WO2018019296A1 - Composé d'aminopyrazine, sel ou isomère, son procédé de préparation et son application - Google Patents

Composé d'aminopyrazine, sel ou isomère, son procédé de préparation et son application Download PDF

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WO2018019296A1
WO2018019296A1 PCT/CN2017/094936 CN2017094936W WO2018019296A1 WO 2018019296 A1 WO2018019296 A1 WO 2018019296A1 CN 2017094936 W CN2017094936 W CN 2017094936W WO 2018019296 A1 WO2018019296 A1 WO 2018019296A1
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group
ethoxy
isopropylamino
diphenylpyrazin
compound
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PCT/CN2017/094936
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English (en)
Chinese (zh)
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王颖
蔡显荣
鄢胜勇
张涛
刘强强
马云龙
乔惠
付海霞
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成都苑东生物制药股份有限公司
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Priority to CN201780041770.2A priority Critical patent/CN109563055B/zh
Publication of WO2018019296A1 publication Critical patent/WO2018019296A1/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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to an aminopyrazine compound having a prostaglandin I 2 (PGI 2 ) receptor agonistic activity, or a salt thereof, an isomer thereof, a preparation method thereof, and a preparation thereof for treating pulmonary hypertension, platelet aggregation or Use in drugs such as arteriosclerosis obliterans.
  • PKI 2 prostaglandin I 2
  • Prostaglandin I 2 is a member of the family of lipids in the eicosanoid family and is an antagonist of thromboxane, and its reduced synthesis promotes thrombosis.
  • the agonistic PGI 2 receptor IP receptor not only inhibits platelet-mediated agglutination but also has a strong vasodilation effect.
  • IP receptor agonists can treat pulmonary hypertension (PAH), PAH associated with various diseases, arteriosclerosis obliterans, coronary artery disease, myocardial infarction, transient ischemic attack, colic, stroke, ischemia Reperfusion injury, restenosis, atrial fibrillation, intermittent claudication, Raynaud's phenomenon, varicose veins, thrombosis, diabetes, diabetic nephropathy, hypertension, hyperlipidemia, cerebral infarction, rheumatoid arthritis, chronic obstructive pulmonary disease Disease (COPD), etc.
  • PAH pulmonary hypertension
  • PAH pulmonary hypertension
  • PGI 2 listed drugs have more or less problems such as short half-life, poor chemical stability and large side effects.
  • endogenous PGI 2 compounds many companies have begun to explore long half-life and good chemical stability.
  • a non-endogenous PGI 2 type IP receptor agonist with higher selectivity and less side effects the structural formula is as follows:
  • the marketed drug Selexipag jointly developed by Nippon Shinyaku and Actelion is an orally effective and highly selective.
  • IP receptor agonist of prostacyclin the active metabolite of which is MRE-269; the clinical phase II compound FK-788 (developed by Astellas) and Ralinepag (developed by Arena); the compound in clinical phase QCC-374 (developed by Novartis) and Ono-1301 (developed by Ono).
  • Patent CN1516690A discloses the compound Selexipag and its metabolically active compound MRE-269, and also provides a human platelet aggregation inhibition test to demonstrate the in vitro activity of such compounds; Patent CN103097385A discloses compound QCC-374, which is determined by using the Perkin Elmer Alpha Screen test.
  • the cAMP accumulation in CHO cells (CHO-IP) stably expressing the IP receptor was evaluated for the activity of the compound on the IP receptor.
  • the inventors have found through long-term large-scale screening that the change of the long chain of the carboxylic acid of the aminopyrazine compound has a great influence on the activity, and the change The length of the chain length reduces the activity against platelet aggregation. Moreover, it was unexpectedly found in the study that the long-chain compound constructed by the ethylene glycol structure (especially the structure of two ethylene glycol-based units) can not only significantly increase the aminopyrazine compound in vitro compared with the MRE-269 compound. The anti-platelet aggregation activity also improves anti-platelet aggregation activity in vivo, lowers mean pulmonary artery pressure, and also improves the stability of the salt solution and reduces drug toxicity.
  • e 0, 1 or 2;
  • R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen-substituted C 1 -C 6 alkyl group, a halogen atom. Substituted C 1 -C 6 alkoxy, hydroxy, amine, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amine;
  • R 4 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 1 -C 6 alkane Acyl group
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halogen atom-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylamino C 1 - C 6 alkyl, di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl, nitrile C 1 -C 6 alkyl;
  • R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 may each be bonded to a C 1 -C 6 alkyl substituted cyclopropane;
  • a and D are each independently selected from NR 15 , O, S, SO or SO 2 , wherein R 15 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 naphthenic ring base;
  • G is selected from the group consisting of a hydroxyl group, a C 1 -C 6 alkoxy group, an amine group, a C 1 -C 6 alkylamino group, a C 1 -C 6 alkylamido group, a C 1 -C 6 alkylsulfonylamino group, a halogen atom Substituted C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino, C 1 -C 6 alkyl substituted C 6 -C 10 arylsulfonylamino, halogen substituted C 6 -C 10 arylsulfonylamino group.
  • the aminopyrazine compound represented by the formula I provided by the present invention can be divided into three small formulas, which are three small formulas Ia corresponding to when e is equal to 0, 1 or 2 in the structure of the formula I. , Ib or Ic:
  • R 1 , R 2 , R 3 , R 4 , A, D, G are the same as defined in the above formula I;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halogen atom-substituted C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylamino C 1 -C 6 alkyl, di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl, nitrile C 1 -C 6 alkyl;
  • R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 may each be bonded to a C 1 -C 6 alkyl substituted cyclopropane.
  • the aminopyrazine compound of the formula I of the present invention or a pharmaceutically acceptable salt or isomer thereof has the structure represented by the formula Ib:
  • R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom-substituted C 1 -C 6 alkyl group;
  • R 4 is selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group;
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkoxy group.
  • R 5 and R 6 , R 7 and R 8 , R 9 and R 10 may be bonded to form a cyclopropane
  • R 11 and R 12 are hydrogen
  • A, D are each independently selected from O, S, SO or SO 2 ;
  • G is selected from the group consisting of a hydroxyl group, a C 1 -C 6 alkoxy group, an amine group, a C 1 -C 6 alkylamino group, a C 1 -C 6 alkylamido group, a C 1 -C 6 alkylsulfonylamino group, a halogen atom Substituted C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino, C 1 -C 6 alkyl substituted C 6 -C 10 arylsulfonylamino, halogen substituted C 6 -C 10 arylsulfonylamino group.
  • aminopyrazine compound represented by the formula Ib of the present invention or a pharmaceutically acceptable salt or isomer thereof:
  • R 1 , R 2 , and R 3 are each independently selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a methoxy group, a halogen atom, and a trifluoromethyl group;
  • R 4 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
  • R 9 and R 10 may be linked to cyclopropane
  • R 11 and R 12 are hydrogen
  • A, D are independently selected from O or S;
  • G is selected from the group consisting of hydroxyl, methoxy, ethoxy, isopropoxy, butoxy, amine, methylamino, formamide, acetamido, methylsulfonyl, trifluoromethylsulfonamide , benzenesulfonylamino, p-toluenesulfonylamino, p-fluorobenzenesulfonylamino.
  • aminopyrazine compound represented by the formula Ib of the present invention or a pharmaceutically acceptable salt or isomer thereof,
  • R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a methyl group, a methoxy group, and a halogen atom;
  • R 4 is an isopropyl group
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
  • R 5 , R 6 , R 7 , R 8 , R 11 and R 12 are hydrogen
  • A, D is O
  • G is selected from the group consisting of a hydroxyl group, an amine group, an acetamide group, a methylsulfonylamino group, a trifluoromethylsulfonylamino group, a benzenesulfonylamino group, a p-toluenesulfonylamino group, and a p-fluorobenzenesulfonylamino group.
  • Another object of the present invention is to provide an aminopyrazine compound having the structure represented by the following formula II or a pharmaceutically acceptable salt or isomer thereof:
  • e 0, 1 or 2;
  • R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen-substituted C 1 -C 6 alkyl group, a halogen atom. Substituted C 1 -C 6 alkoxy, hydroxy, amine, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amine;
  • R 4 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 1 -C 6 alkane Acyl group
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, and a C 1 -C substituted by a halogen atom.
  • R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 may each be bonded to a C 1 -C 6 alkyl substituted cyclopropane;
  • a and D are each independently selected from NR 15 , O, S, SO or SO 2 , wherein R 15 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 naphthenic ring base;
  • G is selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, amine, C 1 -C 6 alkylamino, C 1 -C 6 alkylamido, C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino group.
  • the aminopyrazine compound represented by the general formula II provided by the present invention can be divided into three small general formulas, respectively corresponding to three small general formulas IIa when e is equal to 0, 1 or 2 in the structure of the general formula II. , IIb or IIc:
  • R 1 , R 2 , R 3 , R 4 , A, D, G are the same as defined in the above formula II;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halogen atom-substituted C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylamino C 1 -C 6 alkyl, di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl, nitrile C 1 -C 6 alkyl;
  • R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 may each be bonded to a C 1 -C 6 alkyl substituted cyclopropane;
  • the aminopyrazine compound represented by the formula II of the present invention or a pharmaceutically acceptable salt or isomer thereof has a structure represented by the formula IIb:
  • R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom-substituted C 1 -C 6 alkyl group;
  • R 4 is selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group;
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkoxy group.
  • R 5 and R 6 , R 7 and R 8 , R 9 and R 10 may be bonded to form a cyclopropane
  • R 11 and R 12 are hydrogen
  • A, D are each independently selected from O, S, SO or SO 2 ;
  • G is selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, amine, C 1 -C 6 alkylamino, C 1 -C 6 alkylamido, C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino group.
  • aminopyrazine compound represented by the formula IIb of the present invention or a pharmaceutically acceptable salt or isomer thereof,
  • R 1 , R 2 , and R 3 are each independently selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a methoxy group, a halogen atom, and a trifluoromethyl group;
  • R 4 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
  • R 9 and R 10 may be linked to cyclopropane
  • R 11 and R 12 are hydrogen
  • A, D are independently selected from O or S;
  • G is selected from the group consisting of hydroxyl, methoxy, ethoxy, isopropoxy, butoxy, amine, methylamino, formamide, acetamido, methylsulfonyl, and benzenesulfonyl.
  • aminopyrazine compound represented by the formula IIb of the present invention or a pharmaceutically acceptable salt or isomer thereof,
  • R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a methyl group, a methoxy group, and a halogen atom;
  • R 4 is an isopropyl group
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
  • R 5 , R 6 , R 7 , R 8 , R 11 and R 12 are hydrogen
  • A, D is O
  • G is selected from the group consisting of a hydroxyl group, an amine group, an acetamide group, a methylsulfonylamino group, and a benzenesulfonylamino group.
  • aminopyrazine compound represented by the formula I or formula II of the present invention or a pharmaceutically acceptable salt or isomer thereof
  • preferred compounds include, but are not limited to, the following compounds:
  • the aminopyrazine compound provided by the present invention may be in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt thereof may be selected from the group consisting of an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt; An organic salt such as an amine salt, a diethanolamine salt, a meglumine salt, a piperazine salt or a choline salt Salt; mineral acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrofluoric acid, hydrobromide; acetate, trifluoroacetate, naphthoate, benzoate, tartaric acid Salt, lactate, citrate, fumarate, maleate, malate, oxalate, succinate, methanesulfonate, ethanesulfonate, besylate, p-toluene
  • An acid salt such as an acid salt, a naphthalene s
  • the pharmaceutically acceptable salt of the aminopyrazine compound provided by the present invention may be selected from the group consisting of:
  • the aminopyrazine compound represented by the formula I or the formula II provided by the present invention may contain a plurality of asymmetric carbon atoms, and thus, the provided compound may be in the enantiomeric, diastereomeric, or rotationally different A form of a construct, atropisomer, tautomer or mixture thereof.
  • the isomer of the aminopyrazine compound or a pharmaceutically acceptable salt thereof provided by the present invention may be selected from the group consisting of:
  • the aminopyrazine compound represented by the above formula I or formula II provided by the present invention may be a prodrug having a corresponding carboxylic acid derivative, which can be converted into a corresponding carboxylic acid active metabolite in vivo, and the prodrug is prodrug Included are compounds in which the carboxylic acid group is converted to a group: ethyl carboxylate, isopropyl carboxylate, butyl carboxylate, amide, amidoamine, acylethylamine, acylacetamide, acylsulfonamide, Acetylbenzene sulfonamide.
  • aminopyrazine compound of the formula I or formula II provided by the present invention is selected from the group consisting of the following prodrugs:
  • the compound of formula III and formula IV is refluxed in a solution of NaOH in methanol for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl 3 to form a compound of formula VI, a compound of formula VI and a compound of formula VII-A at 120-200 ° C.
  • the next reaction is 8-48h (preferably 8-20h) to synthesize a compound of formula VIII-A.
  • the compound of the formula VII-A can be synthesized by reacting a primary amine of the formula 1 with a halogenated hydrocarbon R 4 X or by reductive amination of a primary amine of the formula 1 with an alkane aldehyde (NaB(CN)H 3 , NaB(OAc) 3 H or PtO 2 /H 2 ) is synthesized.
  • the compound of formula III and formula IV is refluxed in a solution of NaOH in methanol for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl 3 to form a compound of formula VI, a compound of formula VI and a compound of formula VII-B at 120-200 ° C.
  • the next reaction is 8-48h (preferably 8-20h) to synthesize a compound of formula VIII-B.
  • the compound of formula VIII-B is reacted with a compound of formula IX-B in a solution of toluene KOH or NaH in THF to form a compound of formula XB, a compound of formula XB in LiAlH.
  • G is optionally C 1 -C 6 alkoxy, amine, C 1 -C 6 alkylamino, C 1 -C 6 alkylamido, C 1- C 6 alkylsulfonylamino group, halogen-substituted C 1 -C 6 alkylsulfonylamino group, C 6 -C 10 arylsulfonylamino group, C 1 -C 6 alkyl substituted with C 6 -C 10 arylsulfonyl group or a halogen-substituted C 6 -C 10 arylsulfonyl group.
  • the compound of the formula VII2-B can also be synthesized by reacting the corresponding primary amine of the formula 4-B with a halogenated hydrocarbon R 4 X or by reductive amination with a corresponding primary amine of the formula 4-B and an alkane aldehyde (NaB (CN)
  • the synthesis of H 3 , NaB(OAc) 3 H or PtO 2 /H 2 ) can also be carried out by reacting a primary amine of formula VII with a reagent of carbon tetrabromide and triphenylphosphine to form the corresponding bromo compound of formula 2, formula 2
  • the substitute is reacted with a 2-hydroxy(amine or oxime)methyl acetate compound to form a compound of formula 3-B, which is then hydrogenated to reduce the compound of formula 3-B to form a compound of formula VII2-B.
  • the compound of the formula VIII-B is reacted with a compound of the formula IX-C in a solution of toluene KOH or NaH in THF to form a compound of the formula XC, which is reacted in a solution of LiAlH 4 in THF for 2-6 hours to form a compound of the formula XI-C,
  • the compound of formula XI-C can be synthesized directly by reacting a compound of formula VI with a compound of formula VII2-C at 120-200 ° C for 8-20 h.
  • the compound of the formula XI-C is reacted with a compound of the formula IX-B in a solution of toluene KOH or NaH in THF to form a compound of the formula XII-C.
  • the compound of the formula XII-C is reacted in a solution of LiAlH 4 in THF for 2-6 hours to form the formula XIII.
  • the compound of the formula VII2-C can also be synthesized by reacting the corresponding primary amine of the formula 4-C with the halogenated hydrocarbon R 4 X or by reductive amination with a corresponding primary amine of the formula 4-C and an alkane aldehyde (NaB (CN)
  • the synthesis of H 3 , NaB(OAc) 3 H or PtO 2 /H 2 ) can also be carried out by reacting a primary amine of formula VII with a reagent of carbon tetrabromide and triphenylphosphine to form the corresponding bromo compound of formula 2, formula 2
  • the substitute is reacted with a 2-hydroxy(amine or oxime)methyl acetate compound to form a compound of formula 3-C, which is then hydrogenated to reduce the compound of formula 3-C to form a compound of formula VII2-C.
  • Still another object of the present invention is to provide a process for preparing the aminopyrazine compound represented by the above formula II:
  • the compound of formula III and formula IV is refluxed in a methanol solution of NaOH for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl 3 to form a compound of formula VI, a compound of formula VI and a compound of formula VII-A' at 120-200.
  • the compound of the formula VIII-A' is synthesized by reacting at ° C for 8-48 h (preferably 8-20 h), and the compound of the formula VIII-A' is reacted with the compound of the formula IX-A' in a solution of toluene KOH or NaH in THF to form the formula X-A'.
  • the compound of the formula VII-A' can be synthesized by reacting a primary amine of the formula 1' with a halogenated hydrocarbon R 4 X or by reductive amination of a primary amine of the formula 1 with an alkane aldehyde (NaB(CN)H 3 , NaB( OAc) 3 H or PtO 2 /H 2 ) was synthesized.
  • the compound of formula III and formula IV is refluxed in a solution of NaOH in methanol for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl 3 to form a compound of formula VI, a compound of formula VI and a compound of formula VII-B' at 120-200.
  • the compound of the formula VIII-B' is synthesized by reacting at ° C for 8-48 h (preferably 8-20 h), and the compound of the formula VIII-B' is reacted with a compound of the formula IX-B' in a solution of toluene KOH or NaH in THF to form a compound of the formula X-B'.
  • the compound of formula X-B' is reacted in a solution of LiAlH 4 in THF for 2-6 hours to form a compound of formula XI-B', or directly reacted with a compound of formula VII2-B' at 120-200 ° C for 8-48 h.
  • the compound of the formula VII2-B' can also be synthesized by reacting the corresponding primary amine of the formula 4-B' with the halogenated hydrocarbon R 4 X or by reductive amination with the corresponding primary amine of the formula 4-B' and the alkane aldehyde ( NaB(CN)H 3 , NaB(OAc) 3 H or PtO 2 /H 2 ) is synthesized, and the corresponding formula 2' bromine can also be formed by reacting the primary amine of formula VII' with the reagent carbon tetrabromide and triphenylphosphine.
  • a 2' bromo compound of the formula 2 is reacted with a methyl 2-hydroxy(amine or hydrazinyl)acetate to form a compound of the formula 3-B', and then the lithium aluminum hydride is reduced to form a compound of the formula VII2-B'.
  • the compound of the formula VIII-B' is reacted with a compound of the formula IX-C' in a solution of toluene KOH or NaH in THF to form a compound of the formula X-C', and the compound of the formula X-C' is reacted in a solution of LiAlH 4 in 2-6 THF.
  • the compound of formula XI-C' is formed in an hour, or the compound of formula XI-C' is synthesized directly by reacting a compound of formula VI with a compound of formula VII2-C' at 120-200 ° C for 8-20 h.
  • the compound of the formula XI-C' is reacted with a compound of the formula IX-B' in a solution of toluene KOH or NaH in THF to form a compound of the formula XII-C', and the compound of the formula XII-C' is reacted in a solution of LiAlH 4 in THF for 2-6 hours.
  • the compound of the formula VII2-C' can also be synthesized by reacting the corresponding formula 4-C' primary amine with a halogenated hydrocarbon R 4 X or by reductive amination with a corresponding formula 4-C' primary amine and an alkane aldehyde ( NaB(CN)H 3 , NaB(OAc) 3 H or PtO 2 /H 2 ) is synthesized, and the corresponding formula 2' bromine can also be formed by reacting the primary amine of formula VII' with the reagent carbon tetrabromide and triphenylphosphine.
  • a 2' bromo compound of the formula 2 is reacted with a methyl 2-hydroxy(amine or oxime)acetate to form a compound of formula 3-C', which is then hydrogenated to reduce the compound of formula 3-C' to form a compound of formula VII2-C'.
  • Still another object of the present invention is to provide an aminopyrazine compound represented by the above formula I or formula II or a pharmaceutically acceptable salt thereof, Use of an isomer for the preparation of an IP receptor agonist, in particular as a preparation for activating an IP receptor drug; more specifically, the invention provides a compound of the formula I or formula II or Use of a pharmaceutically acceptable salt or isomer for the preparation of a medicament for the treatment or prevention of pulmonary hypertension (PAH), PAH associated with various diseases, arteriosclerosis obliterans (ASO), Asthma and asthma symptoms, chronic obstructive pulmonary disease, Raynaud's phenomenon, scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, high arteritis, polymyositis and dermatomyositis, atrial septum Defect (ASD), ventricular septal defect (VSD), cardiac fibrosis, pulmonary fibrosis/
  • the present invention also relates to a method of treating a subject having the above-mentioned disease, which comprises administering to a subject in need thereof an aminopyrazine compound of the above formula I or formula II or a pharmaceutically thereof thereof Acceptable salts, isomers.
  • the inventors have found through extensive studies that the change of the long chain of the carboxylic pyrazine compound has a great influence on the activity, and changing the length of the long chain reduces the anti-platelet aggregation activity (see Examples 1, 32), and unexpectedly finds
  • the long chain of carboxylic acid constructed by using the ethylene glycol structure (especially two ethylene glycol structures) provided by the present invention can significantly increase the anti-platelet aggregation activity of the aminopyrazine compound in vivo and in vitro.
  • the aminopyrazine compound of the ethylene glycol structure provided by the invention can significantly reduce the average pulmonary hypertension of the model animal, and the effect is obviously superior to the compound of Preparation Example 1 as a control;
  • the sodium salt provided by the present invention can be stabilized for a long time under the condition of the aqueous solution, and the aqueous solution of the sodium salt of the compound of the preparation example 1 precipitates a white solid within 12 hours. It can be seen that the ethylene glycol structure provided by the invention effectively improves the stability of the aqueous solution.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).
  • the LC-MS is Agilent 6120; the nuclear magnetic resonance ( 1 H NMR) is Bruker AVANCE-400, and the nuclear magnetic resonance ( 1 H NMR) displacement ( ⁇ ) is in parts per million (ppm).
  • the solvent was determined to be d 6 -DMSO, the internal standard was tetramethylsilane (TMS), and the chemical shift was given in units of 10 -6 (ppm).
  • room temperature in the present invention means that the temperature is between 10 and 25 °C.
  • Step 4 Preparation of 2- ⁇ 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy ⁇ acetic acid tert-butyl ester
  • Step 5 Preparation of 2- ⁇ 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy ⁇ acetic acid
  • the synthesis method is the same as that of Example 1, except that the 2-(N-isopropylamino)ethanol in the step 3 of Example 1 is replaced with N-methylaminoethanol to obtain 2- ⁇ 2- in the form of a yellow oil.
  • 2-(N-isopropylamino)ethanol in the step 3 of Example 1 is replaced with N-methylaminoethanol to obtain 2- ⁇ 2- in the form of a yellow oil.
  • Step 4 Preparation of 2- ⁇ 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy ⁇ acetic acid tert-butyl ester
  • Step 6 2- ⁇ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy ⁇ acetic acid tert-butyl ester Preparation
  • Step 7 Preparation of 2- ⁇ 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy ⁇ acetic acid
  • 2,2'-oxydiethylamine (1.04 g, 10 mmol) and PtO 2 (227 mg, 1 mmol) were added to a mixture of 2 mL of ethanol and 2 mL of acetone at room temperature, then a balloon filled with hydrogen and a balloon of hydrogen were added.
  • the hydrogen is used to displace the reaction gas, and the reaction solution is kept at 1-3 atm for 48 hours. Then, the reaction solution is filtered through celite, washed with ethanol, and steamed under reduced pressure to obtain 2,2'-oxybis(N-isopropyl B). Amine) crude product, without purification, is used directly for the next reaction.
  • Step 2 N- ⁇ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethyl ⁇ -N-isopropyl
  • synthesis steps are the same as those in the third step, the second step, the second step, the second step, the second method, the second step, the second step, and the second step.
  • -Isopropylamino)ethoxy]ethanol is replaced by 2,2'-oxybis(N-isopropylethylamine) to give N- ⁇ 2-[2-(N-(5,6) as a yellow oil.
  • -Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethyl ⁇ -N-isopropylglycine, ESI-MS: m/z 476.2 (M+H) + .
  • Step 4 Preparation of 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanoic acid tert-butyl ester
  • Step 5 Preparation of 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanol
  • Step 6 2- ⁇ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy ⁇ acetic acid tert-butyl ester Preparation
  • Step 7 Preparation of 2- ⁇ 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy ⁇ acetic acid
  • N-(2-Bromoethyl)isopropylamine (1.12 g, 6.80 mmol) and (2R)-methyl lactate (10.6 g, 10.2 mmol) were dissolved in diethyl ether, and Ag 2 O was added in five portions over one hour.
  • Methyl (R)-2-[2-(N-isopropylamino)ethoxy]propanoate (190 mg, 1.00 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran under ice-cooling. LiAlH 4 (76.0 mg, 2.00 mmol) was slowly added in the batch. After reacting for 30 min, the mixture was naturally warmed to room temperature, and then reacted for 2 h. The reaction was monitored by LC-MS.
  • Step 4 Preparation of (R)-2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanol
  • Step 5 (R)-2- ⁇ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy ⁇
  • Step 6 (R)-2- ⁇ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy ⁇
  • Step 2 (R)-2- ⁇ 2-[1-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-yloxy] Preparation of ethoxy ⁇ acetic acid
  • Step 2 (S)-2- ⁇ 2-[1-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-yloxy] Preparation of ethoxy ⁇ acetic acid
  • Step 1 Preparation of 2- ⁇ 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy ⁇ -2-fluoroacetic acid tert-butyl ester
  • the synthesis step is the same as the preparation step 1, step 2, step 3, step 4, step 5, and step 6 of the third embodiment, except that the t-butyl bromoacetate in the preparation step 6 of the embodiment 3 is replaced with the bromofluoroacetic acid.
  • Step 2 2- ⁇ 2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy ⁇ -2-methoxyacetic acid tert-butyl ester preparation
  • Step 3 2- ⁇ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy ⁇ -2-yl
  • the synthesis step is the same as that in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the method 1, the step 6, the step 7 of the third embodiment, except that the t-butyl bromoacetate in the step 4 of the preparation of the third embodiment is prepared.
  • the synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7.
  • the only difference is that the t-butyl bromoacetate in the step 4 of the preparation of the third embodiment is prepared.
  • Step 2 Preparation of 2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)acetic acid tert-butyl ester
  • N-cyclopropyl-5,6-diphenylpyrazin-2-amine (288 mg, 1.00 mmol) was dissolved in 2.5 mL of anhydrous tetrahydrofuran under ice-cooling, and NaH (80 mg, 2.00) (mmol), stirring for 30min, then add the compound t-butyl bromoacetate (290mg, 1.50mmol), naturally warmed to room temperature for 2h, LC-MS detection reaction, the reaction of the raw materials is complete, the reaction solution is cooled to 5 ° C, slowly to the reaction solution dropwise ice water, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO 4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, were collected under reduced pressure, and dried in vacuo to give 310mg of yellow Oil tert-butyl 2-(N-(5,6-diphenylpyrazin-2-yl)-N
  • Step 4 Preparation of 2- ⁇ 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)ethoxy]ethoxy ⁇ acetic acid
  • Step 2 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropanoic acid tert-butyl ester preparation
  • reaction of the starting material is complete.
  • Step 3 2- ⁇ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy ⁇ Preparation of acetic acid
  • the synthesis step is the same as the method 1, step 6, and step 7 of the preparation of the step 5 in the third embodiment, except that the 2- ⁇ 2-[N-(5,6-two) in the method 1 of the preparation method of the third embodiment is prepared.
  • Step 2 Preparation of 1-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]cyclopropylcarboxylic acid tert-butyl ester
  • reaction of the starting material is complete.
  • the reaction solution is cooled to 5 ° C, and ice water is slowly added dropwise to the reaction solution, and extracted with ethyl acetate.
  • the organic mixed phase is water and saturated brine.
  • MgSO 4 was dried, filtered, evaporated, evaporated, evaporated, evaporated, evaporated, triazin-2-yl) -N- isopropyl-amino) ethoxy] cyclopropyl-carboxylic acid tert-butyl ester, yield: 31.7%
  • Step 3 2- ⁇ 1-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]cyclopropylmethoxy ⁇ acetic acid
  • the synthesis step is the same as the method 1, step 6, and step 7 of the preparation of the step 5 in the third embodiment, except that 2- ⁇ 2-[N-(5,6-) in the method 1 of the preparation step 5 of the embodiment 3 is used.
  • Step 2 Preparation of 2- ⁇ 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylthio]ethoxy ⁇ acetic acid
  • the synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7 in the third embodiment, except that the 2-(N) in the preparation step 3 of the embodiment 3 is used.
  • -Isopropylamino)ethanol was replaced by N-isopropyl-2-mercaptoethylamine to give 2- ⁇ 2-[2-(N-(5,6-diphenylpyrazine-2-) as a yellow oil.
  • Step 1 Preparation of 2- ⁇ 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy ⁇ acetic acid tert-butyl ester
  • Step 2 2- ⁇ 2-[2-(2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy)ethoxy]B Preparation of oxy ⁇ acetic acid
  • the synthesis step is the same as the method 1, step 6, and step 7 of the preparation of the step 5 in the third embodiment, except that 2- ⁇ 2-[N-(5,6-) in the method 1 of the preparation step 5 of the embodiment 3 is used.
  • reaction mixture was evaporated to dryness, then water was evaporated and evaporated. 4, drying, filtration, de-solvent under reduced pressure, and purified by chromatography on silica gel column, collected under reduced pressure, and dried in vacuo to give 390 mg of 2-[2-[2-(N-(5,6-diphenylpyrazine) as a yellow oil.
  • MRE-269 (4.19 g, 10.0 mmol) and NaOH (420 mg, 10.5 mmol) were suspended in 50 mL of THF and heated to reflux for 4 h. After cooling, most solvent was removed under reduced pressure, filtered, and washed with ethanol.
  • the synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7 in the third embodiment, except that the 2-(N) in the preparation step 3 of the embodiment 3 is used.
  • -Isopropylamino)ethanol was replaced with N-isopropylaminopropanol to give 2- ⁇ 2-[3-(N-(5,6-diphenylpyrazin-2-yl)-N- as a yellow oil.
  • the synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7.
  • the only difference is that the bromoacetic acid tert-but in the preparation step 4 of the embodiment 3.
  • the anti-platelet aggregation activity of the compounds of the examples of the present invention was examined for the inhibition of ADP-induced platelet aggregation in vitro.
  • Platelet aggregation instrument Panmouth LBY-NJ type 4
  • ADP Sigma
  • DMSO 0.9% sodium chloride injection, sodium hydroxide, blood collection tube, and the like.
  • test drugs were weighed and prepared into a stock solution with a concentration of 200 mM in DMSO, fully dissolved and mixed, and the stock solution was aspirated, and 0.9% sodium chloride injection solution was separately added to prepare a series of different concentrations of the test solution. (0.64 ⁇ M-2000 ⁇ M);
  • Rats who had not taken antiplatelet function drugs such as aspirin within 2 weeks were bled with a disposable vacuum blood collection tube (3.2% sodium citrate anticoagulation, anticoagulant to blood ratio 1:9). Transfer to a centrifuge tube, centrifuge at 1000 rpm for 10 min, carefully draw the upper layer of liquid is PRP, the remaining plasma is centrifuged at 3500 rpm for 10 min, and the supernatant is taken as PPP.
  • the ADP was weighed and dissolved in 0.9% sodium chloride injection to prepare an ADP stock solution, which was dispensed into a centrifuge tube and frozen at -20 °C. Reconstituted before use, diluted to 300 ⁇ M with 0.9% sodium chloride injection for use.
  • Example 24 10 Preparation Example 2 30
  • Example 25 15
  • Example 26 10
  • Preparation Example 4 >100
  • Example 27 6.2
  • Preparation Example 5 >300
  • Example 28 8.8
  • Example 1 >100
  • Example 31 12
  • Example 3 2.8
  • Example 32 >100
  • Example 4 twenty two
  • Example 37 2.8
  • Example 5 >100
  • Example 38 1.2
  • Example 6 >100
  • Example 42 1.3
  • Example 7 >100
  • Example 8 20
  • Example 9 1.2
  • Example 10 1.0
  • Example 46 17 Example 11
  • Example 47 18 Example 12
  • Example 48 20
  • Example 15 >100
  • Example 49 15
  • Example 16 >100
  • Example 50 16
  • Example 18 1.5
  • Example 51 twenty three
  • Example 19 1.3
  • Example 52 40
  • Example 20 1.7
  • Example 53 40
  • Example 22 20
  • Example 54 20
  • the compound of Preparation Example 1 and the sodium salt thereof i.e., the compound of Preparation Example 2 have an IC 50 for inhibiting platelet aggregation in vitro of 30 ⁇ M, and Embodiments 3, 4, 8-12, and 18 of the present invention.
  • Example 3 The compounds of Example 9, Example 10, Example 11, Example 18, Example 19, Example 20, Example 37, Example 38, Example 42, Example 43, Example 44 and Example 45 were all When the order of magnitude difference is reached, it can be seen that the anti-platelet aggregation activity of the compounds of the examples of the present invention is significantly better than the compound of Preparation Example 1.
  • the prodrug of Preparation Example 1 (i.e., the compound of Preparation Example 5) had no anti-platelet aggregation activity in vitro, and the prodrugs provided by the present application (i.e., the compounds of Examples 46-54) exhibited very good anti-platelet aggregation in vitro. Active, and detected by LC-MS, during the test Not degraded to the corresponding carboxylic acid structure product, indicating that the prodrugs provided herein are all active.
  • Example 37, Example 38, and Example 43 and the compound of Preparation Example 2 were weighed and dissolved in a 0.9% sodium chloride injection solution to prepare an initial solution having a concentration of 30 mg/mL, and then the initial solution was separately diluted. 15 mg/mL, 5 mg/mL, and 0.5 mg/mL were used as test solutions.
  • Kunming mice were randomly divided into 17 groups of 12 animals per group. The test was to perform acute toxicity tests on four compounds, each of which corresponded to four dose groups, 5 mg/kg, 50 mg/kg, 150 mg/kg, and 300 mg/kg; the blank group did not require injection.
  • test drug of the same volume was administered to the tail vein of the mouse.
  • mice The condition of the mice was observed multiple times within 4 hours after administration, and thereafter observed once a day for 14 days, and the toxicity and death after a single administration were observed and recorded.
  • Example 37 20 mg of each of the compound of Example 37, Example 38, Example 39, Example 40, Example 42, Example 43, Example 44, and Example 45 and the compound of Preparation Example 2 were weighed in a centrifuge tube, respectively. 0.9% sodium chloride injection was dissolved to prepare a solution with a concentration of 1.6 mg/ml, and further diluted into a solution having a concentration of 0.8 mg/mL, 0.4 mg/mL, 0.2 mg/mL, and 0.1 mg/mL, respectively. Sample solution.
  • red blood cells were mixed with a 0.9% sodium chloride injection to prepare a 2% (v/v) red blood cell suspension, and used.
  • test solution Take 2.5 mL of the above-mentioned different concentrations of the test solution in a clean glass test tube, add 2.5 mL of the above 2% red cell suspension as the test tube; and add 2.5 mL of 0.9% sodium chloride injection instead of the negative control tube.
  • the test solution; the positive control tube was added with 2.5 mL of sterile water for injection instead of the test solution.
  • Each test tube, negative control tube and positive control tube were mixed, placed in an incubator and allowed to stand in a temperature range of 37 ⁇ 0.5 ° C. After 3 hours, the observation result was taken out from the incubator.
  • Example 37 As a result of the in vitro hemolytic test, it can be seen that when the concentration of the compound of Preparation Example 2 is 0.05 mg/mL, partial hemolysis is observed, and complete hemolysis is achieved when the concentration reaches 0.1 mg/mL; Example 37, Example 38, and implementation of the present invention When the concentration of the compound of Example 39, Example 40, Example 42, Example 43, Example 44 and Example 45 reached 0.2 mg/mL, partial hemolysis was observed, and complete hemolysis was achieved when the concentration reached 0.4 mg/mL.
  • Example 37, Example 38, Example 39, Example 40, Example 41, Example 42, Example 43, Example 44, and Example 45 and the compound of Preparation Example 2 were each weighed 90 mg each.
  • Example 40, Example 41, Example 42, Example 43, Example 44, and Example 45 and the compound of Preparation Example 2 were each weighed 90 mg each.
  • 0.9% sodium chloride injection dissolved in 0.9% sodium chloride injection and formulated into three different concentrations of 30mg/mL, 6.0mg/mL and 1.0mg/mL as the test solution; also prepared with 5% glucose solution Three different concentrations of solution were used as the test solution.
  • the above test solution was allowed to stand at room temperature for 12 hours, and its stability was observed.
  • Example 2 As can be seen from the above test results, after the compounds of the various embodiments of the present invention are dissolved in 5% glucose or 0.9% sodium chloride injection, the solutions of different concentrations can be kept clear at room temperature for a long time, and the preparation of Example 2 is After the compound was dissolved in 5% glucose or 0.9% sodium chloride injection, the three concentrations of the solution were allowed to stand at room temperature. After 12 hours, a white solid precipitate appeared, indicating that the compound of Preparation 2 was unstable in aqueous solution, visible, The introduction of the compound provided by the present invention significantly increases the stability of the aqueous solution of the drug after introduction of the ethylene glycol chain.
  • a rat pulmonary hypertension model was established to evaluate the effects of each compound on pulmonary hypertension in rats.
  • RM6240BD multi-channel physiological signal acquisition and processing system (Chengdu Instrument Factory), monocrotaline (sigma), 0.9% sodium chloride injection, syringe, rat fixator, polyethylene hose, surgical scissors, surgical fistula, etc.
  • Example 3 The compound of Preparation Example 1, Example 3, the compound of Example 9, the compound of Example 18, the compound of Example 23, the compound of Example 46, and the compound of Example 49 were weighed and injected with 0.9% sodium chloride, respectively.
  • the solution was dissolved and formulated into a solution having a concentration of 1 mg/mL.
  • the state of the rats was observed daily during the test. After the animals were modeled, the pulmonary artery pressure was measured after 15 days of treatment with each test drug described in Table 6 above.
  • Rats in the blank control group and the test drug-administered group had normal reaction, the body hair was clean, and the food was normal. Rats in the model group were generally weak, unresponsive, and reduced in activity.
  • DMSO 0.9% sodium chloride injection, sodium hydroxide, ADP (sigma), blood collection tube (3.2% sodium citrate anticoagulation), platelet aggregation instrument (Plymouth LBY-NJ type 4).
  • Example 1 The compounds of Preparation Example 1, Example 3, Example 9, Example 18, and Example 23 were weighed and dissolved in 0.9% sodium chloride injection solution to prepare a solution having a concentration of 2.5 mg/ml.
  • Example 1 15 rats that had not taken antiplatelet function drugs such as aspirin were randomly divided into 5 groups, 3 in each group, respectively, intravenously injected 10 mg/kg.
  • 10 min after injection use a disposable vacuum blood collection tube (3.2% sodium citrate anticoagulation, anticoagulant to blood ratio of 1:9) 4.5 mL of abdominal aorta, transfer to a centrifuge tube, centrifuge at 1000 rpm for 10 min, be careful The upper layer of liquid is taken as PRP, and the remaining plasma is centrifuged at 3500 rpm for 10 min, and the supernatant is taken as PPP.
  • the temperature was raised to 37 ° C and the test was started.
  • insert the PPP square cup into the test channel press the channel key to automatically detect the zero point.
  • press the channel key take out the PPP square cup, insert the PRP square cup, press the channel key after the value is stable, and the instrument displays ADP, use a micro-sampler to draw ADP into the bottom of the cup, press the channel button, the instrument starts testing.
  • the negative control was an equal volume of 0.9% sodium chloride injection. Record the aggregation rate at the final time point.
  • Platelet aggregation inhibition rate (1 - aggregation rate after administration / aggregation rate of negative control group) ⁇ 100%
  • Example 3 From the platelet aggregation inhibition rate data in rats, it was found that the compounds of Example 3, Example 9, Example 18, and Example 23 were significantly superior to the compound of Preparation Example 1 in inhibiting platelets in rats.

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Abstract

L'invention concerne un composé d'aminopyrazine représenté par la formule (I), ou un sel pharmaceutiquement acceptable ou un isomère de celui-ci. Le composé d'aminopyrazine a une activité agoniste du récepteur de prostaglandine I2 (PGI2) et est utilisé en tant qu'agoniste du récepteur IP pour le traitement des maladies apparentées.
PCT/CN2017/094936 2016-07-29 2017-07-28 Composé d'aminopyrazine, sel ou isomère, son procédé de préparation et son application WO2018019296A1 (fr)

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