WO1994025450A1 - Serine derivative - Google Patents

Serine derivative Download PDF

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Publication number
WO1994025450A1
WO1994025450A1 PCT/JP1994/000697 JP9400697W WO9425450A1 WO 1994025450 A1 WO1994025450 A1 WO 1994025450A1 JP 9400697 W JP9400697 W JP 9400697W WO 9425450 A1 WO9425450 A1 WO 9425450A1
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Prior art keywords
group
hydroxy
lower alkyl
methyl
acceptable salt
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PCT/JP1994/000697
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English (en)
French (fr)
Japanese (ja)
Inventor
Ichio Noda
Masahiro Iwata
Shuichi Sakamoto
Kazuo Koshiya
Takuma Morita
Atsuyuki Kohara
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to EP94913822A priority Critical patent/EP0696586A1/en
Priority to AU65824/94A priority patent/AU681655C/en
Priority to US08/535,047 priority patent/US5834460A/en
Publication of WO1994025450A1 publication Critical patent/WO1994025450A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a serine derivative having an anti-PCP (phencyclidine) action.
  • PCP psychiatric symptoms very similar to those of schizophrenia, including negative symptoms [Am. J. Psychiat., 135, 1081 (1987)].
  • administration of PCP to animals induces various abnormal behaviors. This suggests that drugs that specifically inhibit animal-induced PCP-induced abnormal behavior (anti-PCP action) are useful as therapeutic agents for schizophrenia in humans.
  • dopamine receptor blockers have been mainly used as treatments for schizophrenia.
  • these dopamine blockers are not only ineffective against negative symptoms, but also cause side effects such as extrapyramidal symptoms.
  • the present inventors have conducted intensive studies on compounds having an excellent specific anti-PCP activity, and as a result, have found that the chemical structure of nitrogen-containing cycloalkyl-lower alkyl-substituted phenyl, phenyl, or thienyl radicals, which are completely different from those of conventional compounds.
  • the present invention was completed by creating a zolyl serine derivative or a salt thereof.
  • cherilserin derivatives include unsubstituted cherilserin derivatives (J. Chromatogr., 515, 475-82), 5 — pyridyl chelenylserine derivative [Anal. Scl., 7 (Suppl., Proc. Int. Congr. Anal. Sci., 1991,
  • the present invention is based on the general formula (I)
  • R l, R2 Protecting groups for the same or different hydrogen atom, lower alkyl group or amino group
  • Rl and R2 can together form a 4- to 9-membered nitrogen-containing cycloalkyl group.
  • R 3 hydrogen atom, carboxyl group, protected carboxyl group, aralkyl group or hydroxy-substituted or unsubstituted lower alkyl
  • R4 hydrogen atom or hydroxy group
  • R 5 hydrogen atom or lower alkyl group
  • a 4- to 8-membered nitrogen-containing cycloalkyl group is condensed with a benzene ring Bicyclic nitrogen-containing hydrocarbon ring group
  • R l hydrogen atom, lower alkyl group, lower alkoxycarbonyl group, acyl group, aralkyl group, aralkyloxycarbonyl group or aralkylaminocarbonyl group
  • R2 hydrogen atom or lower alkyl group
  • Rl and R2 together can form a 4- to 9-membered nitrogen-containing cycloalkyl group.
  • R 3 hydrogen atom, carboxyl group, lower alkoxycarbonyl group, aralkyl group or hydroxy-substituted or unsubstituted lower alkyl group
  • R4 hydrogen atom or hydroxy group
  • R5 hydrogen atom or lower alkyl group
  • B 1) a saturated or unsaturated 4- to 10-membered nitrogen-containing cycloalkyl group substituted or unsubstituted with a lower alkyl group or an aralkyl group 2) a 4- to 8-membered nitrogen-containing cycloalkyl group and a benzene ring Condensed bicyclic nitrogen-containing hydrocarbon ring group
  • the above general formula (wherein R2 is a hydrogen atom and B is an aralkyl-substituted or unsubstituted saturated or unsaturated 4- to 10-membered nitrogen-containing cycloalkyl group is a single bond.
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.
  • lower alkyl group examples include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group Group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, and isohexyl group.
  • it is a group having 1 to 3 carbon atoms, such as a methyl group, an ethyl group or an isopropyl group.
  • protecting group for amino group means a protecting group commonly used by those skilled in the art, and is typically a lower protecting group, which is an acyl protecting group.
  • Examples of aralkyl protecting groups include benzyl, P-methoxybenzyl (hereinafter referred to as PMB), benzhydryl, and trityl.
  • Examples of the carbamate-type protecting group include a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, and a p-methoxybenzyloxycarbonyl group.
  • Examples of the urea-based protecting group include a benzylaminophenol group and a p-methoxybenzylaminopropyl group.
  • a tri-lower alkylsilyl group such as a trimethylsilyl group may be mentioned.
  • a lower alkoxycarbonyl group and an aralkyloxycarbonyl group which are carbamate-based protecting groups, and an aralkylaminopropyl group, which is a rare-based protecting group, are used.
  • the protecting group include a benzyl group, a phenyl group, and a phenylpropyl group.
  • “Lower alkoxycarbonyl group” includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, Examples thereof include a tert-butoxycarbonyl group, a pentyl (amyl) oxycarbonyl group, an isopentyl (amyl) oxycarbonyl group, a hexyloxycarbonyl group, and an isohexyloxycarbonyl group.
  • the “acyl group” includes an aliphatic or aromatic carboxylic acid residue such as a lower alkenyl group or an arylcarbonyl group, and a lower alkanoyl group includes a formyl group or an acetyl group.
  • the arylcarbonyl group is a benzoyl group or a naphthyl group, and is preferably a benzoyl group.
  • any of the above lower alkyl groups or lower alkoxy groups may be substituted at any position, and the halogen atom may be a fluorine atom, a chlorine atom.
  • Atoms, bromine atoms, etc., and lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • the “aralkyl group” is a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted by a carbocyclic aryl group such as a phenyl group or a naphthyl group.
  • the “aralkyloxycarbonyl group” includes an aryl group such as a phenyl group, a nitroxyphenyl group, a halogenophenyl group, a lower alkylphenyl group, a lower alkoxyphenyl group, or a naphthyl group.
  • a group substituted at an arbitrary position specifically, a benzyloxycarbonyl group, a phenethyloxycarbonyl group, a fuynylpropoxycarbonyl group, a phenylbutoxycarbonyl group, a Benzyloxycarbonyl group, fluorobenzyloxycarbonyl group, bromobenzyloxycarbonyl group, nitrobenzyloxycarbonyl group, methylbenzyloxycarbonyl group, ethylbenzyloxycarbonyl group, propylbenzyloxycarbonyl group , Methoxybenzyloxycarbonyl group , Ethoxybe And an benzyloxycarbonyl group or a propoxybenzyloxycarbonyl group.
  • the “aralkylamino carbonyl group” means a group in which one aralkyl group is substituted with an aminocarbonyl group, and specifically, a benzylamino carbonyl group, a phenethylamino carbonyl group, A benzylaminocarbonyl group, a phenylbutylaminocarbonyl group, a phenylpentylaminocarbonyl group, a phenylhexylaminocarbonyl group, a naphthylmethylaminocarbonyl group, and the like.
  • Examples of the "protected carboxyl group” include a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a lower alkanoyloxyalkoxycarbonyl group, and the like, and preferably a lower alkoxycarbonyl group. is there.
  • “Hydroxy group fi-substituted lower alkyl group” means a group in which a hydroxy group is substituted at an arbitrary position of the lower alkyl group, such as a hydroxymethyl group, a 2-hydroxyhydroxy group, — Hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl.
  • the unsubstituted lower alkyl group is as described above.
  • “Lower alkylene group” means a straight or branched hydrocarbon chain, and includes methylene group, ethylene group, methylmethylene group, trimethylene group, methylethylene group, tetramethylene group, and methyl group. Examples include a trimethylene group, a pentamethylene group or a hexamethylene group, and a methylpropylene group.
  • Rl and R2 are united to form a 4 to 9-membered nitrogen-containing cycloalkyl group", "substituted or unsubstituted lower alkyl or aralkyl group” A saturated or unsaturated 4- to 10-membered nitrogen-containing cycloalkyl group and a bicyclic nitrogen-containing hydrocarbon ring group obtained by condensing a 4- to 8-membered nitrogen-containing alkyl group with a benzene ring.
  • the “nitrogen cycloalkyl group” is a nitrogen-containing cycloalkyl group containing one or two nitrogen atoms or an oxygen atom or a sulfur atom in addition to a nitrogen atom.
  • the saturated one is specifically azetidinyl.
  • the unsaturated nitrogen-containing cycloalkyl group means one having one to several double bonds in the above-mentioned group.
  • 1,2,3,6-tetrahydropyridinyl group is preferred. I like it.
  • Examples of the "bicyclic nitrogen-containing hydrocarbon ring group in which a 4- to 8-membered nitrogen-containing alkyl group and a benzene ring are condensed" include, for example, those shown below.
  • the compound of the present invention may form a salt with an acid or a base in some cases.
  • salts with such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, especially mineral acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid and fumaric acid.
  • Acid addition salts with organic acids such as, maleic acid, lactic acid, ligonic acid, citric acid, tartaric acid, carbonic acid, picric acid, methansulphonic acid, ethanesulphonic acid or glutamic acid. .
  • Salts with bases include, for example, inorganic bases such as lithium, sodium, potassium, magnesium, calcium or aluminum;
  • examples of such salts include addition salts with organic bases such as ruamine, ethylamine and ethanolamine, and salts with basic amino acids such as lysine and ornithine and ammonium salts.
  • the compound of the present invention When the compound of the present invention has an asymmetric carbon atom or an oxo group, it may be a compound having an asymmetric carbon atom or an oxo group, a stereoisomer such as an optical isomer or an optically active substance, or a double isomer. There are geometric isomers such as cis- and trans-forms based on double bonds. The compound of the present invention includes a mixture of these isomers and an isolated one.
  • the compound of the present invention can form a hydrate or a solvate such as methanol or ethanol.
  • typical compounds included in the present invention include those described in Tables 1 to 3 in addition to those described in Examples described later. be able to.
  • the compound of the present invention can be produced by applying various synthetic methods. Typical production methods are shown below.
  • R 1 is R 1 And R2 'means a hydrogen atom, a lower alkyl group, an acyl group or an aralkyl group.
  • aralkyl groups are limited to arylmethyl groups such as benzyl groups.
  • R l ′ and R 2 ′ may combine to form a 4- to 9-membered nitrogen-containing cycloalkyl group.
  • R 7 represents a protecting group for a lower alkoxycarbonyl group and a carboxyl group in R 3.
  • the compound (VI I) of the present invention is obtained by reacting an aldehyde compound represented by the general formula (IV) with a glycine compound represented by the general formula (V), and then, if necessary, a group R7 or a lower alkoxycarbonyl group of a lower alkoxycarbonyl group. Part, in equation (V)
  • compound (V) is used as a base in an organic solvent such as tetrahydrofuran (THF), ether, or dioxane, for example, lithium diisopropylamide, lithium bis (trimethylsilyl) amide.
  • organic solvent such as tetrahydrofuran (THF), ether, or dioxane
  • the reaction is carried out under cooling or at room temperature, for example, at 180 ° C to room temperature.
  • the removal of the aralkyloxycarbonyl group from R l ' may be carried out by a conventional hydrogen substitution reaction.
  • palladium-carbon or palladium chloride in a mixture of a solvent such as methanol or ethanol or a lower alcohol and an acid Etc., and stirring is performed.
  • the removal of the protecting group may be performed according to a conventional method.
  • the compound (VII) of the present invention is obtained by reacting the aldehyde compound represented by the general formula (IV) with free glycine (VIII). Manufactured.
  • glycine (VIII) and twice the amount of compound (IV) are mixed with water, an organic solvent such as alcohols such as methanol, ethanol and isopropanol, or a mixed solvent thereof.
  • the reaction is carried out under cooling to room temperature, for example, at 0 ° C to 50 ° C in the presence of a base such as sodium hydroxide.
  • Hal is halogen And preferably an iodine atom.
  • the compound ( ⁇ ) of the present invention is obtained by reacting an aldehyde compound represented by the general formula (IV) with trimethylsilyl cyanate (X) in the presence of halogeno zinc (IX) to obtain a corresponding cyanide (XI). ) (The first step), and is produced by reducing this compound (the second step).
  • an aldehyde compound (IV) and a reaction-corresponding amount of trimethylsilyl cyanate (X) are stirred in the presence of halogenozinc (IX) at room temperature or under heating to obtain a cyanide ( XI) (the first step), and the resulting cyanide (XI) is converted to ether, THF, dioxane, using a reducing agent such as lithium aluminum hydride, diborane, aluminum hydride, or triisobutylaluminum.
  • the stirring is carried out in a solvent such as ethylene glycol getyl ether under cooling to room temperature (second step).
  • the compound (XV) of the present invention is obtained by reacting an aldehyde compound represented by the general formula (IV) with nitroethane (XI II) to obtain a nitropropene compound represented by the general formula (XIV) (first step).
  • the second step is produced by reducing the nitropropene compound (XIV).
  • the aldehyde compound (IV) and the corresponding amount of nitro (III) and nitropropene compound (XIV) in a solvent such as acetic acid and the like, and nitropropene compound (XIV) is obtained with stirring at room temperature or under heating (first step).
  • a solvent such as tetrahydrofuran, benzene, dioxane or ether
  • a reducing agent such as lithium aluminum hydride
  • compound (IV) is reacted with compound ( ⁇ ⁇ ⁇ ) in the presence of a catalyst such as sodium hydroxide in a solvent such as methanol or ethanol, and then hydrochloric acid, phthalic anhydride, etc. This is achieved by a dehydration reaction with an acid.
  • a catalyst such as sodium hydroxide in a solvent such as methanol or ethanol
  • compound (XV) can be obtained by hydrogenating compound (XIV) using Raney nickel in acetic acid.
  • R 1 is a lower alkyl group
  • R 1 is an acyl group or an aralkyloxycarbonyl group.
  • R3 is a lower alkyl group substituted with a hydroxy group are produced by reducing the lower alkyl compound substituted with the corresponding carbonyl group.
  • This reduction reaction is carried out in the presence of a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride or diborane, in a solvent such as getyl ether or THF under cooling or heating, for example, at 60 to 70 ° C or reflux. Done below.
  • a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride or diborane
  • a solvent such as getyl ether or THF
  • the compound of the present invention in which R 1 is an acyl group or an aralkyloxycarbonyl group is produced by subjecting an amine compound in which R 1 is a hydrogen atom to an acylation reaction.
  • This acylation reaction may be carried out in accordance with a conventional method, and a compound in which R 1 is a hydrogen atom and an acylating agent (free acid, halide or acid anhydride, etc.) or an aralkyloxycarbonylating agent (free acid, halai) Or acid anhydride)
  • the reaction is carried out with stirring in an inert solvent such as methylene chloride, chloroform, toluene, dioxane, or ether, or in a heterogeneous solvent such as toluene and an aqueous solution of alkylene at room temperature or under heating.
  • a ' represents a bond or a lower alkylene group one carbon less than A.
  • an organic solvent such as methylene chloride, 1,2-dichloroethane, methanol, or carboxylic acid
  • amine (XVI I) to compound (XVI)
  • reducing agents such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, at 0 ° C to 80 ° C.
  • the reaction is performed by adding a borane pyridine complex.
  • the thus-produced compound of the present invention can have a protective group removed according to a conventional method, if necessary, similarly to the first production method.
  • This reaction is carried out in an organic solvent such as tetrahydrofuran, dioxane, ether, hexane, or the like.
  • the compound (XIX) is activated with a base, for example, an organolithium compound such as n-butyllithium, lithium diisopropylamide, and the like, and a reaction-corresponding amount of the compound (XX) is added thereto.
  • the reaction is carried out at 00 ° C. to room temperature. If necessary, the compound of the present invention thus produced can be freed of a protecting group according to a conventional method in the same manner as in the first production method.
  • the compounds obtained by the seventh and eighth processes can be converted to new compounds by the fifth process.
  • R 3 ′ represents an R ′ 3 lower alkoxycarbonyl group.
  • R 6 represents the lower alkyl. Means the group.
  • the compound (II) of the present invention is produced by reacting an aldehyde compound represented by the general formula (IV) with a / 3-ketophosphonate compound (XXI).
  • compound (XXI) is activated with a base, for example, a compound such as sodium hydride, potassium hydride, or the like, in an organic solvent such as tetrahydrofuran, dioxane, or ether.
  • a base for example, a compound such as sodium hydride, potassium hydride, or the like
  • organic solvent such as tetrahydrofuran, dioxane, or ether.
  • Inventive compound (XXIII) is a compound (XXIO) in an organic solvent such as methanol or ethanol. Using palladium carbon, platinum, Raney nickel, etc., hydrogenated to 0 ° C ⁇ 100 The reaction is performed at ° C.
  • the protecting group can be removed in the same manner as in the first production method, according to a conventional method.
  • XXVI Compound of the present invention
  • XXVI is produced by reacting a serine derivative (amino compound) represented by the general formula (XXIV) with an isocyanate compound (XXV).
  • XXV isocyanate compound
  • a reaction amount of oxoguanate (XXV) is required at 0 ° C or room temperature in an organic solvent such as tetrahydrofuran, dioxane, toluene, methanol or ethanol.
  • the reaction may be carried out by heating.
  • the thus-produced compound of the present invention can have a protective group removed according to a conventional method as necessary in the first production method.
  • the compound (XXIX) of the present invention is obtained by converting an amino compound represented by the general formula (XXVI I) into an aralkylhalhalide. And alkyl halide (XXVI II).
  • compound XXIV in an organic solvent such as methanol, ethanol, isopropyl alcohol, or tetrachlorofuran is activated with a base, for example, potassium carbonate, sodium carbonate, sodium hydride, etc.
  • a base for example, potassium carbonate, sodium carbonate, sodium hydride, etc.
  • the reaction is carried out by heating and refluxing the compound XXVI I in an amount corresponding to the reaction at o ° C to room temperature, if necessary.
  • the compound of the present invention thus produced is isolated and purified as free or as a salt thereof.
  • the compound of the present invention produced by these methods is isolated or purified as a free form or a salt thereof.
  • it is isolated as a free compound when treated with a small amount of acid, but can be isolated as a salt by treating with a large amount of acid.
  • Isolation and purification are carried out by applying ordinary chemical operations such as extraction, distillation, crystallization, filtration, recrystallization, and various kinds of mouth chromatography.
  • the free compound or a salt thereof thus obtained can be further converted to another salt by subjecting it to a usual salt formation reaction.
  • the compound of the present invention has two asymmetric carbon atoms. In some cases, optical isomers can be present.
  • isomers can be separated by a conventional method such as fractional crystallization recrystallizing with an appropriate salt or column chromatography. That is, it is divided into diastereomers (R, R) and (S, S), and (R, S) and (S, R). Diastereomers exist as enantiomers, and can generally be separated into two by separation on a column for optical resolution or by recrystallization from an appropriate salt, to give a single optical isomer. Industrial applicability
  • the compound of the present invention has a specific anti-PCP action, as a psychotropic drug, as an anti-schizophrenia drug, as an anti-dementia drug against Alzheimer's disease, etc., and as a drug for improving behavioral problems such as delirium associated with dementia. It is also useful as a treatment for mental retardation and autism in childhood.
  • the anti-PCP action of the compound of the present invention was confirmed by the following test methods.
  • HBA whole-boat paratas
  • the HBA is an open field of 4 Ocm in length and width, with 16 holes of 4 cm in diameter on the floor and 20 cm in height around the wall [Psychopharmacology, 52, 271 (1977)].
  • the rat's momentum (the number of times the locus moves through the 9 divided floors (Locomotion)) and the exploratory behavior (the number of times the head was put into the hole (Dipping)) were measured over 5 minutes.
  • a male male rat (n 8) to which PCP (3 mg / kg) was subcutaneously administered was used as a control group.
  • Example 1 4 3 mg / kgg sc
  • the compounds of the present invention did not inhibit rat self-issue activity (momentum and exploratory behavior) at doses showing an anti-PCP effect.
  • haloperidol a typical dopamine receptor blocker, widely used as an antipsychotic, also antagonized PCP-induced hyperactivity, but similar doses inhibited rat self-issue. did.
  • compositions containing one or more of the compounds of the present invention or salts thereof as active ingredients can be prepared in the form of tablets, buccals, powders, and fine granules using commonly used pharmaceutical carriers, excipients, and other additives. Preparations, granules, capsules, pills, oral solutions (including syrups), injections, inhalants, suppositories, transdermal solutions, ointments, transdermal patches, transmucosal patches ( It is prepared into, for example, an oral patch or a transmucosal solution (for example, a nasal solution), and is administered orally or parenterally.
  • a transmucosal solution for example, a nasal solution
  • Examples of carriers and excipients for pharmaceuticals include solid or liquid non-toxic pharmaceuticals. These include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, arabia gum, olive oil, sesame oil, cocoa batata, ethylene glycol, and the like. Are exemplified.
  • the clinical dosage of the compound of the present invention is appropriately determined in consideration of the disease, body weight, age, sex, administration route, etc. of the patient to which the compound is applied. It is preferably 1 to 200 mg, and intravenously 0.1 to 100 mg, preferably 0.3 to 30 mg per day for an adult, administered once or in 2 to 4 doses.
  • the diastereomer eluted first by silica gel column chromatography is referred to as A-form, and the diastereomer eluted later is referred to as B-form.
  • the diastereomer A-form (or B-form) is used in the reaction as a raw material, and the resulting compound is also the A-form (or B-form).
  • the chromate form methanol (30: 1)
  • the chromate form A mixture of methanol and concentrated aqueous ammonia (300: 30: 1) is flowed in order, and t-butyl 2-amino-3-hydroxy 3-[5- (11-pyrrolidinyl) methyl] — 2.1 g of 2-Chenyl propinate was obtained.
  • Example 2 the compounds of Examples 2 to 4 were obtained in the same manner as in Example 1.
  • Example 2 the compounds of Examples 2 to 4 were obtained in the same manner as in Example 1.
  • Example 13 the compounds of Examples 13 to 20 were obtained in the same manner as in Example 1.
  • Example 13 the compounds of Examples 13 to 20 were obtained in the same manner as in Example 1.
  • Lactose 65 Constarch 16 Hydroxypropyl mouth pill cellulose 4.5 Carboxymethyl cellulose calcium 8.8 Magnesium stearate 0.7 Total 120 mg
  • Example 13-(3) 150 g, Lactose (325 g) and constarch (80 g) were uniformly mixed using a fluidized-granulation coating device. This was granulated by spraying 25 g of a 10% hydroxypropylcellulose solution. After drying, pass through a 20 mesh, add 19 g of calcium carboxymethylcellulose and 8.5 g of magnesium stearate, and use a rotary tableting machine with a 7 mm x 8.4 R mortar and punch. 120 mg tablets were used.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
PCT/JP1994/000697 1993-04-27 1994-04-26 Serine derivative WO1994025450A1 (en)

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JP5/123454 1993-04-27
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JP5/236428 1993-09-22

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Cited By (2)

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WO1998000420A1 (fr) * 1996-07-01 1998-01-08 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de thiophene et compositions medicamenteuses les contenant
JP2002511409A (ja) * 1998-04-14 2002-04-16 ザ ジュネラル ホスピタル コーポレーション 神経精神疾患の治療法

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DE60045821D1 (de) * 1999-09-02 2011-05-19 Shionogi & Co Derivate von aromatische heterocyclen enthaltende integraseinhibitoren
EP1957476A1 (en) * 2005-11-23 2008-08-20 AstraZeneca AB L-alanine derivatives
EP2049490A1 (en) * 2006-06-09 2009-04-22 Astra Zeneca AB N-(benzoyl)-o- [2- (pyridin- 2 -ylamino) ethyl]-l-tyrosine derivatives and related compounds as a5b1 antagonists for the treatment of solid tumors
US20090062267A1 (en) * 2007-01-29 2009-03-05 Astrazeneca Ab L-ALANINE DERIVATIVES AS a5beta1 ANTAGONISTS
WO2008125811A1 (en) * 2007-04-11 2008-10-23 Astrazeneca Ab N-[HETEROARYLCARBONYL]-S-THIENYL-L-ALANINE DERIVATIVES AS α5β1 ANTAGONISTS

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JPH05262759A (ja) * 1992-01-23 1993-10-12 Yoshitomi Pharmaceut Ind Ltd チオフェン化合物

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US4382929A (en) * 1979-10-23 1983-05-10 Glaxo Group Limited Thiophene derivatives and their pharmaceutical compositions and method of use
US4598153A (en) * 1984-12-19 1986-07-01 The United States Of America As Represented By The Department Of Health And Human Services Metaphit, a specific acylating agent for the [3 H] phencyclidine
ATE114305T1 (de) * 1990-03-13 1994-12-15 Hoechst Roussel Pharma 1-alkyl-, 1-alkenyl- und 1-alkynylaryl-2-amino- 1,3-propandiole und verwandte verbindungen, verfahren und zwischenverbindungen zu ihrer herstellung und ihre verwendung als medikamente.
JP3176063B2 (ja) * 1991-04-17 2001-06-11 ファルマシア・アンド・アップジョン・カンパニー 新規中枢神経作用性置換フェニルアザシクロアルカン類
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JPH05262759A (ja) * 1992-01-23 1993-10-12 Yoshitomi Pharmaceut Ind Ltd チオフェン化合物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000420A1 (fr) * 1996-07-01 1998-01-08 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de thiophene et compositions medicamenteuses les contenant
RU2172737C2 (ru) * 1996-07-01 2001-08-27 Яманоути Фармасьютикал Ко., Лтд. Производное тиофена и фармацевтическая композиция на его основе
JP3218045B2 (ja) 1996-07-01 2001-10-15 山之内製薬株式会社 新規なチオフェン誘導体及びその医薬組成物
JP2002511409A (ja) * 1998-04-14 2002-04-16 ザ ジュネラル ホスピタル コーポレーション 神経精神疾患の治療法

Also Published As

Publication number Publication date
HU9503072D0 (en) 1995-12-28
EP0696586A1 (en) 1996-02-14
TW290548B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1996-11-11
HUT75032A (en) 1997-03-28
EP0696586A4 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1996-03-27
CN1121713A (zh) 1996-05-01
CA2160459A1 (en) 1994-11-10
US5834460A (en) 1998-11-10
AU681655B2 (en) 1997-09-04
AU6582494A (en) 1994-11-21

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