WO2000034274A1 - Derives de la cyclohexylpiperidine - Google Patents

Derives de la cyclohexylpiperidine Download PDF

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Publication number
WO2000034274A1
WO2000034274A1 PCT/JP1999/006965 JP9906965W WO0034274A1 WO 2000034274 A1 WO2000034274 A1 WO 2000034274A1 JP 9906965 W JP9906965 W JP 9906965W WO 0034274 A1 WO0034274 A1 WO 0034274A1
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group
compound
ester
acceptable salt
derivative
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PCT/JP1999/006965
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English (en)
Japanese (ja)
Inventor
Takahide Nishi
Toshiyasu Takemoto
Takeshi Yamaguchi
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Sankyo Company, Limited
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Priority to AU16843/00A priority Critical patent/AU1684300A/en
Publication of WO2000034274A1 publication Critical patent/WO2000034274A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is a tachykinin receptor (! ⁇ ! ⁇ ! Receptors, NK 2 receptors and NK 3 receptors) Kishirubiperijin derivative to novel consequent opening having antagonistic action against, for producing how and methods of use.
  • Examples of the compound having an antagonistic effect on a tachykinin receptor and having an oxazolidin ring or a morpholine ring at the center of the molecular structure as in the present invention include, for example, compounds
  • the present invention is a.
  • R 1, R 2 and R 3 are the same or different and each represent a hydrogen atom or a lower alkyl group, and R 4 is an aryl group, a heteroaryl group, or a substituent group.
  • R 4 represents an aryl group substituted by 1 to 3 groups with a group selected from the group consisting of 1 to 3 or a heteroaryl group substituted by 1 to 3 groups with a group selected from the group of the substituents;
  • A represents a methylene group, a carbonyl group or a sulfonyl group
  • B represents a single bond, an alkylene group having 1 to 4 carbon atoms or an alkenylene group having 2 to 4 carbon atoms,
  • D represents an oxygen atom or a sulfur atom
  • L represents> NR 5 or> CR 5 (R 6 ),
  • R 5 is a cyclohexyl group, a saturated heterocyclic group, a group selected from the group consisting of 1 to 3 substituents Represents from 3 to 3 substituted saturated heterocyclic groups,
  • R 6 is a lower alkyl group, an amino group, a lower alkylamino group, an acylamino group, an acylamino group in which a nitrogen atom is substituted with a lower alkyl group, an acylamino lower alkyl group, a hydroxyl group, an aralkyl group, and an oxygen atom.
  • n an integer of 1 to 3
  • n an integer of 1 to 6.
  • preferred compounds include
  • R 1, R 2 and R 3 are all a Kaka R 1, R 2 ⁇ Pi R3 sac Chino two groups methyl is methyl, compound remaining one group is a hydrogen atom,
  • R4 is an aryl group substituted with 1 to 3 groups selected from the substituent group fi ,
  • R4 force a compound which is an aryl group substituted with 1 to 3 halogen atoms
  • R 6 force, lower alkyl group, amino group, lower alkyl amino group, acylamino group, acylamino group in which nitrogen atom is substituted by lower alkyl group, acylamino lower alkyl group, hydroxyl group, hydroxy group lower alkyl group, (wherein, R 7 is lower alkyl, lower alkoxy sheet showing a group or Amin residues.) a lower alkoxy group or a group having the general formula one CO- R 7 is a compound,
  • R6 force? Amino group, lower alkylamino group, acylamino group, hydroxyl group, A compound which is a lower alkoxy group or a group having the general formula C 0 -R 7 (where R 7 represents a lower alkyl group, a lower alkoxy group or an amine residue);
  • Another object of the present invention is to provide a medicament comprising the compound according to any one of the above (1) to (19), a pharmacologically acceptable salt or derivative thereof as an active ingredient.
  • the diseases to which the medicament can be applied include, for example, diseases of the central nervous system including anxiety, depression, psychiatric disorders and schizophrenia; dementia in AIDS, senile dementia of the Alzheimer type, Neurodegenerative diseases including Alzheimer's disease, Down's syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy, and neuralgia; chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, Respiratory diseases including asthma and cough; inflammatory diseases including inflammatory bowel disease (IBD), psoriasis, connective tissue inflammation, osteoarthritis, osteoarthritis, and rheumatoid arthritis; eczema; and allergic diseases including rhinitis ; Hypersensitivity diseases including hypersensitivity diseases to plants; ophthalmologic diseases including conjunctivitis, spring conjunctivitis, spring dysfunction, destruction of blood-aqueous-water barrier, increased intraocular pressure, and miosis associated with various
  • the “lower alkyl group” in the above refers to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexy
  • the ⁇ aryl group '' of the ⁇ substituent group ⁇ an aryl group substituted by 1 to 3 groups selected from the group '' includes, for example, phenyl, indenyl, naphthyl, phenanthrenyl, An aromatic hydrocarbon group having 5 to 14 carbon atoms such as anthracenyl can be exemplified, and a phenyl group is preferable.
  • the “aryl group” may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include a group such as 5-indanyl.
  • Heteroaryl group in the definition of R4 and R'i, and “heteroaryl group” in the group of substituents "1 to 3 heteroaryl groups substituted with one or more groups selected from” in the definition of R4 and R'i.
  • a 5- to 7-membered aromatic heterocyclic group which may contain, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxoxadiazolyl And triazolyl, tetrazolyl, thiaziazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and more preferably pyridyl, imidazolyl, Oxazolyl, birazinyl and thiazolyl.
  • heteroaryl group may be condensed with another cyclic group, and examples thereof include indolyl, benzofuryl, benzochenyl, benzoxazolyl, benzoimidazolyl, isoquinolyl, quinolyl, can be force s include groups such as quinoxalyl.
  • alkylene group having 1 to 4 carbon atoms in the definition of B includes, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, Examples thereof include a linear or branched alkylene group having 1 to 4 carbon atoms such as 3-methyltrimethylene. Preferably, it is a linear or branched alkylene group having 1 to 3 carbon atoms.
  • alkenylene group having 2 to 4 carbon atoms in the definition of B means ethenylene, 2-propylidene, 1-methyl-2-propylidene, 2-methyl-2-propylidene, 2-ethyl-2-propyl Examples thereof include linear or branched alkenylene groups having 2 to 4 carbon atoms such as penenylene and 2-butenylene, preferably ethenylene, 2-propenylene or 3-butenylene, and more preferably. Are ethenylene or 2-propenylene.
  • the “saturated heterocyclic group” in the “saturated heterocyclic group” and the “saturated heterocyclic group substituted by 1 to 3 groups selected from the substituent group ⁇ ” is a sulfur atom, oxygen A 5- to 7-membered saturated heterocyclic group containing 1 to 3 atoms and / or nitrogen atoms, such as azetidinyl, pyrrolidinyl, imidazolidinyl, birazolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl; Such groups can be mentioned. Preferably it contains at least one nitrogen atom and contains oxygen or sulfur atoms.
  • a 5- to 7-membered heterocyclic group which may be, for example, azetidinyl, pyrrolidinyl, imidazolidinyl, virazolidinyl, piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl.
  • azetidino, pyrrolidino, imidazolidino, 1-birazolidinyl, piperidino, piperazino, morpholino, thiomorpholino and particularly preferably pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, thiomorpholino It is.
  • the “saturated heterocyclic group” may be condensed with another cyclic group, and examples of such a group include chromanyl and indolinyl.
  • lower alkylamino group in the definition of R fi refers to a group in which the nitrogen atom of an amino group is substituted by the above “lower alkyl group”, for example, methylamino, ethylamino, n-propylamino , Isopropylamino, n-butylamino, isobutylamino, s-butylamino, tert-butylamino, n-pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylamino, n-butylamino Hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2 —Dimethylbutylamino, 1,1-dimethyl
  • “Lower radicals such as methansulfonyl, ethanesulfonyl, 1-prono, and 'sulfonyl'; Fluorinated “lower alkansulfonyl groups” such as trifluormethanesulfonyl and pentafluoroethanesulfonyl; and “a” such as benzenesulfonyl and p-toluenesulfonyl.
  • Arylsulfonyl Groups ", preferably” aliphatic acyl group "," aromatic acyl group “and” lower alkanesulfonyl group ".
  • it is a lower aliphatic acryl group such as formyl, acetyl, pentionyl, butyryl, isobutyryl, pentanoyl, pinoloyl, norrelyl and isovaleryl.
  • the “aralkyl group” of the “hydroxyl lower alkyl group in which an oxygen atom may be substituted by an aralkyl group” in the definition of R fi includes, for example, benzyl, “mono-naphthylmethyl, ⁇ -naphthylmethyl, diphenylmethyl, Lower alkyl groups substituted with one to three aryl groups such as phenylmethyl, 1-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5—Trimethylbenzyl, 4-Methoxybenzyl, 4-Methoxyphenyldiphenylmethyl, 2-Dibenzyl, 0.412-Trobenzyl, 4-Cross-benzyl, 4-Bromobenzyl
  • the aryl ring is substituted with a lower alkyl, lower alkoxy, nitro, nodogen, or cyano group, such as 4-cyanobenzyl.
  • R fi , R 7 and the “lower alkoxy group” in the definition of [Substituent group ⁇ ] and the “lower alkoxy” in the “lower alkoxycarbonyl group” in the definition of [Substituent group ⁇ ] include the above “lower alkoxy”
  • An “alkyl group” refers to a group bonded to an oxygen atom, such as methoxy, ethoxy, ⁇ -propoxy, isopropoxy, ⁇ -butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, i Sopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1- 1 to 2 carbon atoms such as dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-di
  • Amin residue in the definition of R 7 is an amino group; methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, getylamino, "Lower alkyl group” such as diisopropylamino and dibutylamino; an amino group substituted by 1 or 2 carbon atoms; "carbon such as cyclopentylamino, cyclohexylamino, dicyclopentylamino, dicyclohexylamino"; An amino group substituted by 1 or 2 cycloalkyl groups of the number 5 to 7 "; a saturated cyclic group having a nitrogen atom in the ring such as pyrrolidino, piperidino, piperazino, N-methylbiperazino, morpholino, and thiomorpholino; Minyl residue; aryl or aralkylamino, such as anilino, benzylamino, N
  • Halogen atom in the definition of [Substituent group ⁇ ] is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom or a chlorine atom.
  • halogeno lower alkyl group in the definition of [Substituent group ⁇ ] refers to a group in which a “lower alkyl group” is substituted with a halogen atom, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, Dibromomethyl, Fluoromethyl, 2,2,2-Trifluoroethyl, 2,2,2-Trichloroethyl, 2—Pro.Moethyl, 2—Chloroethyl, 2-Fluoroethyl, 2-Feodoethyl, 3—Chloropropyl , 4-fluorobutyl, 6-iodohexyl and 22-dibromoethyl, and preferably trifluoromethyl.
  • lower aliphatic acyl group in the definition of the "substituent group” and the “lower aliphatic acyl group” of the “lower aliphatic acylamino group” refer to a lower alkanoyl group having 1 to 6 carbon atoms. Is shown. Preferably, it is formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, bivaloyl, relyl or isoreryl. Preferably, it is acetyl.
  • Ester refers to the ester of the compound (I) of the present invention, because it may be able to be converted into an ester in some cases.
  • Such esters include "ester of hydroxyl group” and "carboxy group”.
  • An ester wherein each ester residue is a ⁇ general protecting group '' or a ⁇ protecting group which can be cleaved in vivo by a biological method such as hydrolysis ''.
  • General protecting group refers to a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.
  • the “general protecting group” for the “ester of a hydroxyl group” preferably, formyl, acetyl, propionyl, butylyl, isobutyryl, pentanoyl, pivaloyl, norrelyl, i Sonorelyl, Octanoyl, Nonanoyl, Decanoyl, 3-Methylnonanoyl, 8—Methylnonanoyl, 3—Ethyloctanoyl, 3,7—Dimethyloctanoyl, Pendecanoyl, Dodecanoyl, Tridecanol , Tetradecanoyl, Pentadecanoyl, Hexadecanoyl, 1—Methylpentadecanoyl, 14-Methylpentadecanoyl, 13 and 13—Dimethyltetradecanoyl, Heptadecanoyl, 15—Methyl to Kisadekanoir
  • Tetrahydrodrofuranyl or tetrahydrodiofuranyl group ;
  • tetrahydrodrofuranyl or tetorahydrofuranyl or tetrahydrofurafuranyl or tetrazidrofuranyl Lower hydrothiofuranyl group; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylpropylsilyl, methyldi-t-butyl, such as t-butylsilyl, triisopropylsilyl Alkylsilyl group, diphenylmethylsilyl, diphenylbutylsilyl, diphenylsilicone pillsilyl, phenyl "Silyl groups” such as tri-lower alkylsilyl groups substituted with one or two aryl groups such as di-isopropyls
  • an “aralkyl group” such as a lower alkyl group substituted with a; an "alkenyloxycarbonyl group” such as a vinyloxycarbonyl or an aryloxycarbonyl; a benzyloxycarbonyl or a 4-methoxybenzyloxycarbonyl , 3,4 dimethoxybenzyloxycarbonyl, 2-dinitrobenzyloxycarbonyl, 412-nitrobenzyloxycarbonyl Examples of such an “aralkyloxycarbonyl group” in which the aryl ring may be substituted with 1 to 2 lower alkoxy or 2-hydroxy groups are mentioned.
  • the “general protecting group” for the “ester of a carboxy group” preferably, the above “lower alkyl group”; ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2- Propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl,
  • a protecting group that can be cleaved in vivo by a biological method such as hydrolysis is a protective group that is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. This refers to the protective group generated, and whether such a derivative is used is determined by administering to a test animal such as a rat or a mouse by intravenous injection, and then examining the body fluid of the animal to determine whether the parent compound or its drug is used. Can be determined by the ability to detect a physically acceptable salt,
  • Examples of the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a hydroxyl group” include preferably formyloxymethyl, acetomethyl, and dimethylamino. Noacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pinoloyloxymethyl, pa'relyloxymethyl, isonorelyloxymethyl, hexanoyloxymethyl, 1-formyloxyxetyl, 1-acetoxixyl, 1 1-propionyloxetil, 1-butyryloxetil, .1'-pino s, loyloxetil, 1-renolyloxexetil, 1-isonorelyloxetil, 1-hexanoloxyl Shetyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1 butylic Roxypropyl, 1-Bivaloyloxypropyl, 1-No
  • a lower alkoxy lower alkyl group such as 1-butoxymethyl, t-butoxymethyl; a lower alkoxylated lower alkoxy lower alkyl such as 2-methoxyethoxymethyl Alkyl groups, such as alkyl groups, phenyloxymethyl, lower alkyl groups, 2,2,2—trichloroethoxymethyl, and halogenated lower alkoxylower, such as bis (2-chloroethoxy) methyl “A
  • “Other derivatives” means, when the compound (I) of the present invention has an amino group and / or a carboxy group, a derivative other than the above “ester” and the following “pharmacologically acceptable salts”. Derivatives are shown below. Such derivatives include, for example, amide derivatives.
  • “Pharmacologically acceptable salt thereof” means that the compound (I) of the present invention is reacted with an acid when it has a basic group such as an amino group, When the compound has such an acidic group, it can be converted into a salt by reacting with a base.
  • the salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate And inorganic salts such as sulfates and phosphates; lower alkanesulfonates such as methansulfonate, trifluormethanesulfonate and ethanesulfonate; benzenesulfonate; p-toluenesulfonic acid Aryl sulfonates, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, such as salts, Organic acid salts such as maleates; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornitine salts, glutamate salts, and aspartate salts. .
  • inorganic salts such as sulf
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, or an alkaline earth metal such as a calcium salt or a magnesium salt.
  • Metal salts such as salts, aluminum salts and iron salts; inorganic salts such as ammonium salts, t-yl octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine, guanidine, getylamine, triethylamine, dicyclohexylamine, N, N 'dibenzylethylenediamine, black proline, salt N-benzyl, ethanolamine, N-benzylphenethylamine, piperazine, tetramethylammonium, tris ( Amine salts such as organic salts such as droxy
  • the compound represented by the general formula (I) of the present invention may absorb moisture, become adsorbed water, or form a hydrate when left in the air or recrystallized. Such salts are also included in the present invention.
  • the compound having the general formula (I) of the present invention has various isomers since an asymmetric carbon atom is present in the molecule.
  • these isomers and a mixture of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all these isomers and mixtures of these isomers.
  • Specific examples of the compound having the general formula (I) of the present invention include the compounds described in the following table. O 00/34274
  • More preferred compounds include the compounds of compound numbers 1 to 12, and the compounds of compound numbers 25 to 27. Particularly preferred compounds include
  • the cyclohexylpiperidine derivative of the present invention can be produced by the method described below.
  • R 1 , R 2, R 3, R 4, A, B, D, L, Z, m and n are as defined above.
  • Y is generally not particularly limited as long as it is a group capable of leaving as a nucleophilic residue, but is preferably a halogen atom such as chlorine, bromine or iodine; Re-halogenomethyloxy groups; lower alkenyl sulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno groups such as trifluorene and sulfonyloxy, Lower alkanesulfonyloxy group; arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, and p-2-tosulfone benzenesulfonyloxy; more preferably, halogen; Atom and lower alkane sulfonyloxy group.
  • Step A1 is a step of producing compound (I) of the present invention by reacting compound (II) with compound (III) in a solvent in the presence of a base.
  • Solvents that do not hinder the reaction and dissolve starting materials to some extent ? Force is not particularly limited as long as, preferably, hexane, hepta down, rig port Lee down, Unaryo oil
  • E one ether aliphatic hydrocarbons; benzene, toluene, Fang aromatic, such as xylene carbide Hydrogens; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate Such esters; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxan, dimethoxetane, diethylene glycol dimethyl ether; acetone, methylethyl ketone Ketones such
  • the base to be used is not particularly limited as long as it is used as a base in a usual reaction.
  • a metal iodide such as potassium iodide, Alkali metal carbonates such as sodium, potassium carbonate and lithium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, sodium hydroxide, barium hydroxide, lithium hydroxide
  • inorganic bases such as alkali metal hydroxides or sodium fluoride, alkali metal fluorides such as lithium fluoride, or N— Methyl morpholine, triethylamine, tripro Pyramine, tributylamine, diisopropyrethylamine, dicyclohexylamine, N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picolin, 4- (N, N-dimethylamin
  • the reaction temperature is from 0 ° C to 150 ° C, preferably from 20 ° C to 120 ° C.
  • the reaction time varies mainly depending on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually 30 minutes to 48 hours, preferably 1 hour to 12 hours.
  • the target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration.
  • an immiscible organic solvent such as water and ethyl acetate is added. Is obtained by separating an organic layer containing, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and distilling off the solvent.
  • the obtained target compound can be used in a conventional manner, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-based flourishing.
  • the raw material compounds can be purchased commercially or can be easily synthesized according to known methods.
  • the compound having the general formula (II) can be produced according to EP-776693 or the like, and the compound having the general formula (III) can be prepared by a known method and a reference example described later. It can be manufactured according to it.
  • Kishirubiperi derivative to novel cyclo present invention has excellent antagonism against tachykinin, have a superior antagonistic activity against NK have NK 2 and 1 ⁇ 3 receptors, excellent oral absorbability Because of its excellent pharmacokinetics and low toxicity, it is useful as a medicament (especially a prophylactic or therapeutic agent for tachykinin-mediated diseases), for example, anxiety, depression, psychiatric disorders and Central nervous system diseases including schizophrenia; sleep apnea; dementia in AIDS, senile dementia of Alzheimer's type, Alzheimer's disease, Dunn's syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy Neurodegenerative diseases, including peripheral neuropathy, and neuralgia; chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma, respiratory diseases including cough; inflammatory bowel disease (IBD), psoriasis, fibrositis , Bone joint Inflammatory diseases including osteoarthriti
  • Examples of the dosage form of the compound (I) of the present invention include oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injections or suppositories.
  • These formulations may contain excipients (eg, lactose, sucrose, Sugar derivatives such as glucose, mannite, sorbite; starch derivatives such as corn starch, potato starch, starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropylcellulose Cellulose derivatives such as hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, internally cross-linked carboxymethylcellulose sodium; organic excipients such as arabia gum; dextran; pullulan Ingredients: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphates such as calcium carbonate; carbonates such as calcium carbonate; calcium sulfate Such as sul
  • Lubricants eg, metal salts of stearate such as stearate, calcium stearate, magnesium stearate); talc; colloid silica; Boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium fatty acid salt; sodium lauryl sulfate, lauryl sulfate.
  • Binders eg, polyvinylpyrrolidone, macrogol, and the like
  • Disintegrators for example, the same compounds as the above-mentioned excipients, and croscarme
  • Chemically modified starches such as sodium sodium, carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone can be mentioned.
  • Cell stabilizers such as methylparaben and pulpirparaben Alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid And sorbic acid), flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.), and diluents, etc., are well known. It is manufactured by the method described above. The amount used symptoms, age, by Ri different force 5 on the method of administration, etc. ', for example, in the case of oral administration, per, as a lower limit, 0. 0 1 mg (preferred details, 0.
  • Mass vector FAB (m / z): 663 ([M + H] + )
  • N-t-butoxycarbyl-rubonate 4-cyclohexylbiperidine-1-4 rubonic acid N-t-butoxycarboryl 4-1-phenylbiperidine-1-4 rubonic acid (500 mg, To a solution of 1.64 mmo 1) in acetic acid (10 mL) was added 5% rhodium-alumina (200 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (50 psi) for 3 days. After filtering the reaction solution to remove the catalyst, the solvent was distilled off to obtain a white solid.
  • 5% rhodium-alumina (1.20 g) was added to an acetic acid solution (30 mL) of 4-hydroxy-1-4-phenylbiperidine (3.00 g, 16.9 mm 01). The mixture was stirred at room temperature under a hydrogen atmosphere (60 psi) for 7 hours. After filtering the reaction solution to remove the catalyst, the solvent was distilled off to obtain the target compound (4.00 g, 99%) as a white solid.
  • the preparation of the present invention containing the compound having the general formula (I), a pharmaceutically acceptable salt or a derivative thereof as an active ingredient can be produced, for example, by the following method.
  • a powder is obtained by mixing 5 g of the compound of Example 1, lactose 895 g and 100 g of corn starch in a blender.
  • Coarse membrane specimens were prepared from Hartley male guinea pig lungs. That is, under anesthesia with black-mouthed form, the blood was exsanguinated from the abdominal vena cava and the pulmonary airway tissue was immediately removed.
  • the isolated lung was perfused with a buffer solution (50 mM tris-HCl, pH 7.4), cut into small pieces, and further added to a buffer solution (120 mM sodium chloride and 5 mM chloride). Homogenized with a polytron in a buffer containing a realm.
  • the pellet was resuspended in ice-cold buffer 3 (buffer containing 10 mM EDTA and 300 mM lithium chloride), left at 4 ° C for 60 minutes, and then centrifuged twice. (30,000 X g, 15 minutes, 4 ° C).
  • BSA S gZm l chymosin, 8 g Zm 1 leptin, 80 g m 1 nocitrasin, 20 g no m I phosphoramidone
  • the membrane components were collected on a GFZB glass fiber filter (Whatman) using an automatic filtration device (Brandel).
  • the glass filter was used after being pretreated for about 4 hours with a 0.1% polyethyleneimine solution in order to suppress non-specific binding.
  • the membrane component collection filter was transferred to a mini plastic vial containing 4 ml of Picoflow, and the radioactivity was measured using a liquid scintillation counter (Beckman, LSC 350).
  • the compounds of the present invention showed better NKi receptor binding activity than the prior art compounds.
  • Pen concert Rubitaru (.. 3 0 mg / / kg, i p) in anesthetized guinea pig femoral vein in the dye (Evans blue: 4 0 mg / kg) was administered immediately SP (I ⁇ g / kg) was intravenously injected to induce an increase in vascular permeability. After 15 minutes, the guinea pig was sacrificed under chloroform anesthesia, and the amount of dye leaked into the main trachea was measured according to the Harada method (J. Pharm. Pharmacol. 23, 218 (1971)).
  • test drug is dissolved or suspended in an aqueous solution of 0.1 M cyclodextrin sulfobutyl ether 7-sodium salt (captison, Cidex) and administered intravenously 5 minutes before administration of SP. did.
  • the inhibitory effect was determined from the amount of dye leaked between the test drug administration group and the non-administration group.
  • the compounds of the present invention showed an excellent inhibitory effect on vascular hyperpermeability.
  • Coarse membrane specimens were prepared from the ileum of Hartley male guinea pigs. That is, under anesthesia with a black orifice, the blood was killed by exsanguination from the abdominal vena cava and the ileum was immediately removed.
  • the isolated ileum is rubbed and peeled off the contents of the lumen, secretions, and epithelium using a slide glass, cut into a buffer solution (50 mM Tris-HCl, pH 7.4), and further sliced.
  • a buffer solution a buffer solution containing 120 mM sodium chloride and a 5 mM chloride solution buffer
  • homogenization was performed using a polytron.
  • tissue clumps were removed by filtration using nylon mesh (50 ⁇ m) and centrifuged (30, 000 xg, 30 minutes, 4 ° C).
  • the pellet was resuspended in ice-cold buffer 3 (buffer containing 10 mM EDTA and 300 mM lithium chloride), left at 4 ° C for 60 minutes, and then centrifuged twice. (30, 0000 Xg, 15 minutes, 4 ° C).
  • Mixture 2 501 50 mM Tris-HCl, pH 7.4, 6 mM manganese chloride, 800 g / m1 BSA, 8 g / ml chymosin, 8 gZm leptin , 80 g / m1 nocitracin and 20 g / m1 phosphoramidone
  • 2501 of the crude intestinal membrane preparation was added, and the mixture was incubated at room temperature for 30 minutes.
  • the membrane components were collected on a GFB glass fiber filter (Whatman) using an automatic filtration device (Brandel).
  • the glass filter was used after being pretreated for about 4 hours with a 0.1% polyethyleneimine solution in order to suppress non-specific binding.
  • the membrane component collection filter was transferred to a mini-plastic vial containing 4 ml of Picoflow, and the radioactivity was measured using a liquid scintillation counter (LCSC 350, Beckman).
  • the compounds of the invention were shown to be excellent NK 2 receptor binding activity Ri by compounds of the prior art.
  • a guinea pig anesthetized with pentobarbital (30 mg Z kg, s.c.) was equipped with an airway force neura, and garamine (ga 11 amine 20 mg / kg, i.v.) was used.
  • a positive pressure breath Ugo — Basile, 720
  • the airway pressure of the artificial respiration is amplified and sensed (Nippon Denko, AP-601G) through a pressure transducer (Nippon Denko, TP-200T) attached to the side branch of the tracheal force neura.
  • Recorder I (Nihon Denko, WT— 6 85 G).
  • NKA was intravenously administered at 4 g Z kg to induce airway constriction, and thereafter the airway pressure was measured for 10 minutes.
  • the test drug was prepared in the same manner as in Test Example 2, and administered intravenously 5 minutes before the administration of NKA.
  • the inhibitory effect was determined from the airway pressure area values of the test drug administration group and the non-administration group.
  • the compound of the present invention exhibited an excellent airway contraction inhibitory action.
  • the obtained pellet (membrane component) was suspended in ice-cold buffer 3 (buffer containing 1 O mM EDTA and 300 mM potassium chloride 1), and allowed to stand at 4 ° C for 60 minutes. The cells were washed twice by centrifugation (30,000 g, 15 minutes, 4 ° C). This was suspended in a buffer solution to prepare a crude membrane sample, and stored at 180 ° C until used for a receptor binding test.
  • buffer 3 buffer containing 1 O mM EDTA and 300 mM potassium chloride 1
  • test tubes used for the reaction were prepared in advance using 5 mg / ml of serum albumin (B
  • SA [3H] —Sentide, 6 mM manganese chloride, 800 g / ml BSA, 8 ⁇ g / 1 chymostatin, ⁇ g ⁇ / ml leptin, 80 g Zml nocitrasin and 20; «Buffer containing g / ml phosphoramidone1 1001, buffer containing 400 g Zml BSA 1 1501 and the test drug were added. (The protein concentration was adjusted to 1 mg Zm 1) and the reaction was started by adding 2501. At that time, the final concentration of [ 3 H] -Sentide in the reaction phase is 2.5 nM. ).
  • GF / B glass fiber filter (Whatman) which was incubated for 60 minutes at room temperature and then pre-treated with 0.1% polyethyleneimine for at least 4 hours using an automatic filtration device (Brandel).
  • the membrane components were collected on the top, and ice-cold buffer solution (5 mM tris-hydrochloric acid containing 400 ⁇ g / m 188 and 0.01% sodium dodecyl sulfate, pH 7 4) Washed 3 times with 5 ml.
  • the GFZB glass fiber filter to which the membrane component was attached was transferred to a mini plastic vial containing 4 ml of Picoflow, and the radioactivity was measured using a liquid scintillation counter (AROKA, LSC 350).
  • the inhibition rate of binding of the sentide peptide receptor by the test drug was calculated by the following formula.
  • the compounds of the present invention exhibited excellent NK 3 receptor binding activity.
  • the compound of the present invention is! ⁇ ! ⁇ Receptor, have an excellent antagonistic activity against NK 2 receptors and NK 3 receptors, have excellent oral absorbability, difficulty metabolized rather exhibits excellent body movement status, and, Since it has low toxicity, it is useful as a medicine.

Abstract

LProblème: Les dérivés de la cyclohexylpipéridine, qui sont de puissants antagonistes des tachykinines, présentent une excellente cinétique in vivo et une faible toxicité. Solution: L'invention concerne des composés représentés par la formule générale (I), dans laquelle R1 et R2 sont chacun aryle éventuellement substitué ou hétéroaryle éventuellement substitué; A est CH¿2?, CO ou SO2; B est une simple liaison, alkylène ou alkénylène; D est O ou S; L est > NR?3¿ ou > CR?3(R4); R3¿ est cycloalkyle éventuellement substitué ou un groupe hétérocyclique saturé éventuellement substitué; R4 est alkyle, amino, acylamino, acylaminoalkyle, acylamino alkylé, OH, alkyle inférieur hydroxylé éventuellement aralkylé, alcoxy ou CO-R?5 (où R5¿ est alkyle, alcoxy, un résidu amine, aryle substitué ou hétéroaryle substitué); Z est O ou 2H; m est 0, 1 ou 2; et n est compris entre 1 et 6. L'invention concerne également les sels, les esters et d'autres dérivés desdits composés.
PCT/JP1999/006965 1998-12-10 1999-12-10 Derives de la cyclohexylpiperidine WO2000034274A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16843/00A AU1684300A (en) 1998-12-10 1999-12-10 Cyclohexylpiperidine derivatives

Applications Claiming Priority (2)

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JP10/351286 1998-12-10
JP35128698 1998-12-10

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WO2000034274A1 true WO2000034274A1 (fr) 2000-06-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2824828A1 (fr) * 2001-05-21 2002-11-22 Sanofi Synthelabo Nouveaux derives de piperidinecarboxamide, un procede pour leur preparation et les compositions pharmaceutiques les contenant
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023787A1 (fr) * 1995-01-30 1996-08-08 Sanofi Composes heterocycliques substitues, procede pour leur preparation et compositions pharmaceutiques les contenant
EP0776893A1 (fr) * 1995-12-01 1997-06-04 Sankyo Company Limited Antagonistes azacycliques du récepteur des tachykinines; NK1 et NK2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023787A1 (fr) * 1995-01-30 1996-08-08 Sanofi Composes heterocycliques substitues, procede pour leur preparation et compositions pharmaceutiques les contenant
EP0776893A1 (fr) * 1995-12-01 1997-06-04 Sankyo Company Limited Antagonistes azacycliques du récepteur des tachykinines; NK1 et NK2

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2824828A1 (fr) * 2001-05-21 2002-11-22 Sanofi Synthelabo Nouveaux derives de piperidinecarboxamide, un procede pour leur preparation et les compositions pharmaceutiques les contenant
WO2002094821A1 (fr) * 2001-05-21 2002-11-28 Sanofi-Synthelabo Nouveaux derives de piperidinecarboxamide, un procede pour leur preparation et les compositions pharmaceutiques les contenant
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

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