CN117430522A - GPR139 receptor agonist and preparation method thereof - Google Patents

GPR139 receptor agonist and preparation method thereof Download PDF

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CN117430522A
CN117430522A CN202210833569.0A CN202210833569A CN117430522A CN 117430522 A CN117430522 A CN 117430522A CN 202210833569 A CN202210833569 A CN 202210833569A CN 117430522 A CN117430522 A CN 117430522A
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compound
alkyl
pharmaceutically acceptable
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acceptable salt
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陈景才
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Zhejiang Youning Biomedical Technology Co ltd
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Abstract

The invention provides a compound as shown in formula (I)A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 Etc. have the definitions given in the description. In addition, the invention also provides a preparation method of the compound and pharmaceutically acceptable salts thereof and application of the compound in preparation of medicines for treating GPR139 receptor related diseases.

Description

GPR139 receptor agonist and preparation method thereof
Technical Field
The present invention relates to the field of pharmaceutical chemistry. Specifically, the invention relates to a ligand molecule of a G Protein-coupled Receptor 139 (GPR 139 for short).
Background
G Protein-coupled Receptor 139 (GPR 139 for short) was first discovered by Gloriam as per 2005 (Biochim Biophys Acta 2005; 1722:235-246), also known as GPCR12, PGR3, KOR3L, GPRg1.GPR139 is predominantly expressed in the nucelium, striatal nucleus, thalamus, hypothalamus and pituitary in the Central Nervous System (CNS), with amino acid sequences that are highly conserved among different species such as 96%,92% and 70% homology of the human GPR139 protein sequence to mouse, chicken and zebra fish, respectively. GPR139 receptor is expressed on the cell surface and consists of an N-terminal fragment, 7 membrane penetrating fragments and a C-terminal fragment, wherein the N-terminal fragment consists of 26 amino acids and contains one cysteine. Wang et al reported that GPR139 receptor and dopamine receptor D2 were co-expressed in different tissues of the murine brain, and demonstrated by in vitro cell experiments that GPR139 promoted the agonist of dopamine receptor D2 to produce a calcium flux signal that was inhibited by both an antagonist of dopamine receptor D2 and an antagonist of GPR139 (Frontiers in Neuroscience, march 2019,Volume 13,Article 281). Furthermore, nepomuno et al demonstrated that GPR139 was able to act synergistically with either melanocortin receptor 3 or 5 (MC 3/MC 5). These results indicate that GPR139 is able to form heterodimers with other cell surface receptors to play a physiological role. In addition, our experiments have demonstrated that GPR139 receptor is able to form homodimers via N-terminal cysteines.
While different research teams have sought ligands, including agonists and antagonists, for GPR139, liu et al reported that L-phenylalanine and L-tryptophan are endogenous agonists of GPR139 (Mol Phacol 2015; 88:911-925).
The existing research shows that the GPR139 receptor has important physiological functions and is a potential drug target for resisting anxiety, depression and schizophrenia, treating parkinsonism, treating drugs and alcohol abuse and treating metabolic related diseases. The structural, expression, pharmacological and physiological functional information of the related GPR139 provides a solid basis for the design and synthesis of novel GPR139 agonists.
Disclosure of Invention
In a first aspect of the present invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof
Wherein,
R 1 、R 2 、R 3 、R 4 、R 5 and R is 6 Each independently selected from the group consisting of: hydrogen, halogen, hydroxy, carboxy, C 1-6 Acyl, C 1-3 alkyl-carbonyl-C 1-3 Alkyl, C 1-6 Alkyl-aldehyde group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups;
r7 and R8 are each independently selected from the group consisting of: hydrogen, C1-4 alkyl.
In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 Each independently selected from the group consisting of: hydrogen, fluorine, chlorine, hydroxy, carboxyl, C 1-6 Acyl, C 1-2 alkyl-carbonyl-C 1-2 Alkyl, C 1-3 Alkyl-aldehyde group, C 1-3 Alkyl, C 1-6 Haloalkyl, C 1-3 Haloalkoxy groups.
In some embodiments, R 1 、R 2 And R is 3 Each independently selected from the group consisting of: hydrogen, fluorine, chlorine, hydroxy, carboxyl, C 1-6 Acyl, C 1-3 alkyl-carbonyl-C 1-3 Alkyl, C 1-6 Alkyl-aldehyde group, methyl group, trifluoromethyl group, trifluoromethoxy group.
In some embodiments, R 4 、R 5 And R is 6 Each independently selected from the group consisting of: hydrogen, fluorine, chlorine, hydroxyl, carboxyl, methyl, trifluoromethyl, trifluoromethoxy.
In some embodiments, R 7 And R is 8 Each independently selected from the group consisting of: hydrogen and methyl.
In some embodiments, the compound is selected from the group consisting of:
in a second aspect of the present invention there is provided a process for the preparation of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, comprising the steps of:
or alternatively
Wherein, R ', R ", R'" are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, carboxy, keto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Is defined as before.
In a third aspect of the invention there is provided a pharmaceutical composition comprising a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, there is provided a method for preparing a pharmaceutical composition according to the third aspect of the present invention, comprising the steps of: a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier to form a pharmaceutical mixture.
In a fifth aspect of the invention there is provided the use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention, for the manufacture of a medicament for the treatment of a GPR139 receptor-related disease.
In another preferred embodiment, the GPR139 receptor-related disorder includes anxiety, depression, parkinsonism, drug abuse, and alcohol abuse.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventors have conducted extensive and intensive studies and have unexpectedly found that the compounds of the present invention have excellent GPR139 receptor agonistic activity, thereby conducting a series of synthetic and biological activity tests. The present invention has been completed on the basis of this finding.
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Terminology
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In the compounds of the invention, when any variable occurs more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atom adjacent to the ring. It is to be understood that substituents and substitution patterns of the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that may be readily synthesized from readily available starting materials by techniques in the art and methods set forth below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.
The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1 -C 8 Alkyl "medium" C 1 -C 8 The definition of "includes groups having 1, 2, 3, 4, 5, or 8 carbon atoms in a linear or branched arrangement. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
The term "alkoxy" as used herein represents an alkyl-oxy group, wherein alkyl is as defined above.
As understood by those of skill in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.
The term "haloalkyl" as used herein represents an alkyl group wherein one or more hydrogen atoms are replaced by halogen, wherein the alkyl group is as defined above.
The term "haloalkoxy" as used herein represents an alkyl-oxy group having one or more hydrogen atoms replaced with halogen, wherein alkyl is as defined above.
Active ingredient
In the present invention, an active ingredient effective to agonize the GPR139 receptor is provided. The active ingredient is a compound shown in a general formula (I), and can effectively prevent, treat and/or relieve GPR139 related diseases.
Experiments show that the active ingredients of the invention can effectively excite the GPR139 receptor, thereby preventing, treating and/or relieving GPR139 related diseases.
It is to be understood that the active ingredient of the present invention includes a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof. It is to be understood that the active ingredients of the present invention also include crystalline, amorphous, and deuterated forms of the compounds of formula (I).
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts of the compounds of the invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, and triethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.
Preparation method
The process for preparing the compound of the formula (I) according to the present invention is described in more detail below, but these specific processes do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Typically, in the preparation scheme, each reaction is carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., 0 ℃ C. To 80 ℃ C., preferably 0 ℃ C. To 50 ℃ C.). The reaction time is usually 0.1 hours to 60 hours, preferably 0.5 to 48 hours.
The following general schemes may be used to synthesize the compounds of the structure of formula (I) of the present invention.
Or alternatively
Wherein R ', R', R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 Is defined as before.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent GPR139 receptor agonistic activity, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for treating, preventing and alleviating diseases associated with GPR139 receptor or abnormal expression.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-3000 (active dose range 3-30 mg/kg) mg of the compound of the invention per dose, more preferably 10-2000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiersWetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 6 to 600mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the invention include:
(a) The compounds of the invention are highly potent agonists of the GPR139 receptor, with some compounds having EC50 values < 0.1. Mu.M.
(b) The compound of the invention has simple synthesis and higher yield.
(c) The compound has low toxic and side effects and good pharmaceutical property.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated. The starting materials used in the present invention are commercially available unless otherwise specified.
Examples
Example 1
Preparation of Compound NRB025
S-phenethylamine (171 mg, 1.42 mmol) and diisopropylethylamine (183 mg, 1.42 mmol) were dissolved in 2ml of dichloromethane under nitrogen and cooled to about 5 degrees celsius with an ice water bath. Malonyl chloride (100 mg, 0.71 mmol) was then slowly added dropwise to the reaction solution. The dripping is completed in about 2 minutes. The reaction was stirred for 15 minutes after completion of the dropwise addition. The reaction completion was monitored by TLC. The reaction was completed, the reaction solution was poured into 10ml of saturated ammonium chloride solution, and extracted with dichloromethane (10 ml×2). The organic phase is dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 37.5 mg of product. Analytical data were as follows:
LCMS(ESI+):m/z 311(M+H)；1H-NMR(300MHz,CDCl3)δ7.66-7.26(m,8H),7.08(brs,2H),5.09(m,2H),3.14(s,2H),1.50(d,J＝6.9Hz,6H)。
examples 2 to 5
Preparation of Compounds NRB037, NRB038, NRB040, NRB064
The procedure of example 1 was used, except that: and replacing S-phenethylamine with different substrates to obtain the compound 2-5.
Example 6
Preparation of Compound NRB035
The first step: preparation of intermediate 1
S-phenethylamine (870 mg, 7.32 mmol) and diisopropylethylamine (1.72 g, 13.3 mmol) were dissolved in 20 ml of dichloromethane under nitrogen and cooled to about 5 degrees celsius with an ice water bath. Ethyl chloroformylacetate (1 g, 6.67 mmol) was then slowly added dropwise to the reaction solution. The dripping is completed in about 5 minutes. The reaction was stirred for 15 minutes after completion of the dropwise addition. The reaction completion was monitored by TLC. The reaction was completed, the reaction solution was poured into 50ml of saturated ammonium chloride solution, and extracted with dichloromethane (20 ml×2). The organic phase is dried over sodium sulfate, filtered and concentrated. 1.35 g of oily liquid are obtained. Analysis data: LCMS (ESI+): M/z236 (M+H).
And a second step of: preparation of intermediate 2
Intermediate 1 (1.25 g, 5.32 mmol) was dissolved in tetrahydrofuran (10 ml) and water (10 ml) and lithium hydroxide monohydrate (447 mg, 10.64 mmol) was added in one portion at room temperature. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the pH was adjusted to 3 with dilute hydrochloric acid and extracted with ethyl acetate (50 ml. Times.2). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness to give 1.34 g of an oil. The oil slowly solidified at room temperature. Analysis data: LCMS (ESI-): M/z206 (M-H).
And a third step of: preparation of Compound NRB035
Intermediate 2 (30 mg, 0.14 mmol) and S-4-chlorobenzeneethylamine (33 mg, 0.17 mmol) were dissolved in dichloromethane (2 ml) under nitrogen, followed by the addition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (54 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and diisopropylethylamine (36 mg, 0.28 mmol). The reaction was stirred at room temperature overnight. The reaction completion was monitored by TLC. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 ml), and extracted with dichloromethane (10 ml×2). The organic phase was dried, filtered and concentrated and purified by preparative TLC to give compound NRB035 as a white solid (14 mg). Analytical data were as follows:
LCMS(ESI+):m/z 345,347(M+H)；1H-NMR(300MHz,CD3OD)(m,9H),5.05-4-90(m,2H),3.07(s,2H),1.44(m,6H)。
examples 7 to 25
Preparation of Compounds NRB036, NRB039, NRB041, NRB042, NRB043, NRB044, NRB045, NRB046, NRB047, NRB048, NRB026, NRB032, NRB056, NRB057, NRB058, NRB061, NRB063, NRB065, NRB066
The procedure of example 1 was used, except that: different substrates are used for replacing S-phenethylamine and S-4-chlorophenylethylamine, so that the compounds 6-14 are prepared.
Example 26
Preparation of Compound NRB060
The first step: preparation of intermediate 2
S-1-phenethylamine (100 mg, 0.83 mmol) and potassium cyanate (335 mg, 4.13 mmol) were dissolved in 0.85 ml 1N HCl and 0.5 ml water and reacted for 1 hour at 80℃under microwave conditions.
The reaction was monitored by TLC and completed. The reaction was solid, which was suction filtered and washed three times with n-hexane (3×5 ml). The solid was dried in vacuo to give 120 mg of crude product. Analysis data: LCMS (ESI+): M/z 165 (M+H).
And a second step of: preparation of intermediate 3
Intermediate 2 (120 mg, 0.73 mmol) and pyridine (173 mg, 2.19 mmol) were dissolved in 2ml dichloromethane, phenyl chloroformate (137 mg, 0.88 mmol) was added and stirred at room temperature overnight. The reaction was monitored by TLC and completed. The reaction was taken up in 3ml of water, extracted with dichloromethane (3 x3 ml), dried over anhydrous sodium sulfate and spin-dried over column (ethyl acetate: petroleum ether=1:10) to give 55 mg of product. Analysis data: LCMS (ESI+): M/z 285 (M+H).
And a third step of: preparation of Compound NRB060
Intermediate 3 (45 mg, 0.16 mmol) and starting material a (33 mg, 0.19 mmol) were dissolved in 1ml acetonitrile and potassium carbonate (43.7 mg, 0.32 mmol) was added. The reaction was stirred at 50℃for 5 hours. The reaction was monitored by TLC and completed. The reaction was dried by rotary-drying and purified by preparative TLC to give 20 mg of the product as a white oil. Analysis data: LCMS (ESI+): M/z 326 (M+H).
1 H-NMR(300MHz,CDCl 3 )δ7.66-7.26(m,8H),7.08(br s,2H),5.09(m,2H),3.14(s,2H),1.50(d,J＝6.9Hz,6H).
1 H-NMR(300MHz,CD 3 OD)δ7.34-7.12(m,9H),5.11(q,J＝6.9Hz 1H),5.01-4.95(m,1H),2.36(s,3H),1.45(d,J＝7.5Hz,3H),1.42(d,J＝7.2Hz,3H).
Example 27
Preparation of Compound NRB062
The first step: preparation of intermediate 2
S-1-phenethylamine (200 mg, 1.65 mmol) and S1 (161 mg, 1.10 mmol), EDCl (423 mg, 2.2 mmol), HOBT (297 mg, 2.2 mmol) were dissolved in 5ml dichloromethane and stirred overnight at room temperature.
The reaction was monitored by TLC and completed. Quenched by addition of 1N dilute hydrochloric acid, extracted with dichloromethane (3×5 ml), dried over anhydrous sodium sulfate, and spin-dried to give 240 mg of the product as a white oil by preparative TLC. Analysis data:
LCMS(ESI+):m/z 250(M+H)。
and a second step of: preparation of intermediate 3
Intermediate 2 (240 mg, 0.96 mmol) was dissolved in 3ml tetrahydrofuran and 3ml water, lithium hydroxide monohydrate (122 mg, 2.9 mmol) was added and stirred overnight at room temperature. The reaction was monitored by TLC and completed. The reaction mixture was adjusted to pH 3 to 4 by the addition of 1N diluted hydrochloric acid, extracted with ethyl acetate (3X 10 ml), dried over anhydrous sodium sulfate and spun-dried to give 200 mg of a white solid product. Analysis data: LCMS (ESI+): M/z 222 (M+H).
And a third step of: preparation of Compound NRB062
Intermediate 3 (60 mg, 0.27 mmol) and S2 (35 mg, 0.2 mmol), EDCl (77 mg,
0.4 mmol), HOBT (54 mg, 0.4 mmol), diisopropylethylamine (52 mg, 0.4 mmol) were dissolved in 3ml dichloromethane and stirred at room temperature for 3 hours. The reaction was monitored by TLC and completed. Water 5ml, dichloromethane extraction (3×5 ml), drying over anhydrous sodium sulfate, and purification by preparative TLC (dichloromethane: methanol=10:1) gave 17 mg of a white solid product.
Analysis data: LCMS (ESI+): M/z 339 (M+H).
1 H-NMR(300MHz,DMSO-d 6 )δ
8.20-8.07(m,2H),7.31-7.13(m,9H),5.04-4.83(m,2H),3.21(q,J＝7.2Hz,1H),2.28(d,J＝7.2Hz,3H),1.38-1.23(m,6H),1.14(d,J＝6.9Hz,3H).
Example 28
GPR139 receptor Activity assay
1. Experimental method
HEK293 cells were grown in 10cm dishes containing DMEM complete medium (containing glutamine, sodium pyruvate, penicillin/streptomycin, 10% fetal bovine serum) at 37℃with 5% CO 2 The culture was carried out in an incubator to 90% confluence. And then passaged twice a week at 1:5. At the time of cell passage, the medium was first completely aspirated, washed once with 4mL DPBS, 3mL pancreatin digest was added and gently shaken. To the time of cell rupture, the pancreatin digest was aspirated and 5mL DMEM complete medium was added. After the dispersed cells were blown with a pipette, 1mL of the dispersed cell liquid was added to 5 new 10cm dishes, 7mL of DMEM complete medium was then added, and after mixing, the mixture was left at 37℃with 5% CO 2 Culturing in an incubator.
On the day of cell transfection, cells were digested at appropriate density into a 10cm dish, 6mL of DMEM/F12 medium (containing glutamine, sodium pyruvate, HEPES, fetal bovine serum) was added, and the mixture was incubated at 37℃with 5% CO 2 Culturing in an incubator for 5 hours. A50 mL sterile centrifuge tube A was taken, 1mL serum-free DMEM/F12 medium (containing glutamine, sodium pyruvate, HEPES) was added, and 10. Mu.g of GPR139 DNA was added and mixed well. Another 50mL sterile centrifuge tube B was taken, 1mL serum-free DMEM medium (containing glutamine, sodium pyruvate, HEPES) was added, and 60. Mu.L Fugene HD transfection reagent was added and mixed well. 1mL of Fugene HD transfection reagent was removed from centrifuge tube B, added to centrifuge tube A, mixed well, and left at room temperature for 20 minutes. Adding 2mL of DMEM/F12 medium (containing glutamine, sodium pyruvate, HEPES, and fetal bovine serum) into the centrifuge tube A, mixing, taking out the mixture (4 mL) in the centrifuge tube A, adding into the cells (10 mL liquid) in the 10cm dish, mixing, standing at 37deg.C, and 5% CO 2 Culturing in an incubator for 20-24 hours.
The next day, transfected cells were digested with pancreatin digests, added with appropriate DMEM/F12 medium (containing glutamine, sodium pyruvate, HEPES, penicillin/streptomycin, fetal bovine serum), and seeded into Matrigel coated 384-well plates at a cell density of 6.67×106cells/mL,30 μl/well. Placing 384-well plate at 37deg.C，5％CO 2 Culturing in an incubator.
On the third day, 10. Mu.L/well of FLIPR dye (diluted in HEPES solution containing Pluronic and Probenicid) was added to 384-well cell plates at 37℃with 5% CO 2 Incubate in incubator for 40 min. The diluted compounds were added to the cell plates and the calcium flux signal was read in a FLIPR reader.
Analysis of the data using XL-fit software and the EC for each compound was obtained 50 Values.
2. Experimental results
Table 1, EC50 values for compounds for calcium flux signal detection in GPR139 FLIPR cells
EC50 value (measured data, μm) of GPR139 FLIPR cell calcium flux signal detection compound
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof
Wherein,
R 1 、R 2 、R 3 、R 4 、R 5 and R is 6 Each independently selected from the group consisting of: hydrogen, halogen, hydroxy, carboxy, C 1-6 Acyl, C 1-3 alkyl-carbonyl-C 1-3 Alkyl, C 1-6 Alkyl-aldehyde group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups;
r7 and R8 are each independently selected from the group consisting of: hydrogen, C1-4 alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 Each independently selected from the group consisting of: hydrogen, fluorine, chlorine, hydroxy, carboxyl, C 1-6 Acyl, C 1-2 alkyl-carbonyl-C 1-2 Alkyl, C 1-3 Alkyl-aldehyde group, C 1-3 Alkyl, C 1-6 Haloalkyl, C 1-3 Haloalkoxy groups.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 And R is 3 Each independently selected from the group consisting of: hydrogen, fluorine, chlorine, hydroxy, carboxyl, C 1-6 Acyl, C 1-3 alkyl-carbonyl-C 1-3 Alkyl, C 1-6 Alkyl-aldehyde group, methyl group, trifluoromethyl group, trifluoromethoxy group.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 、R 5 And R is 6 Each independently selected from the group consisting of: hydrogen, fluorine, chlorine, hydroxyl, carboxyl, methyl, trifluoromethyl, trifluoromethoxy.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 7 And R is 8 Each independently selected fromThe following groups: hydrogen and methyl.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
7. a process for the preparation of a compound as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, comprising the steps of:
or alternatively
Wherein, R ', R ", R'" are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, carboxy, keto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Is defined as in claim 1.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
9. A method of preparing a pharmaceutical composition according to claim 8, comprising the steps of: a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier, thereby forming a pharmaceutical mixture.
10. The use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment of a GPR139 receptor-related disease.
In another preferred embodiment, the GPR139 receptor-related disorder includes anxiety, depression, parkinsonism, drug abuse, and alcohol abuse.
CN202210833569.0A 2022-07-14 2022-07-14 GPR139 receptor agonist and preparation method thereof Pending CN117430522A (en)

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