CN107304199B - New himbacine analogue and application thereof in medicine - Google Patents
New himbacine analogue and application thereof in medicine Download PDFInfo
- Publication number
- CN107304199B CN107304199B CN201710264421.9A CN201710264421A CN107304199B CN 107304199 B CN107304199 B CN 107304199B CN 201710264421 A CN201710264421 A CN 201710264421A CN 107304199 B CN107304199 B CN 107304199B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- heteroaryl
- cycloalkyl
- 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.)
- Active
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
- C07D405/06—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
Abstract
The invention relates to a novel himbacine analogue, the compound has a structure shown in a formula (II), and a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or a solvate of the compound shown in the formula (II), a pharmaceutical composition containing the same and application thereof,
Description
Technical Field
The invention relates to the field of organic chemistry and pharmacology, in particular to a novel himbacine analogue, which has a structure shown in a formula (II), a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt or solvate of the compound shown in the formula (II), 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 a formula (II) and a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, or a metabolite and a metabolic precursor or a prodrug thereof,
a compound having the structure of formula (ii) 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, 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;
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 group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, alkoxy, alkyl, or cycloalkyl.
Preferably, the compound of the present invention having a structure of formula (ii) or a stereoisomer, a tautomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof:
wherein the content of the first and second substances,
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;
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.
Preferably, the compound of the structure of formula (iii) or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof:
wherein the content of the first and second substances,
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, substituted with a substituent;
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.
Most preferably, typical compounds of the present invention include, but are not limited to:
the invention relates to a compound in a formula (II) 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 (II) 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 (II) 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 (ii) 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 the formula (II), the invention encompasses all racemates, racemic mixtures, enantiomers, diastereomers and diastereomeric mixtures that may be present in principle without any special indication. 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 (II) are present as diastereomers or mixtures of enantiomers or are obtained as mixtures thereof in the synthesis chosen, the compounds of the formula (II) 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 separate the racemate containing acidic groups in the compound of formula (II), diastereomer salts having 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 components are separated in solid form, and the pure enantiomer is obtained from the diastereomer salt obtained by the above method. Racemates of the compounds of formula (II) containing basic groups such as amino groups can be converted to 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 relates to isotopic substitutions of the compounds of formula (ii) or stereoisomers, tautomers, prodrugs or pharmaceutically acceptable salts or solvates thereof, wherein at least one hydrogen atom may be present in any one of the compounds substituted with a deuterium atom or at least one carbon or fluorine atom substituted with the corresponding isotope.
Another aspect of the present invention is directed to a pharmaceutical composition comprising a compound of any one of formula (ii) 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 (ii) 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 (ii), 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 (ii) 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 (ii) 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 (ii) 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.
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 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-methylpropyl2-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, 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, 2-dimethylhexyl, 2, 3-dimethylhexyl, 4, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, various branched isomers thereof, and the like. 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-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. 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 heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which 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 heterocyclic groups includePyrrolidinyl, 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 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 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(ii) an aryl 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" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 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, when takenWhen substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amino, -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.
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,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] -vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] -9 a-aminoacetic acid (II-1)
N-[(1R,3aR,4aR,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]d odecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-9a-yl]amino acetic acid(II-1)
The first step is as follows:
dissolving 1f (10.7g, 33mmol) in 100mL THF, cooling to 0 deg.C under nitrogen protection, adding n-butyl lithium (13.3mL, 2.5M, 33mmol) dropwise, controlling temperature at about 0 deg.C, and continuing reaction for 1.5 h; dropwise adding a 40mL THF solution of 7a (see J.Med.chem.2005,48, 5884-; the reaction was quenched by adding 100mL of a saturated ammonium chloride solution, extracted 1 time with 100mL of ethyl acetate, washed 1 time with saturated brine, dried, concentrated and purified by column chromatography (EA: PE ═ 1:5) to obtain 4.6g of compound 7b as a white solid (yield 69.6%).
The second step is that:
dissolving 7b (1g, 2.47mmol) in 10mL of anhydrous THF, cooling the system to-78 ℃ under the protection of nitrogen, starting to dropwise add LHMDS (3.8mL, 4.93mmol), and naturally heating to room temperature for reaction for 30 min; cooling the system to-78 ℃, dropwise adding a THF solution of DBAD (1.1g, 4.93mmol), and heating to room temperature for reaction for 1.5h after dropwise adding; the reaction system was poured into 300mL of saturated ammonium chloride solution, separated, the aqueous phase was extracted with 30mL of ethyl acetate, washed with saturated brine, dried and concentrated, the solid was dissolved in 50mL of ethanol, Raney nickel (0.1g) was added, hydrogen was substituted for 3 times, and reacted with 0.1MPa hydrogen for 10 hours, followed by filtration and concentration to obtain 350mg of pale yellow liquid 7c (yield 33.9%).
The third step:
at room temperature, N2Protection, add TEA to 7c (100mg, 0.23mmol) in MeOH and react for 15min at room temperature; adding glyoxylic acid aqueous solution (35mg, 0.23mmol) into the system, and reacting for 30min at room temperature; adding NaBH into the system3CN (15mg, 0.23mmol), 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 ii-1 (40mg, yield 26%) as a pale yellow solid.
1H NMR(DMSO,400MHz):δ8.74(1H,s),8.01(1H,d,J＝8.0Hz),7.53-7.51(6H,m),7.41(1H,d,J＝10.0Hz),7.13(1H,s),6.63(2H,d,J＝3.6Hz),4.79(1H,s),3.55-3.31(2H,m),2.62(1H,d,J＝5.2Hz),2.25(1H,d,J＝3.2Hz),1.78-1.31(14H,m),1.01(1H,m),0.95(1H,m)；
ESI-MS:479.2[M+H]+
Example 2: ethyl N- [ (1R,3aR,4aR,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] -vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] -9 a-aminoacetate (II-2)
N-[(1R,3aR,4aR,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]d odecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-9a-yl]amino acetic acid ethyl ester(II-2)
7c (150mg, 0.35mmol), ethyl bromoacetate (187mg, 1.07mmol), DIPEA (276mg, 2.14mmol) were dissolved in 10mL acetonitrile N at room temperature2Reacting for 10 hours at 85 ℃ under protection; the system was cooled to room temperature, 30mL of water was added, 50mL of ethyl acetate was extracted, the organic phase was concentrated and purified by thin layer chromatography (DCM: EA ═ 4:1) to give compound ii-2 (44mg, yield 24.8%).
1H NMR(DMSO,400MHz):δ8.77(1H,s),7.83(1H,d,J＝2.0Hz),7.49(1H,m),7.37(1H,s),7.28(2H,m),7.09(1H,s),6.63-6.57(2H,m),4.67(1H,m),4.23(2H,m),3.59-3.40(2H,m),2.67(1H,m),2.16(2H,m),1.74-1.09(18H,m),0.92(1H,m),0.86(1H,m)；
ESI-MS:507.6[M+H]+
Example 3: n- [ (1R,3aR,4aR,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] -vinyl ] dodecahydro-1-methyl-3-oxonaphtho [2,3-c ] furan-6-yl ] -9 a-aminoacetonitrile (II-3)
N-[(1R,3aR,4aR,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]d odecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-9a-yl]amino acetonitrile(II-3)
7c (120mg, 0.29mmol), bromoacetonitrile (103mg, 0.86mmol), DIPEA (110mg, 0.86mmol) were dissolved in 10mL acetonitrile N at room temperature2Reacting for 10 hours at 85 ℃ under protection; cooling the system to room temperature, adding 30mL of water and 50mL of ethyl acetate for extraction, drying and concentrating the organic phase, and thenThin layer chromatography (DCM: EA ═ 4:1) purified compound ii-3 (30mg, 23% yield).
1H NMR(DMSO,400MHz):δ8.77(1H,s),7.82(1H,d,J＝2.0Hz),7.44(1H,d,J＝6.0Hz),7.41(1H,s),7.37(4H,s),7.09(1H,d,J＝6.8Hz),6.65(2H,s),4.74(1H,m),3.89(1H,d,J＝17.6Hz),3.52(1H,d,J＝17.6Hz),2.56(1H,m),2.33(1H,m),1.85-1.21(18H,m),0.91(1H,m),0.88(1H,m)；
ESI-MS:460.25[M+H]+
Biological test example: 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 II-1 to II-3: 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.
Final volume of reaction: 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. adding 2X 10 of the sterilized 384-well plate into each well4KNRK 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 PAR1 receptor at different concentrations of the compounds of the invention is as follows:
median inhibitory concentration IC of the derivatives 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 of the compound is equivalent to that of a drug SCH530348 on the market in the range of 0.76-1.1 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 II-1 and II-3 of the invention.
1. Laboratory animal
Healthy adult SD rats were 6, half male and half female, and divided into 3 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. The 6 SD rats were divided into 3 groups of 2 animals each, including SCH530348, II-1 and II-3 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 compound II-3 of the invention in vivo are both superior to those of the marketed medicine SCH530348, and the medicine concentration ratio of the compound II-3 in brain tissues/blood plasma is far less than that of SCH530348, which suggests that the compound II-3 of the invention has weaker ability of crossing the blood brain barrier, the risk of cerebral hemorrhage is probably greatly reduced, and the compound II-3 has better clinical application prospect.
Claims (8)
1. A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
2. the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt of the compound is a conventional non-toxic salt of the compound with an inorganic acid or an organic acid or an inorganic base or an organic base.
3. A pharmaceutical composition comprising a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 in the manufacture of a thrombin receptor antagonist.
5. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment and/or prevention of a thrombin receptor associated disease.
6. The use according to claim 4 wherein the thrombin receptor antagonist is a PAR1 receptor antagonist.
7. The use according to claim 5, wherein the thrombin receptor associated disease is 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, pulmonary embolism, gastrointestinal diseases, rheumatism, asthma, chronic liver fibrosis, tumors and skin diseases.
8. Use of a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, and another cardiovascular agent selected from aspirin, clopidogrel, ticlopidine, abciximab, tirofiban or eptifibatide, as a combination for the manufacture of a medicament for the treatment of a cardiovascular disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610257296 | 2016-04-22 | ||
| CN2016102572964 | 2016-04-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107304199A CN107304199A (en) | 2017-10-31 |
| CN107304199B true CN107304199B (en) | 2021-09-21 |
Family
ID=60116599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710264421.9A Active CN107304199B (en) | 2016-04-22 | 2017-04-21 | New himbacine analogue and application thereof in medicine |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN107304199B (en) |
| TW (1) | TW201738237A (en) |
| WO (1) | WO2017181994A1 (en) |
Families Citing this family (1)
| 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101072772A (en) * | 2004-10-08 | 2007-11-14 | 先灵公司 | Thrombin receptor antagonists |
-
2017
- 2017-04-21 TW TW106113488A patent/TW201738237A/en unknown
- 2017-04-21 WO PCT/CN2017/081450 patent/WO2017181994A1/en active Application Filing
- 2017-04-21 CN CN201710264421.9A patent/CN107304199B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101072772A (en) * | 2004-10-08 | 2007-11-14 | 先灵公司 | Thrombin receptor antagonists |
Non-Patent Citations (1)
| Title |
|---|
| Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist(SCH 530348) with Potent Antiplatelet Activity;Samuel Chackalamannil et al.;《J.Med.Chem.》;20080501;第51卷(第11期);第3061-3064页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2017181994A1 (en) | 2017-10-26 |
| CN107304199A (en) | 2017-10-31 |
| TW201738237A (en) | 2017-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2465971T3 (en) | Kinase inhibitors and method to treat cancer with them | |
| EP3116509B1 (en) | A new class of mu-opioid receptor agonists | |
| JP2008514643A (en) | Novel piperidinylamino-thieno [2,3-D] pyrimidine compounds | |
| WO2012070015A1 (en) | Inhibitors of the activity of complex iii of the mitochondrial electron transport chain and use thereof for treating diseases | |
| TW200804290A (en) | Compounds and uses thereof | |
| JP7374496B2 (en) | N-benzenesulfonylbenzamide compounds, compositions and uses thereof for inhibiting Bcl-2 protein | |
| TW201412737A (en) | Pyrazolo[3,4-c]pyridine derivatives, preparation method and medical use thereof | |
| CN107922340B (en) | 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof | |
| JP6670913B2 (en) | Use of maleimide derivatives to prevent and treat leukemia | |
| TWI723480B (en) | Fused ring derivatives used as fgfr4 inhibitors | |
| JP6908805B2 (en) | Benzofuran derivatives for the treatment of CNS and other disorders | |
| CN102325768A (en) | Compounds and methods for the treatment of pain and other diseases | |
| CN107304199B (en) | New himbacine analogue and application thereof in medicine | |
| CN107304200B (en) | New himbacine analogue and application thereof in medicine | |
| JPH09506880A (en) | Annelated dihydropyridine and its use for preparing pharmaceutical formulations | |
| JP2007262022A (en) | New 2-thiophene carboxamide derivative | |
| US20040152718A1 (en) | 5-cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds | |
| JP6695361B2 (en) | Deuterated thienopiperidine derivative, preparation method and use thereof | |
| PT770082E (en) | DIOXO-TIOPYRANE-PYRIDINOCARBOXYLIC ACID DERIVATIVES AND THEIR USE AS MEDICINES | |
| WO2014172759A1 (en) | α7 NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AND USES THEREOF - III | |
| TW200526642A (en) | Heterocyclic derivatives | |
| US10556872B2 (en) | Fatty acid synthase inhibitors and methods of use | |
| ES2284973T3 (en) | DERIVATIVES OF 2-PIRROLIDIN-2-IL-1H-INDOL SUBSTITUTED FOR THE TREATMENT OF MIGRAINE. | |
| WO2012126275A1 (en) | Spiro-containing dihydropyrazole compounds | |
| KR102649886B1 (en) | Novel pyrimidine-4-one compound and anticancer composition comprising the same |
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 |