CN117693504A - Salt of GLP-1R agonist compound, preparation method and medical application thereof - Google Patents

Salt of GLP-1R agonist compound, preparation method and medical application thereof Download PDF

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CN117693504A
CN117693504A CN202280051627.2A CN202280051627A CN117693504A CN 117693504 A CN117693504 A CN 117693504A CN 202280051627 A CN202280051627 A CN 202280051627A CN 117693504 A CN117693504 A CN 117693504A
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salt
glp
agonist compound
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吴俊军
陆银锁
连小磊
李亲泽
李松
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Shenzhen Salubris Pharmaceuticals Co Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

Salts of a series of GLP-1R agonist compounds, pharmaceutical compositions comprising salts of these compounds, and use of the compounds in medicaments for treating diseases such as diabetes and the like.

Description

Salt of GLP-1R agonist compound, preparation method and medical application thereof Technical Field
The invention belongs to the technical field of chemical medicaments, and provides salts of a series of GLP-1R agonist compounds. The invention also relates to a pharmaceutical composition containing the salts of the compounds and application of the compounds in medicines for treating diseases such as diabetes and the like.
Background
Diabetes affects millions of people worldwide and is considered one of the major threats to death in humans in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys, and nerves. Worldwide, the socioeconomic burden of diabetes is very heavy.
There are two major types of diabetes, designated type I and type II, with type II diabetes (T2 DM) accounting for over 90% of all diabetes worldwide. Type I diabetes is characterized by insulin deficiency, mainly caused by autoimmune-mediated destruction of islet beta cells, and type II diabetes is characterized by abnormal insulin secretion and subsequent insulin resistance. To prevent ketoacidosis, patients with type I diabetes must ingest exogenous insulin to survive. Although type II diabetics do not rely on exogenous insulin as do type I diabetics, they may require exogenous insulin to control blood glucose levels.
Glucagon-like peptide-1 (GLP-1) is one of the incretins, secreted by intestinal epithelial L cells, and exerts a physiological effect by binding to its receptor. The GLP-1 receptor (GLP-1R) belongs to the G protein-coupled receptor subfamily, and when GLP-1 binds to the GLP-1 receptor, a series of biological effects are elicited. It has been shown that GLP-1 promotes insulin secretion in a glucose-dependent manner, i.e., GLP-1 stimulates islet cells to increase insulin secretion and lower blood glucose when blood glucose concentration in humans increases. The GLP-1 receptor agonist is a novel hypoglycemic drug, and can effectively control blood sugar level under the condition of not causing hypoglycemia; but also can effectively lighten the body mass by increasing the feeling of satiety, delaying gastric emptying, suppressing appetite, reducing fat accumulation and the like, thereby achieving the purpose of losing weight.
Currently, polypeptide drugs based on GLP-1 receptor agonists, such as liraglutide, exenatide, and cable Ma Lutai, are already applied to obese type II diabetics and simply obese or overweight patients, and have obvious effect of reducing the body mass, but often have gastrointestinal adverse reactions such as nausea and vomiting. Oral non-polypeptide drugs have been attempted by research institutions for the treatment of type II diabetes and weight loss, but the discovery of glucagon-like peptide-1 receptor small molecule drugs has been limited due to the difficulty in mimicking the interaction of the receptor with the polypeptide by small molecules.
The current patent applications disclosing non-polypeptide GLP-1 receptor agonists are WO2009/111700, WO2010/114824, WO2011/114271, WO2013/090454, WO2018/056453, WO2018/109607, WO2019239319, WO2019239371, WO2020103815, etc. Of these, only TTP-273 from vTv and PF-06882961 from psilon have entered clinical second-phase studies.
Applicants have filed in prior application CN202110415182.9 a series of GLP-1R agonist compounds comprising compound a of the formula:
disclosure of Invention
The invention provides a series of salts of oxopyridazine amide derivatives, a preparation method and medical application thereof.
Specifically disclosed is a salt of a GLP-1R agonist compound represented by the formula (I),
wherein:
n is 0.3-3;
m forms a salt with the carboxyl, wherein the salt is at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ferric salt, zinc salt or ammonium salt; or at least one salt selected from the group consisting of methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, isopropylamine salt, 2-ethylaminoethoxide, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, ammonium salt, tetramethylammonium salt, tetraethylammonium salt, triethanolamine salt, piperidine salt, piperazine salt, morpholine salt, lysine salt, L-lysine salt, arginine salt, L-arginine salt, histidine salt, L-histidine salt, meglumine salt, dimethylglucamine salt, ethylglucamine salt, dicyclohexylamine salt, 1, 6-hexanediamine salt, glucamine salt, sarcosinate, serinate, tris-hydroxymethyl aminomethane salt, aminopropylenexide, ornithine salt and choline salt.
As a preferred embodiment of the present invention, the GLP-1R agonist compound has the structure:
as a preferred embodiment of the present invention, n is 0.33, 0.5, 1, 1.5, 2, 2.5 or 3, and particularly preferably n=1 or 0.5.
As a preferable technical scheme of the invention, the salt is selected from sodium salt, potassium salt, trihydroxymethyl aminomethane salt, calcium salt and magnesium salt.
As a preferred embodiment of the present invention, the salt is selected from sodium salt, n=1; potassium salt, n=1; a tris (hydroxymethyl) aminomethane salt, n=1; calcium salt, n=0.5; magnesium salt, n=0.5.
As a preferred embodiment of the present invention, the salt is selected from the group consisting of:
as a preferred embodiment of the present invention, the salt is selected from the group consisting of:
as a preferred embodiment of the present invention, one or more hydrogen atoms of the compound are replaced with deuterium isotopes.
The invention further provides a pharmaceutical composition comprising the foregoing salt, and one or more pharmaceutically acceptable carriers.
The invention further provides the use of the salt in the preparation of a medicament for the treatment of GLP-1R related diseases, preferably diabetes related diseases.
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Salts of the compounds of the present invention refer to "pharmaceutically acceptable salts" prepared from the compounds having the specified substituents found in the present invention and pharmaceutically acceptable acids or bases.
Salts of certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Optically active (R) -and (S) -isomers, as well as D and L isomers, can be prepared by chiral syntheses or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The atoms of the compound molecule are isotopes, and the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism, improving in vivo activity and the like can be achieved through isotope derivatization. And, an embodiment is included in which at least one atom is substituted with an atom having the same atomic number (proton number) and different mass numbers (proton and neutron sum). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which include 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, respectively. In particular, radioisotopes such as 3H or 14C, which emit radiation as they decay, may be used for the local anatomical inspection of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay or change with their amounts nor are radioactive, and therefore they can be safely used. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes may be converted according to general methods by substituting reagents used in the synthesis with reagents comprising the corresponding isotopes.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds such as deuterium (2H), iodine-125 (125I) or C-14 (14C) may be labeled with a radioisotope. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Further, the compound of the present invention has the effects of prolonging half-life, reducing clearance, metabolizing stability, improving in vivo activity, etc. after deuteration, the compound of the present invention has one or more hydrogen atoms substituted by isotope deuterium (2H).
The method of preparing the isotopic derivatives generally comprises: phase transfer catalysis method. For example, the preferred deuteration method employs a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO 4). The exchange of methylene protons of diphenylmethane compounds using a phase transfer catalyst results in the introduction of higher deuterium than reduction with deuterated silanes (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with lewis acids such as aluminum trichloride using sodium deuterated borate.
The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference may be made to Remington, the Science and Practice of Pharmacy,21st Ed., lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to the carrier, diluent, and/or medium required to make an effective pharmaceutical composition.
For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The term "treatment" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a Bruker AVANCE-III nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3) and Tetramethylsilane (TMS) as the internal standard.
The MS was determined by ISQ EC mass spectrometry (manufacturer: thermo, model: ISQ EC).
High Performance Liquid Chromatography (HPLC) analysis used a Thermo U3000 HPLC DAD high performance liquid chromatograph.
The CombiFlash rapid preparation instrument uses CombiFlash rf+ LUMEN (TELEDYNE ISCO).
The thin layer chromatography silica gel plate uses the tabacco silver dragon HSGF254 or GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.17 mm-0.23 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 100-200 mesh silica gel of Shangbang silica gel as a carrier.
Example 1
Synthesis of 2- ((S) - (1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid
Synthesis of 2- ((R) - (1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid
The specific synthetic route is as follows:
step A: synthesis of tert-butyl 4- (6-chloropyridin-2-yl) piperazine-1-carboxylate
Piperazine-1-carboxylic acid tert-butyl ester (300.0 mg, 1.61 mmol) was dissolved in 1, 4-dioxane (12.0 ml), 2, 6-dichloropyridine (262.0 mg, 1.77 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (135.4 mg, 0.16 mmol) and carbonic acid were addedCesium (788.5 mg, 2.42 mmol). Under the protection of nitrogen, the temperature is raised to 100 ℃, and the reaction is stirred for 5 hours. Spin-drying the solvent, and column chromatography (ethyl acetate: n-hexane=1:10) gave 150.0 mg of t-butyl 4- (6-chloropyridin-2-yl) piperazine-1-carboxylate as a beige solid (yield: 31.3%). LC-MS: rt=1.82 min, [ M ] t Bu+H] + ＝242.36。
And (B) step (B): synthesis of tert-butyl 4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (6-chloropyridin-2-yl) piperazine-1-carboxylate (150.0 mg, 0.51 mmol) was dissolved in 1, 4-dioxane (5.0 ml), 3-fluoro-4- (hydroxymethyl) benzonitrile (76.3 mg, 0.51 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (43.2 mg, 0.05 mmol) and cesium carbonate (246.8 mg, 0.76 mmol) were added. Under the protection of nitrogen, the temperature is raised to 100 ℃, and the reaction is stirred for 15 hours. The solvent was dried by spin-drying and separated by column chromatography (ethyl acetate: n-hexane=1:10) to give 102.0 mg of t-butyl 4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazine-1-carboxylate as a beige solid (yield: 49.1%). LC-MS: rt=2.23 min, [ M ] t Bu+H] + ＝357.23。
Step C: synthesis of 3-fluoro-4- (((6- (piperazin-1-yl) pyridin-2-yl) oxy) methyl) benzonitrile
Tert-butyl 4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazine-1-carboxylate (102.0 mg, 0.25 mmol) was dissolved in methanol (2.0 ml) and hydrochloric acid/1, 4-dioxane solution (0.5 ml, 2.0 mmol) was added. The reaction was stirred at room temperature for 3 hours. Spin-drying solvent73.7 mg of 3-fluoro-4- (((6- (piperazin-1-yl) pyridin-2-yl) oxy) methyl) benzonitrile (yield: 73.5%) were obtained as a white solid. LC-MS: rt=1.68 min, [ m+h] + ＝313.25。
Step D: synthesis of methyl 2- (1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylate
To acetonitrile (8.0 ml) containing 4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazine hydrochloride (652 mg, 2.09 mmol) at 25 degrees celsius was added N, N-diisopropylethylamine (1.0 ml), potassium iodide (420 mg, 3.13 mmol) and potassium carbonate (577 mg, 4.18 mmol) to N, N-dimethylformamide (10.0 ml), and finally 2- ((S) -1-chloroethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b]Pyridine-5-carboxylic acid methyl ester (650 mg, 2.09 mmol), N 2 The reaction was carried out at 60℃for 3.0 hours under protection.
After the completion of the reaction, quenched with water, extracted with ethyl acetate (30 ml. Times.2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting residue was purified by column chromatography over silica gel (eluent: ethyl acetate/n-hexane=2/1.) to give 690 mg of 2- (1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] as a yellow solid]Pyridine-5-carboxylic acid methyl ester (yield: 56.4%, dr=66%). LC-MS rt=1.93 min, [ m+h ]] + ＝586.26。
Step E: synthesis of 2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (Compound A-a) and 2- ((R) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (Compound A-b)
To a mixed solution of tetrahydrofuran (3 ml) and methanol (1 ml) containing methyl 2- (1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylate (690 mg, 1.18 mmol) at zero degrees celsius was added dropwise an aqueous solution (1 ml) of lithium hydroxide (198 mg, 4.72 mmol) at 25 degrees celsius for 30 minutes.
At the end of the reaction, quenched with water, extracted with ethyl acetate (30 ml. Times.2), the organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography over silica gel (eluent: methanol/dichloromethane=1/10. To give 290 mg of 2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4, 5-b) as a white solid]Pyridine-5-carboxylic acid (Compound A-a) (yield: 43.0%) and 59 mg of white solid 2- ((R) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b]Pyridine-5-carboxylic acid (compound a-b) (yield 8.7%). The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows: chromatographic column: agilent 5 Prep-C 18 100mm by 30mm 5. Mu.M; mobile phase: eluting with water (containing 0.1% ammonia water) and acetonitrile; flow rate: 20 ml/min; gradient: compound a-a and compound a-b eluted from 21% acetonitrile at 10.12min and 12.17min, respectively, detection wavelength: 254nm.
Compound a-a HPLC rt=10.12 min. LC-MS rt=1.79 min, [ m+h ]] + ＝572.30。 1 H NMR(400MHz,DMSO-d 6 )δ8.14(d,J＝8.2Hz,1H),7.97(d,J＝8.2Hz,1H),7.87(dd,J＝10.0,1.5Hz,1H),7.69(dd,J＝7.9,1.4Hz,1H),7.64(t,J＝7.6Hz,1H),7.45(t,J＝8.0Hz,1H),6.30(d,J＝8.1Hz,1H),6.10(d,J＝7.8Hz,1H),5.38(s,2H),5.30–5.24(m,1H),4.82–4.70(m,2H),4.63–4.58(m,1H),4.44–4.39(m,1H),4.11–4.06(m,1H),3.43–3.33(m,4H),2.64–2.58(m,1H),2.56–2.52(m,4H),2.39–2.30(m,1H),1.45(d,J＝6.7Hz,3H)。
Compound a-b HPLC rt=12.17 min. LC-MS rt=1.79 min, [ m+h ]] + ＝572.30。 1 H NMR(400MHz,DMSO)δ8.09(d,J＝8.2Hz,1H),7.95(d,J＝8.2Hz,1H),7.87(dd,J＝10.0,1.4Hz,1H),7.69(dd,J＝7.9,1.5Hz,1H),7.67–7.61(m,1H),7.46(t,J＝8.0Hz,1H),6.31(d,J＝8.1Hz,1H),6.11(d,J＝7.8Hz,1H),5.39(s,2H),5.07–5.00(m,2H),4.69–4.49(m,4H),3.47–3.37(m,4H),2.79–2.70(m,1H),2.66–2.52(m,5H),1.42(d,J＝6.8Hz,3H)。
Example 2
Synthesis of sodium salt of 2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylate
2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (1 g, 1.75 mmol) was dissolved in 20 ml of water to give a suspension, aqueous sodium hydroxide solution (0.175 mmol/ml, 10ml, 1.75 mmol) was added dropwise under ice-bath conditions, the solution became clear, ice-bath conditions were maintained stirring was continued for 1 hour, and the sample was lyophilized directly to give a sodium salt sample.
1 H NMR(400MHz,DMSO-d 6 )δ7.96(d,J＝8.2Hz,1H),7.91(d,J＝8.2Hz,1H),7.88(dd,J＝9.9,1.5Hz,1H),7.70(dd,J＝7.9,1.5Hz,1H),7.64(t,J＝7.5Hz,1H),7.45(t,J＝8.0Hz,1H),6.30(d,J＝8.1Hz,1H),6.11(d,J＝7.8Hz,1H),5.39(s,2H),5.22(tt,J＝7.6,3.9Hz,1H),4.83–4.69(m,2H),4.52(q,J＝6.7Hz,1H),4.41(td,J＝8.0,5.7Hz,1H),4.07(dt,J＝9.2,5.7Hz,1H),3.45–2.53(m,4H),2.58–2.53(m,5H),2.41–2.32(m,1H),1.44(d,J＝6.7Hz,3H)。
Example 3
Synthesis of Potassium salt of 2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylate
2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (1 g, 1.75 mmol) was dissolved in 20 ml of water to give a suspension, aqueous potassium hydroxide (0.175 mmol/ml, 10ml, 1.75 mmol) was added dropwise under ice bath conditions, the solution became clear, ice bath conditions were maintained and stirring was continued for 1 hour, and the sample was lyophilized directly to give a potassium salt sample.
1 H NMR(400MHz,DMSO-d6)δ7.91(d,J＝8.2Hz,1H),7.88(dd,J＝10.0,1.5Hz,1H),7.84(d,J＝8.2Hz,2H),7.70(dd,J＝7.9,1.5Hz,1H),7.65(t,J＝7.5Hz,1H),7.45(t,J＝8.0Hz,1H),6.30(d,J＝8.2Hz,1H),6.10(d,J＝7.8Hz,1H),5.39(s,2H),5.29–5.23(m,1H),4.70(dd,J＝15.0,4.1Hz,1H),4.69(dd,J＝15.0,4.1Hz,1H),4.57(q,J＝6.7Hz,1H),4.41(td,J＝8.1,5.8Hz,1H),4.06(dt,J＝9.1,5.9Hz,1H),3.50–3.30(m,5H),2.61–2.50(m,4H),2.40–2.31(m,1H),1.44(d,J＝6.7Hz,3H)。
Example 4
Synthesis of Trihydroxymethylaminomethane salt of 2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid
2- ((S) -1- (4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) ethyl) -3- (((S)) -oxetan-2-yl) methyl) -3H-imidazo [4,5-b]Pyridine-5-carboxylic acid (599.9 mg, 1.05 mmol) was dissolved in 10ml of methanol to give a suspension, an aqueous solution of tris (hydroxymethyl) aminomethane (2 mmol/ml, 524.9. Mu.l, 1.05 mmol) was added at room temperature, the solution became clear after stirring at room temperature for 10 minutes, stirring was continued at room temperature for 2 hours, the clear sample was transferred to room temperature for vacuum drying, 10ml of methyl t-butyl ether was added to the dried solid sample to give a suspension, the suspension was stirred at temperature cycling (50 ℃ C. -5 ℃ C., 0.1 ℃ C./min) for 24 hours, the suspension was centrifuged, and the solid was dried under vacuum at 50 ℃ C. To give a tris (hydroxymethyl) aminomethane salt sample. 1 H NMR(400MHz,MeOD)δ8.10–8.02(m,2H),7.62(t,J＝7.5Hz,1H),7.56–7.51(m,2H),7.42(t,J＝8.0Hz,1H),6.25(d,J＝8.1Hz,1H),6.12(d,J＝7.8Hz,1H),5.42(s,2H),5.41–5.33(m,1H),4.97(dd,J＝15.2,3.8Hz,1H),4.87(dd,J＝15.2,3.6Hz,1H),4.66(q,J＝6.7Hz,1H),4.53(td,J＝8.0,6.0Hz,1H),4.11(dt,J＝9.3,5.9Hz,1H),3.67(s,6H),3.51–3.37(m,4H),2.72–2.56(m,5H),2.44–2.32(m,1H),1.56(d,J＝6.8Hz,3H)。
EXAMPLE 5 solubility investigation of the Compounds of the invention
According to the fourth part of the valve of Chinese pharmacopoeia 2020, the solubility is measured, the compound prepared by the embodiment of the invention is taken and ground into fine powder, the sample is weighed and placed in a solvent with a certain capacity at 25+/-2 ℃ and is strongly shaken for 30 seconds every 5 minutes; dissolution within 30 minutes, such as when no visually observable solute particles or droplets are observed, is considered complete dissolution.
The approximate solubility of a pharmaceutical product is expressed in terms of the following terms:
by very soluble is meant that 1g (mL) of solute is soluble in less than 1mL of solvent;
soluble means that 1g (mL) of solute can be dissolved in 1-less than 10mL of solvent;
dissolving means that 1g (mL) of solute can be dissolved in 10-less than 30mL of solvent;
slightly soluble means that 1g (mL) of solute can be dissolved in 30-less than 100mL of solvent;
slightly soluble means that 1g (mL) of solute can be dissolved in 100-less than 1000mL of solvent;
very slightly soluble means that 1g (mL) of solute can be dissolved in 1000-less than 10000mL of solvent;
by practically insoluble or insoluble is meant that 1g (mL) of solute is not completely soluble in 10000mL of solvent.
The experimental method and the results are as follows:
table one: solubility investigation of the inventive Compounds
Solvent pH EXAMPLE 1 Compound A-a Example 2 Example 4
pH4.5 ＜1mg/ml ＞34mg/ml ＞168mg/ml
pH6.8 ＞1mg/ml,＜10mg/ml ＞35mg/ml ＞168mg/ml
From the above results, the sodium salt and the trihydroxymethyl aminomethane salt of the compound of the present invention have greatly improved solubility relative to the free acid of the compound a-a, which is advantageous for improving the patentability of the drug.
Example 6: stability investigation of the inventive Compounds
Stability measurement is carried out according to the stability guidance of the fourth part of the stability test guidelines of raw materials and preparations of the Chinese pharmacopoeia 2020 edition. The test sample (about 50 mg) of the compound prepared in the embodiment of the invention is weighed in a proper amount, placed in a 10ml penicillin bottle, sealed by a gland, a plurality of samples are packaged in this way, then the samples are respectively placed in a constant temperature and humidity box with the conditions of 30 ℃ +/-2 ℃, 65% +/-5% RH and 20 ℃ +/-2 ℃ and 60% +/-5% RH, the samples are taken out after 10 days, the moisture and related substances are measured, and the test results of the moisture and related substances are compared with the test results of 0 days.
The experimental results are shown in the following table:
and (II) table: stability investigation of the inventive Compounds
From the above results, it can be seen that the sodium, potassium and tris salts of the compounds of the present invention are more stable under a variety of humidity/temperature conditions relative to the compound a-a free acid.
EXAMPLE 7 investigation of the pharmacokinetic profile of the Compounds of the invention in rats
1. Experimental materials
SD rats: male, 180-250g, purchased from Beijing Vietnam laboratory animal technologies Co.
Reagent: sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200mpa.s, lot B1707016, allatin), vitamin E polyethylene glycol succinate (TPGS, lot CSN10842-002, CSNpharm), DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), acetonitrile, formic acid, propranolol (internal standard) are all commercially available.
Instrument: race-mers flilc-MS (Ultimate 3000 UPLC,TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).
2. Preparation of administration vehicles
14.3% (w/v) TPGS solution
Taking 100mL as an example: 14.3g of TPGS was weighed into a suitable container and melted into a liquid state in a water bath at 60 ℃. Adding 100mL of ultrapure water into a proper container, heating to 60 ℃ on a magnetic stirrer, slowly dripping melted TPGS while stirring, and continuously stirring for about 1 hour to obtain a clear and transparent pale yellow liquid.
0.5% (w/v) CMC-Na solution
Taking 100mL as an example: 100mL of ultrapure water is measured and put into a proper container, a magnetic stirrer is put into the container, 0.5g of CMC-Na is weighed and added into the container while stirring, and stirring is continued until the solution is clear and transparent.
3. Formulation of the administration preparation
And respectively weighing a proper amount of three powders of free acid, sodium salt and trihydroxymethyl aminomethane salt of the compound A in a ceramic mortar, wherein the solvent composition is 30% TPGS (14.3 percent) -40% CMC-Na (0.5 percent) and 30% PEG (v/v/v), firstly adding 30% TPGS to grind the medicinal powder until no obvious large particles exist, then adding 40% CMC-Na to grind until no macroscopic particles exist, and finally adding 30% PEG-400 to grind and mix uniformly.
4. Blood sample collection and biological analysis
After the gastric lavage administration of the rat, 200 mu L of venous blood is collected at 15min, 30min, 1h, 2h, 5h, 7h and 24h and is placed in an EDTA-K2 anticoagulant blood collection tube, the blood plasma is separated by centrifugation at 4000rpm and at 2-8 ℃ for 5min, and the blood plasma is frozen at-80 ℃ to be tested. A certain amount of test sample was precisely weighed and dissolved to 2mg/mL with DMSO to be used as a stock solution. Accurately absorbing a proper amount of compound stock solution, and adding acetonitrile to dilute the stock solution to prepare a standard series of solution. Accurately sucking 5 mu L of each standard series solution, adding 45 mu L of blank plasma, mixing uniformly by vortex, preparing into plasma samples with the plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000 and 3000ng/mL, carrying out double-sample analysis on each concentration, and establishing a standard curve. 30. Mu.L of plasma was taken, 150. Mu.L of acetonitrile solution of internal standard propranolol (50 ng/mL) was added, after vortexing and mixing, 100. Mu.L of purified water was added, vortexing and mixing again, centrifugation at 4000rpm for 5min, and the supernatant was taken for LC-MS analysis. LC-MS detection conditions were as follows:
chromatographic column: waters ACQUITYTM PREMIER HSS T, 50 x 2.1mm,1.8 μm.
Mobile phase a: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: gradient elution at 0.5 mL/min:
time (min) A(％) B(％)
0 95％ 5％
1 40％ 60％
2.5 5％ 95％
2.51 95％ 5％
2.8 95％ 5％
5. Data processing
After LC-MS detects the blood concentration, the pharmacokinetic parameters are calculated by adopting WinNonlin 6.1 software and a non-atrioventricular model method, and the result is shown in a third table.
Table three: rat pharmacokinetic parameters of the Compounds of the invention
From the above results, it can be seen that the sodium salt and the tris salt of the compound of the present invention are significantly better exposed to rats than the compound a-a free acid, indicating better absorption relative to the compound a-a free acid.
EXAMPLE 8 beagle pharmacokinetic characterization of the Compound capsules of the invention
1. Reagents and apparatus
Pentapeptide gastrin (sigma, lot number SLCC 6419), gelatin hollow capsule No. 0, ammonium hydroxide (ACS reagent, 28.0-30.0% NH) 3 Ai Lan (Shanghai) chemical technology Co., ltd., batch No. CEC 1070004), LC-MS instrument (Siemens flying multi mate 3000 UPLC,TSQ QUANTUM ULTRA triple quadrupole mass spectrometry).
2. Experimental animal
Beagle dogs 4 males, weighing 5kg-7kg, purchased from Beijing Mas Biotechnology Co.
3. Preparation
The pentagastrin is precisely weighed and dissolved in DMSO to prepare 25mg/mL stock solution, the stock solution is diluted 100 times by normal saline, and 0.1% (v/v) ammonium hydroxide is added to completely dissolve the precipitated precipitate, and the final concentration is 0.25mg/mL.
4. Blood sample collection and biological analysis
Precisely weighing four kinds of powder of free acid, potassium salt, sodium salt and trihydroxymethyl aminomethane salt of the compound A-a, filling into a No. 0 hollow capsule, fixing 4 dogs with serial numbers, taking one capsule per dog, taking 4 dogs per salt type sample, and taking another salt type at intervals of 2-3 days after the first administration of one salt type. Each dog was pre-dosed with pentagastrin.
After oral administration, about 1mL of blood is collected by scalp needle on forelimb or hindlimb vein at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h and 24h respectively, and the blood is placed in an EDTA-K2 anticoagulant blood collection tube, centrifuged at 4000rpm and 2-8 ℃ for 10min to separate blood plasma, and the blood plasma is stored at-80 ℃ to be tested.
A certain amount of test sample was precisely weighed and dissolved to 2mg/mL with DMSO to be used as a stock solution. Stock solutions were diluted with acetonitrile/water (1:1) to 30000, 10000, 3000, 1000, 300, 100, 30, 10, 3ng/mL to give standard curve working solutions. 5 mu L of working solution is added into 45 mu L of blank canine plasma, and the mixture is uniformly mixed by vortex to prepare standard curve samples with the plasma concentration of 3000, 1000, 300, 100, 30, 10, 3, 1 and 0.3 ng/mL. mu.L of standard yeast sample and collected plasma sample are taken, 150 mu.L of propranolol acetonitrile solution (internal standard, 50 ng/mL) is added to precipitate protein, 100 mu.L of water is added to be mixed evenly by vortex, centrifugation is carried out at 4000rpm for 5min, and supernatant liquid is taken for LC-MS analysis. LC-MS detection conditions were as follows:
chromatographic column: waters ACQUITYTM PREMIER HSS T, 50 x 2.1mm,1.8 μm.
Mobile phase a: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: gradient elution at 0.5 mL/min:
time (min) A(％) B(％)
0 95％ 5％
1 40％ 60％
2.5 5％ 95％
2.51 95％ 5％
2.8 95％ 5％
5. Data processing
After LC-MS detection of blood concentration, the pharmacokinetic parameters of beagle dogs after administration were calculated using a non-compartmental model of WinNonlin 6.1 software, and the results are shown in Table IV.
Table four: beagle pharmacokinetic parameters of the inventive compounds
From the above results, the sodium salt, potassium salt and trihydroxymethyl aminomethane salt of the compound of the present invention are significantly better than the compound A-a free acid in oral solid absorption exposure in beagle dogs, indicating better absorption relative to the compound A-a free acid.
Example 9: rat pharmacokinetics study of the Compounds of the invention
1. Experimental materials
SD rats: male, 180-250g, purchased from Beijing Vietnam laboratory animal technologies Co.
Reagent: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.
Instrument: siemens flight LC-MS (U300 UPLC, TSQ QUANTAUMN ULTRA triple quadrupole mass spectrometry).
2. Experimental method
Weighing compound A-a of example 1 and corresponding compounds prepared according to CN201780086550.1, 4A-1 and 10A-77, dissolving in DMSO-PEG-400-normal saline (5:60:35, v/v/v) system, collecting 200 mu L of venous blood in heparinized EP tube after 15min, 30min, 1h, 2h, 5h, 7h and 24h (iv group is added for 5 min) of intravenous blood administration, centrifuging at 12000rpm for 2min, and taking blood plasma for frozen storage at-80 ℃ to be tested. A certain amount of test sample was precisely weighed and dissolved to 2mg/mL with DMSO to be used as a stock solution. Accurately absorbing a proper amount of compound stock solution, and adding acetonitrile to dilute the stock solution to prepare a standard series of solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, mixing uniformly by vortex, preparing into plasma samples with the plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000 and 3000ng/mL, carrying out double-sample analysis on each concentration, and establishing a standard curve. 30. Mu.L of plasma (5 min, 15min, 30min, 1h plasma diluted 10 times) was taken, 200. Mu.L of acetonitrile solution of internal standard propranolol (50 ng/mL) was added, after vortexing, 100. Mu.L of purified water was added, vortexing was again carried out, centrifugation was carried out at 4000rpm for 5min, and the supernatant LC-MS was taken for analysis. LC-MS detection conditions were as follows:
chromatographic column: the Siemens flight HyperSIL GOLD C-18 UPLC column, 100 x 2.1mm,1.7 μm.
Mobile phase: gradient elution with water (0.1% formic acid) -acetonitrile was performed as follows
Time (min) Water (0.1% formic acid) Acetonitrile
0 90％ 10％
0.6 90％ 10％
1 10％ 90％
2.6 10％ 90％
2.61 90％ 10％
4 90％ 10％
3. Data processing
After LC-MS detects the blood concentration, the pharmacokinetic parameters are calculated by adopting WinNonlin 6.1 software and a non-atrioventricular model method, and the results are shown in Table five.
Table five: results of the present compounds on rat pharmacokinetics
Conclusion: from Table five, it can be seen that the compounds of the present invention are orally absorbed well in rats and have high exposure and bioavailability.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (10)

  1. Salts of GLP-1R agonist compounds of formula (I),
    wherein:
    n is 0.3-3;
    m forms a salt with the carboxyl, wherein the salt is at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ferric salt, zinc salt or ammonium salt; or at least one salt selected from the group consisting of methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, isopropylamine salt, 2-ethylaminoethoxide, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, ammonium salt, tetramethylammonium salt, tetraethylammonium salt, triethanolamine salt, piperidine salt, piperazine salt, morpholine salt, lysine salt, L-lysine salt, arginine salt, L-arginine salt, histidine salt, L-histidine salt, meglumine salt, dimethylglucamine salt, ethylglucamine salt, dicyclohexylamine salt, 1, 6-hexanediamine salt, glucamine salt, sarcosinate, serinate, tris-hydroxymethyl aminomethane salt, aminopropylenexide, ornithine salt and choline salt.
  2. The salt of a GLP-1R agonist compound of claim 1, wherein the GLP-1R agonist compound has the structure:
  3. the salt of a GLP-1R agonist compound according to claim 1 or 2, characterized in that n is 0.33, 0.5, 1, 1.5, 2, 2.5 or 3.
  4. A salt of a GLP-1R agonist compound according to claim 1 or 2, characterized in that the salt is selected from the group consisting of sodium, potassium, tris, calcium, magnesium salts.
  5. The salt of a GLP-1R agonist compound according to claim 1 or 2, characterized in that said salt is selected from the group consisting of sodium salt, n=1; potassium salt, n=1; a tris (hydroxymethyl) aminomethane salt, n=1; calcium salt, n=0.5; magnesium salt, n=0.5.
  6. The salt of a GLP-1R agonist compound according to claim 1, wherein the salt is selected from the group consisting of:
  7. the salt of a GLP-1R agonist compound according to claim 1 or 2, characterized in that said salt is selected from the group consisting of:
  8. the salt of a GLP-1R agonist compound according to any one of claims 1 to 7, characterized in that: more than one hydrogen atom of the compound is replaced by isotopic deuterium.
  9. A pharmaceutical composition comprising a salt of a GLP-1R agonist compound of any one of the preceding claims 1-8, and one or more pharmaceutically acceptable carriers.
  10. Use of a salt of a GLP-1R agonist compound according to any one of claims 1-8 for the manufacture of a medicament for the treatment of GLP-1R related diseases, preferably diabetes related diseases.
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