CN109956947A - A kind of novel crystal forms, the Preparation method and use of CNS inhibitor - Google Patents
A kind of novel crystal forms, the Preparation method and use of CNS inhibitor Download PDFInfo
- Publication number
- CN109956947A CN109956947A CN201811578747.XA CN201811578747A CN109956947A CN 109956947 A CN109956947 A CN 109956947A CN 201811578747 A CN201811578747 A CN 201811578747A CN 109956947 A CN109956947 A CN 109956947A
- Authority
- CN
- China
- Prior art keywords
- crystal form
- characteristic peak
- crystal
- formula
- preparation
- 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.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to novel crystal forms, the Preparation method and uses of a kind of CNS inhibitor.Specifically, the present invention relates to 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine- 4- base] methyl propionate tosilate A, B crystal form, Preparation method and use, it is advantageous in terms of stability of crystal form of the invention and hygroscopicity.
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles
[1,2-a] [Isosorbide-5-Nitrae] benzodiazepine- 4- base] methyl propionate tosilate crystal form and its preparation method and application.
Background technique
Formula (I) compound 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzo two
Azepine- 4- base] methyl propionate tosilate contains carboxylate and benzodiazepine *Structure, EP1183243A reports such change
Closing object is short-acting central nervous system (CNS, Central Nervous System) inhibitor, has including tranquilizing soporific, resists
Anxiety, of flaccid muscles and anticonvulsant action.The intravenously administrable that they can be used in following clinical treatment: in during performing the operation
Operation consent is calm, antianxiety and forgets purposes；Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure；?
Component before and/or at the same time of applying other anesthetic and analgesic, as induction and maintenance for general anesthesia；The town ICU
Wait quietly,
CN103221414A discloses I, II, III, IV crystal form of formula (I) compound, the preparation method and application of crystal form.
The different crystal forms of same drug, there may be notable differences for hygroscopicity, stability etc., to influence drug
Curative effect.Therefore, the novel crystal forms of Research-type (I) compound, the information in terms of providing more hygroscopicity and stability for drug research
It has very important significance.
Summary of the invention
The present invention provides the novel crystal forms of formula (I) compound, in terms of providing more hygroscopicity and stability for drug research
Information.
Technical scheme is as follows:
The present invention provides a kind of A crystal form of compound shown in formula (I), it is characterised in that: its X-ray powder diffraction collection
In, it is to have characteristic peak at 6.060,8.006,12.244,17.663,21.333 in 2 θ, without characteristic peak, error range at 7.18
It can be ± 0.3, ± 0.2 or ± 0.1.
Preferably, the A crystal form 6.060,8.006,12.244,17.663,18.671,21.333,23.617,
24.262, have characteristic peak at 27.257,29.074, without characteristic peak at 7.18, error range can be ± 0.3, ± 0.2 or ±
0.1。。
Preferably, the A crystal form 6.060,8.006,11.145,12.244,14.018,14.518,15.727,
16.076、16.756、17.663、18.671、19.794、20.220、21.333、23.617、24.262、24.645、25.305、
27.257, there is characteristic peak at 27.902,28.321,29.074,29.877,30.880, without characteristic peak, error range at 7.18
It can be ± 0.3, ± 0.2 or ± 0.1.
Preferably, the A crystal form 6.060,8.006,11.145,12.244,14.018,14.518,15.727,
16.076、16.756、17.663、18.671、19.794、20.220、21.333、23.617、24.262、24.645、25.305、
26.255、27.257、27.902、28.321、29.074、29.877、30.880、32.546、33.295、34.453、34.905、
35.602, there is characteristic peak at 36.157,39.613,40.291,40.969,41.734,43.037, error range can be ±
0.3, ± 0.2 or ± 0.1.
The present invention provides a kind of B crystal form of compound shown in formula (I), it is characterised in that: its X-ray powder diffraction collection
In, it is to have characteristic peak at 5.543,7.518,10.622,15.159,19.238,20.426 in 2 θ, without characteristic peak at 6.05,
Error range can be ± 0.3, ± 0.2 or ± 0.1.
Preferably, the B crystal form 5.543,7.518,10.622,11.099,15.159,15.800,18.638,
19.238, there is characteristic peak at 20.426,21.300,22.867,24.376,24.640,25.699, without characteristic peak at 6.05,
Error range can be ± 0.3, ± 0.2 or ± 0.1.
It is furthermore preferred that the B crystal form is 5.543,7.518,10.622,11.099,15.159,15.800,16.120,
16.712、18.638、19.238、19.952、20.426、21.300、22.229、22.867、23.503、24.376、24.640、
25.699, have characteristic peak at 26.641,28.039,28.283,29.169,29.967,30.678,32.560, at 6.05 without
Characteristic peak, error range can be ± 0.3, ± 0.2 or ± 0.1.
It is furthermore preferred that the B crystal form is 5.543,7.518,9.658,10.622,11.099,15.159,15.800,
16.120、16.712、17.647、18.638、19.238、19.952、20.426、21.300、22.229、22.867、23.503、
24.376、24.640、25.699、26.641、27.668、28.039、28.283、29.169、29.967、30.678、32.560、
33.788, there is feature at 34.489,35.947,36.862,37.925,38.849,39.805,43.370,46.662,48.478
Peak, error range can be ± 0.3, ± 0.2 or ± 0.1.
The invention further relates to the pharmaceutical composition comprising A crystal form, described pharmaceutical composition include A crystal form with can pharmaceutically connect
Carrier, diluent or the excipient received.
The invention further relates to the pharmaceutical composition comprising B crystal form, described pharmaceutical composition include B crystal form with can pharmaceutically connect
Carrier, diluent or the excipient received.
The invention further relates to a kind of methods for preparing pharmaceutical composition, including connect A crystal form pharmaceutically can at least one
Carrier, diluent or the excipient mixing received.
The invention further relates to a kind of methods for preparing pharmaceutical composition, including connect B crystal form pharmaceutically can at least one
Carrier, diluent or the excipient mixing received.
The invention further relates to the pharmaceutical compositions comprising A crystal form and/or B crystal form to prepare calm, sleeping, antianxiety, flesh
Purposes in meat relaxation or anticonvulsant drug.
By X-ray powder diffraction collection (XRPD), differential scanning calorimetric analysis (DSC), thermogravimetric analysis (TGA) to institute
Obtain the A of compound shown in formula (I), B crystal form carries out structure determination, property research.
Detailed description of the invention
In the description and claims of this application, unless otherwise stated, science used herein and skill
Art noun has the normally understood meaning of those skilled in the art institute.However, for a better understanding of the present invention, being provided below
The definition and explanation of part relational language.In addition, as the definition and explanation of term provided herein and those skilled in the art
When the normally understood meaning of member institute is inconsistent, with the definition of term provided herein and it is construed to quasi-.
" X-ray powder diffraction collection or XRPD " of the present invention refers to according to bragg's formula 2d sin θ=n λ
(in formula, λ is the wavelength of X-ray,The series n of diffraction is any positive integer, generally takes first-order diffraction peak, n=
1), when X-ray is incident on a certain of crystal or partial crystals sample with sweep angle θ (complementary angle of incidence angle, also known as Bragg angle)
When on the atomic plane with d lattice plane spacing, it is just able to satisfy Bragg equation, to measure this group of X-ray powder diffraction
Figure.
" differential scanning calorimetric analysis or DSC " of the present invention refers in sample heating or thermostatic process, measures sample
Temperature difference, differential heat flow between product and reference substance are obtained with characterizing all physical changes related with fuel factor and chemical change
The transformation information of sample.
" 2 θ or 2 θ angles " of the present invention refer to the angle of diffraction, and θ is Bragg angle, and unit is ° or degree the error model of 2 θ
Enclose is ± 0.1~± 0.3, preferably ± 0.2.
The invention further relates to, A and/or B crystal form including formula (I) compound represented, and optionally one or more
The pharmaceutical composition of pharmaceutical carrier and/or diluent.Pharmaceutically acceptable any dosage form can be made in described pharmaceutical composition.
For example, the A of formula (I) compound represented and/or the pharmaceutical preparation of B crystal form of the invention can be formulated as tablet, capsule, ball
(including injection, injection sterile powder and injection are dense molten for agent, granule, solution, suspension, syrup, injection
Liquid), suppository, inhalant or spray.
In addition, pharmaceutical composition of the present invention can also with any suitable administration mode, such as oral, parenteral,
The modes such as rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When being used to be administered orally, institute
Stating pharmaceutical composition can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；Or mouth
Take liquid preparation, such as oral solution, oral suspensions, syrup.When oral preparation is made, the pharmaceutical preparation may be used also
Include suitable filler, adhesive, disintegrating agent, lubricant etc..When being used for parenteral administration, the pharmaceutical preparation be can be made into
Injection, including injection, injection sterile powder and concentrated solution for injection.When injection is made, described pharmaceutical composition
The conventional method in existing pharmaceutical field can be used to be produced.It, can not in the pharmaceutical preparation when preparing injection
Additives are added, suitable additives can also be added according to the property of drug.When being used for rectally, the pharmaceutical preparation can
Suppository etc. is made.When for transpulmonary administration, the pharmaceutical preparation can be made into inhalant or spray etc..In certain preferred implementations
In scheme, the A of formula of the invention (I) compound represented and/or B crystal form are to treat and/or prevention effective dose is present in drug
In composition or drug.In certain preferred aspects, the A of formula (I) compound represented and/or B crystal form with
The form of unit dose is present in pharmaceutical composition or drug.
Formula (I) compound A and/or B crystal form can be used for preparing the drug for the treatment of disease related with CNS or illness
In purposes.Therefore, the application further relates to, and formula (I) compound A and/or B crystal form are used to prepare calm, sleeping, anti-coke
Consider, the purposes in of flaccid muscles or anticonvulsant drug.In addition, the application further relates to a kind of side for treating disease related with CNS
Method comprising formula (I) the compound A and/or B for the treatment of and/or prevention effective dose are applied to subject with this need
Crystal form or pharmaceutical composition of the invention.
Advantageous effect of the invention
Compared with prior art, technical solution of the present invention has the advantage that
Research has shown that advantageous in terms of stability of crystal form of the invention and hygroscopicity.
Detailed description of the invention
Fig. 1 is the XRPD map of compound A crystal form shown in formula (I).
Fig. 2 is the DSC map of compound A crystal form shown in formula (I).
Fig. 3 is the TGA map of compound A crystal form shown in formula (I).
Fig. 4 is the XRPD map of compound B crystal form shown in formula (I).
Fig. 5 is the DSC map of compound B crystal form shown in formula (I).
Fig. 6 is the TGA map of compound B crystal form shown in formula (I).
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate skill of the invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Experiment test equipment used
1, x-ray diffraction pattern (X-ray Powder Diffraction, XRPD)
Instrument model: Bruker D8Discover A25X- ray powder diffractometer
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scanning mode: the θ of θ/2, scanning range: 10-48 °
Voltage: 40KV, electric current: 40mA
2, differential scanning calorimeter (Differential Scanning Calorimeter, DSC)
Instrument model: Mettler Toledo DSC 3+STARe System
Nitrogen purges speed: 50mL/min
Heating rate: 10 DEG C/min
Temperature range: 25-300 DEG C
3, thermogravimetric analysis (Thermogravimetric Analysis, TGA)
Instrument model: Mettler Toledo TGA 2
Nitrogen purges speed: 20mL/min
Heating rate: 10 DEG C/min
Temperature range: 25-300 DEG C
The preparation of embodiment 1:A crystal form
Compound 500mg shown in modus ponens (I), is added in the round-bottomed flask of 50ml, and 15ml water is added, is heated to reflux 10min,
It is completely dissolved solid, stops heating, filters while hot, cooling crystallization, products therefrom is in the vacuum tank for being placed with anhydrous calcium chloride
It is dry, obtain white solid, yield about 62%.The X-ray diffraction spectrogram of the crystallized sample is shown in that Fig. 1, DSC spectrogram are shown in Fig. 2, TGA
Spectrogram is shown in Fig. 3, has fusing absorption peak in about 156.90 DEG C, 198.59 DEG C and 205.85 DEG C, and defining the crystal form is A crystal form, 2 θ
Characteristic peak positions are as shown in table 1 below:
Table 1, A crystal form characteristic peak
The preparation of embodiment 2:B crystal form
Compound 500mg shown in modus ponens (I), is added in the round-bottomed flask of 50ml, and 15ml water is added, is heated to reflux 10min,
It is completely dissolved solid, stops heating, filters while hot, cooling crystallization, 35 DEG C are dried in vacuum overnight, and obtain white solid, yield
About 66%.The X-ray diffraction spectrogram of the crystallized sample is shown in that Fig. 4, DSC spectrogram are shown in Fig. 5, about 76.09 DEG C, 154.81 DEG C,
There is fusing absorption peak at 198.01 DEG C and 205.78 DEG C, TGA spectrogram is shown in Fig. 6, and defining the crystal form is B crystal form, 2 θ feature peak positions
It sets as shown in table 2 below:
Table 2, B crystal form characteristic peak
Embodiment 3: Study on Hygroscopicity
By compound I crystal shown in formula (I) and each 30mg of B crystal form, it is respectively placed in 25 DEG C, humidity 54%, 69%,
24 hours in 75% and 93% environment, the hygroscopicity of I crystal and B crystal form is investigated with TGA, the results are shown in Table 3.
Table 3, I crystal and B crystal form hygroscopicity compare
Embodiment 4: hot test
By compound I crystal shown in formula (I) and each 100mg of A crystal form, opening is placed on 40 DEG C and 60 DEG C of hot conditions respectively
Under, investigate the physical stability of I crystal and A crystal form.
Table 4, I crystal and A crystal form high-temperature stability compare
High temperature experiment display: A crystal form places 1 month stable crystal form under the conditions of 40 DEG C and 60 DEG C.
Embodiment 5: long-term accelerated stability test
By compound I crystal shown in formula (I), A crystal form and B crystal form sample respectively it is silent be placed on it is long-term (25 DEG C,
RH60%), under the conditions of accelerating (40 DEG C, RH75%), the stability of sample is investigated.
Table 5, I crystal, A crystal form and the long-term accelerated stability test result of B crystal form
Long-term accelerated stability experiment display: 6 months chemistry are placed under the conditions of the long-term accelerated stability of A crystal form, B crystal form
Stability is good.
Claims (10)
1. the A crystal form of compound shown in formula (I), it is characterised in that: in its X-ray powder diffraction collection, 2 θ be 6.060,
8.006, there is characteristic peak at 12.244,17.663,21.333, without characteristic peak at 7.18,
2. A crystal form as described in claim 1, which is characterized in that the A crystal form 6.060,8.006,12.244,17.663,
18.671, there is characteristic peak at 21.333,23.617,24.262,27.257,29.074, without characteristic peak at 7.18.
3. A crystal form as described in claim 1, which is characterized in that the A crystal form 6.060,8.006,11.145,12.244,
14.018、14.518、15.727、16.076、16.756、17.663、18.671、19.794、20.220、21.333、23.617、
24.262, there is characteristic peak at 24.645,25.305,27.257,27.902,28.321,29.074,29.877,30.880,
Without characteristic peak at 7.18.
4. the B crystal form of compound shown in formula (I), it is characterised in that: in its X-ray powder diffraction collection, 2 θ be 5.543,
7.518, there is characteristic peak at 10.622,15.159,19.238,20.426, without characteristic peak at 6.05.
5. B crystal form as claimed in claim 4, which is characterized in that the B crystal form 5.543,7.518,10.622,11.099,
15.159, there is feature at 15.800,18.638,19.238,20.426,21.300,22.867,24.376,24.640,25.699
Peak, without characteristic peak at 6.05.
6. B crystal form as claimed in claim 4, which is characterized in that the B crystal form 5.543,7.518,10.622,11.099,
15.159、15.800、16.120、16.712、18.638、19.238、19.952、20.426、21.300、22.229、22.867、
23.503、24.376、24.640、25.699、26.641、28.039、28.283、29.169、29.967、30.678、32.560
There is characteristic peak at place, without characteristic peak at 6.05.
7. a kind of method for preparing pharmaceutical composition, including make A crystal form as described in any one of claims 1-3 and/or such as weigh
Benefit requires B crystal form described in any one of 4-6 to mix at least one pharmaceutically acceptable carrier, diluent or excipient.
8. the medicine containing B crystal form described in any one of the described in any item A crystal forms of claim 1-3 and/or claim 4-6
Compositions also include one or more pharmaceutically acceptable carriers, diluent or excipient.
9. the medicine containing B crystal form described in any one of the described in any item A crystal forms of claim 1-3 and/or claim 4-6
Compositions are preparation is calm, sleeping, antianxiety, the purposes in of flaccid muscles or anticonvulsant drug.
10. A crystal form as described in any one of claims 1-3 or the described in any item B crystal forms of 4-6, it is characterised in that miss at 2 angles θ
Poor range is ± 0.2.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711424141 | 2017-12-25 | ||
| CN2017114241416 | 2017-12-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109956947A true CN109956947A (en) | 2019-07-02 |
Family
ID=67023366
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811578747.XA Pending CN109956947A (en) | 2017-12-25 | 2018-12-24 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109956947A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257904A (en) * | 2002-03-06 | 2008-09-03 | 尼科梅德有限责任公司 | Pharmaceutical composition of a pde4 or a pde3/4 inhibitor and a histamine receptor antagonist |
| CN102007105A (en) * | 2008-02-29 | 2011-04-06 | 麦提卡公司 | 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists |
| CN102964349A (en) * | 2011-08-31 | 2013-03-13 | 江苏恒瑞医药股份有限公司 | Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application |
| CN103202815A (en) * | 2013-05-05 | 2013-07-17 | 王元青 | Injection for treating mental disease |
| CN103232454A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Medicine for treating mental disease |
| CN103230595A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Composition for treating mental diseases |
| CN108264499A (en) * | 2017-01-04 | 2018-07-10 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of benzodiazepine * derivatives |
-
2018
- 2018-12-24 CN CN201811578747.XA patent/CN109956947A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257904A (en) * | 2002-03-06 | 2008-09-03 | 尼科梅德有限责任公司 | Pharmaceutical composition of a pde4 or a pde3/4 inhibitor and a histamine receptor antagonist |
| CN102007105A (en) * | 2008-02-29 | 2011-04-06 | 麦提卡公司 | 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists |
| CN102964349A (en) * | 2011-08-31 | 2013-03-13 | 江苏恒瑞医药股份有限公司 | Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application |
| CN103202815A (en) * | 2013-05-05 | 2013-07-17 | 王元青 | Injection for treating mental disease |
| CN103232454A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Medicine for treating mental disease |
| CN103230595A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Composition for treating mental diseases |
| CN108264499A (en) * | 2017-01-04 | 2018-07-10 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of benzodiazepine * derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6946194B2 (en) | Solid form of compounds that regulate kinases | |
| CN104109149B (en) | Deuterated diaminopyrimidine compounds and the pharmaceutical composition comprising the compound | |
| CN103354809B (en) | A kind of aryl urea compounds, its intermediate and application thereof | |
| TWI804933B (en) | Compounds and uses thereof as CDK7 kinase inhibitors | |
| TW202333743A (en) | Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate | |
| JP2014129386A (en) | Solvate and crystal form of carbamoyl-cyclohexane derivative | |
| AU2018251118A1 (en) | Pharmaceutical composition containing MOR agonist and KOR agonist, and uses thereof | |
| BR112014009084B1 (en) | ARRY-380 CRYSTALLINE POLYMORPHS | |
| TW202320793A (en) | Pharmaceutical composition comprising triazine derivative | |
| EP3927696B1 (en) | Crystalline form of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-(2-(trifluoromethyl)pyridin-4-yl)-1h-pyrazole-4-carboxamide monohydrate | |
| JP2022553833A (en) | Salts and Forms of Estrogen Receptor Modulators | |
| WO2023158668A1 (en) | Neuroactive steroids for treatment of cns-related disorders | |
| JP6972390B2 (en) | Crystal form targeting CDK4 / 6 kinase inhibitors | |
| CN111278808B (en) | Solid forms of 2- (5- (4- (2-morpholinoethoxy) phenyl) pyridin-2-yl) -N-benzyl acetamide | |
| JP2013510176A (en) | Novel crystalline form of (1S, 2R) -2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide | |
| JP2022522395A (en) | New Salts of Selective Estrogen Receptor Degradants | |
| CN108368115A (en) | The salt of Pyrrolopyrimidine compounds | |
| WO2021047528A1 (en) | Maleate of nicotinyl alcohol ether derivative, crystal form thereof, and application thereof | |
| JP2023533040A (en) | Salts and Forms of WEE1 Inhibitors | |
| CN109956947A (en) | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor | |
| CN110028497A (en) | A kind of crystal form and preparation method of the ethanolamine salt of thrombopoietin mimetics | |
| TW201815793A (en) | Crystalline form of free alkali of imidazo isoindole derivative and a preparation method thereof | |
| JP2022540466A (en) | amorphous umbularisib monotosylate | |
| EP3781568A1 (en) | Form of ponatinib | |
| Zhang et al. | A drug–drug cocrystal and a co-amorphous form, prepared from honokiol and ligustrazine, inspired by Chinese patent medicine |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190702 |