WO2015014089A1 - 替格瑞洛的一水合物及其制备方法与在制药中的应用 - Google Patents
替格瑞洛的一水合物及其制备方法与在制药中的应用 Download PDFInfo
- Publication number
- WO2015014089A1 WO2015014089A1 PCT/CN2014/000099 CN2014000099W WO2015014089A1 WO 2015014089 A1 WO2015014089 A1 WO 2015014089A1 CN 2014000099 W CN2014000099 W CN 2014000099W WO 2015014089 A1 WO2015014089 A1 WO 2015014089A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ticagrelor
- monohydrate
- preparation
- water
- solvent
- Prior art date
Links
- LXLCTRJKFYBHRD-VQNGXBDNSA-N (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylsulfanyltriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol hydrate Chemical compound O.C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 LXLCTRJKFYBHRD-VQNGXBDNSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000013078 crystal Substances 0.000 claims abstract description 53
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 claims abstract description 30
- 229960002528 ticagrelor Drugs 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000002425 crystallisation Methods 0.000 claims abstract description 11
- 230000008025 crystallization Effects 0.000 claims abstract description 11
- 239000012046 mixed solvent Substances 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- 150000004682 monohydrates Chemical class 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 150000002191 fatty alcohols Chemical class 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims 1
- 238000001228 spectrum Methods 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000002411 thermogravimetry Methods 0.000 abstract description 2
- 238000000113 differential scanning calorimetry Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
- -1 3, 4-difluorophenyl Chemical group 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 1
- 102100037600 P2Y purinoceptor 1 Human genes 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- OXKUGIFNIUUKAW-UHFFFAOYSA-N n,n-dimethylformamide;hydrazine Chemical compound NN.CN(C)C=O OXKUGIFNIUUKAW-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the invention relates to a medicament, in particular to a medicament hydrate and a preparation method thereof, in particular to a small molecule anticoagulant ticagrelor monohydrate, a preparation method thereof and application in pharmacy. Background technique
- Teguriello is a new, selective small molecule anticoagulant developed by AstraZeneca. This drug can reversibly act on the ⁇ 2 receptor subtype P2Y12 on vascular smooth muscle cells (VSMC).
- Tigril is not a prodrug and therefore does not require metabolic activation. It has platelet aggregation caused by adenosine diphosphate (ADP). It has obvious inhibitory effect and rapid onset after oral administration, which can effectively improve the symptoms of patients with acute coronary heart disease.
- ticagrelor is a reversible antagonist to the P2Y12 ADP receptor, so it is especially useful for patients who need surgery before anticoagulation. .
- AstraZeneca's patent W00192262 (hereinafter referred to as 262' patent) discloses four crystal forms of ticagrelor (Form I, Form II, Form III, Form IV) and amorphous state and preparation method thereof , these four crystal forms and amorphous are "waterless" state.
- solvates and hydrates are mentioned in this patent, the disclosure of this patent does not have any characterization data for the corresponding solvates and hydrates, and no embodiment can demonstrate that AstraZeneca's patent W00192262 does.
- One or more solvates and hydrates are disclosed.
- the crystal form I disclosed in the patent 262' patent needs to be obtained by a complicated temperature control method to add Form I was prepared in the form of a seed crystal, and water was used in a large amount in the solvent, but a hydrate could not be obtained.
- the preparation of Form II disclosed in the '262 patent requires the use of Class I toxic and harmful solvent chloroform, which is unfavorable for industrialization and environmental protection, and is difficult to industrialize;
- Preparation of Form III disclosed in the 262' patent is Form III is prepared by preparing mixed crystals of Forms II and III, and preparing crystals with mixed crystals.
- ACTIVAS patent W02013079589 discloses another crystal form of ticagrelor and a preparation method thereof.
- the preparation method is complicated, the operation procedure is complicated, the conditions are harsh, and it is difficult to control.
- the patent specification Example 1 even drops the anti-solvent at -70 ° C, and the mixed use of three or more organic solvents makes the solvent difficult to recycle and apply. Increased production costs and environmental protection pressures, these are difficult to industrialize production.
- Many compounds may exist in different crystalline forms or polymorphs that have different physical, chemical, and spectral properties.
- certain crystalline forms of the same compound may be more soluble in a particular solvent than other crystalline forms, have better fluidity, or may be more susceptible to compression, for example, Knapman, K. Morden Drug Discoveries, 2000, 53; Dimartino P. Et al, J. Thermal Anal., 1997. 48: 447-458.
- certain solid forms are more readily bioavailable than others, and may be more stable under certain preparation, storage, and biological conditions.
- ticagrelor belongs to the biological drug classification system (BCS) class IV
- BCS biological drug classification system
- ticagrelor is difficult to prepare to form a hydrate because ticagrelor is substantially insoluble in water.
- the technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, and to study the design of triclinol monohydrate crystal form which has good stability or solubility and is suitable for industrial production and its preparation method and in pharmaceutical industry. application.
- the inventors have surprisingly discovered that they are dissolved in water by extensive research and careful exploration of crystallization conditions.
- a proper amount of DMSO or DMF is added to the system of the agent or the alcohol-water solvent, and after standing crystallization, a pure monohydrate crystal form is obtained in a small solvent system and in a high yield.
- the monohydrate crystal form is used as a seed crystal, and by the addition of the monohydrate seed crystal, in a mixed solvent of an organic solvent (the organic solvent is an alcohol, DMS0, DMF) and water, it is not necessary to suspend and static for a long time.
- the organic solvent is an alcohol, DMS0, DMF
- the preparation method comprises the step of preparing a crystalline form of ticagrelor monohydrate.
- the present invention provides a crystalline form of ticagrelor monohydrate.
- thermograviogram of the crystalline form of ticagrelor monohydrate of the present invention is shown at 5 (TC to 140 ° C, and its weight loss rate is 3%, indicating that the structure contains 1 part of crystal water (see Figure 1); Its differential thermal spectrum (DSC) shows two large endothermic peaks at 102 ⁇ 5 ° C and 136 ⁇ 5 ° C (see Figure 2).
- the X-ray powder diffraction pattern of the ticagrelor monohydrate crystal form of the present invention (see Fig. 3), which is measured by Rigaku D/Max-2550 PC, and the position of the diffraction peak (2 ⁇ , in degrees Indicates), the interplanar spacing d (indicated by A), and the intensity of the peak 1/1. (Expressed as %) See Table 1 Table 1 Characteristic diffraction lines of ticagrelor monohydrate crystal form
- the ticagrelor monohydrate crystal form is an orthorhombic system, F222 space group.
- the crystal structure study shows that the smallest symmetrical unit contains a ticagrelor molecule and a water molecule, and the intermolecular hydrogen bonds 04- ⁇ 4 ⁇ 04' and ⁇ 6- ⁇ 6 ⁇ 01" [Symmetric code: (i)- x, y, 1-z; (ii)-x, 2-y, z] join four ticagrelor molecules into a circle to form a cavity (cavity size is about 230A 3 ), four waters The molecule is filled in this cavity, and the water molecule forms a hydrogen bond with the hydroxyl group in the ticagrelor molecule, and the molecular ring extends infinitely along the c direction.
- Another object of the present invention is to provide a process for the preparation of the ticagrelor monohydrate.
- ticagrelor is dissolved in a mixed solvent of an organic solvent and water, cooled, crystallized, filtered, and the solvent is removed, and dried to obtain ticagrelor monohydrate.
- ticagrelor is heated and dissolved in a mixed solvent of an organic solvent and water, and is slowly cooled, and a seed crystal of a monohydrate crystal form is added at 0 ° C -4 (TC), and after standing for 1 to 24 hours, it is obtained.
- Greillo monohydrate is heated and dissolved in a mixed solvent of an organic solvent and water, and is slowly cooled, and a seed crystal of a monohydrate crystal form is added at 0 ° C -4 (TC), and after standing for 1 to 24 hours, it is obtained.
- TC 0 ° C -4
- the ratio of the ticagrelor to the solvent is a weight/volume ratio of 1:25-200 (W/V), preferably 1:30-150 (W/V) o
- the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide or a mixture of dimethyl sulfoxide and a fatty alcohol or N,N-dimethylformamide and a fatty alcohol; wherein dimethyl sulfoxide or N,N-dimethylformamide accounts for 20%-60% by volume of the solvent; the fatty alcohol is methanol or ethanol; and the volume ratio of water to organic solvent is 1: 0. 5-1: 1. 5 .
- the temperature of the ticagrelor is dissolved and maintained at 40 ° C - 80 ° C, preferably 50 ° C - 80 ⁇ ; the crystallization temperature is 0 ° C - 40 ° C, preferably 0 - 10 V;
- This ticagrelor monohydrate can be obtained by drying at 25 ° C - 80 ° C for 1.0 to 5.0 hours for 8 hours, preferably 4 hours.
- the ticagrelor monohydrate crystal form of the invention has good stability
- FIG. 6 is an XRD pattern of ticagrelor monohydrate before and after being placed at 25 ° C for 3 months, indicating that after standing for 3 months at room temperature The crystal form did not change.
- a further object of the invention is to provide the use of said ticagrelor monohydrate in pharmaceuticals.
- the use is the use of ticagrelor monohydrate in the preparation of a medicament for the treatment/prevention of thrombosis.
- the medicament of the present invention is a pharmaceutical composition prepared by a conventional method of ticagrelor monohydrate and a pharmaceutical excipient.
- the ticagrelor monohydrate crystal form of the invention has long-term storage stability, and the preparation method provided by the invention has the advantages of simple operation, environmentally controllable solvent, easy recovery and application, and is suitable for large-scale industrial production.
- Fig. 2 Differential thermal (DSC) curve of ticagrelor monohydrate, the abscissa is temperature (°C), and the ordinate is heat flow (W/g)
- Fig. 3 X-ray diffraction (XRD) image of ticagrelor monohydrate, the abscissa is the diffraction angle 2 ⁇ (.), and the ordinate is the relative intensity (CPS)
- Fig. 6 X powder diffraction (XRD) comparison chart of ticagrelor monohydrate for 3 months before and after, the abscissa is the diffraction angle 2 ⁇ ⁇ ), and the ordinate is the relative intensity (CPS).
- thermogravimetric analyzer Using TA company SDT Q600 thermogravimetric analyzer, the temperature was gradually increased from 30 °C to 38 CTC under the conditions of nitrogen gas velocity of 120 ml/min and temperature rising rate of 10 °C/min.
- DSC differential heat
- the ticagrelor bulk drug used in the examples was purchased from Shanghai Qiyue Chemical Co., Ltd.
- ticagrelor Take 2 g of ticagrelor, add 8 ml of dimethyl sulfoxide and 16 ml of water, stir at 60 ° C for 2 hours, naturally cool to 20-25 ° C, let stand for 20 hours at 20-25 °, suction filtration The mixture was washed with water for 3 times, suction-filtered, and dried at 65 ° C for 2 hours to obtain telgrelor monohydrate 0.14 g, yield 70%.
- thermograviogram of ticagrelor monohydrate showed at 50 ° C to 140 ° C, and its weight loss rate was 3%, indicating that the structure contained 1 part of crystal water (see Figure 1);
- the thermal spectrum (DSC) shows two large endothermic peaks at 102 ⁇ 5 ° C and 136 ⁇ 5 ° C (see Figure 2).
- Example 3 5 ⁇ After adding 0. 5 ⁇ , adding ethanol: dimethyl sulfoxide: water 3: 3: 4 mixed solvent 50 ml, heating at 5 (TC under stirring 0. 5 hours, natural cooling to 30 ° C , (0. 01 g) of seed crystals of ticagrelor monohydrate (prepared in Example 1), incubated at 30 ° C, allowed to stand for 1 hour, filtered, solvent removed, and rinsed 3 times with water. 4 ⁇ Yield 80%. The filgrasin monohydrate was obtained in an amount of 0.4%.
- Example 1 The prepared ticagrelor monohydrate was prepared according to the method reported in the prior art (W02008024044, W02008024045), and the dose of ticagrelor monohydrate was converted according to the ticagrelor raw material, and the preparation was carried out.
- the rui tablets have been tested ("Chinese Pharmacopoeia" 2010 edition) to confirm that they are consistent with existing ticagrelor tablets and, therefore, can be used as a raw material for the preparation of ticagrelor tablets.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种替格瑞洛一水合物晶型被公开,其差示扫描量热图谱在102±5°C以及136±5°C有两个较大的吸热峰,热重图谱显示含一个结晶水,存放稳定性良好、水溶性优于已报导的无水晶型。通过替格瑞洛在有机溶剂和水的混合溶剂中,加热溶解,冷却,析晶,过滤,干燥后得到替格瑞洛一水合物,该制备方法操作简便,溶剂环保可控,并容易回收套用,适于规模型的工业化生产。替格瑞洛一水合物可用于制备治疗/预防血栓形成的药物。
Description
替格瑞洛的一水合物及其制备方法与在制药中的应用 技术领域
本发明涉及药物,具体涉及药物水合物及其制备方法,尤其涉及一种小分子 抗凝剂替格瑞洛的一水合物及其制备方法与在制药中的应用。 背景技术
(IS, 2S, 3R, 5S) -3- [7- [ (1R, 2S) -2- (3, 4 -二氟苯基)环丙胺基]- 5- (丙硫 基) - 3H-[1, 2, 3]三唑 [4, 5-d]并嘧啶 - 3-基] -5- (2-羟乙氧基)环戊基 - 1, 2-二醇 (替格瑞洛, ticagrelor), CAS号为 274693- 27-5, 下列结构式所示:
替格瑞洛
替格瑞洛是美国阿斯利康 (AstraZeneca)公司研发的一种新型的、 具有选择 性的小分子抗凝血药。 该药能可逆地作用于血管平滑肌细胞 (VSMC)上的嘌呤 2 受体亚型 P2Y12,替格瑞洛不是前药,因此不需要代谢激活,对二磷酸腺苷(ADP) 引起的血小板聚集有明显的抑制作用,且口服使用后起效迅速,能有效改善急性 冠心病患者的症状。 与噻吩并吡啶类药物(氯吡格雷、普拉格雷等)不同, 替格 瑞洛对 P2Y12 ADP受体是可逆拮抗剂, 所以对于那些需在先期进行抗凝治疗后再 行手术的病人尤为适用。
阿斯利康公司的专利 W00192262 (以下简称 262' 专利) 公开了替格瑞洛的 四个晶型 (晶型 I, 晶型 II, 晶型 III, 晶型 IV)和无定形状态及其制备方法, 此四种晶型和无定形均是 "无水"状态。尽管在该专利中提到了溶剂化物和水合 物, 但是该专利的公开文本中对于相应的溶剂化物和水合物没有任何表征数据, 且没有任何实施例能够表明阿斯利康公司的专利 W00192262确实制备和公开了 一种或几种溶剂化物以及水合物。
专利 262' 专利公开的晶型 I, 需要通过繁复的温度控制方法获得, 以添加
晶种的方式制备晶型 I,溶剂中大量使用到水,但是却并不能获得水合物。 262' 专利公开的晶型 II的制备, 需要用到 I类的有毒有害溶剂氯仿, 对于工业化和 环境保护均是不利的,是难以实现工业化的; 262' 专利公开的晶型 III的制备, 是通过制备 II和 III晶型的混晶, 并以混晶为晶种制备晶型 III, 这样的操作 在工业上很难控制其晶体纯度,并且在后续的制备中,涉及异丙醇和水 1 : 1的溶 剂体系, 并且同样不能获得水合物; 晶型 IV的制备, 要用到有毒有害, 沸点较 低的乙腈, 同样是不利于环保和工业化生产的。
另外, 阿特维斯(ACTIVAS)公司的专利 W02013079589公开另一种替格瑞洛 的无水晶型及其制备方法。但是其制备方法复杂, 操作手续繁杂, 条件苛刻, 难 以控制, 专利说明书实施例 1甚至在 -70°C下滴加抗溶剂, 并且三种以上有机溶 剂的混合使用,使得溶剂难以回收套用,大大增加了生产成本和环境保护的压力, 这些都难以工业化生产。
许多化合物可以以不同晶型或多晶型物的形式存在, 它们具有不同的物理、 化学和光谱特性。例如, 同一化合物的某些晶型可能比其它晶型更易溶于特定溶 剂、 流动性更好, 或者可能更易于被压縮, 例如, Knapman, K. Morden Drug Discoveries, 2000, 53 ; Dimartino P.等, J. Thermal Anal. , 1997. 48 : 447-458。 对于药物而言,某些固体形式相比于其它形式更易于被生物利用, 同时在某些制 备、 储存和生物条件下可能更加稳定。 由于替格瑞洛是属于生物药剂分类系统 (BCS) IV类, 本发明人发现, 由于替格瑞洛在水中基本不溶, 因此替格瑞洛很 难制备形成水合物。利用现有技术, 根本无法制备出替格瑞洛的水合物, 往往得 到的都是粘稠的油状物, 因此, 为了提高其在水中的溶解度、溶解速率或者长期 存放的稳定性,研究开发一种宜于制备成药物制剂,又易于实现工业化的水合物 是关注的问题。 发明内容
本发明所要解决的技术问题在于克服上述不足之处,研宄设计具有较好稳定 性或者溶解性,适于工业化生产的替格瑞洛的一水合物晶型及其制备方法与在 制药中的应用。
本发明人通过对于结晶条件的大量研宄和仔细探索,惊奇地发现在以水为溶
剂的体系或者醇-水溶剂的体系中加入适量的 DMSO或 DMF, 经过静置析晶, 以较 小的溶剂体系和高收率获得纯的一水合物晶型。将此一水合物晶型作为晶种,通 过一水合物晶种的添加, 在有机溶剂 (所述的有机溶剂为醇、 DMS0、 DMF)和水 的混合溶剂中, 无需长时间混悬、静置、特别低的析晶温度或特别复杂的析晶工 艺, 就能够以较快的速度(析晶时间 1-12小时), 较高的收率(收率大于 80%), 较易工业化的制备方法, 制备获得替格瑞洛一水合物晶型。
本发明提供一种替格瑞洛一水合物晶型。
本发明所述替格瑞洛一水合物晶型的热重谱图显示在 5(TC至 140°C,其失重 率为 3%, 说明结构中含 1份结晶水(见附图 1 ); 其差热谱图 (DSC)显示, 在 102±5°C 以及 136± 5°C有两个较大的吸热峰(见附图 2) 。
本发明所述替格瑞洛一水合物晶型的 X射线粉末衍射图 (见附图 3) , 该图 用 Rigaku D/Max-2550 PC测得, 以衍射峰的位置 (2 Θ, 以度表示) 、 晶面间距 d (以 A表示) , 峰的强度 1/1。 (以百分比 %表示)见表 1 表 1 替格瑞洛一水合物晶型的特征衍射谱线
25.42 3.50 3.4
26.21 3.39 1.8
26.68 3.33 2.5
28.22 3.15 1.9
29.16 3.06 1.2
31.26 2.85 1.1
33.80 2.64 1.3 本发明所述替格瑞洛一水合物晶型, 在 296K下用单晶 X射线衍射分析并确 定了晶体结构。 晶胞参数见表 2; 原子坐标、 各原子间的键长、 各原子间的键角 分别见表 3、 4、 5; 晶体结构见附图 4-5。
根据这些结晶学数据证明: 替格瑞洛一水合物晶型属正交晶系, F222空间 群。晶体结构研宄表明,其最小对称单元中含有一个替格瑞洛分子和一个水分子, 分子间氢键 04- Η4···04'和 Ν6-Η6〜01" [Symmetric code: (i)- x, y, 1-z; (ii)-x, 2-y, z]将四个替格瑞洛分子连成一个圈, 形成一个空腔(空腔大小约为 230A3), 四个水分子就填在这个空腔中,水分子和替格瑞洛分子中的羟基形成氢键,此分 子圈沿 c方向无限延伸。 另两个分子间氢键作用 02- 112"*0 和 01-Η1···Ν6"" [Symmetric code: (iii)x, 1.5- y, 1.5- z; (iiii)- x, 2-y, z]将上述四个分子 组成的分子圈连接在一起, 沿 b方向堆叠, 形成三维空间无限堆叠图。 因此替格 瑞洛一水合物晶型中所包含的这个水分子具有较高的稳定性,也表明其为含水合 物晶型。 表 2 替格瑞洛一水合物晶型的晶系、 空间群和晶胞参数
OV isszA:3/2000166
9
660000/MOZN3/X3d 680 0/SI0Z OAV
/ OH0SSZAV 680:>/:/>d 660000H0zz
LO D CO o CM
CD t> - 00 CO LC CD 00 i―" i ~
i ~ i— ) M o
CJ) o i—> C CM CO
o CM CO CO
o CSI
LO LO LO D 00 00 OS o o LO 00 oo o o SJ
CM CM sl
()9Ti'
/D/:/ O 660000H0¾l£ 680H0ssiAV
680H0:/:0ssi>l>d 66000.
c i Csl CO 00 σ> l>- 00 o o σ¾ CO M
00 < CM CM M CSI Cl CM
(X CO CO
CJ> J
CM CO L 00 00 00 σ¾ en OS o o O CSJ 00
Csl csi SI CSI CM M CM CO
Z z
O o CO CM LC 00 CM CSI 00 O CO o
CSJ O CSJ O
IX o O O o CM CO CM
O o o o J) CJ) z
C2 N6 C5 123. 2 (5)
C22 03 C20 119. 1 (8)
CI SI C14 103. 9 (3) 本发明的另一目的是提供了所述替格瑞洛一水合物的制备方法。
该方法为替格瑞洛在有机溶剂和水的混合溶剂中, 加热溶解, 冷却, 析晶, 过滤, 除去溶剂, 干燥后得到替格瑞洛一水合物。
优选的, 替格瑞洛在有机溶剂和水的混合溶剂中加热溶解, 缓慢冷却, 于 0°C -4(TC时加入一水合物晶型的晶种, 静置 1-24小时后得到替格瑞洛一水合物。
所述替格瑞洛与溶剂的配比为重量 /体积比, 为 1 : 25- 200 (W/V), 优选为 1 : 30-150 (W/V) o
所述有机溶剂为二甲亚砜或 N, N-二甲基甲酰胺或为二甲亚砜与脂肪醇或 N,N-二甲基甲酰胺与脂肪醇的混合物; 其中二甲亚砜或 N,N-二甲基甲酰胺占溶 剂的体积百分比为 20%-60%; 所述的脂肪醇为甲醇或乙醇; 水与有机溶剂的体积 比为 1 : 0. 5-1 : 1. 5。
所述替格瑞洛加热溶解保持的温度为 40°C-80°C , 优选 50°C- 80Ό ; 析晶温 度为 0°C-40'C,优选为 0-10 V;冷却进行 1至 8小时,优选为 4小时,在 25°C-80 °C干燥 1.0-5.0小时, 可获得此替格瑞洛的一水合物。
本发明所述替格瑞洛一水合物晶型具有较好的稳定性,图 6是替格瑞洛一水 合物在 25°C放置 3个月前后的 XRD图, 表明室温放置 3个月后晶型没有发生改 变。
本发明的又一目的是提供了所述替格瑞洛一水合物在制药中的应用。
所述应用为替格瑞洛一水合物在制备治疗 /预防血栓形成的药物中的应用。 本发明所述药物为替格瑞洛一水合物与药用辅料按药物常规方法制成的药 物组合物。
本发明的替格瑞洛一水合物晶型长期存放稳定,本发明提供的制备方法操作 简便, 溶剂环保可控, 并容易回收套用, 适于规模型的工业化生产。 附图说明
图 1 替格瑞洛一水合物的 TG (热重) 曲线, 横坐标为温度(°C), 纵坐标为 失重率(%)
图 2 替格瑞洛一水合物的差热 (DSC) 曲线, 横坐标为温度 (°C), 纵坐标 为热流(W/g)
图 3 替格瑞洛一水合物的 X射线衍射 (XRD) 图, 横坐标为衍射角 2 Θ (。), 纵坐标为相对强度(CPS)
图 4 替格瑞洛一水合物的晶体结构图 (0RTEP图)
图 5 替格瑞洛一水合物的晶体结构堆叠图
图 6 替格瑞洛一水合物放置 3个月前后的 X粉末衍射(XRD) 对比图, 横 坐标为衍射角 2 θ Γ), 纵坐标为相对强度 (CPS) 。 具体实施方式
本发明实施例是在下列条件下测定:
X射线粉末衍射谱:
采用 Cu 射线, 在 Rigaku D/Max-2550 PC X-射线粉末衍射仪上进行 X 射线粉末衍射分析, 测试功率为 40kVX 250mA, 扫描速度 5° /min、 步宽 0. 02° 扫描范围 3-40° (2 Θ ) 的 Θ - 2 Θ 连续扫描。
TG (热重) 曲线:
采用 TA公司 SDT Q600热重分析仪,在氮气速度为 120 ml/min、升温速度 10 °C /min的条件下, 温度从 30°C逐渐上升到 38CTC下测定。
DSC (差热) 曲线- 采用 TA公司 DSC Q100差热量示分析仪, 在氮气速度为 50 ml/min、 升温速度 为 10 TVmin的条件下, 温度从 30°C逐渐上升到 230°C下测定。 单晶 X射线衍射分析:
采用 Rigaku R- AXIS-RAPID单晶衍射仪, 挑选外形完好无缺陷的单晶, 采用 ΜοΚ α ( λ =0. 71073A)射线在 Rigaku R-AXIS-RAPID单晶衍射仪上进行数据收集,
用 SHELXS97 (Sheldrick, 2008)和 SHELXL97 (Sheldrick, 2008)进行结构解析和 修正。 使用 Diamond和 Mercury软件获得结构图。
实施例所用替格瑞洛原料药购自上海齐月化工有限公司
实施例 1
取替格瑞洛 0. 2克,加入 8毫升二甲亚砜和 16毫升水, 60°C搅拌 2小时后, 自然降温到 20-25°C, 在 20-25Ό静置 24小时, 抽滤, 用水淋洗 3次, 抽滤, 在 65°C鼓风干燥 2小时, 得到替格瑞洛一水合物 0. 14克, 收率 70%。
经检测,得到的替格瑞洛一水合物热重谱图显示在 50°C至 140°C,其失重率 为 3%,说明结构中含 1份结晶水(见附图 1 ) ;其差热谱图 (DSC)显示,在 102±5 °C以及 136±5°C有两个较大的吸热峰 (见附图 2) 。
替格瑞洛一水合物晶型的 X射线粉末衍射图 (见附图 3) , 该图用 Rigaku D/Max-2550 PC测得, 以衍射峰的位置 (2 Θ, 以度表示) 、 晶面间距 d (以 A 表示) , 峰的强度 1/1。 (以百分比 %表示)见表 1 表 1 替格瑞洛一水合物晶型的特征衍射谱线
25.42 3.50 3.4
26.21 3.39 1.8
26.68 3.33 2.5
28.22 3.15 1.9
29.16 3.06 1.2
31.26 2.85 1.1
33.80 2.64 1.3 替格瑞洛一水合物晶型, 在 296K下用单晶 X射线衍射分析并确定了晶体结 。 晶胞参数见表 2; 原子坐标、各原子间的键长、各原子间的键角分别见表 3、 5; 晶体结构见附图 4-5。
表 2 替格瑞洛一水合物晶型的晶系、 空间群和晶胞参数
00 o o
00 00 00 3 o 00 o
O D O 00 oo o D - 00 00 oo 00
n o o
o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o
00 to O
00 σ> 00 •S3 •S 00 o o σ
― t o 00 o o o
o 00 csi o o o o σ¾ 00
00 00 o o o o σ> 00 o σ>
00 00 00 00 00 σ¾ σ> en o 00
o o o o o o o o o o o o o o o o o o o o o o o o o o o o
o o o o o o o o o o o o o o o
c 3
C LO σί 00 σ LO LO oo
CSI oo t CM D o 00 o o ( ) O
00 o o 00 00 < 00 σ CO Ό 00 o 00 O o O σ¾ 00 o o 00 00
i o o i o o o
o o o o o o o o o o o o o o o o o o o o o o o o o o o o
o CSI CO CD 00 σ¾ o CM 00
CM CO LO CD 00 CM CM CM C CO
z z 2:
660000/M0ZN3/X3d
9T
N3/X3d 680 0/SI0Z OAV
O 00 CM O O o- οο 00 σ> 00 ~ 1 . ~ 1 i CSI C^I oo 1 O 00
[X → IX ― 1 CSI csi CM CO O O o i―"
LO 00 00 00 o O 1 i ~ 1 M O D C\) CM LO O CD CO O o O LO
1 I C CO z 2 z i ~~ σ¾ o O
2 r-H CS i— 1 r-H ~ 1
J) E J J
) (osi
01 C18 C19 115.8(4)
01 C18 C17 114.2(4)
C19 C18 C17 100.7(4)
02 C19 C18 106.4(4)
02 C19 C20 111.1(5)
C18 C19 C20 103.0(4)
03 C20 C21 110.4(6)
03 C20 C19 109.5(6)
C21 C20 C19 105.5(5)
C20 C21 C17 106.5(5)
03 C22 C23 116.2(11)
04 C23 C22 118,5(9)
C2 Nl CI 119.0(5)
N3 N2 C3 108.1 (4)
N2 N3 N4 108.1 (4)
C4 N4 N3 110.2(4)
C4 N4 C17 127.6(4)
N3 N4 C17 122.2(4)
CI N5 C4 111.6(4)
C2 N6 C5 123.2(5)
C22 03 C20 119.1(8)
CI SI C14 103.9(3) 实施例 2
取替格瑞洛 0.4克,加入 30毫升二甲亚砜和 20毫升水,80°C搅拌 1小时后, 自然降温到 30-35°C, 在 30- 35°C静置 24小时, 抽滤, 除去溶剂, 用水淋洗 3 次,抽滤,在 75°C鼓风干燥 1小时,得到替格瑞洛一水合物 0.27克,收率 67.5%。
经检测, 确证为替格瑞洛一水合物。
实施例 3
取替格瑞洛 0. 5克,加入乙醇: 二甲亚砜: 水 =3: 3: 4 的混合溶剂 50毫升, 在 5(TC下加热搅拌 0. 5小时, 自然降温到 30°C时, 投入(0. 01克) 的替格瑞洛 一水合物的晶种(实施例 1制得), 30°C保温, 静置析晶 1小时, 过滤, 除去溶 剂, 用水淋洗 3次, 抽滤, 在 55°C鼓风干燥 2.5小时, 得到替格瑞洛一水合物 0. 4克, 收率 80%。
经检测, 确证为替格瑞洛一水合物。
实施例 4
取替格瑞洛 3克,加入甲醇: Ν, Ν-二甲基甲酰胺:水 =1 : 5: 4 的混合溶剂 120 毫升, 在 40°C下加热搅拌 1小时, 自然降温到约 10°C时, 投入(0. 06克) 的替 格瑞洛一水合物的晶种(实施例 1制得), 10°C保温析晶 2小时, 过滤, 除去溶 剂,用水淋洗 3次,抽滤,在 45°C鼓风干燥 4小时, 即得替格瑞洛一水合物 2. 7 克, 收率 90%。
经检测, 确证为替格瑞洛一水合物。
实施例 5
取替格瑞洛 1克, 加入 Ν, Ν-二甲基甲酰胺:水的体积比为 1 : 1的混合溶液 30毫升,加热到 60°C,溶解澄清之后, 自然降温至 25〜30'C,静置析晶 12小时, 抽滤, 除去溶剂, 用水淋洗 3次, 抽滤, 在 55°C鼓风干燥 2.5小时, 得到替格 瑞洛一水合物晶型 0. 7克, 收率 70%。
经检测, 确证为替格瑞洛一水合物。
实施例 6
实施例 1 制得的替格瑞洛一水合物按现有报道的方法制备片剂 (W02008024044, W02008024045 ),替格瑞洛一水合物的投料按替格瑞洛原料折算 计量, 制备得到替格瑞洛片剂经检测(《中国药典》 2010版)确证与现有替格瑞 洛片剂一致, 因此, 可用作制备替格瑞洛片剂的原料。
Claims
1、 替格瑞洛一水合物, 其特征在于, 它的分子式为: C23H28F2N604S · H20; 含 1份水; 所述的一水合物晶型属正交晶系, 空间群为 F 222 NO. 22, 在 296K下 显示的单晶 X射线的晶胞参数为: a= 14.2772 A, b= 22.2093 A, c= 34.277 6 A, a =90.00° , e=90.00° , γ=90.00° , 体积 = 10868 3 A3, Z 分子 /晶 胞 =16;
差热谱图显示: 在 102±5°C以及 136±5°C有两个较大的吸热峰; 其 X射线 粉末衍射图具有以衍射角 2Θ ° ±0.1表示的特征衍射峰: 5.1, 7.8, 9.5, 10.7, 13.4, 14.8, 15.5, 17.4, 19.2, 19.5, 20.7, 20.9, 21.1, 21.4, 22.4。
2、 制备如权利要求 1所述的替格瑞洛一水合物的方法, 其特征在于, 该方 法为替格瑞洛在有机溶剂和水的混合溶剂中, 加热溶解, 冷却, 析晶, 过滤, 干 燥后得到替格瑞洛一水合物。
3、 制备如权利要求 1所述的替格瑞洛一水合物的方法, 其特征在于, 该方 法为替格瑞洛在有机溶剂和水的混合溶剂中, 加热溶解, 缓慢冷却, 于 0°C- 40°C 时加入一水合物晶型的晶种, 静置 1-24小时, 后得到替格瑞洛一水合物。
4、 根据权利要求 2或 3所述的制备方法, 其特征在于, 所述替格瑞洛与溶 剂的配比为重量 /体积比为 1:25-200W/V, 优选为 1:30-150W/V。
5、 根据权利要求 2或 3所述的制备方法, 其特征在于, 所述有机溶剂为二 甲亚砜或 N, N-二甲基甲酰胺或为二甲亚砜与脂肪醇或 N, N-二甲基甲酰胺与脂肪 醇的混合物; 其中二甲亚砜或 Ν,Ν-二甲基甲酰胺占溶剂的体积百分比为 20%-60%; 所述的脂肪醇为甲醇或乙醇; 水与有机溶剂的体积比为 1:0.5-1 :1.5。
6、 根据权利要求 2或 3所述的制备方法, 其特征在于, 所述替格瑞洛加热 溶解保持的温度为 40°C-80°C;析晶温度为 0°C-40°C;冷却析晶 1-8小时;过滤, 并在 25°C-80 °C干燥 1.0-5.0小时。
7、 根据权利要求 6所述的制备方法, 其特征在于, 所述替格瑞洛加热溶解 保持的温度为 50°C- 80°C; 析晶温度为 0-10 °C; 冷却析晶 4小时。
8、 如权利要求 1所述的替格瑞洛一水合物在制药中的应用。
9、 根据权利要求 8所述的应用, 其特征在于, 所述应用为替格瑞洛一水合
物在制备治疗 /预防血栓形成的药物中的应用。
10、根据权利要求 8或 9所述的应用, 其特征在于, 所述药物为替格瑞洛一 水合物与药用辅料按药物常规方法制成的药物组合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310333131.7 | 2013-08-02 | ||
CN201310333131.7A CN104341423B (zh) | 2013-08-02 | 2013-08-02 | 替格瑞洛的一水合物及其制备方法与在制药中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015014089A1 true WO2015014089A1 (zh) | 2015-02-05 |
Family
ID=52430933
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2014/000099 WO2015014089A1 (zh) | 2013-08-02 | 2014-01-26 | 替格瑞洛的一水合物及其制备方法与在制药中的应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN104341423B (zh) |
WO (1) | WO2015014089A1 (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015162630A1 (en) | 2014-04-25 | 2015-10-29 | Anlon Chemical Research Organization | Novel processes for preparing triazolo [4,5-d]- pyrimidines, including ticagrelor, vianew intermediates and new route of synthesis. |
WO2016116942A1 (en) | 2015-01-20 | 2016-07-28 | Anlon Chemical Research Organization | Novel pharmaceutical compounds comprising ticagrelor with salts of aspirin |
US10905691B2 (en) | 2016-09-09 | 2021-02-02 | Université de Liège | Use of triazolo(4,5-d)pyrimidine derivatives for prevention and treatment of bacterial infection |
AU2017324655B2 (en) * | 2016-09-09 | 2021-04-29 | Universite De Liege | New use of triazolo(4,5-d)pyrimidine derivatives for prevention and treatment of bacterial infection |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104370912A (zh) * | 2013-08-13 | 2015-02-25 | 开原亨泰制药股份有限公司 | 替卡格雷多晶型体及其制备方法 |
CN104140428B (zh) * | 2014-07-14 | 2017-02-15 | 福建广生堂药业股份有限公司 | 替格瑞洛的水合物及其制备方法 |
CN106946885A (zh) * | 2016-01-07 | 2017-07-14 | 南京济群医药科技股份有限公司 | 一种替格瑞洛单晶的制备方法 |
CN110183436A (zh) * | 2019-06-21 | 2019-08-30 | 南通常佑药业科技有限公司 | 一种非晶型替卡格雷的制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1432018A (zh) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | 三唑并[4,5-d]嘧啶化合物的新晶形和非晶形 |
CN102770434A (zh) * | 2009-12-03 | 2012-11-07 | 阿斯利康(瑞典)有限公司 | 三唑并[4,5-d]嘧啶血小板聚集抑制剂的共晶体 |
WO2012164286A1 (en) * | 2011-06-01 | 2012-12-06 | Astrazeneca Ab | Novel ticagrelor co - crystal |
WO2013079589A1 (en) * | 2011-11-30 | 2013-06-06 | Actavis Group Ptc Ehf | Novel crystalline form of ticagrelor and process for the preparation thereof |
-
2013
- 2013-08-02 CN CN201310333131.7A patent/CN104341423B/zh active Active
-
2014
- 2014-01-26 WO PCT/CN2014/000099 patent/WO2015014089A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1432018A (zh) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | 三唑并[4,5-d]嘧啶化合物的新晶形和非晶形 |
CN102770434A (zh) * | 2009-12-03 | 2012-11-07 | 阿斯利康(瑞典)有限公司 | 三唑并[4,5-d]嘧啶血小板聚集抑制剂的共晶体 |
WO2012164286A1 (en) * | 2011-06-01 | 2012-12-06 | Astrazeneca Ab | Novel ticagrelor co - crystal |
WO2013079589A1 (en) * | 2011-11-30 | 2013-06-06 | Actavis Group Ptc Ehf | Novel crystalline form of ticagrelor and process for the preparation thereof |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015162630A1 (en) | 2014-04-25 | 2015-10-29 | Anlon Chemical Research Organization | Novel processes for preparing triazolo [4,5-d]- pyrimidines, including ticagrelor, vianew intermediates and new route of synthesis. |
WO2016116942A1 (en) | 2015-01-20 | 2016-07-28 | Anlon Chemical Research Organization | Novel pharmaceutical compounds comprising ticagrelor with salts of aspirin |
US10905691B2 (en) | 2016-09-09 | 2021-02-02 | Université de Liège | Use of triazolo(4,5-d)pyrimidine derivatives for prevention and treatment of bacterial infection |
AU2017324655B2 (en) * | 2016-09-09 | 2021-04-29 | Universite De Liege | New use of triazolo(4,5-d)pyrimidine derivatives for prevention and treatment of bacterial infection |
Also Published As
Publication number | Publication date |
---|---|
CN104341423A (zh) | 2015-02-11 |
CN104341423B (zh) | 2017-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2015014089A1 (zh) | 替格瑞洛的一水合物及其制备方法与在制药中的应用 | |
WO2016184436A1 (zh) | 乐伐替尼甲磺酸盐的新晶型及其制备方法 | |
TWI804933B (zh) | 用作cdk7激酶抑制劑的化合物及其應用 | |
CN103951634B (zh) | 一种依帕司他结晶盐水合物和羟基哌啶共晶物及其制备方法和应用 | |
KR102576964B1 (ko) | 헤테로시클리덴 아세트아미드 유도체의 결정 | |
JP2019526628A (ja) | セニクリビロクメシレートの固体形態及びセニクリビロクメシレートの固体形態を製造するプロセス | |
CN104603123A (zh) | 曲格列汀的固态形式及其制备方法和用途 | |
CN104230886A (zh) | 阿昔替尼新晶型 | |
JP7303821B2 (ja) | ピリミジニルアミノ-ピラゾール化合物の多形体及び固体形態、ならびに製造方法 | |
CN106905319A (zh) | 取代苯磺酰苦参丁烷或其盐酸盐的制备方法 | |
WO2014194795A1 (zh) | 吲哚酮化合物或其衍生物及其用途 | |
US10774042B2 (en) | Crystalline forms of apremilast | |
CN112538123A (zh) | 一种舒更葡糖钠晶型m | |
CZ305213B6 (cs) | Polymorf E 2-[4-[(methylamino)karbonyl]-1H-pyrazol-1-yl]adenosinu a způsob jeho přípravy | |
CN104086544B (zh) | 阿哌沙班一水合物及其制备方法和药物组合物 | |
CN105859691A (zh) | 一种胸苷磷酸化酶抑制剂的新型结晶形式及其制备方法 | |
CN106831718B (zh) | 平滑受体配体及其应用 | |
WO2022062401A1 (zh) | 一种泰格列净的制备方法 | |
CN104910147B (zh) | 阿哌沙班晶体及其制备方法 | |
TW201900646A (zh) | 5型磷酸二酯酶抑制劑的甲磺酸鹽多晶物及其製備方法和應用 | |
KR20230031320A (ko) | 2-[4-[(2,3,4-트리메톡시페닐)메틸]피페라진-1-일]에틸 피리딘-3-카르복실레이트의 결정 형태 및 합성 방법 | |
TWI535724B (zh) | 埃克替尼磷酸鹽的新晶型及其用途 | |
WO2008148260A1 (fr) | Nouvelle forme cristalline d'hydrochlorure d'irinotécan et sa préparation | |
TWI824626B (zh) | Ripk1抑制劑的晶型及其酸式鹽和其酸式鹽的晶型 | |
WO2019105359A1 (zh) | Acalabrutinib的晶型及其制备方法和用途 |
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: 14831308 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14831308 Country of ref document: EP Kind code of ref document: A1 |