阅读说明：本技术 一种不饱和酮类化合物、其制备方法和用途 (Unsaturated ketone compound, preparation method and application thereof ) 是由 胡有洪 谢欣 鲁伯埙 张玉芳 郭世猛 王聪聪 王志龙 于 2019-04-09 设计创作，主要内容包括：本发明涉及一种新型的GPR52拮抗剂。具体而言,涉及一种不饱和酮类化合物、其药学上可接受的盐、立体异构体或前药分子；其药物组合物的制备方法；以及作为孤儿G蛋白偶联受体GPR52拮抗剂的用途,进而涉及GPR52拮抗剂在亨廷顿病预防及治疗药物制备中的用途。(The present invention relates to a novel GPR52 antagonist. In particular to an unsaturated ketone compound, and pharmaceutically acceptable salt, stereoisomer or prodrug molecules thereof; a process for the preparation of pharmaceutical compositions thereof; and the application of the antagonist as a GPR52 antagonist of an orphan G protein-coupled receptor, and further relates to the application of the GPR52 antagonist in the preparation of medicaments for preventing and treating Huntington diseases.)

1. An unsaturated ketone compound shown in formula (I), and pharmaceutically acceptable salt, stereoisomer or prodrug thereof,

wherein:

Ar¹and Ar²Each independently selected from a 5-to 10-membered aryl group or a 5-to 10-membered heteroaryl group;

R¹is Ar¹The substituent(s) are independently selected from H, halogen, cyano, hydroxyl, nitro, carboxyl, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, unsubstituted or substituted amino, 5-10 membered aryl, 5-10 membered heteroaryl, and unsubstituted or substituted 3-10 membered heterocyclic group by tert-butoxycarbonyl; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl and tert-butyloxycarbonyl;

R²is Ar²The substituent(s) are independently selected from H, halogen, cyano, hydroxyl, nitro, carboxyl, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, unsubstituted or substituted amino, 5-10 membered aryl, 5-10 membered heteroaryl, and unsubstituted or substituted 3-10 membered heterocyclic group by tert-butoxycarbonyl; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl and tert-butyloxycarbonyl;

m is an integer from 0 to 5;

l is-O-CH₂-、-S-CH₂-、-NR³-CH₂-、-(CHR⁴)_i-CH₂-or L is absent;

R³selected from H, C1-C6 alkyl, tert-butyloxycarbonyl, 5-10 membered aryl or 5-10 membered heteroaryl;

R⁴selected from H, amino or amino substituted by tert-butyloxycarbonyl, halogen, cyano, hydroxyl, nitro, carboxyl, C1-C6 alkyl, 5-10 membered aryl and 5-10 membered heteroaryl;

i is selected from an integer of 0 to 5.

2. The unsaturated ketone compound represented by the formula (I), a pharmaceutically acceptable salt, a stereoisomer or a prodrug thereof according to claim 1, wherein:

Ar¹selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrazolyl, benzothienyl, indolyl; more preferably, Ar¹Selected from phenyl, thienyl;

Ar²selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrazolyl; more preferably, Ar²Selected from phenyl, thienyl, furan, pyridyl;

R¹selected from H, halogen, cyano, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, 5-10 membered aryl, 5-10 membered heteroaryl, unsubstituted or substituted amino, and unsubstituted or tert-butoxycarbonyl substituted 3-10 membered heterocyclic group; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl and tert-butyloxycarbonyl; more preferably, R¹Selected from H, halogen, CF₃Methyl, methoxy;

R²selected from H, halogen, cyano, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, 5-10 membered aryl, 5-10 membered heteroaryl, unsubstituted or substituted amino, and unsubstituted or tert-butoxycarbonyl substituted 3-10 membered heterocyclic group; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl and tert-butyloxycarbonyl; more preferably, R²Selected from H, halogen, CF₃Methyl, methoxy;

m is selected from 0, 1 and 2;

l is selected from-O-CH₂-、-(CHR⁴)_i-CH₂-or L is absent; r⁴Selected from H, halogen, amino, hydroxyl; i is selected from 0, 1, 2, 3,4。

3. The unsaturated ketone compound represented by the formula (I), a pharmaceutically acceptable salt, a stereoisomer or a prodrug thereof according to claim 1, wherein: the unsaturated ketone compound shown in the formula (I) is selected from the following compounds:

4. a process for the preparation of unsaturated ketone compounds of formula (I) according to any one of claims 1 to 3, characterized in that they are selected from the following schemes I and II:

scheme I comprises the following steps:

(1) refluxing the compound I-1 in the presence of methanol and concentrated sulfuric acid to perform esterification reaction to obtain a compound I-2;

(2) carrying out addition and elimination reaction on the compound I-2 and the compound I-3 (dimethyl methyl phosphate) in the presence of THF (tetrahydrofuran) and n-BuLi (n-butyllithium) to obtain a compound I-4;

(3) reacting the compound I-4 with the compound I-5 in the presence of THF and potassium carbonate to obtain a compound I-6 through HWE (Horner-Wadsworth-Emmons) reaction;

wherein Ar is¹、Ar²、R¹、R²L and m are as defined above;

scheme II comprises the following steps:

carrying out aldol condensation reaction on the compound II-1 and the compound II-2 in the presence of ethanol and KOH solution to obtain a product II-3;

wherein Ar is¹、Ar²、R¹、R²As defined above.

5. A pharmaceutical composition, comprising at least one of the unsaturated ketone compound represented by formula (I), a pharmaceutically acceptable salt, a stereoisomer, and a prodrug thereof according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

6. Use of an unsaturated ketone compound represented by the formula (I) as defined in any one of claims 1 to 3, a pharmaceutically acceptable salt, a stereoisomer or a prodrug thereof for the preparation of a GPR52 antagonist.

7. Use of a pharmaceutical composition according to claim 5 for the preparation of a GPR52 antagonist.

8. Use of an unsaturated ketone compound represented by the formula (I), a pharmaceutically acceptable salt, a stereoisomer, or a prodrug thereof according to any one of claims 1 to 3 for the preparation of a medicament for the prevention and/or treatment of huntington's disease.

9. Use of the pharmaceutical composition of claim 5 for the preparation of a medicament for the prevention and/or treatment of huntington's disease.

Technical Field

The present invention relates to a novel GPR52 antagonist. In particular to an unsaturated ketone compound, and pharmaceutically acceptable salt, stereoisomer or prodrug molecules thereof; a process for the preparation of pharmaceutical compositions thereof; and the application of the antagonist as a GPR52 antagonist of an orphan G protein-coupled receptor, and further relates to the application of the GPR52 antagonist in the preparation of medicaments for preventing and treating Huntington diseases.

Background

Huntington's Disease (HD), a delayed neurodegenerative genetic disease controlled by an autosomal chromosome, is mainly caused by a mutated huntington gene (HTT gene), and has a global incidence of one in ten thousandth and a survival rate of only 10 to 20 years after onset. HD often begins to appear in adulthood and is characterized by progressive motor, cognitive and neuropsychiatric impairment. The disease cannot be cured, but some symptomatic treatment means still exist.

The HTT gene encodes Huntington protein, the number of CAG trinucleotide repeats in exon 1 region of the healthy HTT gene is 10-26, while the number of CAG repeats in HD patients is increased (more than 35), resulting in the amplification of the glutamine repeat region (polyQ) of the synthetic variant protein (mHTT). The variant proteins are sheared, aggregated, toxic, and concentrated in the striatum leading to neuronal death and a series of neurological, psychological, and metabolic-related symptoms characteristic of chorea, ultimately leading to early death.

Although the mechanism by which mHTT proteins cause neuronal death is not clear, direct reduction of variant HTT protein levels has been found to have significant therapeutic effects on disease-associated phenotypes in various animal and cellular models. The research in the international HD field mainly focuses on RNA targeting means such as RNA interference, gene therapy, antisense RNA inhibition, CRISPR/Cas9, however, these RNA targeting methods require large biomolecule administration or rely on viral administration, and face many difficulties from both technical and economic perspectives. Research of the Luboxun subject group at the university of Compound Dan discovers that a G protein coupled receptor GPR52 is closely related to generation and development of HD, and the knock-out of the GPR52 gene in a mouse can remarkably save the related phenotype of HD, which suggests that GPR52 may be a potential new HD treatment target. A topic group of Shanghai medicament Xiexin of Chinese academy of sciences adopts a high-throughput screening method to obtain a small molecule compound E7 for specifically blocking GPR52, the compound can effectively reduce the mHTT level on cell, drosophila and mouse models, effectively saves HD-related phenotypes, and strongly proves the potential therapeutic effect of the small molecule medicament targeting GPR52 on HD, so that the discovery and modification of the GPR52 antagonist have very important values on scientific research and clinical application. Based on the need for a GPR52 small molecule drug for the treatment of huntington's disease, the present invention provides a structurally novel class of ketonic small molecule GPR52 antagonists.

Disclosure of Invention

The invention provides a novel ketone GPR52 antagonist, and a preparation method and application thereof.

The invention is implemented by the following technical scheme:

an unsaturated ketone compound shown in formula (I), and pharmaceutically acceptable salt, stereoisomer or prodrug thereof,

wherein:

Ar¹and Ar²Each independently selected from a 5-to 10-membered aryl group or a 5-to 10-membered heteroaryl group;

R¹is Ar¹The substituent(s) are independently selected from H, halogen, cyano, hydroxyl, nitro, carboxyl, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, unsubstituted or substituted amino, 5-10 membered aryl, 5-10 membered heteroaryl, and unsubstituted or substituted 3-10 membered heterocyclic group by tert-butoxycarbonyl; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl group, and tert-butyloxycarbonyl group (Boc group).

R²Is Ar²The substituent(s) are independently selected from H, halogen, cyano, hydroxyl, nitro, carboxyl, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, unsubstituted or substituted amino, 5-10 membered aryl, 5-10 membered heteroaryl, and unsubstituted or substituted 3-10 membered heterocyclic group by tert-butoxycarbonyl; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl group, and tert-butyloxycarbonyl group (Boc group).

m is an integer from 0 to 5;

l is-O-CH₂-、-S-CH₂-、-NR³-CH₂-、-(CHR⁴)_i-CH₂-or L is absent;

R³selected from H, C1-C6 alkyl, tert-butyloxycarbonyl, 5-10 membered aryl or 5-10 membered heteroaryl;

R⁴selected from H, amino or amino substituted by tert-butyloxycarbonyl, halogen, cyano, hydroxyl, nitro, carboxyl, C1-C6 alkyl, 5-10 membered aryl and 5-10 membered heteroaryl;

i is selected from an integer of 0 to 5;

the 5-to 10-membered aryl group is a 5-to 10-membered monocyclic or fused bicyclic ring such as phenyl or naphthyl;

the 5-10 membered heteroaryl is a 5-10 membered heteroaryl ring or fused bicyclic ring containing 1-3 heteroatoms selected from N, O and S, such as pyridyl, furyl, thienyl, indolyl, benzothienyl, benzofuryl, benzopyridyl;

the halogens include fluorine, chlorine, bromine and iodine;

the C1-C6 alkyl is a saturated aliphatic straight chain or branched chain alkyl with 1-6 carbon atoms;

the C1-C6 alkoxy is a straight chain or branched chain alkoxy with 1-6 carbon atoms;

the 3-10 membered heterocyclic group is a saturated or unsaturated 3-10 membered monocyclic or polycyclic aliphatic heterocyclic ring containing one or more heteroatoms selected from N, O, S on the ring, and is preferably a 4-7 membered heterocyclic group such as piperazinyl, piperidinyl or morpholinyl in the invention;

preferably, the pharmaceutically acceptable salt is: hydrochloride, sulfate, phosphate, methanesulfonate, maleate, etc.;

the prodrug is: ester compounds, amide compounds, and carboxamide compounds of unsaturated ketone compounds represented by formula (I).

In the unsaturated ketone compound shown in the formula (I),

preferably, Ar¹Selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrazolyl, benzothienyl, indolyl; more preferably, Ar¹Selected from phenyl, thienyl;

preferably, Ar²Selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrazolyl; more preferably, Ar²Selected from phenyl, thienyl, furan, pyridyl;

preferably, R¹Selected from H, halogen, cyano, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, 5-10 membered aryl, 5-10 membered heteroaryl, unsubstituted or substituted amino, and unsubstituted or tert-butoxycarbonyl substituted 3-10 membered heterocyclic group; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl and tert-butyloxycarbonyl; more preferably, R¹Selected from H, halogen, CF₃Methyl, methoxy;

preferably, R²Selected from H, halogen, cyano, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkoxy, 5-10 membered aryl, 5-10 membered heteroaryl, unsubstituted or substituted amino, and unsubstituted or tert-butoxycarbonyl substituted 3-10 membered heterocyclic group; the substituted C1-C6 alkyl is substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxy; the substituted amino is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl and tert-butyloxycarbonyl; more preferably, R²Selected from H, halogen, CF₃Methyl, methoxy;

preferably, m is selected from 0, 1, 2; more preferably, m is 0;

preferably, L is selected from-O-CH₂-、-(CHR⁴)_i-CH₂-or L is absent; r⁴Selected from H, halogen, amino, hydroxyl; i is selected from 0, 1, 2, 3 and 4.

Preferably, the unsaturated ketone compound shown in the formula (I) is selected from the following compounds:

according to another aspect of the present invention, there is provided a process for the preparation of unsaturated ketone compounds of formula (I), selected from the following scheme I and scheme II:

scheme I comprises the following steps:

(1) refluxing the compound I-1 in the presence of methanol and concentrated sulfuric acid to perform esterification reaction to obtain a compound I-2;

(2) carrying out addition and elimination reaction on the compound I-2 and the compound I-3 (dimethyl methyl phosphate) in the presence of THF (tetrahydrofuran) and n-BuLi (n-butyllithium) to obtain a compound I-4;

(3) HWE of compound I-4 with compound I-5 in the presence of THF and potassium carbonate

(Horner-Wadsworth-Emmons) to obtain a compound I-6;

wherein Ar is¹、Ar²、R¹、R²L and m are as defined above;

scheme II comprises the following steps:

carrying out aldol condensation reaction on the compound II-1 and the compound II-2 in the presence of ethanol and KOH solution to obtain a product II-3;

wherein Ar is¹、Ar²、R¹、R²As defined above.

Preferably, scheme I comprises the steps of:

(1) dissolving a compound I-1 in methanol, adding a catalytic amount of concentrated sulfuric acid, carrying out reflux reaction, stopping the reaction after the TLC monitoring reaction is completed, cooling to room temperature, and separating and purifying to obtain a compound I-2;

(2)N₂under protection, dissolving dimethyl methylphosphonate I-3 in dry THF, cooling to-78 ℃, dropwise adding n-BuLi solution, stirring at-78 ℃ for 30min, adding tetrahydrofuran solution of a compound I-2, and reacting at-78 ℃. After TLC monitoring reaction is complete, raise temperature to 0 deg.C and add saturated NH₄Quenching the Cl solution, separating and purifying to obtain a compound I-4;

(3) dissolving the compound I-4 in THF, adding potassium carbonate, N₂After 3 times of replacement, the reaction mixture was reacted at room temperature for 40 min. Adding THF solution of the compound I-5, moving to 40 ℃ for reaction for 12h, monitoring by TLC to ensure that the reaction system is cooled to room temperature after the reaction is completed, and separating and purifying to obtain the product I-6.

Preferably, scheme II comprises the following steps:

dissolving the compound II-1 and the compound II-2 in ethanol, adding 50% KOH solution, reacting at room temperature, monitoring by TLC (thin layer chromatography) to complete the reaction, stopping the reaction, adding ice water for quenching, neutralizing by 6M hydrochloric acid solution to be neutral, separating out a large amount of solids, filtering to obtain solids, and recrystallizing by EtOH to obtain the product II-3.

In another aspect of the present invention, a pharmaceutical composition is provided, which includes at least one of the unsaturated ketone compound represented by formula (I), a pharmaceutically acceptable salt, a stereoisomer, and a prodrug thereof, and a pharmaceutically acceptable carrier.

The invention also provides application of the unsaturated ketone compound shown in the formula (I), pharmaceutically acceptable salts, stereoisomers or prodrugs thereof or the pharmaceutical composition in preparing GPR52 antagonists.

The compound has the function of reducing mHTT, so the invention also provides the application of the unsaturated ketone compound shown in the formula (I), the pharmaceutically acceptable salt, the stereoisomer or the prodrug thereof or the pharmaceutical composition in preparing the drugs for preventing and/or treating Huntington disease.

Drawings

FIG. 1 is the structure of Compound E7;

FIG. 2 is a graph of the inhibitory activity of representative compounds 23 and 43 on GPR52 and β 2AR and GCGR;

FIG. 3 is a bar graph of the results of Western blot experiments and TR-FRET experiments for representative compounds 23 and 43.

Detailed Description

The following describes in detail specific embodiments of the present invention. The described embodiments are to be considered in all respects only as illustrative and not restrictive.

Examples of preparation of Compound (I)