CN102050867A - Tetrapeptide analog, preparation method and application thereof - Google Patents

Tetrapeptide analog, preparation method and application thereof Download PDF

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Publication number
CN102050867A
CN102050867A CN2009102017843A CN200910201784A CN102050867A CN 102050867 A CN102050867 A CN 102050867A CN 2009102017843 A CN2009102017843 A CN 2009102017843A CN 200910201784 A CN200910201784 A CN 200910201784A CN 102050867 A CN102050867 A CN 102050867A
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methyl
cis
alkyl
alanyl
tetralyl
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白旸
郭建辉
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Shanghai Allist Pharmaceuticals Inc
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Shanghai Allist Pharmaceuticals Inc
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Priority to CN2009102017843A priority Critical patent/CN102050867A/en
Priority to CN201080051130.8A priority patent/CN102753166B/en
Priority to PCT/CN2010/001800 priority patent/WO2011057477A1/en
Publication of CN102050867A publication Critical patent/CN102050867A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention discloses a tetrapeptide analog, a preparation method and application thereof. The tetrapeptide analog is an inhibitor of apoptosis protein (IAP), and has good IAP inhibiting effect and cancer cell proliferation inhibiting effect so that the tetrapeptide analog can be used as a treatment agent for treating tumors.

Description

Tetrapeptide analogs, preparation method and application thereof
Technical field
The present invention relates to suppress Smac albumen and apoptosis protein inhibitor (IAP) bonded tetrapeptide analogs.The present invention includes tetrapeptide analogs and preparation method thereof, and this class thing is as the application of IAP inhibitor and carcinostatic agent.
Background technology
Apoptosis (Apoptosis) or apoptosis are a kind of heredity and biochemical mechanism of regulating of being subjected to, and it is eliminated in irriate or the damaged cells at the adjusting cell quantity and from healthy tissues and plays an important role.Cause the apoptosis defective of necrocytosis shortage to be related with cancer and chronic viral infection (Thompson et al., (1995) Science 267,1456-1462).
Apoptosis signal conduction network is divided into death receptor-the inherent network of ligand interaction mediation and cellular stress is arranged and mitochondrial permeability increases the external network of mediation.Article two, approach finally all concentrates on corresponding halfcystine aspartate specific protease (Caspase).Caspase is one of effector molecule crucial in the procedural apoptosis, in case be activated, Caspase can cut many substrates relevant with necrocytosis, the destruction of causing cell.
Tumour cell has many apoptotic strategies of evading.A kind of molecular mechanism of nearest report relates to apoptosis protein inhibitor (IAP) family member's overexpression.IAP extensively is distributed in the organism from the fruit bat to the mankind.IAP is by directly and in the Caspase interaction also stoping apoptosis with Caspase.Prototype IAP comprises XIAP and cIAP, has three kinds of functional domains, is called BIR1,2 and 3 structural domains.The BIR3 structural domain directly interacts with Caspase 9 and suppresses the ability that it combines and cuts its natural product Caspase3 proenzyme, thus inhibition apoptosis and cause anti-apoptosis effect.
There is report to confirm, short apoptosis mitochondrial protein Smac (being called DIABLO again) can by in combining with the lip-deep protein binding bag of BIR (Smac binding site) and XIAP and or cIAP, thereby stop the interaction between XIAP and/or cIAP and the Caspase 9, thereby cause programmed cell death.
Find that after deliberation the N-end of Smac is four amino acid AVPI, the C-end is four amino acid AVPF.The homology that also has sequence between the IAP inhibitor, the motif of four amino acid AVPI of existence in the N-end of the active protein that process is processed.As if this tetrapeptide be attached in the hydrophobic pocket of BIR structural domain, destroy the BIR structural domain and combine (Chai et al. with Caspase, (2000) Nature 406:855-862, Liu etal., (2000) Nature 408:1004-1008, Wu et al., (2000) Nature 408:1008-1012).
Therefore, the Smac analogue is used for the treatment of cancer and receives much attention as the IAP inhibitor, and becomes one of the research focus in anticancer field.According to the literature, the BIR3 structural domain of Smac analogue and XIAP demonstrates avidity preferably, for example, structure reaches 16 nmoles (nm) as shown in the formula compound shown in (a) and XIAP-BIR3 bonded decomposition value (Kd valve), thereby stop XIAP and Caspase to interact, performance promotes apoptotic effect (Thorsten K.Oost et al., (2004) Journal of Medicinal Chemistry47:4417-4426).
Figure B2009102017843D0000011
International Patent Application WO 2004005248 has been described the proteic inhibitor peptides with apoptosis protein inhibitor bonded SMAC, can be used as the therapeutical agent that treatment comprises the proliferative disorders of cancer.General structure is as shown in the formula shown in (b).R wherein 7And R 8With respect to the acyl substituent of ring on 1 be cis and independently of one another for H ,-OH ,-O-(CH 2) 0-6-aryl, N (R 12) (R 13), R 12And R 13Be independently H ,-(CH 2) 0-6-C 3-C 7-cycloalkyl ,-C (O)-(CH 2) 1-6-C 3-C 7-cycloalkyl ,-C (O)-(CH 2) 0-6-O-fluorenyl ,-C (O)-NH-(CH 2) 0-6-aryl, wherein aryl is a phenyl or naphthyl.
Figure B2009102017843D0000021
International Patent Application WO 2005097791 has disclosed and can suppress Smac albumen and apoptosis protein inhibitor (IAP) bonded new compound.General structure is as shown in the formula shown in (c).Wherein U is shown in structural formula (c2).R wherein 6, R 7, R 6' and R 7' can be H independently of one another;-C 1-C 10Alkyl;-C 1-C 10Alkoxyl group; Aryl--C 1-C 10Alkoxyl group;-OH etc., R in the compound of embodiment 6, R 7, R 6' and R 7' be H.
Figure B2009102017843D0000022
International Patent Application WO 2006017295A2 discloses a kind of excess proliferative disease that is used for the treatment of, for example compound of cancer, composition and method.General structure is as shown in the formula shown in (d).R wherein 8, R 9Can be low alkyl group independently of one another; Low-grade alkenyl; Low-grade alkynyl; Aryl; Heteroaryl etc., R in the compound of embodiment 8For-OH; Phenyl; Methyl; Chain vinyl, perhaps 2 R 8Substituting group forms cyclohexyl or phenyl with the carbon atom that they replaced.
Figure B2009102017843D0000023
International Patent Application WO 2006014361 discloses a kind of IAP inhibitor of novelty, their useful as therapeutics treatment malignant tumour.General structure is as shown in the formula shown in (e).R wherein 1Be H, perhaps R 1And R 2Constitute 5-8 unit ring together; R 6And R 6' be H, alkyl, aryl or aralkyl independently of one another.
Figure B2009102017843D0000024
In sum, apoptotic therapeutic tetrapeptide analogs takes place in the cell that promotion is broken up rapidly thereby novel tetrapeptide analogs can combine with the Smac binding pocket.Specifically, the Smac analogue can combine with the BIR3 structural domain of IAP and eliminate the restraining effect of IAP to activatory Caspase 9, thereby makes the Caspase 9 can cell death inducing.Described tetrapeptide analogs can be used for treating proliferative disease, comprises the treatment for cancer agent.
Summary of the invention
The invention provides a kind of formula (I) compound, or its pharmacy acceptable salt,
Mark in its Chinese style is represented following implication
R 1:-NHCOR 3, R wherein 3For-(CH 2) 0-6-aryl or-(CH 2) 0-6-heteroaryl, above-mentioned aryl or heteroaryl can be unsubstituted or be replaced by 1-5 following substituting group: halogen ,-NH 2,-OH, C 1～C 6Alkyl, contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4, R wherein 4Be C 1～C 6Alkyl;
R 2:-(CH 2) 0-6-aryl ,-(CH 2) 0-6-CH (phenyl) 2,-(CH 2) 0-6-het, aryl wherein are phenyl or naphthyl, and het is indyl or pyridyl.
In the present invention, term " aryl " is meant aromatic cyclic hydrocarbon group, and preferably carbonatoms is 6～14 a aryl, is more preferably phenyl or naphthyl.
In the present invention, " heteroaryl " be meant contain 1-4 be selected from N, S, O heteroatomic 5-6 unit's bicyclic heteroaryl and and phenyl ring condense the 2 ring type heteroaryls that form, it can be a fractional saturation.Here, as bicyclic heteroaryl, for example furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl; As 2 ring type heteroaryls, for example benzofuryl, benzothienyl, diazosulfide base, benzothiazolyl, benzimidazolyl-, indyl, pseudoindoyl, indazolyl, quinolyl, isoquinolyl, quinazolyl.As the heteroaryl of fractional saturation, for example 1,2,3,4-tetrahydric quinoline group etc.
In preferred scheme of the present invention, R 2For-CH (phenyl) 2
In another preferred scheme of the present invention, R 2Be 1,2,3, the 4-tetralyl.
In the more preferred scheme of the present invention, R 3For unsubstituted or by at least one be selected from halogen ,-NH 2,-OH, C 1～C 6Alkyl or contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4The phenyl that replaces, wherein R 4Be C 1～C 6Alkyl.
In another more preferred scheme of the present invention, R 3For unsubstituted or by at least one be selected from halogen ,-NH 2,-OH, C 1～C 6Alkyl or contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4The benzyl that replaces, wherein R 4Be C 1～C 6Alkyl.
On the other hand, the invention provides tetrapeptide analogs or its pharmacy acceptable salt, it is represented by following formula general formula (II):
Figure B2009102017843D0000032
R wherein 1, R 2Definition as mentioned above.
In the present invention, as the represented compound of general formula (II), concrete has:
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-fluorobenzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-methoxybenzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-trifluoromethyl benzoyl))-L-dried meat ammonia] acid amides;
N-(R)-I, 2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(3-methoxybenzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-(methyl-formiate)-benzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-carboxymethyl benzoyl))-L-dried meat ammonia] acid amides;
N-(R)-diphenyl-methyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzyl formyl)-L-dried meat ammonia] acid amides or its pharmacy acceptable salt.
The present invention also provides the method for a kind of preparation formula (II) compound, and it comprises step:
(a), N-Boc-trans-4-hydroxy-l-proline methyl esters replaces earlier under hydroxyl protection, the back reduction obtains compound (7) again after two step condensation reactions;
Wherein, R 2For-(CH 2) 0-6-aryl ,-(CH 2) 0-6-CH (phenyl) 2,-(CH 2) 0-6-het, aryl wherein are phenyl or naphthyl, and het is indyl or pyridyl; R 3For-(CH 2) 0-6-aryl or-(CH 2) 0-6-heteroaryl, described aryl or heteroaryl can be unsubstituted or be replaced by 1-5 following substituting group: halogen ,-NH 2,-OH, C 1～C 6Alkyl, contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4, R wherein 4Be C 1～C 6Alkyl;
(b), N-Boc-N-Me-L-L-Ala and L-Cyclohexylglycine methyl esters reduce after condensation reaction and obtain compound (9):
(c), compound (7) and compound (9) through condensation reaction again deprotection obtain target compound (11).
Figure B2009102017843D0000062
In above-mentioned each preparation process, the abbreviation of required reagent is represented respectively:
Figure B2009102017843D0000063
Figure B2009102017843D0000071
Among the present invention, term " pharmacy acceptable salt " is meant the acid salt or the base addition salt of nontoxic relatively The compounds of this invention.Described acid salt is the salt that formula (I) or formula (II) compound and suitable mineral acid or organic acid form, these salt can prepare in last separation of compound and purification process, or the compound that makes purifying reacts with its free alkali form and suitable organic acid or mineral acid, the salt that forms separated again and makes.Representative acid salt comprises hydrobromate, hydrochloride, vitriol, sulphite, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, toluylate, Citrate trianion, maleate, fumarate, succinate, tartrate, benzoate, mesylate, tosilate, gluconate, Lactobionate and lauryl sulfonate etc.Described base addition salt is the salt that formula (I) or formula (II) compound and suitable mineral alkali or organic bases form, for example comprise the salt that forms with basic metal, alkaline-earth metal, quaternary ammonium cation, as sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, tetramethyl-quaternary ammonium salt, tetraethyl-quaternary ammonium salt etc.; Amine salt comprises and ammonia (NH 3), primary amine, secondary amine or the tertiary amine salt that forms, as methylamine salt, dimethylamine salt, front three amine salt, triethylamine salt, ethylamine salt etc.
Utilize the compound of gained of the present invention can deliver medicine to the people, can be oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical (pulvis, ointment or drops).Described compound can be individually dosed, perhaps with other pharmaceutically acceptable compound Combined Preparation.It may be noted that compound of the present invention can mix administration.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least a conventional inert excipient (or carrier), as Trisodium Citrate or Lin Suanergai, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, lime carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, formulation also can comprise buffer reagent.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.
Except the active ingredient beyond the region of objective existence, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the The compounds of this invention of topical comprises ointment, powder, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.
The present invention also provides a kind of pharmaceutical composition, and it contains the above-mentioned formula I compound of 0.05-50mg or its pharmacy acceptable salt, and pharmaceutically acceptable carrier, vehicle or thinner.
The present invention also provides a kind of method for the treatment of disease, and described disease can IAP is active to be alleviated or treat by suppressing, and comprise step: the patient who treats for needs uses formula I compound or its pharmacy acceptable salt of 0.05-30mg/kg body weight/day.In preference, described disease is a tumour.
Compound of the present invention or its pharmacy acceptable salt can be individually dosed, perhaps with other pharmaceutically acceptable therapeutical agent Combined Preparation, particularly with other antitumor drug combinations.Described therapeutical agent includes but not limited to: (i) DNA-linking agent, for example cis-platinum, endoxan or mustargen; (ii) antimetabolic product, for example cytosine arabinoside, methotrexate (MTX) or 5-gemcitabine; (iii) intercalator (intercalating agents), for example adriamycin (Zorubicin) or mitoxantrone; (iv) microtubule-guide agent, for example taxol, Omaine, colchicine; (v) arimedex, for example aminoglutethimide, Lan Telong, letrozole, Rui Ningde; (vi) topological isomer enzyme toxin I toxin, for example camptothecine; (vii) topological isomer enzyme toxin I toxin, for example Etoposide (VP-16); (viii) epidermal growth factor receptor inhibitor, for example imatinib (Imatinib), Gefitinib (Gefitinib), erlotinib (Erlotinib).Each composition to be made up can simultaneously or in a sequence give, and gives with the unitary agent form or with the form of different preparations.Described combination not only comprises the combination of compound of the present invention and a kind of other promoting agent, and comprises the combination of compound of the present invention and two or more other promoting agents.
The compounds of this invention has the cancer cell multiplication restraining effect by the cell experiment proof, can be used for preparing the medicine for the treatment of cancer.The drug effect of The compounds of this invention anticancer propagation can be measured with ordinary method, a kind of preferred evaluation method is sulphonyl rhodamine B (Sulforhodamine B, SRB) protein staining method: SRB is a kind of protein binding dyestuff, can combine with the basic aminoacids in the biomacromolecule, its optical density(OD) at 510nm (OD) reading and protein content are good linear relationship, so can be used as cell count quantitatively, calculate the inhibiting rate of medicine by the variation of measuring the absorbance value that drug effect produced behind cancer cells to cancer cell multiplication.
Inhibiting rate (%)=(OD contrast-OD inhibitor-OD blank)/(OD contrast-OD blank) * 100%
OD contrast: the OD value in hole that refers to not have the cell of drug effect normal growth.
OD inhibitor: the OD value in hole that refers to add the cell of the positive or compound effects to be screened.
OD blank: the OD value that refers to not have the parallel control hole of inoculating cell.
Half inhibitor concentration (IC 50) value calculates by software GraphPad Prism 5.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
Embodiment
Embodiment 1
N-Boc-is trans-4-mesyloxy-L-proline methyl ester
Add the dissolving of 10ml methylene dichloride among the N-Boc-trans-4-hydroxy-l-proline methyl esters 515mg, be cooled to zero degrees celsius, drip the 0.4ml triethylamine, after dropwising, slowly drip the 0.2ml methylsulfonyl chloride again, zero degrees celsius reacted 4 hours down.Stopped reaction adds the 20ml methylene dichloride, and mixed system passes through dilute hydrochloric acid successively, saturated sodium bicarbonate, after the saturated common salt water washing, the organic phase anhydrous magnesium sulfate drying, filter, obtain after concentrating yellow solid N-Boc-trans-4-mesyloxy-L-proline methyl ester 645mg, yield 95%.Present embodiment gained crude product is without purifying, as raw material mentioned in following examples.
H 1-NMR(CDCl 3)：
δ4.89(m，1H)，4.18(m，1H)，3.80(s，3H)，3.4-3.6(m，2H)，2.94(s，3H)，2.0-2.2(m，2H)，1.3(s，9H)
ESI(+)m/z：324
Embodiment 2
N-Boc-cis-4-azido--L-proline methyl ester
Figure B2009102017843D0000092
N-Boc-is trans-add 10ml DMSO dissolving among 4-mesyloxy-L-proline methyl ester 645mg, add the 260mg sodiumazide, and be warming up to 90 degrees centigrade, stirred 8 hours.Stopped reaction is cooled to room temperature with reaction solution, adds 30ml water, and with ethyl acetate extraction twice, the organic phase anhydrous magnesium sulfate drying after the merging filters, obtain xanchromatic oily matter N-Boc-cis-4-azido--L-proline methyl ester 496mg, yield 92% after concentrating.
Present embodiment gained crude product is without purifying, as raw material mentioned in following examples.
H 1-NMR(CDCl 3)：
δ4.22(m，1H)，3.84(s，3H)，3.2-3.5(m，2H)，1.8-21(m，2H)，1.6(m，1H)，1.3(s，9H)
ESI(+)m/z：271
Embodiment 3
N-Boc-cis-4-amino-L-proline methyl ester
Figure B2009102017843D0000093
Add the 10ml dissolve with methanol among N-Boc-cis-4-azido--L-proline methyl ester 496mg, under the condition of nitrogen protection, add 75mg 10% palladium carbon.Then reaction system is vacuumized, insert hydrogen balloon, at room temperature stirred 8 hours.Stopped reaction removes by filter palladium carbon, obtains yellow oil N-Boc-cis-4-amino-L-proline methyl ester 430mg, yield 96% after concentrating.
Present embodiment gained crude product is without purifying, as raw material mentioned in following examples.
H 1-NMR(CDCl 3)：
δ4.19(m，1H)，3.80(s，3H)，3.5-3.7(m，2H)，2.8(m，1H)，，2.0-2.3(m，2H)，1.3(s，9H)
ESI(+)m/z：245
Embodiment 4
N-Boc-cis-4-benzoylamino-L-proline methyl ester
Figure B2009102017843D0000101
Add the dissolving of 5ml tetrahydrofuran (THF) among N-Boc-cis-4-amino-L-proline methyl ester 244mg, add the 122mg phenylformic acid then successively, 211mg EDCI; 148mg HoBt; the nitrogen protection reaction system adds 0.3ml DIPEA with syringe at last, stirs under the room temperature and spends the night.Stopped reaction, with the tetrahydrofuran (THF) evaporated under reduced pressure, extract in water and ethyl acetate system then, organic phase is used saturated aqueous common salt and washing, anhydrous magnesium sulfate drying after merging successively, filter, concentrate, the quick post of crossing, with sherwood oil: ethyl acetate (2: 1) is an eluent, obtain white solid N-Boc-cis-4-benzoylamino-L-proline methyl ester 297mg, yield 85%.
H 1-NMR(CDCl 3)：
δ7.95(m，2H)，7.4-7.5(m，3H)，4.20(m，1H)，3.80(s，3H)，3.74(m，1H)，3.5-3.7(m，2H)，2.0-2.3(m，2H)，1.3(s，9H)
ESI(+)m/z：348
Embodiment 5
N-Boc-cis-4-benzoylamino-L-proline(Pro)
Figure B2009102017843D0000102
N-Boc-cis-4-benzoylamino-L-proline methyl ester 297mg is dissolved in the 5ml tetrahydrofuran (THF): methyl alcohol: water (3ml: 1ml: in mixed solvent 1ml), add 72mg one hydronium(ion) oxidation lithium then, stirred 2 hours under the room temperature.Stopped reaction transfers to acidity with solution, adds dichloromethane extraction, and anhydrous magnesium sulfate drying filters, and concentrates to obtain light yellow solid N-Boc-cis-4-benzoylamino-L-proline(Pro) 279mg, yield 98%.
Present embodiment gained crude product is without purifying, as raw material mentioned in following examples.
H 1-NMR(CDCl 3)：
δ10.90(s，1H)，7.98(m，2H)，7.4-7.5(m，3H)，4.26(m，1H)，3.74(m，1H)，3.5-3.7(m，2H)，2.0-2.3(m，2H)，1.3(s，9H)
ESI(+)m/z：335
Embodiment 6
N-(R)-1,2,3,4-tetralyl-(N-Boc-cis-4-benzoyl-L-dried meat ammonia) acid amides (compound 6)
The experimental implementation flow process is with embodiment 4, reactant is N-Boc-cis-4-benzoylamino-L-proline(Pro) 279mg, (R)-1,2,3,4-tetrahydro naphthylamine 123mg, finally obtain light yellow solid N-(R)-1,2,3,4-tetralyl-(N-Boc-cis-4-benzoyl-L-dried meat ammonia) acid amides 225mg, yield 58%.
H 1-NMR(CDCl 3)：
δ7.98(m，2H)，7.4-7.5(m，3H)，7.0-7.2(m，5H)，4.96(d，1H)，4.40(m，1H)，3.74(m，1H)，3.5-3.7(m，2H)，2.8-2.9(m，2H)，2.0-2.3(m，2H)，1,7-1.95(m，2H)，1.55-1.65(m，2H)，1.3(s，9H)
ESI(+)m/z：464
Embodiment 7
N-(R)-1,2,3,4-tetralyl-(cis-4-benzoyl-L-dried meat ammonia) acid amides
Figure B2009102017843D0000112
With N-(R)-1,2,3,4-tetralyl-(N-Boc-cis-4-benzoyl-L-dried meat ammonia) acid amides 225mg is dissolved in the 5ml dichloromethane solution, drips the 1ml trifluoroacetic acid again, stirring at room 4 hours.Stopped reaction, decompression is dissolved the solvent evaporate to dryness again with methylene dichloride, add the saturated sodium bicarbonate extraction, with saturated aqueous common salt and washing twice, anhydrous magnesium sulfate drying filters organic phase again, concentrate, obtain light yellow solid N-(R)-1,2,3,4-tetralyl-(cis-4-benzoyl-L-dried meat ammonia) acid amides 173mg, yield 98%.
H 1-NMR(CDCl 3)：
δ7.98(m，2H)，7.4-7.5(m，3H)，7.0-7.2(m，5H)，4.96(d，1H)，4.40(m，1H)，3.74(m，1H)，3.5-3.7(m，2H)，2.8-2.9(m，2H)，2.0-2.3(m，2H)，1,7-1.95(m，2H)，1.55-1.65(m，2H)
ESI(+)m/z：364
Embodiment 8
N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-Cyclohexylglycine methyl esters
Figure B2009102017843D0000121
The experimental implementation flow process is with embodiment 4, and reactant is N-Boc-N-Me-L-L-Ala 2.03g, and L-Cyclohexylglycine methyl esters 1.71g finally obtains white solid N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-Cyclohexylglycine methyl esters 2.46g, yield 69%.
H 1-NMR(CDCl 3)：
δ5.30(dd，1H)，4.64(d，1H)，3.80(s，3H)，3.22(s，3H)，3.12(m，1H)，1.64(d，3H)，1.40-1.60(m，5H)，1.34(s，9H)，1.20-1.40(m，5H)
ESI(+)m/z：357
Embodiment 9
N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-Cyclohexylglycine
The experimental implementation flow process is with embodiment 5, and reactant is N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-Cyclohexylglycine methyl esters 2.46g, finally obtains white solid N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-Cyclohexylglycine 2.36g, yield 100%.
H 1-NMR(CDCl 3)：
δ5.34(dd，1H)，4.66(d，1H)，3.20(s，3H)，3.20(m，1H)，1.64(d，3H)，1.40-1.60(m，5H)，1.34(s，9H)，1.20-1.40(m，5H)
ESI(+)m/z：343
Embodiment 10
N-(R)-1,2,3,4-tetralyl-[N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides
The experimental implementation flow process is with embodiment 4, reactant is N-(R)-1,2,3,4-tetralyl-(cis-4-benzoyl-L-dried meat ammonia) acid amides 173mg, N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-Cyclohexylglycine 163mg, finally obtain light yellow solid N-(R)-1,2,3,4-tetralyl-(N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-cyclohexyl glycyl-cis-4-benzoyl-L-dried meat ammonia) acid amides 105mg, yield 34%.
H 1-NMR(CDCl 3)：
δ8.00(m，2H)，7.4-7.5(m，3H)，7.0-7.2(m，5H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.20(m，1H)，3.12(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.64(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.34(s，9H)，1.20-1.40(m，5H)
ESI(+)m/z：688
Embodiment 11
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides
Figure B2009102017843D0000132
The experimental implementation flow process is with embodiment 7, and reactant is N-(R)-1,2,3,4-tetralyl-(N-tertbutyloxycarbonyl-N-methyl-L-alanyl-L-cyclohexyl glycyl-cis-4-benzoyl-L-dried meat ammonia) acid amides 105mg.Crude product is with methylene dichloride: methyl alcohol (20: 1) is the quick post of crossing of eluent, finally obtain light yellow solid N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides 56mg, yield 62%.
H 1-NMR(CDCl 3)：
δ8.00(m，2H)，7.4-7.5(m，3H)，7.0-7.2(m，5H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：588
Embodiment 12
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-fluorobenzoyl))-L-dried meat ammonia] acid amides
Figure B2009102017843D0000141
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ7.98(dd，2H)，7.0-7.2(m，6H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：606
Embodiment 13
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-methoxybenzoyl))-L-dried meat ammonia] acid amides
Figure B2009102017843D0000142
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ7.84(d，2H)，7.0-7.2(m，4H)，6.98(d，2H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.80(s，3H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)n/z：618
Embodiment 14
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-trifluoromethyl benzoyl))-L-dried meat ammonia] acid amides
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ8.02(d，2H)，7.64(d，2H)，7.0-7.2(m，4H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：656
Embodiment 15
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(3-methoxybenzoyl))-L-dried meat ammonia] acid amides
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ7.46-7.52(m，2H)，7.34(t，1H)，7.00-7.20(m，5H)，6.98(d，2H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.80(s，3H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：618
Embodiment 16
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-carboxyl benzoyl))-L-dried meat ammonia] acid amides
Figure B2009102017843D0000161
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ11.50(s，1H)，8.32(d，2H)，8.16(d，2H)，7.0-7.2(m，4H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：632
Embodiment 17
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-(methyl-formiate)-benzoyl))-L-dried meat ammonia] acid amides
Figure B2009102017843D0000162
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ8.16(d，2H)，8.04(d，2H)，7.0-7.2(m，4H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.80(s，3H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：646
Embodiment 18
N-(R)-diphenyl-methyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides
Figure B2009102017843D0000171
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ8.00(m，2H)，7.4-7.5(m，3H)，7.4-7.06(m，10H)，6.20(s，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.20(m，1H)，3.02(s，3H)，2.40-2.60(m，2H)，1.56(d，3H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：624
Embodiment 19
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzyl formyl)-L-dried meat ammonia] acid amides
Figure B2009102017843D0000172
The experimental implementation flow process is with embodiment 11.
H 1-NMR(CDCl 3)：
δ7.0-7.2(m，9H)，5.34(dd，1H)，5.20(d，1H)，4.86(d，1H)，4.46(m，1H)，4.08(m，1H)，3.86(m，2H)，3.44(s，2H)，3.20(m，1H)，3.02(s，3H)，2.8-2.9(m，2H)，2.40-2.60(m，2H)，1,70-1.95(m，2H)，1.56(d，3H)，1.55-1.65(m，2H)，1.40-1.60(m，5H)，1.20-1.40(m，5H)
ESI(+)m/z：602
Embodiment 20-27
With reference to the synthetic method of the foregoing description 1～embodiment 19 compounds, the synthetic following compounds that obtains:
Figure B2009102017843D0000173
Figure B2009102017843D0000181
Figure B2009102017843D0000191
Embodiment 28 pharmaceutical compositions
Compound 11 20g
Starch 140g
Microcrystalline Cellulose 65g
According to a conventional method, after above-mentioned substance mixed, the common gelatine capsule of packing into obtained 1000 capsules.
By similar approach, make the capsule that contains other embodiment compounds respectively.
Embodiment 29 test implementation examples
Compound is to Proliferation of Human Ovarian Cell (SK-OV-3) or human breast cancer cell (MDA-MB-231) inhibited proliferation
To be in the Proliferation of Human Ovarian Cell of logarithmic phase or human breast cancer cell and be inoculated in 96 well culture plates, 180 μ l/ holes with the density in about 5500/hole.Each concentration is established three multiple holes.And the solvent of establishing respective concentration contrasts and acellular zeroing hole.Adherent growth 24hr adds embodiment compound or positive control (N-(R)-1 again, 2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-L-dried meat ammonia] acid amides) 20 μ l/ holes, cell is at the 10%Hyclone foetal calf serum, cultivates 72hr under 37 ℃, 5%CO2 condition.Cold trichoroacetic acid(TCA) (TCA) 50ul of adding 50% placed fixed cell 1 hour for 4 ℃.The liquid that inclines is with the light and slow washing of distilled water 5 times, seasoning in the air.Adding is by the SRB 4mg/ml solution 100 μ l/ holes of 1% Glacial acetic acid preparation, and dyeing is 15 minutes in the room temperature.Abandon supernatant liquor, with 1% acetic acid washing 5 times, air drying.Every hole adds the Tris solution (pH 10.5) of the 10mM of 150 μ l, dissolving bonded SRB.Microplate reader 510nm wavelength is measured the OD value down, obtains the IC of embodiment compound for SK-OV-3 cell and human breast cancer cell by calculating 50Value:
Figure B2009102017843D0000201
"-" expression does not detect.
Test result shows: embodiment of the invention compound all has good inhibited proliferation to Proliferation of Human Ovarian Cell (SK-OV-3) and human breast cancer cell (MDA-MB-231).
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.

Claims (9)

1. tetrapeptide analogs or its pharmacy acceptable salt, it is represented by following formula general formula (I)
Figure F2009102017843C0000011
Mark in the formula is represented following implication
R 1:-NHCOR 3, R wherein 3For-(CH 2) 0-6-aryl or-(CH 2) 0-6-heteroaryl, above-mentioned aryl or heteroaryl can be unsubstituted or be replaced by 1-5 following substituting group: halogen ,-NH 2,-OH, C 1～C 6Alkyl, contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4, R wherein 4Be C 1～C 6Alkyl;
R 2:-(CH 2) 0-6-aryl ,-(CH 2) 0-6-CH (phenyl) 2,-(CH 2) 0-6-het, aryl wherein are phenyl or naphthyl, and het is indyl or pyridyl.
2. tetrapeptide analogs as claimed in claim 1 or its pharmacy acceptable salt is characterized in that, described R 2For-CH (phenyl) 2Or 1,2,3, the 4-tetralyl.
3. tetrapeptide analogs as claimed in claim 2 or its pharmacy acceptable salt is characterized in that, described R 3For unsubstituted or by at least one be selected from halogen ,-NH 2,-OH, C 1～C 6Alkyl or contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4The phenyl that replaces, wherein R 4Be C 1～C 6Alkyl.
4. tetrapeptide analogs as claimed in claim 2 or its pharmacy acceptable salt is characterized in that, described R 3For unsubstituted or by at least one be selected from halogen ,-NH 2,-OH, C 1～C 6Alkyl or contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4The benzyl that replaces, wherein R 4Be C 1～C 6Alkyl.
5. tetrapeptide analogs or its pharmacy acceptable salt are represented by following formula general formula (II)
Figure F2009102017843C0000012
Wherein, the R in the general formula 1, R 2Definition according to claim 1.
6. tetrapeptide analogs as claimed in claim 5 or its pharmacy acceptable salt is characterized in that it is selected from:
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-fluorobenzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-methoxybenzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-trifluoromethyl benzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(3-methoxybenzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-carboxyl benzoyl))-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-(4-(methyl-formiate)-benzoyl))-L-dried meat ammonia] acid amides;
N-(R)-diphenyl-methyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzoyl)-L-dried meat ammonia] acid amides;
N-(R)-1,2,3,4-tetralyl-[N-methyl-L-alanyl-L-cyclohexyl glycyl-(cis-4-benzyl formyl)-L-dried meat ammonia] acid amides, or its pharmacy acceptable salt.
7. method for preparing the described formula of claim 5 (II) compound, it comprises step:
(a), N-Boc-trans-4-hydroxy-l-proline methyl esters replaces earlier under hydroxyl protection, the back reduction obtains compound (7) again after two step condensation reactions;
Figure F2009102017843C0000031
Wherein, R 2For-(CH 2) 0-6-aryl ,-(CH 2) 0-6-CH (phenyl) 2,-(CH 2) 0-6-het, aryl wherein are phenyl or naphthyl, and het is indyl or pyridyl; R 3For-(CH 2) 0-6-aryl or-(CH 2) 0-6-heteroaryl, described aryl or heteroaryl can be unsubstituted or be replaced by 1-5 following substituting group: halogen ,-NH 2,-OH, C 1～C 6Alkyl, contain the C that 1-3 halogen replaces 1～C 6Alkyl, C 1～C 6Alkoxyl group or contain the C that 1-3 halogen replaces 1～C 6Alkoxyl group ,-COOH ,-COOR 4, R wherein 4Be C 1～C 6Alkyl;
(b), N-Boc-N-Me-L-L-Ala and L-Cyclohexylglycine methyl esters reduce after condensation reaction and obtain compound (9);
Figure F2009102017843C0000041
(c), compound (7) and compound (9) through condensation reaction again deprotection obtain target compound (11).
8. medical composition, it comprises the carrier that allows on the described tetrapeptide analogs of claim 1 or its pharmacy acceptable salt and the pharmacopedics.
9. the application of the formula I compound of claim 1 in preparation medicine for treating tumor thing.
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WO2018033129A1 (en) * 2016-08-18 2018-02-22 Guangzhou Virotech Pharmaceutical Co., Ltd. Use of iap inhibitor and oncolytic virus in preparation of anti-tumor drug
US11814367B2 (en) 2021-03-15 2023-11-14 Maze Therapeutics, Inc. Inhibitors of glycogen synthase 1 (GYS1) and methods of use thereof

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CN101094833A (en) * 2004-07-12 2007-12-26 伊邓药品公司 Tetrapeptide analogs

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WO2018033129A1 (en) * 2016-08-18 2018-02-22 Guangzhou Virotech Pharmaceutical Co., Ltd. Use of iap inhibitor and oncolytic virus in preparation of anti-tumor drug
US10980850B2 (en) 2016-08-18 2021-04-20 Guangzhou Virotech Phamaceutical Co., Ltd. Use of IAP inhibitor and oncolytic virus in preparation of anti-tumor drug
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Application publication date: 20110511