CN109111454A - A kind of Rui Kapabu S- camsilate - Google Patents
A kind of Rui Kapabu S- camsilate Download PDFInfo
- Publication number
- CN109111454A CN109111454A CN201810862537.7A CN201810862537A CN109111454A CN 109111454 A CN109111454 A CN 109111454A CN 201810862537 A CN201810862537 A CN 201810862537A CN 109111454 A CN109111454 A CN 109111454A
- Authority
- CN
- China
- Prior art keywords
- camsilate
- rui kapabu
- crystal forms
- kapabu
- rui
- 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
-
- 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
- C07D487/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Abstract
The present invention provides a kind of Rui Kapabu S- camsilate (chemical combination name: the fluoro- 2- of 8- { 4-[(methylamino) methyl] phenyl } -1,3,4,5- tetrahydro -6H- azepineAnd [5,4,3-cd] indoles -6- ketone S- camsilate；English name: Rucaparib Camsylate) novel crystal forms.Novel crystal forms Rui Kapabu S- camsilate provided by the invention (chemical combination name: 8- fluoro- 2- 4-[(methylamino) and methyl] phenyl } -1,3,4,5- tetrahydro -6H- azepine
Description
Technical field
The present invention relates to a kind of drug, preparation method and the usage, the drug is Rui Kapabu S- camsilate
(Rucaparib Camsylate), exactly the present invention relates to the fluoro- 2- of a kind of 8- { 4-[(methylamino) methyl] phenyl } -1,
3,4,5- tetrahydro -6H- azepineAnd S- camsilate (its English name: Rucaparib of [5,4,3-cd] indoles -6- ketone
Camsylate novel crystal forms) with and its preparation method and application.
Background technique
Compound 8- fluoro- 2- 4-[(methylamino) and methyl] phenyl } -1,3,4,5- tetrahydro -6H- azepineAnd [5,4,3-
Cd] indoles -6- ketone S- camsilate (Rui Kapabu S- camsilate) (Rucaparib Camsylate, CAS:
283173-50-2) be poly- (ADP- ribose) polymerase (PARP) micromolecular inhibitor.Pfizer stops to Rui Kapabu within 2011
New drug development, and license to new drug and market of the Clovis tumour medicine company (Clovis Oncology) to the compound
It is developed；2012, which was used for the research of oophoroma as Orphan drug in US and European, and 2015, the medicine
Three line clinical applications of the object as monotherapy are used for the clinical treatment research of BRCA mutation oophoroma, achieve good effect
Fruit, and therefore obtain the breakthrough sex therapy qualification of U.S. FDA；On FDA in December, 2016 approval Rucaparib Camsylate
City.
Poly ADP transferase (PARP) is the key factor in DNA excision reparation channel, and Rui Kapabu S- camphorsulfonic acid
Salt (Rucaparib Camsylate) is then able to suppress PRAP enzymatic activity, make DNA break it is single-stranded can not repair, genome not
Stability increases, and then can lead to the apoptosis of cell, especially to there are the tumour cells of homologous recombination repair defect to have relatively by force
Killing effect, this binding mode of Rui Kapabu S- camsilate (Rucaparib Camsylate) is allowed to a variety of
The tumour of type has treatment potentiality；In addition, since Rui Kapabu S- camsilate (Rucaparib Camsylate) is to damage
The specificity that the DNA of wound repairs channel inhibits, which can also avoid the tumor drug resistance after chemotherapy, enhances DNA damage, reinforce with
Toward the antitumor curative effect of chemotherapeutics.The PARP inhibitor such as Rui Kapabu S- camsilate (Rucaparib Camsylate)
It is capable of the inhibition of specificity along with the growth of DNA damage or the tumor cell line of homologous recombination repair defect, increases to tumour
The toxicity and anti-tumor activity of cell, and lethal effect is had no to the normal histocyte of DNA repair function, specificity is high, secondary
Act on it is small, be antineoplastic target treatment typical medicaments.
Pfizer discloses the fluoro- 2- of 8- { 4-[(methylamino) methyl] phenyl } -1,3,4 in WO2011/098971,
5- tetrahydro -6H- azepineAnd the S- camsilate and polymorph of [5,4,3-cd] indoles -6- ketone, wherein disclosing camphor
The A of sulfonate, B, tri- kinds of crystal forms of C, and its crystal form is characterized.
The polymorphic of drug has the quality of preparation, production technology, the dissolution of internal drug, biological effectiveness etc.
Significant impact, and therefore influence stability, bioavilability and the curative effect of drug.
Summary of the invention
The present invention provides a kind of fluoro- 2- of 8- { 4-[(methylamino) methyl] phenyl } -1,3,4,5- tetrahydro -6H- azepinesAnd S- camsilate (referred to as: Rui Kapabu S- camsilate) (Rucaparib of [5,4,3-cd] indoles -6- ketone
Camsylate novel crystal forms), it exists with essentially pure crystal habit, described here essentially pure to refer to one kind
Crystal form is substantially free of another or a variety of crystal forms.
The Rui Kapabu S- camsilate of novel crystal forms of the present invention spreads out in the X-ray powder of Cu-Ka ray
Penetrating Fig. 2 theta value is to have characteristic peak at 5.91 °, 11.97 °, 18.11 °, 19.34 °, 22.26 °, 25.53 °.
The Rui Kapabu S- camsilate of novel crystal forms of the present invention spreads out in the X-ray powder of Cu-Ka ray
Penetrating Fig. 2 theta value is to have feature at 13.31,14.62,15.92 °, 16.49 °, 18.94 °, 20.34 °, 23.89 °, 30.56 °
Peak.Its XPRD figure is substantially as shown in Figure 1.In some embodiments, its differential scanning calorimetric analysis (DSC) figure of above-mentioned novel crystal forms
In spectrum, there is absorption peak within the scope of 300-310 DEG C；In some embodiments, its differential thermometric analysis map of above-mentioned novel crystal forms
In, there is absorption peak at 302.37 DEG C；Its differential thermometric analysis figure is substantially as shown in Figure 2.
In some embodiments, in the thermogravimetric analysis figure of above-mentioned novel crystal forms, there is smaller mistake within the scope of 100-310 DEG C
Weight, thermogravimetric analysis (TGA) figure are substantially as shown in Figure 3.
Novel crystal forms provided by the invention can be used for producing the lactation that treatment is mediated by poly- (ADP- ribose) polymerase activity
Animal diseases symptom, the disease condition including such as cancer have DNA repair function in particular for preparation prevention or treatment
Tumour, especially BRCA gene mutation relevant two or more combination cancers such as oophoroma, gastric cancer, breast cancer, and be used for
Tumour medicine relevant to BRCA1 and BRCA2 gene mutation.
Beneficial effects of the present invention:
Above-mentioned novel crystal forms provided by the invention have stability good, and solubility, dissolving out capability are excellent, have patent medicine performance.
The features such as novel crystal forms production technology has mild condition, easy to operate, favorable reproducibility, is suitble to industrialized production.It is new brilliant
Type product places 15 days stability contrast test results under high temperature, high humidity, illumination and normal temperature condition, spreads out from X-ray powder
It penetrates from the point of view of figure, differential thermometric analysis (DSC) and thermogravimetric analysis (TGA) result, novel crystal forms product is very stable under various conditions.It is auspicious
The novel crystal forms of Kappa cloth S- camsilate (Rucaparib Camsylate) are transferred in high temperature, high humidity, illumination and normal temperature condition
XPRD superposition spectrogram after setting 15 days is shown in Fig. 4；
The novel crystal forms of Rui Kapabu S- camsilate (Rucaparib Camsylate) high temperature, high humidity, illumination and often
DSC superposition spectrogram after placing 15 days under the conditions of temperature is shown in Fig. 5；
The novel crystal forms of Rui Kapabu S- camsilate (Rucaparib Camsylate) high temperature, high humidity, illumination and often
TGA superposition spectrogram after placing 15 days under the conditions of temperature is shown in Fig. 6.
Novel crystal forms Rui Kapabu S- camsilate (Rucaparib Camsylate) of the invention can be used for preparing prevention
Or treatment has the tumour of DNA repair function, the especially relevant two or more combination cancer such as ovary of BRCA gene mutation
Cancer, gastric cancer, breast cancer, and the purposes for tumour medicine relevant to BRCA1 and BRCA2 gene mutation.
Detailed description of the invention
The XPRD spectrogram of the novel crystal forms of a: Rui Kapabu S- camsilate of Fig. 1 (Rucaparib Camsylate)；
Fig. 1 b: 2-Theta (°) figure corresponding with Rui Kapabu S camsilate novel crystal forms _ _ XPRD spectrogram of Fig. 1
The DSC spectrogram of the novel crystal forms of Fig. 2: Rui Kapabu S- camsilate (Rucaparib Camsylate)；
The TGA spectrogram of the novel crystal forms of Fig. 3: Rui Kapabu S- camsilate (Rucaparib Camsylate)
The novel crystal forms of Fig. 4: Rui Kapabu S- camsilate (Rucaparib Camsylate) are in high temperature, high humidity, illumination
Spectrogram is superimposed with the XPRD after placing 15 days under normal temperature condition；
The novel crystal forms of Fig. 5: Rui Kapabu S- camsilate (Rucaparib Camsylate) are in high temperature, high humidity, illumination
Spectrogram is superimposed with the DSC after placing 15 days under normal temperature condition.
The novel crystal forms of Fig. 6: Rui Kapabu S- camsilate (Rucaparib Camsylate) are in high temperature, high humidity, illumination
Spectrogram is superimposed with the TGA after placing 15 days under normal temperature condition.
Specific embodiment
In order to make those skilled in the art better understand technical solution of the present invention, further disclose some unrestricted
The present invention is described in further detail for embodiment.
The Rui Kapabu S- camsilate (Rucaparib Camsylate) that the present invention uses can be by side below
Method obtains.
The preparation of the novel crystal forms of 1: Rui Kapabu S- camsilate of embodiment (Rucaparib Camsylate):
100mg Rui Kapabu S- camsilate (Rucaparib Camsylate) is added in reaction flask, is added 10 times
The DMSO of volume heats dissolved clarification, THF is slowly added dropwise to there is solid precipitation at 60 DEG C, temperature control stirring 30min continues to be slowly added dropwise
Stop after to the THF of 20 times of volumes, growing the grain, filters, it is dry, obtain above-mentioned novel crystal forms solid about 80mg.
The preparation of the novel crystal forms of 2: Rui Kapabu S- camsilate of embodiment (Rucaparib Camsylate)
100mg Rui Kapabu S- camsilate (Rucaparib Camsylate) is added in reaction flask, is added 10 times
The DMSO of volume heats dissolved clarification, dioxane is slowly added dropwise at 60 DEG C to there is solid precipitation, temperature control stirring 30min continues slow
Stop after being added dropwise to the dioxane of 15 times of volumes, growing the grain, filters, it is dry, obtain above-mentioned novel crystal forms solid about 78mg.
Embodiment 3
The preparation of the novel crystal forms of Rui Kapabu S- camsilate (Rucaparib Camsylate)
100mg Rui Kapabu S- camsilate (Rucaparib Camsylate) is added in reaction flask, is added 6 times
The DMF of volume heats dissolved clarification, is slowly added dropwise at 40 DEG C to there is solid precipitation, temperature control stirring 30min continues to be slowly added dropwise to 15
The rear stopping of times volume, growing the grain filter, dry, obtain above-mentioned novel crystal forms solid about 75mg.
The preparation of the novel crystal forms of 4: Rui Kapabu S- camsilate of embodiment (Rucaparib Camsylate)
100mg Rui Kapabu S- camsilate (Rucaparib Camsylate) is added in reaction flask, is added 8 times
The DMF of volume, heats dissolved clarification, THF is slowly added dropwise at 50 DEG C to there is a solid precipitation, temperature control stirring 30min, continue to be slowly added dropwise to
Stop after the THF of 15 times of volumes, growing the grain, filters, it is dry, obtain above-mentioned novel crystal forms solid about 82mg.
Claims (6)
1. a kind of Rui Kapabu S- camsilate, it is characterised in that X-ray powder of the novel crystal forms in Cu-Ka ray
Diffraction pattern 2theta value is to have characteristic peak at 5.91 °, 11.97 °, 18.11 °, 19.34 °, 22.26 °, 25.53 °.
2. a kind of Rui Kapabu S- camsilate, it is characterised in that the X-ray powder diffraction figure 2theta of its Cu-Ka ray
Value is to have characteristic peak at 13.31,14.62,15.92 °, 16.49 °, 18.94 °, 20.34 °, 23.89 °, 30.56 °.
3. the preparation method of Rui Kapabu S- camsilate of any of claims 1 or 2, it is characterised in that: in reaction flask
It is added Rui Kapabu S- camsilate (Rucaparib Camsylate), adds the solvent of 10 times of volumes, heat dissolved clarification,
THF is slowly added dropwise at 60 DEG C to there is solid precipitation, temperature control stirring 30min continues to stop after being slowly added dropwise to the THF of 20 times of volumes
Only, growing the grain filters, dry, obtains target compound.
4. the preparation method of Rui Kapabu S- camsilate according to claim 3, it is characterised in that used molten
Agent is DMSO, or is DMF.
5. the preparation method of Rui Kapabu S- camsilate of any of claims 1 or 2, it is characterised in that: in reaction flask
Rui Kapabu S- camsilate is added, adds the DMSO of 10 times of volumes, heats dissolved clarification, dioxane is slowly added dropwise at 60 DEG C
To there is solid precipitation, temperature control stirring 30min continues to stop after being slowly added dropwise to the dioxane of 15 times of volumes, growing the grain, filtering,
It is dry, obtain target compound.
6. Rui Kapabu S- camsilate of any of claims 1 or 2 polymerize enzyme activity by poly- (ADP- ribose) in preparation treatment
The mammalian diseases symptom that property is mediated, the application in the disease medicament including such as cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810862537.7A CN109111454A (en) | 2018-08-01 | 2018-08-01 | A kind of Rui Kapabu S- camsilate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810862537.7A CN109111454A (en) | 2018-08-01 | 2018-08-01 | A kind of Rui Kapabu S- camsilate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109111454A true CN109111454A (en) | 2019-01-01 |
Family
ID=64862488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810862537.7A Pending CN109111454A (en) | 2018-08-01 | 2018-08-01 | A kind of Rui Kapabu S- camsilate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109111454A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020113500A1 (en) * | 2018-12-06 | 2020-06-11 | 上海诚妙医药科技有限公司 | Rucaparib camsylate, preparation method therefor, and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102884066A (en) * | 2010-02-12 | 2013-01-16 | 辉瑞公司 | Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one |
| CN106794185A (en) * | 2014-08-22 | 2017-05-31 | 克洛维斯肿瘤有限公司 | The high dose strength tablet of Rucaparib |
-
2018
- 2018-08-01 CN CN201810862537.7A patent/CN109111454A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102884066A (en) * | 2010-02-12 | 2013-01-16 | 辉瑞公司 | Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one |
| CN106794185A (en) * | 2014-08-22 | 2017-05-31 | 克洛维斯肿瘤有限公司 | The high dose strength tablet of Rucaparib |
| US20180200260A1 (en) * | 2014-08-22 | 2018-07-19 | Clovis Oncology, Inc. | High Dosage Strength Tablets of Rucaparib |
Non-Patent Citations (4)
| Title |
|---|
| ADAM THOMAS GILLMORE，ET AL.: "Multi-Kilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| LE DOCKERY，ET AL.: "Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer", 《ONCOTARGETS AND THERAPY》 * |
| 刘新泳 等: "《实验室有机化合物制备与分离纯化技术》", 31 January 2011, 人民卫生出版社 * |
| 吕扬 等: "《晶型药物》", 31 October 2009, 人民卫生出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020113500A1 (en) * | 2018-12-06 | 2020-06-11 | 上海诚妙医药科技有限公司 | Rucaparib camsylate, preparation method therefor, and uses thereof |
| CN111542527A (en) * | 2018-12-06 | 2020-08-14 | 上海诚妙医药科技有限公司 | Novel crystal form of lucaparins camphorsulfonate, preparation method and application thereof |
| US11352362B2 (en) | 2018-12-06 | 2022-06-07 | Shanghai Begreat Pharmatech | Polymorph of rucaparib camsylate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2004230928B2 (en) | Tie-2 modulators and methods of use | |
| AU2010217929A1 (en) | JAK kinase modulating quinazoline derivatives and methods of use thereof | |
| WO2004091480A2 (en) | Tie-2 modulators and methods of use | |
| CN104003988A (en) | CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor | |
| CN101624376B (en) | Substituted hydrazide compound and application thereof | |
| CN112010839B (en) | Crystalline forms of a targeted silk/threonine kinase inhibitor | |
| CN101928254B (en) | Benzotriazole derivatives and preparation method and use thereof | |
| CN101312958A (en) | 3, 6-dihydro-2-oxo-6H-(1,3,4)thiadiazine derivatives | |
| CN106674136A (en) | Anti-tumor pyrimidine compounds and preparation method thereof | |
| MX2015003151A (en) | Crystalline compounds. | |
| CN109111454A (en) | A kind of Rui Kapabu S- camsilate | |
| CN106554321B (en) | A kind of azophenlyene substance, preparation method and its application | |
| CN104945453B (en) | The polymorph of pyrazole derivatives | |
| CN102108079B (en) | 4-anilino quinazoline derivatives serving as tyrosine kinase inhibitors | |
| CN107973783A (en) | Aniline pyrimidine derivative as ERK inhibitor | |
| CN107513040A (en) | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine | |
| CN111566101B (en) | CDK4/6 inhibitors and pharmaceutically acceptable salts and polymorphs thereof and uses thereof | |
| CN106029664A (en) | Crystalline form of malate of tyrosine kinase inhibitor and preparation method therefor | |
| CN106631975B (en) | The platinum complex and its preparation method and application of the Methyl hydrazinecarbodithioate derivative of indole-2-ketone | |
| WO2019206155A1 (en) | Ezh2 inhibitor and pharmaceutically acceptable salts and polymorphic substances thereof, and application of ezh2 inhibitor | |
| CN103992289B (en) | Substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof | |
| WO2021146903A1 (en) | Crystal form of nitrogen-containing compound | |
| TWI777380B (en) | Crystalline form of 2-indolinolinololylspironone compounds | |
| CN111848677B (en) | Crystal form of ALK kinase inhibitor compound, preparation method and application | |
| CN108864053B (en) | Tubulin inhibitor and application thereof in antitumor drugs |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190101 |
|
| WD01 | Invention patent application deemed withdrawn after publication |