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WO2001046190A1 - Composes tricycliques et sels d'addition de ceux-ci - Google Patents

Composes tricycliques et sels d'addition de ceux-ci Download PDF

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Publication number
WO2001046190A1
WO2001046190A1 PCT/JP2000/009010 JP0009010W WO0146190A1 WO 2001046190 A1 WO2001046190 A1 WO 2001046190A1 JP 0009010 W JP0009010 W JP 0009010W WO 0146190 A1 WO0146190 A1 WO 0146190A1
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group
general formula
atom
compound
added
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PCT/JP2000/009010
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English (en)
Japanese (ja)
Inventor
Jun Asano
Yasuo Takano
Junichiro Uda
Tsuyoshi Anraku
Kazunori Fukuchi
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Kyorin Pharmaceutical Co., Ltd.
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Priority to AU22208/01A priority Critical patent/AU2220801A/en
Publication of WO2001046190A1 publication Critical patent/WO2001046190A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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 a tricyclic quinoline derivative which is effective as an excitatory amino acid receptor antagonist, in particular, a selective antagonist of ⁇ ⁇ ⁇ -NMDA receptor for AMP ⁇ receptor, for treating cerebral nerve cell disorders. It relates to an addition salt thereof and a pharmaceutical composition containing these compounds.
  • Glutamate an excitatory amino acid
  • Glutamate is a major excitatory transmitter in the vertebrate central nervous system and is known to be the most abundant amino acid in the brain.
  • excitatory neuronal death exciototoxicity
  • Glutamate receptors are roughly divided into ion channel receptors and G protein-coupled receptors. These ion channel receptors are further divided into NMDA (N-methyl-D-aspartate) receptors, n 0 n — divided into NMD A receptors.
  • NMDA N-methyl-D-aspartate
  • the latter non-NMDA receptor is composed of AMPA (amino-3-hydroxy-15-methyl-14-isoxazolylpropionic acid) receptor and KA (kainic acid). Classified into receptors.
  • drugs that have antagonism of AMP A receptor of n 0 n-NMD A receptor include drugs that have NMD A receptor antagonism (MK-80 1) has no side effects (learning, memory impairment, schizophrenia-like symptoms, etc.) ⁇ Neurosci. Bioobeh e v. R ev., 1992, 16, 13-24 Exp. T her 1958, 245, 969—974), and that a cranial nerve protective effect can also be expected by administration after ischemia (Scice, 1990). , 2 47, 5 71 1-5 74).
  • R 1 is a hydrogen atom, an alkyl group having 1 to about 10 carbon atoms, a hydroxyalkyl group having 1 to about 6 carbon atoms, a benzyl group which may have one or more substituents, A phenyl) ethyl group which may have one or more substituents, Represents a phenyl group which may have one or more substituents, and R 2 is a hydrogen atom, a trifluoromethyl group, a hydroxyalkyl group having 1 to about 6 carbon atoms, an aminoalkyl group having 1 to about 4 carbon atoms.
  • each alkyl group represents an alkane amide alkyl group having 1 to about 4 carbon atoms, a benzylthio group, a mercapto group, an alkylthio group having 1 to about 4 carbon atoms, an alkyl group having 1 to about 8 carbon atoms, and each R Represents an alkoxy group having 1 to about 4 carbon atoms, an alkyl group having 1 to about 4 carbon atoms, a halogen atom, and n represents an integer of 0 to 2], b) a bronchodilator effect and As the compound having an antiallergic action, a compound represented by the general formula (6) described in JP-A No. 03-264685:
  • R 1 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an aralkyl group, an aralkenyl group, a substituted or unsubstituted aryl group
  • R 2 represents an alkyl group, a cycloalkyl group, an alkoxy group.
  • alkyl group, an alkenyl group, Ararukiru group, Ararukeniru group represents an (C ⁇ 2) ⁇ - ⁇ ⁇ t (also the H et where substitution properly is unsubstituted aromatic heterocyclic group, n represents the 1-3 Represents an integer), (CH 2 ) n C 0 2 R 5 (wherein n represents as described above, R 5 represents the same meaning as R 2 ), and R 3 and R 4 are the same or different , Hydrogen atom, lower alkyl group, trifluoromethyl group, cycloalkyl group, halogen atom, hydroxy group, lower alkoxyl group, lower alkylthio group, nitro group, amino group, lower alkylamino group, lower alkanoylamino Group, Roiruamino group, a lower Arukanoiru group, the compound represented by represents a Aroiru group], c) JP 0 3 as a compound having a bone resorption inhibitory action
  • R 1 represents a hydrogen atom or a lower alkyl group
  • R 2 represents a hydrogen atom, a hydroxyl group, or a thiol group
  • R 3 represents a lower alkyl group or a lower alkoxyalkyl group
  • D a compound having an inhibitory action on the H + K + ATPase enzyme as represented by the general formula (8) described in JP-A-07-21593;
  • R i to R 4 are the same or different and each represents a hydrogen atom, a C 1-4 alkyl group, a C 1-6 alkoxy group, a phenyl group, a C 1-6 alkylthio group, a C 1-4 alkanol group, an amino group Represents a C 1-6 alkylamino group, a di C 1-6 alkylamino group, a halogen atom, a trifluoromethyl group, or a nitro group
  • R 5 to R 9 are the same or different and each represents a hydrogen atom, a C 1— 6 alkyl group, C 1-6 alkoxy group, C 1-6 alkyl
  • Compounds known as ruthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-6 alkanol, trifluoromethyl, and nitro I have.
  • R 1 represents a phenyl group, a phenyl group, a phenyl group (which may have a substituent)
  • R 2 and R 5 are the same or different and each represents a hydrogen atom, a halogen atom
  • 6 represents an alkyl group
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C 16 alkyl group, an amino group, an alkylamino group, or a di C 1-6 alkylamino group.
  • this compound also does not disclose a compound having a different substituent at the 7- or 8-position as an example, and has a structure different from that of the compound of the present invention. It is not described that it has any effect.
  • RR 2 is the same or different and represents a hydrogen atom, a C 1-6 alkyl group, a halogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a S 0 2 NR 4 R 5 (R 4 and R 5 are the same or different and represent a hydrogen atom, a C 1-6 alkyl group), C 0 R 6 (R 6 represents a C 1-6 alkyl), R 3 is a hydrogen atom, A C 1-6 alkyl group or a trifluoromethyl group), f) a compound represented by the general formula (11) described in WO93 / 20777;
  • R 2 is a hydrogen atom, a lower alkyl group, a formula—T-R 3 (where T represents a single bond or a lower alkylene group; 3 represents a mono or di-lower alkylamino group imidazolyl group)] one T- S (0) n- R 4 (wherein T represents as mentioned above, n represents 0, 1, 2, R 4 is lower alk kill group, a cycloalkyl group)] ,
  • T represents as mentioned above, n represents 0, 1, 2, R 4 is lower alk kill group, a cycloalkyl group
  • R 5 and R 6 are the same or different, and are a hydrogen atom, a lower alkyl group, a formula —T—R 3 (where T and R 3 are as described above), - ⁇ -S (0) n -R 4 (where T, R4, and n represent as described above)],
  • a 1 A 2 and A 3 are the same or different and represent C or N (however, at least one of A 1 , A 2 and A 3 represents N), A 4 and A 5 One represents C, the other represents N, and RR 2 is the same or different and is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C 1-4 alkyl group, a phenyl or fused benzo group, or an azide group.
  • Trifluoromethyl group NH 2 S 4 R 4 [R 4 represents a C 1-4 alkyl group, phenyl group, SO 2 NR 5 R 6 (R 5 and R 6 represent a hydrogen atom and a C 1-4 alkyl group, respectively.
  • R 3 represents a hydrogen atom, an alkyl group, an aromatic group, or a trifluoromethyl group; h) a compound represented by the general formula (13) described in WO96 / 105572; ,
  • R 1 represents a hydrogen atom, a C 1-5 alkyl group, a phenyl group, a pyridyl group, a phenyl group (these may have a substituent), and R 2 represents a hydrogen atom, a C 1-5 Represents an alkyl group, a C 3-8 dialkylaminoalkyl group, and R 3 represents a chlorine atom, a bromine atom, a trifluoromethyl group, Represents a cyano group or a nitro group; ring A represents a 5-membered heterocyclic ring containing 1-4 nitrogen atoms or 1-2 nitrogen atoms and one oxygen atom or sulfur atom; R 4 and R 5 represent The same or different, and represents a hydrogen atom, a C15 alkyl group, a C1-5 hydroxyshetyl group, or a phenyl group which may have a substituent, and T is a single bond or a C15 alkylene chain A)
  • R 1 R 2 are the same or different and each represents a hydrogen atom, a lower alkyl group-a lower alkoxy group, a nitro group, a trifluoromethyl group, an amino group, a halogen atom, a cyano group, one S (0) 2 NR 3 R 4 (R 3 and R 4 represent a lower alkyl group)], and all of e) to i) are tricyclic fused quinoxaline or tricyclic fused quinazoline
  • the compound of the present invention is a condensed quinoline represented by the general formula (1) and has a different structure. Also, the reported AMPA receptor antagonism is not sufficient.
  • RR 2 is the same or different and represents a hydrogen atom, a lower alkyl group.
  • [And RR 2 are the same or different in the formula, a hydrogen atom, a hydrocarbon, heterocyclic group, halogen atom, Shiano group, preparative Rifuruoromechiru group, nitro group, one 0 R a, - SR a, one S 0R a, single S ⁇ 2 R a , — S 0 2 NR a R b ,-NR a R — NR a C 0 R b , one NR a C ⁇ 2 R b , one C0R a , one C 0 2 R a , one C ⁇ NR a R b (where R a and R b are the same or different and represent a hydrogen atom, a hydrocarbon, a heterocyclic group) or And R 3 , R 4 , R 5 , and R 6 are the same or different, and represent a hydrogen atom, a hydrocarbon, a heterocyclic group, a halogen atom, a cyano group, a
  • the present invention is directed to a glutamate receptor antagonism, which is considered to be a cause of memory disorders and dementia caused by the above-mentioned diseases and selective cell death, and in particular, has a high affinity for non-NMD A receptor AMP A receptor. And a compound having a selectivity and a protective effect on brain nerve cells. Disclosure of the invention
  • the present inventors aimed at the development of a novel therapeutic agent for cerebral neuronal damage and selected an excitatory amino acid receptor antagonist effective for the treatment of cerebral neuronal damage, in particular, selection of n 0 n-NMDA receptor for AMP A receptor
  • an excitatory amino acid receptor antagonist effective for the treatment of cerebral neuronal damage, in particular, selection of n 0 n-NMDA receptor for AMP A receptor
  • the tricyclic compound of the present invention and its addition salt have excellent AMP A receptor antagonistic activity.
  • V represents an oxygen atom, —NH—
  • W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group.
  • Q represents a nitro group or a trifluoromethyl group
  • X is an oxygen atom, or general formula (4) lo
  • T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents
  • a compound in which X is an oxygen atom or in the general formula (4), T is a methyl group is exemplified. More preferably, a compound in which R is represented by the general formula (2) and E in the general formula (2) is represented by the general formula (3) is exemplified.
  • the compound of the present invention is, for example, a compound represented by the general formula (1) produced by the following production method:
  • the compound is used without solvent or in a suitable solvent such as toluene, anisol, tetrahydrofuran, acetic acid, etc., using a suitable acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or a mixed acid thereof. At 0 to 120 ° C. for 2 to 72 hours.
  • R and R ⁇ Q represent as described above
  • solvent or an appropriate solvent such as water, diluted hydrochloric acid, acetic acid, ethanol, tetrahydrofuran, 1,4-dioxane, N, N—
  • a suitable nitrite such as sodium nitrite or potassium nitrite, or a suitable nitrite such as t-butyl nitrite or nitrite.
  • the compound represented by the general formula (18a) has the general formula (19a)
  • R, R 1 Q represents a as described above, R 2 is a lower alkyl group, also optionally Ararukiru group substituted
  • a compound represented by, for example, water It can be synthesized by reacting with hydrazine or a salt thereof in methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, etc. at 0 to 120 ° C for 1 to 12 hours.
  • X is the general formula (4), C ⁇ .Y is a double bond, Y is an oxygen atom, and C2 z is General formula (17b) in which a single bond and Z is —NH—
  • R, R 1 Q and T represent the same as described above
  • a suitable solvent such as benzene, tetrahydrofuran, 1,4-dioxane, ⁇ , ⁇ -dimethylformamide, etc.
  • a suitable organic base such as triethylamine, ⁇ , diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undesen 7-ene or a mixture thereof. It can be synthesized by reacting with nylphosphoryl azide at 20 to 120 ° C for 1 to 12 hours.
  • R, ⁇ R 2 , Q and T are as described above
  • a suitable solvent such as ethanol, methanol, tetrahydrofuran, water or a mixture thereof. It can be synthesized by hydrolysis for 0.5 to 12 hours at 0 to 100 ° C. in the presence of an alkali, for example, sodium hydroxide, hydroxylating power or the like.
  • the compound represented by the general formula (21) can be prepared by converting the compound represented by the general formula (19a) into a suitable solvent such as benzene, chloroform, methylene chloride, 1,4-dioxane, N, N -In dimethylformamide, etc., in the presence of non-basic or suitable organic bases, such as triethylamine, pyridine, 1,3-collidine, etc., with methanesulfonic acid chloride or maleic sulfonic anhydride. After reacting for 1 to 12 hours at 20 to 120 ° C, the general formula (22)
  • X is an oxygen atom
  • d is a single bond
  • Y is a lower alkyl group
  • C is a double bond.
  • the general formula suitable solvent a compound represented by (1 7 a) For example water, died some evening In the presence of a suitable inorganic or organic base, such as sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, triethylamine, etc., in ethanol, methanol, methanol, etc. After reacting at 120 ° C for 2 to 10 hours, the general formula (23)
  • X is an oxygen atom
  • a suitable solvent such as water, diluted hydrochloric acid, acetic acid, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide
  • a suitable nitrite for example, sodium nitrite, nitrite rim, or a suitable nitrite, for example, t-butyl nitrite, n-butyl nitrite, etc. It can be synthesized by reacting at 0 to 120 ° C for 10 minutes to 24 hours.
  • R, R 2 and Q are as described above
  • a solvent-free or suitable solvent such as water, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, etc.
  • a solvent-free or suitable solvent such as water, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, etc.
  • hydrazine or a salt thereof at 0 to 120 ° C. for 1 to 24 hours.
  • R is a general formula (2)
  • E is the general formula (3)
  • V is an oxygen atom.
  • a suitable solvent such as chloroform, methylene chloride, ethyl acetate, acetonitrile, Benzene, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, In N-dimethylacetamide, dimethylsulfoxide, etc., in the presence of an abasic or a suitable organic base, for example, triethylamine, pyridine, etc., the general formula (24)
  • W represents as described above, and D represents an amino group, a carboxyl group, an amide group, a lower alkoxycarbonyl group, and a carbonylazide group. It can also be synthesized by converting to ester or carbamic acid chloride and reacting in the same manner as in the general formula (24).
  • W is a carboxyl group or a phosphono group.
  • a solvent for example, water, ethanol, 1,4-dioxane, etc.
  • a suitable alkali for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.
  • X is the general formula (4)
  • T is a hydrogen atom
  • T 1 represents an aralkyl group which may have a substituent
  • a solvent or a suitable solvent for example, toluene, 0 to 120 ° ⁇ in anisol, tetrahydrofuran, acetic acid, etc. in the presence of a suitable acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, or a mixed acid thereof. It can be synthesized by reacting for 72 hours.
  • CY is a single bond
  • Z is a nitrogen atom
  • R, Q, X, and Y represent as described above, and R 4 represents a hydrogen atom or a lower alkyl group
  • a suitable solvent such as water, acetic acid, ethanol, or methanol.
  • a suitable acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, or a mixed acid thereof in tetrahydrofuran, etc., at a temperature of 20 to 100 ° (2 to 72 hours).
  • a suitable acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, or a mixed acid thereof in tetrahydrofuran, etc.
  • R, R 1 Q represents a as described above, R 5 is a lower alkyl group, an optionally Ararukiru group which may have a substituent
  • a compound represented by In a suitable solvent for example, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • a suitable organic base for example, triethylamine, diisopropylethylamine or these In the presence of a mixture of the general formula (27)
  • a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, N-
  • a suitable inorganic or organic base such as sodium ethoxide, sodium methoxide, sodium hydride, or potassium butoxide, in dimethylacetamide, etc. It can be synthesized by cyclization at 70 ° (for 2 to 24 hours.
  • a compound represented by the general formula (26) is dissolved in a suitable solvent such as acetonitrile, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, etc.
  • a suitable solvent such as acetonitrile, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, etc.
  • a base for example, ⁇ , ⁇ -diisopropylethylamine, 1,8-diazabicyclo [54.0] indesene-7-ene or a mixture thereof, represented by the general formula (27)
  • Compound at 20 to 120 ° (0.5 to 6 hours at 3) It can also be synthesized by reacting.
  • the compound represented by the general formula (19a) can be obtained by converting the compound represented by the general formula (26) into a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, In the presence of a suitable inorganic or organic base, such as sodium methoxide, sodium methoxide, sodium hydride, potassium t-butoxide, etc. in N-dimethylacetamide, etc. Equation (28)
  • R 2 represents the same as described above, and can be synthesized by reacting with a dialkyl malonate at 20 to 170 ° C. for 2 to 24 hours.
  • R, R 1 Q represents a as described above
  • suitable solvents represented by, for example ethanol, methanol, Te Louisi Dorofu run, N, N-dimethyl formamidine de, N, N-
  • a suitable inorganic or organic base such as sodium ethoxide, sodium methoxide, sodium hydride, or potassium t-butoxide in dimethylacetamide or the like, the general formula It can also be synthesized by reacting with a dialkyl malonate represented by (28) at 20 to 170 ° C for 2 to 24 hours.
  • the anthranilic acid represented by the general formula (30) is converted into a suitable solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc.
  • R 1 represents as described above
  • a general formula (31) which is converted to a suitable solvent, for example, acetonitrile , Tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc., suitable inorganic or organic bases such as sodium carbonate, carbonated carbonate, sodium hydroxide. (33) 5-hal. (33) in the presence of sodium hydride, sodium hydride, triethylamine, etc.
  • a suitable solvent for example, acetonitrile , Tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • suitable inorganic or organic bases such as sodium carbonate, carbonated carbonate, sodium hydroxide. (33) 5-hal. (33) in the presence of sodium hydride, sodium hydride, triethylamine, etc.
  • the anthranilic acid represented by the general formula (30) is converted to a suitable carbonyl in a solvent-free or suitable solvent such as benzene, ether, dioxane, acetonitrile, N, N-dimethylformamide and the like.
  • a solvent-free or suitable solvent such as benzene, ether, dioxane, acetonitrile, N, N-dimethylformamide and the like.
  • a suitable solvent for example, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • a suitable inorganic or organic base such as sodium carbonate, potassium carbonate
  • R and R 5 are as defined above
  • a suitable solvent such as acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethylacetamide, etc.
  • an organic base such as triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] indene-17-ene, etc., it is represented by the general formula (27).
  • reaction After reacting with the compound to be prepared, in a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc., a suitable inorganic or organic base such as sodium The reaction is carried out at 20 to 170 ° C for 2 to 24 hours in the presence of rhodium ethoxide, sodium methoxide, sodium hydride, potassium hydroxide, etc. That.
  • a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • a suitable inorganic or organic base such as sodium
  • the compound represented by the general formula (19b) can be obtained by converting the compound represented by the general formula (35) into a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, In the presence of a suitable inorganic or organic base in N-dimethyl acetate, such as sodium methoxide, sodium methoxide, sodium hydride, potassium butoxide, etc. Can also be synthesized by reacting with a dialkyl malonate represented by the general formula (28) at 20 to 170 ° C for 2 to 24 hours.
  • a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N
  • a suitable inorganic or organic base in N-dimethyl acetate such as sodium methoxide, sodium methoxide, sodium hydride, potassium butoxide, etc.
  • a dialkyl malonate represented by the general formula (28) at 20 to 170 ° C
  • R and Q represent as described above
  • an appropriate solvent for example, ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, N—
  • a suitable inorganic or organic base such as sodium ethoxide, sodium methoxide, sodium hydride, or potassium monobutoxide, in dimethyl acetate amide or the like, the compound represented by the general formula (2 It can also be synthesized by reacting with dialkyl malonate represented by 8) at 20 to 170 ° ⁇ for 2 to 24 hours.
  • the compound represented by the general formula (35) can be synthesized by esterifying the anthranilic acid represented by the general formula (30) by a known method.
  • an anthranilic acid represented by the general formula (30) is dissolved in a solvent or in a suitable solvent such as benzene, tetrahydrofuran, 1,4-dioxane, or the like, and a suitable acid such as hydrochloric acid, sulfuric acid, ⁇ -toluene.
  • a suitable dehydrating agent for example, molecular sieves 4 ⁇
  • R is the general formula (2)
  • E is a hydroxyl group.
  • a commercially available or synthesizable general formula (38) is converted into a suitable solvent such as ether, tetrahydrofuran or the like in a suitable inorganic or organic base, such as lithium t-butoxide, sodium hydride, or the like.
  • a suitable solvent such as ether, tetrahydrofuran or the like
  • a suitable inorganic or organic base such as lithium t-butoxide, sodium hydride, or the like.
  • a suitable solvent for example, water, diluted hydrochloric acid, acetic acid, tetrahydrofuran, or a mixture thereof, using a suitable reducing agent, for example, titanium trichloride, at 20 to 80 ° C for 10 minutes to 6 minutes.
  • a suitable alkali such as potassium hydroxide, sodium hydroxide, lithium hydroxide, or the like
  • an alcohol represented by the general formula (37) using a suitable oxidizing agent such as manganese dioxide.
  • the general formula (42) which can be obtained or synthesized can be obtained by converting a general formula (42) without a solvent or an appropriate solvent, for example, methylene chloride, chloroform, tetrahydrofuran, etc., in an abasic or an appropriate base such as pyridine or triethylamine.
  • a solvent or an appropriate solvent for example, methylene chloride, chloroform, tetrahydrofuran, etc.
  • an abasic or an appropriate base such as pyridine or triethylamine.
  • acetic acid or acetyl chloride acetylation is carried out at 10 to 120 ° C. for 1 to 24 hours to give a general formula (43), which is then converted into a suitable solvent such as nitromethane, acetic acid, or the like.
  • nitrifying agent such as concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate, etc.
  • sulfuric acid sulfuric acid, etc.
  • a suitable solvent for example, water, acetone, methylene chloride, benzene or a mixture thereof
  • a suitable oxidizing agent for example, potassium permanganate, periodate, etc. The reaction is carried out at 0 ° C.
  • the compound represented by the general formula (25) is a compound represented by the general formula (46)
  • R and Q represent the same as described above, and R 6 and R 7 may be the same or different and represent a lower alkyl group, a lower alkoxyl group, or a ring formed by R 6 BR 7
  • the compound of formula (I) is converted into a suitable solvent, for example, chloroform, methylene chloride, ethyl acetate, acetonitril, benzene, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, etc.
  • a suitable palladium catalyst for example, tetraxtriphenylphosphine palladium (0), diphenylphosphinofluorophenyldichloropalladium (II), and a suitable inorganic or organic base such as sodium carbonate;
  • a suitable inorganic or organic base such as sodium carbonate
  • potassium carbonate triethylamine, N, N-diisopropylethylamine, etc.
  • R 4 , X, and Y represent the same as described above, and R 8 represents a bromine atom or an iodine atom
  • R 8 represents a bromine atom or an iodine atom
  • R and Q represent as described above, and R 9 represents a bromine atom or an iodine atom.
  • a compound represented by the formula (I) is dissolved in a suitable solvent, for example, chloroform, methylene chloride, ethyl acetate, acetonitrile, In benzene, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, etc., a suitable palladium catalyst, such as tetraxtriphenylphosphine palladium (0), diphenylphosphinophenylenedichloro Palladium (II) and other suitable inorganic or organic bases, such as sodium carbonate, potassium carbonate, potassium acetate, triethylamine, N, N-diisopropylethylamine, etc.
  • a suitable solvent for example, chloroform, methylene chloride, ethyl acetate, aceton
  • the available or synthesizable general formula (50) is converted into a suitable solvent such as nitromethane, acetic acid, sulfuric acid, etc., and a suitable nitrating agent such as concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate, etc.
  • a suitable solvent such as nitromethane, acetic acid, sulfuric acid, etc.
  • a suitable nitrating agent such as concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate, etc.
  • the reaction is carried out at —10 to 80 ° ⁇ for 0.5 to 2 hours to obtain a general formula (51), which is free of a solvent or an appropriate solvent, for example, methylene chloride, chloroform, tetrahydrofuran.
  • acetic acid or in the presence of an appropriate base for example, pyridin, triethylamine or the like
  • an appropriate base for example, pyridin, triethylamine or the like
  • acetic anhydride or acetyl chloride at —10 to 80 ° C for 0.5 to 6 hours.
  • R 3 is an ethyl group
  • Y is a hydrogen atom
  • X is the general formula (4).
  • ethylcyanoglyoxylate—2-oxime (52) is dissolved in a suitable solvent, for example, methanol, ethanol, tetrahydrofuran, etc., in a suitable palladium catalyst, for example, palladium.
  • a suitable solvent for example, methanol, ethanol, tetrahydrofuran, etc.
  • palladium catalyst for example, palladium.
  • an appropriate solvent such as acetonitrile, tetrahydrofuran, etc.
  • the reaction is carried out with an appropriate trialkyl orthoformate, for example, triethyl orthoformate, at 20 to 100 ° C for 0.5 to 4 hours.
  • an amide represented by the general formula (22) is reacted with an amide represented by the general formula (22) in an appropriate solvent, for example, acetonitril, tetrahydrofuran or the like, at a temperature of 20 to 100 ° C for 0.5 to 4 hours.
  • an appropriate solvent for example, acetonitril, tetrahydrofuran or the like
  • a suitable solvent such as water, diluted hydrochloric acid, acetic acid or a mixture thereof, a suitable nitrite such as sodium nitrite or potassium nitrite and a suitable metal halide such as Daiichi bromide are used. Using copper, calcium iodide, etc. And reacting at 0 to 80 ° C for 0.5 to 2 hours.
  • Trifluoroacetic acid (0.5 ml) was added to a solution of the compound of Example 11 (8.0 mg, 0.0217 mmo 1) in anisol (0.5 ml), and the mixture was added at room temperature for 4 hours. Stirred. The reaction solution was concentrated under reduced pressure, diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with diisopropyl ether, and dried to give 6.30 mg of the title compound as a brown powder. Yield quantitative.
  • Example 5 Using the compound of Example 5 (500 mg, 1.37 mmol) and (4-di (2-propoxy) phosphoryl) benzoyl azide (2.13 g, 6.85 mmol) By a method similar to that in Example 13, 70 mg of the title compound was obtained as a pale yellow powder. Yield 7.9%. Mp.: 204-206 ° C.
  • Example 14 Using the compound of Example 14 (15.0 mg, 0.0231 mm 01), 11.5 mg of the title compound as a white powder was obtained in the same manner as in Example 8. Yield 88%.
  • the aqueous layer was made weakly acidic with 1 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was washed with diisopropyl ether and dried to give 250 mg of the title compound as a tan powder. Yield 32%.
  • 1,8-diazabicyclo [4,5,0] indene 7-ene (0.03000 ml, 0.210 mmol) was added, and the mixture was heated under reflux for 1 hour. After cooling, the reaction solution was dried under reduced pressure, IN hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed successively with a mixed solution of disopropyl ether: methylene chloride (10: 1) and getyl ether, and dried to obtain 15.0 mg of the title compound as a brown powder. Yield 30%.
  • Example 12 Using the compound of Example 12 (200 mg, 0.489 mmo 1), in the same manner as in Reference Example 3, 18.5 mg of the title compound was obtained as a yellow powder. Yield 98%.
  • REFERENCE EXAMPLE 14 The water (1) of the compound (9. ⁇ 0: 39.4 mm 0 1) of 4 To this suspension was added potassium permanganate (12.4 g, 78.7 mm 01), and the mixture was heated under reflux for 8 hours. The reaction solution was filtered while hot using celite, and the residue was washed with hot water. After cooling, the filtrate and the washings are combined, adjusted to pH 1 with 6 ml of 1/1 hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water and dried to give 5.0 g of the title compound as a pale brown powder. 9 g were obtained. Yield 50%.
  • Reference Example 15 A water (200 ml) solution of the compound (33.2 g, 128 mm 01) and sodium hydroxide (15.4 g, 3885 mmol) was prepared. The mixture was heated under reflux for 4 hours. After cooling, the pH was adjusted to pH 4 with 6 ml of 1/1 hydrochloric acid, and the precipitated crystals were collected by filtration and dried to give 20.5 g of the title compound as a dark brown powder. Yield 74%.
  • the obtained powder was dissolved in water and adjusted to pH 4 with 3 m 0 1 1 hydrochloric acid.
  • the precipitated crystals were collected by filtration, washed with water, and dried to give 1.32 g of the title compound as a pale brown powder. Yield 38%.
  • Reference Example 27 1,4 of compound (1.00 g, 4.26 mmol) —Dioxane (50 ml) solution, bispinacol borane (1.19 g, 4.69 mmol), diphenylphosphine phenolic sencyclochloropalladium: methylene chloride (1: 1) complex (1774) mg, 0.213 mm 01) and lithium acetate (1.26 g, 12.8 mm o 1) were added, and the mixture was stirred at 100 ° C for 6 hours. After cooling, the reaction solution was added to a hot-water form, heated in a warm bath, filtered while hot, and insoluble materials were removed by filtration.
  • Reference Example 29 A solution of the compound of Example 9 (1.00 g, 5.91 mmol) in 6 N hydrochloric acid (10 ml) was added at ⁇ 20 ° C. to sodium nitrite (2.04 g). g, 29.6 mmol) in water (10 ml) was added dropwise and stirred at the same temperature for 15 minutes. The reaction solution was heated to 0 ° C., and a solution of potassium iodide (9.8 lg, 59.lmmol) in water (20 ml) was added dropwise. After the addition, the mixture was stirred at the same temperature for 5 hours.
  • the reaction solution was heated to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate.
  • the ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was recrystallized from a mixed solution of ethyl propyl isopropyl ether to give 883 mg of the title compound as a white powder. Yield 53%.
  • Rats selectively bind to adjust crude Shinaputoso Ichimu membrane preparation from cerebral cortex AMP A receptor [3 H] - AMP A (final concentration: 5 nm o 1/1), Chioshian oxide Li um ( (Final concentration: 100 mmol / l) and the test compound were added, and the mixture was incubated at 0 ° C for 30 minutes. After terminating the reaction by suction filtration, the radioactivity on the filter was measured with a liquid scintillation counter. The specific binding of [ 3 H] -AMPA was determined by subtracting the non-specific binding in the presence of glutamate (1 mm 0 1/1) from the total binding.
  • the tricyclic compound of the present invention is a novel compound having an excellent antagonism of the excitatory amino acid receptor, particularly the non-NMDA receptor against the AMP A receptor.
  • These compounds of the present invention inhibit the binding of excitatory amino acids that cause neuronal cell death to AMP A receptors, and are therefore effective for treating excitatory amino acids-induced cerebral nerve cell damage and the like.

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Abstract

L'invention concerne des composés possédant des propriétés antagonistes des récepteurs d'acides aminés excitateurs, notamment le récepteur de AMPA. L'invention concerne particulièrement des composés tricycliques correspondant à la formule générale (1), ainsi que des sels d'addition de ceux-ci. Elle concerne encore des médicaments contenant ces composés ou sels en tant que principe actif. Dans la formule (1), R représente halogéno ou un groupe représenté par la formule générale (2) [où A représente azote ou =CH-, et E représente hydroxyle ou un groupe correspondant à la formule générale (3) (dans laquelle V représente oxygène ou -NH-, W représente halogéno, carboxyle -ou analogue-)], Q représente nitro ou trifluorométhyle, X représente oxygène ou un groupe correspondant à la formule générale (4) (dans laquelle R représente hydrogène alkyle inférieur, aralkyle ou analogue), Y représente hydrogène, alkyle inférieur, ou oxygène et Z représente -NH- ou analogue.
PCT/JP2000/009010 1999-12-22 2000-12-20 Composes tricycliques et sels d'addition de ceux-ci WO2001046190A1 (fr)

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WO2003097641A2 (fr) * 2002-05-21 2003-11-27 Novartis Ag Derives 1h-imidazo[4,5-c]quinoline servant au traitement de maladies dependant de proteines kinases
EP1203766A3 (fr) * 2000-11-06 2004-12-08 Texas Biotechnology Corporation Dérivés d'acides carboxyliques inhibant la liaison des intégrines à leurs récepteurs
JP2008535831A (ja) * 2005-04-01 2008-09-04 コーリー ファーマシューティカル グループ，インコーポレーテッド 環閉鎖および関連する方法および中間体
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
WO2023185811A1 (fr) * 2022-03-29 2023-10-05 首药控股(北京)股份有限公司 Nouveau composé hétérocyclique

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US7812038B2 (en) 1999-05-07 2010-10-12 Encysive Pharmaceuticals, Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
EP1203766A3 (fr) * 2000-11-06 2004-12-08 Texas Biotechnology Corporation Dérivés d'acides carboxyliques inhibant la liaison des intégrines à leurs récepteurs
WO2003097641A3 (fr) * 2002-05-21 2004-05-06 Novartis Ag Derives 1h-imidazo[4,5-c]quinoline servant au traitement de maladies dependant de proteines kinases
US7998972B2 (en) 2002-05-21 2011-08-16 Novartis Ag 1H-imidazo[4,5-c]quinoline derivatives in the treatment of protein kinase dependent diseases
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US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
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US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
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US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
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US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
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US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
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