CN111116582A

CN111116582A - mGluR2 antagonist

Info

Publication number: CN111116582A
Application number: CN201911310474.5A
Authority: CN
Inventors: 韩晓菲
Original assignee: Dalian University
Current assignee: Dalian University
Priority date: 2019-12-18
Filing date: 2019-12-18
Publication date: 2020-05-08
Anticipated expiration: 2039-12-18
Also published as: CN111116582B

Abstract

The invention relates to a [1,2,4] triazolo [4,3-a ] pyridine derivative serving as mGluR2 antagonist or pharmaceutically acceptable salt, solvate and prodrug thereof, and a pharmaceutical composition and application thereof. The compound has good antagonistic effect on mGluR2, and can be used for treating mGluR2 related diseases, such as mood disorder, anxiety disorder, cognitive disorder and the like.

Description

mGluR2 antagonist

Technical Field

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

Background

Glutamate is known to function as the major excitatory neurotransmitter for the regulation of memory, learning, and other higher functions in the central nervous system of mammals. Among them, glutamate-activated metabotropic glutamate receptors (mglurs) have a higher modulatory effect that contributes to the fine-tuning of synaptic efficacy. Among these glutamate receptors, antagonists against mGluR2 exhibit effects of improving cognitive functions, and also exhibit effects such as antidepressant and anxiolytic effects, and are useful for the treatment of diseases such as mood disorders, anxiety disorders, cognitive disorders, and the like.

Thus, there remains a need to develop new antagonists for mGluR 2.

Disclosure of Invention

The invention aims to provide a [1,2,4] triazolo [4,3-a ] pyridine derivative serving as mGluR2 antagonist or pharmaceutically acceptable salt, solvate and prodrug thereof, and a pharmaceutical composition and application thereof.

In one aspect, the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, solvate, prodrug thereof:

wherein R is¹Is selected from C_3-8cycloalkyl-C_1-6Alkyl-, C_1-6Alkoxy radical C_1-6Alkyl-, C_1-6Alkyl-, C_1-6Haloalkyl-;

R²and R³Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl-, or R²And R³Together with the bound N atom, form a 3-8 membered nitrogen containing heterocyclic ring.

In some embodiments, R¹Is selected from C_3-8cycloalkyl-C_1-4Alkyl-, C_1-4Alkoxy radical C_1-4Alkyl-, C_1-4Alkyl-, C_1-4Haloalkyl-;

R²and R³Independently selected from hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl-, or R²And R³Together with the bound N atom, form a 3-6 membered nitrogen containing heterocyclic ring.

In some embodiments, R¹Is selected from C_3-6cycloalkyl-C_1-2Alkyl-, C_1-2Alkoxy radical C_1-2Alkyl-, C_1-2Alkyl-, C_1-2Haloalkyl-;

R²and R³Independently selected from hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl-, or R²And R³Together with the bound N atom, form a 4-6 membered nitrogen containing heterocyclic ring.

In some embodiments, R¹Is selected from C_3-4cycloalkyl-C_1-2Alkyl-, C_1-2Alkoxy radical C_1-2Alkyl-;

R²and R³Independently selected from hydrogen, C_1-3Alkyl, or R²And R³Together with the bound N atom, form a 4-6 membered nitrogen containing heterocyclic ring.

In particular, the 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-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

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

The invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, as a medicament for treating or preventing mGluR 2-related diseases (such as mood disorders, anxiety disorders, cognitive disorders and the like).

Definition of

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

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

"cycloalkyl" defines saturated cyclic hydrocarbon radicals containing from 3 to 8 carbon atoms (preferably 3 to 6, or 3 to 4 carbon atoms), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

"Nitrogen-containing heterocycle" defines a saturated nitrogen-containing heterocycle containing from 3 to 8 ring atoms (preferably from 3 to 6, or from 4 to 6 ring atoms) and 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, 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 (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like; 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 the like.

In the present invention, a solvate of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

In the present invention, there is no particular limitation on the prodrug of the compound of the present invention as long as it can be metabolized into the compound of the present invention in vivo, and includes, without limitation, esters and the like, such as methyl esters, ethyl esters and the like.

Preparation method

In another aspect, the present invention provides a process for preparing a compound of formula I, comprising the steps of:

wherein R in the formula¹，R²And R³As defined above;

step (I): 7-chloro-3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridine is reacted with TMS-protected acetylene under Sonogashira conditions, preferably Pd (PPh3)2Cl2, CuI, Et3N, in toluene.

Step (II): removing an ethynyl protecting group under an alkaline condition, wherein the alkali is NaOH or KOH; the solvent is methanol.

Step (III): under the alkaline condition, 2-chloro-2- (hydroxyimino) methyl acetate reacts with ethynyl to generate isoxazole ring, and the alkali is Na2CO₃And K2CO3, wherein the solvent is ethanol.

Step (IV): prepared isoxazole compounds and R³R²Preparation of amide compounds by NH reaction, in whichThe agent is methanol, ethanol or THF.

Pharmaceutical composition

In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt, solvate, prodrug thereof and one or more pharmaceutically acceptable adjuvants. The pharmaceutical compositions may 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.

Applications of

In another aspect, the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of mGluR 2-related disorders (e.g., mood disorders, anxiety disorders, cognitive disorders, etc.).

Detailed Description

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

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. 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 modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

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

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

To 7-chloro-3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] with protection of N2]Triazolo [4,3-a]Pyridine (11g, 40mmol) in toluene (150mL) was added Pd (PPh)₃)₂Cl₂(1.4g, 2mmol), CuI (0.38g, 2mmol) and Et₃N (30 mL). Trimethylsilylacetylene (11.2mL, 80mmol) was added dropwise at 80 deg.C, and the mixture was stirred for 6 h. The resulting mixture was filtered, 250mL of ethyl acetate was added to the filtrate, and the solution was washed with water, dried with organic phase, and concentrated. The resulting residue was purified by silica gel column, eluting with 25% ethyl acetate/petroleum ether, to give a light brown solid (11.59g, 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 (10.11g, 30mmol) was dissolved in 80mL of methanol. An aqueous solution (15mL) of NaOH (0.12g, 3mmol) was added with stirring at room temperature and the mixture was stirred for 4 h. The mixture was concentrated under reduced pressure and ethyl acetate (250mL) and water (40mL) were added to the residue, the layers were separated, the organic phase was dried, concentrated and the residue was purified on a silica gel column eluting with 30% ethyl acetate/petroleum ether to give a yellow solid (6.2g, 78%).

¹H NMR(400MHz，CDCl₃)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) preparation of 5- (3- (cyclopropylmethyl) -8- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl) isoxazole-3-carboxy methyl ester:

reacting 3- (cyclopropylmethyl) -7-ethynyl-8- (trifluoromethyl) - [1,2,4]Triazolo [4,3-a]Pyridine (5.83g, 22mmol) and sodium carbonate (14.0g, 132mmol) were dissolved in ethanol (100 mL). A solution of methyl 2-chloro-2- (hydroxyimino) acetate (15.1g, 110mmol) in ethanol (50mL) was added dropwise to the 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 (400mL) and water (100mL) were added to the residue, the organic phase was separated, dried, concentrated and the resulting residue was purified on a silica gel column eluting with 30% ethyl acetate/petroleum ether to give a white solid (4.73g, 58.7%), LC-ms (esi) m/z: 366.0938(M + H)⁺。

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

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

¹H NMR(400MHz，CDCl₃)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)⁺(ii) a Melting point: 126.4 ℃.

The compounds of examples 2-6 were prepared according to the methods described above in this application using different organic amine substrates, and the resulting structures of the compounds and their characterization data are shown in table 1:

and (3) biological activity determination: [³⁵S]GTP γ S binding assay

CHO cells stably expressing mGluR2 were incubated at 35 ℃ with 5% CO₂Then, a medium containing 10% fetal bovine serum [ 1% proline, 1mM sodium pyruvate, 1mM succinic acid, 1mM disodium succinate, 80 units/mL penicillin, 80. mu.g/mL streptomycin, 200. mu.g/mL hygromycin B, 3mM L-glutamine ] was used]And (5) culturing. Then, the above cultured cells were washed with PBS (-), dissociated, and centrifuged at 1000rpm for 10min at 5 ℃ to recover the cells. The resulting material was suspended in 20mM HEPES buffer (pH7.4) and homogenized in a homogenizer, and then centrifuged at 5 ℃ for another 15min to obtain particles again, and the obtained particles were further subjected to homogenization and centrifugation operations 2 to 3 times. The resulting particles were homogenized in the above buffer. The above homogenate was diluted with a buffer for binding assay (final concentration: 10mM HEPES, 800mM NaCl, 10mM MgCl)₂10MGDP, 10. mu.g/mL saponin (Sigma-Aldrich, CAS No: 8047-15-2), 0.1% BSA). To the mixture containing 10. mu.g of membrane protein/the above mixture, compounds 1 to 6 were added, respectively, and the resulting mixture was incubated at 30 ℃ for 30 min. Then, glutamate (final concentration: 20(mGluR2) and [ solution ] was added to the above mixture³⁵S]GTP γ S (final concentration: 0.15 nM); and the mixture was incubated at 30 ℃ for 30 min. The resulting incubation solution was suction filtered onto a Wattman GF/C filter to stop the reaction and washed with 3X 500. mu.L of ice-cold 10mM sodium phosphate buffer (pH 7.4). The filter was dried and scintillation fluid was added thereto and the membrane bound radioactivity was measured with a liquid scintillation meter. 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. Inhibition was obtained using non-linear analysis as percent inhibition of specific binding at different concentrations of compoundCurve line. From this inhibition curve, the concentration of compound that inhibits 50% specific binding (IC) was calculated₅₀). The results obtained are shown in Table 2.

[ Table 2]

The above activity results indicate that the compounds of the invention have a very good antagonistic effect on mGluR 2.

The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. 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

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, prodrug thereof:

wherein

R¹Is selected from C_3-8cycloalkyl-C_1-6Alkyl-, C_1-6Alkoxy radical C_1-6Alkyl-, C_1-6Alkyl-, C_1-6Haloalkyl-;

2. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R¹Is selected from C_3-8cycloalkyl-C_1-4Alkyl-, C_1-4Alkoxy radical C_1-4Alkyl-, C_1-4Alkyl-, C_1-4A haloalkyl group-.

3. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R¹Is selected from C_3-6cycloalkyl-C_1-2Alkyl-, C_1-2Alkoxy radical C_1-2Alkyl-, C_1-2Alkyl-, C_1-2A haloalkyl group-.

4. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R¹Is selected from C_3-4cycloalkyl-C_1-2Alkyl-, C_1-2Alkoxy radical C_1-2An alkyl group-.

5. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R²And R³Independently selected from hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl-, or R²And R³Together with the bound N atom, form a 3-6 membered nitrogen containing heterocyclic ring.

6. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R²And R³Independently selected from hydrogen, C_1-3Alkyl radical, C_1-3Haloalkyl-, or R²And R³Together with the bound N atom, form a 4-6 membered nitrogen containing heterocyclic ring.

7. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein R²And R³Independently selected from hydrogen, C_1-3Alkyl, or R²And R³Together with the bound N atom, form a 4-6 membered nitrogen containing heterocyclic ring.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug thereof, wherein the compound is any one of the following compounds:

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

9. A medicament comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, prodrug thereof.

10. Use of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, prodrug thereof, for the manufacture of a medicament for the treatment or prevention of a mGluR 2-related disorder (e.g., mood disorders, anxiety disorders, cognitive disorders, etc.).