WO2016141889A1 - Nouveau dérivé triazolopyrimidine et son utilisation - Google Patents

Nouveau dérivé triazolopyrimidine et son utilisation Download PDF

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WO2016141889A1
WO2016141889A1 PCT/CN2016/076118 CN2016076118W WO2016141889A1 WO 2016141889 A1 WO2016141889 A1 WO 2016141889A1 CN 2016076118 W CN2016076118 W CN 2016076118W WO 2016141889 A1 WO2016141889 A1 WO 2016141889A1
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compound
formula
acid
group
crystalline form
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PCT/CN2016/076118
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Chinese (zh)
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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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四川海思科制药有限公司
广州诺威生物技术有限公司
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Publication of WO2016141889A1 publication Critical patent/WO2016141889A1/fr

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    • 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
    • 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
    • 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

Definitions

  • the invention relates to the field of organic chemistry and pharmacy, in particular to a novel triazolopyrimidine derivative, a crystal form thereof and a preparation method thereof, and a preparation for anticoagulant, antithrombotic, treating or preventing cerebral ischemic diseases or improving sleep. Application in medicine.
  • Thrombosis is formed by platelet aggregation during coagulation. Thrombosis formed in non-injury can reduce blood flow velocity or even block terminal blood vessels, causing ischemic stroke, tissue necrosis, atherosclerosis, myocardial infarction and other diseases.
  • Ischemic stroke refers to a sudden decrease in blood flow perfusion of the local blood supply artery or complete interruption of blood flow, stopping blood supply, oxygen supply, sugar supply, etc., causing dissection and destruction of the local brain tissue.
  • the main causes of ischemic stroke are: 1 thromboembolism caused by atherosclerosis; 2 cerebral embolism caused by cardiac-derived emboli; 3 vasculitis, vascular injury and trauma caused by various causes.
  • Ischemic stroke usually occurs during nighttime sleep. It is often found that the limbs are weak or hemiplegia when getting up in the morning, and there are many unconscious disturbances.
  • the blood pressure can be normal or high, and there may be a history of arteriosclerosis.
  • Ischemic stroke accounts for 60% to 70% of the total number of stroke patients, including cerebral thrombosis and cerebral embolism. Platelet aggregation is often the beginning of cerebral thrombosis formation, thus preventing platelet aggregation medicament useful for the treatment or prevention of ischemic stroke.
  • Platelet activation has a variety of pathways and mechanisms, including P2Y12 receptors involved in fibrinogen receptor activation, thrombosis, thromboxane A2 production, and platelet aggregation triggered by trauma.
  • the human P2Y12 receptor consists of 342 amino acids, mainly distributed in platelets and brain tissue.
  • an endogenous stimulating factor such as ADP activates the P2Y12 receptor, it activates pathways such as PI3K, which in turn activates the Rap1b, Akt, and ERK pathways, which together activate fibrinogen receptors, thereby activating fibrinogen, triggering thrombosis or Platelet aggregation.
  • This process must be achieved with P2Y12 receptor activation, so blocking the P2Y12 receptor can significantly inhibit platelet aggregation and thrombosis induced by ADP and other stimulating factors.
  • Ticagrelor which was developed by AstraZeneca, is the world's first reversible P2Y12 inhibitor, in the EU in December 2010. Approved for the first time, first listed in the UK in February 2011; approved in the US in August 2011 Approved and now available in more than 40 countries around the world.
  • Tigrelor is clinically used primarily to reduce the incidence of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS).
  • the dosage of ticagrelor is: oral, the initial dose is 180mg, the maintenance dose is adjusted to twice a day, 90mg each time; the treatment time is generally at least 12 months.
  • ticagrelor is: (1S, 2S, 3R, 5S)-3-[7- ⁇ [(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ - 5-propylthio-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol
  • the structure is as shown in Formula I, which can be prepared according to the method disclosed in CN1432017A.
  • Ticagrelor has the unique chemical structure of triazolopyrimidine, which can directly reversibly bind to P2Y12 receptor, not only can inhibit the platelet aggregation effect more quickly, but also with the blood concentration within 24 hours of the last dose. Decreased, the inhibition is rapidly attenuated, and the platelet function is quickly restored. Therefore, ticagrelor is a new oral antiplatelet drug that can quickly and effectively inhibit platelet aggregation and is safe. It is undoubtedly a better choice for antiplatelet therapy in patients with acute coronary syndrome (ACS). .
  • ACS acute coronary syndrome
  • ticagrelor there are still some shortcomings in ticagrelor, such as low bioavailability (the average bioavailability of ticagrelor in humans is 36%), and the medication compliance is not high (in long-term medication, it takes two doses a day) , increase the possibility of missing the service) and so on. Therefore, it is necessary to develop new derivatives of ticagrelor in order to further improve bioavailability and enhance drug compliance while maintaining the advantages of ticagrelor as a reversible P2Y12 inhibitor.
  • group-modifying compounds appear to be “simple”, the identification of appropriate physicochemical properties, pharmacokinetic properties, in vivo transformation, and safety is a complex multidisciplinary task due to the complexity of interactions between humans and drugs, so in practice Group-modified compounds, often obtained by "reasonable design", often differ far from the expected results, and even have a physicochemical property or a biological activity that is worse than the parent drug. Decorative compound. Therefore, the development of new compounds that improve the physicochemical properties or in vivo pharmacokinetic properties of the drug by group modification is highly unpredictable, and the solid-state characteristics and new uses of the crystal forms of these new compounds are unpredictable.
  • the present invention surprisingly discovered a novel triazolopyrimidine derivative modified by ticagrelor, which is equivalent to ticagrelor.
  • Oral absorption is better than ticagrelor, which can be metabolized into ticagrelor in the body, which prolongs the action time and provides a good material basis for clinically reducing the number of administrations and improving compliance.
  • the compound can be The solid form of the crystalline form is advantageous for the production, storage and preparation of the preparation; in addition, the compound not only has anticoagulant, antithrombotic effects, but also can be used for treating or preventing cerebral ischemic diseases or improving sleep.
  • Another object of the present invention is to provide a process for the preparation of the novel triazolopyrimidine derivatives.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising the novel triazolopyrimidine derivative or a crystalline form thereof.
  • the present invention first provides a triazolopyrimidine derivative of the formula II, or a pharmaceutically acceptable salt, eutectic, hydrate or solvate thereof,
  • salt is well known to those skilled in the art and refers to a compound formed by the action of an ionic bond between a cation and an anion.
  • Co-Crystals refers to a multi-component crystal having a fixed stoichiometric ratio in which the components are at the molecular level, by hydrogen bonding or other non-covalent bonds, nonionic The roles of the keys combine to coexist.
  • drug eutectic it generally comprises a pharmaceutically active ingredient and another or a plurality of co-crystal formers.
  • solvate When a single pure eutectic former is present in a liquid state at room temperature, the eutectic is also referred to as a "solvate” wherein the solvent is referred to as "hydrate” when it is water.
  • the "eutectic” also includes multi-component crystals having a fixed stoichiometric ratio in which a portion of the pharmaceutically active ingredient and the other components are partially hydrogen-bonded or otherwise non-covalently bonded, and the other portion is passed. The ionic bond or a force between the hydrogen bond and the ionic bond is combined.
  • the “salt” or “eutectic” also includes the form of a salt or a eutectic solvate, hydrate, and the like.
  • a salt or a eutectic is prepared, slurried or crystallized in a solvent, it is possible for the solvent to enter a salt or a eutectic crystal to form a solvate; when the solvent is water, it is possible to form a hydrate.
  • a process for the preparation of a triazolopyrimidine derivative of the formula II, or a pharmaceutically acceptable salt, eutectic, hydrate or solvate thereof which comprises:
  • R 1 is F, Cl, Br, I, OH or OA, wherein A is a hydroxyl activated group
  • the compound of the formula II may be salted, eutectic, hydrated or solvated as needed.
  • the "hydroxyl activating group" in the compound of the formula III means a group which, when introduced into the group, can increase the reactivity of the hydroxyl group as a leaving group, including a sulfonyl group, A sulfinyl group, a hydrocarbon group or the like, and specific examples thereof include a methylsulfonyl group, a trifluoromethanesulfonyl group, a p-toluenesulfonyl group, a trifluoroacetyl group and the like.
  • the "acid adduct” refers to a substance in which an acidic compound is bonded to another compound by the action of an ionic bond, a hydrogen bond or other non-covalent bond, including a salt, a eutectic. , solvates, and the like.
  • the compounds of formula IV are conventional intermediates for the preparation of ticagrelor and are commercially available or can be prepared by literature methods.
  • the acid in the acid addition product of the compound of the formula IV includes an inorganic acid or an organic acid; wherein a suitable inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid; and the suitable organic acid is selected from the group consisting of L - tartaric acid, dibenzoyl-L-tartaric acid, di-p-toluoyl-L-tartaric acid, R-mandelic acid, R- ⁇ -methoxyphenylacetic acid, fumaric acid, D-malic acid, D-camphor Acid, S-keto decanoic acid, oxalic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • a suitable inorganic acid is selected from the group consisting of hydrochloric acid, hydrobro
  • the base includes an organic base or an inorganic base; wherein a suitable organic base includes a tertiary amine (such as triethylamine, diisopropylethylamine, etc.); suitable inorganic bases include alkali metal, alkaline earth metal hydroxides (such as Lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, etc.), hydrogencarbonates (such as sodium bicarbonate, potassium hydrogencarbonate, etc.), phosphates (such as phosphoric acid) Sodium, potassium phosphate, etc.), hydrogen phosphate (such as sodium hydrogen phosphate, potassium hydrogen phosphate, etc.).
  • alkali metal alkaline earth metal hydroxides (such as Lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, etc.), hydrogencarbonates (such as sodium bicarbonate, potassium hydrogencarbonate, etc
  • step (1) when R 1 is OH in the compound of formula III, the step may further comprise first activating OH to OA (A is a hydroxyl activating group, as defined above), and then a compound of formula IV or The process of acid addition reaction.
  • A is a hydroxyl activating group, as defined above
  • the reaction solvent may be selected as a mixed solvent of a water-immiscible solvent and water, wherein the water-immiscible solvent may be selected from the group consisting of toluene, dichloromethane, etc.
  • the reaction solvent can also be selected as non- a protic solvent, wherein the aprotic solvent is selected from the group consisting of acetonitrile, toluene, dichloromethane, acetone, dimethoxyethane, tetrahydrofuran, dioxane, N-methylpyrrolidone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, hexamethylphosphoramide, dimethyl sulfoxide, sulfolane, and the like or a mixture thereof.
  • the aprotic solvent is selected from the group consisting of acetonitrile, toluene, dichloromethane, acetone, dimethoxyethane, tetrahydrofuran, dioxane, N-methylpyrrolidone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, hexamethylphosphoramide, dimethyl sulfoxide, s
  • the molar ratio of the compound of the formula III to the compound of the formula IV or its acid adduct is generally from 0.7:1 to 1.3:1.
  • the reaction temperature is usually -10 ° C to the boiling point of the solvent.
  • the deprotecting reagent is generally an acid selected from the group consisting of organic acids and inorganic acids; suitable organic acids are selected from methanesulfonic acid or trifluoroacetic acid; and suitable inorganic acids are selected from the group consisting of hydrochloric acid and hydrogen. Bromo acid, hydroiodic acid or sulfuric acid.
  • the reaction solvent generally comprises a mixed solvent of water and an organic solvent, wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, dioxane, acetonitrile, acetone, toluene. , dichloromethane, etc.
  • the reaction temperature is usually from 0 ° C to the boiling point of the solvent.
  • the determination of the reaction time can be carried out by a method conventional in the art, such as TLC, HPLC monitoring or the like.
  • the compound of the formula III can be produced by the preparation method provided by the present invention, and the method comprises:
  • R 1 in the formulae VII and VIII is the same as defined above, and R 2 in the formula VII is F, Cl, Br, I or -OA, and A is as defined above;
  • R 1 is as defined above.
  • the acid in the acid addition product of the compound of the formula VI comprises an inorganic acid or an organic acid; wherein the suitable inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid.
  • the suitable organic acid is selected from the group consisting of L-tartaric acid, dibenzoyl-L-tartaric acid, di-p-toluoyl-L-tartaric acid, oxalic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene Acid, etc.
  • the molar ratio of the compound of the formula VII to the compound of the formula VI or its acid adduct is generally from 3:1 to 0.8:1.
  • the base includes an organic base or an inorganic base; wherein a suitable organic base includes a tertiary amine (such as triethylamine, diisopropylethylamine, etc.); suitable inorganic bases include alkali metal, alkaline earth metal hydroxides (such as Lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, etc.), hydrogencarbonates (such as sodium bicarbonate, potassium hydrogencarbonate, etc.), phosphates (such as phosphoric acid) Sodium, potassium phosphate, etc.), hydrogen phosphate (such as sodium hydrogen phosphate, potassium hydrogen phosphate, etc.).
  • alkali metal alkaline earth metal hydroxides (such as Lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, etc.), hydrogencarbonates (such as sodium bicarbonate, potassium hydrogencarbonate, etc
  • the reaction solvent is selected from the group consisting of ethanol, isopropanol, triethylene glycol, tert-butanol, isobutanol, dimethoxyethane, toluene, n-butanol, glycerol, ethylene glycol, Polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600, polyethylene glycol-800, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethyl Acetylamine, hexamethylphosphoramide, dimethyl sulfoxide, sulfolane, dioxane, etc. or a mixture thereof.
  • the reaction temperature is usually from 70 ° C to the boiling point of the solvent.
  • the "diazonium reagent" is selected from the group consisting of nitrous acid or nitrite, and the like, wherein the nitrous acid may be a nitrite (such as sodium nitrite, potassium nitrite, etc.) and an acid (such as hydrochloric acid, Acetic acid or the like is prepared in situ, wherein the nitrite includes isoamyl nitrite and the like.
  • nitrous acid may be a nitrite (such as sodium nitrite, potassium nitrite, etc.) and an acid (such as hydrochloric acid, Acetic acid or the like is prepared in situ, wherein the nitrite includes isoamyl nitrite and the like.
  • step (b) of the above process the molar ratio of the compound of the formula VIII to the diazotizing agent is generally from 1:0.8 to 1:2.
  • the solvent is selected from the group consisting of toluene, acetic acid, water, and the like, or a mixture thereof.
  • the reaction temperature is usually from -15 ° C to 40 ° C.
  • the determination of the reaction time can be carried out by a conventional method in the art, such as TLC, HPLC monitoring or the like.
  • the product may be further isolated or purified by a conventional method in the art or may be used in the next step without further purification.
  • the compound of the formula VII is a usual intermediate for the preparation of ticagrelor, which is commercially available or can be obtained by literature methods; the compound of the formula VI or its acid adduct can be pressed
  • the preparation method in the embodiment is prepared.
  • the invention provides a process for the preparation of a compound of formula VI or an acid adduct thereof, the process comprising:
  • R 3 is an amino protecting group
  • R 4 is hydrogen or together with R 3 serves as an amino protecting group
  • R 5 in formula XI is F, Cl, Br, I, -OH or -OA, A as defined above;
  • R 3 and R 4 in formula XII are as defined above;
  • the compound of formula VI is converted to an acid addition of a compound of formula VI as needed.
  • the compound of the formula IX is a usual intermediate for the preparation of ticagrelor, which is commercially available or can be obtained by literature methods.
  • the acid in the acid addition product of the compound of the formula IX includes an inorganic acid or an organic acid; wherein a suitable inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid; and the like; L-tartaric acid, dibenzoyl-L-tartaric acid, di-p-toluoyl-L-tartaric acid, oxalic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • the "amino protection” is a conventional technique in the art; commonly used amino protecting groups include benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), Allocylcarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-nitro) Benzenesulfonyl (Ns), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb), etc.; said "R 4 together with R 3
  • R 4 and R 3 together represent a phthaloyl
  • the base includes an organic base or an inorganic base; wherein a suitable organic base includes a tertiary amine (such as triethylamine, diisopropylethylamine, etc.); suitable inorganic bases include alkali metal, alkaline earth metal hydroxides (such as Lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, etc.), hydrogencarbonates (such as sodium bicarbonate, potassium hydrogencarbonate, etc.), phosphates (such as phosphoric acid) Sodium, potassium phosphate, etc.), hydrogen phosphate (such as sodium hydrogen phosphate, potassium hydrogen phosphate, etc.).
  • alkali metal alkaline earth metal hydroxides (such as Lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, etc.), hydrogencarbonates (such as sodium bicarbonate, potassium hydrogencarbonate, etc
  • step (ii) of the above process the compound of formula XI is commercially available.
  • the base includes an organic base or an inorganic base; wherein a suitable organic base includes a tertiary amine (such as triethylamine, diisopropylethylamine, etc.).
  • a suitable organic base includes a tertiary amine (such as triethylamine, diisopropylethylamine, etc.).
  • Alkali metal, alkaline earth metal alkoxide such as lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, magnesium tert-butoxide, etc.
  • suitable inorganic bases include alkali metals, Alkaline earth metal hydride (such as sodium hydride, potassium hydride, etc.), alkali metal, alkaline earth metal hydroxide (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), carbonate (such as lithium carbonate, sodium carbonate) , potassium carbonate, etc.), hydrogencarbonate (such as sodium bicarbonate, potassium bicarbonate, etc.), phosphate (such as sodium phosphate, potassium phosphate, etc.), hydrogen phosphate (such as sodium hydrogen phosphate, potassium hydrogen phosphate, etc.).
  • the "removal of the amino protecting group” is a conventional technique in the art, and preferably a method for maintaining the stability of the ether bond in the compound of the formula VI, such as removal of the amino group by using an alkaline reagent, hydrogenolysis or the like. base.
  • step (i), (ii) or (iii), after the end of the reaction the product may be further isolated or purified by a method conventional in the art or after separation and used without further purification.
  • step (i) after the end of the reaction, the product may be further isolated or purified by a method conventional in the art or after separation and used without further purification.
  • the present invention further provides a series of intermediate compounds: a compound of formula III, a compound of formula V, a compound of formula VI, a compound of formula VIII or a compound of formula XII, in addition to the preparation of a triazolopyrimidine derivative of formula II,
  • a compound of formula III a compound of formula III
  • a compound of formula V a compound of formula VI
  • a compound of formula VIII a compound of formula XII
  • the present invention provides a crystalline form of a compound of formula II. Further, the present invention provides a crystalline form of a compound of formula II, which is defined as Form A.
  • the powder X-ray diffraction pattern of the crystalline form A of the compound of the formula II provided by the present invention is characterized by: 2 ⁇ values of 4.4° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.0. Characteristic diffraction peaks at positions such as ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.1° ⁇ 0.2°, 26.2° ⁇ 0.2°, 26.6° ⁇ 0.2°, 27.5° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of Form A of the compound of Formula II provided by the present invention is characterized by a value of ⁇ of 4.4° ⁇ 0.2°, 10.3° ⁇ 0.2°, and 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° Characteristic diffraction peaks at positions of ⁇ 0.2°, 27.5° ⁇ 0.2°, 28.2° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the crystalline form A of the compound of the formula II according to the present invention represented by the 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the crystalline form A of the compound of formula II provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern shown in FIG. 1, that is, the powder X- of the crystalline form A of the compound of the formula II provided by the present invention.
  • the ray diffraction pattern is basically as shown in Fig. 1.
  • the powder X-ray diffraction analysis of the crystalline form A of the compound of the formula II of the present invention is a CuK ⁇ source of the Panaco X'Pert PRO type powder X-ray diffractometer at ambient temperature and ambient humidity. The measurement is completed.
  • the "ambient temperature” is generally 0 to 40 ° C; the “ambient humidity” is generally 30% to 80% relative humidity.
  • the crystalline form A of the compound of formula II provided by the present invention has the characteristic represented by the differential scanning calorimetry (DSC) pattern as shown in FIG. 2, that is, the endothermic peak-to-peak temperature is 150 ° C ⁇ 2 ° C or 150 ° C ⁇ 1 ° C.
  • DSC differential scanning calorimetry
  • the crystalline form A of the compound of formula II provided by the present invention has the characteristics represented by the thermogravimetric analysis (TGA) pattern as shown in FIG. 3, that is, the thermogravimetry of the crystalline form A of the compound of the formula II provided by the present invention.
  • TGA thermogravimetric analysis
  • the analysis (TGA) map is basically as shown in Figure 3.
  • the crystalline form A content (mass content) of the compound of formula II in the crystalline Form A mixture of the compound of Formula II provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the present invention provides a method for preparing a crystalline form A of a compound of formula II, the method comprising:
  • the separated solid is dried.
  • the "ester solvent” is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, and acetic acid.
  • N-propyl ester, n-butyl acetate or the like or a mixed solvent thereof is preferably ethyl acetate, isopropyl acetate, n-propyl acetate or a mixture thereof.
  • the ratio of the selected solvent in units of ml to the amount of the compound of formula II in g is generally from 1:1 to 30:1; dissolution can be carried out by heating.
  • the dissolution temperature of the compound of the formula II is generally from room temperature to the boiling point of the solvent.
  • the method of "precipitating solids” includes cooling the precipitated solids, adding an anti-solvent to precipitate a solid, concentrating a part of the solvent, and then depositing a solid, adding a seed precipitated solid, etc., and these methods may be used alone or in combination.
  • the use can be carried out under static conditions or under stirring.
  • the "anti-solvent” means a solvent which is inferior in solubility to the compound of the formula II at normal temperature, such as isooctane, n-hexane, n-heptane, petroleum ether or the like or a mixture thereof, among which isooctane and n-hexane are preferred. Heptane.
  • the "separation" manner may be by suction filtration or centrifugation.
  • the "drying" temperature is generally 20 to 120 ° C, preferably 40 to 100 ° C; it may be dried at normal pressure or may be dried under reduced pressure.
  • the method of preparing Form A of the compound of Formula II of the present invention comprises:
  • anti-solvent is selected from isooctane, n-hexane, n-heptane, petroleum ether, etc. or a mixture thereof, preferably isooctane or n-heptane;
  • the separated solid is dried; the drying temperature is generally 20 to 120 ° C, preferably 40 to 100 ° C; it can be dried at normal pressure or dried under reduced pressure.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula II, a crystalline compound of the formula II or a crystalline form A of the compound of the formula II and the use of a compound of the formula II, a crystalline compound of the formula II or a crystalline form A of the compound of the formula II
  • the application of human drugs is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula II, a crystalline compound of the formula II or a crystalline form A of the compound of the formula II and the use of a compound of the formula II, a crystalline compound of the formula II or a crystalline form A of the compound of the formula II.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II, a crystalline form of a compound of formula II or a crystalline form A of a compound of formula II, and a pharmaceutically acceptable adjuvant.
  • the invention provides the use of a compound of formula II, a crystalline form of a compound of formula II or a crystalline form A of a compound of formula II for the manufacture of a medicament for anticoagulation, antithrombotic, therapeutic or prophylactic cerebral ischemic diseases or for improving sleep.
  • a therapeutically effective amount of a compound of formula II, a crystalline form of a compound of formula II or a crystalline form A of formula II, together with one or more pharmaceutical excipients A pharmaceutical composition or formulation is prepared which is prepared in a manner well known in the art.
  • the above pharmaceutical composition or preparation can be used as an anticoagulant or antithrombotic drug mainly for treating or preventing thrombosis and complications thereof in patients with coronary, cerebrovascular or peripheral vascular diseases, in particular, for reducing The incidence of thrombotic cardiovascular events in patients with acute coronary syndrome. Further, the above pharmaceutical composition or preparation can be used as a medicine for treating or preventing cerebral ischemic diseases such as ischemic stroke or improving sleep.
  • the dosage form of the above pharmaceutical composition or preparation includes: a tablet, a capsule, a pill, a granule, a syrup, a powder, a sublingual tablet, a suspension, a solution, an injectable preparation, an aerosol, a dry powder, a suppository. , creams, ointments, gels, etc. They are administered orally, sublingually, parenterally (eg, intravenously, intramuscularly, subcutaneously, etc.), transpulmonary/tracheal or transdermal, depending on the characteristics of the respective dosage form.
  • the dosage of the above composition or preparation is adjusted according to the nature and severity of the patient's condition, the route of administration, and the age, weight and the like of the patient.
  • the usual daily dose is between 1 mg and 1 g, preferably between 30 mg and 300 mg; once a day. For administration, it may be administered multiple times.
  • the pharmaceutical composition provided by the present invention is an oral solid preparation, preferably a tablet or capsule.
  • the oral solid preparation further comprises a pharmaceutical excipient in addition to the active compound of the formula II, the crystalline compound of the formula II or the crystalline form A of the compound of the formula II, and the pharmaceutical excipients are conventional pharmaceutical excipients, including fillers. , disintegrants, binders, lubricants, etc.
  • the filler generally comprises mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, lactose, sucrose, calcium sulfate, micronized silica gel, etc., which may be used singly or in combination.
  • the disintegrant generally comprises sodium carboxymethyl starch, sodium carboxymethyl cellulose, croscarmellose sodium, microcrystalline cellulose, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, low substituted hydroxypropyl fiber.
  • A agar, calcium carbonate, sodium hydrogencarbonate, etc., which may be used singly or in combination.
  • the binder generally comprises hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, povidone, microcrystalline cellulose, starch slurry, water, various concentrations of ethanol solution, etc. They can be used alone or in combination.
  • the lubricant generally includes magnesium stearate, talc, stearic acid, calcium stearate, palmitic acid, aluminum silicate, stearic acid amide, solid polyethylene glycol, etc., which may be used alone or in combination. .
  • sweeteners such as sweeteners
  • Spartan, stevioside, etc. coloring agents (such as iron oxide, titanium dioxide, etc.), stabilizers (such as vitamin E, thymol, glycine, etc.), surfactants (such as sodium lauryl sulfate, etc.).
  • the preparation of the above oral solid preparation can be carried out according to a conventional method for preparing an oral solid preparation in the art.
  • the tablet can be prepared by wet granulation tableting or the like
  • the capsule can be prepared by wet granulation capsule or the like.
  • the oral solid preparation is a tablet, it may be further coated as needed to prepare a film-coated tablet or a sugar-coated tablet.
  • the coating base includes cellulose, acrylic resin, sugar, such as hydroxypropyl methylcellulose, sucrose, etc., and a plasticizer, an anti-adhesive agent, and an opacifier may also be added.
  • the compound of formula II, the crystalline compound of formula II or the compound of formula II provided by the present invention has the same activity as ticagrelor, and the oral absorption is superior to ticagrelor, which can be metabolized into ticagrelor in vivo. Thereby prolonging the action time, providing a good material basis for clinically reducing the number of administrations and improving the compliance; further, the physicochemical properties of the compound of the formula II, the crystalline compound of the formula II or the crystalline form A of the compound of the formula II are advantageous for production, Preparation of the preparation and preparation; in addition, the compound not only has anticoagulant, antithrombotic effects, but also can be used for treating or preventing cerebral ischemic diseases or improving sleep.
  • Figure 1 is a powder X-ray diffraction (PXRD) pattern of Form A of the compound of Formula II.
  • DSC differential scanning calorimetry
  • FIG. 3 is a thermogravimetric analysis (TGA) pattern of Form A of the compound of Formula II.
  • the 1 H NMR and 13 C NMR tests in the examples were carried out using deuterated dimethyl sulfoxide as a test solvent, tetramethylsilane as an internal standard, and a Bruke AV-II 400 MHz NMR spectrometer at room temperature.
  • Mass spectrometry in the examples was done in an Agilent Quadrupole LC/MS 6120B, ESI positive mode.
  • the powder X-ray diffraction analysis in the examples was determined by the Dutch PANaco X'Pert PRO type powder X-ray diffractometer under the conditions of ⁇ - ⁇ configuration, scanning range of 4°-50°, step size. For 0.0130°, continuous scanning.
  • the test source was copper target K ⁇ radiation; the voltage and current were 40 kV and 40 mA, respectively.
  • the sample preparation method is: use under environmental conditions The appropriate amount of the sample is placed in the groove of the glass-loaded sample, and the slide is appropriately rolled, so that the sample is evenly distributed in the groove of the sample, and the surface of the sample is flattened by the slide. The sample does not rotate in its own plane during the test.
  • the differential scanning calorimetry in the examples was determined by a DSC 214 Polyma type differential scanning calorimeter manufactured by NETZSCH.
  • the test conditions were: a heating rate of 10 ° C / min, and a test temperature range of 35 ° C - 220 ° C.
  • thermogravimetric analysis in the examples was carried out by a TG 209F3 type thermogravimetric analyzer manufactured by NETZSCH.
  • the test conditions were: a heating rate of 10 ° C / min, and a test temperature range of 35 ° C - 350 ° C.
  • Step i N-[(3aS,4R,6S,6aR)-tetrahydro-6-(2-hydroxyethoxy)-2,2-dimethyl-4H-cyclopentadien-1,3- Preparation of benzyl dioxy-4-yl]-carbamate (compound of formula X-1)
  • Step ii N-[(3aS,4R,6S,6aR)-tetrahydro-6-(2-cyclopropylmethoxyethoxy)-2,2-dimethyl-4H-cyclopentadiene -1,3-Dioxy-4-yl]-carbamic acid benzyl ester (preparation of compound of formula XII-1)
  • Step iii 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxy-4-yl Preparation of oxy]-cyclopropylmethylethyl ether (compound of formula VI)
  • Step a 2-[((3aR,4S,6R,6aS)-6- ⁇ [5-Amino-6-bromo-2-(propylthio)pyrimidin-4-yl]amino ⁇ -2,2- Dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]-1-cyclopropylmethylethyl ether (Formula VIII- Preparation of 2 compounds)
  • Step b 2-[ ⁇ (3aR,4S,6R,6aS)-6-[7-bromo-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d Pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl ⁇ oxy]-1-
  • cyclopropylmethylethyl ether compound of formula III-2
  • Step 1 2-( ⁇ (3aR, 4S,6R,6aS)-6- ⁇ [7- ⁇ [(1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino ⁇ -5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopentane
  • ene[d][1,3]dioxol-4-yl ⁇ oxy]-1-cyclopropylmethylethyl ether compound of formula V
  • the aqueous solution (1.96 g of acetic acid + 245 ml of water) and 250 ml of a saturated aqueous sodium chloride solution were washed to obtain a toluene solution of the compound of the formula V, which was directly used for the next reaction.
  • (+)-ESI-MS 617.3.
  • Step 2 (1S, 2S, 3R, 5S)-3-[7- ⁇ [(1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino ⁇ -5-(propyl Thio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-cyclopropylmethoxyethoxy)-1,2- Preparation of cyclopentanediol (compound of formula II)
  • the toluene solution of the compound of the formula V obtained in the first step is mixed with a methanolic hydrochloric acid solution (concentrated hydrochloric acid 39.4 ml + methanol 55 ml), and stirred at 10 to 15 ° C for about 4.5 hours; 100 ml of water is added, and then adjusted with triethylamine at 0 to 10 ° C.
  • the pH is about 8, the organic phase is separated, and the aqueous phase is back-extracted with isopropyl acetate 250 ml ⁇ 2, and the organic phase is combined.
  • the organic phase is washed with water 200 ml, saturated sodium chloride aqueous solution 200 ml, dried anhydrous sodium sulfate and reduced. Concentration by pressure gives the compound of formula II.
  • (+)-ESI-MS 577.3.
  • the measured powder X-ray diffraction pattern is shown in Fig. 1, and the measured values are as follows (measured values corresponding to diffraction peaks having a relative intensity greater than 5%):
  • the measured differential scanning calorimetry (DSC) pattern is shown in Figure 2.
  • the measured thermogravimetric analysis (TGA) pattern is shown in Figure 3. It should be understood that different temperature readings may be given with other types of equipment or with conditions other than those described above. Therefore, the numbers provided cannot be used as absolute values. Those skilled in the art will appreciate that the exact values of these temperatures will be affected by the purity of the compound, the weight of the sample, the rate of heating, and the particle size.
  • Preparation of mobile phase Take 1.56 g of sodium dihydrogen phosphate dihydrate, dissolve in 1000 ml of water, adjust pH 3.5 with phosphoric acid, filter with 0.22 ⁇ m filter to obtain mobile phase A; take chromatographic acetonitrile as mobile phase B.
  • Test solution (protected from light) Take about 20mg of this product, accurately weigh it, put it in a 10ml volumetric flask, dissolve it with diluent and dilute to the mark, shake it, that is.
  • Determination method according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix VD) test.
  • Component Content (mg/tablet) Formula II
  • Compound A 99.0 Mannitol 126.0 Calcium hydrogen phosphate dihydrate 63.0 Hydroxypropyl cellulose 9.0 Carboxymethyl starch sodium 9.0 Magnesium stearate 3.0
  • Preparation Mix the compound of formula II in the above table, crystal form A, mannitol, calcium hydrogen phosphate dihydrate, hydroxypropyl cellulose and sodium carboxymethyl starch, wet granulation with water, drying, granulating, and Mix magnesium stearate and compress it.
  • the present invention evaluates the in vitro activity of a compound of formula II and ticagrelor by inhibiting ADP-induced rabbit platelet aggregation assay.
  • Rabbits were harvested from the venous blood of the hind limbs, and the platelet-rich plasma was separated and added to the vehicle, a series of concentrations of the compound of formula II or ticagrelor. After incubation for 5 min at 37 ° C, ADP was added to induce platelet aggregation. The maximum platelet aggregation rate (PAGm) within 5 min was measured after the addition of ADP. Each group has 3 parallel tubes.
  • the final concentration of the solvent DMSO in the platelet system was 0.1%, which did not affect the platelet system compared with the blank control group.
  • the present invention evaluates the in vivo activity of the compound of formula II and ticagrelor by the Beagle dog platelet aggregation assay.
  • Platelet-rich plasma was prepared by low speed centrifugation (300 g) for 5 min. The remaining samples were continuously centrifuged at high speed (3000 g) for 10 min to obtain platelet poor plasma (PPP). The PRP was adjusted to a platelet concentration of 2 ⁇ 10 8 /mL by PPP, and the maximum aggregation rate of platelets was measured, and the inhibition rate of platelet aggregation was calculated.
  • the present invention evaluates the in vivo pharmacokinetics of a compound of formula II and ticagrelor by oral administration to SD rats.
  • the compound group of formula II or the ticagrelor group is administered in equimolar amount, but the AUC and Cmax of ticagrelor in the compound group of formula II are significantly higher than that of the ticagrelor group, since the compound of formula II itself also has The similar pharmacodynamic activity of ticagrelor, therefore, the pharmaceutically active active exposure of the compound of the formula II group will be more significantly higher than that of the ticagrelor group if it is based on the pharmacodynamic active. This indicates that the bioavailability of the compound of formula II and its sex metabolite is higher than that of ticagrelor.
  • Example 15 Effect on the volume of cerebral infarction in rats with focal cerebral ischemia
  • the tMCAO model was prepared according to the method of Longa et al. Rats were anesthetized with 10% chloral hydrate (350 mg/kg, i.p.), body temperature was maintained at 37 ⁇ 0.5 °C, and the supine position was fixed on the operating table. The skin was cut along the midline of the neck and the right common carotid artery (CCA), external carotid artery (ECA), and internal carotid artery (ICA) were carefully separated. Cut the ECA ligation and straighten it in line with the ICA.
  • CCA common carotid artery
  • ECA external carotid artery
  • ICA internal carotid artery
  • Rats were randomized into a model control group, water for injection (100 ml/kg), group of compound of formula II (25, 50, 100 mg/kg), MCA blockade resulted in oral administration 10 minutes after ischemia.
  • volume of cerebral infarction (surgical contralateral hemisphere volume - volume of uninfarcted part of the surgical hemisphere) / volume of the contralateral hemisphere of surgery *100%
  • the results of the test showed that the oral administration of the compound of the formula II can significantly reduce the volume of the cerebral infarction compared with the solvent control group, that is, the compound of the formula II has a good effect of improving the symptoms of cerebral ischemia.
  • Animal source Kunming mice, 18-22 grams, male.
  • the test animal breeding room temperature is 22 ⁇ 2° C., relative humidity is 50-70%, animal feed.
  • the compound of formula II was administered at a dose of 25 mg/kg, and a distilled water control group was additionally provided.
  • Sample treatment 25 mg of each sample was added with distilled water to 20 ml, respectively, to make a uniform suspension for testing.
  • mice were randomly divided into the control group and the compound group of the compound of formula II.
  • the samples were administered by continuous gavage for 30 days. After the samples were administered for 15 minutes on the 30th day, 50 mg/kg.bw of pentobarbital sodium per abdomen was given to each group. Injection, the injection volume is 0.2ml/20g.bw, The mouse righting reflex disappeared for more than 1 minute as a criterion for falling asleep, and the sleep time and sleep time of each group of animals within 60 minutes of sodium pentobarbital were observed.
  • mice were randomly divided into the control group and the compound group of the compound of formula II.
  • the samples were administered by continuous gavage for 28 days. After the samples were administered for 15 minutes on the 28th day, the animals were given 30 mg/kg.bw of pentobarbital sodium peritoneal cavity.
  • the injection volume was 0.2 ml/20 g.bw, and the mouse righting reflex disappeared for 1 minute or more as a criterion for falling asleep, and the number of animals sleeping in each group of animals within 25 minutes of sodium pentobarbital was observed.
  • Control group 10 2 20 Compound of formula II 10 6* 60*

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Abstract

L'invention concerne un nouveau dérivé triazolopyrimidine représenté par la formule II, sa forme cristalline et son procédé de préparation, ainsi que son utilisation dans la préparation d'un médicament permettant de résister à la coagulation et au thrombus, permettant de traiter ou de prévenir les maladies ischémiques cérébrales, ou permettant d'améliorer le sommeil.
PCT/CN2016/076118 2015-03-12 2016-03-11 Nouveau dérivé triazolopyrimidine et son utilisation WO2016141889A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1432017A (zh) * 2000-06-02 2003-07-23 阿斯特拉曾尼卡有限公司 新的三唑并嘧啶化合物
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
CN102311437A (zh) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 一种抗血小板凝集药替卡格雷的制备方法
CN102675321A (zh) * 2012-05-11 2012-09-19 上海皓元化学科技有限公司 一种替卡格雷的制备方法
CN102731467A (zh) * 2011-04-15 2012-10-17 博瑞生物医药技术(苏州)有限公司 替卡格雷的中间体及制备替卡格雷的方法
WO2014154908A1 (fr) * 2013-03-29 2014-10-02 Chemo Research, S.L. Alkylation sélective d'alcools cyclopentyliques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1432017A (zh) * 2000-06-02 2003-07-23 阿斯特拉曾尼卡有限公司 新的三唑并嘧啶化合物
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
CN102311437A (zh) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 一种抗血小板凝集药替卡格雷的制备方法
CN102731467A (zh) * 2011-04-15 2012-10-17 博瑞生物医药技术(苏州)有限公司 替卡格雷的中间体及制备替卡格雷的方法
CN102675321A (zh) * 2012-05-11 2012-09-19 上海皓元化学科技有限公司 一种替卡格雷的制备方法
WO2014154908A1 (fr) * 2013-03-29 2014-10-02 Chemo Research, S.L. Alkylation sélective d'alcools cyclopentyliques

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