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CN105949116A - Acyl piperazine compound and preparation method and application thereof - Google Patents

Acyl piperazine compound and preparation method and application thereof Download PDF

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Publication number
CN105949116A
CN105949116A CN201610401989.6A CN201610401989A CN105949116A CN 105949116 A CN105949116 A CN 105949116A CN 201610401989 A CN201610401989 A CN 201610401989A CN 105949116 A CN105949116 A CN 105949116A
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heteroaryl
aryl
compound
alkyl
group
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夏岩
谭伟强
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Qingdao University of Technology
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Qingdao University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of biological medicines, and relates to acyl piperazine compounds, a preparation method and application thereof, wherein the chemical formula is as follows:wherein X is selected from the group consisting of a bond and-NR1-; y is selected from the group consisting of a bond and-NR1-or-CR2R3-; a is selected from aryl or heteroaryl; l is selected from aryl or heteroaryl, G is selected from heteroaryl; r1Selected from hydrogen atoms, alkyl groups; r2、R3Each independently selected from hydrogen atom, alkyl; r4Selected from hydrogen, halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, -C (O) NR2R3The synthetic process is simple, the operation is convenient, the synthesized compound thrombin receptor has strong antagonistic activity, and the aryl or heteroaryl is suitable for treating heart diseases such as myocardial infarction, cerebral embolism and the like caused by platelet aggregation.

Description

Acyl piperazine compounds and its production and use
Technical field:
The invention belongs to biomedicine technical field, relate to a batroxobin receptor antagonist chemical combination Thing and preparation method thereof, particularly acyl piperazine compounds and its preparation method and application, This compounds is applicable to treat the hearts such as the myocardial infarction that causes of platelet aggregation and cerebral embolism In disease.
Background technology:
Thrombotic disease is clinical common cardiovascular disease, mainly includes cerebral vessels embolism, the heart Dirty blood vessel thrombosis, pulmonary infarction and peripheral arterial thrombosis thromboembolism etc., the life to the mankind Life and health have serious harm.Thrombotic disease is by thrombosis (Thrombosis) and thrombosis Caused by two kinds of pathology of thromboembolism (Thromboembolism), wherein thrombosis refers to because of some Inducement, in blood, visible component forms abnormal blood clot at Ink vessel transfusing, blocks blood vessel, thus There is the process of obstacle in the blood supply making corresponding site, is h and E factor phase interaction With, interactional change procedure；Thromboembolism is that the thrombosis of dactylolysis is flowing along with blood During block some blood vessels, cause respective organization or organ ischemia, anoxia, congestion and The pathological process of edema.The pathogeny of thrombotic disease and coagulation and fibrinolysis system, platelet Etc. there being important relationship.
At present, antithrombotic, by the difference of its mechanism of action, can be divided into anticoagulation medicine, haemolysis Bolt medicine and anti-platelet drug three class, wherein, antiplatelet drug is by suppression platelet Adhesion, gathering and release function prevent thrombosis, platelet surface has many differences to be subject to Body, these receptors combine can be activated with corresponding parts, and these receptors mainly include two phosphorus Adenosine monophosphate (Adenosine diphosphate, ADP) receptor, TXA2. (Thromboxane A2, TXA2) receptor, thrombin (Thrombin) receptor etc., the most conventional antiplatelet Medicine has aspirin and Plavix.
Thrombin be non-active group proenzyme under the effect of Xa factor by the side of protein cleavage A kind of serine protease that formula produces, acts on the end of coagulation cascade, the formation to thrombosis Playing the effect of key, thrombin is by activation thrombin receptor (Thrombin receptor) Platelet aggregation, thrombin receptor is made to be also referred to as proteinase-activated receptor-1 (Protease Activated receptor-1, PAR-1), proteinase activated receptors (PAR) belongs to G-protein coupling Receptor, has four hypotypes: PAR-1, PAR-2, PAR-3 and PAR-4, wherein except PAR-2 Be trypsin by external, its excess-three is all thrombin receptor, PAR being distributed at human body Significantly tissue specificity, human body platelet only expresses PAR-1 and PAR-4 receptor, and And PAR-1 receptor plays main effect, PAR-1 receptor exists at the thrombin of lower concentration In the case of just can play its activate platelet aggregation effect, and platelet aggregation reaction speed Degree is faster.
Vorapaxar (SCH 530348) is the novel thrombin receptor in U.S.'s listing in 2014 Antagonist, has heart disease history of attack for treatment but without transient ischemic attack history or apoplexy history Cardiovascular patient.Clinical I phase and II phase result of study show, Vorapaxar can be bright Aobvious suppress hematoblastic gathering, and the bleeding time of the most unhealthful experimenter, with aspirin, Clopidogrel will not increase bleeding risk when using, and carries out Vorapaxar the most again Two large-scale III clinical trial phases.It was found that cardiovascular patient takes Vorapaxar Certain effect, the incidence rate of the disease such as myocardial infarction or cerebral thrombosis is had substantially to reduce. Atopaxar has another name called E5555, is the PAR-1 antagonist of Eisai research and development, and I phase clinical research is tied Fruit shows, E5555 can suppress hematoblastic gathering and toleration good, simultaneously significantly Do not affect the hematoblastic gathering of ADP induction, the most hemorrhage and clotting time, E5555 Having carried out the II phase clinical experiment of double blinding, placebo, result shows, this compound is not Increase bleeding risk, and the test of all dosage all shows that it can suppress platelet aggregation. F16618 is the thrombin receptor antagonist developed by France's Pierre Fabre institute. F16618 can suppress hematoblastic gathering, this effect to have concentration dependent and competitiveness. The F16618 half-life is shorter, and bioavailability is high, from Platelet function Analyzer PAF-100 Analysis result draw, under 20 μMs of concentration, F16618 is to hematoblastic gathering suppression ratio It is 49%.
Summary of the invention:
It is an object of the invention to the shortcoming overcoming prior art to exist, seek to design offer one The acyl piperazine compound of what class was novel have thrombin receptor (PAR-1) antagonistic activity and Its preparation method and its purposes in cardiovascular and cerebrovascular diseases medicament.
To achieve these goals, the chemical formula of the acyl piperazine compounds that the present invention relates to For:
Wherein, X is selected from chemical bond or-NR1-；Y is selected from chemical bond or-NR1-or-CR2R3-；A selects From aryl or heteroaryl；L is selected from aryl or heteroaryl, and this aryl or heteroaryl can optionally have One or more R4Substituent group；G is selected from heteroaryl；R1Selected from hydrogen atom, alkyl；R2、 R3It is each independently selected from hydrogen atom, alkyl；R2、R3Can optionally with the carbon atom being connected Form cycloalkyl together；R4Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl, Alkyl, cycloalkyl ,-C (O) NR2R3, aryl or heteroaryl, wherein said alkoxyl, alkane Base, cycloalkyl, aryl or heteroaryl can by one or more selected from halogen, hydroxyl, cyano group, Nitro, alkoxyl, alkyl, cycloalkyl, aryl, the substituent group of heteroaryl are replaced.
The present invention relates to logical formula (I) compound or its pharmaceutically useful salt, or the medicine containing them Compositions can be used in preparing anticoagulant.
The present invention relates to logical formula (I) compound or its pharmaceutically useful salt, or the medicine containing them Compositions can be used in the medicine of the preparation treatment disease relevant with thrombin receptor, Qi Zhongsuo The disease relevant with thrombin receptor stated includes thrombosis, vascular restenosis, Deep vein blood Bolt disease, pulmonary infarction disease, cerebral infarction, heart disease, hypertension are and malignant tumor.
The present invention relates to logical formula (I) compound or its pharmaceutically useful salt, or the medicine containing them Compositions can be as the medicine of suppression calcium ion transport.
The present invention relates to logical formula (I) compound or its pharmaceutically useful salt, or the medicine containing them Compositions can be as the medicine of enzyme acceptor anticoagulant, and wherein said thrombin receptor is PAR-1 receptor.
" alkyl " of the present invention refers to saturated aliphatic hydrocarbon group, including 1 to 20 carbon atom Straight chain and branched group, preferably comprise the alkyl of 1 to 12 carbon atom, non-limiting reality Execute example include methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, Sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-bis- Methyl-propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, positive heptan Base, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-diformazan Base amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-bis- Methylhexyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-first Base-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc..More Preferably containing the low alkyl group of 1 to 6 carbon atom, non-limiting example includes first Base, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, N-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl Propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl butyrate Base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl Amyl group, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl etc..Alkyl is permissible Being substituted or unsubstituted, when substituted, substituent group can be at any spendable junction point On be replaced.
" cycloalkyl " of the present invention refers to that the saturated or unsaturated monocycle of part or multi-ring cyclic hydrocarbon take Dai Ji, it includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more Preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting enforcement of monocyclic cycloalkyl Example comprise cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, Cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc..
" aryl " of the present invention refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely altogether Enjoy the ring of adjacent carbon atoms pair) group,
(i.e. it is with phase adjacency pair carbon for the pi-electron system with conjugation of the present invention multi-ring The ring of atom) group, preferably 6 to 10 yuan, such as phenyl and naphthyl, described aryl rings Can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein be connected to one with precursor structure The ring risen is aryl rings, comprises:
Aryl of the present invention can be substituted or unsubstituted.
" heteroaryl " of the present invention refers to comprise 1 to 4 hetero atom, and 5 to 14 rings are former The heteroaromatic system of son, wherein hetero atom includes oxygen, sulfur and nitrogen, preferably 6 to 10 yuan； Heteroaryl is preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrroles Base, N-alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc.；Described miscellaneous Aryl rings can condense on aryl, heterocyclic radical or cycloalkyl ring, is wherein connected with precursor structure Ring together is heteroaryl ring, comprises:
Heteroaryl of the present invention can be optionally substituted or unsubstituted.
" alkoxyl " of the present invention refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), its Middle alkyl is as defined above, comprises methoxyl group, ethyoxyl, propoxyl group, butoxy, ring Propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.；Alkoxyl can be optionally to take Generation or unsubstituted.
" hydroxyl " of the present invention refers to-OH group.
" halogen " of the present invention refers to fluorine, chlorine, bromine or iodine.
" amino " of the present invention refers to-NH2。
" cyano group " of the present invention refers to-CN.
" nitro " of the present invention refers to-NO2。
The typical compound of the present invention includes:
Compound that the logical formula I of the present invention represents or its stereoisomer, tautomer, The isotope substituent of prodrug or pharmaceutically acceptable salt or solvate, any of which one Compound can exist at least one hydrogen atom replaced by D-atom.
The present invention relates to the preparation process of compound shown in logical formula (I) by shown in following formula:
Carboxylic acid 1 and piperazine 2 react under conventional amidation reaction condition and generate amide 3.In Mesosome 3 and acid reagent 4 carry out coupling reaction under the conditions of conventional Suzuki coupling reaction, Generate logical formula (I) compound；Or by shown in following formula:
Compound Ia at alkali, such as sodium hydride or double (TMS) Lithamide., effect Lower and alkylating reagent, such as iodomethane or Isosorbide-5-Nitrae-dibromobutane or pentamethylene bromide, send out A raw alkylation or di or cyclization generate logical formula (I) compound；Or it is the most logical Shown in formula:
Intermediate 3 reacts under the conditions of Buchwald aminating reaction with amine reagent 6, generates logical Formulas I b compound, compound Ib further at alkali, such as sodium hydride, effect under and alkyl Change reagent, such as iodomethane, occur alkylated reaction to generate formula Ic compound；
Amine reagent 7 at alkali, such as triethylamine, the lower reaction with triphosgene of effect generates isocyanates 8, Isocyanates 8 at alkali, such as triethylamine, effect is lower and piperazine 2 reacts generation intermediate 9.Intermediate 9 and acid reagent carry out Suzuki coupling reaction, generate formula Id compound； Compound Id can be further at alkali, such as sodium hydride, effect under and alkylating reagent, example Such as iodomethane, alkylated reaction is occurred to generate formula Ie compound.
Compared with prior art, its synthesis technique is simple, easy to operate, synthesis for the present invention Compound Thrombin receptor antagonist activity is strong, it is adaptable to the cardiac muscle that treatment platelet aggregation causes In the heart disease such as infarction and cerebral embolism.
Detailed description of the invention:
Below by instantiation, the invention will be further described.
Embodiment 1:3'-[2-Oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]- Biphenyl-2-carbonitrile, 1-[3-(4-(2-pyridine) piperazine-2-ethyl ketone) phenyl]-2-cyanophenyl I-001, synthesis
The present embodiment prepares the detailed process of I-001:
The first step: in 250mL round-bottomed flask, by 3-bromo-acid (2.15g, 10.0mmol) It is dissolved in dichloromethane (40mL), is sequentially added into HOBT (1.42g, 10.5mmol), EDCI (2.01g, 10.5mmol), DIEA (2.61mL, 15mmol) and 1-(2-pyridine Base) piperazine (1.71g, 10.5mmol), stirring reaction 20 hours under room temperature.Reactant liquor warp After dichloromethane (80mL) dilution, wash with sodium hydroxide solution (1mol/L, 3 × 100mL), Organic facies filters after anhydrous sodium sulfate is dried overnight；After concentrating under reduced pressure, residue flash column Analysis separates (MeOH/CH2Cl2, 3%), obtain white powder compound 7 (3.02g, 83.8%):1H NMR(CDCl3,600MHz)δ8.11(d,1H),7.42(t,1H),7.36 (s,1H),7.31(m,1H),7.13(m,2H),6.59(t,1H),6.56(d, 1H),3.70(t,2H),3.67(s,2H),3.50(t,2H),3.43(m,4 H)；MS(APCI)calcd for C17H18BrN3O(M+H+):360.06.Found: 360.38；
Second step: compound 7 (216mg, 0.6mmol) is dissolved in mixed solvent (toluene/ Ethanol/water=4mL:2mL:1mL) in, be sequentially added into tetrakis triphenylphosphine palladium (34.7mg, 5%mol), potassium carbonate (248.8mg, 1.8mmol) and 2-cyanophenylboronic acid (132mg, 0.9mmol), 120 DEG C of stirrings are reacted 12 hours.Reactant liquor is cooled to room temperature, uses dichloromethane Alkane (3 × 20mL) extracts, and merges organic facies and filters after anhydrous sodium sulfate is dried overnight, decompression Concentrate；Residue rapid column chromatography separates (ethyl acetate/petroleum ether, 2/1), obtains I-001 (colorless oil, 188mg, 82%):1H NMR(CDCl3,600MHz)δ8.17(d, 1H),7.76(d,1H),7.69-7.63(m,2H),7.56-7.42(m,5H), 7.39(d,1H),6.64(t,1H),6.61(d,1H),3.87(s,2H), 3.79-3.45(m,8H)；MS(APCI)calcd for C24H22N4O(M+H+):383.18. Found:383.33。
The synthesis of following compounds is similar with the synthesis of I-001, at second step with 4-cyano group benzene Boric acid replacement 2-cyanophenylboronic acid:
I-003 (colorless oil, 3'-[2-Oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]- Biphenyl-4-carbonitrile) 1-[3-(4-(2-pyridine) piperazine-2-ethyl ketone) phenyl]-4-cyanophenyl:1H NMR (CDCl3,600MHz)δ8.18(d,1H),7.76-7.66(m,4H),7.55(t,1H),7.51-7.43(m,3 H),7.33(d,1H),6.66(t,1H),6.63(d,1H),3.86(s,2H),3.79-3.63(m,4H), 3.51-3.49(m,4H)；MS(APCI)calcd for C24H22N4O(M+H+):383.18.Found: 383.30.
The synthesis of following compounds is similar with the synthesis of I-001, in the first step with 3-bromobenzoic acid Replace 3-bromo-acid, at second step with 4-cyanophenylboronic acid replacement 2-cyanophenylboronic acid:
I-114
(3'-(4-Pyridin-2-yl-piperazine-1-carbonyl)-biphenyl-4-carbonitrile) 1-[3-(4-(2-pyridine) piperazine-1-ketone) phenyl]-4-cyanophenyl:1H NMR(DMSO-d6, 400MHz, 23 DEG C) δ 8.14-8.12 (dd, 1H, H-6-CH of Py), 7.95 (s, 4H, 4 × CH of Ph), 7.88-7.86 (m, 1H, CH of Ph), 7.82-7.81 (t, 1H, CH of Ph), 7.64-7.51 (m, 3H, 2 × CH of Ph and CH of Py), 6.86-6.84 (d, 1H, H-3-CH of Py), 6.69-6.66 (m, 1H, H-5-CH of Py), 3.76 (m, 2H, CH2NCO), 3.62-3.34 (m, 6H, 3 × CH2N)； MS(ES-API)calcd for C23H20N4O(M+H+): 369.43.Found:369.2.
Embodiment 2:2-(3'-Methoxy-biphenyl-4-yl)-1-(4-pyridin-2-yl- Piperazin-1-yl)-propan-1-one, 2-(4-(3-methoxyphenyl))-1-(4-(2-pyridine) piperazine Piperazine)-1-acetone, I-131, synthesis
The concrete preparation process of the present embodiment is: in single port arm reaction bulb, and nitrogen is replaced, Take sodium hydride (400mg, 1.0mmol) to be placed in DMF, after stirring 10min at 0 DEG C, Add compound I-071 (77mg, 0.2mmol), continue stirring 1h, be subsequently adding iodine Methane (498 μ L, 0.8mmol), removes ice bath after 10min, recover to room temperature reaction 3h. Reactant liquor dilutes through saturated ammonium chloride solution, and ethyl acetate extracts, and merges organic facies, uses successively Water (20mL × 3), saturated aqueous common salt (20mL × 3) are washed, and organic facies is through anhydrous sodium sulfate It is dried, filters, concentrating under reduced pressure, residue rapid column chromatography isolated white powder chemical combination Thing I-131 (110mg, 88%,
2-(3'-Methoxy-biphenyl-4-yl)-1-(4-pyridin-2-yl-piperazin-1-yl)-propan-1 -one) 2-(4-(3-methoxyphenyl))-1-(4-(2-pyridine) piperazine)-1-acetone:1H NMR (CDCl3,400MHz)δ8.17(d,1H,H-6-CH of Py),7.57-7.55(d,2H, H-2-CH of Py),7.49-7.45(t,1H,CH of Ph),7.37-7.34(m,3H,3×CH of Ph), 7.18-7.16 (d, 1H, CH ofPh), 7.12 (s, 1H, CH ofPh), 6.91-6.89 (d, 1H,H-3-CH ofPy),6.65-6.62(t,1H,H-5-CH ofPy),6.60-6.58(d,1H, CH of Ph),4.01-3.96(m,1H,CHCO),3.88(s,3H,CH3O),3.68-3.05 (m,8H,4×CH2N),1.54-1.52(d,3H,CH3)；MS(APCI)calcd for C25H27N3O2(M+H+):402.21Found:402.2.
Embodiment 3:
2-(3'-Methoxy-biphenyl-4-yl)-2-methyl-1-(4-pyridin-2-yl- Piperazin-1-yl)-propan-1-one, 2-methyl-2-(4-(3-methoxyphenyl))-1-(4-(2- Pyridine) piperazine)-1-acetone, I-132, synthesis:
In single port arm reaction bulb, nitrogen is replaced, and adds double (TMS) ammonia Base lithium (0.8mL, 0.8mmol, 1M hexane solution) is dissolved in THF, stirs at 0 DEG C After 10min, add compound I-071 (77mg, 0.2mmol), continue stirring 1h, It is subsequently adding iodomethane (1.2mL, 2mmol), after 10min, removes ice bath, recover to room Temperature reaction 3h.；Successively with water (20mL × 3), saturated aqueous common salt (20 after diluted ethyl acetate ML × 3) to wash, organic facies is dried through anhydrous sodium sulfate, filters, and concentrating under reduced pressure, residue is fast Speed column chromatography for separation obtain white powder compound I-132 (108mg, 85%, 2-(3'-Methoxy-biphenyl-4-yl)-2-methyl-1-(4-pyridin-2-yl-piperazin-1-yl) -propan-1-one) 2-methyl-2-(4-(3-methoxyphenyl))-1-(4-(2-pyridine) piperazine)-1-third Ketone:1HNMR(CDCl3,400MHz,23℃)δ8.15-8.14(d,1H,H-6-CH ofPy), 7.61-7.59(d,2H,H-2-CH of Ph),7.47-7.44(t,1H,CH of Py),7.39-7.33(m,2H,2×CH ofPh),7.28(s,1H,CH ofPh),7.21-7.19(d,1H, CH of Ph),7.14(m,1H,CH of Ph),6.64-6.61(t,1H,H-3-CH of Py), 6.57-6.54(d,1H,H-5-CH ofPy),3.89(s,3H,CH3O),3.34(m,8H,4×CH2N), 1.62(s,6H,2×CH3)；MS(APCI)calcd for C26H29N3O2(M+H+): 416.23Found:416.2.
Embodiment 4:2-[3-(4-Pyridin-2-yl-piperazine-1-carbonyl)- Phenylamino]-benzonitrile, 1-(3-(4-(2-pyridine) piperazine-1-ketone) anilino-)-2-benzene Nitrile I-165, synthesis
The synthesis of starting material 1 and example 1, the synthesis first step of I-001 is similar to, with 3-bromine Benzoic acid replaces 3-bromo-acid.
By single port band arm eggplant-shape bottle N2Replace 3 times, add compound 1 (104mg, 0.3 Mmol) and compound 7 (39mg, 0.33mmol), dissolve with the tert-butyl alcohol (1.5mL). Add three (dibenzalacetone) two palladium (14mg, 0.015mmol), 2-cyclohexyl phosphorus-2, 4,6-tri isopropyl biphenyls (14mg, 0.03mmol) and Anhydrous potassium carbonate (166mg, 1.2mmo l), after stirring at normal temperature, it is warming up to 90 DEG C of stirring reaction 20h, then uses dichloro Methane dilutes, washing, merges organic facies；Organic facies is dried through anhydrous sodium sulfate, filters, subtracts Pressure is concentrated to give crude product, crude product rapid column chromatography isolated pale yellow powder shape compound I-165
(31mg, 27%):
2-[3-(4-Pyridin-2-yl-piperazine-1-carbonyl)-phenylamino]-benzonitrile1- (3-(4-(2-pyridine) piperazine-1-ketone) anilino-)-2-cyanophenyl；1H NMR(CDCl3, 400MHz, 26 DEG C) δ 8.23-8.21 (dd, 1H, H-6-CH ofPy), 7.54-7.51 (m, 2H, CH of Ph and H-4-CH ofPy), 7.45-7.41 (m, 2H, 2 × CH ofPh), 7.29-7.24 (m, 3H, 3 × CH ofPh), 7.17-7.16 (d, 1H, H-3-CH ofPy), 6.95-6.91 (t, 1H, H-5-CH ofPy), 6.72-6.68 (dd, 2H, 2 × CH ofPh), 6.32 (s, 1H, NH), 3.91 (s, 2H, CH2NCO), 3.61 (s, 6H, CH2NCO and 2×CH2N)； MS(ES-API)calcd for C23H21N5O(M+H+): 384.45.Found:384.2.
Embodiment 5:2-{Methyl-[3-(4-pyridin-2-yl-piperazine-1-carbonyl)- Phenyl]-amino}-benzonitrile, N-methyl isophthalic acid-(3-(4-(2-pyridine) piperazine-1-ketone) aniline Base)-2-cyanophenyl, I-168, synthesis
In single port band arm eggplant-shape bottle, N2Replace 3 times, add compound I-165 (54m G, 0.14mmol), DMF (2mL) dissolves, and ice bath is cooled to 0 DEG C.It is subsequently adding hydrogenation Sodium (6.8mg, 0.28mmol) stirring reaction 10min, is eventually adding iodomethane (27 μ L, 0.42mmol), it is stirred at room temperature 10min again after stirring 10min.Add 10 ML shrend is gone out, and ethyl acetate extracts, then washes with saturated common salt.Organic facies is through anhydrous slufuric acid Sodium is dried, and filters, and concentrating under reduced pressure obtains crude product, and crude product is light through rapid column chromatography isolated Yellow powder compound I-168 (39mg, 69%): 2-{Methyl-[3-(4-pyridin-2-yl -piperazine-1-carbonyl)-phenyl]-amino}-benzonitrile N-methyl isophthalic acid-(3-(4-(2 -pyridine) piperazine-1-ketone) anilino-)-2-cyanophenyl；1H NMR(CDCl3, 400MHz, 29 DEG C) δ 8.23-8.22 (d, 1H, H-6-CH of Py), 7.68-7.65 (d, 1H, CH Of Ph), 7.62-7.58 (t, 1H, H-4-CH of Py), 7.55-7.50 (t, 1H, CH Of Ph), 7.34-7.28 (m, 2H, 2 × CH of Ph), 7.24-7.22 (t, 1H, C H of Ph), 6.97-6.96 (d, 1H, H-3-CH of Py), 6.92-6.90 (d, 2H, 2 × CH of Ph), 6.70-6.66 (m, 2H, CH of Ph and H-5-CH of Py), 3.88 (s, 2H, CH2NCO), 3.59 (s, 6H, CH2NCO and 2×CH2N), 3. 42 (s, 3H, CH3)；MS(ES-API)calcd for C24H23N5O(M+H+): 39 8.47.Found:398.2.
Embodiment 6:4-Pyridin-2-yl-piperazine-1-carboxylic acid (2'- Carbamoyl-biphenyl-3-yl)-amide, 2-(3-(4-(2-pyridine) piperazine) formamido) benzene Methanamide, I-173, synthesis
3-bromaniline reacts generation isocyanates 1 under the effect of triethylamine with triphosgene, then The isocyanates 1 generated reacts with piperazine 2 under the effect of triethylamine and generates compound 3； Compound 3 and 2-cyanophenylboronic acid generates chemical combination under embodiment 1, second step reaction condition Thing I-173 (4-Pyridin-2-yl-piperazine-1-carboxylic acid (2'-carbamoyl-biphenyl-3-yl)-amide) 2-(3-(4-(2-pyridine) piperazine) formamido) Benzoylamide:1H NMR(DMSO-d6, 400MHz, 30 DEG C) δ 8.15-8.13 (dd, 1H, H-6-CH ofPy), 7.57-7.40 (m, 9H, 8 × CH ofPh and H-4-CH ofPy), 7.35-7.23 (m, 2H, NH2), 7.03-7.01 (d, 1H, NH), 6.89-6.87 (d, 1 H, H-3-CH ofPy), 6.66 (t, 1H, H-5-CH ofPy), 3.59-3.35 (t, 8H, 4×CH2)；MS(ES-API)calcd for C23H23N5O2(M+H+): 402.46.Found: 401.9.
Embodiment 7:
The present embodiment is to compound I-003, I-114, the acyl group piperazine of embodiment 2,3,4 preparation Thrombin receptor (PAR-1) antagonistic activity of piperazine compounds is measured, and measuring principle is: Including PAR-1 at cell (such as HEK293 cell), it can be by TRAP-6 (thrombin Receptor active peptide-6) activate, thus the release of calcium ion in trigger cell, the release of calcium ion is many Can be measured by fluorescence less, add thrombin receptor antagonist and can suppress TRAP-6 pair The activation of PAR-1, therefore can measure blood coagulation by the burst size of fluorescent method test calcium ion The enzyme acceptor antagonist inhibitory activity to PAR-1, specific experiment step is:
The most cultured matrix liquid is added in 96 hole clear bottom blackboards with every hole 30 μ L, 30 Matrix liquid is removed by centrifugation after min, then digests with cell dissociation buffer HEK293/Ga15/PAR1 cell, carrys out bed board with 45000 cells/well, in temperature be 37C, CO2Content is to hatch 24h in the environment of 5%, removes culture medium after having hatched, will configuration The good dye buffer that loads is rapidly added in hole with the amount of every hole 100 μ L, in temperature is still 37C、CO2Content is that lucifuge hatches 1h in the environment of 5%；Embodiment 2,3 and 4 is made Standby target compound is dissolved in dimethyl sulfoxide respectively, dilutes its concentration with HBSS buffer and is 4%, then in each hole, add 25 these diluents of μ L, under room temperature, lucifuge hatches 15min； After completing to hatch, in each hole, add the TRAP-6 of 25 μ L, this plate is placed in simultaneously On Flex Station plate reading machine, additionally, also can detect calcium current signal, test result takes three surveys Examination meansigma methods；PAR-1 suppression ratio computing formula:
The suppression ratio %=of PAR-1 be (fluorescence intensity in blank group hole-sample compound hole Fluorescence intensity) fluorescence intensity × 100% in/blank group hole, the half suppression of test compound Concentration IC50Can be calculated by the suppression ratio under variable concentrations, compound I-003, The compound of I-114, embodiment 2,3 and 4 preparation is respectively 55% at the suppression ratio at 10 μMs, 47%, 27%, 45% and 21%.

Claims (6)

1. an acyl piperazine compounds, it is characterised in that chemical formula is:
Wherein, X is selected from chemical bond or-NR1-；Y is selected from chemical bond or-NR1-or-CR2R3-；A is selected from Aryl or heteroaryl；L is selected from aryl or heteroaryl, and this aryl or heteroaryl can be by one or many Individual R4Substituent group；G is selected from heteroaryl；R1Selected from hydrogen atom, alkyl；R2、R3The most independent Selected from hydrogen atom, alkyl；R2、R3Cycloalkyl can be formed together with the carbon atom being connected；R4 Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl, alkyl, cycloalkyl, -C(O)NR2R3, aryl or heteroaryl, described alkoxyl, alkyl, cycloalkyl, aryl or Heteroaryl can by one or more selected from halogen, hydroxyl, cyano group, nitro, alkoxyl, Alkyl, cycloalkyl, aryl, the substituent group of heteroaryl are replaced.
2. the application of acyl piperazine compounds as claimed in claim 1, it is characterised in that institute State logical formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition containing them can For preparing anticoagulant.
The application of acyl piperazine compounds the most according to claim 2, it is characterised in that Described logical formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition energy containing them It is enough in the medicine of the preparation treatment disease relevant with thrombin receptor, wherein said and blood coagulation The relevant disease of enzyme acceptor includes thrombosis, vascular restenosis, deep vein thrombosis, lung bolt Plug disease, cerebral infarction, heart disease, hypertension are and malignant tumor.
The application of acyl piperazine compounds the most according to claim 2, it is characterised in that Described logical formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition energy containing them Enough medicines as suppression calcium ion transport.
The application of acyl piperazine compounds the most according to claim 2, it is characterised in that Described logical formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition energy containing them Enough medicines as enzyme acceptor anticoagulant, wherein said thrombin receptor is PAR-1 receptor.
6. the preparation method of acyl piperazine compounds as claimed in claim 2, its feature exists In preparation process by shown in following formula:
Or by shown in following formula:
Or by shown in following formula:
Or by shown in following formula:
CN201610401989.6A 2016-06-08 2016-06-08 Acyl piperazine compound and preparation method and application thereof Pending CN105949116A (en)

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