WO2024061362A1 - Compound for preventing and treating vasodilator diseases, preparation method therefor, and use thereof - Google Patents

Compound for preventing and treating vasodilator diseases, preparation method therefor, and use thereof Download PDF

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WO2024061362A1
WO2024061362A1 PCT/CN2023/120823 CN2023120823W WO2024061362A1 WO 2024061362 A1 WO2024061362 A1 WO 2024061362A1 CN 2023120823 W CN2023120823 W CN 2023120823W WO 2024061362 A1 WO2024061362 A1 WO 2024061362A1
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姜宝红
张丽君
张静
曹美芳
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中国科学院上海药物研究所
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
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    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
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    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to medicines for treating vasodilatory diseases and their uses.
  • Aneurysm and arterial dissection are a type of interrelated vasodilation disease that can occur in the thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, epimental artery, inferior mesenteric artery arteries, intracranial arteries and carotid arteries, etc.
  • the advanced development of vasodilatory disease can lead to blood vessel rupture and bleeding, endangering the patient's life. As the disease progresses, blood vessel rupture is the main cause of death.
  • the object of the present invention is to provide the use of a compound of formula I in the preparation of medicaments for treating vasodilatory diseases.
  • the invention provides a compound of formula I, its crystal form, hydrate or solvate, or a pharmaceutically acceptable salt or ester,
  • n 0, 1, 2, 3, 4;
  • Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
  • R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl group with O heteroatom, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-membered heteroatom group with 1-3 heteroatoms selected from the following group of N, S and O 10-membered heteroaryl;
  • R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
  • R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
  • R 5 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 5-10 membered heteroaryl group of O heteroatom;
  • M is C or N.
  • the compound of formula I includes a compound of formula Ia and a compound of formula Ib:
  • R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
  • R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
  • R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
  • R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
  • the compound of formula I is selected from:
  • the compound of formula I is selected from: FA-3, FA-4, FA-9, FA-10, FA-11, FB-3, FB-4, FB-9, FB-10 , FB-11, FB-2, FB-15, FB-16, FB-33 and FB-21, FB-35.
  • the present invention provides the use of the compound of formula I as described in the first aspect of the present invention, its crystal form, hydrate or solvate, or pharmaceutically acceptable salt or ester, for preparing a pharmaceutical composition or preparation; the pharmaceutical composition or preparation is used to prevent and/or treat vascular dilatation lesions selected from the following groups: (i) aneurysm; (ii) intramural hematoma; (iii) arterial dissection and/or (iiii) varicose veins.
  • a pharmaceutical composition or preparation is used to prevent and/or treat arterial lesions selected from the following group: (i) aneurysm; (ii) arterial wall Interstitial hematoma; and/or (iii) arterial dissection;
  • the pharmaceutical composition or preparation is also used for the prevention and/or treatment of venous dilation lesions selected from the group consisting of: varicose veins.
  • the artery is selected from the following group: thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, omental artery, inferior mesenteric artery, cranial artery Internal artery, carotid artery, or combination thereof.
  • the aneurysm is selected from the group consisting of early aneurysm, mid-stage aneurysm, late-stage aneurysm, or a combination thereof.
  • the present invention provides a method for preparing a compound of formula I, comprising the following steps:
  • n 0, 1, 2, 3, 4;
  • Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
  • R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl group with O heteroatom, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-membered heteroatom group with 1-3 heteroatoms selected from the following group of N, S and O 10-membered heteroaryl;
  • R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
  • R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
  • R 5 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 5-10 membered heteroaryl group of O heteroatom;
  • M is C or N.
  • R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
  • R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
  • R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
  • R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
  • the method further comprises the following steps:
  • step (S1) the compound of formula II reacts with the compound of formula III to obtain the compound of formula Ia, and then
  • the compound of formula Ia reacts with R 2 OH to obtain a compound of formula I;
  • R 2 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3 having 1 to 3 heteroatoms selected from the group consisting of N, S and O -10-membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
  • X is a halogen selected from the following group: Br, Cl, I;
  • R 3 and R 5 are each independently substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the following group of N, S and O (preferably, R 3 and R 5 are each independently Substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl).
  • the invention provides a method for preparing a piperazine salt of a compound of formula I, comprising the following steps:
  • n, R 1 , R 3 , R 4 and R 5 are as defined in the first aspect of the present invention.
  • the preparation method of the piperazine salt of the compound of formula I includes the following steps:
  • the clear first solution formed by the compound of formula I and the first solvent is mixed with the second solution formed by piperazine and the second solvent, and the reaction is stirred at room temperature to obtain the piperazine salt of the compound of formula I.
  • the first solvent is a C1-C6 alcohol solvent, a C1-C6 hydrocarbon solvent, or a combination thereof.
  • the compound of formula I is completely dissolved in the first solvent.
  • the first solvent is a mixed solution of methanol and methylene chloride (1:1 v/v).
  • the second solvent is a C1-C6 alcohol solvent or a C1-C6 hydrocarbon solvent.
  • the molar ratio of the compound of formula I to piperazine is (2.5-2):1; preferably, it is 2:1.
  • the method further includes purification; preferably, the purification is column chromatography.
  • the present invention provides a pharmaceutical composition, which includes: (1) the compound of formula I, its crystal form, hydrate or solvate as described in the first aspect of the present invention , or a pharmaceutically acceptable salt or ester, or a combination thereof; and (2) a pharmaceutically acceptable carrier.
  • the present invention provides a method for preventing and/or treating: (i) aneurysm; (ii) arterial intramural hematoma; (iii) arterial dissection and/or (iii) varicose veins, including Step: administering to a subject in need a therapeutically effective amount of a compound of formula I, a crystalline form, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, or a compound containing them, as described in the first aspect of the present invention.
  • Pharmaceutical compositions are examples of a compound of formula I, a crystalline form, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, or a compound containing them, as described in the first aspect of the present invention.
  • Figure 1A is a general view of each group of arteries.
  • Figure 1B is a quantification of the maximum vessel diameter at the arterial lesion site.
  • Figures 2 to 10 show the NMR spectra of the structures of compounds FA-3, FA-4, FA-5, FA-6, FA-7, FA-8, FA-9, FA-10 and FA-11 in sequence.
  • Figure 11A is a general view of arteries in each group.
  • Figure 11B shows the abdominal aortic aneurysm volume at the arterial lesion site.
  • Figure 12A is a general view of each group of arteries.
  • Figure 12B shows the abdominal aortic aneurysm volume at the arterial lesion site.
  • Figures 13-21 show the NMR spectra of the structures of compounds FB-9, FB-10, FB-15, FB-16, FB-21, FB-27, FB-33, FB-34, and FB-35.
  • the inventor discovered for the first time that the compound represented by Formula I has significant therapeutic effects on aneurysms, intramural hematomas and/or arterial dissections.
  • the compound of the present invention can not only slow down the expansion speed of early- and middle-stage aneurysms, but also has obvious therapeutic effects on late-stage aneurysms, can reduce the risk of rupture of late-stage aneurysms, and can be used for the entire course of aneurysms. On this basis, the present invention was completed.
  • alkyl refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (e.g., C1-C8, C1-C6, or C1-C3, where C1- C8 means 1-8 carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl base, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.
  • C3-C10 cycloalkyl refers to a cycloalkyl group having 3 to 10 carbon atoms. It may be a monocyclic ring, such as C4-C7 cycloalkyl or C5-C6 cycloalkyl, specifically such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. Bicyclic forms, such as bridged or spirocyclic forms, are also possible.
  • C1-C8 alkoxy refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy base, butoxy group, isobutoxy group, tert-butoxy group, etc.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O” means having 3-10 atoms and 1-3 of which are Saturated or partially saturated cyclic groups of heteroatoms selected from the group of N, S and O, for example C4-C7 heterocycloalkyl or C5-C6 heterocycloalkyl. It can be a single ring or a double ring, such as a bridged ring or a spiro ring.
  • C6-C10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O” means having 5-10 atoms and 1-3 of which are selected from Cyclic aromatic groups with heteroatoms of the lower group N, S and O. It can be a single ring or a fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halosubstituted” means substituted with atoms selected from the group consisting of F, Cl, Br, and I.
  • Certain compounds of the invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to the unsolvated forms and are intended to be included within the scope of the invention. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute these compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as tritium ( 3H ) or carbon-14 ( 14C ). All isotopic variations of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • compounds may be prepared such that any number of hydrogen atoms are replaced by deuterium ( 2H ). Isotope substitution.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up these compounds.
  • An unnatural proportion of an isotope can be defined as an amount ranging from the amount found in nature to 100% of the atom in question.
  • a compound may incorporate a radioactive isotope, such as tritium ( 3H ) or carbon-14 ( 14C ), or a non-radioactive isotope, such as deuterium ( 2H ) or carbon-13 ( 13C ).
  • treatment include disease-modifying treatments and symptomatic treatments, either of which may be prophylactic (i.e., prior to the onset of symptoms, to prevent, delay, or reduce the severity of symptoms)) or therapeutic (i.e., after the onset of symptoms, to reduce the severity and/or duration of symptoms).
  • compound of the present invention refers to a compound represented by Formula I, and also includes crystalline forms, pharmaceutically acceptable salts or esters, hydrates or solvates of the compound of Formula I.
  • salts refer to salts of compounds of the invention with acids or bases suitable for use as pharmaceuticals.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • One preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid and other organic acids; as well as aspartic acid, glutamic acid and other acidic amino acids.
  • One preferred class of salts are the salts of the compounds of the invention with bases.
  • Bases suitable for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, and piperazine.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate
  • organic bases such as ammonia, triethylamine, diethylamine, and piperazine.
  • esters refers to an ester of a compound of an active ingredient of the present invention with an acid or alcohol suitable for use as a pharmaceutical.
  • a preferred class of esters is one or more hydroxyl groups of the active ingredient of the invention with an acid. The ester formed.
  • Suitable ester-forming acids include, but are not limited to: phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid , picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, etc.; another preferred ester is the ester formed by the carboxyl group of the active ingredient of the present invention and alcohol.
  • Alcohols suitable for forming esters include but are not limited to: C1 -C6 alkyl-OH, such as methanol, ethanol, n-propanol, isopropanol, etc.
  • the compounds of the present invention may be amorphous, crystalline, or mixtures thereof.
  • the compound of formula I of the present invention can be purchased through commercial channels or using commercially available raw materials, or synthesized by synthesis methods in the prior art.
  • Compounds of the present invention can be synthesized by those of ordinary skill in the art according to existing known techniques.
  • the synthesized compounds can be further purified by column chromatography, high performance liquid chromatography, or crystallization.
  • the preparation methods of the compound of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be optionally prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 80°C, preferably 0°C to 50°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • the method for preparing the compound of formula I includes the following steps:
  • n 0, 1, 2, 3, 4;
  • Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
  • R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl group with O heteroatom, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-membered heteroatom group with 1-3 heteroatoms selected from the following group of N, S and O 10-membered heteroaryl;
  • R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
  • R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
  • R 5 is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
  • step (S1) the following sub-steps are included:
  • R2 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3- having 1-3 heteroatoms selected from the group consisting of N, S and O 10-membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl having 1-3 heteroatoms selected from the following group of N, S and O.
  • R 3 and R 5 are each independently a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted group having 1-3 selected from the following group N, S and a 5-10 membered heteroaryl group of heteroatoms of O (preferably, R 3 and R 5 are each independently a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group).
  • the invention also provides a method for preparing the piperazine salt IC of the compound of formula I, which includes the following steps:
  • the compound of formula I is mixed and reacted with piperazine to obtain the compound of formula I;
  • the preparation method of the piperazine salt of the compound of formula I includes the following steps:
  • a clear first solution formed by the compound of formula I and a first solvent is mixed with a second solution formed by piperazine and a second solvent, and the mixture is stirred at room temperature to react to obtain the piperazine salt of the compound of formula I.
  • the present invention also provides a method for preparing the piperazine salt of the compound of formula I, which includes the following steps:
  • the first solvent is a C1-C6 alcohol solvent, a C1-C6 hydrocarbon solvent, or a combination thereof.
  • the compound of formula I is completely soluble in the first solvent.
  • the first solvent is a mixed solution of methanol and methylene chloride (1:1 v/v).
  • the second solvent is a C1-C6 alcohol solvent or a C1-C6 hydrocarbon solvent.
  • the molar ratio of the compound of formula I to piperazine is (2.5-2):1; preferably, it is 2:1.
  • the method further includes purification; preferably, the purification is column layer analysis.
  • the inert solvent is a commonly used reaction solvent in this field, such as C1-C6 alcohol solvents, C1-C6 hydrocarbon solvents, C1-C6 ether solvents, C6-C10 aromatic hydrocarbon solvents, sulfones solvents, amide solvents, or combinations thereof.
  • compositions and methods of administration are provided.
  • the present invention also provides a drug and/or composition that can be used to treat vasodilatory diseases.
  • the pharmaceutical composition contains the compound of formula I of the present invention, its crystal form, hydrate or solvate, or a pharmaceutically acceptable compound. Accepts salt as active ingredient.
  • the pharmaceutical composition of the present invention has excellent effects in preventing and/or treating aneurysms, intramural hematomas and/or arterial dissections.
  • the compound of formula I can be used in the form of pure substance, extract (or mixture), or directly in the form of medicinal materials (or food materials).
  • the pharmaceutical composition of the present invention can be a single prescription (containing one active ingredient) or a compound prescription (containing two or more active ingredients).
  • the pharmaceutical composition of the present invention includes: (1) a first active ingredient selected from the following group: a compound of formula I, its crystal form, hydrate or solvate, or a pharmaceutical Acceptable salts, or combinations thereof; (2) Pharmaceutically acceptable carriers.
  • a "safe and effective amount” refers to an amount of a compound sufficient to significantly improve a condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-500 mg of the compound of the present invention/dose.
  • the "dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compound of formula I without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • solid lubricants such as
  • the administration mode of the pharmaceutical composition of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the active ingredients of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds, including (but not limited to): antihypertensive drugs (such as angiotensin-converting enzyme inhibitors and/or angiotensin receptor body blockers), hypolipidemic drugs (such as statins, fibrates, niacin, cholesterol absorption inhibitors), hypoglycemic drugs (such as sulfonylureas secretagogues, insulin sensitizers, biguanides) , multimeric salvianolic acid, or combinations thereof.
  • antihypertensive drugs such as angiotensin-converting enzyme inhibitors and/or angiotensin receptor body blockers
  • hypolipidemic drugs such as statins, fibrates, niacin, cholesterol absorption inhibitors
  • hypoglycemic drugs such as sulfonylureas secretagogues, insulin sensitizers, biguanides
  • multimeric salvianolic acid or combinations thereof.
  • the general range of therapeutically effective dosage of the compound of formula I will be: for example, for a 50Kg human, about 1-2000mg/day, about 10-1000mg/day, about 10-500mg/day, about 10-250mg /day or about 10-100mg/day.
  • the therapeutically effective dose will be administered in one or more doses.
  • the specific dose of the active ingredient of the present invention for any particular patient will depend on a variety of factors, such as the age, sex, weight, general health, diet, individual response of the patient to be treated, the time of administration, the The severity of the disease being treated, the activity of the specific compound administered, the dosage form, mode of application and concomitant medications.
  • the therapeutically effective amount for a given situation can be determined by routine experimentation and is within the ability and judgment of the clinician or physician.
  • the active ingredient will be administered in multiple doses based on the patient's individual condition and in a manner that allows for the delivery of a therapeutically effective amount.
  • the present invention finds for the first time that the compound of formula I has the effect of slowing down the expansion speed of aneurysm, reducing hematoma between arterial walls, inhibiting arterial dissection, and thereby reducing arterial rupture, and is suitable for the treatment of artery-related diseases.
  • the compound of the present invention can not only slow down the expansion speed of early- and middle-stage aneurysms, but also has obvious therapeutic effects on late-stage aneurysms, can reduce the risk of rupture of late-stage aneurysms, and can be used for the entire course of aneurysms.
  • the compounds and pharmaceutical compositions of the present invention provide a treatment option other than surgical treatment for patients with aneurysms, intramural hematomas and/or arterial dissections.
  • the compounds of the present invention are safe to use and have little toxic and side effects.
  • TMS Tetramethylsilane
  • 13C NMR BrukerBioSpin 1H NMR and 13C NMR spectra were recorded at 400MHz and 100MHz on a GmbH spectrometer (AvanceIII, Switzerland). Coupling constants are in Hz.
  • TLC thin-layer chromatography
  • mice were anesthetized by intraperitoneal injection of Serta at a dose of 50 mg/kg. After the mouse enters anesthesia, the abdominal hair is shaved with a razor, and the hair is further removed thoroughly with depilatory cream. The abdomen is wiped clean and fixed on the operating table. A heating pad is used under the body to maintain body temperature.
  • the length of the exposed abdominal aorta is about 0.5cm, the proximal end does not exceed the bilateral renal arteries, and the distal end does not exceed the femoral artery.
  • mice After suturing, wipe the wound with iodine, and remove iodine with 75% ethanol after 1 minute.
  • the mice were placed in a clean cage, fed 1% ⁇ -aminopropionitrile (BAPN) feed, and had free access to water. The feed was changed every other day.
  • BAPN ⁇ -aminopropionitrile
  • the maximum diameter of the abdominal aorta is expressed as mean ⁇ SE.
  • Statistical analysis was performed using GraphPad Prism 6. The statistical significance of differences between groups was compared multiple times using one-way analysis of variance. After determining the normal distribution and homogeneity of variances, Tukey's test was performed. P ⁇ 0.05 is statistical significance.
  • the corresponding FA series compounds can be prepared using the corresponding phenylacetic acid.
  • the corresponding structures of phenylacetic acid and prepared compounds are shown in Table 1.
  • the animals were given normal saline, sodium ferulate, and FA-3, FA-4, FA-5, FA-6, FA-7, FA-8, FA-9, FA-10, and FA-11 by gavage, with a dose of 50 mg/kg.
  • the administration was continued for 7 days and the activity of the animals was closely observed.
  • the animals were euthanized and arterial tissues were obtained to evaluate the aneurysm expansion and arterial dissection rupture.
  • the mice in the 8-day model control group were sampled and the diameter of the abdominal aortic aneurysm was measured, which was the diameter of the aneurysm at the initial stage of administration.
  • intramural hematoma and arterial dissection models can not only examine the effects of drugs on aneurysm growth, but also examine the effects of drugs on intramural Effects of hematoma and arterial dissection.
  • the experimental results are shown in Figure 1A-B. It can be seen that sodium ferulate, FA-3, FA-9, FA-10 and FA-11 can not only significantly reduce the aneurysm expansion speed (P ⁇ 0.05), but also It can significantly reduce the occurrence of intramural hematoma and arterial dissection in mice, and reduce arterial rupture.
  • mice 8-week-old C57BL/6 mice were put into the animal room to adapt to feeding for one week, and then randomly divided into groups.
  • the day of surgery for porcine pancreatic elastase-induced aneurysm was day 0.
  • mice were given physiological saline or FB series compounds by gavage administration at a dose of 50 mg/kg and continued administration for 7
  • the animals' activities were closely observed.
  • arterial tissue was obtained to evaluate the aneurysm expansion and arterial dissection rupture.
  • samples were collected from the mice in the 5-day model control group, the diameter of the abdominal aortic aneurysm was measured, and the volume of the abdominal aortic aneurysm was calculated. This volume was the volume of the aneurysm at the initial stage of drug administration.
  • the above-mentioned compounds can protect the integrity of the blood vessel structure, inhibit the degradation of the elastic membrane, inhibit the occurrence of intramural hematoma, protect the morphology of the collagen in the vascular adventitia, and reduce the risk of blood vessel tearing and rupture.
  • the compounds FA-3 to FA-11 listed in Table 4 all have certain protective effects, among which the protective effects of FA-3, FA-9, FA-10 and FA-11 are increased by 120-150% compared with sodium ferulate.
  • Aneurysm is a localized or diffuse expansion or bulging of the arterial wall due to the disease or damage of the arterial wall.
  • Intramural hematoma mainly manifests as bleeding in the middle layer of the artery. With the increase in bleeding volume, it can cause vascular rupture.
  • Arterial dissection is a condition of the arterial wall. The blood in the cavity enters the artery wall through the tear, forming a false lumen, and then ruptures.
  • Aneurysm, intramural hematoma and arterial dissection are the main artery-related diseases that can lead to arterial rupture. They are closely related during the disease process and can influence or transform each other.
  • aneurysm and intramural hematoma will evolve into arterial dissection, and intramural hematoma will evolve into arterial dissection.
  • Hematoma can lead to artery dissection and rupture.
  • Aneurysms, arterial dissections, and intramural hematomas all show varying degrees of arterial diameter expansion in the early stages of the disease, and all show arterial diameter expansion in the late stages. rupture, thereby endangering the patient's life.
  • Aneurysms can occur anywhere in the arterial system, including (but not limited to): thoracic aortic aneurysm, abdominal aortic aneurysm, splenic aneurysm, hepatic aneurysm, superior mesenteric aneurysm, celiac trunk aneurysm, renal aneurysm , omental aneurysm, inferior mesenteric aneurysm, intracranial aneurysm and carotid aneurysm, etc.
  • the current treatment for aneurysms, arterial dissections and intramural hematomas is mainly surgical treatment to prevent death caused by their rupture.
  • the abdominal aorta is incubated with porcine pancreatic elastase to cause continuous expansion of the arterial wall, simulating the early and mid-term disease process of aneurysm; the porcine pancreatic elastase is incubated and superimposed with ⁇ -aminopropionitrile feed to induce aneurysms, intramural hematomas and blood vessel tears. Fissure, simulating advanced stages of arterial dissection, intramural hematoma, and aneurysm.
  • the compound of the present invention has a therapeutic effect on early-stage and late-stage aneurysms, and can be used throughout the course of the aneurysm.
  • Arterial disease mainly occurs in the elderly. Arterial dissection, intramural hematoma, and the late stages of aneurysm are likely to lead to rupture of the artery, thereby endangering the patient's life.
  • surgical treatment and postoperative recovery are also There is a high risk, so the compound of the present invention can also provide new treatment methods for patients with advanced aneurysms, which is of great significance.

Abstract

The present invention provides a compound for preventing and treating vasodilator diseases, a preparation method therefor, and use thereof. Specifically, the present invention provides a compound of formula I and use thereof in treating vessel-related diseases. The compound of the present invention has the effects of slowing down the rate of progress of vasodilator diseases, inhibiting the expansion of arterial aneurysm, reducing the occurrence of intramural hematoma, inhibiting the occurrence of aortic dissection and further reducing arteriorrhexis, and is suitable for treating vascular dilation-related diseases. Treatment options other than surgical treatment are provided for aneurysms, intramural hematoma and/or aortic dissection patients. The compound of the present invention is safe in medication and small in toxic and side effects.

Description

用于防治血管扩张性疾病的化合物及其制法和用途Compounds for preventing and treating vasodilatory diseases and preparation methods and uses thereof 技术领域Technical field
本发明属于药物领域，具体地，涉及用于治疗血管扩张性疾病相关的药物及其用途。The present invention belongs to the field of medicine, and specifically relates to medicines for treating vasodilatory diseases and their uses.
背景技术Background technique
动脉瘤和动脉夹层是相互关联的一类血管扩张性疾病，可发生于胸主动脉、腹主动脉、脾动脉、肝动脉、肠系膜上动脉、腹腔干动脉、肾动脉、网膜动脉、肠系膜下动脉、颅内动脉和颈动脉等。血管扩张性疾病发展到后期会导致血管破裂出血，危及患者生命。随着疾病的推进，血管破裂是导致患者死亡的主因。Aneurysm and arterial dissection are a type of interrelated vasodilation disease that can occur in the thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, epimental artery, inferior mesenteric artery arteries, intracranial arteries and carotid arteries, etc. The advanced development of vasodilatory disease can lead to blood vessel rupture and bleeding, endangering the patient's life. As the disease progresses, blood vessel rupture is the main cause of death.
临床上，除手术治疗外，缺乏令人满意的针对动脉瘤、壁间血肿和动脉夹层的预防和治疗药物。Clinically, apart from surgical treatment, there is a lack of satisfactory preventive and therapeutic drugs for aneurysms, intramural hematomas and arterial dissections.
所以本领域迫切的需要一种能够治疗血管扩张性疾病的药物，尤其是危机患者生命安全的动脉瘤、壁间血肿和/或动脉夹层的药物，以给患者提供更多的治疗选择。Therefore, there is an urgent need in this field for a drug that can treat vasodilatory diseases, especially drugs that threaten the life safety of patients with aneurysms, intramural hematomas and/or arterial dissections, so as to provide patients with more treatment options.
发明内容Contents of the invention
本发明的目的就是提供一种式I化合物在制备治疗血管扩张性疾病的药物中的用途。The object of the present invention is to provide the use of a compound of formula I in the preparation of medicaments for treating vasodilatory diseases.
本发明的第一方面，本发明提供了一种式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐或酯，
In a first aspect of the invention, the invention provides a compound of formula I, its crystal form, hydrate or solvate, or a pharmaceutically acceptable salt or ester,
其中，m为0、1、2、3、4； Among them, m is 0, 1, 2, 3, 4;
各个R1独立地选自下组：H、羟基、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C2-C8烯基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、卤素、氨基、硝基；Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
R2选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl group with O heteroatom, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-membered heteroatom group with 1-3 heteroatoms selected from the following group of N, S and O 10-membered heteroaryl;
R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
R4为H、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C4环烷基、取代或未取代的C1-C4烷氧基、卤素、氨基、硝基；R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
R5选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 5 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 5-10 membered heteroaryl group of O heteroatom;
M为C或N。M is C or N.
在另一优选例中，所述式I化合物包括式I-a化合物和式I-b化合物：
In another preferred embodiment, the compound of formula I includes a compound of formula Ia and a compound of formula Ib:
在另一优选例中，R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基。In another preferred embodiment, R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
在另一优选例中，R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基。In another preferred embodiment, R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
在另一优选例中，R5为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基。In another preferred embodiment, R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
在另一优选例中，R5为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基。In another preferred embodiment, R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
在另一优选例中，所述式I化合物选自：







In another preferred embodiment, the compound of formula I is selected from:







在另一优选例中，所述式I化合物选自：FA-3、FA-4、FA-9、FA-10、FA-11、FB-3、FB-4、FB-9、FB-10、FB-11、FB-2、FB-15、FB-16、FB-33和FB-21、FB-35。In another preferred example, the compound of formula I is selected from: FA-3, FA-4, FA-9, FA-10, FA-11, FB-3, FB-4, FB-9, FB-10 , FB-11, FB-2, FB-15, FB-16, FB-33 and FB-21, FB-35.
本发明的第二方面，本发明提供了如本发明第一方面所述的式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐或酯的用途，用于制备一药物组合物或制剂；所述药物组合物或制剂用于预防和/或治疗选自下组的血管扩张性病变：(i)动脉瘤；(ii)动脉壁间血肿；(iii)动脉夹层和/或(iiii)静脉曲张。In the second aspect of the present invention, the present invention provides the use of the compound of formula I as described in the first aspect of the present invention, its crystal form, hydrate or solvate, or pharmaceutically acceptable salt or ester, for preparing a pharmaceutical composition or preparation; the pharmaceutical composition or preparation is used to prevent and/or treat vascular dilatation lesions selected from the following groups: (i) aneurysm; (ii) intramural hematoma; (iii) arterial dissection and/or (iiii) varicose veins.
在另一优选例中，用于制备一药物组合物或制剂；所述药物组合物或制剂用于预防和/或治疗选自下组的动脉病变：(i)动脉瘤；(ii)动脉壁间血肿；和/或(iii)动脉夹层；In another preferred embodiment, it is used to prepare a pharmaceutical composition or preparation; the pharmaceutical composition or preparation is used to prevent and/or treat arterial lesions selected from the following group: (i) aneurysm; (ii) arterial wall Interstitial hematoma; and/or (iii) arterial dissection;
所述药物组合物或制剂还用于预防和/或治疗选自下组的静脉扩张性病变：静脉曲张。The pharmaceutical composition or preparation is also used for the prevention and/or treatment of venous dilation lesions selected from the group consisting of: varicose veins.
在另一优选例中，所述的动脉选自下组：胸主动脉、腹主动脉、脾动脉、肝动脉、肠系膜上动脉、腹腔干动脉、肾动脉、网膜动脉、肠系膜下动脉、颅内动脉、颈动脉，或其组合。In another preferred embodiment, the artery is selected from the following group: thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, omental artery, inferior mesenteric artery, cranial artery Internal artery, carotid artery, or combination thereof.
在另一优选例中，所述动脉瘤选自下组：早期动脉瘤、中期动脉瘤、晚期动脉瘤，或其组合。In another preferred embodiment, the aneurysm is selected from the group consisting of early aneurysm, mid-stage aneurysm, late-stage aneurysm, or a combination thereof.
本发明的第三方面，本发明提供了一种制备式I化合物的方法，包括以下步骤： In a third aspect of the present invention, the present invention provides a method for preparing a compound of formula I, comprising the following steps:
(S1)在惰性溶剂中，式II化合物与式III化合物反应，得到式I化合物；
(S1) In an inert solvent, the compound of formula II reacts with the compound of formula III to obtain the compound of formula I;
各式中，m为0、1、2、3、4；In each formula, m is 0, 1, 2, 3, 4;
各个R1独立地选自下组：H、羟基、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C2-C8烯基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、卤素、氨基、硝基；Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
R2选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl group with O heteroatom, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-membered heteroatom group with 1-3 heteroatoms selected from the following group of N, S and O 10-membered heteroaryl;
R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
R4为H、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C4环烷基、取代或未取代的C1-C4烷氧基、卤素、氨基、硝基；R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
R5选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 5 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 5-10 membered heteroaryl group of O heteroatom;
M为C或N。M is C or N.
在另一优选例中，R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基。In another preferred embodiment, R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
在另一优选例中，R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基。In another preferred embodiment, R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
在另一优选例中，R5为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基。In another preferred embodiment, R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.
在另一优选例中，R5为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基。In another preferred embodiment, R 5 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
在另一优选例中，还包括以下步骤： In another preferred embodiment, the method further comprises the following steps:
在步骤(S1)中，式II化合物与式III化合物反应得到式Ia化合物，然后In step (S1), the compound of formula II reacts with the compound of formula III to obtain the compound of formula Ia, and then
在惰性溶剂中，式Ia化合物与R2OH反应，得到式I化合物；
In an inert solvent, the compound of formula Ia reacts with R 2 OH to obtain a compound of formula I;
其中，m、R1、R3、R4、R5的定义如上文中所述，Among them, the definitions of m, R 1 , R 3 , R 4 and R 5 are as mentioned above,
R2为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。R 2 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3 having 1 to 3 heteroatoms selected from the group consisting of N, S and O -10-membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
在另一优选例中，还包括以下步骤：In another preferred embodiment, the following steps are also included:
(S1a')当R3＝H或R5＝H时，先通过式II化合物与式III化合物反应得到式Ib或Ic化合物；(S1a') When R 3 =H or R 5 =H, first obtain the compound of formula Ib or Ic by reacting the compound of formula II with the compound of formula III;
(S1b')在惰性溶剂中，式Ib化合物与R3X反应，得到式I化合物
(S1b') In an inert solvent, the compound of formula Ib reacts with R 3 X to obtain the compound of formula I
或or
在惰性溶剂中，式Ic化合物与R5X反应，得到式I化合物
In an inert solvent, the compound of formula Ic reacts with R 5 X to obtain the compound of formula I
其中，in,
X选自下组的卤素：Br，Cl，I；X is a halogen selected from the following group: Br, Cl, I;
m、R1、R2、R4的定义如上文中所述；The definitions of m, R 1 , R 2 and R 4 are as mentioned above;
而R3和R5各自独立地为取代或未取代的C1-C8烷基、取代或未取代的 C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基(优选地，R3和R5各自独立地为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基)。And R 3 and R 5 are each independently substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the following group of N, S and O (preferably, R 3 and R 5 are each independently Substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl).
在本发明的第四方面，本发明提供了一种制备式I化合物的哌嗪盐的方法，包括以下步骤：
In a fourth aspect of the invention, the invention provides a method for preparing a piperazine salt of a compound of formula I, comprising the following steps:
在惰性溶剂中，式I化合物与哌嗪混合反应，得到式I-C化合物；In an inert solvent, the compound of formula I and piperazine are mixed and reacted to obtain the compound of formula I-C;
其中，m、R1、R3、R4、R5的定义如本发明第一方面中所述。Wherein, m, R 1 , R 3 , R 4 and R 5 are as defined in the first aspect of the present invention.
在另一优选例中，式I化合物的哌嗪盐的制备方法包括如下步骤：In another preferred embodiment, the preparation method of the piperazine salt of the compound of formula I includes the following steps:
将式I化合物与第一溶剂形成的澄清的第一溶液，与哌嗪和第二溶剂形成的第二溶液混合，在室温下搅拌反应，得到所述的式I化合物的哌嗪盐。The clear first solution formed by the compound of formula I and the first solvent is mixed with the second solution formed by piperazine and the second solvent, and the reaction is stirred at room temperature to obtain the piperazine salt of the compound of formula I.
在另一优选例中，所述的第一溶剂为C1-C6醇类溶剂、C1-C6烃类溶剂，或其组合。In another preferred embodiment, the first solvent is a C1-C6 alcohol solvent, a C1-C6 hydrocarbon solvent, or a combination thereof.
在另一优选例中，所述的式I化合物在第一溶剂中完全溶解。In another preferred embodiment, the compound of formula I is completely dissolved in the first solvent.
在另一优选例中，所述的第一溶剂为甲醇与二氯甲烷(1:1v/v)的混合溶液。In another preferred embodiment, the first solvent is a mixed solution of methanol and methylene chloride (1:1 v/v).
在另一优选例中，所述的第二溶剂为C1-C6醇类溶剂、C1-C6烃类溶剂。In another preferred embodiment, the second solvent is a C1-C6 alcohol solvent or a C1-C6 hydrocarbon solvent.
在另一优选例中，式I化合物与哌嗪的摩尔比为(2.5-2):1；较佳地为2:1。In another preferred embodiment, the molar ratio of the compound of formula I to piperazine is (2.5-2):1; preferably, it is 2:1.
在另一优选例中，所述的方法还包括纯化；较佳地，所述的纯化为柱层析。In another preferred embodiment, the method further includes purification; preferably, the purification is column chromatography.
本发明的第五方面，本发明提供了一种药物组合物，所述药物组合物包括：(1)如本发明第一方面所述的式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐或酯，或其组合；和(2)药学上可接受的载体。In a fifth aspect of the present invention, the present invention provides a pharmaceutical composition, which includes: (1) the compound of formula I, its crystal form, hydrate or solvate as described in the first aspect of the present invention , or a pharmaceutically acceptable salt or ester, or a combination thereof; and (2) a pharmaceutically acceptable carrier.
本发明的第六方面，本发明提供了一种预防和/或治疗：(i)动脉瘤；(ii)动脉壁间血肿；(iii)动脉夹层和/或(iiii)静脉曲张的方法，包括步骤：对有需要的对象施用治疗有效量的如本发明第一方面所述的式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐或酯，或包含它们的药物组合物。 In a sixth aspect of the present invention, the present invention provides a method for preventing and/or treating: (i) aneurysm; (ii) arterial intramural hematoma; (iii) arterial dissection and/or (iii) varicose veins, including Step: administering to a subject in need a therapeutically effective amount of a compound of formula I, a crystalline form, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, or a compound containing them, as described in the first aspect of the present invention. Pharmaceutical compositions.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1A是为各组动脉大体图。Figure 1A is a general view of each group of arteries.
图1B是动脉病变部位的最大血管直径的定量。Figure 1B is a quantification of the maximum vessel diameter at the arterial lesion site.
图2-图10依次为化合物FA-3，FA-4，FA-5，FA-6，FA-7，FA-8，FA-9，FA-10和FA-11结构的核磁谱图。Figures 2 to 10 show the NMR spectra of the structures of compounds FA-3, FA-4, FA-5, FA-6, FA-7, FA-8, FA-9, FA-10 and FA-11 in sequence.
图11A为各组动脉大体图。Figure 11A is a general view of arteries in each group.
图11B为动脉病变部位的腹主动脉瘤体积。Figure 11B shows the abdominal aortic aneurysm volume at the arterial lesion site.
图12A为各组动脉大体图。Figure 12A is a general view of each group of arteries.
图12B为动脉病变部位的腹主动脉瘤体积。Figure 12B shows the abdominal aortic aneurysm volume at the arterial lesion site.
图13-21依次为化合物FB-9，FB-10，FB-15，FB-16，FB-21，FB-27，FB-33，FB-34，FB-35结构的核磁谱图。Figures 13-21 show the NMR spectra of the structures of compounds FB-9, FB-10, FB-15, FB-16, FB-21, FB-27, FB-33, FB-34, and FB-35.
具体实施方式Detailed ways
本发明人经过广泛而深入的研究，通过大量筛选和测试，首次发现了式I所示化合物对动脉瘤、壁间血肿和/或动脉夹层的具有显著的治疗效果。令人惊讶的是，本发明化合物不仅能减缓早中期动脉瘤的扩张速度，而且对晚期动脉瘤具有明显的治疗效果，可降低晚期动脉瘤的破裂风险，可用于动脉瘤全病程。在此基础上完成了本发明。After extensive and in-depth research, and through extensive screening and testing, the inventor discovered for the first time that the compound represented by Formula I has significant therapeutic effects on aneurysms, intramural hematomas and/or arterial dissections. Surprisingly, the compound of the present invention can not only slow down the expansion speed of early- and middle-stage aneurysms, but also has obvious therapeutic effects on late-stage aneurysms, can reduce the risk of rupture of late-stage aneurysms, and can be used for the entire course of aneurysms. On this basis, the present invention was completed.
术语the term
除非另有定义，否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
如本文所用，术语“烷基”本身或作为另一取代基的一部分，是指具有指定碳原子数的直链或支链烃基(例如C1-C8、C1-C6或C1-C3，其中C1-C8表示1-8个碳)。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁 基、仲丁基、正戊基、正己基、正庚基、正辛基等。As used herein, the term "alkyl," by itself or as part of another substituent, refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (e.g., C1-C8, C1-C6, or C1-C3, where C1- C8 means 1-8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl base, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.
如本文所用，术语“C3-C10环烷基”指具有3-10个碳原子的环烷基。其可以是单环，例如C4-C7环烷基或C5-C6环烷基,具体地，如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。As used herein, the term "C3-C10 cycloalkyl" refers to a cycloalkyl group having 3 to 10 carbon atoms. It may be a monocyclic ring, such as C4-C7 cycloalkyl or C5-C6 cycloalkyl, specifically such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. Bicyclic forms, such as bridged or spirocyclic forms, are also possible.
如本文所用，术语“C1-C8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。As used herein, the term "C1-C8 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy base, butoxy group, isobutoxy group, tert-butoxy group, etc.
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团，例如C4-C7杂环烷基或C5-C6杂环烷基。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" means having 3-10 atoms and 1-3 of which are Saturated or partially saturated cyclic groups of heteroatoms selected from the group of N, S and O, for example C4-C7 heterocycloalkyl or C5-C6 heterocycloalkyl. It can be a single ring or a double ring, such as a bridged ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
如本文所用，术语“C6-C10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。As used herein, the term "C6-C10 aryl" refers to an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" means having 5-10 atoms and 1-3 of which are selected from Cyclic aromatic groups with heteroatoms of the lower group N, S and O. It can be a single ring or a fused ring. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halosubstituted" means substituted with atoms selected from the group consisting of F, Cl, Br, and I.
本发明某些化合物可以非溶剂化形式以及溶剂化形式存在，包括水合形式。通常，溶剂化形式等同于未溶剂化形式，并且旨在包括在发明的范围内。本公开的某些化合物可以以多种结晶或无定形形式存在。通常，所有物理形式对于本公开所考虑的用途是等同的，并且旨在落入本公开的范围内。Certain compounds of the invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to the unsolvated forms and are intended to be included within the scope of the invention. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.
本发明的化合物还可以在构成这些化合物的一个或多个原子上含有非天然比例的原子同位素。例如，化合物可以用放射性同位素放射性标记，例如氚(3H)或碳-14(14C)。无论是否具有放射性，本公开化合物的所有同位素变体都包括在本公开的范围内。例如，可以制备化合物，使得任何数量的氢原子被氘(2H) 同位素取代。本发明的化合物还可以在构成这些化合物的一个或多个原子上含有非天然比例的原子同位素。非天然比例的同位素可以定义为从自然界中发现的量到由所讨论的原子的100％组成的量。例如，化合物可以掺入放射性同位素，例如氚(3H)或碳-14(14C)，或非放射性同位素，例如氘(2H)或碳-13(13C)。The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute these compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium ( 3H ) or carbon-14 ( 14C ). All isotopic variations of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure. For example, compounds may be prepared such that any number of hydrogen atoms are replaced by deuterium ( 2H ). Isotope substitution. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up these compounds. An unnatural proportion of an isotope can be defined as an amount ranging from the amount found in nature to 100% of the atom in question. For example, a compound may incorporate a radioactive isotope, such as tritium ( 3H ) or carbon-14 ( 14C ), or a non-radioactive isotope, such as deuterium ( 2H ) or carbon-13 ( 13C ).
如本文所用，术语“治疗”或“治疗”包括疾病调节治疗和对症治疗，其中任一种都可以是预防性的(即，在症状发作之前，以预防、延迟或减轻症状的严重性))或治疗性的(即，在症状发作后，为了减轻症状的严重性和/或持续时间)。As used herein, the terms "treatment" or "treatment" include disease-modifying treatments and symptomatic treatments, either of which may be prophylactic (i.e., prior to the onset of symptoms, to prevent, delay, or reduce the severity of symptoms)) or therapeutic (i.e., after the onset of symptoms, to reduce the severity and/or duration of symptoms).
活性成分active ingredients
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括式I化合物的晶型、药学上可接受的盐或酯、水合物或溶剂合物。As used herein, "compound of the present invention" refers to a compound represented by Formula I, and also includes crystalline forms, pharmaceutically acceptable salts or esters, hydrates or solvates of the compound of Formula I.
如本文所用，“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于：氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱，氨水、三乙胺、二乙胺、哌嗪等有机碱。As used herein, "pharmaceutically acceptable salts" refer to salts of compounds of the invention with acids or bases suitable for use as pharmaceuticals. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid and other organic acids; as well as aspartic acid, glutamic acid and other acidic amino acids. One preferred class of salts are the salts of the compounds of the invention with bases. Bases suitable for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, and piperazine.
如本文所用，“药学上可接受的酯”指本发明活性成分的化合物与酸或醇形成的适合用作药物的酯一类优选的酯为本发明的活性成分的一个或多个羟基与酸形成的酯，适合形成酯的酸包括但并不限于：磷酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等；另一类优选的酯为本发明的活性成分的羧基与醇形成的酯，适合形成酯的醇包括但并不限于：C1-C6烷基-OH，如甲醇、乙醇、正丙醇、异丙醇等。As used herein, "pharmaceutically acceptable ester" refers to an ester of a compound of an active ingredient of the present invention with an acid or alcohol suitable for use as a pharmaceutical. A preferred class of esters is one or more hydroxyl groups of the active ingredient of the invention with an acid. The ester formed. Suitable ester-forming acids include, but are not limited to: phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid , picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, etc.; another preferred ester is the ester formed by the carboxyl group of the active ingredient of the present invention and alcohol. Alcohols suitable for forming esters include but are not limited to: C1 -C6 alkyl-OH, such as methanol, ethanol, n-propanol, isopropanol, etc.
本发明化合物可以是无定形的、晶型或其混合物。 The compounds of the present invention may be amorphous, crystalline, or mixtures thereof.
本发明的式I化合物可通过商业途径购买或者利用市售原料，或通过现有技术中合成方法合成。本领域的普通技术人员根据现有公知技术可以来合成本发明的化合物。合成的化合物可以进一步通过柱色谱法、高效液相色谱法或结晶等方式进一步纯化。The compound of formula I of the present invention can be purchased through commercial channels or using commercially available raw materials, or synthesized by synthesis methods in the prior art. Compounds of the present invention can be synthesized by those of ordinary skill in the art according to existing known techniques. The synthesized compounds can be further purified by column chromatography, high performance liquid chromatography, or crystallization.
合成化学改造、保护官能团方法学对合成应用化合物是很有帮助的，并且是现有技术中公知的技术，可以参见R.Larock，《全面有机转换(Comprehensive Organic Transformations)》，VCH出版社(VCH Publishers)(1989)；T.W.Greene and P.G.M.Wuts，《有机合成中的保护基(Protective Groups in Organic Synthesis)》，第三版(3rd Ed.)，约翰威立公司(John Wiley and Sons)(1999)；L.Fieser and M.Fieser，《费氏试剂在有机合成中的应用(Fieser and Fieser's Reagents for Organic Synthesis)》，约翰威立公司(John Wiley and Sons)(1994)；和L.Paquette，ed.《有机合成试剂大全(Encyclopedia of Reagents for Organic Synthesis)》，约翰威立公司(John Wiley and Sons)(1995)等文献。Synthetic chemical transformation and protection of functional group methodologies are very helpful for the synthesis of application compounds, and are well-known techniques in the prior art. You can refer to R. Larock, "Comprehensive Organic Transformations (Comprehensive Organic Transformations)", VCH Publishing House (VCH Publishers)(1989); T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis)", 3rd Edition (3rd Ed.), John Wiley and Sons (1999) ; L.Fieser and M.Fieser, "Fieser and Fieser's Reagents for Organic Synthesis (Fieser and Fieser's Reagents for Organic Synthesis)", John Wiley and Sons (1994); and L.Paquette, ed. ."Encyclopedia of Reagents for Organic Synthesis", John Wiley and Sons (1995) and other documents.
制备方法Preparation
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。The preparation methods of the compound of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be optionally prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～80℃，优选0℃～50℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 80°C, preferably 0°C to 50°C). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
制备式I化合物的方法，包括以下步骤：The method for preparing the compound of formula I includes the following steps:
(S1)在惰性溶剂中，式II化合物与式III化合物反应，得到式I化合物；
(S1) In an inert solvent, the compound of formula II reacts with the compound of formula III to obtain the compound of formula I;
各式中，m为0、1、2、3、4； In each formula, m is 0, 1, 2, 3, 4;
各个R1独立地选自下组：H、羟基、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C2-C8烯基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、卤素、氨基、硝基；Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
R2选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl group with O heteroatom, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-membered heteroatom group with 1-3 heteroatoms selected from the following group of N, S and O 10-membered heteroaryl;
R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
R4为H、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C4环烷基、取代或未取代的C1-C4烷氧基、卤素、氨基、硝基；R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
R5选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。R 5 is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
在另一优选例中，在步骤(S1)中，包括以下子步骤：In another preferred example, in step (S1), the following sub-steps are included:
(S1a)式II化合物与式III化合物反应得到式Ia化合物，其中，R2＝H，而m、R1、R3、R4、R5的定义如上文中所述；(S1a) The compound of formula II reacts with the compound of formula III to obtain a compound of formula Ia, wherein R 2 =H, and m, R 1 , R 3 , R 4 and R 5 are as defined above;
(S1b)在惰性溶剂中，式Ia化合物与R2OH反应，得到式I化合物；
(S1b) In an inert solvent, the compound of formula Ia reacts with R 2 OH to obtain the compound of formula I;
其中，m、R1、R3、R4、R5的定义如上文中所述；Among them, the definitions of m, R 1 , R 3 , R 4 and R 5 are as mentioned above;
R2为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。R2 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3- having 1-3 heteroatoms selected from the group consisting of N, S and O 10-membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl having 1-3 heteroatoms selected from the following group of N, S and O.
在另一优选例中，还包括以下步骤：In another preferred embodiment, the following steps are also included:
(S1a')当R3＝H或R5＝H时，先通过式II化合物与式III化合物反应得到式Ib或Ic化合物； (S1a') When R 3 =H or R 5 =H, first obtain the compound of formula Ib or Ic by reacting the compound of formula II with the compound of formula III;
(S1b')在惰性溶剂中，式Ib化合物与R3X反应，得到式I化合物
(S1b') In an inert solvent, the compound of formula Ib reacts with R 3 X to obtain the compound of formula I
或or
在惰性溶剂中，式Ic化合物与R5X反应，得到式I化合物
In an inert solvent, the compound of formula Ic reacts with R 5 X to obtain the compound of formula I
其中，in,
m、R1、R2、R4、和X的定义如上文中所述；The definitions of m, R 1 , R 2 , R 4 , and X are as described above;
而R3和R5各自独立地为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基(优选地，R3和R5各自独立地为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基)。And R 3 and R 5 are each independently a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted group having 1-3 selected from the following group N, S and a 5-10 membered heteroaryl group of heteroatoms of O (preferably, R 3 and R 5 are each independently a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group).
在另一优选例中，4-羟基-3-甲氧基苯甲醛与对应的苯乙酸反应得到式IV化合物：
In another preferred example, 4-hydroxy-3-methoxybenzaldehyde reacts with the corresponding phenylacetic acid to obtain a compound of formula IV:
在另一优选例中，式IV化合物与醇发生酯化反应得到式Ib化合物(R5＝-CH3)：
In another preferred example, the compound of formula IV undergoes an esterification reaction with an alcohol to obtain the compound of formula Ib (R 5 =-CH 3 ):
在另一优选例中，式Ib化合物与卤代烃反应制备得到式I化合物(R5＝-CH3)：
In another preferred example, the compound of formula Ib is reacted with a halogenated hydrocarbon to prepare a compound of formula I (R 5 =-CH 3 ):
本发明还提供了一种制备式I化合物的哌嗪盐I-C的方法，包括以下步骤：
The invention also provides a method for preparing the piperazine salt IC of the compound of formula I, which includes the following steps:
在惰性溶剂中，式I化合物与哌嗪混合反应，得到式I化合物；In an inert solvent, the compound of formula I is mixed and reacted with piperazine to obtain the compound of formula I;
其中，m、R1、R3、R4、R5的定义如上所述。Among them, m, R 1 , R 3 , R 4 and R 5 are defined as above.
一个实施方式中，式I化合物的哌嗪盐的制备方法包括如下步骤：In one embodiment, the preparation method of the piperazine salt of the compound of formula I includes the following steps:
将式I化合物与第一溶剂形成的澄清的第一溶液，与哌嗪和第二溶剂形成的第二溶液混合，在室温下搅拌反应，得到所述的式I化合物的哌嗪盐。A clear first solution formed by the compound of formula I and a first solvent is mixed with a second solution formed by piperazine and a second solvent, and the mixture is stirred at room temperature to react to obtain the piperazine salt of the compound of formula I.
具体地，本发明还提供了式I化合物的哌嗪盐的制备方法，包括如下步骤：
Specifically, the present invention also provides a method for preparing the piperazine salt of the compound of formula I, which includes the following steps:
取原料(320mg,1.11mmol)溶于二氯甲烷和甲醇的混合溶液(各5mL，保证溶解)。后称哌嗪(48mg,0.55mmol)溶于甲醇(1mL)，并加入上混合溶液，室温搅拌1h后，旋干，过柱，得到纯品。其中，R1如上所述。Dissolve the raw material (320 mg, 1.11 mmol) in a mixed solution of methylene chloride and methanol (5 mL each to ensure dissolution). Dissolve piperazine (48 mg, 0.55 mmol) in methanol (1 mL), add the above mixed solution, stir at room temperature for 1 hour, spin to dryness, and pass through the column to obtain the pure product. Where, R 1 is as described above.
另一个实施方式中，所述的第一溶剂为C1-C6醇类溶剂、C1-C6烃类溶剂，或其组合。In another embodiment, the first solvent is a C1-C6 alcohol solvent, a C1-C6 hydrocarbon solvent, or a combination thereof.
另一个实施方式中，所述的式I化合物在第一溶剂中完全溶解。In another embodiment, the compound of formula I is completely soluble in the first solvent.
另一个实施方式中，所述的第一溶剂为甲醇与二氯甲烷(1:1v/v)的混合溶液。In another embodiment, the first solvent is a mixed solution of methanol and methylene chloride (1:1 v/v).
另一个实施方式中，所述的第二溶剂为C1-C6醇类溶剂、C1-C6烃类溶剂。In another embodiment, the second solvent is a C1-C6 alcohol solvent or a C1-C6 hydrocarbon solvent.
另一个实施方式中，式I化合物与哌嗪的摩尔比为(2.5-2):1；较佳地为2:1。In another embodiment, the molar ratio of the compound of formula I to piperazine is (2.5-2):1; preferably, it is 2:1.
另一个实施方式中，所述的方法还包括纯化；较佳地，所述的纯化为柱层 析。In another embodiment, the method further includes purification; preferably, the purification is column layer analysis.
在另一个实施方式中，所述的惰性溶剂为本领域常用的反应溶剂，例如C1-C6醇类溶剂、C1-C6烃类溶剂、C1-C6醚类溶剂、C6-C10芳烃类溶剂、砜类溶剂、酰胺类溶剂，或其组合。In another embodiment, the inert solvent is a commonly used reaction solvent in this field, such as C1-C6 alcohol solvents, C1-C6 hydrocarbon solvents, C1-C6 ether solvents, C6-C10 aromatic hydrocarbon solvents, sulfones solvents, amide solvents, or combinations thereof.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
本发明还提供了一种可用于治疗血管扩张性疾病的药物和或组合物，所述的药物组合物含有本发明的式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐作为活性成分。本发明的药物组合物具有优异地预防和/或治疗动脉瘤、壁间血肿和/或动脉夹层的效果。The present invention also provides a drug and/or composition that can be used to treat vasodilatory diseases. The pharmaceutical composition contains the compound of formula I of the present invention, its crystal form, hydrate or solvate, or a pharmaceutically acceptable compound. Accepts salt as active ingredient. The pharmaceutical composition of the present invention has excellent effects in preventing and/or treating aneurysms, intramural hematomas and/or arterial dissections.
在本发明中，所述的式I化合物可以以纯净物、提取物(或混合物)方式使用，或直接以药材(或食材)方式使用。In the present invention, the compound of formula I can be used in the form of pure substance, extract (or mixture), or directly in the form of medicinal materials (or food materials).
本发明的药物组合物可以是单方(含有一种活性成分)或复方(含有二种以上活性成分)。The pharmaceutical composition of the present invention can be a single prescription (containing one active ingredient) or a compound prescription (containing two or more active ingredients).
在另一优选例中，本发明药物组合物包括：(1)第一活性成分，所述第一活性成分选自下组：式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐、或它们的组合；(2)药学上可接受的载体。In another preferred embodiment, the pharmaceutical composition of the present invention includes: (1) a first active ingredient selected from the following group: a compound of formula I, its crystal form, hydrate or solvate, or a pharmaceutical Acceptable salts, or combinations thereof; (2) Pharmaceutically acceptable carriers.
如本文所用，“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。As used herein, a "safe and effective amount" refers to an amount of a compound sufficient to significantly improve a condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-500 mg of the compound of the present invention/dose. Preferably, the "dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和式I化合物相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility" here means that the components of the composition can be blended with the compound of formula I without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明的药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The administration mode of the pharmaceutical composition of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredients, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。 适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
本发明活性成分可以单独给药，或者与其他药学上可接受的化合物联合给药，包括(但并不限于)：降血压药(例如：血管紧缩素转换酶抑制剂和/或血管紧张素受体阻断剂)、降血脂药(例如：他汀类、贝特类、烟酸类、胆固醇吸收抑制剂)、降糖药(例如：磺脲类促泌剂、胰岛素增敏剂、双胍类)、多聚体丹酚酸、或其组合。The active ingredients of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds, including (but not limited to): antihypertensive drugs (such as angiotensin-converting enzyme inhibitors and/or angiotensin receptor body blockers), hypolipidemic drugs (such as statins, fibrates, niacin, cholesterol absorption inhibitors), hypoglycemic drugs (such as sulfonylureas secretagogues, insulin sensitizers, biguanides) , multimeric salvianolic acid, or combinations thereof.
在本发明中，式I化合物的治疗有效剂量的一般范围将是：例如，对于50Kg的人，约1-2000mg/天、约10-1000mg/天、约10-500mg/天、约10-250mg/天或约10-100mg/天。治疗有效剂量将以一个或多个剂量给予。然而，应理解，对于任何特定患者的本发明活性成分的特定剂量将取决于多种因素，例如，待治疗的患者的年龄、性别、体重、一般健康状况、饮食、个体响应，给予时间、待治疗的疾病的严重性、施用的具体化合物的活性、剂型、应用模式和伴用药物。给定情况的治疗有效量能用常规实验测定，并在临床医生或医师能力和判断范围内。在任何情况中，所述活性成分将基于患者的个体情况以多个剂量给予并以允许递送治疗有效量的方式给予。In the present invention, the general range of therapeutically effective dosage of the compound of formula I will be: for example, for a 50Kg human, about 1-2000mg/day, about 10-1000mg/day, about 10-500mg/day, about 10-250mg /day or about 10-100mg/day. The therapeutically effective dose will be administered in one or more doses. However, it is to be understood that the specific dose of the active ingredient of the present invention for any particular patient will depend on a variety of factors, such as the age, sex, weight, general health, diet, individual response of the patient to be treated, the time of administration, the The severity of the disease being treated, the activity of the specific compound administered, the dosage form, mode of application and concomitant medications. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the ability and judgment of the clinician or physician. In any event, the active ingredient will be administered in multiple doses based on the patient's individual condition and in a manner that allows for the delivery of a therapeutically effective amount.
本发明的主要优点包括：The main advantages of the present invention include:
1.首次合成了能够用于治疗血管相关疾病的式I化合物。1. For the first time, a compound of formula I that can be used to treat blood vessel-related diseases was synthesized.
2.本发明首次发现式I化合物具有减慢动脉瘤扩张速度，减少动脉壁间血肿，抑制动脉夹层，进而降低动脉破裂的效果，适用于治疗动脉相关疾病。2. The present invention finds for the first time that the compound of formula I has the effect of slowing down the expansion speed of aneurysm, reducing hematoma between arterial walls, inhibiting arterial dissection, and thereby reducing arterial rupture, and is suitable for the treatment of artery-related diseases.
3.本发明化合物不仅能减缓早中期动脉瘤的扩张速度，而且对晚期动脉瘤也具有明显的治疗效果，可降低晚期动脉瘤的破裂风险，可用于动脉瘤全病程。3. The compound of the present invention can not only slow down the expansion speed of early- and middle-stage aneurysms, but also has obvious therapeutic effects on late-stage aneurysms, can reduce the risk of rupture of late-stage aneurysms, and can be used for the entire course of aneurysms.
4.本发明化合物及药物组合物为动脉瘤、动脉壁间血肿和/或动脉夹层患者提供了手术治疗之外的治疗选择。4. The compounds and pharmaceutical compositions of the present invention provide a treatment option other than surgical treatment for patients with aneurysms, intramural hematomas and/or arterial dissections.
5.本发明化合物用药安全、毒副作用小。 5. The compounds of the present invention are safe to use and have little toxic and side effects.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.
试剂
Reagents
实验仪器
laboratory apparatus
其他常用试剂可以通过商购获得。自动脱水机、包埋机、石蜡切片机、摊片机、烤片机、冷台均购自德国Leica公司。Other commonly used reagents can be obtained through commercial purchase. Automatic dehydration machine, embedding machine, paraffin slicer, slide spreader, baking machine, and cold stage were all purchased from Leica, Germany.
系列化合物合成的通用方法General methods for the synthesis of series compounds
除非另有规定，否则使用试剂时无需进一步纯化。在使用常规方法之前，将溶剂干燥并重新蒸馏。使用四甲基硅烷(TMS)作为内标，在BrukerBioSpin  GmbH光谱仪(瑞士AvanceIII)上记录400MHz和100MHz下的1H NMR和13C NMR谱。耦合常数以Hz为单位。使用岛津LCMS-IT-TOF质谱仪获得高分辨率质谱。使用从青岛海阳化工有限公司(有限公司)购买的硅胶(200e300目)进行快速柱层析。所有反应过程均通过预涂硅胶GF254(青岛海阳化学有限公司)上的薄层色谱(TLC)进行监测，并在紫外光(254nm)下检测斑点。Unless otherwise specified, reagents were used without further purification. The solvent is dried and redistilled before using conventional methods. Tetramethylsilane (TMS) was used as internal standard in BrukerBioSpin 1H NMR and 13C NMR spectra were recorded at 400MHz and 100MHz on a GmbH spectrometer (AvanceIII, Switzerland). Coupling constants are in Hz. High-resolution mass spectra were obtained using a Shimadzu LCMS-IT-TOF mass spectrometer. Flash column chromatography was performed using silica gel (200e300 mesh) purchased from Qingdao Haiyang Chemical Co., Ltd. (Co., Ltd.). All reaction processes were monitored by thin-layer chromatography (TLC) on precoated silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd.), and spots were detected under UV light (254 nm).
模型制备和统计方法Model preparation and statistical methods
动脉瘤、壁间血肿和动脉夹层模型的制备Preparation of Aneurysm, Intramural Hematoma and Arterial Dissection Models
按照50mg/kg的剂量，腹腔注射舒泰进行小鼠麻醉。等待小鼠进入麻醉状态后，剃毛刀剃掉腹毛，脱毛膏进一步彻底脱毛，擦净腹部后固定于手术台上，身下用加热垫保持体温。碘酒擦拭腹部皮肤后75％乙醇脱碘，在腹部正中剪开约1.5cm的切口，用镊子小心推离脏器，然后用3％青霉素-链霉素润湿的纱布将肠道分至左右两侧，用镊子仔细分离主动脉表面的结缔组织和肌肉组织，使腹主动脉充分暴露。暴露腹主动脉长度约0.5cm左右，近端不超过双侧肾动脉，远端不超过股动脉。The mice were anesthetized by intraperitoneal injection of Serta at a dose of 50 mg/kg. After the mouse enters anesthesia, the abdominal hair is shaved with a razor, and the hair is further removed thoroughly with depilatory cream. The abdomen is wiped clean and fixed on the operating table. A heating pad is used under the body to maintain body temperature. Wipe the abdominal skin with iodine, remove iodine with 75% ethanol, make an incision of about 1.5cm in the middle of the abdomen, use tweezers to carefully push away the organs, and then use gauze moistened with 3% penicillin-streptomycin to divide the intestines to the left and right On both sides, use forceps to carefully separate the connective tissue and muscle tissue on the surface of the aorta to fully expose the abdominal aorta. The length of the exposed abdominal aorta is about 0.5cm, the proximal end does not exceed the bilateral renal arteries, and the distal end does not exceed the femoral artery.
将灭菌吸水纸(0.3cm×0.3cm)在猪胰弹力蛋白酶(PPE)中充分浸润，随即敷在暴露的腹主动脉上，敷育时间为50分钟，在腹腔切口上方放置一块用3％青霉素-链霉素的生理盐水润湿的纱布防止腹腔水分过度流失。50分钟后，小心取出主动脉上的吸水纸，并用含3％青霉素-链霉素的生理盐水，冲洗腹腔，以3/8缝合针、5/0缝合线缝合腹膜及皮肤。缝合完毕后碘酒擦拭创口，1分钟后用75％乙醇脱碘。将小鼠放入干净的饲养笼，进食1％的β-氨基丙腈(BAPN)饲料、自由饮水，隔日更换饲料。Fully infiltrate sterilized absorbent paper (0.3cm × 0.3cm) in porcine pancreatic elastase (PPE), and then apply it on the exposed abdominal aorta. The incubation time is 50 minutes. Place a piece above the abdominal incision with 3% Penicillin-streptomycin and saline-moistened gauze prevent excessive loss of abdominal fluid. After 50 minutes, carefully remove the absorbent paper from the aorta, flush the abdominal cavity with physiological saline containing 3% penicillin-streptomycin, and suture the peritoneum and skin with 3/8 suture needles and 5/0 sutures. After suturing, wipe the wound with iodine, and remove iodine with 75% ethanol after 1 minute. The mice were placed in a clean cage, fed 1% β-aminopropionitrile (BAPN) feed, and had free access to water. The feed was changed every other day.
统计学分析Statistical analysis
腹主动脉的最大直径以平均值±SE表示。使用GraphPad Prism 6进行统计分析。采用单因素方差分析法对各组间差异的统计学意义进行了多次比较。在确定了正态分布和方差齐性后，进行了Tukey检验。P<0.05为统计学意义。The maximum diameter of the abdominal aorta is expressed as mean ± SE. Statistical analysis was performed using GraphPad Prism 6. The statistical significance of differences between groups was compared multiple times using one-way analysis of variance. After determining the normal distribution and homogeneity of variances, Tukey's test was performed. P<0.05 is statistical significance.
制备通用方法General methods of preparation
步骤1：向500毫升的圆底烧瓶中分别加入3-羟基-4-甲氧基苯甲醛(17.8g， 0.1mol 1.0eq)和1.1eq对应的苯乙酸(见表1)，醋酐(80ml)和三乙胺(40ml)，加热回流2-9小时，直至TLC反应完毕，冷却至室温，加热200ml水搅拌2小时，大量固体析出，过滤，烘干得到粗品，把粗品柱层析(PE/EA＝6：1-3：1)真空干燥过夜，得到固体IV化合物。Step 1: Add 3-hydroxy-4-methoxybenzaldehyde (17.8g, 0.1mol 1.0eq) and 1.1eq corresponding phenylacetic acid (see Table 1), acetic anhydride (80ml) and triethylamine (40ml), heat and reflux for 2-9 hours until the TLC reaction is completed, cool to room temperature, and heat 200ml water After stirring for 2 hours, a large amount of solid precipitated, filtered, and dried to obtain a crude product. The crude product was subjected to column chromatography (PE/EA=6:1-3:1) and vacuum dried overnight to obtain a solid IV compound.
步骤2：向500ml的圆底烧瓶中分别加入IV化合物(0.1mol 1.0eq)、5.0eq R2OH搅拌30分钟，室温下缓慢滴加20-60ml浓硫酸，50-110℃回流2-6小时，直至TLC检测显示反应完毕，旋干溶剂，加入乙酸乙酯萃取3次，水洗3次，有机相旋干，柱层析(PE/EA＝9：1-3：1)真空干燥过夜，得到固体Ib化合物。Step 2: Add IV compound (0.1mol 1.0eq) and 5.0eq R 2 OH to a 500ml round-bottom flask respectively, stir for 30 minutes, slowly add 20-60ml concentrated sulfuric acid dropwise at room temperature, and reflux at 50-110°C for 2-6 hours. , until TLC detection shows that the reaction is completed, spin the solvent to dryness, add ethyl acetate to extract 3 times, wash with water 3 times, spin the organic phase to dryness, and column chromatography (PE/EA=9:1-3:1) vacuum dry overnight to obtain Solid Ib compound.
步骤3：在圆底烧瓶中分别加入Ib化合物(1mmol，1.0eq)和K2CO3(0.41g，3mmol，3.0eq)，丙酮10ml，再加入R3Br(1.2mmol)，40-70℃回流4-9小时，直至TLC检测显示反应完毕，加入乙酸乙酯萃取三次，水洗3-4次，有机相旋干，柱层析(PE/EA＝8：1)，得到白色固体对应的式I化合物。Step 3: Add Ib compound (1mmol, 1.0eq), K 2 CO 3 (0.41g, 3mmol, 3.0eq) and 10ml of acetone into a round-bottomed flask respectively, then add R 3 Br (1.2mmol), 40-70°C Reflux for 4-9 hours until TLC detection shows that the reaction is complete. Add ethyl acetate for extraction three times, wash with water 3-4 times, spin the organic phase to dryness, and perform column chromatography (PE/EA=8:1) to obtain the formula corresponding to the white solid. I compound.
按照上述制备方法，使用对应的苯乙酸即可制备得到相应的FA系列化合物。相应的苯乙酸与制备得到的化合物结构见表1。According to the above preparation method, the corresponding FA series compounds can be prepared using the corresponding phenylacetic acid. The corresponding structures of phenylacetic acid and prepared compounds are shown in Table 1.
表1



Table 1



重复上述步骤，不同点在于：使用4-羟基-3-甲氧基苯甲醛替换3-羟基-4-甲氧基苯甲醛，并采用使用对应的苯乙酸，从而得到相应的FB系列化合物。相应的苯乙酸与制备得到的化合物结构见表2。Repeat the above steps, except that 4-hydroxy-3-methoxybenzaldehyde is used to replace 3-hydroxy-4-methoxybenzaldehyde, and the corresponding phenylacetic acid is used to obtain the corresponding FB series compounds. The corresponding structures of phenylacetic acid and prepared compounds are shown in Table 2.
表2



Table 2



FA系列和FB系列化合物使用核磁初步确定纯度，结果表明，纯度＞90％。The purity of FA series and FB series compounds was preliminarily determined using nuclear magnetic resonance, and the results showed that the purity was >90%.
部分化合物FA-3、FA-4、FA-5、FA-6、FA-7、FA-8、FA-9、FA-10、FA-11结构的1H NMR核磁鉴定结果如图2-图10，纯度见表3。The 1 H NMR nuclear magnetic identification results of the structures of some compounds FA-3, FA-4, FA-5, FA-6, FA-7, FA-8, FA-9, FA-10 and FA-11 are shown in Figure 2-Fig. 10. See Table 3 for purity.
表3

table 3

测试例test case
FA系列化合物对动脉瘤、壁间血肿和动脉夹层的防治作用Preventive and therapeutic effects of FA series compounds on aneurysms, intramural hematomas and arterial dissections
动物给药及分组情况：65只8周龄C57BL/6小鼠进入动物房适应饲养一周， 然后随机分为正常对照组、8天模型对照组，15天模型对照组、阿魏酸钠治疗组以及FA-3,FA-4,FA-5,FA-6,FA-7,FA-8,FA-9,FA-10和FA-11(每组n＝5)，猪胰弹力蛋白酶诱导动脉瘤手术当天为第0天，从第8天开始对动物采用灌胃给药的方式分别给予生理盐水、阿魏酸钠，以及FA-3，FA-4，FA-5，FA-6，FA-7，FA-8，FA-9，FA-10和FA-11，给药剂量为50mg/kg，持续给药7天并且严密观察动物的活动情况，在第15天对动物安乐死后取得动脉组织评价动脉瘤扩张和动脉夹层破裂的情况。在手术后第8天，对8天模型对照组的小鼠实施取材，量取腹主动脉瘤直径，该直径为给药起始阶段动脉瘤的直径。Animal dosing and grouping: 65 8-week-old C57BL/6 mice were placed in the animal room for one week of acclimatization. Then the mice were randomly divided into a normal control group, an 8-day model control group, a 15-day model control group, a sodium ferulate treatment group, and FA-3, FA-4, FA-5, FA-6, FA-7, FA-8, FA-9, FA-10, and FA-11 (n=5 in each group). The day of the pig pancreatic elastase-induced aneurysm surgery was day 0. From day 8, the animals were given normal saline, sodium ferulate, and FA-3, FA-4, FA-5, FA-6, FA-7, FA-8, FA-9, FA-10, and FA-11 by gavage, with a dose of 50 mg/kg. The administration was continued for 7 days and the activity of the animals was closely observed. On day 15, the animals were euthanized and arterial tissues were obtained to evaluate the aneurysm expansion and arterial dissection rupture. On day 8 after the operation, the mice in the 8-day model control group were sampled and the diameter of the abdominal aortic aneurysm was measured, which was the diameter of the aneurysm at the initial stage of administration.
实验结果与分析：采用猪胰弹力蛋白酶和1％的β-氨基丙腈饲料喂养诱导动脉瘤、壁间血肿和动脉夹层模型既可以考察药物对动脉瘤增长的影响，还可以考察药物对壁间血肿和动脉夹层破裂的影响。实验结果如图1A-B所示，可以看出阿魏酸钠、FA-3、FA-9、FA-10和FA-11等不但能明显减小动脉瘤扩张速度(P<0.05)，还能明显的减少小鼠壁间血肿和动脉夹层的发生，降低动脉的破裂。从组织学分析可以看出阿魏酸钠、FA-3、FA-9、FA-10和FA-11等保护血管结构的完整性，抑制弹力层的降解、抑制壁间血肿的发生、保护血管外膜胶原的形态、降低血管撕裂和破裂的风险。Experimental results and analysis: Using porcine pancreatic elastase and 1% β-aminopropionitrile feed to induce aneurysm, intramural hematoma and arterial dissection models can not only examine the effects of drugs on aneurysm growth, but also examine the effects of drugs on intramural Effects of hematoma and arterial dissection. The experimental results are shown in Figure 1A-B. It can be seen that sodium ferulate, FA-3, FA-9, FA-10 and FA-11 can not only significantly reduce the aneurysm expansion speed (P<0.05), but also It can significantly reduce the occurrence of intramural hematoma and arterial dissection in mice, and reduce arterial rupture. From histological analysis, it can be seen that sodium ferulate, FA-3, FA-9, FA-10 and FA-11 protect the integrity of the blood vessel structure, inhibit the degradation of the elastic layer, inhibit the occurrence of intramural hematoma, and protect blood vessels. The morphology of adventitial collagen reduces the risk of blood vessel tearing and rupture.
FB系列化合物对动脉瘤、壁间血肿和动脉夹层的防治作用The preventive and therapeutic effects of FB series compounds on aneurysms, intramural hematomas and arterial dissections
动物给药及分组情况：8周龄C57BL/6小鼠进入动物房适应饲养一周，然后随机分分组。一个批次的实验动物随机分为正常对照组、5天模型对照组，15天模型对照组、FB-2、FB-9、FB-10、FB-21、FB-33、FB-34和FB-35(每组n＝5)；另一个批次的实验动物随机分为正常对照组、5天模型对照组，15天模型对照组、FB-15和FB-16(每组n＝5)。猪胰弹力蛋白酶诱导动脉瘤手术当天为第0天，从第5天开始对动物采用灌胃给药的方式分别给予生理盐水、或FB系列化合物，给药剂量为50mg/kg，持续给药7天并且严密观察动物的活动情况，在第15天对动物安乐死后取得动脉组织评价动脉瘤扩张和动脉夹层破裂的情况。在手术后第5天，对5天模型对照组的小鼠实施取材，量取腹主动脉瘤直径，计算腹主动脉瘤体积，该体积为给药起始阶段动脉瘤的体积。Animal administration and grouping: 8-week-old C57BL/6 mice were put into the animal room to adapt to feeding for one week, and then randomly divided into groups. A batch of experimental animals were randomly divided into normal control group, 5-day model control group, 15-day model control group, FB-2, FB-9, FB-10, FB-21, FB-33, FB-34 and FB -35 (n=5 for each group); another batch of experimental animals were randomly divided into normal control group, 5-day model control group, 15-day model control group, FB-15 and FB-16 (n=5 for each group) . The day of surgery for porcine pancreatic elastase-induced aneurysm was day 0. Starting from day 5, animals were given physiological saline or FB series compounds by gavage administration at a dose of 50 mg/kg and continued administration for 7 On the 15th day, the animals' activities were closely observed. After the animals were euthanized on the 15th day, arterial tissue was obtained to evaluate the aneurysm expansion and arterial dissection rupture. On the 5th day after surgery, samples were collected from the mice in the 5-day model control group, the diameter of the abdominal aortic aneurysm was measured, and the volume of the abdominal aortic aneurysm was calculated. This volume was the volume of the aneurysm at the initial stage of drug administration.
实验结果与分析：采用猪胰弹力蛋白酶和1％的β-氨基丙腈饲料喂养诱导动 脉瘤、壁间血肿和动脉夹层模型既可以考察药物对动脉瘤增长的影响，还可以考察药物对壁间血肿和动脉夹层破裂的影响。实验结果如图11A-B及12A-B所示，可以看出FB-2、FB-10、FB-15、FB-16、FB-33和FB-35等不但能明显减小动脉瘤扩张速度(P<0.05)，还能明显的减少小鼠壁间血肿和动脉夹层的发生，降低动脉的破裂。从组织学分析可以看出上述化合物具有保护血管结构的完整性，抑制弹力层的降解、抑制壁间血肿的发生、保护血管外膜胶原的形态、降低血管撕裂和破裂的风险。Experimental results and analysis: Porcine pancreatic elastase and 1% β-aminopropionitrile feed were used to induce animal The aneurysm, intramural hematoma and arterial dissection model can not only examine the effect of drugs on the growth of aneurysms, but also the effect of drugs on the rupture of intramural hematoma and arterial dissection. The experimental results are shown in Figures 11A-B and 12A-B. It can be seen that FB-2, FB-10, FB-15, FB-16, FB-33 and FB-35 can not only significantly reduce the aneurysm expansion speed (P<0.05), it can also significantly reduce the occurrence of intramural hematoma and arterial dissection in mice, and reduce arterial rupture. From histological analysis, it can be seen that the above-mentioned compounds can protect the integrity of the blood vessel structure, inhibit the degradation of the elastic membrane, inhibit the occurrence of intramural hematoma, protect the morphology of the collagen in the vascular adventitia, and reduce the risk of blood vessel tearing and rupture.
各化合物结构与药效见表4：The structure and efficacy of each compound are shown in Table 4:
其中，对于猪胰弹力蛋白酶和1％的β-氨基丙腈饲料喂养诱导壁间血肿和动脉夹层模型(PPE+BAPN模型)，表3列出了相较于同等剂量的阿魏酸钠，各式I化合物的防治效果。以阿魏酸钠抑制动脉扩张的疗效作为100％，则“非常弱”表示有保护趋势但效果不及阿魏酸钠的25％；“弱”表示有保护效果，约为阿魏酸钠疗效的25-50％；“较弱”表示有保护效果，约为阿魏酸钠疗效的50-80％，“相当”表示保护效果约为阿魏酸钠疗效的90-110％；“强”表示有明确保护效果，且优于阿魏酸钠，约为110-120％；“非常强”表示显著优于阿魏酸钠，抑制动脉扩张的效果＞120％。Among them, for the porcine pancreatic elastase and 1% β-aminopropionitrile feed-induced intramural hematoma and arterial dissection model (PPE+BAPN model), Table 3 lists the results compared with the same dose of sodium ferulate. Control effects of compounds of formula I. Taking the efficacy of sodium ferulate in inhibiting arterial dilation as 100%, "very weak" means there is a protective tendency but the effect is less than 25% of that of sodium ferulate; "weak" means it has a protective effect, which is about 25% of the effect of sodium ferulate. 25-50%; "weak" means protective effect, about 50-80% of sodium ferulate's efficacy; "fair" means protective effect about 90-110% of sodium ferulate's efficacy; "strong" means It has a clear protective effect and is better than sodium ferulate, about 110-120%; "very strong" means it is significantly better than sodium ferulate, and the effect of inhibiting arterial dilation is >120%.
表4

Table 4

表4中所列化合物FA-3至FA-11都具有一定的防治效果，其中，FA-3、FA-9、FA-10、FA-11的保护效果相较于阿魏酸钠提高120-150％之间。The compounds FA-3 to FA-11 listed in Table 4 all have certain protective effects, among which the protective effects of FA-3, FA-9, FA-10 and FA-11 are increased by 120-150% compared with sodium ferulate.
讨论discuss
动脉瘤是由于动脉壁的病变或损伤，形成动脉壁局限性或弥漫性扩张或膨出，壁间血肿主要表现为动脉的中层出血，伴随出血量的增加可以引起血管破裂，动脉夹层是动脉壁的撕裂，腔内血液经破口进入动脉壁内形成假腔、进而破裂。动脉瘤、壁间血肿和动脉夹层是主要的可导致动脉破裂的动脉相关疾病，它们在疾病进程中密切关联，可相互影响或转化，如动脉瘤和壁间血肿会演变为动脉夹层，壁间血肿可导致动脉夹层和破裂。动脉瘤、动脉夹层和壁间血肿在疾病发生的早期，都不同程度表现出动脉直径的扩张，到晚期都表现为动脉 的破裂，进而危及患者生命。Aneurysm is a localized or diffuse expansion or bulging of the arterial wall due to the disease or damage of the arterial wall. Intramural hematoma mainly manifests as bleeding in the middle layer of the artery. With the increase in bleeding volume, it can cause vascular rupture. Arterial dissection is a condition of the arterial wall. The blood in the cavity enters the artery wall through the tear, forming a false lumen, and then ruptures. Aneurysm, intramural hematoma and arterial dissection are the main artery-related diseases that can lead to arterial rupture. They are closely related during the disease process and can influence or transform each other. For example, aneurysm and intramural hematoma will evolve into arterial dissection, and intramural hematoma will evolve into arterial dissection. Hematoma can lead to artery dissection and rupture. Aneurysms, arterial dissections, and intramural hematomas all show varying degrees of arterial diameter expansion in the early stages of the disease, and all show arterial diameter expansion in the late stages. rupture, thereby endangering the patient's life.
动脉瘤可以发生在动脉系统的任何部位，包括(但并不限于)：胸主动脉瘤、腹主动脉瘤、脾动脉瘤、肝动脉瘤、肠系膜上动脉瘤、腹腔干动脉瘤、肾动脉瘤、网膜动脉瘤、肠系膜下动脉瘤、颅内动脉瘤和颈动脉瘤等。Aneurysms can occur anywhere in the arterial system, including (but not limited to): thoracic aortic aneurysm, abdominal aortic aneurysm, splenic aneurysm, hepatic aneurysm, superior mesenteric aneurysm, celiac trunk aneurysm, renal aneurysm , omental aneurysm, inferior mesenteric aneurysm, intracranial aneurysm and carotid aneurysm, etc.
目前对于动脉瘤、动脉夹层以及壁间血肿的治疗手段主要是通过手术治疗，预防其破裂导致的死亡。在全世界范围内，目前尚未有新药被开发出来用于动脉瘤、动脉夹层和壁间血肿的预防与治疗。The current treatment for aneurysms, arterial dissections and intramural hematomas is mainly surgical treatment to prevent death caused by their rupture. Worldwide, no new drugs have yet been developed for the prevention and treatment of aneurysms, arterial dissections and intramural hematomas.
本发明通过猪胰弹力蛋白酶孵育腹主动脉造成动脉壁的持续扩张，模拟动脉瘤的早中期疾病进程；通过猪胰弹力蛋白酶孵育叠加β氨基丙腈饲料诱导造成动脉瘤、壁间血肿和血管撕裂，模拟动脉夹层、壁间血肿以及动脉瘤的晚期阶段。In the present invention, the abdominal aorta is incubated with porcine pancreatic elastase to cause continuous expansion of the arterial wall, simulating the early and mid-term disease process of aneurysm; the porcine pancreatic elastase is incubated and superimposed with β-aminopropionitrile feed to induce aneurysms, intramural hematomas and blood vessel tears. Fissure, simulating advanced stages of arterial dissection, intramural hematoma, and aneurysm.
本发明中，意外地观察到本发明的化合物对于中早期和晚期动脉瘤都有治疗效果，可用于整个动脉瘤病程。动脉疾病主要发生在老年人身上，动脉夹层、壁间血肿以及动脉瘤的晚期阶段很可能导致动脉的破裂，进而危及患者生命，但手术治疗及其术后康复(尤其对于老年人而言)也存在很大风险，所以本发明的化合物还可以给晚期动脉瘤患者提供新的治疗手段，具有重要意义。In the present invention, it was unexpectedly observed that the compound of the present invention has a therapeutic effect on early-stage and late-stage aneurysms, and can be used throughout the course of the aneurysm. Arterial disease mainly occurs in the elderly. Arterial dissection, intramural hematoma, and the late stages of aneurysm are likely to lead to rupture of the artery, thereby endangering the patient's life. However, surgical treatment and postoperative recovery (especially for the elderly) are also There is a high risk, so the compound of the present invention can also provide new treatment methods for patients with advanced aneurysms, which is of great significance.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (11)

  1. 一种式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐或酯，
    A compound of formula I, a crystalline form, a hydrate or a solvate, or a pharmaceutically acceptable salt or ester thereof,
    其中，m为0、1、2、3、4；Among them, m is 0, 1, 2, 3, 4;
    各个R1独立地选自下组：H、羟基、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C2-C8烯基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、卤素、氨基、硝基；Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
    R2选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl group with O heteroatom, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-membered heteroatom group with 1-3 heteroatoms selected from the following group of N, S and O 10-membered heteroaryl;
    R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
    R4为H、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C4环烷基、取代或未取代的C1-C4烷氧基、卤素、氨基、硝基；R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
    R5选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 5 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 5-10 membered heteroaryl group of O heteroatom;
    M为C或N。M is C or N.
  2. 如权利要求1所述的式I化合物，其特征在于，所述式I化合物选自：







    The compound of formula I as claimed in claim 1, characterized in that, the compound of formula I is selected from:







  3. 一种如权利要求1或2所述的式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐或酯的用途，其特征在于，用于制备一药物组合物或制剂；所述药物组合物或制剂用于预防和/或治疗选自下组的血管扩张性病变：(i)动脉瘤；(ii)动脉壁间血肿；(iii)动脉夹层和/或(iiii)静脉曲张。A use of the compound of formula I, its crystal form, hydrate or solvate, or pharmaceutically acceptable salt or ester as claimed in claim 1 or 2, characterized in that it is used to prepare a pharmaceutical composition or Preparation; the pharmaceutical composition or preparation is for the prevention and/or treatment of vasodilatory lesions selected from the group consisting of: (i) aneurysm; (ii) intramural hematoma; (iii) arterial dissection and/or (iii) )Varicose veins.
  4. 如权利要求3所述的用途，其特征在于，用于制备一药物组合物或制剂；所述药物组合物或制剂用于预防和/或治疗选自下组的动脉病变：(i)动脉瘤；(ii)动脉壁间血肿；和/或(iii)动脉夹层；The use according to claim 3, characterized in that it is used to prepare a pharmaceutical composition or preparation; the pharmaceutical composition or preparation is used to prevent and/or treat arterial lesions selected from the following group: (i) aneurysm ; (ii) arterial intramural hematoma; and/or (iii) arterial dissection;
    所述药物组合物或制剂还用于预防和/或治疗选自下组的静脉扩张性病变：静脉曲张。The pharmaceutical composition or preparation is also used for the prevention and/or treatment of venous dilation lesions selected from the group consisting of: varicose veins.
  5. 如权利要求4所述的用途，其特征在于，所述的动脉选自下组：胸主动脉、腹主动脉、脾动脉、肝动脉、肠系膜上动脉、腹腔干动脉、肾动脉、网膜动脉、肠系膜下动脉、颅内动脉、颈动脉，或其组合。The use according to claim 4, wherein the artery is selected from the group consisting of: thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, and omental artery. , inferior mesenteric artery, intracranial artery, carotid artery, or combinations thereof.
  6. 如权利要求3所述的用途，其特征在于，所述动脉瘤选自下组：早期动脉瘤、中期动脉瘤、晚期动脉瘤，或其组合。The use of claim 3, wherein the aneurysm is selected from the group consisting of early aneurysm, intermediate aneurysm, late aneurysm, or a combination thereof.
  7. 一种制备式I化合物的方法，包括以下步骤：A method for preparing a compound of formula I, comprising the following steps:
    (S1)在惰性溶剂中，式II化合物与式III化合物反应，得到式I化合物；
    (S1) In an inert solvent, the compound of formula II reacts with the compound of formula III to obtain the compound of formula I;
    各式中，m为0、1、2、3、4；In each formula, m is 0, 1, 2, 3, 4;
    各个R1独立地选自下组：H、羟基、取代或未取代的C1-C8烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C2-C8烯基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、卤素、氨基、硝基；Each R1 is independently selected from the group consisting of: H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C2-C8 alkenyl, substituted or unsubstituted 5-10 membered heteroaryl, halogen, amino, nitro having 1-3 heteroatoms selected from the following group of N, S and O;
    R2选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或 未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 2 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 3-10 membered heterocycloalkyl, substituted or Unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the following group of N, S and O;
    R3为H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 3 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 heteroatoms selected from the group consisting of N, S and O 5-10 membered heteroaryl;
    R4为H、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C4环烷基、取代或未取代的C1-C4烷氧基、卤素、氨基、硝基；R 4 is H, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, amino, nitro;
    R5选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；R 5 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 selected from the following group N, S and 5-10 membered heteroaryl group of O heteroatom;
    M为C或N。M is C or N.
  8. 如权利要求7所述的方法，其特征在于，在步骤(S1)中，式II化合物与式III化合物反应得到式Ia化合物，然后The method of claim 7, wherein in step (S1), the compound of formula II reacts with the compound of formula III to obtain the compound of formula Ia, and then
    在惰性溶剂中，式Ia化合物与R2OH反应，得到式I化合物；
    In an inert solvent, the compound of formula Ia reacts with R 2 OH to obtain the compound of formula I;
    其中，m、R1、R3、R4、R5的定义如上文中所述，Wherein, m, R 1 , R 3 , R 4 , and R 5 are as defined above.
    R2为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。R 2 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3 having 1 to 3 heteroatoms selected from the group consisting of N, S and O -10-membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.
  9. 如权利要求7所述的制备方法，其特征在于，还包括以下步骤：The preparation method according to claim 7, further comprising the following steps:
    (S1a')当R3＝H或R5＝H时，先通过式II化合物与式III化合物反应得到式Ib或Ic化合物；(S1a') When R 3 =H or R 5 =H, first obtain the compound of formula Ib or Ic by reacting the compound of formula II with the compound of formula III;
    (S1b')在惰性溶剂中，式Ib化合物与R3X反应，得到式I化合物
    (S1b') In an inert solvent, the compound of formula Ib reacts with R 3 X to obtain the compound of formula I
    或or
    在惰性溶剂中，式Ic化合物与R5X反应，得到式I化合物
    In an inert solvent, the compound of formula Ic reacts with R 5 X to obtain the compound of formula I
    其中，in,
    X为选自下组的卤素：Br，Cl，I；X is a halogen selected from the following group: Br, Cl, I;
    m、R1、R2、R4的定义如上文中所述；The definitions of m, R 1 , R 2 and R 4 are as mentioned above;
    而R3和R5各自独立地为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基(优选地，R3和R5各自独立地为取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基)。And R 3 and R 5 are each independently a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted group having 1-3 selected from the following group N, S and a 5-10-membered heteroaryl group of heteroatoms of O (preferably, R 3 and R 5 are each independently a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group).
  10. 一种制备式I化合物的哌嗪盐的方法，其特征在于，包括以下步骤：
    A method for preparing the piperazine salt of the compound of formula I, which is characterized in that it includes the following steps:
    在惰性溶剂中，式I化合物与哌嗪混合反应，得到式I-C化合物；In an inert solvent, the compound of formula I is mixed with piperazine to react to obtain a compound of formula I-C;
    其中，m、R1、R3、R4、R5的定义如权利要求1中所述。Wherein, m, R 1 , R 3 , R 4 and R 5 are as defined in claim 1.
  11. 一种药物组合物，所述药物组合物包括：(1)如权利要求1所述的式I化合物、其晶型、水合物或溶剂合物，或药学上可接受的盐或酯，或其组合；和(2)药学上可接受的载体。 A pharmaceutical composition, said pharmaceutical composition comprising: (1) the compound of formula I as claimed in claim 1, its crystal form, hydrate or solvate, or a pharmaceutically acceptable salt or ester, or its combination; and (2) a pharmaceutically acceptable carrier.
PCT/CN2023/120823 2022-09-22 2023-09-22 Compound for preventing and treating vasodilator diseases, preparation method therefor, and use thereof WO2024061362A1 (en)

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