JP2013116863A - EXPRESSION SUPPRESSOR OR EXPRESSION ENHANCER OF VARIOUS mRNA, AND PROPHILAXIS AND/OR THERAPEUTIC AGENT OF NEOPLASTIC DISEASE - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic and/or preventive agent of neoplastic diseases.SOLUTION: This agent is a compound expressed by formula (I). In formula, Rto Reach represents a specific substituent group.

Description

  The present invention includes HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN, CYP19A1 DNMT3L and / or MMP11 mRNA expression inhibitor, PCDH8 and / or EMP1 mRNA expression enhancer, and tumor diseases The present invention relates to a preventive and / or therapeutic agent.

  A tumor refers to a group of neoplastic cells that are relatively independent of a living body, and is generated when genetic information is not normally expressed. This is called a neoplastic disease. A tumor that has just started or has metastasized is a population of several cells. This is a benign tumor that stops growing at a certain size, and a malignant tumor that does not stop growing. Is called cancer, and a malignant tumor that occurs in other cells is called sarcoma. The number of deaths due to tumors in Japan increased 5.5 times from 32670 in 1950 to 179140 in 2000, and 3.6 times from 31758 to 116344 in girls. The expected number of deaths per year is 200,000 males and 130,000 females (Non-Patent Document 1). In recent years, the number of deaths from gastric cancer has shown a tendency to decrease from stagnation, but the number of deaths from tumors at other sites has been increasing. In addition, the ideal of chemotherapeutic drugs (hereinafter referred to as anticancer agents), which is one of the methods for treating tumors, is to destroy only tumor cells as targets, but such drugs are not known at present.

  In addition, it is said that one in two national boys and one in three girls suffered from cancer during their lifetime, and one in three people died of cancer. It is difficult to say that the level of satisfaction has been reached. As a means of reducing cancer mortality, improvement of lifestyle habits and early detection may be effective, but it is expected that it will take a considerable amount of time to prove its effectiveness, and improvement in treatment results will reduce cancer mortality. Therefore, the development of an effective cancer therapeutic agent is strongly desired.

  Homeobox A6 (HOXA6) is a gene encoding homeobox A6, which is a sequence-specific transcription factor of the Antp homeobox family involved in morphogenesis and differentiation (GenBank accession number: NM_024014). Self-healing of hematopoietic stem cells and hematopoietic progenitor cells depends on the homeobox gene, and although overexpression of homeobox6 in hematopoietic stem cells causes abnormal growth, the effect on differentiation is negligible, so it is necessary to control homeobox expression It has been reported that leukemia occurs when an abnormality occurs (Non-patent Document 2). Therefore, suppression of HOXA6 expression is expected to have a therapeutic effect on hematopoietic tumors such as leukemia.

  Goosecoid (GSC) is a gene encoding a goosecoid protein, which is a protein having an organogenic ability (GenBank accession number: NM — 173849). It has been reported that when GSC is highly expressed in breast cancer and abnormally expressed ectopically, it contributes to metastatic ability such as epithelial hepatic lobe migration, and is particularly involved in metastasis to the lung (Non-patent Document 3). Therefore, suppression of GSC expression is expected to have an effect on suppression of cancer metastasis.

  Protocadherin 8 (PCDH8) is a gene encoding Protocadherin8, a calcium-dependent glycoprotein that functions in cell adhesion, and is known to be expressed in the fetus and adult brain (GenBank accession number: NM_002590) . In mantle cell lymphoma and renal cell carcinoma, it has been reported that genes such as PCDH8 are methylated (Non-patent Document 4), and that the decreased expression of PCDH8 promotes human carcinogenesis (Non-patent Document 5). ), PCDH8 expression promotion is expected to prevent carcinogenesis.

  Gastrin (GAST) is a gene encoding gastrin, which is a hormone that stimulates gastric acid secretion in the gastric mucosa and digestive enzyme secretion in the pancreas (GenBank accession number: NM_000805). It is also known to cause mitosis in the gastrointestinal mucosa and participate in proliferative diseases. GAST is expressed in gastric cancer, colon cancer, pancreatic cancer, and esophageal cancer. It has been reported that GAS inhibits apoptosis through PKB / Akt activation and exacerbates esophageal adenocarcinoma (Non-patent Document 6). Considering these, it is expected that if the expression of GAST is suppressed, a therapeutic effect for neoplastic diseases is brought about.

  Single-minded homolog 2 (SIM2) is a gene that is distributed in the brain and encodes a transcription factor single-minded homolog 2 involved in nerve catabolism and development (GenBank accession number: NM_009586). SIM2 is located on chromosome 21 which is a factor of Down syndrome when trisomy occurs. A variant of the SIM2 protein encodes the shortest isoform containing another C-terminus encoded by part of intron 10 and is overexpressed in colorectal, prostate, and pancreatic cancers, and It is known to be involved in the onset (Non-patent Document 7). In addition, it has been reported that when an antisense targeting SIM2 is administered to human colon cancer xenograft nude mice, the growth of cancer is suppressed (Patent Document 1). Taking these into consideration, suppression of SIM2 expression is expected to produce a therapeutic effect for neoplastic diseases.

  Cyclin D2 (CCND2) is a gene well known to be associated with cancer (GenBank accession number: NM_001759). The CCDN2 protein encoded by this gene regulates phosphorylation of CDK4,6 protein and tumor suppressor protein Rb during the G1 / S phase transition of white blood cells. CCDN2 knockout mice die from heart disease and anemia during mid- to late gestation, so CCDN2 is essential for the development of hematopoietic stem cells, and when CCDN2 is lowly expressed, it is less likely to cause oncogenic transformation (Non-Patent Document 8). Taking these into consideration, suppression of CCDN2 expression is expected to bring about a therapeutic effect on neoplastic diseases.

  Insulin receptor substrate 4 (IRS4) is a gene encoding protein IRS4 that mediates between tyrosine kinase activity and growth factors, as well as between the SH2 domain and intracellular signaling molecules (GenBank accession number: NM_003604). Insulin receptors are tyrosine kinases that phosphorylate intracellular substrates, which are activated by the binding of insulin. Furthermore, as a function of the insulin receptor, when observing mutant animals of the Drosophila homologue of the IRS family, it was found that the degree of growth of the homozygote was slower than that of the heterozygote, thereby controlling cell size and growth. Has been reported (Non-Patent Document 9). Furthermore, it has been reported that IRS4 is overexpressed in T cell acute lymphocytic leukocytes and is involved in cell proliferation, suggesting that overexpression of IRS4 may exacerbate T cell acute lymphocytic leukocytes. (Non-Patent Document 10). Considering these, it is expected that the suppression of IRS4 expression may have a therapeutic effect on lymphoproliferative diseases.

  Fibroblast growth factor 7 (FGF7) is a gene encoding FGF7 protein, which is a keratinocyte growth factor involved in epithelial morphogenesis, wound healing, and hair growth (Non-patent Document 26, GenBank accession number: NM_002009). FGF7 is a mitogenic factor for epithelial tissues.When FGF7 expression was observed in healthy individuals and those with stomach diseases, FGF7 protein, FGF7 mRNA and antisense RNA were highly expressed in gastritis patients and gastric adenocarcinoma patients. Turned out to be. This has been reported to suggest that the protein level is controlled after transcription, and that FGF7 is involved in cancer progression and metastasis (Non-patent Document 11). Furthermore, FGF7 protein is expressed in the nasal epithelium / parenchyma, leukocytes, and macrophages of nasal polyp patients, and is suggested to be involved in the progression of this disease (Non-patent Document 12). Considering these, it can be expected that the suppression of FGF7 expression has a therapeutic effect on neoplastic diseases.

Transient receptor potential cation channel, subfamily M, member 2 (TRPM2) is a TRPM family gene in the TRP superfamily and is specifically activated by adenosine diphosphate ribose (ADPR). (Non-patent Document 13). TRPM2 is a temperature receptor distributed in the pancreas, a multimodal signal that regulates Ca ²⁺ mobilization in β-cells through membrane depolarization, Ca ²⁺ influx, and Ca ²⁺ release from intracellular storage sites Known as a transfer element. Monocytes and macrophages have been reported to be involved in chemokine production by recognizing reactive oxygen species and opening Ca ²⁺ channels, and suppression of TRPM2 expression has a therapeutic effect on inflammatory diseases (Non-Patent Document 14). In addition, it has been reported that when TRPM2 is knocked down with siRNA in prostate cancer, the growth of cancer cells is suppressed and is essential for cancer proliferation (Non-patent Document 15). Considering these, it is expected that suppression of TRPM2 expression will show a therapeutic effect on neoplastic diseases.

  Fatty acid synthase (FASN, FAS) is known to be overexpressed in cancer. FAS protein is an enzyme that synthesizes palmitic acid from acetyl-CoA and malonyl-CoA, and is known to induce apoptosis (Non-patent Document 16). While cancer progression, FASN expression is reduced and is involved in resistance to apoptosis, but FASN is rarely lost completely, and many cancer cells are highly sensitive to FASN in vitro. It is known that cancer patients also have an increase in FASN ligand. Recently, it has been reported that the growth of cancer cells requires constant FASN activation via JNK by the FASN ligand produced by the cancer cell, and FASN deficiency is the cause of cancer development in uterine cancer and liver cancer model mice. It was shown to suppress growth (Non-patent Document 17).

  Cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1) is a gene encoding aromatase (GenBank accession number: NM_000103). Aromatase is an enzyme that catalyzes the rate-limiting step in the conversion of androgen to estrogen, and is distributed in muscle, adipose tissue, blood vessels, center, bone, placenta, ovary, cancer cells, fibroblasts, etc. (Annu. Rev. Pharm. Toxicol. 26: 333-369, 1986). Aromatase inhibitors and aromatase antagonists are widely used as breast cancer treatments, but recently, aromatase protein and mRNA are expressed in lung tumor cells, and their inhibition has an effect on reducing cell proliferation ability. And an application of an aromatase inhibitor to the treatment of lung cancer has also been reported (Non-patent Document 18). Therefore, suppression of CYP19A1 expression is expected to have a therapeutic effect on tumors such as breast cancer and lung cancer.

  Epithelial membrane protein 1 (EMP1) is a gene encoding glycoprotein Epithelial membrane protein 1, and this protein acts on cell-cell interaction (GenBank accession number: NM_001423). It is known that EMP1 gene is isolated from kidney germ cells and distributed in kidney, brain and intestine in embryo, and in organs other than brain, liver, pancreas and leukocyte in adults (Non-patent Document 19). Non-patent document 20). The function of EMP1 has been reported to be involved in cell-cell interaction and cell proliferation from the function of PMP22, which has 39% amino acid in common (Non-patent Document 19), and as a resistance marker for gefitinib, an anticancer drug. It has been reported (Non-Patent Document 21). In addition, in experiments using transgenic mice knocked out of Trefoil factor-1 (Tff1), which has the ability to suppress gastric cancer in order to identify factors that contribute to the development of gastric cancer, it was reported that EMP1 etc. are overexpressed (Non-patent Document 22), taking these into consideration, increasing the expression of EMP1 is expected to have a therapeutic effect on tumor diseases including cancer.

  DNA (cytosine-5-)-methyltransferase 3-like, transcript variant 1 (DNMT3L) is a gene encoding Cytosine-5-methyltransferase 3-like protein (GenBank accession number: NM_013369). DNMT3L is known as a DNA methylase and is an embryonic factor that is expressed in embryonic germ cells in the short term and determines future testicular function. DNMT3L is rarely present in postnatal cells, adult germ cells, somatic cells, or somatic cancers, and is reported to be a growth factor for human embryonal cancer (testis tumor) and a novel marker. (Non-patent Document 23). The etiology of testicular tumors is considered to be testicular growth failure and fetal excess estrogen, which makes it a suitable therapeutic target for fetal cancer and its application to the development of new testicular tumor therapeutics using reduced expression of DNMT3L. I can expect.

  Matrix metalloproteinase 11 (MMP11) is a gene that encodes Matrix metalloproteinase 11 (GenBank accession number: NM_005940). This protein is expressed in various cancer cells, and its expression correlates with cancer progression, It is known to have the ability to control cell growth and to control the progression of gastric cancer (Non-patent Document 24). It has been reported that new angiogenesis and cancer cell proliferation were not observed in MMP11 knockout mice (Non-patent Document 25), and it can be easily expected that suppression of MMP11 expression is effective for cancer treatment.

  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 compounds that inhibit such CETP activity, for example, torcetrabib (patent document 2), anacetrapib (patent document 3), darcetrapib (patent document 4) and the like are known.

  On the other hand, a compound having CETP inhibitory activity can suppress the expression of HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 mRNA and enhance the expression of PCDH8 mRNA It is not known to be useful for the prevention or treatment of neoplastic diseases.

  On the other hand, Patent Document 5 discloses a pyrimidine compound which has excellent cholesterol ester transfer protein inhibitory activity (CETP (cholesteryl ester transfer protein) inhibitory activity) and is useful as a therapeutic agent for hyperlipidemia. However, these compounds are not known to have an effect on the expression of EMP1, DNMT3L and / or MMP11 mRNA, the production of EMP1, DNMT3L and / or MMP11 protein, and the treatment and / or prevention of neoplastic diseases.

Special Publication 2004-505637 International Publication No. 00/017164 International Publication No. 06/014357 International Publication No. 98/035937 International Publication No. 08/129951

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  An object of the present invention is to provide a preventive and / or therapeutic agent for neoplastic diseases. Further, the object of the present invention is to suppress the expression of HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN, CYP19A1, DNMT3L and / or MMP11 mRNA, and suppress the expression of PCDH8 and / or EMP1 mRNA. An object of the present invention is to provide a preventive and / or therapeutic agent for neoplastic diseases caused by enhancement.

  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 PCDH8 mRNA and an excellent expression suppressing action on HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 mRNA And that this substance has a PCDH8 mRNA protein production enhancing action and a HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 protein production inhibitory action. As a result, it was found that this substance is also useful for the prevention and treatment of neoplastic diseases, and the present invention 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] HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 mRNA containing a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient Expression inhibitor.
[2] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof is represented by the following formula (I) or (II):

[In formulas (I) and (II), R _{1 to} R ₁₃ are the same as described above. ]
The expression inhibitor according to [1], which is a compound represented by the formula: or a salt thereof, or a solvate thereof.
[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 PCDH8 mRNA expression enhancer comprising a compound having 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, enhanced expression according to [5] Agent.

[9] HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 containing a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient Protein production inhibitor.
[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-methyloxazolidin-2-one or a salt thereof, or a solvate thereof as an active ingredient, the protein production according to [9] Inhibitor.

[13] A PCDH8 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 prophylactic and / or therapeutic agent for neoplastic 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 neoplastic 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 neoplastic 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-methyloxazolidin-2-one or a salt thereof, or a solvate thereof, as an active ingredient according to [17] Disease prevention and / or treatment agent.
[21] The neoplastic disease is a breast tumor, bone tumor, digestive organ tumor, nervous system tumor, neural tissue tumor, hematopoietic tumor, endocrine gland tumor, urogenital tumor, liver tumor, leukemia or lymphoma. [17] The preventive and / or therapeutic agent according to 1.

[22] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvation thereof for suppressing the expression of HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 mRNA object.
[23] 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. [22] or a salt thereof, or a solvate thereof.
[24] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for enhancing the expression of PCDH8 mRNA.
[25] 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. [24] or a salt thereof, or a solvate thereof.
[26] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvation thereof for suppressing protein production of HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 object.
[27] 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. [26] or a salt thereof, or a solvate thereof.
[28] A compound having cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof, for enhancing PCDH8 protein production.
[29] 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. , [28] or a salt thereof, or a solvate thereof.
[30] 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 neoplastic diseases.
[31] 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. , [30] or a salt thereof, or a solvate thereof.

[32] HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or a compound having a cholesterol ester transfer protein inhibitory activity or its salt for producing an expression inhibitor of CYP19A1 mRNA, or a salt thereof Use of solvates.
[33] 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. [32] Use.
[34] 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 PCDH8 mRNA expression enhancer.
[35] 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. [34] Use.
[36] A compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof for producing a protein production inhibitor of HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1, or a salt thereof Use of solvates.
[37] 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. [36] Use.
[38] 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 PCDH8 protein production enhancer.
[39] 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. , [38].
[40] Use of a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof for the manufacture of a preventive and / or therapeutic agent for a neoplastic disease.
[41] 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. [40] Use.

[42] HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or a compound characterized by administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof Alternatively, a method for suppressing the expression of CYP19A1 mRNA.
[43] 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. [42] The expression suppression method according to
[44] A method for enhancing the expression of PCDH8 mRNA, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[45] 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. [44] The method for enhancing expression.
[46] HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof Alternatively, a method for suppressing protein production of CYP19A1.
[47] 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. [46] The method for inhibiting protein production according to [46].
[48] A method for enhancing PCDH8 protein production, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[49] 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. [48] The method for enhancing protein production according to [48].
[50] A method for preventing and / or treating a neoplastic disease, comprising administering a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof.
[51] 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. [50] The method for preventing and / or treating a neoplastic disease according to [50].

  In addition, as a result of continual research to achieve the above object, the present inventors have found that a compound represented by the following general formula (I), a salt thereof, or a solvate thereof is superior to EMP1 mRNA. Have an excellent expression-inhibiting action and have an excellent expression-inhibiting action on DNMT3L and / or MMP11 mRNA, and this substance has an EMP1 protein production-enhancing action, and DNMT3L and / or MMP11 protein production. It was found to have an inhibitory action. As a result, the present inventors have found that the compound represented by the general formula (I), a salt thereof, or a solvate thereof is also useful for the prevention and treatment of neoplastic diseases.

  Formula (I):

[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. ]

That is, this invention relates to the invention shown below.
[1] The following formula (I):

[In the formula (I), R _{1 to} R ₆ are the same as described above. ]
DNMT3L and / or MMP11 mRNA expression inhibitor comprising the compound represented by the formula (1) or a salt thereof, or a solvate thereof as an active ingredient.
[2] 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 [1] The expression inhibitor according to [1].
[3] An EMP1 mRNA expression enhancer comprising the compound represented by the formula (I) or a salt thereof, or a solvate thereof as an active ingredient.
[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, (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 [3] The expression enhancer according to [3].
[5] A protein production inhibitor of DNMT3L and / or MMP11 comprising the compound represented by the formula (I) or a salt thereof, or a solvate thereof as an active ingredient.
[6] 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 [5] The protein production inhibitor according to [5].
[7] A protein production enhancer of EMP1 mRNA comprising the compound represented by the formula (I) or a salt thereof, or a solvate thereof as an active ingredient.
[8] 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 And a protein production enhancer according to [7].

[9] The compound represented by the above formula (I) or a salt thereof, or a solvate thereof for suppressing the expression of DNMT3L and / or MMP11 mRNA.
[10] The compound represented by the formula (I) or a salt thereof, or a solvate thereof for enhancing the expression of EMP1 mRNA.
[11] A compound represented by the above formula (I) or a salt thereof, or a solvate thereof for suppressing protein production of DNMT3L and / or MMP11.
[12] A compound represented by the formula (I) or a salt thereof, or a solvate thereof, for enhancing protein production of EMP1 mRNA.

[13] The above formula (I) for producing DNMT3L and / or MMP11 mRNA expression inhibitor
Or a salt thereof, or a solvate thereof.
[14] Use of the compound represented by the formula (I) or a salt thereof, or a solvate thereof for the production of an agent that enhances the expression of EMP1 mRNA.
[15] Use of the compound represented by the formula (I) or a salt thereof, or a solvate thereof for the production of a DNMT3L and / or MMP11 protein production inhibitor.
[16] Use of the compound represented by the formula (I) or a salt thereof, or a solvate thereof for the production of an EMP1 mRNA protein enhancer.

[17] A method for inhibiting the expression of DNMT3L and / or MMP11 mRNA, comprising administering the compound represented by the formula (I) or a salt thereof, or a solvate thereof.
[18] A method for enhancing expression of EMP1 mRNA, comprising administering the compound represented by the formula (I) or a salt thereof, or a solvate thereof.
[19] A method for inhibiting protein production of DNMT3L and / or MMP11, comprising administering the compound represented by the formula (I) or a salt thereof, or a solvate thereof.
[20] A method for enhancing protein production of EMP1 mRNA, comprising administering the compound represented by the formula (I) or a salt thereof, or a solvate thereof.

  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.

  A compound having CETP inhibitory activity or a salt thereof, or a solvate thereof has a strong expression enhancing action on PCDH8 mRNA, as specifically disclosed in the examples described later, and HOXA6, GSC, It has a strong expression inhibitory action on GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 mRNA. In addition, these compounds have PCDH8 protein production enhancing action, and HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 protein production inhibitory action. It can be used effectively for prevention and / or treatment.

  The compound represented by the formula (I) or a salt thereof, or a solvate thereof has a strong expression enhancing action on EMP1 mRNA, as specifically disclosed in Examples described later, and It has a strong expression inhibitory effect on DNMT3L and / or MMP11 mRNA. Moreover, these compounds can be effectively used for the prevention and / or treatment of neoplastic diseases by having an EMP1 protein production enhancing action and a DNMT3L and / or MMP11 protein production inhibitory action.

It is a figure which shows the relative value of the CYP19A1 mRNA expression level of the cell which added the compound 2 and anacetrapib. It is a figure which shows the relative value of the MMP11 mRNA expression level of the cell which added the compound 2 and 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. Preferably, the compound represented by the general formula (I) or a salt thereof, or a solvate thereof and anacetrapib can be mentioned.

  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).

  As used herein, the term “neoplastic disease” includes eye tumor, breast tumor, anal gland tumor, bone tumor, pelvic tumor, digestive organ tumor, nervous system tumor, hematopoietic tumor, head and neck tumor, endocrine gland tumor, Soft tissue tumor, breast tumor, breast tumor, spleen tumor, genitourinary tumor, skin tumor, abdominal tumor, plasma cell tumor, vascular tissue tumor, connective tissue tumor, soft tissue tumor, neural tissue tumor, gonadal tissue tumor, glandular epithelium Sex tumors, leukemias, complex and mixed tumors, melanomas, lymphomas and the like.

  More preferably, the neoplastic diseases to which the compounds according to the present invention can be applied are breast tumors (breast cancer etc.), bone tumors (bone meat species etc.), digestive organ tumors (colon tumor etc.), endocrine gland tumors (pancreatic tumor etc.) ), Genitourinary tumors (renal cell tumors, prostate tumors, etc.), leukemias, lymphomas (mantril lymphoma, lymphoproliferative disease, multiple myeloma), and the like, particularly preferably lymphomas ( Mental lymphoma, lymphoproliferative disease, multiple myeloma) 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 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, and is within the above range. There is no limit.

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) to give 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, Yield 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 is 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 was added to HepG2 cells, a human liver cancer cell line, and the CYP19A1 mRNA expression level after 24 hours of culture was measured by real-time RT-PCR. That is, HepG2 cells are seeded in a 24-well plate at a concentration of 2 × 10 ⁵ cells / well and cultured overnight, then compound 2 is added to dimethyl sulfoxide (DMSO) to 0.1 mM, 1 mM, 10 mM, and anacetrapib is added. It melt | dissolved so that it might become 1mM and 10mM, and it added the 1/1000 volume 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). The expression level of human CYP19A1 mRNA was measured using TaqMAn Gene Expression Assay (Applied Biosystems, catalog number Hs00903413_m1) and TaqMan Fast Universal PCR Master Mix (Applied Biosystems, catalog number 4436486) for human CYP19A1. The measuring instrument was a 7900HT Fast Realtime PCR system.

  The measured value was corrected by the expression level of β-Actin mRNA, the CYP19A1 mRNA expression level of the cells to which only DMSO was added was 1, and the CYP19A1 mRNA expression level of the cells to which compound 2 or anacetrapib was added was calculated as a relative value. The results are shown in FIG.

Test example 2
A test compound 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, HepG2 cells are seeded in a 24-well plate at a concentration of 2 × 10 ⁵ cells / well, cultured overnight, and then compound 2 in dimethyl sulfoxide (DMSO) is adjusted to 1 μM and 10 μM, and anacetrapib is adjusted to 10 μM. It melt | dissolved and it added the 1/1000 volume 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. 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), 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 having CETP inhibitory activity including the general formula (I) or (II) has a strong and persistent PCDH8 mRNA expression enhancing action, and HOXA6, GSC, GAST, SIM2, It was revealed that CCND2, IRS4, FGF7, TRPM2, FASN, and / or CYP19A1 mRNA expression inhibitory action was obtained.

Test example 3
A test compound was added to HepG2 cells, a human hepatoma cell line, and the expression level of MMP11 mRNA after 24 hours of culture was measured by real-time RT-PCR. That is, HepG2 cells were seeded in a 24-well plate at a concentration of 2 × 10 ⁵ cells / well and cultured overnight, and then 2 μl of anacetrapib was added to dimethyl sulfoxide (DMSO) to 0.1 μM, 1 μM, and 10 μM. It melt | dissolved so that it might be set to 10 micromol, and added 1/1000 volume 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). The expression level of human MMP11 mRNA was measured using TaqMAn Gene Expression Assay for Human MMP11 (Applied Biosystems, catalog number Hs00968295_m1) and TaqMan Fast Universal PCR Master Mix (Applied Biosystems, catalog number 4436486). The measuring instrument was a 7900HT Fast Realtime PCR system.

  The measured value was corrected by the expression level of β-Actin mRNA, and the MMP11 mRNA expression level of the cells to which only DMSO was added was 1, and the MMP11 mRNA expression level of the cells to which compound 2 was added was calculated as a relative value. The results are shown in FIG. As can be seen from FIG. 2, since this action is not expressed in the other CETP inhibitor anacetrapib, this action is not caused by the CETP inhibitory action but is considered to be an action specific to the compound of the present invention. .

Test example 4
A test compound 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, HepG2 cells are seeded in a 24-well plate at a concentration of 2 × 10 ⁵ cells / well, cultured overnight, and then compound 2 in dimethyl sulfoxide (DMSO) is adjusted to 1 μM and 10 μM, and anacetrapib is adjusted to 10 μM. It melt | dissolved and it added the 1/1000 volume 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. 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 2.

  Since this action is not expressed in the other CETP inhibitor anacetrapib (Anacetrapib), this action is not caused by the CETP inhibitory action but is considered to be an action specific to the compound of the present invention.

  From the above pharmacological test results, it has been clarified that the compound of the general formula (I) has a strong and sustained EMP1 mRNA expression enhancing action and also has a DNMT3L and / or MMP11 mRNA expression suppressing action. .

  A compound with CETP inhibitory activity has a strong expression enhancing effect on PCDH8 mRNA and strongly suppresses expression on HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 mRNA Since it has an action and is useful for the prevention and / or treatment of neoplastic diseases, it has industrial applicability.

  The compound represented by the general formula (I) of the present invention or a salt thereof, or a solvate thereof has a strong expression enhancing action on EMP1 mRNA and has a strong expression on DNMT3L and / or MMP11 mRNA. Since it has an inhibitory action and is useful for the prevention and / or treatment of neoplastic diseases, it has industrial applicability.

Claims (29)

  Suppressing expression of HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 mRNA containing a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient Agent. 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 PCDH8 mRNA expression enhancer 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 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.   Inhibition of protein production of HOXA6, GSC, GAST, SIM2, CCND2, IRS4, FGF7, TRPM2, FASN and / or CYP19A1 containing a compound having a cholesterol ester transfer protein inhibitory activity or a salt thereof, or a solvate thereof as an active ingredient Agent. 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 PCDH8 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 neoplastic diseases 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 preventive and / or therapeutic agent for neoplastic 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 neoplastic diseases according to claim 17.   (4S, 5R) -5- [3,5-Bis (trifluoromethyl) phenyl] -3-((4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)-[ The prevention of neoplastic 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 neoplastic disease is a breast tumor, bone tumor, digestive organ tumor, nervous system tumor, neural tissue tumor, hematopoietic tumor, endocrine tumor, genitourinary tumor, liver tumor, leukemia or lymphoma according to claim 17. Prophylactic and / or therapeutic agent. Formula (I):
[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. ]
DNMT3L and / or MMP11 mRNA expression inhibitor comprising the compound represented by the formula (1) or a salt thereof, or a solvate thereof as an active ingredient.   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 22. Formula (I):
[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. ]
Or a salt thereof, or a solvate thereof as an active ingredient.   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 24. Formula (I):
[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. ]
A protein production inhibitor of DNMT3L and / or MMP11, which comprises, as an active ingredient, a compound represented by the formula: or a salt thereof, or a solvate thereof.   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 26. Formula (I):
[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. ]
Or a salt thereof, or a solvate thereof, as an active ingredient, a protein production enhancer of EMP1 mRNA.   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 28.