CN105585583A - Non-peptide IAP (inhibitor of apoptosis protein) antagonist as well as synthetic method and application thereof - Google Patents
Non-peptide IAP (inhibitor of apoptosis protein) antagonist as well as synthetic method and application thereof Download PDFInfo
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- CN105585583A CN105585583A CN201610038275.3A CN201610038275A CN105585583A CN 105585583 A CN105585583 A CN 105585583A CN 201610038275 A CN201610038275 A CN 201610038275A CN 105585583 A CN105585583 A CN 105585583A
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- 108091007065 BIRCs Proteins 0.000 title abstract description 7
- 239000005557 antagonist Substances 0.000 title abstract description 5
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- 102000055031 Inhibitor of Apoptosis Proteins Human genes 0.000 title abstract 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 40
- 229940083346 IAP antagonist Drugs 0.000 claims abstract description 27
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- 238000002360 preparation method Methods 0.000 claims description 20
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- XYOMDMGVLCQTEV-DUIPJYSDSA-N C[C@@H](/C=N/[C@@H](CSCC[C@@H](CC1)N2[C@@H]1C(N[C@H]1c3ccccc3CCC1)=O)C2=O)NC(OC(C)(C)C)=O Chemical compound C[C@@H](/C=N/[C@@H](CSCC[C@@H](CC1)N2[C@@H]1C(N[C@H]1c3ccccc3CCC1)=O)C2=O)NC(OC(C)(C)C)=O XYOMDMGVLCQTEV-DUIPJYSDSA-N 0.000 description 1
- ZNAIFKYHWUYVPA-NFGITUDRSA-N C[C@@H](CSCC(C1)[C@@]1(CC1)N2[C@@H]1C(N[C@H]1c3ccccc3CCC1)=O)C2=O Chemical compound C[C@@H](CSCC(C1)[C@@]1(CC1)N2[C@@H]1C(N[C@H]1c3ccccc3CCC1)=O)C2=O ZNAIFKYHWUYVPA-NFGITUDRSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 101710136259 E3 ubiquitin-protein ligase XIAP Proteins 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FIMJSWFMQJGVAM-UHFFFAOYSA-N chloroform;hydrate Chemical compound O.ClC(Cl)Cl FIMJSWFMQJGVAM-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 210000000969 egg white Anatomy 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical class COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- AKRYBBWYDSDZHG-UHFFFAOYSA-N nitrosobis(2-oxopropyl)amine Chemical compound CC(=O)CN(N=O)CC(C)=O AKRYBBWYDSDZHG-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
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- 238000007616 round robin method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
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- 150000003385 sodium Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a non-peptide IAP (inhibitor of apoptosis protein) antagonist as well as a synthetic method and an application thereof, aims to provide a non-peptide IAP antagonist with better anti-cancer effect and a structural formula of the non-peptide IAP antagonist and belongs to the technical field of pharmaceutical synthesis.
Description
Technical field
The invention discloses a kind of anticancer non-peptide medicine of new small molecule that can cell death inducing, specifically,Be a kind of non-peptide class IAP antagonist, belong to medical technical field.
Background technology
Treatment of cancer is huge challenge concerning the mankind always, at present cancer treatment method comprise operation excision, chemotherapy,Radiation treatment, deathbed care etc., but be which kind of mode is all difficult to thoroughly cure. In the past few decades,Along with the progress of medical technology, treatment of cancer means are also in constantly progressive and development. But existing cancer therapy drug hasVarious limitation, this is also in treatment of cancer, to need the huge obstacle gone beyond.
The most cells poison therapy (comprising chemotherapy and radiotherapy) that is applied in now cancer clinical treatment be all based onCancer cell specific induction of apoptosis. Apoptosis refers to for maintaining homeostasis, by autonomous orderly dead of the cell of gene controlDie. Apoptosis is different from meronecrosis, and it is not autologous damage under pathological conditions, but raw for adapting to betterDis environment and a kind of death process of initiatively striving for. Apoptosis pathway dysfunction is the important pathological characteristics of cancer, andCancer cell stimulates and produces tolerance various cell toxicants, thereby Apoptosis Mechanism was lost efficacy, and is that current many cancers are controlledTreat the reason of clinical practice failure. Past, vicennial research showed, IAP (IAPs) is ApoptosisKey regulate son, taking IAP as target spot, the new small molecule anticarcinogen that exploitation can cell death inducingThing becomes the focus of cancer research. Compared with peptide medicament, the limited Non-peptide mimics of conformation can more effectively overcomeThe limitation of nature peptide and peptide mimics, for example cell-penetrating is poor, body internal stability is poor and bioavailability is low.Therefore, develop non-peptide and efficient IAP antagonist, in treatment of cancer, there is huge application prospect.
Summary of the invention
For the problems referred to above, the object of this invention is to provide a kind of non-peptide class apoptosis with better anticancer effect and suppress eggWhite antagonist the present invention also provides the preparation method of this antagonist.
For the problems referred to above, first technical scheme provided by the invention is such:
A kind of non-peptide class IAP antagonist, its structural formula as shown in Equation 1:
Wherein:
R1Be selected from following substituent one of them:
R2Be selected from following substituent one of them:
Above-mentioned X is selected from one of them of F, Cl, Br, Me, OMe;
Y is selected from S or O;
Formula 1.
Second technical scheme of the present invention is to provide the preparation method of this non-peptide class IAP antagonist, the partyMethod comprises the steps: successively
1), at-10～15 DEG C, mesyl chloride, DMAP, organic base are added in the chlorohydrocarbon solution of intermediate A,Stir 2～60 minutes, reactant liquor dilutes with chlorohydrocarbon, and process weak acid is washed successively, weak base is washed, saturated common salt water washing,Dry, concentrated, without being further purified, obtain intermediate B; At-10～15 DEG C, NaH is added toIn the solution of Boc-Cys-OH, the suspension agitation reactant liquor of 1～60 minute, then the solution of intermediate B is addedTo reactant liquor, mixed room temperature stirs 0.5～10 hour, concentrated, collects respectively organic phase and Liquid Residue, Liquid ResidueDilute with water, regulates pH value to acid, adopts after organic solvent extraction, merge after organic phase, then through water washing,Dry, reduced pressure concentration, the thick product of gained is crossed post purifying, obtains faint yellow oily intermediate C;
Wherein, the mol ratio of described mesyl chloride, DMAP, intermediate A, NaH, Boc-Cys-OH is: 0.9～5：0.05～3：1：1.6～10：0.8～5；
2) metallic catalyst is added in the polar solvent of intermediate C, suspension is at H2Middle stirring is spent the night, reactionAfter, to filter, filtrate decompression is concentrated, obtains faint yellow oily intermediate D; At-10～15 DEG C, condensing agent is addedEnter to the chlorohydrocarbon solution of intermediate D, then add organic base, mixed liquor stirring at room temperature 4～72 hours, has reactedBi Hou, is concentrated into half volume by reactant liquor, and process weak acid is washed successively, weak base is washed, saturated common salt water washing, dry,Concentrated, purifying, obtains colorless oil intermediate E;
Wherein, the mol ratio of described condensing agent, intermediate D is: 0.8～20:1;
3), at-10～15 DEG C, TIPS is added in the chlorohydrocarbon solution of intermediate E, then adds TFA, mixed liquorStir 0.5～10 hour, solvent evaporated, collects aqueous layer, residue dilute with water, then use ether washed twice, thenMerge with the aqueous layer of collecting, dry, obtain intermediate F; Be dissolved in MeCN/H2In O, add Boc2O、Organic base, mixed liquor stirred overnight at room temperature, concentrated, collect respectively organic phase and Liquid Residue, Liquid Residue dilute with water,Regulate pH value to acid, adopt after organic solvent extraction, after merging organic phase, wash with water, lotion, dry, obtainsIntermediate G;
Wherein: described TIPS, intermediate E, Boc2O mol ratio is: 0.1～10:1:0.9～3;
4) at-10～15 DEG C, intermediate G is dissolved in organic solvent, adds aromatic amine, condensing agent and additive,Then add organic base, mixed liquor stirred overnight at room temperature, then wash successively, weak base is washed, saturated common salt by weak acid for reactant liquorWater washing, dry, the concentrated thick product of gained is crossed post purifying, obtains colorless oil intermediate H;
Wherein, the mol ratio of described intermediate G, aromatic amine, condensing agent, additive be 1:0.9～10:0.9～20：0.1～20；
5) at-10～15 DEG C, TFA is added in the chlorohydrocarbon solution of intermediate H, mixed liquor stirs 0.1～5Hour, the concentrated intermediate compound I that obtains;
6), under the protection of inert gas, the aldehyde of tertbutyloxycarbonyl protection is added in the solution of intermediate compound I, then addsEnter enough drier, stirring at room temperature 1～20 hour, filters, concentrated, obtains thick product J. At-10～15 DEG C, willIntermediate J is dissolved in the chlorohydrocarbon heavily steaming, and adds reducing agent. Reaction is stirred and is spent the night, and after completion of the reaction, adds saturatedSodium bicarbonate solution cancellation reaction, then with organic solvent extraction repeatedly, merge organic phase. Organic phase saturated common saltWater washing, desiccant dryness, concentrated, obtain product K. At-10～15 DEG C, intermediate K is dissolved in chlorohydrocarbon,Add TFA, mixed liquor stirs 0.1～5 hour, concentrated, repurity, and freeze drying, obtains white solid finished product L.
Wherein, described intermediate compound I, the aldehyde of tertbutyloxycarbonyl protection, the mol ratio of reducing agent are: 1:0.95～5:0.95～5。
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, described organic base be triethylamine,Or DBU or DIEA or N-methylmorpholine.
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, described organic metal catalysis isRaney's nickel water slurry or palladium catalyst.
Preferably, above-mentioned condensing agent be BOP or DCC or EDCI or DIC or PyBOP or TBTU,Or HBTU or HATU or TATU.
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, described additive be HOBt,Or HOOBt or HOSu.
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, described aromatic amine is diphenylMethylamine or benzene methanamine or 5,6,7,8-tetrahydrochysene-naphthalidine or (R)-2,3-dihydro-1H-indenes-1-amine or (S)-naphthalene-2-base (benzeneBase) methylamine or 2-phenylethylamine or 2-(trifluoroethyl) benzene methanamine or 4-phenyl-1,2,3 ,-thiadiazoles-5-amine or 3-Methyl isophthalic acid-phenyl-1H-pyrazoles-5-amine or (4-fluoro) benzene methanamine or (4-chloro) benzene methanamine or (4-bromo) benzene methanamine,Or (4-methyl) benzene methanamine or (4-methoxyl group) benzene methanamine or 2-furylamine or 2-thenylaminine.
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, described tertbutyloxycarbonyl protectionAmido aldehyde be N-tertbutyloxycarbonyl-L-the third ammonium aldehyde or (S)-2-(tertbutyloxycarbonyl) aminobutyl aldehyde or (S)-2-((tertiary fourth oxygenCarbonyl) methylamino) propionic aldehyde or (S)-2-((tertbutyloxycarbonyl) methylamino) butyraldehyde.
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, described drier be magnesium sulfate,Sodium sulphate, calcium chloride, molecular sieve.
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, described reducing agent is triacetylOxygen base sodium borohydride, sodium cyanoborohydride.
Preferably, the preparation method of above-mentioned non-peptide class IAP antagonist, the structure of described intermediate AFormula is:
Last technical scheme provided by the invention is that non-peptide class IAP antagonist is as antineoplasticApplication.
Compared with prior art, the binding affinity of the technical scheme providing of the present invention and XIAP-BIR3 is strong, non-peptideFeature is more obvious, is a kind of novel, non-peptide class, efficient XIAP antagonist, has better anticancer effect, toolThere is good application prospect.
Brief description of the drawings
Fig. 1 is compound L 11HNMR detects spectrogram;
Fig. 2 is compound L 21HNMR detects spectrogram;
Fig. 3 is compound L 31HNMR detects spectrogram;
Fig. 4 is that compound L 3 suppresses curve with XIAP-BIR3 competitive binding.
Detailed description of the invention
Below in conjunction with detailed description of the invention, claim of the present invention is described in further detail, but does not formAny limitation of the invention, the amendment of anyone limited number of time making in the claims in the present invention protection domain, stillWithin claim protection domain of the present invention.
All reagent, without special instruction, is commercially available analysis pure, without being further purified, directly uses. Anhydrous and oxygen-freeThe glass apparatus of reaction before use, dry in baking oven, and reaction is carried out under Ar protection. Solvent heavily steams all at ArUnder protection, carry out, THF is dry under the condition of sodium metal and benzophenone, carrene, ethyl acetate calcium hydrideDry. Column chromatography uses 63～200 order silica gel, and thin-layer chromatography uses MerckTLCsilicagel60F254 plastics lookSpectrum plate, by the ethanolic solution color developing detection of 254nm ultraviolet lighting or iodine vapor or 2% ninhydrin. Nuclear magnetic resonanceSpectrum is used BrukerAVANCEIII400NMR spectrometer to measure, and chemical displacement value is taking ppm as unit record. Mass spectrumUse LCTPremierXE type time of-flight mass spectrometer to measure. Optical value is measured with JASCOP-1010 polarimeter.
High performance liquid chromatography (HPLC) condition: (1) preparation HPLC: PerkinElmerSeries200UV/VISDetector; PerkinElmerSeries200 two-phase pump; Vacuum degasser; GilsonFC203b cut receiving instrument; (2)Analytic type HPLC:PerkinElmerSeries225 automatic sampler; PerkinElmerSeries220UV/VIS inspectionSurvey device; PerkinElmerSeries200 tetra-phase pumps; Vacuum degasser. Mobile phase: (1) mobile phase A: water+0.045%TFA; (2) Mobile phase B: 10% water+90% acetonitrile+0.038%TFA.
Embodiment 1
The synthetic method of intermediate A is as follows:
(S)-1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid (2)
Triethylamine (38mL, 0.273mol) is added to Pidolidone (20.0g, 0.140mol) and benzaldehyde (17.4G, 0.160mol) methanol solution (200mL) in. After mixture stirring at room temperature 1 hour, solution temperature is reducedTo 0 DEG C, then by NaBH4(5.67g, 0.150mol) is slowly added in reactant liquor. Stir after 2 hours, willReactant liquor is poured in the 4MHCl solution (50mL) of ice. By formed suspension reduced pressure concentration be heated to solidAll dissolve. After cooling a period of time, filtering the solid obtaining is compound 1. Without purifying, under can directly carrying outSingle step reaction. 1 the aqueous solution (300mL) is heated to reflux, and stirring is spent the night. Reactant liquor is cooled to room temperature,By dichloromethane extraction 3 times, organic phase dried over mgso, filter, reduced pressure concentration, thick product is crossed post purifying (streamMoving phase: from cyclohexane/ethyl acetate=1/1 to methylene chloride/methanol=15/1), obtain colorless oil 2 (17.4g,Three step gross production rates are 58%)
1HNMR(400MHz,CDCl3):δ11.10(br,1H),7.35-7.22(m,5H),5.17(d,J＝14.8Hz,1H),4.05-3.98(m,2H),2.70-2.61(m,1H),2.56-2.48(m,1H),2.35-2.24(m,1H),2.21-2.14(m,1H).
(S)-1-benzyl-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (3)
At Ar protection and 0 DEG C, the acetonitrile solution of oxalyl chloride (6.40mL, 70.0mmol) (5.2mL) is addedTo the mixed solvent of acetonitrile (40mL) and DMF (15mL), stir 15 minutes, add compound 2 (14.8G, 70.0mmol). Stir again after 15 minutes, add the pyridine (16.5mL) of the tert-butyl alcohol (16.2mL, 0.170mol)Solution. Mixed liquor stirring at room temperature 15 hours. After completion of the reaction, use 20%KHCO3Solution (150mL) cancellation is anti-Should. Ether for organic phase (2 × 150mL) extraction, then uses 1MHCl solution (2 × 100mL), saturated successivelySodium bicarbonate solution, saturated common salt water washing. Organic phase dried over mgso, concentrated, the thick product distillation purifying of gained(0.07mbar, 155 DEG C), obtain white solid 3 (11.24g, 60%).
1HNMR(400MHz,CDCl3):δ7.25-7.12(m,5H),4.97(d,J＝14.7Hz,1H),3.88(d,J＝14.8Hz,1H),3.82-3.74(m,1H),2.51-2.42(m,1H),2.35-2.27(m,1H),2.18-2.07(m,1H),1.98-1.90(m,1H),1.35(s,9H).
(S)-1-benzyl-5-sulfo-pyrrolidines-2-carboxylic acid tert-butyl ester (4)
By P4S10(10.7g, 20.0mmol) in three batches, was added to compound 3 (10.9g, 40.0mmol) in 2 hoursTHF solution (400mL) in. Stirring at room temperature 8 hours, filters, and gained is ether (500mL) washing for solid.Filtrate is concentrated, and residue is dissolved in ether (250mL), uses successively 20%KHCO3Solution (170mL) and saturatedSaline solution (170mL) washing. Meanwhile, water is used extracted with diethyl ether again. Organic phase is merged, dried over mgso,Reduced pressure concentration, the thick product of gained is crossed post purifying (cyclohexane/ethyl acetate=6/1), obtains faint yellow grease 4 (9.69g,83％)。
1HNMR(400MHz,CDCl3):δ7.37-7.28(m,5H),5.82(d,J＝14.6Hz,1H),4.29(dd,J＝14.6,0.8Hz,1H),4.16(dd,J＝9.6,3.6Hz,1H),3.21-3.05(m,2H),2.30-2.20(m,1H),2.14-2.07(m,1H),1.45(s,9H).
(S, E)-1-benzyl-5-(2-methoxyl group-2-oxo ethylidene) pyrrolidines-2-carboxylic acid tert-butyl ester (5)
Compound 4 (9.60g, 30.0mmol) and monobromo-acetic acid methyl esters (6.05g, 40.0mmol) are dissolved in to acetonitrile (27ML), in, gained mixed liquor stirring at room temperature 42 hours, is then cooled to-5 DEG C. Within 20 minutes, by triphenylThe dichloromethane solution (200mL) of phosphine (13.0g, 50.0mmol) is added in reactant liquor, then adds triethylamine(13.8mL, 100mmol). Stirring at room temperature 30 hours, organic phase 1MNaH2PO4Solution (75mL) is washedWash, water is used carrene (3 × 20mL) extraction again. Merge organic phase, dried over mgso, reduced pressure concentration, crosses postPurifying (cyclohexane/ethyl acetate=15/1), obtains faint yellow grease 5 (8.97g, 82%).
1HNMR(400MHz,CDCl3):δ7.36-7.19(m,5H),4.77(s,1H),4.55(d,J＝15.6Hz,1H),4.21(d,J＝15.6Hz,1H),3.96(dd,J＝9.0,3.0Hz,1H),3.63(s,3H),3.46-3.38(m,1H),3.14-3.05(m,1H),2.27-2.17(m,1H),2.12-2.05(m,1H),1.43(s,9H)；13CNMR(100MHz,CDCl3):δ171.43,169.89,165.42,135.88,129.04,127.94,127.91,82.36,80.57,65.42,50.41,49.75,31.30,28.23,26.64.
(2S, 5R)-1-benzyl-5-(2-methoxyl group-2-oxoethyl) pyrrolidines-2-carboxylic acid tert-butyl ester (6)
Compound 5 (500mg, 1.50mmol) is dissolved in ethyl acetate (10mL), under Ar protection with freezingThe pump round-robin method of thawing degasification, then adds 5%Pt/C (250mg), and suspension is at H2(3.2bar) in, stir 20Hour, diatomite filtration, filtrate is concentrated, obtains colorless oil 6 (390mg, 78%). Without purifying, directly enterNext step reaction of row.
1HNMR(400MHz,CDCl3):δ7.33-7.20(m,5H),3.86,3.80(ABq,J＝13.9Hz,2H),3.62(s,3H),3.30-3.16(m,2H),2.57(dd,J＝15.4,4.0Hz,1H),2.33(dd,J＝15.1,8.9Hz,1H),2.07-1.81(m,3H),1.70-1.61(m,1H),1.35(s,9H)；13CNMR(100MHz,CDCl3):δ173.88,172.96,139.13,129.35,128.41,127.26,80.47,67.17,61.77,58.11,51.62,40.67,31.06,28.61,28.20.
(2S, 5R)-1-benzyl-5-(2-ethoxy) pyrrolidines-2-carboxylic acid tert-butyl ester (A)
By LiBH4(26mg, 1.20mmol) is added to the diethyl ether solution of compound 6 (333mg, 1.00mmol)(5mL) in, stirring at room temperature 4 hours. Reaction adds 1MK2CO3Solution (10mL) cancellation, organic phase is usedSaturated common salt water washing, dried over mgso, reduced pressure concentration. Thick product is crossed post purifying (cyclohexane/ethyl acetate=3/1),Obtain colorless oil intermediate A (221mg, 72%).
1HNMR(400MHz,CDCl3):δ7.33-7.22(m,5H),5.21(br,1H),4.08-3.99(m,2H),3.76-3.71(m,1H),3.56(d,J＝12.9Hz,1H),3.28(dd,J＝8.6,5.6Hz,1H),3.24-3.18(m,1H),2.11-2.02(m,2H),1.93-1.81(m,3H),1.55-1.49(m,1H),1.27(s,9H)；13CNMR(100MHz,CDCl3):δ173.99,137.73,130.23,128.62,127.68,81.02,67.03,64.22,60.28,58.73,32.56,29.72,28.62,28.05.
Embodiment 2 (non-peptide class IAP antagonist L1)
(R)-3-(2-((2R, 5S)-1-benzyl-5-tert-butyl ester base) pyrrolidines) ethylmercapto group)-2-(tert-butoxy formamido) propionic acid (centreBody C)
At-10 DEG C, by mesyl chloride (174 μ L, 2.25mmol), DMAP (15mg, 0.125mmol), three secondAmine (1mL) is added in the dichloromethane solution (10mL) of intermediate A (765mg, 2.5mmol), stirs60 minutes, reactant liquor diluted with carrene, then use dilute hydrochloric acid solution successively, saturated sodium bicarbonate solution, saturated foodSalt water washing, dried over mgso, concentrated, obtain intermediate B. Without purifying, directly carry out next step reaction.
At-10 DEG C, NaH (96mg, 4mmol) is added to the DMF of Boc-Cys-OH (443mg, 2mmol)In solution (10mL), suspension agitation 60 minutes. Then the DMF solution (10mL) of B is added to reactionIn liquid, mixed liquor stirring at room temperature 10 hours, concentrated, residue dilute with water, with watery hydrochloric acid adjusting pH value to 2.Water is extracted with ethyl acetate three times, merges organic phase, and organic phase washes with water, and anhydrous magnesium sulfate drying reduces pressure denseContracting. The thick product of gained is crossed post purifying (methylene chloride/methanol=15/1), obtain faint yellow grease C (756mg,Two step gross production rates are 66%).
1HNMR(400MHz,MeOD):δ7.37-7.22(m,5H),4.25-4.16(m,1H),4.08(d,J＝13.4Hz,1H),3.80(d,J＝13.5Hz,1H),3.42(t,J＝8.1Hz,1H),3.11-2.97(m,2H),2.83(dd,J＝13.6,7.2Hz,1H),2.74-2.68(m,1H),2.58-2.51(m,1H),2.12-1.98(m,3H),1.86-1.58(m,3H),1.44(s,9H),1.32(s,9H)；13CNMR(100MHz,MeOD):δ175.27,173.90,157.75,136.93, 131.31,129.61,129.19,83.00,80.56,68.03,66.79,58.82,55.44,35.35,34.25,30.47,29.92,29.06,28.76,28.14；MS(ESI):m/z509.3(M+H)+；[α]D 24 :45.99(C1.0,CHCl3).
(5R, 8S, 10aR)-5-(tert-butoxy formamido)-6-carbonyl thia azatropylidene [1,5] pyrrolizine [2,1-d]-8-tert-butyl ester(intermediate E)
The water slurry of enough Raney's nickels (active catalyst, Ni >=89%, Al:6-9%) is added to Compound CIn the methanol solution (20mL) of (908mg, 1.79mmol), suspension is at H2Middle stirring is spent the night. React completeAfter, diatomite filtration, filtrate decompression is concentrated, obtains faint yellow grease D (648mg, 87%). Without purifying,Directly carry out next step reaction.
At 0 DEG C, PyBOP (16.13g, 31mmol) is added to the dry of Compound D (648mg, 1.55mmol)In dry dichloromethane solution (310mL), then add DIEA (1.5mL). Mixed liquor stirring at room temperature 4 hours,After completion of the reaction, reactant liquor is concentrated into half volume, use successively dilute hydrochloric acid solution, saturated sodium bicarbonate solution, water,Saturated common salt water washing, dried over mgso, concentrated obtains thick product, then cross post purifying (cyclohexane/ethyl acetate=4/1), obtain colorless oil E (373mg, 60%).
1HNMR(400MHz,CDCl3):δ5.96(d,J＝6.8Hz,1H),4.70-4.64(m,1H),4.60-4.55(m,1H),4.37(t,J＝8.8Hz,1H),2.97-2.90(m,2H),2.77-2.69(m,2H),2.41-2.34(m,1H),2.12-1.91(m,3H),1.81-1.65(m,2H),1.47(s,9H),1.41(s,9H)；13CNMR(100MHz,CDCl3):δ171.45,169.95,154.71,81.56,79.65,60.58,56.56,55.98,38.26,36.86,31.00,30.38,28.35,28.05,26.79；ESIMS:m/z401.2(M+H)+；HRESIMSforC19H33N2O5Srequired401.2110,found:401.2107；[α]D 24:-110.23(C1.0,CHCl3).
(5R, 8S, 10aR)-N-benzhydryl 5-(tert-butoxy formamido)-6-carbonyl thia azatropylidene [1,5] pyrrolizine[2,1-d]-8-carboxylic acid amides (intermediate H1)
At 0 DEG C, TIPS (18 μ L, 0.09mmol) is added to two of compd E (353mg, 0.88mmol)In chloromethanes solution (4mL), then add the dichloromethane solution (4mL) of TFA (8mL). Mixed liquor stirs0.5 hour, solvent evaporated, residue dilute with water, then use ether washed twice. By water freeze drying, obtain thickProduct F.
Thick product F is dissolved in to MeCN/H2In O (10mL/0.5mL), add Boc2O(576mg,2.64mmol)、Triethylamine (500 μ L), mixed liquor stirred overnight at room temperature, concentrated. Residue dilute with water, regulates PH with watery hydrochloric acidValue is to 2. Be extracted with ethyl acetate three times, merge organic phase, then use saturated common salt water washing, anhydrous sodium sulfate drying,Obtain thick product G (270mg, two-step reaction gross production rate is 89%).
At 0 DEG C, G (89mg, 0.26mmol) is dissolved in dry carrene (5mL), adds diphenylMethylamine (43mg, 0.23mmol), BOP (102mg, 0.23mmol), HOBt (4mg, 0.03mmol),Then add DIEA (0.5mL), mixed liquor stirred overnight at room temperature, then reactant liquor is successively with dilute hydrochloric acid solution, fullWith sodium bicarbonate solution, saturated common salt water washing, anhydrous magnesium sulfate drying, the concentrated thick product of gained is crossed post purifying (ringHexane/ethyl acetate=2/1), obtain colorless oil H1 (88mg, 75%).
1HNMR(400MHz,CDCl3):δ7.33-7.23(m,10H),6.23(d,J＝8.7Hz,1H),5.81(d,J＝7.5Hz,1H),4.77-4.67(m,2H),4.51-4.47(m,1H),2.97(dd,J＝13.9,3.4Hz,1H),2.60-2.50(m,2H),2.30(dd,J＝13.8,10.9Hz,1H),2.19-1.97(m,3H),1.84-1.74(m,2H),1.70-1.60(m,1H),1.44(s,9H)；13CNMR(100MHz,CDCl3):δ170.98,169.62,154.67,141.88,141.17,128.64,128.51,127.75,127.53,127.29,80.12,60.24,58.11,57.03,54.35,37.57,36.16,30.95,29.66,28.36,24.39；ESIMS:m/z510.2(M+H)+；[α]D 21 :-52.22(C1.0,CHCl3).
(5R, 8S, 10aR)-N-diphenyl methyl 5-(((S)-2-aminopropyl) amino)-6-carbonyl thia azatropylidene [1,5] pyrrolizine[2,1-d]-8-carboxylic acid amides (compound L 1)
At 0 DEG C, by the dichloromethane solution (1.0mL) of TFA (600 μ L) be added to intermediate H1 (32.0mg,63 μ mol) dichloromethane solution (2.0mL) in, mixed liquor stirs 2.5 hours, concentrated, obtains thick product I 1.
Under Ar protection, thick product I 1 is dissolved in dry carrene (4mL), and adds enough MgSO4(approximately 1.0g), then add the dry methylene chloride solution (1mL) of Boc-the third ammonium aldehyde (54.4mg, 315 μ mol).Mixed liquor stirring at room temperature 1 hour, filters, concentrated, obtains thick product J 1.
At 0 DEG C, in the dichloromethane solution of thick product J 1, add NaBH3CN(19.8mg,315μmol)。Stirring is spent the night, and after completion of the reaction, adds saturated sodium bicarbonate solution cancellation reaction. Then use dichloromethane extraction 3 times,Merge organic phase, then use saturated common salt water washing, dried over mgso, reduced pressure concentration, obtains thick product K 1.
At 0 DEG C, thick product K 1 is dissolved in carrene (2mL), adds the carrene of TFA (600 μ L)Solution (1.0mL), mixed liquor stirs 2.5 hours, and concentrated, the thick product HPLC obtaining is purified, freeze drying,Obtain white solid L1 (4.7mg, four-step reaction gross production rate 14%). Detect chromatogram and consult Fig. 1.
1HNMR(400MHz,D2O):δ7.35-7.14(m,10H),6.02-5.96(m,1H),4.54-4.37(m,3H),3.64-3.53(m,1H),3.17-3.09(m,2H),3.06-2.98(m,1H),2.78-2.62(m,2H),2.59-2.49(m,1H),2.41-2.30(m,1H),2.08-1.92(m,2H),1.83-1.70(m,3H),1.33-1.26(m,3H)；13CNMR(100MHz,D2O):δ173.31,173.29,162.79,140.28,140.23,128.88,128.75,127.95,127.85,127.58,127.53,127.51,62.36,60.14,59.78,59.74,57.57,49.90,49.76,46.26,35.33,34.26,34.14,31.22,29.17,27.45,15.75,15.66；ESIMS:m/z467.2(M+H)+；HRESIMSforC26H35N4O2Srequired467.2481,found:467.2475.
Embodiment 3 (compound K 2)
(R)-3-(2-((2R, 5S)-1-benzyl-5-tert-butyl ester base) pyrrolidines) ethylmercapto group)-2-(tert-butoxy formamido) propionic acid (centreBody C)
At 0 DEG C, by mesyl chloride (580 μ L, 7.5mmol), DMAP (458mg, 3.75mmol), DIEA (1ML) be added in the chloroformic solution (10mL) of intermediate A (765mg, 2.5mmol), stir 30 minutes,Reactant liquor dilutes with chloroform, then use saturated ammonium chloride solution successively, saturated sodium carbonate solution, saturated common salt water washing,Dried over sodium sulfate, concentrated, obtain intermediate B. Without purifying, directly carry out next step reaction.
At 0 DEG C, NaH (240mg, 10mmol) is added to Boc-Cys-OH's (1660mg, 7.5mmol)In DMF solution (10mL), suspension agitation 30 minutes. Then the DMF solution (10mL) of B is addedTo reactant liquor, mixed liquor stirring at room temperature 5 hours, concentrated, residue dilute with water, regulates pH value extremely with watery hydrochloric acid2. Water chloroform extraction three times, merge organic phase, and organic phase washes with water, anhydrous sodium sulfate drying, reduced pressure concentration.The thick product of gained is crossed post purifying (methylene chloride/methanol=15/1), obtains faint yellow grease C (813mg, two stepsGross production rate is 64%).
1HNMR(400MHz,MeOD):δ7.37-7.22(m,5H),4.25-4.16(m,1H),4.08(d,J＝13.4Hz,1H),3.80(d,J＝13.5Hz,1H),3.42(t,J＝8.1Hz,1H),3.11-2.97(m,2H),2.83(dd,J＝13.6,7.2Hz,1H),2.74-2.68(m,1H),2.58-2.51(m,1H),2.12-1.98(m,3H),1.86-1.58(m,3H),1.44(s,9H),1.32(s,9H)；13CNMR(100MHz,MeOD):δ175.27,173.90,157.75,136.93,131.31,129.61,129.19,83.00,80.56,68.03,66.79,58.82,55.44,35.35,34.25,30.47,29.92,29.06,28.76,28.14；MS(ESI):m/z509.3(M+H)+；[α]D 24:45.99(C1.0,CHCl3).
(5R, 8S, 10aR)-5-(tert-butoxy formamido)-6-carbonyl thia azatropylidene [1,5] pyrrolizine [2,1-d]-8-tert-butyl ester(intermediate E)
By enough 20% Pd (OH)2/ C is added to the DMF solution (20 of Compound C (908mg, 1.79mmol)ML), in, suspension is at H2Middle stirring is spent the night. After completion of the reaction, diatomite filtration, filtrate decompression is concentrated, obtainsFaint yellow grease D (630mg, 84%). Without purifying, directly carry out next step reaction.
At 15 DEG C, BOP (535mg, 1.21mmol) is added to Compound D (631mg, 1.51mmol)In dry chloroformic solution (310mL), then add triethylamine (1.5mL). Mixed liquor stirring at room temperature 36 hours,After completion of the reaction, reactant liquor is concentrated into half volume, use successively dilute hydrochloric acid solution, saturated sodium carbonate solution, water,Saturated common salt water washing, anhydrous sodium sulfate drying, concentrates and obtains thick product, then crosses post purifying (cyclohexane/acetic acid secondEster=4/1), obtain colorless oil E (323mg, 67%).
1HNMR(400MHz,CDCl3):δ5.96(d,J＝6.8Hz,1H),4.70-4.64(m,1H),4.60-4.55(m,1H),4.37(t,J＝8.8Hz,1H),2.97-2.90(m,2H),2.77-2.69(m,2H),2.41-2.34(m,1H),2.12-1.91(m,3H),1.81-1.65(m,2H),1.47(s,9H),1.41(s,9H)；13CNMR(100MHz,CDCl3):δ171.45,169.95,154.71,81.56,79.65,60.58,56.56,55.98,38.26,36.86,31.00,30.38,28.35,28.05,26.79；ESIMS:m/z401.2(M+H)+；HRESIMSforC19H33N2O5Srequired401.2110,found:401.2107；[α]D 24:-110.23(C1.0,CHCl3).
(5R, 8S, 10aR)-N-phenethyl 5-(tert-butoxy formamido)-6-carbonyl thia azatropylidene [1,5] pyrrolizine [2,1-d]-8-Carboxylic acid amides (intermediate H2)
At 15 DEG C, TIPS (901 μ L, 4.4mmol) is added to the chlorine of compd E (353mg, 0.88mmol)Imitate in solution (4mL), then add the chloroformic solution (4mL) of TFA (8mL). Mixed liquor stirs 5 hours,Solvent evaporated, residue dilute with water, then use ether washed twice. By water freeze drying, obtain thick product F.
Thick product F is dissolved in to MeCN/H2In O (10mL/0.5mL), add Boc2O(384mg,1.76mmol)、DIEA (500 μ L), mixed liquor stirred overnight at room temperature, concentrated. Residue dilute with water, regulates pH value with watery hydrochloric acidTo 2. With dichloromethane extraction three times, merge organic phase, then use saturated common salt water washing, anhydrous magnesium sulfate drying,To thick product G (265mg, two-step reaction gross production rate is 88%).
At 15 DEG C, G (89mg, 0.26mmol) is dissolved in dry chloroform (5mL), adds 2-phenylethylamine(157mg, 1.3mmol), EDCI (498mg, 2.6mmol), HOOBt (424mg, 2.6mmol), then addEnter triethylamine (0.5mL), mixed liquor stirred overnight at room temperature, then reactant liquor is used saturated ammonium chloride solution, saturated successivelySodium carbonate liquor, saturated common salt water washing, anhydrous magnesium sulfate drying, the concentrated thick product of gained cross post purifying (cyclohexane/Ethyl acetate=1/1), obtain colorless oil H2 (103mg, 89%).
1HNMR(400MHz,CDCl3):δ7.37(br,1H),7.32-7.15(m,5H),5.65(d,J＝7.9Hz,1H),4.76-4.66(m,1H),4.57(t,J＝8.2Hz,1H),4.40-4.29(m,1H),3.70-3.64(m,1H),3.51-3.40 (m,1H),3.07(dd,J＝13.5,4.5Hz,1H),2.89-2.77(m,2H),2.73-2.61(m,1H),2.53-2.42(m,1H),2.32(dd,J＝13.1,11.5Hz,1H),2.25-2.13(m,2H),2.11-2.00(m,1H),1.74-1.47(m,4H),1.42(s,9H)；13CNMR(100MHz,CDCl3):δ171.82,170.91,155.09,139.28,129.18,128.81,126.69,80.53,61.51,59.27,52.94,40.43,37.26,36.50,35.57,31.86,30.03,28.65,26.74；ESIMS:m/z448.2(M+H)+,470.2(M+Na)+；HRESIMSforC23H34N3O4Srequired448.2270,found:448.2276；[α]D 23:-47.82(C1.0,CHCl3).
(5R, 8S, 10aR)-N-phenethyl 5-(((S)-2-aminopropyl) amino)-6-carbonyl thia azatropylidene [1,5] pyrrolizine[2,1-d]-8-carboxylic acid amides (K2)
At-10 DEG C, the chloroformic solution (1.0mL) of TFA (600 μ L) is added to intermediate H2 (32.0mg, 63 μ mol)Chloroformic solution (2.0mL) in, mixed liquor stirs 5 hours, concentrated, obtains thick product I 2.
Under Ar protection, thick product I 2 is dissolved in dry chloroform (4mL), and adds enough molecular sieves (largeAbout 1.0g), then add the dry chloroformic solution (1mL) of Boc-the third ammonium aldehyde (32.7mg, 189 μ mol). MixLiquid stirring at room temperature 20 hours, filters, concentrated, obtains thick product J 2.
At-10 DEG C, in the chloroformic solution of thick product J 2, add sodium triacetoxy borohydride (40.1mg, 189 μ mol).Stirring is spent the night, and after completion of the reaction, adds saturated sodium bicarbonate solution cancellation reaction. Then use chloroform extraction 3 times, closeAnd organic phase, then use saturated common salt water washing, dried over sodium sulfate, reduced pressure concentration, obtains thick product K 2.
At-10 DEG C, thick product K 2 is dissolved in chloroform (2mL), adds the chloroformic solution (1.0 of TFA (600 μ L)ML), mixed liquor stirs 5 hours, and concentrated, the thick product HPLC obtaining is purified, and freeze drying, obtains whiteSolid L2 (5.1mg, four-step reaction gross production rate 13%). Detect chromatogram and consult Fig. 2.
1HNMR(400MHz,CDCl3):δ7.27-7.10(m,5H),4.43-4.33(m,1H),4.33-4.21(m,2H),3.59-3.42(m,2H),3.41-3.31(m,1H),3.17-3.05(m,2H),3.00-2.91(m,1H),2.78-2.44(m,5H),2.27-2.16(m,1H),1.98-1.84(m,1H),1.72-1.53(m,3H),1.37-1.19(m,4H)；13CNMR (100MHz,CDCl3):δ173.60,167.92,167.71,138.99,129.01,128.72,126.60,62.17,60.75,60.65,59.64,59.61,49.38,49.29,45.20,45.05,39.70,34.72,34.19,33.00,32.89,30.94,29.45,27.55,15.90,15.75；ESIMS:m/z405.2(M+H)+；HRESIMSforC21H33N4O2Srequired405.2324,found:405.2331.
Embodiment 4 (compound K 3)
(R)-3-(2-((2R, 5S)-1-benzyl-5-tert-butyl ester base) pyrrolidines) ethylmercapto group)-2-(tert-butoxy formamido) propionic acid (centreBody C)
At 15 DEG C, by mesyl chloride (967 μ L, 12.5mmol), DMAP (916mg, 7.5mmol), N-methylMorpholine (1mL) is added in the dichloromethane solution (10mL) of intermediate A (765mg, 2.5mmol), stirsMix 2 minutes, reactant liquor dilutes with carrene, then use saturated ammonium chloride solution successively, saturated sodium bicarbonate solution,Saturated common salt water washing, dried over mgso, concentrated, obtain intermediate B. Without purifying, directly carry out that next step is anti-Should.
At-10 DEG C, NaH (600mg, 25mmol) is added to Boc-Cys-OH (2766mg, 12.5mmol)DMF solution (10mL) in, suspension agitation 2 minutes. Then the DMF solution (10mL) of B is addedTo reactant liquor, mixed liquor stirring at room temperature 0.5 hour, concentrated, residue dilute with water, regulates pH value with watery hydrochloric acidTo 2. Water dichloromethane extraction three times, merge organic phase, and organic phase washes with water, and anhydrous magnesium sulfate drying subtractsPress concentrated. The thick product of gained is crossed post purifying (methylene chloride/methanol=15/1), obtain faint yellow grease C (730mg,Two step gross production rates are 57%).
1HNMR(400MHz,MeOD):δ7.37-7.22(m,5H),4.25-4.16(m,1H),4.08(d,J＝13.4Hz,1H),3.80(d,J＝13.5Hz,1H),3.42(t,J＝8.1Hz,1H),3.11-2.97(m,2H),2.83(dd,J＝13.6,7.2Hz,1H),2.74-2.68(m,1H),2.58-2.51(m,1H),2.12-1.98(m,3H),1.86-1.58(m,3H),1.44(s,9H),1.32(s,9H)；13CNMR(100MHz,MeOD):δ175.27,173.90,157.75,136.93,131.31,129.61,129.19,83.00,80.56,68.03,66.79,58.82,55.44,35.35,34.25,30.47,29.92,29.06,28.76,28.14；MS(ESI):m/z509.3(M+H)+；[α]D 24:45.99(C1.0,CHCl3).
(5R, 8S, 10aR)-5-(tert-butoxy formamido)-6-carbonyl thia azatropylidene [1,5] pyrrolizine [2,1-d]-8-tert-butyl ester(intermediate E)
Enough 10% Pd/C is added to the tetrahydrofuran solution (20 of Compound C (908mg, 1.79mmol)ML), in, suspension is at H2Middle stirring is spent the night. After completion of the reaction, diatomite filtration, filtrate decompression is concentrated, obtainsFaint yellow grease D (556mg, 74%). Without purifying, directly carry out next step reaction.
At-10 DEG C, EDCI (2.55g, 13.3mmol) is added to Compound D (556mg, 1.33mmol)In dry methylene chloride solution (310mL), then add triethylamine (1.5mL). Mixed liquor stirring at room temperature 72 is littleTime, after completion of the reaction, reactant liquor is concentrated into half volume, use successively saturated ammonium chloride solution, saturated sodium bicarbonateSolution, water, saturated common salt water washing, dried over mgso, concentrated obtains thick product, then cross post purifying (cyclohexane/Ethyl acetate=4/1), obtain colorless oil E (353mg, 66%).
1HNMR(400MHz,CDCl3):δ5.96(d,J＝6.8Hz,1H),4.70-4.64(m,1H),4.60-4.55(m,1H),4.37(t,J＝8.8Hz,1H),2.97-2.90(m,2H),2.77-2.69(m,2H),2.41-2.34(m,1H),2.12-1.91(m,3H),1.81-1.65(m,2H),1.47(s,9H),1.41(s,9H)；13CNMR(100MHz,CDCl3):δ171.45,169.95,154.71,81.56,79.65,60.58,56.56,55.98,38.26,36.86,31.00,30.38,28.35,28.05,26.79；ESIMS:m/z401.2(M+H)+；HRESIMSforC19H33N2O5Srequired401.2110,found:401.2107；[α]D 24:-110.23(C1.0,CHCl3).
(5R, 8S, 10aR)-N-((R)-1,2,3,4-naphthane-1) 5-(tert-butoxy formamido)-6-carbonyl thia azatropylidene [1,5] alsoPyrrolidines [2,1-d]-8-carboxylic acid amides (intermediate H3)
At-10 DEG C, TIPS (1.8mL, 8.8mmol) is added to two of compd E (353mg, 0.88mmol)In chloromethanes solution (4mL), then add the dichloromethane solution (4mL) of TFA (8mL). Mixed liquor stirs10 hours, solvent evaporated, residue dilute with water, then use ether washed twice. By water freeze drying, obtain thickProduct F.
Thick product F is dissolved in to MeCN/H2In O (10mL/0.5mL), add Boc2O(173mg,0.79mmol)、DBU (500 μ L), mixed liquor stirred overnight at room temperature, concentrated. Residue dilute with water, regulates PH with watery hydrochloric acidValue is to 2. Be extracted with ethyl acetate three times, merge organic phase, then use saturated common salt water washing, anhydrous magnesium sulfate drying,Obtain thick product G (256mg, two-step reaction gross production rate is 94%).
At-10 DEG C, G (89mg, 0.26mmol) is dissolved in dry carrene (5mL), adds 5,6,7,8-Tetrahydrochysene-naphthalidine (382mg, 2.6mmol), DCC (1072mg, 5.2mmol), HOSu (599mg, 5.2mmol),Then add N-methylmorpholine (0.5mL), mixed liquor stirred overnight at room temperature, it is molten that then reactant liquor is used watery hydrochloric acid successivelyLiquid, saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous magnesium sulfate drying, it is pure that the concentrated thick product of gained is crossed postChange (cyclohexane/ethyl acetate=1/1), obtain colorless oil H3 (96mg, 78%).
1HNMR(400MHz,CDCl3):δ7.60(d,J＝8.2Hz,1H),7.23-7.04(m,4H),5.70(d,J＝7.7Hz,1H),5.18-5.09(m,1H),4.76-4.60(m,2H),4.48-4.39(m,1H),3.04(dd,J＝13.7,4.1Hz,1H),2.84-2.66(m,3H),2.50-2.31(m,3H),2.30-2.19(m,1H),2.18-2.05(m,1H),2.04-1.94(m,1H),1.92-1.69(m,6H),1.41(s,9H)；13CNMR(100MHz,CDCl3)δ170.75,170.11,154.72,137.51,136.51,129.22,128.75,127.26,125.95,80.12,61.19,58.55,53.35,47.51,37.34,36.35,31.49,29.94,29.67,29.09,28.34,25.96,19.60；ESIMS:m/z474.2(M+H)+,496.2(M+Na)+；HRESIMSforC25H36N3O4Srequired474.2427,found:474.2447；[α]D 23:-57.60(C1.0,CHCl3).
(((S)-2-aminopropyl) amino)-6-carbonyl thia azatropylidene [1,5] also for (5R, 8S, 10aR)-N-((R)-1,2,3,4-naphthane) 5-Pyrrolidines [2,1-d]-8-carboxylic acid amides (K3)
At 15 DEG C, by the dichloromethane solution (1.0mL) of TFA (600 μ L) be added to intermediate H3 (32.0mg,63 μ mol) dichloromethane solution (2.0mL) in, mixed liquor stirs 0.1 hour, concentrated, obtains thick product I 3.
Under Ar protection, thick product I 3 is dissolved in dry carrene (4mL), and adds enough magnesium sulfate(approximately 1.0g), then add the dry methylene chloride solution (1mL) of Boc-the third ammonium aldehyde (10.4mg, 60 μ mol).Mixed liquor stirring at room temperature 10 hours, filters, concentrated, obtains thick product J 3.
At 15 DEG C, in the dichloromethane solution of thick product J 3, add sodium cyanoborohydride (3.8mg, 60 μ mol).Stirring is spent the night, and after completion of the reaction, adds saturated sodium bicarbonate solution cancellation reaction. Then use dichloromethane extraction 3 times,Merge organic phase, then use saturated common salt water washing, dried over sodium sulfate, reduced pressure concentration, obtains thick product K 3.
At 15 DEG C, thick product K 3 is dissolved in carrene (2mL), adds the dichloromethane of TFA (600 μ L)Alkane solution (1.0mL), mixed liquor stirs 0.1 hour, and concentrated, the thick product HPLC obtaining is purified, freezing dryDry, obtain white solid L3 (7.5mg, four-step reaction gross production rate 19%). Detect chromatogram and consult Fig. 3.
1HNMR(400MHz,CDCl3):δ8.27(d,J＝8.2Hz,1H),7.17-7.02(m,4H),4.90-4.81(m,1H),4.46-4.29(m,3H),3.60-3.46(m,1H),3.21-3.03(m,2H),3.00-2.91(m,1H),2.71-2.50(m,5H),2.40-2.28(m,1H),2.07-1.91(m,2H),1.87-1.51(m,7H),1.29-1.21(m,3H)；13CNMR(100MHz,D2O):δ172.54,168.36,168.15,138.27,135.05,129.30,128.71,128.70,127.73,126.21,62.39,60.69,60.56,59.72,59.69,49.41,49.36,48.00,45.34,45.20,34.84,34.81,33.16,33.06,31.12,29.53,28.91,28.31,27.55,19.00,15.88,15.76；ESIMS:m/z431.3(M+H)+；HRESIMSforC23H35N4O2Srequired431.2481,found:431.2502.
Compound L 4～L64 can adopt the method identical with preparing L1 to make, and is not both:
Adopt BOP or DCC or EDCI or DIC or TBTU or HBTU or HATU or TATUPyBOP in alternative embodiment 2;
Adopt HOOBt or HOSu to replace the HOBt in embodiment 2;
Adopt benzene methanamine or 5,6,7,8-tetrahydrochysene-naphthalidine or (R)-2,3-dihydro-1H-indenes-1-amine or (S)-naphthalene-2-base (benzeneBase) methylamine or 2-phenylethylamine or 2-(trifluoroethyl) benzene methanamine or 4-phenyl-1,2,3 ,-thiadiazoles-5-amine or 3-Methyl isophthalic acid-phenyl-1H-pyrazoles-5-amine or (4-fluoro) benzene methanamine or (4-chloro) benzene methanamine or (4-bromo) benzene methanamine,Or (4-methyl) benzene methanamine or (4-methoxyl group) benzene methanamine or 2-furylamine or 2-thenylaminine alternative embodiment 2In diphenyl methylamine;
Adopt (S)-2-(tertbutyloxycarbonyl) aminobutyl aldehyde or (S)-2-((tertbutyloxycarbonyl) methylamino) propionic aldehyde or(S)-2-((tertbutyloxycarbonyl) methylamino) butyraldehyde is replaced and implemented amino acid in 2 is N-tertbutyloxycarbonyl-L-the third ammonium aldehyde.
For effect of the present invention is better described, below in conjunction with providing the example that experimental results show that of the present invention:
Taking L3 as example, in fluorescence polarization test, mensuration L3 antagonism X-Linked Inhibitor of Apoptosis Protein in Children (XIAP)Active.
1, experimental section
1.1 materials and instrument
(1) fluorescently-labeled polypeptide ligand
By synthetic seven peptide molecule H-AVPFAQK-(the 6-FAM)-NH of colleague2, on the ε of its lysine side chain amino, do glimmeringSignal. The structure of this fluorescence peptide is confirmed by ESI-MS, analyzes through HPLC, and its purity is higher than 98%. Fluorescence peptideBe dissolved in ultra-pure water, its solution concentration is defined as 467 μ M through ultraviolet absorption method. The every 10 μ L packing of solution, use tinfoilParcel lucifuge ,-20 DEG C of preservations.
(2) XIAP-BIR3 recombinant protein
XIAP-BIR3 recombinant protein is purchased from R&DSystemsInc.. Albumen is Escherichia coli sources, containsAsn252-Thr356 residue, is with a N end Met and 6-His label. Every 50 μ g packing, are kept at-20 DEG CThe pH value of 50 μ L is 8.0, containing 50mMTris – HCl, 300mMKCl, 50 μ M zinc acetates, 1mMDTTCushioning liquid in.
(3) reaction buffer
The reaction buffer that this test is used comprises 20mMHepes, 2mMdithiothreitol (DTT), 100mMNaCl, 0.1%Bovineserumalbumin (BSA), pH instrument regulates its pH value to 7.4. Agents useful for same is all purchased fromSigma-Aldrich company, purity is highest level.
(4) preparation of sample solution
First compound L 3 is dissolved in to ultra-pure water, is formulated as the mother liquor of 10mM, then mother liquor is diluted to required denseDegree.
(5) laboratory apparatus
PerkinElmerEnVision multiple labeling microwell plate detector (EnVisionMultilabelReader), pH meter,UV absorption detector, 384 hole check-out consoles.
1.2 experimental technique
(1) prepare 384 hole check-out consoles
First, the XIAP-BIR3 albumen of the fluorescence peptide of 2.5nM and 250nM is added in reaction buffer,Form test cushioning liquid, and hatch half an hour. Meanwhile, sample mother liquor is diluted to a series of concentration, concentrationScope is 5mM to 5nM.
Then,, on 384 hole check-out consoles, three of each concentration point repeat sample. First, use liquid-transfering gun to 384 holesIn the hole of check-out console, add the test cushioning liquid of 16 μ L, then add 4 μ L sample solutions. After mixing, Kong ZhongrongLiquid is long-pending becomes 20 μ L, so the concentration of fluorescence peptide and XIAP-BIR3 becomes respectively best test concentrations, i.e. 2nMAnd 200nM. The ultimate density of sample becomes 1mM to 1nM. By 384 hole check-out console room temperature hatching 20～30 minutes,With microwell plate detector reading. Then check-out console is hatched 20～30 minutes again to reading again.
(2) data processing
All data are all used the nonlinear regression curve fitting procedure analysis of GraphPadPrism.
1.3 results and discussion
The final test concentration of fluorescence peptide and XIAP-BIR3 albumen is fixed as respectively 2nM and 200nM, institute's test specimensThe ultimate density scope of product is 1mM to 1nM. Compound L 3 and XIAP-BIR3 competitive binding suppress curve asShown in Fig. 4, taking mP value as Y-axis, logC is X-axis (C is the concentration of test sample). Result shows, chemical combinationThing L3 has preferably and the binding affinity of XIAP-BIR3. Because compound L 3 is to XIAP-BIR3 competitivenessIn conjunction with suppressing, its binding curve is S type, and mP value reduces with the increase of test sample concentration, works as sample concentrationWhen enough low, mP value reaches maximum, no longer changes. Otherwise in the time that sample concentration is enough high, mP value reachesLittle value, suppresses saturated. The data of surveying are analyzed through GraphPadPrism, draw the IC of compound L 350Value is 11.6 μ M,Under same condition, positive control---the IC of tetrapeptide molecule AVPI (Ala-Val-Pro-Ile)50Value is 0.8 μ M.Compare with AVPI, although compound L 3 activity decrease, its non-peptide feature is fairly obvious, is expected to applicationIn the drug development for the treatment of of cancer.
Breviary vocabulary (alphabet sequence)
Claims (10)
1. a non-peptide class IAP antagonist, is characterized in that, its structural formula as shown in Equation 1:
Wherein:
R1Be selected from following substituent one of them:
R2Be selected from following substituent one of them:
Above-mentioned X is selected from one of them of F, Cl, Br, Me, OMe;
Y is selected from S or O;
Formula 1.
2. the method for preparation non-peptide class IAP antagonist claimed in claim 1, is characterized in that, successively bagDraw together following method:
1) at-10～15 DEG C, mesyl chloride, DMAP, organic base are added in the chlorohydrocarbon solution of intermediate A, stirMix 2～60 minutes, reactant liquor dilutes with chlorohydrocarbon, and process weak acid is washed successively, weak base is washed, saturated common salt water washing, dryDry, concentrated, without being further purified, obtain intermediate B; At-10～15 DEG C, NaH is added to Boc-Cys-OHSolution in, the suspension agitation reactant liquor of 1～60 minute, then the solution of intermediate B is added in reactant liquor, mixedClose stirring at room temperature 0.5～10 hour, concentrated, collect respectively organic phase and Liquid Residue, Liquid Residue dilute with water, regulates pHValue, to acid, adopts after organic solvent extraction, merges after organic phase, then through water washing, dry, reduced pressure concentration, gainedThick product is crossed post purifying, obtains faint yellow oily intermediate C;
Wherein, the mol ratio of described mesyl chloride, DMAP, intermediate A, NaH, Boc-Cys-OH is: 0.9～5:0.05～3：1：1.6～10：0.8～5；
2) metallic catalyst is added in the polar solvent of intermediate C, suspension is at H2Middle stirring is spent the night, and reacts completeAfter, to filter, filtrate decompression is concentrated, obtains faint yellow oily intermediate D; At-10～15 DEG C, during condensing agent is added toIn the chlorohydrocarbon solution of mesosome D, then add organic base, mixed liquor stirring at room temperature 4～72 hours, after completion of the reaction, will be anti-Answer liquid to be concentrated into half volume, process weak acid is washed successively, weak base is washed, saturated common salt water washing, dry, concentrated, purifying,Obtain colorless oil intermediate E;
Wherein, the mol ratio of described condensing agent, intermediate D is: 0.8～20:1;
3) at-10～15 DEG C, TIPS is added in the chlorohydrocarbon solution of intermediate E, then adds TFA, mixed liquor stirsMix 0.5～10 hour, solvent evaporated, collects aqueous layer, residue dilute with water, then use ether washed twice, then with receiptsThe aqueous layer that collection arrives merges, dry, obtains intermediate F; Be dissolved in MeCN/H2In O, add Boc2O, organic base,Mixed liquor stirred overnight at room temperature, concentrated, collect respectively organic phase and Liquid Residue, Liquid Residue dilute with water, regulates pH value extremelyAcidity, adopts after organic solvent extraction, after merging organic phase, washes with water, and lotion, dry, obtains intermediate G;
Wherein: described TIPS, intermediate E, Boc2O mol ratio is: 0.1～10:1:0.9～3;
4) at-10～15 DEG C, intermediate G is dissolved in organic solvent, adds aromatic amine, condensing agent and additive, thenAdd organic base, mixed liquor stirred overnight at room temperature, then wash successively, weak base is washed, saturated common salt water washing by weak acid for reactant liquor,Dry, the concentrated thick product of gained is crossed post purifying, obtains colorless oil intermediate H;
Wherein, the mol ratio of described intermediate G, aromatic amine, condensing agent, additive be 1:0.9～10:0.9～20：0.1～20；
5) at-10～15 DEG C, TFA is added in the chlorohydrocarbon solution of intermediate H, mixed liquor stirs 0.1～5 hour,The concentrated intermediate compound I that obtains;
6) under the protection of inert gas, the amido aldehyde of tertbutyloxycarbonyl protection is added in the solution of intermediate compound I, thenAdd enough drier, stirring at room temperature 1～20 hour, filters, concentrated, obtains thick product J. At-10～15 DEG C, willIntermediate J is dissolved in the chlorohydrocarbon heavily steaming, and adds reducing agent. Reaction is stirred and is spent the night, and after completion of the reaction, adds unsaturated carbonateHydrogen sodium solution cancellation reaction, then with organic solvent extraction repeatedly, merge organic phase. Organic phase saturated common salt water washing,Desiccant dryness, concentrated, obtain product K. At-10～15 DEG C, intermediate K is dissolved in chlorohydrocarbon, adds TFA,Mixed liquor stirs 0.1～5 hour, concentrated, repurity, and freeze drying, obtains white solid finished product L.
Wherein, described intermediate compound I, the aldehyde of tertbutyloxycarbonyl protection, the mol ratio of reducing agent are: 1:0.95～5:0.95～5。
3. the preparation method of non-peptide class IAP antagonist according to claim 2, is characterized in that instituteThe organic base of stating is triethylamine or DBU or DIEA or N-methylmorpholine.
4. the preparation method of non-peptide class IAP antagonist according to claim 2, is characterized in that instituteThe organic metal catalysis of stating is Raney's nickel water slurry or palladium catalyst.
5. the preparation method of non-peptide class IAP antagonist according to claim 2, is characterized in that instituteThe condensing agent of stating be BOP or DCC or EDCI or DIC or PyBOP or TBTU or HBTU orHATU or TATU.
6. the preparation method of non-peptide class IAP antagonist according to claim 2, is characterized in that instituteThe additive of stating is HOBt or HOOBt or HOSu.
7. the preparation method of non-peptide class IAP antagonist according to claim 2, is characterized in that instituteThe aromatic amine of stating is diphenyl methylamine or benzene methanamine or 5,6,7,8-tetrahydrochysene-naphthalidine or (R)-2,3-dihydro-1H-indenes-1-amine,Or (S)-naphthalene-2-base (phenyl) methylamine or 2-phenylethylamine or 2-(trifluoroethyl) benzene methanamine or 4-phenyl-1,2,3 ,-thiadiazoles-5-amine or 3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-amine or (4-fluoro) benzene methanamine or (4-chloro) benzene methanamine or (4-bromo)Benzene methanamine or (4-methyl) benzene methanamine or (4-methoxyl group) benzene methanamine or 2-furylamine or 2-thenylaminine.
8. the preparation method of non-peptide class IAP antagonist according to claim 2, is characterized in that instituteThe amido aldehyde of the tertbutyloxycarbonyl protection of stating be N-tertbutyloxycarbonyl-L-the third ammonium aldehyde or (S)-2-(tertbutyloxycarbonyl) aminobutyl aldehyde,Or (S)-2-((tertbutyloxycarbonyl) methylamino) propionic aldehyde or (S)-2-((tertbutyloxycarbonyl) methylamino) butyraldehyde.
9. the preparation method of non-peptide class IAP antagonist according to claim 2, is characterized in that instituteThe structural formula of the intermediate A of stating is:
10. non-peptide class IAP antagonist claimed in claim 1 is as the application of antineoplastic.
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| CN106188224A (en) * | 2016-07-06 | 2016-12-07 | 广东工业大学 | A kind of multiple target-point anti-cancer medicine and preparation method and application |
| US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
| WO2023246631A1 (en) * | 2022-06-22 | 2023-12-28 | 中国药科大学 | Preparation method for diazabicyclo peptidomimetic derivative and use thereof |
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| CN1964970A (en) * | 2004-04-07 | 2007-05-16 | 诺瓦提斯公司 | Inhibitors of IAP |
| CN101094833A (en) * | 2004-07-12 | 2007-12-26 | 伊邓药品公司 | Tetrapeptide analogs |
| CN101374829A (en) * | 2005-12-19 | 2009-02-25 | 健泰科生物技术公司 | Inhibitors of IAP |
| CN101516904A (en) * | 2006-07-24 | 2009-08-26 | 泰特拉洛吉克药业公司 | Dimeric IAP antagonists |
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| CN1964970A (en) * | 2004-04-07 | 2007-05-16 | 诺瓦提斯公司 | Inhibitors of IAP |
| CN101094833A (en) * | 2004-07-12 | 2007-12-26 | 伊邓药品公司 | Tetrapeptide analogs |
| CN101374829A (en) * | 2005-12-19 | 2009-02-25 | 健泰科生物技术公司 | Inhibitors of IAP |
| CN101516904A (en) * | 2006-07-24 | 2009-08-26 | 泰特拉洛吉克药业公司 | Dimeric IAP antagonists |
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| US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
| CN106188224A (en) * | 2016-07-06 | 2016-12-07 | 广东工业大学 | A kind of multiple target-point anti-cancer medicine and preparation method and application |
| CN106188224B (en) * | 2016-07-06 | 2019-10-29 | 广东工业大学 | A kind of multiple target-point anti-cancer drug and the preparation method and application thereof |
| WO2023246631A1 (en) * | 2022-06-22 | 2023-12-28 | 中国药科大学 | Preparation method for diazabicyclo peptidomimetic derivative and use thereof |
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