WO2016011940A1 - Dérivé d'indole-amide, son procédé de préparation et son application en médecine - Google Patents

Dérivé d'indole-amide, son procédé de préparation et son application en médecine Download PDF

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Publication number
WO2016011940A1
WO2016011940A1 PCT/CN2015/084751 CN2015084751W WO2016011940A1 WO 2016011940 A1 WO2016011940 A1 WO 2016011940A1 CN 2015084751 W CN2015084751 W CN 2015084751W WO 2016011940 A1 WO2016011940 A1 WO 2016011940A1
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group
compound
cycloalkyl
enantiomer
formula
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PCT/CN2015/084751
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English (en)
Chinese (zh)
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杨方龙
瞿健
王春飞
董庆
孙飘扬
应永铖
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201580002260.5A priority Critical patent/CN105658641B/zh
Publication of WO2016011940A1 publication Critical patent/WO2016011940A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel class of nitrogen hydrazine-amide derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same, and their use as therapeutic agents, in particular as XIa factor inhibitors, and in the preparation of treatment and/or prevention Use in drugs for diseases such as thromboembolism.
  • cardiovascular and cerebrovascular diseases such as cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease and arteriosclerosis take nearly 12 million lives, which is close to 1/4 of the world's total death toll, becoming the number one enemy of human health.
  • the number of people dying from cardiovascular disease in China each year is more than 2.6 million, and 75% of surviving patients are disabled, and more than 40% of them are severely disabled.
  • the problem of thrombosis caused by cardiovascular and cerebrovascular diseases and diabetes and its complications has become an urgent problem to be solved today.
  • the human coagulation system contains two processes: the intrinsic pathway and the extrinsic pathway and a common pathway (Annu. Rev. Med. 2011. 62: 41-57).
  • the exogenous pathway also known as the tissue factor pathway, acts as a foreign pathway, and under the injury and various external stimuli, the tissue activator and activated factor VIIa (FVIIa) constitute a complex of activator X (FX), forming factor Xa.
  • FXa tissue activator and activated factor VIIa
  • activated FXa can convert prothrombin (PT) into thrombin, which acts as a central catalytic enzyme in the coagulation process, catalyzing the formation of fibrin by fibrinogen and acting as a coagulation.
  • the process involves fewer enzymes and is quicker.
  • the endogenous pathway belongs to the body's intrinsic pathway, and all the factors involved in blood coagulation come from the blood.
  • the cascade activates factor XII (FXII), factor XI (FXI), and factor IX (FIX), which in turn activates FXa to downstream prothrombin ( PT) is converted to thrombin, which in turn activates FXI.
  • FXII factor XII
  • FXI factor XI
  • FIX factor IX
  • FXI and FXIa play an extremely important role throughout the coagulation process.
  • antagonists As a co-regulator of exogenous and endogenous coagulation pathways, antagonists have been widely developed for the treatment of various thrombi.
  • a variety of FXa antagonists have been marketed, and their significant effectiveness has occupied the majority of cardiovascular and cerebrovascular markets. However, their side effects have become more and more significant. Among them, "bleeding risk" is the most serious problem (N Engl J Med 1991; 325: 153-8, Blood. 2003; 101: 4783-4788).
  • BMS-654457 shows a significant dose-dependent potential efficacy in a rabbit model of experimental arterial thrombosis induced by direct current stimulation, with no bleeding side effects (22nd Int Symp Med Chem (Sept 2-6, Berlin) 2012, Abst L63).
  • the pharmacokinetic data of BMS-262084 showed that the compound as a FXIa inhibitor significantly improved the experimental model of thrombosis, and its side effects were extremely small (J Thromb Thrombolysis (2011) 32: 129-137).
  • the object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof.
  • Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl;
  • Ring B is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • R 1 each being the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group or -C(O)R 4 , wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl or cycloalkane. Substituted by a substituent of the group;
  • R 2 is selected from a hydrogen atom, a halogen or an alkyl group
  • R 3 is each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • Base -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O NHR 4 or -NHC(O)NHOR 4 ;
  • R 4 is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, Substituted by a hydroxyalkyl group, a cycloalkyl group, a substituent of -OC(O)OR 5 or -NR 5 R 6 ;
  • R 5 or R 6 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group;
  • n 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein ring A is selected from the group consisting of:
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein each R 1 is the same or different and each independently selected from halogen, heteroaryl or -C(O)R 4 , wherein R 4 is as defined (I) stated.
  • a compound of the formula (I) or tautomerized thereof a form, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • R 2 is a hydrogen atom
  • R 3 is selected from a hydrogen atom, an aryl group, -C(O)OR 4 or -NHC(O)OR 4 ;
  • R 4 is selected from a hydrogen atom or an alkyl group, and the alkyl group is optionally further substituted with one or more -OC(O)OR 5 ;
  • R 5 is selected from a hydrogen atom, an alkyl group or a cycloalkyl group.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A, R 1 , R 2 , R 3 , m and n are as defined in formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 are each the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • q 0, 1 or 2;
  • Rings A, R 2 , R 3 and n are as defined in formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • R 8 or R 9 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O)NHR 4 or -NHC (O) NHOR 4 ;
  • R 4 is as defined in the general formula (I);
  • q 0, 1, or 2.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 is each the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • Ring C is selected from heteroaryl, aryl, heterocycloalkyl or cycloalkyl, preferably 5- or 6-membered heteroaryl, aryl, heterocycloalkyl or cycloalkyl, more preferably 5 or 6 Heterocycloalkyl;
  • R 10 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O)NHR 4 or -NHC (O) NHOR 4 ; preferably halogen, oxo, -C(O)OR 4 , -C(O)R 4 , -NHC(O
  • R 4 is as defined in the general formula (I);
  • Each of p and q is independently selected from 0, 1, or 2.
  • a typical compound of the formula (I) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Medicinal salts including but not limited to:
  • Another aspect of the invention provides a compound of the formula (IIIC) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof or a mixture, or a pharmaceutically acceptable salt thereof, which can be used to prepare a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer An intermediate of the isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl;
  • R 2 is selected from a hydrogen atom, a halogen or an alkyl group
  • R 3 is each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • R 4 is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkane. Substituted by a substituent of a cycloalkyl group, -OC(O)OR 5 or -NR 5 R 6 ;
  • R 5 or R 6 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group;
  • R 7 is each the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • q 0, 1, or 2
  • n 0, 1, or 2.
  • Another aspect of the invention provides a compound of the formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof or a method of the mixture, or a pharmaceutically acceptable salt thereof, the method comprising:
  • the first step is a condensation reaction of a compound of the formula (IIIA) with a compound of the formula (IIIB) to obtain a compound of the formula (IIIC), and a second step of the compound of the formula (IIIC) obtained by a ring-forming reaction to obtain a formula ( III) a compound;
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and excipient.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a prophylactic and/or therapeutic cardio-cerebral vascular disease, preferably a thromboembolic disease, more preferably an acute heart attack, angina pectoris, angioplasty Re-occlusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis after surgery or aortic coronary shunt.
  • a prophylactic and/or therapeutic cardio-cerebral vascular disease preferably a thromboembolic disease, more preferably an acute heart attack, angina pectoris, angioplasty Re-occlusion and restenosis, stroke, transient ischemic attack, peripheral arterial
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for preventing and/or treating a disease which is positively affected by inhibition of factor XIa; for use in the preparation of a medicament for treating disseminated intravascular coagulation And the use in the preparation of a medicament for inhibiting factor XIa.
  • Another aspect of the invention relates to a method of modulating factor XIa activity, preferably inhibiting factor XIa, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • a compound of formula (I) or a tautomer thereof A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a method of treating and/or preventing cardiovascular and cerebrovascular diseases, the method comprising A therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, administered to a subject in need thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the disease described therein is preferably a thromboembolic disease, more preferably re-occlusion and restenosis after arrhythmia, angina pectoris, or aortic coronary artery bypass, stroke, transient ischemic attack, peripheral arterial occlusion Disease, pulmonary embolism or deep vein thrombosis.
  • Another aspect of the invention relates to a method of preventing and/or treating a disease which is positively affected by inhibition of factor XIa, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof.
  • a compound of formula (I) or a tautomer thereof An isomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a method of treating a disseminated intravascular coagulopathy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, mesogenic a form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of cardiovascular and cerebrovascular diseases, preferably thromboembolic diseases, more preferably cardiac arrest, angina pectoris, angioplasty or aortic coronary artery shunt Postoperative reocclusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.
  • cardiovascular and cerebrovascular diseases preferably thromboembolic diseases, more preferably cardiac arrest, angina pectoris, angioplasty or aortic coronary artery shunt Postoperative reocclusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for preventing and/or treating a disease which is positively affected by inhibition of factor XIa; for treating disseminated intravascular coagulation; and for inhibiting factor XIa activity.
  • Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 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-dimethylbutyl, 2,2-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,
  • 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 alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
  • 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 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring to form a "fused cycloalkyl" wherein the ring to which the parent structure is attached is a cycloalkyl group.
  • Non-limiting examples include tetrahydronaphthyl, benzocycloheptyl,
  • 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 nitrogen, oxygen or S(O) m ( Wherein m is a hetero atom of 0 to 2, but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the heterocyclic ring comprises 3 to 12 ring atoms, wherein 1 to 4 are hetero atoms; more preferably, the heterocyclic ring contains 3 to 10 ring atoms, of which 1 to 3 are hetero atoms; more preferably, the heterocyclic ring contains 5 to 6 ring atoms, of which 1 to 2 are heteroatoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring to form a "fused heterocyclic group" wherein the ring to which the parent structure is attached is a heterocyclic group.
  • Non-limiting examples include:
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably benzene.
  • the base and naphthyl are most preferably phenyl.
  • the aryl ring may be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring to form a "fused aryl" wherein the ring to which the parent structure is attached is an aryl ring, unrestricted
  • the sexual embodiment includes:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • Base amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O)NHR 4 or -NHC(O)NHOR 4 ; wherein R 4 is as defined in the compound of formula (I).
  • Heteroaryl refers to a 5 to 14 membered aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan.
  • the heteroaryl group is preferably 5 or 6 members, and preferred examples include, but are not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl , pyridazinyl and the like.
  • the heteroaryl ring may be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring to form a "fused heteroaryl" wherein the ring to which the parent structure is attached is a heteroaryl ring
  • Non-limiting examples include:
  • the heteroaryl 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 alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O) R 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 or —NHC(O)NHOR
  • Haloalkyl means that the alkyl group is substituted by one or more halogens, wherein the alkyl group is as defined above.
  • Hydrophilicity refers to an -OH group.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxylic acid group means -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • 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.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “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 compound of the formula (IIIA) and the compound of the formula (IIIB) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (IIIC), and the second step is a compound of the formula (IIIC).
  • a sodium azide, trimethyl orthoformate is subjected to a ring-forming reaction under glacial acetic acid to obtain a compound of the formula (III);
  • the ring A, n, q, R 2 , R 3 or R 7 is as defined in the formula (III).
  • the compound of the formula (IVA) and the compound of the formula (IVB) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (IVC), and the second step is a compound of the formula (IVC).
  • the ring-forming reaction is carried out with sodium azide and trimethyl orthoformate under glacial acetic acid to obtain a compound of the formula (IV);
  • R 2 , q, R 7 to R 10 are as defined in the formula (IV).
  • the first step reaction is a compound of the formula (VA) and a compound of the formula (VB) which are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (VC), and the second step is a compound of the formula (VC).
  • the ring-forming reaction is carried out with sodium azide and trimethyl orthoformate under glacial acetic acid to obtain a compound of the formula (V);
  • the reagent for providing basic conditions includes an organic base and an inorganic base, and the organic base includes, but not limited to, 1-hydroxybenzotriazole, triethylamine, N,N-diisopropyl.
  • the inorganic bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
  • Condensing agents include, but are not limited to, bicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide Amine, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzoate Triazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azo Benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Or
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR chemical shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone System, D: ethyl acetate and dichloromethane system, E: ethyl acetate and dichloromethane and n-hexane, F: ethyl acetate and dichloromethane and acetone, the volume ratio of the solvent is different depending on the polarity of the compound Adjustment, can also be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine and acetic acid.
  • Methyl 6-amino-1H-indole-2-carboxylate 200 mg, 1 mmol, prepared by the method disclosed in the patent application "WO 2012101013"
  • (S)-7-(2-amino-5-chloro Phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b 304 mg, 1 mmol
  • 1-hydroxybenzotriazole 150 mg, 1.1 mmol
  • bicyclo Hexylcarbodiimide 220 mg, 1.1 mmol was dissolved in 3 mL of N,N-dimethylformamide and stirred at room temperature for 4 hours.
  • the obtained residue was purified by silica gel column chromatography elutd elut elut elut elut elut elut elut elut elut elut elut elut elut 1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,5-tetrahydroindolizine-3-carboxamide 7b (100 mg, pale yellow solid), yield: 55.0% .
  • Tetramethylethylenediamine (12.5 mL, 82.8 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -78 °C with argon.
  • n-Butyllithium (33.4 mL, 82.8 mmol, 2.5 M in tetrahydrofuran) was added dropwise to the above reaction mixture. After the completion of the dropwise addition, stirring was continued at 78 ° C for 1 hour.
  • Methyl 5-amino-1H-indole-2-carboxylate 1a (76 mg, 0.4 mmol), (S)-7-(2-acetyl-5-chlorophenyl)-5-oxo-1, 2,3,5-tetrahydroindolizine-3-carboxylic acid 10b (132 mg, 0.4 mmol), 1-hydroxybenzotriazole (65 mg, 0.48 mmol), dicyclohexylcarbodiimide (99 mg, 0.48 mmol) Dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 16 hours.
  • Examples 11-26 were synthesized according to the synthesis method of Examples 1-10 of the present invention using different starting materials.
  • the spectral parameters of Examples 11-26 are shown in Table 2 below:
  • the experimental method in which the specific conditions are not indicated in the test examples of the present invention is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer of the product.
  • Reagents without specific source are routine reagents purchased from the market.
  • Test Example 1 Fluorometric detection of biological activity of factor XIa inhibitor
  • Buffer 100 mM tris-HCl, 200 mM NaCl, 0.02% tween 20, pH 7.4.
  • Example 27 Compound number IC 50 (factor XIa) / (nM) Example 2 6.4 Example 3 284.5 Example 4 17.2 Example 5 20.1 Example 7 60.6 Example 8 25.3 Example 9 12.5 Example 11 57.2 Example 15 96.6 Example 18 214.0 Example 20 290.4 Example 21 34.3 Example 24 70.7 Example 25 132.9 Example 27 132.7
  • the compounds of the present invention have significant inhibitory activity against factor XIa.
  • Test Example 2 Determination of anticoagulant effect in human blood in vitro
  • Plasma human blood was collected in a blood collection tube containing no anticoagulant, adding 3.8% sodium citrate (volume ratio 1:9), centrifuged at 2500 rpm for 10 min at room temperature, and the plasma was collected and stored at -80 ° C;
  • APTT reagent activated partial thromboplastin time assay kit, SIEMENS, item number B4218-1
  • PT reagent prothrombin time assay kit, SIEMENS, item number OUHP29
  • calcium chloride solution calcium chloride solution
  • the divided plasma was melted at room temperature and mixed evenly. 10000 uM test compound dissolved in 100% DMSO was diluted to 3000, 300, 200, 150, 75, 30, 10, 3, 0.3 uM with 100% DMSO and the blank was 100% DMSO. The reagent, plasma, and compound are placed in the corresponding positions in the coagulation instrument, and the APTT and PT of the compound are detected.
  • Example 2 Compound number Inhibition of platelet aggregation CT 2 ( ⁇ M) Example 2 1.83 Example 5 36.58 Example 8 21.71 Example 9 3.84 Example 24 10.74
  • the compounds of the present invention have significant inhibitory activity against human blood agglutination.
  • Test Example 3 Pharmacokinetic Testing of Compounds of the Inventive Examples
  • SD rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compounds of Examples 1 and 2 by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • PEG polyethylene glycol
  • CMC-Na sodium carboxymethyl cellulose
  • the rats in the gavage administration group collected blood at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h before and after the administration.
  • 0.2 ml was placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 min, and stored at -20 °C.
  • the content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.

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Abstract

La présente invention concerne un dérivé d'indole-amide, son procédé de préparation et son application en médecine. Plus particulièrement, la présente invention concerne un dérivé d'indole-amide représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le dérivé, son utilisation en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur du facteur XIa, et son utilisation dans la préparation de médicaments pour le traitement et/ou la prévention de maladies telles qu'une thromboembolie, la définition des substituants dans la formule générale (I) étant la même que celle dans la description.
PCT/CN2015/084751 2014-07-25 2015-07-22 Dérivé d'indole-amide, son procédé de préparation et son application en médecine WO2016011940A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039094A1 (fr) 2016-08-22 2018-03-01 Merck Sharp & Dohme Corp. Dérivés de pyridine-1-oxyde et leur utilisation en tant qu'inhibiteurs du facteur xia
JP2020012004A (ja) * 2014-12-10 2020-01-23 小野薬品工業株式会社 ジヒドロインドリジノン誘導体
JP2021514944A (ja) * 2018-02-27 2021-06-17 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． オキソピコリナミド誘導体の結晶形及びそれらの製造方法
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)

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CN1222909A (zh) * 1996-04-23 1999-07-14 麦克公司 吡嗪酮凝血酶抑制剂
WO2008079787A2 (fr) * 2006-12-20 2008-07-03 Takeda San Diego, Inc. Activateurs de glucokinase
WO2013093484A1 (fr) * 2011-12-21 2013-06-27 Ono Pharmaceutical Co., Ltd. Dérivés de pyridinone et de pyrimidinone comme inhibiteurs du facteur xia
WO2015120777A1 (fr) * 2014-02-14 2015-08-20 四川海思科制药有限公司 Dérivé de pyrimidone ou de pyridone, procédé de préparation associé et application correspondante

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1222909A (zh) * 1996-04-23 1999-07-14 麦克公司 吡嗪酮凝血酶抑制剂
WO2008079787A2 (fr) * 2006-12-20 2008-07-03 Takeda San Diego, Inc. Activateurs de glucokinase
WO2013093484A1 (fr) * 2011-12-21 2013-06-27 Ono Pharmaceutical Co., Ltd. Dérivés de pyridinone et de pyrimidinone comme inhibiteurs du facteur xia
WO2015120777A1 (fr) * 2014-02-14 2015-08-20 四川海思科制药有限公司 Dérivé de pyrimidone ou de pyridone, procédé de préparation associé et application correspondante

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020012004A (ja) * 2014-12-10 2020-01-23 小野薬品工業株式会社 ジヒドロインドリジノン誘導体
WO2018039094A1 (fr) 2016-08-22 2018-03-01 Merck Sharp & Dohme Corp. Dérivés de pyridine-1-oxyde et leur utilisation en tant qu'inhibiteurs du facteur xia
JP2021514944A (ja) * 2018-02-27 2021-06-17 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． オキソピコリナミド誘導体の結晶形及びそれらの製造方法
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11370773B1 (en) 2019-10-16 2022-06-28 Morphic Therapeutic, Inc. Inhibiting human integrin (alpha-4) (beta-7)

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