WO1993020053A1 - Derive de pyridylserine - Google Patents

Derive de pyridylserine Download PDF

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Publication number
WO1993020053A1
WO1993020053A1 PCT/JP1993/000356 JP9300356W WO9320053A1 WO 1993020053 A1 WO1993020053 A1 WO 1993020053A1 JP 9300356 W JP9300356 W JP 9300356W WO 9320053 A1 WO9320053 A1 WO 9320053A1
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Prior art keywords
group
amino
tert
pyridyl
butyl
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Application number
PCT/JP1993/000356
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English (en)
Japanese (ja)
Inventor
Shuichi Sakamoto
Ichio Noda
Yutaka Kondoh
Kazuo Koshiya
Kazuyuki Hidaka
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Yamanouchi Pharmaceutical Co., Ltd.
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Publication of WO1993020053A1 publication Critical patent/WO1993020053A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 acts on the glutamate binding site and / or glycine binding site of the NMDA (N-methyl-D-aspartate) receptor, and particularly, serine having an anti-PCP (phencyclidine) action. It relates to a derivative or a salt thereof.
  • NMDA N-methyl-D-aspartate
  • PCP phencyclidine
  • the glutamate receptor subtype the N-methyl-D-aspartate (NMDA) receptor
  • NMDA receptor protein forms a functional complex, and has a glutamate binding site to which the agonist NMDA-glutamic acid binds and a glycine binding site to which the aosteric agonist binds. Stimulation of the binding site activates the receptor and transmits information.
  • Substances that block NMDA receptors cause psychiatric abnormalities, such as delirium, in humans.
  • PCP is known to induce psychiatric symptoms very similar to those of schizophrenia, including negative symptoms [Am. J. Psychiat., 135, 1081 (1978)].
  • An object of the present invention is to provide a compound which acts on a glutamate binding site and / or a glycine binding site of an NMDA receptor and exerts an excellent specific anti-PCP action by peripheral administration.
  • the present inventors have created various compounds and proceeded with screening, and as a result, the pyridylserine derivative represented by the following general formula (I) and a salt thereof were converted to the glutamate binding site of the NMD A receptor and Z or glycine.
  • the present inventors have found that they have a specific anti-PCP effect and act on a binding site and can achieve a clinical purpose, and have completed the present invention.
  • 2-amino-3-hydroxy-3- (2-pyridyl) propionic acid is disclosed in JP-A-57-192346 and JP-A-57-193432
  • 2-amino-3-hydroxy-3- (3- Pyridyl) propionic acid is disclosed in JP-A-54-141723, JP-A-48-88282
  • Synthes is, 3,216 (1979) r Arch. Pha rm., 308 (7), 514 (1975), ibid, 308 ( 2), 135 (1975)
  • 2-amino-3-hydroxy-3- (4-pyridinole) propionic acid was added to Helv. Chim. Act a. 70 (1), and to 4- or 6-position of pyridyl group.
  • compounds having an alkyl group or an alkynyl group are described in JP-A No. 4-235145.
  • the compound of the present invention is a novel compound having a chemical structural characteristic in that an amino or thio group is substituted for a pyridyl group directly or via an alkyl group.
  • carboxyl groups and / or Or a compound protected with an amino group is useful as an intermediate.
  • the pyridylserine derivative of the present invention is represented by the following general formula (I).
  • R 1 a protecting group for a hydrogen atom or an amino group
  • R 2 hydrogen or carboxyl protecting group
  • R 3 , R 4 identical or different, hydrogen atom; substituted with amino group, lower alkylamino group or carbocyclic aryl group, or unsubstituted lower alkyl group; substituted with amino group, or Terminally substituted acyl group; an aminocarbonyl group substituted or unsubstituted with a lower alkyl group or a cycloalkyl group;
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms.
  • R 1 as "protecting group Amino group” include benzyl group, benzhydryl group, trityl group, benzyl-based protecting group such as 4-menu Tokishibenjiru group, a formyl group, Asechiru group, Ashiru group such as propionyl group Protecting groups, aralkyloxycarbonyl such as benzyloquincarbonyl group It is a lower alkoxycarbonyl group such as a bonyl group or a t-butoxycarbonyl group, preferably an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, or a lower alkoxycarbonyl group such as a t-butoxycarbonyl group. .
  • Examples of the "protecting group for carboxyl group" in R 2 include lower alkyl groups such as methyl group, ethyl group and 5-butyl group, and benzyl protecting groups such as benzyl group. is there.
  • the “lower alkylene group” includes methylene, ethylene, methylmethylene, trimethylene, 2-propylene, dimethylmethylene, tetramethylene, 1-methyltrimethylene, and 2-methyltrimethylene.
  • “Unsubstituted lower alkyl group” includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3-dimethylbutyl group, 1 Monoethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-
  • the “amino lower alkyl group” means that any position of the lower alkyl group is amino. These are, for example, aminomethyl, aminoethyl, aminobutyl, aminopropyl, aminopropyl, aminobutyl, and aminopentyl (amyl) groups.
  • the “lower alkylamino lower alkyl group” is a group in which an amino group in the above amino lower alkyl group is substituted with a lower alkyl group.
  • a methylaminomethyl group a methylaminoethyl group , Methylaminopropyl, methylaminoisopropyl.
  • Methylaminopentyl (amyl) ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, pentyla Minomethyl group, pentylaminoethyl group, hexylaminoethyl group, hexylaminopropyl group, dimethylaminomethyl group, dimethylaminoethyl group, dimethylaminopentyl (amyl) group, ethylmethylaminomethyl group, A methylmethylaminoethyl group, an ethylmethylaminopentyl (amyl) group, These are the ethylmethylaminohexyl group and the 5-ethylmethylamin
  • the “carbocyclic aryl lower alkyl group” includes lower alkyl Any position of the group may be substituted with a carbon ring reel group such as a phenyl group or a naphthyl group, specifically, a phenylmethyl group, a phenylethyl group, a phenylpropyl group, a phenylhexyl group, Examples include a naphthylbutyl group and a naphthylhexyl group.
  • amino group substituted or unsubstituted with an amino group examples include, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, bivaloyl group, hexanoyl group, aminoacetyl group. , An aminopropionyl group, an aminobutyryl group, an aminoisobutyryl group, and an aminoaminohexanoyl group.
  • Examples of the lower alkyl group in the “lower alkyl group or a substituted or unsubstituted aminocarbonyl group with a cycloalkyl group” include those described above.
  • Examples of the cycloalkyl group include the following. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptinol group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, and a cycloundecyl group. One or two of these groups can be substituted.
  • “Lower alkoxycarbonyl group” includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group , Pentyloxy (amyloxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group, 2-methylbutoxycarbonyl group, 1,2-dimethylpropoxycarbonyl group, 1-ethylpropoxy group And a carbonyl group and a hexyloxy group.
  • a methoxycarbonyl group preferred are a methoxycarbonyl group, an ethoxycarbonyl group, a propoxypropyl group, an isopropoxycarbonyl group, and a butoxycarbonyl group.
  • the “cycloalkylcarbonyl group” means a saturated carbocyclic carbonyl group having 4 to 7 carbon atoms. Typical examples are a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group and a cycloheptylcarbonyl group, preferably a cyclopentylcarbonyl group and a cyclohexylcarbonyl group. It is a carbonyl group.
  • a “nitrogen-containing heterocyclic group” is a 4- to 6-membered ring having one nitrogen atom. Representative examples are as described below, preferably azetidinyl group, pyrrolidinyl group, piperidino group, homopiperidinyl group and the like.
  • the “nitrogen-containing heterocyclic group” formed by R a and R 4 as one body includes, in addition to the nitrogen atom to which R 3 and R 4 are condensed, an oxygen atom or a nitrogen atom.
  • Suitable heterocyclic groups include, for example, azetidinyl, hexahydroazepinyl, octahydroazodinyl, octahydroazolinyl, decahydroazinyl, azacycloundecanyl, azacyclotridecanyl, homopiperazinyl, homopiperazinyl, , Pyrrolyl, pyrrolylyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, dihydropyridyl, tetrahydropyridyl, piperidyl Oxazolyl group, oxazolinyl group, oxazolidinyl group, isoxazolyl group, oxdiazolyl group, pyrimidinyl group, pyrida
  • the nitrogen-containing heterocyclic group may have a substituent.
  • the substituent include a hydroxyl group, a hydroxy lower alkyl group, an amino group, a mono or di-lower alkylamino group, an oxo group, and an aralkyl group (for example, a benzyl group and a phenethyl group).
  • the “condensed nitrogen-containing heterocyclic group” is a 5- or 6-membered ring having a benzene ring as a condensed ring, and may have an oxygen atom in addition to a nitrogen atom.
  • bridged nitrogen-containing heterocyclic group examples include a noropenpan ring group, an 8-azabicyclo [3.2.1] octane ring group, a 6-azabicyclo [3.2.1] octane ring group, and a 2-azabicyclo group.
  • Octane ring group 3-azabicyclo [3.2.2] Octane ring group, 2-azabicyclo [3.3.1] Nonane ring group, 3-azabicyclo [3.3.1] And a nonane ring group.
  • Examples of the lower alkyl group or cycloalkyl group in the “lower alkyl group or cycloalkyl group-substituted or unsubstituted thio group” include those described above.
  • Preferred examples of the substituted thio group include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a hexylthio group, a cyclobutylthio group, a cyclopentylthio group, and a cyclohexylthio group. , Cyclobutylthio group and the like.
  • the compound (I) of the present invention forms a salt with an acid and a base.
  • salts with acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid.
  • Acid addition salts with organic acids such as acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned.
  • Examples of the salt with a base include inorganic bases such as lithium, sodium, potassium, magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, and ethanolamine; lysine; Salts with basic amino acids such as ordinine and the like can be mentioned.
  • inorganic bases such as lithium, sodium, potassium, magnesium, calcium, and aluminum
  • organic bases such as methylamine, ethylamine, and ethanolamine
  • lysine Salts with basic amino acids such as ordinine and the like can be mentioned.
  • the compound of the present invention contains an asymmetric carbon atom or an oxo group, and therefore there are tautomers, optical isomers and optically active isomers based on these.
  • the compound of the present invention includes a mixture of these isomers and an isolated one.
  • the compounds of the present invention can form hydrates and solvates.
  • the compound of the present invention can be produced by applying various synthetic methods.
  • the typical production method is exemplified below.
  • R 1 is a protecting group for an amino group
  • R 2 is a protecting group for a carboxyl group
  • a and B have the above-mentioned meanings.
  • the compound (la) of the present invention is produced by reacting an aldehyde compound represented by the general formula (II) with a protected glycine represented by the general formula (III), and then, if necessary, removing a protecting group. You.
  • compound (III) is activated with a base, for example, an organic lithium compound such as n-butyllithium, or sodium hydroxide in an organic solvent such as tetrahydrofuran, ether, or dioxane. It is advantageous to add (II) and react under cooling to room temperature, for example, at -80 to room temperature.
  • a base for example, an organic lithium compound such as n-butyllithium, or sodium hydroxide in an organic solvent such as tetrahydrofuran, ether, or dioxane.
  • the t-butyl group can be easily removed by treatment with trifluoroacetic acid, and the methyl and ethyl groups can be easily hydrolyzed under basic conditions. According to this method, the compound ( ⁇ ) and the compound ( ⁇ ) need only be equimolar, and the stereoisomers can be easily separated because they are not inverted by this reaction.
  • the compound (la) of the present invention is produced by reacting an aldehyde compound represented by the general formula (II) with free glycine represented by the general formula (Ilia).
  • the compound (I) of the present invention produced by these production methods is isolated and purified as it is or as a salt thereof. In the process of the present invention, it is finally isolated as a free compound when treated with a small amount of acid. If treated with a large amount of acid, it can be isolated as a salt. Isolation and purification are performed by applying ordinary chemical operations such as extraction, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the free compound thus obtained or a salt thereof can be further converted to another salt by subjecting it to a usual salt formation reaction.
  • the compound of the present invention has at least an asymmetric carbon atom.
  • 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 a suitable salt to form a single optical isomer. Industrial applicability
  • the compound (I) of the present invention acts on the NMD A receptor, particularly on the glutamate binding site and the glycine binding site of the NMD A receptor, and has a specific anti-PCP activity. It is useful as an anti-dementia drug for diseases, etc., as a drug for improving behavioral problems such as delirium associated with dementia, and as a drug for treating mental retardation and autism in childhood.
  • the anti-PCP activity of the compound (I) of the present invention was confirmed by the following test methods.
  • test compound and PCP (2 to 4 mgZkg) were subcutaneously administered to male Wistar rats (body weight 200 to 300), and 30 minutes later, they were placed in Hollander paratus (HBA).
  • HBA Hollander paratus
  • the HBA has 16 holes of 4 cm in diameter on the floor and a wall of 20 cm in height and 40 cm in length. [Psychopharmacology, 52, 271 (1977)].
  • the rat's momentum (number of times the floor was divided into 9 sections) and exploratory behavior (the number of times the head was put in the hole) were measured over 5 minutes in HBA.
  • the compound of the present invention antagonized the increase in locomotor activity induced by PCP (Table A below). Moreover, the compound 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 at similar doses inhibited rat self-issue.
  • the anti-PCP action of the compound of the present invention is a specific antagonist for the glycine binding site of the NMD A receptor.
  • (+)-HA966 ((+)-(3R ) -3-araino-1-hydroxypyrrol idin-2-one) [Br. J. Pharmacol., 103, 2037 (1991)].
  • the anti-PCP effect of 3 OmgZkg (subcutaneous administration) of the compound of Example 4 was antagonized by (+)-HA966 3 or 1 OmgZkg (subcutaneous administration), respectively. This suggested that the compound of the present invention exerts an anti-PCP action by acting on the NMDA receptor.
  • Formulations containing one or more of the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared using commonly used carriers for pharmaceuticals, excipients, and other additives.
  • 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 butter, ethylene glycol, and the like, and other commonly used ones.
  • the clinical dose of the compound of the present invention is appropriately determined in consideration of the disease, weight, age, sex, administration route, etc. of the patient to which the compound is applied.
  • Omg preferably l-200 mg, intravenously 0.1 to adult / day: I 0 Omg, preferably 0.3-30 mg, given once or in 2-4 divided doses.
  • Mass spectrometry value (mZ z): FAB (Pos.) 207 (M ++ 1, base peak)
  • the extract was extracted from black-mouthed form, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporation under reduced pressure, the residue was subjected to silica gel column chromatography. A mixture of chloroform: methanol 50: 1 to 30: 1 and chromatography: methanol: concentrated aqueous ammonia (100: 1: 0: 1) was used. The eluted solution gave 4.12 g of the desired 6- (4-benzyloxycarbonyl-l-phomopiperazinylmethyl) -12-pyridinemethanol.
  • Triethylamine 111 ml was added to the reaction solution, and the mixture was stirred for 2 hours while gradually warming to room temperature.
  • the precipitated crystals were collected by filtration, dissolved in 600 ml of methylene chloride, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • N, N'-I-Imidazolecarboxylic acid prepared from carbonyldiimidazole and cyclopentylamine
  • Oxalyl chloride 1. 78 in 13 ml of 50 ml of methylene chloride solution. Under a stream of C and argon, 2.26 ml of dimethyl sulfoxide was added dropwise, and 10-ml of a solution of 1.83 g of 6- (N-methyl-N-phenethylamino) methyl-2-pyridinemethanol in 10 ml of methylene chloride was added dropwise, followed by stirring for 30 minutes. Triethylamine (6.8 ml) was added, and the mixture was further stirred for 1.5 hours. Methylene chloride and water were added for extraction, and the organic layer was washed with saturated saline and dried over magnesium sulfate.
  • 6- (3-azabicyclo [3.2.2] non-3-ylmethyl) -12-pyridinecarboxyaldehyde was obtained in the same manner as in Reference Example 20.
  • Mass spectrometry value (mZz): FAB (N eg) 264 (M + -1) nuclear magnetic resonance spectrum H, 400 MHz, D 20 , TSP-d 4 internal standard)
  • Example 11 The same treatment as in Example 11 was performed to obtain 2-amino-3-hydroxy-3- [6- (N-methylaminomethyl) pyridin-2-yl] propionic acid.

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Abstract

On décrit un dérivé de pyridylserine représenté par la formule générale suivante (I) ou un sel qui en est pharmaceutiquement acceptable, où R1 représente hydrogène ou un groupe de protection des amino, R2 représente hydrogène ou un groupe de protection du carboxyle, A représente un alkylène inférieur ou à simple liaison, B représente -NR3R4 ou mercapto auquel peut se substituer alkyle inférieur ou cycloalkyle, R3 et R4, qui peuvent être identiques ou différents, représentent chacun hydrogène; un groupe alkyle inférieur auquel peut se substituer amino, alkylamino inférieur ou aryle carbocyclique; un groupe acyle auquel peut se substituer amino; un groupe aminocarbonyle auquel peut se substituer alkyle inférieur ou cycloalkyle; alcoxycarbonyle inférieur; cycloalkylecarbonyle; un groupe hétérocyclique azoté; ou bien R3 et R4 peuvent se combiner pour représenter un groupe hétérocyclique azoté, un groupe hétérocyclique azoté condensé ou un groupe hétérocyclique azoté réticulé. Ce dérivé présente un effet anti-PCP et se révèle utile en tant que psychotrope.
PCT/JP1993/000356 1992-03-27 1993-03-25 Derive de pyridylserine WO1993020053A1 (fr)

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JP4/102159 1992-03-27
JP10215992 1992-03-27

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WO1993020053A1 true WO1993020053A1 (fr) 1993-10-14

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024060A3 (fr) * 2002-09-11 2004-06-24 Astrazeneca Ab Composes
WO2010137302A1 (fr) * 2009-05-27 2010-12-02 日本曹達株式会社 Dérivés hétéroaryles contenant de l'azote et fongicides pour utilisation agricole et horticole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 116, No. 3, 128669f, (1992). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024060A3 (fr) * 2002-09-11 2004-06-24 Astrazeneca Ab Composes
WO2010137302A1 (fr) * 2009-05-27 2010-12-02 日本曹達株式会社 Dérivés hétéroaryles contenant de l'azote et fongicides pour utilisation agricole et horticole

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AU3767693A (en) 1993-11-08

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