HK1056868B - Novel dicarboxylic acid derivatives - Google Patents

Description

Novel dicarboxylic acid derivatives

Technical Field

The present invention relates to pharmaceutically acceptable 2-amino-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic acid derivatives. Specifically, the present invention relates to a novel 2-amino-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic acid derivative having a therapeutic and/or prophylactic effect on: schizophrenia, anxiety and related diseases, psychomedical diseases such as depression, bipolar disorder and epilepsy, and neurological diseases such as drug-dependent diseases, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia with myotonia, cerebral ischemia, cerebral insufficiency, spinal cord disorders and head disorders.

Background

In recent years, it has been discovered through cloning of glutamate receptor genes that there are a surprising number of subtypes in glutamate receptors. At present, glutamate receptors are roughly classified into two types, namely "ionotropic (ionotropic) receptors having an ion channel-type structure" and "metabotropic (metabropic) receptors conjugated to G-proteins" (Science, 258, 597-603, 1992). Furthermore, ionotropic receptors are divided pharmacologically into 3 types, including NMDA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and 2-carboxymethyl-3-isopropenylproline (Sciense, 258, 597-.

Metabotropic glutamate receptors are pharmacologically classified into 3 groups. Group 2 (mGluR2/mGllur3) among these bind to adenine cyclase and inhibit forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmacol. Sci., 14, 13(1993)), so compounds that antagonize metabotropic glutamate receptors should be effective in the treatment or prevention of acute and chronic psychiatric and neurological disorders.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide an agent for antagonizing group 2 metabotropic glutamate receptors, which has a therapeutic and/or prophylactic effect on the following diseases, including: schizophrenia, anxiety and related diseases, psychiatric diseases such as depression, bipolar disorder and epilepsy, and neurological diseases such as drug-dependent diseases, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia with myotonia, cerebral ischemia, cerebral insufficiency, spinal cord disorder and head disorder.

The present inventors have conducted intensive studies on 2-amino-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic acid derivatives and ester derivatives thereof, and as a result, have found novel 2-amino-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic acid derivatives and ester derivatives thereof having an effect on group 2 metabotropic glutamate receptors, and have completed the present invention.

One of the present invention is a 2-amino-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic acid derivative represented by the following formula [ I ] and a pharmaceutically acceptable salt thereof,

in the formula, R¹And R²The same or different represent a hydrogen atom, C_1-10Alkyl, phenyl C_1-6An alkyl group;

R³and R⁴When R is³R being hydroxy⁴Is a hydrogen atom; or R³And R⁴Together form a C-C single bond.

The present invention also relates to a pharmaceutical preparation comprising as an active ingredient a compound of the formula [ I ] or a pharmaceutically acceptable salt thereof, particularly a therapeutic and/or prophylactic agent for a psychiatric disorder and/or a neurological disease, and a group 2 metabotropic glutamate receptor antagonist.

Another invention of the present invention is the use of the compound of the formula [ I ] and pharmaceutically acceptable salts thereof for the preparation of group 2 metabotropic glutamate receptor antagonists and therapeutic and/or prophylactic agents for psychiatric disorders and/or neurological diseases.

The terms used in the present invention are defined as follows. In the present invention, "Cn to m" means that the group bonded thereto has n to m carbon atoms.

C_1-10Alkyl represents a straight or branched chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, 1-ethylpropyl, hexyl, isohexyl, 2-ethylbutyl, heptyl, isoheptyl, octyl, nonyl, decyl, and the like.

C_3-8Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

C_3-8Cycloalkyl radical C_1-6Examples of the alkyl group include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group and the like.

Aryl is phenyl, naphthyl, etc., preferably phenyl. Aryl radical C_1-6Alkyl represents a straight or branched chain C substituted by at least 1 or more aryl groups, preferably phenyl groups_1-6Alkyl groups such as benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl and the like.

C_1-6Alkoxy radical C_1-6The alkyl group having C_1-6Alkoxy and C_1-6Alkyl complex morphology. Wherein, C_1-6Alkoxy means straight or branched chain alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, and the like. C_1-6Alkoxy radical C_1-6Examples of alkyl groups include: methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl, pentyloxyethyl, isopentyloxyethyl and the like.

C_1-6Hydroxyalkyl denotes C substituted by at least 1 hydroxy group_1-6An alkyl group. C_1-6Examples of hydroxyalkyl groups include 2-hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl and the like.

C_1-6Alkylthio group C_1-6The alkyl group having C_1-6Alkylthio radicals and C_1-6Alkyl complex morphology. Wherein, the alkylthio group means straight-chain or branched alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, isopentylthio and the like. C_1-6Alkylthio group C_1-6Examples of the alkyl group include methylthiomethyl group, 2-methylthioethyl group and the like.

C_1-6Mercaptoalkyl represents C substituted by at least 1 mercapto group_1-6An alkyl group. Thus, C_1-6Examples of mercaptoalkyl groups include 2-mercaptoethyl, 3-mercaptopropyl, 2, 3-dimercaptopropyl and the like.

Examples of the pharmaceutically acceptable salts in the present invention include salts with inorganic acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and benzenesulfonic acid, salts with amines such as trimethylamine and methylamine, and salts with metal ions such as sodium ions and potassium ions.

Formula [ I]There are 4 or 5 asymmetric carbon atoms in the compound. Thus, the compounds of the present invention exist as mixtures of enantiomers, optically active forms, enantiomers, racemates, and the like. That is, the compounds of the present invention include all compounds represented by the formula [ I]An enantiomeric mixture and a diastereomeric mixture of the compound shown, such as an optically active compound, an enantiomer or a racemate thereof. Preferably of the formula [ I]In R³Is hydroxy, R⁴A compound which is a hydrogen atom. More preferably of the formula [ I]In R¹、R²And R⁴Is a hydrogen atom, R³Compounds which are hydroxy, particularly preferably (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-hydroxy-bicyclo [3.1.0]Hexane-2, 6-dicarboxylic acid. The compound of the present invention may exist in the form of various solvates, but a hydrate is particularly preferable from the viewpoint of applicability as a pharmaceutical.

In addition, formula [ I]In R¹And R²When none of 1 or 2 of them is a hydrogen atom, the ester derivative is not affected by group 2 metabotropic glutamate receptors. However, the ester derivative is hydrolyzed in vivo and converted into group 2 metabolic formsA glutamate receptor. Therefore, the ester derivative has a function as a prodrug and is a very useful compound.

Formula [ I]The compound can be prepared by the following method (in the following reaction scheme, R¹、R²、R³And R⁴Same as above)

Step 1: compound (1) is reacted with a trifluoromethanesulfonylating agent such as trifluoroacetic anhydride, N-phenyl-bis (trifluoromethanesulfonimide) or the like in an inert solvent in the presence of a base to give compound (2).

Examples of the inert solvent include hydrocarbon solvents such as benzene, toluene and hexane, halogen-containing solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran, diethyl ether and 1, 2-dimethoxyethane, and acetonitrile, and a mixed solvent of these solvents can also be used.

Examples of the base include amines such as triethylamine, N-methylmorpholine, diisopropylethylamine, and pyridine, inorganic bases such as potassium hydride and sodium hydride, amino metals such as lithium diisopropylamide and potassium bis (trimethylsilyl) amide, and metal alcoholates such as sodium methylate and potassium tert-butoxide.

Step 2: reacting the compound (2) with carbon monoxide and R in the presence of an organic base such as triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine or an inorganic base such as potassium carbonate or sodium hydrogencarbonate in an inert solvent in the presence of a transition metal catalyst²OH reacts to form compound (3) (see j. org. chem.57，5979(1992))。

The transition metal catalyst is, for example, an O-valent palladium reagent, and is prepared in a reaction system using, for example, 2-valent palladium such as palladium (II) acetate and a ligand such as triphenylphosphine and 2, 2' -bis (diphenylphosphino) -1, 1-Binaphthyl (BINAP). An O-valent palladium reagent such as tetrakis (triphenylphosphine) palladium (O) may be used as it is.

Examples of the inert solvent include hydrocarbon solvents such as benzene, toluene and hexane, ether solvents such as tetrahydrofuran, diethyl ether and 1, 2-dimethoxyethane, acetonitrile and the like, and mixed solvents thereof.

And step 3: compound (3) is oxidized to the diol in an inert solvent by a conventional glycolation reaction using osmium tetroxide or the like (see oximation in Organic Chemistry, Milos Hudlick), or by Sharpless asymmetric cis-dihydroxylation reaction using AD-mix as a reagent (Sharpless AD) as described in Tetrahedron Asymmetry 4(1), 133(1993) incorporated herein by reference, to form compound (4).

The inert solvent is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, an ether solvent such as tetrahydrofuran, diethyl ether or 1, 2-dimethoxyethane, acetonitrile, acetone, N-dimethylformamide or water, or a mixed solvent of these solvents.

And 4, step 4: the compound (4) is reacted with thionyl chloride in the presence of an organic base such as triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine, or an inorganic base such as potassium carbonate or sodium hydrogencarbonate, in an inert solvent such as a hydrocarbon solvent such as benzene, toluene or hexane, a halogen-containing solvent such as dichloromethane or chloroform, an ether solvent such as tetrahydrofuran, diethyl ether or 1, 2-dimethoxyethane, acetonitrile or a mixed solvent of these solvents.

The reaction product is then oxidized with a conventional oxidizing agent (see Oxidations in Organic Chemistry, Milos Hudlicky) such as hydrogen peroxide, potassium hydrogen persulfate (Oxone), ruthenium trichloride, sodium metaperiodate, etc., in an inert solvent such as a hydrocarbon solvent such as benzene, toluene, hexane, etc., a halogen-containing solvent such as methylene chloride, chloroform, etc., an ether solvent such as tetrahydrofuran, diethyl ether, 1, 2-dimethoxyethane, etc., an inert solvent such as acetonitrile, acetone, water, or a mixed solvent of these solvents, to form the compound (5).

And 5: compound (5) is reacted with sodium azide in an inert solvent such as an ether solvent such as tetrahydrofuran, a ketone solvent such as acetone, N, N-dimethylformamide, water or a mixed solvent of these solvents to form compound (6).

Step 6: the compound (6) is reacted with a trifluoromethanesulfonylating agent such as trifluoroacetic anhydride or N-phenyl-bis (trifluoromethanesulfonylimide) in an inert solvent such as a hydrocarbon solvent such as benzene, toluene or hexane, a halogen-containing solvent such as dichloromethane or chloroform, an ether solvent such as tetrahydrofuran, diethyl ether or 1, 2-dimethoxyethane, acetonitrile or a mixed solvent of these solvents, in the presence of an inorganic base such as triethylamine, diisopropylethylamine or pyridine, potassium carbonate or sodium hydrogencarbonate, to form the compound (7).

And (7): compound (7) is reacted with an amine such as triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] -7-undecene, an inorganic base such as potassium carbonate, sodium hydrogen carbonate, sodium hydride, or a metal alkoxide such as sodium methoxide, potassium tert-butoxide, in an inert solvent such as a hydrocarbon solvent such as benzene, toluene, hexane, etc., a halogen-containing solvent such as dichloromethane, chloroform, etc., an ether solvent such as tetrahydrofuran, diethyl ether, 1, 2-dimethoxyethane, etc., acetonitrile, or a mixed solvent of these solvents, to form compound (8).

And 8: compound (9) can be formed from compound (8) by a Staudinger reaction using triethyl phosphite, triphenylphosphine, or the like (see Bull. chem. Soc. Fr., 815(1985)) or a conventional azide reduction reaction using lithium borohydride or the like described in reduction in Organic Synthesis (AhmedF. Abdel-magic), which is incorporated herein by reference), in an inert solvent such as a hydrocarbon solvent such as benzene, toluene, hexane, or the like, a halogen-containing solvent such as methylene chloride, chloroform, or the like, an ether solvent such as tetrahydrofuran, diethyl ether, 1, 2-dimethoxyethane, or the like, acetonitrile, acetone, water, or a mixed solvent thereof.

And step 9: using Protective Groups in organic Synthesis (Theroora), which is incorporated herein by referenceGreene and Peter g.m.wuts) hydrolyzes the ester site of compound (9) and the R is hydrolyzed¹And R²Simultaneously or sequentially converted to a hydrogen atom to form the compound (10).

Step 10: compound (6) is hydrogenated in an inert solvent such as an alcohol (e.g., ethanol or methanol), an ester (e.g., ethyl acetate), N, N-dimethylformamide, water or a mixed solvent of these solvents in the presence of a metal catalyst (e.g., palladium on carbon or palladium black) to form compound (11) of the present invention.

Step 11: the ester moiety of compound (11) is hydrolyzed and converted to a carboxylic acid to form the compound of the present invention, compound (12), using a conventional method described in Protective Groups in organic synthesis (Theodora W.Greene and Peter G.M.WUTS), which is incorporated herein by reference.

The compound of the present invention can be combined with 1 or more than 1 pharmaceutically acceptable carriers, excipients and/or diluents to prepare a pharmaceutical preparation. Examples of the carriers, excipients and diluents include: water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methyl cellulose, polyvinylpyrrolidone, alkyl paraben, talc, magnesium stearate, stearic acid, glycerol, castor oil, olive oil, soybean oil, and other various oils.

The compound of the present invention can be mixed with such carriers, excipients or diluents and, if necessary, additives such as conventional extenders, binders, disintegrants, pH adjusters, and dissolving agents, and then formulated into oral or non-oral drugs such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, and transdermal patches by conventional formulation techniques, and in particular, can be formulated into group 2 metabotropic glutamate receptor antagonists. The compound of the present invention can be administered to an adult patient in an amount of 0.01 to 500 mg/day, 1 or several times per day, and may be administered orally or parenterally, and oral administration is preferred from the viewpoint of ease of use and drug efficacy. The dose can be increased or decreased as appropriate depending on the type of disease to be treated, the age, weight, and symptoms of the patient.

The present invention will be specifically described below with reference to examples and test examples, but the present invention is not limited to the examples.

Example 1

Synthesis of 2-benzyl (1R, 5R, 6R) -6-fluoro-bicyclo [3.1.0] hex-2-ene-2, 6-dicarboxylate 6-ethyl ester

To an 84ml solution of 7.83g of diisopropylamine cooled to 0 ℃ in tetrahydrofuran was added 28.8ml of a 2.47M butyllithium hexane solution, and the mixture was stirred for 15 minutes. After cooling the solution to-62 ℃, 40ml of a tetrahydrofuran solution containing 12.0g of ethyl (1R, 5R, 6R) -6-fluoro-2-oxo-bicyclo [3.1.0] hexane-6-carboxylate was added dropwise while maintaining the temperature of-62 to-58 ℃. After 1 hour, 25.3g of N-phenyl-bis (trifluoromethanesulfonamide) solution in 84ml of tetrahydrofuran were added dropwise over 15 minutes while maintaining the temperature between-62 and-60 ℃. The reaction solution was allowed to warm to room temperature naturally and stirred for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ether. After washing with water and a saturated aqueous sodium chloride solution, the extract was dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel: WAKOGEL C200 (Wako pure chemical industries, Ltd.) and hexane-ethyl acetate (developing solvent: 20: 1)). The obtained ethyl (1R, 5R, 6R) -6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo [3.1.0] hex-2-ene-6-carboxylate was immediately dissolved in 195ml of N, N-dimethylformamide, and 389mg of palladium acetate, 910mg of triphenylphosphine, and 12.5g of benzyl alcohol were added thereto, followed by 11.7g of triethylamine was further added thereto, followed by stirring at room temperature for 4.5 hours under a carbon monoxide atmosphere. 1M hydrochloric acid was added to the reaction solution, and extraction was performed with diethyl ether 2 times. The organic layers were combined, washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After a drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: WAKOGEL C200 (Wako pure chemical industries, Ltd.) and a developing solvent: hexane-ethyl acetate: 10: 1 to 1: 1) to obtain 6.42g of (1R, 5R, 6R) -6-fluoro-bicyclo [3.1.0] hex-2-ene-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester

mp.90-91℃

Example 2

Synthesis of 6-ethyl (1R, 2S, 3R, 5R, 6R) -6-fluoro-2, 3-dihydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2-benzyl ester

6.36g of (1R, 5R, 6R) -6-fluoro-bicyclo [3.1.0] hex-2-ene-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester was suspended in 150ml of t-butanol and 150ml of water, and 29.3g of AD-mix-. beta. (manufactured by Aldrich) and 5.96g of methanesulfonamide were added thereto and stirred at 4 ℃ for 5 days. Sodium hydrogen sulfite was added to the reaction solution, and after stirring at room temperature for 15 minutes, water was added and extraction was performed 3 times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: WAKOGEL C200 (Wako pure chemical industries, Ltd.) and a developing solvent: hexane-ethyl acetate: 10: 1 to 3: 2) to obtain 4.21g of (1R, 2S, 3R, 5R, 6R) -6-fluoro-2, 3-dihydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.

¹H-NMR(CDCl₃)δ1.29(3H，t，J＝7.2Hz)，2.06-2.21(2H，m)，2.30(1H，dd，J＝7.6，2.6Hz)，2.47(1H，dd，J＝13.2，7.6Hz)，2.50(1H，dd，J＝9.2，1.2Hz)，4.02(1H，s)，4.24(2H，q，J＝7.2Hz)，4.34-4.46(1H，m)，5.23(1H，d，J＝12.5Hz)，5.28(1H，d，J＝12.5Hz)，7.27-7.42(5H，m)。

MS(ESI)m/z；361(M+Na)⁺。

Example 3

(1R, 1aR, 1bS, 4aR, 5aR) -1-fluoro-3, 3-dioxo-tetrahydro-2, 4-dioxa-3. lamda. (R, 1aR, 1bS, 4aR, 5aR) -1-fluoro-3, 3-dioxo-tetrahydro-2, 4-dioxa-3. lamda.)⁶-thia-cyclopropane[a]Synthesis of 1 b-benzyl 1-ethyl pentalene-1, 1 b-dicarboxylate

3.96g (1R, 2S, 3R, 5R, 6R) -6-fluoro-2, 3-dihydroxy-bicyclo [3.1.0] cooled to 4 deg.C]Hexane-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester in 20ml dichloromethane solution, adding 1.70ml thionyl chloride, at 40 degrees C stirring for 13 hours. The solvent and excess reagent were distilled off under reduced pressure, and the residue was dissolved in 12ml of carbon tetrachloride, 12ml of acetonitrile and 20ml of water. To the solution were added 3.76g of sodium metaperiodate 3.76g and 50mg of ruthenium trichloride hydrate, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, and extraction was performed with diethyl ether 3 times. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: WAKOGEL C200 (Wako pure chemical industries, Ltd.), and a developing solvent: hexane-ethyl acetate 5: 1 to 2: 1) to obtain 4.11g of (1R, 1aR, 1bS, 4aR, 5aR) -1-fluoro-3, 3-dioxo-tetrahydro-2, 4-dioxa-3. lambda⁶-thia-cyclopropa [ a ]]1 b-benzyl pentalene-1, 1 b-dicarboxylate 1-ethyl ester.

¹H-NMR(CDCl₃)δ1.29(3H，t，J＝7.2Hz)，2.53-2.61(1H，m)，2.72(1H，ddd，J＝15.2，7.6，0.9Hz)，2.78-2.89(1H，m)，2.83(1H，dd，J＝7.2，2.3Hz)，4.19-4.31(2H，m)，5.26(1H，d，J＝12.1Hz)，5.33(1H，d，J＝12.1Hz)，5.45(1H，dt，J＝7.6，3.8Hz)，7.28-7.43(5H，m)。

MS(ESI)m/z；423(M+Na)⁺。

Example 4

(1R, 2R, 3R, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester

3.73g (1R, 1aR, 1bS, 4aR, 5aR) -1-fluoro-3, 3-dioxo-tetrahydro-2, 4-dioxa-3. lambda⁶-thia-cyclopropa [ a ]]1 b-benzyl pentalene-1, 1 b-dicarboxylate 1-ethyl ester was dissolved in 37ml of N, N-dimethylformamide and 3.7ml of water, and thereto was added 1.09g of sodium azide, followed by stirring at 50 ℃ for 14 hours. Reduced pressure steamingThe solvent was distilled off, and the residue was dissolved in 187ml of diethyl ether and 5.2ml of water, followed by addition of 15ml of 20% sulfuric acid and stirring at room temperature for 8 hours. Water was added to the reaction solution, and extraction was performed with diethyl ether 3 times. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: WAKOGEL C200 (Wako pure chemical industries, Ltd.) and a developing solvent: hexane-ethyl acetate 5: 1 to 1: 1) to obtain 3.02g of (1R, 2R, 3R, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [ 3.1.0%]Hexane-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.

¹H-NMR(CDCl₃)δ1.32(3H，t，J＝7.2Hz)，2.18-2.54(5H，m)，4.22-4.36(1H，m)，4.26(2H，q，J＝7.2Hz)，5.27(1H，d，J＝12.2Hz)，5.35(1H，d，J＝12.2Hz)，7.31-7.45(5H，m)。

MS(ESI)m/z；386(M+Na)⁺。

Example 5

Synthesis of 2-benzyl (1R, 2S, 5R, 6R) -2-azido-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylate 6-ethyl ester

2.00g of (1R, 2R, 3R, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester was dissolved in 80ml of methylene chloride, and 1.31g of pyridine was added thereto and then cooled to-70 ℃. To the solution was added 2.33g of trifluoromethanesulfonic anhydride, and the mixture was stirred at 4 ℃ for 1 hour. The reaction mixture was poured into cold water and extracted with ether 3 times. The organic layers were combined, washed with a saturated aqueous copper sulfate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After a drying agent was filtered off, the filtrate was concentrated under reduced pressure, the residue was dissolved in 15ml of tetrahydrofuran, 1.26g of 1, 8-diazabicyclo [5.4.0] -7-undecene was added, and the solution was stirred at 50 ℃ for 5 hours, at room temperature for 8 hours, and then diluted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After a drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: WAKOGEL C200 (Wako pure chemical industries, Ltd.) and a developing solvent: hexane-ethyl acetate: 10: 1 to 5: 1) to obtain 1.39g of (1R, 2S, 5R, 6R) -2-azido-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.

¹H-NMR(CDCl₃)δ1.31-1.38(3H，m)，2.74-2.83(1H，m)，2.84-2.90(1H，m)，4.25-4.35(2H，m)，5.26(2H，q，J＝3.4Hz)，5.90(1H，dd，J＝5.4，0.8Hz)，5.94-6.00(1H，m)，7.30-7.44(5H，m)。

MS(ESI)m/z；368(M+Na)⁺。

Example 6

Synthesis of 2-benzyl (1R, 2S, 5R, 6R) -2-amino-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylate 6-ethyl ester

650mg of (1R, 2S, 5R, 6R) -2-azido-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester was dissolved in 45ml of tetrahydrofuran and 5ml of water, and 1.21g (3mmol/g) of triphenylphosphine on a polymer was added thereto, followed by stirring at 60 ℃ for 9.5 hours. After the resin was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: WAKOGEL C200 (Wako pure chemical industries, Ltd.) and a developing solvent: hexane-ethyl acetate 5: 1 to 1: 1) to obtain 146mg of (1R, 2S, 5R, 6R) -2-amino-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.

¹H-NMR(CDCl₃)δ1.32(3H，t，J＝7.2Hz)，2.63-2.69(1H，m)，2.73-2.79(1H，m)，4.27(2H，q，J＝7.2Hz)，5.22(2H，d，J＝3.0Hz)，5.70-5.74(1H，m)，5.75-5.79(1H，m)，7.28-7.41(5H，m)。

MS(ESI) m/z；342(M+Na)⁺。

Example 7

Synthesis of (1R, 2S, 5R, 6R) -2-amino-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylic acid

90mg of (1R, 2S, 5R, 6R) -2-amino-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester was dissolved in 2ml of tetrahydrofuran, and 25mg of lithium hydroxide hydrate dissolved in 5ml of water was added thereto, followed by stirring at room temperature for 2 hours. After concentrating the solvent under reduced pressure, the residue was purified with an ion exchange Resin (AG 50W-X8 Resin (type H), developing solvent: water, 50% aqueous tetrahydrofuran solution, 10% aqueous pyridine solution) to obtain 24mg of (1R, 2S, 5R, 6R) -2-amino-6-fluoro-bicyclo [3.1.0] hex-3-ene-2, 6-dicarboxylic acid.

Mp. > 174 deg.C (decomposition)

Example 8

Synthesis of (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid

218mg of (1R, 2R, 3R, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2-benzyl ester 6-ethyl ester was dissolved in 2.5ml of acetic acid and 0.5ml of water, and after adding 15mg of 10% palladium on charcoal, the mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 7.8ml of 10% hydrochloric acid and heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange Resin (AG 50W-X8 Resin (type H), developing solvent: water, 50% aqueous tetrahydrofuran solution, 10% aqueous pyridine solution) to give 104mg of (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid.

Mp. > 172 deg.C (decomposition)

Test example (Effect of test drugs on cAMP accumulation)

Using 10% dialyzed fetal bovine serum in Dalbeco modified Eagle's Medium [ 1% proline, 50units/ml penicillin, 50. mu.g/ml streptomycin, 2mM L-glutamic acid (added at the time of use)]In a 1.26X 10⁴Cells/well/0.32 cm²A96-well plate was seeded with CHO cells stably expressing mGluR2 as metabotropic glutamate receptor at a rate of 150. mu.l at 37 ℃ with 5% CO₂The cells were cultured for 2 days. Thereafter, the medium was changed to a medium containing no L-glutamic acid, the supernatant was aspirated off after 4 hours, and 150. mu.l of PBS (+) -IBMX (10mMPBS (-), 1mMMgCl₂，1mM CaCl₂1mM MIBMX) at 37 deg.C, 5% CO₂Incubate under conditions for 20 minutes. The supernatant was removed by aspiration again, and 10 containing 60. mu.l of the supernatant was added^-5M forskolin, 30. mu.M glutamic acid, 10^-10-10^-4PBS (+) -IBMX of M specimen at 37 ℃ and 5% CO₂Incubation for 15 minutes under the conditions to examine the antagonistic effect of the test drug on inhibition of forskolin-stimulated cAMP accumulation of glutamic acid [ blank No-addition compound (Tanabe et al, Neuron, 8, 169-179(1992) ].)]. Mu.l of ice-cooled ethanol was added to stop the reaction, and the whole amount of the supernatant was collected on the other plate, dried at room temperature using an evaporator, and stored at-20 ℃. The amount of cAMP was quantified on the dried sample by using cAMP EIA kit (manufactured by Amasham). Blank values were subtracted from each cAMP amount. Inhibition was determined to antagonize 50% of 30. mu.M glutamic acid (vs. 10)^-5Increased cAMP by forskolin stimulation of M), i.e., IC₅₀The value is obtained.

The compounds of the present invention showed a low IC in the measurement described in this test example₅₀The value is obtained.

In the measurement described in this test example, (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-hydroxy-bicyclo [3.1.0] described in example 8 of the present invention]IC of hexane-2, 6-dicarboxylic acid₅₀＝476nM。

The present invention may provide antagonists to metabotropic glutamate receptors.

The compounds of the present invention may be used for the treatment and/or prevention of the following diseases: schizophrenia, anxiety and related diseases, psychomedical diseases such as depression, bipolar disorder and epilepsy, and neurological diseases such as drug-dependent diseases, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia with myotonia, cerebral ischemia, cerebral insufficiency, spinal cord disorders and head disorders.

Claims (7)

1. A 2-amino-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic acid derivative having a relative steric configuration represented by the following formula [ I ] and a pharmaceutically acceptable salt thereof or a hydrate thereof,

in the formula, R¹And R²The same or different represent a hydrogen atom, C_1-10Alkyl, phenyl C_1-6An alkyl group;

R³and R⁴When R is³R being hydroxy⁴Is a hydrogen atom; or R³And R⁴Together form a C-C single bond.

2. The derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 1, represented by the formula [ I]R in (1)³Is hydroxy, R⁴Is a hydrogen atom.

3. The derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 1, represented by the formula [ I]R in (1)³Is hydroxy, R¹、R²And R⁴Is a hydrogen atom.

4. The derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 3, which is (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid.

5. A group 2 metabotropic glutamate receptor antagonist comprising the pharmaceutical composition according to any one of claims 1 to 4 as an active ingredient.

6. Use of a compound according to any one of claims 1 to 4 for the preparation of group 2 metabotropic glutamate receptor antagonists.

7. Use of a compound according to any one of claims 1 to 4 for the preparation of a therapeutic and/or prophylactic agent for psychiatric disorders and/or neurological diseases associated with group 2 metabotropic glutamate receptors.