WO2024012532A1 - 一种gpr139受体激动剂及其制备方法 - Google Patents

一种gpr139受体激动剂及其制备方法 Download PDF

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WO2024012532A1
WO2024012532A1 PCT/CN2023/107260 CN2023107260W WO2024012532A1 WO 2024012532 A1 WO2024012532 A1 WO 2024012532A1 CN 2023107260 W CN2023107260 W CN 2023107260W WO 2024012532 A1 WO2024012532 A1 WO 2024012532A1
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alkyl
compound
pharmaceutically acceptable
acceptable salt
group
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French (fr)
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陈景才
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浙江友宁生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/02—Monocyclic hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a type of ligand molecule for G protein-coupled receptor 139 (G Protein-coupled Receptor 139, GPR139 for short).
  • G protein-coupled receptor 139 G Protein-coupled Receptor 139, GPR139 for short.
  • G Protein-coupled Receptor 139 was first discovered by Gloriam et al. in 2005 (Biochim Biophys Acta 2005; 1722:235-246), and is also known as GPCR12, PGR3, KOR3L, and GPRg1.
  • GPR139 is mainly expressed in the habenula, striatum, thalamus, hypothalamus and pituitary gland in the central nervous system (CNS). Its amino acid sequence is highly conserved in different species. For example, the human GPR139 protein sequence is similar to that of mice, chickens and zebras. The homology of fish is 96%, 92% and 70% respectively.
  • the GPR139 receptor When the GPR139 receptor is expressed on the cell surface, it consists of an N-terminal fragment, seven membrane-penetrating fragments, and a C-terminal fragment.
  • the N-terminal fragment consists of 26 amino acids and contains a cysteine.
  • GPR139 can act synergistically through melanocortin receptor 3 or 5 (MC3/MC5). These results indicate that GPR139 can form heterodimers with other receptors on the cell surface to exert physiological effects. In addition, our experiments have confirmed that the GPR139 receptor can form homodimers through the N-terminal cysteine.
  • GPR139 receptor has important physiological functions and is a potential drug target for anti-anxiety, anti-depression, anti-schizophrenia, treatment of Parkinson's syndrome, treatment of drug and alcohol abuse, and treatment of metabolism-related diseases.
  • Information on the structure, expression, pharmacology, and physiological functions of relevant GPR139 provides a solid foundation for the design and synthesis of new GPR139 agonists.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of: hydrogen, halogen, hydroxyl, carboxyl, 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;
  • R7 and R8 are each independently selected from the group consisting of hydrogen and C1-4 alkyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, carboxyl, C 1-6 acyl, C 1-2 Alkyl-carbonyl-C 1-2 alkyl, C 1-3 alkyl-aldehyde, C 1-3 alkyl, C 1-6 haloalkyl, C 1-3 haloalkoxy.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, carboxyl, C 1-6 acyl, C 1-3 alkyl-carbonyl-C 1-3 Alkyl, C 1-6 alkyl-aldehyde, methyl, trifluoromethyl, trifluoromethoxy.
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, carboxyl, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen and methyl.
  • the compound is selected from the group consisting of:
  • R', R", R"' are each independently selected from the following group: hydrogen, halogen, hydroxyl, carboxyl, ketone, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.
  • a pharmaceutical composition which is characterized by comprising the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • a method for preparing a pharmaceutical composition as described in the third aspect of the present invention which is characterized in that it includes the step of: adding the compound as described in the first aspect of the present invention, or its pharmaceutical composition
  • the above acceptable salt is mixed with a pharmaceutically acceptable carrier to form a pharmaceutical mixture.
  • a compound as described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition as described in the third aspect of the present invention, which is characterized by It is used to prepare drugs for treating GPR139 receptor-related diseases.
  • the GPR139 receptor-related diseases include anxiety, depression, Parkinson's disease, drug and alcohol abuse.
  • the inventor unexpectedly found that the compound of the present invention has excellent GPR139 receptor agonistic activity, and thus conducted a series of synthesis and biological activity tests. On this basis, the present invention was completed.
  • the "plurality” mentioned in the present invention means two or more.
  • “And/or” describes the relationship between related objects, indicating that there can be three relationships.
  • a and/or B can mean: A exists alone, A and B exist simultaneously, and B exists alone.
  • the character “/” generally indicates that the related objects are in an "or” relationship.
  • alkyl as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms.
  • C 1 -C 8 in “C 1 -C 8 alkyl” includes groups having 1, 2, 3, 4, 5, or 8 carbon atoms arranged in a straight or branched chain.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
  • alkoxy represents an alkyl-oxy group, where alkyl is as defined above.
  • halogen as used herein is meant to include chlorine, fluorine, bromine and iodine.
  • haloalkyl represents an alkyl group in which one or more hydrogen atoms are substituted by halogen, wherein alkyl is as defined above.
  • haloalkoxy represents an alkyl-oxy group having one or more hydrogen atoms substituted by halogen, wherein alkyl is as defined above.
  • an active ingredient that can effectively stimulate the GPR139 receptor is provided.
  • the active ingredient is a compound represented by general formula (I), and the active ingredient can effectively prevent, treat and/or alleviate GPR139-related diseases.
  • Tests have shown that the active ingredients of the present invention can effectively stimulate GPR139 receptors, thereby preventing, treating and/or alleviating GPR139-related diseases.
  • the active ingredients of the present invention include compounds represented by general formula (I), or pharmaceutically acceptable salts thereof, or prodrugs thereof. It should be understood that the active ingredient of the present invention also includes the crystalline form, amorphous compound, deuterated compound and other forms of the compound of general formula (I).
  • pharmaceutically acceptable salts refers to salts of compounds of the invention with acids or bases suitable for use as pharmaceuticals.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • One preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as 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 proline Acid, phenylalanine, aspartic acid, glutamic acid and other amino acids.
  • salts of the compounds of the invention with bases for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g.
  • lower alkanol ammonium salts salts and other pharmaceutically acceptable amine salts
  • amine salts such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine respectively.
  • the preparation methods of the compound of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be optionally prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 80°C, preferably 0°C to 50°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • R', R", R"', R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent GPR139 receptor agonistic activity
  • the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the compound of the present invention contain the compound of the present invention as the main active ingredient
  • the pharmaceutical composition can be used to treat, prevent and alleviate diseases related to GPR139 receptor or abnormal expression.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg/kg) mg of the compound of the invention/dose, more preferably, it contains 10-2000 mg of the compound of the invention/dose.
  • the "dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • solid lubricants such as
  • administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited.
  • Representative administration modes 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.
  • the active compound is mixed 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, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings 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 waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain 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 non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention 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 that may be required.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 6 to 600 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the compounds of the present invention can efficiently agonize GPR139 receptors, and the EC50 values of some compounds are ⁇ 0.1 ⁇ M.
  • the compound of the present invention is simple to synthesize and has a high yield.
  • the compound of the present invention has low toxic and side effects and good medicinal properties.
  • Compound 2-5 was prepared by using the method of Example 1, with the difference that different substrates were used to replace S-phenylethylamine.
  • intermediate 2 (30 mg, 0.14 mmol) and S-4-chlorophenylethylamine (33 mg, 0.17 mmol) were dissolved in dichloromethane (2 ml), and then 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol), and diisopropyl ethyl Amine (36 mg, 0.28 mmol). The reaction was stirred at room temperature overnight. Reaction completion was monitored by TLC.
  • Compound 6-14 was prepared by using the method of Example 1, with the difference that different substrates were used to replace S-phenylethylamine and S-4-chlorophenylethylamine.
  • HEK293 cells were grown in a 10cm culture dish containing DMEM complete medium (containing glutamine, sodium pyruvate, penicillin/streptomycin, and 10% fetal calf serum) and cultured at 37°C in a 5% CO2 incubator. 90% confluence. Then passaged twice a week at 1:5. When cells are passaged, first completely aspirate the culture medium, wash once with 4 mL of DPBS, add 3 mL of trypsin digestion solution, and shake gently. When the cells split, aspirate the trypsin digestion liquid and add 5 mL of DMEM complete culture medium. Disperse the cells with a pipette and add 1 mL of dispersed cell solution to five new 10 cm culture dishes. Then add 7 mL of DMEM complete culture medium to each dish. After mixing, place them in a 37°C, 5% CO 2 incubator.
  • DMEM complete medium containing glutamine, sodium pyruvate, penicillin/strepto
  • DMEM/F12 medium containing glutamine, sodium pyruvate, HEPES, fetal calf serum
  • DMEM/F12 medium containing glutamine, sodium pyruvate, HEPES, penicillin/streptomycin, fetal bovine serum
  • inoculate the cells In Matrigel-coated 384-well plates, the cell density was 6.67 ⁇ 106 cells/mL, 30 ⁇ L/well. Place the 384-well plate in a 37°C, 5% CO 2 incubator.

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Abstract

提供一种如式(I)所示的化合物或其在药学上可接受的盐。此外，还提供所述化合物及其药学上可接受的盐的制备方法，以及其在制备GPR139受体相关疾病的药物中的应用。

Description

一种GPR139受体激动剂及其制备方法 技术领域
本发明涉及药物化学领域。具体地，本发明涉及一类G蛋白偶联受体139(G Protein-coupled Receptor 139，简称GPR139)的配体分子。
背景技术
G蛋白偶联受体139(G Protein-coupled Receptor 139，简称GPR139)是Gloriam等于2005年首次发现(Biochim Biophys Acta 2005；1722:235-246)，也被称为GPCR12,PGR3,KOR3L,GPRg1。GPR139主要表达在中枢神经系统(CNS)中的缰核、纹状核、丘脑、下丘脑和垂体中，其氨基酸序列在不同物种中具有高度保守性如人GPR139蛋白序列与小鼠、鸡和斑马鱼的同源性分别为96％，92％和70％。GPR139受体表达在细胞表面时，由N-端片段、7个穿膜片段和C-端片段组成，其中N-端片段由26个氨基酸组成，并含有一个半胱氨酸。Wang等报道，GPR139受体和多巴胺受体D2共表达于鼠脑的不同组织中，并通过体外细胞实验证实GPR139能促进多巴胺受体D2的激动剂产生钙流信号，且该钙流信号既能被多巴胺受体D2的拮抗剂，也能被GPR139的拮抗剂所抑制(Frontiers in Neuroscience,March 2019,Volume 13,Article 281)。此外，Nepomuceno等证实GPR139能通黑色皮质素受体3或5(MC3/MC5)起协同作用。这些结果表明，GPR139能与细胞表面其它受体形成异源二聚体发挥生理作用。此外，我们的实验已证实GPR139受体能通过N-端的半胱氨酸形成同源二聚体。
不同研究团队在寻找GPR139的配体，包括激动剂和拮抗剂，的同时，Liu等报告了L-苯丙氨酸和L-色氨酸为GPR139内源性激动剂(Mol Pharmacol 2015；88:911-925)。
现有的研究表明，GPR139受体具有重要的生理功能，是抗焦虑、抗抑郁、抗精神分裂，治疗帕金森综合症，治疗药物和酒精滥用，治疗代谢相关疾病的潜在药物靶点。相关GPR139的结构、表达、药理、生理功能信息为设计和合成全新的GPR139激动剂提供了坚实的基础。
发明内容
在本发明的第一方面，提供了一种如式(I)所示的化合物，或其药学上可接受的盐
其中，
R1、R2、R3、R4、R5和R6各自独立地选自下组：氢、卤素、羟基、羧基、C1-6酰基、C1-3烷基-羰基-C1-3烷基、C1-6烷基-醛基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基；
R7、R8各自独立选自下组：氢、C1-4烷基。
在部分实施方式中，R1、R2、R3、R4、R5和R6各自独立选自下组：氢、氟、氯、羟基、羧基、C1-6酰基、C1-2烷基-羰基-C1-2烷基、C1-3烷基-醛基、C1-3烷基、C1-6卤代烷基、C1-3卤代烷氧基。
在部分实施方式中，R1、R2和R3各自独立选自下组：氢、氟、氯、羟基、羧基、C1-6酰基、C1-3烷基-羰基-C1-3烷基、C1-6烷基-醛基、甲基、三氟甲基、三氟甲氧基。
在部分实施方式中，R4、R5和R6各自独立选自下组：氢、氟、氯、羟基、羧基、甲基、三氟甲基、三氟甲氧基。
在部分实施方式中，R7和R8各自独立选自下组：氢和甲基。
在部分实施方式中，所述化合物选自下组：


在本发明的第二方面，提供了一种如本发明第一方面所述的化合物、或其药学上可接受的盐的制备方法，包括步骤：

其中，R’、R”、R”’各自独立选自下组：氢、卤素、羟基、羧基、酮基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基；
R1、R2、R3、R4、R5、R6、R7和R8的定义如前所述。
在本发明的第三方面，提供了一种药物组合物，其特征在于，包括如本发明第一方面所述的化合物、或其药学上可接受的盐；和药学上可接受的载体。
在本发明的第四方面，提供了一种如本发明第三方面所述的药物组合物的制备方法，其特征在于，包括步骤：将如本发明第一方面所述的化合物、或其药学上可接受的盐，与药学上可接受的载体进行混合，从而形成药物混合物。
在本发明的第五方面，提供了一种如本发明第一方面所述的化合物、或其药学上可接受的盐，或者如本发明第三方面所述的药物组合物的用途，其特征在于，用于制备治疗GPR139受体相关疾病的药物。
在另一优选例中，所述GPR139受体相关疾病包括焦虑症、抑郁症、帕金森综合症、药物及酒精滥用。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现本发明化合物具有优异的GPR139受体激动活性，从而进行了一系列合成和生物活性测试。在此基础上完成了本发明。
本发明下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂，均为市售产品。
除非另有定义，本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不用于限制本发明。
术语
本发明的术语“包括”和“具有”以及它们任何变形，意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块，而是可选地还包括没有列出的步骤，或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤。
在本发明中提及的“多个”是指两个或两个以上。“和/或”，描述关联对象的关联关系，表示可以存在三种关系，例如，A和/或B，可以表示：单独存在A，同时存在A和B，单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本发明所述化合物中，当任何变量在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C8烷基”中“C1-C8”的定义包括以直链或支链排列的具有1、2、3、4、5、、或8个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
本文所用术语“烷氧基”代表烷基-氧基基团，其中烷基的定义如上所示。
正如本领域技术人员所理解的，本文中所用“卤素”意指包括氯、氟、溴和碘。
本文所用术语“卤代烷基”代表其中有一个或多个氢原子被卤素取代的烷基基团，其中烷基的定义如上所示。
本文所用术语“卤代烷氧基”代表有一个或多个氢原子被卤素取代的烷基-氧基基团，其中烷基的定义如上所示。
活性成分
在本发明中，提供了一种可有效激动GPR139受体的活性成分。该活性成分为通式(I)所示的化合物，该活性成分可有效预防、治疗和/或缓解GPR139相关疾病。
试验表明，本发明的活性成分可有效地激动GPR139受体，从而预防、治疗和/或缓解GPR139相关疾病。
应理解，本发明的活性成分包括通式(I)所示的化合物、或其药学上可接受的盐、或其前药。应理解，本发明的活性成分还包括通式(I)化合物的晶型、无定形化合物、以及氘代化合物等形式。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～80℃，优选0℃～50℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
下面的通用制备路线可以用于合成本发明式(I)结构的化合物。

其中，R’、R”、R”’、R1、R2、R3、R4、R5和R6的定义如前所述。
药物组合物和施用方法
由于本发明化合物具有优异的GPR139受体激动活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与GPR139受体或表达异常相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-3000(活性剂量范围3-30mg/kg)mg本发明化合物/剂，更佳地，含有10-2000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如， 滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选6～600mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(a)本发明化合物可高效地激动GPR139受体，部分化合物的EC50值＜0.1μM。
(b)本发明化合物合成简单，产率较高。
(c)本发明化合物的毒副作用低，成药性好。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。 本发明中用到的起始原料未经特别说明，均为商业购买。
实施例
实施例1
化合物NRB025的制备
在氮气保护下，将S-苯乙胺(171毫克，1.42毫摩尔)和二异丙基乙胺(183毫克，1.42毫摩尔)用2毫升二氯甲烷溶解，并用冰水浴冷却至5摄氏度左右。再将丙二酰氯(100毫克，0.71毫摩尔)缓慢滴加到上述反应液中。2分钟左右时间滴完。滴加完反应继续搅拌15分钟。通过TLC来监控反应完成情况。反应完成，将反应液倒入10毫升的饱和氯化铵溶液中，并用二氯甲烷来萃取(10毫升x2)。有机相用硫酸钠干燥，过滤之后进行浓缩。用柱层析来进行纯化，得到37.5毫克的产品。分析数据如下：
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)。
实施例2-5
化合物NRB037、NRB038、NRB040、NRB064的制备
采用实施例1的方法，不同点在于：采用不同底物替换S-苯乙胺，从而制得化合物2-5。

实施例6
化合物NRB035的制备
第一步：中间体1的制备
在氮气保护下，将S-苯乙胺(870毫克，7.32毫摩尔)和二异丙基乙胺(1.72克，13.3毫摩尔)用20毫升二氯甲烷溶解，并用冰水浴冷却至5摄氏度左右。再将氯甲酰乙酸乙酯(1克，6.67毫摩尔)缓慢滴加到上述反应液中。5分钟左右时间滴完。滴加完反应继续搅拌15分钟。通过TLC来监控反应完成情况。反应完成，将反应液倒入50毫升的饱和氯化铵溶液中，并用二氯甲烷来萃取(20毫升x2)。有机相用硫酸钠干燥，过滤之后进行浓缩。得到1.35克的油状液体。分析数据：LCMS(ESI+):m/z236(M+H)。
第二步：中间体2的制备
将中间体1(1.25克，5.32毫摩尔)用四氢呋喃(10毫升)和水(10毫升)溶解，室温下一次性加入氢氧化锂一水合物(447毫克，10.64毫摩尔)。在室温下搅拌反应3小时。反应结束后用稀盐酸调节pH值到3,并用乙酸乙酯萃取(50毫升x2)。有机相用硫酸钠干燥，过滤后浓缩干得到1.34克的油状物。该油状物放置室温条件下缓慢固化。分析数据：LCMS(ESI-):m/z206(M-H)。
第三步：化合物NRB035的制备
在氮气保护下，将中间体2(30毫克，0.14毫摩尔)和S-4-氯苯乙胺(33毫克，0.17毫摩尔)用二氯甲烷(2毫升)溶解，再依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(54毫克，0.28毫摩尔)、1-羟基苯并三唑(38毫克，0.28毫摩尔)以及二异丙基乙胺(36毫克，0.28毫摩尔)。该反应在室温条件下搅拌过夜。通过TLC来监控反应完成情况。反应结束后，将反应液倒入饱和的氯化铵水溶液中(10毫升)，并用二氯甲烷萃取(10毫升x2)。有机相干燥，过滤浓缩后通过制备TLC来进行纯化，得到化合物NRB035，为白色固体(14毫克)。分析数据如下：
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)。
实施例7-25
化合物NRB036、NRB039、NRB041、NRB042、NRB043、NRB044、NRB045、NRB046、NRB047、NRB048、NRB026、NRB032、NRB056、NRB057、NRB058、NRB061、NRB063、NRB065、NRB066的制备
采用实施例1的方法，不同点在于：采用不同底物替换S-苯乙胺和S-4-氯苯乙胺，从而制得化合物6-14。




实施例26
化合物NRB060的制备
第一步：中间体2的制备
将S-1-苯乙胺(100毫克，0.83毫摩尔)和氰酸钾(335毫克，4.13毫摩尔)用0.85毫升1N HCl和0.5毫升水溶解，微波80摄氏度反应1小时。
通过TLC来监测，反应完成。反应中有固体，抽滤，固体用正己烷洗三次(3x5毫升)。固体真空干燥，得到120毫克的粗产品。分析数据：LCMS(ESI+):m/z 165(M+H)。
第二步：中间体3的制备
将中间体2(120毫克，0.73毫摩尔)和吡啶(173毫克，2.19毫摩尔)用2毫升二氯甲烷溶解，加入氯甲酸苯酯(137毫克，0.88毫摩尔)，室温搅拌过夜。通过TLC来监测，反应完成。反应液加入3毫升水，二氯甲烷萃取(3x3毫升)，无水硫酸钠干燥，旋干过柱(乙酸乙酯：石油醚＝1:10)得到55毫克产品。分析数据：LCMS(ESI+):m/z 285(M+H)。
第三步：化合物NRB060的制备
将中间体3(45毫克，0.16毫摩尔)和原料A(33毫克，0.19毫摩尔)用1毫升乙腈溶解，加入碳酸钾(43.7毫克，0.32毫摩尔)。反应在50度搅拌5小时。通过TLC来监测，反应完成。反应液旋干通过制备TLC进行纯化得到20毫克白色油状产品。分析数据：LCMS(ESI+):m/z 326(M+H)。
1H-NMR(300MHz,CDCl3)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).
1H-NMR(300MHz,CD3OD)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).
实施例27
化合物NRB062的制备
第一步：中间体2的制备
将S-1-苯乙胺(200毫克，1.65毫摩尔)和S1(161毫克，1.10毫尔),EDCl(423毫克，2.2毫摩尔)，HOBT(297毫克，2.2毫摩尔)，二异丙基乙胺(284毫克，2.2毫摩尔)用5毫升二氯甲烷溶解，室温搅拌过夜。
通过TLC来监测，反应完成。加入1N稀盐酸淬灭，二氯甲烷萃取(3x5毫升)，无水硫酸钠干燥，旋干通过制备TLC进行纯化得到240毫克白色油状产品。分析数据：LCMS(ESI+):m/z 250(M+H)。
第二步：中间体3的制备
将中间体2(240毫克，0.96毫摩尔)用3毫升四氢呋喃和3毫升水溶解，加入氢氧化锂一水合物(122毫克，2.9毫摩尔)，室温搅拌过夜。通过TLC来监测，反应完成。 反应液加入1N稀盐酸调节pH 3到4，乙酸乙酯萃取(3x10毫升)，无水硫酸钠干燥，旋干得到200毫克白色固体产品。分析数据：LCMS(ESI+):m/z 222(M+H)。
第三步：化合物NRB062的制备
将中间体3(60毫克，0.27毫摩尔)和S2(35毫克，0.2毫摩尔)，EDCl(77毫克，0.4毫摩尔)，HOBT(54毫克，0.4毫摩尔)，二异丙基乙胺(52毫克，0.4毫摩尔)用3毫升二氯甲烷溶解，室温搅拌3小时。通过TLC来监测，反应完成。加水5毫升，二氯甲烷萃取(3x5毫升)，无水硫酸钠干燥，旋干通过制备TLC(二氯甲烷：甲醇＝10:1)进行纯化得到17毫克白色固体产品。
分析数据：LCMS(ESI+):m/z 339(M+H)。
1H-NMR(300MHz,DMSO-d6)δ8.20-8.07(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).
实施例28
GPR139受体活性测定
1.实验方法
HEK293细胞生长在含DMEM完全培养基(含有谷氨酰胺、丙酮酸钠、青霉素/链霉素、10％胎牛血清)的10cm培养皿中，于37℃，5％CO2培养箱中培养至90％汇合度。然后传代，每周1:5传代两次。细胞传代时，首先完全吸去培养基，用4mL的DPBS洗一次，加3mL的胰酶消化液，轻摇匀。至细胞裂开时，吸去胰酶消化液，加5mL的DMEM完全培养基。用吸管吹打分散细胞后各加入1mL的分散细胞液至5个新的10cm培养皿中，然后各补加7mL的DMEM完全培养基，混匀后放置37℃，5％CO2培养箱中培养。
在转染细胞的当天，按照适当的密度消化细胞到一个10cm培养皿中，加入6mL的DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES、胎牛血清)，于37℃，5％CO2培养箱中培养5小时。取一个50mL的无菌离心管A，加1mL无血清DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES)，再加10μg的GPR139DNA，混合均匀。取另一个50mL的无菌离心管B，加1mL无血清DMEM培养基(含有谷氨酰胺、丙酮酸钠、HEPES)，再加60μL的Fugene HD转染试剂，混合均匀。从离心管B中取1mL的Fugene HD转染试剂，加入到离心管A中，混合均匀，并于室温放置20分钟。加2mL DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES、胎牛血清)至离心管A中，混合均匀，然后 取出离心管A中的混合物(4ml)，加到上述10cm培养皿的细胞中(共10mL液体)，混匀后置37℃，5％CO2培养箱中培养20-24小时。
第二天，用胰酶消化液消化转染后的细胞，加适当的DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES、青霉素/链霉素、胎牛血清)，将细胞接种于Matrigel包被的384-孔板中，细胞密度为6.67×106cells/mL,30μL/孔。将384-孔板置37℃，5％CO2培养箱中培养。
第三天，加10μL/孔FLIPR染料(稀释于含有Pluronic和Probenicid的HEPES溶液中)至384-孔细胞板中，于37℃，5％CO2培养箱中培养40分钟。加入稀释后的化合物到细胞板中，在FLIPR读板仪中读取钙流信号。
用XL-fit软件进行数据分析，并得到每个化合物的EC50值。
2.实验结果
表1、GPR139 FLIPR细胞钙流信号检测化合物的EC50值

GPR139 FLIPR细胞钙流信号检测化合物的EC50值(实测数据，μM)
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种如式(I)所示的化合物，或其药学上可接受的盐
    其中，
    R1、R2、R3、R4、R5和R6各自独立地选自下组：氢、卤素、羟基、羧基、C1-6酰基、C1-3烷基-羰基-C1-3烷基、C1-6烷基-醛基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基；
    R7、R8各自独立选自下组：氢、C1-4烷基。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐，其特征在于，R1、R2、R3、R4、R5和R6各自独立选自下组：氢、氟、氯、羟基、羧基、C1-6酰基、C1-2烷基-羰基-C1-2烷基、C1-3烷基-醛基、C1-3烷基、C1-6卤代烷基、C1-3卤代烷氧基。
  3. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R1、R2和R3各自独立选自下组：氢、氟、氯、羟基、羧基、C1-6酰基、C1-3烷基-羰基-C1-3烷基、C1-6烷基-醛基、甲基、三氟甲基、三氟甲氧基。
  4. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R4、R5和R6各自独立选自下组：氢、氟、氯、羟基、羧基、甲基、三氟甲基、三氟甲氧基。
  5. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R7和R8各自独立选自下组：氢和甲基。
  6. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述化合物选自下组：


  7. 如权利要求1-6任一项所述的化合物、或其药学上可接受的盐的制备方法，包括步骤：
    或者
    其中，R’、R”、R”’各自独立选自下组：氢、卤素、羟基、羧基、酮基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基；
    R1、R2、R3、R4、R5、R6、R7和R8的定义如权利要求1中所述。
  8. 一种药物组合物，其特征在于，包括如权利要求1-6任一项所述的化合物、或其药学上可接受的盐；和药学上可接受的载体。
  9. 如权利要求8所述的药物组合物的制备方法，其特征在于，包括步骤：将权利要求1-6任一项所述的化合物、或其药学上可接受的盐，与药学上可接受的载体进行混合，从而 形成药物混合物。
  10. 如权利要求1-6任一项所述的化合物、或其药学上可接受的盐，或者如权利要求8所述的药物组合物的用途，其特征在于，用于制备治疗GPR139受体相关疾病的药物。
    在另一优选例中，所述GPR139受体相关疾病包括焦虑症、抑郁症、帕金森综合症、药物及酒精滥用。
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