WO2012157746A1 - Médicament thérapeutique pour maladie auto-immune - Google Patents

Médicament thérapeutique pour maladie auto-immune Download PDF

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WO2012157746A1
WO2012157746A1 PCT/JP2012/062782 JP2012062782W WO2012157746A1 WO 2012157746 A1 WO2012157746 A1 WO 2012157746A1 JP 2012062782 W JP2012062782 W JP 2012062782W WO 2012157746 A1 WO2012157746 A1 WO 2012157746A1
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alkyl
amino
hydroxyphosphoryloxy
alkoxy
phenyl
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PCT/JP2012/062782
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Japanese (ja)
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青木　淳賢
久美子 巻出
飛鳥 井上
智彦 大和田
仁也 井久保
優子 尾谷
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国立大学法人東北大学
国立大学法人東京大学
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
    • C07F9/6518—Five-membered rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the present invention relates to a screening method for compounds useful as autoimmune therapeutic agents.
  • the present invention also relates to a therapeutic agent for autoimmune diseases.
  • the invention further relates to lysophosphatidylserine and novel derivatives thereof.
  • Lysophospholipid is a general term for phospholipids having one acyl group.
  • the lysophospholipid has a property that it is less hydrophobic than the diacylphospholipid constituting the cell membrane and can be easily released from the cell membrane.
  • Some lysophospholipids function as signal molecules between cells or between membranes and have been found to have an important role in vivo.
  • Patent Document 1 Japanese Patent Application Laid-Open No. 2007-267601.
  • lysophosphatidylserine which is a kind of lysophospholipid, is involved in acute inflammation caused by mast cell degranulation (Non-patent Documents 1 and 2).
  • LPS 1 GPR34
  • LPS 2 P2Y10
  • LPS 3 A630033H20Rik
  • LPS 4 GPR174
  • LPS 1 is involved in signal transduction that induces or enhances degranulation of mast cells and can be a target for the treatment of allergic diseases and chronic inflammatory diseases
  • Patent Document 2 a specific lysophosphatidylserine derivative
  • lysophosphatidylthreonine strongly promotes the degranulation reaction of mast cells
  • Autoimmune disease is a general term for diseases that cause symptoms when the immune system, which is originally a defense mechanism against foreign substances, reacts excessively and attacks even normal cells and tissues of itself.
  • systemic autoimmune diseases that affect the whole body and organ-specific diseases that affect only specific organs.
  • autoimmune diseases often become chronic diseases or intractable diseases, and some of them are designated as diseases for which specific diseases are researched by the Ministry of Health, Labor and Welfare.
  • Much research has been conducted on methods for treating autoimmune diseases, for example, methods for treating chronic inflammation caused by autoimmune diseases using cytokine-specific antibodies involved in inflammation (Patent Document 2), and pathogenic self.
  • Patent Document 3 A method for treating diseases by neutralizing antibodies
  • autoimmune diseases many causes of autoimmune diseases have not been elucidated, and effective treatments have not yet been established for many autoimmune diseases.
  • drugs that suppress the immune system and anti-inflammatory drugs stereos or non-steroid drugs that relieve inflammation are used as the first selection agent.
  • An object of the present invention is to provide a new treatment method for autoimmune diseases. Furthermore, the present invention is to provide a method for assaying compounds useful for the treatment of autoimmune diseases.
  • the inventors of the present invention have made extensive studies in order to achieve the above-mentioned problems. As a result, the compounds having agonist activity of LPS 2 (P2Y10) and LPS 4 (GPR174) have been found to have therapeutic and preventive effects on autoimmune diseases. Completed the invention.
  • the following screening method is provided.
  • a screening method for a therapeutic or prophylactic agent for an autoimmune disease comprising using P2Y10 or GPR174 to evaluate the agonist activity or antagonist activity of a test compound for a lysophosphatidylserine receptor.
  • the method according to (1) above wherein the agonist activity is evaluated.
  • the method according to (1) or (2) above for screening for an interleukin 2 production inhibitor.
  • EGFR human epidermal growth factor receptor
  • AP alkaline phosphatase
  • TGF ⁇ transforming growth factor ⁇
  • R 11 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or benzyl
  • R 12 and R 13 are each independently a hydrogen atom, C 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkoxy C 1-6 alkyl, or benzyloxy Selected from carbonyl
  • R 15 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkylcarbonyloxy C 1-6 alkyl, C 1-6 alkoxycarbonyloxy C 1-6 alkyl, Phenyl, benzyl, phthalidyl, dioxolenoneylmethyl, or furylmethyl
  • p is an integer selected from 2 to 6
  • Y 1 is a direct bond or —C ( ⁇ O) —
  • R 16 is C 3-30 alkyl, wherein one or more phen
  • the phenyl or heteroaryl may be substituted with one or more substituents selected from C 1-10 alkyl, C 1-10 alkoxy and a halogen atom;
  • the above benzyl, benzyloxy, phenyl, phthalidyl, dioxolenoneylmethyl, furylmethyl, phenylene, and heteroarylene are C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 alkylcarbonyloxy, nitro May be substituted with one or more substituents selected from phenyl and halogen atoms] Or a pharmaceutically acceptable salt thereof.
  • R 16 is C 10-24 alkyl (wherein one or more —CH 2 — of alkyl may be replaced by —O—, and one or more single bonds between carbon atoms are double bonds) Or may be replaced by a triple bond), or selected from the formula: — (CH 2 ) r —Q 1 ; r is an integer selected from 2 to 20; Q 1 is phenyl or 5-6 membered heteroaryl, which is C 1-10 alkyl, C 1-10 alkoxy, phenyl C 1-10 alkyl, phenyl C 1-10 alkoxy, 5- The compound according to the above (11), or a pharmaceutically acceptable salt thereof, which may be substituted with 6-membered heteroaryl C 1-10 alkyl or 5-6-membered heteroaryl C 1-10 alkoxy.
  • R 16 is C 12-20 alkyl (wherein alkyl 1 to 3 —CH 2 — may be replaced by —O—, and one single bond between carbon atoms is a double bond) Or is selected from the formula: — (CH 2 ) r —Q 1 ; r is an integer selected from 2 to 7; Q 1 is phenyl or 5-6 membered heteroaryl, which is C 1-10 alkyl, C 1-10 alkoxy, phenyl C 1-3 alkyl, phenyl C 1-3 alkoxy, 5- The compound according to the above (12), or a pharmaceutically acceptable salt thereof, which may be substituted by 6-membered heteroaryl C 1-3 alkyl or 5-6-membered heteroaryl C 1-3 alkoxy.
  • R 21 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or benzyl
  • R 22 and R 23 are each independently a hydrogen atom, C 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkoxy C 1-6 alkyl, or benzyloxy Selected from carbonyl
  • R 24 is a hydrogen atom or C 1-3 alkyl
  • R 25 represents a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkylcarbonyloxy C 1-6 alkyl, C 1-6 alkoxycarbonyloxy C 1-6 alkyl, Phenyl, benzyl, phthalidyl, dioxolenoneylmethyl, or furylmethyl
  • X 2 is a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkoxy, formyloxy
  • a 2 is the following formula:
  • R 21 , R 22 and R 23 are as defined in (14) above, or a pharmaceutically acceptable salt thereof.
  • R 26 is C 12-20 alkyl (wherein 1 to 3 —CH 2 — of alkyl may be replaced by —O—, and one single bond between carbon atoms is a double bond) Or is selected from the formula: — (CH 2 ) s —Q 2 ; s is an integer selected from 2 to 7; Q 2 is phenyl or 5-6 membered heteroaryl, which is C 1-10 alkyl, C 1-10 alkoxy, phenyl C 1-3 alkyl, phenyl C 1-3 alkoxy, 5- The compound according to the above (14) or (15), or a pharmaceutically acceptable salt thereof, which may be substituted with 6-membered heteroaryl C 1-3 alkyl, or 5-6-membered heteroaryl C 1-3 alkoxy .
  • lysophosphatidylserine derivatives have therapeutic and preventive effects on autoimmune diseases, and have completed the present invention. That is, according to still another aspect of the present invention, the following therapeutic or preventive agent is provided.
  • R 1 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or benzyl
  • R 2 and R 3 are each independently a hydrogen atom, C 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkoxy C 1-6 alkyl, or benzyloxy Selected from carbonyl
  • R 4 is a hydrogen atom or C 1-3 alkyl
  • R 5 represents a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkylcarbonyloxy C 1-6 alkyl, C 1-6 alkoxycarbonyloxy C 1-6 alkyl, Phenyl, benzyl, phthalidyl, dioxolenoneylmethyl, or furylmethyl
  • X is a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkoxy, formyloxy,
  • the phenyl or heteroaryl may be substituted with one or more substituents selected from C 1-10 alkyl, C 1-10 alkoxy and a halogen atom;
  • R 7 is a hydrogen atom or C 1-6 alkyl;
  • the above benzyl, benzyloxy, phenyl, phthalidyl, dioxolenoneylmethyl, furylmethyl, phenylene, and heteroarylene are C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 alkylcarbonyloxy, nitro May be substituted with one or more substituents selected from phenyl and halogen atoms]
  • the therapeutic agent or preventive agent of an autoimmune disease containing the compound represented by these, or its pharmaceutically acceptable salt.
  • R 6 is C 10-24 alkyl (wherein one or more —CH 2 — of alkyl may be replaced by —O—, and one or more single bonds between carbon atoms are double bonds) Or may be replaced by a triple bond), or selected from the formula: — (CH 2 ) m —Q; m is an integer selected from 2 to 20; Q is phenyl or 5-6 membered heteroaryl, which is C 1-10 alkyl, C 1-10 alkoxy, phenyl C 1-10 alkyl, phenyl C 1-10 alkoxy, 5-6
  • R 6 is C 12-20 alkyl (wherein the alkyl 1-3 —CH 2 — may be replaced by —O—, and one single bond between carbon atoms is a double bond) Or may be selected from the formula: — (CH 2 ) m —Q; m is an integer selected from 2 to 7; Q is phenyl or 5-6 membered heteroaryl, which is C 1-10 alkyl, C 1-10 alkoxy, phenyl C 1-3 alkyl, phenyl C 1-3 alkoxy, 5-6
  • the therapeutic or prophylactic agent according to the above (19) which may be substituted with a member heteroaryl C 1-3 alkyl or a 5-6 membered heteroaryl C 1-3 alkoxy.
  • (21) (2S) -2-Amino-3-[(3-oleoyloxypropoxy) -hydroxyphosphoryloxy] propionic acid; (2S) -2-Amino-3-[(3-basenoyloxypropoxy) -hydroxyphosphoryloxy] propionic acid; (2S) -2-amino-3-[(3-Elideyloxypropoxy) -hydroxyphosphoryloxy] propionic acid; (2S) -2-amino-3-[(3-palmitoleoyloxypropoxy) -hydroxyphosphoryloxy] propionic acid; (2S) -2-amino-3-[(3-palmitoyloxypropoxy) -hydroxyphosphoryloxy] propionic acid; (2S) -2-amino-3-[(3-palmitoyloxypropoxy) -hydroxyphosphoryloxy] propionic acid; (2S) -2-amino-3-[(3-myristoyloxypropoxy) -hydroxyphosphoryloxy] propionic acid;
  • the autoimmune diseases are malignant rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Graves' disease, antiphospholipid antibody syndrome, Sjogren's syndrome, primary biliary cirrhosis, polymyositis, and autoimmunity
  • the compound according to any one of (11) to (16) above, or the compound of the formula (I) defined in any one of (17) to (21) above, Or the pharmaceutical composition for treating or preventing an autoimmune disease containing the pharmaceutically acceptable salt is provided.
  • an interleukin 2 production inhibitor containing a pharmaceutically acceptable salt thereof is provided.
  • the compound according to any one of (11) to (16) above, or the compound of the formula (I) defined in any one of (17) to (21) above Alternatively, a lymphocyte adhesion inhibitor containing a pharmaceutically acceptable salt thereof is provided.
  • the compound according to any one of (11) to (16) above, or the compound of the formula (I) defined in any one of (17) to (21) above Alternatively, a method of treating or preventing autoimmune disease comprising administering to a patient a pharmaceutically acceptable salt thereof.
  • a therapeutic or prophylactic agent for autoimmune diseases which is a new method for treating autoimmune diseases. Furthermore, the present invention provides an efficient screening method for compounds useful for the treatment of autoimmune diseases.
  • FIG. 1 is a graph showing the evaluation test results (Test Example 1) of agonist activity of lysophosphatidylserine or its analogs against the P2Y10 receptor.
  • FIG. 2 is a graph showing the evaluation test results (Test Example 1) of agonist activity of lysophosphatidylserine or its analogs against the GPR174 receptor.
  • FIG. 3 is a graph showing the white blood cell count of a 17-week-old systemic lupus erythematosus spontaneously developing mouse in Test Example 2.
  • FIG. 4 is a graph showing autoantibody production in 17-week-old systemic lupus erythematosus spontaneously developing mice in Test Example 2.
  • FIG. 1 is a graph showing the evaluation test results (Test Example 1) of agonist activity of lysophosphatidylserine or its analogs against the GPR174 receptor.
  • FIG. 3 is a graph showing the white blood cell count of a 17-week-old systemic lupus
  • FIG. 5 is a graph showing changes in the spleen of 17-week-old spontaneously lupus erythematosus spontaneously developing mice in Test Example 2.
  • 6 is a graph showing changes in mesenteric lymph nodes in 17-week-old spontaneously lupus erythematosus mice in Test Example 2.
  • FIG. 7 is a diagram showing the deposition of immune complexes in the kidneys of 17-week-old systemic lupus erythematosus spontaneously developing mice in the PBS administration group (control group) in Test Example 2.
  • FIG. 8 is a graph showing the deposition of immune complexes on the kidneys of 17-week-old spontaneously lupus erythematosus spontaneously developing mice in the test compound administration group in Test Example 2.
  • FIG. 9 is a graph showing blood alanine transaminase (ALT) values of human autoimmune disease hepatitis model mice in Test Example 3.
  • FIG. 10 is a photograph showing the site of liver injury in the liver section of a human autoimmune disease hepatitis model mouse (PBS administration group) in Test Example 3.
  • FIG. 11 is a photograph showing the site of liver injury in a liver section of a human autoimmune disease hepatitis model mouse (LPS (18: 1) administration group) in Test Example 3.
  • FIG. 12 is a graph obtained by quantifying the sites of liver injury in liver sections of human autoimmune disease model mice (PBS administration group, LPS (18: 1) administration group) in Test Example 3.
  • FIG. 10 is a photograph showing the site of liver injury in the liver section of a human autoimmune disease hepatitis model mouse (PBS administration group) in Test Example 3.
  • FIG. 11 is a photograph showing the site of liver injury in a liver section of a human autoimmune disease hepatitis model mouse (LP
  • FIG. 13 is a photograph showing the site of liver injury in a liver section of a human autoimmune disease hepatitis model mouse (deoxy-LPSLP (18: 1) administration group) in Test Example 3.
  • FIG. 14 is a photograph showing the site of liver injury in a liver section of a human autoimmune disease hepatitis model mouse (LPalloTlo (18: 1) administration group) in Test Example 3.
  • FIG. 15 is a graph showing the expression level of P2Y10 in spleen-derived lymphocytes activated with concanavalin A (Test Example 4).
  • FIG. 16 is a graph showing the expression level of GPR174 in spleen-derived lymphocytes activated with concanavalin A (Test Example 4).
  • FIG. 17 is a graph showing the influence of a test compound on adhesion of spleen-derived lymphocytes activated with concanavalin A to ICAM-1 (Test Example 5).
  • FIG. 18 is a graph showing the influence of a test compound on IL-2 production of spleen-derived lymphocytes activated with concanavalin A (Test Example 6).
  • FIG. 19 shows human, mouse and rat oligonucleotides used as forward and reverse primers for the P2Y10 gene (SEQ ID NO: 1-6) and oligonucleotides used as forward primer and reverse primer for the GPR174 gene (SEQ ID NO: 7- It is a figure showing the base sequence of 12).
  • FIG. 20 shows the base sequence of the human P2Y10 gene (SEQ ID NO: 13).
  • FIG. 21 shows the base sequence of the mouse P2Y10 gene (SEQ ID NO: 14).
  • FIG. 22 is a diagram showing the base sequence of the rat P2Y10 gene (SEQ ID NO: 15).
  • FIG. 23 shows the base sequence of the human GPR174 gene (SEQ ID NO: 16).
  • FIG. 24 is a diagram showing the base sequence of the mouse GPR174 gene (SEQ ID NO: 17).
  • FIG. 25 is a diagram showing the base sequence of the rat GPR174 gene (SEQ ID NO: 18).
  • FIG. 26 shows the sequences of human, mouse and rat P2Y10 proteins (SEQ ID NOs: 19 to 21).
  • FIG. 27 shows the sequences of human, mouse and rat GPR174 proteins (SEQ ID NOs: 22 to 24).
  • FIG. 28 is a diagram showing the base sequences of oligonucleotides (SEQ ID NOs: 25 to 30) used as primers in the real-time PCR method of Test Example 4.
  • a method for screening a pharmaceutical compound comprising using P2Y10 or GPR174 to evaluate an agonist activity or antagonist activity of a test compound at a lysophosphatidylserine receptor.
  • the test compound to be screened is not particularly limited, and examples thereof include organic compounds and inorganic compounds (particularly low molecular compounds), proteins, peptides, and the like.
  • the screening is not particularly limited as long as it uses P2Y10 or GPR174.
  • a cell expressing a gene encoding P2Y10 or GPR174, a transgenic non-human mammal overexpressing a gene encoding P2Y10 or GPR174, A transgenic non-human mammal expressing a gene encoding human P2Y10 or human GPR174 can be used.
  • the cell to be used for screening is not particularly limited, and examples thereof include commonly used known microorganisms such as Escherichia coli or yeast, or known cultured cells such as HUVEC cells. Examples of non-human mammals include mice, rats, rabbits, dogs, cats, monkeys and the like. Screening may also use animal tissues and cells. In that case, administration of the test compound can be performed by allowing the test compound to act on the subject, for example, by including the test compound in a solution or medium in which the tissue or cells are retained.
  • the screening method of the present invention can be used for screening a compound having agonistic activity of a test compound against P2Y10 or GPR174. Due to the function of P2Y10 or GPR174, a compound having the agonist activity becomes a candidate compound for a medicament used as a therapeutic or prophylactic agent for diseases such as autoimmune diseases.
  • the autoimmune disease may be any of systemic diseases and organ-specific diseases, such as malignant rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Graves' disease, antiphospholipid antibody syndrome, Examples include Sjogren's syndrome, primary biliary cirrhosis, polymyositis, and autoimmune hepatitis.
  • the screening method of the present invention can be performed using a cultured cell that expresses a gene encoding P2Y10 or GPR174, and the use of the cultured cell is preferred in terms of screening efficiency.
  • the assay can be performed using calcium response, cAMP production, reporter gene, and the like as indicators.
  • the cultured cell is allowed to express a gene encoding a further labeled human epidermal growth factor receptor (EGFR) ligand, and the assay is performed by quantifying the amount of the labeled compound to be cleaved. It can be carried out.
  • EGFR human epidermal growth factor receptor
  • the labeled EGFR ligand include a fusion protein of an EGFR ligand and alkaline phosphatase (AP).
  • AP alkaline phosphatase
  • the EGFR ligand to be labeled include transforming growth factor ⁇ (TGF ⁇ ), heparin-binding EGF-like growth factor (HB-EGF), and amphiregulin.
  • TGF ⁇ transforming growth factor ⁇
  • HB-EGF heparin-binding EGF-like growth factor
  • amphiregulin amphiregulin.
  • an interleukin-2 production inhibitor or a lymphocyte adhesion inhibitor comprising evaluating the agonist activity of a test compound for a lysophosphatidylserine receptor using P2Y10 or GPR174.
  • a method for screening is provided.
  • GPR174 is used in the screening method for interleukin 2 production inhibitor
  • P2Y10 is used in the screening method for lymphocyte adhesion inhibitor.
  • P2Y10 used in the screening method of the present invention is not particularly limited as long as it is a polypeptide having lysophosphatidylserine receptor activity as P2Y10.
  • P2Y10 derived from mammals such as humans, mice, and rats is used. . Specific examples include the following polypeptides.
  • A a polypeptide comprising an amino acid sequence represented by SEQ ID NOs: 19 to 21;
  • B a polypeptide comprising the amino acid sequence represented by SEQ ID NOs: 19 to 21 and having lysophosphatidylserine receptor activity;
  • C a polypeptide comprising an amino acid sequence in which 1 to 10 amino acids are deleted, substituted, added and / or inserted in the amino acid sequence represented by SEQ ID NOs: 19 to 21 and having lysophosphatidylserine receptor activity ;
  • D an amino acid sequence having a homology with the amino acid sequence represented by SEQ ID NOs: 19 to 21 of 80% or more, preferably 90% or more, more preferably 95% or more, and having lysophosphatidylserine receptor activity Having a polypeptide.
  • GPR174 used in the screening method of the present invention is not particularly limited as long as it is a polypeptide having lysophosphatidylserine receptor activity as GPR174.
  • GPR174 derived from mammals such as humans, mice and rats is used. . Specific examples include the following polypeptides.
  • A a polypeptide comprising an amino acid sequence represented by SEQ ID NOs: 22 to 24;
  • B a polypeptide comprising the amino acid sequence represented by SEQ ID NOs: 22 to 24 and having lysophosphatidylserine receptor activity;
  • C a polypeptide comprising an amino acid sequence in which 1 to 10 amino acids are deleted, substituted, added and / or inserted in the amino acid sequence represented by SEQ ID NOs: 22 to 24 and having lysophosphatidylserine receptor activity ;
  • D an amino acid sequence having a homology with the amino acid sequences represented by SEQ ID NOs: 22 to 24 of 80% or more, preferably 90% or more, more preferably 95% or more, and having lysophosphatidylserine receptor activity Having a polypeptide.
  • the numerical value of homology may be a numerical value calculated using a homology search program known to those skilled in the art.
  • BLAST Basic Local Alignment Search Tool
  • Altschul SF Gish by Altschul et al. W, Miller W, Myers EW, Lipman DJ., J. Mol. Biol., 215: p403-410 (1990)
  • Altschyl SF Madden TL, Schaffer AA, Zhang J, Miller W, Lipman DJ, Acids . 25: p3389-3402 (1997)
  • amino acid sequence numerical values calculated using default parameters in BLAST2N [Nucleic Acids Res., 25, (3389 (1997); Genome ⁇ ⁇ Res., 7, 649 (1997)] can be mentioned.
  • the mutant or homologue when a mutant or homologue of a specific amino acid sequence is used, can be prepared using DNA encoding the amino acid sequence of the mutant or homologue.
  • DNA encoding such a mutant or homologue can also be prepared by any method known to those skilled in the art, such as chemical synthesis, genetic engineering techniques, and mutagenesis. Specifically, DNA encoding the sequences described in SEQ ID NOs: 13 to 18 is used, and desired DNA can be obtained by introducing mutations into these DNAs. For example, it can be carried out using a method of bringing DNA into contact with a drug that becomes a mutagen, a method of irradiating ultraviolet rays, a genetic engineering method, or the like.
  • Site-directed mutagenesis which is one of the genetic engineering methods, is useful because it can introduce a specific mutation at a specific position.
  • Molecular cloning 2nd edition Current Protocols in Molecular. Biology, Nucleic Acids Research, 10, 6487, 1982, Nucleic Acids Research, 12, 9441, 1984, Nucleic Acids Research, 13, 4431, 1985, Nucleic Acids Research, 13, 8749,1985, Proc. Na Sci.Acad. USA, 79, 6409, 1982, Proc. Natl. Acad. Sci. USA, 82, 488, 1985, Gene, 34, 315, 1985, Gene, 102, 67, 1991, etc. Can do.
  • lysophosphatidylserine or an analog thereof can be used as a control compound, examples of which include the compounds of the above formulas (I), (Ia) and (Ib), and more specifically And the compounds described in the examples.
  • C 1-3 alkyl means a linear, branched, or cyclic alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, Cyclopropyl is included.
  • C 1-6 alkyl means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl. I-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and the like, for example, C 1-4 alkyl And C 1-3 alkyl and the like are also included.
  • C 1-10 alkyl in the definition of the compounds herein, refers to a linear, branched, cyclic or partially cyclic alkyl group having 1 to 10 carbon atoms, e.g., C 1-
  • linear, branched, cyclic or partially cyclic represented by C 7 H 15 , C 8 H 17 , C 9 H 19 , and C 10 H 21 These alkyl groups are included.
  • C 3-30 alkyl means a linear, branched, cyclic or partially cyclic alkyl group having 7 to 30 carbon atoms, such as C 1-6 alkyl.
  • C 1-6 alkylcarbonyl means an alkylcarbonyl group having a C 1-6 alkyl group already defined as the alkyl moiety, such as methylcarbonyl (acetyl), ethylcarbonyl, tert-butylcarbonyl. In addition, C 1-4 alkylcarbonyl and the like are included.
  • C 1-6 alkoxy means an alkyloxy group having an alkyl group having 1 to 6 carbon atoms already defined as an alkyl moiety, and includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen Toxic, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, etc. are included, for example, C 1-4 alkoxy and C 1 Also included are -3 alkoxy and the like. In this specification, “C 1-4 alkoxy” includes, for example, C 1-3 alkoxy and the like.
  • C 1-6 alkoxycarbonyl means an alkoxycarbonyl group having a C 1-6 alkoxy group already defined as an alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, C 1-3 alkoxycarbonyl and the like are included.
  • C 1-6 alkoxy C 1-6 alkyl in the present specification includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl and the like.
  • benzyl means a group represented by the formula: C 6 H 5 CH 2 —.
  • benzyloxy means a group represented by the formula: C 6 H 5 CH 2 O—.
  • benzyloxycarbonyl means a group represented by the formula: C 6 H 5 CH 2 OC ( ⁇ O) —.
  • 5-6-membered heteroaryl refers to a monocyclic aromatic heterocyclic group having 5 to 6 ring atoms, including one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom Means.
  • Specific examples include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl and the like.
  • phenylene means a divalent group in which benzene is substituted at two positions, and may be any of 1,2-substituted, 1,3-substituted, and 1,4-substituted. Good.
  • 5-6-membered heteroarylene refers to a monocyclic aromatic heterocycle having 5 to 6 ring atoms, including one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom Means a divalent group substituted at two positions.
  • Specific examples of the heterocyclic ring constituting the group include pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, furan, thiophene, oxazole, oxadiazole, thiazole, thiadiazole and the like.
  • phenylene or 5-6 membered heteroarylene when one or more phenylene or 5-6 membered heteroarylene is inserted into alkyl, the insertion position of phenylene and 5-6 membered heteroarylene, and the substitution position of phenylene and 5-6 membered heteroarylene are There is no particular limitation.
  • the number of inserted phenylene and 5-6 membered heteroarylene is, for example, 1 to 5, preferably 1 to 3.
  • —CH 2 — of alkyl when one or more —CH 2 — of alkyl is replaced with —O—, the position of —CH 2 — to be replaced is not particularly limited as long as it can be replaced. Further, phenylene or a 5-6 membered heteroarylene may be inserted between the substituted —O— and —CH 2 — or between —O— and —O—.
  • the number of —O— to be replaced is, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 3.
  • the position of the replaced single bond is not particularly limited as long as it can be replaced.
  • the double bond may be a cis configuration or a trans configuration.
  • the number of double bonds and triple bonds replaced is, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 3.
  • the “pharmaceutically acceptable salt” of the compound of the present invention is not particularly limited as long as it is a salt that can be used as a pharmaceutical product.
  • Examples of the salt formed by the compound of the present invention with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine.
  • the salt may be an acid addition salt.
  • the salt examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; and formic acid, Examples include acid addition salts with organic acid acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid. .
  • the compounds of the present invention also include hydrates, various solvates and crystal polymorphs.
  • the atoms (for example, hydrogen atom, carbon atom, oxygen atom, nitrogen atom, sulfur atom and phosphorus atom) contained in the compound of the present invention are isotope atoms other than the most naturally occurring isotopes.
  • the isotope atom may be a radioactive conductor atom. That is, according to one aspect of the present invention there is provided a compound of formula (I), (Ia) or (Ib) as defined herein, or a salt thereof, labeled with an isotope atom. .
  • labeling with an isotope atom may be, for example, labeling with a radioisotope ( 3 H, 14 C, 32 P, etc.). From the aspect of ease of preparation of the compound, 3 H Labeling is preferred.
  • the 3 H-labeled compound of the present invention can be synthesized, for example, by using a 3 H-labeled fatty acid or a derivative thereof.
  • the compounds of formula (I), (Ia) and (Ib) are administered as prodrugs and are converted in vivo into active compounds.
  • R 5 of formula (I), R 15 of (Ia) and R 25 of (Ib) may be a group forming a phosphate ester. Specific examples thereof include groups described in Journal of Medicinal Chemistry, 2008, 51 (8), 2337, and the like.
  • C 1-6 alkyl eg, tert-butyl
  • C 1-6 alkoxy C 1- 6 alkyl eg methoxymethyl
  • C 1-6 alkylcarbonyloxy C 1-6 alkyl eg pivaloyloxymethyl
  • C 1-6 alkoxycarbonyloxy C 1-6 alkyl eg isopropoxycarbonyloxy) Methyl
  • optionally substituted phenyl eg, C 1-3 alkoxyphenyl
  • optionally substituted benzyl eg, C 1-6 alkoxy, hydroxy, C 1-6 alkylcarbonyloxy, nitro, and benzyl which may be substituted by a group of 1 to 3 selected from a halogen atom
  • phthalidyl e.g., C 1-6 Good -isobenzofuranone-3-yl optionally substituted by a group having 1 to 4 selected from alkoxy
  • di-oxo Lennon yl methyl e
  • R 1a and R 2a are each independently selected from C 1-6 alkyl ]
  • the compound of the formula (I) can be prepared by condensing the compound 1-1 and the compound 1-2 and then oxidizing.
  • the first stage condensation reaction is carried out in a suitable solvent such as methylene chloride, tetrahydrofuran, N, N′-dimethylformamide, toluene, diethyl ether, 1,4-dioxane, etc. (for example, 1H-tetrazole, etc.) )
  • This step is not particularly limited, but can be performed, for example, at a reaction temperature of 0 to 70 ° C., preferably 15 to 30 ° C., and a reaction time of, for example, 10 minutes to 2 days, preferably 1 to 2 hours.
  • it is desirable that compound 1-1 and compound 1-2 are dissolved in a suitable solvent, mixed and then subjected to azeotropic treatment with a solvent such as toluene or benzene.
  • the second stage oxidation step is carried out in a suitable solvent such as, for example, tert-butylhydrochloride in a suitable solvent such as methylene chloride, tetrahydrofuran, N, N′-dimethylformamide, toluene, diethyl ether, 1,4-dioxane.
  • a suitable solvent such as methylene chloride, tetrahydrofuran, N, N′-dimethylformamide, toluene, diethyl ether, 1,4-dioxane.
  • This step is not particularly limited, but can be performed, for example, at a reaction temperature of 0 to 70 ° C., preferably 15 to 30 ° C., and a reaction time of, for example, 5 minutes to 1 day, preferably 30 minutes to 1 hour.
  • the oxidation reaction in the second stage can be performed on the product obtained by post-treating the condensation reaction in the first stage, but can be performed as a one-pot reaction without
  • the obtained compound 1-3 has a protecting group, it can be subjected to appropriate deprotection conditions and / or by further substituent substitution to obtain the desired formula (I), (Ia) and (Ib ) Can be obtained.
  • the compound of formula (I) can be prepared by acylating compound 2-1 with an acid chloride of compound 2-2.
  • the reaction is carried out in a suitable solvent such as methylene chloride, tetrahydrofuran, N, N′-dimethylformamide, toluene, diethyl ether, 1,4-dioxane and the like in the presence of a suitable base (for example, 4-dimethylaminopyridine).
  • a suitable base for example, 4-dimethylaminopyridine
  • This step is not particularly limited, but can be performed at a reaction temperature of, for example, 0 to 70 ° C., preferably 15 to 30 ° C., and a reaction time of, for example, 10 minutes to 2 days.
  • the acylation can also be carried out using a carboxylic acid corresponding to compound 2-2 and a suitable condensing agent (for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride).
  • a suitable condensing agent for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
  • the obtained compound 2-3 has a protecting group, it can be subjected to appropriate deprotection conditions and / or by further substituent substitution to obtain the desired formula (I), (Ia) and (Ib). ) Can be obtained.
  • the pharmaceutical composition of the present invention can be used in various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, syrups for oral administration.
  • parenteral preparations include, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; transdermal administration or patches , Ointments or lotions; sublingual and buccal patches for buccal administration; and aerosols for nasal administration, but not limited thereto. These preparations can be produced by known methods usually used in the preparation process.
  • the compounds of formula (I), (Ia) and (Ib) are preferably administered as parenteral agents.
  • the pharmaceutical composition may contain various commonly used components, such as one or more pharmaceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, and coloring agents. , Sweeteners, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffering agents, binders, stabilizers, coating agents and the like.
  • the pharmaceutical composition of the present invention may be in a sustained or sustained release dosage form.
  • the dosage of the therapeutic agent, prophylactic agent, or pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, the patient's body shape, age, physical condition, degree of disease, elapsed time after onset, etc.
  • the pharmaceutical composition can comprise a therapeutically effective amount and / or a prophylactically effective amount of a compound of formula (I), (Ia), or (Ib) above.
  • the compound of the above formula (I), formula (Ia) or formula (Ib) can be generally used at a dose of 1 to 10000 mg / day / adult.
  • the pharmaceutical composition may be administered in a single dose or multiple doses, such as immunosuppressants (cyclosporine, tacrolimus, sirolimus, methotrexate, azathioprine, etc.), steroidal anti-inflammatory drugs (hydrocortisone, prednisolone, dexamethasone) Etc.), non-steroidal anti-inflammatory drugs (such as loxoprofen sodium, indomethacin, diclofenac sodium), or antibody drugs (such as infliximab, adalimumab, tocilizumab, sertolizumab pegol, etanercept) You can also.
  • immunosuppressants cyclosporine, tacrolimus, sirolimus, methotrexate, azathioprine, etc.
  • steroidal anti-inflammatory drugs hydrocortisone, prednisolone, dexamethasone
  • non-steroidal anti-inflammatory drugs such as loxoprofen sodium
  • the therapeutic agent or prophylactic agent of the present invention may contain a conventionally known coloring agent, preservative, flavoring, flavoring agent, coating agent, antioxidant, vitamin, amino acid, peptide, protein, and mineral content (iron, zinc, if necessary). , Magnesium, iodine, etc.).
  • the therapeutic agent or prophylactic agent of the present invention is in a form suitable for pharmaceutical compositions, functional foods, health foods, beverages, supplements, etc., such as granules (including dry syrup), capsules (soft capsules, hard capsules). , Prepared in the form of various solid preparations such as tablets (including chewables), powders (powder), pills, or liquid preparations for internal use (including liquids, suspensions, syrups) May be.
  • the therapeutic agent or prophylactic agent of the present invention can be used as it is as a pharmaceutical composition, functional food, health food, supplement or the like.
  • additives for formulation for example, excipients, lubricants, binders, disintegrants, fluidizers, dispersants, wetting agents, preservatives, thickeners, pH adjusters, colorants, Examples include flavoring agents, surfactants, and solubilizing agents.
  • thickeners such as pectin, xanthan gum, and guar gum, can be mix
  • thickeners such as pectin, xanthan gum, and guar gum
  • it can also be set as a coating tablet using a coating agent, or it can also be set as a paste-form glue. Furthermore, even if it is a case where it prepares in another form, what is necessary is just to follow the conventional method.
  • Reagents and data measurement reagents are available from Sigma-Aldrich Chemical Co. Those purchased from Tokyo Chemical Industry, Wako Pure Chemicals, and Kanto Chemical were used without further purification. 1 H- and 13 C-NMR were measured using a BRUKER AVANCE 400 spectrometer (400 MHz), and the chemical shift was deuterated chloroform (7.26 ppm ( 1 H-NMR), 77.00 ppm ( 13 C-NMR)). In ppm. 31 P-NMR chemical shifts are expressed in ppm relative to phosphoric acid in water (85% w / w, 0.00 ppm).
  • Mass spectrometry was measured in the BRUKER microTOF-05 spectrometer (ESI-TOF) or a SHIMADZU AXIMA-TOF (MALDI-TOF) positive and negative ion mode.
  • Silica gel used for column chromatography was purchased from Kanto Chemical. Elemental analysis was performed using a Yanaco MT-6 CHN CORDER spectrometer.
  • 1,3-Diisopropylcarbodiimide (6.325 g, 50.1 mmol) and CuCl (50.8 mg, 0.513 mmol) were dissolved in anhydrous tBuOH (4.556 g, 59.9 mmol), and at room temperature under argon atmosphere for 3 days Stir. A small portion of the reaction mixture was taken and the completion of the reaction was confirmed by 1 H-NMR. Anhydrous CH 2 Cl 2 (25 ml) and polyvinylpyrrolidone (1.004 g) were added to the reaction mixture, stirred for 15 minutes and filtered through Celite®. The filtrate was concentrated to give the title compound (8.18 g, 40.47 mmol, 81%, green oil). The obtained compound was used as an esterification reagent without further purification.
  • Step 2 Preparation of N-tert-butoxycarbonylserine tert-butyl ester
  • L-serine (1.025 g, 9.756 mmol) was dissolved in a mixture of 1N NaOH aqueous solution (1N, 10 ml), H 2 O (10 ml) and dioxane (20 ml), and the mixture was stirred at 0 ° C.
  • Di-tert-butyl dicarbonate (3.192 g, 14.63 mmol) was added to the solution at 0 ° C., and the mixture was stirred as it was for 10 minutes and then at room temperature for 24 hours.
  • 5% KHSO 4 aqueous solution was added to the reaction mixture to bring the pH to 3 and extracted with AcOEt (150 ml ⁇ 3). The organic layers were combined, washed with brine and dried over Na 2 SO 4 .
  • N-Boc serine was distilled off to give N-Boc serine as a crude product (2.228 g, colorless oil).
  • Step 3 Preparation of (2S) -3-[(diisopropylamino) -tert-butoxyphosphinooxy] -2- (tert-butoxycarbonylamino) propionic acid tert-butyl ester
  • 1,3-propanediol (623.3 mg, 8.192 mmol) and pyridine (0.2 ml) were dissolved in CH 2 Cl 2 (15 ml) and oleoyl chloride (623.4 mg in CH 2 Cl 2 (5 ml). , 2.072 mmol) was added dropwise at 0 ° C.
  • the reaction mixture was stirred for 24 hours and quenched with 5% KHSO 4 aqueous solution (15 ml).
  • the organic layer was separated, washed with 5% aqueous KHSO 4 solution and brine, dried over Na 2 SO 4 and concentrated.
  • Step 5 Preparation of (2S) -2- (tert-butoxycarbonylamino) -3-[(3-oleoyloxypropoxy) -tert-butoxy-phosphoryloxy] propionic acid tertbutyl ester
  • Example 9 In the production of Example 9, the following compounds were used as synthetic intermediates.
  • Example 13 In the production of Example 13, the following compounds were used as synthetic intermediates.
  • Step 1 Preparation of 8-azidooctanoic acid N 3 — (CH 2 ) 7 COOH
  • DMF DMF
  • NaN 3 5.76 g, 88.60 mmol
  • KHSO 4 aqueous solution 1N, 50 ml
  • hexane 100 ml ⁇ 3
  • Step 2 Preparation of 8- (4-heptyl-1,2,3-triazol-1-yl) octanoic acid
  • 1,3-propanediol 324.4 mg, 4.263 mmol
  • 6- ⁇ 4-hexyl- (2Z) -2-buten-1-yloxy ⁇ hexanoic acid 300.2 mg, 1.048 mmol
  • 4-dimethyl Aminopyridine (14.3 mg, 0.119 mmol) was dissolved in CH 2 Cl 2 (10 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (212.5 mg, 1.109 mmol) was added to 0. The mixture was added at ° C and stirred at room temperature for 19 hours.
  • Example 16 In the production of Example 16, the following compounds were used as synthetic intermediates.
  • Step 1 3-tert-butyldimethylsilyloxy-1-propanol TBSO- (CH 2 ) 3 —OH NaH (790.9 mg, 19.77 mmol) was suspended in THF (3 ml) and stirred at 0 ° C. To the suspension was added dropwise a solution of 1,3-propanediol (1000.4 mg, 13.15 mmol) in THF (3 ml) and stirred at 0 ° C. for 30 minutes. A solution of tert-butyldimethylsilyl chloride (2.3841 g, 5.82 mmol) in THF (4 ml) was added dropwise and stirred at room temperature for 22.5 hours.
  • Step 3 3-tert-butyldimethylsilyloxy-propionic acid TBSO- (CH 2 ) 2 —COOH 3-tert-butyldimethylsilyloxy-1-propanal (1.0438 g, 5.542 mmol) and 2-methyl-2-butene (1.7191 g, 24.51 mmol) were dissolved in t BuOH (15 ml) and H A solution of NaH 2 PO 4 .2H 2 O (867.8 mg, 5.562 mmol) and NaClO 2 (2.0425 g, 22.58 mmol) in 2 O (5 ml) was added and stirred at room temperature for 1 hour.
  • Step 1 Preparation of N-tert-butoxycarbonyl-L-allo-threonine tert-butyl ester
  • Step 2 (2S, 3S) -3-[(Diisopropylamino) -tert-butoxyphosphinooxy] -2- (tert-butoxycarbonylamino) -3-methyl-propionic acid tert-butyl ester
  • Step 1 Preparation of (R) -4- (4-methoxyphenoxy) methyl-2,2-dimethyl-1,3-dioxolane
  • Step 5 (2S, 3S) -2-tert-butylcarbonylamino-3-[((2R) -2- (tert-butyldimethylsilyloxy) -3- (4-methoxyphenoxy) propoxy) -tert-butoxy [Phosphoryloxy] butyric acid tert-butyl ester
  • tert-butyl hydroperoxide (TBHP) decane solution (5.0-6.0 M, 0.251 ml, 1.255 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours. did.
  • Step 7 (2S, 3S) -2-tert-Butylcarbonylamino-3-[((2R) -2- (tert-butyldimethylsilyloxy) -3-hydroxypropoxy) -tert-butoxyphosphoryloxy] butyric acid tert -Preparation of butyl esters
  • Step 8 Preparation of (2S, 3S) -2-amino-3-[((2R) -2-hydroxy-3-oleoyloxypropoxy) -hydroxyphosphoryloxy] butyric acid
  • reaction mixture was stirred at room temperature for 3.5 hours, tert-butyl hydroperoxide (TBHP) decane solution (5.0-6.0 M, 0.431 ml, 2.155 mmol) was added at room temperature, and the mixture was further stirred for 1.5 hours. did.
  • TBHP tert-butyl hydroperoxide
  • Step 7 Preparation of (2S) -2-amino-3-[((2R) -2-hydroxy-3- ⁇ 3- (2-heptyloxyphenyl) propionyloxy ⁇ propoxy) -hydroxyphosphoryloxy] propionic acid
  • Step 1 Cloning of P2Y10 and GPR174 genes
  • Full-length cDNAs of human, mouse, and rat P2Y10 and GPR174 genes were obtained by PCR using HUVEC cells, mouse tail genome, and rat tail genome as templates.
  • the oligonucleotide consisting of the nucleotide sequence represented by SEQ ID NO: 1-6 is used as a forward primer
  • the oligonucleotide consisting of the nucleotide sequence represented by SEQ ID NO: 7-12 is used as a reverse primer Using.
  • a base sequence containing a restriction enzyme KpnKI recognition site is added to the 5 ′ end of each of the forward primers.
  • a base sequence including a restriction enzyme Sma I recognition site is added to the 3 ′ ′ end of human P2Y10 of the reverse primer, and restriction enzyme EcoR is added to the 3 ′ ′ end of human GPR174, mouse and rat P2Y10 and GPR174.
  • Each nucleotide sequence including a V recognition site is added.
  • PrimeSTARPrimHS # R010Q, 010TAKARA
  • the base sequences represented by SEQ ID NOs: 13 to 15 have open reading frames (O R F) of 984 bases, 987 bases, and 987 bases in human, mouse, and rat, respectively, and are predicted from this O R F.
  • the amino acid sequences (328 amino acids, 329 amino acids, and 329 amino acids) were as shown in SEQ ID NOs: 19 to 21, respectively.
  • the base sequences represented by SEQ ID NOs: 16 to 18 have ORFs of 1002 bases, 1008 bases and 1008 bases in human, mouse and rat, respectively, and amino acid sequences predicted from these ORFs (each 334 Amino acids, 336 amino acids, 336 amino acids) were as shown in the amino acid sequences represented by SEQ ID NOs: 22 to 24.
  • Step 2 Evaluation of agonist activity by TGF ⁇ cleavage assay HEK293 cells are suspended in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS) at 2.0x10 5 cells / mL, and 4 mL in a 60 mm dish. Seeded one by one. After culturing for 24 hours in the presence of 5% CO 2 , various expression vectors were transfected using LipofectAMINE 2000 (Invitrogen). 1 ⁇ g of AP-tagged TGF ⁇ plasmid vector and 1 ⁇ g of mouse P2Y10 or GPR174 plasmid vector were used per 60 mm dish.
  • DMEM Dulbecco's modified Eagle's medium
  • FCS fetal calf serum
  • AP-labeled TGF ⁇ is a protein in which human placental alkaline phosphatase is fused to the N-terminal side of membrane-bound pro-TGF ⁇ , and the AP-labeled TGF ⁇ plasmid vector is Tokumaru et al., J Cell Biol 151, 209-220 ( 2000). Twenty-four hours after transfection, the cells were detached using trypsin / EDTA, resuspended in a culture solution to 2.0 ⁇ 10 4 cells / well, and seeded in a 96-well plate. When stimulating with a compound, Hanks balanced salt solution (HBSS, containing 5 mM HEPES) was used for resuspension.
  • HBSS Hanks balanced salt solution
  • test compounds were added, and the mixture was further allowed to stand for 1 hour in the presence of 5% CO 2 .
  • the 96-well plate was centrifuged (190 ⁇ g, 3 minutes), and 80 ⁇ L of the supernatant was transferred to another 96-well plate.
  • 80 ⁇ L of a reaction buffer 40 mM Tris-HCl (pH 9.5)
  • p-NPP p-nitrophenyl phosphate
  • OD405 was measured with a microplate reader (background), heated at 37 ° C. for 1 hour, and then measured again.
  • the AP activity was calculated by applying a value obtained by subtracting the background from the second absorbance to the following equation.
  • Example 34 LPS (18: 1)
  • Example 1 deoxy-LPS (18: 1)
  • Example 19 LPalloT (18: 1)
  • deoxy-LPS (18: 1) is an agonist having selectivity for P2Y10
  • LPalloT (18: 1) is a selectivity for GPR174.
  • Emax maximum response value
  • MRL-lpr / lpr mice (hereinafter also referred to as MRL / lpr mice, 8-9 weeks old, rabbit) were purchased from Japan SLC Co., Ltd.
  • the compound of Example 34 (LPS (18: 1), purchased from Avanti Polar Lipids, 858143C) was taken into a silicon-coated glass tube (Asahi Techno Glass, 9831-1207) with a microsyringe and dried to nitrogen, 0.01% (w / v) BSA-PBS was added, vortexed, and sonicated with a bath sonicator for 2 minutes to prepare 10 mM LPS.
  • a small osmotic pump (Alzet, model 2006) was soaked in physiological saline (Otsuka raw food injection) and incubated at 37 ° C for 60 hours. Thereafter, each osmotic pump was filled with 200 ⁇ L of LPS solution and 0.01% (w / v) BSA-PBS using a 1 mL syringe (TERUMO, SS-01T) and the attached 27G needle. After administration of Nembutal anesthetic to Balb / c mice at 100 mg / kg, a small osmotic pump was implanted vertically into the abdominal cavity of the mouse, and the peritoneum and abdominal wall were sutured.
  • MRL / lpr mice ( ⁇ , 9 weeks old) were filled with the compound of Example 34 (LPS (18: 1), 10 mM) (small discharge rate 0.15 ⁇ L / hr, 42 days) ) Was implanted into the abdominal cavity to provide a continuous supply of LPS (18: 1).
  • LPS low-density polypeptide
  • VetScan HM2 fully automated blood cell device
  • Measurement of the amount of autoantibodies was performed by the following procedure.
  • a 96-well assay plate was coated with a poly-L-lysine solution (50 ⁇ L / well) and allowed to stand at room temperature for 8 hours to coat the well bottom.
  • 100 ⁇ l / well of 1 ng / ⁇ L DNA solution was added and incubated at 37 ° C. for 8 hours to bind to the plate.
  • 180 ⁇ L / well of blocking buffer was added, and blocking was performed at room temperature for 2 hours.
  • a serum sample diluted with assay buffer was added at 50 ⁇ L / well and allowed to stand at room temperature for 2 hours. Then wash 3 times with TTBS using Skan Washer 400 (Molecular Devices), add 50 ⁇ L / well of biotinylated anti-mouse IgG (H + L) (Vector, BA2001) diluted 2000 times with Assay buffer, and react for 2 hours. I let you.
  • kidney paraffin sections were prepared and immunocomplexes were stained with anti-mouse IgG antibodies. Paraffin sections were deparaffinized by sequentially immersing them in Xylen (3 times), 100% (3 times), 90%, 70%, and 50% EtOH for 3 minutes each, and then washed with running water for 5 minutes. Thereafter, the slide was immersed in 3% H 2 O 2 for 30 minutes to inactivate the tissue's endogenous peroxidase, and washed again with running water for 5 minutes. Using a pressure cooker, the slide glass was immersed in 1 mM EDTA to activate the antigen, and then endogenous biotin was blocked using an Avidin / Biotin Blocking kit (VECTOR, SP-2001).
  • VECTOR Avidin / Biotin Blocking kit
  • the plate was washed with PBS, DAPI was added and nuclear staining was performed for 5 minutes, and then the excess solution was washed off with PBS and encapsulated using an encapsulating agent, Aqueous Mounting Medium, PermaFluor (Thermo, TA-030-FM).
  • an encapsulating agent Aqueous Mounting Medium, PermaFluor (Thermo, TA-030-FM).
  • the small osmotic pump is used in the same procedure as in Test Example 2. Implanted in the abdominal cavity of mice. After 4 days, the animals were fasted for 12 hours, and concanavalin A (ConA) was intravenously injected at 20 mg / kg. After a certain time, blood was collected to prepare serum. After perfusion with PBS, the liver was removed and paraffin blocks and sections were prepared. Alanine transaminase (ALT) in serum was measured using transaminase CII test Wako. Paraffin sections were stained with hematoxylin and eosin and observed using an optical microscope.
  • ConA concanavalin A
  • spleen cells activated with ConA were collected, and total RNA was extracted using GenElute Mammalian Total RNA kit (SIGMA-ALDRICH). Further, cDNA was obtained by reverse transcription using a high capacity cDNA RT kit (Applied Biosystems) according to a conventional method. cDNA, a primer for measuring a target gene, and SYBR Green PCR Master Mix (Applied Biosystems) were mixed, and PCR products were quantified by real-time PCR using 7300 Real-Time PCR System. Oligonucleotides shown in SEQ ID NOs: 25 to 28 were used as primers. Further, GAPDH primers used as control genes are shown in SEQ ID NOs: 29 and 30. The expression levels of P2Y10 receptor and GPR174 receptor are shown in FIGS. It was confirmed that the expression level of any receptor increased upon stimulation with concanavalin A.
  • Spleen cells activated with ConA were collected, washed twice with PBS, suspended in PBS containing 1 ⁇ M CMFDA, and fluorescently labeled at 37 ° C. for 1 hour. Further, the spleen cells were washed twice with PBS and suspended in RPMI1640 medium (containing 0.01% bovine serum albumin (BSA)). A 96-well black plate was treated with 2.5 ⁇ g / ml recombinant mouse ICAM Fc at 4 ° C. for 24 hours, and blocked with PBS containing 0.5% BSA for 30 minutes. 96 well palte was washed 3 times with PBS, and spleen cells were seeded at 2 ⁇ 10 5 cells / well.
  • BSA bovine serum albumin
  • LPS (18: 1), deoxy LPS (18: 1), and LPalloT (18: 1) were used.
  • the test results are shown in FIG. From the test results, it was confirmed that LPS (18: 1) and deoxy LPS (18: 1) inhibit adhesion of spleen cells to ICAM-1, but LPalloT (18: 1) does not inhibit this adhesion ( Compound final concentration: 10 ⁇ M).
  • mice Male, body weight 20-25 g
  • RPMI1640 medium 100 mU / ml penicillin, 100 ⁇ g
  • streptomycin 2 mM L-glutamine, 10% FBS
  • Stimulation was performed in the presence of 1 ⁇ g / ml ConA, and the cells were cultured at 37 ° C. for 60 hours.
  • Spleen cells activated with ConA were collected, suspended in RPMI1640 medium (containing 0.01% BSA), and seeded on a 96-well plate at 5 ⁇ 10 5 cells / well.
  • Activated spleen cells in the presence of test compounds were stimulated at 37 ° C. with 1 ⁇ / ml ConA to promote IL-2 production.
  • the culture supernatant was collected from the 96 well plate.
  • the concentration of IL-2 in the supernatant was determined by sandwich ELISA using Mouse IL-2 Matched Antibody Pairs for ELISA (eBioscience, BMS601MST). The measured value was expressed as mean value ⁇ standard error after several repeated experiments using spleen cells collected from different mouse individuals.
  • LPS (18: 1), deoxy-LPS (18: 1), and LPalloT (18: 1) were used.
  • the test results are shown in FIG. From the test results, LPS (18: 1) and LPalloT (18: 1) inhibit IL-2 production in spleen cells in a concentration-dependent manner, but deoxy-LPS (18: 1) inhibits IL-2 production. It was confirmed not to.

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Abstract

La présente invention porte sur un procédé de criblage d'un agent préventif ou thérapeutique pour une maladie auto-immune, ledit procédé de criblage consistant à évaluer une activité agoniste ou une activité antagoniste d'un composé d'essai sur un récepteur de lysophosphatidylsérine à l'aide de P2Y10 ou de GPR174.
PCT/JP2012/062782 2011-05-19 2012-05-18 Médicament thérapeutique pour maladie auto-immune WO2012157746A1 (fr)

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WO2014119649A1 (fr) 2013-01-31 2014-08-07 国立大学法人 東京大学 Composé présentant une activité régulatrice sur la fonction des récepteurs de la lysophosphatidylsérine
JP2016017037A (ja) * 2014-07-04 2016-02-01 国立大学法人 東京大学 脂肪酸サロゲートを含むリゾホスファチジルセリン誘導体
US9856278B2 (en) 2014-07-04 2018-01-02 The University Of Tokyo Lysophosphatidylserine derivative
CN112707813A (zh) * 2020-12-25 2021-04-27 山东益丰生化环保股份有限公司 一种月桂酸丙二醇酯型抗磨剂的制备方法
WO2021195555A1 (fr) * 2020-03-27 2021-09-30 Travecta Therapeutics, Pte. Ltd. Composés de palmitoyléthanolamide
WO2023145873A1 (fr) * 2022-01-27 2023-08-03 国立大学法人東京大学 Analogue de lysophosphatidylsérine, et composition pharmaceutique contenant un analogue de lysophosphatidylsérine pour le traitement ou la prévention de la fibrose

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014119649A1 (fr) 2013-01-31 2014-08-07 国立大学法人 東京大学 Composé présentant une activité régulatrice sur la fonction des récepteurs de la lysophosphatidylsérine
JP2014148480A (ja) * 2013-01-31 2014-08-21 Univ Of Tokyo リゾホスファチジルセリン受容体機能調節活性を有する化合物
US9469665B2 (en) 2013-01-31 2016-10-18 The University Of Tokyo Compound having lysophosphatidylserine receptor function modulation activity
JP2016017037A (ja) * 2014-07-04 2016-02-01 国立大学法人 東京大学 脂肪酸サロゲートを含むリゾホスファチジルセリン誘導体
US9856278B2 (en) 2014-07-04 2018-01-02 The University Of Tokyo Lysophosphatidylserine derivative
WO2021195555A1 (fr) * 2020-03-27 2021-09-30 Travecta Therapeutics, Pte. Ltd. Composés de palmitoyléthanolamide
CN112707813A (zh) * 2020-12-25 2021-04-27 山东益丰生化环保股份有限公司 一种月桂酸丙二醇酯型抗磨剂的制备方法
WO2023145873A1 (fr) * 2022-01-27 2023-08-03 国立大学法人東京大学 Analogue de lysophosphatidylsérine, et composition pharmaceutique contenant un analogue de lysophosphatidylsérine pour le traitement ou la prévention de la fibrose

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