WO2020119590A1 - Composé de 3-cyanopyridine, composition pharmaceutique le contenant, son procédé de préparation et ses applications - Google Patents

Composé de 3-cyanopyridine, composition pharmaceutique le contenant, son procédé de préparation et ses applications Download PDF

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WO2020119590A1
WO2020119590A1 PCT/CN2019/123507 CN2019123507W WO2020119590A1 WO 2020119590 A1 WO2020119590 A1 WO 2020119590A1 CN 2019123507 W CN2019123507 W CN 2019123507W WO 2020119590 A1 WO2020119590 A1 WO 2020119590A1
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compound
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alkyl
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halogen
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杨玉社
孔德瑜
薛涛
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中国科学院上海药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicinal chemistry and antithrombotic diseases, in particular to a 3-cyanopyridine compound, its enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceuticals An acceptable salt or a pharmaceutical composition containing the above compound, a method for preparing the same, and use for preparing an anti-thrombotic drug.
  • Thromboembolic diseases include acute coronary syndrome (ACS), stroke, deep vein thrombosis, pulmonary embolism, ischemic stroke, and myocardial infarction. According to statistics, about 12 million people worldwide die from thromboembolic diseases every year. Thrombotic diseases have occupied the first place in the global total mortality rate of diseases. Current treatment strategies include antiplatelet, anticoagulant, and thrombolytic, of which antiplatelet drugs account for about 70% of the market share of antithrombotic drugs.
  • the rupture of atherosclerotic plaques or the implantation of artificial materials in the patient’s coronary arteries can cause platelet activation, and the activated platelets can release organisms such as hemoglobin A 2 (TXA 2 ) and adenosine diphosphate (ADP).
  • ADP adenosine diphosphate
  • glycoproteins (GPII b /III a ) on the surface of platelet membranes bind to fibrinogen, so that adjacent platelets adhere to each other to form a thrombus.
  • ADP is an important platelet agonist in vivo, which mainly exerts its physiological activity by binding to two G-protein coupled receptors P2Y 1 and P2Y 12 on the surface of platelets.
  • P2Y 1 receptor participates in platelet deformation and is widely distributed, while P2Y 12 receptor plays an important role in enhancing the release of platelet particles, the production of thromboxane A2, maintaining GPII b /IIIa activation and stabilizing platelet aggregation, and is mainly distributed in platelets On the membrane, therefore, P2Y 12 receptor antagonists are the most important area for the development of anti-platelet aggregation drugs (Thrombosis Research, 2014 (134), 693–703).
  • the clinically used P2Y 12 antagonists include clopidogrel, prasugrel, ticagrelor and cangrelor.
  • Clopidogrel is an irreversible oral prodrug of P2Y 12 antagonists and requires the metabolic activation of CYP450 to function.
  • Clopidogrel and aspirin combination therapy has become the standard antiplatelet therapy.
  • Prasugrel is a third-generation irreversible P2Y 12 antagonist and does not require CYP450 enzyme metabolic activation, so it has a faster onset of action.
  • prasugrel Compared with clopidogrel, prasugrel has higher anti-platelet activity and is more effective in different populations. The response difference is lower, but high activity brings its higher risk of bleeding (Thrombosis Research 134 (2014) 693–703).
  • Clopidogrel and prasugrel are potent and irreversible inhibitors of platelets. Platelets can recover function about seven days after drug withdrawal (platelet regeneration cycle is about 7-14 days).
  • Tigrelo developed by AstraZeneca, is the first reversible direct P2Y 12 receptor antagonist. It does not require metabolic activation to function. Its effectiveness is not affected by genetic polymorphisms, compared with clopidogrel The clinical effect is better.
  • ticagrelor after clinical administration of ticagrelor, patients had a black frame warning of increased mortality caused by stroke, and side effects such as dyspnea and ventricular pause.
  • the above side effects may be caused by ticagrelor having an ADP structure and inhibiting the off-target effect caused by the equilibrative nucleoside transporter 1 (ENT1).
  • ENT1 equilibrative nucleoside transporter 1
  • AZD1283 is a new generation of reversible non-nuclear glycoside P2Y 12 receptor antagonist developed by AstraZeneca. It has entered phase II clinical research, but because the ester structure in the molecular structure is easily hydrolyzed into an ineffective carboxyl group, it is in the human body. Absorption and metabolic properties are extremely poor, which in turn leads to insignificant efficacy and stops at Clinical II (Bioorg. Med. Chem. Lett. 26 (2016) 2739-2754).
  • prasugrel and ticagrelor were marketed in 2009 and 2011, respectively, the two have been recommended for first-line treatment of ACS, and clopidogrel (formerly the first-line treatment drug) is only recommended for the first two intolerance Of ACS patients.
  • the prasugrel and ticagrelor treatment guidelines stipulate a course of treatment of at least 12 months, but in clinical practice, these powerful antiplatelet drugs have long-term treatment because of side effects, especially the higher risk of bleeding compared to clopidogrel It's very difficult.
  • Highly activated platelets will be completely replaced by new platelets within 1-2 weeks after the onset of ACS. Patients with high levels of platelet antagonism may be necessary only a few days or weeks after the acute attack of ACS. After the condition stabilizes, treatment needs The conversion from high-level platelet inhibitors (prasugrel, ticagrelor) to medium-strength, safer inhibitors helps to reduce the risk of bleeding from long-term antiplatelet therapy. Therefore, finding an oral, safe, effective, and reversible P2Y 12 receptor antagonist is still an urgent clinical need and has important significance.
  • the inventors designed and synthesized a series of compounds using AZD1283 as the lead compound, conducted a systematic structure-activity relationship study, and structured all new compounds Confirm and evaluate their in vitro anti-platelet aggregation activity, pharmacokinetic properties, CYP (cytochrome) enzyme inhibitory activity, in vivo anti-thrombotic activity, a new class of 3-cyanopyridine compounds were discovered for the first time Platelet activity, in vivo antithrombotic activity and metabolic properties are significantly better than AZD1283, and safety is better than clopidogrel.
  • the new compound of the invention overcomes all the defects of AZD-1238, has better medicine forming property, and is suitable as a novel oral antiplatelet drug for the treatment of thrombotic diseases. On this basis, the inventor completed the present invention.
  • a compound represented by general formula (I) there is provided a compound represented by general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts thereof .
  • R 1 is selected from hydrogen or C 1 -C 6 alkyl; preferably selected from hydrogen, methyl, ethyl or propyl;
  • R 2 is selected from H, halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy; preferably H, halogen, C 1 -C 3 alkyl, hydroxy, C 1 -C 3 alkoxy ;
  • R 3 is selected from a substituted or unsubstituted 5-7 membered aromatic heterocyclic group, the substituent is selected from one or more of halogen, C 1 -C 6 alkyl, cyano, trifluoromethyl, the The aromatic heterocyclic group contains one or more hetero atoms selected from N, O, and S; or Wherein R 6 and R 7 are each independently selected from hydrogen, C 1 -C 6 alkyl, halogen, or R 6 and R 7 are connected to the connected carbon atom to form a 3-6 membered aliphatic ring, and R 8 is selected from substituted Or an unsubstituted 5-10 membered aromatic heterocyclic group (preferably a substituted or unsubstituted 5-7 membered aromatic heterocyclic group), a substituted or unsubstituted C 6 -C 12 aryl group, or a substituted or unsubstituted C 6- C 12 aralkyl, the substituent is selected from one or more of halogen, cyan
  • R 3 is selected from unsubstituted or halogen substituted thienyl, or Wherein R 6 and R 7 are each independently selected from hydrogen, C 1 -C 6 alkyl, halogen, or R 6 and R 7 are connected to the connected carbon atoms to form a 3-6 membered aliphatic ring, R 9 represents one or Multiple, preferably 1, 2 or 3 substituents selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl; preferably R 3 is selected from Unsubstituted or fluorine-substituted or chlorine-substituted thienyl, or Wherein R 6 and R 7 are each independently selected from hydrogen, C 1 -C 3 alkyl, fluorine, chlorine, or R 6 and R 7 are connected to the connected carbon atoms to form a 3-6 membered aliphatic ring, R 9 represents One or more selected from hydrogen, fluorine, chlorine,
  • R 4 is H or halogen; preferably H, fluorine or chlorine;
  • R 5 is H or C 1 -C 6 alkyl, preferably H, methyl, ethyl or propyl;
  • n 0, 1 or 2;
  • Ring B is a 4-8 membered saturated nitrogen heterocycle, preferably a 4-6 membered saturated nitrogen heterocycle, such as azetidine ring, pyrrolidine ring or piperidine ring.
  • the compound represented by the general formula (I) of the present invention is a compound of the following general formula (II):
  • R 1 , R 2 , R 3 , X, and n are the same as in the general formula (I), and Y and Z are each independently methylene, ethylene, propylene, and butylene.
  • the compound represented by the general formula (I) of the present invention is the following compound:
  • R 1 , R 2 , R 3 , X and n are the same as in the general formula (I).
  • X is O.
  • n is 0 or 1.
  • R 1 is hydrogen or methyl.
  • the compound represented by the general formula (I) of the present invention is selected from the compounds in Table 1 below.
  • the enantiomer is, for example,
  • the pharmaceutically acceptable salt of the present invention may be a pharmaceutically acceptable salt of a 3-cyanopyridine compound of general formula (I) formed with an organic or inorganic base or a pharmaceutically acceptable salt formed with an organic or inorganic acid Acceptable salt.
  • the organic base or inorganic base includes, for example, sodium hydroxide, potassium hydroxide, magnesium hydroxide, ethanolamine, etc.
  • the pharmaceutically acceptable salts include, without limitation, alkali metal and alkaline earth metal salts, such as sodium salt, potassium salt , Magnesium salts, calcium salts, etc.; ammonium salts; inorganic acid salts, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc.; organic acid salts, such as formate, acetate, propionic acid Salt, benzoate, maleate, fumarate, succinate, tartrate, citrate, alkyl sulfonate (such as methylsulfonate, ethylsulfonate, etc.), aromatic Sulfonate (such as benzenesulfonate, p-toluenesulfonate, etc.), etc.
  • alkali metal and alkaline earth metal salts such as sodium salt, potassium salt , Magnesium salts, calcium salts, etc.
  • ammonium salts such as hydrochloride, hydrobro
  • the pharmaceutically acceptable salt is, for example,
  • the C 1 -C 6 alkyl group refers to a linear or branched alkyl group containing 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, n-propyl, isopropyl Base, n-butyl, tert-butyl.
  • the C 1 -C 6 alkoxy group refers to a straight-chain or branched-chain alkyloxy group containing 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, propylene Oxy, tert-butoxy.
  • the C 6 -C 12 aryl group refers to a monocyclic or polycyclic aromatic cyclic group containing 6-12 carbon atoms on the ring and not containing hetero atoms, including phenyl, Naphthyl.
  • the C 6 -C 12 aralkyl group refers to an arylalkyl group containing 6-12 carbon atoms and not containing hetero atoms, and includes, without limitation, benzyl group and phenethyl group.
  • the 5-10 membered aromatic heterocyclic group refers to an aromatic ring group containing 5-10 atoms on the ring and at least one hetero atom selected from O, N, and S, which is not limited Including quinolinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, thienyl, thiazolyl, pyridyl, furyl, pyrrolyl, pyrazolyl;
  • the 5-7 member Aromatic heterocyclic group refers to an aromatic ring group containing 5-7 atoms on the ring and containing at least one hetero atom selected from O, N, and S, including, without limitation, thienyl, thiazolyl, pyridyl, Furyl, pyrrolyl, pyrazolyl.
  • the 4-8 membered saturated nitrogen heterocycle refers to a saturated ring containing 4-8 atoms and at least one N atom in the ring, including, without limitation, azetidine ring and pyrrolidine Ring, piperidine ring, homopiperidine ring, morpholine ring, etc.
  • the 3-6 membered aliphatic ring refers to a saturated ring containing 3-6 carbon atoms on the ring, including, without limitation, a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, and the like.
  • the halogen includes fluorine, chlorine, bromine, and iodine.
  • a pharmaceutical composition comprising the compound of general formula (I), its enantiomer, diastereomer, racemate and the like Mixtures, or pharmaceutically acceptable salts thereof; and pharmaceutically acceptable carriers or excipients.
  • the 3-cyanopyridine derivatives provided by the present invention can be used alone, or mixed with pharmaceutically acceptable adjuvants (such as excipients, diluents, etc.), and formulated into tablets or capsules for oral administration. Granules or syrups. Or it can be formulated into injections for non-oral administration.
  • pharmaceutically acceptable adjuvants such as excipients, diluents, etc.
  • Another aspect of the present invention provides the compounds represented by the above general formula (I), their enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof for preparation It is used in the prevention or treatment of thromboembolic diseases, especially the use of drugs in coronary artery syndrome (ACS), stroke, coronary heart disease, atrial fibrillation and other diseases.
  • ACS coronary artery syndrome
  • the compound represented by the general formula (I) of the present invention can be prepared by the method shown in the following route, however, the conditions of the method, such as reactants, solvents, bases, the amount of the compound used, the reaction temperature, the time required for the reaction, etc. are not limited to The following explanation.
  • the compounds of the present invention can optionally be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs. The method is selected from one of the following routes:
  • Rings R 2 , R 3 , R 5 and B are as defined above
  • the condensing agent is, for example, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 2-(7-azobenzotriazole Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDCI)/1-hydroxybenzotriazole (HOBT) mixture;
  • the organic base is for example: triethylamine or diisopropylethylamine;
  • the inorganic base is for example sodium bi
  • Compound I-1 is removed in a polar aprotic solvent by tert-butoxycarbonyl protecting group under the action of acid to obtain compound I-2.
  • the polar aprotic solvent is, for example, dichloromethane or tetrahydrofuran;
  • the acid is, for example, formic acid or dilute hydrochloric acid (2mol/L);
  • Compound I-4 reacts with cyanoacetamide in a polar protic solvent, in the presence of an organic base or an inorganic base, for example, at room temperature, to produce the corresponding compound I-5; It is: 20% NaOEt, triethylamine or diisopropylethylamine; the inorganic base is for example sodium bicarbonate, sodium carbonate or potassium bicarbonate; the solvent is for example methanol or ethanol;
  • Compound I-5 is added to a polar aprotic solvent, acid chloride is added, DMF catalyzes the reaction, for example, reacts at 70°C overnight, to produce the corresponding compound I-6;
  • the polar aprotic solvent is for example tetrahydrofuran Or dichloromethane;
  • the acid chloride is, for example, acetyl chloride or oxalyl chloride;
  • Compound I-7 is reacted with ammonia water or a C 1 -C 6 alkylamine aqueous solution in a polar solvent, for example, at room temperature for 5 hours to produce compound II;
  • the polar solvent is, for example, methanol or ethanol;
  • compounds 1 and 2 of the present application can be prepared from Route 1;
  • Rings R 2 , R 3 , R 4 and B are as defined above
  • Compound II-2 reacts with halogenated (eg, fluorinated or chlorinated) reagents in a polar aprotic solvent to produce compound II-3;
  • the fluorinated reagent is, for example, 1-chloromethyl-4- Fluorine-1,4-diazonium dicyclo 2.2.2 octane bis(tetrafluoroborate), the chlorinating agent is NCS for example;
  • the polar aprotic solvent can be acetonitrile, 1,4- Dioxane, tetrahydrofuran or dimethylformamide (DMF);
  • Compound II-3 is added in a polar solvent solvent, acid chloride, DMF catalyzes the reaction, for example, at 70 °C overnight to produce the corresponding compound II-4;
  • the polar solvent is for example tetrahydrofuran or dichloromethane ;
  • the acid chloride is, for example, acetyl chloride or oxalyl chloride;
  • Compound II-4 is reacted with Compound I-2 obtained in Route 1 in the presence of an organic base in a polar protic solvent, for example, at 60-72°C to produce Compound I-II;
  • the polar protic solvent is, for example, methanol or ethanol;
  • the organic base is, for example, triethylamine or diisopropylethylamine;
  • Rings R 1 , R 2 , R 3 and B are as defined above
  • Compound III-6 and a fluorinating reagent are reacted in a polar aprotic solvent, for example, at room temperature for 18 hours to produce the corresponding compound III-7;
  • the fluorinating reagent may be tetrabutylamine fluoride ;
  • the polar aprotic solvent may be: 1,4-dioxane, tetrahydrofuran, dimethylformamide (DMF);
  • Compound III-7 is hydrolyzed in a polar solvent in the presence of a strong base, for example at room temperature, to obtain compound III-8
  • the polar solvent is for example ethanol or methanol
  • the strong base is for example sodium hydroxide or hydroxide Potassium
  • Ring B and R 3 are as defined above
  • Compound IV-5 and cyanoacetamide are reacted in a polar aprotic solvent in the presence of an organic base, for example at room temperature for 12 hours to produce the corresponding compound IV-6;
  • the polar aprotic solvent can It is: acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide (DMF);
  • the organic base is, for example, sodium methoxide or sodium ethoxide;
  • Compound IV-6 and a fluorinating reagent are reacted in a polar aprotic solvent, for example, at room temperature for 12 hours to produce the corresponding compound IV-7;
  • the fluorinating reagent may be tetrabutylammonium fluoride ;
  • the polar aprotic solvent may be: 1,4-dioxane, tetrahydrofuran, dimethylformamide (DMF);
  • Compound IV-7 is hydrolyzed in a polar protic solvent in the presence of a strong base, for example at room temperature to obtain compound IV-8, the polar solvent is ethanol or methanol; the strong base is sodium hydroxide or hydroxide Potassium
  • Compound IV-9 reacts with Compound I-2 obtained in Scheme 1 in the presence of an organic base in a polar protic solvent, for example, at 60-72°C to produce Compound I-IV;
  • the polar protic solvent is, for example, methanol or ethanol;
  • the organic base is, for example, triethylamine or diisopropylethylamine;
  • the compounds of the present invention can be prepared by the following routes 5-7.
  • R 2 , R 6 , R 7 and R 8 are as defined above
  • (a) Compound V-1 and bis(3,4-dimethylbenzyl)amine are reacted in a polar aprotic solvent in the presence of an organic base, for example, at room temperature for 5 hours to produce the corresponding compound V- 2.
  • the polar aprotic solvent may be: 1,4-dioxane or tetrahydrofuran;
  • the organic base is, for example: DMAP, imidazole, pyridine, triethylamine or diisopropylethylamine;
  • Compound V-2 is reacted with a fluorination reagent or an alkylation reagent in a polar aprotic solvent in the presence of a strong base, for example, at -80°C for 6 hours, to produce compound V-3;
  • the fluorinating reagent may be; N-fluorobisbenzenesulfonamide;
  • the alkylating reagent may be methyl iodide, ethyl iodide, iodopropane or 1,3,2-dioxolane 2,2 -Dioxide;
  • the polar aprotic solvent may be tetrahydrofuran or methylene chloride; strong bases such as n-butyl lithium, lithium diisopropylamide or sodium bistrimethylsilylamide;
  • R 2 and R 9 are as defined above
  • a polar aprotic solvent is used as a solvent to react, for example, at room temperature for 18 hours, to obtain compound VI-5
  • the condensing agent is, for example, O-benzotriazole -N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea Mixture of hexafluorophosphate (HATU) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT);
  • the organic base is for example: triethylamine or diisopropylethylamine;
  • the inorganic base is sodium bicarbonate, sodium carbonate or potassium bicarbonate; the polar aprotic a
  • Compound VI-5 is removed in a polar aprotic solvent by tert-butoxycarbonyl protecting group in the presence of an acid to obtain compound VI-6;
  • the polar aprotic solvent is, for example, dichloromethane or tetrahydrofuran;
  • the acid is, for example, formic acid or dilute hydrochloric acid (2mol/L);
  • R 2 and R 9 are as defined above;
  • the structure of the compound is determined by nuclear magnetic resonance (NMR). NMR is measured with Varian-MERCURY Plus-400 nuclear magnetic resonance spectrometer or AVANCE III 500 or 600 nuclear magnetic resonance spectrometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ) Or deuterated heavy water (D 2 O), the chemical shift is expressed in ⁇ (ppm); the mass spectrometry is measured by LTQ linear ion trap mass spectrometer or Thermo DFS magnetic high resolution mass spectrometer. Silica gel for separation is 200-300 mesh without explanation, and the ratio of eluent is volume ratio.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • D 2 O deuterated heavy water
  • ppm deuterated heavy water
  • the mass spectrometry is measured by LTQ linear ion trap mass spectrometer or Thermo D
  • 1,3-Cyclohexanedione (5g, 44.59mmol) was dissolved in 20mL of N,N-dimethylformamide dimethyl acetal and reacted at 80°C overnight. After the reaction was completed, the low-boiling substance was distilled off and acetic acid was used. Ethyl acetate/n-hexane was beaten to obtain 7.45 g of yellow solid, yield: 99.89%.
  • Example 1 Using 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.5g, 2.49mmol) and benzylsulfonamide (0.5g, 2.6mmol) as raw materials, according to (b) in Example 1 Prepared by the method described, and dried in vacuum to obtain 0.45 g of white solid in a yield of 45%.
  • N-(benzylsulfonyl)pyrrolidine-3-carboxamide (80 mg, 0.30 mmol) and 2-chloro-5-oxo-5,7-dihydrofuro[3,4-b]pyridine-3- Carboxynitrile (58 mg, 0.30 mmol) was prepared as the raw material according to the method of (g) in Example 5, and dried in vacuo to obtain 90 mg of a white solid with a yield of 71%.
  • Example 20 Using N,N-bis(2,4-dimethoxybenzyl)-1-phenylmethanesulfonamide (3g, 6.37mmol) and methyl iodide (2.17g, 15.3mmol) as raw materials, according to Example 20 Prepared by the method of (b) to obtain 2.3 g of white solid with a yield of 77%.
  • RN-(benzylsulfonyl)pyrrolidine-3-carboxamide (80mg, 0.30mmol) and 2-chloro-5-oxo-5,7-dihydrofuro[3,4-b]pyridine-3- Carboxynitrile (58 mg, 0.30 mmol) was used as the raw material to prepare according to the method of (g) in Example 5, and dried under vacuum to obtain 72 mg of white solid in a yield of 57%.
  • the venous blood of the volunteers was drawn to anticoagulate with 1:6 dextrorotatory citrate ACD (85mmol/L sodium citrate, 71.38mmol/L citric acid, 27.78mmol/L glucose), and centrifuged at 300g for 10 minutes at room temperature. Platelet-rich plasma (PRP) is separated.
  • the platelet aggregation test using the turbidimetry method was carried out on a Chrono-Log dual-channel optical platelet aggregation instrument, and the walking speed of the icon recorder was set to 1 cm/min to record the aggregation curve.
  • inhibition rate (%) [(maximum aggregation rate of control tube-maximum aggregation rate of test tube)/maximum aggregation rate of control tube] x 100%.
  • Cytochrome P405 enzyme is the main enzyme system for drug metabolism in the human body. When inhibitors of CYP450 enzymes are used simultaneously with other drugs, they may change the metabolic parameters of other drugs and cause potential drug-drug interactions. Lead compound AZD-1283 has a strong inhibitory effect on CYP2C9 and CYP3A4 enzymes, and there is a risk of drug interaction. In this experiment, the inhibitory activity of the compounds of the present invention on the major isoforms of CYP450 enzymes was determined to evaluate the risk of potential drug interactions.
  • PBS phosphate buffer
  • NADPH reduced coenzyme II
  • a using phenacetin as substrate; b: using tolbutamide as substrate; c: using s-mephenytoin as substrate; d: using dextromethorphan as substrate; e: using mida Zazolam as substrate; f: testosterone as substrate;
  • the data collection and control system software is Analyst 1.5.1 software (Applied Biosystem).
  • the peak integration mode of the spectrum sample is automatic integration; the ratio of the peak area of the sample and the peak area of the internal standard is used as an index, and the concentration of the sample is used for regression.
  • Regression method linear regression.
  • the pharmacokinetic parameters were analyzed and processed with WinNonlin Professional v6.3 (Pharsight, USA) using a non-compartmental model.
  • the data collection and control system software is Analyst 1.5.1 software (Applied Biosystem).
  • the peak integration mode of the spectrum sample is automatic integration; the ratio of the peak area of the sample and the peak area of the internal standard is used as an index, and the concentration of the sample is used for regression.
  • Regression method linear regression.
  • Pharmacokinetic parameters were analyzed and processed with WinNonlin Professional v6.3 (Pharsight, USA) using non-compartmental model.
  • C max is the measured maximum blood drug concentration
  • the area under the blood drug concentration-time curve AUC(0 ⁇ t) is calculated by the trapezoidal method
  • T max is the time when the blood drug concentration reaches the peak after administration.
  • T max peak time
  • T 1/2 half-life
  • C max maximum blood concentration
  • AUC area under the blood concentration-time curve
  • MRT mean residence time
  • the inhibitory effect of the representative compound of the present invention series 32 on carotid artery thrombosis was evaluated, and the antithrombotic activity in vivo was initially screened.
  • Rats 110 rats, acclimated in the laboratory overnight, fasted for 8 hours, room temperature 22 ⁇ 2°C, humidity 60%. No abnormal reaction was observed during the adaptation period. Rats were randomly divided into 11 groups according to their body weights, 10 rats in each group, which were model control group 0.5% CMC-Na (sodium carboxymethyl cellulose) and compound 32 in different dose groups (2.5, 5, 10, 20, 40, 80mg/kg), clopidogrel in different dose groups (2.5, 5, 10, 20mg/kg). Weigh a certain amount of the corresponding compound, suspend it with 0.5% CMC-Na solution after grinding, and administer it by intragastric administration in a volume of 10 ml/kg.
  • CMC-Na sodium carboxymethyl cellulose
  • the rats were anesthetized with 2% pentobarbital sodium (50 mg/kg), fixed supine, cut the neck skin, and bluntly separated the left carotid artery 1.5 cm long and placed 1.0 A plastic strip of ⁇ 1.5 cm protects nearby tissues, and then wrap the separated common carotid artery with a filter paper strip (0.8 ⁇ 1.0 cm) soaked with 20 ⁇ l of 20% FeCl 3 solution and seal with a plastic strip. After 10 minutes, the filter paper strip was removed and rinsed 3 times with cotton balls saturated with normal saline to allow thrombus formation for 30 minutes.
  • Thrombus weight When the experiment is completed, ligature the blood vessels at both ends of the filter paper with a cotton string, accurately cut the blood vessel segment (0.8cm) wrapped by the filter paper strip, use the clean filter paper to dry the residual blood in the blood vessel, and accurately weigh the weight of the blood vessel containing the thrombus. After taking out the thrombus, the weight is weighed out. The subtraction of the two is the weight of the thrombus.
  • the experimental results prove that the compound of the present invention has strong antithrombotic biological activity, the minimum effective dose is only 5 mg/kg, and the drug effect has a good dose dependence.
  • mice 100 rats were acclimated in the laboratory overnight, fasted for 8 hours, room temperature 22 ⁇ 2°C, humidity 60%. No abnormal reaction was observed during the adaptation period.
  • the rats were randomly divided into 10 groups according to their body weight, 10 rats in each group, which were model control group 0.5% CMC-Na (sodium carboxymethyl cellulose) and compound 32 in different dose groups (2.5, 5, 10, 20, 40 mg/ kg) and clopidogrel in different dose groups (2.5, 5, 10, 20 mg/kg).
  • CMC-Na sodium carboxymethyl cellulose
  • the rats were anesthetized with 2% pentobarbital sodium (50 mg/kg). After anesthesia, it was fixed to the mouse board, and the tail was disinfected with iodine and alcohol.
  • the mouse tail was placed in 37°C physiological saline for 3 minutes. After the end, it was cut off with a scalpel at a distance of 4 mm from the tip of the mouse tail, causing bleeding.
  • the 3cm tail of the mouse was immersed vertically in 37°C saline to observe the bleeding.
  • the representative compound 32 of the present invention has an obvious, dose-dependent antithrombotic effect, and more importantly, the compound 32 of the present invention and clopidogrel have ED 100 respectively It is: 7.58 mg/kg and 2.36 mg/kg, indicating that the bleeding risk of the compound of the present invention is significantly lower than that of clopidogrel, and the safety is higher.
  • Clopidogrel's clinical daily dose of 75 mg/tablet corresponds to an average thrombus inhibitory activity of approximately 60% (Thrombosis Research 134 (2014) 693–703). It can be seen from Table 8 that when the thrombus inhibitory activity (57%) in the same rats is the same, the bleeding time and amount of the compound of the present invention are significantly lower than that of clopidogrel, indicating that the bleeding risk of the compound of the present invention is significantly lower than that of clopidogrel, The treatment window is wider than clopidogrel and safer.
  • the compounds of the present invention overcome the shortcomings of the existing drugs, have good drug formation and safety, and are expected to become long-term oral antiplatelet drugs for preventing or treating thrombosis-related diseases.

Abstract

Font l'objet de la présente invention un composé de formule (I), son énantiomère, son diastéréo-isomère, son racémate, leur mélange, son sel pharmaceutiquement acceptable, une composition pharmaceutique associée, ainsi que les applications associées dans la préparation d'un médicament pour la prévention ou le traitement de maladies, telles que la thrombose et, en particulier, le syndrome coronaire aigu (SCA), les accidents vasculaires cérébraux, la coronaropathie et la fibrillation atriale.
PCT/CN2019/123507 2018-12-11 2019-12-06 Composé de 3-cyanopyridine, composition pharmaceutique le contenant, son procédé de préparation et ses applications WO2020119590A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101137643A (zh) * 2005-01-06 2008-03-05 阿斯利康(瑞典)有限公司 新型吡啶化合物
WO2008085119A1 (fr) * 2007-01-12 2008-07-17 Astrazeneca Ab Nouveaux analogues de la pyridine viii 518
CN101263133A (zh) * 2005-07-13 2008-09-10 阿斯利康(瑞典)有限公司 新的吡啶类似物
WO2010005385A1 (fr) * 2008-07-07 2010-01-14 Astrazeneca Ab Dérivés de pyridine substitués par 2-amino-6-alkyle utiles comme inhibiteurs de p2y12

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101137643A (zh) * 2005-01-06 2008-03-05 阿斯利康(瑞典)有限公司 新型吡啶化合物
CN101263133A (zh) * 2005-07-13 2008-09-10 阿斯利康(瑞典)有限公司 新的吡啶类似物
WO2008085119A1 (fr) * 2007-01-12 2008-07-17 Astrazeneca Ab Nouveaux analogues de la pyridine viii 518
WO2010005385A1 (fr) * 2008-07-07 2010-01-14 Astrazeneca Ab Dérivés de pyridine substitués par 2-amino-6-alkyle utiles comme inhibiteurs de p2y12

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