CN110117272A - The salt and its crystal form of cell cycle protein dependent kinase inhibitor - Google Patents
The salt and its crystal form of cell cycle protein dependent kinase inhibitor Download PDFInfo
- Publication number
- CN110117272A CN110117272A CN201910106868.2A CN201910106868A CN110117272A CN 110117272 A CN110117272 A CN 110117272A CN 201910106868 A CN201910106868 A CN 201910106868A CN 110117272 A CN110117272 A CN 110117272A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- cancer
- xrpd
- logical formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Virology (AREA)
- Psychiatry (AREA)
- Molecular Biology (AREA)
- Hospice & Palliative Care (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pain & Pain Management (AREA)
- AIDS & HIV (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the salt of cell cycle protein dependent kinase inhibitor and its crystal forms.The preparation method and application of (4- (cyclopropylamino) piperidin-1-yl) (6- ((the fluoro- 4- of 5- (1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base) pyrimidine -2-base) amino) -2- picoline -3- base) ketone and its salt with logical formula (I) structure that the present invention relates to a kind of and the pharmaceutical composition of the salt containing therapeutically effective amount.CDK4/6 highly selective inhibitor can be clinically used for the patient with breast cancer for the treatment of HR+/HER2-.Furthermore, it may also be used for the treatment of non-small cell lung cancer, head and neck cancer, brain tumor, melanoma etc., each substituent group in formula of (I) are identical as the definition in specification.
Description
Technical field
The invention belongs to biomedicine fields, and being related to (4- (cyclopropylamino) piperidin-1-yl), ((((1- is different by the fluoro- 4- of 5- by 6-
Propyl -2- methyl-1 H- benzo [d] imidazoles -6- base) pyrimidine -2-base) amino) -2- picoline -3- base) ketone and its salt
Preparation method and application, the invention discloses it as CDK4/6 highly selective inhibitor, the disease for treatment include cancer,
Myelodysplastic syndrome, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape
And AIDS.
Background technique
Cell cycle protein dependent kinase (cyclin-dependent kinase, CDK) be a kind of serine (Ser)/
Threonine (Thr) kinases, the family include 13 members, and respectively cyclin points are A-L.Different CDK and cyclin
(cyclin) CDK-cyclin compound is formed, by CDK kinase activity, is catalyzed different substrate phosphorylations, starting DNA is synthesized,
Realize the propulsion and conversion of cell cycle difference phase;Controlling gene transcription, participate in the growth of cell, proliferation, suspend mode or
Into apoptosis.Therefore, CDKs has important in all cells in proliferation and dead regulation including tumour cell and normal cell
Function.Wherein, CDK4/6-Cyclin D compound plays a significant role from the G1 phase into the conversion of S phase in cell.In the G1 phase,
After CDK4/6 is in conjunction with cyclin D, make to include that Retinoblastoma Protein (Retinoblastoma protein, Rb) exists
A series of interior substrate phosphorylations.Albumen in connection and by its inhibition, mainly transcription factor E2F are discharged after Rb phosphorylation
It activates and is transcribed into some genes necessary to the S phase Deng, E2F, promote the conversion of cell G1/S.The study found that CDK4/6 is special
Anisotropic activation is closely related with the proliferation of some tumours, and the exception of cyclinD-CDK4/6-INK4-Rb access is generally existing.
Show themselves in that (1) p16INK4a gene delection, point mutation or DNA methylation cause p16INK4a to inactivate;(2) CDK4 gene expands
Increasing or point mutation (R24C), lose and p16INK4a binding ability;(3) cyclinD1 is because of gene rearrangement or gene magnification
And it over-expresses.The change of this access accelerates G1 phase process, so that tumor cell proliferation is accelerated and obtains survival advantage.
Therefore, a kind of therapeutic strategy is become to its intervention, therefore CDK4/6 becomes antitumor one of target spot.Pfizer
Palbociclib (PD0332991) is the CDK4/6 micromolecular inhibitor of first FDA approval listing treatment breast cancer.In addition,
There are also including Novartis (LEE011), some pharmaceuticals including gift next (LY2835219) etc. have compound to grind in clinic
The therapeutic effect studied carefully, and performed well.Other than breast cancer, studies have shown that selectivity CDK4/6 inhibitor oophoroma,
Have in the kinds of tumors such as non-small cell lung cancer, B cell lymphoma, liver cancer, glioma, colon cancer, Huppert's disease
There is good anti-tumor activity.Therefore, the micromolecular inhibitor for developing new CDK4/6 becomes new the having of these tumours for the treatment of
Efficacious prescriptions method motivates scientists generation upon generation of constantly to make efforts thus.
Summary of the invention
The present invention relates to or mixtures thereof a kind of logical formula (I) compound represented, its stereoisomer form,
Wherein:
M is inorganic acid or organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphorus
Acid, 2,5- dihydroxy-benzoic acid, 1- hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid,
4- chlorobenzenesulfonic acid, benzoic acid, 4- acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, octanoic acid, cinnamic acid, citric acid,
Cyclohexane sulfamic acid, camphorsulfonic acid, asparatate, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, different Vitamin C
Acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulphate, dibenzoyl tartaric acid, ethane -1,2- two
Sulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentianic acid, glutaric acid, 2-oxoglutaric acid, glycolic, hippuric acid, hydroxyl second
Base sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, two sulphur of 1,5- naphthalene
Acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid, salicylic acid, 4-ASA,
Decanedioic acid, stearic acid, succinic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and L- apple
Acid;And
X is selected from 1,2,3 or 4.
A preferred embodiment of the invention, logical formula (I) compound can form hydrate form shown in logical formula (II),
Wherein:
Y is 0-3, preferably 0,1,2 or 3;
M is inorganic acid or organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphorus
Acid, 2,5- dihydroxy-benzoic acid, 1- hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid,
4- chlorobenzenesulfonic acid, benzoic acid, 4- acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, octanoic acid, cinnamic acid, citric acid,
Cyclohexane sulfamic acid, camphorsulfonic acid, asparatate, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, different Vitamin C
Acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulphate, dibenzoyl tartaric acid, ethane -1,2- two
Sulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentianic acid, glutaric acid, 2-oxoglutaric acid, glycolic, hippuric acid, hydroxyl second
Base sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, two sulphur of 1,5- naphthalene
Acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid, salicylic acid, 4-ASA,
Decanedioic acid, stearic acid, succinic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and L- apple
Acid;And
X is selected from 1,2,3 or 4.
A preferred embodiment of the invention, compound shown in the logical formula (I), its stereoisomer, hydrate or its
Form of mixtures, preferably methanesulfonic acid, sulfuric acid, phosphoric acid, benzene sulfonic acid, maleic acid, adipic acid, p-methyl benzenesulfonic acid, citric acid, the third two
Acid or L MALIC ACID;Most preferably p-methyl benzenesulfonic acid.
A preferred embodiment of the invention, compound shown in the logical formula (I), its stereoisomer, hydrate or its
Form of mixtures, it is characterised in that: x 1.
A preferred embodiment of the invention, or mixtures thereof compound, its stereoisomer shown in logical formula (I) shape
Formula, free alkali crystal form have and show at (± 0.2 °) of 2 θ of the angle of diffraction of 4.2,13.8,15.9,17.0 and 18.1 ± 0.2 °
Show the XRPD at peak;(± 0.2 °) of 2 θ of the angle of diffraction further preferably at 8.7,9.6,12.4,19.7,24.6 and 25.8 ± 0.2 ° is aobvious
The XRPD for showing peak is the melting peak on DSC with 193.4 ± 0.5 DEG C.
A preferred embodiment of the invention, compound shown in the logical formula (I), or mixtures thereof stereoisomer shape
Formula, when M is p-methyl benzenesulfonic acid, as toluenesulfonate, crystal form I be characterized in that: have 7.5,9.7,10.7,11.1,
15.3, (± 0.2 °) of 2 θ of the angle of diffraction of 16.2,17.8,20.5,20.9,21.5,22.7,25.9 and 27.9 ± 0.2 ° shows peak
XRPD;Further preferably at 12.1,12.8,13.6,14.0,16.8,24.0,26.8,29.3,31.5,33.6,39.4 ± 0.2 °
(± 0.2 °) of 2 θ of the angle of diffraction display peak XRPD,
Crystal form II is characterized in that: have 7.4,9.6,11.4,12.6,14.5,17.1,17.7,19.7,21.9,22.8 with
The XRPD at 27.5 ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak;Further preferably 5.7,12.1,13.6,20.9,24.1,
24.8, the XRPD at 28.7,30.3,32.4,34.6,38.2 ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak,
Crystal form III is characterized in that: have 7.1,7.8,11.4,12.1,12.8,13.3,15.1,18.2,20.6,21.5,
The XRPD at (± 0.2 °) of 2 θ of the angle of diffraction of 21.8 and 23.5 ± 0.2 ° display peak, further preferably 9.0,9.4,13.9,14.1,
14.4、15.8、16.9、17.2、17.4、19.2、19.4、21.2、22.0、25.7、26.1、26.7、27.1、27.3、27.5、
28.1, (± 0.2 °) of 2 θ of the angle of diffraction of 28.8,29.0,29.2,31.7,33.1,35.5,37.3 and 39.3 ± 0.2 ° shows peak
XRPD is that the melting peak on DSC with 185.8 ± 0.5 DEG C, the crystal form III of toluenesulfonate are sulfuric monohydrate.
Compound shown in the logical formula (I) is prepared the invention further relates to a kind of, stereoisomer, hydrate or it is mixed
The method of solvate form, includes the following steps:
1) prepared by stock solution: general formula compound free alkali is taken, organic solvent dissolution is added, obtains clarification deposit liquor,
The preferred 50mg/mL of solution concentration;
2) prepared by counter ion acid solution: counter ion acid being added in organic solvent or water, it is molten to obtain clear counter ion acid
Liquid;Organic solvent is preferably ethyl alcohol, and concentration is preferably 0.25~2 mol/L;
3) prepared by compound salt: counter ion acid solution is added in stock solution, obtains clarification salting liquid, volatilizes naturally, is dried in vacuo
The salt of compound shown in logical formula (I) is obtained afterwards;Preferably 40 DEG C of true temp, the amount of counter ion acid preferably 1~1.2 equivalent;
Wherein:
The organic solvent be selected from methanol, ethyl alcohol, ethyl acetate, methylene chloride, acetone, n-hexane, petroleum ether, benzene,
It is toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethanes, tetrahydrofuran, 2- butanone, propione, heptane, methyl tertiary butyl ether(MTBE), different
Propyl ether, Isosorbide-5-Nitrae-dioxane, the tert-butyl alcohol or n,N-Dimethylformamide;It is preferred that 88% acetone, methanol or tetrahydrofuran;
The counter ion acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from
2,5- dihydroxy-benzoic acid, 1- hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzene
Sulfonic acid, 4- chlorobenzenesulfonic acid, benzoic acid, 4- acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, octanoic acid, cinnamic acid, lemon
It is lemon acid, cyclohexane sulfamic acid, camphorsulfonic acid, asparatate, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, different anti-
Bad hematic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulphate, dibenzoyl tartaric acid, ethane -1,
2- disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentianic acid, glutaric acid, 2-oxoglutaric acid, glycolic, hippuric acid,
Isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5- naphthalene
Disulfonic acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid, salicylic acid, 4- aminosalicyclic
Acid, decanedioic acid, stearic acid, succinic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and L- apple
Tartaric acid;It is preferred that methanesulfonic acid, sulfuric acid, phosphoric acid, benzene sulfonic acid, maleic acid, adipic acid, p-methyl benzenesulfonic acid, citric acid, malonic acid or L-
Malic acid;Most preferably p-methyl benzenesulfonic acid.
Of the invention further relates to a kind of preparation method, prepares compound shown in the logical formula (I), stereoisomer,
The method of or mixtures thereof hydrate form, includes the following steps:
1) suitable free alkali is weighed, is dissolved with good solvent;The preferred methylene chloride of good solvent, methanol or tetrahydro furan
It mutters;
2) suitable counter ion acid is weighed, is dissolved with organic solvent;Organic solvent preferred alcohol;The amount of counter ion acid is preferred
1.2 equivalent;
3) above two solution is merged, if poor solvent is added dropwise until occurring muddy without Precipitation after stirring a few hours
It is turbid, it is stirred overnight;The preferred isopropyl ether of poor solvent;
4) rapid centrifugation or stand dry up compound shown in logical formula (I) salt;
Wherein:
The good solvent is selected from acetone, 2- butanone, tetrahydrofuran, 1,4- dioxane, propione, 2- methyl tetrahydro
Furans, ethyl acetate or acetonitrile;It is preferred that 88% acetone, methanol or tetrahydrofuran.
The organic solvent be selected from methanol, ethyl alcohol, ethyl acetate, methylene chloride, acetone, n-hexane, petroleum ether, benzene,
It is toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethanes, tetrahydrofuran, 2- butanone, propione, heptane, methyl tertiary butyl ether(MTBE), different
Propyl ether, Isosorbide-5-Nitrae-dioxane, the tert-butyl alcohol or n,N-Dimethylformamide;It is preferred that 88% acetone, methanol or tetrahydrofuran;It is above-mentioned good
Property solvent and organic solution using when need to dissolve each other;
The poor solvent is selected from heptane, methylene chloride, water, methyl tertiary butyl ether(MTBE), toluene, isopropyl ether or ethyl alcohol;It is excellent
Select base tertbutyl ether and isopropyl ether;
The counter ion acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, and the organic acid is selected from
2,5- dihydroxy-benzoic acid, 1- hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzene
Sulfonic acid, 4- chlorobenzenesulfonic acid, benzoic acid, 4- acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, octanoic acid, cinnamic acid, lemon
It is lemon acid, cyclohexane sulfamic acid, camphorsulfonic acid, asparatate, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, different anti-
Bad hematic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulphate, dibenzoyl tartaric acid, ethane -1,
2- disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentianic acid, glutaric acid, 2-oxoglutaric acid, glycolic, hippuric acid,
Isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5- naphthalene
Disulfonic acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid, salicylic acid, 4- aminosalicyclic
Acid, decanedioic acid, stearic acid, succinic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and L- apple
Tartaric acid;It is preferred that methanesulfonic acid, sulfuric acid, phosphoric acid, benzene sulfonic acid, maleic acid, adipic acid, p-methyl benzenesulfonic acid, citric acid, malonic acid or L-
Malic acid;Most preferably p-methyl benzenesulfonic acid.
Of the invention further relates to a kind of preparation method, prepares compound shown in the logical formula (I), stereoisomer,
The method of or mixtures thereof hydrate form, wherein the solvent is ethyl acetate or ethyl alcohol.
It is of the invention further relate to it is a kind of prepare compound shown in the logical formula (I), stereoisomer, hydrate or it is mixed
The method of solvate form, wherein the counter ion acid is benzene sulfonic acid and p-methyl benzenesulfonic acid.
The invention further relates to a kind of pharmaceutical compositions, compound shown in the logical formula (I) containing therapeutically effective amount,
Or mixtures thereof its stereoisomer, hydrate form and one or more pharmaceutically acceptable carriers, diluent or tax
Shape agent.
A preferred embodiment of the invention, or mixtures thereof the logical formula (I) compound, its stereoisomer, hydrate
Form or the pharmaceutical composition are related by the cancer mediated of CDK4 and/or 6 or tumour for treating and/or preventing in preparation
Purposes in the drug of disease.
A preferred embodiment of the invention, or mixtures thereof the logical formula (I) compound, its stereoisomer, hydrate
Form or the composition are being prepared for preventing and/or treating in the drug with HR+/HER2- related disease feature
Purposes.
Above-described purposes, wherein the disease is selected from cancer, myelodysplastic syndrome, Alzheimer
Disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS;The cancer is preferably selected from cream
Gland cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma,
Kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanoma, glioma, mind
Through glue blastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung
Cancer;It is preferred that non-small cell lung cancer, head and neck cancer, brain tumor, melanoma
The invention further relates to the colors that there is CDK4/6 highly selective inhibitor to mediate for a kind of Prevention and/or Prevention
The method of the disease of the pathological characteristics of propylhomoserin metabolic pathway comprising the logical formula (I) institute for the treatment of effective dose is applied to patient
The compound shown or its tautomer, hydrate, mesomer, racemic modification, enantiomter, diastereoisomer or its
Form of mixtures or its officinal salt, or the pharmaceutical composition comprising it.These diseases include the sense of the virus such as AIDS
Dye, the cell infections such as Lyme disease and streptococcal infection, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease
With clap the gloomy disease of gold), autoimmune disease, depression, anxiety disorder, cataract, mental handicape, AIDS, (including T is thin for cancer
Born of the same parents' leukaemia and colon cancer), ocular disease state (such as cataract and age-related yellow) and autoimmune disease
Disease.
Another aspect of the present invention is related to a kind of method for the treatment of cancer, and this method includes applying treatment effective dose to patient
Logical formula (I) of the invention described in compound or its tautomer, hydrate, mesomer, racemic modification, enantiomerism
Or mixtures thereof body, diastereoisomer form or its officinal salt.This method shows curative effect outstanding and less secondary work
With wherein the cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, skin
Skin cancer, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor,
IV phase melanoma, glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia,
Lymthoma, myeloma and non-small cell lung cancer, preferably fallopian tube cneoplasms, peritoneal tumor, IV phase melanoma, myeloma and cream
Gland cancer, more preferably breast cancer.
Detailed description of the invention
Fig. 1-Fig. 3 is that XRPD, DSC-TGA of free alkali are illustrated.
XRPD, DSC-TGA that Fig. 4-Fig. 6 is tosilate crystal form III are illustrated.
Fig. 7-Fig. 9 is that XRPD, DSC-TGA of succinate are illustrated.
Figure 10-Figure 12 is that XRPD, DSC-TGA of fumarate are illustrated.
Figure 13 is that the XRPD of hydrochloride is illustrated.
Figure 14 is that the XRPD of tartrate is illustrated.
Figure 15 is that the XRPD of maleate is illustrated.
Figure 16 is that the XRPD of mesylate is illustrated.
Figure 17 is that the XRPD of citrate is illustrated.
Figure 18 is phosphatic XRPD diagram.
Figure 19 is that the XRPD of sulfate is illustrated.
Figure 20 is that the XRPD of hydrobromate is illustrated.
Figure 21 is that the XRPD of adipate is illustrated.
Figure 22 is that the XRPD of nitrate is illustrated.
Figure 23 is that the XRPD of benzene sulfonate is illustrated.
The XRPD that Figure 24 is tosilate crystal form I is illustrated.
The XRPD that Figure 25 is tosilate crystal form II is illustrated.
Figure 26 is the infrared spectrum of tosilate crystal form III.
Figure 27 is the mono-crystalline structures figure of tosilate crystal form III.
Specific embodiment
Unless stated to the contrary, the term used in the specification and in the claims has following meanings.
The different terms such as " X is selected from A, B or C ", " X is selected from A, B and C ", " X A, B or C ", " X A, B and C " are expressed
Identical meaning, i.e. expression X can be any one or a few in A, B, C.
" optional " or " optionally " mean event or environment described later can with but need not occur, which includes
The occasion that the event or environment occur or do not occur.
" alloisomerism " includes geometrical isomerism (cis-trans isomerism), optical isomerism, conformational isomerism three classes.
Hydrogen atom of the present invention can be replaced its isotope deuterium, in embodiment compound of the present invention
Any hydrogen atom also can be replaced by D-atom.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or
The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine
The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
" officinal salt " refers to the salt of the compounds of this invention, has safety when this kind of salt is used in the mammalian body and has
Effect property, and there is due bioactivity.
" TGA " refers to that thermogravimetric analysis (TGA) is tested.
" DSC " refers to that differential scanning calorimetry (DSC) is tested.
" XRPD " refers to that X-ray powder diffraction (XRPD) is tested.
" IR " refers to that infrared spectroscopy (IR) is tested.
" HPLC " refers to that high performance liquid chromatography (HPLC) is tested.
" PK " refers to that pharmacokinetics (PK) is tested.
The present invention is further described with reference to embodiments, but these embodiments not limit the scope of the present invention.
1.1 laboratory apparatus
1.1.1 some parameters of physical chemistry detecting instrument
1.2 liquid phase analysis conditions
1.2.1 instrument and equipment
1.2.2 chromatographic condition
Chromatographic column: Waters X-Bridge (C18,3.5 μm, 4.6*100mm)
Flow velocity: 1.1mL/min
Column temperature: 40 DEG C
Detection wavelength: 266nm
Sampling volume: 5.0 μ L
Runing time: 11min
Diluent: methanol-water (v/v, 4:1)
Mobile phase: A: water (0.1% trifluoroacetic acid);B: methanol (0.1% trifluoroacetic acid)
T(min) | B (%) |
0.00 | 10 |
6.00 | 90 |
8.00 | 90 |
8.01 | 10 |
11.00 | 10 |
Embodiment one: dry process is waved naturally
1.1 experiment purposes:
Different counter ion acid is selected, using method is volatilized naturally, detects which counter ion acid can form compound salt.
1.2 experimental procedures:
1) instrument and equipment
Title | Model | Source |
Assay balance | BSA224S-CW | Sartorius |
Ultrasonic washing instrument | SK5200LHC | Shanghai section leads ultrasonic instrument |
Liquid-transfering gun | Eppendorf(5mL,1000μL) | Eppendorf |
2) operation sequence
1. prepared by stock solution
General formula compound free alkali 156mg is taken, 2 × 3.25mL of tetrahydrofuran (using 5mL pipettor) is added, ultrasound is molten
Solution, obtains clear solution, solution concentration are as follows: 24mg/mL.
2. salting liquid prepares (free alkali that counter ion acid additional amount is 1-1.2 equivalent)
0.42mL stock solution 1. in salting liquid 2. is added, after volatilizing naturally, accordingly changed after 60 DEG C of vacuum drying
Close the salt of object.
Embodiment two: crystallization of solution or the preparation of anti-solvent method
2.1 experiment purposes:
Good solvent dissolved compound is selected, if being crystallized out compound with poor solvent without Precipitation.
Good solvent: acetone, 2- butanone (MEK), tetrahydrofuran (THF), 1,4- dioxane, propione, 2- methyl four
Hydrogen furans, ethyl acetate, acetonitrile;
Poor solvent: heptane, methylene chloride, water, methyl tertiary butyl ether(MTBE), toluene, isopropyl ether, ethyl alcohol;
Counter ion acid: methanesulfonic acid, sulfuric acid, phosphoric acid, benzene sulfonic acid, maleic acid, adipic acid, p-methyl benzenesulfonic acid, citric acid, third
Diacid, L MALIC ACID.
2.2 experimental procedure
1) instrument and equipment
Title | Model | Source |
Assay balance | BSA224S-CW | Sartorius |
Ultrasonic washing instrument | SK5200LHC | Shanghai section leads ultrasonic instrument |
Circulating water pump | SHB-III | The Zhengzhou Great Wall easy Co., Ltd of science, industry and trade |
2) operation sequence
Salt prepares the specific implementation method of good solvent and anti-solvent selection:
1) free alkali 200mg or 100mg are weighed, is dissolved with 2 or 4mL methanol or 8mL ethyl alcohol;
2) 1.2 equivalent counter ion acid are weighed, are dissolved with ethyl alcohol or water;
3) free aqueous slkali and counter ion acid solution dissolve each other;
4) if poor solvent is added dropwise until there is muddiness, is stirred overnight without precipitating;
5) rapid centrifugation obtains solid salt.
The solution ratio of free alkali and counter ion acid is as follows:
2.2.3 physical characterization is tested
Fig. 1-Fig. 3 is that XRPD, DSC-TGA of free alkali are illustrated.
XRPD, DSC-TGA that Fig. 4-Fig. 6 is tosilate crystal form III are illustrated.
Fig. 7-Fig. 9 is that XRPD, DSC-TGA of succinate are illustrated.
Figure 10-Figure 12 is that XRPD, DSC-TGA of fumarate are illustrated.
Figure 13 is that the XRPD of hydrochloride is illustrated.
Figure 14 is that the XRPD of tartrate is illustrated.
Figure 15 is that the XRPD of maleate is illustrated.
Figure 16 is that the XRPD of mesylate is illustrated.
Figure 17 is that the XRPD of citrate is illustrated.
Figure 18 is phosphatic XRPD diagram.
Figure 19 is that the XRPD of sulfate is illustrated.
Figure 20 is that the XRPD of hydrobromate is illustrated.
Figure 21 is that the XRPD of adipate is illustrated.
Figure 22 is that the XRPD of nitrate is illustrated.
Figure 23 is that the XRPD of benzene sulfonate is illustrated.
2.3 experiment conclusion
By XRPD, the analysis of DSC-TGA (differential thermal-thermogravimetric analysis) data, and compared with the data of free alkali, table
Bright all of above counter ion acid can form the salt of compound.
The XRPD diffraction data of 2.4 free alkalis and various salt
1, the XRPD diffraction data of free alkali:
2, the XRPD ray diffraction data of mesylate:
3, the XRPD ray diffraction data of sulfate:
4, the XRPD ray diffraction data of citrate:
5, phosphatic XRPD ray diffraction data:
6, the XRPD ray diffraction data of succinate:
7, the XRPD ray diffraction data of sulfate:
8, the XRPD ray diffraction data of hydrobromate:
9, the XRPD ray diffraction data of adipate:
10, the XRPD ray diffraction data of nitrate:
11, the XRPD ray diffraction data of benzene sulfonate:
12, the XRPD ray diffraction data of maleate:
13, the XRPD ray diffraction data of tartrate:
14, the XRPD ray diffraction data of fumarate:
15, the XRPD ray diffraction data of hydrochloride:
16, the XRPD ray diffraction data of tosilate crystal form I:
17, the XRPD ray diffraction data of tosilate crystal form II:
18, the XRPD ray diffraction data of tosilate crystal form III:
Embodiment three: solubility experiment in artificial stomach is simulated
3.1 experiment purposes:
Compare the different salt of the compound solubility size in simulating artificial gastro-intestinal Fluid, for salt can druggability assess provide according to
According to.
3.2 experimental programs:
About 2mg compound is suspended to 1mL artificial simulation gastric juices (SGF), fasting artificial simulation intestinal juice (FaSSIF), non-taboo
It eats in artificial simulation intestinal juice (FeSSIF) and pure water 24 hours, with HPLC, the thermodynamics of external standard method compound at room temperature
Solubility.
3.3 experimental results:
From compound and its salt after solubility results can be seen that into salt in water or biological associated intermediary compound in water
In solubility have different degrees of promotion.
Example IV: stability experiment
4.1 experiment purposes:
The free alkali for investigating candidate compound or candidate salt form are under the conditions of acceleration environment or influence factor, the object of compound
Physicochemical stability provides foundation for salt form screening and the storage of compound salt.
4.2 experimental programs:
Chemistry takes free alkali or salt about 5mg, and closed to set 70 DEG C of baking ovens, in lighting box (5000lx ± 500lx), opening sets 50
DEG C &RH75% (saturation NaCl aqueous solution) investigates 5 days and 10 days, with HPLC, the content of external standard method salt, and uses chromatographic peak
Area normalization method calculates variation of the salt in relation to substance.Investigate 10 days salt samples simultaneously, measure its XRPD, and with 0 day
XRPD is compared.
4.3 experimental results:
1) the physical and chemical stability result of free alkali and salt:
The free alkali of compound is extremely unstable at 70 DEG C of high temperature, places 10 days rear impurities and increases by 20% or more, in illumination
Under the conditions of place 10 days, place 10 days rear impurities and increase 37%, it is therefore desirable to by the stability for increasing compound at salt
Tosilate is very stable under high temperature and humidity illumination condition in the salt form of compound, almost without impurity
Increase, and other salt form related substance at 70 DEG C of high temperature will increase.
XRPD the result shows that, toluenesulfonate is investigated 10 days under 50 DEG C/RH75%, 70 DEG C, illumination condition, brilliant
Type is compared with 0 day sample, and there is no transformations for crystal form.
4.4 summarize:
Compound stability maintenance the result shows that, compound as its free base is extremely unstable under high temperature and high light conditions, at
Tosilate is in high temperature after salt, high humidity, and impurity is more stable compared with other salt almost without increase under high light conditions, because
This tosilate is most preferably salt form.
Embodiment five: hygroscopicity test
5.1 experiment purpose
It is moist to investigate compound drawing under different relative humidities, provides foundation for the screening of compound salt and storage.
5.2 experimental programs:
Compound salt is placed in the saturated steam of different relative humidity, so that compound and vapor is reached dynamic flat
Weighing apparatus, and the percentage that compound moisture absorption increases weight after calculated equilibrium.
5.3 experimental results:
Toluenesulfonate moisture absorption weight gain about 0.93% under the conditions of RH80%, slightly draws moist, fumarate exists
Under the conditions of RH80% moisture absorption weight gain 5%, have draw it is moist, hydrochloride under the conditions of RH80% moisture absorption weight gain 16%, it is great draw it is moist.
And toluenesulfonate recycles 1 time through moisture absorption under 0-95% relative humidities and solution moisture absorption, and XRPD simultaneously has not been changed, that is, does not have
There is crystal transfer;
From moist angle is drawn, toluenesulfonate is better than other salt form.
Embodiment six: polycrystalline screening experiment
6.1 experiment purposes: being screened by polycrystalline, finds the more stable crystal form to toluene sulphur salt.
6.2 experimental programs: selection has organic solvent, the water of certain solubility, compound is suspended in dicyandiamide solution, room
Warm stirring to pulp is after 1 week, centrifugation, discards supernatant, for solid after 40 DEG C of condition vacuum drying (- 0.1Mpa) are stayed overnight, measurement is solid
The XRPD of body, and compared with the XRPD of compound salt.
6.3 experimental results:
1) toluenesulfonate crystal form I preparation method:
The free alkali of 50.0mg is weighed, the ethyl alcohol that 1.0mL is added goes to dissolve, and 1.1 equivalents are added under agitation
The p-methyl benzenesulfonic acid ethanol solution of 1.0M, after precipitating is precipitated, filtering drying obtains the crystal form I sample of tosilate, methyl
The XRPD of benzene sulfonate crystal form I is as shown in attached drawing 24.
2) toluenesulfonate crystal form II preparation method:
The free alkali of 100.0mg is weighed, the methanol that 2.0mL is added goes to dissolve, and 1.1 equivalents are added under agitation
Anti-solvent methyl tertiary butyl ether(MTBE) is gradually added dropwise in the p-methyl benzenesulfonic acid ethanol solution of 1.0M, stops being added dropwise after there is cloud point, continues to stir
It mixes, after precipitating is precipitated, filtering drying obtains the crystal form II sample of tosilate, and the XRPD of toluenesulfonate crystal form II is shown in
Shown in attached drawing 25.
3) toluenesulfonate crystal form III preparation method:
The free alkali of 100.0mg is weighed, the tetrahydrofuran that 2.0mL is added goes to dissolve, and sample is heated to 50 DEG C, in stirring bar
The p-methyl benzenesulfonic acid aqueous solution of the 1.0M of 1.1 equivalents is added under part, after precipitating is precipitated, filtering drying obtains tosilate
Crystal form III sample, for the XRPD of toluenesulfonate crystal form III as shown in attached drawing 4, infrared spectrum is shown in Figure 26.
4) polymorphic competitive trials
By crystal form I and crystal form III, the mass mixings such as crystal form II and crystal form III, the ethyl acetate that addition is saturated with free alkali
XRPD is tested in solution, room temperature mashing two days later.
By crystal form competition experiments the results show that the crystal form III of tosilate is most stable crystal form at this stage.
Embodiment seven: the moisture measurement of tosilate crystal form III
7.1 experiment purposes: the moisture content in tosilate crystal form III is tested by Karl-Fischer method.
7.2 embodiments: weigh 15-20mg to toluene sulphur salt crystal form III sample, test it with karl Fischer coulomb method
Moisture content.
7.3 experimental results: karl Fischer moisture measurement result is respectively 2.483%, the theoretical value with a molecular water
2.425% is consistent, it was demonstrated that tosilate crystal form III contains a molecular water.
Embodiment eight: single crystal cultivation
8.1 experiment purposes: by single crystal cultivation, whether verifying and confirmation tosilate crystal form III are monohydrate.
8.2 experimental programs: selection has the organic solvent of certain solubility, compound is dissolved in dicyandiamide solution, preferably
N,N dimethylformamide, anti-solvent ethyl acetate are spread at room temperature using vapor phase grafting, obtain tosilate
Monocrystalline.
8.3 experimental results:
Single crystal data shows that compound tosilate crystal form III is monohydrate.
Single crystal data is as shown in the table:
Specific structure is shown in Figure 27: compound tosilate crystal form III mono-crystalline structures figure
Embodiment nine: animal PK research
9.1 experiment purposes: being studied by animal PK, compares the exposure of the free alkali and three kinds of salt of compound in animal body
Measure difference.
9.2 experimental programs: by the fumarate of compound, toluenesulfonate (crystal form III) and succinate, with containing
After CMC-Na (0.5%) aqueous solution of 0.1%Tween80 is suspended uniformly, stomach-filling, rat administration, parallel two rats, to medicament
Amount is 50mg/kg, and the amount of compound is all converted to the amount of identical free alkali.
By the free alkali of compound, after being suspended uniformly containing CMC-Na (0.5%) aqueous solution, stomach-filling, rat administration, in parallel
Two rats, dosage 5mg/kg.
9.3 experimental results:
P of Rats K is as the result is shown: compared with free alkali, these three salt have good exposed amount.
Embodiment ten: stoichiometry research
10.1 experiment purposes: being added the counter ion of different molar reactive ratios, investigates under set 4 Crystallization, raw
At the stability of toluenesulfonate metering ratio.
10.2 experimental programs: by the inventory molar ratio of counter ion be changed to 0.55 with 2.10 (molar ratio is that counter ion rubs
The ratio of your number and free alkali molal quantity), the feasibility and reactant salt for investigating salt crystallization processes measure ratio.Using HPLC, external standard
Method measures the mass percentage of free alkali in crystalline product, and is compared with the mass percentage of theoretical stoichiometry
Compared with.
10.3 experimental result:
Change the counter ion amount to feed intake, free alkali is carried out to the solid crystallized out and is quantified, still formation 1:1 reaction mole
The salt of ratio, because the inventory molar ratio of tosilate is preferably 1.0-1.2.
Claims (17)
1. a kind of or mixtures thereof compound, its stereoisomer shown in logical formula (I) form,
Wherein:
M is inorganic acid or organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid,
The organic acid is selected from 2,5- dihydroxy-benzoic acid, 1- hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetyl oxygen
Oxime acid, adipic acid, benzene sulfonic acid, 4- chlorobenzenesulfonic acid, benzoic acid, 4- acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid,
Octanoic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, camphorsulfonic acid, asparatate, camphoric acid, gluconic acid, glucose aldehyde
Acid, glutamic acid, arabo-ascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulphate, dibenzoyl
Tartaric acid, ethane -1,2- disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentianic acid, glutaric acid, 2-oxoglutaric acid,
Glycolic, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, the third two
Acid, methanesulfonic acid, 1,5- naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid,
It is salicylic acid, 4-ASA, decanedioic acid, stearic acid, succinic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzene sulfonic acid, right
Toluenesulfonic acid and L MALIC ACID;And
X is selected from 0,1,2,3 or 4.
2. or mixtures thereof logical formula (I) compound according to claim 1, its stereoisomer form, which is characterized in that
It is hydrate shown in logical formula (II),
Wherein:
Y is 0-3;
The definition of M and x is as shown in claim 1.
3. or mixtures thereof compound, its stereoisomer shown in logical formula (I) according to claim 1 or 2 form, special
Sign is: M is selected from methanesulfonic acid, sulfuric acid, phosphoric acid, benzene sulfonic acid, maleic acid, adipic acid, p-methyl benzenesulfonic acid, citric acid, malonic acid
Or L MALIC ACID;It is preferred that p-methyl benzenesulfonic acid.
4. or mixtures thereof compound, its stereoisomer shown in logical formula (I) according to claim 1-3 shape
Formula, it is characterised in that: x 1.
5. the free alkali crystal form of the described in any item logical formula (I) compounds of claim 1-4, have 4.2,13.8,
The XRPD at (± 0.2 °) of 2 θ of the angle of diffraction of 15.9,17.0 and 18.1 ± 0.2 ° display peak, further preferably 8.7,9.6,12.4,
The XRPD at 19.7,24.6 and 25.8 ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak.
6. free alkali crystal form according to claim 5, which is characterized in that molten with 193.4 ± 0.5 DEG C on DSC
Melt peak.
7. the crystal form of compound salt shown in the described in any item logical formula (I)s of claim 1-4, which is characterized in that have with
Lower three kinds of crystal forms,
Crystal form I is characterized in that: have 7.5,9.7,10.7,11.1,15.3,16.2,17.8,20.5,20.9,21.5,22.7,
The XRPD at 25.9 and 27.9, ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak;Further preferably 12.1,12.8,13.6,
14.0, the XRPD at 16.8,24.0,26.8,29.3,31.5,33.6,39.4 ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak,
Crystal form II is characterized in that: having 7.4,9.6,11.4,12.6,14.5,17.1,17.7,19.7,21.9,22.8 and 27.5
The XRPD at ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak;Further preferably 5.7,12.1,13.6,20.9,24.1,
24.8, the XRPD at 28.7,30.3,32.4,34.6,38.2 ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak,
Crystal form III is characterized in that: having 7.1,7.8,11.4,12.1,12.8,13.3,15.1,18.2,20.6,21.5,21.8
With the XRPD at 23.5 ± 0.2 ° of (± 0.2 °) of 2 θ of angle of diffraction display peak;Further preferably 9.0,9.4,13.9,14.1,
14.4、15.8、16.9、17.2、17.4、19.2、19.4、21.2、22.0、25.7、26.1、26.7、27.1、27.3、27.5、
28.1, (± 0.2 °) of 2 θ of the angle of diffraction of 28.8,29.0,29.2,31.7,33.1,35.5,37.3 and 39.3 ± 0.2 ° shows peak
XRPD。
8. the crystal form of compound salt shown in logical formula (I) according to claim 7, which is characterized in that crystal form III exists
There is 185.8 ± 0.5 DEG C of melting peak on DSC, and/or, crystal form III is sulfuric monohydrate, and/or, lead to chemical combination shown in formula (I)
The salt of object is fumarate, succinate or toluenesulfonate.
9. a kind of prepare compound, its stereoisomer, its mixture shown in the described in any item logical formula (I)s of claim 1-8
The method of form or its hydrate, includes the following steps:
1) prepared by stock solution: general formula (I) compound free alkali is taken, organic solvent dissolution is added, obtains clarification deposit liquor, it is molten
The preferred 50mg/mL of liquid concentration;
2) prepared by counter ion acid solution: counter ion acid being added in organic solvent or water, clear counter ion acid solution is obtained;
3) prepared by compound salt: stock solution being added in counter ion acid solution, clarification salting liquid is obtained, volatilizes naturally, vacuum is dry
The salt of compound shown in logical formula (I) is obtained after dry;Preferably 40 DEG C of true temp, the amount of counter ion acid preferably 1~1.2 equivalent;
Wherein:
The organic solvent is selected from 88% acetone, methanol, ethyl alcohol, ethyl acetate, methylene chloride, acetone, toluene, acetonitrile, four
Hydrogen furans, heptane, methyl tertiary butyl ether(MTBE), isopropyl ether or n,N-Dimethylformamide;
The counter ion acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5- dihydroxy-benzoic acid, 1-
Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzene sulfonic acid, 4- chlorobenzenesulfonic acid, benzene first
Acid, 4- acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid,
It is camphorsulfonic acid, asparatate, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, arabo-ascorbic acid, lactic acid, malic acid, flat
Peach acid, pyroglutamic acid, tartaric acid, dodecyl sulphate, dibenzoyl tartaric acid, ethane -1,2- disulfonic acid, ethanesulfonic acid, formic acid,
It is fumaric acid, galactonic acid, gentianic acid, glutaric acid, 2-oxoglutaric acid, glycolic, hippuric acid, isethionic acid, lactobionic acid, anti-bad
Hematic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5- naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, niacin,
Oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid, salicylic acid, 4-ASA, decanedioic acid, stearic acid, fourth two
Acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and L MALIC ACID.
10. preparation method according to claim 9, wherein the organic solvent is 88% acetone, methanol, ethyl alcohol or four
Hydrogen furans;When organic solvent is ethyl alcohol in step (2), concentration is 0.25~2 mol/L;The counter ion acid is methanesulfonic acid, sulphur
Acid, phosphoric acid, benzene sulfonic acid, maleic acid, adipic acid, fumaric acid, succinic acid, p-methyl benzenesulfonic acid, citric acid, malonic acid or L- apple
Acid.
11. it is a kind of prepare or mixtures thereof compound shown in logical formula (I) described in claim 1-8, its stereoisomer form,
Or the method for its hydrate, include the following steps:
1) suitable free alkali is weighed, is dissolved with good solvent;
2) suitable counter ion acid is weighed, is dissolved with organic solvent;The amount of counter ion acid preferably 1.2 equivalents;
3) above two solution is merged, if dropwise addition poor solvent is muddy up to occurring without Precipitation after stirring a few hours, is stirred
It mixes overnight;
4) rapid centrifugation or stand dry up compound shown in logical formula (I) salt;
Wherein:
The good solvent is selected from 88% acetone, methanol, ethyl alcohol, methylene chloride, acetone, tetrahydrofuran;
The organic solvent is selected from 88% acetone, methanol, ethyl alcohol, ethyl acetate, methylene chloride, acetone, toluene, acetonitrile, four
Hydrogen furans, heptane, methyl tertiary butyl ether(MTBE), isopropyl ether or n,N-Dimethylformamide;It is preferred that 88% acetone, methanol or tetrahydro furan
It mutters;Above-mentioned good solvent and organic solution using when need to dissolve each other;
The poor solvent is selected from heptane, ethyl acetate, methyl tertiary butyl ether(MTBE), isopropyl ether;It is preferred that methyl tertiary butyl ether(MTBE) and different
Propyl ether;
The counter ion acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5- dihydroxy-benzoic acid, 1-
Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzene sulfonic acid, 4- chlorobenzenesulfonic acid, benzene first
Acid, 4- acetaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid,
It is camphorsulfonic acid, asparatate, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, arabo-ascorbic acid, lactic acid, malic acid, flat
Peach acid, pyroglutamic acid, tartaric acid, dodecyl sulphate, dibenzoyl tartaric acid, ethane -1,2- disulfonic acid, ethanesulfonic acid, formic acid,
It is fumaric acid, galactonic acid, gentianic acid, glutaric acid, 2-oxoglutaric acid, glycolic, hippuric acid, isethionic acid, lactobionic acid, anti-bad
Hematic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5- naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, niacin,
Oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid, salicylic acid, 4-ASA, decanedioic acid, stearic acid, fourth two
Acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and L MALIC ACID.
12. preparation method according to claim 11, wherein the organic solvent is 88% acetone, methanol or tetrahydro furan
It mutters;The counter ion acid be methanesulfonic acid, sulfuric acid, phosphoric acid, benzene sulfonic acid, maleic acid, adipic acid, fumaric acid, succinic acid, to methylbenzene
Sulfonic acid, citric acid, malonic acid or L MALIC ACID.
13. according to preparation method described in claim 9-12 any one, wherein the counter ion acid is fumaric acid, fourth two
Acid or p-methyl benzenesulfonic acid.
14. a kind of pharmaceutical composition, shown in the logical formula (I) of any of claims 1-8 containing therapeutically effective amount
Or mixtures thereof compound, its stereoisomer form or its hydrate and one or more pharmaceutically acceptable loads
Body, diluent or excipient.
15. according to claim 1 or mixtures thereof logical formula (I) compound, its stereoisomer form described in any one of -7,
Or pharmaceutical composition described in its hydrate or claim 14 is mediated for treating and/or preventing by CDK4 and/or 6 in preparation
Cancer or tumor-related illness drug in purposes.
16. according to claim 1 or mixtures thereof logical formula (I) compound, its stereoisomer form described in any one of -7,
Or its hydrate or composition according to claim 14 are being prepared for preventing and/or treating with HR+/HER2- phase
Purposes in the drug of related disorders feature.
17. purposes according to claim 15 or 16, wherein the disease is selected from cancer, myeloproliferative disorder synthesis
Sign, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS;The cancer
Disease is preferably selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, preceding
Column gland cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanoma,
The renal tumor of glioma, spongioblastoma, hepatocellular carcinoma, mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma
And non-small cell lung cancer;It is preferred that non-small cell lung cancer, head and neck cancer, brain tumor, melanoma.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810114009 | 2018-02-05 | ||
CN2018101140093 | 2018-02-05 | ||
CN2018104642547 | 2018-05-15 | ||
CN201810464254 | 2018-05-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110117272A true CN110117272A (en) | 2019-08-13 |
CN110117272B CN110117272B (en) | 2021-12-10 |
Family
ID=67520436
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910106868.2A Active CN110117272B (en) | 2018-02-05 | 2019-02-02 | Salts of cyclin dependent kinase inhibitors and crystalline forms thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110117272B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264725A (en) * | 2008-12-22 | 2011-11-30 | 伊莱利利公司 | Protein kinase inhibitors |
CN105153119A (en) * | 2015-09-11 | 2015-12-16 | 广州科擎新药开发有限公司 | Pyridylpyrimidyl amine compounds or pyridylpyridyl amine compounds and application thereof |
CN105294683A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application thereof |
-
2019
- 2019-02-02 CN CN201910106868.2A patent/CN110117272B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264725A (en) * | 2008-12-22 | 2011-11-30 | 伊莱利利公司 | Protein kinase inhibitors |
CN105294683A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application thereof |
CN105294655A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application therefore |
CN105153119A (en) * | 2015-09-11 | 2015-12-16 | 广州科擎新药开发有限公司 | Pyridylpyrimidyl amine compounds or pyridylpyridyl amine compounds and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN110117272B (en) | 2021-12-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018201897B2 (en) | Solid Forms of an Epidermal Growth Factor Kinase Inhibitor | |
US11292772B2 (en) | Salts of an epidermal growth factor receptor kinase inhibitor | |
CN103384670B (en) | Imidazo [1, the 2-b] pyridazine replacing | |
CN101638423B (en) | Phloridzin derivative as well as preparation method and application thereof | |
CN105980389B (en) | A kind of crystal form of disulfate of jak kinase inhibitor and preparation method thereof | |
CN106572999A (en) | SYK inhibitors | |
CN105121409B (en) | Crystalline form of dolutegravir sodium salt and preparation method therefor | |
CN106459091B (en) | C-Met inhibitor crystal type free alkali or its crystal type acid salt and its preparation method and application | |
CN106795159B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
CN105980390B (en) | A kind of crystal form of disulfate of jak kinase inhibitor and preparation method thereof | |
WO2011023146A1 (en) | Imatinib mesylate polymorphs generated by crystallization in aqueous inorganic salt solutions | |
CN106279126B (en) | Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition | |
WO2022028367A1 (en) | Solid form of compound | |
JP2021523120A (en) | Solid form of CERDULATINIB | |
CN105924444B (en) | The crystal form and preparation method thereof of JAK inhibitor | |
WO2023193563A1 (en) | Crystal form a of thienopyridine compound, and preparation method therefor and pharmaceutical composition thereof | |
CN110117272A (en) | The salt and its crystal form of cell cycle protein dependent kinase inhibitor | |
CN113646312B (en) | Solid BRD4 inhibitor compound and preparation method and application thereof | |
CN110092789B (en) | Indolo [2,3-b ] carbazole derivative and application thereof | |
WO2018099451A1 (en) | Crystal form of compound | |
JP2022517396A (en) | EGFR inhibitor salt, crystalline form and method for producing it | |
CN111732597A (en) | Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy | |
CN105085421B (en) | Bit piperazine fumarate difficult to understand, hydrate, crystal formation and preparation method thereof | |
CN110698484B (en) | Pyrazolo [1,5-a ] pyrimidine-containing derivative, pharmaceutical composition and application | |
CN111848580B (en) | Crystal form of quinoline compound containing 1,2, 4-triazine-3, 5-diketone as well as preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |