CN111116582B - mGluR2 antagonist - Google Patents

Abstract

The present invention relates to a [1,2,4]triazolo[4,3-a]pyridine derivative or a pharmaceutically acceptable salt, solvate, prodrug thereof as a mGluR2 antagonist, and a compound comprising them Pharmaceutical compositions and uses. The compounds of the present invention have a good antagonistic effect on mGluR2, and can be used for the treatment of mGluR2-related diseases, such as mood disorders, anxiety disorders, cognitive disorders and the like.

Description

A mGluR2 antagonist

technical field

The present invention relates to a [1,2,4]triazolo[4,3-a]pyridine derivative or a pharmaceutically acceptable salt thereof having an antagonistic effect on mGluR2, and a pharmaceutical composition comprising the compound as an active ingredient .

Background technique

Glutamate is known to work as the primary excitatory neurotransmitter for regulating higher functions such as memory, learning, and the like in the mammalian central nervous system. Among them, glutamate-activated metabotropic glutamate receptors (mGluRs) have a higher regulatory effect that contributes to fine-tuning of synaptic efficacy. Among these glutamate receptors, antagonists against mGluR2 have been shown to improve cognitive function, and have also shown effects such as antidepressant and anti-anxiety, and can be used to treat disorders such as mood disorders, anxiety disorders, cognitive disorders and other diseases.

Therefore, there remains a need to develop novel mGluR2 antagonists.

SUMMARY OF THE INVENTION

The present invention aims to provide a [1,2,4]triazolo[4,3-a]pyridine derivative or a pharmaceutically acceptable salt, solvate, prodrug thereof as an mGluR2 antagonist, and a compound including Their pharmaceutical compositions and uses.

One aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate and prodrug thereof:

Wherein, R ¹ is selected from C _3-8 cycloalkyl-C _1-6 alkyl-, C _1-6 alkoxy C _1-6 alkyl-, C _1-6 alkyl-, C _1-6 haloalkane base-;

R ² and R ³ are independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl-, or R ² and R ³ together with the bound N atom form a 3-8 membered nitrogen-containing heterocycle.

In some embodiments, R ¹ is selected from C _3-8 cycloalkyl-C _1-4 alkyl-, C _1-4 alkoxy C _1-4 alkyl-, C _1-4 alkyl-, C _1-4 haloalkyl-;

R ² and R ³ are independently selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl-, or R ² and R ³ together with the bound N atom form a 3-6 membered nitrogen-containing heterocycle.

In some embodiments, R ¹ is selected from C _3-6 cycloalkyl-C _1-2 alkyl-, C _1-2 alkoxy C _1-2 alkyl-, C _1-2 alkyl-, C _1-2 haloalkyl-;

R ² and R ³ are independently selected from hydrogen, C _1-3 alkyl, C _1-3 haloalkyl-, or R ² and R ³ together with the bound N atom form a 4-6 membered nitrogen-containing heterocycle.

In some embodiments, R ¹ is selected from C _3-4 cycloalkyl-C _1-2 alkyl-, C _1-2 alkoxy C _1-2 alkyl-;

R ² and R ³ are independently selected from hydrogen, C _1-3 alkyl, or R ² and R ³ together with the bound N atom form a 4-6 membered nitrogen-containing heterocycle.

In particular, the present invention provides the following specific compounds:

5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N,N- Dimethylisoxazole-3-carboxamide

5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N,N- Diethylisoxazole-3-carboxamide

5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-ethyl Isoxazole-3-carboxamide

5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-methyl Isoxazole-3-carboxamide

(5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)isoxazole- 3-yl)(pyrrolidin-1-yl)methanone

(5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)isoxazole- 3-yl)(piperidin-1-yl)methanone

Further, the present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug and pharmaceutically acceptable excipients thereof.

The present invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug thereof, for use in the treatment or prevention of mGluR2-related diseases (such as mood disorders, anxiety disorders, cognitive disorders, etc.) drugs.

definition

Unless otherwise specified, "alkyl" herein defines a straight or branched chain saturated hydrocarbon group containing 1-6 carbon atoms, preferably 1-4, 1-3 or 1-2 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl, and the like.

"Alkoxy" defines a straight or branched chain saturated hydrocarbyloxy group containing 1-6 carbon atoms, preferably 1-4, 1-3 or 1-2 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, or hexyloxy, and the like

"Cycloalkyl" defines a saturated cyclic hydrocarbon group containing 3-8 carbon atoms (preferably 3-6, or 3-4 carbon atoms), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

"Nitrogen-containing heterocycle" defines a saturated nitrogen-containing heterocycle containing 3-8 ring atoms (preferably 3-6, or 4-6 ring atoms), one of which is nitrogen, such as aziridinyl, Pyrrolidinyl, piperidinyl.

"Halogen" means fluorine, chlorine, bromine or iodine, with fluorine or chlorine being preferred.

In the present invention, the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts of the free base compounds thereof with conventional acids such as: inorganic acids such as hydrohalic acids (such as hydrochloric acid or hydrobromide) acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, Citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and similar acids.

In the present invention, the solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvate-forming solvents include, but are not limited to, water, methanol, ethanol, isopropanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

In the present invention, the prodrugs of the compounds of the present invention are not particularly limited as long as they can be metabolized into the compounds of the present invention in vivo, and include esters and the like, such as methyl esters, ethyl esters, and the like without limitation.

Preparation

Another aspect of the present invention provides a method for preparing the compound shown in formula I, which comprises the following steps:

Wherein, in the above formula, R ¹ , R ² and R ³ are defined as described above;

Step (I): 7-Chloro-3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with TMS protected Acetylene is reacted under Sonogashira conditions, preferably Pd(PPh3)2Cl2, CuI, Et3N, and the solvent is toluene.

Step (II): removing the ethynyl protecting group under alkaline conditions, the base is NaOH, KOH; the solvent is methanol.

Step (III): under alkaline conditions, methyl 2-chloro-2-(hydroxyimino)acetate reacts with an ethynyl group to generate an isoxazole ring, the bases are _Na2CO3 , K2CO3, and the solvent is ethanol.

Step (IV): the prepared isoxazole compound is reacted with R ³ R ² NH to prepare an amide compound, wherein the solvent is methanol, ethanol or THF.

pharmaceutical composition

Another aspect of the present invention provides a pharmaceutical composition comprising at least one compound represented by formula I or a pharmaceutically acceptable salt, solvate, prodrug thereof and one or more pharmaceutically acceptable compounds adjuvant. Pharmaceutical compositions can be formulated as liquids, powders, injectable solutions, suspensions, suppositories and the like. And all modes of administration are contemplated, such as oral, rectal, parenteral, topical, or by intravenous, intramuscular, intrasternal or subcutaneous injection, or in a form suitable for inhalation.

application

Another aspect of the present invention provides the use of a compound represented by formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for the treatment or prevention of mGluR2-related diseases (such as mood disorders, anxiety disorders, cognitive impairment, etc.).

Detailed ways

The present invention is described in more detail below to facilitate understanding of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

Example 1: 5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)- Preparation of N,N-dimethylisoxazole-3-carboxamide

(I) 3-(Cyclopropylmethyl)-8-(trifluoromethyl)-7-((trimethylsilyl)ethynyl)-[1,2,4]triazolo[4,3 -a]Pyridine preparation

Under the protection of N2, 7-chloro-3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (11 g, 40 mmol) in toluene (150 mL) was added Pd( _PPh3 )2Cl2 (1.4 g, ₂ mmol), CuI (0.38 g, ₂ mmol) and _Et3N (30 mL). At 80°C, trimethylsilylacetylene (11.2 mL, 80 mmol) was added dropwise, and the mixture was stirred for 6 h. The resulting mixture was filtered, 250 mL of ethyl acetate was added to the filtrate, the above solution was washed with water, the organic phase was dried, and concentrated. The resulting residue was purified by silica gel column eluting with 25% ethyl acetate/petroleum ether to give a light brown solid (11.59 g, 86%), LC-MS (ESI) m/z: 338.1226 (M+H) ⁺ .

(II) Preparation of 3-(cyclopropylmethyl)-7-ethynyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

3-(Cyclopropylmethyl)-8-(trifluoromethyl)-7-((trimethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-a ] Pyridine (10.11 g, 30 mmol) was dissolved in 80 mL of methanol. At room temperature, with stirring, an aqueous solution (15 mL) of NaOH (0.12 g, 3 mmol) was added, and the mixture was stirred for 4 h. The mixture was concentrated under reduced pressure, and to the residue were added ethyl acetate (250 mL) and water (40 mL), the layers were separated, the organic phase was dried and concentrated, and the resulting residue was purified by silica gel column with 30% eluent Ethyl acetate/petroleum ether gave a yellow solid (6.2 g, 78%).

¹ H NMR (400 MHz, CDCl ₃ ) δppm 0.21-0.38 (m, 2H), 0.44-0.60 (m, 2H), 1.02-1.15 (m, 1H), 3.01 (d, 2H), 3.28 (s, 1H) , 7.35 (d, 1H), 8.22 (d, 1H); LC-MS (ESI) m/z: 266.0831 (M+H) ⁺ .

(III) 5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)isoxoxane Preparation of oxazole-3-carboxymethyl ester:

3-(Cyclopropylmethyl)-7-ethynyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (5.83 g, 22 mmol) and Sodium carbonate (14.0 g, 132 mmol) was dissolved in a solution of ethanol (100 mL). A solution of methyl 2-chloro-2-(hydroxyimino)acetate (15.1 g, 110 mmol) in ethanol (50 mL) was added dropwise to the above solution at room temperature with stirring. The resulting reaction mixture was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure, and ethyl acetate (400 mL) and water (100 mL) were added to the residue, the layers were separated, the organic phase was dried and concentrated, and the obtained residue was purified by silica gel column with 30% eluent Ethyl acetate/petroleum ether gave a white solid (4.73 g, 58.7%), LC-MS (ESI) m/z: 366.0938 (M+H) ⁺ .

(IV) 5-(3-(Cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N , Preparation of N-dimethylisoxazole-3-carboxamide

A 40% aqueous dimethylamine solution (18.5 mL, 150 mmol) was added dropwise to 5-(3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4] ,3-a]pyridin-7-yl)isoxazole-3-carboxymethyl ester (3.66 g, 10 mmol) in methanol (20 mL), the reaction mixture was stirred at 60 °C for 4 h. The solvent was removed under reduced pressure and the residue was purified using a silica gel column eluting with 45% ethyl acetate/petroleum ether to give a white solid (3.45 g, 91%).

¹ H NMR (400 MHz, CDCl ₃ ) δppm 0.23-0.40 (m, 2H), 0.47-0.62 (m, 2H), 1.07-1.19 (m, 1H), 2.89 (s, 3H), 2.97 (s, 3H) , 3.03(d, 2H), 7.28(s, 1H), 7.60(d, 1H), 8.46(d, 1H); LC-MS (ESI) m/z: 380.1259 (M+H) ⁺ ; melting point: 126.4 °C.

According to the above-mentioned method of the present application, different organic amine substrates were used to prepare the compounds of Examples 2-6, and the structures of the obtained compounds and their characterization data are shown in Table 1:

[Table 1]

Biological activity assay: [ ³⁵ S]GTPγS binding assay

CHO cells stably expressing mGluR2 were incubated at 35°C in 5% _CO using medium containing 10% fetal bovine serum [1% proline, 1 mM sodium pyruvate, 1 mM succinic acid, 1 mM disodium succinate, 80 units /mL penicillin, 80 μg/mL streptomycin, 200 μg/mL hygromycin B, 3 mM L-glutamine] culture. Then, the cultured cells were washed with PBS(-), dissociated, and centrifuged at 1000 rpm for 10 min at 5°C to recover the cells. The resulting material was suspended in 20 mM HEPES buffer (pH 7.4) and homogenized in a homogenizer, followed by centrifugation at 5°C for another 15 min to obtain particles again, and the resulting particles were further homogenized 2-3 times. and centrifugation operations. The resulting particles were homogenized in the above buffer. The above homogenate was diluted with buffer for binding assay (final concentrations: 10 mM HEPES, 800 mM NaCl, 10 mM MgCl ₂ , 10 MGDP, 10 μg/mL Saponin (Sigma-Aldrich, CAS No: 8047-15-2), 0.1 % BSA). Compounds 1-6 were added to the mixture containing 10 μg of membrane protein/above, respectively, and the resulting mixture was incubated at 30° C. for 30 min. Then, glutamate (final concentration: 20(mGluR2) and [ ³⁵ S]GTPγS (final concentration: 0.15 nM) were added to the above mixture; and the mixture was incubated at 30° C. for 30 min. The resulting incubation solution was suction filtered onto a Waterman GF/C filter to stop the reaction and wash with 3 x 500 μL of ice-cold 10 mM sodium phosphate buffer (pH 7.4). Dry the filter and add scintillation fluid to it and measure the membrane with a liquid scintillation meter Binding radioactivity. The residual radioactivity in the absence of glutamate was defined as non-specific binding, and the difference in residual radioactivity in the presence of glutamate was defined as specific binding. Specific binding at different concentrations of compound For percent inhibition, a non-linear analysis was used to obtain an inhibition curve. From this inhibition curve, the concentration of the compound that inhibited 50% of specific binding ( _IC50 ) was calculated. See Table 2 for the results obtained.

[Table 2]

The above activity results show that the compounds of the present invention have a good antagonistic effect on mGluR2.

The preferred embodiments of the present invention have been described above, but are not intended to limit the present invention. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims (4)

1. A compound, or a pharmaceutically acceptable salt thereof, as shown below, wherein the compound is any one of the following:

5- (3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl) -N, N-dimethylisoxazole-3-carboxamide

5- (3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl) -N, N-diethylisoxazole-3-carboxamide

5- (3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl) -N-ethylisoxazole-3-carboxamide

5- (3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl) -N-methylisoxazole-3-carboxamide

(5- (3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl) isoxazol-3-yl) (pyrrolidin-1-yl) methanone

(5- (3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl) isoxazol-3-yl) (piperidin-1-yl) methanone.

2. A medicament comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a mGluR 2-related disorder.

4. Use of a compound according to claim 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a mGluR 2-associated disorder, wherein the mGluR 2-associated disorder is a mood disorder, an anxiety disorder, or a cognitive disorder.