CN112724141A - GPR109A protein receptor inhibitor and preparation and application thereof - Google Patents
GPR109A protein receptor inhibitor and preparation and application thereof Download PDFInfo
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Abstract
The invention provides a GPR109A protein receptor inhibitor and preparation and application thereof, and particularly provides a compound shown as a formula I in the specification, or a pharmaceutically acceptable salt thereof. The compound has excellent GPR109A protein inhibition activity.
Description
Technical Field
The invention relates to the field of small molecule protein inhibitors, and particularly provides preparation and application of a compound with a GPR109A protein regulation effect.
Background
G protein-coupled receptors (GPCRs) are the most versatile family of receptors because of their ability to respond to different chemical ligands. Despite the considerable effort of researchers over the last decades, over 100 individual GPCRs whose endogenous ligands are unknown. More recently, ligands forming GPR109A, GPR109B and GPR81 of the GPCR subfamily were discovered. The physiological ligands for these receptors are the ketone body 3-hydroxybutyrate, the metabolite 2-hydroxypropionate (lactate) and the β -oxidation intermediate 3-hydroxyoctanoate. Thus, this receptor subfamily is activated by hydroxycarboxylic acid ligands, which are intermediates of energy metabolism.
GPR109A is a G protein-coupled receptor for nicotinic acid, but recognizes butyric acid with low affinity. GPR109A is expressed in the lumen-facing apical membrane of colon and intestinal epithelial cells and the receptor recognizes butyrate as a ligand. Expression of GPR109A is silenced in human colon cancer, intestinal/colon cancer mouse models and colon cancer cell lines, a class of tumor-associated silencing involving direct or indirect DNA methylation. Re-expression of GPR109A in colon cancer cells induces apoptosis, major changes in this apoptotic process including down-regulation of Bcl-2, Bcl-xL and cyclin D1 and up-regulation of the death receptor pathway. In addition, GPR 109A/butyrate inhibited nuclear factor- κ B activation in normal and cancer colon cell lines as well as in the colon of normal mice.
Therefore, the development of compounds with novel structures for regulating the activity or expression amount of GPR109A is urgently needed in the art.
Disclosure of Invention
The invention aims to provide a novel GPR109A protein receptor inhibitor.
In a first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
m is selected from the group consisting of: 0. 1,2,3 or 4;
n is selected from the group consisting of: 2.3, 4, 5, 6, 7, 8 or 9;
x is selected from the group consisting of: -CH2-, C (O), O or NH; provided that each X together forms a stable structure;
r is selected from the group consisting of: H. hydroxy, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
y is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl.
In a further preferred embodiment of the method,
m is selected from the group consisting of: 1. 2,3 or 4;
n is selected from the group consisting of: 2.3, 4, 5 or 6;
x is selected from the group consisting of: -CH2-or O;
r is selected from the group consisting of: H. hydroxy, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
y is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C4 alkyl;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl.
In another preferred embodiment, the compound of formula I has the structure shown in formula II below:
n is selected from the group consisting of: 2.3, 4, 5, 6, 7, 8 or 9.
In another preferred embodiment, the compound of formula I has the structure shown in formula III below:
wherein each R is independently selected from the group consisting of: H. hydroxyl, halogen, C1-C4 alkyl. In another preferred embodiment, the compound of formula I has the structure shown in formula IV below:
wherein R is1And R2Each independently selected from the group consisting of: H. hydroxyl, halogen, C1-C4 alkyl. In another preferred embodiment, the compound of formula I is selected from the group consisting of:
in a second aspect of the invention, there is provided a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (2) a pharmaceutically acceptable carrier.
In a third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition according to claim 7, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with the activity or expression level of the GPR109A protein receptor.
In another preferred embodiment, the disease is selected from the group consisting of: bone degenerative diseases, bone marrow interstitial cell aging related diseases, osteoclast proliferation related diseases, and bone resorption related diseases.
In another preferred embodiment, the disease is selected from the group consisting of: osteoporosis, arthritis.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor designs and synthesizes a novel GPR109A protein receptor inhibitor through long-term and intensive research. On this basis, the inventors have completed the present invention.
Term(s) for
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.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C8Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C2-C6Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C2-C6Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
As used herein, the term "C3-C8Cycloalkyl radicals "Refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.
As used herein, the term "C1-C8Alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless otherwise specified, the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, haloGeneration C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.
A compound of formula I
The invention provides a compound shown as the following formula I, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
m is selected from the group consisting of: 0. 1,2,3 or 4;
n is selected from the group consisting of: 2.3, 4, 5, 6, 7, 8 or 9;
x is selected from the group consisting of: -CH2-, C (O), O or NH; provided that each X together forms a stable structure;
r is selected from the group consisting of: H. hydroxy, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
y is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl.
Preferred compounds of formula I are the specific compounds shown in the examples of this application.
Preparation of Compounds of formula I
The present invention also provides a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:
reaction of the alkyl chain with commercially available tetrazole I gives the coupling product II. The alkyl chain can vary by different chain lengths and heteroatoms. Alcohol II is coupled with purine 2, 6-dione III to form the main backbone IV. Purine-2, 6-dione III was prepared according to the method described in the literature (WO 2007/017262). Deprotection on allyl and SEM groups gives product V.
Pharmaceutical compositions and methods of administration
The compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound as a main active ingredient can be used for preventing and/or treating diseases (for example, cancers) related to GPR109A signal pathway, because the compound of the present invention has excellent inhibitory activity on GPR 109A.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with 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 composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing 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 sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, 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, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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 extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 using 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 delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may 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. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed 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 such materials and the like.
In addition to these inert diluents, the compositions can also contain 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, 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 vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When administered in combination, the pharmaceutical composition further comprises one or more other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Synthesis of 8-chloro-1- (4- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) butyl) -3, 7-dihydro-1H-purine-2, 6-dione (Compound 1)
Step 1: synthesis of 4- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) butan-1-ol. Sodium hydride (100mg, 60% 2.50mmol in oil) was added to a solution of 5- (2-fluorophenyl) -2-tetrazole (326mg, 1.99mmol) in THF at 0 deg.C. The reaction was stirred for 20 min and 4-chlorobutan-1-ol (324mg, 3.00mmol) was added. The mixture was warmed to room temperature, poured into ice-water, and extracted with ethyl acetate (20mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on a Biotage System (100g) eluting with EtOAc-hexane (1: 1) to give the title compound (250mg, 53% yield) as a yellow oil. MS (ESI)237.5(M + H)+；1H NMR(400 MHz，CDCl3)：δ7.40-7.70(m，2H)，7.40-7.60(m，1H)，7.20-7.30(m，1H)，4.00(br，s，1H)，3.71(t，J＝7.8Hz，2 H)，3.46(t，J＝8.2 HZ，2 H)，1.90-2.00(m，2H)，1.40-1.50(m，2H)。
Step 2: synthesis of 7-allyl-8-chloro-1- (4- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) butyl) -3- ((2- (trimethylsilyl) ethoxy) methyl) -3, 7-dihydro-1H-purine-2, 6-dione. Dibenzyl azodicarboxylate (0.65 g, 2.12 mmol) was added to a solution of 4- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) butan-1-ol (250mg, 1.06mmol), 7-allyl-8-chloro-3- (((2- (trimethylsilyl) ethoxy) methyl) -3, 7-dihydro-1H-purine-2, 6-dione (0.72g, 2.00mmol) and triphenylphosphine (0.53g, 2.00mmol) in anhydrous THF (20mL) the mixture was stirred at 0 ℃ for 30 minutes then under nitrogen at room temperature for 18 hours the solvent was evaporated and the residue was purified on a Biotage system (100g) eluting with EtOAc-hexane (1: 1) to give the title compound (300mg, 49% yield) as a yellow oil. MS (ESI)575.5(M + H)+。
And step 3: synthesis of 8-chloro-1- (4- (5- (2- (fluorophenyl) -2H-tetrazol-2-yl) butyl) -3, 7-dihydro-1H-purine-2, 6-dione.
To a solution of 7-allyl-8-chloro-1- (4- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) butyl) -3- ((2- (trimethyl-silyl) ethoxy) methyl) -3, 7-dihydro-1H-purine-2, 6-dione (300mg, 0.52mmol) in anhydrous DMF (5mL) was added Pd (PPh3)4(50mg, 0.05mmol) followed by morpholine (87mg, 1.00 mmol). The mixture was stirred at 60 ℃ for 16 hours. The solvent was removed using a vacuum centrifuge and the residue was dissolved in THF (10 mL). 1N HCl (2mL) was added to the solution and stirred for 2 h. The mixture was extracted with CH 2 Cl 2(10mL × 2). The combined organic layers were washed with brine (10mL), dried over sodium sulfate, filtered and dried. The residue was purified by Biotage System (100g) eluting with MeOH/CH 2 Cl 2 (1: 10) to give the title compound (152mg, 72% yield) as a yellow solid. MS (ESI)405.5(M + H) +. 1H NMR (400MHz, DMSO-d 6). delta.13.00 (br, s, 1H), 12.00(br, s, 1H)7.60-7.80(m, 2H), 7.20-7.50(m, 2H), 3.60-3.80(m, 4H), 1.90-2.00(m, 2H), 1.40-1.60(m, 2H).
The following compounds of examples 2 to 7 were synthesized according to the experiment in example 1 using different triazoles and alkyl linkers.
Example 8
8-chloro-1- (2- (2- (2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethoxy) ethyl) -3, 7-dihydro-1H-purine-2, 6-dione
Step 1: synthesis of 2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethan-1-ol.
Sodium hydride (100mg, 60% in oil, 2.50mmol) was added to a solution of 5- (2-fluorophenyl) -2-tetrazole (330mg, 2.0mmol) in THF at 0 deg.C. The reaction was stirred for 20 min and 2-chloroethanol (250mg, 3.0mmol) was added. The mixture was warmed to room temperature, poured into ice-water, and extracted with ethyl acetate (20mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on a Biotage System (100g)Alkylation, eluting with EtOAc-hexanes (2: 3) gave the title compound (300mg, 72% yield) as a yellow oil. MS (ESI)209.5(M + H)+。
Step 2: synthesis of 2- (2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethoxy) ethan-1-ol.
Sodium hydride (100mg, 60% in oil, 2.50mmol) was added to a solution of 2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethan-1-ol (300mg, 1.44mmol) and dissolved in THF at 0 ℃. The reaction was stirred for 20 min and 2-chloroethanol (250mg, 3.0mmol) was added, followed by warming to room temperature. The mixture was poured into ice water and extracted with ethyl acetate (20mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on a Biotage System (100g) eluting with EtOAc-hexanes (1: 2) to give the title compound (310mg, 85% yield) as a yellow oil. MS (ESI)253.5(M + H)+。
And step 3: 7-allyl-8-chloro-1- (2- (2- (2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethoxy) ethyl) -3- ((2- (trimethylsilyl) ethoxy) methyl) -3, 7-dihydro-1H-purine-2, 6-dione.
Dibenzyl azodicarboxylate (0.72g, 2.38mmol) was added to a solution of 2- (2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethoxy) ethan-1-ol (300mg, 1.19mmol), 7-allyl-8-chloro-3- ((2- (trimethylsilyl) ethoxy) methyl) -3, 7-dihydro-1H-purine-2, 6-dione (534mg, 1.50mmol) and triphenylphosphine (623 it was stirred in dry THF (20 mL). The mixture was stirred at 0 ℃ for 30 minutes and then at room temperature under nitrogen for 18 hours. The solvent was evaporated and the residue was purified on a Biotage system (100g) eluting with EtOAc-hexanes (2: 1) to give the title compound (310mg, 44% yield) as a yellow oil. MS (ESI)591.5(M + H)+。
And 4, step 4: synthesis of 8-chloro-1- (2- (2- (2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethoxy) ethyl) -3, 7-dihydro-1H-purine-2, 6-dione to 7-allyl-8-chloro-1- (2- (2- (5- (2- (fluorophenyl) -2H-tetrazol-2-yl) ethoxy) ethyl) -3- ((2- (trimethylsilylethoxy) methyl) -3, 7-dihydro-1H-purine-2, 6-dione (300mg, 0.51mmol) in dry DMF (5mL) was added Pd (PPh3)4(52mg, 0.05mmol),then morpholine (88mg, 1.0mmol) was passed through. The mixture was stirred at 60 ℃ for 16 hours. The solvent was removed using a vacuum centrifuge and the residue was dissolved in THF (10 mL). 1N HCl (2mL) was added to the reaction and stirred for 2 h. The mixture was extracted with CH 2 Cl 2(10mL × 2). The combined organic layers were washed with brine (10mL), dried over sodium sulfate, filtered and dried. The residue was purified by Biotage System (100g) with MeOH-CH2Cl2(1: 10) to give the title compound (125mg, 58% yield) as a yellow solid. MS (ESI)422.5(M + H)+。1H NMR(400MHz，DMSO-d6)δ13.00(br，s，1H)，12.00(br，s，1H)7.70-7.80(m，2H)，7.20-7.50(m，2H)，3.80-4.05(m，4H)，3.60-3.70(m，2H)，3.30-3.40(m，2H)。
Example 9
8-chloro-1- (2- (2- (2- (2- (5- (2-fluorophenyl) -2H-tetrazol-2-yl) ethoxy) ethyl) -3, 7-dihydro-1H-purine-2, 6-dione
Example 9 was synthesized by the same method as example 8. After obtaining the product by step 2, step 2 is repeated once to extend the linker one more unit to obtain the corresponding alcohol. Subsequent coupling and deprotection of the purine as in steps 3 and 4, respectively, gave the title compound as a white solid. MS (ESI)405.5(M + H)+。1H NMR(400MHz，DMSO-d6)δ13.00(br，s，1H)，12.00(br，s，1H)，7.70-7.80(m，2H)，7.25-7.55(m，2H)，3.80-3.95(m，4H)，3.30-3.70(m，8H)。
Bioassay example GPR109A TANGO analysis
For GPR109A TANGO assay, TANGO cells were plated in 96 well cell culture plates overnight at a density of 10000 cells/well in DMEM supplemented with 10% FBS. On the following day (day 2), the compounds tested were preincubated with cells for 1 hour, then GPCR 109A agonist was added to each well, and the cells were incubated for an additional 48 hours. T was observed using a plate reader (Infinite 200, Tecan)Fluorescence of ANGO cells, and calculation of IC50。
The results are shown in the following table, when IC50Below 100nM, the activity range is denoted A. When measured IC50At 100 and 500nM, the activity range is recorded as B; when IC50The activity range was recorded at 500-1000nM, C. When IC50Above 1000nM, an activity range D was recorded.
The results show that the compounds of the invention have excellent half inhibitory activity on GPR 109A.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
m is selected from the group consisting of: 0. 1,2,3 or 4;
n is selected from the group consisting of: 2.3, 4, 5, 6, 7, 8 or 9;
x is selected from the group consisting of: -CH2-, C (O), O or NH; provided that each X together forms a stable structure;
r is selected from the group consisting of: H. hydroxy, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
y is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof,
m is selected from the group consisting of: 1. 2,3 or 4;
n is selected from the group consisting of: 2.3, 4, 5 or 6;
x is selected from the group consisting of: -CH2-or O;
r is selected from the group consisting of: H. hydroxy, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
y is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C4 alkyl;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure shown in formula II below:
n is selected from the group consisting of: 2.3, 4, 5, 6, 7, 8 or 9.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure shown in formula III below:
wherein each R is independently selected from the group consisting of: H. hydroxyl, halogen, C1-C4 alkyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure shown in formula IV below:
wherein R is1And R2Each independently selected from the group consisting of: H. hydroxyl, halogen, C1-C4 alkyl.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the group consisting of:
7. a pharmaceutical composition comprising (1) a compound of claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; (2) a pharmaceutically acceptable carrier.
8. Use of a compound according to claim 1 or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 7, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of diseases which are associated with the activity or the expression level of the GPR109A protein receptor.
9. The use according to claim 8, wherein the disease is selected from the group consisting of: bone degenerative diseases, bone marrow interstitial cell aging related diseases, osteoclast proliferation related diseases, and bone resorption related diseases.
10. The use according to claim 8, wherein the disease is selected from the group consisting of: osteoporosis, arthritis.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006045564A1 (en) * | 2004-10-22 | 2006-05-04 | Smithkline Beecham Corporation | Xanthine derivatives with hm74a receptor activity |
| WO2007017262A1 (en) * | 2005-08-10 | 2007-02-15 | Smithkline Beecham Corporation | Xanthine derivatives as selective hm74a agonists |
| CN101103030B (en) * | 2004-02-14 | 2010-10-13 | 史密丝克莱恩比彻姆公司 | Medicaments with HM74A receptor activity |
| CN109364056A (en) * | 2018-09-25 | 2019-02-22 | 浙江欧谱生物科技有限公司 | Application of the g protein coupled receptor 109A inhibitor in medicine preparation |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101103030B (en) * | 2004-02-14 | 2010-10-13 | 史密丝克莱恩比彻姆公司 | Medicaments with HM74A receptor activity |
| WO2006045564A1 (en) * | 2004-10-22 | 2006-05-04 | Smithkline Beecham Corporation | Xanthine derivatives with hm74a receptor activity |
| WO2007017262A1 (en) * | 2005-08-10 | 2007-02-15 | Smithkline Beecham Corporation | Xanthine derivatives as selective hm74a agonists |
| CN109364056A (en) * | 2018-09-25 | 2019-02-22 | 浙江欧谱生物科技有限公司 | Application of the g protein coupled receptor 109A inhibitor in medicine preparation |
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