CN104177332A - Amido substituted indolonaphthalenone derivatives and medicinal uses thereof - Google Patents

Amido substituted indolonaphthalenone derivatives and medicinal uses thereof Download PDF

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CN104177332A
CN104177332A CN201310187705.4A CN201310187705A CN104177332A CN 104177332 A CN104177332 A CN 104177332A CN 201310187705 A CN201310187705 A CN 201310187705A CN 104177332 A CN104177332 A CN 104177332A
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compound
alkyl
yuan
pharmaceutically acceptable
general formula
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张翱
耿美玉
丁健
宋子兰
艾菁
李晓刚
彭霞
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention relates to amido substituted indolonaphthalenone derivatives and medicinal uses thereof, and concretely relates to compounds with tyrosine kinase ALK selective inhibition activity, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, preparation methods of the compounds and the salts or solvates, a medicinal composition containing the compounds, uses of the above compounds in the preparation of medicines for preventing or treating biological anaplastic lymphoma kinase related abnormal cell proliferation, form change and/or hyperkinesias associated diseases, uses in the preparation of medicines for treating or preventing angiogenesis or cancerometastasis related diseases, and especially uses in the preparation of medicines for treating or preventing the growth and transfer of tumors.

Description

Indoles naphthalene ketone derivant and medicinal use thereof that amide group replaces
Technical field
The present invention relates to the synthetic field of medical compounds, particularly, relate to compound and pharmacy acceptable salt or pharmaceutically acceptable solvate that a class has Tyrosylprotein kinase selective inhibitory activity, its preparation method, the pharmaceutical composition that comprises this compound, and these compounds for the preparation of prevention or treatment relevant to gradually changeable lymphoma enzyme in organism follow abnormal cell proliferation, purposes in the medicine of the disease of metamorphosis and hypoerkinesia etc., and the purposes in the medicine for the preparation of prevention or the treatment disease relevant to angiogenesis or metastasis of cancer, especially the purposes in the medicine for the preparation of prevention or treatment tumor growth and transfer.
Background technology
Gradually changeable lymphoma enzyme (ALK) is a kind of receptor tyrosine kinase, is under the jurisdiction of insulin receptor superfamily.Be found in the earliest in gradually changeable large celllymphoma (ALCL), in the ALCL of about 60%-85%, have the expression of ALK, and ALK is single-minded normally, be expressed in neural system, in especially neonatal brain.In human body, ALK gene expression dose declines along with reaching maturity of brain, and the amount in ripe cerebral tissue is very low, expresses and has certain regionality; Other system is not especially found the expression of ALK in hemopoietic system.ALK gene lacks expression in the non-hematopoietic system cancer of the overwhelming majority and healthy tissues, and the distribution range that shows alk protein is extremely narrow.
ALK gene is positioned at karyomit(e) 2p23 site, and the transcribed generation size of ALK in normal circumstances servant source is the mRNA of 6222bp, consists of the I type membrane-spanning protein ALK of 1620 aminoacid sequence 200KDa of coding 29 exons.ALK gene, conventionally in dormant state, causes cell deterioration to develop into malignant tumour owing to occurring to merge with other genes.Yet can have much with the gene that its occurs to merge, at nonsmall-cell lung cancer (non-small cell lung cancer, NSCLC) in, be mainly to merge with EML4 gene (echinoderms microtubule-associated protein sample 4), between echinoderms microtubule-associated protein sample 4-, becoming lymphoma kinases (EML4-ALK) fusion gene is 2%～7% in the incidence of NSCLC.
Along with deepening continuously of nonsmall-cell lung cancer (NSCLC) molecular biology research, the individualized treatment based on molecular marked compound has been gone to clinical from laboratory, and in NSCLC patient's treatment, has obtained significant clinical progress late.It is also important that, except traditional histopathology classification, the difference that NSCLC can also express according to various molecular marked compounds, carry out molecular phenotype classification, and to take the driven nature gene relevant to tumorigenesis be target spot, research and develop new medicine, carry out individuation molecular targeted therapy targetedly, improve patient's prognosis.In the ideal situation, all NSCLC patients should implement treatment targetedly in the advance detection of line correlation molecular marked compound for the treatment of in the situation that fully understanding patient tumors developed by molecule feature, improve result for the treatment of.Under such background, Tyrosylprotein kinase has become in recent years very powerful and exceedingly arrogant molecular target, its selective depressant or become the focus of antitumor drug research around many target spots micromolecular inhibitor of ALK.
At present, the micromolecular inhibitor Crizotinib of Pfizer company exploitation is ratified listing by U.S. FDA on August 26th, 2011, and this is also the micromolecular inhibitor of a unique ALK who has gone on the market.But existing clinical study shows Crizotinib to occur resistance, Crizotinib bioavailability in vivo has much room for improvement simultaneously.Now do not have the inhibitor listing of a kind of single target ALK, alectinib in clinical 2 phases (having another name called CH5424802) is ALK selective depressant, and its unique Fourth Ring structure causes everybody extensive concern (Bioorganic & Medicinal Chemistry20 (2012) 1271 – 1280; J.Med.Chem.2011,54,6286 – 6294).In order to improve alectinib bioavailability and metabolic stability in vivo, and acquisition has the new ALK inhibitor of independent intellectual property right, we are retaining on the basis of its main body framework in design, adopt different measures to transform alectinib, especially on side chain, introduce water soluble group and metabolic stability group, obtained the new derivative of a class, the inhibition with better ALK is active.
Summary of the invention
The inventor designs and has synthesized a class and take compound, its pharmacy acceptable salt or the pharmaceutically acceptable solvate that Fourth Ring is mother nucleus structure.Described compound is a class tyrosine kinase inhibitor, and ALK is had to good restraining effect.
One object of the present invention is for providing the compound shown in following general formula I, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof:
General formula I
Wherein:
R 1for hydrogen atom, halogen or C1～C4 alkyl; T is-(CH 2) m-, wherein m is 0,1 or 2;
R 2for replacing or the unsubstituted saturated or unsaturated heterocycle base that contains 1-4 heteroatomic 4 yuan to 10 yuan, the substituting group of the saturated or unsaturated heterocycle base of described replacement is the saturated heterocyclyl that contains 1-2 heteroatomic 4 yuan to 10 yuan, the C1-C4 alkyl that hydroxyl replaces, C1-C4 alkyl, C1-C4 alkyl, halogen, C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group or the C1-C4 alkoxy carbonyl that halogen replaces, wherein, described heteroatoms is N, O or S;
Preferably, R 2for replacing or a saturated heterocyclyl of the unsubstituted 1-2 of containing heteroatomic 4 yuan to 8 yuan or for replacing or unsubstitutedly containing 1-4 heteroatomic 9 membered unsaturated heterocycle bases, the substituting group of the saturated heterocyclyl of described replacement is C1-C4 alkyl, C1-C4 alkyl or the C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group that contains 1-2 heteroatomic 6 yuan of saturated heterocyclyls, hydroxyl replacement, the substituting group of the unsaturated heterocycle base of described replacement is C1-C4 alkyl, halogen or the C1-C4 alkoxy carbonyl that halogen replaces, wherein, described heteroatoms is N, O or S;
More preferably, R 2for replacing or the saturated heterocyclyl of 4 yuan, 6 yuan of the unsubstituted 1-2 of a containing nitrogen-atoms or 8 yuan or be replacement or the unsubstituted 9 membered unsaturated heterocycle bases that contain 4 nitrogen-atoms, the substituting group of the saturated heterocyclyl of described replacement is C1-C4 alkyl, C1-C4 alkyl or the C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group that contains 1-2 heteroatomic 6 yuan of saturated heterocyclyls, hydroxyl replacement, the substituting group of the unsaturated heterocycle base of described replacement is C1-C4 alkyl, halogen or the C1-C4 alkoxy carbonyl that halogen replaces, wherein, described heteroatoms is N or O;
Most preferably, R 2for that replace or unsubstituted or or for replace or do not replace wherein, described replacement or substituting group be c1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group that hydroxyl replaces, described replacement substituting group be C1-C4 alkyl, halogen or the C1-C4 alkoxy carbonyl that 1-3 halogen replaces.
Wherein, described C1-C4 alkyl is C1-C4 straight or branched alkyl; Described halogen is F, Cl, Br or I.
The pharmacy acceptable salt of the compound that described general formula I represents comprises without limitation: inorganic acid salt, example hydrochloric acid salt, hydrobromate, nitrate, vitriol, phosphoric acid salt etc.; Organic acid salt, as formate, acetate, propionic salt, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion etc.; Alkylsulfonate, as metilsulfate, ethyl sulfonate etc.; Arylsulphonate, as benzene sulfonate, tosilate etc.
The pharmaceutically acceptable solvate of the compound that described general formula I represents comprises the solvate of compound that general formula I represents and water, ethanol, Virahol, ether, acetone etc. without limitation.
Typical compound of the present invention includes but not limited to the compound shown in table one:
Table one:
The preparation method that another object of the present invention is the compound, its pharmacy acceptable salt and the pharmaceutically acceptable solvate thereof that provide general formula I to represent, described preparation method comprises following two kinds of syntheti c routes:
Route one: when T is-(CH 2) m-, wherein m is 0 o'clock, this route comprises the steps
Wherein, identical with compound of Formula I of the definition of R1 and R2,
The synthetic of compound i can be with reference to CN102459172.Compound i is by obtaining compound ii with the aminating reaction of ammoniacal liquor generation copper catalysis, compound ii and triphosgene and by HR 2the nitrogen heterocyclic ring reaction representing obtains compound iii;
Route two: when T is-(CH 2) m-, wherein m is 1 or 2 o'clock, this route comprises the steps
Wherein, identical with compound of Formula I of the definition of R1 and R2,
The synthetic of compound i can be with reference to CN102459172.Compound ii synthetic is that the aminating reaction by compound i and the catalysis of ammoniacal liquor generation copper obtains, compound ii with replace acyl chlorides after reacting generating compound iv again with by HR 2the nitrogenous heterocyclic compound representing carries out substitution reaction and obtains compound v.
Another object of the present invention is for a kind of pharmaceutical composition is provided, and it comprises and is selected from the compound shown in general formula I, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof one or more; With pharmaceutically acceptable auxiliary material.
Another object of the present invention for provide described compound for the preparation of prevention or treatment relevant to gradually changeable lymphoma enzyme in organism the medicine of disease in purposes, wherein, described disease is followed the symptoms such as abnormal cell proliferation, metamorphosis and hypoerkinesia.Preferably, provide the purposes of described compound in the medicine for the preparation of prevention or the treatment disease relevant to angiogenesis or metastasis of cancer.More preferably, provide the purposes of described compound in the medicine for the preparation of prevention or treatment tumor growth and transfer.
Embodiment:
Below in conjunction with specific embodiment, the present invention is further elaborated.These embodiment are only for purpose of explanation, and do not limit the scope of the invention and essence.
1H-NMR measures with Varian MercuryAMX300 type instrument; Praseodynium iron [Fe (acac) 3], cuprous iodide [CuI], be purchased from J & K Chemica lark prestige chemical reagents corporation, ammoniacal liquor [NH 3.H 2o] be purchased from Alfa Aesar, all the other reagent are produced by Chinese Medicine reagent company limited.All solvents all pass through re-distillation before use, and the anhydrous solvent using is all to obtain by standard method drying treatment; Except special instruction, it is all under nitrogen protection, to carry out and TLC tracking that institute responds, and during aftertreatment, all through saturated sodium-chloride water solution, washs and anhydrous sodium sulfate drying process; The purifying of product is all used silica gel (200-300 order) column chromatography except special instruction; Wherein silica gel (200-300 order) is produced by Haiyang Chemical Plant, Qingdao, and GF-254 thin-layer silicon offset plate is produced by Yantai Jiang You silica gel development corporation, Ltd..
The preparation of Preparation Example 1 compound S 1
The synthesized reference CN102459172 of compound 1-1.
Compound 1-2's is synthetic:
Compound 1-1 is dissolved in ethanol, under nitrogen protection, adds 0.2eq cuprous iodide (CuI) and 0.2eq triacetyl acetone iron (Fe (acac) 3) finish configuration sodium hydroxide ammonia soln, 2eq dissolution of sodium hydroxide, in 10eq ammoniacal liquor, is added this sodium hydroxide ammonia soln in reaction solution to 90 ℃ of reaction 48h of tube sealing.After having reacted, by reacting liquid filtering, with chloroform and water, extract organic phase silica gel mixed sample upper prop, CHCl 3: MeOH:NH 3.H 2o=100:1:1～100:20:1 (volume ratio) obtains compound 1-2.
1H?NMR(300MHz,CDCl 3)δ10.19(s,1H),8.51(d,J=8.1Hz,1H),8.14(s,1H),7.67(s,1H),7.50(dd,J=8.2,1.4Hz,1H),6.81(s,1H),4.15(s,2H),2.55(q,J=7.4Hz,3H),1.80(s,6H),1.37–1.25(m,3H)。
Synthesizing of compound S 1:
Compound 1-2 is dissolved in methylene dichloride (DCM), adds 1.5eq triethylamine (Et 3n) and 0.6eq triphosgene (BTC), after 15min, add 4-(4-piperidyl) the morpholine DCM solution of 5eq, stirring at room.After reacting completely, directly add silica gel mixed sample upper prop, CHCl 3: MeOH:NH 3.H 2o=100:1:1～100:20:1 obtains compound S 1.
1H?NMR(300MHz,CDCl 3)δ11.02(s,1H),8.42(d,J=8.1Hz,1H),8.21(s,1H),8.16(s,1H),7.58(s,1H),7.45(d,J=8.2Hz,1H),6.73(s,1H),4.15(d,J=13.4Hz,2H),3.81–3.68(m,4H),3.05(t,J=11.6Hz,2H),2.67(t,J=7.5Hz,2H),2.63–2.52(m,4H),2.45(s,1H),1.98(d,J=11.0Hz,2H),1.57(m,8H),1.31(t,J=7.5Hz,3H)。
The preparation of Preparation Example 2 compound Ss 2
Synthesizing of compound S 2:
Except using compound 2-(4-piperidyl)-2-propyl alcohol to replace 4-(4-piperidyl) morpholine, synthesizing of compound S 2 is identical with compound S 1.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.30(dd,J=8.2,0.7Hz,1H),8.04(s,1H),7.97(s,1H),7.65(dd,J=1.4,0.7Hz,1H),7.38(dd,J=8.2,1.4Hz,1H),4.06(d,J=13.1Hz,2H),2.79(t,J=11.8Hz,2H),2.57(q,J=7.5Hz,2H),1.76(d,J=11.6Hz,2H),1.63(s,6H),1.22(m,5H),1.06(s,6H)。
The preparation of Preparation Example 3 compound Ss 3
Synthesizing of compound S 3:
Except using compound 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-a] pyrazine is replaced outside 4-(4-piperidyl) morpholine, and synthesizing of compound S 3 is identical with compound S 1.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.36(d,J=8.2Hz,1H),8.16(s,1H),7.73(s,1H),7.72(s,1H),7.42(dd,J=8.2,1.4Hz,1H),4.99(s,2H),4.23(t,J=5.2Hz,2H),4.02(t,J=5.3Hz,2H),2.65(q,J=7.5Hz,2H),1.68(s,6H),1.23(t,J=7.5Hz,3H)。
The preparation of Preparation Example 4 compound Ss 4
Synthesizing of compound S 4:
Except using compound 4-(azetidine-3-yl) morpholine to replace 4-(4-piperidyl) morpholine, synthesizing of compound S 4 is identical with compound S 1.
1H?NMR(400MHz,CDCl 3)δ11.39(s,1H),8.49(d,J=8.2Hz,1H),8.41(s,1H),8.23(s,1H),7.88(s,1H),7.52(dd,J=8.2,1.4Hz,1H),6.25(s,1H),4.15(t,J=7.6Hz,2H),4.03(dd,J=8.0,5.2Hz,2H),3.82–3.72(m,4H),3.29(s,1H),2.67(q,J=7.5Hz,2H),2.44(s,4H),1.79(s,6H),1.34(t,J=7.5Hz,3H)。
The preparation of Preparation Example 5 compound Ss 5
Synthesizing of compound S 5:
Except using compound 3-azabicyclo [3.1.0] octane-6-base methyl alcohol to replace 4-(4-piperidyl) morpholine, synthesizing of compound S 5 is identical with compound S 1.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.41(d,J=8.2Hz,1H),8.32(s,1H),8.13(s,1H),7.71(s,1H),7.46(d,J=8.2Hz,1H),3.68(d,J=9.7Hz,2H),3.58(d,J=9.4Hz,2H),3.49(d,J=6.8Hz,2H),2.62(q,J=7.5Hz,2H),1.68(d,J=9.0Hz,6H),1.61(s,2H),1.30(t,J=7.5Hz,3H),1.00(dd,J=6.6,3.3Hz,1H)。
The preparation of Preparation Example 6 compound s 6s
Compound 6-1's is synthetic:
Compound 1-1 is dissolved in DCM, adds 3eq triethylamine, under ice bath, slowly drip the DCM solution of 1.5eq chloroacetyl chloride, finish and slowly rise to room temperature and react.After reacting completely, reaction solution pressurization is steamed except rear and used ethyl acetate and 1N hcl as extraction agent, then wash with saturated sodium bicarbonate, saturated common salt washing, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product 6-1.
Synthesizing of compound s 6:
Compound 6-1 is dissolved in acetonitrile, adds 1.5eq2-methyl-octahydro pyrroles [3,4-C] pyrroles and 3eq salt of wormwood, finish reflux and spend the night.After reacting completely, by insolubles filtering, filtrate adds silica gel mixed sample upper prop, CHCl 3: MeOH:NH 3.H 2o=100:1:1～100:20:1 obtains compound s 6.
1H?NMR(300MHz,CDCl 3)δ10.26(s,1H),9.76(s,1H),8.73(s,1H),8.51(d,J=8.0Hz,1H),8.26(s,1H),7.76(s,1H),7.54(dd,J=8.2,1.4Hz,1H),3.37(s,2H),2.84(s,4H),2.79–2.61(m,6H),2.39(m,5H),1.79(s,6H),1.34(t,J=7.5Hz,3H)。
The preparation of Preparation Example 7 compound Ss 7
Synthesizing of compound S 7:
Except using compound 3-azabicyclo [3.1.0] octane-6-base methyl alcohol to replace outside 2-methyl-octahydro pyrroles [3,4-C] pyrroles, synthesizing of compound S 7 is identical with compound s 6.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.45(s,1H),8.24(d,J=8.0Hz,1H),8.00(s,1H),7.62(s,1H),7.33(d,J=8.0Hz,1H),3.27(d,J=6.4Hz,2H),3.16(s,2H),3.05(d,J=8.9Hz,2H),2.54(dd,J=16.0,8.2Hz,4H),1.60(s,6H),1.29(s,2H),1.18(t,J=7.5Hz,3H)0.67(d,J=8.1Hz,1H)。
The preparation of Preparation Example 8 compound Ss 8
The synthesized reference CN102459172 of compound 8-1.
Synthesizing of compound S 8:
Except using compound 8-1 to replace compound 1-1, synthesizing of compound S 8 is identical with compound S 1.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.52(d,J=8.2Hz,1H),8.35(d,J=8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.55(s,1H),7.52(s,1H),7.36(d,J=8.0Hz,1H),4.15(d,J=13.4Hz,2H),3.81–3.68(m,4H),3.05(t,J=11.6Hz,2H),2.67(t,J=7.5Hz,2H),2.63–2.52(m,2H),2.45(s,1H),1.98(d,J=11.0Hz,2H),1.57(m,8H)。
The preparation of Preparation Example 9 compound Ss 9
Synthesizing of compound S 9:
Bromo-5,6,7 except using compound 3-, 8-tetrahydrochysene-[1,2,4] triazolos [4,3-A] pyrazine is replaced outside compound 4-(4-piperidyl) morpholine, compound S 9 synthetic identical with compound S 1.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.39(d,J=8.2Hz,1H),8.13(s,1H),7.75(s,1H),7.78(s,1H),7.41(dd,J=8.2,1.4Hz,1H),4.97(s,2H),4.25(t,J=5.2Hz,2H),4.08(t,J=5.3Hz,2H),2.63(q,J=7.5Hz,2H),1.66(s,6H),1.21(t,J=7.5Hz,3H)。
The preparation of Preparation Example 10 compound Ss 10
Synthesizing of compound S 10:
Except using compound 2-(4-piperidyl)-2-propyl alcohol to replace outside 2-methyl-octahydro pyrroles [3,4-c] pyrroles, synthesizing of compound S 10 is identical with compound s 6.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.43(s,1H),8.22(d,J=8.0Hz,1H),8.03(s,1H),7.61(s,1H),7.35(d,J=8.0Hz,1H),3.16(s,2H),3.01(d,J=13.1Hz,2H),2.57(m,4H),1.76(d,J=11.6Hz,2H),1.63(s,6H),1.21(m,5H),1.04(s,6H)。
The preparation of Preparation Example 11 compound Ss 11
Synthesizing of compound S 11:
Except use compound cis-2-Boc-hexahydropyrrolo also [3,4-c] pyrroles replace outside 2-methyl-octahydro pyrroles [3,4-c] pyrroles, compound S 11 synthetic identical with compound s 6.
1H?NMR(300MHz,CDCl 3)δ10.23(s,1H),9.74(s,1H),8.72(s,1H),8.55(d,J=8.0Hz,1H),8.21(s,1H),7.75(s,1H),7.53(dd,J=8.2,1.4Hz,1H),3.32(s,2H),2.81(s,4H),2.79–2.61(m,6H),2.36(m,2H),1.71(s,6H),1.32(t,J=7.5Hz,3H)。
The preparation of Preparation Example 12 compound Ss 12
Synthesizing of compound S 12:
Methoxyacetic acid is dissolved in dry DCM, adds thionyl chloride, stirred overnight at room temperature, after reacting completely removes reaction solution under reduced pressure, then adds dry DCM, then solvent is steamed and to be removed, this step in triplicate after, obtain oily matter standby.
Compound S 7 is dissolved in dry chloroform, adds 4eq triethylamine, under ice bath, slowly drip the DCM solution of upper step oily matter, finish placement room temperature reaction.After reacting completely, reaction solution is removed under reduced pressure, add water, saturated common salt washing, silica gel mixed sample upper prop after anhydrous sodium sulfate drying, CHCl 3: MeOH=100:1～30:1 obtains compound S 12.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.42(s,1H),8.21(d,J=8.0Hz,1H),8.01(s,1H),7.65(s,1H),7.32(d,J=8.0Hz,1H),4.36(s,2H),4.27(d,J=6.4Hz,2H),3.35(s,3H),3.16(s,2H),3.05(d,J=8.9Hz,2H),2.54(dd,J=16.0,8.2Hz,4H),1.60(s,6H),1.29(s,2H),1.18(t,J=7.5Hz,3H)0.66(d,J=8.1Hz,1H)。
The preparation of Preparation Example 13 compound Ss 13
Synthesizing of compound S 13:
Except using compound 3-ethoxycarbonyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazolos [4,3-A] pyrazine is replaced outside compound 4-(4-piperidyl) morpholine, and synthesizing of compound S 13 is identical with compound S 1.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.35(d,J=8.2Hz,1H),8.11(s,1H),7.72(s,1H),7.76(s,1H),7.40(dd,J=8.2,1.4Hz,1H),4.94(s,2H),4.32(q,J=7.5Hz,2H),4.23(t,J=5.2Hz,2H),4.04(t,J=5.3Hz,2H),2.61(q,J=7.5Hz,2H),1.65(s,6H),1.31(t,J=7.5Hz,3H),1.27(t,J=7.5Hz,3H)。
The preparation of Preparation Example 14 compound Ss 14
Synthesizing of compound S 14:
Except using compound 8-1 to replace compound 1-1, compound 2-(4-piperidyl)-2-propyl alcohol is replaced outside compound 4-(4-piperidyl) morpholine, and synthesizing of compound S 14 is identical with compound S 1.
1H?NMR(300MHz,CDCl 3+MeOD)δ8.55(d,J=8.2Hz,1H),8.36(d,J=8.1Hz,1H),7.72(d,J=8.1Hz,1H),7.57(s,1H),7.54(s,1H),7.37(d,J=8.0Hz,1H),4.02(d,J=13.1Hz,2H),2.76(t,J=11.8Hz,2H),1.77(d,J=11.6Hz,2H),1.62(s,6H),1.26(m,2H),1.03(s,6H)。
EXPERIMENTAL EXAMPLE: molecular receptor SRCA LK molecular level activity rating
1. acceptor propylhomoserin kinases ALK molecular level enzyme is lived and is suppressed preliminary assessment experiment
(1) enzyme reaction substrate Poly (Glu, Tyr) in PBS (sodium hydrogen phosphate salt buffer) (the 10mM sodium phosphate buffer of the ratio of 4:1 without potassium ion, 150mM NaCl, pH7.2-7.4) be diluted to 20 μ g/mL, 125 μ L/ hole coated elisa plates, put 37 ° of C reaction 12-16 hour.Discard liquid in hole.Wash plate, with the T-PBS (containing the PBS without potassium ion of 0.1%Tween-20) in 200 μ L/ holes, wash plate three times, each 5 minutes.Dry enzyme plate 1-2 hour in 37 ° of C baking ovens.
(2) every hole adds with reaction buffer (50mM HEPES (4-hydroxyethyl piperazine ethanesulfonic acid) pH7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM DTT (dithiothreitol (DTT))) ATP (Triphosaden) the solution 49 μ L of dilution, add 1 μ L compound in every hole, add compound to be tested, add 50 μ L to start reaction with each kinases territory recombinant protein of reaction buffer dilution, each experiment need be established without ATP control wells two holes again.Put 37 ° of C shaking tables (100rpm) reaction 1 hour.Discard liquid in hole, T-PBS washes plate three times.
(3) add antibody PY99100 μ L/ hole (the T-PBS1:500 dilution containing BSA (bovine serum albumin) 5mg/mL for antibody), 37 ° of C shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(4) add the anti-100 μ L/ holes of sheep anti mouse two (the T-PBS1:2000 dilution containing BSA5mg/ml for antibody) of horseradish peroxidase-labeled, 37 ° of C shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(5) add OPD (O-Phenylene Diamine) the nitrite ion 100 μ L/ holes (with 0.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution that contains 0.03%H2O2) of 2mg/ml, 25 ° of C lucifuge reaction 1-10 minute.
(6) add 2M H2SO450 μ L/ hole stopped reaction, with the wavelengthtunable orifice plate microplate reader VERSAmax reading that declines, wavelength is 490nm.
(7) interpretation of result
2. receptor tyrosine kinase ALK enzyme is lived and is suppressed IC 50evaluation experimental
Table two: compound is to receptor tyrosine kinase ALK enzyme inhibition level alive
The test result demonstration of representative compound, the application's compound is under the concentration of 0.1 μ M, and all compounds all have restraining effect, majority of compounds IC to ALK 50being less than 10nM, is therefore very potential ALK inhibitor.

Claims (9)

1. the compound shown in a following general formula I, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof:
General formula I
Wherein:
R 1for hydrogen atom, halogen or C1～C4 alkyl; T is-(CH 2) m-, wherein m is 0,1 or 2;
R 2for replacing or the unsubstituted saturated or unsaturated heterocycle base that contains 1-4 heteroatomic 4 yuan to 10 yuan, the substituting group of the saturated or unsaturated heterocycle base of described replacement is the saturated heterocyclyl that contains 1-2 heteroatomic 4 yuan to 10 yuan, the C1-C4 alkyl that hydroxyl replaces, C1-C4 alkyl, C1-C4 alkyl, halogen, C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group or the C1-C4 alkoxy carbonyl that halogen replaces, wherein, described heteroatoms is N, O or S;
Wherein, described C1-C4 alkyl is C1-C4 straight or branched alkyl; Described halogen is F, Cl, Br or I.
2. the compound shown in general formula I according to claim 1, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof, wherein,
R 2for replacing or a saturated heterocyclyl of the unsubstituted 1-2 of containing heteroatomic 4 yuan to 8 yuan or for replacing or unsubstitutedly containing 1-4 heteroatomic 9 membered unsaturated heterocycle bases, the substituting group of the saturated heterocyclyl of described replacement is C1-C4 alkyl, C1-C4 alkyl or the C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group that contains 1-2 heteroatomic 6 yuan of saturated heterocyclyls, hydroxyl replacement, the substituting group of the unsaturated heterocycle base of described replacement is C1-C4 alkyl, halogen or the C1-C4 alkoxy carbonyl that halogen replaces, wherein, described heteroatoms is N, O or S.
3. the compound shown in general formula I according to claim 2, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof, wherein,
R 2for replacing or the saturated heterocyclyl of 4 yuan, 6 yuan of the unsubstituted 1-2 of a containing nitrogen-atoms or 8 yuan or be replacement or the unsubstituted 9 membered unsaturated heterocycle bases that contain 4 nitrogen-atoms, the substituting group of the saturated heterocyclyl of described replacement is C1-C4 alkyl, C1-C4 alkyl or the C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group that contains 1-2 heteroatomic 6 yuan of saturated heterocyclyls, hydroxyl replacement, the substituting group of the unsaturated heterocycle base of described replacement is C1-C4 alkyl, halogen or the C1-C4 alkoxy carbonyl that halogen replaces, wherein, described heteroatoms is N or O.
4. the compound shown in general formula I according to claim 3, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof, wherein,
R 2for that replace or unsubstituted or or for replace or do not replace wherein, described replacement or substituting group be c1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy C 1-C4 alkylidene group ketonic oxygen base C1-C4 alkylidene group that hydroxyl replaces, described replacement substituting group be C1-C4 alkyl, halogen or the C1-C4 alkoxy carbonyl that 1-3 halogen replaces.
5. the compound shown in general formula I according to claim 1, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof, the compound shown in described general formula I is following compound:
6. the compound shown in general formula I according to claim 1, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof, wherein, described pharmacy acceptable salt is inorganic acid salt or organic acid salt, wherein, described inorganic acid salt is hydrochloride, hydrobromate, nitrate, vitriol or phosphoric acid salt, and described organic acid salt is formate, acetate, propionic salt, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion, alkylsulfonate or benzene sulfonate; Preferably, described alkylsulfonate is metilsulfate or ethyl sulfonate; Described arylsulphonate is benzene sulfonate or tosilate;
Described pharmaceutically acceptable solvate is the solvate of the compound shown in described general formula I and water, ethanol, Virahol, ether or acetone.
7. a pharmaceutical composition, it comprises and is selected from the compound shown in general formula I claimed in claim 1, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof one or more; With pharmaceutically acceptable auxiliary material.
8. compound, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof the purposes in the medicine for the preparation of prevention or treatment and the disease that in organism, gradually changeable lymphoma enzyme is relevant according to claim 1, wherein, described disease is followed abnormal cell proliferation, metamorphosis and/or hypoerkinesia symptom.
9. compound according to claim 1, its pharmacy acceptable salt and pharmaceutically acceptable solvate thereof the purposes in the medicine for the preparation of prevention or the treatment disease relevant to angiogenesis or metastasis of cancer, is preferably the purposes of described compound in the medicine for the preparation of prevention or treatment tumor growth and transfer.
CN201310187705.4A 2013-05-20 2013-05-20 Amido substituted indolonaphthalenone derivatives and medicinal uses thereof Pending CN104177332A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012023597A1 (en) * 2010-08-20 2012-02-23 中外製薬株式会社 Composition containing tetracyclic compound
CN102459172A (en) * 2009-06-10 2012-05-16 中外制药株式会社 Tetracyclic compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459172A (en) * 2009-06-10 2012-05-16 中外制药株式会社 Tetracyclic compound
WO2012023597A1 (en) * 2010-08-20 2012-02-23 中外製薬株式会社 Composition containing tetracyclic compound

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