WO2000050416A1 - Derives d'acide heteroquinolinecarboxylique 6-substitues et sels d'addition associes, et procedes de preparation de ces derives et de leurs sels - Google Patents
Derives d'acide heteroquinolinecarboxylique 6-substitues et sels d'addition associes, et procedes de preparation de ces derives et de leurs sels Download PDFInfo
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- WO2000050416A1 WO2000050416A1 PCT/JP2000/001077 JP0001077W WO0050416A1 WO 2000050416 A1 WO2000050416 A1 WO 2000050416A1 JP 0001077 W JP0001077 W JP 0001077W WO 0050416 A1 WO0050416 A1 WO 0050416A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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 relates to 6-substituted heteroquinoline carboxylic acid derivatives, their addition salts, and their production methods.
- the present invention relates to a 6-substituted heteroquinoline carboxylic acid, which is effective as an excitatory amino acid receptor antagonist, in particular, a selective antagonist of non-NMDA receptor for AMP ⁇ receptor, for treating cerebral nerve cell disorders.
- the present invention relates to a derivative, an addition salt thereof, a production method thereof, and a pharmaceutical composition containing these compounds.
- Glutamate an excitatory amino acid
- Glutamate an excitatory amino acid
- Glutamate is the major excitatory transmitter in the vertebrate central nervous system and is known to be the most abundant amino acid in the brain.
- it is known that when released beyond the end of the axon, it is overexcited by postsynaptic glutamate receptors, causing neuronal death. This is called excitatory nerve cell death (exi totoxi city).
- Glutamate receptors are roughly classified into ion channel-type receptors and G-protein-coupled receptors.
- NMD A N-methyl-D-aspartate receptor
- n on — NMD A receptor NMD A receptor
- AMPA hydroxyamino-3-hydroxy-15-methyl-14-isoxazolylpropionic acid
- KA kainic acid
- drugs that have non-NMDA receptor AMPA receptor antagonism include drugs that have NMDA receptor antagonism (MK-8 ⁇ 1st) should not have side effects (learning, memory impairment, schizophrenia-like symptoms, etc.) (Neurosci. Biobehav. Rev., 1992, 16, 13-24;
- R represents an aldehyde group, an amide group, a carboxyl group, etc.
- R 2 represents a hydrogen atom) and a compound having an anti-muscarinic action from Istituto De Angeli SpA as a compound represented by the general formula (14) described in EP 3862887.
- R represents a hydrogen atom or an alkyl group
- R i and R 2 represent a hydrogen atom, a halogen, an alkyl group, an alkoxycarbonyl group, a nitro group, a cyano group, etc.
- R 3 represents a hydrogen atom or an alkyl group.
- A represents C0, CS, etc .
- Z represents no R 3 ; and when D—Z is a single bond, a nitrogen atom is represented.
- Z is a carbon atom
- D is C—R when D—Z is a double bond
- X is an oxygen atom
- N—R etc.
- Y is a substituted aminoalkyl group
- quinuc a compound having an anticancer effect (a tyrosine kinase inhibitory effect) from Biosignal Inc. as a compound represented by the general formula (15) described in WO 93/16464. )
- X represents an oxygen atom, etc.
- Y represents an oxygen atom, a sulfur atom, NH
- R 2 And R 4 represents a hydrogen atom, a hydroxyl group, an amino group, a trifluoromethyl group, an alkyl group, etc.
- R 3 represents a hydroxyl group, an amino group, an alkylamino group, a nitroso group, a trifluoromethyl group, etc.
- R 5 is a hydroxyl group, an alkyl group, or a halogen one
- X represents an oxygen atom
- NH represents 0 to 6
- A represents a haloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, a cyano group, an amide group, etc.
- X represents ⁇ or NH
- Y is 2- (ethylamino) ethyl, 8-methyl-8-azabicyclo [3,2,1] octa-3-yl, quinuclidine-13 —Yl, 1-ethylbiperidine-14-yl and the like
- these compounds do not have a substituent on the benzene ring, have a different structure from the compound of the present invention, and have an AMP A receptor antagonistic activity of an excitatory amino acid receptor. It has not been.
- adipyl company has a more excitatory amino acid pathway. ⁇
- R 2 and R 3 represent a hydrogen atom, a halogen atom, an alkyl group, a nitro group, a cyano group, an aminosulfonyl group, etc.
- R 4 and R 5 represent a hydrogen atom, an alkyl group, etc.
- R 8 represents a hydrogen atom, an alkyl group
- R 3 represents a hydrogen atom, an alkyl group, a carboxyl group, a cyano group, etc.
- R 4 represents a hydrogen atom, an alkyl group, an alkoxy group, etc.
- R 5 represents R 6 represents a hydrogen atom
- R 7 represents a hydroxyl group, an amino group, an alkylamino group, etc.
- this compound is not related to a drug and has an AMP A receptor antagonistic activity of an excitatory amino acid receptor.
- R and RR 2 represent a hydrogen atom, a chlorine atom, a fluorine atom, and a nitro group, and X represents a carboxylic acid, a phosphonic acid, a boric acid, an amide, etc.
- X is a phosphonic acid in the general formula (22)
- the compound has an asymmetric substituent at the 6- or 7-position of the quinoline ring as in the compound of the present invention.
- the reported AMP A antagonism and glycine antagonism are not considered to be sufficient. ⁇
- the disclosed pharmacological data is only for the NMD A receptor, and no specific data for the AMP A receptor is disclosed as in the compound of the present invention.
- the present invention provides a receptor antagonistic action of glutamate, which is considered to be a cause of memory disorders and dementia caused by the above-mentioned diseases and selective cell death, and particularly has a high antagonism against AMP A receptor of n 0 n-NMD A receptor.
- An object of the present invention is to provide a compound having affinity and selectivity and having a brain nerve cell protective effect. Disclosure of the invention
- the present inventors aimed at developing a novel therapeutic agent for cerebral neuronal damage, which is an excitatory amino acid receptor antagonist effective for the treatment of cerebral neuronal damage, particularly an AM of n 0 n-NMD A receptor.
- an excitatory amino acid receptor antagonist effective for the treatment of cerebral neuronal damage, particularly an AM of n 0 n-NMD A receptor.
- Y represents a nitrogen atom, two CH—, ⁇
- V represents a single bond, methylene (CH 2 ),
- T represents a hydroxyl group, an amino group, a lower alkoxycarbonyl group, a carboxy group, an aldehyde group,
- W is an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof. May have one or more substituents), a lower alkyl group which may be substituted with a halogen atom, or a cyclic alkyl group),
- W is an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these are aromatic rings and heterocyclic rings). May have one or more substituents), a lower alkyl group and a cyclic alkyl group which may be substituted with a halogen atom.
- R represents a nitro group, a trifluoromethyl group, or a halogen atom, and R 1 represents a hydroxyl group or a lower alkoxy group).
- AMP A which is excellent in a 6-substituted heteroquinoline carboxylic acid derivative and an addition salt thereof They have found that they have receptor antagonism, and have completed the present invention.
- R is preferably a nitro group, a trifluoromethyl group or a chloro group, and R 1 is a hydroxyl group or a lower group.
- R is a nitro group, a trifluoromethyl group or a chloro group
- R 1 is a hydroxyl group
- V is methylene (CH 2 )
- T is a group represented by the general formula (2) or the general formula In (3), a compound in which X is an oxygen atom may be mentioned.
- Dro-2-oxoquinoline_3 Carboxylic acid. BEST MODE FOR CARRYING OUT THE INVENTION
- an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these include one or more substituents on an aromatic ring or a heterocyclic ring) )
- a substituted or unsubstituted amino group a cyano group, a carboxyl group, an aldehyde group, a carboxy lower alkyl group and the like.
- the “lower alkyl group” is methyl, ethyl, n-propyl, is 0-propyl and other straight or branched ones having 1 to 6 carbon atoms.
- Cyclic alkyl group refers to cyclopropyl, cyclopentyl, cyclohexyl, etc.
- Halogen atoms include fluorine, chlorine, bromine, and iodine;
- lower alkoxy groups include straight-chains such as methoxy, ethoxy, and propoxy.
- lower alkylthio group includes linear or branched ones having 1 to 6 carbon atoms such as methylthio, ethylthio, and propylthio.
- alkoxycarbonyl group includes linear or branched ones having 1 to 4 carbon atoms such as methoxycarbonyl and ethoxycarbonyl.
- aralkyloxy group includes benzyloxy, phenylethyloxy, and phenylpropyl.
- Aralkylthio groups include benzylthio, phenylethylthio, phenylpropylthio, etc.
- ⁇ heterocycle '' in the above refers to a saturated or unsaturated monocyclic or polycyclic heterocyclic ring which may have one or more substituents, and which can contain one or more nitrogen, oxygen and sulfur atoms.
- pyridine piperidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, furanyl, chenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, and viracyl.
- the “condensed ring” refers to a benzene condensed ring of the above “heterocycle” and includes, for example, indolyl, tetrahydroquinolyl, benzoxazolidinyl, benzyl V thiazolidinyl, benzofurel, benzochenyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl and the like.
- the compound of the present invention is produced, for example, by the following production method.
- the compound represented by the general formula (1) is represented by the general formula (4)
- R 2 may have a lower alkyl group which may be substituted with a halogen atom, and may have one or more substituents.
- Aralkyl group) in a solvent-free or suitable solvent for example, water, acetic acid, methanol, etc., a suitable acid, for example, ⁇
- It can be synthesized by reacting with hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or a mixed acid thereof at 20 to 120 ° C for 0.5 to 72 hours.
- the compound represented by the general formula (1) is a compound represented by the general formula (4)
- R 1 is a lower alkoxy group
- the compound is converted to an appropriate solvent, water
- a solvent such as methanol or ethanol
- a suitable alkali for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, etc. at 0.5 to 7 ° C at 20 to 100 ° C.
- a suitable solvent such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or a solvent-free or suitable solvent such as water, acetic acid, methanol, etc. It can also be synthesized by reacting at 20 to 120 ° C. for 0.5 to 72 hours using a mixed acid or the like.
- the compound represented by the general formula (1) is a compound represented by the general formula (4)
- R 1 is a lower alkoxy group
- the compound is dissolved in a suitable solvent or without solvent.
- a suitable solvent for example, water, acetic acid, methanol, or the like
- an appropriate acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, or a mixed acid thereof, in the range of 20 to 1; 2 at 0 ° C 3 ⁇
- a suitable alkali such as potassium hydroxide, sodium hydroxide, lithium hydroxide, etc. Can also be synthesized by reacting at 20 to 100 ° C. for 5 to 72 hours.
- a compound in which R 1 is a lower alkoxy group is prepared by dissolving the compound in a suitable solvent, a solvent such as water, methanol, ethanol, or the like. The reaction is carried out at 20 to 100 ° C for 0.5 to 10 hours using hydration power, sodium hydroxide, lithium hydroxide, lithium hydroxide, etc., and the compound in which R 1 is a hydroxyl group. Can be synthesized.
- the compound wherein Y is di-CH— is represented by the general formula (5)
- T and V represent the same as described above, and R 3 represents a lower alkyl group optionally substituted with a halogen atom, or an aralkyl group optionally having one or more substituents
- a solvent-free or suitable solvent for example, tetrahydrofuran, benzene, toluene, acetic acid, ethanol, methanol, etc.
- a suitable inorganic or organic acid such as hydrochloric acid, sulfuric acid, ⁇
- 17 tosylic acid may be added), but the reaction can also be carried out at 20 to 120 ° C. for 0.5 to 5 hours.
- Z is an aralkyl group, a phenyl group, a naphthyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), halogen, Xa represents an oxygen or sulfur atom, which represents a lower alkyl group or a cyclic alkyl group which may be substituted with an atom, and a suitable solvent, for example, tetrahydrofuran, dioxane, N, N-dimethyl In formamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene, etc., abasic or a suitable organic base such as triethylamine, pyridine, etc. It can also be synthesized by reacting at 20 to 120 ° C. for 1 to 15 hours using
- Z represents as described above, represents a single bond, and D represents an amino group, a carboxyl group, an amide group, or a lower alkoxycarbonyl group
- D represents an amino group, a carboxyl group, an amide group, or a lower alkoxycarbonyl group
- Z represents as described above, represents a single bond, and D represents an amino group, a carboxyl group, an amide group, or a lower alkoxycarbonyl group
- it can be synthesized by converting the compound to isocyanate (isothiocyanoate) ester or hepatic acid chloride and reacting with general formula (7) in the same manner as general formula (8).
- D when D is an amino group, use a suitable solvent such as tetrahydrofuran, dioxane, benzene, toluene, etc. in an abasic or suitable organic base such as triethylamine.
- Phosgene thiophosgene
- phosgene dimer chloro 2,2,2-trichloromethyl ester
- a homologue thereof chloro-formic acid 4-12-methyl phenyl ester, etc.
- the reaction can be carried out at 0 ° C for 1 to 5 hours to obtain potassium chloride or isocyanate (isothiocyanate).
- D is a carboxyl group
- the lipoxyl group is converted to an acid azide, and then Crutius transfer reaction or Schmidt transfer reaction is used, and when D is an amide group, Hofmann transfer reaction is performed.
- D is a carboxyl group
- it can be converted to isocyanic acid (isothiocyanic acid) ester by one-pot using DPPA (diphenylphosphoric acid azide).
- DPPA diphenylphosphoric acid azide
- the compound represented by the general formula (1) is a compound represented by the general formula (23)
- R 4 represents a lower alkyl group
- a suitable solvent for example, ethanol, methanol, tetrahydrofuran, etc.
- a suitable base for example, sodium ethoxide
- It can also be synthesized by reacting at 25 to 100 ° C for 2 to 24 hours in the presence of sodium methoxide, potassium ter-butoxide, potassium hydroxide and the like.
- ⁇ , V, and ⁇ represent the same as described above
- a suitable solvent for example, tetrahydrofuran, dioxane, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide.
- Base ⁇ -methylpyrrolidone, acetonitrile, benzene, toluene, etc., in an abasic or suitable inorganic or organic base such as sodium hydride, sodium carbonate, potassium carbonate, It can be synthesized by reacting with triethylamine or the like at 20 to 160 ° for 0.5 to 24 hours.
- a suitable solvent for example, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N—
- a suitable solvent for example, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N—
- a suitable organic base such as triethylamine, pyridine, etc., at 20 to 120 ° C and 1 to 15 ° C. It can be synthesized by reacting for a time.
- D when D is an amino group, use a suitable solvent such as tetrahydrofuran, dioxane, benzene, toluene, etc. in an abasic or suitable organic base such as triethylamine.
- Phosgene thiophosgene
- phosgene dimer chloroformitic acid 2,2,2-trichloromethyl ester
- a homologue thereof chloroformitic acid formic acid
- It can be 21-basic chloride or isocyanate (isothiocyanate) ester.
- D is a carboxyl group
- the carboxyl group is converted to an acid azide, and then Crutius transfer reaction or Schmidt transfer reaction is used, and when D is an amide group, Hofmann transfer reaction is performed.
- D is a carboxyl group
- it can be converted to isocyanic acid (isothiocyanic acid) ester by one-port using DPPA (diphenylphosphoric acid azide).
- DPPA diphenylphosphoric acid azide
- ⁇ , ⁇ , and V represent the same as described above
- a solvent or in a suitable solvent for example, tetrahydrofuran, dioxane, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide.
- Suitable solvents a compound represented by (wherein A, X b, R, R 1 represents as defined above), for example, benzene, toluene, black hole Holm, methylene chloride, in like Te Jerusalemi Dorofuran, suitable silver Using a catalyst, for example, silver oxide, silver carbonate, or the like, an alkyl halide, for example, methyl iodide, or an aralkyl halide, for example, 4-methoxybenzyl chloride, etc. at 20 to 120 ° C. It can be synthesized by reacting for up to 10 hours.
- a compound represented by the general formula (25) is dissolved in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran, or the like, in a form of borate, for example, tetramethyl oxonium borate. It can also be synthesized by reacting with a salt or the like at 0 to 120 ° C for 2 to 6 hours.
- Appropriate solvent a compound represented by (wherein R, R ⁇ R 2 represents as defined above), for example, carbon tetrachloride, black hole Holm, in such as acetic acid, halogen agents such as N- bromo succinic It can be synthesized by reacting with acid imide (NBS), N-chlorosuccinic acid imid (NCS), bromine or the like at 20 to 100 ° C for 1 to 12 hours.
- NBS acid imide
- NCS N-chlorosuccinic acid imid
- bromine bromine
- R, and RR 2 represent the same as described above, and R 5 and R 6 are the same or different and each represent a hydrogen atom or an amino-protecting group).
- a suitable solvent for example, water, acetic acid, methanol, ethanol, or the like, use an appropriate acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, or a mixed acid thereof. It can be synthesized by reacting at ⁇ 120 ° C for 3 to 72 hours.
- a suitable solvent for example, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
- a suitable solvent for example, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
- suitable inorganic or organic bases such as sodium hydride, sodium carbonate, sodium carbonate, triethylamine, etc. in don, acetonitrile, benzene, toluene, etc. It can be synthesized by reacting at 20 to 160 ° for 0.5 to 48 hours.
- R 1 represents the same as described above.
- a solvent suitable for the compound (29) for example, an alcohol such as ethanol, ethanol, tetrahydrofuran, N, N-dimethylformamide and the like
- a suitable base for example, sodium ethoxide, potassium ter-butoxide, potassium hydroxide, etc.
- a malonic ester for example, getyl malonate
- compound (30) After reaction with C for 2 to 24 hours to give compound (30), this is reduced by catalytic hydrogenation, that is, in a suitable solvent such as ethanol, methanol, acetic acid or the like, a suitable catalyst such as Hydrogenation in the presence of palladium carbon, platinum oxide, rhodium-alumina, etc., at 25-8 ° C under normal pressure-5 atm (507 KPa) for 2-24 hours, leads to compound ( 3 1) can be synthesized.
- Compound (30) is dissolved in a suitable solvent such as ethanol, dilute hydrochloric acid, acetic acid or a mixed solvent thereof in the presence of tin chloride, zinc, iron, hydrosulfite sodium, etc. 0 0. It can be synthesized even if the reaction is performed for 1 to 7 hours.
- the available or synthesizable compound (32) is converted into a suitable solvent, for example, nitromethane, acetic acid, sulfuric acid, etc., and a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, lithium nitrate,
- a suitable solvent for example, nitromethane, acetic acid, sulfuric acid, etc.
- a suitable nitrating agent for example, concentrated nitric acid, fuming nitric acid, lithium nitrate
- the compound (33) is reacted at 110 to 80 ° (0.5 to 2 hours) using acetyl chloride or the like, and reduced by catalytic hydrogenation, that is, an appropriate solvent such as ethanol or methanol.
- a suitable catalyst for example, palladium carbon, platinum oxide, rhodium monoalumina, etc., at 25 to 80 ° C.
- the compound is hydrogenated and further acetylated to give compound (34) in a suitable solvent, for example, nitromethane, acetic acid, sulfuric acid, etc., and a suitable nitrating agent such as concentrated nitric acid, fuming nitric acid, nitric acid Using calcium, acetyl nitrate, etc.—10 to 8
- a suitable solvent such as water or acetone
- a suitable oxidizing agent such as potassium permanganate.
- the reaction is carried out at 0 to 120 ° C for 1 to 15 hours using sodium periodate or the like to obtain the compound (36), followed by a suitable solvent such as water, ethanol, or methanol. Or a mixture thereof, using a suitable base, for example, sodium hydroxide, sodium hydroxide, etc., at 20 to 100 ° C for 1 to 10 hours, or by using a suitable solvent.
- a suitable base for example, sodium hydroxide, sodium hydroxide, etc.
- the compound is hydrolyzed with water, ethanol, methanol, etc., or a mixture thereof with a suitable acid such as hydrochloric acid, hydrobromic acid, etc. at 20 to 100 ° C. for 1 to 10 hours.
- compound (37) is converted to an appropriate solvent, for example, ether, tetrahydrofuran, dioxa. Hitoshichu, a suitable reducing agent, one
- a borane complex such as a borane-tetrahydrofuran complex, a borane-dimethylsulfide complex, or a borane-pyridine complex is reacted at 20 to 150 ° C. for 1 to 10 hours to react with the general formula (38 )
- a suitable solvent for example, chloroform, methylene chloride, tetrahydrofuran, etc.
- a suitable oxidizing agent for example, manganese dioxide at 20 to 100 ° C for 1 to 24 ° C.
- the compound (29) can be reacted for a time.
- ⁇ , ⁇ , and V represent the same as described above
- a solvent or in a suitable solvent for example, tetrahydrofuran, dioxane, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide.
- R and RXc represent the same as described above.
- a solvent suitable for the general formula (42) for example, an alcohol such as ethanol or methanol, tetrahydrofuran, or N, N-dimethylformamide
- a suitable base for example, sodium ethoxide, potassium ter-butoxide, potassium hydroxide, etc.
- a malonic ester for example, getyl malonate
- the available or synthesizable general formula (43) is acetylated with acetic anhydride at room temperature to obtain the general formula (44), which is then dissolved in an appropriate solvent.
- a suitable nitrating agent such as concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate, etc. at a temperature of 0.5 to 10 ° to 10 to 80 ° C.
- the reaction is carried out for 2 hours to give the general formula (45), which is dissolved in a suitable solvent, for example, water, acetate, etc., and a suitable oxidizing agent, for example, sodium permanganate, sodium periodate.
- a suitable solvent for example, water, acetate, etc.
- a suitable oxidizing agent for example, sodium permanganate, sodium periodate.
- the reaction is carried out at 0 to 120 ° C. for 1 to 15 hours using, for example, sodium chloride to obtain the general formula (46).
- This is dissolved in a suitable solvent, for example, water, ethanol, methanol or a mixture thereof, using a suitable base, for example, sodium hydroxide, potassium hydroxide, etc. at 20 to 100 ° C.
- the general formula (47) is converted into a suitable solvent, for example, ether, tetrahydrofuran, dioxane or the like, and a suitable reducing agent, for example, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, borane
- a suitable solvent for example, ether, tetrahydrofuran, dioxane or the like
- a suitable reducing agent for example, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, borane
- a suitable oxidizing agent such as manganese dioxide, is reacted at 20 to 100 ° for 1 to 24 hours to obtain the general formula (42). it can.
- the available general formula (49) is acetylated with acetic anhydride at room temperature to obtain the general formula (50), which is then dissolved in an appropriate solvent.
- a suitable nitrating agent for example, concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate, etc. at 0.5 to 10 to 80 ° C.
- the reaction is carried out for 2 to 2 hours to obtain the general formula (51), which is dissolved in a suitable solvent, for example, water, ethanol, methanol, or a mixture thereof, with a suitable base, for example, sodium hydroxide, Hydrolysis with lithium or the like at 20 to 100 ° C for 1 to 10 hours, or in a suitable solvent such as water, ethanol, methanol, etc., or a mixture thereof, a suitable acid, for example, hydrochloric acid
- the general formula ( 5 2) is converted to an appropriate solvent, for example, chloroform, methylene chloride, tetrahydrofuran, benzene, water, or the like, using an appropriate oxidizing agent, for example, manganese dioxide or the like.
- a suitable solvent for example, an alcohol such as ethanol or methanol, tetrahydrofuran, N, N-dimethylformamide, or the like
- a suitable base for example, sodium ethoxide, potassium A malonic ester such as getyl malonate was reacted at 25 to 100 ° C for 2 to 24 hours in the presence of ter-butoxide, potassium hydroxide, etc., to give the general formula (54).
- a suitable solvent for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran, etc.
- an appropriate silver catalyst for example, an alkyl halide using silver oxide, silver carbonate, etc., for example,
- methyl iodide or an aralkyl halide such as 4-methoxybenzyl chloride
- a compound represented by the general formula (54) is dissolved in a suitable solvent such as benzene, toluene, chloroform, methylene chloride, tetrahydrofuran, or the like in a borate such as tetramethyl oxonium borate.
- a suitable solvent such as benzene, toluene, chloroform, methylene chloride, tetrahydrofuran, or the like
- a borate such as tetramethyl oxonium borate.
- the compound represented by the general formula (55) in which R is halogen, V is methylene, and T 1 is a hydroxyl group is represented by the following scheme It can also be synthesized by the method shown in 7.
- R 1 and R 2 represent as described above, and hal. Represents a halogen atom.
- a compound represented by the general formula (56) is added to a suitable solvent such as dimethyl sulfoxide, acetone, Tonitrile, acetic acid, water, or these ⁇
- nitrite for example, sodium nitrite or a nitrite, for example, t-butyl nitrite and the like
- a halide for example, potassium chloride, bromide Potassium or copper halide (I or II) such as copper chloride, copper bromide or copper iodide is reacted at 20 to 50 ° C for 1 to 8 hours to obtain a compound represented by the general formula (57).
- the compound represented by the formula (1) is dissolved in a suitable solvent such as ethanol, methanol, isopropanol, water, or a mixed solution thereof using a suitable reducing agent such as sodium borohydride, and It can be synthesized by reduction at 00 ° C.
- a suitable solvent such as ethanol, methanol, isopropanol, water, or a mixed solution thereof using a suitable reducing agent such as sodium borohydride, and It can be synthesized by reduction at 00 ° C.
- the compound represented by the general formula (55) can be obtained by adding a compound represented by the general formula (56) to a suitable solvent such as dimethyl sulfoxide, acetonitrile, acetic acid, water, or a mixture thereof.
- a suitable solvent such as dimethyl sulfoxide, acetonitrile, acetic acid, water, or a mixture thereof.
- a suitable nitrite for example, sodium nitrite or a nitrite, for example, t-butyl nitrite
- a halide for example, potassium chloride, bromide Or copper halide (I or II), for example, copper chloride, copper bromide, or copper iodide, may be reacted at 0 to 50 ° C. for 0.5 to 2 hours to obtain directly.
- the compound represented by the general formula (56) is a compound represented by the general formula (10) in which R is a nitrogen group, V is methylene, and T 1 is a hydroxyl group.
- the compound represented by the formula (58) is added to a suitable solvent such as ethanol, methanol, acetic acid or a mixed solution thereof in the presence of a suitable catalyst such as palladium carbon, platinum oxide or the like. It can be obtained by hydrogenation at 0 ° C under normal pressure to 5 atm (507 KPa) for 2 to 24 hours (Scheme 8). ⁇
- the compound represented by the general formula (5 6) has the general formula (5 8) indicates the compound in a suitable solvent such as ethanol , Methanol, acetic acid, hydrochloric acid, water, or a mixed solution thereof, and a suitable reducing agent, for example, reduced iron, tin, tin (II) chloride, titanium trichloride, etc. at 25 to 100 ° C. It can be obtained by reacting for 2 to 24 hours.
- a suitable solvent such as ethanol , Methanol, acetic acid, hydrochloric acid, water, or a mixed solution thereof
- a suitable reducing agent for example, reduced iron, tin, tin (II) chloride, titanium trichloride, etc. at 25 to 100 ° C. It can be obtained by reacting for 2 to 24 hours.
- Example 1 To a suspension of the compound of Example 2 (8.00 mg, 15.3 mol) in water (1 ml) was added 1 one
- Example 13 Using the compound of Example 13 (17.0 mg, 32.6 mol), 12.0 mg of the title compound was obtained as a yellow powder in the same manner as in Example 15. Yield 75% mp> 300. C.
- the obtained crystals were suspended in water and adjusted to pH 4 with 3 mol / L hydrochloric acid under ice-cooling.
- the precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 768 mg of the title compound as a colorless powder. Yield 39%.
- Example 18 A suspension of the compound of Example 18 (1.13 g, 1.97 mmol) in ethanol (30 ml) ⁇
- a 1 mol / L aqueous solution of lithium hydroxide (9.26 ml, 9.26 mmol) and then water (15 ml) were added to 40, and the mixture was stirred at room temperature for 4 hours and left to stand overnight. After stirring at 30 ° C for 16 hours, ice water was added to the reaction solution, and the insoluble matter was removed by filtration. Water was added to the obtained residue, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure. After the obtained powder was suspended in water (40 ml), a 1 mol / L aqueous solution of lithium hydroxide (9.26 ml, 9.26 mmol) was added, and the mixture was stirred at 50 ° C for 30 minutes.
- Example 23 Using the compound of Example 23 (100 mg, 200 imol), in the same manner as in Example 19, 87.0 mg of the title compound was obtained as a white powder. Yield 92%. mp 178-180. C.
- Example R Using the compound of Example 17 and by a method similar to that in Example 25, the compounds shown in Table 2 below were obtained.
- Example R Example R
- Acetic acid (30 ml) and then 10% palladium-carbon (206 mg) were added to a solution of the compound of Example 1 (2.06 g, 5.3 mmol) in ethanol (30 ml), and the mixture was subjected to a hydrogenation reaction at normal temperature and normal pressure. After completion of the reaction, the catalyst was removed by filtration using celite, and the solvent was distilled off. The obtained powder was suspended in acetonitrile (30 ml), and a solution of cupric chloride (1.23 g, 9.18 mmol) and 1- butyl nitrite (947 mg, 9.18 mmol) in acetonitrile (70 ml) was used. Was added. After stirring at room temperature for 8 hours, the mixture was heated under reflux for 8 hours.
- Example 35 Concentrated hydrochloric acid (5 ml) was added to a solution of the compound of Example 5 (740 mg, 1.97 mmol) in ethanol (50 ml), and the mixture was heated under reflux for 16 hours, equipped with a Dine Stark reflux device equipped with Molecular Sieves 4A. did. After cooling, the precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure to obtain 994 mg of the title compound as a pale brown powder. The yield was quantitative.
- Example 36 Using the compound of Example 36 and in the same manner as in Example 37, the compounds shown in Table 3 below were obtained.
- Example 37 Using the compound of Example 37 (44.0 mg, 94.2 inol) and in the same manner as in Example 19, 36.0 mg of the title compound was obtained as a white powder. Yield 82. m 180-182 ° C.
- Example 38 Using the compound of Example 38 (49.0 mg, 91.6 imol) and in the same manner as in Example 19, 21.0 mg of the title compound was obtained as a white powder. Yield 45 ° ⁇
- Example 39 Using the compound of Example 39 (81.0 mg, 150-11101) and in the same manner as in Example 19, 23.0 mg of the title compound was obtained as a white powder. Yield 30 ° mp 263-265 ° C (decomposition).
- Example 40 Using the compound of Example 40 (50.0 mg, 92.8 zmol) and in the same manner as in Example 19, 33.6 mg of the title compound was obtained as a white powder. Yield 69 ° mp 249-251 °. ⁇
- Example 36 Using the compound of Example 36 and in the same manner as in Example 25, the compounds shown in Table 4 below were obtained.
- [ 3 H] -AMPA final concentration: 5 nmol / L
- calcium thiosinate final concentration
- the test compound were added, and the mixture was incubated at 0 ° C for 30 minutes. After the reaction was stopped by suction filtration, the radioactivity on the filter was measured by liquid scintillation counting.
- the specific binding amount of [ 3 H] -AMPA was determined by subtracting the non-specific binding amount in the presence of glutamate (0.1 mmol / L) from the total binding amount.
- the [ 3 H] -AMPA binding in the absence of the test compound was defined as 100, and the concentration (IC 5 value) of the compound that reduced 50% was determined. This was converted to a Ki value, and the AMPA receptor of each compound was calculated. The ability to bind to was calculated. (Eur. J. Pharmacol., 1993, 246, 195-204)
- the 6-substituted heteroquinoline carboxylic acid derivative of the present invention is a novel compound having an excellent excitatory amino acid receptor, particularly an AMP A receptor antagonistic action of a non-NMDA receptor.
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Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/926,054 US6562839B1 (en) | 1999-02-26 | 2000-02-25 | 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both |
EP00905327A EP1156044B1 (en) | 1999-02-26 | 2000-02-25 | 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both |
DE60013257T DE60013257T2 (de) | 1999-02-26 | 2000-02-25 | In 6-stellung substituierte heterochinolincarbonsäure-derivate und ihre additionssalze und verfahren zur herstellung beider |
AT00905327T ATE274509T1 (de) | 1999-02-26 | 2000-02-25 | In 6-stellung substituierte heterochinolincarbonsäure-derivate und ihre additionssalze und verfahren zur herstellung beider |
AU26920/00A AU2692000A (en) | 1999-02-26 | 2000-02-25 | 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both |
CA002364754A CA2364754A1 (en) | 1999-02-26 | 2000-02-25 | 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5023999 | 1999-02-26 | ||
JP11/50239 | 1999-02-26 | ||
JP2000/41814 | 2000-02-18 | ||
JP2000041814A JP2000309585A (ja) | 1999-02-26 | 2000-02-18 | 6−置換ヘテロキノリンカルボン酸誘導体とその付加塩及びそれらの製造方法 |
Publications (1)
Publication Number | Publication Date |
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WO2000050416A1 true WO2000050416A1 (fr) | 2000-08-31 |
Family
ID=26390687
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2000/001077 WO2000050416A1 (fr) | 1999-02-26 | 2000-02-25 | Derives d'acide heteroquinolinecarboxylique 6-substitues et sels d'addition associes, et procedes de preparation de ces derives et de leurs sels |
Country Status (8)
Country | Link |
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US (1) | US6562839B1 (ja) |
EP (1) | EP1156044B1 (ja) |
JP (1) | JP2000309585A (ja) |
AT (1) | ATE274509T1 (ja) |
AU (1) | AU2692000A (ja) |
CA (1) | CA2364754A1 (ja) |
DE (1) | DE60013257T2 (ja) |
WO (1) | WO2000050416A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1372654A2 (en) * | 2001-04-06 | 2004-01-02 | SmithKline Beecham Corporation | Quinoline inhibitors of hyak1 and hyak3 kinases |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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GB0416730D0 (en) | 2004-07-27 | 2004-09-01 | Novartis Ag | Organic compounds |
GB0507298D0 (en) * | 2005-04-11 | 2005-05-18 | Novartis Ag | Organic compounds |
WO2012164085A1 (en) | 2011-06-03 | 2012-12-06 | Merz Pharma Gmbh & Co. Kgaa | Glycine b antagonists |
JP6786900B2 (ja) * | 2016-06-16 | 2020-11-18 | 日本製鉄株式会社 | 二方向性電磁鋼板及びその製造方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0489458A1 (en) * | 1990-12-05 | 1992-06-10 | MERCK SHARP & DOHME LTD. | Hydroxyquinolone derivatives |
WO1993010783A2 (en) * | 1991-11-29 | 1993-06-10 | Merck Sharp & Dohme Limited | Quinolone derivatives and their use as ampa and nmda receptor antagonists |
WO1999011632A1 (fr) * | 1997-09-01 | 1999-03-11 | Kyorin Pharmaceutical Co., Ltd. | Derives d'acide quinoxalinecarboxylique disubstitues en position 6,7-asymetrique, sels d'addition de ces derives, et procedes de preparation de ces derives et de ces sels |
Family Cites Families (7)
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FR640612A (fr) | 1926-08-02 | 1928-07-18 | Procédé et appareil pour produire des images, des inscriptions, des dessins, etc., sur des écrans couverts d'un enduit lumineux | |
FR818449A (fr) | 1937-02-27 | 1937-09-25 | Prise de courant formant interrupteur et réalisant la rupture en vase clos | |
FR2709489B1 (fr) * | 1993-08-31 | 1995-10-20 | Adir | Nouveaux dérivés de 2-(1H)-quinoléinone, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
DE4340045A1 (de) * | 1993-11-24 | 1995-06-01 | Basf Ag | Neue Chinoxaline und Arzneimittel daraus |
US5607928A (en) * | 1994-08-05 | 1997-03-04 | Zeneca Limited | Carbapenem derivatives containing a bicyclic ketone substituent and their use as anti-infectives |
DE19624808A1 (de) * | 1996-06-21 | 1998-01-02 | Basf Ag | Pyrrolylchinoxalindione, ihre Herstellung und Verwendung |
FR2750988B1 (fr) * | 1996-07-11 | 1998-09-18 | Adir | Nouveaux derives de 2-(1h)-quinoleinone, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
-
2000
- 2000-02-18 JP JP2000041814A patent/JP2000309585A/ja active Pending
- 2000-02-25 WO PCT/JP2000/001077 patent/WO2000050416A1/ja active IP Right Grant
- 2000-02-25 AU AU26920/00A patent/AU2692000A/en not_active Abandoned
- 2000-02-25 CA CA002364754A patent/CA2364754A1/en not_active Abandoned
- 2000-02-25 EP EP00905327A patent/EP1156044B1/en not_active Expired - Lifetime
- 2000-02-25 AT AT00905327T patent/ATE274509T1/de not_active IP Right Cessation
- 2000-02-25 US US09/926,054 patent/US6562839B1/en not_active Expired - Fee Related
- 2000-02-25 DE DE60013257T patent/DE60013257T2/de not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0489458A1 (en) * | 1990-12-05 | 1992-06-10 | MERCK SHARP & DOHME LTD. | Hydroxyquinolone derivatives |
WO1993010783A2 (en) * | 1991-11-29 | 1993-06-10 | Merck Sharp & Dohme Limited | Quinolone derivatives and their use as ampa and nmda receptor antagonists |
WO1999011632A1 (fr) * | 1997-09-01 | 1999-03-11 | Kyorin Pharmaceutical Co., Ltd. | Derives d'acide quinoxalinecarboxylique disubstitues en position 6,7-asymetrique, sels d'addition de ces derives, et procedes de preparation de ces derives et de ces sels |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1372654A2 (en) * | 2001-04-06 | 2004-01-02 | SmithKline Beecham Corporation | Quinoline inhibitors of hyak1 and hyak3 kinases |
EP1372654A4 (en) * | 2001-04-06 | 2007-10-03 | Smithkline Beecham Corp | QUINOLINE INHIBITORS OF HYAK1 AND HYAK3 KINASES |
Also Published As
Publication number | Publication date |
---|---|
EP1156044B1 (en) | 2004-08-25 |
CA2364754A1 (en) | 2000-08-31 |
JP2000309585A (ja) | 2000-11-07 |
EP1156044A1 (en) | 2001-11-21 |
US6562839B1 (en) | 2003-05-13 |
EP1156044A4 (en) | 2002-06-19 |
DE60013257T2 (de) | 2005-08-11 |
AU2692000A (en) | 2000-09-14 |
ATE274509T1 (de) | 2004-09-15 |
DE60013257D1 (de) | 2004-09-30 |
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