CN107304200A - A kind of new himbacine analogs and its application in medicine - Google Patents

A kind of new himbacine analogs and its application in medicine Download PDF

Info

Publication number
CN107304200A
CN107304200A CN201710264296.1A CN201710264296A CN107304200A CN 107304200 A CN107304200 A CN 107304200A CN 201710264296 A CN201710264296 A CN 201710264296A CN 107304200 A CN107304200 A CN 107304200A
Authority
CN
China
Prior art keywords
heteroaryl
aryl
heterocyclyl
cycloalkyl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710264296.1A
Other languages
Chinese (zh)
Other versions
CN107304200B (en
Inventor
夏岩
韩民
李伟
褚扬
白贵荣
田文莉
李菊
周微
王国成
何毅
马晓慧
周水平
孙鹤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Tasly Diyi Pharmaceutical Co Ltd
Original Assignee
Jiangsu Tasly Diyi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Tasly Diyi Pharmaceutical Co Ltd filed Critical Jiangsu Tasly Diyi Pharmaceutical Co Ltd
Publication of CN107304200A publication Critical patent/CN107304200A/en
Application granted granted Critical
Publication of CN107304200B publication Critical patent/CN107304200B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of new himbacine analogs, the compound has formula (Ι) structure, and the stereoisomer, dynamic isomer, prodrug or pharmaceutically acceptable salt or solvate and the pharmaceutical composition containing them of formula (Ι) compound, with and application thereof.

Description

New himbacine analogue and application thereof in medicine
Technical Field
The invention relates to the field of organic chemistry and pharmacology, in particular to a novel himbacine analog, which has a structure shown in a formula (I), a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate of the compound shown in the formula (I), a pharmaceutical composition containing the same and application thereof.
Background
Cardiovascular and cerebrovascular events include Acute Coronary Syndrome (ACS), myocardial infarction, cerebral thrombosis, etc., and are characterized by high morbidity and mortality. The world health organization also indicates that ischemic cardiovascular and cerebrovascular events are the leading cause of death. At present, more than 300 million people die of cardiovascular and cerebrovascular diseases every year in China, and account for 40.3 percent of all dead people. The pathological reason of the diseases is that the platelets are activated to aggregate to form thrombus, so that the ischemia of body tissues is caused, and therefore, the antithrombotic treatment is the main mode for preventing the occurrence of cardiovascular and cerebrovascular events at present.
Platelet adhesion is followed by platelet activation, which involves the release of various autocrine and paracrine factors, including Adenosine Diphosphate (ADP), thrombin, epinephrine, thromboxane a2, which not only signal amplification and maintenance of the initial response of platelets, but also the progressive formation of hemostatic plugs by the platelets in the blood circulation. Activation of various coagulation factors bound to the surface of platelets promotes the conversion of prothrombin to thrombin, which in turn promotes the aggregation of platelets and the conversion of fibrinogen to fibrin, which are the main causes of promoting blood coagulation and hemostasis. The platelet response to thrombin is mediated by platelet surface G protein-coupled receptors, the thrombin receptor. Further studies have found that the thrombin receptor is Activated by proteolysis, and thus the thrombin receptor is also known as the Protease Activated Receptors (PARs). There are 4 subtypes of PARs, widely distributed in tissues, and PAR-1, PAR-3, PAR-4 are activated by thrombin, and PAR-2 is activated by trypsin or tryptase. Human platelets express only two receptors, PAR-1 and PAR-4, with PAR-1 playing the most central role in thrombin-mediated platelet activation. Murine platelets express both the PAR-1 and PAR-3 receptors.
Currently marketed oral antithrombotic agents all act by inhibiting the platelet activation pathway. The cyclooxygenase inhibitor aspirin can inhibit the production of thromboxane A2. The thiophene pyridine medicine (such as clopidogrel) can be irreversibly combined with ADP receptor P2Y12 on the surface of a platelet, thereby inhibiting the platelet activation of ADP. The platelet activation pathway caused by ADP and thromboxane A2 is a key step for conventional pathological thrombosis and hemostasis, so that the combined application of a cyclooxygenase inhibitor and a thiophene pyridine medicament plays an antithrombotic role and inevitably leads to the increase of the risk of bleeding complications. Therefore, although the antiplatelet therapy has achieved better clinical effects at present, the bleeding risk caused by the antiplatelet therapy is still of concern.
The platelet activation pathway mediated by PAR-1 has a major role in pathological thrombosis. PAR-1 receptor inhibitors block thrombin-mediated platelet activation without affecting thrombin-mediated fibrinogen cleavage, and PAR-1 receptor inhibitors do not affect factors involved in platelet adhesion, activation or aggregation pathways, such as collagen, vWF, ADP and procoagulant (see Coughlin SR.; J Thromb Haemost.,2005,3: 1800-. In addition, thrombin receptor antagonists may also be administered in combination with aspirin, clopidogrel, and the like to increase antithrombotic effects. Thrombin receptor antagonists also hold promise for the development of new anti-arteriosclerosis and anti-cancer drugs.
Since the discovery of thrombin receptor, many pharmaceutical companies have been working on the development of new drugs targeting thrombin receptor. A series of patent applications for thrombin receptor antagonists have been disclosed, such as WO03089428 disclosing a class of himbacine derivatives; WO2002085855 discloses 2-iminopyrrolidine derivatives. In phase III clinical tests, a thrombin receptor antagonist SCH530348 developed by Merck shows that SCH530348 obviously reduces the incidence rate of cardiovascular diseases such as myocardial infarction or cerebral thrombosis, but also shows that hemorrhagic adverse reactions, particularly patients suffering from stroke, transient cerebral ischemia and cerebral hemorrhage, increase the intracranial hemorrhage probability, so that the applicable population of the existing thrombin receptor antagonist is greatly reduced. The development of new thrombin receptor antagonists with fewer bleeding side effects and better therapeutic efficacy remains a major challenge.
The compound disclosed by the invention has a large structural difference with the compound specifically disclosed in the prior art, and shows excellent effect and action.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a novel himbacine analogue shown in the structure of formula (I), and a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, or a metabolite and a metabolic precursor or prodrug thereof,
a compound having the structure of formula (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof:
wherein:
R1selected from the group consisting of heterocyclyl, aryl or heteroaryl, wherein said heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
R2selected from-C (O) OR3、-CN、-C(O)NR3R4Heterocyclyl, aryl or heteroaryl, wherein said heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
x is selected from CH or N;
n is selected from 0, 1, 2 or 3, and when N is 0 and X is N, R is2Is selected from heteroaryl, wherein said heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
R3and R4Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said heterocyclyl, aryl or heteroaryl group may be further optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, amine, alkoxy, alkyl or cycloalkyl.
Preferably, the compound of formula (i) according to the present invention, or a stereoisomer, a tautomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof:
wherein,
R1selected from the group consisting of heterocyclyl, aryl or heteroaryl, wherein said heterocyclyl, aryl or heteroaryl may further optionally be substituted by one or more groups selected from the group consisting of halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl;
R2selected from-C (O) OR3、-CN、-C(O)NR3R4Or heteroaryl, wherein said heteroaryl may be further optionally substituted with one or more groups selected from halogen, hydroxy, cyano, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl;
x is selected from CH or N;
n is selected from 0, 1 or 2, and when N is 0 and X is N, R is2Is selected from heteroaryl, wherein said heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cyclicThe alkyl, heterocyclyl, aryl or heteroaryl groups may further optionally be substituted by one or more groups selected from halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl; (ii) a
R3And R4Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said heterocyclyl, aryl or heteroaryl groups may be further optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amine, alkoxy, alkyl or cycloalkyl.
Further preferably, the compound according to the formula (ii) or a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is preferably selected from the group consisting of:
wherein:
R1selected from the group consisting of heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
in the structure of formula (II-1), R2Selected from-C (O) OR3、-CN、-C(O)NR3R4Heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxyRadical, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
in the structure of formula (II-2), R2Is selected from heteroaryl; said heteroaryl group being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
R3and R4Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, said heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, alkoxy, alkyl or cycloalkyl.
The invention relates to a compound in a formula (I) or a stereoisomer, a tautomer, a prodrug of the compound in a pharmaceutically acceptable salt or a solvate, wherein the pharmaceutically acceptable salt is a conventional non-toxic salt formed by the compound and inorganic acid/organic acid or inorganic base/organic base, and the salt can be a single salt, a double salt, a triple salt or a multiple salt which is determined by a salt forming functional group contained in the compound. Wherein if said compound of formula (i) contains a basic functional group, acid addition salts may be formed with sulfuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulfonic, p-toluenesulfonic, oxalic or succinic acid, which salts may be synthesized according to conventional chemical methods from a compound of the invention containing a basic functional group and the corresponding inorganic/organic acid; if the compounds of formula (I) contain acidic functional groups, they can form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia or organic bases such as trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tromethamine or other basic amino acids such as lysine, ornithine or arginine and the like; these salts can be synthesized according to conventional chemical methods from the compounds of the invention containing an acidic functional group and the corresponding inorganic/organic bases.
The invention also relates to pharmaceutically acceptable solvates of said compounds, including conventional solvates, e.g. solvates formed during the preparation of the compounds of the invention due to the presence of solvents, solvates formed from the presence of water or ethanol may be mentioned as non-limiting examples.
Another aspect of the present invention relates to isomers of any of the compounds of the structure of formula (i) wherein one or more carbon-carbon double bonds are present, cis-trans isomers may be present, and the present invention includes all possible cis-trans isomers or mixtures of isomers in different proportions, unless otherwise specified; while one or more chiral centers may be present in the compounds of formula (I), the present invention encompasses all racemates, racemic mixtures, enantiomers, diastereomers and diastereomeric mixtures that may exist in principle without specific recitation. The chemical structural formula and the chemical name in the invention comprise all isomers of the compound which can exist in theory.
If the compounds of the formula (I) are present as diastereomers or mixtures of enantiomers or are obtained as mixtures thereof in the synthesis chosen, the compounds of the formula (I) can be separated into optically pure stereoisomers by the following method: chromatographic separation on an optionally chiral carrier material or, if the racemic compound is capable of forming a salt, fractional crystallization with an optically active base or an optically active acid-forming diastereoisomeric salt as auxiliary. Examples of suitable chiral stationary phases for diastereomer thin layer chromatography or column chromatography are modified silica gel supports (to Pirkle phase) and high molecular weight hydrocarbons such as triacetyl cellulose. In order to isolate the racemate containing acidic groups in the compound of formula (I), diastereomer salts with different solubilities are formed with optically active bases such as (-) -nicotine, (+) -and (-) -phenylethylamine, quinine base, L-lysine, L-arginine and D-arginine, the less soluble fractions are separated in solid form and the pure enantiomers are obtained from the diastereomer salts obtained in the above way. Racemates of the compounds of formula (I) containing basic groups such as amino groups can be converted into the pure enantiomers using optically active acids such as (+) -camphor-10-sulfonic acid, D-and L-tartaric acid, D-and L-lactic acid, D-and L-mandelic acid in the manner described above.
Another aspect of the present invention is directed to isotopic substitutions of the compounds of formula (i) or stereoisomers, tautomers, prodrugs or pharmaceutically acceptable salts or solvates thereof, wherein at least one hydrogen atom in any one of the compounds can be replaced by a deuterium atom or at least one carbon or fluorine atom can be replaced by the corresponding isotope.
Another aspect of the present invention is directed to a pharmaceutical composition comprising a compound of any one of formula (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
Another aspect of the present invention pertains to the use of a compound of any one of the formulas (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for the manufacture of a medicament for a thrombin receptor antagonist.
Another aspect of the present invention pertains to the use of a compound of any one of the formulas (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for the manufacture of a medicament for a thrombin receptor antagonist, wherein the thrombin receptor antagonist is a PAR1 receptor antagonist.
Another aspect of the present invention pertains to the use of a compound of any one of the formulas (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for the manufacture of a medicament for the inhibition of platelet aggregation.
Another aspect of the present invention is directed to the use of a compound of any one of formula (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for the manufacture of a medicament for the treatment and/or prophylaxis of thrombin receptor-related diseases selected from the group consisting of arterial and venous thrombosis, acute coronary syndrome, restenosis, stable angina pectoris, cardiac rhythm disorders, myocardial infarction, hypertension, heart failure, stroke, inflammatory diseases, pulmonary embolism and other pulmonary diseases, gastrointestinal diseases, rheumatism, asthma, chronic liver fibrosis, tumors and skin diseases.
Another aspect of the present invention is directed to a compound of any one of the formulas (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a product of a pharmaceutical composition and another cardiovascular agent, as a combination product for simultaneous or separate use in the treatment of a cardiovascular disease, wherein said another cardiovascular agent is an anti-platelet aggregation agent selected from the group consisting of aspirin, clopidogrel, ticlopidine, abciximab, tirofiban and eptifibatide.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
"halogen" means fluorine, chlorine, bromine, iodine.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups having 1 to 12 carbon atoms are preferred, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylhexyl, 2-methyl-2-ethylhexyl, 2-dimethyl-3-ethylhexyl, 2, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutylA group such as 1, 3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, and 2, 3-dimethylbutyl group. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
"spirocycloalkyl" refers to 5 to 20 membered polycyclic groups having a single ring sharing a single carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered.
"bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycleOn an alkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from N, O or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are C. Preferably 3 to 12 ring atoms of which 1 to 4 are heteroatoms, more preferably cycloalkyl rings contain 3 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like; polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
"Spiroheterocyclyl" means a 5-to 20-membered polycyclic heterocyclic group with a single ring atom (referred to as the spiro atom) shared between rings, wherein one or more of the ring atoms is selected from N, O or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are C. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered.
"fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from N, O or S (O)m(wherein m is an integer of 0 to2) The remaining ring atoms are C. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups.
"bridged heterocyclyl" means a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from N, O or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are C. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl; the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring; aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
"heteroaryl" means a group containing 1 to 4 heteroatoms,heteroaromatic systems of 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. Preferably 6 to 10, more preferably 5 or 6, members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring; heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
"alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
The invention also includes pharmaceutical compositions comprising a compound of the invention, or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof.
The pharmaceutical composition of the invention can be in any form of medicine which can be taken: such as tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, salves, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops or patches.
The pharmaceutical compositions of the present invention are preferably in the form of a unit dose pharmaceutical formulation.
When the pharmaceutical composition is prepared into a medicament, the medicament with unit dose can contain 0.1-1000mg of the pharmaceutical active substance, and the balance is a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be 0.01-99.99% by weight of the total weight of the formulation.
The composition of the present invention is used in an amount determined according to the condition of the patient, for example, 1 to 3 times a day. 1-10 tablets at a time, etc.
Preferably, the composition of the present invention is an oral preparation or an injection.
Wherein the oral preparation is selected from one of capsules, tablets, dripping pills, granules, concentrated pills, oral liquid and mixture.
Wherein, the injection is selected from one of injection, freeze-dried powder injection and water injection.
The pharmaceutical composition of the present invention, the preparation for oral administration thereof, may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents or wetting agents, and the tablet may be coated if necessary.
Suitable fillers include cellulose, mannitol, lactose or other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone or starch derivatives, preferably sodium starch glycolate. A suitable lubricant is magnesium stearate. A suitable wetting agent is sodium lauryl sulphate.
The pharmaceutical composition of the present invention can be prepared into solid oral compositions by conventional methods such as mixing, filling, tabletting and the like. Repeated mixing can result in distribution of the active throughout the composition using a large amount of filler.
Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerides, propylene glycol or ethyl alcohol; preservatives, for example p-hydroxybenzoic acid methyl ester, propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
For injections, liquid unit dosage forms are prepared containing the active substances of the invention and a sterile carrier. Depending on the carrier and concentration, the compound may be suspended or dissolved. Solutions are generally prepared by dissolving the active substance in a carrier, filter sterilising before filling it into a suitable vial or ampoule and then sealing. Adjuvants such as a local anaesthetic, preservatives and buffering agents may also be dissolved in the vehicle. To improve its stability, the composition can be frozen after filling into vials and the water removed under vacuum.
The pharmaceutical composition of the invention can be optionally added with a suitable pharmaceutically acceptable carrier when being prepared into a medicament, and the pharmaceutically acceptable carrier is selected from one or more of the following: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, EDTA disodium, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.
The dosage form of the invention is not limited to this, and it can be prepared into more dosage forms, such as dripping pills, sustained release preparations and any other administrable pharmaceutical forms.
Detailed Description
The invention is further illustrated by the following specific examples, which set forth the synthesis of representative compounds and the associated structural identification data, and which are intended to be illustrative of the invention and not limiting thereof, and all such modifications which come within the spirit of the invention are desired to be protected.
Example 1: n- [ (1R,3aR,4aR,6R,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] -vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] aminoacetic acid (I-1)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]aminoacetic acid(Ι-1)
The first step is as follows:
adding the compound 1a (30g,0.275mol) and pyridine (32g) into 300mL DCM, and cooling to 0 ℃ under the protection of nitrogen; dropwise adding trifluoromethanesulfonic anhydride (93g, 0.33mol), and heating the reaction system to room temperature; after 1h the reaction was poured into 400mL of water, extracted with 150mL of dichloromethane, and the organic phase was washed once with 2N dilute hydrochloric acid (100mL), once with saturated brine, dried and concentrated to give Compound 1b as a brown liquid (62g, 93% yield).
The second step is that:
compound 1b (62g, 0.257mol), 1c (43.2g, 0.308mol), potassium carbonate (106g, 0.77mol), Pd (PPh)3)4Sequentially adding the mixture into 400mL of methylbenzene, replacing the mixture with nitrogen for 3 times, raising the temperature of a system to 90 ℃, and carrying out reflux reaction for 6 hours; cooling the system to room temperature, pouring the cooled system into 400mL of water, filtering the system through diatomite, washing the filtrate once with water, washing the filtrate once with saturated salt solution, drying and concentrating to obtain 145g of brown liquid; the crude product was purified by column chromatography (PE: EA ═ 20: 1) and concentrated to give compound 1d (42g, yield 87%) as a brown liquid.
The third step:
under the protection of nitrogen, dropwise adding n-butyl lithium into a-40 ℃ solution of diisopropylamine THF (280mL) for reacting at-30 ℃ for 1.5 h; dissolving 1d (48g, 0.256mol) in 500mL THF, cooling to-60 ℃ under the protection of nitrogen, dropwise adding the LDA into the system, and reacting at-60 ℃ for 1 h; dropwise adding 1e (53g, 0.308mol) into the system, and reacting for 1.5h at-50 ℃; the reaction mixture was poured into 1L of saturated ammonium chloride, the aqueous phase was extracted with ethyl acetate (400mL × 2), the organic phases were combined and concentrated to dryness to give a red-brown liquid, which was purified by column chromatography (DCM: MeOH ═ 50:1) to give compound 1f (38g, yield 79.7%) as a red-brown liquid.
The fourth step:
N2under protection, LHMDS THF is added dropwise into 1f (600mg, 1.8mmol) THF (6mL) at 0 ℃, and after the addition, the temperature is kept for 30 min; mixing Ti (i-OPr)4Adding THF (1mL) dropwise into the system, and reacting for 10 min; 1g (see Bioorganic for synthetic methods)&Medicinal Chemistry Letters, 20, 2010, 6676 (200mg, 0.61mmol) of THF (1.5mL) was added dropwise to the system, and then returned to room temperature for 3 h; 20mL of saturated aqueous solution of potassium sodium tartrate was added to the system, extracted with ethyl acetate, and the organic phase was dried. Purification by column chromatography gave a pale white solid for 1h (130mg, 22% yield).
The fifth step:
dissolving 1h (0.8g, 1.6mmol) in concentrated hydrochloric acid at room temperature, and heating to 120 ℃ for reaction for 3 hours; the compound 1i is obtained by spin-drying and directly put into the next step.
And a sixth step:
at room temperature, N2Protection, TEA was added to 1i (200mg, 0.43mmol) of MeOH and reacted at room temperature for 15 min; adding glyoxylic acid aqueous solution (65mg, 0.43mmol) into the system, and reacting for 30min at room temperature; adding NaBH into the system3CN (28mg, 0.43mmol), reaction at room temperature for 1 h; adding a small amount of water-methanol to the system for quenching, directly concentrating, spin-drying, and preparing by thin layer chromatography (MeCN: H)2O ═ 5:1), and concentrated to give compound I-1(50mg, yield 24%) as a pale yellow solid.
1H NMR(DMSO,400MHz):8.65(1H,s),7.95(1H,d,J＝6.0Hz),7.48(1H,d,J＝8.0Hz),7.40(2H,m),7.33(1H,d,J＝9.6Hz),7.05(1H,s),6.55(2H,d,J＝3.6Hz),4.74(1H,m),3.46(2H,m),3.21(1H,m),2.65(1H,m),2.35(2H,t,J＝1.6Hz),2.03(2H,m),1.85(2H,m),1.30-1.18(12H,m),0.80(2H,m),0.77(2H,m)；
ESI-MS:479.2[M+H]+
Example 2: n- [ (1R,3aR,4aR,6R,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] -vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] aminoacetonitrile (I-2)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]aminoacetonitrile(Ι-2)
Adding 1i (0.39g, 0.92mmol), bromoacetonitrile (0.14g, 1.21mmol) and DIPEA (0.36g, 2.78mmol) into acetonitrile at room temperature, and reacting at 40 ℃ for 5h under the protection of nitrogen; saturated 100mL NaHCO was added to the reaction system3Extracting the solution with ethyl acetate, concentrating and drying the organic phase to obtain 0.185g of crude product; purification by thin layer chromatography (DCM: MeOH ═ 15:1) gave i-2 as a white solid (60mg, 25% yield).
1H NMR(DMSO,400MHz):8.78(1H,s),7.82(1H,d,J＝6.4Hz),7.47(1H,m),7.37(1H,m),7.28(4H,m),7.10(1H,m),6.61-6.53(2H,m),4.75(1H,m),3.64(2H,m),2.73(2H,m),2.39(2H,m),2.01-1.91(4H,m),1.61-0.89(12H,m)；
ESI-MS:460.2[M+H]+
Example 3: n- [ (1R,3aR,4aR,6R,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] -vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] -N- (4-methylpyrimidinyl-2) -amino (I-3)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-N-(4-methylpyrimidin-2-yl)amino(Ι-3)
1i (150mg, 0.36mmol), 3a (92mg, 0.71mmol), DIPEA (1mL) were added to 5mL DMSO, N2Heating to 150 ℃ for reaction for 10h under protection; the reaction system is cooled to room temperature, 20mL of water is added to precipitate a solid, the solid is filtered, and a filter cake is washed with water to obtain a white solid I-3 (40mg, the yield is 21.9%)。
1H NMR(DMSO,400MHz):8.70(1H,s),8.04(1H,d,J＝4.0Hz),7.74(1H,d,J＝11.2Hz),7.37(1H,m),7.34(1H,m),7.28(1H,m),7.02(1H,m),6.55(2H,m),6.31(1H,d,J＝4.8Hz),4.83(1H,d,J＝7.6Hz),4.68(1H,m),3.82(1H,m),2.67(1H,m),2.53(1H,m),2.31(2H,m),2.22(3H,s),2.02(2H,m),1.88(2H,m),1.37(3H,s),1.24-0.80(8H,m)；
ESI-MS:513.35[M+H]+
Example 4: n- [ (1R,3aR,4aR,6R,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] -vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] -N- (benzoxazolyl-2) -ammonia (I-4)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-N-(benzo[d]oxazol-2-yl)amino(Ι-4)
1i (110mg, 0.26mmol), 4a (80mg, 0.52mmol), potassium carbonate (69mg, 0.52mmol) were added to 10mL DMF, N at room temperature2Heating to 100 ℃ for reaction for 10h under protection, cooling the reaction system to room temperature, adding 20mL of water, extracting with ethyl acetate (20mL of × 2), combining organic phases, drying, concentrating, and purifying by high pressure preparative chromatography to obtain a white solid I-4 (29mg, yield 20.7%).
1H NMR(DMSO,400MHz):8.82(1H,s),7.87(1H,d,J＝2.0Hz),7.48(1H,s),7.47(2H,m),7.46-7.06(6H,m),6.63(2H,m),5.43(1H,d,J＝12.6Hz),4.80(1H,d,J＝12.6Hz),3.85(1H,m),2.76(1H,m),2.44(2H,d,J＝8.0Hz),2.28(2H,m),2.02(3H,m),1.48(3H,s),1.36-1.01(7H,m)；
ESI-MS:538.60[M+H]+
Example 5 Ethyl N- [ (1R,3aR,4aR,6R,8aR,9S,9aS) -9- [ (1E) -2- (3 '-fluoro-1, 1' -biphenyl) -4-vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] carbamate (I-5)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[3'-fluoro-(1,1'-biphenyl)-4-yl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]carbamic acidethyl ester(Ι-5)
The first step is as follows:
NaH (139mg, 2.7mmol) was added to a solution of 5a (1.78g, 2.7mmol) in 10mL THF at 0 deg.C and the reaction was continued for 1 h; 1g (450mg, 1.38mmol) of THF (10mL) solution is added dropwise, and the reaction is raised to room temperature for 2 h; saturated NH for system4And (3) quenching with a Cl aqueous solution, extracting with ethyl acetate, and drying and concentrating the organic phase to obtain a compound 5b which is directly used in the next step.
The second step is that:
at room temperature, add 5c (0.48g, 3.4mmol), Pd (PPh)3)4(140mg, 0.7mmol) was added to 5b (0.66g, 1.3mmol) of toluene-EtOH-Na2CO3In a mixture of aqueous solutions (10mL-5mL-5mL), N2Protecting and heating to 85 ℃ overnight; to the system was added 50mL of water, extracted with ethyl acetate, the organic phases were combined, dried, concentrated and purified by silica gel column chromatography to give I-5 (100mg, yield 15.6%) as a white solid.
1H NMR(DMSO,400MHz):8.65(1H,s),7.54(2H,d,J＝8.0Hz),7.40(4H,m),7.27(1H,d,J＝10.8Hz),7.04(1H,s),6.47(1H,d,J＝16.0Hz),5.95(1H,m),4.72(1H,d,J＝4.0Hz),4.55(1H,m),4.10(2H,m),3.56(1H,m),2.70(1H,m),2.37(2H,m),2.04(2H,m),1.90(2H,m),1.44(3H,s),1.27(6H,m),0.97(2H,m),0.91(2H,m)；
ESI-MS:492.20[M+H]+
Example 6: ethyl N- [ (1R,3aR,4aR,6R,8aR,9S,9aS) -9- [ (1E) -4- (2-pyridyl) -styryl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] carbamate (I-6)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[4-(pyridin-2-yl)-phenyl]ethenyl]dode cahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]carbamic acidethyl ester(Ι-6)
At 0 ℃ under Ar protection, n-BuLi was added dropwise to a solution of 6a (590mg, 1.9mmol) in THF (6mL) and reacted at 0 ℃ for 30 min; 1g (250mg, 0.77mmol) of THF (6mL) solution is added dropwise to the system and reacted for 1 h; saturated NH4The reaction was quenched with aqueous Cl, extracted with ethyl acetate, and the organic phase was concentrated and dried and purified by silica gel column chromatography (PE: EA ═ 1:2) to give i-6 (140mg, yield 38.2%) as a white solid.
1H NMR(DMSO,400MHz):8.69(1H,s),7.98(2H,d,J＝6.8Hz),7.75(2H,d,J＝8.6Hz),7.44(2H,d,J＝6.8Hz),7.25(1H,d,J＝7.6Hz),6.48(1H,d,J＝7.6Hz),5.97(1H,m),4.73(1H,m),4.5(1H,m),4.10(2H,d,J＝6.0Hz),3.50(1H,m),2.69(1H,m),2.39(2H,m),2.04(2H,m),1.93(2H,m),1.43(3H,s),1.23(6H,m),1.07(2H,m),0.92(2H,m)；
ESI-MS:475.25[M+H]+
Biological test example 1: calcium ion transport inhibition assay
The model described below indicates that the compounds of the present invention are PAR-1 receptor inhibitors. In various cell types, activation of the PAR-1 receptor by selective PAR-1 agonists triggers intracellular signaling pathways leading to the release of calcium ions by the endoplasmic reticulum. Calcium release in the pair receptor activated by SFLLR was determined by fluorescence techniques using calcium ion selective probes in a KNRK cell line expressing human PAR 1. The intensity of the fluorescence emission is proportional to the activity and concentration of the PAR-1 antagonist. This method allows the determination of the effect of the compounds of the invention on PAR-1 mediated calcium ion transport.
Firstly, experimental materials:
reagent: HBSS buffer, HEPES, probenecid, BSA, Calcium 4dye was purchased from Invitrogen. TFLLR-NH2Reagents such as SCH-79797 were supplied by the company SEREP, France.
Cell line: a KNRK cell line stably expressing human PAR 1.
Fluorescence microscopy: CellLux (PerkinElmer).
Compounds I-1 to I-6: supplied by the research institute of Tianshili pharmaceutical group, Inc.
Preparing a buffer solution and a stock solution:
assay buffer: 1 × HBSS buffer, prepared as a buffer containing 20mM HEPES, 2.5mM probenecid, 0.1% BSA, PH 7.4(probenecid and BSA need to be freshly prepared);
loading buffer: 1 × HBSS buffer, prepared as a buffer containing 20mM HEPES, 2.5mM probenecid, 0.1% BSA, pH 7.4(probenecid and BSA should be freshly prepared), 2 μ M calcium 4 dye;
compound stock (5 × CPD): compounds were first dissolved in 100% DMSO to give a final concentration of 10 mM. During experiment, the stock solution is prepared into a solution with concentration of 5 times by using an assay buffer for later use;
6×TFLLR-NH2: haTRAP was diluted with assay buffer to a final concentration of 30uM for use.
The final volume of the reaction was 20uL loading buffer, 5uL 5 × CPD, 5uL 6 × TFLLR-NH2(haTRAP, final concentration 5 uM).
II, an experiment step:
1. treating a sterile 384-well plate with 1 time of Matrigel in advance, and standing for 15-30min at 37 ℃;
2. 2 × 10 was added to each well of the sterilized 384-well plate4KNRK cells stably expressing human PAR1 were cultured in a cell culture incubator for 24 hours;
3. removing the cell culture solution in the 384-well plate, and adding 20uL loading buffer containing Calcium 4 dye;
4. culturing in incubator in dark place for 60 min;
5. then 5uL of 5 times of compound stock solution (the final concentration of DMSO is 1%) is added into the culture well, the culture is continued for 15min, and then 5uL of 6 times of TFLLR-NH is added2The fluorescence intensity was recorded under a fluorescence microscope for 100 seconds.
6. Inhibitor activity in the experimental results was expressed as a percentage of the fluorescence intensity duty cycle of the inhibitor at different concentrations versus the fluorescence intensity of the hasrap excitation. The inhibition of PAR-1 by the test compounds was calculated according to the following formula: IR ═ FNC-FTC)/FNC％
FNCFluorescence intensity of wells of negative control group
FTCFluorescence intensity of test compound wells
At a concentration of 10 μ M, the calcium signal antagonism is > 60% and the derivatives of the invention are identified as PAR-1 receptor antagonists.
7. The half inhibitory concentration IC50 of the test compound can be calculated from the inhibition at different concentrations.
Thirdly, experimental results:
the inhibition of the PAR-1 receptor at different concentrations of the compounds of the invention is as follows:
median inhibitory concentration IC of the Compounds of the invention50The assay was as follows:
and (4) conclusion: the test compound has obvious inhibition effect on PAR-1 mediated calcium ion transport and calcium signal antagonism effect IC50The activity is superior to or similar to that of a drug SCH530348 on the market in the range of 0.18-2.1 mu M, and the compound is identified as a PAR-1 receptor antagonist.
Biological test example 2: pharmacokinetic testing of Compounds of the invention
The pharmacokinetic behavior of the compounds of the invention in rats was evaluated by studying the drug concentrations in plasma and brain tissue at different times for the compounds of examples I-2, I-3, and I-6 of the invention.
1. Laboratory animal
Healthy adult SD rats were 8, half male and half female, and divided into 4 groups on average. Purchased from experimental animal technology, ltd, Wei Tong Li Hua, Beijing.
2. Dosage to be administered
The study was a single dose administration experiment. Each half of 8 SD rats were divided into 4 groups of 2 rats each, namely SCH530348, I-2, I-3 and I-6 groups. Fasting was 12h before dosing. The dose administered was 5 mg/kg.
3. Pharmaceutical formulation
Weighing appropriate amount of the medicine, adding 0.5% sodium carboxymethylcellulose, grinding until the sample is uniformly suspended, wherein the sample concentration is 2.0mg/ml, and preparing the medicine at the time of use.
4. Blood sampling scheme
The blood is collected from orbit 0.5mL 0min, 5min, 15min, 25min, 40min, 1h, 2h, 4h, 8h,12h, 24h after administration to rat, and then centrifuged at 4500rpm for 10min to collect blood plasma. And (4) preserving in a refrigerator at the temperature of minus 20 ℃.
5. Sample preparation
Taking 50uL of a plasma sample, adding 20uL of 1ug/ml diazepam internal standard solution, adding 10uL of methanol and 400uL of ethyl acetate, fully whirling for 3min, centrifuging at 17000r/min for 10min, taking 300uL of supernatant, blowing nitrogen for drying, and then using 100uL of methanol: redissolving with water at a ratio of 1:1, fully vortexing for 1min, and directly injecting sample for LC-MS analysis.
The pharmacokinetic parameters of the compounds of the invention are given in the following table:
and (4) conclusion: the half-life period and the blood concentration of the compounds I-2 and I-6 of the invention in vivo are both superior to those of the medicines SCH530348 on the market, and the medicine concentration ratio of the compounds I-2 and I-6 in brain tissues/blood plasma is far less than that of SCH530348, which indicates that the compounds I-2 and I-6 of the invention have weaker ability of crossing blood brain barrier, the risk of cerebral hemorrhage can be greatly reduced, and the invention has better clinical application prospect.

Claims (11)

1. A compound having the structure of formula (i) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof:
wherein:
R1selected from the group consisting of heterocyclyl, aryl and heteroaryl, wherein said heterocyclyl, aryl or heteroaryl may further optionally be substituted by one or more substituents selected from the group consisting ofHalogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
R2selected from-C (O) OR3、-CN、-C(O)NR3R4Heterocyclyl, aryl or heteroaryl, wherein said heterocyclyl, aryl or heteroaryl may further optionally be substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
x is selected from CH or N;
n is selected from 0, 1, 2 or 3, and when N is 0 and X is N, R is2Is selected from heteroaryl, wherein said heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
R3and R4Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said heterocyclyl, aryl or heteroaryl group may be further optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, amine, alkoxy, alkyl or cycloalkyl.
2. A compound according to claim 1, or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof:
wherein:
R1selected from the group consisting of heterocyclyl, aryl or heteroaryl, wherein said heterocyclyl, aryl or heteroaryl may further optionally be substituted by one or more groups selected from the group consisting of halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl;
R2selected from-C (O) OR3、-CN、-C(O)NR3R4Or heteroaryl, wherein said heteroaryl may be further optionally substituted with one or more groups selected from halogen, hydroxy, cyano, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl;
x is selected from CH or N;
n is selected from 0, 1 or 2, and when N is 0 and X is N, R is2Is selected from heteroaryl, wherein said heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally substituted by one or more groups selected from halogen, hydroxy, cyano, amino, -NR3R4Alkoxy, alkyl, cycloalkyl; (ii) a
R3And R4Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said heterocyclyl, aryl or heteroaryl groups may be further optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amine, alkoxy, alkyl or cycloalkyl.
3. A compound according to claim 1 or 2, or a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is preferably selected from the group consisting of:
wherein:
R1selected from the group consisting of heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group being optionally substitutedOne or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
in the structure of formula (II-1), R2Selected from-C (O) OR3、-CN、-C(O)NR3R4Heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
in the structure of formula (II-2), R2Is selected from heteroaryl; said heteroaryl group being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, -NR3R4Alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituted with the substituent(s); said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amine, -NR3R4Alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
R3and R4Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, said heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, amino, alkoxy, alkyl or cycloalkyl.
4. A compound according to claim 3, or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:
5. the compound of claim 1, or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, wherein said compound isomers comprise all possible theoretical cis-trans isomers, cis-trans isomer mixtures, racemates, racemate mixtures, enantiomers, diastereomers and diastereomer mixtures; the pharmaceutically acceptable salt of the compound is a conventional non-toxic salt formed by the compound and inorganic acid/organic acid or inorganic base/organic base.
6. The compound of claim 1, or a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate thereof, wherein there may be substitution of at least one hydrogen atom by a deuterium atom or substitution of at least one carbon or fluorine atom by the corresponding isotope.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
8. Use of a compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 7, for the preparation of a thrombin receptor antagonist, a medicament for the treatment and/or prevention of a thrombin receptor-related disease, an inhibitor of platelet aggregation.
9. The use according to claim 8, wherein the thrombin receptor antagonist is a PAR1 receptor antagonist.
10. The use according to claim 8, wherein the thrombin receptor related diseases are selected from the group consisting of pulmonary diseases such as arterial and venous thrombosis, acute coronary syndrome, restenosis, stable angina, cardiac rhythm disorders, myocardial infarction, hypertension, heart failure, stroke, inflammatory diseases, pulmonary embolism, gastrointestinal diseases, rheumatism, asthma, chronic liver fibrosis, tumors and skin diseases.
11. Use of a compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate thereof, and another cardiovascular agent, as a combination product, for the simultaneous or separate use in the manufacture of a medicament for the treatment of a cardiovascular disease, wherein said another cardiovascular agent is an anti-platelet aggregation agent selected from the group consisting of aspirin, clopidogrel, ticlopidine, abciximab, tirofiban and eptifibatide.
CN201710264296.1A 2016-04-22 2017-04-21 New himbacine analogue and application thereof in medicine Active CN107304200B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610257993 2016-04-22
CN201610257993X 2016-04-22

Publications (2)

Publication Number Publication Date
CN107304200A true CN107304200A (en) 2017-10-31
CN107304200B CN107304200B (en) 2021-09-21

Family

ID=60115718

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710264296.1A Active CN107304200B (en) 2016-04-22 2017-04-21 New himbacine analogue and application thereof in medicine

Country Status (3)

Country Link
CN (1) CN107304200B (en)
TW (1) TW201738221A (en)
WO (1) WO2017181993A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110559294A (en) * 2018-06-06 2019-12-13 杨仑 Preventive and therapeutic drug for fatty liver disease and related diseases

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659162A (en) * 2002-04-16 2005-08-24 先灵公司 Tricyclic thrombin receptor antagonists
CN1878552A (en) * 2003-11-10 2006-12-13 先灵公司 Methods of use of thrombin receptor antagonists
CN101384259A (en) * 2005-12-22 2009-03-11 先灵公司 Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery
WO2009124103A2 (en) * 2008-04-02 2009-10-08 Schering Corporation Combination therapies comprising par1 antagonists with par4 antagonists
US20110065676A1 (en) * 2009-06-24 2011-03-17 Schering Corporation Combination therapies comprising par1 antagonists with nar agonists

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659162A (en) * 2002-04-16 2005-08-24 先灵公司 Tricyclic thrombin receptor antagonists
CN1878552A (en) * 2003-11-10 2006-12-13 先灵公司 Methods of use of thrombin receptor antagonists
CN101384259A (en) * 2005-12-22 2009-03-11 先灵公司 Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery
WO2009124103A2 (en) * 2008-04-02 2009-10-08 Schering Corporation Combination therapies comprising par1 antagonists with par4 antagonists
US20110065676A1 (en) * 2009-06-24 2011-03-17 Schering Corporation Combination therapies comprising par1 antagonists with nar agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R.B. 西尔弗曼: "《有机药物化学》", 31 January 2008 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110559294A (en) * 2018-06-06 2019-12-13 杨仑 Preventive and therapeutic drug for fatty liver disease and related diseases

Also Published As

Publication number Publication date
WO2017181993A1 (en) 2017-10-26
TW201738221A (en) 2017-11-01
CN107304200B (en) 2021-09-21

Similar Documents

Publication Publication Date Title
CN101723936B (en) Kinase suppressor and pharmaceutical application thereof
WO2020259679A1 (en) Pyrimidine five-membered nitrogen heterocyclic derivative, preparation method thereof and pharmaceutical use thereof
JP2021519766A (en) Factor XIIa inhibitor
JP2021523887A (en) Factor XIIa inhibitor
AU2014234909B2 (en) Acyclic cyanoethylpyrazolo pyridones as Janus kinase inhibitors
CN103097340A (en) Therapeutically active compositions and their method of use
KR20140040774A (en) Imidazopyridine compound
JP6670913B2 (en) Use of maleimide derivatives to prevent and treat leukemia
EP3707126A1 (en) Ire1 small molecule inhibitors
WO2018130124A1 (en) Tricyclic compound as selective estrogen receptor down-regulator and use thereof
JP6545262B2 (en) RIPK2 inhibitor and method of treating cancer using the same
CN116789674B (en) NLRP3 inflammatory corpuscle inhibitor
TW201514150A (en) Histone deacetylase inhibitors and compositions and methods of use thereof
JP2020527166A (en) N-Benzenesulfonylbenzamide compounds for inhibiting the Bcl-2 protein, their compositions and uses
TWI723480B (en) Fused ring derivatives used as fgfr4 inhibitors
EP3814331B9 (en) Novel lxr modulators with bicyclic core moiety
JP7402170B2 (en) Compounds as modulators of TLR2 signaling
CN105658641A (en) Indole-amide derivative, preparation method therefor and application thereof in medicine
KR20240004634A (en) Tricyclic ubiquitin-specific protease 1 inhibitors and uses thereof
CN107304200B (en) New himbacine analogue and application thereof in medicine
CN107304199B (en) New himbacine analogue and application thereof in medicine
WO2020232403A1 (en) Treatment of fibrosis with ire1 small molecule inhibitors
WO2019189555A1 (en) Heterocyclic compound
JP2018520128A (en) Deuterated thienopiperidine derivatives, methods of preparation, and uses thereof
KR20170095243A (en) Heterocyclyl linked imidazopyridazine derivatives as pi3kbeta inhibitors

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant