CN117430561A - GPR139 receptor agonist and preparation method thereof - Google Patents

GPR139 receptor agonist and preparation method thereof Download PDF

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CN117430561A
CN117430561A CN202210834434.6A CN202210834434A CN117430561A CN 117430561 A CN117430561 A CN 117430561A CN 202210834434 A CN202210834434 A CN 202210834434A CN 117430561 A CN117430561 A CN 117430561A
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pharmaceutically acceptable
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陈景才
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Zhejiang Youning Biomedical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention provides a compound shown as a formula (I), or pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 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 L is 1 Selected from the group consisting of: none, or
R1 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
ring A is a C3-10 carbocyclyl group, or a 3-10 membered heterocyclyl group;
wherein each of said carbocyclyl or heterocyclyl is optionally substituted with a substituent selected from the group consisting of: halogen, oxo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
and, the carbocyclyl and heterocyclyl include fused, bridged and spiro ring structures.
In some embodiments, the compound has a structure represented by formula (II):
wherein the dashed bond represents a single bond or a double bond;
w is selected from the group consisting of: C. n;
x is selected from the group consisting of: c=o or CR2; wherein R2 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl;
y is selected from the group consisting of: CH. NR3; wherein R3 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
z is selected from the group consisting of: CR4, wherein R4 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl;
d is selected from the group consisting of: n, CH;
e is selected from the group consisting of: CR5, N, NR6, wherein R5 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl; r6 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
or any two adjacent R2, R3, R4 and R5, namely R2 and R3, R3 and R4 or R4 and R5, together with the carbon atom to which they are attached form a substituted or unsubstituted C5-7 carbocyclic ring or a 5-7 membered heterocyclic ring;
l1 and R1 are as defined above.
In some embodiments, R1 is selected from the group consisting of: -OCF3.
In some embodiments, the ring a has a structure selected from the group consisting of:
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' is selected from the group consisting of: hydrogen, C1-4 alkyl;
r1, L1 and ring A are as defined above.
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: the compound of 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', R1, R2, R3, R4, R5 and R6 are as defined above.
Pharmaceutical compositions and methods of administration
Because the compounds of the present invention have excellent GPR139 receptor agonistic activity, the compounds of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present invention as a main active ingredient are useful for the treatment, prevention and alleviation of diseases associated with GPR 139.
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, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.) Wetting agents (such as 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 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 NRB104
The first step:
a solution of 2-iodoaniline (1000 mg,4.57 mmol), 3-butyn-1-ol (560 mg,7.99 mmol), triethylamine (700 mg,6.92 mmol), palladium (PPh 3) 4 (530 mg,0.459 mmol) and copper iodide (170 mg,0.893 mmol) in 20mL of water was stirred at 80℃for 2 hours, then diluted with 150mL of water and extracted with ethyl acetate (3X 100 mL). The organic phase was washed with 150mL of brine and then dried over anhydrous sodium sulfate. After filtration, concentration was carried out to obtain 800mg of intermediate 4- (2-aminophenyl) but-3-yn-1-ol.
And a second step of:
to 9.0mL of water was added 1mL of sulfuric acid, followed by the addition of 4- (2-aminophenyl) but-3-yn-1-ol (800 mg,4.96 mmol), cooling to 0℃and dropwise adding 4mL of an aqueous solution containing sodium nitrite NaNO2 (520 mg,7.537mmol,1.52 equiv) at 0 ℃. The mixture was stirred at room temperature overnight, the suspension was cooled to 0 ℃, filtered and washed with 2mL of water to give 400mg of intermediate 3- (2-hydroxyethyl) -1H-cinnolin-4-one.
And a third step of:
a5 mL DMF solution containing 3- (2-hydroxyethyl) -1H-cinnolin-4-one (400 mg,2.17mmol,1 equiv), methyl iodide (360 mg,2.54 mmol) and potassium carbonate (440 mg,3.18 mmol) was stirred at room temperature for 12H and purified by a C18 reverse phase column to give 100mg of the intermediate 3- (2-hydroxyethyl) -1-methylcinnolin-4-one.
Fourth step:
to a solution of 3- (2-hydroxyethyl) -1-methylcinnolin-4-one (100 mg,0.490 mmol) and sodium periodate (420 mg,1.96 mmol) in 1mL of acetonitrile was added 1.5mL of water, 1mL of ethyl acetate, and after mixing, ruthenium trichloride (55 mg,0.244 mmol) was added and then stirred at room temperature for 48 hours. After concentration of the reaction mixture in vacuo, it was purified by a C18 reverse phase column to give 30mg of intermediate (1-methyl-4-oxocinnolin-3-yl) acetic acid.
Fifth step:
1mL of a solution containing (1-methyl-4-oxocinnolin-3-yl) acetic acid (30.0 mg,0.137 mmol), hydroxybenzotriazole (23.0 mg,0.170 mmol) and diisopropylethylamine (55.0 mg,0.426 mmol) was stirred at room temperature for 15 minutes, then (1S) -1- [4- (trifluoromethoxy) phenyl ] ethylamine (30.0 mg,0.146 mmol) and EDCI (40 mg,0.209 mmol) were added and stirred at room temperature for 2 hours. Purifying the above mixture with preparative HLPC to give the final product compound NRB104:2- (1-methyl-4-oxocinnolin-3-yl) -N- [ (1S) -1- [4- (trifluoromethoxy) phenyl ] ethyl ] acetamide.
1H NMR(300MHz,DMSO-d6)δ8.54(d,J＝7.8Hz,1H),8.12(d,J＝8.1Hz,1H),7.89–7.85(m,1H),7.74(d,J＝8.7Hz,1H),7.51–7.46(m,3H),7.32(d,J＝8.1Hz,2H),5.00–4.89(m,1H),4.07(s,3H),3.60(s,2H),1.38(d,J＝7.0Hz,3H).
Example 2
Preparation of Compound NRB103
The first step:
a solution of 1, 4-dioxane containing 2, 3-dibromopyridine (2.00 g,8.44 mmol) was stirred overnight at 110℃and concentrated to give 1.4g of the intermediate 3-bromo-2-hydrazinopyridine.
And a second step of:
a solution of 3-bromo-2-hydrazinopyridine (1.40 g,7.45 mmol) in 5.0mL of trimethyl orthoformate was stirred at 105℃for 4 hours, then concentrated under reduced pressure, trimethyl orthoformate was added, stirred at 110℃overnight, and the mixture was concentrated under reduced pressure to give 1g of intermediate 8-bromo- [1,2,4] triazolo [4,3-a ] pyridine.
And a third step of:
a6 mL1, 4-dioxane solution containing 8-bromo- [1,2,4] triazolo [4,3-a ] pyridine (600 mg,3.03 mmol), ethyl cyanoacetate (415 mg,3.67 mmol), potassium tert-butoxide (853 mg,7.61 mmol) and 1,1' -bisdiphenylphosphino ferrocene palladium dichloride (223 mg,0.304 mmol) was stirred at 70℃for 4 hours. The solvent was removed in vacuo and then purified by silica gel chromatography to give 200mg of the intermediate ethyl 2-cyano-2- { [1,2,4] triazolo [4,3-a ] pyridin-8-yl } acetate (200 mg, 14%).
Fourth step:
ethyl 2-cyano-2- { [1,2,4] triazolo [4,3-a ] pyridin-8-yl } acetate (200 mg,0.869 mmol) was dissolved in 1 ml_ mso, 0.5 ml_ brine was added, treated at 120 ℃ for 2 hours, and extracted with ethyl acetate (3 x8 ml_). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give intermediate 2- { [1,2,4] triazolo [4,3-a ] pyridin-8-yl } acetonitrile.
Fifth step:
a1 mL of the solution containing 2- { [1,2,4] triazolo [4,3-a ] pyridin-8-yl } acetonitrile (100 mg,0.564 mmol), EDCI (162 mg,0.847 mmol), hydroxybenzotriazole (91.6 mg,0.678 mmol) was reacted with N, N-diisopropylethylamine (146 mg,1.130 mmol) at room temperature for 30 minutes, then (1S) -1- [4- (trifluoromethoxy) phenyl ] ethylamine (140 mg,0.682 mmol) was added dropwise, reacted at room temperature for 1.5 hours and then purified by reverse phase chromatography to give the final product compound NRB103:2- { [1,2,4] triazolo [4,3-a ] pyridin-8-yl } -N- [ (1S) -1- [4- (trifluoromethoxy) phenyl ] ethyl ] acetamide.
1 H NMR(400MHz,DMSO-d6)δ9.25(d,J＝2.0Hz,1H),8.77(d,J＝6.4Hz,1H),8.45(d,J＝6.8Hz,1H),7.48(d,J＝8.4Hz,2H),7.28(d,J＝8.4Hz,2H),7.18(d,J＝6.8Hz,1H),6.95–6.89(m,1H),4.98–4.95(m,1H),3.88(s,2H),1.39(d,J＝7.0Hz,3H).
Example 3
Preparation of Compound NRB105
The first step:
dimethyl butynedioate (1.56 g,11.0 mmol) was added to 10mL of methanol containing 2-hydrazinopyridine (1.00 g,9.16 mmol), and the mixture was reacted at room temperature for 3 hours. The mixture was concentrated to 1g of the intermediate 1, 4-dimethyl (2Z) -2- [2- (pyridin-2-yl) hydrazino-1-ylidene ] succinate.
And a second step of:
1, 4-dimethyl (2Z) -2- [2- (pyridin-2-yl) hydrazino-1-ylidene ] butanedioic acid ester (1.00 g,3.98 mmol) was dissolved in 10mL of acetic acid, and after stirring at room temperature, microwave irradiation was performed at 140℃for 40 minutes. The reaction was poured into 50mL of water and then extracted with ethyl acetate (3X 80 mL). The organic phase was washed with brine, then dried over sodium sulfate, filtered and concentrated to yield 1.2g of the intermediate methyl 2- { 4-oxopyrido [2,1-c ] [1,2,4] triazin-3-yl } acetate.
And a third step of:
(1S) -1- [4- (trifluoromethoxy) phenyl ] ethylamine (122 mg,0.593 mmol) was dissolved in 13mL of xylene, trimethylaluminum (256.8 mg) was added and reacted at 0℃for 30 minutes, followed by addition of methyl 2- { 4-oxopyrido [2,1-c ] [1,2,4] triazin-3-yl } acetate (130 mg,0.634 mmol), reacted at 110℃for 6 hours and stirred at 140℃for 6 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase column to give the final product, 2- { 4-oxopyrido [2,1-c ] [1,2,4] triazin-3-yl } -N- [ (1S) -1- [4- (trifluoromethoxy) phenyl ] ethyl ] acetamide, compound NRB 105.
1H NMR(400MHz,DMSO-d6)δ8.74(d,J＝7.2Hz,1H),8.58(d,J＝8.0Hz,1H),7.95–7.91(m,1H),7.82(d,J＝9.2Hz,1H),7.47(d,J＝8.8Hz,2H),7.42–7.34(m,1H),7.31(d,J＝8.4Hz,2H),4.99–4.96(m,1H),3.85(s,2H),1.38(d,J＝6.9Hz,3H).
Example 4
Preparation of Compound NRB115
The first step:
to a solution of 6mL of methylene chloride containing t-butoxycarbonylaminoacetic acid (300 mg, 1.719 mmol) were added (1S) -1- [4- (trifluoromethoxy) phenyl ] ethylamine (316.24 mg,1.541 mmol), hydroxybenzotriazole (462.83 mg,3.425 mmol), and EDCI (656.58 mg,3.425 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction was extracted with ethyl acetate (3×40 mL) and water (80 mL). The organic phase was concentrated in vacuo and then purified by column on silica gel to give 300mg of intermediate tert-butyl { [ (1S) -1- (4-trifluoromethoxy-phenyl) -ethylcarbamoyl ] -methyl } -carbamate.
And a second step of:
{ [ (1S) -1- (4-trifluoromethoxy-phenyl) -ethylcarbamoyl ] -methyl } -carbamic acid tert-butyl ester (300 mg, 1.719 mmol) was added to hydrochloric acid (4 mL,0.773 mmol) and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give 175mg of 2-amino-N- [ (1S) -1- (4-trifluoromethoxy-phenyl) -ethyl ] -acetamide.
And a third step of:
to a solution of 2-amino-N- [ (1S) -1- (4-trifluoromethoxy-phenyl) -ethyl ] -acetamide (175 mg,0.667 mmol) in 3mL of pyridine was added compound 5 (82.16 mg,0.667 mmol), phosphorus oxychloride (0.093 mL,1.001 mmol) and stirred at room temperature for 1 hour. The reaction was extracted with ethyl acetate (3×50 mL) and saturated sodium bicarbonate (100 mL). After drying in vacuo, crystallization from 10mL of methanol gives the final product compound NRB115 (D15).
1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝5.1Hz,1H),8.66(d,J＝4.2Hz,1H),8.51(d,J＝7.6Hz,1H),8.02(dt,J＝15.3,7.6Hz,2H),7.65–7.58(m,1H),7.45(d,J＝8.4Hz,2H),7.31(d,J＝8.1Hz,2H),4.98(t,J＝6.9Hz,1H),3.98(dd,J＝11.9,8.1Hz,2H),1.38(d,J＝7.0Hz,3H).
Example 5
Preparation of Compound NRB118
The first step:
to a solution of 2H-cinnolin-3-one (300 mg,2.053 mmol) in 5mL of dimethylformamide was added methyl chloroacetate (267.31 mg,2.463 mmol) and potassium carbonate (851.04 mg,6.158 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction was extracted with ethyl acetate (3×40 mL) and saturated sodium chloride (100 mL). The organic phase was separated by vacuum concentration and then purified by silica gel column to obtain 200mg of intermediate (3-oxo-3H-cinnolin-2-yl) -acetic acid methyl ester.
And a second step of:
lithium hydroxide (115.38mg,2.750mmol,1mL H2O) was added to a solution of methyl (3-oxo-3H-cinnolin-2-yl) -acetate (200 mg,0.917 mmol) in tetrahydrofuran (3 mL). The organic phase was separated by vacuum concentration and then acidified with 1M hydrochloric acid and extracted with ethyl acetate (5X 30 mL) and water (100 mL). Concentrated in vacuo to give 80mg of intermediate (3-oxo-3H-cinnolin-2-yl) -acetic acid.
And a third step of:
to a solution of (3-oxo-3H-cinnolin-2-yl) -acetic acid (80 mg, 0.390 mmol) in dimethylformamide (3 mL) was added compound 5 (80.39 mg, 0.390 mmol), hydroxybenzotriazole (105.89 mg,0.784 mmol), triethylamine (203 mg,2.32 mmol) and EDCI (150.21 mg,0.784 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was extracted with ethyl acetate (3×30 mL) and water (80 mL). The organic phase was separated, washed with saturated sodium chloride (80 mL), concentrated in vacuo and purified by silica gel column to give the final product compound NRB118 (D18): 2- (3-oxocinnolin-2-yl) -N- [ (1S) -1- {4- [ (trifluoromethyl) oxy ] phenyl } ethyl ] acetamide.
1 H NMR(400MHz,DMSO-d 6 )δ8.79(d,J＝7.6Hz,1H),7.55(d,J＝9.0Hz,1H),7.48(dd,J＝8.5,4.2Hz,3H),7.36–7.24(m,5H),5.04(s,2H),4.95(dd,J＝14.1,7.0Hz,1H),1.40(d,J＝7.0Hz,3H).
Example 6
GPR139 receptor Activity assay for Compounds of the invention
1. Experimental method
HEK293 cells were grown in 10cm dishes containing DMEM complete medium (containing glutamine, sodium pyruvate, penicillin/streptomycin, 10% fetal bovine serum) and incubated to 90% confluency in a 5% co2 incubator at 37 ℃. 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 each of the dispersed cell solutions was added to 5 new 10cm dishes, 7mL of DMEM complete medium was then added to each, and after mixing, the mixture was placed in a 37℃and cultured in a 5% CO2 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 incubated in a 5% CO2 incubator at 37℃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. 2mL of DMEM/F12 medium (containing glutamine, sodium pyruvate, HEPES, fetal bovine serum) was added to the centrifuge tube A, and mixed well, then the mixture (4 mL) in the centrifuge tube A was taken out, added to the cells (10 mL liquid in total) in the 10cm dish, and after mixing well, incubated in a 5% CO2 incubator at 37℃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. 384-well plates were incubated at 37℃in a 5% CO2 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 and incubated for 40 min at 37℃in a 5% CO2 incubator. The diluted compounds were added to the cell plates and the calcium flux signal was read in a FLIPR reader.
Data analysis was performed using XL-fit software and EC50 values were obtained for each compound.
1. Experimental results
Table 1, EC50 values for compounds for calcium flux signal detection in GPR139 FLIPR cells
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 (9)

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof,
wherein L is 1 Selected from the group consisting of: none, or
R1 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
ring A is a C3-10 carbocyclyl group, or a 3-10 membered heterocyclyl group;
wherein each of said carbocyclyl or heterocyclyl is optionally substituted with a substituent selected from the group consisting of: halogen, oxo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
and, the carbocyclyl and heterocyclyl include fused, bridged and spiro ring structures.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (II):
wherein the dashed bond represents a single bond or a double bond;
w is selected from the group consisting of: C. n;
x is selected from the group consisting of: c=o or CR2; wherein R2 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl;
y is selected from the group consisting of: CH. NR3; wherein R3 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
z is selected from the group consisting of: CR4, wherein R4 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl;
d is selected from the group consisting of: n, CH;
e is selected from the group consisting of: CR5, N, NR6, wherein R5 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl; r6 is selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1-4 haloalkoxy;
or any two adjacent R2, R3, R4 and R5, namely R2 and R3, R3 and R4 or R4 and R5, together with the carbon atom to which they are attached form a substituted or unsubstituted C5-7 carbocyclic ring or a 5-7 membered heterocyclic ring;
l1 and R1 are defined as in claim 1.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: -OCF3.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a has a structure selected from the group consisting of:
5. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
6. a process for the preparation of a compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, comprising the steps of:
or alternatively
Wherein R' is selected from the group consisting of: hydrogen, C1-4 alkyl;
r1, L1 and ring A are as defined in claim 1.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
8. A method of preparing a pharmaceutical composition according to claim 7, comprising the steps of: a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier, thereby forming a pharmaceutical mixture.
9. The use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, 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.
CN202210834434.6A 2022-07-14 2022-07-14 GPR139 receptor agonist and preparation method thereof Pending CN117430561A (en)

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