WO2019218955A1 - Composé servant d'inhibiteur du récepteur activé par la protéase 4 (par4) pour le traitement de l'agrégation plaquettaire - Google Patents

Composé servant d'inhibiteur du récepteur activé par la protéase 4 (par4) pour le traitement de l'agrégation plaquettaire Download PDF

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WO2019218955A1
WO2019218955A1 PCT/CN2019/086556 CN2019086556W WO2019218955A1 WO 2019218955 A1 WO2019218955 A1 WO 2019218955A1 CN 2019086556 W CN2019086556 W CN 2019086556W WO 2019218955 A1 WO2019218955 A1 WO 2019218955A1
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acid
pyridin
group
mmol
methoxyimidazo
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PCT/CN2019/086556
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English (en)
Chinese (zh)
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吴俊军
李硕
温晓明
阳华
魏国平
胡允金
钱苏
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深圳信立泰药业股份有限公司
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Priority to CN201980030142.3A priority Critical patent/CN112074523B/zh
Publication of WO2019218955A1 publication Critical patent/WO2019218955A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention is in the field of chemical pharmaceutical technology, and particularly provides a series of compounds as protease inhibitory receptor 4 (PAR4) inhibitors for treating platelet aggregation and their medical uses.
  • PAR4 protease inhibitory receptor 4
  • Thromboembolic disease remains one of the leading causes of death, although available anticoagulants such as warfarin, heparin, and antiplatelet agents such as aspirin and clopidogrel, ticagrelor, rivaroxaban and many more.
  • thrombosis The main physiological function of platelets is to participate in thrombosis and hemostasis. Any blood coagulation process involves the activation of platelets, which is a complex signal cascade process in which thrombin plays a central role.
  • Thrombin-activated platelets are mediated primarily by a family of G-protein-coupled protease-activated receptors (PARs). Human platelets express both PAR1 and PAR4 receptors. Thrombin can bind and cleave PAR1 or PAR4, exposing a new N-terminus, which acts as a binding ligand for intramolecular binding to the receptor, thereby stimulating transmembrane signaling. , causing platelet aggregation, release, and a series of changes in membrane glycoproteins.
  • PAR1 G-protein-coupled protease-activated receptors
  • PAR4 inhibitor patent applications disclose, such as CN104640869A and CN104583218A, respectively, disclose a series of uses of the following formulas I and II as protease activated receptor 4 (PAR4) inhibitors for inhibiting or preventing platelet aggregation. .
  • PAR4 protease activated receptor 4
  • the nucleus of the quintuple should contain oxygen atoms to have the corresponding PAR4 activity.
  • the present invention provides a series of compounds as protease activated receptor 4 (PAR4) inhibitors for the treatment of platelet aggregation, the structural nucleus of the compound of the present invention is different from A PAR4 inhibitor has been disclosed.
  • PAR4 protease activated receptor 4
  • the present invention first provides a series of compounds as compounds of a protease activated receptor 4 (PAR4) inhibitor for the treatment of platelet aggregation, or a pharmaceutically acceptable salt thereof, the mother nucleus of which is as follows:
  • PAR4 protease activated receptor 4
  • the nuclear is as shown in the following formula (I):
  • X is selected from the group consisting of a carbonyl group, a thiocarbonyl group, a sulfoxide group, and a sulfone group;
  • W, Y and Z are each independently selected from CH, N;
  • n 1, 2, 3, 4;
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1-4 alkoxy, C 1-4 alkylthio;
  • R 2 is selected from a substituted or unsubstituted C 1-4 alkoxy group, said substituent being selected from halogen;
  • R 3 is selected from hydroxy, C 1-4 alkoxy, substituted or unsubstituted C 6-12 aryl, C 6-10 heteroaryl, C 3-6 heterocycloalkyl, thiazole, oxazole, imidazole
  • the substituent is selected from a halogen; and -NR 4 R 5 , wherein R 4 , R 5 are selected from hydrogen, hydroxy, substituted or unsubstituted C 1-6 alkyl, C 1-4 alkoxy a C 3-12 cycloalkyl group selected from the group consisting of halogen, cyano, C 6-12 aryl, C 6-10 heteroaryl, C 3-6 heterocycloalkyl, C 3 -
  • the 6 -cycloalkyl group, the C 1-4 amino group, the C 6-12 aryl group and the C 6-10 heteroaryl group may be further substituted with a C 1-6 alkyl group or a hydroxyl group.
  • the C 1-4 alkoxy group is selected from the group consisting of a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, and a sec-butyl group. Oxyl, tert-butoxy.
  • the C 1-4 alkylthio group is selected from the group consisting of methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, and sec Sulfur-based, tert-butylthio.
  • the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • the C 6-12 aryl group is selected from the group consisting of C 6-10 heteroaryl is selected from
  • C 3-6 heterocycloalkyl is selected from
  • the C 1-6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylcyclopropane, n-pentyl , isoamyl, tert-butylmethyl, n-hexyl, isohexyl, methylcyclobutane, methylcyclopentanyl; said C 3-12 cycloalkyl is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane Alkane, cyclohexane, tricyclo[3.3.1.13.7] decane, bicyclo[1.1.1]pentane.
  • the amino group of C 1-4 is selected from the group consisting of methylamino, ethylamino, dimethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino and tert-butylamino.
  • the mother nucleus of the compound is represented by the following formula (II).
  • R 1 , R 2 , R 4 , R 5 , W, Y, Z, and n are as defined above.
  • the pharmaceutically acceptable salt is selected from the group consisting of inorganic acids or organic acid salts selected from the group consisting of 2-acetoxybenzoic acid and 2-hydroxyethanesulfonic acid.
  • Acid formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid , glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane Sulfonic acid, nitric acid, oxalic acid, pamoic acid, panto
  • the invention is preferably derived from the following compounds:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a pharmaceutical use which is a pharmaceutical use for the preparation of a compound for the treatment of a thrombosis-related disease, or a pharmaceutically acceptable salt thereof.
  • the thrombosis-related disease is selected from the group consisting of an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, a cerebrovascular thromboembolic disorder, and a thromboembolic disorder in the heart chamber or peripheral circulation.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, amber Acids, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, cit
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, Trifluoroacetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, valley Acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid , nitric acid, oxalic acid, pamoic acid, pantothenic acid
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • a compound can be labeled with a radioisotope such as hydrazine (3H), iodine-125 (125I) or C-14 (14C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation carrier or vehicle that is capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient.
  • Representative carriers include water, oil. , vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • Step A Synthesis of ((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1, 5-a]pyridin-4-yl)oxy)acetate
  • Step A Synthesis of (6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5 -a]pyridin-4-yloxy)acetic acid
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-methylacetamide
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N,N-dimethylacetamide
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-1-acetophenone
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-1-morpholino
  • Step A Synthesis of N-(2-(dimethylamino)ethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3, 4]thiadiazole-6-yl)pyrazolo[1,5a]pyridin-4-yloxy)acetamide
  • 2-morpholinoethylamine (65 mg, 0.50 mmol) was dissolved in dichloromethane (2.0 mL). Subsequently, bromoacetyl chloride (78 mg, 0.50 mmol) was added to the above solution. Stir at room temperature for 3 hours.
  • Step B Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-(2-morpholinoethyl)acetamide
  • Step A Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-1-(pyridin-4-yl)ethan-1-one
  • Step A Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-1-(pyridin-2-yl)ethan-1-one
  • Step A Synthesis of 1-(2-fluorophenyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole -6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethanone
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-(oxetan-3-ylmethyl)acetamide
  • Step A Synthesis of N-(2-cyclopropylethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiophene Diazol-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of 2-((2-acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)acetic acid
  • reaction solution was diluted with hydrochloric acid (1.0 mol/liter) to quench the reaction and the pH of the system was adjusted to about 4.
  • the mixture was extracted with ethyl acetate (25 mL ⁇ 3 ⁇ ).
  • the combined organic layers were washed with brine (10 mL ⁇ 3 ⁇ ) and then dried over anhydrous sodium sulfate.
  • 2-((2-Acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)acetic acid 260 mg was obtained as a white solid. No purification is required.
  • Step B Synthesis of 2-((2-acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide
  • Step C Synthesis of 2-((2-(2-bromoacetyl)-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl) Acetamide
  • reaction mixture was quenched by aqueous saturated sodium hydrogen sulfate (5 mL).
  • the mixture was extracted with ethyl acetate (10 mL ⁇ 3 ⁇ ).
  • the organic phases were combined and the organic phase was concentrated.
  • the residue obtained was dissolved in tetrahydrofuran (6.0 mL).
  • a solution of N-bromosuccinimide (593 mg, 3.33 mmol) in tetrahydrofuran (4.0 mL). Stir at 0 ° C for 1 hour.
  • Step D Synthesis of 2-((2-(2-bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxypyrazolo[1, 5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide
  • Step E Synthesis of N-(cyclopropylmethyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiene) Zol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide
  • Step A Synthesis of N-isopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of N-cyclobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of N-benzyl-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl) Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-(2,2,2-trifluoroethyl)acetamide
  • Step A Synthesis of N-isobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of N-ethyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • the thiosemicarbazide (500 mg, 5.49 mmol) was dissolved in 1,4-dioxane (3.0 ml) under ice-water bath. Subsequently, 2,2-difluoropropionic acid (450 mg, 4.09 mmol) and phosphorus oxychloride (840 mg, 5.49 mmol) were sequentially added to the above solution. The reaction solution was heated to 90 ° C and stirred for 5 hours.
  • reaction solution was cooled to room temperature, and water (15 ml) was added to the reaction mixture to quench the reaction.
  • Sodium hydroxide (40% by weight) was added to the reaction solution to adjust the pH of the system to about 9.
  • the mixture was extracted with ethyl acetate (20 mL ⁇ 3 ⁇ ). The combined organic layers were washed with brine (20 mL ⁇ 3 ⁇ ) and dried over anhydrous sodium sulfate.
  • Step D Synthesis of 2-(2-(2-(1,1-difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-A Oxypyrazolo[1,5-a]pyridin-4-yloxy)-N-methylacetamide
  • Step A Synthesis of N-(cyclobutylmethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6 -yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of N-butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of N-tert-butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of N-cyclopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-pentylacetamide
  • Step A Synthesis of N-cyclohexyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide
  • Step A Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide
  • Step A Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-(oxetan-3-yl)acetamide
  • Step A Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-phenylacetamide
  • Step A Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-(2-methylthiazol-5-yl)acetamide
  • Step A 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Subsequently, 2-bromo-1-(pyrrolidin-1-yl)ethan-1-one (60 mg, 0.32 mmol) and anhydrous potassium carbonate (43 mg, 0.32 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (75 ⁇ L, 0.08 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, triethylamine (109 mg, 1.08 mmol) and tert-butylamine (23 mg, 0.32 mmol) were sequentially added to the reaction mixture. The reaction solution was stirred at room temperature for 2 hours.
  • EtOAc EtOAc
  • Step A 2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.38 ml, 0.64 mmol, 50% by weight), N-ethylhydroxylamine hydrochloride (78 mg, 0.79 mmol) and three were sequentially added to the above solution. Ethylamine (0.38 ml).
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.2 ml, 0.29 mmol, 50% by weight) was added dropwise to the above solution.
  • Step A Ethyl 4-bromobutyrate (194 mg, 1.00 mmol) was dissolved in acetone (1.0 mL). Subsequently, sodium iodide (180 mg, 1.20 mmol) was added to the above solution. The reaction solution was heated to 60 ° C and stirred for 1 hour.
  • reaction solution was cooled to room temperature. Filtration and EtOAc (3 mL) It was used directly in the next reaction without purification.
  • Step B 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (90 mg, 0.28 mmol), ethyl 4-iodobutanoate (137 mg, 0.57 mmol) and potassium carbonate (117 mg, 0.85 mmol) were added to N,N-dimethyl Formamide (3.0 ml). The reaction solution was stirred at room temperature for 8 hours.
  • Step C 4-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ Ethyl 1,5-a]pyridin-4-yloxy)butanoate (60 mg, 0.14 mmol) was dissolved in tetrahydrofurane (1.5 mL). Subsequently, an aqueous solution (1.5 ml) of lithium hydroxide (17 mg, 0.70 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 5 hours.
  • Step D 4-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)butanoic acid (45 mg, 0.11 mmol) was dissolved in acetonitrile (9.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (138 mg, 0.22 mmol, 50% by weight) was added to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.13 ml, 0.22 mmol, 50% by weight), N-ethyl-O-methylhydroxylamine hydrochloride (30 mg, 0.27 m) was sequentially added to the above solution. Mole) and triethylamine (0.13 ml). The reaction solution was stirred at room temperature for 1 hour.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (0.2 ml, 0.33 mmol, 50% by weight) was added to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) and 4-(aminomethyl)phenol (20 mg, 0.16 mmol) were dissolved in dichloromethane (2.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (122 mg, 0.19 mmol, 50% by weight) and triethylamine (32 mg, 0.32 mmol) were added to the above solution. The reaction solution was stirred at room temperature for 1 hour.
  • Step A 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Subsequently, 2-bromo-1-thiazol-5-yl-ethanone hydrobromide (90 mg, 0.32 mmol) and anhydrous potassium carbonate (65 mg, 0.47 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (130 mg, 0.20 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 30 minutes, 2-ethylaminemethylimidazole (65 mg, 0.67 mmol) and triethylamine (94 mg, 0.93 mmol) were sequentially added to the reaction mixture. The reaction solution was stirred at room temperature for 1 hour.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in dichloromethane (2.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (184 mg, 0.29 mmol, 50% by weight) was added to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in tetrahydrofurane (5.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.25 ml, 0.42 mmol, 50% by weight) was added dropwise to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (4.0 mL). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (138 mg, 0.22 mmol, 50% wt) was added to the solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (100 mg, 0.27 mmol) was dissolved in dichloromethane (2.0 mL). Subsequently, a solution of 1-propylphosphonic anhydride in ethyl acetate (305 mg, 0.48 mmol, 50% wt) was added to the solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.075 ml, 0.12 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, n-butylamine (12 mg, 0.16 mmol) and triethylamine (0.075 ml, 0.54 mmol) were sequentially added to the mixture. The reaction solution was stirred at room temperature for 1 hour.
  • EtOAc EtOAc
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.13 ml, 0.22 mmol, 50% by weight), 4-fluorobenzylamine (66 mg, 0.53 mmol) and triethylamine (s) were sequentially added to the above solution. 0.13 ml). The reaction solution was stirred at room temperature for 1 hour.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (0.25 ml, 0.42 mmol, 50% by weight) was added to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] , 5-a]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (3.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (138 mg, 0.22 mmol, 50% by weight) was added to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (4.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (138 mg, 0.22 mmol, 50% by weight) was added to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] , 5-a]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (3.0 mL). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.4 ml, 0.67 mmol, 50% by weight) was added dropwise to the above solution.
  • Step A 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] , 5-a]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in acetonitrile (3.0 mL). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution.
  • Step A 3-Aminopropanenitrile (275 mg, 3.93 mmol) and potassium carbonate (530 mg, 3.84 mmol) were added to dichloromethane (15.0 mL). Subsequently, a solution of bromoacetyl bromide (392 mg, 1.94 mmol) in dichloromethane (5.0 ml) was slowly added dropwise to the above solution. The reaction solution was stirred at room temperature for 12 hours.
  • Step B 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] pyridin-4-ol (70 mg, 0.22 mmol), 2-bromo-N-(2-cyanoethyl)acetamide (140 mg, 0.73 mmol) and anhydrous potassium carbonate (210 mg, 1.52) Millimol) was added to N,N-dimethylformamide (7.0 mL). The reaction solution was stirred at room temperature for 1 hour.
  • the mammalian cell expression vector containing human PAR4 cDNA was introduced into Flp-In-TREx-293 cells by conventional transfection method, and the stably high-expression Flp-In-TREx-293-PAR4 cell line was obtained by corresponding antibiotic screening. Functional verification was performed using the PAR4FLIPR calcium ion outflow assay. According to the literature, HEK293 cells express endogenously high expression of PAR4, so Flp-In-TREx-293-PAR4 cell line can be used for screening experiments of PAR4 small molecule inhibitors.
  • the medium was cultured in a 37 ° C, 5% CO 2 cell incubator.
  • the cells were seeded into poly-d-lysine-treated 384-well cell culture plates (Corning, 3845) at a seeding density of 8,000 cells/well/25 ⁇ l of cell seeding matrix (DMEM high glucose, 10% fetal bovine serum, 2 mM GlutaMAX). ) Incubate overnight in a cell culture incubator.
  • DMEM high glucose, 10% fetal bovine serum, 2 mM GlutaMAX cell seeding matrix
  • test compound and the PAR4 agonist were diluted to a 6X concentration using the experimental buffer, 10 ⁇ l of the 6X test compound was added to the 384-well cell culture plate, and after incubation for 30 minutes at room temperature, 10 ⁇ l of the 6X PAR4 agonist was added to the 384-well cell using FLIPR Tetra. The plates were incubated and the data were measured and analyzed. The entire reaction system was 60 ⁇ l, the final concentration of the PAR4 agonist was 1.3 ⁇ M (EC50), and the final concentration of DMSO was 0.3%.
  • SAL02-190 B 13 SAL02-208 A 14 SAL02-213 A 15 SAL02-211 A 16 SAL02-214 B 17 SAL02-216 A 18 SAL02-218 A 19 SAL02-221 B 20 SAL02-211 A twenty one SAL02-227 B twenty two SAL02-229 A twenty three SAL02-239 B twenty four SAL02-194 B 25 SAL02-241 B 26 SAL02-240 A 27 SAL02-242 B 28 SAL02-213 A 29 SAL02-232 B 30 SAL02-247 B 31 SAL02-234 A 32 SAL02-248 A 33 SAL02-250 B 34 SAL02-251 B
  • platelet-rich plasma samples were centrifuged at 1300 g (Eppendorf Model 5810R centrifuge) for 6 minutes at room temperature; after centrifugation, the supernatant liquid was discarded and carefully resuspended and washed with ACD buffer. Once again.
  • PPP platelet-poor plasma
  • the measurement time was set to 600 s, and the measurement mode was Aggr mode; the washed platelet samples after 280 uL incubation were added to a cuvette (Beijing Shidi Scientific Instrument Co., Ltd.). Join a shocking bead (Beijing Shidi Scientific Instrument Co., Ltd.) and warm up for 1 minute. After the preheating is completed, place the cuvette in the test channel. After pressing the start button for 10 seconds, slowly add 20uL of PAR4-AP agonist or 20ul of lead compound. During the addition process, the tip does not enter the deep surface. Position, get the MAR value.
  • Negative agonist control As in the operation of 2, only the last added PARP-AP agonist was replaced with the vehicle used for the agonist (15% HBSS + 20 mM HEPES physiological saline solution), and the test result was a negative agonist control. .
  • Platelet aggregation inhibition rate (%) 1 - (test compound MAR% - negative agonist MAR%) / (negative control MAR% - negative agonist MAR%) * 100%
  • the test compound is provided by the client.
  • the control compound ketoconazole was purchased from Sigma.
  • Plasma EDTA-K 2 anticoagulation
  • test substance containing the concentration of 1 ⁇ M was separately added to the balanced dialysis membrane of the HTDialysis apparatus in human, monkey, canine, rat and mouse plasma samples and phosphate buffer, respectively, at 37 ° C, Samples were taken after dialysis for 6 hours at a speed of about 100 rpm in a 5% CO 2 atmosphere, and the percentage of free concentration of the test substances in human, monkey, dog, rat, and mouse plasma at different concentrations was determined. According to the experimental requirements, the experiment was performed using plasma diluted with phosphate buffer.
  • test powder and the control drug ketoconazole were prepared into a high concentration of DMSO stock solution and diluted to 200 ⁇ M working solution in DMSO.
  • An alkaline solution of 14.2 g/L of Na 2 HPO 4 and 8.77 g/L of NaCl and an acidic solution of 12.0 g/L of NaH 2 PO 4 and 8.77 g/L of NaCl were placed in ultrapure water, and the two solutions were stored in 4 ° C refrigerator, valid for 7 days.
  • the buffer solution of pH 7.4 was prepared by using two kinds of solutions of acid and alkali, and the prepared buffer was stored in a refrigerator at 4 ° C for 7 days.
  • the water bath and incubator temperature were adjusted to 37 °C in advance.
  • the plasma was taken out from -80 ° C, thawed in a room temperature water environment, centrifuged at a temperature of 3220 g and a temperature of 4 ° C for 10 minutes, the clot was removed and the supernatant was transferred to a new centrifuge tube. Test and record the pH of the plasma. (Remarks: a. Use only plasma with a pH range between 7 and 8. b. Use only plasma that does not melt more than twice after arrival.)
  • the equilibrated dialysis membrane was immersed in pure water for 60 minutes, then immersed in 20% ethanol for 20 minutes, and finally immersed in dialysis buffer for 20 minutes.
  • the soaked dialysis membrane is then plated onto a clean HTDialysis splint device and the dialysis device is installed according to the product manual.
  • the remaining incubation system was also incubated for 6 hours under the same conditions. After the incubation, 50 ⁇ L of the incubation system was transferred for treatment. For the stability test of test drugs. The stable sample is processed in the same manner as the dialysis incubation sample.
  • 0.1 ml of blood was collected before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 h after administration, placed in heparinized tubes, and centrifuged at 3500 rpm for 10 min to separate plasma at -20 ° C. save.
  • the content of the test compound in the plasma of rats after intravenous administration of different compounds was determined by LC/MS/MS method.

Abstract

L'invention concerne une série de composés utilisés en tant qu'inhibiteurs du récepteur activé par la protéase 4 (PAR4) pour le traitement de l'agrégation plaquettaire et leur utilisation médicale, se rapportant au domaine technique des médicaments chimiques.
PCT/CN2019/086556 2018-05-16 2019-05-13 Composé servant d'inhibiteur du récepteur activé par la protéase 4 (par4) pour le traitement de l'agrégation plaquettaire WO2019218955A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104540835A (zh) * 2012-04-26 2015-04-22 百时美施贵宝公司 用于治疗血小板聚集的作为蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑衍生物
CN104640869A (zh) * 2012-04-26 2015-05-20 百时美施贵宝公司 作为用于治疗血小板聚集的蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑和咪唑并哒嗪衍生物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104540835A (zh) * 2012-04-26 2015-04-22 百时美施贵宝公司 用于治疗血小板聚集的作为蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑衍生物
CN104640869A (zh) * 2012-04-26 2015-05-20 百时美施贵宝公司 作为用于治疗血小板聚集的蛋白酶激活受体4(par4)抑制剂的咪唑并噻二唑和咪唑并哒嗪衍生物

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