 hours. The reaction solution was extracted from ethyl acetate / n-hexane (1: 1) and water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 111.5 mg of 1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl azide (crude product: 111.5 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.61 (3H, d, J = 6.8 Hz), 4.79 (1H, q, J = 6.8 Hz), 7.78 (2H, s), 7 .84 (1H, s)

  The obtained 1- [3,5-bis (trifluoromethyl) phenyl] ethyl azide (crude product: 111.5 mg) was dissolved in methanol (6 mL), palladium-fibroin (18 mg) was added and the atmosphere was replaced with hydrogen. For 1 hour. The residue obtained by filtering through Celite and concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 50: 1 to 5: 1) to obtain 77.6 mg of 1- [3,5-bis. (Trifluoromethyl) phenyl] ethylamine was obtained as a colorless oil (yield: 91%, 2 steps).

¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 6.8 Hz), 1.58 (2H, br-s), 4.30 (1H, q, J = 6.8 Hz) , 7.75 (1H, s), 7.85 (2H, s)

The specific rotation of the obtained 1- [3,5-bis (trifluoromethyl) phenyl] ethylamine was as follows.
[Α] _D ²⁵ -15.9 (c = 1.31, CHCl ₃ )

On the other hand, the specific rotation of a commercially available standard product ((S) -1- [3,5-bis (trifluoromethyl) phenyl] ethylamine (manufactured by Central Glass Co., Ltd .: Lot. 0102000: optical purity: 99% ee) is It was as follows.
[Α] _D ²⁵ -15.9 (c = 1.15, CHCl ₃ )

  Since the sign of the measured value of specific rotation coincided with the sign of a commercially available standard product, the obtained 1- [3,5-bis (trifluoromethyl) phenyl] ethylamine may be in the (S) form. confirmed. Since the amine is obtained from 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane through a nucleophilic substitution reaction of an azide ion, the above 1- (a) It was confirmed that the obtained 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane was an (R) isomer.

1- (b): Production of (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane, part 2
Phosphorus tribromide in an atmosphere of (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (1) (300 g, 1.16 mol, 96% ee) in a water bath at 20 ° C. or lower. (157.3 g, 0.58 mol) was added dropwise and stirred at 19-22 ° C. for 30 minutes. The reaction solution was cooled, hydrogen bromide (30% acetic acid solution) (228 mL, 1.16 mol) was added dropwise at 0 ° C. or lower, and the mixture was stirred at 13-15 ° C. for 16 hours. The reaction solution was poured into ice water and extracted with n-hexane (3 L × 2). The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate (3 L) and saturated brine (3 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure (90-100 mmHg) to obtain 389.2 g of a crude product. The obtained crude product was purified by column chromatography (silica gel 900 g, developing solvent: n-hexane) to obtain 349.8 g of (R) -1-bromo-1- [3,5-bis (trifluoromethyl). ) Phenyl] ethane (2) was obtained as a colorless oil (93.8% yield).
In addition, since the first peak appeared as a main peak in chiral HPLC analysis as described below, 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane produced in 1- (b) As in 1- (a), it was confirmed to be (R) isomer.

Chiral HPLC analysis: optical purity> 93.9% ee (main peak: first peak), conversion 97.8%
¹ H-NMR (CDCl ₃ ) δ: 2.08 (3H, d, J = 7.1 Hz), 5.21 (1H, q, J = 7.1 Hz), 7.81 (1H, s), 7 .87 (2H, s)

Step 2: trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, production of (S) -dominant semi-chiral isomer under argon atmosphere, Patent Document 2 (International Publication No. 2008/129951) Trans- [4-([(ethyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (tri Fluoromethyl) phenyl} amino] methyl) cyclohexyl] ethyl acetate (3) (565.4 g, 0.99 mol) in anhydrous tetrahydrofuran (THF, 2 .26 L) NaH (60% in oil, 119 g, 2.98 mol) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to −30 ° C., and (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (2) (682 g, 1.99 mol, obtained in Step 1) was obtained. A solution of 93.9% ee) in anhydrous N, N-dimethylformamide (4.53 L) was added dropwise so that the inside of the reaction system was −15 ° C. or lower, and the mixture was stirred at −15 ° C. to −1 ° C. for 5 hours. The reaction solution was poured into a mixed solution of ice water (35 L) and toluene (30 L), citric acid was added until the pH reached 6.9, and the organic layer was separated.

  The aqueous layer was extracted twice with toluene (20 L), and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethanol (8 L), 2M NaOH aqueous solution (1.24 L, 2.48 mol) was added under ice cooling, and the mixture was stirred at 50 ° C. for 3.5 hours. 1M HCl aqueous solution was added to the reaction solution under ice cooling until pH 5.4, poured into water (25 L), and extracted twice with ethyl acetate (22 L). The organic layer was washed with saturated brine (12 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (silica gel 21 g, developing solvent: heptane / acetone = 7/1 → 3/1). ) -Trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Il} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (4) was obtained (yellow oil, 744.1 g, yield 96%). .

  In addition, (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (2) whose absolute configuration was confirmed as described in Step 1 above was used as a raw material, and amine ( Since the nucleophilic substitution reaction according to 3) proceeds, the obtained semichiral body (4) is predominantly the (S) body.

¹ H-NMR (CDCl ₃ ) δ: 0.85-0.96 (7H, m), 1.35-1.45 (4H, m), 1.60-1.78 (5H, m), 2 18-2.21 (5H, m), 2.69 (1H, m), 2.81-2.91 (5H, m), 4.16 (2H, q, J = 6.8 Hz), 4 .61 (1H, d, J = 17.1 Hz), 4.85 (1H, d, J = 17.1 Hz), 6.22 (1H, q, J = 6.8 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.23 (1H, s), 7.37 (1H, d, J = 8.3 Hz), 7.70 (1H, s), 7.73 (2H, s) , 8.14 (2H, s)

Step 3: trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester, production of (S) -dominant semi-chiral isomer trans- obtained in step 2 under argon atmosphere {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl]- 4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S) -dominant semi-chiral product (4) (744.1 g, 0.95 mol) Benzyl alcohol (113.1 g, 1.05 mol), WSC · HCl (200.5 g, 1.05 mol) and DMAP (11.9 g, 98 mmol) were added to a water dichloroethane (11.6 L) solution under ice cooling, Stir at room temperature overnight. Water (10 L) was added to the reaction mixture, and the mixture was extracted with chloroform (19 L, 14 L). The organic layer was washed with saturated brine (12 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purification by column chromatography (silica gel 28 g, developing solvent: heptane / ethyl acetate = 6/1), trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl ) Phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester (5) was obtained (yellow oil, 745.8 g, yield 90%).

  In addition, the obtained semi-chiral body (5) is superior to the (S) body in the same manner as the semi-chiral body (4).

¹ H-NMR (CDCl ₃ ) δ: 0.87-0.95 (7H, m), 1.37 (1H.m), 1.43 (3H, d, J = 7.1 Hz), 1.65 -1.77 (5H, m), 2.20 (2H, d, J = 6.8 Hz), 2.22 (3H, s), 2.66-2.71 (2H, m), 2.82 -2.91 (4H, m), 4.15 (2H, t, J = 6.6 Hz), 4.62 (1H, d, J = 17.1 Hz), 4.85 (1H, d, J = 17.1 Hz), 5.10 (2H, s), 6.21 (1H, q, J = 7.1 Hz), 7.10 (1H, d, J = 8.3 Hz), 7.22 (1H, s), 7.28-7.38 (6H, m), 7.70 (1H, s), 7.73 (2H, s), 8.14 (2H, s)

Step 4: trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester, (S) isomer-dominant semi-chiral isomer production trans obtained in step 3 under argon atmosphere -{4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (Trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester, (S) -dominant semi-chiral product (5) (745.8 g) 0.87 mol) in 2-propanol (15.2 L), tantalum pentachloride (31.3 g, 87.3 mmol) and 30% aqueous hydrogen peroxide (496 mL, 4.38 mol) were added, and the mixture was stirred at room temperature for 5 hours. Stir for hours. The reaction solution was quenched with saturated aqueous sodium hydrogen sulfite solution (3.1 L), water (15 L) was added, extracted with chloroform (14 L, 12 L), the organic layer was washed with saturated brine (20 L), and anhydrous magnesium sulfate The resulting residue was purified by column chromatography (silica gel 26 kg, developing solvent: heptane / ethyl acetate = 3/1 → 2/1), thereby trans- {4-[({ 2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoro Methyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester semi-chiral product (6) was obtained (yellow amorphous, 619.5 g, Rate 79%).

  In addition, as for the obtained semichiral body (6), (S) body is dominant like a semichiral body (4) and a semichiral body (5).

Chiral HPLC analysis: optical purity 67.7% ee (main peak: second peak)
¹ H-NMR (CDCl ₃ ) δ: 0.87-0.96 (7H, m), 1.38 (1 H.m), 1.45 (3H, d, J = 7.1 Hz), 1.65 -1.80 (5H, m), 2.21 (2H, d, J = 6.6 Hz), 2.69 (1H, m), 2.81-2.91 (3H, m), 3.08 (3H, s), 3.44 (2H, t, J = 5.4 Hz), 4.44 (2H, t, J = 5.4 Hz), 4.64 (1H, d, J = 17.1 Hz) , 4.86 (1H, d, J = 17.3 Hz), 5.10 (2H, s), 6.19 (1H, q, J = 6.9 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.19 (1H, s), 7.30-7.39 (6H, m), 7.71 (1H, s), 7.72 (2H, s), 8.16 (2H) , S)

Step 5: Substantially optically pure (S) -trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2 Preparation of-(Methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester trans- { 4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl]- 4- (Trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester, (S) -dominant semi-chiral product (6) (111.7 g, 123.7) mmol, 67.7% ee) is dissolved in ethanol (825 mL), and 2.0 mg of separately prepared seed crystals (racemic crystals produced in Step 7 below) are added at 15 ° C. to 20 ° C. at the same temperature. The mixture was stirred for 21 hours at 0 ° C. for 3 hours. The precipitate was filtered off, washed with cold ethanol (165 mL), and the mother liquor was concentrated under reduced pressure to give substantially optically pure trans- {4-[({2-[({1- [3 , 5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) Methyl] cyclohexyl} acetic acid benzyl ester (7) was obtained (yellow amorphous, 66.38 g, yield 59%).
The obtained trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine-2 -Il} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester (7) is from (S) -dominant semi-chiral (6) to racemic-dominant Since it is obtained by filtering the crystals, it is the (S) form.

Chiral HPLC analysis: optical purity> 99% ee (main peak: second peak)
[Α] _D ²⁰ −42.36 (c = 1.0 w / v%, CHCl ₃ )

  As a result of chiral HPLC analysis, the optical purity of the racemate-predominant crystal separated by filtration was 22% ee (43.39 g, yield 39%).

Step 6: Substantially optically pure (S) -trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid Obtained in step 5 under nitrogen atmosphere ( S) -trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester (7) (34.2 g, 37.88 mmol,> 99% ee) 10% Pd-C (wet) (3.4 g) was added to an ethanol (340 mL) solution, and after hydrogen substitution, the mixture was stirred at room temperature for 2 hours. The reaction suspension was filtered through Celite, washed with ethanol (50 mL), and the washing was concentrated under reduced pressure to give substantially optically pure trans- {4-[({2-[({1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino ) Methyl] cyclohexyl} acetic acid (compound 2) was obtained (white amorphous, 31.78 g, 100% yield).
In addition, the obtained compound was a levorotatory compound as shown in the following specific rotation. Moreover, since the obtained compound was obtained by deprotecting the ester from the benzyl ester (7) which is the (S) form, it is similarly the (S) form.

Chiral HPLC analysis: optical purity> 99% ee (main peak: second peak)
[Α] _D ²⁰ −46.68 (c = 1.0, CHCl ₃ )
IR (ATR) cm ⁻¹ : 2921, 1706, 1479, 1279, 1134
¹ H-NMR (CDCl ₃ ) δ: 0.80-0.96 (7H, m), 1.38 (1 H.m), 1.47 (3H, d, J = 7.1 Hz), 1.65 -1.77 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.72 (1 H, m), 2.81-2.91 (3H, m), 3.08 (3H, s), 3.45 (2H, t, J = 5.2 Hz), 4.44 (2H, q, J = 5.4 Hz), 4.62 (1H, d, J = 17.1 Hz) , 4.86 (1H, d, J = 17.4 Hz), 6.21 (1H, q, J = 7.1 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.19 ( 1H, s), 7.38 (1H, d, J = 6.6 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.15 (2H, s)

Step 7: trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl } Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} production of racemic seed crystals of benzyl ester Patent Document 2 (International Publication No. 2008/129951) Example 45 Trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- synthesized by the described method 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (racemic compound) (I)) (20 g, 24.61 mmol) in anhydrous dichloromethane (200 mL) under ice-cooling, benzyl alcohol (2.93 g, 27.07 mmol), DMAP (300 mg, 2.46 mmol) and WSC · HCl (5 .19 g, 27.07 mmol) was added, the temperature was raised to room temperature, and the mixture was stirred for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (500 mL). The organic layer was washed with 2M aqueous hydrochloric acid (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 350 g, developing solvent: N-hexane / ethyl acetate = 3/1 → 1/1), whereby trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) Amino) methyl] cyclohexyl} acetic acid benzyl ester (21.15 g, 95.2% yield) was obtained as a white amorphous.

  The resulting white amorphous trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid benzyl ester (7.9 g) is dissolved in ethanol (40 mL) and stirred at room temperature for 15 hours. The precipitate obtained by the above is collected by filtration, washed with cold ethanol (20 mL), and dried under reduced pressure at 60 ° C. for 4 hours, thereby trans- {4-[({2-[({1- [3,5 -Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) Give Eniru} (ethyl) amino) methyl] cyclohexyl} racemate crystals of acetic acid benzyl ester (white crystalline powder, 6.98 g, recovery rate 88.4%) of.

  In Production Example 2, a compound having a medium optical purity (a compound having an optical purity of about 50 to 90% ee, preferably about 70 to 90% ee, obtained as a result of a decrease in optical purity by partial racemization. Is further referred to as a “semi-chiral body.” In addition, in the semi-chiral body, when an asymmetric carbon atom in an S configuration is present in an excessive amount as compared with a compound in an R configuration, the “(S) body-dominated semi-chiral body” It is called.

Test example 1
A test compound group was added to HepG2 cells, a human hepatoma cell line, and TAT and IRF5 mRNA expression levels after 24 hours of culture were measured by real-time RT-PCR. In other words, HepG2 cells are seeded in a 24-well plate at a concentration of 2 × 10 ⁵ cells / well, cultured overnight, and then anacetrapib is added to dimethyl sulfoxide (DMSO) so that the test compound 2 is 0.1 μM, 1 μM, and 10 μM. It melt | dissolved so that it might become 1 micromol and 10 micromol, and added 1/1000 time amount with respect to the culture solution. After culturing at 37 ° C. for 24 hours in a CO ₂ incubator, 500 μL of ISOGEN (Nippon Gene, catalog number 31-02501) was added, and total RNA was extracted. CDNA was synthesized from the extracted total RNA using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems, catalog number 4368813). Human TAT and IRF5 mRNA expression levels were determined using TaqMan Gene Expression Assay (Applied Biosystems, catalog number Hs00356930_m1, Hs00158114_m1) and TaqMan Fast Universal PCR Master Mix (Applied Biosystems, catalog number 4436486) for human TAT and IRF5. It was measured. The measuring instrument was a 7900HT Fast Realtime PCR system.

  The measured value was corrected by the expression level of β-Actin mRNA, the TAT and IRF5 mRNA expression levels of the cells added with DMSO alone were 1, and the TAT and IRF5 mRNA expression levels of the cells added with the test compound 2 or anacetrapib were relative Calculated by value. The results are shown in FIGS.

Test example 2
A test compound group was added to HepG2 cells, a human hepatoma cell line, and the gene expression profile after 24 hours of culture was measured with a DNA microarray from Agilent. That is, after seeding HepG2 cells in a 24-well plate at a concentration of 2 × 10 ⁵ cells / well and culturing overnight, the test compound 2 is 10 μM in dimethyl sulfoxide (DMSO) so that the test compound 2 becomes 1 μM and 10 μM. The resultant was dissolved and added in an amount of 1/1000 of the culture solution. After culturing at 37 ° C. for 24 hours in a CO ₂ incubator, 500 μL of ISOGEN (Nippon Gene, catalog number 31-02501) was added, and total RNA was extracted. Cy3-labeled cRNA was synthesized from 200 ng of RNA using Low Input Quick Amp Labeling Kit (Agilent, catalog number 5190-2308). The synthesized Cy3-labeled cRNA was hybridized to Whole Human Genome (4 × 44K) (Agilent, catalog number G4110F) using GE Hybridization Buffer HI-RPM (Agilent, catalog number 5190-0403). After hybridization, the DNA microarray was washed with Gene Expression Wash Buffer (Agilent, catalog number 5188-5327), and the data was read with a scanner (Agilent). The analysis was performed using GeneSpring (Agilent).

The analysis was performed using GeneSpring (Agilent), and the change rate of each gene expression level was calculated.
(Change rate) = (Each gene expression level in compound-treated cells) / (Each gene expression level in compound-untreated cells)
The results are shown in Table 1.

  From the above pharmacological test results, the compound of the general formula (I) or (II) has a strong and sustained TAT mRNA expression enhancing action, and the expression of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA It became clear that it has an inhibitory action.

  CETP inhibitor or a drug containing the same has a strong expression enhancing action on TAT mRNA and a strong expression suppressing action on NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA, and immune system Since it is useful for the prevention and / or treatment of diseases, it has industrial applicability.

Claims (24)

  An expression inhibitor of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5 mRNA comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient. A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof has the following formula (I) or (II):
[In the formula (I), R ₁ represents a C _1-6 alkylthio C _1-6 alkyl group, a C _1-6 alkylsulfinyl C _1-6 alkyl group or a C _1-6 alkylsulfonyl C _1-6 alkyl group. ,
R ₂ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₃ represents a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₄ and R ₅ are the same or different from each other, and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, or a C _1-6 alkoxy group optionally substituted with a halogen atom. Or a cyano group,
R ₆ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may be substituted with a halogen atom;
In the formula (II), R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are the same or different from each other and are substituted with a hydrogen atom, a hydroxy group, a halogen atom or a halogen atom. It shows also a C _1-6 alkoxy group optionally substituted by also C _1-6 alkyl group or a halogen atom. ]
The expression inhibitor of Claim 1 which is a compound represented by these, its salt, or those solvates.   trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [3,5 -Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] Cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-yl} ami No) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, or a solvate thereof, or at least one compound selected from the group consisting of The expression inhibitor according to claim 1.   (4S, 5R) -5- [3,5-Bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)-[ The expression inhibitor according to claim 1, comprising 1,1'-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient.   A TAT mRNA expression enhancer comprising, as an active ingredient, a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof. A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof has the following formula (I) or (II):
[In the formula (I), R ₁ represents a C _1-6 alkylthio C _1-6 alkyl group, a C _1-6 alkylsulfinyl C _1-6 alkyl group or a C _1-6 alkylsulfonyl C _1-6 alkyl group. ,
R ₂ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₃ represents a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₄ and R ₅ are the same or different from each other, and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, or a C _1-6 alkoxy group optionally substituted with a halogen atom. Or a cyano group,
R ₆ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may be substituted with a halogen atom;
In the formula (II), R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are the same or different from each other and are substituted with a hydrogen atom, a hydroxy group, a halogen atom or a halogen atom. It shows also a C _1-6 alkoxy group optionally substituted by also C _1-6 alkyl group or a halogen atom. ]
The expression enhancer of Claim 5 which is a compound represented by these, its salt, or those solvates.   trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [3,5 -Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] Cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-yl} ami No) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, or a solvate thereof, or at least one compound selected from the group consisting of The expression enhancer according to claim 5.   (4S, 5R) -5- [3,5-Bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)-[ The expression enhancer according to claim 5, comprising 1,1'-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient.   A protein production inhibitor of NFKBIL1, ITGAX, FCER1A, PHACTR1 and / or IRF5, comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient. A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof has the following formula (I) or (II):
[In the formula (I), R ₁ represents a C _1-6 alkylthio C _1-6 alkyl group, a C _1-6 alkylsulfinyl C _1-6 alkyl group or a C _1-6 alkylsulfonyl C _1-6 alkyl group. ,
R ₂ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₃ represents a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₄ and R ₅ are the same or different from each other, and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, or a C _1-6 alkoxy group optionally substituted with a halogen atom. Or a cyano group,
R ₆ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may be substituted with a halogen atom;
In the formula (II), R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are the same or different from each other and are substituted with a hydrogen atom, a hydroxy group, a halogen atom or a halogen atom. It shows also a C _1-6 alkoxy group optionally substituted by also C _1-6 alkyl group or a halogen atom. ]
The protein production inhibitor of Claim 9 which is a compound represented by these, its salt, or those solvates.   trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [3,5 -Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] Cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-yl} ami No) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, or a solvate thereof, or at least one compound selected from the group consisting of The protein production inhibitor according to claim 9.   (4S, 5R) -5- [3,5-Bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)-[ The protein production inhibitor according to claim 9, comprising 1,1'-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient.   A TAT protein production enhancer comprising a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient. A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof has the following formula (I) or (II):
[In the formula (I), R ₁ represents a C _1-6 alkylthio C _1-6 alkyl group, a C _1-6 alkylsulfinyl C _1-6 alkyl group or a C _1-6 alkylsulfonyl C _1-6 alkyl group. ,
R ₂ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₃ represents a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₄ and R ₅ are the same or different from each other, and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, or a C _1-6 alkoxy group optionally substituted with a halogen atom. Or a cyano group,
R ₆ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may be substituted with a halogen atom;
In the formula (II), R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are the same or different from each other and are substituted with a hydrogen atom, a hydroxy group, a halogen atom or a halogen atom. It shows also a C _1-6 alkoxy group optionally substituted by also C _1-6 alkyl group or a halogen atom. ]
The protein production enhancer of Claim 13 which is a compound represented by these, its salt, or those solvates.   trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [3,5 -Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] Cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-yl} ami No) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, or a solvate thereof, or at least one compound selected from the group consisting of The protein production enhancer according to claim 13.   (4S, 5R) -5- [3,5-Bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)-[ The protein production enhancer according to claim 13, comprising 1,1'-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient.   A preventive and / or therapeutic agent for immune system diseases comprising a compound having cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient. A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof has the following formula (I) or (II):
[In the formula (I), R ₁ represents a C _1-6 alkylthio C _1-6 alkyl group, a C _1-6 alkylsulfinyl C _1-6 alkyl group or a C _1-6 alkylsulfonyl C _1-6 alkyl group. ,
R ₂ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₃ represents a C _1-6 alkyl group which may be substituted with a halogen atom,
R ₄ and R ₅ are the same or different from each other, and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, or a C _1-6 alkoxy group optionally substituted with a halogen atom. Or a cyano group,
R ₆ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may be substituted with a halogen atom;
In the formula (II), R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are the same or different from each other and are substituted with a hydrogen atom, a hydroxy group, a halogen atom or a halogen atom. It shows also a C _1-6 alkoxy group optionally substituted by also C _1-6 alkyl group or a halogen atom. ]
The preventive and / or therapeutic agent for immune system diseases according to claim 17, which is a compound represented by the formula:   trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, (S)-(−)-trans- {4-[({2-[({1- [3,5 -Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] Cyclohexyl} acetic acid and (R)-(+)-trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-yl} ami No) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid, or a solvate thereof, or at least one compound selected from the group consisting of The preventive and / or therapeutic agent for an immune system disease according to claim 17.   (4S, 5R) -5- [3,5-Bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)-[ 18. Prevention of immune system diseases according to claim 17, comprising 1,1′-biphenyl] -2-yl) methyl) -4-methyloxazolidine-2-one or a salt thereof, or a solvate thereof as an active ingredient. And / or therapeutic agent.   The preventive and / or therapeutic agent according to claim 17, wherein the immune system disease is an allergic disease or an autoimmune disease.   The preventive and / or therapeutic agent according to claim 17, wherein the immune system disease is hay fever, nasal allergy, airway hypersensitivity, systemic lupus erythematosus or rheumatoid arthritis.   The preventive and / or therapeutic agent according to claim 22, wherein the nasal allergy is rhinitis.   The preventive and / or therapeutic agent according to claim 22, wherein the airway hypersensitivity is asthma.