CN105968113A - A novel triazolopyrimidine derivative and applications thereof - Google Patents

A novel triazolopyrimidine derivative and applications thereof Download PDF

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Publication number
CN105968113A
CN105968113A CN201610122570.7A CN201610122570A CN105968113A CN 105968113 A CN105968113 A CN 105968113A CN 201610122570 A CN201610122570 A CN 201610122570A CN 105968113 A CN105968113 A CN 105968113A
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compound
formula
acid
crystal form
preparation
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CN105968113B (en
Inventor
袁道义
赵雄
陈真
李学超
彭丹
欧兴蓉
程鹤
罗杰
严庞科
宫爱申
向志祥
王明霞
刘国强
王庚禹
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Guangzhou Nuowei Biological Technology Co Ltd
Sichuan Haisco Pharmaceutical Co Ltd
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Guangzhou Nuowei Biological Technology Co Ltd
Sichuan Haisco Pharmaceutical Co Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

A novel triazolopyrimidine derivative shown as a formula II, a crystal form thereof, a preparing method of the derivative, and applications of the derivative in preparation of anticoagulation medicines, antithrombotic medicines and medicines for treating or preventing cerebral ischemic diseases or improving sleeping are provided.

Description

A kind of novel triazolopyrimidines derivant and application thereof
Technical field
The present invention relates to organic chemistry and pharmaceutical field, be specifically related to a kind of novel triazolopyrimidines derivant and crystal formation thereof And preparation method, and preparing anticoagulation, antithrombotic, treating or prevent cerebral ischemia diseases or improve in the medicine slept Application.
Background technology
Thrombosis is formed by platelet aggregation in coagulation process, and the thrombosis formed in the case of non-damaging can drop Low blood flow rate even blocks tail vein thus causes cerebral infarction, tissue necrosis, medicated porridge sample arteriosclerosis, myocardial infarction Etc. disease.
The cerebral tissue local feeding artery blood perfusion that cerebral infarction refers to occur suddenly reduce or blood flow completely in Disconnected, stop blood supply, oxygen supply, supply sugar etc., make this local brain tissue disintegrate destroy.The main cause of cerebral infarction is: 1. move Thromboembolism caused by pulse atherosclerosis；2. cerebral embolism caused by the embolus in heart source；3. a variety of causes causes vasculitis, blood vessel Damage and wound etc..Cerebral infarction is typically fallen ill in nighttime sleep, find when Chang Weici gets up morning limb adynamia or Hemiplegia, how unconscious obstacle, blood pressure can be normal or higher, can have arteriosclerosis history.It is total that cerebral infarction accounts for cerebral apoplexy patient The 60%～70% of number, mainly includes cerebral thrombosis and cerebral embolism.Hematoblastic cohesion is often the beginning of cerebral thrombosis, Therefore the medicine preventing platelet aggregation can be used to treat or prevent cerebral infarction.
Hematoblastic activation has number of ways and mechanism, and wherein P2Y12 receptor participates in fibrinogen deceptor activation, thrombosis The processes such as formation, the platelet aggregation that thromboxane A2 generates, wound causes.The P2Y12 receptor of the mankind is by 342 aminoacid groups Become, be distributed mainly in platelet and cerebral tissue.When the endogenous stimulus factor such as ADP etc. activates P2Y12 receptor, can activate The paths such as PI3K, and then activate Rap1b, Akt, ERK path, jointly cause the activation of fibrinogen deceptor, thus activate fibre Fibrillarin is former, causes thrombosis or platelet aggregation.This process must just can be real in the case of P2Y12 receptor activation Existing, therefore block P2Y12 receptor and can significantly inhibit the platelet aggregation and thrombosis shape caused by ADP and other stimulating factor Become.
At present, the existing multiple P2Y12 acceptor inhibitors in the whole world successfully develop listing, wherein by AstraZeneca (AstraZeneca) ticagrelor (Ticagrelor) of exploitation listing is the first reversible P2Y12 inhibitor in the whole world, 2010 December obtains listing approval first in European Union, and in February, 2011 is in Britain's Initial Public Offering；In August, 2011 is also approved listing in the U.S. Approval, in the country's listing of more than 40, the whole world.Ticagrelor is mainly used to reduce acute coronary syndrome clinically (ACS) incidence rate of the thrombotic cardiovascular event of patient.The usage and dosage of ticagrelor is: oral, initial dose 180mg, Maintenance dose is adjusted to one day twice, each 90mg；General at least 12 months for the treatment of time.
Ticagrelor chemistry is entitled: (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] Amino }-5-rosickyite base-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-1,2-ring penta 2 Alcohol, structure is as shown in formula I, and it can be prepared by the method disclosed in CN1432017A.
Ticagrelor has the unique chemical moieties of triazolo pyrimidine, can directly be combined, not only with P2Y12 receptor reversibility Suppression platelet aggregation effect can be played quickly, and in 24 hours of final dose, along with the decline of blood drug level, press down Making rapid decay, platelet function the fastest quick-recovery.Therefore, ticagrelor be one can quick acting, potent press down The new oral antiplatelet drug that platelet aggregation processed, safety are good, acute coronary syndrome the most clinically (ACS) more preferably the selecting of patient's Antiplatelet therapy.
But in place of ticagrelor still suffers from some shortcomings, such as bioavailability is relatively low, and (in human body, ticagrelor biology is sharp Expenditure average out to 36%), medication compliance the highest (in long-term prescription, needing medication in a day twice, increase and miss probability) etc.. Therefore, it is necessary to the new derivative of exploitation ticagrelor, to keeping ticagrelor as reversible P2Y12 inhibitor advantage On the basis of, improve bioavailability further, strengthen medication compliance.
Physical and chemical properties of drugs or internal pharmacokinetic property can be improved by rational base group modification, improve oral raw Thing availability, this is known in those skilled in the art.Although in theory can be reasonable according to the chemical functional group in molecule The modification of design assumption, but female medicine produces after base group modification is brand-new molecular entity, and this noval chemical compound often shows Female medicine non-existent harmful physical chemistry or bioactive properties.Although base group modification compound seems " simply ", but due to people Body and the complexity of drug interaction, identify have suitable physicochemical property, pharmacokinetic property, conversion in the body and safety Property be complicated multidisciplinary task, the base group modification compound therefore obtained often through " appropriate design " in reality, often with Expected result differs greatly, and even obtains physicochemical property or mother's biological activity ratio medicine worse base group modification compound.Cause This, developed by base group modification and improve the noval chemical compound of physical and chemical properties of drugs or internal pharmacokinetic property and have very much not Predictability, the solid state characterization such as crystal formation of these noval chemical compounds, new application are the most unpredictable.
The present invention, in the research process to ticagrelor base group modification, is surprisingly found that the one of ticagrelor is through base The novel triazolopyrimidines derivant that group modifies, this compound activity is suitable with ticagrelor, and oral absorption is better than ticagrelor, Ticagrelor can be metabolized in vivo, thus extend action time, for reducing administration number of times clinically, improving compliance offer Good material base；Furthermore, this compound can exist with the solid-state form of crystal formation, is conducive to producing, storing and preparation Preparation；It addition, this compound not only have anticoagulation, antithrombotic effect but also can be used for treating or preventing cerebral ischemia Property disease or improve sleep.
Summary of the invention
It is an object of the present invention to provide a kind of novel triazolopyrimidines derivant, this compound not only has anticoagulant Blood, antithrombotic effect, can be used for treating or preventing cerebral ischemia diseases or improve sleep, and pharmacokinetic property be better than Ticagrelor.
Another object of the present invention is to provide the preparation method of this novel triazolopyrimidines derivant.
A further object of the present invention is the system of a kind of crystal formation and this crystal formation providing this novel triazolopyrimidines derivant Preparation Method.
A further object of the present invention is to provide the drug regimen comprising this novel triazolopyrimidines derivant or its crystal formation Thing.
A further object of the present invention be to provide this novel triazolopyrimidines derivant or its crystal formation prepare anticoagulation or Purposes in antithrombotic medicine.
A further object of the present invention is to provide this novel triazolopyrimidines derivant or its crystal formation in preparation treatment or pre- Purposes in the medicine of anti-cerebral ischemia diseases or improvement sleep.
In order to realize foregoing invention purpose, present invention firstly provides the triazolopyrimidine derivative shown in a kind of formula II or Its officinal salt, eutectic, hydrate or solvate,
The definition of described " salt " is well known to those skilled in the art of the present technique, refers to be passed through ion by cation and anion The effect of key and the compound that formed.
Described " eutectic " (Co-Crystals) refers to a kind of multicomponent crystal with fixing stoichiometric proportion, at this crystalline substance In body, each component is with molecular level, is combined by the effect of hydrogen bond or other non-covalent bonds, nonionic key and coexists.At medicine In eutectic, generally comprise active constituents of medicine and another kind of or multiple eutectic forms body (Co-crystal former).When individually Pure eutectic formed body at room temperature with liquid in the presence of, this eutectic also referred to as " solvate ", quilt when wherein solvent is water It is referred to as " hydrate ".Described " eutectic " also includes that so some have the multicomponent crystal of fixing stoichiometric proportion, brilliant at these Between body pharmaceutical active composition and other components, a part is by hydrogen bond or other non-covalent bond effects, and another part passes through Ionic bond or the active force between hydrogen bond and ionic bond and combine.
Described " salt " or " eutectic " also include the form such as salt or the solvate of eutectic, hydrate.When salt or eutectic are at certain When planting preparation in solvent, pulp or crystallization, this solvent is likely to enter in salt or eutectic crystal, forms solvate；When this When solvent is water, i.e. it is likely to form hydrate.
The method determining " eutectic " or " salt " is well known to those skilled in the art of the present technique, as divided with Advances in crystal X-ray diffraction Analysis etc..
According to the purpose of the present invention, the invention provides the triazolopyrimidine derivative shown in formula II or its officinal salt, The preparation method of eutectic, hydrate or solvate, the method includes:
(1), formula III compound is reacted production V compound with formula IV compound or its acid addition product,
In formula III, R1For F, Cl, Br, I, OH or OA, wherein A is hydroxy activated base；
(2), formula V compound deprotection is obtained formula II compound,
(3), optional, as required formula II compound is made salt, makes eutectic, make hydrate or make solvent and close Thing.
In said method step (1), " hydroxy activated base " in described formula III compound refers to such a group, introduces After this group, the reactivity of the hydroxyl as leaving group can be improved, including sulfonyl, sulfinyl, hydrocarbon acyl group etc., concrete Such as mesyl, trifyl, p-toluenesulfonyl, trifluoroacetyl group etc..
In said method step (1), described " acid addition product " refer to a certain acid compound by ionic bond, hydrogen bond or its The material that the effect of his non-covalent bond combines with another compound, including salt, eutectic, solvate etc..Described formula IV chemical combination Thing is the conventional intermediate preparing ticagrelor, commercially viable buy or by literature method prepare.Described formula IV idic acid adds The acid in thing is become to include mineral acid or organic acid；The most suitable mineral acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid Or sulphuric acid etc.；Suitable organic acid is selected from L-TARTARIC ACID, dibenzoyl-L-tartaric, two pairs of toluyl groups-L-winestones Acid, R-MA, R-α-methoxyphenylacetic acid, fumaric acid, D-malic acid, D-camphorsulfonic acid, S-ketone group pinic acid, oxalic acid, acetic acid, Trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid etc..
In said method step (1), typically need to add in a certain amount of alkali and react the acid produced or by formula IV compound The acid that acid addition product introduces.Described alkali includes organic base or inorganic base；The most suitable organic base include tertiary amine (as triethylamine, Diisopropyl ethyl amine etc.)；Suitable inorganic base include alkali metal, alkaline-earth metal hydroxide (such as Lithium hydrate, hydroxide Sodium, potassium hydroxide etc.), carbonate (such as lithium carbonate, sodium carbonate, potassium carbonate etc.), bicarbonate is (such as sodium bicarbonate, potassium bicarbonate Deng), phosphate (such as sodium phosphate, potassium phosphate etc.), hydrophosphate (such as dibastic sodium phosphate, potassium hydrogen phosphate etc.) etc..
In said method step (1), as R in described formula III compound1During for OH, this step can farther include first by OH Activation is OA (A is hydroxy activated base, is defined as above), then the process reacted with formula IV compound or its acid addition product.
In said method step (1), reaction dissolvent is chosen as the mixed solvent of solvent and the water being immiscible in water, Qi Zhongsuo State and be immiscible in the solvent of water and be selected from toluene, dichloromethane etc. or their mixture；Reaction dissolvent is also chosen as non-proton Solvent, wherein said aprotic solvent selected from can acetonitrile, toluene, dichloromethane, acetone, dimethoxy-ethane, oxolane, two Oxygen six ring, N-Methyl pyrrolidone, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, hexamethyl phosphoramide, dimethyl are sub- Sulfone, sulfolane etc. or their mixture.
In said method step (1), described formula III compound and formula IV compound or the molar ratio of its acid addition product Generally 0.7:1 to 1.3:1.
In said method step (1), reaction temperature generally-10 DEG C is to solvent boiling point.
In said method step (2), the generally acid of the reagent of described deprotection, selected from organic acid and mineral acid；Suitable Organic acid is selected from methanesulfonic acid or trifluoroacetic acid etc.；Suitable mineral acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid or sulphuric acid etc..
In said method step (2), reaction dissolvent generally comprises the mixed solvent of water and organic solvent composition, the most organic Solvent selected from methanol, ethanol, isopropanol, the tert-butyl alcohol, oxolane, dioxane, acetonitrile, acetone, toluene, dichloromethane etc..
In said method step (2), reaction temperature is generally 0 DEG C to solvent boiling point.
In said method step (1) or (2), the method that the determination in response time can use this area conventional is carried out, as adopted With TLC, HPLC monitoring etc..
In said method step (1), described formula III compound can be prepared by the preparation method that the present invention provides, the method Including:
(a), formula VI compound or its acid addition product are reacted with formula VII compound and to obtain formula VIII compound,
R in formula VII and VIII1It is defined as above, the R in formula VII2For F, Cl, Br, I or-OA, A is defined as above；
(b), formula VIII compound is changed into formula III compound in the presence of diazo reagent,
In formula III and VIII, R1It is defined as above.
In said method step (a), the acid in the sour addition product of described formula VI compound includes mineral acid or organic acid；Its In suitable mineral acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulphuric acid etc.；Suitable organic acid is selected from L-winestone Acid, dibenzoyl-L-tartaric, two pairs of toluyl groups-L-TARTARIC ACIDs, oxalic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzene sulphurs Acid, p-methyl benzenesulfonic acid etc..
In said method step (a), described formula VII compound and formula VI compound or the molar ratio of its acid addition product Generally 3:1 to 0.8:1.
In said method step (a), typically need to add in a certain amount of alkali and react the acid produced or by formula VI compound The acid that acid addition product introduces.Described alkali includes organic base or inorganic base；The most suitable organic base include tertiary amine (as triethylamine, Diisopropyl ethyl amine etc.)；Suitable inorganic base include alkali metal, alkaline-earth metal hydroxide (such as Lithium hydrate, hydroxide Sodium, potassium hydroxide etc.), carbonate (such as lithium carbonate, sodium carbonate, potassium carbonate etc.), bicarbonate is (such as sodium bicarbonate, potassium bicarbonate Deng), phosphate (such as sodium phosphate, potassium phosphate etc.), hydrophosphate (such as dibastic sodium phosphate, potassium hydrogen phosphate etc.) etc..
In said method step (a), reaction dissolvent is selected from ethanol, isopropanol, triethylene glycol, the tert-butyl alcohol, isobutanol, diformazan Epoxide ethane, toluene, n-butyl alcohol, glycerol, ethylene glycol, Polyethylene Glycol-200, PEG-4000, Polyethylene Glycol-600, poly-second Glycol-800, N-Methyl pyrrolidone, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, hexamethyl phosphoramide, dimethyl Sulfoxide, sulfolane, dioxane etc. or their mixture.
In said method step (a), reaction temperature is generally 70 DEG C to solvent boiling point.
In said method step (b), described " diazo reagent " is selected from nitrous acid or nitrites etc., and wherein nitrous acid can By nitrite (such as sodium nitrite, potassium nitrite etc.) and acid (example hydrochloric acid, acetic acid etc.) preparation in situ, wherein nitrites includes Amyl nitrite etc..
In said method step (b), described formula VIII compound is generally 1:0.8 extremely with the molar ratio of diazo reagent 1:2。
In said method step (b), solvent is selected from toluene, acetic acid, water etc. or its mixture.
In said method step (b), reaction temperature generally-15 DEG C～40 DEG C.
In said method step (a) or (b), the method that the determination in response time can use this area conventional is carried out, as adopted With TLC, HPLC monitoring etc..
In said method step (a) or (b), after the completion of reaction, the method pair conventional with this area can be farther included The post processings such as product carries out separating, purification or separated after be directly used in next step without further purification.
In said method step (a), described formula VII compound is the conventional intermediate preparing ticagrelor, commercially viable purchases Obtain or press literature method to prepare；Described formula VI compound or its acid addition product can be by the preparation method systems in following embodiment ?.
In one embodiment, the invention provides a kind of formula VI compound or the preparation method of its acid addition product, the party Method includes:
(), by formula Ⅸ compound or its acid addition product obtain formula Ⅹ compound through amido protecting,
In formula Ⅹ, R3For amino protecting group, R4For hydrogen or and R3In the lump as amino protecting group；
(), formula Ⅹ compound reacted with formula Ⅺ compound obtain formula Ⅻ compound,
R in formula Ⅹ and Ⅻ3And R4It is defined as above, the R in formula Ⅺ5For F, Cl, Br, I ,-OH or-OA, A is defined as above；
(), by formula Ⅻ compound removal amino protecting group obtain formula VI compound,
R in formula Ⅻ3And R4It is defined as above；
(), optional, converts the sour addition product of an accepted way of doing sth VI compound as required by formula VI compound.
In said method step (), described formula Ⅸ compound is the conventional intermediate preparing ticagrelor, commercially viable purchases Obtain or press literature method to prepare.Acid in the sour addition product of described formula Ⅸ compound includes mineral acid or organic acid；The most suitable Mineral acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulphuric acid etc.；Suitable organic acid selected from L-TARTARIC ACID, two Benzoyl-L-TARTARIC ACID, the two pairs of toluyl groups-L-TARTARIC ACIDs, oxalic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, right Toluenesulfonic acid etc..
In said method step (), described " amido protecting " is the ordinary skill in the art；Conventional amino protecting group bag Include benzyloxycarbonyl group (Cbz), tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl group (Fmoc), allyloxycarbonyl (Alloc), trimethyl silicane second Oxygen carbonyl (Teoc), phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), adjacent (to) Nitrobenzol Sulfonyl (Ns), trityl (Trt), 2,4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (Pmb) etc.；Described " R4With R3 In the lump as amino protecting group " situation such as, when amino protecting group select phthalyl (Pht) time, R4With R3Generation in the lump Table phthalyl.When selecting amino protecting group, preferred amino protecting group is by being made when removing this amino protecting group Method be conducive in formula VI compound ehter bond to keep stable.
In said method step (), typically need to add in a certain amount of alkali and react the acid produced or by formula Ⅸ compound The acid that acid addition product introduces.Described alkali includes organic base or inorganic base；The most suitable organic base include tertiary amine (as triethylamine, Diisopropyl ethyl amine etc.)；Suitable inorganic base include alkali metal, alkaline-earth metal hydroxide (such as Lithium hydrate, hydroxide Sodium, potassium hydroxide etc.), carbonate (such as lithium carbonate, sodium carbonate, potassium carbonate etc.), bicarbonate is (such as sodium bicarbonate, potassium bicarbonate Deng), phosphate (such as sodium phosphate, potassium phosphate etc.), hydrophosphate (such as dibastic sodium phosphate, potassium hydrogen phosphate etc.) etc..
In said method step (), described formula Ⅺ compound is commercially viable to be buied.
In said method step (), typically need to add a certain amount of alkali, described alkali includes organic base or inorganic base；Wherein Suitable organic base includes tertiary amine (such as triethylamine, diisopropyl ethyl amine etc.), alkali metal, alkaline-earth metal alcoholates (such as uncle Butanol lithium, sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol magnesium etc.) etc.；Suitable inorganic base includes the hydrogenation of alkali metal, alkaline-earth metal Thing (such as sodium hydride, hydrofining etc.), alkali metal, alkaline-earth metal hydroxide (such as Lithium hydrate, sodium hydroxide, potassium hydroxide Deng), carbonate (such as lithium carbonate, sodium carbonate, potassium carbonate etc.), bicarbonate (such as sodium bicarbonate, potassium bicarbonate etc.), phosphate (such as sodium phosphate, potassium phosphate etc.), hydrophosphate (such as dibastic sodium phosphate, potassium hydrogen phosphate etc.) etc..
In said method step (), described " removal amino protecting group " is the ordinary skill in the art, is preferred beneficial for In formula VI compound, ehter bond keeps stable method, such as uses the method such as alkaline reagent, hydrogenolysis to remove amino protecting group.
In said method step (), () or (), after the completion of reaction, can farther include by this area routine The post processings such as product is separated by method, purification or separated after be directly used in next step without further purification.
The present invention is on the basis of the triazolopyrimidine derivative shown in formula II is prepared in offer, it is further provided in series Intermediate compounds therefor: formula III compound, formula V compound, formula VI compound, formula VIII compound or formula Ⅻ compound, their structure And preferred compound is summarized in down:
R in formula1For F, Cl, Br, I, OH
Or OA, wherein A is hydroxy activated
Base,
R in formula1For F, Cl, Br, I, OH
Or OA, wherein A is hydroxy activated
Base,
R in formula3For amino protecting group, R4For.Hydrogen or and R3In the lump as amido protecting
Base,
According to the purpose of the present invention, the invention provides the formula II compound of a kind of crystalline state, further, the present invention carries Supply a kind of crystal formation of formula II compound, be defined as crystal formation A.
The feature of powder x-ray diffraction collection of illustrative plates of formula II compound crystal form A that the present invention provides is: be 4.4 ° in 2 θ values ±0.2°、15.4°±0.2°、15.7°±0.2°、18.8°±0.2°、20.0°±0.2°、20.7°±0.2°、21.1°± 0.2 °, 26.2 ° ± 0.2 °, 26.6 ° ± 0.2 °, 27.5 ° ± 0.2 ° equipotential be equipped with characteristic diffraction peak.
In one embodiment, the powder x-ray diffraction collection of illustrative plates of formula II compound crystal form A that the present invention provides Be characterized as: 2 θ values be 4.4 ° ± 0.2 °, 10.3 ° ± 0.2 °, 15.4 ° ± 0.2 °, 15.7 ° ± 0.2 °, 17.3 ° ± 0.2 °, 18.8°±0.2°、20.0°±0.2°、20.7°±0.2°、21.1°±0.2°、21.7°±0.2°、26.2°±0.2°、26.6° ± 0.2 °, 27.5 ° ± 0.2 °, 28.2 ° ± 0.2 ° equipotential be equipped with characteristic diffraction peak.
Further, the powder x-ray diffraction collection of illustrative plates that formula II compound crystal form A of the present invention represents with 2 θ angles There is characteristic diffraction peak and relative intensity in following position:
In one embodiment, formula II compound crystal form A that the present invention provides has powder X-ray as shown in Figure 1-penetrate Feature representated by ray diffraction diagram spectrum, i.e. the powder x-ray diffraction collection of illustrative plates of formula II compound crystal form A that the present invention provides are basic As shown in Figure 1.
The powder x-ray diffraction analysis of formula II compound crystal form A of the present invention is under ambient temperature and ambient humidity, CuK α source through Holland's PANalytical X`Pert PRO type Powder X-ray DiffractometerMeasure." environment temperature Degree " it is usually 0～40 DEG C；" ambient humidity " is usually the relative humidity of 30%～80%.
In one embodiment, formula II compound crystal form A that the present invention provides has differential scanning as shown in Figure 2 Feature representated by calorimetry (DSC) collection of illustrative plates, i.e. its endotherm peak temperature are 150 DEG C ± 2 DEG C or 150 DEG C ± 1 DEG C.
In one embodiment, formula II compound crystal form A that the present invention provides has thermogravimetric analysis as shown in Figure 3 (TGA) thermogravimetric analysis (TGA) collection of illustrative plates of formula II compound crystal form A that the feature representated by collection of illustrative plates, the i.e. present invention provide is the most such as Shown in Fig. 3.
In one embodiment, formula II chemical combination in the formula II compound crystal form A mixture of the preparation that the present invention provides Thing crystal formation A content (mass content) generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.
The invention provides the preparation method of a kind of formula II compound crystal form A, the method includes:
(1), formula II compound is dissolved in esters solvent；
(2), solid is separated out；
(3), isolated solid is divided；
(4), optionally, the solid separated is dried.
In said method step (1), described " esters solvent " is selected from ethyl acetate, methyl acetate, isopropyl acetate, acetic acid N-propyl, n-butyl acetate etc. or their mixed solvent, ethyl acetate, isopropyl acetate, n-propyl acetate or they Mixture.
In said method step (1), the selected solvent load in units of ml and the formula II compound amount in units of g Ratio be generally 1:1 to 30:1；The mode that can use heating is dissolved.
In said method step (1), the solution temperature of formula II compound is generally room temperature to solvent boiling point.
In said method step (2), the mode of described " precipitation solid " includes that cooling separates out solid, adds anti-solvent precipitation Solid, concentrating out and separate out solid after partial solvent, add crystal seed and separate out solid etc., these methods can be used alone can also group Close and use, can carry out under static conditions, it is also possible to carry out under agitation.It is the most right that described " anti-solvent " refers to The solvent that the dissolubility of formula II compound is bad, such as isobutyltrimethylmethane., normal hexane, normal heptane, petroleum ether etc. or their mixture, its In preferably isobutyltrimethylmethane., normal heptane.
In said method step (3), the mode of described " separation " can use sucking filtration or centrifugal.
In said method step (4), the temperature of described " being dried " is generally 20～120 DEG C, preferably 40～100 DEG C；Permissible Constant pressure and dry, it is also possible to drying under reduced pressure.
In one embodiment, the preparation method of formula II compound crystal form A of the present invention includes:
(1), formula II compound is dissolved in isopropyl acetate；
(2), cool down or add anti-solvent crystallize；Wherein anti-solvent is selected from isobutyltrimethylmethane., normal hexane, normal heptane, petroleum ether etc. Or their mixture, preferably isobutyltrimethylmethane., normal heptane；
(3), isolated solid is divided；
(4), optionally, the solid separated is dried；Baking temperature is generally 20～120 DEG C, preferably 40～100 ℃；Can be with constant pressure and dry, it is also possible to drying under reduced pressure.
Another object of the present invention is to provide brilliant containing formula II compound, crystalline state formula II compound or formula II compound The pharmaceutical composition of type A and formula II compound, crystalline state formula II compound or formula II compound crystal form A are used for manufacturer's medication The application of thing.
In order to realize this purpose, on the one hand the invention provides a kind of comprise therapeutically effective amount formula II compound, crystallization Stance II compound or formula II compound crystal form A and the pharmaceutical composition of pharmaceutic adjuvant.
On the other hand, the invention provides formula II compound, crystalline state formula II compound or formula II compound crystal form A in system For anticoagulation, antithrombotic, treat or prevent cerebral ischemia diseases or improve the application in the medicine slept.It is usually and treatment is had The formula II compound of effect amount, crystalline state formula II compound or formula II compound crystal form A and one or more pharmaceutic adjuvants make medicine Compositions or preparation, this pharmaceutical composition or preparation be known in the art in the way of be prepared.
Aforementioned pharmaceutical compositions or preparation can be mainly used in treatment or prevention as a kind of anticoagulation or antithrombotic medicine There is coronary artery, cerebrovascular or the thrombosis of peripheral blood vessel patient and complication thereof, particularly, acute for reducing The incidence rate of the thrombotic cardiovascular event of coronary syndrome patient.It addition, aforementioned pharmaceutical compositions or preparation can conducts The medicine that a kind for the treatment of or prevention cerebral ischemia diseases (as ischemic cerebral apoplexy is medium) or improvement are slept.
The dosage form of aforementioned pharmaceutical compositions or preparation includes: tablet, capsule, pill, granule, syrup, powder, tongue Lower tablet, suspensoid, solution, injectable formulation, aerosol, dry powder doses, suppository, ointment, ointment, gel etc..It Feature according to respective dosage form, route of administration includes being administered orally, Sublingual, parenterally is (such as intravenous injection, intramuscular injection, subcutaneous note Penetrate), transpulmonary/trachea or percutaneous etc..
The dosage of above-mentioned composition or preparation according to conditions of patients character and seriousness, route of administration and patient age, Body weight etc. are adjusted, and general daily dose is between 1mg to 1g, between preferably 30mg to 300mg；Every day can with single administration, Can also multiple dosing.
Aforementioned pharmaceutical compositions or preparation can also comprise other suitable active component.
In one embodiment, the pharmaceutical composition that the present invention provides is oral solid formulation, preferred tablet or glue Wafer.This oral solid formulation in addition to active component formula II compound, crystalline state formula II compound or formula II compound crystal form A, Possibly together with pharmaceutic adjuvant, described pharmaceutic adjuvant is all the pharmaceutic adjuvant that this area is conventional, including filler, disintegrating agent, bonding Agent, lubricant etc..
Described filler generally comprise mannitol, calcium hydrogen phosphate, microcrystalline Cellulose, pregelatinized Starch, lactose, sucrose, Calcium sulfate, micropowder silica gel etc., they can be used alone and can also be used in mixed way.
Described disintegrating agent generally comprises carboxymethyl starch sodium, sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, crystallite Cellulose, crospolyvinylpyrrolidone, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, agar, calcium carbonate and carbonic acid Hydrogen sodium etc., they can be used alone and can also be used in mixed way.
Described binding agent generally comprises hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Polyethylene Glycol, polyvidone, micro- Crystalline cellulose, starch slurry, water, the ethanol solution etc. of various concentration, they can be used alone and can also be used in mixed way.
Described lubricant generally comprises magnesium stearate, Pulvis Talci, stearic acid, calcium stearate, Palmic acid, aluminium silicate, hard Acyl amine, solid polyethylene glycol etc., they can be used alone and can also be used in mixed way.
If necessary, it is also possible in aforementioned pharmaceutical compositions or preparation, add other adjuvants, as sweeting agent (as Ah Si Patan, steviosin etc.), coloring agent (such as ferrous oxide, titanium dioxide etc.), stabilizer is (such as vitamin E, thymol, sweet ammonia Acid etc.), surfactant (such as sodium laurylsulfate etc.) etc..
The preparation of above-mentioned oral solid formulation can be according to the conventional method preparing oral solid formulation in the art Carry out, such as: tablet can be prepared to use the mode such as wet granule compression tablet, the capsule mode system such as wet granulation can be used encapsulated Standby.When described oral solid formulation is tablet, film coated tablet or coated tablet can be made as required to its further coating Agent.Coated substrate includes cellulose family, crylic acid resin, saccharide, such as hydroxypropyl level methylcellulose, sucrose etc., the most also may be used Add plasticizer, antiplastering aid, opacifier.
Test shows, formula II compound, crystalline state formula II compound or the formula II compound crystal form A activity that the present invention provides Suitable with ticagrelor, oral absorption is better than ticagrelor, can be metabolized to ticagrelor in vivo, thus when extending effect Between, for reducing administration number of times clinically, raising compliance provides good material base；Furthermore, formula II compound, crystalline state The physicochemical property of formula II compound or formula II compound crystal form A is conducive to producing, storing and the preparation of preparation；It addition, this chemical combination Thing not only has anticoagulation, antithrombotic effect, but also can be used for treating or preventing cerebral ischemia diseases or improve sleep.
Accompanying drawing explanation
Fig. 1 is powder x-ray diffraction (PXRD) collection of illustrative plates of formula II compound crystal form A.
Fig. 2 is means of differential scanning calorimetry (DSC) collection of illustrative plates of formula II compound crystal form A.
Fig. 3 is thermogravimetric analysis (TGA) collection of illustrative plates of formula II compound crystal form A.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, can make professional and technical personnel in the field more fully Understand the present invention, but limit the scope of the present invention never in any form.
In embodiment1H NMR and13C NMR test is using deuterated dimethyl sulfoxide as test solvent, with tetramethylsilane Make internal standard, at room temperature measure by Bruke AV-II 400MHz nuclear magnetic resonance analyser.
In embodiment, mass spectrometric measurement is to use Agilent Quadrupole LC/MS 6120B, and ESI holotype completes.
In embodiment, powder x-ray diffraction analysis is by Holland's PANalytical X`Pert PRO type Powder X-ray Diffractometer Measuring, test condition is for being 4 °-50 ° with θ-θ configuration, sweep limits, and step-length is 0.0130 °, scans continuously.Testing light source is Copper target K α radiation；Voltage and current is respectively 40kV and 40mA.Method for making sample is: take appropriate sample with spoon at ambient conditions Originally it is placed in the groove of glass load sample sheet, suitably rolls with microscope slide, make sample be evenly distributed in load sample sheet groove, then with carrying Sample surfaces is struck off by slide.During test, sample does not rotates in himself plane.
In embodiment, differential scanning calorimetric analysis is to be surveyed by the resistance to DSC 214Polyma type differential scanning calorimeter speeding to produce Fixed.Test condition is: heating rate is 10 DEG C/min, and Range of measuring temp is 35 DEG C-220 DEG C.
In embodiment, thermogravimetric analysis is to be measured by the resistance to TG 209F3 type thermogravimetric analyzer speeding to produce.Test condition is: Heating rate is 10 DEG C/min, Range of measuring temp 35 DEG C-350 DEG C.
Embodiment 1 2-[[(3aR, 4S, 6R, 6aS)-6-amino tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3- Two epoxide-4-bases] epoxide] preparation of-Cvclopropvlmethvl ethylether (formula VI compound)
Step: N-[(3aS, 4R, 6S, 6aR)-tetrahydrochysene-6-(2-hydroxyl-oxethyl)-2,2-dimethyl-4H-cyclopentadiene And-1,3-two epoxide-4-base] preparation of-benzyq carbamate (formula Ⅹ-1 compound)
By 2-[[(3aR, 4S, 6R, 6aS)-6-amino tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxa- 4-yl] epoxide]-ethanol L-TARTARIC ACID salt (the L-TARTARIC ACID salt of formula Ⅸ compound) 106.06g, hexone 1500ml, potassium carbonate 131.61g and water 658ml mixing, then drip benzyl chloroformate (Cbz-Cl) at 25～35 DEG C 54.16g, continues stir about 14 hours after dripping, and stopped reaction separates upper organic phase, aqueous phase hexone 500ml back extraction, merges organic facies, and concentrating under reduced pressure, concentrate obtains formula Ⅹ-1 compound through silica gel column chromatography purification.
1H NMR (400MHz, DMSO-d6) δ: 1.215 (s, 3H)；1.359 (s, 3H)；(1.715-1.769 m, 1H)； (2.083-2.147 m, 1H)；(3.415-3.509 m, 4H)；(3.785-3.839 m, 2H)；(4.406-4.420 d, 1H)； (4.467-4.482 d, 1H)；(4.714-4.739 m, 1H)；(5.027 s, 2H)；(6.855-6.875 d, 1H)；7.293-7.372 (m, 5H).
(+)-ESI-MS:352.2。
Step: N-[(3aS, 4R, 6S, 6aR)-tetrahydrochysene-6-(2-cyclopropyl-methoxy base oxethyl)-2,2-dimethyl- 4H-cyclopenta-1,3-two epoxide-4-base] preparation of-benzyq carbamate (formula Ⅻ-1 compound)
Under nitrogen protection, formula Ⅹ-1 compound 48.00g and DMF 300ml are mixed, then-5～ It is dividedly in some parts potassium tert-butoxide 18.37g at 5 DEG C, then stir about drips bromomethyl cyclopropane (formula Ⅺ-1 after 1 hour at-5～5 DEG C Compound) 22.14g and the mixed solution of DMF 15ml, continue stirring reaction about after adding at-5～5 DEG C 5 hours；The 200ml cancellation that adds water is reacted, and then adds the extraction of ethyl acetate 400ml, separates organic facies, and organic facies is successively through water 400ml × 3 are washed, saturated sodium-chloride water solution 200ml washs, anhydrous sodium sulfate is dried, concentrating under reduced pressure, and concentrate is through silicagel column Chromatography purification obtains formula Ⅻ-1 compound.
1H NMR (400MHz, DMSO-d6) δ :-0.023-0.012 (m, 2H)；0.276-0.319 (m, 2H)；0.803- 0.874 (m, 1H)；(1.154 s, 3H)；(1.297 s, 3H)；(1.679-1.714 m, 1H)；(1.998-2.061 m, 1H)； (3.039-3.180 m, 2H)；(3.428-3.525 m, 4H)；(3.743-3.809 m, 2H)；(4.350-4.366 d, 1H)； (4.415-4.431 d, 1H)；(4.912-4.986 m, 2H)；(6.561-6.582 d, 1H)；(7.254-7.324 m, 5H).
(+)-ESI-MS:406.2。
Step: 2-[[(3aR, 4S, 6R, 6aS)-6-amino tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-two Epoxide-4-base] epoxide] preparation of-Cvclopropvlmethvl ethylether (formula VI compound)
Ⅻ-1 compound 29.00g, dehydrated alcohol 250ml and 10% palladium carbon 11.60g are mixed, are passed through hydrogen, 20～ Stir about 21 hours at 25 DEG C；Filtering, wash filter cake with dehydrated alcohol 50ml and integrate with filtrate, filtrate obtains formula through concentrating under reduced pressure VI compound.
(+)-ESI-MS:272.3.
Embodiment 2 2-[{ (3aR, 4S, 6R, 6aS)-6-[the bromo-5-of 7-(rosickyite base)-3H-[1,2,3] triazol [4,5- D] pyrimidin-3-yl]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] Dioxol-4-yl } epoxide]-1- The preparation of Cvclopropvlmethvl ethylether (formula III-2 compound)
Step a:2-[((3aR, 4S, 6R, 6aS)-6-{ [the bromo-2-of 5-amido-6-(rosickyite base) pyrimidine-4-yl] amino }- 2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] Dioxol-4-yl) epoxide]-1-Cvclopropvlmethvl ethyl The preparation of ether (formula VIII-2 compound)
Formula VI compound 17.20g, formula VII-1 compound 23.87g and N-Methyl pyrrolidone 67ml are mixed, adds three Ethamine 22.45g, nitrogen protection under at 86～93 DEG C stir about 6 hours；Add water 70ml and isopropyl acetate 200ml extraction, point Go out organic facies, aqueous phase isopropyl acetate 100ml back extraction, merge organic facies, organic facies is successively through the washing of water 150ml × 3, decompression Concentrating, concentrate obtains formula VIII-2 compound after purification through silica gel column chromatography.
1H NMR (400MHz, DMSO-d6) δ: 0.113-0.150 (m, 2H)；0.407-0.453 (m, 2H)；0.940- 0.977 (m, 4H)；1.226 (s, 3H)；(1.383 s, 3H)；(1.597-1.689 m, 2H)；(1.794-1.850 m, 1H)； (2.244-2.309 m, 1H)；(2.957-2.993 m, 2H)；(3.229-3.246 d, 2H)；(3.498-3.601 m, 4H)； (3.865-3.886 t, 1H)；(4.260-4.302 m, 1H)；(4.508-4.549 m, 2H)；(4.626 s, 2H)；6.556-6.573 (d, 1H).
(+)-ESI-MS:517.2,519.2.
Step b:2-[{ (3aR, 4S, 6R, 6aS)-6-[the bromo-5-of 7-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] Pyrimidin-3-yl]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] Dioxol-4-yl } epoxide]-1-ring The preparation of hydroxypropyl methyl ethylether (formula III-2 compound)
VIII-2 compound 24.50g and toluene 245ml are mixed, be then sequentially added at 0～10 DEG C acetic acid 15.61g and Sodium nitrite in aqueous solution (sodium nitrite 5.55g+ water 8.9ml), continues stir about 1 hour at 0～10 DEG C after adding；Add Wet chemical (potassium carbonate 17.00g+ water 94ml) cancellation is reacted, and separates organic facies, and the toluene obtaining formula III-2 compound is molten Liquid, can be directly used for next step reaction.
(+)-ESI-MS:528.2,530.2.
Embodiment 3 (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3,4-difluorophenyl)-cyclopropyl] amino }-5- (rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-5-(2-cyclopropyl-methoxy base oxethyl)-1,2-ring penta The preparation of alkane glycol (formula II compound)
Step 1:2-({ (3aR, 4S, 6R, 6aS)-6-{ [7-{ [(1R, 2S)-2-(3,4-difluorophenyl)-cyclopropyl] ammonia Base }-5-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-2,2-dimethyl tetrahydro-3aH-cyclopentadiene And [d] [1,3] Dioxol-4-yl epoxide] preparation of-1-Cvclopropvlmethvl ethylether (formula V compound)
By the toluene solution of formula III-2 compound of embodiment 2 gained, water 70ml and (1R, 2S)-2-(3,4-difluorobenzene Base) cyclopropylamine R-MA salt (the R-MA salt of formula IV compound) 15.18g mixing, at 0～10 DEG C, then drip three Ethamine 11.95g, stir about 2 hours at 10～20 DEG C again after dripping off；Separating organic facies, organic facies is successively through acetic acid aqueous solution The toluene solution of formula V compound is obtained after (acetic acid 1.96g+ water 245ml) and saturated sodium-chloride water solution 250ml washing, can be direct React for next step.
(+)-ESI-MS:617.3.
Step 2:(1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3,4-difluorophenyl)-cyclopropyl] amino }-5- (rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-5-(2-cyclopropyl-methoxy base oxethyl)-1,2-ring penta The preparation of alkane glycol (formula II compound)
By toluene solution and the methanol hydrochloride solution (concentrated hydrochloric acid 39.4ml+ methanol 55ml) of step 1 gained formula V compound Mixing, stir about 4.5 hours at 10～15 DEG C；Add water 100ml, then adjusts pH to be about 8 with triethylamine at 0～10 DEG C, point Go out organic facies, aqueous phase isopropyl acetate 250ml × 2 back extraction, merge organic facies, organic facies successively through water 200ml washing, saturated Sodium-chloride water solution 200ml washing, anhydrous sodium sulfate are dried and concentrating under reduced pressure, obtain formula II compound.
1H NMR (400MHz, DMSO-d6) δ: 0.127-0.163 (m, 2H)；0.417-0.462 (m, 2H)；0.807- 0.843and 0.941-1.006 (m, 4H)；(1.343-1.393 m, 1H)；1.468-1.579and 1.661-1.715 (m, 3H)；(2.011-2.081 m, 1H)；2.103-2.149and 2.253 (m, 1H)；(2.601-2.676 m, 1H)；2.821- (2.890 m, 1H)；(2.916-2.985 m, 1H)；3.083-3.093and 3.129-3.178 (m, 1H)；3.232-3.249 (d, 2H)；(3.509-3.631 m, 4H)；(3.759-3.785 m, 1H)；(3.950 m, 1H)；(4.546-4.596 m, 1H)；4.941- (5.009 q, 1H)；(5.031-5.041 d, 1H)；(5.099-5.115 d, 1H)；(7.066 m, 1H)；7.262-7.350 (m, 2H)；8.913-8.924and 9.326-9.336 (d, 1H).
13C NMR (100MHz, DMSO-d6) δ: 3.30,10.96,13.42,15.44,22.77,24.48,32.82, 33.62,34.51,61.09,68.94,69.61,74.26,74.76,75.17,82.32,115.24,115.42,117.38, 117.55,123.25,123.28,123.31,123.66,139.37,139.68,139.72,139.74,139.78,146.99, 147.11,148.59,148.72,149.41,149.53,149.86,151.02,151.15,154.43,155.85,168.79, 169.65。
(+)-ESI-MS:577.3.
The preparation of embodiment 4 formula II compound crystal form A
Formula II compound 2g is dissolved in isopropyl acetate 6ml at 40～50 DEG C, is subsequently adding isobutyltrimethylmethane. 6ml, stirring Crystallize about 4 hours, filters, and filter cake is drying under reduced pressure at 40～45 DEG C, obtains formula II compound crystal form A.
Fig. 1 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, and its measured value such as following table (takes the relative intensity diffraction more than 5% The measured value that peak is corresponding):
Fig. 2 is shown in by means of differential scanning calorimetry (DSC) collection of illustrative plates surveyed.Fig. 3 is shown in by thermogravimetric analysis (TGA) collection of illustrative plates surveyed.Should manage Solution other types equipment or different temperature readings may be provided with being different from above-mentioned condition.Therefore, the numeral provided Cannot function as absolute value.Skilled artisan will appreciate that these temperature exact value will by compound purity, example weight, add Hot speed and the impact of particle diameter.
The preparation of embodiment 5 formula II compound crystal form A
Formula II compound 2g is dissolved in isopropyl acetate 2ml at 50～55 DEG C, is subsequently adding isobutyltrimethylmethane. 4ml, stirring Crystallize about 4 hours, filters, obtains crystal formation A.
The preparation of embodiment 6 formula II compound crystal form A
Formula II compound 2g is at room temperature dissolved in isopropyl acetate 12ml, is subsequently adding isobutyltrimethylmethane. 20ml, stirring analysis Crystalline substance about 4 hours, filters, and filter cake is drying under reduced pressure at 70～75 DEG C, obtains crystal formation A.
The preparation of embodiment 7 formula II compound crystal form A
Formula II compound 2g is dissolved in ethyl acetate 4ml at 40～50 DEG C, is subsequently cooled to-10～0 DEG C, stirring analysis Crystalline substance about 2 hours, filters, and drying under reduced pressure at filter cake 40～45 DEG C obtains crystal formation A.
The preparation of embodiment 8 formula II compound crystal form A
Formula II compound 2g is dissolved in isopropyl acetate 20ml at 40～50 DEG C, is subsequently adding normal heptane 40ml, stirs Mixing crystallize about 4 hours, filter, filter cake is drying under reduced pressure at 40～45 DEG C, obtains crystal formation A.
The preparation of embodiment 9 formula II compound crystal form A
Formula II compound 2g is dissolved in isopropyl acetate 4ml and ethyl acetate 2ml at 40～50 DEG C, is subsequently adding different Octane 8ml, stirring and crystallizing about 4 hours, filters, drying under reduced pressure at filter cake 90～100 DEG C, obtains crystal formation A.
Embodiment 10 formula II compound crystal form A stability test
Hereinafter test under high temperature, super-humid conditions for formula II compound crystal form A, after 15 days, carry out relevant material and crystalline substance Type detects.
Related substance HPLC method is had to detect:
Chromatographic condition: with octadecylsilane chemically bonded silica (Agilent ZORBAX SB-C18, 4.6 × 150mm, 1.8 μ M) for fixing phase, with the NaH of 0.01mol/L2PO4Buffer solution (with phosphorus acid for adjusting pH to 3.5) is that mobile phase A, acetonitrile are for flowing Phase B, column temperature is 40 DEG C, and flow velocity is 1ml/min, and detection wavelength is 242nm, according to following table gradient elution:
Time (min) A% (V/V) B% (V/V)
0 80 20
20 55 45
25 55 45
45 30 70
50 30 70
55 80 20
60 80 20
The preparation of flowing phase: take two hypophosphite monohydrate sodium dihydrogen 1.56g, the 1000ml that adds water and dissolve, regulate pH3.5 with phosphoric acid, Mobile phase A is i.e. obtained with 0.22 μm membrane filtration；Taking chromatograph acetonitrile is Mobile phase B.
Need testing solution: (lucifuge operation) takes this product about 20mg, accurately weighed, puts in 10ml measuring bottle, dissolves with diluent And it is diluted to scale, shake up, to obtain final product.
Algoscopy: according to high performance liquid chromatography (Chinese Pharmacopoeia two annex V D of version in 2010) test.
Testing result is as follows:
This result of the test shows: formula II compound crystal form A has good stability.
Embodiment 11 contains tablet and the preparation thereof of formula II compound crystal form A
Prescription:
Component Content (mg/ sheet)
Formula II compound crystal form A 99.0
Mannitol 126.0
Calcium phosphate dibasic dihydrate 63.0
Hydroxypropyl cellulose 9.0
Carboxymethyl starch sodium 9.0
Magnesium stearate 3.0
Preparation: by formula II compound crystal form A in upper table component, mannitol, calcium phosphate dibasic dihydrate, hydroxypropyl cellulose Mix with carboxymethyl starch sodium, use water wet granulation, be dried, granulate, mix with magnesium stearate, tabletting, to obtain final product.
The Pharmacodynamics in vitro test of embodiment 12 antiplatelet aggregation
The present invention is external by suppression ADP induction rabbit platelet aggregation test evaluation formula II compound and ticagrelor Activity.
Take rabbit hind leg venous blood to be centrifuged, separate rich in hematoblastic blood plasma, be separately added into solvent, the formula II of a series of concentration Compound or ticagrelor, after jointly hatching 5min at 37 DEG C, add ADP induced platelet aggregation.5min is detected after adding ADP Interior maximum platelet aggregation rate (PAGm).Each group is all provided with 3 parallel pipes.
Packet and sample-adding situation are as follows:
Solvent DMSO in platelet system final concentration of 0.1%, compared with blank group, will not be to platelet body System produces impact.
Group Maximum agglutination rate (%) Suppression ratio (%)
Negative control group 49.7±1.5 -
DMSO Vehicle controls group 49.0±0.6 -
The formula II compound of variable concentrations is as follows with the contrast of maximum agglutination rate in ticagrelor group 5min and suppression ratio:
This result of the test shows: formula II compound has the anti-platelet activity similar with ticagrelor in vitro.
The internal pharmacodynamics test of embodiment 13 antiplatelet aggregation
The present invention have rated the activity in vivo of formula II compound and ticagrelor by Beagle dog PAgT.
Article 6, male Beagle dog is randomly divided into 2 groups, gives formula II chemical combination according to equimolar than per os respectively after overnight fasting Thing and ticagrelor.Clean 7 days after first administration, carry out the 2nd and take turns administration.After administration, timing takes hematometry corresponding index.
Every time 0.5,1,1.5,2,4,8,24,30 respectively to gather whole blood 2mL, 3.2% sodium citrate 1:9 anti-before medicine and after medicine Solidifying.Low-speed centrifugal (300g) 5min produces platelet rich plasma (PRP).Remaining sample continues high speed centrifugation (3000g) 10min system Take platelet poor plasma (PPP).PRP is adjusted to PC for 2 × 10 with PPP8/ mL, detects maximum platelet aggregation rate, Calculate platelet aggregation inhibition rate.
This result of the test shows, the platelet aggregation inhibition rate of formula II compound is auspicious less than for lattice in 8 hours upon administration Lip river, but after 8 hours, higher than ticagrelor.
Pharmacokinetic trial in embodiment 14 body
The present invention is administered the internal pharmacokinetics that have rated formula II compound with ticagrelor by SD rat oral.
16 SD rats, are randomly divided into 2 groups, and often 8 (male and female half and half) of group, give respectively according to equimolar ratio after overnight fasting Give formula II compound, ticagrelor.Respectively at be administered before and administration after 0.133 (8min), 0.25 (15min), 0.5 (30min), 1,2,4,8,12 and 24h whole blood 200 μ L, anticoagulant heparin are respectively gathered.In 4 DEG C, 3200rpm/min is centrifuged 10min separated plasma, inspection Survey wherein formula II compound and the concentration of ticagrelor.
Each group main pharmacokinetic parameters is as follows:
This result of the test shows:
(1), after formula II compound or ticagrelor per os give rat, all there is sex difference, former with ticagrelor grind In data, the situation after Oral Administration in Rats ticagrelor is consistent.
(2), formula II compound group detects substantial amounts of ticagrelor, show that formula II compound in vivo can be smoothly Metabolism is ticagrelor.
(3), formula II compound group or ticagrelor group equimolar be administered, but the AUC of formula II compound group ticagrelor, CmaxApparently higher than ticagrelor group, owing to formula II compound itself also has a drug activity similar with ticagrelor, therefore, If based on drug activity thing, the drug activity thing exposed amount of formula II compound group will be apparent from higher than ticagrelor group.This shows The bioavailability of formula II compound and property metabolite thereof is higher than ticagrelor.
(4), the Tmax of formula II compound group ticagrelor than the delay of ticagrelor, when being conducive to extending drug effect Between.
The embodiment 15 impact on local rats with cerebral ischemia cerebral infarct volume
(1), test material and method
Wistar rat, body weight 250-280g.Perioperatively is individually raised, and room temperature keeps 23-25 DEG C, has feed by oneself and enters Water.TMCAO model is prepared according to the method for longa etc..Rat 10% chloral hydrate anesthesia (350mg/kg, i.p.), body temperature Maintaining 37 ± 0.5 DEG C, dorsal position is fixed on operating-table.Cut skin along neck median line, carefully separate right carotid (CCA), external carotid artery (ECA), internal carotid artery (ICA).ECA ligation is cut off, stretches with ICA in line.ECA cuts one Osculum, by root length 4.0cm, round end silication nylon rope (being coated with 0.1% poly-D-lysine) the thus opening of diameter 0.26mm Insert ICA about 1.85-2.00cm, refer to rat brain prerolandic artery Rolando section start, block the supply of blood flow of middle cerebral artery.Ischemia 2 is little Carefully extracting nylon wire time after out, ligation ECA opening suture operation otch, animal is put back to and fills in cage 24 hours again.
(2), test packet and administration
Rat random packet: model control group, water for injection (100ml/kg), formula II compound administration group (25,50, 100mg/kg), oral administration when 10 minutes after MCA blocking-up causes ischemia.
(3), the mensuration of cerebral infarct volume
After rat reperfusion injury 24 hours, broken end takes brain at once, removes tractus olfactorius, cerebellum and low brain stem, and it is crown Be cut into 6 (first to the 5th 2mm/ sheet, the 6th 4mm), be immediately placed in 5ml contain 1.5ml4%TTC and 0.1ml1MK2HPO4Solution in dye (37 DEG C, lucifuge) 20-30 minute, stirred once every 5 minutes therebetween.Dye through TTC After, normal structure deeply contaminates and takes on a red color, and infarction tissue is white.To often organize brain sheet marshalling, preservation of taking pictures.Seek the stalk calculating every Unleavened dough amasss, and final superposition is converted into infarct volume.Infarct volume represents with shared Interhemispheric percentage rate, to eliminate brain The impact of edema.
Cerebral infarct volume (the %)=volume of contralateral hemisphere volume-operation side non-infarcted portion of hemisphere (operation)/perform the operation is right The volume * 100% of side hemisphere
(4), result of the test
2 hours Reperfu-sion of ischemia are after 24 hours, and the cerebral infarct volume (%) of solvent control group is 33.8%.Sham operated rats does not has Any cerebral infarction is had to occur.Other group cerebral infarct volume results are as follows:
This result of the test shows: with solvent control group ratio, formula II compound oral administration all can be reduced significantly cerebral infarction Volume, i.e. formula II compound have the good effect improving symptoms of cerebral ischemia.
The embodiment 16 impact on Sleep in Rats effect
(1), test material
Animal origin: Kun Ming mice, 18-22 gram, male.Bio Clean Room for Animal experiment temperature 22 ± 2 DEG C, relative humidity 50-70%, animal feeding material.
This test sets formula II compound dosage as 25mg/kg, separately sets distilled water matched group.
Sample treatment: respectively take sample 25mg and add distilled water respectively to 20ml, make uniformly suspension, for examination.
(2), pentobarbital sodium above threshold dosage hypnosis test
Mice is randomly divided into matched group and formula II compound administration group, and continuous gavage, to sample 30 days, fills in the 30th day sample After stomach 15 minutes, to the pentobarbital sodium lumbar injection of each treated animal 50mg/kg.b.w, injection volume is 0.2ml/20g.b.w, Using mice righting reflex loss reach more than 1 minute as sleep criterion, observe to each group in pentobarbital sodium 60 minutes dynamic The time for falling asleep of thing and the length of one's sleep.
The impact of formula II compound on animals body weight is as follows:
This result of the test shows: formula II compound treated animal body weight compared with matched group, difference that there are no significant.
Above threshold the impact of pentobarbital sodium inducing mouse length of one's sleep of dosage is as follows:
Group Number of animals (only) Time for falling asleep (is divided) The length of one's sleep (divides)
Matched group 10 5.79±2.05 40.96±8.16
Formula II compound 10 5.78±1.88 55.16±7.80*
* P < 0.05 (Analysis of variance) compared with matched group
This result of the test shows: formula II compound treated animal above threshold dose of sodium pentobarbitone induce under the length of one's sleep with Matched group is compared, and has significant difference.
(3), pentobarbital sodium sub-threshold dose hypnosis test
Mice is randomly divided into matched group and formula II compound administration group, and continuous gavage, to sample 28 days, fills in the 28th day sample After stomach 15 minutes, to the pentobarbital sodium lumbar injection of each treated animal 30mg/kg.b.w, injection volume is 0.2ml/20g.b.w, with Mice righting reflex loss reach more than 1 minute as sleep criterion, observe to each treated animal in pentobarbital sodium 25 minutes There is the number of animals of sleep.
The impact of the pentobarbital sodium inducing mouse sleep incidence rate of sub-threshold dose is as follows:
Group Number of animals (only) Sleep number of animals (only) Sleep incidence rate (%)
Matched group 10 2 20
Formula II compound 10 6* 60*
* P < 0.05 compared with matched group (through X 2 test)
This result of the test shows: formula II compound group sub-threshold dose pentobarbital sodium induce under sleep number of animals and sleep Dormancy incidence rate, compared with matched group, all has significance poor.
Above-mentioned result of the test shows: formula II compound has the good effect improving sleep.

Claims (11)

1. the triazolopyrimidine derivative shown in formula II or its officinal salt, eutectic, hydrate or a solvate,
。
2. the triazolopyrimidine derivative shown in a formula II or the preparation of its officinal salt, eutectic, hydrate or solvate Method, the method includes:
(1), formula III compound is reacted production V compound with formula IV compound or its acid addition product,
In formula III, R1For F, Cl, Br, I, OH or OA, wherein A is hydroxy activated base；
(2), formula V compound deprotection is obtained formula II compound,
；
(3), optional, as required formula II compound is made salt, makes eutectic, make hydrate or make solvate.
3. for preparing the midbody compound of formula II compound, it is selected from: formula III compound, formula III-1 compound, formula III-2 are changed Compound, formula V compound, formula VI compound, formula VIII compound, formula VIII-1 compound, formula VIII-2 compound, formula Ⅻ compound, formula Ⅻ-1 compound or formula Ⅻ-2 compound.
4. the formula II compound of crystalline state.
Crystalline state formula II compound the most according to claim 4, its crystal formation is crystal formation A, and the powder X-ray of this crystal formation spreads out Penetrate collection of illustrative plates 2 θ values be 4.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 15.7 ° ± 0.2 °, 18.8 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.1 ° ± 0.2 °, 26.2 ° ± 0.2 °, 26.6 ° ± 0.2 °, the position of 27.5 ° ± 0.2 ° have feature diffraction Peak.
Formula II compound crystal form A the most according to claim 5, in its powder x-ray diffraction collection of illustrative plates 2 θ values be 4.4 ° ± 0.2°、10.3°±0.2°、15.4°±0.2°、15.7°±0.2°、17.3°±0.2°、18.8°±0.2°、20.0°±0.2°、 20.7°±0.2°、21.1°±0.2°、21.7°±0.2°、26.2°±0.2°、26.6°±0.2°、27.5°±0.2°、28.2° There is characteristic diffraction peak the position of ± 0.2 °.
Formula II compound crystal form A the most according to claim 6, its powder x-ray diffraction collection of illustrative plates is the most as shown in Figure 1.
8. a preparation method for formula II compound crystal form A, the method includes:
(1), formula II compound is dissolved in esters solvent；
(2), solid is separated out；
(3), isolated solid is divided；
(4), optionally, the solid separated is dried.
Preparation method the most according to claim 8, wherein, in step (1), esters solvent is selected from ethyl acetate, acetic acid first Ester, isopropyl acetate, n-propyl acetate, n-butyl acetate or their mixed solvent, ethyl acetate, isopropyl acetate, N-propyl acetate or their mixture；The mode separating out solid in step (2) separates out solid selected from cooling, adds anti-solvent analysis Go out solid, concentrate out precipitation solid or addition crystal seed precipitation solid after partial solvent.
10. a pharmaceutical composition, it comprises the formula II compound described in the claim 1 of therapeutically effective amount or it is pharmaceutically acceptable Salt, eutectic, hydrate or solvate, or the crystalline state formula II compound described in the claim 4 of therapeutically effective amount, or treatment Formula II compound crystal form A described in any one of claim 5 ~ 7 of effective dose, and pharmaceutic adjuvant.
Formula II compound or pharmaceutically acceptable salt thereof, eutectic, hydrate or solvate described in 11. claim 1, or claim Crystalline state formula II compound described in 4, or formula II compound crystal form A described in any one of claim 5 ~ 7 prepare anticoagulation, Antithrombotic, treat or prevent cerebral ischemia diseases or improve sleep medicine in application.
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