CN112107583A - Composition of crystal form A compound of chroman-6-sulfonamide ROR gamma regulator and preparation method and application thereof - Google Patents
Composition of crystal form A compound of chroman-6-sulfonamide ROR gamma regulator and preparation method and application thereof Download PDFInfo
- Publication number
- CN112107583A CN112107583A CN202010755023.9A CN202010755023A CN112107583A CN 112107583 A CN112107583 A CN 112107583A CN 202010755023 A CN202010755023 A CN 202010755023A CN 112107583 A CN112107583 A CN 112107583A
- Authority
- CN
- China
- Prior art keywords
- compound
- chroman
- sulfonamide
- ror
- crystal form
- 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
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a composition of a crystal form A compound of chroman-6-sulfonamide ROR gamma regulator, a preparation method and an application thereof, wherein the particle size distribution of the crystal form A compound is as follows: dv (10): 5-7 um; dv (50): 7-14 um; dv (90): 21-33 um; the 2 theta values of characteristic peaks in an X-ray powder diffraction spectrogram are 3.46, 7.02, 10.97, 15.20, 19.35 and 22.89, and the error of the 2 theta diffraction angle is 0.2; DSC endotherms at 159 + -2 ℃ and 254 + -2 ℃; TG had almost no significant weight loss before 200 ℃ and started to gasify and lose weight rapidly after 250 ℃. The A crystal form compound prepared by the invention has simple and repeatable process and is easy for industrial amplification production. The A crystal form compound preparation prepared by the invention can reach the dissolution rate of more than 80% within 15 minutes, and has good solubility; the stability is also very good in high-temperature, illumination and high-humidity stability experiments accelerated for 10 days. As a candidate compound for preclinical development, the crystal form has wide development prospect.
Description
Technical Field
The invention relates to a compound composition, a preparation method and application thereof; in particular to a composition of a crystal form A compound of a chroman-6-sulfonamide ROR gamma regulator and a preparation method and application thereof.
Background
Retinoic acid receptor-Related Orphan Receptors (RORs) are ligand-dependent transcription factors and play an important role in a series of physiological and pathological processes such as reproductive development, circadian rhythm regulation, metabolic disorders, inflammation generation, and immune system regulation. RORs are members of the nuclear receptor superfamily, including ROR α, ROR β, ROR γ. ROR α is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood, and is involved in the pathophysiological processes such as hepatic gluconeogenesis, lipid metabolism, and atherosclerosis. ROR β is distributed primarily in the central nervous system, including the brain, retina and pineal gland, and is primarily involved in the processing of sensitive information by the spinal cord, thalamus, and cerebellar cortex. ROR γ is highly expressed in thymus, and is also distributed in kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas, and is associated with autoimmune diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
ROR γ T has been reported as a key regulator of Th17 cell differentiation, and it has recently been found that Th17 cells are a subset of T helper cells that preferentially produce cytokines IL-17A, IL-17F, IL-21 and IL-22. ROR γ T induces transcription of genes encoding IL-17A and IL-17F in primary CD4+ T helper cells. ROR γ t deficient mice show very few Th17 cells. The inhibition and deletion of ROR gamma t can improve EAE
Patent CN108218845A reports a class of compounds represented by formula I, which have utility in treating ROR γ -mediated inflammatory, metabolic and autoimmune diseases.
Wherein, the compound N-isobutyl-N- (2-methyl-6-morpholine pyridine-3-yl) -4-ketone-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide has better ROR gamma t enzyme inhibition activity (IC)50About 50nM) and the drug compatibility, and is suitable for the development of systematic salt form and crystal form screening. The present study is mainlyThe particle size of crystalline form (a) N-isobutyl-N- (2-methyl-6-morpholinopyridin-3-yl) -4-one-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide, compositions containing the compound and uses of the compositions are reported.
Disclosure of Invention
The purpose of the invention is as follows: for the first purpose: the compound shown as the formula I and the composition thereof are used as a better ROR gamma t enzyme inhibitor, are suitable for carrying out systematic salt form and crystal form screening and better drug forming property;
for the second purpose: a process for preparing the compound composition;
for the third purpose: the application of the compound composition.
The technical scheme is as follows: the present application provides a composition of chroman-6-sulfonamide ROR γ modulator as crystalline form a compound characterized by: use of
Radiation with characteristic peaks in X-ray powder diffraction spectrum of 3.46, 7.02, 10.97, 15.20, 19.35 and 22.89 in 2 theta value; the error of the 2 theta diffraction angle is 0.2, and the structural formula is shown as a formula I.
Wherein the endothermic transition of the above compound in DSC is 159 + -2 deg.C and 254 + -2 deg.C.
Further, the composition further comprises mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate.
Preferably, the composition comprises the following components in parts by weight: 12-13 parts of crystal form A compound, 50-60 parts of mannitol, 40-50 parts of microcrystalline cellulose, 1-2 parts of hydroxypropyl methyl cellulose, 5-8 parts of low-substituted hydroxypropyl cellulose and 1-2 parts of magnesium stearate.
The invention also provides a preparation method of the crystal form A of the chroman-6-sulfonamide ROR gamma regulator, which comprises the following steps:
(1) dissolving N-isobutyl-N- (2-methyl-6-morpholinopyridin-3-yl) -4-one-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide in ethyl acetate;
(2) cooling the solution of step (1) to obtain a precipitate;
(3) washing, separating and drying the precipitate obtained in the step (2) to obtain the crystal form A of the chroman-6-sulfonamide ROR gamma regulator.
And (3) cooling in the step (2) is stirring cooling, and stirring time is 1-1.5 hours.
Further, the cooling of the step (2) is carried out until the temperature is room temperature.
Preferably, the washing of step (3) is washing with ethyl acetate; the drying is carried out for 10 to 12 hours at the temperature of 35 to 40 ℃.
Preferably, the amount of ethyl acetate extracted in step (1) is about 1: 50;
preferably, the stirring and dissolving temperature mentioned in the step (1) is reflux;
preferably, the temperature of the step (2) is reduced to room temperature;
preferably, the micronization conditions in step (3) are: the air source pressure is 8.0-9.0 bar; feeding pressure: 7.0 to 7.5 bar; crushing pressure: 6.5 to 7.0 bar; pulverizing for 25 min. Particle size distribution Dv (10): 2-4 um; dv (50): 6-13 um; dv (90): 20-32 um;
further, the concentration of the hydroxypropyl cellulose aqueous solution in the step (4) is 1.5 percent;
further, in the step (5), the rotation speed of the mixer is 10 rpm, and the mixing time is 20 minutes.
The invention discloses a crystal form A compound with higher purity obtained by recrystallization, and a tablet form of the medicine is obtained by a preparation method.
The invention also provides application of the composition of the crystal form A compound of the chroman-6-sulfonamide ROR gamma regulator in preparing medicines for treating inflammatory, metabolic and autoimmune diseases mediated by ROR gamma.
Preferably, the disease is psoriasis.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the A crystal form provided by the invention has no report; the method for preparing the crystal form A has the advantages of stable crystal form purity, simple operation, short production period and good repeatability, and is suitable for being used as an industrial production process;
(2) the invention can obtain a tablet form with good stability and high dissolution rate through a preparation process, and has good clinical development prospect when being used as an inhibitor of ROR gamma t.
Drawings
FIG. 1 is an XRD pattern for form A compound of N-isobutyl-N- (2-methyl-6-morpholin-pyridin-3-yl) -4-one-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide;
FIG. 2 is a DSC of compound of form A of N-isobutyl-N- (2-methyl-6-morpholin-pyridin-3-yl) -4-one-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide;
figure 3 is a TGA diagram of crystalline form a compound of N-isobutyl-N- (2-methyl-6-morpholinopyridin-3-yl) -4-one-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide.
Detailed Description
The invention is further illustrated by the following figures and examples.
Example 1
Form A: in a 100mL single neck flask, N-isobutyl-N- (2-methyl-6-morpholinopyridin-3-yl) -4-keto-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide (10.0g, 18.42mmol, 1eq), ethyl acetate (50mL) were added, dissolved under reflux with stirring, slowly cooled to room temperature, a white solid precipitated, filtered after stirring for 1H, the filter cake was washed with ethyl acetate (20mL 2 times), dried under vacuum (40 ℃) for 12 hours to give 8.50g of off-white solid with 85% yield, HPLC: 99.5 percent.
The particle size 1 is distributed in: dv (10): 5-7 um; dv (50): 7-14 um; dv (90): 21-33 um.
Example 2
Reference example 1 preparation of 100g of crystalline form a of N-isobutyl-N- (2-methyl-6-morpholinopyridin-3-yl) -4-one-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide compound crystalline form a (Dv (10): 5-7 um; Dv (50): 7-14 um; Dv (90): 21-33um) was micronized under micronization conditions: the air source pressure is 8.0-9.0 bar; feeding pressure: 7.0 to 7.5 bar; crushing pressure: 6.5 to 7.0 bar; pulverizing for 25 min.
Particle size 2 distribution Dv (10): 2-4 um; dv (50): 6-13 um; dv (90): 20-32 um.
DSC endotherms at 159 + -2 ℃ and 254 + -2 ℃ in FIG. 2;
TGA in figure 3 shows almost no significant weight loss before 200 ℃ and a rapid weight loss after 250 ℃.
Example 3
The preparation process comprises the following steps:
the N-isobutyl sulfamide is the abbreviation of N-isobutyl-N- (2-methyl-6-morpholinepropyl-3-yl) -4-ketone-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfamide.
1.5g of hydroxypropyl cellulose was dissolved in pure water to prepare a 1.5% hydroxypropyl cellulose aqueous solution.
12.8g of N-isobutyl sulfamide crystal form A compound, 58g of mannitol, 45g of microcrystalline cellulose and 6g of low-substituted hydroxypropyl cellulose are placed in a wet granulator, premixed for 10min, fully mixed, added with 1.5% of hydroxypropyl cellulose aqueous solution to prepare soft materials, granulated by 24 meshes, dried at 60 ℃, and dried particles are screened by a 20-mesh screen to complete the granules.
The granules obtained are mixed homogeneously with 1g of magnesium stearate at a mixer speed of 10 revolutions per minute for 20 minutes, tabletted and coated.
Example 4
Example 5
Preparation process the same as example 3.
Example 6
Example 7
Example 8
Dissolution study of the compound of form a of N-isobutylsulfonamide with different particle sizes in examples 3 and 4:
dissolution medium: pH4.5 acetate buffer was used as dissolution medium.
The method comprises the following steps: second method (slurry method) for determining dissolution and release of four 0931 according to Chinese pharmacopoeia 2015 year edition
Rotating speed: 50 revolutions per minute
Sampling points are as follows: when the filtrate is respectively passed through 5, 10, 15, 20 and 30, 10mL of the dissolution liquid is taken, filtered through a 0.8-micron filter membrane, and simultaneously added with the dissolution medium with the same amount and temperature. The results are shown in Table 1.
Example 9
Refer to the 9001 guidelines of stability tests of raw materials and preparations in the four pharmacopoeia 2015 edition. The sample is placed under the conditions of strong light (4500Lx +/-500 Lx), high humidity (RH 92.5%, 25 ℃) and high temperature (60 ℃), the sample is taken for 10 days, and appearance characters, weight increasing and losing, dissolution, related substances, genotoxic impurities and contents are detected according to a method.
The influencing factors experimental results are shown in table 2:
example 10
Experimental Material
1) Animal(s) production
BALB/c mice, spf grade, 18-22g females, Shanghai Jiesi laboratory animals GmbH, license number SCXK (Shanghai) 2013-.
2) Drugs and agents
Grinding the solid powder of the crystal form A compound of the N-isobutyl sulfamide into fine powder.
5% imiquimod cream, Hubeike department of Yi-drug industry GmbH, lot number: 160801
5% imiquimod cream, specification 3 g/count, Sichuan mingxin pharmaceutical industry, product batch number: 17020140
3) Instrument for measuring the position of a moving object
An electronic balance: manufactured by beijing sydolis instruments systems limited.
A centrifuge: manufactured by Shanghai medical instruments (group) Co., Ltd.
4) Method and results
Female BALB/c mice (inbred, 10 weeks old) were 100 in total and randomized into 5 groups of 20 mice each. After the experiment is started, the hair on the back of the mouse is shaved to form an exposed area with the size of about 2cm x 3cm, the test medicament is infused into the stomach every day for 3 days, the corresponding solvent (excipient) is applied to the model group and the negative group, the model is started on the 4 th day of administration, 62.5 mg/day of 5% imiquimod cream is continuously applied to the back skin of the mouse for 7 days to induce psoriasis, the vaseline with the same dosage is applied to the control group, the model is continuously applied every day while the administration is continued every day, the model is formed after the administration every day, and the interval between the administration and the model formation is 2 h. The animal is obtained on the 8 th day of molding, the eyeball is picked and blood is taken, the centrifugation is carried out at 3000r/min for 10min, and the upper serum is taken and stored in a kit to be tested in a low-temperature refrigerator at minus 80 ℃. Animals were sacrificed by cervical dislocation and dorsal skin was fixed in 10% formaldehyde solution for pathological examination. The serum inflammatory factor results are shown in table 3.
Table 3 effect of test compounds on serum IL-6 levels in imiquimod-induced psoriasis in mice (n ═ 6, x ± sd)
##p<0.01, compared to blank; p<0.01, compared to model set
As can be seen from Table 3, the IL-6 level in the serum of the mice was significantly increased (p <0.01) in the model group compared with the blank group, indicating that the modeling was successful, while the IL-6 level of the drug I was significantly decreased (p <0.01) compared with the model group, indicating that the drug can decrease the IL-6 level in the mice with psoriasis caused by imiquimod.
Claims (10)
1. A composition of a chroman-6-sulfonamide ROR γ modulator compound in crystal form a characterized by: the compounds, use
Radiation with characteristic peaks in X-ray powder diffraction spectrum of 3.46, 7.02, 10.97, 15.20, 19.35 and 22.89 in 2 theta value; the error of the 2 theta diffraction angle is 0.2, and the structural formula is shown as a formula I.
2. The composition of chroman-6-sulfonamide ROR γ modulator of crystalline form a compound of claim 1, characterized in that: the compounds have DSC endotherms at 159 + -2 ℃ and 254 + -2 ℃.
3. The composition of chroman-6-sulfonamide ROR γ modulator of crystalline form a compound of claim 1, characterized in that: also includes mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate.
4. A composition of chroman-6-sulfonamide ROR γ modulator crystalline form a compound of claim 1 characterized in that the composition comprises the following components in parts by weight: 12-13 parts of crystal form A compound, 50-60 parts of mannitol, 40-50 parts of microcrystalline cellulose, 1-2 parts of hydroxypropyl methyl cellulose, 5-8 parts of low-substituted hydroxypropyl cellulose and 1-2 parts of magnesium stearate.
5. A process for preparing a crystalline form a of chroman-6-sulfonamide ROR γ modulator of claim 1, characterized by the steps of:
(1) dissolving N-isobutyl-N- (2-methyl-6-morpholinopyridin-3-yl) -4-one-2- (tetrahydro-2H-pyran-4-yl) chroman-6-sulfonamide in ethyl acetate;
(2) cooling the solution of step (1) to obtain a precipitate;
(3) washing, separating and drying the precipitate obtained in the step (2) to obtain the crystal form A of the chroman-6-sulfonamide ROR gamma regulator.
6. The method of claim 5, wherein: and (3) stirring and cooling are adopted as cooling in the step (2), and stirring time is 1-1.5 hours.
7. The method of claim 5, wherein: and (3) cooling to room temperature in the step (2).
8. The method of claim 5, wherein: the washing of the step (3) is washing by using ethyl acetate; the drying is carried out for 10 to 12 hours at the temperature of 35 to 40 ℃.
9. Use of the chroman-6-sulfonamide ROR γ modulator crystalline form a compound composition of claims 1-4 in the preparation of a medicament for the treatment of rorγ mediated inflammatory, metabolic and autoimmune diseases.
10. Use of the composition of chroman-6-sulfonamide ROR γ modulator crystalline form a compounds for the manufacture of a medicament for the treatment of rory mediated inflammatory, metabolic and autoimmune diseases according to claims 1-4, characterized in that: the disease is psoriasis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010755023.9A CN112107583A (en) | 2020-07-31 | 2020-07-31 | Composition of crystal form A compound of chroman-6-sulfonamide ROR gamma regulator and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010755023.9A CN112107583A (en) | 2020-07-31 | 2020-07-31 | Composition of crystal form A compound of chroman-6-sulfonamide ROR gamma regulator and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112107583A true CN112107583A (en) | 2020-12-22 |
Family
ID=73799605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010755023.9A Pending CN112107583A (en) | 2020-07-31 | 2020-07-31 | Composition of crystal form A compound of chroman-6-sulfonamide ROR gamma regulator and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112107583A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999032475A1 (en) * | 1997-12-19 | 1999-07-01 | Bayer Corporation | Novel sulfonamide substituted chroman derivatives useful as beta-3 adrenoreceptor agonists |
| CN104721828A (en) * | 2013-12-23 | 2015-06-24 | 天津泰普药品科技发展有限公司 | Medicinal composition for improving stability of crystal medicines, and preparation method thereof |
| WO2016097394A1 (en) * | 2014-12-19 | 2016-06-23 | Galderma Research & Development | Bicyclic sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ror gamma (t)) |
| WO2018113201A1 (en) * | 2016-12-21 | 2018-06-28 | 南京柯菲平盛辉制药有限公司 | CHROMAN-6-SULFAMIDE RORγ REGULATOR AND USE THEREOF |
-
2020
- 2020-07-31 CN CN202010755023.9A patent/CN112107583A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999032475A1 (en) * | 1997-12-19 | 1999-07-01 | Bayer Corporation | Novel sulfonamide substituted chroman derivatives useful as beta-3 adrenoreceptor agonists |
| CN104721828A (en) * | 2013-12-23 | 2015-06-24 | 天津泰普药品科技发展有限公司 | Medicinal composition for improving stability of crystal medicines, and preparation method thereof |
| WO2016097394A1 (en) * | 2014-12-19 | 2016-06-23 | Galderma Research & Development | Bicyclic sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ror gamma (t)) |
| WO2018113201A1 (en) * | 2016-12-21 | 2018-06-28 | 南京柯菲平盛辉制药有限公司 | CHROMAN-6-SULFAMIDE RORγ REGULATOR AND USE THEREOF |
Non-Patent Citations (1)
| Title |
|---|
| 国家药典委员会: "《中国药典》", 30 April 2019, 中国医药科技出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4187423B2 (en) | Ziprasidone composition | |
| CN101267810A (en) | Capsule formulation of pirfenidone and pharmaceutically acceptable excipients | |
| CN105017060B (en) | A kind of FCE-26743A novel crystal forms and preparation method thereof | |
| JP2014141524A (en) | Five crystal forms of nicousamide compound and preparation method, pharmaceutical composition and usage thereof | |
| TWI747906B (en) | A new crystal form of dapagliflozin, its preparation method and use thereof | |
| CN102452951B (en) | Agomelatine and pharmaceutical composition thereof | |
| CN1931159B (en) | Superfine Iguratimod powder and quick released oral preparation | |
| JP2020528881A (en) | Phenolamine G-type crystal, its production method, its composition and use | |
| CN112107583A (en) | Composition of crystal form A compound of chroman-6-sulfonamide ROR gamma regulator and preparation method and application thereof | |
| DE60222643T2 (en) | CRYSTALLINE ISOXAZOLE DERIVATIVE AND MEDICAL PREPARATION THEREOF | |
| CN101993417A (en) | Stable novel crystal form of dimemorfan phosphate | |
| CN114644642A (en) | Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition thereof | |
| JP5809368B2 (en) | Crystalline polymorph β of levonorgestrel and method for producing the same | |
| CN111574396B (en) | Ubenimex acetate monocrystal and preparation method and application thereof | |
| CN114053282B (en) | Application of tormentic acid and anisodamine capsules in preparation of medicine for treating diabetes | |
| US20230406876A1 (en) | Arabinose and preparation and use thereof | |
| JP2020522472A (en) | Solid state form of PKC inhibitor | |
| CN115124419B (en) | Rhein and cytisine eutectic crystal, preparation method, composition and application thereof | |
| US20230212156A1 (en) | Method for producing nitrofurantoin anhydrate, and product thereof | |
| CN113214065B (en) | Gossypol crystal III substance, preparation method, composition and application thereof | |
| CN102304088A (en) | Ivabradine compound, preparation method and pharmaceutical composition thereof | |
| CN104356036A (en) | Alpha crystal form of racecadotril and preparation method of alpha crystal form | |
| ES2717254T3 (en) | Solid state forms of sofosbuvir | |
| CN105287409A (en) | Medicinal meclofenoxate hydrochloride composition freeze-dried powder injection for treating senile dementia | |
| CN106478616A (en) | A kind of crystal form of GPR40 agonist and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20201222 |
|
| RJ01 | Rejection of invention patent application after publication |