CN104119321B - The 2-maleate and its polymorph of indolinone derivative - Google Patents
The 2-maleate and its polymorph of indolinone derivative Download PDFInfo
- Publication number
- CN104119321B CN104119321B CN201310153347.5A CN201310153347A CN104119321B CN 104119321 B CN104119321 B CN 104119321B CN 201310153347 A CN201310153347 A CN 201310153347A CN 104119321 B CN104119321 B CN 104119321B
- Authority
- CN
- China
- Prior art keywords
- compound
- polymorph
- dimethyl
- methyl
- bases
- 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.)
- Active
Links
- 0 *=C(C=CC(O)=N)O Chemical compound *=C(C=CC(O)=N)O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The 2-maleate and its polymorph of indolinone derivative.The invention belongs to field of medicine and chemical technology, and in particular to N（5‑（（Z）(5 fluorine, 2 carbonyl indoles 3 is sub-) methyl）The base of 2,4 dimethyl, 1 hydrogen pyrroles 3）‑3‑（The base of 4 methyl piperazine 1）Propionamide 2-maleate（Compound I）And its polymorph.The invention further relates to the preparation method of compound I polymorphs, the Pharmaceutical composition of inclusion compound I and its polymorph, and the compound I and its polymorph pharmaceutical applications.The compound I of present invention polymorph has good crystallinity and physically and/or chemically stability.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）-
2,4- -1 hydrogen of dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide 2-maleate（Compound I）, its polycrystalline
Type thing and preparation method, the pharmaceutical composition containing compound I and its polymorph, and the compound I and its polymorphic
The pharmaceutical applications of thing.
Background technology
Cancer is still the dead first cause of global human at present.According to statistics, annual global 12,000,000 people are diagnosed as
Cancer, 9,600,000 people die from cancer.Account for the 13% of all death tolls.Whole world pathogenesis of cancer number and death toll are by continuation
Rise, if not taking intervening measure, it is contemplated that the year two thousand thirty the whole world will have 26,000,000 new cases, death toll reaches 17,000,000
People.The cancer that the death rate ranks in the top has lung cancer, stomach cancer, liver cancer, colorectal cancer etc..
EGFR-TK is that γ-phosphoric acid is transferred to the kinases on protein-tyrosine residue on class catalysis ATP, can be catalyzed many
Substrate protein white matter tyrosine residue phosphorylation is planted, is played an important roll in cell growth, propagation, differentiation.The egg found so far
Majority is the oncoprotein for belonging to oncornavirus RNA in white EGFR-TK, can also be produced by the proto-oncogene of vertebrate.
Tyrosine kinase inhibitor can be used as atriphos（ATP）The competitive inhibitor combined with EGFR-TK, also can conduct
The analog of tyrosine, blocks the activity of EGFR-TK, suppresses cell propagation, can be developed into antineoplastic.
Small molecule tyrosine kinase inhibitors can be used for each as anti-tumor drugs targeting clinically extensive use
Solid tumor and neoplastic hematologic disorder are planted, is that the clinical treatment of tumour has made very big contribution.WO0160814, WO2008067756,
WO2008138184, WO2008138232, WO2007085188, WO2005058309 and WO2006002422 etc. disclose pyrroles
The derivative of substituted dihydroindolone structure type, with the activity for suppressing EGFR-TK.In the medicine of the structure type,
The Sunitinib for having Pfizer to develop listed, belongs to multiple receptor tyrosine kinases inhibitor, there is very strong anti-angiogenic life
Into effect, and tumor cell proliferation can be suppressed.Since ratifying from January, 2006 through U.S. FDA, clinical efficacy is definite, at present
In more than 60 country's listings, still it is being in progress for treating through treatment with imatinib disease or be not resistant to the stomach of medicine treatment
Enteron aisle stromal tumor and progressive clear-cell carcinoma.
WO2011153814A1 discloses N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,4- dimethyl-
1 hydrogen-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propanamide compounds and preparation method thereof, and the compound has exploitation
Into the potentiality of antineoplastic.But the compound solubility very little, therefore, having demand to find has more excellent physics and/or change
The form of property is learned, to meet the application of drug delivery.
The content of the invention
Inventor is successfully prepared N- by many experiments（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,
- 1 hydrogen of 4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）The 2-maleate form of propionamide and its a variety of crystallizations
Type, and prove that its solubility in pH6.8 or so phosphate solution preferably, is conducive to body absorption；And with more preferable
Stability, is conducive to packing and stores, this completes the present invention.
First aspect present invention provides the compound shown in formula I：
The compound is named as N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,4- dimethyl -1
Hydrogen-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide 2-maleate, in the present invention, also known as chemical compounds I.
Compound according to a first aspect of the present invention, it is polymorph.
（1）Compound according to a first aspect of the present invention, it is characterised in that the crystal formation is radiated using Cu-K α, with 2 θ angles
The X-ray powder diffraction represented is spent, with the characteristic absorption peak at about following position：5.5±0.20°、8.3±0.20°、
13.8±0.20°、16.6±0.20°、22.2±0.20°、25.1±0.20°、26.3±0.20°、27.9±0.20°；
Preferably, it has the characteristic absorption peak at about following position：5.5±0.20°、6.5±0.20°、8.3±
0.20°、9.8±0.20°、11.0±0.20°、13.0±0.20°、13.8±0.20°、16.6±0.20°、18.3±0.20°、
22.2±0.20°、22.8±0.20°、23.5±0.20°、25.1±0.20°、26.3±0.20°、27.9±0.20°、28.7
±0.20°；
In embodiments of the invention, it has X-ray powder diffraction collection substantially as shown in Figure 1.
Compound according to a first aspect of the present invention, it is characterised in that differential scanning calorimetric analysis show that the crystal formation exists
194~220 DEG C have endothermic peak, confirm that compound starts fusing.
In specific embodiments of the present invention, it is crystal formation A.
In specific embodiments of the present invention, the thermogravimetric analysis of the crystal formation A is shown, the crystal formation at 40~170 DEG C about
Weightlessness 8.5%, but do not have corresponding thermal change, it is not solvate or hydrate, its weight lost, which is represented, free molten
Agent is present；Continue weightless at 200 DEG C, compound I fusings.
（2）Compound according to a first aspect of the present invention, it is characterised in that the crystal formation is radiated using Cu-Ka, with 2 θ angles
The X-ray powder diffraction represented is spent, with the characteristic absorption peak at about following position：6.4±0.2°、9.7±0.20°、
12.4±0.20°、13.0±0.20°、16.3±0.20°、22.9±0.20°、24.3±0.2°、25.2±0.2°、26.2±
0.20°；
Preferably, it has the characteristic absorption peak at about following position：6.4±0.20°、7.5±0.20°、8.8±
0.20°、9.7±0.20°、12.4±0.20°、13.0±0.20°、16.3±0.20°、17.4±0.20°、18.0±0.20°、
18.8±0.20°、19.6±0.20°、21.8±0.20°、22.9±0.20°、24.3±0.20°、25.2±0.20°、26.2
±0.20°、26.9±0.20°、33.0±0.20°；
In embodiments of the invention, it has X-ray powder diffraction collection substantially as shown in Figure 4.
Compound according to a first aspect of the present invention, it is characterised in that differential scanning calorimetric analysis show that the crystal formation exists
188-274 DEG C has endothermic peak, confirms compound melts heat absorption.
In specific embodiments of the present invention, it is crystal formation B.
In specific embodiments of the present invention, the thermogravimetric analysis of the crystal formation B is shown, the crystal formation about weightlessness 0.56%, is
Solvent-free anhydride.
（3）Compound according to a first aspect of the present invention, it is characterised in that the crystal formation is radiated using Cu-K α, with 2 θ angles
The X-ray powder diffraction represented is spent, with the characteristic absorption peak at about following position：2.8±0.20°、5.6±0.20°、
8.4±0.20°、16.4±0.20°、22.5±0.20°、25.4±0.20°、26.6±0.20°、28.2±0.20°；
Preferably, it has the characteristic absorption peak at about following position：2.8±0.20°、5.6±0.20°、8.4±
0.20°、11.2±0.20°、16.4±0.20°、19.5±0.20°、22.5±0.20°、24.0±0.20°、25.4±
0.20°、26.6±0.20°、28.2±0.20°；
In embodiments of the invention, it has X-ray powder diffraction collection substantially as shown in Figure 7.
Compound according to a first aspect of the present invention, it is characterised in that differential scanning calorimetric analysis show that the crystal formation exists
150~185 DEG C and 209~230 DEG C have endothermic peak at two.First endothermic peak is caused by losing the DMF in solvate second
Individual endothermic peak represents that compound I starts fusing.
In specific embodiments of the present invention, it is crystal formation C.
In specific embodiments of the present invention, the thermogravimetric analysis analysis display of the crystal formation C, the crystal formation is about weightless
12.1%, it is DMF（DMF）Solvate, contains about 1 DMF molecule.
（4）Compound according to a first aspect of the present invention, it is characterised in that the crystal formation is radiated using Cu-Ka, with 2 θ angles
The X-ray powder diffraction represented is spent, with the characteristic absorption peak at about following position：5.6±0.20°、8.4±0.20°、
14.0±0.20°、22.5±0.20°、23.8±0.20°、25.4±0.20°、26.5±0.20°、28.3±0.20°；
Preferably, it has the characteristic absorption peak at about following position：5.6±0.20°、8.4±0.20°、9.0±
0.20°、14.0±0.20°、14.7±0.20°、15.6±0.20°、16.6±0.20°、18.1±0.20°、22.5±
0.20°、23.8±0.20°、24.6±0.20°、25.4±0.20°、26.5±0.20°、28.3±0.20°、29.5±
0.20°；
In embodiments of the invention, it has X-ray powder diffraction collection substantially as shown in Figure 10.
Compound according to a first aspect of the present invention, it is characterised in that differential scanning calorimetric analysis show that the crystal formation exists
182~201 DEG C, 202~225 DEG C have endothermic peak at two.First endothermic peak is caused by losing the DMSO in solvate second
Individual endothermic peak represents that compound I starts fusing.
In specific embodiments of the present invention, it is crystal formation D.
In specific embodiments of the present invention, crystal formation D thermogravimetric analysis analysis is shown, the crystal formation about weightlessness 11.8% is
Dimethyl sulfoxide (DMSO)（DMSO）Solvate, contains about 1 diformazan pressure sulfone molecule.
The second aspect of the present invention further relates to the preparation method of the compound of any one of first aspect present invention：
（1）First aspect present invention（3）The preparation method of the compound of item：
N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4-
Methylpiperazine-1-yl）Propionamide is with maleic acid in N,N-dimethylformamide（DMF）Middle stirring reaction, obtains the present invention first
Aspect（3）The compound of item；Wherein described N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,4- dimethyl-
1 hydrogen-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）The mol ratio of propionamide and maleic acid is 1:2；
（2）First aspect present invention（4）The preparation method of the compound of item：
N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4-
Methylpiperazine-1-yl）Propionamide and maleic acid stirring reaction in dimethyl sulfoxide, obtain first aspect present invention the（4）
Compound；Wherein described N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles -3-
Base）-3-（4- methylpiperazine-1-yls）The mol ratio of propionamide and maleic acid is 1:2；
（3）First aspect present invention（1）The preparation method of the compound of item：
N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4-
Methylpiperazine-1-yl）Propionamide and maleic acid tetrahydrofuran, tetrahydrofuran/water, acetone, ethyl acetate, isopropyl acetate,
Stirring reaction in dichloromethane, chloroform, ethanol, isopropanol, n-butanol, dioxane, obtains first aspect present invention
（1）The compound of item；Wherein described N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrrole
Cough up -3- bases）-3-（4- methylpiperazine-1-yls）The mol ratio of propionamide and maleic acid is 1:2；
（4）First aspect present invention（2）The preparation method of the compound of item：
N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4-
Methylpiperazine-1-yl）Propionamide is with maleic acid in water, DMF/ water, DMAC N,N' dimethyl acetamide（DMAC）/ water, methanol, second two
Stirring reaction in alcohol, acetonitrile, obtains first aspect present invention（2）The compound of item；Wherein described N-（5-（（Z）- (5- is fluoro-
2- carbonyl indoles -3- is sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide and horse
It is 1 to carry out sour mol ratio:2；As long as the content of the in the mixed solvent water of described DMF, DMAC and water is not 0, wherein it is preferred that
1:0.5~20；
Or,
By first aspect present invention（3）Or（4）The compound of item obtains this hair after being beaten stirring, filtration drying in water
Bright first aspect（2）The compound of item；
Or,
By first aspect present invention（3）Or（4）The compound of item is dried at 150~200 DEG C, obtains the present invention first
Aspect（2）The compound of item.
In the present invention, N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,4- dimethyl -1 hydrogen-pyrroles -
3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is that those of ordinary skill in the art can prepare according to prior art,
In one exemplary method, N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,4- dimethyl -1 hydrogen-pyrroles -
3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is referred to document WO2011153814A1 preparations.
The third aspect of the present invention is related to pharmaceutical composition, and it contains the compound of any one of first aspect present invention, with
And optionally one or more pharmaceutically acceptable carriers or excipient.
Fourth aspect present invention be related to compound described in any one of first aspect present invention preparing for preventing and/or
Treat the purposes in the medicine of mammal (including people) disease related to receptor tyrosine kinase or illness.
In the present invention, the disease related to receptor tyrosine kinase or illness refer to, by receptor tyrosine kinase
The propagation and migration of the tumour of mediation or the tumour cell driven by receptor tyrosine kinase；
In the present invention, the tumour mediated by receptor tyrosine kinase or the tumour driven by receptor tyrosine kinase
The propagation of cell and migration refer to, erbB receptor tyrosine kinase cancer susceptibles, being driven such as the expression of EGFR or Her2 height and EGF
Tumour, including entity tumor for example bile duct, bone, bladder, brain/central nervous system, breast, Colon and rectum, endometrium, stomach, head and
Neck, liver, lung (especially non-small cell lung cancer), neuron, esophagus, ovary, pancreas, prostate, kidney, skin, testis, first shape
The cancer of gland, uterus and vulva etc., and non-solid tumors such as leukaemia, Huppert's disease or lymthoma etc..
The invention further relates to the compound described in any one of first aspect present invention receptor tyrosine kinase is used as in preparation
Purposes in the medicine of inhibitor.
The invention further relates to prevent and/or treat mammal (including people) disease related to receptor tyrosine kinase or
The method of illness, methods described includes giving the present invention that mammal in need applies prevention and/or therapeutically effective amount the
The step of compound described in any one of one side.
The present invention will be described in detail further below：
All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary
Offer expressed implication with it is of the invention inconsistent when, be defined by the statement of the present invention.In addition, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explained that the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
In the present invention, the polymorph refers to that material is brilliant formed by molecule or ion are differently arranged
Body；In specific embodiments of the present invention, the polymorph of the compound I refers to compound I crystal formation A, crystal formation B, crystalline substance
Type C, crystal formation D.
The X-ray powder diffraction characteristic peak that the compound I of present invention polymorph is represented with 2 θ angles, wherein " ±
0.2 ° " it is the measurement error scope allowed.
The compound I of present invention polymorph can be used with other active ingredient combinations, as long as it does not produce other
Detrimental effect, such as allergic reaction.
Reactive compound shown in the compounds of this invention I polymorph can be used as unique cancer therapy drug, or
It can be used in combination with other one or more antineoplastics.Therapeutic alliance by by each therapeutic component simultaneously, order or
Administration is separated to realize.
Term used herein " composition " or " pharmaceutical composition " mean to include each specified composition comprising specified amount
Product, and any product directly or indirectly produced from the combination of each specified composition of specified amount.
Those skilled in the art can use known pharmaceutical carrier, and by the compound I of the present invention, or compound I's is more
Crystal formation thing is prepared into suitable pharmaceutical composition.Described pharmaceutical composition especially particular formulation can be supplied into solid or liquid form
It is administered orally, for parental injection or supplies rectally.
Described pharmaceutical composition can be configured to many formulations, be easy to administration, for example, oral formulations (such as tablet, capsule
Agent, solution or suspension)；Injectable preparation (solution or suspension of such as injectable, or injectable dried powder,
It can be used immediately after adding medicine solvent before the injection).
Term used herein " treatment and/or prevention effective dose " be cause researcher, animal doctor, doctor or other people
Sought tissue, system, the amount of the medicine or pharmaceutical preparation of animal or the biology of people or medical science response.
When for above-mentioned treatment and/or prevention, the compounds of this invention I or compound I polymorph and drug regimen
Total consumption per day of thing must be maked decision by attending physician in reliable medical judgment scope.For any specific patient, tool
Depending on the treatment effective dose level of body must be according to many factors, the factor includes the serious of treated obstacle and the obstacle
Degree；The activity of the particular compound used；The concrete composition used；The age of patient, body weight, general health shape
Condition, sex and diet；Administration time, method of administration and the excretion rate of the particular compound used；Treat the duration；With institute
The particular compound of use is applied in combination or medicine used at the same time；And similar factor known to medical field.For example, this area
Way be that the dosage of compound is since the level required less than therapeutic effect needed for obtaining, gradually incremental dose, directly
Effect to needed for obtaining.It is, in general, that the dosage that the compounds of this invention I polymorph is used for mammal particularly people can
With between 0.001~1000mg/kg body weight/days, such as between 0.01~100mg/kg body weight/days, such as between 0.01~
10mg/kg body weight/days.
Brief description of the drawings
Fig. 1 is the compound I crystal A of embodiment 2 X-ray powder diffraction collection.
Fig. 2 composes for the compound I crystal A of embodiment 2 differential scanning calorimetric thermogram.
Fig. 3 is the compound I crystal A of embodiment 2 thermogravimetric analysis collection of illustrative plates.
Fig. 4 is the compound I crystal B of embodiment 8 X-ray powder diffraction collection.
Fig. 5 composes for the compound I crystal B of embodiment 8 differential scanning calorimetric thermogram.
Fig. 6 is the compound I crystal B of embodiment 8 thermogravimetric analysis collection of illustrative plates.
Fig. 7 is the compound I crystal C of embodiment 6 X-ray powder diffraction collection.
Fig. 8 composes for the compound I crystal C of embodiment 6 differential scanning calorimetric thermogram
Fig. 9 is the compound I crystal C of embodiment 6 thermogravimetric analysis collection of illustrative plates.
Figure 10 is the compound I crystal D of embodiment 7 X-ray powder diffraction collection.
Figure 11 composes for the compound I crystal D of embodiment 7 differential scanning calorimetric thermogram
Figure 12 is the compound I crystal D of embodiment 7 thermogravimetric analysis collection of illustrative plates.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is unreceipted specific in embodiment
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument, be
Can be by the conventional products of acquisition purchased in market.
It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operating method are
It is well known in the art；Temperature is represented with degree Celsius (DEG C), is operated in room temperature or normal temperature（Generally 10~30 DEG C）Carried out under environment.
Detecting instrument used in the present invention：
（1）Nuclear magnetic resoance spectrum
INSTRUMENT MODEL：Varian INOVA-400 NMRs.
Test condition：Solvent DMSO-d6。
（2）X-ray powder diffraction instrument
INSTRUMENT MODEL：PANalytical Empyrean X-ray powder diffraction analyzers
Method of testing：Sample (100mg) after will be finely ground is filled out in glass plate groove, with slide by its plane and glass
After face extension is flushed, sample is placed in PANalytical Empyrean X-ray powder diffraction analyzers, 40kV, 40mA is used
Copper X-ray source, scanning range be 3~45 °（2θ）, °/minute of sweep speed 4,6 minutes sweep times.Scan error usual
For ± 0.2 degree (2 θ).
（3）TGA/DSC1 synchronous solvings
INSTRUMENT MODEL：METTLER TGA/DSC1.
Method of testing：Weight 10mg sample is placed in the sealed aluminum pan with small pin hole, balance is kept at 30 DEG C, so
Afterwards 250 DEG C are heated to 10 DEG C/min sweep speed.Drying nitrogen is used as purge gas.
N- can be prepared according to the method described in WO2011153814A1（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5-
It is sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide, such as example 1 below institute
Show.
Embodiment 1：N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles -3-
Base）-3-（4- methylpiperazine-1-yls）The preparation of propionamide：
A.N- 5- [the fluoro- 2- oxos -1,2- Dihydro-indoles of 5--(3Z)-ylidenylmethyl] -2,4- dimethyl -1H- pyrroles -
3- yls } the bromo- propionamides of -3- synthesis：
By 3- bromo-propionic acids（338mg,1.2eq）It is dissolved in 5ml N,N-dimethylformamides（DMF）In, it is stirred at room temperature to molten
Solution；Add 4- (4,6- dimethoxy-triazine -2- bases) -4- methyl morpholine hydrochlorides（DMTMM）（618mg,1.2eq）, room temperature stirs
20min is mixed, then adds (3Z)-[(3,5- dimethyl -4- amino -1- hydrogen pyrroles -2- bases) ylidenylmethyl] -5- fluorine Yin thereto
Diindyl -2- ketone (501mg, 1.0eq), is stirred at room temperature reaction 2h, TLC detection reaction and finishes, reaction solution is added into 200ml acetic acid second
In ester, solid is separated out, filtering, ethyl acetate is washed, and is dried, is obtained target product 548mg（Yield 73%）.
B.N- 5- [the fluoro- 2- oxos -1,2- Dihydro-indoles of 5--(3Z)-ylidenylmethyl] -2,4- dimethyl -1H- pyrroles -
3- yls } -3- (4- methylpiperazine-1-yls) propionamide synthesis：
By N- 5- [the fluoro- 2- oxos -1,2- Dihydro-indoles of 5--(3Z)-ylidenylmethyl] -2,4- dimethyl -1H- pyrroles -
3- yls } the bromo- propionamides of -3-（548mg,1.0eq）It is dissolved in 4ml DMF, is stirred at room temperature to dissolving, then adds 4- methyl thereto
Piperazine (850mg, 4.0eq), is heated to 50 DEG C of reaction 4h, TLC detection reactions and finishes, reaction solution is added into 200ml acetic acid second
In ester, solid is separated out, filtering, ethyl acetate washing is dried, column chromatography obtains N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-)
Methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide.
1H-NMR(600MHz,DMSO,δppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),
2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),7.63（s,1H),9.16(s,1H),10.74
(s,1H),13.56(s,1H)。
Embodiment 2：Compound I crystal formation A preparation：
1g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-
（4- methylpiperazine-1-yls）Propionamide is mixed 10 minutes with 20ml water, and the tetrahydrofuran solution of 1g maleic acids, stirring is added dropwise
5~10 hours, suction filtration, 40 DEG C of vacuum drying obtained the solid 1.39g of crocus, yield 90% is examined through X-ray powder diffraction
Survey, its XRPD collection of illustrative plates as shown in figure 1, through differential scanning calorimetric analysis and thermogravimetric analysis, itself DSC and DSC collection of illustrative plates respectively such as Fig. 2 and
Shown in Fig. 3；
1H-NMR(600MHz,DMSO,δppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),
2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),7.63（s,1H),
9.16(s,1H),10.74(s,1H),13.56(s,1H)。
Embodiment 3：Compound I crystal formation A preparation：
10g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-
3-（4- methylpiperazine-1-yls）Propionamide is mixed 20 minutes with 100ml ethyl acetate, adds 8g maleic acids, stirring 3~6
Hour, suction filtration, 50 DEG C of vacuum drying obtain the solid 12.4g of crocus, yield 80.2% is detected through X-ray powder diffraction,
Its XRPD collection of illustrative plates is substantially consistent with Fig. 1.
Embodiment 4：Compound I crystal formation A preparation：
2g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-
（4- methylpiperazine-1-yls）Propionamide is mixed 10 minutes with 20ml n-butanols, adds 2g maleic acids, and stirring 30~40 is small
When, suction filtration, 40 DEG C of vacuum drying obtain the solid 2.0g of crocus, and yield 64.5% is detected through X-ray powder diffraction,
Its XRPD collection of illustrative plates is substantially consistent with Fig. 1.
Embodiment 5：Compound I crystal formation A preparation：
1g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-
（4- methylpiperazine-1-yls）Propionamide is mixed 10 minutes with 20ml dioxane, adds 1g maleic acids, and stirring 5~10 is small
When, suction filtration, 40 DEG C of vacuum drying obtain the solid 1.39g of crocus, yield 90% is detected through X-ray powder diffraction, its
XRPD collection of illustrative plates is substantially consistent with Fig. 1.
Embodiment 6：Compound I crystal formation C preparation：
At ambient temperature, by 20mlDMF（N,N-dimethylformamide）With 1g N-（5-（（Z）- (the fluoro- 2- carbonyls Yin of 5-
Diindyl -3- is sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is mixed, stirring, plus
Enter 1g maleic acids, immediately dissolved clarification, solid is separated out after ten minutes, continue after stirring 2 hours, filtering, the drying 6 hours of 60 DEG C of vacuum
To 1.0g（It is brick-red）Obtained product is carried out X-ray powder diffraction detection by color crystalline powder, yield 64.9%, its
XRPD collection of illustrative plates is as shown in fig. 7, through differential scanning calorimetric analysis and thermogravimetric analysis, DSC and TGA collection of illustrative plates difference is as shown in Figure 8,9；
1H-NMR(600MHz,DMSO,δppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),
2.812.90（S, 6H）3.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),
7.63（s,1H),8.02（S, 1H）9.16(s,1H),10.74(s,1H),13.56(s,1H).
Embodiment 7：Compound I crystal formation D preparation：
At ambient temperature, by 20mlDMSO（Dimethyl sulfoxide (DMSO)）With 1g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5-
It is sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is mixed, stirring, adds 1g
Maleic acid, dissolved clarification, separates out solid immediately after ten minutes, continues after stirring 2 hours, filtering, 60 DEG C of dryings of vacuum are obtained for 8 hours
Obtained product is carried out X-ray powder diffraction detection, its XRPD collection of illustrative plates such as Figure 10 by 1.1g crystalline powders, yield 71.4%
Shown, through differential scanning calorimetric analysis and thermogravimetric analysis, DSC and TGA collection of illustrative plates difference is as shown in Figure 11,12；
1H-NMR(600MHz,DMSO,δppm)：2.182.21(S,6H),2.50（S, 6H）2.54(t,3H),2.75(s,
3H),2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),7.63（s,
1H),9.16(s,1H),10.74(s,1H),13.56(s,1H)。
Embodiment 8：Compound I crystal formation B preparation（Crystal formation C mashing in water prepares crystal formation B）：
At ambient temperature, by 20mlDMF（N,N-dimethylformamide）With 1g N-（5-（（Z）- (the fluoro- 2- carbonyls Yin of 5-
Diindyl -3- is sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is mixed, stirring, plus
Enter 1g maleic acids, immediately dissolved clarification, solid is separated out after ten minutes, continue after stirring 2 hours, filtering, gained filter cake is in 20ml water
Stirring to pulp 2h, obtains the brick-red crystalline powders of 1.24g, and yield 80.0%, purity 99.3% penetrates obtained product progress X-
Line powder diffraction detects that its XRPD collection of illustrative plates is as shown in figure 4, through differential scanning calorimetric analysis and thermogravimetric analysis, DSC and TGA collection of illustrative plates
Respectively as shown in Figure 5,6；
1H-NMR(600MHz,DMSO,δppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),
2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),7.63（s,1H),
9.16(s,1H),10.74(s,1H),13.56(s,1H)。
Embodiment 9：Compound I crystal formation B preparation：
At ambient temperature, by 20ml water and 1g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,4-
The hydrogen of dimethyl-1-pyrroles's-3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is mixed, and adds 1g maleic acids, after stirring 5 hours,
Suction filtration, 40 DEG C are dried in vacuo 15 hours, obtain the brick-red crystalline powders of 1.4g, and obtained product is carried out X- by yield 90.9%
Ray powder diffraction detects that its XRPD collection of illustrative plates and Fig. 4 are basically identical.
Embodiment 10：Compound I crystal formation B preparation（Crystal formation D mashing in water prepares crystal formation B）：
At ambient temperature, by 20mlDMSO（Dimethyl sulfoxide (DMSO)）With 1g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5-
It is sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is mixed, stirring, adds 1g
Maleic acid, dissolved clarification, cooling, separate out solid immediately after 15 minutes, continue after stirring 2 hours, filtering, gained filter cake is in 30ml water
Stirring to pulp 4h, obtains the brick-red crystalline powders of 1.35g, and obtained product is carried out X-ray powder diffraction by yield 87.0%
Detection, its XRPD collection of illustrative plates and Fig. 4 are basically identical.
Embodiment 11：Compound I crystal formation B preparation：
At ambient temperature, by 20ml methanol and 1g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 2,
- 1 hydrogen of 4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is mixed, and adds 1g maleic acids, is stirred 5 hours
Afterwards, suction filtration, 40 DEG C are dried in vacuo 15 hours, obtain the brick-red crystalline powders of 1.1g, yield 71.5% enters obtained product
Row X-ray powder diffraction detects that its XRPD collection of illustrative plates and Fig. 4 are basically identical.
Embodiment 12：Compound I crystal formation B preparation：
At ambient temperature, by 20ml water, 10mlDMF and 1g N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) first
Base）- 1 hydrogen of -2,4- dimethyl-pyrroles's -3- bases）-3-（4- methylpiperazine-1-yls）Propionamide is mixed, and is added 0.9g maleic acids, is stirred
Mix after 5 hours, suction filtration, 40 DEG C are dried in vacuo 15 hours, obtain the brick-red crystalline powders of 1.2g, yield 78.0%, by what is obtained
Product carries out X-ray powder diffraction detection, and its XRPD collection of illustrative plates and Fig. 4 are basically identical.
Embodiment 13：Compound I crystal formation B preparation：
The crystal formation C that embodiment 6 is prepared is heated to after 180 DEG C, constant temperature 5min natural with baking oven under nitrogen protection
Room temperature is cooled to, gained crystal formation detects that its XRPD collection of illustrative plates is substantially consistent with Fig. 4 through powder X-ray diffraction.
Embodiment 14：Solubility test
Prepare two kinds of KH2PO4/ NaOH buffer solutions（PH value is respectively：PH=6.8, pH=2.5）, respectively take 0.2mL buffer solutions and
The N- that 2mg embodiments 1 are obtained（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles -3-
Base）-3-（4- methylpiperazine-1-yls）Crystal formation A, B, C, D of propionamide and compound I（Respectively embodiment 2, embodiment 8, real
Example 6, embodiment 7 is applied to be prepared）, it is slowly stirred more than 24 hours, with consolidating that 0.22 μm of micro-pore-film filtration is not completely dissolved
Body, solubility is determined with HPLC method（The method that HPLC is referred to second annex V D of Chinese Pharmacopoeia 2010 edition）, dissolving
Degrees of data is as shown in table 1.
Dissolving of the compound, compound I crystal A, B, C, D of the embodiment 1 of table 1 in pH2.5, pH6.8 phosphate buffer
Spend result of the test
| Compound | Solubility（μg/ml）, pH2.5 | Solubility（μg/ml）, pH6.8 |
| The compound that embodiment 1 is obtained | 4.82 | 3.13 |
| Compound I crystal formation A | 29.18 | 31.74 |
| Compound I crystal formation B | 21.65 | 35.75 |
| Compound I crystal formation C | 22.10 | 39.74 |
| Compound I crystal formation D | 14.45 | 31.66 |
As can be seen that N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles -3-
Base）-3-（4- methylpiperazine-1-yls）The solubility of the various crystal formations of propionamide 2-maleate is above the dissolving of free alkali
Degree.
Embodiment 15：Stability test
Take compound I crystal A, B, C, D（Respectively embodiment 2, embodiment 8, embodiment 6, embodiment 7 are prepared）'s
Each two parts of sample, portion is wrapped up with aluminium-foil paper, and room temperature, avoid light place 48 hours, portion are placed on 25 DEG C, 4500lx illumination rays
Under the stable case of illumination in 48 hours, investigate the stability of different crystal forms, the results are shown in Table 2.
Compound I crystal A, B, C, D each two parts of sample, portion is separately taken to be deposited 7 days under the conditions of being placed on 60 DEG C, Yi Fenfang
Put and deposited 7 days under the conditions of 40 DEG C/75%R.H., investigate the stability of different crystal forms, the results are shown in Table 2.
The method that the method for specific study on the stability is referred to second annex XIX C of Chinese Pharmacopoeia 2010 edition；It is pure
HPLC methods are used in degree detection, the method for being referred to second annex V D of Chinese Pharmacopoeia 2010 edition.The detection be the same as Example of crystal formation
Method.
Stability test result under the conditions of the compound I crystal A/B/C/D illumination of table 2, constant temperature and humidity
As can be seen that N-（5-（（Z）- (the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl）- 1 hydrogen of -2,4- dimethyl-pyrroles -3-
Base）-3-（4- methylpiperazine-1-yls）The stability of the various crystal formations of propionamide 2-maleate is preferable, wherein with crystal formation B more
To be stable, crystal formation A, C, D high temperature or it is hot and humid under the conditions of the meeting degraded that has produce impurity or occur to turn crystalline substance.
Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change the guarantor in the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Claims (30)
1. the compound shown in formula I
It is polymorph, wherein, the polymorph is radiated using Cu-K α, the X-ray powder diffraction represented with 2 θ angles,
With the characteristic absorption peak at following position：5.5±0.20°、8.3±0.20°、13.8±0.20°、16.6±0.20°、22.2
± 0.20 °, 25.1 ± 0.20 °, 26.3 ± 0.20 ° and 27.9 ± 0.20 °.
2. the compound of claim 1, wherein, the polymorph is radiated using Cu-K α, the X-ray powder represented with 2 θ angles
Last diffraction, with the characteristic absorption peak at following position：5.5±0.20°、6.5±0.20°、8.3±0.20°、9.8±
0.20°、11.0±0.20°、13.0±0.20°、13.8±0.20°、16.6±0.20°、18.3±0.20°、22.2±
0.20 °, 22.8 ± 0.20 °, 23.5 ± 0.20 °, 25.1 ± 0.20 °, 26.3 ± 0.20 °, 27.9 ± 0.20 ° and 28.7 ±
0.20°。
3. the compound of claim 1, wherein, the polymorph is radiated using Cu-K α, the X-ray powder represented with 2 θ angles
Last diffraction, with X-ray powder diffraction collection substantially as shown in Figure 1.
4. any one of claim 1-3 compound, differential scanning calorimetric analysis are shown, the polymorph is at 194~220 DEG C
There is endothermic peak.
5. the compound shown in formula I,
It is polymorph, wherein, the polymorph is radiated using Cu-Ka, the X-ray powder diffraction represented with 2 θ angles,
With the characteristic absorption peak at following position：6.4±0.2°、9.7±0.20°、12.4±0.20°、13.0±0.20°、16.3
± 0.20 °, 22.9 ± 0.20 °, 24.3 ± 0.2 °, 25.2 ± 0.2 ° and 26.2 ± 0.20 °.
6. the compound of claim 5, wherein, the polymorph is radiated using Cu-Ka, the X-ray powder represented with 2 θ angles
Last diffraction, with the characteristic absorption peak at following position：6.4±0.20°、7.5±0.20°、8.8±0.20°、9.7±
0.20°、12.4±0.20°、13.0±0.20°、16.3±0.20°、17.4±0.20°、18.0±0.20°、18.8±
0.20°、19.6±0.20°、21.8±0.20°、22.9±0.20°、24.3±0.20°、25.2±0.20°、26.2±
0.20 °, 26.9 ± 0.20 ° and 33.0 ± 0.20 °.
7. the compound of claim 5, wherein, the polymorph is radiated using Cu-Ka, the X-ray powder represented with 2 θ angles
Last diffraction, with X-ray powder diffraction collection substantially as shown in Figure 4.
8. any one of claim 5-7 compound, differential scanning calorimetric analysis are shown, the polymorph is at 188-274 DEG C
There is endothermic peak.
9. the compound shown in formula I,
It is polymorph, wherein, the polymorph is radiated using Cu-K α, the X-ray powder diffraction represented with 2 θ angles,
With the characteristic absorption peak at following position：2.8±0.20°、5.6±0.20°、8.4±0.20°、16.4±0.20°、22.5
± 0.20 °, 25.4 ± 0.20 °, 26.6 ± 0.20 ° and 28.2 ± 0.20 °.
10. the compound of claim 9, wherein, the polymorph is radiated using Cu-Ka, the X-ray represented with 2 θ angles
Powder diffraction, with the characteristic absorption peak at following position：2.8±0.20°、5.6±0.20°、8.4±0.20°、11.2±
0.20°、16.4±0.20°、19.5±0.20°、22.5±0.20°、24.0±0.20°、25.4±0.20°、26.6±0.20°
With 28.2 ± 0.20 °.
11. the compound of claim 9, wherein, the polymorph is radiated using Cu-Ka, the X-ray represented with 2 θ angles
Powder diffraction, with X-ray powder diffraction collection substantially as shown in Figure 7.
12. any one of claim 9-11 compound, differential scanning calorimetric analysis are shown, the polymorph is 150~185
DEG C and 209~230 DEG C have endothermic peak at two.
13. the compound shown in formula I,
It is polymorph, wherein, the polymorph is radiated using Cu-Ka, the X-ray powder diffraction represented with 2 θ angles,
With the characteristic absorption peak at following position：5.6±0.20°、8.4±0.20°、14.0±0.20°、22.5±0.20°、23.8
± 0.20 °, 25.4 ± 0.20 °, 26.5 ± 0.20 ° and 28.3 ± 0.20 °.
14. the compound of claim 13, wherein, the polymorph is radiated using Cu-Ka, the X-ray represented with 2 θ angles
Powder diffraction, with the characteristic absorption peak at following position：5.6±0.20°、8.4±0.20°、9.0±0.20°、14.0±
0.20°、14.7±0.20°、15.6±0.20°、16.6±0.20°、18.1±0.20°、22.5±0.20°、23.8±
0.20 °, 24.6 ± 0.20 °, 25.4 ± 0.20 °, 26.5 ± 0.20 °, 28.3 ± 0.20 ° and 29.5 ± 0.20 °.
15. the compound of claim 13, wherein, the polymorph is radiated using Cu-Ka, the X-ray represented with 2 θ angles
Powder diffraction, with X-ray powder diffraction collection substantially as shown in Figure 10.
16. any one of claim 13-15 compound, differential scanning calorimetric analysis are shown, the polymorph 182~
201 DEG C, 202~225 DEG C have endothermic peak at two.
17. the preparation method of any one of claim 9-12 compound：
N- (5- ((Z)-(the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl)--1 hydrogen of 2,4- dimethyl-pyrroles -3- bases) -3- (4- methyl
Piperazine -1- bases) propionamide and maleic acid stirring reaction in DMF, obtain any one of claim 9-12 institutes
The compound stated；Wherein described N- (5- ((Z)-(the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl) -2,4- dimethyl -1 hydrogen-pyrroles -
3- yls) mol ratio of -3- (4- methylpiperazine-1-yls) propionamides and maleic acid is 1:2.
18. the preparation method of any one of claim 13-16 compound：
N- (5- ((Z)-(the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl)--1 hydrogen of 2,4- dimethyl-pyrroles -3- bases) -3- (4- methyl
Piperazine -1- bases) propionamide and maleic acid stirring reaction in dimethyl sulfoxide, obtain the change described in claim any one of 13-16
Compound；Wherein described N- (5- ((Z)-(the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl)--1 hydrogen of 2,4- dimethyl-pyrroles -3- bases) -
The mol ratio of 3- (4- methylpiperazine-1-yls) propionamides and maleic acid is 1:2.
19. the preparation method of any one of claim 1-4 compound：
N- (5- ((Z)-(the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl)--1 hydrogen of 2,4- dimethyl-pyrroles -3- bases) -3- (4- methyl
Piperazine -1- bases) propionamide and maleic acid be in tetrahydrofuran, tetrahydrofuran/water, acetone, ethyl acetate, isopropyl acetate, dichloro
Stirring reaction in methane, chloroform, ethanol, isopropanol, n-butanol, dioxane, is obtained described in claim any one of 1-4
Compound；Wherein described N- (5- ((Z)-(the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl)--1 hydrogen of 2,4- dimethyl-pyrroles -3-
Base) mol ratio of -3- (4- methylpiperazine-1-yls) propionamides and maleic acid is 1:2.
20. the preparation method of any one of claim 5-8 compound：
N- (5- ((Z)-(the fluoro- 2- carbonyls indoles -3- of 5- are sub-) methyl)--1 hydrogen of 2,4- dimethyl-pyrroles -3- bases) -3- (4- methyl
Piperazine -1- bases) propionamide and maleic acid be in water, N,N-dimethylformamide/water, DMAC N,N' dimethyl acetamide/water, methanol, second
Stirring reaction in glycol or acetonitrile, obtains any one of the claim 5-8 compounds；The wherein N- (5- ((Z)-(5- is fluoro-
2- carbonyl indoles -3- is sub-) methyl)--1 hydrogen of 2,4- dimethyl-pyrroles -3- bases) -3- (4- methylpiperazine-1-yls) propionamides and horse
It is 1 to carry out sour mol ratio:2；As long as the in the mixed solvent of the N,N-dimethylformamide or DMAC N,N' dimethyl acetamide and water
The content of water is not 0；Or,
Any one of claim 9-16 compound is beaten after stirring, filtration drying in water to obtain claim 5-8 any
Compound described in；
Or,
Any one of claim 9-16 compound is dried at 150~200 DEG C, obtained described in claim any one of 5-8
Compound.
21. the preparation method of claim 20, wherein, the DMF or DMA and water
The ratio of in the mixed solvent N,N-dimethylformamide or DMAC N,N' dimethyl acetamide and water is 1:0.5~20.
22. pharmaceutical composition, it contains any one of claim 1-16 compound, and optionally it is one or more pharmaceutically
Acceptable carrier or excipient.
23. the compound described in claim any one of 1-16 is being prepared for preventing and/or treating mammal and acceptor junket
Purposes in the medicine of the related disease of histidine kinase or illness.
24. the purposes of claim 23, wherein, the mammal is behaved.
25. the purposes of claim 23 or 24, wherein, the disease related to receptor tyrosine kinase or illness refer to, by
The tumour of receptor tyrosine kinase mediation or propagation and the migration of the tumour cell driven by receptor tyrosine kinase.
26. the purposes of claim 25, wherein, the tumour mediated by receptor tyrosine kinase or by receptor tyrosine kinase
The propagation of the tumour cell of driving and migration refer to, erbB receptor tyrosine kinase cancer susceptibles.
27. the purposes of claim 26, wherein, the erbB receptor tyrosine kinases cancer susceptible is EGFR or Her2 height expression
And the tumour of EGF drivings, including entity tumor and non-solid tumors.
28. the purposes of claim 27, wherein, the entity tumor is selected from bile duct, bone, bladder, brain/central nervous system, breast
Room, Colon and rectum, endometrium, stomach, head and neck, liver, lung, neuron, esophagus, ovary, pancreas, prostate, kidney, skin, testis
Ball, thyroid gland, the cancer of uterus and vulva.
29. the purposes of claim 28, wherein the cancer of the lung is non-small cell lung cancer.
30. the purposes of claim 27, wherein, the non-solid tumors is selected from leukaemia, Huppert's disease and lymthoma.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310153347.5A CN104119321B (en) | 2013-04-28 | 2013-04-28 | The 2-maleate and its polymorph of indolinone derivative |
| PCT/CN2014/076124 WO2014177011A1 (en) | 2013-04-28 | 2014-04-24 | Dimaleate of indolinone derivative, and polymorphs thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310153347.5A CN104119321B (en) | 2013-04-28 | 2013-04-28 | The 2-maleate and its polymorph of indolinone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104119321A CN104119321A (en) | 2014-10-29 |
| CN104119321B true CN104119321B (en) | 2017-09-08 |
Family
ID=51764985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310153347.5A Active CN104119321B (en) | 2013-04-28 | 2013-04-28 | The 2-maleate and its polymorph of indolinone derivative |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN104119321B (en) |
| WO (1) | WO2014177011A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110655484A (en) * | 2018-06-28 | 2020-01-07 | 中国科学院上海药物研究所 | Salt of 3-alkenyl indolone compound, crystal form thereof, pharmaceutical composition thereof and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ286951A (en) * | 1995-07-13 | 1998-02-26 | Anormed Inc Substituted Under | N-n-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine dimaleate |
| EP1255752B1 (en) * | 2000-02-15 | 2007-08-08 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| WO2008138184A1 (en) * | 2007-05-14 | 2008-11-20 | Shanghai Hengrui Pharmaceutical Co.Ltd. | Derivatives of pyrroloazacycles, the method of making them and the use thereof as inhibitors of protein kinases |
| CN102276584A (en) * | 2010-06-08 | 2011-12-14 | 齐鲁制药有限公司 | Pyrrole-substituted 2-dihydroindolone derivative and preparation method and application thereof |
-
2013
- 2013-04-28 CN CN201310153347.5A patent/CN104119321B/en active Active
-
2014
- 2014-04-24 WO PCT/CN2014/076124 patent/WO2014177011A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014177011A1 (en) | 2014-11-06 |
| CN104119321A (en) | 2014-10-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10793543B2 (en) | Selective C-KIT kinase inhibitor | |
| CN104530061B (en) | Icotinib hydrochloride crystal forms, medicine composition and application of icotinib hydrochloride crystal forms | |
| CN105153122B (en) | [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application | |
| JP7320823B2 (en) | Use of pteridinone derivatives as EGFR inhibitors | |
| CN107531678B (en) | EGFR inhibitor and pharmaceutically acceptable salts and polymorphs thereof and uses thereof | |
| CN107759600A (en) | Crystallization as the Pyrrolopyrimidine compounds of JAK inhibitor | |
| US10323035B2 (en) | Co-crystal of a CDK inhibitor and an MEK inhibitor and process of preparation thereof | |
| CN107245075A (en) | Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines | |
| CN108047205A (en) | 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared | |
| CN112010839A (en) | Crystalline forms of a targeted silk/threonine kinase inhibitor | |
| CN102036667A (en) | Compositions comprising quinazoline derivatives, preparation methods and uses thereof | |
| WO2016023330A1 (en) | Quinazoline derivative | |
| CN112239466B (en) | Succinate salt of a selective CDK4/6 inhibitor and crystalline forms thereof | |
| WO2016101867A1 (en) | Α-crystal form of naproxen imatinib p-toluene sulfonate, preparation method thereof, and pharmaceutical composition containing same | |
| WO2021121146A1 (en) | Crystal form a of aminopyrimidine mesylate compound, preparation method therefor, and application thereof | |
| US20220315576A1 (en) | Polymorph of cdk9 inhibitor and preparation method for polymorph and use thereof | |
| CN102066362A (en) | Dihydroindolinone derivatives | |
| CN110467616B (en) | Preparation and application of triazolopyrazine compound containing heteroaryl substituted pyridazinone structure | |
| CN104119321B (en) | The 2-maleate and its polymorph of indolinone derivative | |
| WO2020172906A1 (en) | New-type pan-raf kinase inhibitor and use thereof | |
| US20230322687A1 (en) | Salt of arylaminoquinazoline-containing compound, and preparation method therefor and use thereof | |
| CN107892691A (en) | 2,8,9 3 substitution 9H purine compounds and its salt and application | |
| CN110407839B (en) | Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure | |
| US20140011856A1 (en) | Salt form of tyrosine kinase inhibitor | |
| JP2022517396A (en) | EGFR inhibitor salt, crystalline form and method for producing it |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |