WO2015092638A1 - N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidone polymorphic forms - Google Patents
N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidone polymorphic forms Download PDFInfo
- Publication number
- WO2015092638A1 WO2015092638A1 PCT/IB2014/066849 IB2014066849W WO2015092638A1 WO 2015092638 A1 WO2015092638 A1 WO 2015092638A1 IB 2014066849 W IB2014066849 W IB 2014066849W WO 2015092638 A1 WO2015092638 A1 WO 2015092638A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbamoylmethyl
- pyrrolidone
- phenyl
- crystalline form
- polymorph
- 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.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Definitions
- Dissolution rate of the Polymorph II is better than that of Polymorph I. This property may positively influence bioavailability of the active ingredient of the dosage form upon dissolution in organism.
- Polymorphs obtained by methods according to this invention are suitable for preparation of pharmaceutical compositions.
- Pharmaceutical composition, comprising N- carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone polymorph and at least one pharmaceutically acceptable excipient is suitable for use as psychometabolic stimulator.
- N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone (40 g) was dissolved in isopanol (140 ml) at reflux temperature. Then the solution was slowly cooled down to 50-55 °C and N- carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone polymorph II crystal seeds (0.5 g) were added. The obtained suspension was slowly cooled down to 45-49 °C and kept at this temperature for 30 min. Then the suspension was slowly cooled down to 1 -5 °C and kept at this temperature for 5 h. Then the precipitated crystals were filtered off and washed on filter with isopropanol (40 ml) and then dried at 45-50 °C for 8 h. Yield 35.9-37.5 g (90-94%).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention is related to N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidone crystalline polymorphic forms and their production methods, as well as to the use of said polymorphic forms for pharmaceutical compositions manufacturing.
Description
N-CARBAMOYLMETHYL-4(i?)-PHENYL-2-PYRROLIDONE POLYMORPHIC FORMS
Field of invention
Current invention is related to the pharmaceutical industrial product N-carbamoylmethyl-4(i?)- phenyl-2-pyrrolidone crystalline polymorphic forms and their production methods. Current invention is related also to the use of said polymorphic forms for preparation of pharmaceutical compositions.
Background of invention
N-carbamoylmethyl-4(i?,<S -phenyl-2-pyrrolidone (Carphedon, Phenotropil, Phenylpiracetam, Noophen) is well known and is widely used as a psychometabolic stimulator (J. Med. Chem, 1984; Pharm. Chem. Journal, 1980, 14, 11, 776). It has been recently shown that N- carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone is a pharmacologically active isomer of the racemic N-carbamoylmethyl-4(i?,,S)-phenyl-2-pyrrolidone (EP2013166, WO2007104780, US2010022784, etc.).
During the process of a pharmaceutical product manufacturing it is very important to keep control over the active substance crystalline form. Solid crystalline substances may exist in various crystalline forms. Crystals of different forms are called polymorphs. Different polymorphs may have distinct chemical and physical properties, such as solubility, melting point, dissolution rate, stability, etc. These properties may directly influence the possibility of obtaining the active substance and pharmaceutical product, as well as stability and bioavailability of the product. Therefore polymorphism may influence the medicament quality, safety and efficiency.
Methods are known in the art, which may be used to characterize the active substance polymorphism. Polymorphism is proved by demonstration of the structures non-equivalence using single crystal X-ray structural analysis. To detect polymorphism, X-ray powder diffraction method may also be used. Various analytical methods may be used to characterize polymorphic forms, including microscopy, thermal analyses (DSC, TGA), and spectroscopic analysis (IR, Raman, solid state NMR).
The synthesis of N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone was first described in WO2007104780 but polymorphism of the obtained product has not been studied.
Description of invention
During the study of different crystallization methods of N-carbamoylmethyl-4(i?)-phenyl-2- pyrrolidone we have unexpectedly discovered, that in different conditions or using different solvents, non-identical substances are obtained. IR spectra used for proof of identity were also different in this case. Recrystallizing N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone from toluene, a stable crystalline form was obtained, named Polymorph I. Polymorph I may be characterized with various analytical methods, including X-ray powder diffraction (XRPD) pattern, differential scanning calorimetry (DSC) and infrared spectroscopy (IR) methods. The characteristic XRPD pattern of Polymorph I is shown in Fig. 1. Diffraction pattern peaks distribution and those relative intensity for Polymorph I are summarized in Table 1.
Polymorph I Polymorph II
2Θ Relative 2Θ Relative
intensity, % intensity, %
7.298 1.3 5.185 0.5
10.548 0.3 7.603 0.2
12.973 16.9 8.408 100.0
13.631 0.8 8.877 51.3
14.757 4.6 10.399 3.2
15.187 21.3 11.891 0.4
15.217 24.0 14.472 1.2
15.683 7.2 14.823 4.5
16.947 36.7 14.994 5.4
18.228 11.1 15.724 10.3
18.862 19.3 16.110 17.6
19.795 14.9 16.641 21.4
20.080 4.9 16.909 77.8
21.269 8.7 17.928 6.7
21.885 0.4 17.475 18.4
22.266 1.1 17.710 12.8
22.864 100.0 18.228 19.1
23.145 20.1 18.749 17.3
23.844 3.9 19.386 7.9
24.035 7.9 20.171 22.3
25.461 10.8 20.468 13.8
Polymorph I Polymorph II
2Θ Relative 2Θ Relative
intensity, % intensity, %
25.827 1.4 20.883 9.9
26.510 6.1 21.809 11.7
27.331 5.9 22.122 12.1
28.814 1.7 24.291 19.0
29.539 9.6 24.777 5.2
30.371 0.2 24.862 3.9
30.849 1.1 25.468 3.0
31.725 1.5 25.831 8.2
31.924 1.3 26.079 2.6
32.835 1.8 26.388 3.6
33.529 0.3 27.112 6.7
34.039 0.3 28.592 2.1
29.210 4.2
30.064 8.8
31.085 1.1
31.750 3.1
32.443 2.1
33.331 1.5
33.511 1.1
34.356 1.4
Peak 2Θ angles may differ by approx. ±0,2°. Characteristic DSC curve of the Polymorph I is shown in the Fig. 2 with characteristic peak at approx. 118 °C or 117±1°C. IR spectrum of the Polymorph I is shown in Fig. 3.
Recrystallizing N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone from isopropanol, pure Polymorph II was obtained. The characteristic XRPD pattern of Polymorph II is shown at Fig. 4. Diffraction pattern peaks distribution and those relative intensity for Polymorph I are summarized in Table 1. Peak 2Θ angles may differ by approx. ±0,2°. Characteristic DSC curve for the Polymorph II is shown at the Fig. 5. Thermogram shows an endothermic effect of melting of the form II with maximum at 111 °C where recrystallization into form I (high-temperature) proceeds, and the second endothermic effect with maximum at 118 °C characterizes melting of the form I. Said maximums may differ by approx. 1 °C. IR spectrum of the Polymorph II is shown at Fig. 6.
Recrystallizing N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone from isopropanol-water mixture at 60 °C, a mixture of Polymorphs I and II was obtained, but recrystallization from water at 60 °C gave pure Polymorph I. Polymorph II of N-carbamoylmethyl-4(i?)-phenyl-2- pyrrolidone was recrystallized from water, isopropanol, water-isopropanol mixture at 22 °C, and from isopropanol at -4 °C, as well it was suspended in these solvents and co-milled in the presence of these solvents without changes in the diffraction pattern.
If crystalline form contains impurity of another polymorph, it may lead to instability and conversion into another polymorph. Therefore it is very important to obtain crystalline forms with high degree of polymorphic purity to prevent such conversion. According to this invention, a method for obtaining pure Polymorphs I and II is provided. Obtaining a pure polymorphic form and characterization of its properties allows better control of the manufacturing process. Well-controlled and reproducible methods of synthesis of pure polymorphic forms are suitable for industrial use, as well as pure polymorphs may be used for improvement of properties of pharmaceutical compositions.
According to the current invention, a method of preparation of the pure N-carbamoylmethyl- 4(i?)-phenyl-2-pyrrolidone polymorphic form comprises dissolution of the said compound in a suitable solvent, optionally followed by seeding of desired polymorph crystals, followed by cooling of the solution and filtering off the product. Obtained crystals may be washed with suitable solvent if necessary. Depending on the solvent used and crystallization conditions, pure Polymorph I or II is obtained.
We have studied the dissolution rate of both polymorphic forms in phosphate buffer solution (Fig, 7, Table 2).
Table 2.
Time, Dissolution rate, %
min Polymorph II Polymorph I
0 0 0
1 67.2 24.7
3 69.7 33.1
5 70.9 45.0
7 74.3 53.0
9 77.4 62.2
11 78.2 68.3
Time, Dissolution rate, %
min Polymorph II Polymorph I
13 80.1 75.3
15 83.0 80.1
21 86.3 86.6
29 89.3 90.8
39 93.1 93.9
49 96.0 96.6
59 98.0 98.2
69 98.0 99.2
81 99.3 100.0
Dissolution rate of the Polymorph II is better than that of Polymorph I. This property may positively influence bioavailability of the active ingredient of the dosage form upon dissolution in organism. Polymorphs obtained by methods according to this invention are suitable for preparation of pharmaceutical compositions. Pharmaceutical composition, comprising N- carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone polymorph and at least one pharmaceutically acceptable excipient is suitable for use as psychometabolic stimulator.
The current invention is illustrated by the following non-limiting examples.
Instrumental methods
X-ray powder diffraction (XRPD)
X-ray powder diffraction patterns were recorded using Bruker D8 Advance instrument equipped with positional sensitive detector LynxEye. Recording mode: 3-35 0 2 Θ, speed 0.2 s/0.02 °. Samples were ground in agate pestle before analysis.
Differential scanning calorimetry (DSC)
Differential scanning calorimetry curves were recorded using differential scanning calorimeter Mettler TA 4000 according to the device manufacturer instructions. DSC curves were recorded in a temperature range from 50 °C to 150 °C with heating rate 5.0 °C/min in nitrogen atmosphere.
Infrared spectra (TR)
Infrared spectra were recorded with Nicolet IR200 spectrometer in the range of 4000-600 cm using test samples pressed into KBr pellets.
Examples
Example 1. Obtaining of N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone polymorph I.
N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone (40 g) was dissolved in toluene (560 ml) at 90- 95 °C. Then the solution was slowly cooled down to 75 °C and N-carbamoylmethyl-4(i?)- phenyl-2-pyrrolidone polymorph I crystal seeds (0.5 g) were added. The obtained suspension was slowly cooled down to 1-5 °C and kept at this temperature for 5 h. Then the precipitated crystals were filtered off and washed on filter with toluene (40 ml) and then dried at 45-50 °C for 8 h. Yield 36.7-37.6 g (92-94%).
Example 2. Obtaining of N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone polymorph II.
N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone (40 g) was dissolved in isopanol (140 ml) at reflux temperature. Then the solution was slowly cooled down to 50-55 °C and N- carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone polymorph II crystal seeds (0.5 g) were added. The obtained suspension was slowly cooled down to 45-49 °C and kept at this temperature for 30 min. Then the suspension was slowly cooled down to 1 -5 °C and kept at this temperature for 5 h. Then the precipitated crystals were filtered off and washed on filter with isopropanol (40 ml) and then dried at 45-50 °C for 8 h. Yield 35.9-37.5 g (90-94%).
Study of dissolution rate
Substance sample (5.0509 g) was placed into a 0.5 L calibrated flask and phosphate buffer solution was added upon stirring (50 rpm) to the flask marked point. Solution samples (15 ml) were taken at appropriate intervals and measured for light absorption (258 nm) in comparison with absorption of a standard sample at that wavelength (spectrophotometer Agilent 8453 No. CN22805904). The results were used to build dissolution curves.
Claims
1. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form I, characterized by an X-ray diffraction pattern having following characteristic peaks expressed in degrees 2Θ at 13.0±0.2; 15.2±0.2; 16.9±0.2; 22.9±0.2; 25.5±0.2; 29.5±0.2.
2. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form I according to claim 1, characterized by an X-ray diffraction pattern comprising following characteristic peaks expressed in degrees 2Θ at 13.0±0.2; 15.2±0.2; 16.9±0.2; 18.2±0.2; 18.9±0.2; 19.8±0.2; 21.3±0.2; 22.9±0.2; 24.0±0.2; 25.5±0.2; 26.5±0.2; 29.5±0.2.
3. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form I according to claim 1, having a DSC profile showing an endothermic peak with onset temperature of about 117.7 °C.
4. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form I according to claim 1, having an infrared spectrum comprising peaks at wavenumbers of 3366, 3200, 1674, 1628 and 1487 cm"1.
5. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form II, characterized by an X-ray diffraction pattern having following characteristic peaks expressed in degrees 2Θ at 8.4±0.2; 8.9±0.2; 16.9±0.2; 20.2±0.2; 24.3±0.2.
6. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form II according to claim 5, characterized by an X-ray diffraction pattern comprising following characteristic peaks expressed in degrees 2Θ at 8.4±0.2; 8.9±0.2; 10.4±0.2; 14.8±0.2; 15.0±0.2; 15.7±0.2; 16.6±0.2; 16.9±0.2; 17.5±0.2; 18.2±0.2; 20.2±0.2; 20.9±0.2; 21.8±0.2; 22.1±0.2; 24.3±0.2.
7. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form II according to claim 5, having a DSC profile showing endothermic peaks with onset temperature of about 109.8 °C and 117.2 °C.
8. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form II according to claim 5, having an infrared spectrum comprising peaks at wavenumbers of 3320, 3167, 1699, 1684, 1664 and 1484 cm"1.
9. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form according to any of the claims 1 to 8, wherein the content of the other N-carbamoylmethyl-4(i?)-phenyl-2- pyrrolidone crystalline form is less than 10%.
10. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidone crystalline form according to any of the claims 1 to 8 for use in a pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA201691191A EA029298B1 (en) | 2013-12-18 | 2014-12-12 | N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidone polymorphic forms |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVP-13-215A LV15016B (en) | 2013-12-18 | 2013-12-18 | Polymorphic forms of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone |
| LVP-13-215 | 2013-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2015092638A1 true WO2015092638A1 (en) | 2015-06-25 |
Family
ID=52462347
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2014/066849 Ceased WO2015092638A1 (en) | 2013-12-18 | 2014-12-12 | N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidone polymorphic forms |
Country Status (3)
| Country | Link |
|---|---|
| EA (1) | EA029298B1 (en) |
| LV (1) | LV15016B (en) |
| WO (1) | WO2015092638A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007104780A2 (en) | 2006-03-16 | 2007-09-20 | Akciju Sabiedriba 'olainfarm' | N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use |
-
2013
- 2013-12-18 LV LVP-13-215A patent/LV15016B/en unknown
-
2014
- 2014-12-12 WO PCT/IB2014/066849 patent/WO2015092638A1/en not_active Ceased
- 2014-12-12 EA EA201691191A patent/EA029298B1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007104780A2 (en) | 2006-03-16 | 2007-09-20 | Akciju Sabiedriba 'olainfarm' | N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use |
| EP2013166A2 (en) | 2006-03-16 | 2009-01-14 | Akciju Sabiedriba "Olainfarm" | N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use |
| US20100022784A1 (en) | 2006-03-16 | 2010-01-28 | Joint Stock Company "Olainfarm" | N-Carbamoylmethyl-4-(R)-Phenyl-2-Pyrrolidinone, Method of its Preparation and Pharmaceutical Use |
Non-Patent Citations (4)
| Title |
|---|
| "CRYSTALLINE FORM OF N-(CARBAMOYLMETHYL-4-PHENYL-2-PYRROLIDINONE AND INTERMEDIATES THEREOF", IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 17 November 2011 (2011-11-17), XP013148057, ISSN: 1533-0001 * |
| J. MED. CHEM, 1984 |
| M VORONA ET AL: "NOVEL METHODS FOR THE SYNTHESIS OF 2-[(4R)-2-OXO-4-PHENYLPYRROLIDIN-1-YL]- ACETAMIDE ((R)-PHENOTROPIL)", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, 1 January 2012 (2012-01-01), pages 720 - 723, XP055177579, Retrieved from the Internet <URL:http://rd.springer.com/content/pdf/10.1007/s10593-012-1050-y.pdf> [retrieved on 20150318] * |
| PHARM. CHEM. JOURNAL, vol. 14, no. 11, 1980, pages 776 |
Also Published As
| Publication number | Publication date |
|---|---|
| EA201691191A1 (en) | 2016-12-30 |
| EA029298B1 (en) | 2018-03-30 |
| LV15016B (en) | 2016-01-20 |
| LV15016A (en) | 2015-06-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI589575B (en) | Novel crystal form of benzimidazole derivative and preparation method thereof | |
| JP5058151B2 (en) | Crystalline form of asenapine maleate | |
| JP6554617B2 (en) | Novel crystal form of 1- (5- (2,4-difluorophenyl) -1-((3-fluorophenyl) sulfonyl) -4-methoxy-1H-pyrrol-3-yl) -N-methylmethanamine salt | |
| KR20080044841A (en) | Polymorphs of Imatinib Mesylate and Processes for Producing Novel and Amorphous and α-forms | |
| KR20150036336A (en) | Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof | |
| EP3337485B1 (en) | Crystalline forms of ibrutinib | |
| WO2012123325A1 (en) | NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID | |
| TWI646093B (en) | 1-((2R,4R)-2-(1H-benzo[D]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea Crystalline form | |
| US20090281315A1 (en) | Forms of lapatinib ditosylate and processes for preparation thereof | |
| US20160264565A1 (en) | Crystalline dasatinib process | |
| US20110230553A1 (en) | Crystallized form of dronedarone base | |
| CN114380833B (en) | Ketorolac and 4-pyridine carboxamide eutectic crystal and preparation method thereof | |
| KR20120098745A (en) | Crystalline forms of substituted pyrazolopyrimidines | |
| TW201840557A (en) | Crystalline form of (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)-methanol | |
| JP7152122B2 (en) | edaravone salt | |
| WO2015092638A1 (en) | N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidone polymorphic forms | |
| WO2012160568A1 (en) | Process for preparing docetaxel trihydrate polymorph | |
| KR20170032476A (en) | 6-aryl amino pyridone formamide compound crystal and preparation method therefor | |
| US9643950B2 (en) | Solid forms of {s-3-(4-amino-1-oxo-isoindolin-2-yl)(piperidine-3,4,4,5,5-d5)-2,6-dione} | |
| KR20090044694A (en) | Novel and analogous isomers of mosaprid | |
| JP6831496B2 (en) | Crystals of benzoxazole derivatives | |
| US20100113550A1 (en) | New Crystal Forms | |
| CN110300745B (en) | Sodium ion channel inhibitor, pharmaceutically acceptable salt and polymorph thereof and application thereof | |
| EP3088402A1 (en) | CRYSTALS (2) OF PYRAZINO[2,1-c][1,2,4]TRIAZINE COMPOUND | |
| EP3473623B1 (en) | Crystal forms of nbi-98854, preparation method therefor and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14835499 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| WWE | Wipo information: entry into national phase |
Ref document number: A201606171 Country of ref document: UA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 14196 Country of ref document: GE |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 201691191 Country of ref document: EA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2016/12855 Country of ref document: TR |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 14835499 Country of ref document: EP Kind code of ref document: A1 |
|
| ENP | Entry into the national phase |
Ref document number: 14524 Country of ref document: GE |