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WO2024061362A1 - Composé pour la prévention et le traitement de maladies vasodilatatrices, son procédé de préparation et son utilisation - Google Patents

Composé pour la prévention et le traitement de maladies vasodilatatrices, son procédé de préparation et son utilisation 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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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—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 
    • 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
    • A61K31/21—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • 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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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • 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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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • 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
    • C07C69/54—Acrylic acid esters; Methacrylic acid esters
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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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    • 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
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • 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.

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Abstract

La présente invention concerne un composé pour la prévention et le traitement de maladies vasodilatatrices, son procédé de préparation et son utilisation. En particulier, la présente invention concerne un composé de formule I et son utilisation dans le traitement de maladies liées aux vaisseaux. Le composé selon la présente invention a pour effet de ralentir la vitesse de progression de maladies vasodilatatrices, d'inhiber l'expansion de l'anévrisme artériel, de réduire l'apparition d'hématome intramural, d'inhiber l'apparition d'une dissection aortique et de réduire davantage l'arteriorrhexis, et est approprié pour traiter des maladies liées à la dilatation vasculaire. Des options de traitement autres que le traitement chirurgical sont fournies pour des patients atteints d'anévrismes, d'hématomes intramuraux et/ou de dissections aortiques. Le composé selon la présente invention est sûr en termes de médication et est à faibles effets toxiques et secondaires.
PCT/CN2023/120823 2022-09-22 2023-09-22 Composé pour la prévention et le traitement de maladies vasodilatatrices, son procédé de préparation et son utilisation Ceased WO2024061362A1 (fr)

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DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS : "Benzeneacetic acid, α-[(3-ethoxy-4-methoxyphenyl)methylene]- (CA INDEX NAME)", XP093150626, retrieved from STNext Database accession no. 938331-89-6 *
DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS : "Benzeneacetic acid, α-[(4-methoxy-3-propoxyphenyl)methylene]- (CA INDEX NAME)", XP093150627, retrieved from STNext Database accession no. 938258-44-7 *
DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS : "Benzeneacetic acid, α-[[3-(hexyloxy)-4-methoxyphenyl]methylene]- (CA INDEX NAME)", XP093150629, retrieved from STNext Database accession no. 938256-36-1 *
DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS : "Benzeneacetic acid, α-[[3-methoxy-4-(1- methylethoxy)phenyl]methylene]- (CA INDEX NAME)", XP093150618, retrieved from STNext Database accession no. 938237-56-0 *
DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS : "Benzeneacetic acid, α-[[4-(hexyloxy)-3-methoxyphenyl]methylene]- (CA INDEX NAME)", XP093150619, retrieved from STNext Database accession no. 938126-24-0 *
DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS : "Benzeneacetic acid, α-[[4-methoxy-3-(pentyloxy)phenyl]methylene]- (CA INDEX NAME)", XP093150624, retrieved from STNext Database accession no. 938355-62-5 *
DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS: "Benzeneacetic acid, α-[(3-methoxy-4-propoxyphenyl)methylene]- (CA INDEX NAME)", XP093150612, retrieved from STNext Database accession no. 938356-85-5 *
DATABASE Registry 22 June 2007 (2007-06-22), ANONYMOUS: "Benzeneacetic acid, α-[(4-ethoxy-3-methoxyphenyl)methylene]- (CA INDEX NAME)", XP093150610, retrieved from STNext Database accession no. 938368-04-8 *
DATABASE Registry 22 June 2022 (2022-06-22), ANONYMOUS : "Benzeneacetic acid, α-[(4-butoxy-3-methoxyphenyl)methylene]- (CA INDEX NAME)", XP093150615, retrieved from STNext Database accession no. 938323-78-5 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, 4-fluoro-α-[(3-hydroxy-4- methoxyphenyl)methylene]- (CA INDEX NAME)", XP093150574, retrieved from STNext Database accession no. 1564110-66-2 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, 4-fluoro-α-[(3-methoxy-4- propoxyphenyl)methylene]- (CA INDEX NAME)", XP093150594, retrieved from STNext Database accession no. 1564115-95-2 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, 4-fluoro-α-[(4-hydroxy-3- methoxyphenyl)methylene]- (CA INDEX NAME)", XP093150593, retrieved from STNext Database accession no. 1564130-36-4 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, 4-fluoro-α-[(4-methoxy-3- propoxyphenyl)methylene]- (CA INDEX NAME)", XP093150578, retrieved from STNext Database accession no. 1564121-60-3 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, 4-fluoro-α-[[3-methoxy-4-(1- methylethoxy)phenyl]methylene]- (CA INDEX NAME)", XP093150604, retrieved from STNext Database accession no. 1564111-18-7 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, 4-fluoro-α-[[3-methoxy-4-(2- methylpropoxy)phenyl]methylene]- (CA INDEX NAME)", XP093150596, retrieved from STNext Database accession no. 1564114-50-6 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, 4-fluoro-α-[[4-methoxy-3-(1- methylethoxy)phenyl]methylene]- (CA INDEX NAME)", XP093150583, retrieved from STNext Database accession no. 1564120-43-9 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, α-[(3-butoxy-4-methoxyphenyl)methylene]-4-fluoro- (CA INDEX NAME)", XP093150587, retrieved from STNext Database accession no. 1564115-73-6 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, α-[(3-ethoxy-4-methoxyphenyl)methylene]-4-fluoro- (CA INDEX NAME", XP093150590, retrieved from STNext Database accession no. 1564109-23-4 *
DATABASE Registry 7 March 2014 (2014-03-07), ANONYMOUS: "Benzeneacetic acid, α-[(4-ethoxy-3-methoxyphenyl)methylene]-4-fluoro- (CA INDEX NAME)", XP093150609, retrieved from STNext Database accession no. 1564109-49-4 *
DING, DJ ET AL.: "Synthesis and Antioxidant Activity of Hydroxylated Phenanthrenes as cis-Restricted Resveratrol Analogues", FOOD CHEMISTRY, vol. 135, no. 3, 26 May 2012 (2012-05-26), XP028935632, ISSN: 0308-8146, DOI: 10.1016/j.foodchem.2012.05.074 *
JAIN NILESH, SINGHAL SARITA, JAIN SURENDRA KUMAR: "SYNTHESIS, CHARACTERIZATION AND ANTI-INFLAMMATORY ACTIVITY OF NOVEL SUBSTITUTED CIS-STILBENE DERIVATIVES", INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH, SOCIETY OF PHARMACEUTICAL SCIENCES AND RESEARCH, IN, vol. 4, no. 5, 1 May 2013 (2013-05-01), IN , pages 1982 - 1993, XP093149444, ISSN: 0975-8232, DOI: 10.13040/IJPSR.0975-8232.4(5).1982-93 *
KATHRIN WEHMING; MORITZ SCHUBERT; GREGOR SCHNAKENBURG; SIEGFRIED R. WALDVOGEL: "Oxidative Cyclization Reaction of 2‐Aryl‐Substituted Cinnamates To Form Phenanthrene Carboxylates by Using MoCl5", CHEMISTRY - A EUROPEAN JOURNAL, JOHN WILEY & SONS, INC, DE, vol. 20, no. 39, 17 July 2014 (2014-07-17), DE, pages 12463 - 12469, XP071840332, ISSN: 0947-6539, DOI: 10.1002/chem.201403442 *

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