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WO2006115285A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2006115285A1
WO2006115285A1 PCT/JP2006/308919 JP2006308919W WO2006115285A1 WO 2006115285 A1 WO2006115285 A1 WO 2006115285A1 JP 2006308919 W JP2006308919 W JP 2006308919W WO 2006115285 A1 WO2006115285 A1 WO 2006115285A1
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WIPO (PCT)
Prior art keywords
group
compound
pharmaceutical composition
reaction
solid pharmaceutical
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PCT/JP2006/308919
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English (en)
Japanese (ja)
Inventor
Naomi Nagaoka
Shigeyuki Marunaka
Makoto Fukuta
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of WO2006115285A1 publication Critical patent/WO2006115285A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P13/06—Anti-spasmodics
    • 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
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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 functional characteristics of an orally administered product are basically evaluated by the absorption efficiency of the drug (active ingredient).
  • drug active ingredient
  • bioavailability biological property of the drug, physicochemical Determined by nature.
  • N ⁇ 2-[(3 R, 4 S)-4-( ⁇ 2 ⁇ ⁇ Methoxy-5— [5— (Trifluoronorenomethinole) 1 1 H-Tetrazonol 1 1] Benzyl ⁇ amino) 1-3-phenylpiperidicy 1-yl] 1-2-oxoethyl ⁇ acetamide or Or a prodrug thereof, a saccharide, and a solid pharmaceutical composition containing a hydrophilic water-insoluble substance;
  • [12] A method for producing a solid pharmaceutical composition according to [11], which is granulated by a wet granulation method;
  • a solid pharmaceutical composition comprising mannitol, crystalline cellulose, and a tachycun receptor antagonist having a basic group;
  • [21] A method for preventing / treating lower urinary tract disease, digestive system disease or central nervous disease, which comprises administering an effective amount of the solid composition according to [1] to a mammal;
  • Ar represents an optionally substituted aryl group, aralkyl group or aromatic heterocyclic group
  • R 1 represents a hydrogen atom or an optionally substituted hydrocarbon group.
  • X an oxygen atom or an imino group which may have a substituent
  • Z a methylene group which may have a substituent.
  • Ring A represents a piperidine ring which may further have a substituent
  • ring B represents an aromatic ring which may have a substituent.
  • the compound (I) may be a solid pharmaceutical composition containing a compound represented by formula (I) (hereinafter also simply referred to as compound (I)) or a salt thereof or a prodrug thereof. I) can be stably released over time.
  • the solid pharmaceutical composition of the present invention containing the compound has a lower urinary tract symptom, digestive tract disease or central nervous disease. Useful as a preventive / therapeutic agent.
  • Ar represents an optionally substituted aryl group, aralkyl group or aromatic heterocyclic group
  • R 1 represents a hydrogen atom or an optionally substituted hydrocarbon group.
  • X an oxygen atom or an imino group which may have a substituent
  • Z a methylene group which may have a substituent.
  • a ring represents a piperidine ring which may further have a substituent
  • B ring represents an aromatic ring which may have a substituent.
  • Ar represents an aryl group, an aralkyl group or an aromatic heterocyclic group, each of which may have a substituent.
  • aryl group for example, a C 6 14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl and the like are used, and phenyl is preferable.
  • aralkyl group for example, a C 7 19 aralkyl group such as benzyl, naphthylethyl, benzhydryl, trityl and the like are used, and preferably benzyl or benzhydryl.
  • substituents of the “aryl group”, “aralkyl group” and “aromatic heterocyclic group” include, for example,
  • Halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • Ci-s alkylene dioxy eg, methylene dioxy, ethylene dioxy, etc.
  • Nono halogenated which may also be C 2 - 6 alkynyl
  • G Ci Ci- 6 alkylamino eg, dimethylamino, jetylamino, etc.
  • Ci-16 alkyl has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). which may be d one 6 alkyl, and the like (e.g., methyl, Echiru, propyl, isopropyl, butyl, Isobuchinore, sec one Puchinore, tert Buchinore, pen chill, hexyl and the like to).
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • Examples of the “optionally substituted hydrocarbon group” represented by 4 ′ include, for example, the “optionally substituted group” represented by R 1 described later. The same as the “hydrocarbon group”.
  • substituted of the “amino group optionally having substituent (s)” represented by R 3 , for example, a hydrocarbon group optionally having substituent (s), which may have substituent (s) Examples thereof include a hydroxy group and an acyl group.
  • a hydroxy group and an alkoxy group for example, methoxy, ethoxy, propoxy, isopropoxy group, etc.
  • acyl group as the “substituent” of the “optionally substituted amino group” represented by R 3 , for example,
  • Examples of the “5- to 7-membered saturated cyclic amino” in the above-mentioned “optionally substituted 5- to 7-membered saturated cyclic amino” include monoreforino, thiomorpholino, piperazi N-1 _yl, piperidino, pyrrolidine 1-1-yl and the like.
  • the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” includes, for example, C 6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec. Puchinore, tert Buchinore, hexyl, etc.
  • R 1 represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent.
  • Lower alkoxy groups for example, C alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentinoreoxy, hexyloxy, etc.
  • Mono-lower alkylamino groups for example, mono-amino such as methinoreamino and ethylamino
  • Lower alkyl group for example, C ⁇ s alkylcarbonyl group such as acetyl and propionyl
  • Mono-lower alkyl group rubermoyl group for example, mono-C 6 alkyl unit rubermoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.
  • Aryl force rubamoyl group for example, C such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • Aryl force rubamoyl group for example, C such as phenylcarbamoyl, naphthylcarbamoyl, etc.
  • Ariru group e.g., phenyl, C 6 of naphthyl - like 1 0 Ariru group
  • Ariruokishi group e.g., Fueninoreokishi, C 6 such Nafuchiruokishi - like 1 0 ⁇ Li Ruokishi group
  • a lower alkylcarbonylamino group which may be halogenated for example, a halogenated group such as acetylamino, trifluoroacetylamino, etc.
  • Examples of the “5- or 6-membered heterocyclic group” represented as the “substituent” of the “hydrocarbon group optionally having substituent (s)” represented by R 1 include a nitrogen atom in addition to a carbon atom.
  • Examples of the above-mentioned “5- or 6-membered non-aromatic heterocyclic group” include pyrrolidier, tetrahydrofuryl, tetrahydrochenyl, piperidyl, tetrahydropyraenole, morpholinyl, thiomorpholinole, piperazil and the like.
  • non-aromatic heterocyclic groups may further be condensed with other aromatic or non-aromatic homocyclic rings or heterocyclic rings.
  • the “5- or 6-membered heterocyclic group” may have a substituent such as an oxo group.
  • Examples of the “acinole group” represented by R 1 include the same “acyl” as a substituent of the “aryl group”, “aralkyl group” and “aromatic heterocyclic group” represented by Ar above. .
  • heterocyclic group of the “heterocyclic group optionally having substituent (s)” represented by R 1 is, for example, one or two selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom 1 to 4 (preferably 1 to 3) heteroatoms containing 5 or 1 to 4 members (preferably 5 to 10 members) (monocyclic to tricyclic, preferably monocyclic or Bicyclic) and heterocyclic groups.
  • Lower alkenyl groups e.g., Bulle, Ariru, isopropenyl, Puteyuru, C 2 _ 6 alkenyl groups such as iso Buteyuru etc.
  • one or two heteroatoms selected from nitrogen, oxygen and sulfur atoms are 5 to 6-membered aromatic or non-aromatic heterocyclic group, etc., which may be substituted by 1 or 2 oxo groups, etc.
  • X is preferably 0 or NH.
  • hydrocarbon group optionally having substituent (s) examples include those similar to the “hydrocarbon group optionally having substituent (s)” represented by R 1 above.
  • Z is preferably a methylene group.
  • Power, et 1 a substituent selected to 3 have also been good Le , hydrocarbon radical (C ⁇ e al Kill group, C 7 - 19 Ararukiru group (benzyl group) or a C 6 - 14 Ariru group (Fuel group, etc.)),
  • X is 0 or NH
  • ring a represents a piperidine ring which may further have a substituent
  • Halogen atoms eg, fluorine, chlorine, bromine, iodine
  • Ariruokishi group e.g., such as C 6 _ Ariruokishi group such as phenoxy.
  • Lower Arukanoiru group e.g., formyl; Asechiru, propionyl, butyryl, etc.
  • C WINCH 6 alkyl one carbonyl group such Isobuchirinore
  • Aryl group eg C 6 — 10 aryl group such as benzoyl, naphthoyl, etc.
  • Mono-lower alkylamino groups for example, monoalkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.
  • Arylthio groups for example, C such as phenylthio, naphthylthio, etc.
  • Alkylsulfonyl groups for example, Ci-ealkylsulfonyl groups such as methinoresulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.
  • arylsulfonyl groups for example, phenylsulfonyl, naphthylsulfonyl, etc.
  • Mono-lower alkylamino group for example, monoamino such as methylamino and ethylamino
  • the “C ⁇ 6 alkyl group” of the “optionally substituted C ⁇ s alkyl group” has 1 to 5 of the above substituents at the substitutable position of the alkyl group, preferably 1 Or 3 substituents, and when the number of substituents is 2 or more, each substituent may be the same or different.
  • It is preferably a 6- alkyl group optionally having 3 substituents selected from ureido, and the like.
  • R 13 is
  • R 12 is a hydrogen atom, C 3 alkyl group or a C 3 - shows the 6 cycloalkyl group.
  • the a ring represents a piperidine ring which may further have a substituent. That is, the a ring may further have 1 to 8 substituents in addition to the R 11 4-position NH at the 1-position and the 3-position phenyl group.
  • R 13 and R 14 may have an oxo group and may form a 5- to 7-membered ring.
  • salts in “compound (I) or salt thereof” and “compound (A) or salt thereof” include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, and organic acids. And salts with basic or acidic amino acids.
  • metal salt include alkali metal salts such as sodium salt and strong salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Compound (a) can also be produced by the following method.
  • the raw material compound includes a case where a salt is formed, and examples of such a salt include the same salts as those described later.
  • the compound obtained in each step can be used as a crude crude product in the reaction solution for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be recrystallized, distilled, chromatographed. It can be easily purified by such separation means.
  • a compound in the formula is commercially available, a commercially available product can be used as it is.
  • the compound (a a) has the formula (a b):
  • Examples of the base include sodium hydroxide, lithium hydroxide hydroxide, etc .; hydrogen carbonates such as sodium hydrogen carbonate, hydrogen carbonate lithium; carbonates such as sodium carbonate, carbonated lithium Acetates such as sodium acetate; tertiary amines such as trimethylamine, triethylamine and ⁇ -methylmorpholine; aromatic amines such as pyridine, picoline, ⁇ and ⁇ ⁇ ⁇ ⁇ -dimethylaniline, and the like.
  • the amount of the base to be used is, for example, about 1 to about 100 mol, preferably about 1 to about 10 mol, per 1 mol of compound (ab).
  • the amount of compound (ba) to be used is generally about 1 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (ab).
  • Conversion of compound (d) to imine or oxime can be carried out using a known method, for example, using various amines in a solvent inert to the reaction.
  • metal hydrides examples include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanohydride, dibutylaluminum hydride.
  • Aluminum hydride, lithium aluminum hydride, borane complex (borane-THF complex, catecholborane, etc.), sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like are preferred.
  • the amount of the metal hydride to be used is, for example, about 1 to about 50 mol, preferably about 1 to about 10 mol, per 1 mol of imine or oxime.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C to about 1550 ° C, preferably about 20 ° C to about 100 ° C, and the reaction time is usually about 5 minutes to about 72 hours, Preferably, it is about 0.5 hours to about 40 hours.
  • the following reduction reaction can be carried out without isolating the intermediate imine or oxime, and the amine compound (c) can be obtained directly from the compound (d) force.
  • the pH of the reaction mixture is preferably about 4 to about 5.
  • Examples of reactive derivatives of compound (e) include the formula (e a):
  • a salt thereof hereinafter referred to as a reactive derivative (e a)
  • compound (f) a salt thereof (hereinafter referred to as compound (f)), and the resulting imine or iminium ion is subjected to a reduction reaction.
  • compound a salt thereof (hereinafter referred to as “compound”), and the resulting imine or iminium ion is subjected to a reduction reaction.
  • the imine or imminium ion formation reaction and its reduction reaction can be carried out according to the method described in Step 1, V.
  • R 12 ′ represents a hydrocarbon group which may have a substituent
  • ring b represents a benzene ring which may have a substituent and may be condensed
  • Other symbols are as defined above.
  • Examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R 12 ′ include, for example, a lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, pentinole, isobutinore , sec- Puchinore, tert- Puchinore, pen chill, C WINCH 6 alkyl cyclohexyl, etc., etc., to), a cycloalkyl group (e.g., cyclopropyl, Shikuropuchinore, consequent opening pentyl, C 3 of cyclohexyl, etc., to a consequent opening - 6 Shikuroa alkyl group), lower alkyl -
  • prop Rugiru - like 6 alkynyl group a lower alkenyl group (e.g., Bulle, ⁇ Li Le, isopropenyl, Buteyuru, c 2 _ 6 alkenyl groups such as Isobuteyuru etc.), ⁇ aralkyl group (e.g., benzyl, alpha - methylbenzyl, such as phenethyl C 7 — ij aralkyl group, etc.), aryl groups (eg, C 6 — i such as phenyl, naphthyl, etc., aryl groups, etc., preferably phenol groups, etc.).
  • aralkyl group e.g., benzyl, alpha - methylbenzyl, such as phenethyl C 7 — ij aralkyl group, etc.
  • aryl groups eg, C 6 — i such as phenyl, naphthy
  • This step consists of compound (d) and formula (h):
  • the amount of the optically active amine (h) to be used is about 0.9 to about 10 mol, preferably about 1 to about 2 mol, per 1 mol of compound (d).
  • the reaction temperature varies depending on the solvent used.
  • the reaction temperature is usually about 30 ° C. to about 20 ° C., preferably about 50 ° C. to about 150 ° C.
  • the reaction time is usually about 0. 1 hour to about 48 hours, preferably about 0.1 hour to about 24 hours.
  • reaction can be promoted by an azeotropic dehydration operation known per se.
  • T H F complex T H F complex, catechol poran, etc.
  • sodium borohydride, sodium cyanoborohydride, sodium acetooxyborohydride and the like are preferable.
  • the amount of metal hydride to be used is, for example, about 1 to about 50 mol, preferably about 1 to about 10 mol, per 1 mol of imine.
  • the catalytic hydrogenation reaction is usually performed in a solvent inert to the reaction.
  • a solvent include methanol, ethanol, propanol, butanol, Alcohols such as benzyl alcohol; aliphatic hydrocarbons such as heptane and hexane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include ethers such as tilether, dimethoxetane, dioxane, and tetrahydrofuran; esters such as ethyl acetate; amides such as N, N-dimethylformamide; carboxylic acids such as acetic acid; water or a mixture thereof.
  • a preferred solvent is an alcohol, with ethanol being particularly preferred.
  • the solvent can be used in a solvent-free state up to about 100 times by weight or less of the imine solvent.
  • the catalytic hydrogenation reaction can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • the catalyst used include a heterogeneous catalyst in which a transition metal is supported on a support.
  • Non-homogeneous catalysts include, for example, palladium carbon, palladium hydroxide carbon, palladium oxide such as palladium oxide; nickel such as developed nickel catalyst; platinum such as platinum oxide and platinum carbon; rhodium such as rhodium carbon Etc.
  • heterogeneous catalysts supporting palladium are preferable, and palladium carbon and palladium carbon hydroxide are particularly preferable.
  • This reaction is more preferably a reductive alkylation reaction, and it is preferable that ⁇ — ⁇ 2-[(3 R, 4 S) 4-1 4-amino-3-phenylbiperidine -1-yl] -1--2-oxoethyl ⁇ acetamide or Its salt and formula
  • Ethers such as tetrahydrofuran, dioxane, esters such as ethyl acetate, forces such as acetic acid / reponic acids, methanol, ethanol, 2-propanoles, butanols, alcohols such as benzalkanols, -Trinoles such as acetoetryl, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, Tyl sulfoxide or the like is used. These solvents may be used by mixing at an appropriate ratio.
  • the imine produced here can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography, etc., but it is preferable to carry out the reductive reaction as it is without isolation.
  • Examples of the reduction reaction of imine or imidium ion include a method using a metal hydride and a method using a catalytic hydrogenation reaction.
  • metal hydride as a reducing agent examples include the metal hydrides exemplified in Process B, but preferably sodium borohydride, sodium cyanoborohydride, sodium triacetoxyhydrogen borohydride and the like. And most preferably sodium triacetoxyborohydride.
  • the amount of the reducing agent to be used is, for example, about 1 to about 50 mol, preferably about 1 to about 10 mol, per 1 mol of imine or imime ion.
  • Preferred solvents are strength rubonic acids, halogenated hydrocarbons and esters. More preferably, it is a mixed solvent of sulfonic acids and halogenated hydrocarbons, carboxylic acids and esters.
  • acetic acid is preferable for carboxylic acids
  • dichloromethane is preferable for halogenated hydrocarbons
  • ethyl acetate is preferable for esters.
  • a mixed solvent of dichloromethane and acetic acid, ethyl acetate and succinic acid is preferable.
  • the reaction temperature is usually about _80 ° C to about 80 ° C, preferably about _40 ° C to about 40 ° C, and the reaction time is usually about 5 minutes to about 48 hours. Preferably from about 1 hour to about 24 hours.
  • the catalytic hydrogenation reaction can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • a catalyst examples include the catalysts exemplified in Step B of Step B, preferably palladium such as palladium carbon, palladium hydroxide carbon, and acid palladium, and most preferably palladium carbon.
  • the catalyst is used in an amount of about 0.01 to about 1 equivalent, preferably about 0.01 to about 0.5 equivalent.
  • solvents may be mixed and used at an appropriate ratio.
  • toluene is preferred.
  • the amount of solvent used is appropriately determined according to the solubility of N— [2-oxo-2- (4-oxo-1-3-biperiperidine)] ethyl] acetamide and (VII). .
  • the reaction temperature varies depending on the solvent used, but is usually about 30 ° C to about 20 ° C (preferably about 50 ° C to about 150 ° C, and the reaction time is usually about 0 ° C. 1 hour to about 48 hours, preferably about 0.1 hour to about 24 hours.
  • the imine is hydrogenated to be converted into an optically active compound ().
  • [(1 S) _ 1 _phenylethyl] amine is used as the optically active amine (h ′)
  • the optically active compound () is optically active.
  • the compound (i ') is N— [2—oxo 2—
  • the amount of the reducing agent to be used is, for example, about 1 to about 50 mol, preferably about 1 to about 10 mol, per 1 mol of the substrate (imine).
  • the solvent used in this case is not particularly limited as long as it does not adversely affect the reaction and solubilizes the raw material compound.
  • aromatic hydrocarbons such as toluene and xylene, heptane, hexane, etc.
  • the catalytic hydrogenation reaction can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • a catalyst examples include the catalysts exemplified in Step B of Step B, preferably a nickel catalyst, particularly preferably a developed nickel catalyst.
  • the amount used is about 0.01 to about 10 equivalents, preferably about 0.1 to about 5 equivalents.
  • the catalytic hydrogenation reaction is usually performed in a solvent inert to the reaction.
  • solvents include alcohols such as methanol, ethanol, propanol, butanol and benzyl alcohol; aliphatic hydrocarbons such as heptane and hexane; aromatic hydrocarbons such as benzene, toluene and xylene.
  • a preferred solvent is an alcohol, with ethanol being particularly preferred.
  • the solvent can be used in a solvent-free state up to 100 weight times or less of the solvent of the substrate, but it is usually preferable to use about 5 to about 30 times weight of the substrate.
  • Hydrogenation can be carried out by either batch or continuous reaction.
  • the hydrogen pressure at which the reaction is carried out is, for example, usually about 0.1 to about 5 MPa, preferably about 0.1 to about IMP a.
  • the reaction temperature is usually about 0 ° C to about 200 ° C, preferably about 20 ° C to about 60 ° C, and the reaction time is usually about 5 minutes to about 120 hours.
  • N— ⁇ 2-[(3 R, 4 S) 1-41amino-3_phenylpiperidine-1-1] -1-oxoethyl ⁇ acetamide is obtained as a free compound
  • inorganic acids eg, hydrochloric acid, sulfuric acid, hydrogen bromide
  • organic acids eg methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.
  • N-acetylyldaricin When N-acetylyldaricin is used as the acylating agent, it can be produced, for example, by using a condensing agent.
  • the “condensation agent” include N, N′-dicyclohexyl carpositimide, 1-ethyl-3- (3-dimethylaminopropinole) carposimide hydrochloride, carbodidiimidazole, and G (N-succin).
  • the “organic phosphorus compound” is reacted in the presence of a base according to the method described in, for example, JP-A-5-8-43979.
  • the “organophosphorus compounds” include methenore phenylene phosphate, etheno ole o-phenylene phosphate (EPPA) and other ano quinoles o_phenylene phosphite, fenenore o-phenylene phosphite, p —Caroline fenenole o-phenylene phosphite and other aryleno olefins—diphenyl / phospholinoleazide are used.
  • the amount of the "condensing agent" to be used is generally 1 to 10 mol, preferably 1 to 3 mol, relative to 1 mol of the substrate.
  • the amount of the reactive derivative (b a ') to be used is generally about 1 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of substrate.
  • the reaction temperature is usually about 10 ° C to about 15 ° C, preferably about 0 ° C to about 100 ° C, and the reaction time is usually about 15 minutes to about 24 ° C. Time, preferably about 30 minutes to about 16 hours.
  • N-acetylyldaricin is most preferred.
  • a method using a condensing agent is desirable, and it is more preferable to add a base.
  • inorganic acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
  • organic acid for example, methanesulfonic acid, benzene
  • Sulfonic acid for example, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.
  • inorganic bases for example, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonia
  • organic bases eg, trimethy / reamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, or N, N'-dibenzylethylenediamine, etc.
  • the compound (a) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography, etc.
  • Compound (a) When it contains an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, these are also included as the compound (a), and also known synthesis methods and separation methods (for example, Concentration, solvent extraction, column chromatography, recrystallization, etc.) can be obtained individually. For example, when compound (a) has an optical isomer, an optical isomer resolved from the compound is also included in compound (a).
  • the optical isomer can be produced by a method known per se. Specifically, an optically active synthetic intermediate is used, or an optical isomer is obtained by optical resolution of the final racemate according to a conventional method.
  • the compound (I) when the compound (I) has hydroxy or 1,2 secondary amino acid in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy-1- ⁇ - (trifluoromethyl) phenol / Reacetic acid], (1) -menthoxyacetic acid, etc.) are subjected to a condensation reaction to give diastereomers of ester form or amido form, respectively.
  • an amide or ester diastereomer when the compound (I) has a carboxylic acid group, an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or an alcohol reagent to a condensation reaction. The separated diastereomer is converted to the optical isomer of the original compound by subjecting to acid hydrolysis or basic hydrolysis.
  • Compound (a) may be a crystal.
  • the crystal of compound (a) can be produced by crystallization by applying a crystallization method known per se to compound (a).
  • examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, and a crystallization method from a melt.
  • the “crystallization from solution” includes saturation by changing factors related to the solubility of the compound (dissolved and dissolved, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent.
  • there is a method of shifting from a non-saturated state to a supersaturated state Specifically, for example, concentration method, slow cooling method, reaction method (diffusion method, electrolytic method), hydrothermal growth Law and flux method.
  • Solvents used include, for example, aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chlorophenol), saturated hydrocarbons (eg, hexane, heptane, etc.) , Cyclohexane, etc.), ethers (eg, jetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile), ketones (eg, acetone, etc.), sulfoxides (eg, , Dimethyl sulfoxide, etc.), acid amides (eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), water Etc. are used. These solvents may be
  • crystallization from melt examples include normal breathing method (lifting method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method ( VLS method, liquid phase epitaxy method) and the like.
  • a preferred example of the crystallization method is obtained by dissolving the compound (a) in a suitable solvent (eg, alcohols such as methanol and ethanol) at a temperature of 20 to 120 ° C. And a method of cooling the solution to a temperature equal to or lower than the melting temperature (for example, 0 to 50 ° C. (preferably, 0 to 20 ° C.)).
  • a suitable solvent eg, alcohols such as methanol and ethanol
  • the crystals thus obtained can be isolated by, for example, filtration.
  • a method for analyzing the obtained crystal a crystal analysis method by powder X-ray diffraction is generally used.
  • examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • the melting point of about 124 ° C to about 134 ° C, and by interfacial spacing (d value) of about 7.26, about 4.61, about 4.54, about 4.38 by powder X-ray crystal diffraction.
  • d value interfacial spacing
  • the “A-type crystal” is preferably crystallized from a supersaturated state at a low temperature.
  • the supersaturated temperature is preferably less than 46 ° C, more preferably 30 ° C or less, and most preferably 20 ° C or less.
  • a crystal having a melting point of about 107 ° C. to about .119 ° C. may be added as a seed crystal.
  • the “crystallization method” exemplified for the compound (a) or a salt thereof can be applied, but the “crystallization method from solution” is preferably applied.
  • the “B-type crystal” is preferably crystallized from a supersaturated state at a high temperature.
  • the temperature in the supersaturated state is preferably 46 ° C. or higher, more preferably 50 ° C. or higher, and most preferably 55 ° C. or higher.
  • crystals having a melting point of about 1 24 ° C. to about 1 3 4 ° C. may be added as seed crystals.
  • the crystallization method the “crystallization method” exemplified in the compound (a) or a salt thereof can be applied, but the “crystallization method from solution” is preferably applied.
  • binder examples include pregelatinized starch, gelatin, gum arabic powder, polyvinyl pyrrolidone, dextrin, and punoleran.
  • lubricant examples include stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica and the like.
  • coloring agent examples include yellow ferric iron oxide and iron sesquioxide.
  • Examples of the “light-shielding agent” include titanium oxide, talc, calcium carbonate, and magnesium carbonate.
  • Examples of the “plasticizer” include polyethylene glycol, propylene glycol, and copolyvidone.
  • a preferred embodiment of the pharmaceutical composition of the present invention includes those containing talc or / and magnesium stearate in addition to the above components.
  • the “basic group” in the above-mentioned “tachykinin receptor antagonist having a basic group” is a group having affinity with a hydrogen ion, or a group showing donation of an electron pair.
  • Group, guanidino group and the like is a group having affinity with a hydrogen ion, or a group showing donation of an electron pair.
  • the solid pharmaceutical composition of the present invention can be produced by combining known methods employed according to the dosage form.
  • the conditions for each process may be determined according to conventional methods.
  • the tablet obtained above may be further coated with a film to form a coated preparation.
  • a pan coating apparatus is usually used as the film coating operation.
  • the film-coated tablet include a film-coated round tablet, a film-coated tablet type tablet, and a film-coated type tablet.
  • the film coating solution can be prepared by dissolving or suspending a high molecular weight for film coating such as hydroxypropylmethylcellulose in a solvent such as water. It is preferable to add a colorant and a light-shielding agent to the film coating solution.
  • the product (tablet) temperature when spraying the film coating solution is preferably controlled to about 10 to 100 ° C. More preferably, the temperature is controlled at about 30 to 80 ° C, and more preferably about 40 to 60 ° C.
  • the pharmaceutical composition of the present invention containing the above compound can be used for mammals (eg, mice, rats, hamsters, rabbits, cats, nu, ushi, hidge, monkeys, humans, etc.) It can be used as a safe preventive or therapeutic agent for such substance P-related diseases.
  • Lower urinary tract disease for example, frequent urination, urinary incontinence, overactive bladder, dysuria such as interstitial cystitis, pelvic visceral pain, etc.
  • Gastrointestinal diseases eg, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, clone disease, urease-positive helical gram-negative bacteria (eg, Helicopactor pylori) ( Gastritis, gastric ulcer, etc.), gastric cancer, post-surgery disorders, dyspepsia, esophageal ulcer, vaginitis, colon polyp, fl dandruff, hemorrhoid disease, peptic ulcer, local ⁇ regeneration S recruitment, vomiting Nausea)
  • Gastrointestinal diseases eg, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, clone disease, urease-positive helical gram-negative bacteria (eg, Helicopactor pylori) ( Gastritis, gastric ulcer, etc.), gastric cancer, post-surgery disorders, dyspepsia, esophageal ulcer, vaginitis, colon polyp,
  • Inflammatory or allergic diseases e.g., allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, dermatitis, herpes, psoriasis, tracheositis, hemorrhoids, retinopathy, surgery, post traumatic Inflammation, remission of swelling, sore throat, cystitis, meningitis, inflammatory eye disease, etc.
  • Bone and joint diseases eg, rheumatoid arthritis (rheumatoid arthritis), osteoarthritis, rheumatoid myelitis, osteoporosis, abnormal proliferation of cells, fracture, re-fracture, bone softening , Osteopenia, osteopaget disease, ankylosing myelitis, osteoarthritis of knee osteoarthritis, and destruction of joint tissues in similar diseases
  • Respiratory diseases for example, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus * pulmonary embolism, pulmonary sarcoidosis, pulmonary tuberculosis, interstitial pneumonia, silicosis, adult respiratory distress syndrome, chronic obstructive pulmonary disease Cough etc.
  • Infectious diseases [HIV infection, cytomegaloinoles, influenza virus. Herpes virus and other viral infections, rickettsial infection, bacterial infection, sexually transmitted disease, carini pneumonia, Helicopactor pylori infection, systemic Infectious fungal infection, tuberculosis, invasive staphylococcal infection, acute vinores encephalitis, acute bacterial meningitis, AIDS encephalopathy, sepsis, sepsis, severe sepsis, septic shock, endotoxic shock, toxin shock syndrome, etc. ]
  • Cancer eg, primary, metastatic or recurrent breast cancer, prostate cancer, knee cancer, stomach cancer, lung cancer, colon cancer (colon cancer, rectal cancer, anal cancer), esophageal cancer, duodenal cancer, Cervical cancer
  • Central neurological diseases eg, neurodegenerative diseases (eg, Alzheimer's disease, Down syndrome, Parkinson's disease, Creutzfeldt ⁇ Jacob disease, amyotrophic spinal sclerosis (ALS), Huntington's chorea, diabetic neuropathy, multiple occurrences Sclerosis) (eg, schizophrenia), depression, mania, anxiety, threatening neuropathy, panic disorder, epilepsy, alcoholism, anxiety, uncomfortable mental state Central and peripheral neuropathy (eg, head injury, spinal cord injury, brain edema, sensory dysfunction, sensory dysfunction, autonomic dysfunction, autonomic dysfunction, whiplash etc.), memory impairment Harm (eg, senile dementia, amnesia, cerebral vascular dementia, etc.), cerebrovascular disorders (eg, cerebral hemorrhage, cerebral infarction, etc.
  • neurodegenerative diseases eg, Alzheimer's disease, Down syndrome, Parkinson's disease, Creutzfeldt ⁇ Jacob disease, amyotrophic spinal sclerosis (ALS), Huntington's chorea, diabetic neuropathy, multiple occurrences
  • asymptomatic cerebrovascular disorder e.g., transient cerebral ischemia Seizures, hypertensive encephalopathy, cerebral blood barrier disorders, etc.
  • recurrence and sequelae of cerebrovascular disorders eg, neurological symptoms, psychiatric symptoms, subjective symptoms, movements of daily living
  • central hypofunction after cerebrovascular occlusion e.g. Cerebral circulation: impaired or abnormal renal circulation automatic regulation, sleep disorder (insomnia), etc.
  • Cardiovascular diseases eg, acute coronary syndromes (eg, acute myocardial infarction, unstable angina), peripheral arterial occlusion, Reino's disease, Birja's disease, coronary intervention (percutaneous coronary artery formation) Restenosis after surgery (PTCA), atherectomy (DCA), stent placement, restenosis after coronary artery bypass surgery, other peripheral arteries (angioplasty, atherectomy, stent placement, etc.) and Restenosis after bypass surgery, ischemic heart disease (eg, myocardial infarction, angina pectoris), myocarditis, intermittent claudication, ratane infarction, arteriosclerosis (eg, atherosclerosis), heart failure (Acute heart failure, chronic heart failure including congestive), Arrhythmia, Atherosclerotic lesion development, Thrombosis, Hypertension, Hypertensive tinnitus, Hypotension, etc.)
  • ischemic heart disease eg, myocardial infar
  • Liver disease eg, chronic hepatitis, cirrhosis, interstitial liver disease, etc.
  • Knee diseases [eg, chronic knee inflammation]
  • Metabolic disorders eg, diabetes (insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetic microangiopathy, diabetic neuropathy, etc.), glucose intolerance, obesity, prostatic hypertrophy, sexual dysfunction etc.
  • Endocrine diseases for example, Addison's disease, Cushing syndrome, brown cell types, primary aldosteronism, etc.
  • Abnormal properties of blood and blood cell components for example, increased platelet aggregation ability, abnormal red blood cell deformability, increased white blood cell adhesion ability, increased blood viscosity, erythrocytosis, vascular purpura, self-immune hemolytic anemia , Disseminated intravascular coagulation syndrome (DIC), multiple myelopathy, etc.
  • Gynecological diseases eg climacteric disorder, pregnancy poisoning, endometriosis, uterine fibroids, ovarian disease, breast disease, etc.
  • Skin diseases eg keloids, hemangiomas, psoriasis, epilepsy, etc.
  • Eye diseases eg glaucoma, ocular hypertension, etc.
  • Otorhinolaryngological disorders eg Menuel syndrome, tinnitus, taste disorder, dizziness, flatness, dysphagia, etc.
  • the pharmaceutical composition of the present invention can also be produced by methods other than granulation, for example, conventional methods such as mixing, kneading, tableting, coating, sterilization, and emulsification. Regarding the manufacture of the drug product, for example, you can refer to each section of the Japanese Pharmacopoeia General Rules for Preparations. Further, the pharmaceutical preparation of the present invention may be formed into a sustained release agent containing an active ingredient and a biodegradable polymer compound.
  • the sustained-release agent can be prepared according to the method described in JP-A No. 9 2 6 3 5 4 5.
  • the dosage of the pharmaceutical composition of the present invention varies depending on the compound ( ⁇ ) or compound (I) or the type, administration route, symptoms, patient age, etc. For example, orally to an adult patient with abnormal urination When administered, compounds per kg body weight per day
  • the pharmaceutical composition of the present invention containing about 0.05 to 5 Omg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg as (A) or compound (I) Can be administered in divided doses.
  • the dosage is the type and content of compound (A) or compound (I), dosage form, duration of drug release, animal to be administered (eg, Mammals such as humans, rats, mice, cats, dogs, rabbits, rabbits, pigs, etc.), depending on the purpose of administration, for example, when applied parenterally, about 0.1 to about 1 week 10 Omg of compound (A) or compound (I) should be released from the dosage form.
  • animal to be administered eg, Mammals such as humans, rats, mice, cats, dogs, rabbits, rabbits, pigs, etc.
  • the pharmaceutical composition of the present invention may contain an appropriate amount of a pharmaceutically active ingredient other than the compound (A) or the compound (I), as long as it does not impair elution stability. It can also be used in combination with other pharmaceutically active ingredients.
  • compound (A) or compound (I) and other pharmaceutically active ingredients are used in combination, (1) compound (A) or compound (I) or other active pharmaceutical ingredient is administered alone Compared with, the dose can be reduced. More specifically, when compound (A) or compound (I) is used in combination with an anticholinergic agent or an NK-2 receptor antagonist, compared to when an anticholinergic agent or an NK-2 receptor antagonist is administered alone. Since the dose can be reduced, for example, side effects such as boil can be reduced;
  • the treatment period can be set longer by selecting Compound (A) or another pharmaceutically active ingredient with a different mechanism of action from Compound (I);
  • the therapeutic effect can be sustained by selecting Compound (A) or another pharmaceutically active ingredient having a different mechanism of action from Compound (I);
  • Insulin preparations eg, ushi, animal insulin preparations extracted from porcine knees; E. coli, yeast-engineered human insulin preparations; insulin insulin; protamine insulin zinc; insulin fragments Or derivatives (eg, I NS-1 etc.)), insulin sensitivity enhancers (eg, piodaritazone hydrochloride, troglitazone, oral diglitazone or its maleate, JTT-501, MCC-555, YM-440, GI— 262570, KRP-297, FK-614, CS-011, etc.), ⁇ -Dalcosidase inhibitor (eg, voglibose, acarbose, miglitol, emidatetate, etc.), biguanide (eg, phenformin, metformin, buformin, etc.) Sulfonylureas (e.g.
  • insulin secretion promoters eg, levaglinide, senaglinide, mitiglinide or its calcium salt hydrate, GLGL_1, nateglinide, etc.
  • di Peptidyl peptidase IV inhibitors eg, NVP—DPP—278, ⁇ —100, ⁇ 32/98, etc.
  • 33 agonists eg, CL_316243, S R-5861 1—A, UL—TG—307, AJ-9677, AZ40140, etc.
  • amylin agonists eg, plumlintide, etc.
  • phosphotyrosine phosphatase inhibitors eg, vanadic acid, etc.
  • gluconeogenesis inhibitors eg, glycogen phosphorylase inhibitors, glucose-6-
  • Aldose reductase inhibitors eg, torrestat, epalrestat, zenarestat, zoponolestat, fidarestat (SNK-860), minarelet Stat (AR 1-509), CT-112, etc., Neurotrophic factor (eg, NGF, NT-3 etc.), AGE inhibitor (eg, ALT-945, Pimagedin, Piratoxatin, N-Phenacillthiazoliu) Mubuguchi mid (ALT-766), EXO-226, etc., active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, thioprid, etc.), etc.
  • Neurotrophic factor eg, NGF, NT-3 etc.
  • AGE inhibitor eg, ALT-945, Pimagedin, Piratoxatin, N-Phenacillthiazoliu
  • Mubuguchi mid ALT-766
  • EXO-226, etc. active oxygen
  • Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, sympastatin, lovastatin, atorvastatin, funolepastatin, serivastatin or their salts (eg, sodium salt)), squalene synthase inhibitor or triglyceride lowering action (For example, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) etc.
  • cholesterol synthesis inhibitors eg, pravastatin, sympastatin, lovastatin, atorvastatin, funolepastatin, serivastatin or their salts (eg, sodium salt)
  • squalene synthase inhibitor or triglyceride lowering action eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.
  • Angiotensin converting enzyme inhibitors eg, captopril, enalapril, delapril, etc.
  • angiotensin II antagonists eg, oral sultan, candesartan cilexetil, etc.
  • calcium inhibitors eg, manidipine, diphedipine, amlodipi
  • Efonidipine, dicanorespine, etc. clonidine, etc.
  • Central anti-obesity drugs eg, dexfenfluramine, fenfluramine, fuenteolamine, sibutramine, amphepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.
  • ⁇ lipase inhibitors eg, Orlistat, etc.
  • 33 agonists eg, CL 316243, SR-586 1 1 A, UL—TG—307, AJ—9677, AZ40140, etc.
  • peptide appetite suppressants eg, lebutin
  • CNTF ciliary neurotrophic factor
  • cholecyst hunagoest eg, lynchtrypto, FPL-15849, etc.
  • Xanthine derivatives eg, sodium salicylate theobromine, calcimuteopromine salicylate
  • thiazide preparations eg, ethiazide, cyclopenthiazi
  • Trikuguchi lumetiazide hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorthiazide, penflutide, polythiazide, methiclotiazide etc.
  • anti-aldosterone preparations eg, spironolactone, triamterene, etc.
  • Chlorbenzenesulfonamide-based preparations eg, chlorthalidone, mefluside, indapamide, etc.
  • azosemide isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, etc.
  • Alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • metabolic antagonists eg, methotrexate, 5-fluorouracil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plant-derived anticancer agents eg, E.g., vincristine, vindesine, taxonole, etc.
  • cisplatin etopoxide, etc.
  • 5-flurouracil derivatives such as frutsone or neofluxone.
  • Microbial or bacterial components eg, muramyl dipeptide derivatives, picibanil, etc.
  • polysaccharides with immunopotentiating activity eg, lentinan, schizophyllan, krestin, etc.
  • cyto force-in obtained by genetic engineering techniques (eg, interferon, interferon, etc.) Mouth chicken (IL), etc.
  • colony stimulating factor eg, granulocyte colony stimulating factor, erythropoietin, etc.
  • IL-1, IL-2, IL-12 among others IL-1, IL-2, IL-12.
  • Progesterone derivatives eg, megestero-monoreacetate
  • Metoku Oral pramide drugs Tetrahydrocannabinol drugs (the literature is the same as above)
  • Fat metabolism improvers eg, eicosapentaenoic acid, etc.
  • Mon I GF-1, or antibodies to cachexia-inducing factors TNF-III, LIF, IL-6, Oncostatin M, etc.
  • Steroids eg, dexamethasone
  • sodium hyaluronate e.g., sodium hyaluronate
  • cycloxygenase inhibitors eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, oral fuecoxip, etc.
  • Glycation inhibitors eg, Dic-711 etc.
  • nerve regeneration promoters eg, Y-128, V X853, prosaptide, etc.
  • central nervous system drugs eg, desibramin, amitriptyline, imipramine, floxetine, paroxetine, doxepin
  • Antidepressants eg, desibramin, amitriptyline, imipramine, floxetine, paroxetine, doxepin
  • Antidepressants eg, antiepileptic drugs (eg, lamotrigine, carbamazepine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT—59 4), endothelin receptor antagonists (eg, ABT) — 627), monoamine uptake inhibitors (eg, tramadol), indoleamine uptake inhibitors (eg, floxetine, paroxetine), n
  • Cabsaicin protein kinase C inhibitors (eg, LY-333531), anxiolytics (eg, benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, apomorphine), dopamine receptors Antagonists (eg, haloperidonor), serotonin receptor agonists (eg, tandospirone taenoate, sumatriptan, tegaserod), serotoene receptor antagonists (eg, cyproheptadine hydrochloride, ondansetron), serotonin uptake inhibitors (eg, , Flupoxamine maleate, floxetine, paroxetine), sleep inducers (eg, triazolam, zolpidem), hypnotics (eg, ramelteon), anticholinergic drugs, a receptor blockers (eg, tamsulosin
  • NK-2 receptor antagonists examples include GR 1 5 9 8 9 7, GR 1 4 9 8 6 1, SR48 9 6 8 (saredutant), SR 1 44 1 90, Y ⁇ 3 5 3 75, ⁇ 3 8 3 3 6, ZD 7 944, L 1 743 9 8 6, MD L 1 0 5 2 1 2 A, ZD 6 0 2 1, MDL 1 05 1 7 2A, SCH 20 5 5 2 8, SC H6 Piperidine derivatives such as 2 3 73, R_ 1 1 3 28 1, Perhydroisoindole derivatives such as RPR-1 06 1 4 5, Quinolines such as SB-4 14240 Derivatives, pyropyrimidine derivatives such as ZM-253270, pseudopeptide derivatives such as MEN1 1420 (nepa du tant), SCH217048, L 659877, PD-1 47714 (CAM-2291), MEN 10376 S 16474, etc. , GR 100679, DNK333, GR 9480, UK—22467
  • the pharmaceutical composition of the present invention in which compound (A) or compound (I) and a concomitant drug are combined or used in combination includes (1) a pharmaceutical composition comprising compound (A) or compound (I) and a concomitant drug. These include those formulated in a single form, and (2) those in which the pharmaceutical composition containing Compound (A) or Compound (I) and the concomitant drug are separately formulated. Hereinafter, these are collectively referred to as the combination agent of the present invention.
  • the concomitant drug of the present invention comprises the compound (A) or compound (I) and the active ingredient of the concomitant drug separately or simultaneously, as they are or mixed with a pharmaceutically acceptable carrier, etc. It can be formulated by the same method as the composition.
  • the daily dose of the concomitant drug of the present invention depends on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical composition, formulation, type, type of active ingredient, etc. It is different and is not particularly limited.
  • the total dose of Compound (A) or Compound (I) and the concomitant drug is not particularly limited as long as it does not cause side effects, but it is usually about 0.005 to 1 per kg body weight of mammals by oral administration. 00 mg, preferably about 0.05 to 50 mg, more preferably about 0.2 to 30 mg, which is usually administered in 1 to 3 divided doses per day.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered first, it is used in combination within 1 minute to IS, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the pharmaceutical composition of the present invention.
  • a method of administering a drug can be mentioned.
  • a concomitant drug formed into an oral administration preparation is orally administered, and the pharmaceutical composition of the present invention formed into an oral administration preparation after about 15 minutes.
  • about 0.005 to 10 Omg / kg is orally administered as a daily dose.
  • Solvent Liquid A; 0.05% Trifluoroacetic acid-containing water, Liquid B; 0.04% Trifluoroacetic acid-containing acetonitrile
  • Injection volume 2 ⁇ L
  • flow rate 0.5 mL / min
  • detection method UV 220 nm MS conditions
  • Injection volume 2 A (L, flow rate: 0.5 mL / min, detection method: UV220 nm MS conditions
  • Solvent Liquid A; 0.1% Trifluoroacetic acid-containing water, Liquid B; 0.1% Trifanoleo mouth Acetic acid-containing acetonitrile
  • step 5 A solution of the compound obtained in step 3 (2. OO g), hydrochloric acid (0.2 mL) and palladium carbon (10 wt%, 0.30 g) in ethanol (3 OmL) was added to 0.5 M Pa of hydrogen. The mixture was stirred at 40 ° C for 3 hours in an atmosphere. After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure to obtain crude 3-ferro-4-piperidone as a pale yellow powder. The obtained product was used in the next step without further purification. (Process 5)
  • Di-tert-butyl dicarbonate (6.55 g) was added to a solution of the compound obtained in step 4 (3.47 g) and Et 3 N (2.76 mL) in acetonitrile (5 OmL). Stir for hours. After pouring the reaction mixture into water, the product was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous citrate solution and saturated brine, dried, and the solvent was evaporated under reduced pressure.
  • step 1 To a solution of the compound obtained in step 1 (1.20 g) in THF (12 mL) was added 1MK-se 1 ectride / THF (7 mL) solution at _78 ° C and stirred at 0 ° C for 1 hour. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and the solvent was evaporated under reduced pressure.
  • Reference Example 12 The following Reference Example compounds are described in Reference Example 12, using tert-butyl 4-oxo-1-piperidinecarboxylate and the corresponding halogenated compounds (4-fluoro-2-methylbromobenzene, 2-chloropyridine). It was synthesized by reacting and processing in the same way as the method.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant l’acétamide N-[2-[(3R,4S)-4-([2-méthoxy-5-[5-(trifluorométhyl)-1H-tétrasol-1-yl]benzyl]amino)-3-phénylpipéridine-1-yl]-2-oxoéthyl] ou un sel de celui-ci, un saccharide et une substance hydrophile non hydrosoluble Cette composition pharmaceutique présente une excellente stabilité d’élution dans le temps.
PCT/JP2006/308919 2005-04-21 2006-04-21 Composition pharmaceutique Ceased WO2006115285A1 (fr)

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JP2012505173A (ja) * 2008-10-09 2012-03-01 エフ．ホフマン−ラ ロシュ アーゲー ピロリジンｎ−ベンジル誘導体
US8455520B2 (en) 2007-07-17 2013-06-04 Merck Sharp & Dohme Corp. Soluble epoxide hydrolase inhibitors, compositions containing such compounds and methods of treatment
WO2021172488A1 (fr) * 2020-02-28 2021-09-02 東レ株式会社 Dérivé d'amine cyclique et son utilisation pharmaceutique
CN114348969A (zh) * 2022-01-12 2022-04-15 嘉兴学院 一种不溶性硫磺的制备方法

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JP2001524956A (ja) * 1997-04-16 2001-12-04 シーマ・ラブス・インコーポレイテッド 迅速溶解性の頑丈な投与形態物
WO2003009831A1 (fr) * 2001-07-27 2003-02-06 Yamanouchi Pharmaceutical Co., Ltd. Compositions contenant des grains fins a liberation prolongee pour comprimes a desagregation rapide dans la cavite buccale et procede de production associe
WO2003097102A1 (fr) * 2002-05-22 2003-11-27 Shionogi & Co., Ltd. Preparation pharmaceutique dans laquelle la propriete de dissolution d'un medicament faiblement soluble dans l'eau est amelioree
WO2003101964A1 (fr) * 2002-05-31 2003-12-11 Takeda Pharmaceutical Company Limited Derive piperidine, procede de production, et utilisation
WO2005110987A1 (fr) * 2004-05-12 2005-11-24 Pfizer Products Inc. Derives de piperidine en tant qu'antagonistes de nk1 et nk3
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JP2001524956A (ja) * 1997-04-16 2001-12-04 シーマ・ラブス・インコーポレイテッド 迅速溶解性の頑丈な投与形態物
WO2003009831A1 (fr) * 2001-07-27 2003-02-06 Yamanouchi Pharmaceutical Co., Ltd. Compositions contenant des grains fins a liberation prolongee pour comprimes a desagregation rapide dans la cavite buccale et procede de production associe
WO2003097102A1 (fr) * 2002-05-22 2003-11-27 Shionogi & Co., Ltd. Preparation pharmaceutique dans laquelle la propriete de dissolution d'un medicament faiblement soluble dans l'eau est amelioree
WO2003101964A1 (fr) * 2002-05-31 2003-12-11 Takeda Pharmaceutical Company Limited Derive piperidine, procede de production, et utilisation
WO2005110987A1 (fr) * 2004-05-12 2005-11-24 Pfizer Products Inc. Derives de piperidine en tant qu'antagonistes de nk1 et nk3
WO2006030975A1 (fr) * 2004-09-17 2006-03-23 Takeda Pharmaceutical Company Limited Derives de piperidine et leur utilisation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455520B2 (en) 2007-07-17 2013-06-04 Merck Sharp & Dohme Corp. Soluble epoxide hydrolase inhibitors, compositions containing such compounds and methods of treatment
JP2012505173A (ja) * 2008-10-09 2012-03-01 エフ．ホフマン−ラ ロシュ アーゲー ピロリジンｎ−ベンジル誘導体
WO2021172488A1 (fr) * 2020-02-28 2021-09-02 東レ株式会社 Dérivé d'amine cyclique et son utilisation pharmaceutique
CN114348969A (zh) * 2022-01-12 2022-04-15 嘉兴学院 一种不溶性硫磺的制备方法

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