WO2014142086A1 - Dérivé acétate de pyrrolidin-3-yle et dérivé d'acétate de piperidin-3-yle - Google Patents

Dérivé acétate de pyrrolidin-3-yle et dérivé d'acétate de piperidin-3-yle Download PDF

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WO2014142086A1
WO2014142086A1 PCT/JP2014/056234 JP2014056234W WO2014142086A1 WO 2014142086 A1 WO2014142086 A1 WO 2014142086A1 JP 2014056234 W JP2014056234 W JP 2014056234W WO 2014142086 A1 WO2014142086 A1 WO 2014142086A1
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methyl
mmol
piperidin
tert
added
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均 原田
信久 渡辺
芳章 大橋
裕二 鬼澤
泰信 松本
忠志 岡部
吉田　一郎
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エーザイ・アール・アンド・ディー・マネジメント株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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

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  • the present invention relates to pyrrolidin-3-ylacetic acid derivatives and piperidin-3-ylacetic acid derivatives. More particularly, the present invention relates to pyrrolidin-3-ylacetic acid derivatives and piperidin-3-ylacetic acid derivatives that have applicability as therapeutic agents for inflammatory bowel disease.
  • Chemokines are the main cell migration factors in the body, and control tissue infiltration of lymphocytes through enhancement of cell movement and activation of cell adhesion molecules. Chemokines are classified into four subfamilies, CC, CXC, C, and CX3C, based on the sequence of their first two cysteine residues.
  • Fractalkine is the only member of the CX3C chemokine, and its structure and function have distinctive features not found in other chemokines.
  • fractalkine binding to the receptor CX3CR1 it is possible to mediate strong adhesion alone without the intervention of selectins and integrins even in the presence of a physiological blood flow rate. That is, the fractalkine-CX3CR1 cell invasion system mediates a function similar to the multistage cell invasion mechanism via selectins and integrins in a single step reaction.
  • Fractalkine is induced when vascular endothelial cells are treated with inflammatory cytokines TNF and IL-1.
  • CX3CR1 is expressed in a part of T cells in monocytes and NK cells, but not in neutrophils.
  • the fractalkine-CX3CR1 cell invasion system appears to be a very efficient mechanism for recruiting certain immune cells on or into the endothelial cells of damaged tissues.
  • Non-Patent Document 1 Regarding the relationship between the fractalkine-CX3CR1 system and the pathological condition, the fractalkine-CX3CR1 system is involved in the pathogenesis and pathology of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, lupus nephritis, and multiple sclerosis.
  • Non-Patent Document 2 Regarding inflammatory bowel disease in particular, it has been reported that the expression of fractalkine is enhanced at the inflammatory site of the large intestine tissue of the patient, and that CX3CR1 plays an important role in infiltration of immune cells into the intestinal tissue.
  • Patent Document 7 is described as being useful as an antagonist of the chemokine CCR2 receptor, the target chemokine family is different.
  • the problem to be solved by the present invention is to provide a compound having an inhibitory action in the fractalkine-CX3CR1 pathway.
  • the present invention [1] 2- ⁇ 1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl ⁇ acetic acid, 2- (1-[(2-Chloro-6-methylphenyl) methyl] -3- ⁇ [(1-cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ piperidin-3-yl ) Acetic acid, 2-[(3S, 4R) -3- ⁇ [1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -1-[(2,6-dichloro-3-fluorophenyl ) Methyl] -4-methylpyrrolidin-3-yl] acetic acid, 2-[(3S * , 4S *
  • a medicament comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for inflammatory bowel disease comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
  • An inhibitor of the fractalkine-CX3CR1 pathway comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a fractalkine inhibitor comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a CX3CR1 inhibitor comprising the compound according to [1] or a pharmacologically acceptable salt thereof as an active ingredient.
  • a method for treating inflammatory bowel disease comprising administering the compound according to [1] or a pharmacologically acceptable salt thereof to a patient.
  • the method according to [8], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • a method for inhibiting the fractalkine-CX3CR1 pathway which comprises administering to the patient a compound according to [1] or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting fractalkine comprising administering the compound of [1] or a pharmacologically acceptable salt thereof to a patient.
  • a method for inhibiting CX3CR1, comprising administering the compound of [1] or a pharmacologically acceptable salt thereof to a patient.
  • [18] Use of the compound of [1] or a pharmacologically acceptable salt thereof in the manufacture of a therapeutic agent for inflammatory bowel disease.
  • [20] Use of the compound of [1] or a pharmaceutically acceptable salt thereof in the manufacture of a fractalkine-CX3CR1 pathway inhibitor.
  • [21] Use of the compound of [1] or a pharmaceutically acceptable salt thereof in the production of a fractalkine inhibitor.
  • [22] Use of the compound of [1] or a pharmacologically acceptable salt thereof in the manufacture of a CX3CR1 inhibitor.
  • the compound according to the present invention has an inhibitory action in the fractalkine-CX3CR1 pathway. Therefore, the compound according to the present invention has applicability as a therapeutic agent for inflammatory bowel disease.
  • Example 6 is a graph showing the results of Test Example 2 regarding the compound of Example 7.
  • the present invention is not limited to a specific crystal form, although a crystal polymorph may exist, and a single substance of any crystal form may be a mixture. There may be. Further, the present invention includes amorphous forms, and the compounds according to the present invention include anhydrides, hydrates and solvates.
  • the “pharmacologically acceptable salt” in the present specification is not particularly limited as long as it forms a salt with the compound according to the present invention and is pharmacologically acceptable.
  • inorganic acid salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like
  • organic acid salts include, for example, acetate, succinate and fumarate.
  • Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt and the like, and preferred examples of organic base salts Examples thereof include diethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.
  • acidic amino acid salts include aspartate and glutamate
  • basic amino acid salts include arginine salt, lysine salt and ornithine salt.
  • the compound according to the present invention or a pharmacologically acceptable salt thereof can be formulated by a conventional method.
  • the dosage form include oral preparations (tablets, granules, powders, capsules, syrups, etc.). ), Injections (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration), external preparations (transdermal absorption preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories Etc.).
  • solid preparations such as tablets, capsules, granules, and powders are usually 0.001 to 99.5% by weight, preferably 0.01 to 90% by weight of the compound according to the present invention or a pharmaceutically acceptable product thereof. Possible salts.
  • the compound according to the present invention or a pharmacologically acceptable salt thereof if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, etc.
  • an excipient if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, etc.
  • excipient examples include lactose, corn starch, crystalline cellulose, and the like.
  • binder examples include hydroxypropylcellulose and hydroxypropylmethylcellulose.
  • disintegrant examples include carboxymethylcellulose calcium and croscarmette. Examples include sodium loose.
  • Examples of the lubricant include magnesium stearate and calcium stearate, and examples of the colorant include titanium oxide.
  • Examples of the film coating agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like.
  • any of the above-mentioned additives is not limited to these.
  • the compound according to the present invention or a pharmacologically acceptable salt thereof is used as necessary.
  • PH adjusters, buffers, suspending agents, solubilizers, antioxidants, preservatives (preservatives), isotonic agents, and the like can be added, and can be produced by conventional methods. Alternatively, it may be freeze-dried to obtain a freeze-dried preparation that is dissolved at the time of use.
  • These injections can be administered intravenously, subcutaneously, intramuscularly and the like.
  • pH adjusting agents and buffering agents include organic acids or inorganic acids and / or salts thereof.
  • suspending agents include methyl cellulose, polysorbate 80, sodium carboxymethyl cellulose, and so on.
  • the agent include glucose, sodium chloride, mannitol and the like, but of course not limited thereto.
  • injection solutions can usually contain 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound according to the present invention or a pharmacologically acceptable salt thereof.
  • a base material is added to the compound according to the present invention or a pharmacologically acceptable salt thereof, and if necessary, the above-mentioned emulsifier, preservative, pH adjuster, coloring
  • a transdermal absorption preparation an ointment, a patch, etc.
  • an eye drop a nasal drop, a suppository, and the like can be produced by adding conventional preparations and the like.
  • various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used.
  • animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, purified water And other raw materials can be used.
  • These external preparations can usually contain 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound according to the present invention or a pharmacologically acceptable salt thereof.
  • the dose of the pharmaceutical agent according to the present invention usually varies depending on symptoms, age, sex, weight, etc., but may be an amount sufficient for producing a desired effect.
  • about 0.1 to 5000 mg (preferably 0.5 to 1000 mg, more preferably 1 to 600 mg) per day is once per day or 2 to 6 times a day. Used in divided times.
  • the present invention also includes isotope-labeled compounds of the compounds of the present invention, which have an atomic mass or mass number that differs from the atomic mass or mass number in which one or more atoms are normally found in nature. It is the same as the compound according to the present invention except that it is replaced by an atom having it.
  • the isotopes that can be incorporated into the compounds according to the present invention are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. 2 H, 3 H, 11 C, 14 C, 13 N, 15 O, 18 F, 32 P, 35 S, 123 I, 125 I and the like are included.
  • Isotopically-labeled compounds of the present invention for example, compounds incorporating radioactive isotopes such as 3 H and / or 14 C, are useful in pharmaceutical and / or substrate tissue distribution assays. 3 H and 14 C are considered useful because of their ease of preparation and detection.
  • the isotopes 11 C and 18 F are considered useful in PET (positron emission tomography), and the isotope 125 I is considered useful in SPECT (single photon emission computed tomography), all useful in brain imaging. It is.
  • the isotope-labeled compounds of the compounds of the present invention can be prepared by using readily available isotope-labeled reagents in place of non-isotopically-labeled reagents and the procedures disclosed in the following schemes and / or examples. It can be uniformly prepared by carrying out.
  • the compound according to the present invention can be used as a chemical probe for capturing a target protein of a physiologically active low-molecular compound. That is, the compound according to the present invention is different from the structural portion essential for the expression of the activity of the compound in a portion different from J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5 2003, p492-498 or WO2007 / 139149 can be converted into affinity chromatography, photoaffinity probe, etc. by introducing a labeling group, a linker, etc. by the method described in WO2007 / 139149.
  • Examples of the labeling group and linker used for the chemical probe include groups shown in the following groups (1) to (5).
  • Photoaffinity labeling groups for example, benzoyl group, benzophenone group, azide group, carbonyl azide group, diaziridine group, enone group, diazo group and nitro group
  • chemical affinity groups for example, alpha carbon atom is halogen
  • a protein labeling group such as a ketone group substituted with an atom, a carbamoyl group, an ester group, an alkylthio group, a Michael acceptor such as an ⁇ , ⁇ -unsaturated ketone, an ester, and an oxirane group
  • a cleavable linker such as —SS—, —O—Si—O—, monosaccharide (glucose group, galactose group, etc.) or disaccharide (lactose etc.), and oligopeptide cleavable by enzymatic reaction Link
  • a probe prepared by introducing a labeling group selected from the group consisting of the above (1) to (5) into the compound according to the present invention according to the method described in the above document is a new drug discovery target. It can be used as a chemical probe for the identification of a labeled protein that is useful for searching for a protein.
  • the compounds according to the present invention can be produced, for example, by the methods described in the following examples, and the effects of the compounds according to the present invention can be confirmed by the methods described in the following test examples. However, these are illustrative, and the present invention is not limited to the following specific examples in any case.
  • Example 1a tert-butyl N- (1-pentylpiperidin-4-yl) carbamate tert-butyl N- (piperidin-4-yl) carbamate (61 g, 304.6 mmol), acetic acid (6.1 mL), and A mixture of tetrahydrofuran (dehydrated) (700 mL) was cooled in an ice bath. To the mixture was added a solution of valeraldehyde (38.4 mL, 365.5 mmol) in tetrahydrofuran (dehydrated) (100 mL). After 20 minutes, sodium triacetoxyborohydride (84 g, 396.0 mmol) was added to the mixture.
  • the reaction mixture was stirred at room temperature for 14 hours and 40 minutes.
  • the reaction mixture was cooled in an ice bath, and water (700 mL) was added to stop the reaction.
  • the resulting mixture was made alkaline by adding 5N aqueous sodium hydroxide solution (240 mL), and the resulting solution was extracted twice with ethyl acetate (600 mL).
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, the desiccant was filtered, and concentrated under reduced pressure to give the title compound as a crude product (86.43 g).
  • Example 1b 1-pentylpiperidin-4-amine
  • tert-butyl N- (1-pentylpiperidin-4-yl) carbamate (86.43 g, 319.6 mmol) obtained in Example 1a and methanol (300 mL).
  • the mixture was cooled in an ice bath, to which 5N hydrochloric acid (300 mL, 1500 mmol) was added.
  • the reaction solution was stirred at room temperature for 15 hours and 45 minutes. Further, 5N hydrochloric acid (130 mL, 650 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was washed twice with tert-butyl methyl ether (500 mL).
  • the aqueous layer was basified with 5N aqueous sodium hydroxide solution (495 mL) to pH 12-13, and the resulting solution was extracted three times with ethyl acetate (500 mL).
  • the combined organic layers were washed with saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure.
  • Ethyl acetate was added to the resulting residue, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure to obtain the title compound (42.08 g, yield: 77%).
  • Example 1d (3RS) -1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-3-carboxylic acid 1-benzyl 3 obtained in Example 1c 5N water for a solution of ethyl (3RS) -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarboxylate (100.7 g, 248.3 mmol) in ethanol (700 mL) An aqueous alkali solution prepared from an aqueous sodium oxide solution (400 mL, 2000 mmol) and water (600 mL) was added, and the mixture was stirred at room temperature for 118 hours 30 minutes.
  • the reaction mixture was extracted 3 times with tert-butyl methyl ether, and the extracted layers were combined and concentrated.
  • Water and ethyl acetate (1 L) were added to the residue, and 2N hydrochloric acid (250 mL) was further added under ice cooling.
  • the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate (1 L).
  • the aqueous layer produced upon extraction with tert-butyl methyl ether was acidified with 5N hydrochloric acid and extracted with ethyl acetate.
  • the ethyl acetate layers were combined and dried over magnesium sulfate, and the desiccant was filtered and concentrated under reduced pressure.
  • Example 1e Benzyl (3RS) -3- [2- (tert-butoxy) -2-oxoethyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidine-1-carboxylate
  • Example 1d (3RS) -1-[(benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-3-carboxylic acid (10.0 g, 26.5 mmol) obtained in Example
  • Example 1f tert-Butyl 2- ⁇ (3RS) -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl ⁇ acetate benzyl (3RS) -3- obtained in Example 1e [2- (tert-Butoxy) -2-oxoethyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidine-1-carboxylate (71.8 g, 135.6 mmol) and methanol (350 mL) To the mixture, 10% Pd / C (7.2 g) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere.
  • Example 1g tert-butyl 2- ⁇ (3RS) -1-[(2,6-dichlorophenyl) methyl] -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl ⁇ acetate
  • Tert-butyl 2- ⁇ (3RS) -3-[(1-pentylpiperidin-4-yl) carbamoyl] piperidin-3-yl ⁇ acetate (54.7 g, 138.4 mmol) obtained in Example 1f was ice-cooled. Under mixing with potassium carbonate (38.2 g, 276.7 mmol) in dimethylformamide (200 mL).
  • Example 2a 1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-amine
  • tert-butyl N- (piperidin-4-yl) was obtained.
  • the title compound (57.0 g) was obtained from carbamate (65 g, 325 mmol) and 1-cyclohexene-1-carboxaldehyde (42.9 g, 389 mmol).
  • Example 2b 1-benzyl 3-ethyl 3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarbochelate optically active substance
  • Example 1c 1-benzyl 3-ethyl (3RS) -3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarboxylate (5 g) obtained in 1 above was repeatedly optically resolved under the following conditions: The title compound (1.59 g) was obtained by fractionating a peak having a long retention time.
  • Example 2c 1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy)]-2-oxoethyl] piperidine-3-carboxylic acid optically active substance 1-benzyl obtained in Example 2b 3-ethyl 3- [2- (tert-butoxy) -2-oxoethyl] piperidine-1,3-dicarbosichelate optically active substance (1.59 g, 3.92 mmol) was dissolved in ethanol (12 mL) and iced. Under cooling, 2N aqueous sodium hydroxide solution (16 mL, 32 mmol) was added, and the mixture was stirred at room temperature for 92 hours 30 minutes.
  • Example 2d benzyl 3- [2- (tert-butoxy) -2-oxoethyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ piperidine- Optically active form of 1-carboxylate Optically active form of 1-[(benzyloxy) carbonyl] -3- [2- (tert-butoxy)]-2-oxoethyl] piperidine-3-carboxylic acid obtained in Example 2c (40 mg, 0.106 mmol), 1- (cyclohex-1-en-1-ylmethyl) piperidin-4-amine (33 mg, 0.17 mmol), triethylamine (0.045 mL, 0.323 mmol) obtained in Example 2a ), Bis (2-oxo-3-oxazolidinyl) phosphinic chloride (51 mg, 0.2 mmol), and tetra A mixture of hydrofuran (1.5 mL) was stir
  • Example 2e tert-butyl 2- ⁇ 1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl ] Carbamoyl] piperidin-3-yl ⁇ acetate optically active benzyl 3- [2- (tert-butoxy) -2-oxoethyl] -3- ⁇ [1- (cyclohex-1-ene] obtained in Example 2d -1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ piperidine-1-carboxylate optically active substance (49 mg, 0.089 mmol) was mixed with 10% Pd / C (6.5 mg) in methanol under a hydrogen atmosphere.
  • tert-butyl 2- ⁇ 1-[(2-chloro-6-methylphenyl) methyl obtained in Example 2e ]
  • the optically active substance (7 mg, 0.013 mmol) of 3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl] piperidin-3-yl ⁇ acetate From the optically active substance (7 mg, 0.013 mmol) of 3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl] piperidin-3-yl ⁇ acetate, the title compound (4.5 mg, yield: 71.7%) was obtained.
  • Example 3a (2,6-Dichloro-3-fluorophenyl) methanol 10M borane-dimethylsulfide with respect to a solution of 2,6-dichloro-3-fluorobenzoic acid (1 g, 4.78 mmol) in tetrahydrofuran (10 mL) Complex (0.718 mL, 7.18 mmol) was added at room temperature. The mixture was stirred for 10 hours under heating to reflux. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with ethyl acetate.
  • Example 3b (4-Methoxyphenyl) methyl (2E) -but-2-enoate
  • Crotonic acid (17.2 g, 200 mmol) was cooled to N, N-dimethylformamide (100 mL) in an ice bath under nitrogen.
  • Dissolve and add powdered potassium carbonate (15.2 g, 110 mmol).
  • the mixture was stirred for 30 minutes before 4-methoxybenzyl chloride (29.8 g, 190 mmol) was added dropwise over 15 minutes.
  • the reaction mixture was stirred at room temperature for 4 hours and at 45 ° C. for 14 hours.
  • Ethyl acetate (500 mL) and water (200 mL) were added to the reaction solution.
  • Example 3c (4-Methoxyphenyl) methyl (3RS, 4RS) -1-benzyl-4-methylpyrrolidine-3-carboxylate (4-Methoxyphenyl) methyl (2E) -but-- obtained in Example 3b
  • 2-Enoate (40.6 g, 197 mmol) was dissolved in dichloromethane (250 mL) under nitrogen and the mixture was cooled in an ice / water bath with stirring. Trifluoroacetic acid (0.758 mL, 9.84 mmol) was added, and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (51.4 g, 216 mmol) was added dropwise while washing with dichloromethane (5 mL).
  • reaction was allowed to reach room temperature and stirred for 14 hours.
  • the reaction solution was concentrated and purified by column chromatography (silica gel, elution solvent: ethyl acetate / heptane). The fraction containing the desired compound was concentrated to obtain the title compound (57.86 g, yield: 86.5%).
  • Example 3d (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate
  • Example 3c (4-Methoxyphenyl) methyl (3RS, 4RS) -1-benzyl-4-methylpyrrolidine-3-carboxylate (56.7 g, 166 mmol) obtained in 1 above was equipped with two 200 mL dropping funnels and a thermometer. It was poured into a 3 L 4-neck flask that had been dried in an oven in advance while washing with tetrahydrofuran (dehydrated) (total 800 mL). The solution was cooled to ⁇ 74.5 ° C.
  • Example 3f (3RS, 4SR) -1-[(benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid
  • Example 3e The obtained (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (9.84 g, 40.5 mmol), acetone (39 mL) and water ( (49 mL), 2N aqueous sodium hydroxide solution (20.2 mL) was added under ice-cooling and stirring (0-1 ° C.), and the mixture was stirred for 45 minutes to obtain a reaction mixture.
  • benzyl chloroformate (6.35 mL, 44.5 mmol) and 2N aqueous sodium hydroxide solution (22.3 mL) were simultaneously added with ice-cooling and stirring (0-1 ° C.) at an internal temperature of 3.5 ° C. or less. It was added dropwise over 20 minutes.
  • the reaction solution was stirred in an ice bath and gradually returned to room temperature.
  • the mixture was stirred at room temperature overnight.
  • the reaction solution was adjusted to pH 12 by adding 1N aqueous sodium hydroxide solution (10 mL) under ice-cooling and stirring (internal temperature around 15 ° C.). The reaction solution was returned to room temperature and washed three times by adding ethyl ether.
  • the aqueous layer was adjusted to pH 2-3 by sequentially adding ice-cold stirring (internal temperature of 5 ° C. or lower), 2N hydrochloric acid (20.2 mL), and 1N hydrochloric acid (13 mL).
  • the aqueous layer was returned to room temperature and extracted three times with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed 4 times with water and then with saturated brine.
  • Example 3g 1,3-dibenzyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate obtained in Example 3f (3RS, 4SR) -1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (14.5 g, 38.5 mmol) Benzyl bromide (4.48 mL, 37.7 mmol) was added to a mixture of potassium carbonate (10.6 g, 77 mmol) and N, N-dimethylformamide (50 mL) under ice-cooling and stirring (internal temperature: 3-7 ° C.).
  • Example 3h (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 1,3-dibenzyl (3RS, obtained in Example 3g) 4SR) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate (9.1 g) is optically repeated under the following two preparative conditions A or B: Divided.
  • Example 3i tert-Butyl 2-[(3S, 4R) -3- ⁇ [1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -1-[(2, 6-Dichloro-3-fluorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetate (2,6-Dichloro-3-fluorophenyl) methanol obtained in Example 3a (150 mg, 0.77 mmol) in dichloromethane (5 mL), triphenylphosphine (303 mg, 1.16 mmol), and carbon tetrabromide (383 mg, 1.16 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 3j 2-[(3S, 4R) -3- ⁇ [1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -1-[(2,6-dichloro -3-Fluorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetic acid
  • the title compound (35 mg, yield: 46.6%) was obtained from 3-yl] acetate (83 mg, 0.139 mmol).
  • Example 4 2-[(3S * , 4S * )-1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-ene- 1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • the absolute configuration is unknown, but if the relative configuration is known, * Used to indicate.
  • Example 4a 2- (Bromomethyl) -1-chloro-3- (trifluoromethyl) benzene [2-Chloro-6- (trifluoromethyl) phenyl] methanol (150 g, 713 mmol) in tetrahydrofuran (1.5 L) The solution was stirred under ice cooling, and triethylamine (199 mL, 1.43 mol) was added thereto. Further, methanesulfonyl chloride (82.8 mL, 1.07 mol) was added dropwise over 1 hour and 10 minutes in a nitrogen stream. After 10 minutes, water (1.5 L) and ethyl acetate (1.5 L) were added, and the aqueous layer was removed.
  • Example 4b 1-benzyl 4-tert-butyl 2- (dimethoxyphosphoryl) butanedioate To a solution of sodium hydride (5.41 g, 135 mmol) in tetrahydrofuran (200 mL) under ice-cooling, benzyl 2- (dimethoxyphosphoryl) Acetate (27 g, 104 mmol) was added and stirred at room temperature for 6 hours. Tert-butyl bromoacetate (20.4 g, 104 mmol) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 4c 1-benzyl 4-tert-butyl 2-ethylidenebutanedioate 1-benzyl 4-tert-butyl 2- (dimethoxyphosphoryl) butanedioate (3.4 g, 9.15 mmol) obtained in Example 4b
  • Tetrohydrofuran 34 mL
  • potassium tert-butoxide (1.13 g, 10.1 mmol) was added under ice cooling, followed by stirring for 15 minutes.
  • Acetaldehyde (1.03 mL, 18.4 mmol) was then added dropwise. After returning to room temperature and stirring for 30 minutes, water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Example 4d Benzyl (3RS, 4RS) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate 1-Benzyl obtained in Example 4c 4-tert-butyl 2-ethylidenebutanedioate (2,03 g, 6.99 mmol) versus N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (2.49 g, 10.5 mmol), dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure.
  • Example 4e (3RS, 4RS) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid benzyl (3RS, 4RS) -1 obtained in Example 4d -Benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (1 g, 2.36 mmol) in methanol (20 mL) and 20% palladium hydroxide (300 mg) And stirred overnight at room temperature under a hydrogen atmosphere. The reaction vessel was purged with nitrogen, water was added, and the mixture was stirred for 5 minutes.
  • Example 4f tert-butyl 2-[(3RS, 4RS) -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-ene -1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (3RS, 4RS) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 4e ] -4-methylpyrrolidine-3-carboxylic acid (280 mg, 1.15 mmol) was added to 1- (cyclohex-1-en-1-ylmethyl) piperidin-4-amine (290 mg, 1.5 mmol) obtained in Example 2a.
  • Example 4g tert-butyl 2-[(3S * , 4S * )-1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1 -En-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate tert-Butyl obtained in Example 4f 2-[(3RS, 4RS) -1- ⁇ [2- Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] Acetate (302 mg) was optically resolved repeatedly under the following preparative conditions, and a peak with a short retention time was collected to obtain the title compound (132 mg).
  • Example 4h 2-[(3S * , 4S * )-1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-ene- 1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • the title compound (80 mg, yield: 66.6%) was obtained from carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (132 mg, 0.216 mmol).
  • Example 5a (2-Bromo-6-chlorophenyl) methanol From 2-bromo-6-chlorobenzoic acid (4 g, 17 mmol) in the same manner as described in Example 3a, the title compound (3.3 g) was obtained. Yield: 87.6%).
  • Example 5b [2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methanol 1 of (2-bromo-6-chlorophenyl) methanol (2.2 g, 10 mmol) obtained in Example 5a , 2-dimethoxyethane (44 mL) and water (15.5 mL) were mixed with 2-methoxypyridine-4-boronic acid (1.68 g, 10.8 mmol), sodium carbonate (1.6 g, 14.8 mmol). And 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) (363 mg, 0.498 mmol) were added at room temperature.
  • the mixture was heated and stirred at an external temperature of 100 degrees for 4.5 hours.
  • the reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure.
  • the residue was purified twice by column chromatography (NH silica gel, elution solvent: ethyl acetate / heptane and silica gel, elution solvent: ethyl acetate / heptane) to obtain the title compound (1.6 g, yield: 64.1%). It was.
  • Example 5c 4- [3-Chloro-2- (chloromethyl) phenyl] -2-methoxypyridine [2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] obtained in Example 5b
  • thionyl chloride 0.73 mL, 10 mmol
  • To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice cooling, and the mixture was extracted with ethyl acetate.
  • Example 5d tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex Su-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate obtained in Example 3h by a method similar to that described in Example 4f (3S , 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (105 mg, 0.432 mmol), 1- (cyclohex-1) obtained in Example 2a -En-1-ylmethyl) piperidin-4-amine (126 mg, 0.648 mmol) and 4- [3-chloro-2- (chloromethyl) obtained in a manner similar to that described in Example 5c.
  • Example 5e 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1 -En-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
  • tert-butyl 2- [(3S, 4R) -1- ⁇ [2-Chloro-6- (2-methoxypyridin-4-yl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl)
  • the title compound (100 mg, yield: 69.7%) was obtained from piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (157 mg, 0.241 mmol).
  • Example 6a (2-Methylcyclohex-1-en-1-yl) methanol ethyl 2-oxocyclohexane-1-carboxylate (10 g, 58.75 mmol) in a similar manner to that described in WO02068384 A2. The title compound (1.49 g) was obtained.
  • 1 H-NMR (400 MHz, CDCl 3 ) ⁇ (ppm): 1.26 (1H, t, J 8.0 Hz), 1.50-1.65 (4H, m), 1.70 (3H, s ), 1.90-1.98 (2H, m), 2.06-2.15 (2H, m), 4.06-4.15 (2H, m).
  • Example 6b 2-Methylcyclohex-1-ene-1-carbaldehyde (2-Methylcyclohex-1-en-1-yl) methanol (1.49 g, 11.81 mmol) obtained in Example 6a , Triethylamine (8.23 mL, 59.04 mmol), dimethyl sulfoxide (3.69 mL, 51.95 mmol) in dichloromethane (60 mL), sulfatrioxide pyridine complex (8.27 g, 51.95 mmol) at 0 ° C. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure until the solvent amount was reduced to about half.
  • Example 6c tert-Butyl N- ⁇ 1-[(2-methylcyclohex-1-en-1-yl) methyl] piperidin-4-yl ⁇ carbamate
  • 2-methylcyclohex-1-ene-1-carbaldehyde 8.59 g, content: 9.55%, 6.60 mmol
  • heptane obtained in Example 6b
  • tert-butyl N- piperidine-
  • the title compound (1.63 g, yield: 80%) was obtained from 4-yl) carbamate (1.59 g, 7.92 mmol).
  • Example 6d 1-[(2-Methylcyclohex-1-en-1-yl) methyl] piperidin-4-amine tert-butyl N- ⁇ 1-[(2-methylcyclohexyl) obtained in Example 6c
  • 5N hydrochloric acid (10 mL, 50 mmol) was added to ethanol (10 mL) of (S-1-en-1-yl) methyl] piperidin-4-yl ⁇ carbamate (1.63 g, 5.28 mmol) and stirred at room temperature for 17 hours. did.
  • the reaction mixture was ice-cooled, 5N aqueous sodium hydroxide solution (10 mL, 50 mmol) was added, and the solvent was evaporated.
  • Example 6e 2,6-Dichloro-3-fluorobenzaldehyde (2,6-Dichloro-3-fluorophenyl) methanol (1.93 g, 9.90 mmol) obtained in the same manner as described in Example 3a )
  • dimethyl sulfoxide (30 mL) was added triethylamine (11.0 mL, 78.9 mmol) and sulfatrioxide pyridine complex (7.88 g, 49.48 mmol) under water cooling, and the mixture was stirred for 110 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 6f (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methylpyrrolidine- 3-Carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (200 mg, 0.822 mmol) obtained in Example 3h, acetic acid To a mixture of (0.047 mL, 0.822 mmol) and methanol (4 mL) was added 2,6-dichloro-3-fluorobenzaldehyde (159 mg, 0.820 mmol) obtained in Example 6e and sodium triacetoxyborohydride (180 mg, 0.85 mmol) was added, and the mixture was stirred at an external temperature of 45 ° C.
  • Example 6g tert-butyl 2-[(3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-( ⁇ 1-[(2-methyl Cyclohex-1-en-1-yl) methyl] piperidin-4-yl ⁇ carbamoyl) pyrrolidin-3-yl] acetate obtained in Example 6f by a method similar to that described in Example 1e (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (60 mg, 0 From the 1-[(2-methylcyclohex-1-en-1-yl) methyl] piperidin-4-amine (38.7 mg, 0.186 mmol) obtained in Example 6d.
  • Example 6h 2-[(3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-( ⁇ 1-[(2-methylcyclohex- 1-en-1-yl) methyl] piperidin-4-yl ⁇ carbamoyl) pyrrolidin-3-yl] acetic acid
  • the tert-butyl 2- [ (3S, 4R) -1-[(2,6-dichloro-3-fluorophenyl) methyl] -4-methyl-3-( ⁇ 1-[(2-methylcyclohex-1-en-1-yl)
  • the title compound (47 mg, yield: 82.5%) was obtained from (methyl) piperidin-4-yl ⁇ carbamoyl) pyrrolidin-3-yl] acetate (63 mg, 0.103 mmol).
  • Example 7a tert-Butyl N- [1- (3-phenylpropyl) piperidin-4-yl] carbamate
  • tert-butyl N- (piperidin-4-yl) The title compound (2.1 g, yield: 66.0%) was obtained from carbamate (2 g, 9.99 mmol) and 3-phenylpropanal (1.47 g, 10.99 mmol).
  • Example 7b 1- (3-Phenylpropyl) piperidin-4-amine
  • tert-butyl N- [1- (3-phenylpropyl) obtained in Example 7a was used.
  • Piperidin-4-yl] carbamate (2.1 g, 6.594 mmol) gave the title compound (1.5 g, yield: quantitative).
  • Example 7c (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid obtained in Example 3h by a method similar to that described in Example 6f ( The title compound (10.27 g, yield: 89%) was obtained from 7 g, 28.77 mmol) and 2,6-dichlorobenzaldehyde (12.59 g, 71.93 mmol).
  • Example 7d tert-butyl 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -4-methyl-3- ⁇ [1- (3-phenylpropyl) piperidine-4- Yl] carbamoyl ⁇ pyrrolidin-3-yl] acetate (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl obtained in Example 7c by a method similar to that described in Example 1e ] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (70 mg, 0.174 mmol) and 1- (3-phenylpropyl) piperidine-4 obtained in Example 7b -The title compound (94 mg, yield: 90%) was obtained from the amine (45.6 mg, 0.209 mmol).
  • Example 7e 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -4-methyl-3- ⁇ [1- (3-phenylpropyl) piperidin-4-yl] carbamoyl ⁇ Pyrrolidin-3-yl] acetic acid
  • Example 8 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3- ⁇ [1- (3-phenylpropyl) Piperidin-4-yl] carbamoyl ⁇ pyrrolidin-3-yl] acetic acid
  • Example 8a (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl Pyrrolidine-3-carboxylic acid (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methyl obtained in Example 3h by a method similar to that described in Example 6f From the pyrrolidine-3-carboxylic acid (0.2 g, 0.822 mmol) and 2-chloro-6- (trifluoromethyl) benzaldehyde (0.857 g, 4.11 mmol), the title compound (0.252 g, yield: 70 .3%) was obtained.
  • Example 8b 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3- ⁇ [1- (3-phenylpropyl) Piperidin-4-yl] carbamoyl ⁇ pyrrolidin-3-yl] acetic acid (3S, 4R) -3- [2- (tert-butoxy) obtained in Example 8a by a method similar to that described in Example 1e -2-Oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methylpyrrolidine-3-carboxylic acid (50 mg, 0.115 mmol) and 1 obtained in Example 7b From-(3-phenylpropyl) piperidin-4-amine (30.1 mg, 0.138 mmol), tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoro (Chyl)
  • Example 9a 1-Benzyl 3-ethyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-1,3-dicarboxylate optically active substance 1-benzyl 3-ethyl (3RS) -pyrrolidine
  • 1,3-dicarboxylate (16 g, 57.7 mmol) in tetrahydrofuran (dehydrated) (250 mL) was cooled with dry ice-acetone and 1.14 M lithium bis (trimethylsilyl) amide / tetrahydrofuran solution (55.7 mL, 63 0.5 mmol) was added dropwise at -78 ° C.
  • tert-butyl bromoacetate (12.6 g, 70.7 mmol) was added dropwise over 40 minutes. Stirring was continued at ⁇ 78 ° C. for 3 hours, and then the temperature was gradually raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the desiccant was filtered and concentrated.
  • Example 9b 1-[(Benzyloxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-3-carboxylic acid optically active substance 1-benzyl 3 obtained in Example 9a -Ethyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-1,3-dicarboxylate optically active substance (4.2 g, 10.7 mmol), tetrahydrofuran (5 mL), methanol (20 mL), A mixture of 2N aqueous sodium hydroxide (10 mL) was stirred at room temperature for 3 hours. The mixture was concentrated, 2N hydrochloric acid (10 mL) and ethanol were added and concentrated.
  • Example 9c 1-benzyl 3-methyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-1,3-dicarboxylate optically active substance 1-[(benzyl) obtained in Example 9b Oxy) carbonyl] -3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-3-carboxylic acid optically active substance (1 g, 2.75 mmol), tetrahydrofuran (5 mL) and methanol (10 mL) in a mixture. Trimethylsilyldiazomethane (4.13 mL, 8.25 mmol) was added at room temperature and stirred for 1 hour.
  • Example 9e Optical activity of methyl 3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ pyrrolidine-3-carboxylate
  • the optically active form (545 mg, 2.24 mmol) of methyl 3- [2- (tert-butoxy) -2-oxoethyl] pyrrolidine-3-carboxylate obtained in Example 9d and N, N-dimethylformamide (4 mL) was stirred at room temperature, potassium carbonate (619 mg, 4.48 mmol), 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene (796 mg, 2.91 mmol) and N, N-dimethylformamide ( 3 mL) of the mixture was added.
  • the mixture was stirred for 11 hours and 20 minutes.
  • the reaction mixture was extracted with ethyl acetate and water.
  • the aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over sodium sulfate. After filtering the desiccant, the filtrate was concentrated under reduced pressure and purified by NH silica gel column chromatography to obtain the title compound (897 mg, yield: 91.9%).
  • Example 9f Optically active substance of 3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ pyrrolidine-3-carboxylic acid
  • Example 9g tert-butyl 2- [1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) Optically active form of piperidin-4-yl] carbamoyl ⁇ pyrrolidin-3-yl] acetate 3- [2- (tert-butoxy) -2 obtained in Example 9f by a method similar to that described in Example 1e -Oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ pyrrolidine-3-carboxylic acid optically active substance (59 mg, 0.14 mmol) and 1- (obtained in Example 2a) The title compound (74 mg, yield: 88%) was obtained from cyclohex-1-en-1-ylmethyl) piperidin-4-amine (32.6 mg, 0.168 mmol).
  • Example 9h 2- [1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidine-4 -Il] carbamoyl ⁇ pyrrolidin-3-yl] acetic acid optically active substance tert-butyl 2- [1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3-] obtained in Example 9g ⁇ [1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ pyrrolidin-3-yl] acetate optically active substance (70 mg, 0.117 mmol) in toluene (2 mL, 18.
  • the precipitated solid was filtered and washed with a mixed solution of ethanol and tert-butyl methyl ether (75 mL + 150 mL). The obtained solid was dried at 50 ° C. under reduced pressure to obtain the title compound (106.40 g, yield: 70.9%).
  • the obtained organic layer was washed twice with water (60 mL, 60 mL) and concentrated at 30 ° C. under reduced pressure.
  • Methanol (150 mL) and palladium hydroxide (885 mg) were added to the obtained concentrate, and the mixture was stirred under hydrogen pressure (0.35 MPa) for 7 hours and 20 minutes.
  • Water (200 mL) and tetrahydrofuran (100 mL) were added to the reaction solution and filtered, and the catalyst was washed successively with methanol (50 mL) and water (50 mL ⁇ 2). The filtrate was concentrated at 50 ° C.
  • Oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 500 mg
  • hydrogen phosphate (R)-( ⁇ )-1,1′-binaphthyl-2,2′-diyl 359 mg
  • ethanol 10.0 mL
  • water 10.0 mL
  • the precipitated solid was collected by filtration and washed with a 1: 1 ethanol-water mixture (2 mL).
  • the wet substance was dried under reduced pressure at 40 ° C. for about 1 hour to obtain the title compound (269 mg, yield: 20.5%).
  • the white solid (8.85 mg) was weighed into a screw glass container. To this was added MilliQ water (0.2 mL) and 99.5% ethanol (0.8 mL). This was then aliquoted into 1.5 mL LCMS vials, loosely capped and left at room temperature. After 9 days, it was observed that crystals were deposited in the vial. Using the obtained single crystal (0.40 ⁇ 0.40 ⁇ 0.06 mm), an X-ray diffraction experiment was conducted with R-AXIS RAPID II (Rigaku Corporation). Crystallographic data and structural analysis results are shown in Table 1, and atomic coordinate data are shown in Tables 2 to 4. From these results, the absolute structure of the title compound was identified.
  • the number of cells that migrated to the lower layer was evaluated using CellTiter (manufactured by Promega).
  • the amount of cell migration in the presence of fractalkine / test compound [A] was determined as [C] by the following formula, and the 50% inhibitory concentration (IC 50 ) was calculated based on this.
  • Inhibition rate (%) [1- ⁇ (AC) / (BC) ⁇ ] ⁇ 100
  • T cell transfer colitis model (Test Example 2) Body weight reduction inhibitory effect in T cell transfer colitis model (1) Method Using a colitis model induced by transferring CD4 positive CD45RB high positive cells collected from Balb / c mice into scid mice, The body weight reduction inhibitory effect of the example compounds was examined. The experiment was carried out over 28 days. On the first day, CD4 positive CD45RB high positive cells (5 ⁇ 10 5 cells / mouse) collected from the spleen of Balb / c mice were intravenously administered. From the 14th day to the 28th day, the Example compounds were orally administered once a day, and body weights were measured on the 14th, 17th, 19th, 21st, 23rd, 25th and 28th days.
  • the body weight reduction inhibitory effect was evaluated by the body weight change rate (BW gain,%) on the 14th, 17, 19, 21, 23, 25, and 28th days.
  • the body weight on the 14th day is [A]
  • the body weight on each body weight measurement day is [B]
  • the rate (%) was determined.
  • Body weight change rate (%) B / A ⁇ 100

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Abstract

L'invention concerne un dérivé acétate de pyrrolidin-3-yle ou dérivé d'acétate de piperidin-3-yle, ou un sel pharmacologiquement acceptable de ces derniers, ayant un effet d'inhibition de la voie fractalkine-CX3CR1.
PCT/JP2014/056234 2013-03-13 2014-03-11 Dérivé acétate de pyrrolidin-3-yle et dérivé d'acétate de piperidin-3-yle WO2014142086A1 (fr)

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