WO2017181993A1 - 一种新的喜巴辛类似物及其在医药中的应用 - Google Patents

一种新的喜巴辛类似物及其在医药中的应用 Download PDF

Info

Publication number
WO2017181993A1
WO2017181993A1 PCT/CN2017/081449 CN2017081449W WO2017181993A1 WO 2017181993 A1 WO2017181993 A1 WO 2017181993A1 CN 2017081449 W CN2017081449 W CN 2017081449W WO 2017181993 A1 WO2017181993 A1 WO 2017181993A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
heteroaryl
aryl
cycloalkyl
alkyl
Prior art date
Application number
PCT/CN2017/081449
Other languages
English (en)
French (fr)
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
Original Assignee
江苏天士力帝益药业有限公司
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 江苏天士力帝益药业有限公司 filed Critical 江苏天士力帝益药业有限公司
Publication of WO2017181993A1 publication Critical patent/WO2017181993A1/zh

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

Definitions

  • the present invention relates to the field of organic chemistry and pharmacy, in particular, the present invention relates to a novel bisulphonin analog having a structure of the formula ( ⁇ ), and stereoisomers of the compound of the formula ( ⁇ ), Isomers, prodrugs or pharmaceutically acceptable salts or solvates and pharmaceutical compositions containing them, and uses thereof.
  • Cardiovascular and cerebrovascular events include acute coronary syndrome (ACS), myocardial infarction, cerebral thrombosis, etc., with high morbidity and high mortality.
  • the World Health Organization also pointed out that ischemic cardiovascular and cerebrovascular events are the leading cause of death. At present, more than 3 million people die from cardiovascular and cerebrovascular diseases every year in China, accounting for 40.3% of all deaths. The pathological cause of such diseases is due to the accumulation of thrombus after platelet activation, which leads to ischemia of the body tissues. Therefore, antithrombotic therapy is the main way to prevent cardiovascular and cerebrovascular events.
  • Platelet adhesion is the activation process of platelets, including the release of a variety of autocrine and paracrine factors, including adenosine diphosphate (ADP), thrombin, adrenaline, thromboxane A2, which are not only
  • ADP adenosine diphosphate
  • thrombin thrombin
  • adrenaline thromboxane A2
  • thromboxane A2 thrombin
  • the initial reaction of platelets acts as a signal amplification and maintenance, and causes platelets in the blood circulation to gradually form a thrombus.
  • Activation of various coagulation factors on the surface of platelets promotes the conversion of prothrombin to thrombin, which promotes platelet aggregation and promotes the conversion of fibrinogen to fibrin, which is the main cause of coagulation and hemostasis.
  • thrombin receptor The response of platelets to thrombin is mediated by platelet surface G-protein coupled receptors, the thrombin receptor. Further studies have found that thrombin receptors can be activated by proteolytic hydrolysis, so thrombin receptors are also known as Protease Activated Receptors (PARs).
  • PARs Protease Activated Receptors
  • PAR-1, PAR-3, PAR-4 can be activated by thrombin
  • PAR-2 is activated by trypsin or tryptase.
  • Human platelets express only two receptors, PAR-1 and PAR-4, of which PAR-1 plays a major role in thrombin-mediated platelet activation.
  • Murine platelets express both PAR-1 and PAR-3 receptors.
  • cyclooxygenase inhibitors that are currently on the market all play a role in inhibiting the platelet activation pathway.
  • the cyclooxygenase inhibitor aspirin inhibits the production of thromboxane A2.
  • Thiophene pyridines (such as clopidogrel) can irreversibly bind to the ADP receptor P2Y12 on the surface of platelets, thereby inhibiting platelet activation of ADP.
  • the platelet activation pathway induced by ADP and thromboxane A2 is a critical step for conventional pathological thrombosis and hemostasis. Therefore, the combination of cyclooxygenase inhibitors and thienopyridines is inevitable in exerting antithrombotic effects. The risk of bleeding complications increases. Therefore, although antiplatelet therapy has achieved good results in clinical practice, the risk of bleeding is still worthy of attention.
  • the PAR-1 mediated platelet activation pathway is primarily responsible for pathological thrombosis.
  • PAR-1 receptor inhibitors block thrombin-mediated platelet activation without affecting thrombin-mediated fibrinogen cleavage, while PAR-1 receptor inhibitors also do not affect platelet adhesion, activation, or aggregation pathways.
  • Related factors such as collagen, vWF, ADP and procoagulant (see Coughlin SR.; J Thromb Haemost., 2005, 3: 1800-1814), so PAR-1 receptor inhibitors have both antithrombotic effects and possible It does not increase the risk of bleeding and is an ideal antiplatelet drug.
  • thrombin receptor antagonists can also be combined with aspirin, clopidogrel, etc. to increase antithrombotic effects.
  • Thrombin receptor antagonists are also expected to be developed as new drugs against arteriosclerosis and cancer.
  • thrombin receptor antagonists have been disclosed, such as WO03089428, which discloses a class of bisulphonin derivatives; and WO2002085855 discloses a 2-iminopyrrolidine derivative.
  • WO03089428 discloses a class of bisulphonin derivatives
  • WO2002085855 discloses a 2-iminopyrrolidine derivative.
  • the thrombin receptor antagonist SCH530348 developed by Merck showed that SCH530348 significantly reduced the incidence of cardiovascular diseases such as myocardial infarction or cerebral thrombosis, but also found adverse reactions to bleeding, especially stroke and transient.
  • thrombin receptor antagonists In patients with cerebral ischemia and cerebral hemorrhage, the risk of intracranial hemorrhage increases, which greatly reduces the current population of thrombin receptor antagonists. The development of new thrombin receptor antagonists with fewer bleeding side effects and better efficacy remains a major challenge.
  • the present invention is designed to have a compound represented by the formula (I), and the compound of the present invention has a large structural difference from the compound specifically disclosed in the prior art, and exhibits an excellent effect and effect.
  • R 1 is selected from heterocyclic, aryl or heteroaryl, wherein said heterocyclic, aryl or heteroaryl may be further optionally selected from one or more selected from the group consisting of halogen, hydroxy, cyano and nitro , amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR 3 , -OC(O)R 3 , -C Substituted by a substituent of (O)R 3 , —NHC(O)R 3 , —C(O)NR 3 R 4 wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group is substituted
  • a heteroaryl group may be further optionally selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl
  • R 2 is selected from -C(O)OR 3 , -CN, -C(O)NR 3 R 4 , heterocyclyl, aryl or heteroaryl, wherein said heterocyclyl, aryl or heteroaryl Further optionally, one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Substituted with a substituent of aryl, -C(O)OR 3 , -OC(O)R 3 , -C(O)R 3 , -NHC(O)R 3 , -C(O)NR 3 R 4 ;
  • the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group described therein may be further optionally selected from one or more selected from the group consisting of halogen, hydroxy, cyano,
  • X is selected from CH or N;
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, aryl group or heteroaryl group may be further optionally Substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, alkoxy, alkyl or cycloalkyl.
  • R 1 is selected from a heterocyclic group, an aryl group or a heteroaryl group, and the heterocyclic group, aryl group or heteroaryl group is optionally selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR 3 , -OC(O)R 3 , -C(O)R 3, -NHC (O) R 3 , -C (O) NR 3 R 4 substituents of; the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl any of Substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, ary
  • R 2 is selected from -C(O)OR 3 , -CN, -C(O)NR 3 R 4 , heterocyclic group, aryl or heteroaryl group, said heterocyclic ring
  • the aryl, aryl or heteroaryl group is optionally selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -C(O)OR 3 , -OC(O)R 3 , -C(O)R 3 , -NHC(O)R 3 , -C(O)NR 3 R 4 Substituted with a substituent; the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro,
  • R 2 is selected from heteroaryl; the heteroaryl is optionally selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR 3 , -OC(O)R 3 , -C(O)R 3 , -NHC( Substituted with a substituent of R 3 , —C(O)NR 3 R 4 ; the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally being one or more Substituted by a substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, aryl, heteroaryl;
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the heterocyclic group, aryl group or heteroaryl group is optionally one or more Substituted by a substituent selected from a halogen, a hydroxyl group, a cyano group, a nitro group, an amine group, an alkoxy group, an alkyl group or a cycloalkyl group.
  • typical compounds of the invention include, but are not limited to:
  • the present invention relates to a compound of any one of formula (I), or a stereoisomer, tautomer or prodrug thereof, in a pharmaceutically acceptable salt or solvate, wherein the pharmaceutically acceptable salt is the compound and Conventional non-toxic salts formed from inorganic/organic acids or inorganic bases/organic bases, which may be mono-, di-, tri- or poly-salts, as determined by the salt-forming functional groups contained in the compounds.
  • the compound of the formula (I) contains a basic functional group, it can be combined with sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, p-toluene Sulfonic acid, oxalic acid or succinic acid form acid addition salts which can be synthesized according to conventional chemical methods from the reaction of a compound of the invention comprising a basic functional group with a corresponding inorganic acid/organic acid; if the compound of formula (I) contains an acidic functional group Forming a stable alkali metal salt, an alkaline earth metal salt or an optionally substituted ammonium salt with an alkaline agent such as a hydroxide, a carbonate, a hydrogencarbonate, an alkoxide, and ammonia, or An organic base such as trimethylamine, triethylamine, ethanolamine, diethanolamine
  • the invention further relates to pharmaceutically acceptable solvates of the compounds, including conventional solvates, such as solvates formed by the presence of a solvent in the preparation of the compounds of the invention, solvates formed by the presence of water or ethanol. It can be used as a non-limiting example.
  • Another aspect of the invention relates to an isomer of any one of the compounds of formula (I), wherein one or more carbon-carbon double bonds are present in the compound of formula (I), and cis-trans isomers may be present Unless otherwise specified, the present invention encompasses all possible cis-trans isomers or mixtures of different ratios of isomers; while one or more chiral centers are present in the compounds of formula (I), unless otherwise stated.
  • the present invention encompasses all racemic, racemic mixtures, enantiomers, diastereomers and mixtures of diastereomers which are theoretically possible.
  • the chemical structural formulas and chemical names referred to in the present invention include all isomers which are theoretically possible in the compounds.
  • the compound of formula (I) can be isolated as follows Optically pure stereoisomers: chromatographic separation on a carrier material, or if the racemic compound is capable of forming a salt, it can also be diastereomeric with an optically active base or optically active acid as an auxiliary.
  • the body salt is subjected to fractional crystallization.
  • suitable chiral stationary phases for diastereomeric thin layer chromatography or column chromatography are modified silica support (becoming a Pirkle phase) and high molecular weight hydrocarbons such as triacetyl cellulose.
  • racemate containing a basic group such as an amino group in the compound of the formula (I) can be used as described above with an optically active acid such as (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid, D- and L-mandelic acid are converted to the pure enantiomers.
  • an optically active acid such as (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid, D- and L-mandelic acid are converted to the pure enantiomers.
  • Another aspect of the invention relates to an isotopic substitution of a compound of formula (I), or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, wherein any one of the compounds There is at least one hydrogen atom replaced by a deuterium atom or at least one carbon or fluorine atom is substituted by a corresponding isotope.
  • Another aspect of the invention relates to a pharmaceutical composition
  • 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 invention relates to a compound of any one of formula (I), or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof Use in drugs for thrombin receptor antagonists.
  • Another aspect of the invention relates to a compound of any one of formula (I), or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof Use in a medicament for a thrombin receptor antagonist, wherein the thrombin receptor antagonist is a PAR1 receptor antagonist.
  • Another aspect of the invention relates to a compound of any one of formula (I), or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof Use in drugs for platelet aggregation inhibitors.
  • Another aspect of the invention relates to a compound of any one of formula (I), or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof
  • a medicament for treating and/or preventing a thrombin receptor-related disease wherein the thrombin receptor-related disease is selected from the group consisting of arterial and venous thrombosis, acute coronary syndrome, restenosis, stable angina, Heart disease, myocardial infarction, hypertension, heart failure, stroke, inflammatory disease, pulmonary embolism and other lung diseases, gastrointestinal diseases, rheumatism, asthma, chronic liver fibrosis, tumors and skin diseases.
  • Another aspect of the invention relates to any one of the compounds of formula (I), or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition and additionally
  • a cardiovascular drug product which is used as a combination product at the same time or separately for the treatment of cardiovascular diseases, wherein the other type of cardiovascular drug is selected from the group consisting of aspirin, clopidogrel, ticlopidine, and abci Antiplatelet aggregation drugs such as monoclonal antibody, tirofiban or eptifibatide.
  • Halogen means fluoro, chloro, bromo, iodo.
  • Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 12 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl 1,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano. , nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 One carbon atom.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • Spirocycloalkyl means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group.
  • “Bridge cycloalkyl” means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The ⁇ -electron system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from N, O or S(O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are C. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like; polycyclic heterocyclic groups include spiro, thick Heterocyclic groups of the ring and bridged ring.
  • Spiroheterocyclyl means a polycyclic heterocyclic group of 5 to 20 members in which one atom (referred to as a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from N, O or S(O) m (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are C. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group.
  • “Fused heterocyclyl” refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atoms of a polycyclic heterocyclic group with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from heteroatoms of N, O or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are C. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • It may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group according to the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably a 5-member/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. .
  • “Bridge heterocyclyl” refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings have a complete conjugation
  • a ⁇ -electron system in which one or more ring atoms are selected from heteroatoms of N, O or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are C. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group; the heterocyclic group may be optionally substituted or unsubstituted When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, naphthenic Base, aryl, heteroaryl.
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system of multiple rings (ie, having adjacent pairs)
  • the ring group of a carbon atom is preferably 6 to 10 members such as a phenyl group and a naphthyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring; the aryl group may be substituted or unsubstituted, when When substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, cycloalkyl, aryl Base, heteroaryl.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 6 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl Wait.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring; the heteroaryl may be optionally substituted or unsubstituted When substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, -NR 3 R 4 , alkoxy, alkyl, ring Alkyl, aryl, heteroaryl.
  • Alkoxy means -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.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amine, - NR 3 R 4 , alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts 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 present invention may be any pharmaceutical form that can be taken: such as tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, oral liquids, mouths. Containing agents, granules, granules, pills, powders, ointments, elixirs, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops or patches.
  • the pharmaceutical composition of the present invention is preferably in the form of a unit dose of a pharmaceutical preparation.
  • a unit dose of the medicament may contain 0.1 to 1000 mg of the pharmaceutically active substance of the present invention, and the balance is a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be from 0.01 to 99.99% by weight based on the total weight of the formulation.
  • composition of the present invention is used in a dosage according to the condition of the patient, such as 1-3 times a day.
  • a dosage according to the condition of the patient such as 1-3 times a day.
  • the composition of the present invention is an oral preparation or an injection.
  • the oral preparation is selected from the group consisting of a capsule, a tablet, a dropping pill, a granule, a concentrated pill, an oral liquid, and a mixture.
  • the injection is selected from the group consisting of an injection solution, a lyophilized powder injection, and an aqueous injection.
  • the pharmaceutical composition of the present invention may contain a usual excipient such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent or a moisturizing agent.
  • a usual excipient such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent or a moisturizing agent.
  • the tablets can 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 sulfate.
  • the pharmaceutical composition of the present invention can be prepared into a solid oral composition by a usual method such as mixing, filling, tableting or the like. Repeated mixing allows the active material to be distributed throughout the composition using a large amount of filler.
  • the oral liquid preparation may be in the form of an aqueous or oily suspension, solution, emulsion, syrup or elixir, or it may be a dry product which may be formulated with water or other suitable carrier before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats.
  • Emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters such as glycerides, propylene glycol or ethanol; preservatives For example, p-hydroxybenzyl ester, propyl paraben or sorbic acid, and if desired, may contain conventional flavoring or coloring agents.
  • the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle.
  • This compound can be suspended or dissolved depending on the carrier and concentration.
  • the solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing. Excipients such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier.
  • the composition can be frozen after filling the vial and the water removed under vacuum.
  • the pharmaceutical composition of the present invention may optionally be added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, the pharmaceutically acceptable carrier being selected from one or more of the following: mannitol, sorbitol, sodium metabisulfite. , sodium hydrogen sulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA, monovalent alkali metal carbonate, acetate, phosphate or Aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derived , cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerin,
  • the pharmaceutical dosage form of the present invention is not completely limited thereto, and it can be prepared into more dosage forms such as dropping pills, sustained release preparations and the like which can be administered in any form.
  • n-butyl lithium was added dropwise to a solution of diisopropylamine THF (280 mL) at -40 ° C, and reacted at -30 ° C for 1.5 h; 1 d (48 g, 0.256 mol) was dissolved in 500 mL of THF under nitrogen atmosphere.
  • the temperature was lowered to -60 ° C, the above LDA was added dropwise to the system, and the reaction was kept at -60 ° C for 1 h; 1e (53 g, 0.308 mol) was added dropwise to the system, and reacted at -50 ° C for 1.5 h; the system was poured into 1 L.
  • the THF of LHMDS was added dropwise to a solution of 1f (600 mg, 1.8 mmol) in THF (6 mL) at 0 ° C, added, and kept for 30 min; THF (1 mL) of Ti(i-OPr) 4 was dropped Adding to the system, reacting for 10 min; 1 g [synthesis method see Bioorganic & Medicinal Chemistry Letters, 20, 2010, 6676] (200 mg, 0.61 mmol) in THF (1.5 mL) was added dropwise to the system, and then returned to room temperature for 3 h; To the system was added 20 mL of an aqueous solution of saturated sodium potassium tartrate, extracted with ethyl acetate, and dried to dryness. After purification by column chromatography, a pale white solid was obtained for 1h (130mg, yield 22%).
  • Example 3 N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridyl]-vinyl ]Dodehydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-N-(4-methylpyrimidinyl-2)-ammonium ( ⁇ -3)
  • EtOAc EtOAc
  • Example 4 N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridyl]-vinyl ]Dodehydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-N-(benzoxazolyl-2)-ammonium ( ⁇ -4)
  • the model described below indicates that the compound of the present invention is a PAR-1 receptor inhibitor.
  • activation of the PAR-1 receptor by a selective PAR-1 agonist triggers an intracellular signaling pathway that causes the endoplasmic reticulum to release calcium ions.
  • calcium release from the receptor activated by SFLLR was determined by fluorescence technique using a calcium ion selective probe. The emission intensity of the fluorescence is proportional to the activity and concentration of the PAR-1 antagonist. This method can determine the effect of the compounds of the invention on PAR-1 mediated calcium ion transport.
  • Reagents HBSS buffer, HEPES, probenecid, BSA, Calcium 4dye were purchased from Invitrogen. Reagents such as TFLLR-NH 2 and SCH-79797 are supplied by SEREP, France.
  • Cell line KNRK cell line stably expressing human PAR1.
  • Compound stock solution (5 x CPD): The compound was first dissolved in 100% DMSO to give a final concentration of 10 mM. During the experiment, the above stock solution was prepared into a 5-fold concentration solution by using an assaybuffer;
  • Inhibitor activity in the experimental results is expressed as the percentage of fluorescence intensity of the inhibitor at different concentrations as a percentage of the fluorescence intensity of the blank control haTRAP.
  • the calcium signal antagonism was >60%, and the derivative of the present invention was identified as a PAR-1 receptor antagonist.
  • half maximal inhibitory concentration of test compound IC 50 can be calculated by the inhibition rate at different concentrations.
  • the inhibitory rate of the PAR-1 receptor at different concentrations of the compounds of the invention is as follows:
  • the test compound of the present invention has a significant inhibitory effect on PAR-1 mediated calcium transport.
  • the IC 50 of calcium signal antagonism is in the range of 0.18-2.1 ⁇ M, and the activity is better or similar to that of the marketed drug SCH530348.
  • the compound was identified as a PAR-1 receptor antagonist.
  • the drug concentrations in the plasma and brain tissues of the compounds of Examples I-2, I-3 and I-6 of the present invention were investigated at different times, and the pharmacokinetic behavior of the compounds of the present invention in rats was investigated, and their pharmacokinetic characteristics were evaluated.
  • This study is a single dose administration experiment. Eight SD rats were divided into four groups, with an average of 4 groups, 2 in each group, which were SCH530348 group, I-2 group, I-3 group and I-6 group. Fasted for 12 h before administration. The dose administered was 5 mg/kg.
  • Rats were given 0.5 mL of blood from the eyelids at 0 min, 5 min, 15 min, 25 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h after administration, and plasma was taken by centrifugation at 4500 rpm for 10 minutes. Store in a -20 ° C refrigerator.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:

Abstract

本发明涉及有机化学和药物学领域，具体而言，本发明涉及一种新的喜巴辛类似物，所述化合物具有式（Ι）结构，以及式（Ι）化合物的立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物和含有它们的药物组合物，以及其用途。

Description

一种新的喜巴辛类似物及其在医药中的应用 技术领域
本发明涉及有机化学和药物学领域，具体而言，本发明涉及一种新的喜巴辛类似物，所述化合物具有式(Ι)结构，以及式(Ι)化合物的立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物和含有它们的药物组合物，以及其用途。
背景技术
心脑血管事件包括急性冠脉综合征(acute coronary syndrome，ACS)、心肌梗塞、脑血栓等，具有高发病率和高死亡率的特点。世界卫生组织也指出缺血性心脑血管事件是导致死亡的首要因素。目前我国每年有超过300万人死于心脑血管疾病，占全部死亡人数的40.3％。此类疾病的病理原因是由于血小板活化后聚集形成血栓，进而导致机体组织的缺血，因此抗血栓治疗是目前预防心脑血管事件发生的主要方式。
血小板发生黏附后是血小板的活化过程，包括多种自分泌和旁分泌因子的释放，这些因子包括二磷酸腺苷(adenosine diphosphate，ADP)、凝血酶、肾上腺素、血栓烷素A2，它们不仅对血小板的最初反应起信号放大和维持作用，而且使血液循环中的血小板逐渐形成止血栓子。血小板表面结合的多种凝血因子激活促使凝血酶原转化为凝血酶，凝血酶可促进血小板的聚集又可促进纤维蛋白原转化为纤维蛋白，这是促进凝血和止血的主要原因。血小板对凝血酶的反应由血小板表面G蛋白偶联受体，即凝血酶受体介导。进一步研究发现凝血酶受体可被蛋白酶水解所激活，因此凝血酶受体又被称为蛋白酶激活受体(Protease ActivatedReceptors，PARs)。有4种PARs亚型，广泛分布于组织中，PAR-1，PAR-3，PAR-4可被凝血酶激活，PAR-2则被胰蛋白酶或类胰蛋白酶激活。人类血小板只表达PAR-1和PAR-4两种受体，其中PAR-1在凝血酶介导的血小板激活中起着最主要的作用。鼠类血小板表达PAR-1和PAR-3两种受体。
目前已上市的口服抗血栓药物均通过抑制血小板活化途径发挥作用。环氧化酶抑制剂阿司匹林可以抑制血栓烷素A2的产生。噻吩吡啶类药物(如氯吡格雷)可与血小板表面的ADP受体P2Y12产生不可逆结合，从而抑制ADP的血小板活化作用。ADP和血栓烷素A2引起的血小板活化途径对于常规病理性血栓形成和止血都是关键性步骤，因而联合应用环氧化酶抑制剂和噻吩吡啶类药物在发挥抗栓作用的同时，不可避免地导致出血并发症风险的上升。因此尽管抗血小板治疗在目前临床上已取得了较好的效果，但其所带来的出血风险仍值得关注。
由PAR-1介导的血小板活化途径主要对病理性血栓形成有作用。PAR-1受体抑制剂可阻断凝血酶介导的血小板激活而不影响凝血酶介导的纤维蛋白原裂解，同时PAR-1受体抑制剂也不影响参与血小板黏附、激活或聚集途径的相关因子，如胶原，vWF，ADP和促凝血素(参见Coughlin SR.；J Thromb Haemost.,2005,3:1800-1814)，因此PAR-1受体抑制剂既有抗血栓的作用又有可能不会增加出血风险，是理想的抗血小板药物。另外，凝血酶受体拮抗剂还可与阿司匹林、氯吡格雷等联合用药以增加抗血栓作用。凝血酶受体拮抗剂也有希望开发成抗动脉硬化和抗癌的新药。
自凝血酶受体发现以来，许多制药公司都致力于以凝血酶受体为靶点的新药开发研究。目前已经公开了一系列凝血酶受体拮抗剂的专利申请，如WO03089428公开一类喜巴辛衍生物；WO2002085855公开了一种2-亚氨基吡咯烷类衍生物。Merck公司开发的凝血酶受体拮抗剂SCH530348在Ⅲ期临床试验中显示，SCH530348明显降低了心肌梗塞或脑血栓等心血管疾病的发病率，但同时也发现有出血不良反应，尤其是中风、短暂性脑缺血以及脑出血患者，脑颅内出血几率增加，这使得目前凝血酶受体拮抗剂的适用人群大大减少。研发出血副反应更少，疗效更优的新型凝血酶受体拮抗剂仍具有很大挑战。
本发明设计具有通式(I)所示的化合物，本发明化合物同现有技术中具体公开的化合物具有较大的结构差异，且表现出优异的效果和作用。
发明内容
为了克服现有技术的不足之处，本发明的目的是提供具有式(Ι)结构所示的新的喜巴辛类似物，以及它们的立体异构体、互变异构体、或药学上可接受的盐或溶剂化物，或代谢产物和代谢前体或前药，
一种具有式(Ι)结构的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物：
Figure PCTCN2017081449-appb-000001
其中：
R1选自杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步任选的被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步任选的被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
R2选自-C(O)OR3、-CN、-C(O)NR3R4、杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步任选的被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
X选自CH或N；
n选自0、1、2或3，且当n＝0，X＝N时，R2选自杂芳基，其中所述的杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；其中所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的杂环基、芳基或杂芳基可进一步的任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、烷氧基、烷基或环烷基的取代基所取代。
优选的，如式(Ⅱ)结构的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物：
Figure PCTCN2017081449-appb-000002
其中：
R1选自杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、 -NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
式(Ⅱ-1)结构中，R2选自-C(O)OR3、-CN、-C(O)NR3R4、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
式(Ⅱ-2)结构中，R2选自杂芳基；所述的杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、烷氧基、烷基或环烷基的取代基所取代。
最优选的，本发明的典型化合物包括，但不限于：
Figure PCTCN2017081449-appb-000003
Figure PCTCN2017081449-appb-000004
本发明涉及式(Ⅰ)中任何一项化合物或其立体异构体、互变异构体、前药在药学上可接受的盐或溶剂化物，其中药学上可接受的盐为所述化合物与无机酸/有机酸或无机碱/有机碱形成的常规无毒盐，这些盐可以为单盐、二盐、三盐或者多盐，由所述化合物所含的可成盐官能团所决定。其中如果所述式(Ⅰ)化合物含有碱性官能团，则可与硫酸、盐酸、氢溴酸、磷酸、酒石酸、富马酸、马来酸、柠檬酸、乙酸、甲酸、甲磺酸、对甲苯磺酸、草酸或琥珀酸形成酸加成盐，这些盐可以根据常规化学方法从包含碱性官能团的本发明化合物和相应无机酸/有机酸反应合成；如果所述式(Ⅰ)化合物含有酸性官能团，则可与碱性试剂形成稳定的碱金属盐、碱土金属盐或任选取代的铵盐，所述碱性试剂为例如氢氧化物、碳酸盐、碳酸氢盐、烷氧化物和氨或者有机碱，例如三甲基胺、三乙基胺、乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇或其他碱性氨基酸，例如赖氨酸、鸟氨酸或精氨酸等；这些盐可以根据常规化学方法从包含酸性官能团的本发明化合物和相应无机碱/有机碱反应合成。
本发明还涉及所述化合物在药学上可接受的溶剂化物，包括常规溶剂化物，例如本发明所述化合物在制备过程中由于溶剂存在而形成的溶剂化物，由水或者乙醇的存在形成的溶剂化物可以作为非限制性实例。
本发明的另一方面涉及所述式(Ⅰ)结构中任何一项化合物的异构体，式(Ⅰ)结构所述化合物中存在一个或多个碳碳双键，可能存在顺反异构体，没有特殊说明下本发明包含所有可能存在的顺反异构体或者不同比例异构体组成的混合物；同时式(Ⅰ)结构所述化合物中还存在一个或多个手性中心，没有特殊说明下本发明包含所有理论上可能存在的消旋体、消旋体混合物、对映异构体、非对映异构体及非对应异构体混合物。本发明中所述的化学结构式、化学名称包括所述化合物所有理论上可能存在的异构体。
如果式(Ⅰ)所述化合物以非对映异构体或者对映异构体的混合物形式存在或在所选合成中以其混合物形式得到，则式(Ⅰ)所述化合物可按如下方法分离成光学纯立体异构体：在任选手性的载体物质上进行色谱分离，或如果外消旋化合物能够形成盐，则也可与作为助剂的光学活性碱或者光学活性酸形成的非对映异构体盐进行分级结晶。对于非对映异构体薄层色谱分离或者柱色谱的合适手性固定相的实例为改性硅胶载体(成为Pirkle相)和高分子量烃例如三乙酰基纤维素。为了分离式(Ⅰ)所述化合物中含有酸性基团的外消旋体，与光学活性碱例如(-)-烟碱、(+)-和(-)-苯基乙基胺、奎宁碱、L-赖氨酸、L-精氨酸和D-精氨酸形成具有不同溶解度的非对映异构体盐，溶解度较小的组分以固体形式来分离，纯的对映异构体由以上方法得到的非对映异构体盐来得到。式(Ⅰ)所述化合物中含有碱性基团例如氨基的外消旋体可按上述方法用光学活性酸例如(+)-樟脑-10-磺酸、D-和L-酒石酸、D-和L-乳酸、D-和L-扁桃酸转化成纯的对映异构体。
本发明的另一方面涉及式(Ⅰ)所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物的同位素取代物，其中任何一个化合物中可以存在至少一个氢原子被氘原子取代或至少一个碳原子或氟原子被相应的同位素取代。
本发明的另一方面涉及一种药物组合物，其含有式(Ⅰ)中任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物及可药用的载体。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备凝血酶受体拮抗剂的药物中的用途。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备凝血酶受体拮抗剂的药物中的用途，其中凝血酶受体拮抗剂是PAR1受体拮抗剂。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备血小板凝集抑制剂的药物中的用途。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物在制备治疗和/或预防与凝血酶受体有关疾病的药物中的用途，其中所述的与凝血酶受体有关疾病选自动脉和静脉血栓症、急性冠状动脉综合征、再狭窄、稳定型心绞痛、心律紊乱、心肌梗塞、高血压、心衰竭、中风、炎性疾病、肺栓塞症等肺部疾病、胃肠疾病、风湿、哮喘、慢性肝纤维化、肿瘤和皮肤病。
本发明的另一方面涉及式(Ⅰ)中所述任何一项化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或药物组合物和另外一种心血管类药物的产品，作为组合产品同时、或分别用于心血管疾病治疗，其中所述的另一类心血管类药物是选自阿司匹林、氯吡格雷、噻氯匹啶、阿昔单抗、替罗非班或依替巴肽等抗血小板凝集药物。
发明的详述
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
“卤素”指氟、氯、溴、碘。
“烷基”指饱和的脂肪族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至12个碳原子的烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4_二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正癸基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。
“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或未取代的，当被取 代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。优选包括3至12个环原子，其中1～4个是杂原子，更优选环烷基环包含3至10个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等；多环杂环基包括螺环、稠环和桥环的杂环基。
“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。
“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自N、O或S(O)m(其中m是整数0至2)的杂原子，其余环原子为C。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基；杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“芳基”指6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环；芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“杂芳基”指包含1至4个杂原子，5至14个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。优选为6至10元，更优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环；杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自为卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明还包括，含有本发明化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物的药物组合物。
本发明的药物组合物，可以是任何可服用的药物形式：如片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂或贴剂。
本发明的药物组合物，优选的是单位剂量的药物制剂形式。
本发明的药物组合物，在制成药剂时，单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg，其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.01-99.99％。
本发明的组合物在使用时根据病人的情况确定用法用量，如一日1-3次。一次1-10片等。
优选的，本发明的组合物为口服制剂或注射剂。
其中，所述口服制剂选自胶囊剂、片剂、滴丸、颗粒剂、浓缩丸、口服液和合剂中的一种。
其中，所述注射剂选自注射液、冻干粉针剂和水针剂中的一种。
本发明的药物组合物，其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂或湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖或其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮或淀粉衍生物，优选羟基乙酸淀粉钠。适宜的润滑剂为硬脂酸镁。适宜的湿润剂为十二烷基硫酸钠。
本发明的药物组合物可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的组合物中。
口服液体制剂的形式可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，也可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯、对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
本发明的药物组合物，在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体选自如下的一种或几种：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物剂型不完全局限于此，它可以制备成更多的剂型，如滴丸、缓释制剂等任何可服用的药物形式。
具体实施方式
下面通过具体的实施例进一步说明本发明，下述实施例中给出了代表性化合物的合成及相关结构鉴定数据，其用于说明本发明而不是对本发明的限制，根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1：
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c] 呋喃-6-基]氨基乙酸(Ι-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]amino acetic acid(Ι-1)
Figure PCTCN2017081449-appb-000005
第一步：
将化合物1a(30g，0.275mol)和吡啶(32g)加入到300mLDCM中，氮气保护下降温至0℃；滴加三氟甲磺酸酐(93g，0.33mol)，反应体系升至室温；1h后反应体系倒入400mL水中，150mL二氯甲烷萃取，有机相用2N的稀盐酸(100mL)洗一次，饱和食盐水洗一次，干燥浓缩得棕色液体化合物1b(62g，收率93％)。
第二步：
将化合物1b(62g，0.257mol)、1c(43.2g，0.308mol)、碳酸钾(106g，0.77mol)、Pd(PPh3)4依次加入到400mL甲苯中，氮气置换3次，将体系温度升至90℃，回流反应6h；体系降至室温后，倒入400mL水中，体系经硅藻土过滤，滤液经水洗一次，饱和食盐水洗一次，干燥浓缩得145g棕色液体；粗品经柱层析纯化(PE:EA＝20：1)，浓缩得棕色液体化合物1d(42g，收率87％)。
第三步：
氮气保护下，将正丁基锂滴加到-40℃的二异丙胺THF(280mL)溶液中，-30℃反应1.5h；将1d(48g，0.256mol)溶于500mL THF中，氮气保护下，降温至-60℃，将上述LDA滴加到该体系中，-60℃保温反应1h；将1e(53g，0.308mol)滴加到体系中，-50℃反应1.5h；将体系倒入1L的饱和氯化铵中，水相用乙酸乙酯(400mL×2)萃取，合并有机相，浓缩干得红棕色液体，经柱层析纯化(DCM:MeOH＝50:1)，得红棕色液体化合物1f(38g，收率79.7％)。
第四步：
N2保护下，0℃，将LHMDS的THF滴加到1f(600mg，1.8mmol)的THF(6mL)溶液中，加毕，保温30min；将Ti(i-OPr)4的THF(1mL)滴加到体系中，反应10min；将1g【合成方法见Bioorganic&Medicinal Chemistry Letters，20，2010，6676】(200mg，0.61mmol)的THF(1.5mL)滴加到体系中，然后恢复至室温反应3h；向体系中加入20mL饱和酒石酸钾钠的水溶液，乙酸乙酯萃取，干燥旋干有机相。后经柱色谱纯化得淡白色固体1h(130mg，收率22％)。
第五步：
室温下将1h(0.8g，1.6mmol)溶于浓盐酸中，升至120℃反应3小时；旋干得化合物1i，并直接投入下一步。
第六步：
室温下，N2保护，将TEA加入到1i(200mg，0.43mmol)的MeOH中，室温反应15min；向体系中加入乙醛酸水溶液(65mg，0.43mmol)，室温反应30min；向体系中加入NaBH3CN(28mg，0.43mmol)，室温反应1h；向体系中加入少量的水-甲醇淬灭，直接浓缩旋干，薄层色谱制备(MeCN:H2O＝5:1)，浓缩得淡黄色固体化合物I-1(50mg，收率24％)。
1H NMR(DMSO,400MHz):δ8.65(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]+
实施例2：
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]氨基乙腈(Ι-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]amino acetonitrile(Ι-2)
Figure PCTCN2017081449-appb-000006
室温下，将1i(0.39g，0.92mmol)、溴乙腈(0.14g，1.21mmol)、DIPEA(0.36g，2.78mmol)加入到乙腈中，氮气保护下40℃反应5h；反应体系中加入饱和100mLNaHCO3溶液，乙酸乙酯萃取，有机相浓缩干燥得0.185g粗产品；经薄层色谱纯化(DCM:MeOH＝15:1)后得白色固体I-2(60mg，收率25％)。
1H NMR(DMSO,400MHz):δ8.78(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]+
实施例3：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]-N-(4-甲基嘧啶基-2)-氨(Ι-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)
Figure PCTCN2017081449-appb-000007
将1i(150mg，0.36mmol)、3a(92mg，0.71mmol)、DIPEA(1mL)加入至5mLDMSO中，N2保护 下，加热至150℃反应10h；反应体系降至室温，加入20mL水析出固体，过滤，滤饼用水洗，得白色固体Ι-3(40mg，收率21.9％)。
1H NMR(DMSO,400MHz):δ8.70(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]+
实施例4：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-氟苯)-2-吡啶基]-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]-N–(苯并恶唑基-2)-氨(Ι-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)
Figure PCTCN2017081449-appb-000008
室温下，将1i(110mg，0.26mmol)、4a(80mg，0.52mmol)、碳酸钾(69mg，0.52mmol)加入至10mL DMF中，N2保护下，加热至100℃反应10h；反应体系降至室温，加入20mL水，乙酸乙酯(20mL×2)萃取，合并有机相，干燥浓缩后经高压制备色谱纯化得到白色固体Ι-4(29mg，收率20.7％)。
1H NMR(DMSO,400MHz):δ8.82(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]+
实施例5:N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-(3’-氟-1,1’-联苯基)-4-乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]氨基甲酸乙酯(Ι-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 acid ethyl ester(Ι-5)
Figure PCTCN2017081449-appb-000009
第一步：
0℃下，将NaH(139mg，2.7mmol)加入到5a(1.78g，2.7mmol)的10mLTHF溶液中，继续反应1h；滴加1g(450mg，1.38mmol)的THF(10mL)溶液，升至室温反应2h；体系用饱和NH4Cl水溶液淬灭，乙酸乙酯萃取，有机相干燥浓缩后得化合物5b直接用于下一步。
第二步：
室温下，将5c(0.48g，3.4mmol)、Pd(PPh3)4(140mg，0.7mmol)加入到5b(0.66g，1.3mmol)的甲苯-EtOH-Na2CO3水溶液(10mL-5mL-5mL)的混合液中，N2保护升温到85℃过夜；向体系中加入50mL水，乙酸乙酯萃取，合并有机相，干燥浓缩后经硅胶柱色谱纯化得白色固体Ι-5(100mg，收率15.6％)。
1H NMR(DMSO,400MHz):δ8.65(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]+
实施例6：N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-4-(2-吡啶基)-苯乙烯基]十二氢-1-甲基-3-氧代萘并[2,3-c]呋喃-6-基]氨基甲酸乙酯(Ι-6)
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[4-(pyridin-2-yl)-phenyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]carbamic acid ethyl ester(Ι-6)
Figure PCTCN2017081449-appb-000010
0℃下，Ar保护，将n-BuLi滴加到6a(590mg，1.9mmol)的THF(6mL)溶液中，并在0℃下反应30min；向体系滴加1g(250mg，0.77mmol)的THF(6mL)溶液，反应1h；饱和NH4Cl水溶液淬灭反应，乙酸乙酯萃取，有机相浓缩干燥后经硅胶柱色谱纯化(PE:EA＝1:2)得白色固体I-6(140mg，收率38.2％)。
1H NMR(DMSO,400MHz):δ8.69(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]+
生物测试例1：钙离子转运抑制实验
下面所述的模型表明本发明所述化合物是PAR-1受体抑制剂。在各种细胞类型中，通过选择性PAR-1激动剂激活PAR-1受体触发细胞内信号通路导致内质网释放钙离子。在表达人类PAR1的KNRK细胞系中，使用钙离子选择性探针通过荧光技术测定通过SFLLR激活的对受体里的钙释放。荧光的发射强度与PAR-1拮抗剂的活性和浓度成正比。该方法可以测定本发明化合物对PAR-1介导的钙离子转运的影响。
一、实验材料：
试剂：HBSS缓冲液，HEPES，probenecid，BSA，Calcium4dye购自Invitrogen。TFLLR-NH2，SCH-79797等试剂由法国SEREP公司提供。
细胞系：稳定表达人类PAR1的KNRK细胞系。
荧光显微镜：CellLux(PerkinElmer)。
化合物I-1～I-6：由天士力制药集团股份有限公司研究院提供。
缓冲液与原液配制：
Assaybuffer：1×HBSS缓冲液，配制成含20mM HEPES，2.5mMprobenecid，0.1％BSA，PH＝7.4(probenecid与BSA需要新鲜配制)的缓冲液；
Loadingbuffer：1×HBSS缓冲液，配制成含20mM HEPES，2.5mMprobenecid，0.1％BSA，PH＝7.4 (probenecid与BSA需要新鲜配制)，2μM calcium 4dye的缓冲液；
化合物原液(5×CPD)：首先用100％DMSO溶解化合物，使化合物终浓度为10mM。实验时，将上述原液用assaybuffer配制成5倍浓度溶液备用；
6×TFLLR-NH2：用assaybuffer将haTRAP稀释成终浓度为30uM备用。
反应终体积：20uL loading buffer，5uL 5×CPD，5uL 6×TFLLR-NH2(haTRAP，终浓度为5uM)。
二、实验步骤：
1、预先用1倍Matrigel处理无菌384孔板，37℃放置15-30min；
2、将上述处理好的无菌384孔板的每孔中加入2×104个稳定表达人类PAR1的KNRK细胞，细胞培养箱中培养24小时；
3、将384孔板中的细胞培养液去除，加入20uL含Calcium4dye的loadingbuffer；
4、在培养箱中避光培养60min；
5、然后再培养孔中加入5uL 5倍化合物原液(DMSO的终浓度为1％)，继续培养15min，然后加入5uL6倍TFLLR-NH2，在荧光显微镜下记录荧光强度100秒。
6、实验结果中抑制剂活性表示为抑制剂在不同浓度下的荧光强度占空白对照haTRAP激发荧光强度的百分比。测试化合物对PAR-1的抑制率按以下公式计算：IR＝(FNC-FTC)/FNC％
FNC:阴性对照组孔的荧光强度
FTC:测试化合物孔的荧光强度
在10μM浓度下，钙信号拮抗作用>60％，本发明的衍生物被鉴定为PAR-1受体拮抗剂。
7、测试化合物的半数抑制浓度IC50可以通过不同浓度下的抑制率计算得出。
三、实验结果：
本发明化合物不同浓度下对PAR-1受体的抑制率如下：
Figure PCTCN2017081449-appb-000011
本发明化合物的半数抑制浓度IC50测定如下：
Figure PCTCN2017081449-appb-000012
结论：本发明测试化合物对PAR-1介导的钙离子转运具有明显的抑制作用，钙信号拮抗作用IC50在0.18～2.1μM范围内，活性优于或近似于上市药物SCH530348，本发明所述化合物被鉴定为PAR-1受体拮抗剂。
生物测试例2：本发明化合物的药代动力学测试
研究本发明实施例I-2、I-3、I-6化合物不同时刻血浆及脑组织中的药物浓度，研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
1.实验动物
健康成年SD大鼠8只，雌雄各半，平均分成4组。购买于北京维通利华实验动物技术有限公司。
2.给药剂量
本研究为单剂量给药实验。8只SD大鼠雌雄各半，平均分成4组，每组2只，分别为SCH530348组、I-2组、I-3组、I-6组。给药前禁食12h。给药剂量为5mg/kg。
3.药物配制
称取适量药物，加入0.5％羧甲基纤维素钠研磨至样品均匀混悬，样品浓度为2.0mg/ml，临用时配制。
4.采血方案
大鼠给药后0min，5min，15min，25min，40min，1h，2h，4h，8h，12h，24h眼眶取血0.5mL，于4500rpm离心10分钟取血浆。-20℃冰箱保存。
5.样品制备
取血浆样品50uL，加入20uL1ug/ml的地西泮内标溶液，再加入10uL甲醇，400uL的乙酸乙酯，充分涡旋3min后，17000r/min离心10min，取上清300uL，氮吹吹干后，用100uL的甲醇：水＝1:1复溶，充分涡旋1min后直接进样进行LC-MS分析。
本发明化合物的药代动力学参数如下表：
Figure PCTCN2017081449-appb-000013
结论：本发明化合物I-2和I-6化合物在体内的半衰期和血药浓度均优于已上市药物SCH530348，并且I-2和I-6化合物在脑组织/血浆中的药物浓度比值要远远小于SCH530348，提示本发明化合物I-2和I-6穿越血脑屏障能力更弱，脑出血的风险可能会大大减小，具有更好的临床应用前景。

Claims (15)

  1. 一种具有式(Ι)结构的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物：
    Figure PCTCN2017081449-appb-100001
    其中：
    R1选自杂环基、芳基或杂芳基；
    R2选自-C(O)OR3、-CN、-C(O)NR3R4、杂环基、芳基或杂芳基；
    X选自CH或N；
    n选自0、1、2或3，且当n＝0，X＝N时，R2选自杂芳基；
    R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，其特征在于，
    R1选自杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
    R2选自-C(O)OR3、-CN、-C(O)NR3R4、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
    X选自CH或N；
    n选自0、1或2，且当n＝0，X＝N时，R2选自杂芳基，所述的杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
    R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、烷氧基、烷基或环烷基的取代基所取代。
  3. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，其特征在于，该化合物优选自：
    Figure PCTCN2017081449-appb-100002
    其中：
    R1选自杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
    式(Ⅱ-1)结构中，R2选自-C(O)OR3、-CN、-C(O)NR3R4、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
    式(Ⅱ-2)结构中，R2选自杂芳基；所述的杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、杂环基、芳基、杂芳基、-C(O)OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4的取代基所取代；所述的烷氧基、烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、-NR3R4、烷氧基、烷基、环烷基、芳基、杂芳基的取代基所取代；
    R3和R4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，所述的杂环基、芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、硝基、胺基、烷氧基、烷基或环烷基的取代基所取代。
  4. 根据权利要求1、2、3所述的化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，其特征在于，该化合物选自：
    Figure PCTCN2017081449-appb-100003
  5. 根据权利要求1所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，其特征在于，所述化合物的异构体包含所有理论上可能存在的顺反异构体、顺反异构体混合物、外消旋体、消 旋体混合物、对映异构体、非对映异构体及非对应异构体混合物。
  6. 根据权利要求1所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，其特征在于，所述化合物中可以存在至少一个氢原子被氘原子取代或至少一个碳原子或氟原子被相应的同位素取代。
  7. 根据权利要求1所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，其特征在于，所述化合物药学上可接受的盐为所述化合物与无机酸/有机酸或无机碱/有机碱形成的常规无毒盐。
  8. 一种药物组合物，其特征在于，含有权利要求1-7任意一项所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物及可药用的载体。
  9. 权利要求1-7任意一项所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或权利要求8所述药物组合物在制备凝血酶受体拮抗剂的药物中的用途。
  10. 根据权利要求9所述的用途，其特征在于，所述的凝血酶受体拮抗剂是PAR1受体拮抗剂。
  11. 权利要求1-7任意一项所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或权利要求8所述药物组合物在制备血小板凝集抑制剂的药物中的用途。
  12. 权利要求1-7任意一项所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，或权利要求8所述药物组合物在制备治疗和/或预防与凝血酶受体有关疾病的药物中的用途。
  13. 根据权利要求12所述的用途，其特征在于，所述的与凝血酶受体有关疾病选自动脉和静脉血栓症、急性冠状动脉综合征、再狭窄、稳定型心绞痛、心律紊乱、心肌梗塞、高血压、心衰竭、中风、炎性疾病、肺栓塞症等肺部疾病、胃肠疾病、风湿、哮喘、慢性肝纤维化、肿瘤和皮肤病。
  14. 权利要求1-7任意一项所述化合物或其立体异构体、互变异构体、前药或药学上可接受的盐或溶剂化物，和另外一种心血管类药物作为组合产品同时、或分别用于制备治疗心血管疾病的药物中的用途。
  15. 根据权利要求14所述的用途，其特征在于，所述的另一类心血管类药物选自阿司匹林、氯吡格雷、噻氯匹啶、阿昔单抗、替罗非班或依替巴肽等抗血小板凝集药物。
PCT/CN2017/081449 2016-04-22 2017-04-21 一种新的喜巴辛类似物及其在医药中的应用 WO2017181993A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610257993 2016-04-22
CN201610257993.X 2016-04-22

Publications (1)

Publication Number Publication Date
WO2017181993A1 true WO2017181993A1 (zh) 2017-10-26

Family

ID=60115718

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/081449 WO2017181993A1 (zh) 2016-04-22 2017-04-21 一种新的喜巴辛类似物及其在医药中的应用

Country Status (3)

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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110559294A (zh) * 2018-06-06 2019-12-13 杨仑 脂肪性肝病及其相关疾病的预防和治疗性药物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659162A (zh) * 2002-04-16 2005-08-24 先灵公司 三环凝血酶受体拮抗剂
CN1878552A (zh) * 2003-11-10 2006-12-13 先灵公司 凝血酶受体拮抗剂的使用方法
CN101384259A (zh) * 2005-12-22 2009-03-11 先灵公司 作为预防来自心肺外科手术的并发症的凝血酶受体拮抗剂
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 (zh) * 2002-04-16 2005-08-24 先灵公司 三环凝血酶受体拮抗剂
CN1878552A (zh) * 2003-11-10 2006-12-13 先灵公司 凝血酶受体拮抗剂的使用方法
CN101384259A (zh) * 2005-12-22 2009-03-11 先灵公司 作为预防来自心肺外科手术的并发症的凝血酶受体拮抗剂
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

Also Published As

Publication number Publication date
TW201738221A (zh) 2017-11-01
CN107304200B (zh) 2021-09-21
CN107304200A (zh) 2017-10-31

Similar Documents

Publication Publication Date Title
ES2858312T3 (es) Agonistas del receptor de apelina y métodos de uso
CN105793253B (zh) 自分泌运动因子抑制剂化合物
WO2020259679A1 (zh) 嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用
ES2376161T3 (es) Indoles sustituidos y su utilización como antagonistas de integrinas.
JP2021519766A (ja) ＸＩＩａ因子インヒビター
JP2021523887A (ja) ＸＩＩａ因子インヒビター
JP6676541B2 (ja) 置換された４−フェニルピペリジン、その調製及び使用
KR20140040774A (ko) 이미다조피리딘 화합물
CN103097340A (zh) 治疗活性组合物及其使用方法
AU2014234909B2 (en) Acyclic cyanoethylpyrazolo pyridones as Janus kinase inhibitors
JP6670913B2 (ja) 白血病を予防および治療するためのマレイミド誘導体の使用
TW202003472A (zh) 鈣蛋白酶(calpain)調節劑及其醫療用途
TW201514150A (zh) 組蛋白去乙醯酶抑制劑及組成物，暨其使用之方法
CN102066322A (zh) 具有npy y5受体拮抗作用的化合物
JP2013525445A (ja) イミダゾピリダジニル化合物および癌に対するそれらの使用
ES2222576T3 (es) Nueva quinolina- y naftalenocarboxamidas, composiciones farmaceuticas y procedimientos que inhiben el calpain.
JPH09506880A (ja) アネレーションされたジヒドロピリジン及び医薬製剤を調製するためのその使用
CA3152508A1 (en) Perk inhibiting pyrrolopyrimidine compounds
JP7282743B2 (ja) 複素環化合物
CN107304200B (zh) 一种新的喜巴辛类似物及其在医药中的应用
CN107304199B (zh) 一种新的喜巴辛类似物及其在医药中的应用
JP2007262022A (ja) 新規２−チオフェンカルボキサミド誘導体
JP7370032B2 (ja) Ｐａｒｒ阻害剤としてのキナゾリン―２．４―ジオン誘導体
CN104530046B (zh) 二氮杂螺类化合物及其在药物中的应用
JP6407257B2 (ja) アルキニルインダゾール誘導体及びその用途

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17785477

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17785477

Country of ref document: EP

Kind code of ref document: A1