WO2015199234A1 - ハロゲン置換へテロ環化合物の塩 - Google Patents
ハロゲン置換へテロ環化合物の塩 Download PDFInfo
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- WO2015199234A1 WO2015199234A1 PCT/JP2015/068575 JP2015068575W WO2015199234A1 WO 2015199234 A1 WO2015199234 A1 WO 2015199234A1 JP 2015068575 W JP2015068575 W JP 2015068575W WO 2015199234 A1 WO2015199234 A1 WO 2015199234A1
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- WAPNOHKVXSQRPX-SSDOTTSWSA-N C[C@H](c1ccccc1)O Chemical compound C[C@H](c1ccccc1)O WAPNOHKVXSQRPX-SSDOTTSWSA-N 0.000 description 3
- 0 COC(C1(CC1)c(cc1)ccc1-c(c(OC)c1)ccc1C1=SC(Cl)=C*1)=O Chemical compound COC(C1(CC1)c(cc1)ccc1-c(c(OC)c1)ccc1C1=SC(Cl)=C*1)=O 0.000 description 2
- PJAIPOURWYZKNH-UHFFFAOYSA-N CCOC(C1(CC1)c(cc1)ccc1-c(c(OC)c1)ccc1-c([s]c(Cl)c1)c1C(N)=O)=O Chemical compound CCOC(C1(CC1)c(cc1)ccc1-c(c(OC)c1)ccc1-c([s]c(Cl)c1)c1C(N)=O)=O PJAIPOURWYZKNH-UHFFFAOYSA-N 0.000 description 1
- KRIPRTUJBRGLKG-UHFFFAOYSA-N CCOC(C1(CC1)c(cc1)ccc1-c(c(OC)c1)ccc1-c([s]c(F)c1)c1C(OC(C)(C)C)=O)=O Chemical compound CCOC(C1(CC1)c(cc1)ccc1-c(c(OC)c1)ccc1-c([s]c(F)c1)c1C(OC(C)(C)C)=O)=O KRIPRTUJBRGLKG-UHFFFAOYSA-N 0.000 description 1
- GKMDOOLJKGFSEZ-UHFFFAOYSA-N Cc1c(-c2ccc(-c3ccc(C4(CC4)C(O)=O)cc3)c(OC)c2)[s]c(Cl)c1 Chemical compound Cc1c(-c2ccc(-c3ccc(C4(CC4)C(O)=O)cc3)c(OC)c2)[s]c(Cl)c1 GKMDOOLJKGFSEZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- 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
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a salt of a novel ⁇ -position halogen-substituted thiophene compound useful as a medicine. Since the salt of the ⁇ -position halogen-substituted thiophene compound of the present invention has a lysophosphatidic acid (LPA) receptor antagonistic action, it is useful for the prevention and / or treatment of diseases caused by LPA.
- LPA lysophosphatidic acid
- Lysophosphatidic acid is a physiologically active phospholipid present in the living body.
- LPA binds to a specific G protein-coupled receptor (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) and transmits a signal into the cell, cell proliferation, differentiation, survival, migration, adhesion, invasion, morphology Regulates formation.
- LPA is also known to be involved in diseases involving fibrosis in various organs.
- Non-Patent Documents 1, 2, and 3 LPA promotes the proliferation and contraction of stellate cells and migration of myofibroblasts, which play an important role in the process of fibrosis of the liver.
- LPA production and LPA1 expression are increased in unilateral ureteral ligated mice, an animal model of renal fibrosis, and that renal fibrosis is suppressed by LPA1 deficiency or administration of an LPA receptor antagonist (See Non-Patent Documents 4 and 5).
- LPA concentration in alveolar lavage fluid of patients with idiopathic pulmonary fibrosis is increased, and LPA1 is most abundantly expressed in fibroblasts having an important role in the process of lung fibrosis.
- LPA1 deficiency or LPA receptor antagonist administration in bleomycin intratracheally administered mice which are animal models of pulmonary fibrosis (see Non-Patent Documents 6 and 7).
- Non-Patent Document 8 It has been reported that skin fibrosis is suppressed by LPA1 deficiency or LPA receptor antagonist administration in bleomycin subcutaneously administered mice, which are scleroderma models, in the skin (see Non-Patent Document 8).
- LPA is also known to be involved in immune / inflammatory diseases. LPA has been reported to enhance migration of human monocytic cells and to be involved in T cell proliferation and invasion. In addition, it is reported that synovial cells of rheumatic patients express LPA receptor, and migration or production of IL-6 and IL-8 by LPA stimulation are inhibited by LPA receptor antagonists. (See Non-Patent Documents 9, 10, and 11).
- LPA and LPA1 are involved in the development of neuropathic pain (see Patent Document 12), LPA is involved in urinary system diseases by constricting the isolated urethral specimen and prostate specimen and increasing the urethral pressure.
- LPA is involved in cancer-related diseases by promoting invasion of cancer cells, promoting proliferation of ovarian cancer cells, or promoting proliferation of prostate cancer cells.
- Non-patent documents 13, 14, and 15 have been reported.
- drugs that antagonize LPA receptors prevent fibrosis-related diseases, immune / inflammatory diseases, central / peripheral nervous system diseases, urological diseases, cancer-related diseases, And / or may be useful for treatment.
- Patent Documents 2 to 23 disclose compounds having an LPA receptor antagonistic action
- Patent Documents 5 to 23 disclose compounds having an LPA receptor antagonistic action
- Patent Document 17 discloses a (2′-methoxy- [1,1′-biphenyl] -4-yl) acetic acid derivative
- Patent Document 19 discloses a 3-chloroisothiazole derivative. There is no disclosure of compounds.
- the present inventors aim to develop excellent therapeutic or preventive drugs for diseases associated with fibrosis, immune / inflammatory diseases, central / peripheral nervous system diseases, urinary system diseases, cancer-related diseases, etc.
- Research on salts of substituted heterocycles, new ⁇ -position halogen-substituted thiophene compound salts with specific structures have excellent LPA receptor antagonistic activity, and drugs (especially diseases associated with fibrosis, immunity / inflammation)
- the present invention was found to be useful for the prevention and / or treatment of sex diseases, central / peripheral nervous system diseases, urinary system diseases, and cancer-related diseases.
- the present invention has a powerful LPA receptor antagonistic action, and particularly treats and / or prevents diseases associated with fibrosis, immune / inflammatory diseases, central / peripheral nervous system diseases, urinary system diseases, cancer-related diseases.
- the present invention provides a salt of a novel ⁇ -position halogen-substituted thiophene compound useful as a drug (preferably a therapeutic drug).
- the present invention provides the following.
- R represents a hydrogen atom or a methoxy group
- X represents a halogen atom
- A is the following group:
- M represents an alkali metal or an alkaline earth metal; n represents 1 when M is an alkali metal, and 2 when M is an alkaline earth metal. ) Salt.
- An LPA receptor antagonist comprising the salt described in any one of (1) to (12) as an active ingredient.
- a pharmaceutical composition comprising the salt described in any one of (1) to (12) as an active ingredient.
- the salt of the ⁇ -position halogen-substituted thiophene compound represented by the general formula (I) of the present invention has a potent LPA receptor antagonistic action, it can be used as a medicine for diseases involving fibrosis, immune / inflammatory diseases, It is useful as a therapeutic and / or prophylactic agent for central / peripheral nervous system diseases, urological diseases and cancer-related diseases.
- halogen atom represented by X is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- halogen atom represented by X is preferably a fluorine atom, a chlorine atom, or a bromine atom, and more preferably a fluorine atom or a chlorine atom.
- alkali metal represented by M include lithium, sodium, potassium, rubidium, cesium, and the like, preferably sodium or potassium.
- alkaline earth metal represented by M include magnesium, calcium, strontium, barium and the like, preferably calcium.
- the salt represented by the general formula (I) of the present invention contains optical isomers, geometric isomers or rotational isomers, these isomers are also included in the scope of the present invention, and proton tautomerism Are present, the tautomers thereof are also included in the scope of the present invention.
- the salt represented by the general formula (I) of the present invention can form a hydrate or a solvate, and each or a mixture thereof is included in the present invention.
- the salt represented by the formula (I) of the present invention may contain one or more non-natural proportions of atomic isotopes.
- atomic isotopes include deuterium ( 2 H), tritium ( 3 H), carbon-14 ( 14 C), fluorine-18 ( 18 F), sulfur-35 ( 35 S), or iodine-125. ( 125 I). These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variants of the salts of formula (I) of the present invention are encompassed by the present invention, whether radioactive or not.
- R, X, A, M and n are as defined above, M ′ and n ′ are as defined above as M and n, and Z ⁇ is a hydroxide ion, halide ion, or An anion such as acetate ion, and R 1 represents a protecting group for carboxylic acid that is deprotected by hydrolysis of an alkyl group or the like.
- the salt of the general formula (I) according to the present invention can be synthesized by any of the above steps 1 to 3.
- the solvent used in the reaction of each of the following steps 1 to 18 is not particularly limited as long as it does not inhibit the reaction and can partially dissolve the starting material.
- reaction temperature varies depending on the solvent, starting material, reagent, etc.
- reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
- the salt of general formula (I) is compoundable by making compound (1) react in a reaction solvent using the hydroxide of an alkali metal or an alkaline-earth metal.
- the reaction solvent is preferably water or a mixed solvent of water / organic solvent, more preferably water, a mixed solvent of acetonitrile / water, or a mixed solvent of acetonitrile / tetrahydrofuran / water.
- Step 2 A salt of general formula (I) can be synthesized by subjecting compound (I ′) and compound (2) to a salt exchange reaction in a reaction solvent.
- the reaction solvent is preferably water or a mixed solvent of water / organic solvent, more preferably water or a mixed solvent of acetonitrile / water.
- Step 3 The salt of the general formula (I) can be synthesized by subjecting the compound (3) to hydrolysis reaction in a reaction solvent using an alkali metal or alkaline earth metal hydroxide.
- the reaction solvent is preferably water or a mixed solvent of water / organic solvent, more preferably a mixed solvent of 2-propanol / water or 2-propanol / tetrahydrofuran / water.
- R, X, A, M, M ′, n, n ′, Z ⁇ and R 1 have the same meaning as described above.
- L, L a, and, M represents a substituent necessary for the coupling reaction, for example, L, or L a is a chlorine atom, a bromine atom, an iodine atom, or, when referring to a trifluoromethanesulfonyloxy group, etc.
- M is boronic acid, boronic acid ester, show a trialkyl tin, L, or, L a boronic acid, boronic acid ester, when showing a trialkyl tin, M is a chlorine atom, a bromine atom, an iodine atom Or a trifluoromethanesulfonyloxy group or the like.
- Step 4 Reaction to compound (4) according to the method described in, for example, Tetrahedron, 64 (2008) pages 9733-9737 or Bioorganic and Medicinal Chemistry Letters, 21 (2011) pages 528-530
- Compound (5) can be synthesized by halogenation in a solvent using a halogenating agent.
- the reaction solvent is preferably an aliphatic hydrocarbon, halogenated hydrocarbon, ether, nitrile, carboxylic acid, amide, sulfoxide, water, or a mixed solvent thereof, more preferably N , N-dimethylformamide.
- Halogenating agents include iodine, N-iodosuccinimide, bromine, N-bromosuccinimide, 1,2-dibromoethane, 1,2-dibromo-1,1,2,2-tetrafluoroethane, chlorine, N-chloro
- Examples include succinimide, xenon difluoride, N-fluorobenzenesulfonimide, N-fluoro-N ′-(chloromethyl) triethylenediaminebis (tetrafluoroborate), and the like.
- a reaction solvent is prepared according to the method described in, for example, Tetrahedron Letters, 51 (2010) 4526-4529, or Journal of Medicinal Chemistry, 54 (2011) 2687-2700.
- the compound (5) can be synthesized by converting it to an anion using a base and then treating with a halogenating agent.
- the reaction solvent is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, or a mixed solvent thereof, more preferably an ether, an aliphatic hydrocarbon, Or, a mixed solvent thereof.
- the base examples include alkyl lithiums such as n-butyl lithium, sec-butyl lithium, or tert-butyl lithium; lithium diisopropylamide, or lithium amide such as lithium 2,2,6,6-tetramethylpiperidide Grignard reagents such as ethylmagnesium bromide, ethylmagnesium chloride, isopropylmagnesium chloride, and phenylmagnesium chloride; Magnesium amides such as diisopropylamide magnesium chloride, 2,2,6,6-tetramethylpiperidine magnesium chloride; Examples thereof include disilazane bases such as lithium 1,1,1,3,3,3-hexamethyldisilazane and potassium 1,1,1,3,3,3-hexamethyldisilazane.
- alkyl lithiums such as n-butyl lithium, sec-butyl lithium, or tert-butyl lithium
- lithium diisopropylamide, or lithium amide such as lithium
- halogenating agent examples include iodine, N-iodosuccinimide, bromine, N-bromosuccinimide, carbon tetrabromide, 1,2-dibromoethane, 1,2-dibromo-1,1,2,2-tetrafluoroethane, Examples include chlorine, N-chlorosuccinimide, carbon tetrachloride, xenon difluoride, N-fluorobenzenesulfonimide, or N-fluoro-N ′-(chloromethyl) triethylenediaminebis (tetrafluoroborate).
- Step 5 Compound (6) and Compound (7) are converted into a coupling catalyst, a ligand, and / or a reaction solvent in a reaction solvent in accordance with, for example, the method described in Tetrahedron, 58 (2002) pages 9633-9695.
- Compound (8) can be synthesized by reacting in the presence of a base.
- the reaction solvent is preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, ketones, esters, nitriles, alcohols, amides, sulfoxides, sulfones, water, or a mixture thereof
- the coupling catalyst tetrakis (triphenylphosphine) palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, methylene chloride adduct, bis (triphenylphosphine) palladium (II ) Palladium catalysts such as dichloride, tris (dibenzylideneacetone) dipalladium (0), or palladium (II) acetate; nickel catalysts such as bis (triphenylphosphine) nickel (II) dichloride.
- the ligand may be contained in the coupling catalyst itself, but is triphenylphosphine, [1,1′-bis (diphenylphosphino) ferrocene], dibenzylideneacetone, triphenylarsine, tri (o-tolyl) phosphine. , Tri-tert-butylphosphine, tricyclohexylphosphine, and the like.
- the base examples include fluoride salts such as potassium fluoride or cesium fluoride; carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or thallium carbonate; sodium hydroxide, potassium hydroxide, water
- fluoride salts such as potassium fluoride or cesium fluoride
- carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or thallium carbonate
- metal hydroxides such as barium oxide or thallium hydroxide
- phosphates such as potassium phosphate
- organic bases such as triethylamine or diisopropylethylamine.
- it is sodium carbonate.
- Step 6 Compound (8) is prepared from a palladium catalyst, a ligand, a boronic acid reagent, and a boron catalyst in a reaction solvent according to the method described in, for example, Journal of the American Chemical Society, 129 (2007), pages 4595-4605. / Or Compound (9) can be synthesized by reacting in the presence of a base.
- L represents a chlorine atom, a bromine atom, an iodine atom, a trifluoromethanesulfonyloxy group or the like
- M represents a boronic acid, a boronic acid ester or the like.
- the reaction solvent is preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, ketones, esters, nitriles, alcohols, amides, sulfoxides, sulfones, water, or a mixture thereof
- a solvent and more preferably 1,4-dioxane.
- the palladium catalyst examples include tetrakis (triphenylphosphine) palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, methylene chloride adduct, bis (triphenylphosphine) palladium (II) Examples thereof include dichloride, tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, methylene chloride adduct or palladium (II) acetate is preferred.
- the ligand may be contained in the coupling catalyst itself, but is triphenylphosphine, [1,1′-bis (diphenylphosphino) ferrocene], dibenzylideneacetone, triphenylarsine, tri (o-tolyl) phosphine. , Tri-tert-butylphosphine, tricyclohexylphosphine, and the like. Preferably, it is tricyclohexylphosphine.
- Examples of the boronic acid reagent include 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane), 4,4,5, Examples include 5-tetramethyl-1,3,2-dioxaborolane.
- Examples of the base include potassium acetate and sodium acetate.
- the compound (9) can be synthesized by treating with a boronic acid reagent.
- the reaction solvent is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an amide, a sulfoxide, a sulfone, or a mixed solvent thereof, more preferably Ethers, aliphatic hydrocarbons, or mixed solvents thereof.
- the base include alkyl lithiums such as n-butyl lithium, sec-butyl lithium, or tert-butyl lithium; Grignard reagents such as ethyl magnesium bromide, ethyl magnesium chloride, isopropyl magnesium chloride, and phenyl magnesium chloride. Can be mentioned.
- boronic acid reagent examples include trimethyl borate, triisopropyl borate, trihexadecyl borate, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and the like.
- Step 7 and Step 8 Compound (10) or Compound (12) is synthesized by reacting Compound (5) or Compound (11) and Compound (9) in the same manner as in Step 5. can do.
- Step 9 Compound (13) can be synthesized in the same manner as in Step 4 for compound (12).
- Step 10 Compound (14) can be synthesized by deprotecting compound (13) with an acid in a reaction solvent or without solvent.
- the reaction solvent is preferably an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ketone, ester, nitrile, carboxylic acid, alcohol, amide, sulfoxide, sulfone. Water, or a mixed solvent thereof, more preferably methylene chloride.
- the acid examples include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid, trifluoroacetic acid, and trichloroacetic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Trifluoroacetic acid.
- Step 11 Compound (15) can be synthesized by subjecting compound (10) to a hydrolysis reaction in the presence of an acid or a base in a reaction solvent.
- the reaction solvent is preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, nitriles, carboxylic acids, alcohols, amides, sulfoxides, sulfones, water Or a mixed solvent thereof, more preferably a mixed solvent of ethanol / tetrahydrofuran / water or 2-propanol / tetrahydrofuran / water.
- the acid or base examples include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid and trifluoroacetic acid; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; lithium hydroxide, Alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkaline metal carbonates such as potassium carbonate or sodium carbonate are mentioned, preferably a base, more preferably lithium hydroxide or water Sodium oxide.
- inorganic acids such as hydrochloric acid and sulfuric acid
- organic acids such as acetic acid and trifluoroacetic acid
- sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid
- lithium hydroxide Alkali metal hydroxides such as sodium hydroxide or potassium hydroxide
- alkaline metal carbonates such as
- Step 12 Compound (15) is condensed with trimethylsilylethanol using a condensing agent in the presence or absence of a base in the reaction solvent in the presence or absence of an additive.
- the reaction solvent is preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, sulfoxides, sulfones, or their A mixed solvent, more preferably N, N-dimethylformamide.
- Examples of the base include sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or carbonates such as thallium carbonate; pyridines such as pyridine, 2,6-lutidine, or 4-picoline; triethylamine or diisopropylethylamine And organic bases such as Diisopropylethylamine is preferable.
- Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, or N-cyclohexyl-N ′-(2-morpholino).
- Carbodiimide condensing agents such as ethyl) carbodiimide meth-p-toluenesulfonate; imidazole condensing agents such as N, N′-carbonyldiimidazole; 4- (4,6-dimethoxy-1,3,5-triazine -2-yl) -4-methylmorpholinium chloride or trifluoromethanesulfonic acid (4,6-dimethoxy-1,3,5-triazin-2-yl)-(2-octoxy-2-oxoethyl) dimethyl Triazine condensing agents such as ammonium; 1H-benzotriazol-1-yloxytris Phosphonium condensing agents such as (dimethylamino) phosphonium hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, or chlorotripyrrolidino
- O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate is preferred.
- the additive include 1-hydroxybenzotriazole or benzotriazoles such as 1-hydroxyazabenzotriazole; pyridines such as N, N-dimethylaminopyridine; or a combination thereof, preferably N, N-dimethylaminopyridine.
- Step 13 Compound (17) is synthesized by reducing compound (17) with a reducing agent in a reaction solvent according to the method described in, for example, Tetrahedron Letters, 47 (2006), pages 5261-5264, etc. Can do.
- the reaction solvent is preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, nitriles, alcohols, amides, sulfoxides, sulfones, water, or These mixed solvents.
- Examples of the reducing agent include borohydrides such as lithium borohydride, sodium borohydride, potassium borohydride, or sodium trimethoxyborohydride; lithium aluminum hydride, sodium aluminum hydride, diisobutylaluminum hydride, or And aluminum hydrides such as trimethoxylithium aluminum hydride.
- borohydrides such as lithium borohydride, sodium borohydride, potassium borohydride, or sodium trimethoxyborohydride
- lithium aluminum hydride sodium aluminum hydride, diisobutylaluminum hydride, or
- aluminum hydrides such as trimethoxylithium aluminum hydride.
- optically active compound (18) can be synthesized.
- the compound (18) obtained by these methods can raise optical purity by well-known methods, such as using an enzyme or an optical resolution agent, or those combinations.
- Step 14 and Step 15 Compound (10) or Compound (16) can be prepared in a reaction solvent or in accordance with the method described in, for example, Organic Synthesis, 66 (1988), pages 132-137.
- the compound (3) or the compound (19) can be synthesized by performing the Hofmann rearrangement reaction using the compound (18) and the oxidizing agent in the presence or absence of a solvent and a base, respectively.
- the reaction solvent is preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, sulfoxides, sulfones, or their A mixed solvent, more preferably toluene.
- Examples of the base include organic amines such as triethylamine or diisopropylethylamine; pyridines such as pyridine, 2,6-lutidine, or 4-picoline. Pyridine is preferable.
- Examples of the oxidizing agent include [bis (acetoxy) iodo] benzene, [bis (trifluoroacetoxy) iodo] benzene, and high-valent iodine compounds such as iodosylbenzene, preferably [bis (trifluoroacetoxy) Iodo] benzene.
- Step 16 Compound (14) can be prepared by reacting compound (18), diphenyl in a reaction solvent or without solvent according to the method described in, for example, Journal of the American Chemical Society, 94 (1972) 6203-6205.
- the compound (3) can be synthesized by performing a Curtius rearrangement reaction using phosphoryl azide and a base.
- the reaction solvent is preferably an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ketone, ester, nitrile, amide, sulfoxide, sulfone, water, or A mixed solvent thereof, more preferably toluene.
- the base include organic amines such as triethylamine or diisopropylethylamine, and triethylamine is preferable.
- Step 17 Compound (1) can be synthesized in the same manner as in Step 11 for compound (3).
- Step 18 Compound (1) can be synthesized by reacting compound (19) with a deprotection reagent in a reaction solvent.
- the reaction solvent is preferably an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ketone, ester, nitrile, carboxylic acid, alcohol, amide, sulfoxide, sulfone. Water, or a mixed solvent thereof, more preferably N, N-dimethylformamide.
- deprotecting reagents include hydrofluoric acid; inorganic fluoride salts such as potassium fluoride; organic fluoride such as pyridine hydrofluoride, triethylamine hydrofluoride, or 1-hexadecane hydrofluoride Hydrogen salt; ammonium fluorides such as tetraethylammonium fluoride or tetrabutylammonium fluoride; difluorotrimethylsilicates such as tris (dimethylamino) sulfonium difluorotrimethylsilicate. Tetrabutylammonium fluoride is preferred.
- the compound of the formula (I ′) can be synthesized from the compound of the formula (1) according to the method of Step 1 using M ′ n ′ + (OH ⁇ ) n ′ .
- the target compound produced in each reaction can be obtained from the reaction mixture according to a conventional method.
- a solid containing the target product can be obtained by filtering the reaction mixture.
- the target compound or a part of the target compound is dissolved in the reaction mixture, the target compound is removed by removing the solvent as it is or after removing the insoluble substance by filtration (for example, lyophilization). can get.
- a desiccant such as anhydrous magnesium sulfate or anhydrous sodium sulfate
- the target compound can be obtained by distilling off the solvent.
- the obtained target compound is commonly used in conventional methods, for example, washing with water, an organic solvent, or a mixed solvent thereof; recrystallization; reprecipitation; or usually separating and purifying organic compounds.
- Method for example, adsorption column chromatography using a carrier such as silica gel or alumina; ion exchange chromatography; or normal phase / reverse phase column chromatography using silica gel or alkylated silica gel (preferably high performance liquid chromatography
- the salt represented by the general formula (I) of the present invention when used as a medicine, it can be administered as it is (as it is in the bulk), or an appropriate pharmacologically acceptable excipient, dilution Tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions, transdermal absorption agents, suppositories, ointments, lotions, inhalations Oral or parenteral (intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, transrespiratory administration, intradermal administration, subcutaneous administration, etc.) in the form of an agent or injection can do.
- an appropriate pharmacologically acceptable excipient dilution Tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions, transdermal absorption agents, suppositories, ointments, lotions, inhalations
- compositions are produced by a known method using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, or diluents.
- Excipients include, for example, organic excipients or inorganic excipients.
- organic excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; Dextran; or pullulan and the like.
- inorganic excipient include light anhydrous silicic acid; or sulfates such as calcium sulfate.
- Lubricants include, for example, stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or gallow; boric acid; adipic acid; sulfate such as sodium sulfate; glycol Fumaric acid; sodium benzoate; D, L-leucine; sodium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or starch derivatives in the above-mentioned excipients.
- binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds shown by the above-mentioned excipients.
- Disintegrants are, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked carboxymethylcellulose calcium; crosslinked polyvinylpyrrolidone; or chemically modified such as carboxymethyl starch or carboxymethyl starch sodium A starch or a cellulose derivative is mentioned.
- the emulsifier is, for example, colloidal clay such as bentonite or bee gum; an anionic surfactant such as sodium lauryl sulfate; a cationic surfactant such as benzalkonium chloride; or a polyoxyethylene alkyl ether or a polyoxyethylene sorbitan fatty acid.
- colloidal clay such as bentonite or bee gum
- anionic surfactant such as sodium lauryl sulfate
- a cationic surfactant such as benzalkonium chloride
- a polyoxyethylene alkyl ether or a polyoxyethylene sorbitan fatty acid Nonionic surfactants such as esters or sucrose fatty acid esters are listed.
- Stabilizers include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; acetic anhydride Or sorbic acid.
- parahydroxybenzoates such as methylparaben or propylparaben
- alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol
- benzalkonium chloride phenols such as phenol or cresol
- thimerosal acetic anhydride Or sorbic acid.
- sweeteners such as saccharin sodium or aspartame
- acidulants such as citric acid, malic acid or tartaric acid
- flavors such as menthol, lemon extract or orange extract.
- Diluents are compounds that are commonly used as diluents, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch , Polyvinyl pyrrolidone, or a mixture thereof.
- the dose of the salt represented by the general formula (I) of the present invention may vary depending on conditions such as the patient's symptoms, age, weight, etc., but in the case of oral administration, the lower limit is 0.001 mg per dose. / Kg (preferably 0.01 mg / Kg), upper limit 20 mg / Kg (preferably 10 mg / Kg), in the case of parenteral administration, the lower limit is 0.0001 mg / Kg (preferably 0.0005 mg per dose), respectively. / Kg), and an upper limit of 10 mg / Kg (preferably 5 mg / Kg) can be administered to adults 1 to 6 times per day depending on the symptoms.
- Rf values in the physical properties of Examples and Reference Examples are values measured using thin layer chromatography (manufactured by Merck, TLC plate silica gel 60F 254 (trade name)), and the description in parentheses is a developing solvent (volume ratio). Represents.
- the COOH column in silica gel column chromatography refers to Chromatorex (registered trademark) Q-PACK COOH silica gel pre-packed column manufactured by Fuji Silysia Chemical.
- the ultrapure water used was Wako Pure Chemical Industries (214-01301).
- the mass spectrum ionization mode DUIS is a mixed mode of ESI and APCI.
- Me in the chemical structural formula represents a methyl group.
- the title compound was synthesized as follows.
- the reaction mixture was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to separate the layers.
- the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution. Further, it was washed with a 5% by weight aqueous potassium hydrogen sulfate solution and again with saturated saline.
- the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
- the title compound was synthesized as follows.
- the obtained organic layer was washed successively with aqueous sodium hydrogen sulfite solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
- oxalyl chloride (0.80 ml, 9.1 mmol) was added dropwise with stirring at 0 ° C. in a nitrogen atmosphere, and the mixture was warmed to room temperature and stirred for 30 minutes.
- 3.7 ml (48 mmol) of 28 wt% aqueous ammonia was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour.
- reaction mixture was added dropwise to an aqueous solution in which 1.0 g (30 mmol) of potassium iodide was dissolved in a 48 wt% aqueous hydrobromic acid solution (30 ml) while stirring at room temperature, and the mixture was stirred at the same temperature for 1 hour. .
- the reaction mixture was added little by little to a mixed solution of an aqueous sodium carbonate solution and methylene chloride, and the basicity of the aqueous layer was confirmed, followed by liquid separation.
- the title compound was synthesized as follows.
- N, N-dimethylformamide (10 ml), N, N-dimethylaminopyridine 23.0 mg (0.188 mmol), trimethylsilylethanol 0.42 ml (2.8 mmol), and N, N-diisopropylethylamine 0.98 ml ( 5.6 mmol) was added.
- 1.06 g (2.81 mmol) of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate was added in an ice bath, and the mixture was stirred at room temperature for 18 hours. Stir for hours.
- the title compound can improve the optical purity as follows.
- the title compound can improve the optical purity as follows.
- Carboxylic acid ethyl ester 2.0 g (4.4 mmol), (R) -1-phenylethanol (manufactured by Tokyo Chemical Industry) 0.80 g (6.6 mmol) and pyridine 1.2 ml (15 mmol) in toluene (20 ml)
- 2.4 g (5.6 mmol) of [bis (trifluoroacetoxy) iodo] benzene was added at room temperature, followed by heating and stirring at 60 ° C. for 1.5 hours.
- reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate.
- organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
- reaction mixture was acidified with 1N hydrochloric acid and extracted with methylene chloride.
- organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
- LPA L7260, Sigma, final concentration of 100 nM
- the membrane fraction is collected on glass fiber filter paper (GF / B, manufactured by Whatman) using a cell harvester (M30, manufactured by Brandel), and washed with 10 mM phosphate buffer (pH 7.4).
- the radioactivity of the membrane fraction was measured using a liquid scintillation analyzer (2900TR, manufactured by Packard), and the test compound concentration (IC 50 ) that inhibits the binding of LPA1 receptor and [ 35 S] GTP ⁇ S by 50% was measured using EXSAS ( Obtained by nonlinear regression analysis using version 7.6.0 (manufactured by Arm Systex).
- the absorbance (570 nm) of the filter was measured, and the test compound concentration (IC 50 ) that inhibits the cell migration activity of LPA by 50% was subjected to nonlinear regression analysis using EXSAS (version 7.6.0, manufactured by Arm Systex). Asked.
- the compound of the present invention showed excellent activity.
- the IC 50 values of the compounds of Examples 1 to 15 were 200 nM or less.
- mice LPA-induced histamine release test The mouse LPA-induced histamine release test was performed according to the method of Swaney et al. (The Journal of Pharmacology and Experimental Therapeutics, 336 (2011) pp. 693-700). The test compound was suspended in a 0.5% methylcellulose solution (133-14255, manufactured by Wako Pure Chemical Industries, Ltd.) and orally administered to male CD1 mice (body weight 30-40 g, supplied by Charles River, Japan) at a dose of 10 mL / kg. . Four hours after administration, LPA (857130P, manufactured by Avanti) dissolved in PBS containing 0.1% BSA was administered from the tail vein (300 ⁇ g per mouse).
- mice were anesthetized with isoflurane, and blood was collected from the vein 2 minutes after LPA administration.
- the blood was transferred to a test tube containing EDTA and centrifuged at 2,000 ⁇ g for 10 minutes at 4 ° C. to obtain plasma.
- the histamine concentration in plasma was measured with an EIA kit (62HTMPEB, manufactured by Cisbio Bioassays). From the histamine concentration in the plasma of mice administered with the test compound, the inhibition rate (%) for the 0.5% methylcellulose solution administration group was calculated for each individual, and the proportion of individuals exhibiting an inhibition rate of 80% or more was the effective rate (%) Expressed as:
- the compound of the present invention showed excellent activity, and for example, the effective rate of the compounds of Examples 1 to 15 was 50% or more when administered at 10 mg / kg.
- Bleomycin-induced pulmonary fibrosis model A pulmonary fibrosis model was prepared by administering bleomycin hydrochloride (Nippon Kayaku) to mice. The test compound was orally administered every day from the start of bleomycin administration. Alveolar lavage fluid (BALF) or lungs were collected under isoflurane anesthesia 3 to 42 days after bleomycin treatment. BALF was centrifuged at 800 ⁇ g for 10 minutes to obtain a supernatant. The protein amount of the supernatant was measured using DC protein assay kit (500-0114, manufactured by Biorad), and the amount of collagen was measured using Sircol soluble collagen assay kit (S111, manufactured by Biocolor).
- DC protein assay kit 500-0114, manufactured by Biorad
- S111 Sircol soluble collagen assay kit
- biomarkers related to inflammation and fibrosis in the supernatant were measured using the ELISA method.
- the amount of hydroxyproline in the tissue was measured by modifying the method of Woessner (Archives of Biochemistry and Biophysics, 93 (1961) 440-447).
- a part of the lung was fixed with 10% neutral buffered formalin, and histopathological changes were observed.
- the results were statistically analyzed using EXSAS (version 7.6.0, manufactured by Arm Systex).
- UUO Unilateral ureteral ligation
- a mouse is anesthetized with isoflurane and then the abdomen is opened.
- the left ureter is ligated with silk thread to create a UUO model.
- the test compound is orally administered daily from the date of UUO preparation.
- On the 8th, 14th, or 21st day after UUO production the kidney is removed and the wet weight is measured.
- RNA is extracted from a part of the kidney, and the expression level of the fibrosis marker gene is measured by quantitative PCR. Further, the amount of hydroxyproline or collagen in the renal tissue is measured. Results are statistically analyzed using EXSAS.
- Carbon tetrachloride (CCl 4 ) -induced liver fibrosis model A mouse is treated with diluted CCl 4 (035-01273, manufactured by Wako Pure Chemical Industries) twice a week to produce a liver fibrosis model. The test compound is orally administered every day from the start of CCl 4 administration. From 3 to 28 days after the start of CCl 4 administration, the liver is collected under isoflurane anesthesia, and the wet weight is measured. RNA is extracted from a part of the liver, and the expression of a fibrosis marker gene is measured by quantitative PCR. Furthermore, the amount of hydroxyproline or collagen in the liver tissue is measured. A part of the liver is fixed with 10% neutral buffered formalin, and histopathological changes are observed. Results are statistically analyzed using EXSAS.
- Rat non-alcoholic steatohepatitis (NASH) model Rats are loaded with a methionine / choline deficiency (MCD) diet to create a NASH model. Rats are allowed to freely take a normal diet or an MCD diet for 20 weeks. The test compound is orally administered every day from the start of the MCD diet. After breeding for 20 weeks, the liver is collected under isoflurane anesthesia and the wet weight is measured. RNA is extracted from a part of the liver, and the expression of a fibrosis marker gene is measured by quantitative PCR. Furthermore, the amount of hydroxyproline or collagen in the liver tissue is measured. A part of the liver is fixed with 10% neutral buffered formalin, and histopathological changes are observed. Results are statistically analyzed using EXSAS.
- MCD methionine / choline deficiency
- mice were 200 mg of streptozotocin (manufactured by Sigma-Aldrich) once subcutaneously administered to 2 day old male mice, and a high fat diet (High Fat Diet 32, manufactured by CLEA Japan, Inc.) from 4 weeks of age. It is produced by rearing (Medical Molecular Morphology, 46 (2013), pages 141-152). Test compounds are orally administered daily from 5 or 6 weeks of age.
- RNA is extracted from a part, and the expression of marker genes for inflammation and fibrosis is measured by quantitative PCR. Further, the amount of hydroxyproline or collagen in the liver tissue is measured. A paraffin section or a frozen section is prepared from a part of the liver, a histopathological examination is performed, and NAFLD Activity score, Fibrosis area or Inflammation area is measured. The results are statistically analyzed using EXSUS (version 8.0, manufactured by CAC Excicare) or Prism 4 (manufactured by GraphPad Software).
- mice were bred on a choline-deficient 0.1% methionine-containing high fat diet (A06071302, manufactured by Research Diet) to produce a NASH model (International Journal of Experimental Pathology, 94 (2013) 93-103).
- the test compound is orally administered every day from the start of CDAHFD loading.
- the liver is collected under isoflurane anesthesia and the wet weight is measured.
- RNA is extracted from part of the liver, and the expression of marker genes for inflammation and fibrosis is measured by quantitative PCR. Further, the amount of hydroxyproline or collagen in the liver tissue is measured. A part of the liver is fixed with 10% neutral buffered formalin, and histopathological changes are observed. The results are statistically analyzed using EXSUS (version 8.0, manufactured by CAC Excicare).
- Acetonitrile was added to the obtained plasma, deproteinization pretreatment (mixed with 50 ⁇ L of plasma + 200 ⁇ L of acetonitrile), filtered with a filter (PTFE, 0.2 ⁇ m), LC-MS / MS (AB SCIEX 3200QTrap, and Shimadzu Corporation)
- the compound concentration in plasma was measured with LC-20A or LC-30A series. From the obtained plasma concentration transition, AUC (area under blood concentration) was calculated by Phoenix WinNonlin (CERTARA).
- the salt of the ⁇ -position halogen-substituted thiophene compound of the present invention has an LPA receptor antagonistic action, particularly a disease accompanied by fibrosis, immune / inflammatory disease, central / peripheral nervous system It is useful as a therapeutic and / or prophylactic agent (preferably therapeutic agent) for diseases, urological diseases and cancer-related diseases.
- Soft capsules A mixture of digestible oils such as soybean oil and olive oil, and the salt of the compound of the example is injected into gelatin so as to contain 100 mg of the active ingredient, and soft capsules Is manufactured, washed and dried.
- the salt of the ⁇ -position halogen-substituted thiophene compound represented by the general formula (I) of the present invention has excellent properties in terms of potent LPA receptor antagonism, sustained drug efficacy, solubility, etc. It is useful as a disease associated with fibrosis, an immune / inflammatory disease, a central / peripheral nervous system disease, a urological disease, a cancer-related disease therapeutic agent and / or a preventive agent).
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Abstract
Description
腎臓において、腎線維症動物モデルである片側尿管結紮マウスでLPAの産生やLPA1の発現が亢進していること、LPA1欠損あるいはLPA受容体拮抗剤投与により腎線維化が抑制されることが報告されている(非特許文献4、5を参照)。
Rは、水素原子、又は、メトキシ基を示し、
Xは、ハロゲン原子を示し、
Aは、以下の基:
(R)-1-[4’-(5-クロロ-3-{[(1-フェニルエトキシ)カルボニル]アミノ}チオフェン-2-イル)-2’-メトキシ-[1,1’-ビフェニル]-4-イル]シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
(R)-1-{4’-[5-クロロ-3-({[1-(2,5-ジフルオロフェニル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
(R)-1-{4’-[3-({[1-(2-クロロフェニル)エトキシ]カルボニル}アミノ)-5-フルオロチオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
(R)-1-{4’-[5-クロロ-3-({[1-(チオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
(R)-1-{4’-[5-フルオロ-3-({[1-(4-メチルチオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
(式中、R、X、A、M、nは前記と同意義を示し、M’、n’はそれぞれM、nと同意義を示す。Z-は水酸化物イオン、ハロゲン化物イオン、又は、酢酸イオン等の陰イオンを示し、R1はアルキル基等の加水分解により脱保護されるカルボン酸の保護基を示す。)
反応溶媒は、好ましくは、水、又は、水/有機溶媒の混合溶媒であり、より好ましくは、水、アセトニトリル/水の混合溶媒、又は、アセトニトリル/テトラヒドロフラン/水の混合溶媒である。
反応溶媒は、好ましくは、水、又は、水/有機溶媒の混合溶媒であり、より好ましくは、水、又は、アセトニトリル/水の混合溶媒である。
反応溶媒は、好ましくは、水、又は、水/有機溶媒の混合溶媒であり、より好ましくは、2-プロパノール/水、又は、2-プロパノール/テトラヒドロフラン/水の混合溶媒である。
また、以下の合成ルートにおける、R、X、A、M、M’、n、n’、Z-、R1は前記と同意義を示す。L、La、及び、Mはカップリング反応に必要な置換基を示し、例えば、L、又は、Laが塩素原子、臭素原子、ヨウ素原子、又は、トリフルオロメタンスルホニルオキシ基等を示すときは、Mはボロン酸、ボロン酸エステル、トリアルキルスズ等を示し、L、又は、Laがボロン酸、ボロン酸エステル、トリアルキルスズ等を示すときは、Mは塩素原子、臭素原子、ヨウ素原子、又は、トリフルオロメタンスルホニルオキシ基等を示す。
反応溶媒は、好ましくは、脂肪族炭化水素類、ハロゲン化炭化水素類、エーテル類、ニトリル類、カルボン酸類、アミド類、スルホキシド類、水、又は、それらの混合溶媒であり、より好ましくは、N,N-ジメチルホルムアミドである。
ハロゲン化剤としては、ヨウ素、N-ヨードスクシンイミド、臭素、N-ブロモスクシンイミド、1,2-ジブロモエタン、1,2-ジブロモ-1,1,2,2-テトラフルオロエタン、塩素、N-クロロスクシンイミド、キセノンジフルオリド、N-フルオロベンゼンスルホンイミド、又は、N-フルオロ-N’-(クロロメチル)トリエチレンジアミンビス(テトラフルオロボラート)等が挙げられる。
また、化合物(4)に対して、例えば、Tetrahedron Letters, 51(2010)4526-4529頁、又は、Journal of Medicinal Chemistry,54(2011)2687-2700頁等に記載の方法に準じて、反応溶媒中、塩基を用いてアニオンとした後、ハロゲン化剤で処理し化合物(5)を合成することができる。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、又は、それらの混合溶媒であり、より好ましくは、エーテル類、脂肪族炭化水素類、又は、それらの混合溶媒である。
塩基としては、n-ブチルリチウム、sec-ブチルリチウム、又は、tert-ブチルリチウム等のアルキルリチウム類;リチウムジイソプロピルアミド、又は、リチウム2,2,6,6-テトラメチルピペリジド等のリチウムアミド類;臭化エチルマグネシウム、塩化エチルマグネシウム、塩化イソプロピルマグネシウム、及び、塩化フェニルマグネシウム等のグリニヤール試薬類;ジイソプロピルアミド塩化マグネシウム、2,2,6,6-テトラメチルピペリジン塩化マグネシウム等のマグネシウムアミド類;リチウム1,1,1,3,3,3-ヘキサメチルジシラザン、カリウム1,1,1,3,3,3-ヘキサメチルジシラザン等のジシラザン塩基類が挙げられる。
ハロゲン化剤としては、ヨウ素、N-ヨードスクシンイミド、臭素、N-ブロモスクシンイミド、四臭化炭素、1,2-ジブロモエタン、1,2-ジブロモ-1,1,2,2-テトラフルオロエタン、塩素、N-クロロスクシンイミド、四塩化炭素、キセノンジフルオリド、N-フルオロベンゼンスルホンイミド、又は、N-フルオロ-N’-(クロロメチル)トリエチレンジアミンビス(テトラフルオロボラート)等が挙げられる。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アルコール類、アミド類、スルホキシド類、スルホン類、水、又は、それらの混合溶媒であり、より好ましくは、1,4-ジオキサン/水の混合溶媒である。
カップリング触媒としては、テトラキス(トリフェニルホスフィン)パラジウム(0)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) ジクロリド 塩化メチレン付加物、ビス(トリフェニルホスフィン)パラジウム(II) ジクロリド、トリス(ジベンジリデンアセトン)ジパラジウム(0)、又は、酢酸パラジウム(II)等のパラジウム触媒;ビス(トリフェニルホスフィン)ニッケル(II) ジクロリド等のニッケル触媒が挙げられる。
リガンドとしては、カップリング触媒自体に含まれる場合もあるが、トリフェニルホスフィン、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]、ジベンジリデンアセトン、トリフェニルアルシン、トリ(o-トリル)ホスフィン、トリ-tert-ブチルホスフィン、又は、トリシクロヘキシルホスフィン等が挙げられる。
塩基としては、フッ化カリウム、又は、フッ化セシウム等のフッ化物塩;炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、又は、炭酸タリウム等の炭酸塩;水酸化ナトリウム、水酸化カリウム、水酸化バリウム、又は、水酸化タリウム等の金属水酸化物;燐酸カリウム等のリン酸塩;トリエチルアミン、又は、ジイソプロピルエチルアミン等の有機塩基が挙げられる。好ましくは、炭酸ナトリウムである。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アルコール類、アミド類、スルホキシド類、スルホン類、水、又は、それらの混合溶媒であり、より好ましくは、1,4-ジオキサンである。
パラジウム触媒としては、テトラキス(トリフェニルホスフィン)パラジウム(0)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) ジクロリド 塩化メチレン付加物、ビス(トリフェニルホスフィン)パラジウム(II) ジクロリド、トリス(ジベンジリデンアセトン)ジパラジウム(0)、又は、酢酸パラジウム(II)等が挙げられる。好ましくは、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) ジクロリド 塩化メチレン付加物、又は、酢酸パラジウム(II)である。
リガンドとしては、カップリング触媒自体に含まれる場合もあるが、トリフェニルホスフィン、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]、ジベンジリデンアセトン、トリフェニルアルシン、トリ(o-トリル)ホスフィン、トリ-tert-ブチルホスフィン、又は、トリシクロヘキシルホスフィン等が挙げられる。好ましくは、トリシクロヘキシルホスフィンである。
ボロン酸試薬としては、4,4,4’,4’,5,5,5’,5’-オクタメチル-2,2’-ビ(1,3,2-ジオキサボロラン)、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン等が挙げられる。
塩基としては、酢酸カリウム、酢酸ナトリウム等が挙げられる。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、アミド類、スルホキシド類、スルホン類、又は、それらの混合溶媒であり、より好ましくは、エーテル類、又は、脂肪族炭化水素類、又は、それらの混合溶媒である。
塩基としては、n-ブチルリチウム、sec-ブチルリチウム、又は、tert-ブチルリチウム等のアルキルリチウム類;臭化エチルマグネシウム、塩化エチルマグネシウム、塩化イソプロピルマグネシウム、及び、塩化フェニルマグネシウム等のグリニヤール試薬類が挙げられる。
ボロン酸試薬としては、ホウ酸トリメチル、ホウ酸トリイソプロピル、ホウ酸トリヘキサデシル、又は、2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン等が挙げられる。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、カルボン酸類、アルコール類、アミド類、スルホキシド類、スルホン類、水、又は、それらの混合溶媒であり、より好ましくは、塩化メチレンである。
酸としては、塩酸、硫酸等の無機酸;酢酸、トリフルオロ酢酸、トリクロロ酢酸等の有機酸;メタンスルホン酸、ベンゼンスルホン酸、又は、p-トルエンスルホン酸等のスルホン酸が挙げられ、好ましくは、トリフルオロ酢酸である。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、ニトリル類、カルボン酸類、アルコール類、アミド類、スルホキシド類、スルホン類、水、又は、それらの混合溶媒であり、より好ましくはエタノール/テトラヒドロフラン/水、又は、2-プロパノール/テトラヒドロフラン/水の混合溶媒である。
酸、又は、塩基としては、塩酸、硫酸等の無機酸;酢酸、トリフルオロ酢酸等の有機酸;メタンスルホン酸、ベンゼンスルホン酸、又は、p-トルエンスルホン酸等のスルホン酸;水酸化リチウム、水酸化ナトリウム、又は、水酸化カリウム等のアルカリ金属水酸化物;炭酸カリウム、又は、炭酸ナトリウム等のアルカリ金属炭酸塩が挙げられ、好ましくは、塩基、より好ましくは、水酸化リチウム、又は、水酸化ナトリウムである。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アミド類、スルホキシド類、スルホン類、又は、それらの混合溶媒であり、より好ましくは、N,N-ジメチルホルムアミドである。
塩基としては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、又は、炭酸タリウム等の炭酸塩;ピリジン、2,6-ルチジン、又は、4-ピコリン等のピリジン類;トリエチルアミン、又は、ジイソプロピルエチルアミン等の有機塩基が挙げられる。好ましくは、ジイソプロピルエチルアミンである。
縮合剤としては、N,N’-ジシクロヘキシルカルボジイミド、N,N’-ジイソプロピルカルボジイミド、塩酸 1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、又は、N-シクロヘキシル-N’-(2-モルホリノエチル)カルボジイミド メト-p-トルエンスルホン酸塩等のカルボジイミド系縮合剤;、N,N’-カルボニルジイミダゾール等のイミダゾール系縮合剤;4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウム クロリド、又は、トリフルオロメタンスルホン酸 (4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-(2-オクトキシ-2-オキソエチル)ジメチルアンモニウム等のトリアジン系縮合剤;1H-ベンゾトリアゾール-1-イルオキシトリス(ジメチルアミノ)ホスホニウム ヘキサフルオロリン酸塩、1H-ベンゾトリアゾール-1-イルオキシトリピロリジノホスホニウム ヘキサフルオロリン酸塩、又は、クロロトリピロリジノホスホニウム ヘキサフルオロリン酸塩等のホスホニウム縮合剤;({[(1-シアノ-2-エトキシ-2-オキソエチリデン)アミノ]オキシ}-4-モルホリノメチレン)ジメチルアンモニウム ヘキサフルオロリン酸塩、O-(ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロリン酸塩、O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロリン酸塩、O-(N-スクシンイミジル)-N,N,N’,N’-テトラメチルウロニウム テトラフルオロほう酸塩、又は、O-(3,4-ジヒドロ-4-オキソ-1,2,3-ベンゾトリアジン-3-イル)-N,N,N’,N’-テトラメチルウロニウム テトラフルオロほう酸塩等のウロニウム縮合剤が挙げられる。好ましくはO-(ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロリン酸塩である。
添加剤としては、1-ヒドロキシベンゾトリアゾール、又は、1-ヒドロキシアザベンゾトリアゾール等のベンゾトリアゾール類;N,N-ジメチルアミノピリジン等のピリジン類;又は、それらの併用が挙げられ、好ましくはN,N-ジメチルアミノピリジンである。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、エステル類、ニトリル類、アルコール類、アミド類、スルホキシド類、スルホン類、水、又は、それらの混合溶媒である。
還元剤としては、水素化ホウ素リチウム、水素化ホウ素ナトリウム、水素化ホウ素カリウム、又は、トリメトキシ水素化ホウ素ナトリウム等の水素化ホウ素類;水素化リチウムアルミニウム、水素化ナトリウムアルミニウム、水素化ジイソブチルアルミニウム、又は、トリメトキシ水素化リチウムアルミニウム等の水素化アルミニウム類が挙げられる。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アミド類、スルホキシド類、スルホン類、又は、それらの混合溶媒であり、より好ましくは、トルエンである。
塩基としては、トリエチルアミン、又は、ジイソプロピルエチルアミン等の有機アミン類;ピリジン、2,6-ルチジン、又は、4-ピコリン等のピリジン類が挙げられる。好ましくは、ピリジンである。
酸化剤としては、[ビス(アセトキシ)ヨード]ベンゼン、[ビス(トリフルオロアセトキシ)ヨード]ベンゼン、又は、ヨードシルベンゼン等の高原子価ヨウ素化合物が挙げられ、好ましくは[ビス(トリフルオロアセトキシ)ヨード]ベンゼンである。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アミド類、スルホキシド類、スルホン類、水、又は、それらの混合溶媒であり、より好ましくは、トルエンである。
塩基としては、トリエチルアミン、又は、ジイソプロピルエチルアミン等の有機アミン類が挙げられ、好ましくは、トリエチルアミンである。
反応溶媒は、好ましくは、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、カルボン酸類、アルコール類、アミド類、スルホキシド類、スルホン類、水、又は、それらの混合溶媒であり、より好ましくは、N,N-ジメチルホルムアミドである。
脱保護試薬としては、フッ化水素酸;フッ化カリウム等の無機フッ化物塩;ピリジン フッ化水素酸塩、トリエチルアミン フッ化水素酸塩、又は、1-ヘキサデカン フッ化水素酸塩等の有機フッ化水素酸塩;テトラエチルアンモニウム フルオリド、又は、テトラブチルアンモニウム フルオリド等のアンモニウムフルオリド類;トリス(ジメチルアミノ)スルホニウム ジフルオロトリメチルケイ酸等のジフルオロトリメチルケイ酸塩類が挙げられる。好ましくはテトラブチルアンモニウム フルオリドである。
(R)-1-[4’-(5-クロロ-3-{[(1-フェニルエトキシ)カルボニル]アミノ}チオフェン-2-イル)-2’-メトキシ-[1,1’-ビフェニル]-4-イル]シクロプロパンカルボン酸 ナトリウム (化合物番号I-2)
マススペクトル(ESI+,m/z):570[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.44 (1H, brs), 7.43-7.22 (10H, m), 7.21-7.14 (2H, m), 7.08 (1H, dd, J = 7.8, 1.4 Hz), 5.75 (1H, q, J = 6.1 Hz), 3.73 (3H, s), 1.56-1.38 (3H, m), 1.16 (2H, dd, J = 5.6, 2.6 Hz), 0.66 (2H, dd, J = 5.7, 2.7 Hz)。
(R)-1-[4’-(5-クロロ-3-{[(1-フェニルエトキシ)カルボニル]アミノ}チオフェン-2-イル)-2’-メトキシ-[1,1’-ビフェニル]-4-イル]シクロプロパンカルボン酸 カリウム (化合物番号I-4)
マススペクトル(ESI+,m/z):586[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.44 (1H, brs), 7.43-7.14 (12H, m), 7.08 (1H, dd, J = 7.8, 1.4 Hz), 5.75 (1H, q, J = 6.2 Hz), 3.73 (3H, s), 1.54-1.39 (3H, m), 1.11 (2H, dd, J = 5.8, 2.7 Hz), 0.60 (2H, dd, J = 5.8, 2.6 Hz)。
(R)-1-[4’-(5-クロロ-3-{[(1-フェニルエトキシ)カルボニル]アミノ}チオフェン-2-イル)-2’-メトキシ-[1,1’-ビフェニル]-4-イル]シクロプロパンカルボン酸 1/2カルシウム (化合物番号I-6)
マススペクトル(ESI+,m/z):1133[2M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.42 (1H, brs), 7.41-7.25 (10H, m), 7.19-7.15 (2H, m), 7.07 (1H, dd, J = 7.9, 1.3 Hz), 5.75 (1H, q, J = 6.2 Hz), 3.72 (3H, s), 1.54-1.38 (3H, m), 1.38-1.22 (2H, m), 0.90-0.80 (2H, m)。
(R)-1-{4’-[5-クロロ-3-({[1-(2,5-ジフルオロフェニル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 ナトリウム (化合物番号I-8)
マススペクトル(ESI+,m/z):606[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.56 (1H, brs), 7.36-7.14 (10H, m), 7.08 (1H, dd, J = 7.8, 1.4 Hz), 5.91 (1H, q, J = 6.6 Hz), 3.75 (3H, s), 1.61-1.36 (3H, m), 1.16 (2H, dd, J = 5.6, 2.8 Hz), 0.66 (2H, dd, J = 5.6, 2.6 Hz)。
(R)-1-{4’-[5-クロロ-3-({[1-(2,5-ジフルオロフェニル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 カリウム (化合物番号I-10)
マススペクトル(ESI+,m/z):622[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.56 (1H, brs), 7.33-7.14 (10H, m), 7.08 (1H, dd, J = 7.8, 1.1 Hz), 5.91 (1H, q, J = 6.1 Hz), 3.75 (3H, s), 1.58-1.40 (3H, m), 1.12 (2H, dd, J = 5.7, 2.7 Hz), 0.61 (2H, dd, J = 5.6, 2.5 Hz)。
(R)-1-{4’-[5-クロロ-3-({[1-(2,5-ジフルオロフェニル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 1/2カルシウム (化合物番号I-12)
マススペクトル(ESI+,m/z):1205[2M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.55 (1H, brs), 7.38-7.14 (10H, m), 7.07 (1H, dd, J = 7.8, 1.6 Hz), 5.90 (1H, q, J = 6.4 Hz), 3.75 (3H, s), 1.60-1.40 (3H, m), 1.40-1.20 (2H, m), 0.91-0.78 (2H, m)。
(R)-1-{4’-[3-({[1-(2-クロロフェニル)エトキシ]カルボニル}アミノ)-5-フルオロチオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 ナトリウム (化合物番号I-14)
マススペクトル(ESI+,m/z):588[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.55 (1H, brs), 7.62-7.22 (9H, m), 7.14-7.20 (1H, m), 7.07 (1H, dd, J = 7.8, 1.2 Hz), 6.84 (1H, d, J = 2.5 Hz), 6.00 (1H, q, J = 5.6 Hz), 3.76 (3H, s), 1.59-1.35 (3H, m), 1.16 (2H, dd, J = 5.7, 2.7 Hz), 0.66 (2H, dd, J = 5.6, 2.6 Hz)。
(R)-1-{4’-[3-({[1-(2-クロロフェニル)エトキシ]カルボニル}アミノ)-5-フルオロチオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 カリウム (化合物番号I-16)
マススペクトル(ESI+,m/z):604[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.56 (1H, brs), 7.60-7.21 (9H, m), 7.19-7.14 (1H, m), 7.07 (1H, dd, J = 7.9, 1.4 Hz), 6.84 (1H, d, J = 2.4 Hz), 6.00 (1H, q, J = 6.4 Hz), 3.76 (3H, s), 1.55-1.37 (3H, m), 1.12 (2H, dd, J = 5.8, 2.7 Hz), 0.61 (2H, dd, J = 5.8, 2.6 Hz)。
(R)-1-{4’-[3-({[1-(2-クロロフェニル)エトキシ]カルボニル}アミノ)-5-フルオロチオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 1/2カルシウム (化合物番号I-18)
マススペクトル(ESI+,m/z):1169[2M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.54 (1H, brs), 7.58-7.25 (9H, m), 7.17 (1H, d, J = 1.3 Hz), 7.07 (1H, dd, J = 7.8, 1.1 Hz), 6.84 (1H, d, J = 2.5 Hz), 6.00 (1H, q, J = 6.5 Hz), 3.75 (3H, s), 1.57-1.38 (3H, m), 1.38-1.18 (2H, m), 0.90-0.79 (2H, m)。
(R)-1-{4’-[5-クロロ-3-({[1-(チオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 ナトリウム (化合物番号I-20)
マススペクトル(ESI+,m/z):546[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.34 (1H, brs), 7.70-7.65 (2H, m), 7.57-7.40 (6H, m), 7.35-7.30 (2H, m), 7.23-7.16 (1H, m), 7.16-7.08 (1H, m), 5.82 (1H, q, J = 6.4 Hz), 1.61-1.40 (3H, m), 1.18 (2H, dd, J = 5.8, 2.8 Hz), 0.68 (2H, dd, J = 5.7, 2.7 Hz)。
(R)-1-{4’-[5-クロロ-3-({[1-(チオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 カリウム (化合物番号I-22)
マススペクトル(ESI+,m/z):562[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.34 (1H, brs), 7.71-7.64 (2H, m), 7.58-7.39 (6H, m), 7.33-7.27 (2H, m), 7.24-7.16 (1H, m), 7.16-7.07 (1H, m), 5.82 (1H, q, J = 6.5 Hz), 1.61-1.41 (3H, m), 1.13 (2H, dd, J = 5.8, 2.7 Hz), 0.62 (2H, dd, J = 5.8, 2.7 Hz)。
(R)-1-{4’-[5-クロロ-3-({[1-(チオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 1/2カルシウム (化合物番号I-24)
マススペクトル(ESI+,m/z):1085[2M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.32 (1H, brs), 7.74-7.64 (2H, m), 7.59-7.49 (5H, m), 7.47-7.40 (1H, m), 7.40-7.34 (2H, m), 7.22-7.16 (1H, m), 7.16-7.08 (1H, m), 5.82 (1H, q, J = 6.4 Hz), 1.62-1.40 (3H, m), 1.40-1.20 (2H, m), 0.90-0.78 (2H, m)。
(R)-1-{4’-[5-フルオロ-3-({[1-(4-メチルチオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 ナトリウム (化合物番号I-26)
マススペクトル(ESI+,m/z):544[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.33 (1H, brs), 7.69-7.63 (2H, m), 7.54-7.39 (5H, m), 7.35-7.29 (2H, m), 7.16 (1H, d, J = 1.9 Hz), 6.83 (1H, brs), 5.74 (1H, q, J= 6.5 Hz), 2.17 (3H, s), 1.59-1.43 (3H, m), 1.18 (2H, dd, J = 5.8, 2.8 Hz), 0.68 (2H, dd, J = 5.8, 2.8 Hz)。
(R)-1-{4’-[5-フルオロ-3-({[1-(4-メチルチオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 カリウム (化合物番号I-28)
マススペクトル(ESI+,m/z):560[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.34 (1H, brs), 7.69-7.63 (2H, m), 7.56-7.41 (5H, m), 7.34-7.27 (2H, m), 7.16 (1H, d, J = 2.0 Hz), 6.83 (1H, brs), 5.74 (1H, q, J= 6.5 Hz), 2.17 (3H, brs), 1.57-1.45 (3H, m), 1.14 (2H, dd, J = 5.9, 2.8 Hz), 0.63 (2H, dd, J = 5.8, 2.6 Hz)。
(R)-1-{4’-[5-フルオロ-3-({[1-(4-メチルチオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 1/2カルシウム (化合物番号I-30)
マススペクトル(ESI+,m/z):1081[2M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.32 (1H, brs), 7.70-7.63 (2H, m), 7.57-7.31 (8H, m), 7.14 (1H, d, J = 1.9 Hz), 6.82 (1H, brs), 5.74 (1H, q, J = 6.5 Hz), 2.17 (3H, s), 1.61-1.41 (3H, m), 1.41-1.20 (2H, m), 0.91-0.78 (2H, m)。
マススペクトル(EI,m/z):262[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.32 (1H, d, J = 5.8 Hz), 7.18 (1H, d, J= 5.8 Hz), 1.59 (9H, s)。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:7.63 (1H, d, J = 5.8 Hz), 7.28 (1H, d, J= 5.8 Hz), 1.53 (9H, s)。
マススペクトル(DUIS+,m/z):240[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:7.75 (1H, brs), 7.58 (1H, brs), 7.33 (1H, s)。
マススペクトル(EI,m/z):312[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.61 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J= 2.1 Hz), 6.87 (1H, dd, J = 8.2, 2.1 Hz), 3.88 (3H, s)。
マススペクトル(EI,m/z):374[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.45-7.41 (2H, m), 7.39-7.35 (2H, m), 7.19 (1H, d, J = 8.0 Hz), 7.15 (1H, dd, J = 8.0, 1.8 Hz), 7.10 (1H, d, J = 1.8 Hz), 4.12 (2H, q, J = 7.1 Hz), 3.81 (3H, s), 1.61 (2H, dd, J = 7.0, 4.0 Hz), 1.22 (2H, dd, J = 7.0, 4.0 Hz), 1.19 (3H, t, J = 7.1 Hz)。
マススペクトル(EI,m/z):330[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.45-7.41 (2H, m), 7.39-7.35 (2H, m), 7.25 (1H, d, J = 8.2 Hz), 7.00 (1H, dd, J = 8.2, 2.0 Hz), 6.96 (1H, d, J = 2.0 Hz), 4.12 (2H, q, J = 7.1 Hz), 3.81 (3H, s), 1.61 (2H, dd, J = 6.9, 3.9 Hz), 1.22 (2H, dd, J = 7.0, 4.0 Hz), 1.19 (3H, t, J = 7.1 Hz)。
マススペクトル(EI,m/z):422[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.52-7.46 (3H, m), 7.40-7.33 (4H, m), 4.12 (2H, q, J= 7.1 Hz), 3.86 (3H, s), 1.60 (2H, dd, J= 6.9, 3.9 Hz), 1.36 (12H, s), 1.22 (2H, dd, J = 7.0, 4.0 Hz), 1.19 (3H, t, J = 7.1 Hz)。
マススペクトル(EI,m/z):425[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.69-7.65 (2H, m), 7.58-7.53 (4H, m), 7.46-7.42 (2H, m), 7.33 (1H, s), 5.44 (2H, brs), 4.12 (2H, q, J = 7.1 Hz), 1.65 (2H, dd, J = 7.0, 4.0 Hz), 1.23 (2H, dd, J = 7.0, 4.0 Hz), 1.19 (3H, t, J = 7.1 Hz)。
マススペクトル(EI,m/z):455[M]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:7.73 (1H, brs), 7.50 (1H, brs), 7.48-7.43 (2H, m), 7.39-7.33 (3H, m), 7.32 (1H, s), 7.25 (1H, d, J= 1.6 Hz), 7.13 (1H, dd, J = 7.8, 1.6 Hz), 4.05 (2H, q, J = 7.1 Hz), 3.79 (3H, s), 1.51 (2H, dd, J= 6.8, 4.0 Hz), 1.23 (2H, dd, J= 7.0, 4.0 Hz), 1.12 (3H, t, J= 7.1 Hz)。
マススペクトル(EI,m/z):448[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.64-7.60 (2H, m), 7.59-7.55 (2H, m), 7.55-7.51 (2H, m), 7.48 (1H, d, J= 5.4 Hz), 7.45-7.41 (2H, m), 7.23 (1H, d, J = 5.3 Hz), 4.13 (2H, q, J= 7.1 Hz), 1.64 (2H, dd, J = 6.9, 3.9 Hz), 1.38 (9H, s), 1.23 (2H, dd, J = 7.2, 4.1 Hz), 1.20 (3H, t, J = 7.2 Hz)。
マススペクトル(EI,m/z):478[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.53-7.48 (2H, m), 7.47 (1H, d, J = 5.4 Hz), 7.41-7.36 (2H, m), 7.34 (1H, d, J = 7.8 Hz), 7.23 (1H, d, J = 5.4 Hz), 7.12 (1H, dd, J = 7.7, 1.6 Hz), 7.07 (1H, d, J = 1.6 Hz), 4.13 (2H, q, J = 7.1 Hz), 3.83 (3H, s), 1.62 (2H, dd, J = 6.8, 4.0 Hz), 1.40 (9H, s), 1.23 (2H, dd, J = 6.8, 3.8 Hz), 1.20 (3H, t, J = 7.1 Hz)。
マススペクトル(CI,m/z):467[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:7.78-7.72 (2H, m), 7.68-7.63 (2H, m), 7.56-7.50 (2H, m), 7.46-7.41 (2H, m), 7.03 (1H, d, J = 2.4 Hz), 4.05 (2H, q, J = 7.1 Hz), 1.52 (2H, dd, J = 6.9, 3.9 Hz), 1.31 (9H, s), 1.24 (2H, dd, J = 7.1, 4.1 Hz), 1.12 (3H, t, J = 7.1 Hz)。
マススペクトル(DUIS+,m/z):497[M+1]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.52-7.46 (2H, m), 7.41-7.36 (2H, m), 7.33 (1H, d, J = 7.8 Hz), 7.08 (1H, dd, J = 7.8, 1.6 Hz), 7.03 (1H, d, J = 1.5 Hz), 6.84 (1H, d, J = 2.3 Hz), 4.13 (2H, q, J = 7.1 Hz), 3.82 (3H, s), 1.62 (2H, dd, J = 6.9, 3.9 Hz), 1.37 (9H, s), 1.23 (2H, dd, J = 6.5, 3.5 Hz), 1.20 (3H, t, J = 7.2 Hz)。
マススペクトル(CI,m/z):411[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:12.92 (1H, s), 7.74-7.70 (2H, m), 7.68-7.64 (2H, m), 7.60-7.55 (2H, m), 7.46-7.41 (2H, m), 7.05 (1H, d, J= 2.4 Hz), 4.05 (2H, q, J = 7.1 Hz), 1.52 (2H, dd, J = 6.9, 3.9 Hz), 1.24 (2H, dd, J = 7.0, 4.1 Hz), 1.11 (3H, t, J = 7.1 Hz)。
マススペクトル(EI,m/z):440[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.53-7.48 (2H, m), 7.40-7.37 (2H, m), 7.34 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 1.6 Hz), 7.13-7.10 (1H, m), 6.94 (1H, d, J = 2.3 Hz), 4.12 (2H, q, J = 7.1 Hz), 3.82 (3H, s) , 1.62 (2H, dd, J = 6.9, 3.9 Hz), 1.23 (2H, dd, J = 7.0, 4.0 Hz), 1.20 (3H, t, J = 7.1 Hz)。
マススペクトル(DUIS+,m/z):428[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:12.35 (1H, brs), 7.75 (1H, brs), 7.52 (1H, brs), 7.45-7.41 (2H, m), 7.38-7.35 (2H, m), 7.33 (1H, d, J= 7.9 Hz), 7.32 (1H, s), 7.24 (1H, d, J= 1.8 Hz), 7.13 (1H, dd, J = 7.8, 1.6 Hz), 3.79 (3H, s), 1.47 (2H, dd, J = 6.7, 3.8 Hz), 1.18 (2H, dd, J = 6.9, 3.9 Hz)。
マススペクトル(DUIS+,m/z):528[M+1]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:7.75 (1H, brs), 7.52 (1H, brs), 7.46-7.42 (2H, m), 7.38-7.34 (2H, m), 7.33 (1H, d, J = 7.8 Hz), 7.32 (1H, s), 7.24 (1H, d, J = 1.6 Hz), 7.13 (1H, dd, J = 7.8, 1.7 Hz), 4.14-4.07 (2H, m), 3.78 (3H, s), 1.49 (2H, dd, J = 6.8, 3.8 Hz), 1.22 (2H, dd, J = 7.0, 4.1 Hz), 0.91-0.84 (2H, m), -0.05 (9H, s)。
マススペクトル(CI,m/z):141[M+1]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.99 (1H, d, J = 3.1 Hz), 6.91 (1H, dq, J = 3.1, 1.0 Hz), 2.53 (3H, s), 2.46 (3H, d, J = 1.0 Hz)。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.25-7.19 (1H, m), 7.01-6.87 (2H, m), 5.22-5.14 (1H, m), 1.88 (1H, d, J = 4.3 Hz), 1.50 (3H, d, J= 6.4 Hz)。
光学純度分析条件
カラム:CHIRALCEL OJ-RH(商品名、ダイセル製)
サイズ:0.46cmI.D.×25cmL.
移動相:0.03容量%トリフルオロ酢酸水溶液/アセトニトリル=75/25(V/V)
流速 :1.0mL/min.
温度 :40℃
波長 :254nm
1H-NMRスペクトル(400MHz,DMSO-d6)δ:7.44 (1H, dd, J = 5.0, 3.0 Hz), 7.25 (1H, ddd, J = 3.0, 1.2, 0.9 Hz), 7.07 (1H, dd, J = 5.0, 1.2 Hz), 5.11 (1H, d, J = 4.8 Hz), 4.80-4.71 (1H, m), 1.34 (3H, d, J= 6.4 Hz)。
光学純度分析条件
カラム:CHIRALPAK IA(商品名、ダイセル製)
サイズ:0.46cmI.D.×25cmL.
移動相:ヘキサン:2-プロパノール=99.5:0.5(V/V)
流速 :1.0mL/min.
温度 :40℃
波長 :254nm
1H-NMRスペクトル(400MHz,CDCl3)δ:7.30 (1H, dd, J = 5.0, 2.9 Hz), 7.25-7.22 (1H, m), 7.09 (1H, dd, J = 5.0, 1.3 Hz), 6.00 (1H, q, J = 6.6 Hz), 2.07 (3H, s), 1.56 (3H, d, J = 6.5 Hz)。
マススペクトル(EI,m/z):142[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.23-7.21 (1H, m), 6.92 (1H, dq, J = 3.1, 0.9 Hz), 4.92 (1H, qdd, J = 6.4, 4.8, 0.8 Hz), 2.27 (3H, d, J = 0.9 Hz), 1.63 (1H, d, J = 4.6 Hz), 1.53 (3H, d, J = 6.4 Hz)。
光学純度分析条件
カラム:CHIRALPAK IA(商品名、ダイセル製)
サイズ:0.46cmI.D.×25cmL.
移動相:ヘキサン:2-プロパノール=99.5:0.5(V/V)
流速 :1.0mL/min.
温度 :40℃
波長 :254nm
1H-NMRスペクトル(400MHz,CDCl3)δ:7.23 (1H, d, J = 3.3 Hz), 6.94-6.90 (1H, m), 5.94 (1H, qd, J = 6.5, 0.9 Hz), 2.23 (3H, d, J = 1.0 Hz), 2.07 (3H, s), 1.55 (3H, d, J = 6.5 Hz)。
光学純度分析条件
カラム:CHIRALPAK IA(商品名、ダイセル製)
サイズ:0.46cmI.D.×25cmL.
移動相:A液:B液=95:1(V/V)
A液:ヘキサン:2-プロパノール=99.5:0.5(V/V)
B液:2-プロパノール
流速 :1.0mL/min.
温度 :40℃
波長 :254nm
光学純度分析条件
カラム:CHIRALPAK IA(商品名、ダイセル製)
サイズ:0.46cmI.D.×25cmL.
移動相:ヘキサン:2-プロパノール=99.5:0.5(V/V)
流速 :1.0mL/min.
温度 :40℃
波長 :254nm
1H-NMRスペクトル(400MHz,CDCl3)δ:7.11-7.05 (1H, m), 7.03-6.90 (2H, m), 6.09 (1H, q, J = 6.6 Hz), 2.11 (3H, s), 1.52 (3H, d, J = 6.5 Hz)。
(R)-1-(2,5-ジフルオロフェニル)エタノール15.8g(100mmol、光学純度92.2%ee)、酢酸ビニル20.0ml(200mmol)のジイソプロピルエーテル(70ml)溶液に、室温で撹拌しながらLipasePS AmanoSD(和光純薬)16gを加え、45℃で64.5時間撹拌した。得られた反応混合液を濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;ヘキサン:酢酸エチル=90:10(V/V))に付し、目的物を含む画分を減圧濃縮することにより、標記化合物19.2g(96mmol、収率96%、光学純度99.7%ee)を淡黄色油状物として得た。
光学純度分析条件
カラム:CHIRALPAK IA(商品名、ダイセル製)
サイズ:0.46cmI.D.×25cmL.
移動相:A液:B液=99:1(V/V)
A液:ヘキサン:2-プロパノール=99.5:0.5(V/V)
B液:2-プロパノール
流速 :1.0mL/min.
温度 :40℃
波長 :254nm
1H-NMRスペクトル(400MHz,CDCl3)δ:7.25-7.19 (1H, m), 7.01-6.87 (2H, m), 5.22-5.14 (1H, m), 1.88 (1H, d, J = 4.3 Hz), 1.50 (3H, d, J = 6.4 Hz)。
(R)-1-{4’-[5-クロロ-3-({[1-(チオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 エチルエステル
マススペクトル(DUIS-,m/z):550[M-1]-。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.69-7.63 (2H, m), 7.63-7.51 (3H, m), 7.48-7.40 (4H, m), 7.31 (1H, dd, J = 5.0, 2.9 Hz), 7.28-7.26 (1H, m), 7.11 (1H, dd, J = 5.0, 1.3 Hz), 6.72 (1H, s), 5.99 (1H, q, J = 6.6 Hz), 4.13 (2H, q, J = 7.1 Hz), 1.64 (2H, dd, J = 7.0, 4.0 Hz), 1.62 (3H, d, J = 6.5 Hz), 1.23 (2H, dd, J = 7.0, 4.0 Hz), 1.19 (3H, t, J = 7.1 Hz)。
(R)-1-[4’-(5-クロロ-3-{[(1-フェニルエトキシ)カルボニル]アミノ}チオフェン-2-イル)-2’-メトキシ-[1,1’-ビフェニル]-4-イル]シクロプロパンカルボン酸 エチルエステル
マススペクトル(CI,m/z):575[M]+。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.39 (1H, brs), 7.40-7.26 (10H, m), 7.23-7.16 (2H, m), 7.10 (1H, dd, J = 7.8, 1.6 Hz), 5.75 (1H, q, J = 6.4 Hz), 4.06 (2H, q, J= 7.1 Hz), 3.73 (3H, s), 1.56-1.41 (5H, m), 1.23 (2H, dd, J = 7.0, 4.0 Hz), 1.13 (3H, t, J = 7.0 Hz)。
(R)-1-{4’-[5-クロロ-3-({[1-(2,5-ジフルオロフェニル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 2-(トリメチルシリル)エチルエステル
マススペクトル(DUIS-,m/z):682[M-1]-。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.55 (1H, brs), 7.45-7.40 (2H, m), 7.39-7.17 (8H, m), 7.10 (1H, dd, J = 7.9, 1.5 Hz), 5.91 (1H, q, J = 6.3 Hz), 4.14-4.07 (2H, m), 3.76 (3H, s), 1.55-1.42 (3H, m), 1.49 (2H, dd, J = 6.8, 3.9 Hz), 1.23 (2H, dd, J = 7.0, 4.0 Hz), 0.91-0.84 (2H, m), -0.05 (9H, s)。
(R)-1-{4’-[5-フルオロ-3-({[1-(4-メチルチオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 エチルエステル
マススペクトル(DUIS-,m/z):548[M-1]-。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:9.31 (1H, brs), 7.74-7.68 (2H, m), 7.66-7.61 (2H, m), 7.57-7.40 (5H, m), 7.17-7.13 (1H, m), 6.83 (1H, brs), 5.74 (1H, q, J = 6.5 Hz), 4.05 (2H, q, J = 7.2 Hz), 2.17 (3H, brs), 1.60-1.43 (3H, m), 1.51 (2H, dd, J = 6.8, 4.0 Hz), 1.23 (2H, dd, J = 7.1, 4.1 Hz), 1.11 (3H, t, J = 7.1 Hz)。
(R)-1-{4’-[3-({[1-(2-クロロフェニル)エトキシ]カルボニル}アミノ)-5-フルオロチオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸 エチルエステル
マススペクトル(EI,m/z):593[M]+。
1H-NMRスペクトル(400MHz,CDCl3)δ:7.52-7.48 (2H, m), 7.43-7.17 (9H, m), 7.06 (1H, dd, J = 7.8, 1.6 Hz), 6.97 (1H, d, J = 1.6 Hz), 6.23 (1H, q, J = 6.7 Hz), 4.13 (2H, q, J = 7.1 Hz), 3.82 (3H, s), 1.63 (2H, dd, J = 6.9, 3.9 Hz), 1.57 (3H, d, J = 6.7 Hz), 1.24 (2H, dd, J = 7.0, 4.0 Hz), 1.20 (3H, t, J = 7.2 Hz)。
(R)-1-{4’-[5-クロロ-3-({[1-(チオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸
マススペクトル(DUIS-,m/z):522[M-1]-。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:12.37 (1H, brs), 9.33 (1H, brs), 7.74-7.68 (2H, m), 7.65-7.60 (2H, m), 7.58-7.50 (3H, m), 7.48-7.37 (3H, m), 7.25-7.07 (2H, m), 5.82 (1H, q, J = 6.4 Hz), 1.56-1.44 (3H, m), 1.48 (2H, dd, J = 6.7, 3.8 Hz), 1.19-1.16 (2H, m)。
(R)-1-[4’-(5-クロロ-3-{[(1-フェニルエトキシ)カルボニル]アミノ}チオフェン-2-イル)-2’-メトキシ-[1,1’-ビフェニル]-4-イル]シクロプロパンカルボン酸
マススペクトル(DUIS-,m/z):546[M-1]-。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:12.34 (1H, brs), 9.40 (1H, brs), 7.45-7.25 (10H, m), 7.21-7.16 (2H, m), 7.09 (1H, dd, J = 7.9, 1.6 Hz), 5.75 (1H, q, J = 6.4 Hz), 3.73 (3H, s), 1.54-1.41 (5H, m), 1.18-1.12 (2H, m)。
(R)-1-{4’-[5-フルオロ-3-({[1-(4-メチルチオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸
マススペクトル(DUIS-,m/z):520[M-1]-。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:12.38 (1H, brs), 9.33 (1H, brs), 7.73-7.67 (2H, m), 7.65-7.59 (2H, m), 7.57-7.50 (2H, m), 7.49-7.38 (3H, m), 7.19-7.12 (1H, m), 6.83 (1H, brs), 5.74 (1H, q, J = 6.4 Hz), 2.17 (3H, brs), 1.59-1.44 (3H, m), 1.48 (2H, dd, J = 6.7, 3.8 Hz), 1.18 (2H, dd, J = 6.9, 3.9 Hz)。
(R)-1-{4’-[3-({[1-(2-クロロフェニル)エトキシ]カルボニル}アミノ)-5-フルオロチオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸
マススペクトル(DUIS-,m/z):564[M-1]-。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:12.35 (1H, brs), 9.55 (1H, brs), 7.60-7.28 (9H, m), 7.18 (1H, d, J = 1.5 Hz), 7.09 (1H, dd, J = 7.8, 1.4 Hz), 6.84 (1H, d, J = 2.5 Hz), 6.00 (1H, q, J = 6.1 Hz), 3.77 (3H, s), 1.55-1.39 (5H, m), 1.21-1.10 (2H, m)。
(R)-1-{4’-[5-クロロ-3-({[1-(2,5-ジフルオロフェニル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸
マススペクトル(DUIS-,m/z):582[M-1]-。
1H-NMRスペクトル(400MHz,DMSO-d6)δ:12.35 (1H, brs), 9.54 (1H, brs), 7.44-7.39 (2H, m), 7.39-7.19 (7H, m), 7.18 (1H, d, J = 1.6 Hz), 7.10 (1H, dd, J = 7.9, 1.6 Hz), 5.91 (1H, q, J = 6.5 Hz), 3.76 (3H, s), 1.56-1.43 (3H, m), 1.47 (2H, dd, J = 6.7, 3.7 Hz), 1.18 (2H, dd, J = 6.8, 4.0 Hz)。
LPA1受容体GTPγS結合試験
ヒトLPA1受容体を発現させたRH7777細胞の膜画分(A324、ChanTest製)5μgを反応緩衝液(20mM HEPES、100mM NaCl、10mM MgCl2、10μM GDP、5μgサポニン、0.2%BSA、0.1nM[35S]GTPγS(NEG030X、Perkin Elmer製)、pH7.4)に懸濁した後、濃度を変えてDMSOに溶解した試験化合物をそれぞれ加える。30℃で15分間プレインキュベートした後、LPA(L7260、Sigma製、終濃度100nM)を加えて30℃で30分間インキュベートする。セルハーベスター(M30、Brandel製)を使用して膜画分をガラス繊維ろ紙(GF/B、Whatman製)に回収し、10mMリン酸緩衝液(pH7.4)で洗浄する。液体シンチレーションアナライザー(2900TR、Packard製)を使用して膜画分の放射活性を測定し、LPA1受容体と[35S]GTPγSの結合を50%阻害する試験化合物濃度(IC50)を、EXSAS(バージョン7.6.0、アームシステックス製)を使用した非線形回帰分析にて求める。
細胞遊走試験
細胞遊走試験はChemo-Tx(登録商標)(116-8、Neuroprobe製)を使用して行った。A2058ヒトメラノーマ細胞(European Collection of Cell Cultureから入手)を無血清EMEM培地で24時間培養した後、0.1%BSAを含むDMEM培地に再懸濁し、細胞懸濁液とした。濃度を変えてDMSOに溶解した試験化合物を、それぞれ細胞懸濁液に加えて37℃で15分間培養した(最終DMSO濃度0.5%)。0.1%BSAを含むDMEM培地に溶解したLPA(終濃度100nM)をChemo-Tx96穴プレートに加え、0.001%Fibronectinにて両面をコートしたChemo-Txフィルターをプレートに乗せた。培養した細胞懸濁液(細胞数25000個)をフィルター上面に加えて、更に37℃で3時間培養した後、フィルター上面の細胞を除去した。フィルターを取り出して乾燥させた後、DiffQuik染色液(16920、Sysmex製)を使用して、フィルターの下面に遊走した細胞を染色した。フィルターの吸光度(570nm)を測定し、LPAの細胞遊走活性を50%阻害する試験化合物濃度(IC50)を、EXSAS(バージョン7.6.0、アームシステックス製)を使用した非線形回帰分析にて求めた。
マウスLPA誘発ヒスタミン遊離試験
マウスLPA誘発ヒスタミン遊離試験はSwaneyらの方法(The Journal of Pharmacology and Experimental Therapeutics,336(2011)693-700頁)に準じて行った。試験化合物は0.5%メチルセルロース溶液(133-14255、和光純薬工業製)に懸濁し、雄性CD1マウス(体重30~40g、日本チャールス・リバー社供給)に10mL/kgの用量で経口投与した。投与4時間後に0.1%BSAを含むPBSに溶解したLPA(857130P、Avanti製)を尾静脈から投与(マウス当り300μg)した。ただちにマウスをイソフルランを用いて麻酔し、LPA投与から2分後に静脈から血液を採取した。血液はEDTAを含む試験管に移し、4℃で2,000×g、10分間遠心分離して血漿を得た。
血漿中のヒスタミン濃度はEIAキット(62HTMPEB、Cisbio Bioassays製)で測定した。
試験化合物を投与したマウスの血漿中ヒスタミン濃度から、0.5%メチルセルロース溶液投与群に対する抑制率(%)を個体ごとに算出し、抑制率80%以上を示す個体の割合を有効率(%)として表わした。
ブレオマイシン誘発肺線維症モデル
マウスに塩酸ブレオマイシン(日本化薬製)を投与して肺線維症モデルを作製した。試験化合物はブレオマイシン投与開始日より毎日経口投与した。ブレオマイシン処置後3日-42日目にイソフルラン麻酔下にて肺胞洗浄液(BALF)、又は、肺を採取した。BALFは800×g、10分間遠心分離し、上清を得た。上清はDC protein assay kit(500-0114、Biorad製)を用いて蛋白質量を測定し、Sircol solble collagen assay kit(S111、Biocolor製)を用いてコラーゲン量を測定した。更に、上清中の炎症、線維化に関わるバイオマーカーをELISA法を用いて測定した。肺は湿重量を測定した後、組織中のヒドロキシプロリン量をWoessnerの方法(Archives of Biochemistry and Biophysics,93(1961)440-447頁)を改変して測定した。肺の一部は10%中性緩衝ホルマリンにて固定し、病理組織学的変化を観察した。結果は、EXSAS(バージョン7.6.0、アームシステックス製)を使用して統計学的解析を行った。
片側尿管結紮(UUO)腎線維症モデル
マウスをイソフルランにて麻酔した後、腹部を切開する。左側尿管を絹糸にて結紮し、UUOモデルを作製する。試験化合物はUUO作製日より毎日経口投与する。UUO作製後、8、14、又は、21日目に、腎臓を摘出し、湿重量を測定する。腎臓の一部からRNAを抽出し、線維化のマーカー遺伝子の発現量を定量PCR法にて測定する。また、腎組織中のヒドロキシプロリン量、又は、コラーゲン量を測定する。結果は、EXSASを使用して統計学的解析を行う。
四塩化炭素(CCl4)誘発肝線維症モデル
マウスに、希釈したCCl4(035-01273、和光純薬工業製)を週に2回投与して肝線維症モデルを作製する。試験化合物はCCl4投与開始日より毎日経口投与する。CCl4投与開始後3日-28日目にイソフルラン麻酔下にて肝臓を採取し、湿重量を測定する。肝臓の一部からRNAを抽出し、線維化のマーカー遺伝子の発現を定量PCR法にて測定する。更に肝組織中のヒドロキシプロリン量、又は、コラーゲン量を測定する。肝臓の一部は10%中性緩衝ホルマリンにて固定し、病理組織学的変化を観察する。結果は、EXSASを使用して統計学的解析を行う。
ラット非アルコール性脂肪性肝炎(NASH)モデル
ラットにメチオニン・コリン欠乏(MCD)食を負荷し、NASHモデルを作製する。ラットに通常食あるいはMCD食を20週間自由摂取させる。試験化合物はMCD食負荷開始日から毎日経口投与する。20週間飼育後、イソフルラン麻酔下にて肝臓を採取し、湿重量を測定する。肝臓の一部からRNAを抽出し、線維化のマーカー遺伝子の発現を定量PCR法にて測定する。更に肝組織中のヒドロキシプロリン量、又は、コラーゲン量を測定する。肝臓の一部は10%中性緩衝ホルマリンにて固定し、病理組織学的変化を観察する。結果は、EXSASを使用して統計学的解析を行う。
マウス非アルコール性脂肪性肝炎(NASH)モデル
NASHモデルとしてSTAM(登録商標)マウス(株式会社ステリック再生医科学研究所製)を使用する。STAM(登録商標)マウスは、2日齢の雄マウスにストレプトゾトシン(シグマアルドリッチ製)200μgを背部皮下に1回投与し、生後4週齢から高脂肪食(High Fat Diet 32、日本クレア製)で飼育することによって作製(Medical Molecular Morphology, 46(2013)141-152頁)する。
試験化合物は5あるいは6週齢から毎日経口投与する。9あるいは10週齢時に麻酔下に血液および肝臓を採取し、血液は生化学検査を実施する。肝臓は湿重量を測定した後、一部からRNAを抽出し、炎症及び線維化のマーカー遺伝子の発現を定量PCR法にて測定する。更に肝組織中のヒドロキシプロリン量またはコラーゲン量を測定する。肝臓の一部からパラフィン切片あるいは凍結切片を作成して病理組織学的検査を実施し、NAFLD Activity score、Fibrosis areaあるいはInflammation areaを測定する。結果は、EXSUS(バージョン8.0、CACエクシケア製)あるいはPrism 4(GraphPad Software製)を使用して統計学的解析を行う。
マウス非アルコール性脂肪性肝炎(NASH)モデル
マウスをコリン欠乏0.1%メチオニン含有高脂肪食(A06071302、リサーチダイエット製)で飼育し、NASHモデルを作製(International Journal of Experimental Pathology,94 (2013) 93-103頁 )する。
試験化合物はCDAHFD負荷開始日から毎日経口投与する。8~12週間後、イソフルラン麻酔下に肝臓を採取し、湿重量を測定する。肝臓の一部からRNAを抽出し、炎症及び線維化のマーカー遺伝子の発現を定量PCR法にて測定する。更に肝組織中のヒドロキシプロリン量またはコラーゲン量を測定する。肝臓の一部は10%中性緩衝ホルマリンにて固定し、病理組織学的変化を観察する。結果は、EXSUS(バージョン8.0、CACエクシケア製)を使用して統計学的解析を行う。
サル薬物動態試験
試験前日の夕方より絶食したカニクイサルに、ディスポーザブルカテーテルを鼻腔から胃内に挿入し、注射筒を用いて、10mg/2mLに調製した化合物含有0.5%メチルセルロース懸濁液、又は、溶液を、2ml/kgの投与量で単回経口投与した。投与前、投与後15、30分、1、2、4、8、12、及び、24時間に、大腿静脈から注射筒を用いて採血した。採取した血液にEDTA-2Kを加え、遠心分離(4℃、1710×g、3000rpm、15分間)して血漿を得た。得られた血漿にアセトニトリルを添加し、除タンパク前処理(血漿50μL+アセトニトリル200μL混和)、及び、フィルター(PTFE、0.2μm)濾過後、LC-MS/MS(AB SCIEX社 3200QTrap、及び、島津製作所LC-20A、又は、LC-30Aシリーズ)にて血漿中の化合物濃度を測定した。得られた血漿中濃度推移よりPhoenix WinNonlin(CERTARA社)にてAUC(血中濃度下面積)を算出した。
標準二分式ハ-ドゼラチンカプセルに、粉末状の実施例の化合物の塩(100mg)、ラクト-ス(150mg)、セルロ-ス(50mg)、及び、ステアリン酸マグネシウム(6mg)を充填して、ハ-ドカプセルを製造し、洗浄した後、乾燥する。
大豆油、オリ-ブ油のような消化性油状物、及び、実施例の化合物の塩の混合物を、100mgの活性成分を含有するようにゼラチン中に注入してソフトカプセルを製造し、洗浄した後、乾燥する。
実施例の化合物の塩(100mg)、コロイド性二酸化ケイ素(0.2mg)、ステアリン酸マグネシウム(0.2mg)、微結晶性セルロ-ス(0.2mg)、デンプン(0.2mg)、及び、ラクト-ス(98.8mg)を用いて、製剤学の分野で周知の方法に従って錠剤を製造する。得られた錠剤には、必要に応じてコーティングを施すことができる。
Claims (15)
- アルカリ金属、又は、アルカリ土類金属がナトリウム、カリウム、又は、カルシウムである請求項1記載の塩。
- (R)-1-[4’-(5-クロロ-3-{[(1-フェニルエトキシ)カルボニル]アミノ}チオフェン-2-イル)-2’-メトキシ-[1,1’-ビフェニル]-4-イル]シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
- アルカリ金属、又は、アルカリ土類金属がナトリウム、カリウム、又は、カルシウムである請求項3記載の塩。
- (R)-1-{4’-[5-クロロ-3-({[1-(2,5-ジフルオロフェニル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
- アルカリ金属、又は、アルカリ土類金属がナトリウム、カリウム、又は、カルシウムである請求項5記載の塩。
- (R)-1-{4’-[3-({[1-(2-クロロフェニル)エトキシ]カルボニル}アミノ)-5-フルオロチオフェン-2-イル]-2’-メトキシ-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
- アルカリ金属、又は、アルカリ土類金属がナトリウム、カリウム、又は、カルシウムである請求項7記載の塩。
- (R)-1-{4’-[5-クロロ-3-({[1-(チオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
- アルカリ金属、又は、アルカリ土類金属がナトリウム、カリウム、又は、カルシウムである請求項9記載の塩。
- (R)-1-{4’-[5-フルオロ-3-({[1-(4-メチルチオフェン-3-イル)エトキシ]カルボニル}アミノ)チオフェン-2-イル]-[1,1’-ビフェニル]-4-イル}シクロプロパンカルボン酸のアルカリ金属、又は、アルカリ土類金属の塩。
- アルカリ金属、又は、アルカリ土類金属がナトリウム、カリウム、又は、カルシウムである請求項11記載の塩。
- 請求項1乃至12のいずれかに記載された塩を有効成分として含有するLPA受容体拮抗剤。
- 請求項1乃至12のいずれかに記載された塩を有効成分として含有する医薬組成物。
- 線維化を伴う疾患、免疫・炎症性疾患、中枢・末梢神経系疾患、泌尿器系疾患、癌関連疾患の治療もしくは予防のための、請求項14に記載された医薬組成物。
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BR112016030018-1A BR112016030018B1 (pt) | 2014-06-27 | 2015-06-26 | Sal composto de heterocíclico substituído com halogênio, antagonista do receptor de lpa, composição farmacêutica e uso do referido sal |
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EP3162801B1 (en) | 2020-07-22 |
BR112016030018A8 (pt) | 2023-05-09 |
US10023554B2 (en) | 2018-07-17 |
CA2953472C (en) | 2022-08-02 |
US20170158663A1 (en) | 2017-06-08 |
CN106458964A (zh) | 2017-02-22 |
RU2017102513A (ru) | 2018-07-27 |
EP3162801A1 (en) | 2017-05-03 |
KR20170016988A (ko) | 2017-02-14 |
JPWO2015199234A1 (ja) | 2017-04-27 |
CN106458964B (zh) | 2019-11-22 |
RU2017102513A3 (ja) | 2018-12-11 |
AU2015281021A1 (en) | 2017-01-19 |
AU2015281021B2 (en) | 2019-03-14 |
AU2015281021B9 (en) | 2019-03-28 |
RU2689315C2 (ru) | 2019-05-27 |
MX2016017371A (es) | 2017-05-01 |
ES2824801T3 (es) | 2021-05-13 |
EP3162801A4 (en) | 2018-01-24 |
BR112016030018A2 (pt) | 2017-08-22 |
KR102433588B1 (ko) | 2022-08-19 |
MX370408B (es) | 2019-12-11 |
CA2953472A1 (en) | 2015-12-30 |
JP6579103B2 (ja) | 2019-09-25 |
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