WO2006117616A1 - Polymorphic form i of lumefantrine and processes for its preparation - Google Patents
Polymorphic form i of lumefantrine and processes for its preparation Download PDFInfo
- Publication number
- WO2006117616A1 WO2006117616A1 PCT/IB2006/001037 IB2006001037W WO2006117616A1 WO 2006117616 A1 WO2006117616 A1 WO 2006117616A1 IB 2006001037 W IB2006001037 W IB 2006001037W WO 2006117616 A1 WO2006117616 A1 WO 2006117616A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lumefantrine
- polymorphic form
- pure
- solvents
- solution
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the solution may be seeded with crystals of Form I resulting in the precipitation of the Form I of lumefantrine and removing the solvent there from by filtration, filtration under vacuum, decantation or centrifugation.
- the product obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer.
Abstract
The invention relates to a novel polymorphic form of lumefantrine and processes for its preparation. More particularly, it relates to the preparation of polymorphic form of lumefantrine designated as Form I. The invention also relates to pharmaceutical compositions that include the polymorphic Form I and use of said compositions for treatment of malaria.
Description
POLYMORPHIC FORM I OF LUMEFANTRINE AND PROCESSES FOR ITS
PREPARATION
Field of the Invention The field of the invention relates to a novel polymorphic form of lumefantrine and processes for its preparation. More particularly, it relates to the preparation of polymorphic form of lumefantrine designated as Form I. The invention also relates to pharmaceutical compositions that include the polymorphic Form I and use of said compositions for treatment of malaria. Background of the Invention
Lumefantrine is chemically, (Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene]- ce-[(dibutylamino)methyl]]-9H-fluorene-4-methanol having the structural Formula I.
FORMULA I Lumefantrine belongs to the class of antimalarial agents and is reported to be originally synthesized in the 1970's by the Academy of Military Medical Sciences, China. Artemether + Lumefantrine, a fixed dose combination of two active ingredients, artemether, a sesquiterpene lactone derivative of a naturally occurring substance, artemisinin, and lumefantrine, a synthetic racemic fluorene derivative, is indicated in artemisinin-based combination therapy (ACT) used to treat malaria including the stand by-emerging treatment of adults and children with infections due
to Plasmodium falciparum or mixed infections including Plasmodium falciparum -the deadliest form of the disease. The combination has gametocytocidal action.
Plasmodium falciparum and Plasmodium virax are the two dominant species with relative frequency of 60% and 40%, respectively. However, this proportion varies from place to place and from season to season. In malaria epidemic situations, Plasmodium falciparum is the dominant parasite species and almost all malaria deaths happen due to infections by this species. Moreover, the biological diversity of Plasmodium falciparum, its ability to develop resistance to a number of anti-malarial drugs has been a major challenge in malaria chemotherapy. Chinese Patent No. CN 1029680C discloses a five-step process for the preparation of lumefantrine, which is obtained as yellow crystals. However, the lumefantrine is not obtained in pure form.
Summary of the Invention The present inventors have found a new polymorphic form of lumefantrine and have developed a process for preparation of the polymorphic form. The new polymorphic form of lumefantrine is designated as Form I of lumefantrine.
In one general aspect there is provided a polymorphic Form I of lumefantrine.
The Form I of lumefantrine may have the X-ray diffraction pattern of Figure 1, differential scanning calorimetry thermogram of Figure 2, and infrared spectrum of Figure 3.
In one general aspect there is provided a process for the preparation of Form I of lumefantrine. The process includes obtaining a solution of lumefantrine in one or more organic solvents; cooling the solution to 25°C or less; and isolating the polymorphic Form I of lumefantrine by the removal of the solvents.
Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.
The process may include further drying the product obtained.
In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the polymorphic Form I of lumefantrine; and one or more pharmaceutically acceptable carriers, excipients or diluents. The present inventors have noticed that lumefantrine when prepared as per the process reported in the prior art is not pure and has a purity of about 90% or less. The present inventors have now developed a process to get lumefantrine in pure form which is suitable for making dosage forms.
In another general aspect there is provided a pure lumefantrine. In another general aspect there is provided a process for preparing pure lumefantrine. The process includes treating 2-(dibutylamino)-l-(2,7-dichloro-9H- fluoren-4-yl)ethanol with p- chlorobenzaldehyde in the presence of a base and one or more organic solvents; cooling reaction mixture of to 100C or less; isolating lumefantrine from the reaction mass; obtaining a solution of lumefantrine so obtained in one or more organic solvents; cooling the solution to 25°C or less; and isolating the pure lumefantrine by the removal of the solvents.
The process may produce the pure lumefantrine having purity more than 95%. In particular, it may produce the pure lumefantrine having purity more than 98%, for example more than 99%. In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the pure lumefantrine; and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another general aspect there is provided a method of treating or preventing malaria in a warm blooded animal, the method comprising providing a dosage form to the warm blooded animal that includes pure lumefantrine.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Description of the Drawings
Figure 1 is an X-ray powder diffraction pattern of polymorphic Form I of lumefantrine.
Figure 2 is a differential scanning calorimetric (DSC) thermogram of polymorphic Form I of lumefantrine.
Figure 3 is a Fourier Transform Infrared (FTIR) spectrum of polymorphic Form I of lumefantrine.
Detailed Description of the Invention The inventors have developed a process for the preparation of a new polymorphic form of lumefantrine. More particularly, the inventors have developed a process for the preparation of a polymorphic Form I of lumefantrine.
The term "Form I" of lumefantrine refers to a polymorph of lumefantrine having X-ray diffraction pattern as depicted in Figure 1. A first aspect of the invention provides a process for the preparation of polymorphic Form I of lumefantrine wherein the process includes the steps of: a) obtaining a solution of lumefantrine in one or more organic solvents: b) cooling the solution to 250C or less; and c) isolating the polymorphic Form I of lumefantrine by the removal of the solvents.
The inventors also have developed pharmaceutical compositions that contain the polymorphic Form I of lumefantrine in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.
In general, the solution of lumefantrine may be obtained by dissolving lumefantrine in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction in which lumefantrine is formed. The solvent containing lumefantrine may be heated to obtain a solution. It may be heated from about 300C to about reflux temperature of the solvent used, for example from about 500C to about
1000C. It may be heated from about 10 minutes to about 24 hours. More particularly, it may be heated for about 1-2 hours.
The lumefantrine which is used as the starting material can be prepared by any of the known processes, for example, process as disclosed in CN 1029680C. The term "obtaining" includes dissolving, slurrying, stirring or a combination thereof.
The term "suitable solvents" includes any solvent or solvent mixture in which lumefantrine can be solubilized, including, for example, alkanols, ketones, nitriles, chlorinated hydrocarbons, polar aprotic solvents, esters, ethers, or mixtures thereof. The alkanol may include one or more of methanol, ethanol, n-propanol, isopropanol andbutanol. The ketone may include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, and diisobutyl ketone.
Examples of nitrile include acetonitrile. A suitable chlorinated hydrocarbon includes one or more of chloroform, dichloromethane, and 1,2-dichloroethane. Examples of polar aprotic solvents include solvents such as dimethylsulfoxide and dimethylformamide. Examples of esters include solvents such as methyl acetate, ethyl acetate, and isopropyl acetate. Examples of ethers include solvents such as dioxane and tetrahydrofuran. Mixtures of all of these solvents are also contemplated.
In general, the solution may be cooled to obtain Form I of lumefantrine. It may be cooled to about room temperature or less, for example from about 250C to about -1O0C.
In one aspect, the solution may be seeded with crystals of Form I resulting in the precipitation of the Form I of lumefantrine and removing the solvent there from by filtration, filtration under vacuum, decantation or centrifugation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer.
In general, the polymorphic Form I of lumefantrine may be characterized by X-ray diffraction peaks at about 5.50, 10.76, 11.06, 13.50, 14.30, 14.90, 15.42, 16.98, 18.00, 18.50, 19.12, 19.78, 20.08, 20.90, 21.54, 21.92, 22.98, 23.70, 24.20, 25.32,
26.48, 26.98, 27.50, 28.16, 28.54, 28.98, 30.14, 31.48, 31.96, 32.10, 32.74, 34.52, 36.92, 38.02 ± 0.2 degrees two-theta values.
The polymorphic Form I of lumefantrine may also be characterized by Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure II having characteristic endothermic absorption between 12O0C and 13O0C.
The inventors also have developed a process for the preparation of pure lumefantrine. A second aspect of the present invention provides highly pure lumefantrine, wherein the purity is 95% or more by HPLC. More preferably highly pure lumefantrine refers to lumefantrine having purity of 98% or more by HPLC. Another aspect of the invention provides a process for the preparation of pure lumefantrine wherein the said process comprises of, a) treating 2-(dibutylamino)-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol with p- chlorobenzaldehyde in the presence of a base and one or more organic solvents; b) cooling reaction mixture of step a) to 100C or less; c) isolating lumefantrine from the reaction mass; d) obtaining a solution of lumefantrine obtained in step c) in one or more organic solvents; e) cooling the solution to 250C or less; and f) isolating the pure lumefantrine by the removal of the solvents.
The solvent may be, for example, one or more of alkanols, ketones, nitriles, chlorinated hydrocarbons, polar aprotic solvents, esters, ethers, or mixtures thereof.
Examples of base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide and potassium t-butoxide, and the like. The reaction mixture of step b) may be cooled from about 50C to about 1O0C.
The resulting pure lumefantrine may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the
medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
The pure lumefantrine has a purity of more than 95% as determined by HPLC. More particularly, the purity of lumefantrine is more than 98%, for example more than 99%.
The pure lumefantrine can be admim'stered for the prevention and treatment of malaria in a warm-blooded animal.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 : Preparation of polymorphic Form I of lumefantrine a) Preparation of lumefantrine
To a mixture of ethanol (600 ml) and 2-(dibutylamino)-l-(2,7-dichloro-9H- fluoren-4-yl)ethanol (40 g), was added sodium hydroxide (4.74 g) at room temperature. This mixture was stirred for 0.5 hours and p-chlorobenzaldehyde (15.96 g) was added at room temperature followed by further stirring for 60 hours. The reaction mixture was cooled to 5 to 100C and filtered. The solid so obtained was washed with water (500 ml) and dried first at room temperature and then at 45 to 500C to obtain crude lumefantrine.
Yield = 31 g b) Preparation of pure polymorphic Form I of lumefantrine
Crude lumefantrine (30 g) was taken in ethanol (360 ml) and heated to 65- 700C for 30 minutes. The solution was allowed to cool to 25°C and stirred for 2 hours. The product so obtained was filtered, washed with ethanol (15 ml) and dried under vacuum at 45 to 5O0C for 6 hours to get pure polymorphic Form I of lumefantrine.
Yield = 18 g
Purity = 99.15% (by HPLC)
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. For example, the compounds described herein can be formulated into dosage forms that are suitable for administering to patients in need of the compound for treating a medical condition for which the compound is indicated, approved, or otherwise beneficial. Specifically, the Form I of lumefantrine can be formulated with one or more pharmaceutically acceptable excipients and/or with one or more active ingredients into a dosage form and administered to treat malaria.
Claims
WE CLAIM: 1. A polymorphic Form I of lumefantrine.
2. A polymorphic Form I of lumefantrine having characteristic X-ray diffraction peaks at 2-theta values of about 5.50, 10.76, 11.06, 13.50, 14.30, 14.90, 15.42, 16.98, 18.00, 18.50, 19.12, 19.78, 20.08, 20.90, 21.54, 21.92, 22.98, 23.70, 24.20, 25.32, 26.48, 26.98, 27.50, 28.16, 28.54, 28.98, 30.14, 31.48, 31.96, 32.10, 32.74, 34.52, 36.92, and 38.02.
3. The polymorphic Form I of lumefantrine of claim 2 having differential scanning calorimetric thermogram of Figure 2.
4. The polymorphic Form I of lumefantrine of claim 2 having differential scanning calorimetric melting exotherms at about 120-13O0C.
5. Lumefantrine having a purity of more than 95% by HPLC .
6. The lumefantrine of claim 5 having a purity of more than 98% by HPLC.
7. The pure lumefantrine of claim 6, wherein the lumefantrine has the X-ray diffraction pattern of Figure 1.
8. A process for the preparation of polymorphic form I of lumefantrine, the process comprising: a) obtaining a solution of lumefantrine in one or more organic solvents: b) cooling the solution to 250C or less; and c) isolating the polymorphic Form I of lumefantrine by the removal of the solvents.
9. The process of claim 8, wherein the organic solvent comprises one or more of alkanols, ketones, nitriles, chlorinated hydrocarbons, polar aprotic solvents, esters, ethers, or mixtures thereof.
10. The process of claim 9, wherein the alkanol comprises one or more of methanol, ethanol, n-propanol, isopropanol, butanol and isobutanol.
11. The process of claim 8, wherein removing the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.
12. The process of claim 8, further comprising additional drying of the product obtained.
13. The process of claim 8, wherein the polymorphic Form I of lumefantrine has the X-ray diffraction pattern of Figure 1.
14. A process for preparation of pure lumefantrine, the process comprising: a) treating 2-(dibutylamino)-l-(2,7-dichloro-9H-fluoren-4-yl)ethanol with p- chlorobenzaldehyde in the presence of a base and one or more organic solvents; b) cooling reaction mixture to 1O0C or less; c) isolating lumefantrine from the reaction mass; d) obtaining a solution of lumefantrine in one or more organic solvents; e) cooling the solution to 250C or less; and f) isolating the pure lumefantrine by the removal of the solvents.
15. The process of claim 14, wherein the organic solvent comprises one or more of alkanols, ketones, nitriles, chlorinated hydrocarbons, polar aprotic solvents, esters, ethers, or mixtures thereof.
16. The process of claim 15, wherein the the alkanol comprises one or more of methanol, ethanol, n-propanol, isopropanol, butanol and isobutanol.
17. A pharmaceutical composition comprising a therapeutically effective amount of pure lumefantrine having a purity of 95% or more by ΗPLC, and one or more pharmaceutically acceptable carriers, excipients or diluents.
18. A pharmaceutical composition comprising a therapeutically effective amount of Form I of lumefantrine, and one or more pharmaceutically acceptable carriers, excipients or diluents.
19. A method oftreating or preventing malaria in a warm blooded animal, the method comprising providing a dosage form to the warm blooded animal that includes pure lumefantrine having a purity of 95% or more by HPLC.
20. A method of treating or preventing malaria in a warm blooded animal, the method comprising providing a dosage form to the warm blooded animal that includes polymorphic Form I of lumefantrine.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1097/DEL/2005 | 2005-05-03 | ||
IN1097DE2005 | 2005-05-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006117616A1 true WO2006117616A1 (en) | 2006-11-09 |
Family
ID=36637486
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2006/001037 WO2006117616A1 (en) | 2005-05-03 | 2006-04-27 | Polymorphic form i of lumefantrine and processes for its preparation |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2006117616A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011099018A1 (en) * | 2010-02-15 | 2011-08-18 | Hetero Research Foundation | Polymorphs of bortezomib |
CN113149947A (en) * | 2021-04-16 | 2021-07-23 | 天津大学 | Michellac dimethylamine lactone-p-hydroxybenzoate as well as preparation method and application thereof |
CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1042535C (en) * | 1993-02-05 | 1999-03-17 | 伊莱利利公司 | Improved process for isolation of cefaclor after enzymatic acylation |
-
2006
- 2006-04-27 WO PCT/IB2006/001037 patent/WO2006117616A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1042535C (en) * | 1993-02-05 | 1999-03-17 | 伊莱利利公司 | Improved process for isolation of cefaclor after enzymatic acylation |
Non-Patent Citations (4)
Title |
---|
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; DENG, RONGXIAN ET AL: "Improved synthesis of antimalarial fluorenemethanol derivative", XP002390180, retrieved from STN Database accession no. 1991:6046 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; DENG, RONGXIAN ET AL: "Synthesis of antimalarial drug benflumetol", XP002390179, retrieved from STN Database accession no. 2000:90938 * |
DENG R X, ET AL: "THE STRUCTURE OF LUMEFANTRINE (BENFLUMETOL)", XP002390176, Retrieved from the Internet <URL:http://www.malariaandhealth.com/professional/poster/scientificposter.htm> [retrieved on 20060713] * |
YAOXUE XUEBAO , 35(1), 22-25 CODEN: YHHPAL; ISSN: 0513-4870, 2000 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011099018A1 (en) * | 2010-02-15 | 2011-08-18 | Hetero Research Foundation | Polymorphs of bortezomib |
CN113149947A (en) * | 2021-04-16 | 2021-07-23 | 天津大学 | Michellac dimethylamine lactone-p-hydroxybenzoate as well as preparation method and application thereof |
CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2017167180A1 (en) | Vortioxetine pamoic acid salt and crystal form thereof | |
JP2005538096A (en) | Antiviral 7-deaza D-nucleosides and methods of use thereof | |
US20080234323A1 (en) | Amorphous and Three Crystalline Forms of Rimonabant Hydrochloride | |
CN110776481B (en) | Biscationic compound, preparation method and application thereof | |
KR20170061615A (en) | New salt of fimasartan | |
KR20170061616A (en) | New salt of fimasartan | |
CN107540710B (en) | Liver delivery antiviral prodrug nucleoside cyclic phosphate ester compound and application thereof | |
KR102502749B1 (en) | Liver Delivery Entecavir Prodrug Nucleotide Cyclophosphate Compounds and Applications | |
EP1966167B1 (en) | Diaryltriazolmethylamine derivatives, preparation and therapeutic use thereof | |
WO2006117616A1 (en) | Polymorphic form i of lumefantrine and processes for its preparation | |
CN103058972A (en) | Phenyl C-glucoside derivatives containing cyclohexane structure as well as preparation method and application thereof | |
JP7222909B2 (en) | Crystal Forms of (S)-Afoxolaner | |
AU2007315833A1 (en) | A salt of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one | |
AU2017329753B2 (en) | Crystalline polymorphic form of 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2lambda5-(1,2)oxaphosphinane | |
CN109956986A (en) | Liver delivers gemcitabine pro-drug nucleosides cyclic phosphate compound and application | |
KR20040051485A (en) | Optically active bicyclol, preparation thereof and composition containing the same and the use | |
KR101743783B1 (en) | Novel compounds | |
JP6908657B2 (en) | Polymorphs of 4- [2-dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenyl4-methylbenzoate hydrochloride, methods of making them and their use | |
CN115160227A (en) | Heterozygote of R-or S-2- (1-acetoxy-n-pentyl) benzoic acid and 4-fluoro-edaravone, and preparation and application thereof | |
JP7266676B2 (en) | Potassium salt monohydrate of thienopyridone derivative and its preparation | |
CN107540677B (en) | Sitagliptin derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
CN113072564A (en) | Heteroaromatic ring compound and application thereof | |
WO2005030698A1 (en) | Process for the preparation of voglibose | |
CA3034535C (en) | Novel salt of (r)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and a crystal form thereof | |
KR102239776B1 (en) | Novel salt of (r)-(1-methylpyrrolidin -3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and crystalline forms thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: DE |
|
NENP | Non-entry into the national phase |
Ref country code: RU |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: RU |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 06744581 Country of ref document: EP Kind code of ref document: A1 |