CN117003749A - Polymorphs of Compound A-a and pharmaceutical compositions containing the polymorphs - Google Patents
Polymorphs of Compound A-a and pharmaceutical compositions containing the polymorphs Download PDFInfo
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- CN117003749A CN117003749A CN202310508926.0A CN202310508926A CN117003749A CN 117003749 A CN117003749 A CN 117003749A CN 202310508926 A CN202310508926 A CN 202310508926A CN 117003749 A CN117003749 A CN 117003749A
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- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
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- 229940126586 small molecule drug Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of chemical medicine preparation, and particularly relates to a polymorph of a GLP-1R agonist compound A-a and a pharmaceutical composition containing the polymorph.
Description
Technical Field
The invention belongs to the technical field of chemical medicaments, and particularly relates to a polymorph of a GLP-1R agonist compound A-a and a pharmaceutical composition containing the polymorph.
Background
Diabetes affects millions of people worldwide and is considered one of the major threats to death in humans in the 21 st 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 weight 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 body weight, but are often accompanied with gastrointestinal adverse reactions such as nausea, vomiting and the like. 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.
Presently disclosed non-polypeptide GLP-1 receptor agonists are patent applications 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.
Disclosure of Invention
It is an object of the present invention to provide a polymorph of GLP-1R agonist compound A-a.
The chemical name of the compound A-a is: 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 of formula: c (C) 30 H 30 FN 7 O 4 The chemical structural formula is shown as the following formula (I),
form a, which is a polymorph of compound a-a, having characteristic peaks at 6.22 °, 13.91 °, 17.63 °, 18.18 ° and 26.93 ° in an X-ray diffraction pattern, expressed in terms of 2θ degrees, with an error of ±0.2 °.
As a preferred embodiment of the present invention, form a of the compound a-a has characteristic peaks expressed in terms of 2θ in an X-ray diffraction pattern at 6.22 °, 13.91 °, 15.88 °, 16.34 °, 17.63 °, 18.18 °, 19.72 °, 21.97 °, 26.56 ° and 26.93 ° with an error of ±0.2 °.
As a preferred embodiment of the present invention, form a of the compound a-a has characteristic peaks in the X-ray diffraction pattern at angles of 2θ of 6.22 °, 8.79 °, 12.44 °, 13.91 °, 14.44 °, 15.88 °, 16.34 °, 17.63 °, 18.18 °, 19.10 °, 19.72 °, 21.97 °, 22.41 °, 23.77 °, 25.71 °, 26.56 ° and 26.93 ° with an error of ±0.2 °.
As a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form A of the compound A-a is shown in figure 1 or figure 2.
As a preferred embodiment of the present invention, the differential thermal analysis pattern of form A of the compound A-a has an endothermic peak at 173.8.+ -. 5 ℃.
As a preferred embodiment of the present invention, the differential thermal analysis pattern of form A of compound A-a is shown in FIG. 3. As a preferred embodiment of the present invention, the TG pattern of the crystal form A of the compound A-a is shown in FIG. 4.
As an amorphous form of the polymorph of compound a-a, the amorphous X-ray powder diffraction pattern of compound a-a has no sharp diffraction peaks.
As a preferred embodiment of the present invention, the amorphous X-ray powder diffraction pattern of the compound A-a has a non-sharp diffraction peak.
As a preferred embodiment of the present invention, the amorphous X-ray powder diffraction pattern of the compound A-a is shown in FIG. 5.
Another object of the present invention is to provide a pharmaceutical composition containing the crystalline form a or amorphous form of compound a-a described above, and one or more pharmaceutically acceptable carriers.
The carrier comprises various medicinal auxiliary materials, packaging materials, delivery tools and the like, and is selected according to the preparation requirement, for example, the auxiliary materials comprise filling agents, disintegrating agents, adhesives, lubricants and the like, and the carrier can be suitable for oral administration, inhalation, parenteral administration or surface use; dosage forms include, but are not limited to, injection, solution, tablet, capsule, granule, and the like.
The pharmaceutical composition can be used for preparing medicines for treating 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.
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 (+) -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 synthesis 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 invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, each of which includes 2 H、 3 H、 13 C、 14 C、 15 N、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 36 Cl. In particular, radioactive isotopes which emit radiation as they decay, e.g. 3 H or 14 C can be used for the local anatomic examination 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 may be labeled with radioisotopes, such as deuterium 2 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite 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 one or more hydrogen atoms isotopically deuterium 2 H) The compound of the invention has the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism, improving in vivo activity and the like after being substituted by deuterium.
The method of preparing the isotopic derivatives generally comprises: phase transfer catalysis method. For example, a preferred deuteration method employs a phase transfer catalyst (e.g., tetrabutylammonium bromide, TBAB). 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.
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.
Drawings
FIG. 1 is an X-ray diffraction pattern of a crystalline form A of the compound A-a obtained in example 2 of the present invention
FIG. 2 is an X-ray diffraction pattern of crystalline form A of Compound A-a obtained in example 3 of the present invention
FIG. 3 is a DSC chart of form A of Compound A-a obtained in example 2 of the present invention
FIG. 4 is a TG pattern of form A of Compound A-a obtained in example 2 of the present invention
FIG. 5 is an X-ray diffraction pattern of an amorphous form of the compound A-a obtained in example 4 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.) of 10 -6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-III nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
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.
The polymorphs of the present invention were tested using the following equipment and conditions, unless otherwise indicated: x-ray powder diffraction (XRPD), XRPD patterns were collected on an X-ray powder diffraction analyzer manufactured by PANalytacal, scan parameters as follows:
thermogravimetric analysis (TGA) and Differential Scanning Calorimeter (DSC), TGA and DSC plots were collected on a TA Q5000/5500 thermogravimetric analyzer and a TA2500 differential scanning calorimeter, respectively, with the following test parameters:
EXAMPLE 1 preparation of Compound A-a
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)
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 (Compound A-b)
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), and 2, 6-dichloropyridine (262.0 mg, 1.77 mmol) was added) Methane sulphonic 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 cesium carbonate (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. The solvent was dried by spin-drying and separated by column chromatography (ethyl acetate: n-hexane=1:10) to give 150.0 ml 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. Room temperature stripThe reaction was stirred for 3 hours under stirring. Spin-drying the solvent gave 73.7 mg of 3-fluoro-4- (((6- (piperazin-1-yl) pyridin-2-yl) oxy) methyl) benzonitrile as a white solid (yield: 73.5%). 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 3-fluoro-4- (((6- (piperazin-1-yl) pyridin-2-yl) oxy) methyl) benzonitrile (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 5Prep-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 preparation of form A of Compound A-a
Column chromatography purification gave solid compound a-a (10.5 g) which was dissolved in dichloromethane (30 ml) and dried by rotary evaporator to give a foamy solid which was completely dissolved in a small amount of methanol (10 ml), and the solution was stirred at 50 degrees celsius to slowly precipitate a white solid, which was filtered and dried to give 6.1 g of a white powdery solid form a.
The X-ray diffraction pattern of the crystal form A of the compound A-a is shown in figure 1, and specific characteristic absorption peaks are as follows: characteristic peaks at 6.22 °, 8.79 °, 12.44 °, 13.91 °, 14.44 °, 15.88 °, 16.34 °, 17.63 °, 18.18 °, 19.10 °, 19.72 °, 21.97 °, 22.41 °, 23.77 °, 25.71 °, 26.56 ° and 26.93 °. The DSC spectrum is shown in figure 3, and the differential thermal analysis spectrum has an endothermic peak at 173.8 ℃. The TG profile is shown in figure 4.
EXAMPLE 3 preparation of form A of Compound A-a
The solid compound A-a obtained by column chromatography purification is dissolved in tetrahydrofuran and isopropanol (volume ratio of 2:3), stirred for 1 hour to form a saturated solution, filtered (Jinteng PTFE,0.22 μm) and volatilized at room temperature for 5 days to obtain a crystal form A solid of the compound A-a.
The X-ray diffraction pattern of the crystal form A of the compound A-a is shown in figure 2, and specific characteristic absorption peaks are as follows: characteristic peaks at 6.20 °, 8.75 °, 12.41 °, 13.88 °, 14.45 °, 15.85 °, 16.33 °, 17.55 °, 18.10 °, 19.07 °, 19.65 °, 21.96 °, 22.38 °, 23.76 °, 25.69 °, 26.45 ° and 26.82 °.
The comparison of the absorption peaks of FIGS. 1 and 2 is shown in Table one below, with an error of + -0.2 deg..
Table one: x-ray diffraction data for form A of Compound A-a
Wherein No. =serial number, rel.int. = Relative Intensity, pos. [ ° 2Th. ] =position [ ° 2Theta ], error is ±0.2 °. Rel.int.= Relative Intensity is only an approximate intensity case representing the intensity of the characteristic peak, and should not be taken as a limitation of the specific crystal form.
Summarizing: according to the XRD patterns and characteristic peak data of fig. 1 and 2, the strongest characteristic absorption peak at 18.18 ° is expressed as 2θ angle, the error is ±0.2° and the relative absorption intensity is 100%.
Further, the crystal forms have characteristic peaks at 6.22 degrees, 13.91 degrees, 17.63 degrees, 18.18 degrees and 26.93 degrees, the error is +/-0.2 degrees, and the relative absorption intensity is more than 20 percent.
Specifically, the crystal forms have characteristic peaks at 6.22 degrees, 13.91 degrees, 15.88 degrees, 16.34 degrees, 17.63 degrees, 18.18 degrees, 19.72 degrees, 21.97 degrees, 26.56 degrees and 26.93 degrees, the error is +/-0.2 degrees, the relative absorption intensity is greater than 13 degrees, and other substances can be distinguished in detail to represent the crystal forms. More specifically, the crystal forms have characteristic peaks at 6.22 °, 8.79 °, 12.44 °, 13.91 °, 14.44 °, 15.88 °, 16.34 °, 17.63 °, 18.18 °, 19.10 °, 19.72 °, 21.97 °, 22.41 °, 23.77 °, 25.71 °, 26.56 ° and 26.93 °, the error is ±0.2°, the relative absorption intensity is greater than 5%, and other substances can be distinguished in more detail to represent the crystal forms. While other weak absorption peaks may vary significantly due to experimental operating errors, other absorption peaks may be considered unnecessary absorption peaks by those skilled in the art when characterizing the present crystalline form.
EXAMPLE 4 amorphous preparation of Compound A-a
Column chromatography was carried out to obtain a solid compound A-a (10.5 g) which was dissolved in methylene chloride (30 ml), and the amorphous solid of the compound A-a was obtained after spin-drying by a rotary evaporator, and the amorphous X-ray powder diffraction pattern of the obtained compound A-a was shown in FIG. 5.
EXAMPLE 5 stability investigation
Putting a compound A-a crystal form A and an amorphous sample into a dried penicillin bottle, putting the penicillin bottle into a self-sealing bag filled with a drying agent, examining the stability of the sample under the conditions of 2-8 ℃, 20 ℃/60% RH and 30 ℃/65% RH, sampling for 9 days and 30 days, and examining the HPLC purity of the sample.
The experimental results are as follows:
from the results, the amorphous compound A-a has better stability under the low-temperature condition, and the crystal form A of the compound A-a has higher purity and better stability than an amorphous sample and has better stability under various conditions.
EXAMPLE 6 rat pharmacokinetic Studies
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-18UPLC 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 a second table.
And (II) table: results of the present compounds on rat pharmacokinetics
Conclusion: from Table II, it can be seen that the compounds of the present invention are orally absorbed well in rats and have high exposure and bioavailability.
Example 7: research on hERG potassium ion channel action
1. Cell culture
The chinese hamster ovary cell line CHO-hERG stably expressing hERG potassium ion channel was used in this experiment. The cells were cultured in F12 complete medium, 10% fetal bovine serum, 1% antibiotic (G418), 89. Mu.g/mL hygromycin. The recovery medium is F12 medium, 10% fetal bovine serum, and 5% CO at 37deg.C 2 And (5) culturing under the condition.
2. hERG assay
The inhibitory activity of the compound series gradient concentration of the present invention on potassium ion channels in CHO-hERG was determined using a manual patch clamp system.
3. Data processing
hERG current values were imported into EXCEL for data analysis, measured IC 50 The values are shown in Table three.
Table three: results of inhibition of hERG Potassium ion channels by Compounds of the invention
Conclusion: from Table III, it can be seen that the polymorphic forms of the compounds of the invention have a weak hERG inhibition and IC 50 Above 100 μm, cardiovascular-related side effects caused by hERG can be significantly reduced.
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 (12)
1. Form a of compound a-a, characterized in that: form a of the compound a-a has characteristic peaks at 6.22 °, 13.91 °, 17.63 °, 18.18 ° and 26.93 ° in an X-ray diffraction diagram in terms of 2θ angle, and the error is ±0.2 °; the method comprises the steps of carrying out a first treatment on the surface of the The chemical structural formula of the compound A-a is shown in the following formula (I),
2. form a of the compound of claim 1, wherein: form a of the compound a-a has characteristic peaks at 6.22 °, 13.91 °, 15.88 °, 16.34 °, 17.63 °, 18.18 °, 19.72 °, 21.97 °, 26.56 ° and 26.93 ° in the X-ray diffraction diagram expressed in terms of 2θ angles, and the error is ±0.2 °.
3. Form a of the compound of claim 1, wherein: form a of the compound a-a has characteristic peaks at 6.22 °, 8.79 °, 12.44 °, 13.91 °, 14.44 °, 15.88 °, 16.34 °, 17.63 °, 18.18 °, 19.10 °, 19.72 °, 21.97 °, 22.41 °, 23.77 °, 25.71 °, 26.56 ° and 26.93 ° in terms of 2θ angles in an X-ray diffraction pattern, and the error is ±0.2 °.
4. A crystalline form a of compound a-a according to any one of claims 1 to 3, characterized in that: the X-ray powder diffraction pattern of the crystal form A of the compound A-a is shown in the accompanying figure 1 or the accompanying figure 2.
5. Form a of compound a-a according to any one of claims 1 to 4, characterized in that: the differential thermal analysis spectrum of the crystal form A of the compound A-a has an endothermic peak at 173.8+/-5 ℃.
6. Form a of compound a-a according to any one of claims 1 to 5, characterized in that: the differential thermal analysis chart of the crystal form A of the compound A-a is shown in figure 3.
7. Form a of compound a-a according to any one of claims 1 to 6, characterized in that: the TG pattern of the crystal form A of the compound A-a is shown in figure 4.
8. Amorphous form of compound a-a, characterized in that: the amorphous X-ray powder diffraction pattern of the compound A-a has no sharp diffraction peak; the chemical structural formula of the compound A-a is shown in the following formula (I),
9. the amorphous form of compound a-a of claim 8, wherein: the amorphous X-ray powder diffraction pattern of the compound A-a has a non-sharp diffraction peak.
10. The amorphous form of compound a-a according to any one of claims 8 to 9, characterized in that: the amorphous X-ray powder diffraction pattern of the compound A-a is shown in figure 5.
11. A pharmaceutical composition characterized by: the pharmaceutical composition contains the crystal form A or amorphous form of the compound A-a as claimed in any one of claims 1 to 10 and more than one pharmaceutically acceptable carrier.
12. Use of a pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment of GLP-1R related diseases, preferably diabetes related diseases.
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