CN106188098B - A kind of hydridization cancer therapy drug and preparation method and application - Google Patents
A kind of hydridization cancer therapy drug and preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of hydridization cancer therapy drug and preparation method and application, belong to pharmaceutical technology field.The structural formula of hydridization cancer therapy drug of the present invention is as shown in formula I：Wherein：X is selected from SCH2, CH=CH or (CH2)2One kind in substituent；Y is selected from O or OCH2One kind in O；R2Selected from CN or ONO2In one kind.The binding affinity of of the invention designed and synthesis hydridization cancer therapy drug and XIAP BIR3 is stronger, promotes cancer cell-apoptosis, non-peptide feature is more obvious, can act on multiple target spots, play multi-efficiency.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of hydridization cancer therapy drug and preparation method and application.
Background technology
In the past few years, in order that medicine has dual or multiple action, by two pharmacophore hydridization in a medicine
Hydridization medicine in thing molecule has become the new focus in new drug development.Because cancer, neurodegenerative disease etc. are many serious
The complexity of disease, these diseases are difficult to be cured by the pharmacophore of a high selectivity, this be also hydridization medicine in recent years
The reason for by paying special attention to.Compared to common drug, hydridization medicine can reduce for improving molecule affinity and selectivity
Side effect etc..The composition unit of hybrid molecule can be engineer or natural organic molecule, polypeptide, nucleic acid etc..Pin
To action target spot, it is expected to play a part of collaboration between these pharmacophores.
Apoptosis is a series of apoptosis behavior by orderly signal stream regulation and control in multicellular organism body, is
Body eliminates unwanted cells, prevents the normal physiological processes of cell hyperproliferation, in the growing of organism, maintains interior environment
Stabilization in play an important role.Research shows that Apoptosis Mechanism imbalance is the important pathological characteristicses of the diseases such as cancer.
Between in the past few decades, although treatment of cancer has made some progress, tumour cell stimulates generation resistance to various cell toxicants
By Apoptosis is disorderly and lacks of proper care, and is still the major obstacle that treatment of cancer has to overcome.
IAP (Inhibitor of apoptosis, IAP) is to suppress cell death in Apoptosis path
Key regulator.IAP is over-expressed in kinds of tumor cells.At present, IAPs families include eight into
Member, is Cp-IAP, Op-IAP, XIAP, c-IAP1, c-IAP2, NAIP, Livin/ML-IAP and Survivin respectively, wherein four
IAP XIAP, c-IAP1, c-IAP2 and ML-IAP is planted directly to participate in adjusting Apoptosis, these IAPs albumen masters
If suppressing Apoptosis by suppressing caspase (caspase).
Smac/DIABLO (the cystine zymoexciter/low isoelectric point IAP in second mitochondria source is directly in conjunction with albumen)
It is that one kind is discharged from mitochondria to cytoplasmic IAP endogenous antagonists.The Ala-Val-Pro-Ile that Smac passes through its N-terminal
(AVPI) four peptide motifs are combined with IAPs, so as to remove inhibitory action of the IAPs to Apoptosis, promote Apoptosis.With AVPI
Four peptide molecules are lead compound, design and synthesize non-peptide micromolecular Smac analogies, using IAPs as target spot, and exploitation induction is thin
The cancer therapy drug of born of the same parents' apoptosis turns into the study hotspot of field of cancer treatment.
The content of the invention
To overcome shortcoming and deficiency present in above-mentioned prior art, primary and foremost purpose of the invention is to provide a kind of hydridization
Cancer therapy drug.In the middle of described hydridization cancer therapy drug energy antagonism iap protein effect and the methide of generation quinone
Body.
Another object of the present invention is to provide the preparation method of above-mentioned hydridization cancer therapy drug.
It is still another object of the present invention to provide the application of above-mentioned hydridization cancer therapy drug.
The purpose of the present invention is achieved through the following technical solutions：A kind of hydridization cancer therapy drug, its structural formula is as shown in formula I：
Wherein：
X is selected from-SCH2- ,-CH=CH- or-(CH2)2One kind in-substituent：
Y is selected from-O- or-OCH2One kind in O-；
R1It is selected fromOne kind in substituent；
R2Selected from-CN or-ONO2In one kind.
The preparation method of above-mentioned hydridization cancer therapy drug, comprises the steps：
1) compound A and inorganic base are dissolved in polar organic solvent, suspension is stirred 1~30 minute, then adds iodine
Methane or iodoethane, mixed liquor are stirred at room temperature 4~12 hours under the protection of inert gas, concentration, and gained residue is dissolved in non-
In polar organic solvent, organic phase is washed with water, desiccant dryness, and concentration gained crude product crosses post purifying, obtains colorless oil
Thing B；
Wherein, the mol ratio of described compound A, inorganic base, iodomethane or iodoethane is：1：1~10：1~5；
2) at -10~15 DEG C, TFA chlorohydrocarbon solution is added into compound B chlorohydrocarbon solution, mixed liquor stirring
0.3~5 hour, it is concentrated to give at crude product amine C, -10~15 DEG C, compound C is dissolved in dry chlorohydrocarbon solution, adds
Amino acid, condensing agent and the additive of tertbutyloxycarbonyl protection, then add organic base and adjust reaction solution pH to alkalescence, mixed liquor
It is stirred overnight at room temperature, reaction solution uses dilute acid soln, dilute alkaline soln, saturated common salt water washing successively, dries, the gained that is concentrated under reduced pressure is thick
Product crosses post purifying, obtains colorless oil D；
Wherein, described compound C, the amino acid of tertbutyloxycarbonyl protection, condensing agent, the mol ratio of additive are 1：1
~5：1~20：0.25~20；
3) compound D is dissolved in the in the mixed solvent of polar organic solvent and water, highly basic is added, suspension is stirred at room temperature 2
~7 hours, concentration, residue diluted with water adjusted pH value to acidity, aqueous solution non-polar organic solvent with dilute hydrochloric acid solution
Extraction three times, merges organic phase, and desiccant dryness is concentrated to give colorless oil E；
Wherein, described compound D, the mol ratio of highly basic are 1：1~5；
4) at -10~15 DEG C, compound E is dissolved in dry chlorohydrocarbon solution, organic base or condensing agent is added and organic
The mixing chlorohydrocarbon solution of alkali, then adds 2- (4- (chloromethoxy) phenyl) acetonitriles or 2- (4- (chloromethoxy) phenyl)
Methyl nitrate or 2- (4- hydroxy phenyls) acetonitriles or 2- (4- hydroxy phenyls) methyl nitrate, mixed liquor is in inert gas shielding
Under, it is stirred overnight at room temperature, is concentrated to give crude product F, -10~15 DEG C, TFA is added into compound F chlorohydrocarbon solution, mixes
Close liquid to stir 0.1~5 hour, concentration, efficient liquid phase purifying, freeze-drying obtains white finished product G；
Wherein, described compound E, 2- (4- (chloromethoxy) phenyl) acetonitrile or 2- (4- (chloromethoxy) phenyl)
Methyl nitrate or 2- (4- hydroxy phenyls) acetonitriles or 2- (4- hydroxy phenyls) methyl nitrate, organic base, mole of condensing agent
Than for 1：1~5：1~20：1~20.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described compound A general structure is：Wherein, X is-SCH2- ,-CH=CH- or-(CH2)2- in one kind.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described inorganic base is K2CO3、Na2CO3、KHCO3、
NaHCO3, one or more in KOH, NaOH or LiOH.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described highly basic is KOH, NaOH, Ca (OH)2、NaH、
One or more in KH or LiOH.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described polar organic solvent is DMF, DMSO, THF
Or the one or more in MeCN.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described non-polar organic solvent is ethyl acetate, two
One or more in chloromethanes, chloroform or ether.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described inert gas is nitrogen or argon gas.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described chlorohydrocarbon solution is dichloromethane or chloroform.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, the amino acid of described tertbutyloxycarbonyl protection is N-
Tert-butoxycarbonyl-l-alanine, (S) -2- (tertbutyloxycarbonyl) aminobutyric acid, (S) -2- ((tertbutyloxycarbonyl) methylamino) third
One or more in acid or (S) -2- ((tertbutyloxycarbonyl) methylamino) butyric acid.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described condensing agent is BOP, DCC, EDCI, DIC,
One or more in PyBOP, TBTU, HBTU, HATU or TATU.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, during described additive is HOBt, HOOBt or HOSu
One or more.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described organic base is triethylamine, pyridine, DBU,
One or more in DIEA or N-methylmorpholine.
It is preferred that, the preparation method of above-mentioned hydridization cancer therapy drug, described drier is anhydrous magnesium sulfate, anhydrous slufuric acid
One kind in sodium, Anhydrous potassium carbonate or anhydrous calcium chloride.
Above-mentioned hydridization cancer therapy drug as cancer therapy drug application.Compared with prior art, the skill of offer of the invention
Art scheme and XIAP-BIR3 binding affinity are stronger, and non-peptide feature is more obvious, and are expected to act on multiple anticancer target spots.
The present invention has the following advantages and effect relative to prior art：
The present invention substitutes Smac analogies carbon teminals to strengthen the active anticancer of Smac analogies with a new group
Hydrophobic group, designs and has synthesized a class hydridization cancer therapy drug.Introduced new group is not only acted on IAP,
Under the hydrolysis of esterase, the methide of quinone can also be generated.The methide intermediate of quinone is highly electrophilic, can participate in many
Item physiology course, inducing cell death and suppression cell growth.Therefore, such hydridization medicine includes two pharmacophores：One
Pharmacophore is combined with IAPs, inhibitory action of the antagonism IAPs to Apoptosis；Another pharmacophore is produced in the methide of quinone
Mesosome, participates in multinomial physiology course.Therefore, the combination of the hydridization cancer therapy drug and XIAP-BIR3 of of the invention designed and synthesis
Affinity is stronger, and non-peptide feature is more obvious, can act on multiple target spots, play multi-efficiency.
Brief description of the drawings
Fig. 1 is compound G1's1H NMR detect spectrogram；
Fig. 2 is compound G2's1H NMR detect spectrogram；
Fig. 3 is compound G3's1H NMR detect spectrogram；
Fig. 4 is compound G1With XIAP-BIR3 competitive binding suppression curves；
Fig. 5 is compound G1With synergies of the TRAIL to MDA-MB-231 Apoptosis.
Embodiment
With reference to embodiment, the claim to the present invention is described in further detail, but is not constituted
Any limitation of the invention, the modification of anyone limited number of time made in the claims in the present invention protection domain, still at this
Within the claims of invention.
All reagents are that commercially available analysis is pure, without being further purified, directly used without special instruction.Anhydrous and oxygen-free is anti-
The glass apparatus answered before use, dried in an oven, and reaction is carried out under Ar protections.Solvent steams again to be entered under Ar protections
OK, THF is dried under conditions of metallic sodium and benzophenone, and dichloromethane, ethyl acetate are dried with calcium hydride.Column chromatography is used
63~200 mesh silica gel, thin-layer chromatography uses Merck TLC silica gel 60F254 plastics chromatosheets, uses 254nm ultraviolet lights
According to or iodine vapor or 2% ninhydrin ethanol solution color developing detection.Nuclear magnetic resoance spectrum uses Bruker AVANCE III
400NMR spectrometers are determined, and chemical displacement value is recorded in units of ppm.Mass spectrum uses LCT Premier XE type flight time mass spectrums
Instrument is determined.Optical value is determined with JASCO P-1010 polarimeters.
High performance liquid chromatography (HPLC) condition：(1) preparation HPLC：Perkin Elmer Series 200UV/VIS are examined
Survey device；The two-phase pumps of Perkin Elmer Series 200；Vacuum degasser；Gilson FC203b cut receiving instruments；(2) analyze
Type HPLC：The automatic samplers of Perkin Elmer Series 225；Perkin Elmer Series 220UV/VIS detectors；
The phase pumps of Perkin Elmer Series 200 4；Vacuum degasser.Mobile phase：(1) mobile phase A：Water+0.045%TFA；(2)
Mobile phase B：Acetonitrile+the 0.038%TFA of 10% water+90%.
(the hydridization cancer therapy drug G of embodiment 11)
Compound A1(A1Structural formula see shown in formula II) synthetic method with reference to Chinese patent 201610036840.2 the
[0046] to the preparation method of [0083] section.
(5R, 8S, 10aR) -5- ((tertiary butyloxy formylamido) -6- carbonyl thia azatropylidene [1,5] pyrrolizine [2,1-
D] -8- carboxylate methyl esters (compound B1) preparation：
By compound A1(36mg, 0.10mmol) and K2CO3(69mg, 0.50mmol) is dissolved in DMF (2mL).Suspension is stirred
Mix 15 minutes, then add iodomethane (31 μ L, 0.50mmol).Mixed liquor is stirred at room temperature 8 hours under Ar protections, concentrates, institute
Residue is obtained to be dissolved in ethyl acetate.Organic phase is washed with water, and anhydrous magnesium sulfate is dried, and concentration gained crude product crosses post purifying
(cyclohexane/ethyl acetate=3/1), obtains colorless oil B1(28mg, 78%), shown in reactive chemistry equation as formula II.
1H NMR(400MHz,CDCl3):δ 5.87 (d, J=6.9Hz, 1H), 4.71-4.66 (m, 1H), 4.61-4.56 (m,
1H), 4.49 (t, J=9.0Hz, 1H), 3.74 (s, 3H), 2.96-2.88 (m, 2H), 2.75-2.67 (m, 2H), 2.43-2.36
(m, 1H), 2.14-1.91 (m, 3H), 1.80 (dd, J=11.7,6.7Hz, 1H), 1.75-1.66 (m, 1H), 1.40 (s, 9H)；13C NMR(100MHz,CDCl3):δ173.29,170.41,154.97,80.06,59.67,56.82,56.34,52.63,
38.43,31.40,30.49,28.64,27.04.
(5R, 8S, 10aR) -5- ((S) -2- (tertiary butyloxy formylamido) propionamido-) -6- carbonyl thia azatropylidenes [1,5]
Pyrrolizine [2,1-d] -8- carboxylate methyl esters (compound D1) preparation：
At -10 DEG C, TFA (300 μ L) dichloromethane solution (1mL) is added to compound B1(28mg,0.08mmol)
Dichloromethane solution (2mL) in.Mixed liquor stirs 5h, is concentrated to give compound amine C1.At -10 DEG C, by the compound C of gained1
Be dissolved in dry dichloromethane (3mL), add Boc-Ala-OH (15mg, 0.08mmol), EDCI (307mg, 1.6mmol),
HOBt (216mg, 1.6mmol), then adds DIEA and adjusts reaction solution to alkalescence.Mixed liquor is stirred overnight at room temperature, reaction solution according to
Secondary use dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated common salt water washing.Organic phase is dried with anhydrous magnesium sulfate, is depressurized dense
Contracting, gained crude product crosses post purifying (cyclohexane/acetone=3/1), obtains colorless oil D1(25mg, two-step reaction gross production rate
73%), reactive chemistry equation is shown in formula III.
1H NMR(400MHz,CDCl3):δ 7.33 (d, J=4.2Hz, 1H), 5.02 (d, J=6.1Hz, 1H), 4.81-
4.76 (m, 1H), 4.72-4.67 (m, 1H), 4.49 (t, J=9.0Hz, 1H), 4.19-4.05 (m, 1H), 3.74 (s, 3H),
2.98-2.86 (m, 2H), 2.76-2.65 (m, 2H), 2.44-2.37 (m, 1H), 2.15-1.92 (m, 3H), 1.81 (dd, J=
11.8,6.8Hz, 1H), 1.72 (tt, J=13.9,4.5Hz, 1H), 1.42 (s, 9H), 1.32 (d, J=7.1Hz, 3H)；13C
NMR(100MHz,CDCl3):δ173.18,171.85,169.90,155.52,80.38,59.72,56.39,55.76,52.67,
50.63,38.01,37.09,31.54,31.38,28.62,27.02,19.13.
(5R, 8S, 10aR) -5- ((S) -2- (tertiary butyloxy formylamido) propionamido-) -6- carbonyl thia azatropylidenes [1,5]
Pyrrolizine [2,1-d] -8- carboxylic acids (compound E1) preparation：
By compound D1(25mg, 0.06mmol) is dissolved in MeCN/H2O(1:1,2mL) in the mixed solvent, adds KOH
(3.3mg,0.06mmol).Suspension is stirred at room temperature 2 hours, concentration, and residue diluted with water adjusts pH value with dilute hydrochloric acid solution
To 2.The aqueous solution is extracted with ethyl acetate three times, merges organic phase, and anhydrous magnesium sulfate is dried, and is concentrated to give colorless oil E1
(23mg, 95%).It need not be further purified, directly carry out next step reaction.Reactive chemistry equation is shown in formula IV.
1H NMR(400MHz,MeOD):δ 4.84 (dd, J=10.1,2.3Hz, 1H), 4.76-4.71 (m, 1H), 4.48
(t, J=8.8Hz, 1H), 4.08 (q, J=7.2Hz, 1H), 2.98-2.72 (m, 4H), 2.49-2.43 (m, 1H), 2.20-2.00
(m, 3H), 1.86 (dd, J=11.1,6.1Hz, 1H), 1.80-1.72 (m, 1H), 1.46 (s, 9H), 1.33 (d, J=7.2Hz,
3H)；13C NMR(100MHz,MeOD):δ177.10,175.63,172.01,158.56,81.59,62.07,58.77,57.62,
52.57,38.94,38.71,32.69,32.16,29.55,28.76,18.87.
(5R, 8S, 10aR)-(4- (cyanogen methyl) phenoxy group) methyl 5- ((S) -2- amino propionamido-) -6- carbonyl thias
Azatropylidene [1,5] pyrrolizine [2,1-d] -8- carboxylate trifluoroacetates (G1) preparation：
At -10 DEG C, by compound E1(23mg, 0.06mmol) is dissolved in dry methylene chloride solution (3mL), adds three second
Amine (8 μ L, 0.06mmol), then adds the drying dichloro of 2- (4- (chloromethoxy) phenyl) acetonitrile (11mg, 0.06mmol)
Dichloromethane (2mL).Mixed liquor is stirred overnight at room temperature under Ar protections, is concentrated to give crude product F1.At -10 DEG C, by compound
F1It is dissolved in dichloromethane (2mL), adds TFA (300 μ L) dichloromethane solution (1mL), mixed liquor is stirred 5 hours, concentration
Gained residue is purified through HPLC, freeze-drying, obtains white solid G1(7.8mg, two step gross production rates 23%).Reactive chemistry side
Formula is shown in formula V.Compound G1's1H NMR detection spectrograms are as shown in Figure 1.
1H NMR(400MHz,D2O):δ 7.27 (d, J=8.8Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 5.84,5.76
(ABq, J=6.8Hz, 2H), 4.49-4.44 (m, 1H), 4.35 (t, J=9.1Hz, 1H), 3.97 (q, J=7.1Hz, 1H),
3.76 (s, 2H), 2.76 (dd, J=14.1,3.0Hz, 1H), 2.67 (dt, J=15.6,4.5Hz, 1H), 2.32-2.24 (m,
3H), 2.07-1.97 (m, 1H), 1.93-1.83 (m, 1H), 1.72-1.62 (m, 3H), 1.36 (d, J=7.1Hz, 3H)；13C
NMR(100MHz,D2O):δ172.82,172.77,170.92,170.88,169.81,169.77,155.11,155.05,
129.72,129.67,125.71,125.63,120.19,120.13,117.22,117.14,86.23,86.15,60.62,
60.57,57.94,57.88,54.70,54.65,48.91,48.83,35.94,35.88,34.73,34.66,30.89,
30.83,29.48,29.42,26.47,26.41,22.03,21.98,16.44,16.39；MS(ESI):m/z 461.2(M+H
)+；HR ESI MS for C22H29N4O5S required 461.1859,found:461.1880.
(the hydridization cancer therapy drug G of embodiment 22)
Compound A2(A2Structural formula see shown in formula VI) synthetic method with reference to Duggan, H.M. et al. exists
Organic&biomolecular chemistry(《Organic and biological molecular chemistry》) magazine the 3rd phase in 2005 reports of page 2287
Method.
(3S, 6S, 10aR) -6- (tertiary butyloxy formylamido) -5- carbonyl -1,2,3,5,6,7,10,10a- octahydro pyrrolo-es
[1,2-a] azepine cyclo-octene -3- carboxylic acid, ethyl esters (compound B2) preparation：
By compound A2(32mg, 0.10mmol) and Na2CO3(106mg, 1.00mmol) is dissolved in DMSO (2mL).Suspend
Liquid is stirred 30 minutes, then adds iodoethane (8 μ L, 0.10mmol).Mixed liquor is in N2Under protection, it is stirred at room temperature 4 hours, it is dense
Contracting, gained residue is dissolved in dichloromethane.Organic phase is washed with water, anhydrous sodium sulfate drying, and concentration gained crude product crosses post
Purify (cyclohexane/ethyl acetate=6/1), obtain colorless oil B2(25mg, 72%).Reactive chemistry equation is shown in formula VI.
1H NMR(400MHz,CDCl3):δ 5.83-5.72 (m, 1H), 5.72-5.62 (m, 1H), 5.56 (d, J=7.5Hz,
1H), 4.86-4.76 (m, 1H), 4.50-4.39 (m, 1H), 4.12 (q, J=7.1Hz, 3H, containing 1H), 2.76-
2.70(m,2H),2.45-2.33(m,1H),2.32-2.19(m,1H),2.15-2.06(m,1H),2.06-1.98(m,1H),
1.98-1.82 (m, 2H), 1.39 (s, 9H), 1.22 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3):δ171.89,
171.05,155.23,129.32,125.92,79.58,60.97,60.38,58.74,51.91,35.37,33.03,32.97,
28.42(3C),27.29,14.21.
(3S, 6S, 10aR) -6- ((S) -2- (tertiary butyloxy formylamido) propionamido-) -5- carbonyl -1,2,3,5,6,7,
10,10a- octahydros pyrrolo- [1,2-a] azepine cyclo-octene -3- carboxylic acid, ethyl esters (compound D2) preparation：
At 0 DEG C, TFA (300 μ L) dichloromethane solution (1mL) is added to compound B2(28mg, 0.08mmol's)
In dichloromethane solution (2mL).Mixed liquor stirs 2.5h, is concentrated to give compound amine C2.At 0 DEG C, by the compound C of gained2It is molten
In dry dichloromethane (3mL), add Boc-Ala-OH (38mg, 0.20mmol), BOP (35mg, 0.08mmol),
HOOBt (3mg, 0.02mmol), then adds NEt3Reaction solution is adjusted to alkalescence.Mixed liquor is stirred overnight at room temperature, reaction solution according to
Secondary use saturated ammonium chloride solution, saturated potassium hydrogen carbonate solution, saturated common salt water washing.Organic phase anhydrous sodium sulfate drying, subtracts
Pressure concentration, gained crude product crosses post purifying (cyclohexane/ethyl acetate=5/1), obtains colorless oil D2(26mg, two steps are anti-
Answer gross production rate 77%).Reactive chemistry equation is shown in formula VII.
1H NMR(400MHz,CDCl3):δ 7.06 (d, J=5.7Hz, 1H), 5.93-5.78 (m, 1H), 5.78-5.62 (m,
1H), 5.13-4.90 (m, 2H), 4.46 (dd, J=8.9,3.9Hz, 1H), 4.28-4.05 (m, 4H), 2.87-2.66 (m, 2H),
2.54-2.38(m,1H),2.38-2.24(m,1H),2.24-2.08(m,1H),2.08-1.82(m,3H),1.43(s,9H),
1.33 (d, J=7.0Hz, 3H), 1.26 (t, J=7.1Hz, 3H)
(3S, 6S, 10aR) -6- ((S) -2- (tertiary butyloxy formylamido) propionamido-) -5- carbonyl -1,2,3,5,6,7,
10,10a- octahydros pyrrolo- [1,2-a] azepine cyclo-octene -3- carboxylic acids (compound E2) preparation：
By compound D2(25mg, 0.06mmol) is dissolved in THF/H2O(1:1,2mL) in the mixed solvent, adds LiOH
(4.3mg,0.18mmol).Suspension is stirred at room temperature 4.5 hours, concentration, and residue diluted with water adjusts PH with dilute hydrochloric acid solution
It is worth to 2.The aqueous solution is extracted three times with dichloromethane, merges organic phase, and anhydrous sodium sulfate drying is concentrated to give colorless oil E2
(22mg, 93%).It need not be further purified, directly carry out next step reaction.Reactive chemistry equation is shown in formula VIII.
1H NMR(400MHz,CDCl3):δ9.55(bs,1H),7.63(bs,1H),7.50(bs,1H),5.96-5.62(m,
2H),5.35-5.14(m,1H),4.71-4.45(m,1H),4.33-4.08(m,2H),3.00-2.70(m,2H),2.54-2.32
(m, 1H), 2.32-2.14 (m, 2H), 2.14-1.98 (m, 2H), 1.98-1.84 (m, 1H), 1.44 (d, J=5.0Hz, 9H),
1.37 (dd, J=6.9,3.5Hz, 3H)；13C NMR(100MHz,CDCl3):δ172.33,155.85,129.25,125.94,
80.54,60.73,59.29,50.52,49.93,34.59,33.07,32.78,28.46,26.59,19.56,14.33.
(3S, 6S, 10aR)-(4- second cyano-phenyl) -6- ((S) -2- amino propionamido-) -5- carbonyl -1,2,3,5,6,
7,10,10a- octahydros pyrrolo- [1,2-a] Azacyclooctane -3- carboxylate trifluoroacetates (G2) preparation：
At 0 DEG C, by compound E2(22mg, 0.06mmol) is dissolved in dry chloroform (5mL), addition EDCI (115mg,
0.60mmol) and DIEA (99 μ L, 0.60mmol) mixing chloroformic solution, then add 2- (4- hydroxy phenyls) acetonitrile (24mg,
0.18mmol), mixed liquor is stirred overnight at room temperature.Decompressing and extracting solvent, obtains pale yellow oil F2.By F2It is dissolved in chloroform
(3mL), is cooled to 0 DEG C, is added dropwise after TFA (0.5mL), 2.5h, solvent evaporated, and concentration gained residue is purified through HPLC, and freezing is dry
It is dry, obtain white solid G2(3.1mg, two-step reaction gross production rate 10%).Reactive chemistry equation is shown in formula Ⅸ.Compound G2's1H
NMR detection spectrograms are as shown in Figure 2.
1H NMR(400MHz,CDCl3):δ 7.70 (bs, 1H), 7.32 (d, J=8.3Hz, 2H), 7.07 (d, J=8.3Hz,
2H), 5.85-5.51 (m, 2H), 5.16-5.04 (m, 1H), 4.64 (d, J=5.9Hz, 1H), 4.33-4.16 (m, 1H), 4.16-
3.99 (m, 1H), 3.72 (s, 2H), 2.86-2.59 (d, J=14.8Hz, 2H), 2.51-2.34 (m, 1H), 2.25-2.20 (m,
2H),2.20-2.07(m,3H),2.06-1.90(m,2H),1.55-1.43(m,3H).MS(ESI):m/z 411.2(M+H)+；
HR ESI MS for C22H27N4O4required 411.1954,found:411.1932.
(the hydridization cancer therapy drug G of embodiment 33)
Compound A2(A2Structural formula see shown in formula Ⅹ) synthetic method with reference to Duggan, H.M. et al. exists
Organic&biomolecular chemistry(《Organic and biological molecular chemistry》) magazine the 3rd phase in 2005 reports of page 2287
Method.
(3S, 6S, 10aR) -6- (tertiary butyloxy formylamido) -5- carbonyl -1,2,3,5,6,7,10,10a- octahydro pyrrolo-es
[1,2-a] azepine cyclo-octene -3- carboxylic acid, ethyl esters (compound B2) preparation：
By compound A2(32mg, 0.10mmol) and KOH (6mg, 0.10mmol) are dissolved in THF (2mL).Suspension is stirred
1 minute, then add iodoethane (20 μ L, 0.25mmol).Mixed liquor is in N2Under protection, it is stirred at room temperature 12 hours, concentrates, gained
Residue is dissolved in chloroform.Organic phase is washed with water, Anhydrous potassium carbonate dry, concentration gained crude product cross post purifying (hexamethylene/
Ethyl acetate=6/1), obtain colorless oil B2(29mg, 82%).Reactive chemistry equation is shown in formula Ⅹ.
1H NMR(400MHz,CDCl3):δ 5.83-5.72 (m, 1H), 5.72-5.62 (m, 1H), 5.56 (d, J=7.5Hz,
1H), 4.86-4.76 (m, 1H), 4.50-4.39 (m, 1H), 4.12 (q, J=7.1Hz, 3H, containing 1H), 2.76-
2.70(m,2H),2.45-2.33(m,1H),2.32-2.19(m,1H),2.15-2.06(m,1H),2.06-1.98(m,1H),
1.98-1.82 (m, 2H), 1.39 (s, 9H), 1.22 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3):δ171.89,
171.05,155.23,129.32,125.92,79.58,60.97,60.38,58.74,51.91,35.37,33.03,32.97,
28.42(3C),27.29,14.21.
(3S, 6S, 10aR) -6- ((S) -2- (tertiary butyloxy formylamido) propionamido-) -5- carbonyl -1,2,3,5,6,7,
10,10a- octahydros pyrrolo- [1,2-a] azepine cyclo-octene -3- carboxylic acid, ethyl esters (compound D2) preparation：
At 15 DEG C, TFA (300 μ L) chloroformic solution (1mL) is added to compound B2The chloroform of (28mg, 0.08mmol)
In solution (2mL).Mixed liquor stirs 0.3h, is concentrated to give compound amine C2.At 15 DEG C, by the compound C of gained2It is dissolved in drying
Chloroform (3mL) in, add Boc-Ala-OH (76mg, 0.40mmol), DCC (165mg, 0.80mmol), HOSu (92mg,
0.80mmol), then add DBU and adjust reaction solution pH to alkalescence.Mixed liquor is stirred overnight at room temperature, and reaction solution uses saturation chlorine successively
Change ammonium salt solution, saturated potassium hydrogen carbonate solution, saturated common salt water washing.Organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained
Crude product crosses post purifying (cyclohexane/ethyl acetate=5/1), obtains colorless oil D2(23mg, two-step reaction gross production rate
68%).Reactive chemistry equation is shown in formula Ⅺ.
1H NMR(400MHz,CDCl3):δ 7.06 (d, J=5.7Hz, 1H), 5.93-5.78 (m, 1H), 5.78-5.62 (m,
1H), 5.13-4.90 (m, 2H), 4.46 (dd, J=8.9,3.9Hz, 1H), 4.28-4.05 (m, 4H), 2.87-2.66 (m, 2H),
2.54-2.38(m,1H),2.38-2.24(m,1H),2.24-2.08(m,1H),2.08-1.82(m,3H),1.43(s,9H),
1.33 (d, J=7.0Hz, 3H), 1.26 (t, J=7.1Hz, 3H)
(3S, 6S, 10aR) -6- ((S) -2- (tertiary butyloxy formylamido) propionamido-) -5- carbonyl -1,2,3,5,6,7,
10,10a- octahydros pyrrolo- [1,2-a] azepine cyclo-octene -3- carboxylic acids (compound E2) preparation：
By compound D2(25mg, 0.06mmol) is dissolved in MeCN/H2O(1:1,2mL) in the mixed solvent, adds NaOH
(12mg,0.30mmol).Suspension is stirred at room temperature 7 hours, concentration, and residue diluted with water adjusts pH value with dilute hydrochloric acid solution
To 2.The aqueous solution is extracted three times with chloroform, merges organic phase, and Anhydrous potassium carbonate is dried, and is concentrated to give colorless oil E2(20mg,
84%).It need not be further purified, directly carry out next step reaction.Reactive chemistry equation is shown in formula Ⅻ.
1H NMR(400MHz,CDCl3):δ9.55(bs,1H),7.63(bs,1H),7.50(bs,1H),5.96-5.62(m,
2H),5.35-5.14(m,1H),4.71-4.45(m,1H),4.33-4.08(m,2H),3.00-2.70(m,2H),2.54-2.32
(m, 1H), 2.32-2.14 (m, 2H), 2.14-1.98 (m, 2H), 1.98-1.84 (m, 1H), 1.44 (d, J=5.0Hz, 9H),
1.37 (dd, J=6.9,3.5Hz, 3H)；13C NMR(100MHz,CDCl3):δ172.33,155.85,129.25,125.94,
80.54,60.73,59.29,50.52,49.93,34.59,33.07,32.78,28.46,26.59,19.56,14.33.
(3S, 6S, 10aR)-(4- nitrate methylene phenyl) -6- ((S) -2- amino propionamido-) -5- carbonyl -1,2,
3,5,6,7,10,10a- octahydros pyrrolo- [1,2-a] Azacyclooctane -3- carboxylate trifluoroacetates (G3) preparation：
At 15 DEG C, by compound E2(20mg, 0.05mmol) is dissolved in dry chloroform (5mL), add DCC (206mg,
1mmol) with DIEA (165 μ L, 1mmol) mixing chloroformic solution, 2- (4- hydroxy phenyls) methyl nitrate is then added
(42mg, 0.25mmol), mixed liquor is stirred overnight at room temperature.Decompressing and extracting solvent, obtains pale yellow oil F3.By F3It is dissolved in chlorine
Imitative (3mL), at 15 DEG C, is added dropwise after TFA (0.5mL), 0.3h, solvent evaporated, and concentration gained residue is purified through HPLC, is freezed
Dry, obtain white solid G3(2.3mg, 8%).Reactive chemistry equation is shown in formula Ⅹ III.Compound G3's1H NMR detect spectrogram
As shown in Figure 3.
1H NMR(400MHz,CDCl3):δ7.46-7.29(m,2H),7.27-7.10(m,2H),5.95-5.66(m,2H),
5.04-4.80 (m, 1H), 4.67 (dd, J=7.7,6.1Hz, 1H), 4.24-4.10 (m, 2H), 4.07-3.99 (m, 1H),
3.71-3.51 (m, 1H), 2.77-2.47 (m, 2H), 2.47-2.23 (m, 1H), 2.20-1.45 (m, 7H), 1.54 (d, J=
6.4Hz,3H).MS(ESI):m/z 447.2(M+H)+；HR ESI MS for C21H27N4O7required 446.1801,
found:446.1859.
Compound G4~G48It can use with preparing G1Or G2Identical method is made, and is not both：
Using in BOP or DCC or PyBOP or DIC or TBTU or HBTU or HATU or TATU alternative embodiments 1
EDCI；
Using the HOBt in HOOBt or HOSu alternative embodiments 1；
Using 2- (4- (chloromethoxy) phenyl) methyl nitrates or 2- (4- hydroxy phenyls) acetonitriles or 2- (4- hydroxy benzenes
Base) 2- (4- (chloromethoxy) phenyl) acetonitrile in methyl nitrate alternative embodiment 1；
Using (S) -2- (tertbutyloxycarbonyl) aminobutyric acids or (S) -2- ((tertbutyloxycarbonyl) methylamino) propionic acid or
(S) the N- tert-butoxycarbonyl-l-alanines in -2- ((tertbutyloxycarbonyl) methylamino) butyric acid alternative embodiment 1.
Using the DIEA and triethylamine in pyridine or DBU or N-methylmorpholine alternative embodiment 1.
In order to better illustrate the effect of the present invention, with reference to providing the experiment proves that example：
1st, experiment proves example 1
X- Linked Inhibitor of Apoptosis Protein in Children (XIAP) is the important member of IAP protein families, XIAP by directly with
Caspase-3, caspase-7, caspase-9 are combined, to suppress caspase activity, so as to suppress Apoptosis.The present invention
With G1、G2And G3Exemplified by, in fluorescence polarization assay, G is determined respectively1、G2And G3Antagonism X- Linked Inhibitor of Apoptosis Protein in Children
(XIAP) ability of BIR3 domains activity.
1.1 experiment materials and instrument
(1) polypeptide ligand of fluorescence labeling
Heptapeptide molecule H-AVPFAQK- (6-FAM)-NH is synthesized by colleague2, fluorescence is done on the ε amino of its lysine side chain
Mark.The structure of the fluorescent peptide is confirmed by ESI-MS, is analyzed through HPLC, and its purity is higher than 98%.Fluorescent peptide is dissolved in ultra-pure water,
Its solution concentration is defined as 467 μM through ultraviolet absorption method.The every 10 μ L packing of solution, lucifuge, -20 DEG C of preservations are wrapped up with tinfoil.
(2) XIAP-BIR3 recombinant proteins
XIAP-BIR3 recombinant proteins are purchased from R＆D Systems Inc..Albumen is Escherichia coli, containing Asn252-
Thr356 residues, one N-terminal Met and 6-His label of band.Every 50 μ g are dispensed, and the pH value that 50 μ L are stored at -20 DEG C is 8.0, is contained
In 50mM Tris-HCl, 300mM KCl, 50 μM of zinc acetates, 1mM DTT cushioning liquid.
(3) reaction buffer
The reaction buffer that this test is used includes 20mM Hepes, 2mM dithiothreitol (DTT), 100mM
NaCl, 0.1%Bovine serum albumin (BSA), pH instrument adjust its pH value to 7.4.Agents useful for same is purchased from Sigma-
Aldrich, purity is highest level.
(4) preparation of sample solution
First by compound G1、G2And G3Ultra-pure water is dissolved in respectively, is formulated as 10mM mother liquor, is then diluted mother liquor
To required concentration.
(5) laboratory apparatus
Perkin Elmer EnVision multiple labeling micropores board detectors (EnVision Multilabel Reader),
PH meter, UV absorbance detection instrument, 384 hole detection plates.
1.2 experimental method
(1) 384 hole detection plates are prepared
First, 2.5nM fluorescent peptide and 250nM XIAP-BIR3 albumen are added into reaction buffer, forms test
Cushioning liquid, and hatch half an hour.At the same time, sample mother liquor is diluted to a series of concentration, concentration range is 5mM to 5nM.
Then, in 384 hole detection plates, three repeating samples of each concentration point.First, detected with liquid-transfering gun to 384 holes
16 μ L test cushioning liquid is added in the hole of plate, 4 μ L sample solution are added.After mixing, liquor capacity is changed into 20 μ in hole
L, then, fluorescent peptide and XIAP-BIR3 concentration are changed into optimal test concentrations, i.e. 2nM and 200nM respectively.Sample it is final dense
Degree is changed into 1mM to 1nM.By 384 hole detection plate incubation at room temperature 20~30 minutes, with micropore board detector reading.Then will detection
Plate hatches 20~30 minutes again, again reading.
(2) data processing
All data are with GraphPad Prism nonlinear regression curve fit procedure analysis.
1.3 results are with discussing
Fluorescent peptide and the final test concentration of XIAP-BIR3 albumen are fixed to 2nM and 200nM, institute's test sample
Ultimate density scope is 1mM to 1nM.Compound G1With XIAP-BIR3 competitive bindings suppression curve as shown in figure 4, with mP values
For Y-axis, log C are X-axis (C is the concentration of test sample).As a result show, compound G1With preferably with XIAP-BIR3's
Binding affinity.Due to compound G1XIAP-BIR3 competitive bindings are suppressed, its binding curve is S types, i.e. mP values are with test
The increase of sample concentration and reduce, when sample concentration is sufficiently low, mP values reach maximum, no longer change.Conversely, when sample is dense
When spending sufficiently high, mP values reach minimum value, suppress saturation.Surveyed data are analyzed through GraphPad Prism, draw compound G1
IC50It is worth for 3.6 μM.
Under identical condition, with same detection method, G is measured2IC50It is worth for 6.7 μM, G,3IC50It is worth for 8.3 μ
M.In addition, positive control --- four peptide molecule AVPI (Ala-Val-Pro-Ile) IC50It is worth for 0.8 μM.Although G1、G2With
And G3IC50It is worth and is not so good as AVPI, but compound G1、G2And G3Non-peptide feature it is more obvious, and be expected to act on multiple anti-
Cancer target spot.Fluorescence polarization assay result shows, compound G1、G2And G3It is a kind of new, more efficient non-peptide antagonisms of XIAP
Agent.
2nd, experiment proves example 2
With G1Exemplified by, in MDA-MB-231 breast carcinoma cell strains, determine G1Make together with another cancer therapy drug TRAIL
With to the synergy of Apoptosis.
2.1 experiment materials and method
(1) cell culture and reagent
All compounds are dissolved in DMSO, are formulated as the stock solution that concentration is 10mM.Cell is supplementing 10% tire ox blood
Cultivated clearly in (FBS), penicillin (100U/mL), the DMEM culture mediums of streptomysin (100mg/mL).TRAIL is purchased from PeproTech
Inc.。
(2) 3- (4,5- dimethylthiazoles -2) -2,5- diphenyltetrazolium bromide bromides (MTT) are tested
Cell survival rate is tested with mtt assay.First, cell is placed in 96 orifice plates (1 × 106Cells/well), then add phase
That answers concentration surveys compound and TRAIL, maintain 24 in culture dish, 48,96 hours.Finally, 20 μ L MTT (5mg/ are added
ML phosphate buffer) add into Tissue Culture Dish, hatch 2 hours at 37 DEG C.Gained crystal is dissolved in 200 μ L DMSO
In, measure absorption intensity under 490nm wavelength with Vector3.
2.2 results are with discussing
First, in MDA-MB-231 cell lines, tested with MTT, test 10ng/mL, 50ng/mL, 100ng/mL
Influences of the TRAIL of three concentration when being used alone to Apoptosis.As a result as shown in figure 5, growth over time, Yi Jisui
The increase of TRAIL concentration, cell survival rate reduction.But, generally speaking, under 100ng/mL concentration conditions,
TRAIL nor too substantially, after cell culture 96 hours, still there is 65% to the cells apoptosis of MDA-MB-231 cancer cells
Cancer cell survival.
Then, tested with MTT, test 5 μM of G1Respectively with tri- concentration of 10ng/mL, 50ng/mL, 100ng/mL
TRAIL collective effects, the influence to Apoptosis.As a result as shown in figure 5, after cell culture 48 hours, compound G1With TRAIL
Show good dose-dependent synergy, and this synergy seems become apparent at higher concentrations.According to
Acquired results, can be inferred that Apoptosis is more active, and this synergy is more obvious.For example, after hatching in 96 hours, 100ng/
ML TRAIL is used alone, 65% cell survival, however, TRAIL and 5 μM of G1When being used together, only 31% cell survival,
Active anticancer is greatly improved.
Result of the test shows, such hydridization medicine can effectively antagonism IAPs effect, in MDA-MB-231 breast cancer
In cell line, the MDA-MB-231 cells for producing medicine tolerance to TRAIL originally can be made to become sensitive to TRAIL, so as to accelerate
Apoptosis.Such hydridization medicine can as new anticancer drug lead compound, the exploitation for new anticancer drug
In research.
Breviary vocabulary (alphabet sequence)
Above-described embodiment is preferably embodiment, but embodiments of the present invention are not by above-described embodiment of the invention
Limitation, other any Spirit Essences without departing from the present invention and the change made under principle, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (6)
1. a kind of compound of structural formula as shown in formula I：
Wherein：
X is selected from-SCH2- ,-CH=CH- or-(CH2)2One kind in-substituent：
Y is selected from-O- or-OCH2One kind in O-；
R1It is selected fromOne kind in substituent；
R2Selected from-CN or-ONO2In one kind.
2. the preparation method of compound of the structural formula as shown in formula I described in claim 1, it is characterised in that：Including following steps
Suddenly：
1) compound A and inorganic base are dissolved in polar organic solvent, suspension is stirred 1~30 minute, then adds iodomethane
Or iodoethane, mixed liquor is stirred at room temperature 4~12 hours under the protection of inert gas, concentrates, gained residue is dissolved in nonpolar
In organic solvent, organic phase is washed with water, desiccant dryness, and concentration gained crude product crosses post purifying, obtains compound B；
Wherein, the mol ratio of described compound A, inorganic base, iodomethane or iodoethane is：1：1~10：1~5；
2) at -10~15 DEG C, TFA chlorohydrocarbon solution is added into compound B chlorohydrocarbon solution, mixed liquor stirring 0.3
~5 hours, it is concentrated to give at compound C, -10~15 DEG C, compound C is dissolved in dry chlorohydrocarbon solution, adds tertiary fourth
Amino acid, condensing agent and the additive of oxygen carbonyl protection, then add organic base and adjust reaction solution pH to alkalescence, mixed liquor room temperature
It is stirred overnight, reaction solution uses dilute acid soln, dilute alkaline soln, saturated common salt water washing successively, dries, is concentrated under reduced pressure gained crude product
Post purifying is crossed, compound D is obtained；
Wherein, described compound C, the amino acid of tertbutyloxycarbonyl protection, condensing agent, the mol ratio of additive are 1：1~5：1
~20：0.25~20；
3) compound D is dissolved in the in the mixed solvent of polar organic solvent and water, highly basic is added, it is small that suspension is stirred at room temperature 2~7
When, concentration, residue diluted with water adjusts pH value to acidity, the aqueous solution is extracted with non-polar organic solvent with dilute hydrochloric acid solution
Three times, merge organic phase, desiccant dryness is concentrated to give compound E；
Wherein, described compound D, the mol ratio of highly basic are 1：1~5；
4) at -10~15 DEG C, compound E is dissolved in dry chlorohydrocarbon solution, organic base or condensing agent and organic base is added
Chlorohydrocarbon solution is mixed, 2- (4- (chloromethoxy) phenyl) acetonitriles or 2- (4- (chloromethoxy) phenyl) methyl is then added
Nitrate or 2- (4- hydroxy phenyls) acetonitriles or 2- (4- hydroxy phenyls) methyl nitrate, mixed liquor under inert gas shielding,
It is stirred overnight at room temperature, is concentrated to give compound F, -10~15 DEG C, TFA is added into compound F chlorohydrocarbon solution, mixes
Liquid is stirred 0.1~5 hour, concentration, and efficient liquid phase purifying, freeze-drying obtains compound of the structural formula as shown in formula I；
Wherein, described compound E, 2- (4- (chloromethoxy) phenyl) acetonitrile or 2- (4- (chloromethoxy) phenyl) methyl
Nitrate or 2- (4- hydroxy phenyls) acetonitriles or 2- (4- hydroxy phenyls) methyl nitrate, organic base, the mol ratio of condensing agent are
1：1~5：1~20：1~20；
Described compound A general structure is：Wherein, X is-SCH2- ,-CH=CH- or-
(CH2)2- in one kind；
Described inorganic base is K2CO3、Na2CO3、KHCO3、NaHCO3, one or more in KOH, NaOH or LiOH；
Described highly basic is KOH, NaOH, Ca (OH)2, one or more in NaH, KH or LiOH；
Described polar organic solvent is the one or more in DMF, DMSO, THF or MeCN；
Described non-polar organic solvent is the one or more in ethyl acetate, dichloromethane, chloroform or ether；
Described condensing agent is the one or more in BOP, DCC, EDCI, DIC, PyBOP, TBTU, HBTU, HATU or TATU；
Described additive is the one or more in HOBt, HOOBt or HOSu；
Described organic base is the one or more in triethylamine, pyridine, DBU, DIEA or N-methylmorpholine.
3. the preparation method of compound of the structural formula according to claim 2 as shown in formula I, it is characterised in that：Described
Inert gas is nitrogen or argon gas；
Described chlorohydrocarbon solution is dichloromethane or chloroform.
4. the preparation method of compound of the structural formula according to claim 2 as shown in formula I, it is characterised in that：Described
Tertbutyloxycarbonyl protection amino acid for N- tert-butoxycarbonyl-l-alanines, (S) -2- (tertbutyloxycarbonyl) aminobutyric acid, (S) -
One or more in 2- ((tertbutyloxycarbonyl) methylamino) propionic acid or (S) -2- ((tertbutyloxycarbonyl) methylamino) butyric acid.
5. the preparation method of compound of the structural formula according to claim 2 as shown in formula I, it is characterised in that：
Described drier is one kind in anhydrous magnesium sulfate, anhydrous sodium sulfate, Anhydrous potassium carbonate or anhydrous calcium chloride.
6. application of compound of the structural formula as shown in formula I in cancer therapy drug is prepared described in claim 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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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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