CN1304447A - Treatment of parasitic diseases by inhibition of cysteine proteases of papain superfamily - Google Patents

Treatment of parasitic diseases by inhibition of cysteine proteases of papain superfamily Download PDF

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CN1304447A
CN1304447A CN99807012A CN99807012A CN1304447A CN 1304447 A CN1304447 A CN 1304447A CN 99807012 A CN99807012 A CN 99807012A CN 99807012 A CN99807012 A CN 99807012A CN 1304447 A CN1304447 A CN 1304447A
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base carbonyl
leucyl
thiazole
hydrazides
amino
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S·K·托姆普逊
D·F·维贝尔
T·A·托马斯泽克
D·G·图
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SmithKline Beecham Corp
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Abstract

The present invention relates to compounds and pharmaceutical compositions which inhibit proteases, such as cysteine proteases. In particular, the present invention relates to compounds and pharmaceutical compositions which inhibit cysteine proteases of the papain superfamily. The compounds and pharmaceutical compositions of the present invention are useful for treating diseases, particularly parasitic diseases, which are mediated by such proteases. In particular, the present invention relates to a method of treating malaria by inhibiting the cysteine protease falcipain.

Description

By suppressing the L-Cysteine HCL Anhydrous treatment parasitosis of papoid superfamily
Invention field
The present invention relates to treat method, compound and the medicinal compositions of malaria.Be specially said composition and contain compound as the inhibitor of the L-Cysteine HCL Anhydrous of single-minded inhibition papoid superfamily.The compounds of this invention is used for the treatment of the disease of being brought out by these protease activities, especially parasitosis.Particularly, the present invention relates to by suppressing the method for falcipain treatment malaria.
Background of invention
People more than 200,000,000 8 thousand ten thousand infects plasmodium falciparum (the most strong human body malaria disease substance), according to estimates it make annual more than 100 ten thousand people's death (Gibbons, A.Science 1992,256,1135; Walsh, J.A.Ann.N.Y.Acad Sci.1989,569,1135).Plasmodium falciparum parasites has 48 hours life cycle in host's red corpuscle, this is the reason that causes all Clinical symptoms of pernicious malaria.In this cycle, red corpuscle is infected by merozoite, cytozoon is the higher trophont of metabolic activity from ring bodies evolution in period then, asexual split, become schizont, make host's erythrocyte fragmentation at last, discharge red corpuscle that the filial generation merozoite infects other again from newly beginning this circulation.In the trophont stage, the oxyphorase in host's red corpuscle is degraded as the main origin of amino acid of parasite.
Rosenthal and co-worker have identified 28kD trophont L-Cysteine HCL Anhydrous (TCP or falcipain) (Rosenthal, the P.J. that can bring out hemoglobin degrading from malarial parasite; McKerrow, J.H.; Aikawa, M.; Nagasawa, H.; Leech, J.H.J.Clin.Invest.1988,82,1560), and it only is expressed in trophont stage (Rosenthal, P.J.; Kim, J.H.; McKerrow, J.H.; Leech, J.H.J.Exp.Med.1987,166,816).Suppress parasite (Rosenthal, P.J. that this enzyme can be blocked the degraded of oxyphorase and kill cultivation; Wollish, W.S.; Palmer, J.T.; Rasnick, D.J.J.Clin.Invest.1991,88,1467; Li, R.; Kenyon, G.L.; Cohen, F.E; Chen, X.; Gong, B.; Dominguez, J.N.; Davidson, E.; Kurzban, G.; Miller, R.E.; Nuzum, E.O; Rosenthal, P.J.; McKerrow, J.H.J.Med.Chem.1995,38,5031).In by P.vinckei (similar mouse malarial parasite) mice infected model, with cystatin treatment, 80% animal has and reaches secular healing effect (＞75 days) (Rosenthal, P.J.; Lee, G.K.; Smith, R.E.J.Clin.Invest.1993,91,1052).Therefore, the selective depressant of falcipain can be effective antimalarial therapeutical agent, itself or with the quinoline derivatives drug combination or as the surrogate of quinoline derivatives medicine.
Except that plasmodium falciparum, other parasite also can utilize L-Cysteine HCL Anhydrous in their life cycles.These parasites comprise schizotrypanum cruzi, trypanosoma bocagei [trypanosomiasis (nelavan, the Chagas disease)], leishmania mexicana, the pifanoi leishmania, leishmania major (leishmaniasis), Schistosoma mansoni (schistosomicide), Onchocerca caecutiens [onchocerciasis (onchocerciasis)], brugia pahangi, the entamoeba histolytica worm, the blue Bai Shi flagellate of intestines, worm, haemonchus contortus and liver fluke, and the Vermes palace tapeworm that changes, trichinella, plate mouth nematode and roundworm and protozoa Cryptosporidium, Eimeria, toxoplasma gondii is returned worm (McKerrow with receiving, J.H. the Perspect of (1995), Drug Dis.Des. the 2nd edition; Craik, C.S., Debouck, C., 437-444 page or leaf; Robertson, C.D., Coombs, G.H., North, M.J., Mottram, the Perspect of J.C. (1996), Drug Dis.Des. the 6th edition, McKerrow, J.H. and James, M.N.G., 99-118 page or leaf).
Have now found that some compound is a proteinase inhibitor, the inhibitor of falcipain particularly, these compounds can be used for the treatment of the disease that is caused by L-Cysteine HCL Anhydrous, especially malaria.
Summary of the invention
The purpose of this invention is to provide proteinase inhibitor, as cystatin.Especially, the present invention relates to suppress L-Cysteine HCL Anhydrous, particularly the compound of the L-Cysteine HCL Anhydrous of papoid superfamily.The compounds of this invention can be used for treating disease, parasitosis especially, and it is by changing the variation that these protease activities are treated.Particularly, the present invention relates to by suppressing the method for falcipain treatment malaria.
Therefore, first aspect the invention provides the method that wherein can change the disease of this nosopathology with one or more following compounds treatments by arrestin enzyme (as L-Cysteine HCL Anhydrous): 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide; (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides; L-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone; N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides; N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides; 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone; (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides; 1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; 1-[N-[4-[2-(N, N-dimethylamino) oxyethyl group] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-b-cyclopropyl alanyl] hydrazides.
Especially, these compounds can be used for treating in the method for the present invention of disease (especially parasitosis) by the L-Cysteine HCL Anhydrous that suppresses the papoid superfamily.Particularly, the invention provides by using these compounds to suppress the method that falcipain treats malaria.
Detailed Description Of The Invention
The invention provides patient (preferred animal by needing this kind treatment, more preferably Mammals, optimum is chosen) one or more following compounds, treat the method for disease (especially parasitosis), it treats variation by the activity that changes L-Cysteine HCL Anhydrous.
Figure A9980701200111
2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide;
Figure A9980701200121
(3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone;
Figure A9980701200122
(1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides;
Figure A9980701200123
1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone;
Figure A9980701200124
N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides;
(1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides;
Figure A9980701200132
1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone;
N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridyl methoxycarbonyl)-L-leucyl] hydrazides;
Figure A9980701200134
N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides;
N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides;
Figure A9980701200142
(3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone;
Figure A9980701200143
N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N ' [N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides;
Figure A9980701200144
1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone;
Figure A9980701200151
(3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone;
Figure A9980701200152
N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides;
Figure A9980701200153
1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone;
Figure A9980701200154
1-[N-[4-[2-(N, N-dimethylamino) oxyethyl group] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With
N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-two-methylamino-) oxyethyl group] cumarone-2-base carbonyl]-L-b-cyclopropyl alanyl] hydrazides.
Especially, the inventive method provides (the preferred animal by the patient who needs this kind treatment, more preferably Mammals, optimum is chosen) one or more above listed compounds, treat disease (especially parasitosis) by the L-Cysteine HCL Anhydrous that suppresses the papoid superfamily.
Knownly utilize the parasite of the L-Cysteine HCL Anhydrous in its life cycle to comprise schizotrypanum cruzi, trypanosoma bocagei [trypanosomiasis (nelavan, the Chagas disease)], leishmania mexicana, the pifanoi leishmania, leishmania major (leishmaniasis), Schistosoma mansoni (schistosomicide), Onchocerca caecutiens [onchocerciasis (onchocerciasis)], brugia pahangi, the entamoeba histolytica worm, the blue Bai Shi flagellate of intestines, worm, haemonchus contortus and liver fluke, and the Vermes palace tapeworm that changes, trichinella, plate mouth nematode and roundworm and protozoa Cryptosporidium, Eimeria, toxoplasma gondii is returned worm with receiving.The inventive method provides (the preferred animal by the patient who needs this kind treatment, more preferably Mammals, optimum is chosen) one or more above listed compounds, treat the disease that causes by these parasitic infection by the L-Cysteine HCL Anhydrous that suppresses the papoid superfamily.
More particularly, the invention provides patient (preferred animal by needing this kind treatment, more preferably Mammals, optimum is chosen) one or more above listed compounds, by suppressing the method that falcipain treats the malaria that is caused by falciparum infection.
The inventive method can combine and should be used for carrying out by giving above listed compound separately or go up compounds effective with other treatment.
Some group adopts abbreviated form herein.T-Bu refers to the tertiary butyl, and Boc refers to tert-butoxycarbonyl, and Fmoc refers to the fluorenyl methoxy carbonyl, and Ph refers to phenyl, and Cbz refers to benzyloxycarbonyl.
The present invention includes all esters, hydrate, solvate, mixture and the prodrug of above listed compound used in the inventive method.Prodrug is the compound that can discharge any covalent bonding of active parent drug in vivo.If there is the isomery center of chiral centre or other form in the The compounds of this invention, the form of ownership of these isomer comprises enantiomorph and diastereomer, is also included within the scope of the invention.Can with the invention compound that contains chiral centre as racemic mixture, be rich in the mixture of enantiomorph, the perhaps available technology of knowing also can be used single enantiomorph separately with racemic mixture.Compound has under the situation of unsaturated carbon-to-carbon double bond therein, and cis (Z) and trans (E) isomer are all within the scope of the present invention.Compound exists under the situation of tautomeric forms therein, as the keto-enol tautomerism body, no matter is to exist with the form that balance or a kind of form are taken as the leading factor, and every kind of tautomer all comprises within the scope of the present invention.
Synthetic method
Below synthetic draft refer in this specification sheets and this synthetic schemes in determined midbody compound and end product.Use following examples and describe the preparation of The compounds of this invention in detail, but be to disclose described chemical reaction according to the generic principles for preparing L-Cysteine HCL Anhydrous inhibition compound of the present invention.For each included compound in the open scope of the present invention, can not be applied to this reaction sometimes.Those skilled in the art are easy to identify these compounds that occurred.Under all these situations; these reactions or can successfully carry out by the general modification known to the those skilled in the art (promptly disturbing group by due care; by becoming other common agents), perhaps change reaction conditions and successfully carry out by routine.In addition, other reaction disclosed in this invention or other reaction commonly used also are suitable for preparing the compound of correspondence of the present invention.In all preparation methods, all starting raw materials all are known or are easy to compound with known feedstock production; All temperature are centigradetemperature; Except as otherwise noted, all umbers and percentage are all by weight.
Reagent is bought from the supplier, as Aldrich Chemical Company, TCI, Sigma, Lancaster Synthesis, Bionet, Fluka, Maybridge or Bachem, unless otherwise indicated, when reagent uses without further purifying.Unless otherwise indicated, all solvents can be used those skilled in the art standard method purifying easy to know.Raw material can or can prepare by the ordinary method the canonical reference book from commercially available acquisition, book of reference such as Compendium of Organic Synthetic Methods, I-IV volume (Wiley-Interscience publication).
The present invention forms the couling process of amido linkage and knows in this area usually.The THE PRACTICE OF PEPTIDESYNTHESIS of the general visible Bodansky of peptide synthetic method etc., Springer-Verlag, Berlin, 1984; E.Gross and J.Meienhofer, THE PEPTIDES, the 1st volume, 1-284 page or leaf (1979); With J.M.Stewart and J.D.Young, SOLID PHASE PEPTIDE SYNTHESIS, the 2nd edition, PierceChemical Co., Rockford, III., 1984, they generally carry out technical specification, and are attached among the present invention as a reference.
The synthetic method of preparation The compounds of this invention generally adopts protecting group to come protective reaction functional group or unwanted side reaction is reduced to minimum.These protecting groups are generally seen Green, T.WPROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley ﹠amp; Sons is described in the New York (1981).Term " amino protecting group " generally is meant Boc, ethanoyl, benzoyl, Fmoc and Cbz group and the derivative of being familiar with this area thereof.The protection of amino protecting group and deprotection and be well-known with the method for other group displacement.
The acid salt of the used above compound of carrying can be by standard method in the inventive method, in appropriate solvent, with this parent compound and acid, example hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, toxilic acid, succsinic acid or methylsulfonic acid prepare.
Some compound of the present invention contains one or more asymmetric center, therefore can produce enantiomorph, diastereomer and other stereoisomer form.The present invention includes all possible steric isomers and racemic modification thereof and optically pure form.Optical activity (R) and (S) isomer can use the preparation of chiral synthon, chiral reagent, perhaps available technology commonly used splits.When The compounds of this invention contained the two key of alkene, it comprised E and Z geometrical isomer.
Scheme 1
Figure A9980701200191
A) H 2NNH 2H 2O, MeOH; B) Cl 2CO, PhMe; C) R 2CO 2H, EDCHCl, 1-HOBT, DMF.
In protonic solvent (as methyl alcohol or ethanol), the processing of 1-scheme 1 usefulness hydrazine hydrate is obtained 2-scheme 1, in toluene, the latter is obtained 3-scheme 1 with the light gas disposal.In protonic solvent (as methyl alcohol or ethanol), this material is handled the 4-scheme 1 that obtains with hydrazine hydrate.In aprotic solvent (as DMF), 4-scheme 1 usefulness carboxylic acid (as N-benzyloxycarbonyl glycine) and peptide coupler (as EDCHCl/1-HOBT) are handled the 5-scheme 1 that obtains.
Scheme 2
Figure A9980701200201
A) Boc 2O, CH 2Cl 2B) m-CPBA, CH 2Cl 2C) NaN 3, NH 4Cl, MeOH/H 2O; D) H 2, 10%Pd/C, MeOH; E) R 1CO 2H, EDCHCl, 1-HOBT, DMF; F) HCl R 2CO 2H, EDCHCl, 1-HOBT, DMF; H) Jones reagent, acetone.
In methylene dichloride, the processing of 1-scheme 2 usefulness hydrogen-carbonate di-t-butyl esters is obtained 2-scheme 2, in methylene dichloride, the latter is handled the 3-scheme 2 that obtains with metachloroperbenzoic acid.In methanol, this material is obtained 4-scheme 2 with sodiumazide and ammonium chloride processing, in methyl alcohol, in the presence of 10% palladium-carbon, obtain 5-scheme 2 again with hydrogen treat.In aprotic solvent (as DMF), this material is obtained 6-scheme 2 with carboxylic acid (as the 4-phenoxy benzoic acid) and peptide coupler (as EDC.HCl/1-HOBT) processing, in ethyl acetate, it is obtained 7-scheme 2 with the HCl gas disposal.In aprotic solvent (as DMF), 7-scheme 2 usefulness carboxylic acids (as N-benzyloxycarbonyl-L-leucine) and peptide coupler (as EDCHCl/1-HOBT) processing are obtained 8-scheme 2, in acetone, it is obtained 9-scheme 2 with the Jones agent treated.
Scheme 3 A) i-BuOCOCl, NMM, NH 3, THF; B) LawessonShi reagent, THF; C) ⅰ .EtO 2CCOCH 2Br; ⅱ .TFAA, Py, CH 2Cl 2D) H 2NNH 2H 2O, EtOH; E) R 1CO 2H, EDCHCl, 1-HOBT, DMF.
In THF,, 1-scheme 3 is changed into 2-scheme 3 by with chloroformic acid isobutyl, N-methylmorpholine and ammonia treatment.In THF, 2-scheme 3 usefulness LawessonShi agent treated are obtained thioamides 3-scheme 3.This material by being converted into thiazole with the ketone ester condensation, then in methylene dichloride, is handled the 4-scheme 3 that obtains with trifluoroacetic anhydride and pyridine, handle the 5-scheme 3 that changes into the hydrazine monohydrate again.In aprotic solvent (as DMF), 5-scheme 3 usefulness carboxylic acids (as N-(2-pyridyl methoxycarbonyl)-L-leucine or N-(3-pyridyl methoxycarbonyl)-L-leucine) and peptide coupler (as EDCHCl/1-HOBT) are handled the 6-scheme 2 that obtains.
Scheme 4
Figure A9980701200221
A) R 1CO 2H, EDCMeI, 1-HOBT, DMF; B) R 2SO 2Cl, N-methylmorpholine, DMF or R 2CO 2H, EDCMeI, 1-HOBT, DMF; C) Jones reagent, acetone or Dess-Martin reagent, CH 2Cl 2D) R 1=N-benzyloxycarbonyl-amino acid, H 2, 10%Pd/C, EtOH; R 1=N-tert-butoxycarbonyl-amino acid, TFA, CH 2Cl 2E) R 4CO 2H, EDCMeI, 1-HOBT, DMF.
In aprotic solvent (as DMF), with 1-scheme 4 usefulness carboxylic acids (as N-benzyloxycarbonyl-L-leucine or N-tert-butoxycarbonyl-L-leucine) and peptide coupler (as EDCHCl/1-HOBT, EDCMeI/1-HOBT or HBTU) handle the 2-scheme 4 that obtains, in aprotic solvent (as DMF), the latter is handled the 3-scheme 4 that obtains with SULPHURYL CHLORIDE (as 2-benzyloxy benzene sulfonyl chloride or 4-phenoxyphenylsulfonyhalides chlorine) and N-methylmorpholine.In addition, in aprotic solvent (as DMF), 2-scheme 4 usefulness carboxylic acids (as 3-(2-pyridyl) toluylic acid) and peptide coupler (as EDCHCl/1-HOBT, EDCMeI/1-HOBT or HBTU) are handled the 3-scheme 4 that obtains.Then 3-scheme 4 is obtained 4-scheme 4 with Jones reagent or in methylene dichloride with the Dess-Martin agent treated in acetone.Work as R 1When CO is a N-benzyloxycarbonyl-amino acid, in ethanol, in the presence of 10% palladium-carbon, 3-scheme 4 usefulness hydrogen treat are obtained 5-scheme 4.In addition, work as R 1When CO is a N-tert-butoxycarbonyl-amino acid, in methylene dichloride, 3-scheme 4 usefulness trifluoroacetic acids are handled the 5-scheme 4 that obtains.In aprotic solvent (as DMF), 5-scheme 4 usefulness urea chlorides (as 4-morpholine formyl chloride) and tertiary amine base (as N-methylmorpholine) are handled the 6-scheme 4 that obtains.In addition, in aprotic solvent (as DMF), 5-scheme 4 usefulness carboxylic acids (as thiophene-2-carboxylic acid, benzoxazole-5-carboxylic acid or 4-[2-(N, N-dimethylamino) oxyethyl group] phenylformic acid) and peptide coupler (as EDCHCl/1-HOBT, EDCMeI/1-HOBT or HBTU) are handled the 6-scheme 4 that obtains.In methylene dichloride, 6-scheme 4 usefulness Dess-Martin agent treated are obtained 7-scheme 4.
Scheme 5
Figure A9980701200241
A) thiocarbamide, EtOH; B) ⅰ .NaNO 2, the 16%HBr aqueous solution; ⅱ .CuBr, the 16%HBr aqueous solution; ⅲ .HBr (catalysis), EtOH; C) ArB (OH) 2, Pd (PPh 3) 4, CsF, DME; D) H 2NNH 2H 2O, EtOH; E) R 1CO 2H, EDCHCl, 1-HOBT, DMF; F) R 1CO 2H=N-tert-butoxycarbonyl-amino acid, TFA, CH 2Cl 2G) R 3CO 2H, EDCHCl, 1-HOBT, DMF.
In the ethanol that refluxes, ethyl bromide acetone (1-scheme 5) is handled the 2-scheme 5 that obtains with thiocarbamide, use the 16%HBr aqueous solution of Sodium Nitrite and cuprous bromide (I) to handle continuously the latter, again in ethanol, the HBr of this product and catalytic amount is heated the 3-scheme 5 that obtains.In backflow DME, this material is handled the 4-scheme 5 that obtains with aryl boric acid (as 2-benzyloxy phenyl-boron dihydroxide or 1-naphthyl boric acid), four (triphenyl phosphine) palladium (0) and cesium fluoride.In ethanol, 4-scheme 5 usefulness hydrazine hydrates are handled the 5-scheme 5 that obtains, in aprotic solvent (as DMF), 5-scheme 5 usefulness carboxylic acids (as N-tert-butoxycarbonyl-L-leucine, N-(3-pyridyl methoxycarbonyl)-L-leucine or N-(4-pyridyl methoxycarbonyl)-L-leucine) and peptide coupler (as EDCHCl/1-HOBT) are handled the 6-scheme 5 that obtains again.Work as R 1When CO is a N-tert-butoxycarbonyl-amino acid, in methylene dichloride, 6-scheme 5 usefulness trifluoroacetic acids are handled the 7-scheme 5 that obtains, in aprotic solvent (as DMF), the latter is handled the 8-scheme 5 that obtains with carboxylic acid (as pyrazine carboxylic acid or 1-benzyl-5-Methylimidazole-4-carboxylic acid) and peptide coupler (as EDCHCl/1-HOBT).
Scheme 6 A) NaN 3, NH 4Cl, MeOH/ water; B) H 2, 10%Pd/C, EtOH; C) BocNHCH (R 1) CO 2H, Me 3COCl, N, N-diisopropylethylamine, CH 2Cl 2D) TFA, CH 2Cl 2E) R 2CO 2H, (EtO) 2POCN, Et 3N, CH 2Cl 2F) Dess-Martin reagent, CH 2Cl 2
In methanol, 1-scheme 6 usefulness sodiumazide and ammonium chloride processing are obtained 2-scheme 6, in ethanol, in the presence of 10% palladium-carbon, the latter is obtained 3-scheme 6 with hydrogen treat.In aprotic solvent (as methylene dichloride), 3-scheme 6 usefulness N-tert-butoxycarbonyl amino acid, pivalyl chloride and tertiary amine base (as N, the N-diisopropylamine) are obtained 4-scheme 6, in methylene dichloride, handle the 5-scheme 6 that obtains again with trifluoroacetic acid.In aprotic solvent (as DMF or methylene dichloride), 5-scheme 6 usefulness carboxylic acids (as 3-benzyloxy phenylformic acid) and peptide coupler (as EDCHCl/1-HOBT, EDCMeI/1-HOBT, HBTU or diethyl phosphorocyanidate) processing are obtained 6-scheme 6, in methylene dichloride, obtain 7-scheme 6 again with the Dess-Martin agent treated.
Scheme 7
Figure A9980701200261
A) ⅰ .R 1NH 2, CH 2Cl 2ⅱ .Na (OAc) 3BH; B) PhCONCS, CHCl 3C) K 2CO 3, MeOH, H 2O; D) EtO 2CCOCH 2Br, EtOH; E) H 2NNH 2H 2O, EtOH; F) R 3CO 2H, EDCHCl, 1-HOBT, DMF; G) R 3CO 2H=N-tert-butoxycarbonyl-amino acid, TFA, CH 2Cl 2H) R 5CO 2H, EDCHCl, 1-HOBT, DMF.
In aprotic solvent (as methylene dichloride), aldehyde (1-scheme 7) is handled with primary amine (as cyclopropylamine), then handle the 2-scheme 7 that obtains, in chloroform, handle the 3-scheme 7 that obtains again with the isothiocyanic acid benzoyl ester with reductive agent (as sodium triacetoxy borohydride).In methanol, 3-scheme 7 usefulness salt of wormwood are handled the 4-scheme 7 that obtains, in backflow ethanol, handle the 5-scheme 7 that obtains again with ethyl bromide acetone, then in ethanol, handle the 6-scheme 7 that obtains with hydrazine hydrate.In aprotic solvent (as DMF), 6-scheme 7 usefulness carboxylic acids (as N-tert-butoxycarbonyl-L-leucine) and peptide coupler (as EDCHCl/1-HOBT) are handled the 7-scheme 7 that obtains.Work as R 3When CO is a N-tert-butoxycarbonyl-amino acid, in methylene dichloride, 7-scheme 7 usefulness trifluoroacetic acids are handled the 8-scheme 7 that obtains, in aprotic solvent (as DMF), the latter is obtained 9-scheme 7 with carboxylic acid (as 5-methyl-2-benzene base oxazole-4-formic acid, 7-methoxyl group benzo furans-2-carboxylic acid or 5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-carboxylic acid) and peptide coupler (as EDCHCl/1-HOBT) processing.
Scheme 8
Figure A9980701200281
A) ⅰ. chloroformic acid isobutyl, N-methylmorpholine, THF; ⅱ .CH 2N 2, Et 2O; ⅲ .30%HBr/HOAc; B) NaN 3, KF, DMF; C) NaBH 4, MeOH; D) 1,3-dimercaptopropane, Et 3N, MeOH; E) R 2CO 2H, EDCMeI, 1-HOBT, DMF; F) H 2, 10%Pd/C, EtOH; G) BocNHCH (R 3) CO 2H, HBTU, DMF; H) HCl, dioxane, CH 2Cl 2I) R 4CO 2H, HBTU, DMF; J) Dess-Martin reagent, CH 2Cl 2
With 1-scheme 8 in THF with chloroformic acid isobutyl and N-methylmorpholine, in ether, obtain 2-scheme 8 with the 30%HBr processed in sequence with diazomethane and in acetate, in DMF, the latter is handled the 3-scheme 8 that obtains with sodiumazide and Potassium monofluoride again.In methyl alcohol, 3-scheme 8 usefulness sodium borohydrides are handled the 4-scheme 8 that obtains, in methyl alcohol, with 1,3-dimercaptopropane and triethylamine are handled the 5-scheme 8 that obtains with the latter again.In aprotic solvent (as DMF), 5-scheme 8 usefulness carboxylic acids (as 3-(2-pyridyl) phenylacetic acid) and peptide coupler (as EDCHCl/1-HOBT, EDCMeI/1-HOBT or HBTU) are handled the 6-scheme 8 that obtains, in ethanol, in the presence of 10% palladium-carbon, obtain 7-scheme 8 again with hydrogen treat.In aprotic solvent (as DMF), 7-scheme 8 usefulness N-tert-butoxycarbonyl amino acid (as N-tert-butoxycarbonyl-L-leucine) and peptide coupler (as EDCHCl/1-HOBT, EDCMeI/1-HOBT or HBTU) are handled the 8-scheme 8 that obtains, in dioxane/methylene dichloride, handle the 9-scheme 8 that obtains again with HCl.In aprotic solvent (as DMF), 9-scheme 8 usefulness carboxylic acids (as benzothiazole-6-carboxylic acid) and peptide coupler (as EDCHCl/1-HOBT, EDCMeI/1-HOBT or HBTU) processing are obtained 10-scheme 8, in methylene dichloride, obtain 11-scheme 8 again with the Dess-Martin agent treated.
The present invention also provides medicinal compositions, and it comprises one or more following compounds and pharmaceutically acceptable carrier, thinner or vehicle: 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide; (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides; 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone; N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides; N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides; 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone; (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides; 1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; 1-[N-[4-[2-N, the N-dimethylamino) oxyethyl group] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-b-cyclopropyl alanyl] hydrazides.
Therefore, available above listed compound medicine.Can be with solution or the lyophilize powder preparation of making by the medicinal compositions of the above listed compound of the above preparation for parenteral admin.Can be before use, by adding suitable dilution agent or other pharmaceutically acceptable carrier, the reorganization powder formulation.Liquid preparation can be the buffering, etc. ooze, water-soluble solution.Suitably the example of thinner is 5% D/W or the buffered sodium acetate or the ammonium acetate solution of physiology normal isotonic saline solution, standard.These preparations are particularly suitable for parenteral admin, but also can be for oral administration or be loaded in metered-dose inhaler or the atomizer for the spray administration.Can add vehicle on request, as polyvinylpyrrolidone, gelatin, hydroxylated cellulose, Sudan Gum-arabic, polyoxyethylene glycol, mannitol, sodium-chlor or Trisodium Citrate.
In addition, can with these compound packings, compressing tablet make emulsion or syrup with for oral administration.Can add pharmaceutically acceptable solid or liquid vehicle to improve or stable said composition or be easy to prepare said composition.Solid carrier comprises starch, lactose, calcium sulfate dihydrate, terra alba, Magnesium Stearate or stearic acid, talcum powder, pectin, Sudan Gum-arabic, agar or gelatin.Liquid vehicle comprises syrup, peanut oil, sweet oil, salt solution and water.This carrier also comprises sustained-release materials, as glyceryl monostearate or distearin itself or with the mixture of wax.Can change the amount of solid carrier, but preferred per unit dosage is at about 20mg extremely between about 1g.Medicinal preparations can comprise grinding, mixing, granulate and compacting, tablet forming type in case of necessity according to pharmaceutical technology preparation commonly used; Perhaps grind, mix and be filled to the hard gelatin capsule form.When using liquid vehicle, formulation can be syrup, elixir, emulsion is water-soluble or the form of non-water-soluble suspensoid.Can or be packed in the soft gelatin capsule the direct administration of these liquid preparations.
For rectal administration, also The compounds of this invention can be mixed with vehicle (as theobroma oil, glycerine, gelatin or polyoxyethylene glycol), pressing mold is made suppository then.
According to the present invention, one or more the above listed compound that gives significant quantity is with inhibition and specific symptoms or disease proteins associated enzyme.Certainly, this dosage will change according to the type of giving compound.For example, for acute treatment, preferred parenteral gives the The compounds of this invention of significant quantity.Though intramuscularly is also effective, the most effectively 5% D/W or the normal saline solution of intravenous injection The compounds of this invention perhaps have the similar formulations of suitable vehicle.Usually, the dosage of parenteral admin is approximately 0.01-100mg/kg; Preferably at 0.1-20mg/kg, this mode can keep the concentration of blood plasma Chinese traditional medicine on the effective concentration of energy arrestin enzyme (as falcipain).The level that gives The compounds of this invention 1-4 time every day is about 0.4-400mg/kg/ day with the total dose that reaches every day.For the accurate amount of the effective The compounds of this invention of treat and the best route of administration of The compounds of this invention, be easy to by persons skilled in the art according to relatively the blood levels and the required concentration that reaches result of treatment of this reagent are determined.
This compound can be with the prodrug form administration, and prodrug is generally to be designed to strengthen the compound that absorbs and can break to form effective constituent in vivo.Effectively the metabolite or the biological isologue of the pharmaceutical active that level also can be by giving this compound are realized.The prodrug of The compounds of this invention can be by any appropriate means preparation.
Can also give the patient The compounds of this invention in oral mode, treat index and make drug concentrations be enough to suppress L-Cysteine HCL Anhydrous (particularly falcipain) or reach any other disclosed herein.Usually, according to patient's symptom, the oral administration dosage of medicinal compositions that contains this compound is between 0.1-50mg/lg.Oral dosage preferably is about 0.1-50mg/kg, every day 1-2 time.
When giving The compounds of this invention, there is not unacceptable toxic side effect according to the present invention.
A kind of in more available biological tests experimentizes to The compounds of this invention, determines to have the compound concentrations of the pharmacological effect that requires.For example, the test that definite plasmodium falciparum L-Cysteine HCL Anhydrous catalytic activity test is provided and has determined the amount of The compounds of this invention inhibition L-Cysteine HCL Anhydrous.
The test of all plasmodium falciparum L-Cysteine HCL Anhydrouss all use the trophont extract carry out (Rosenthal, P.J. etc., J.Clin.Invest.1991,88,1467-1472).Measure the standard test condition of power constant and use the fluorescence peptide substrates, Cbz-Phe-Arg-AMC (Bachem) measures in the 100mM sodium acetate that contains the 5mM halfcystine of pH5.5.The deposit substrate solution DMSO formulations prepared from solutions of 10mM in the experiment, final concentration of substrate is 10 μ M.Final DMSO concentration is 2%, and final volume is 100 μ L.All experiments are all at room temperature gone.After forming the AMC product, in 20-30 minute, draw product process curve.
With this process curve method assessment potential inhibitor.Test is carried out in the presence of the test compound of various concentration.Start reaction by in the buffered soln of inhibitor and substrate, adding enzyme.Decide according to the shape of this process curve under the inhibitor existence, carry out data analysis according to a method in two methods.For the process curve is linear compound, according to equation (1) (Brandt etc., Biochemistry, 1989,28,140) calculate apparent inhibition constant (ki, app):
V=V mA/[k a(I+I/k I, app)+A] (1) wherein v be speed of response, V mBe maximum reaction velocity, A is a concentration of substrate, k aBe the Michaelis constant, I is an inhibitor concentration.
Going out for the process curve display is the compound of the curvilinear characteristic downward according to the inhibition time, and the individual data that draws according to equation (2) analysis calculates k Obs:
[AMC]=v SsT+ (v 0-v Ss) [I-exp (k ObsT)] k Obs(2) wherein [AMC] is the production concentration that forms with the t time, v 0Be initial reaction speed, v SsIt is final speed of steady state.Analyze k then ObsValue (inhibitor concentration linear function item) is to produce the apparent secondary rate constant (k that describes according to the inhibition of time Obs/ inhibitor concentration or k Obs/ [I]).The complete discussion of this dynamics process is elaborated (Morrison etc., Adv.Enzymol.Relat.Areas Mol, Biol., 1988,61,201).
The example of listing in the following table I according to the collected The compounds of this invention of above-described method suppresses data.
The table I
Compound K i(nM) 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-9.5L-leucyl)] carbohydrazide; (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group 15 benzoyls) amino] tetramethyleneimine-4-ketone; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-55 basic carbonyls]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides; 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzene sulfonyl 54 bases) amino-third-2-ketone; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl 41 methoxycarbonyl)-L-leucyl] hydrazides; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-75 basic carbonyls]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-benzene oxygen 130 basic benzenesulfonyls) amino-third-2-ketone; N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridyl methoxyl group 18 carbonyls)-L-leucyl] hydrazides; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-28L-leucyl) hydrazides; N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-35[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrochysene furan 230 mutters-4-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-38N '-[N-(5-methyl-2-Ben Ji oxazole-4-base the carbonyl)-bright amino of L-] hydrazides; 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-bright 94 aminoacyl amino of L-] third-2-ketone; (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-81 pyridyl) phenyl kharophen] fourth-2-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-550N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides; 1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridine 47 bases) phenyl kharophen] third-2-ketone; 1-[N-[4-[2-(N, N-dimethylamino) oxyethyl group] benzoyl]-L-leucyl 77 amino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-22 N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-b-cyclopropyl alanyl] hydrazides.
Data show that The compounds of this invention is effective inhibitor of plasmodium falciparum L-Cysteine HCL Anhydrous in the table I, therefore, if give this compound, can effectively treat malaria and other above mentioned parasitosis of animal (especially Mammals, people especially) according to the inventive method.
Embodiment
In following synthetic embodiment, unless otherwise indicated, all raw materials are all from commercially available acquisition.Without detailed description, be sure of that those skilled in the art can use above explanation and farthest utilize the present invention.These embodiment do not limit this only for explanation the present invention's usefulness
Scope of invention.
Flash chromatography adopts silica gel 60 (Merck Art 9385) to carry out. 1H NMR (300MHz) spectrum is at CDCl 3Middle mensuration adopted Varian 300 instruments, measures with Varian UNITYplus300 function software.Chemical shift is to be the part of internal labeling record in per 1,000,000/(ppm) low fields with the tetramethylsilane, and coupling constant is represented with hertz.Adopt following abbreviation expression spin multiplicity: the br=broad peak, s=is unimodal, d=doublet, t=triplet, q=quartet, m=multiplet, the complicated multiplet of cm=.Infrared (IR) spectrum is with Perkin-Elmer 1600 serial FTIR spectrophotometer, with wave number (cm -1) oneself records.
Embodiment 1 preparation 2-[N-(N-benzyloxycarbonyl glycyl)] a) N-benzyloxycarbonyl-L-leucine methyl esters of-2 ' [N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide
To the L-leucine methyl ester hydrochloride that stirs (2.0g, 11.0mmol) 1, add Na in 4-two-oxygen six ring (20mL) solution 2CO 3(12.1ml, the 2M aqueous solution), then add chloroformic acid benzyl ester (1.96g, 11.5mmol).Under the room temperature this mixed solution was stirred 4 hours, between ethyl acetate and water, distribute then.Organic layer salt water washing, dry (MgSO 4), filter, concentrate the title compound (3.1g, 100%) that obtains colorless oil. 1H?NMR(400?MHz,CDCl3)d7.34(m,5H),5.27(d,1H),5.12(s,2H),4.41(s,2H),3.75(s,3H),1.65(m,3H),0.96(m,6H)。B) N-benzyloxycarbonyl-L-leucine base hydrazides
To embodiment 1 (a) compound that stirs (3.1g, add in 15mL methanol solution 11.0mmol) the hydrazides hydrate (5.9g, 118mmol).With this solution stirring 16 hours, concentrate the title compound (3.1g, 100%) that obtains pale solid then under the room temperature.MS(ESI):280.2(M+H) +。C) (1S)-1-benzyloxycarbonyl amino-3-methyl isophthalic acid-(1,3,4-oxadiazole-2-ketone-5-yl) butane
(3.0g adds phosgene (56mL, the toluene liquid of 1.93M) in toluene 10.8mmol) (50mL) solution to embodiment 1 (b) compound that stirs.With this vlil 4 hours, concentrate then and obtain the foamed title compound of lark (3.15g, 96%).MS(ESI):306.1(M+H) +。D) 2-[N-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide
According to the method for embodiment 1 (b), but with (1S)-1-benzyloxycarbonyl amino-3-methyl isophthalic acid-(1,3,4-oxadiazole-2-ketone-5-yl) butane replaces N-benzyloxycarbonyl-L-leucine methyl esters, the preparation title compound, it is white foam shape thing (0.097g, 60%).MS(ESI):338.2(M+H) +。E) 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide
To embodiment 1 (d) compound (0.2g, 0.593mmol), N-benzyloxycarbonyl glycine (0.137g, 0.653mmol) and I-hydroxybenzotriazole (0.016g, 0.119mmol) DMF (6mL) solution in add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.125g, 0.653mmol).Stir after 16 hours under the room temperature, this solution is diluted with ethyl acetate, use saturated sodium bicarbonate aqueous solution, water and salt water washing in turn.With organic layer drying (MgSO 4), filter, concentrate.Residue is through column chromatography (silica gel; Methylene chloride) obtains the title compound (0.204g, 65%) of white solid.MS(ESI):529.2(M+H +)。
Embodiment 2 preparation (3RS)-1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] a) 1-tert-butoxycarbonyl-3-pyrroline of tetramethyleneimine-4-ketone
3-pyrroline under room temperature (5.0g, CH 72.35mmol) 2Cl 2(25mL) add hydrogen-carbonate di-t-butyl ester (16.58g, CH 75.97mmol) in the solution 2Cl 2(50mL) solution.Should react and stir 1 hour, vacuum concentration obtains title compound, not purified being directly used in the next step. 1H?NMR(200MHz,CD 3OD)d?5.12(m,2H),3.92(m,4H),1.38(s,9H)。B) 1-tert-butoxycarbonyl-3,4-epoxy tetramethyleneimine
To embodiment 2 (a) compound (5.0g, CH 29.5mmol) 2Cl 2(200mL) add NaHCO in the solution 3(9.03g, 118.2mmol) and metachloroperbenzoic acid (15.29g, 88.6mmol).Should react to stir under the room temperature and spend the night, concentrate then, filter with sherwood oil.With the saturated K of petroleum ether layer 2CO 3(2x), water and saturated brine wash dry (MgSO 4), filter, concentrate and obtain clear colorless oil shape thing.This oily matter is through column chromatography (4: 1 hexanes: ethyl acetate) obtain title compound, be directly used in next step. 1H?NMR(200MHz,CDCl 3)3.85-3.20(m,6H),1.43(s,9H)。C) anti--3-azido--1-tert-butoxycarbonyl-4-hydroxyl pyrrolidine
To embodiment 2 (b) compound that stirs (2.03g, methane 10.96mmol): add in water (8: 1 solution of the 18mL) solution ammonium chloride (2.5g, 10.96mmol) and sodium azide (3.56g, 54.8mmol).Under 60 ℃, should react heated overnight, then with the sherwood oil dilution, with pH4 damping fluid, saturated sodium bicarbonate and saturated brine washing, dry (MgSO 4), filter, concentrate and obtain 2.12g title compound, the not purified next step that is directly used in. 1H?NMR(400MHz,CDCl 3)4.21(brs,1H),3.92(brs,1H),3.71-3.30(m,4H),1.43(s,9H)。D) anti--3-amino-1-tert-butoxycarbonyl-4-hydroxyl pyrrolidine
To embodiment 2 (c) compound (210mg, CH 0.92mmol) 3The Pd-C of adding 10% in OH (10mL) solution.This mixture is stirred under hydrogen until the completely dissolve of TLC analysis revealed raw material.Should react by Celite pad CH 2Cl 2Filter, concentrate and obtain the 202mg title compound, it is directly used in next step.E) instead-(3RS, 4RS)-1-tert-butoxycarbonyl-4-hydroxyl-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine
Method according to embodiment 1 (e); but replacing 2-[N-(N-benzyloxycarbonyl-L-leucyl) with anti--3-amino-1-tert-butoxycarbonyl-4-hydroxyl pyrrolidine] also with 4-phenoxy benzoic acid replacement N-benzyloxycarbonyl glycine, the preparation title compound also carries out next step reaction to carbohydrazide.F) instead-(3RS, 4RS)-4-hydroxyl-3-[N-(4-phenoxy group benzoyl) amino] pyrrolidine hydrochloride
(228mg fed HCl gas about 5 minutes in dry EtOAc (5.0mL) solution 0.57mmol) to embodiment 2 (e) compound.Stir this reaction and fall raw material until the completely consumed of TLC analysis revealed.This reaction of vacuum concentration obtains 168mg (88%) title compound then, uses it for next step.G) instead-(3RS, 4RS)-1-(N-benzyloxycarbonyl-L-leucyl)-4-hydroxyl-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine
Method according to embodiment 1 (e); but with anti--(3RS; 4RS)-and 4-hydroxyl-3-[N-(4-phenoxy group benzoyl) amino] pyrrolidine hydrochloride replacement 2-[N-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide and usefulness N-benzyloxycarbonyl-L-leucine in place N-benzyloxycarbonyl glycine, the preparation title compound.MS(ESI):546.3(M+H) +,568.2(M+Na) +。H) (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone
Drip Jones reagent in acetone (5mL) solution of embodiment 2 (g) compound (150mg) under 0 ℃ and keep brown until solution.This reaction is warmed to room temperature, stirred about 18 hours, should react with the Virahol quencher then,, use saturated K successively with the EtOAc dilution 2CO 3, the washing of water and saturated brine.With organic layer drying (MgSO 4), filter and concentrate.Residue is through column chromatography (2: 1 EtOAc: hexane) obtain the 49mg title compound.MS(ESI):544.2(M+H) +。
Embodiment 3 preparation (1S)-N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyls] thiazole-4-base carbonyl]-a) N-benzyloxycarbonyl-L-leucyl amine of N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides
(4.6g adds N-methylmorpholine (3.68g, 36.4mmol in THF solution 17.3mmol) to being cooled to-40 ℃ of N-benzyloxycarbonyl-L-leucines that stir down; 4.0mL) and chloroformic acid isobutyl (2.37g, 17.3mmol; 2.25mL).Stir after 15 minutes, in this solution, fed ammonia 5 minutes.This solution is warmed to room temperature, and evaporation is dissolved in residue in the ethyl acetate, with 0.1N HCl washing, and again with the saturated brine washing, dry then (MgSO 4), filter, be evaporated to the dried title compound (4.58g, 100%) that obtains white solid.B) N-benzyloxycarbonyl-L-leucine thioamides
Under the room temperature, (4.58g is 17.3mmol) with LawessonShi reagent (4.21g, THF solution stirring 10.4mmol) 16 hours with embodiment compound 3 (a).With this solution concentration, residue obtained the title compound (3.74g, 77%) of light yellow solid through flash chromatography on 230-400 order silica gel with 1: 3 EtOAc/ hexane wash-out.C) (1S)-1-benzyloxycarbonyl amino-1-(4-ethoxycarbonyl thiazol-2-yl)-3-methylbutane
With embodiment compound 3 (b) (2.20g 7.83mmol) is dissolved in the acetone (35mL), is cooled to-10 ℃, add ethyl bromide acetone (1.68g, 8.62mmol, 1.08mL).Stir after 1 hour, this solution is poured in methylene dichloride/water, pour saturated NaHCO then into 3In the aqueous solution.The water layer dichloromethane extraction washs the organic layer that merges again with saturated brine, dry (MgSO 4), filter, concentrate.Residue is dissolved in the methylene dichloride, is cooled to-20 ℃, add pyridine (1.36g, 17.2mmol, 1.39mL) and trifluoroacetic anhydride (1.81g, 8.62mmol, 1.22mL).Stir after 1 hour, the saturated NaHCO of this solution 3The aqueous solution and saturated brine washing, dry (MgSO 4), filter, concentrate.Residue obtains the title compound (2.36g, 80%) of light yellow oily through flash chromatography on the 230-400 of 90g order silica gel with 1: 3 EtOAc/ hexane wash-out. 1H?NMR(400?MHz,CDCl 3)d?8.08(s,1H),7.38(m,5H),5.42(s,3H),5.23-5.07(m,3H),4.42(q,2H),2.01-1.62(m,3H),1.41(t,3H),0.99(d,6H)。D) (1S)-1-benzyloxycarbonyl amino-1-(4-diazanyl carbonyl thiazol-2-yl)-3-methylbutane
With embodiment compound 3 (c) (2.16g 5.73mmol) is dissolved in the ethanol (60mL), add hydrazine hydrate (2.87g, 57.3mmol, 2.8mL), under 75 ℃, with this solution stirring 1 hour.With this solution cooling, be evaporated to the dried light yellow foamed title compound that obtains, (2.01g, 97%). 1H?NMR(400MHz,CDCl 3)d?8.35(bs,1H),8.03(s,1H),7.37(m,5H),5.29(d,1H),5.14-5.09(m,3H),4.07(bs,2H),1.92-1.82(m,1H),1.79-1.66(m,2H),1.00(d,6H)。E) α-[isocyanato (isocyanato)-L-leucine methyl esters
With L-leucine methyl ester hydrochloride (25g 0.14mol) is dissolved in the methylene dichloride (450mL), is cooled to 0 ℃, add pyridine (43.5g, 0.55mol, 44.5mL), slowly add again the 1.93M phosgene toluene solution (0.18mol, 92.7mL).After stirring 2 hours under 0 ℃, this mixed solution is poured in 0.5N HCl (1400mL) and the ice (900mL).Organic layer is washed with 0.5NHCl (1400mL) and ice (900mL).Water layer extracts with methylene dichloride (450mL), with the organic layer that merges saturated brine (1400mL) and ice (900mL) washing, subsequent drying (MgSO 4), filter, concentrate.With (56-58 ℃ of residue distillation; 0.78mmHg) obtain the title compound (20.4g, 86%) of colourless liquid. 1H?NMR(250MHz,CDCl 3)d?4.04(dd,1H),3.82(s,3H),1.92-1.72(m,1H),1.69-1.62(m,2H),0.96(d,3H),0.94(d,3H)。F) N-(2-pyridyl methoxycarbonyl)-L-leucine methyl esters
(5.5g is 32.3mmol) with 2-pyridyl methyl alcohol (3.5g, toluene 32.3mmol) (35mL) vlil 24 hours with embodiment compound 3 (e).With this solution concentration, residue obtains the title compound (8.06g, 89%) of light yellow oily through flash chromatography on the 230-400 of 60g order silica gel with 30% eluent ethyl acetate in the hexane.MS(ESI):281.2(M+H) +。G) N-(2-pyridyl methoxycarbonyl)-L-leucine
(745mg, the water of adding 3mL adds LiOHH then in THF 2.6mmol) (3mL) solution to the embodiment compound 3 (f) that stirs 2O (120mg, 2.86mmol).This mixture was stirred 30 minutes, concentrate then.In residue water-soluble again (4mL), add 3N HCl (0.95mL).This solution lyophilize is obtained white solid (680mg, 94%).MS(ESI):267.2(M+H) +。H) (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides
Method according to embodiment 1 (e); but replace 2-[N-(N-benzyloxycarbonyl-L-leucyl) with (1S)-1-benzyloxycarbonyl amino-1-(4-diazanyl carbonyl thiazol-2-yl)-3-methylbutane] carbohydrazide and usefulness N-(2-pyridyl methoxycarbonyl)-L-leucine in place N-benzyloxycarbonyl glycine, the title compound of preparation white solid.(125mg,65％),MS(ESI):611.2(M+H) +。
Embodiment 4 preparation 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone are 1-amino-3-(N-benzyloxycarbonyl-L-leucylamino) propan-2-ol a)
With 1, (6.75g 75mmol) is dissolved among the DMF (100mL) 3-diamino-propan-2-ol.Add I-hydroxybenzotriazole hydrate (11.0g then, 81.5mmol), N-benzyloxycarbonyl-L-leucine (20g, 75.5mmol) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide methiodide (15.5g 81.2mmol), stirs this reaction mixture and spends the night.Vacuum is removed DMF then, and this reaction mixture is diluted with ether (150mL) and MeOH (90mL).(1M 100mL), forms rubber cement, uses ether (200mL) to extract again to add 1M HCl ether solution then.The organic phase that vacuum concentration merges, chromatography (silica gel then; 1: 10: 89 trifluoroacetic acid: MeOH: methylene dichloride) obtain title compound.MS(ESI):338.3(M+H +)。B) 2-benzyloxy benzene sulfonyl chloride
With the little crystallization of iodine join the magnesium powder (0.63g, 26.25mmol) and 2-benzyloxy bromobenzene (Friesen, Richard W.; Sturino, Claudio F.; J.Org.Chem.55; 9; 1990; 2572-2574,6.0g, in THF 22.8mmol) (20mL) slurry, reflux is 1 hour then.This reaction is cooled to 0 ℃, adds SO 2Cl 2(3.5ml 43.6mmol), should react under the room temperature and stir 2 hours.Should react and use the frozen water quencher, use ether extraction.The organic layer that merges is washed dry (MgSO with saturated brine 4), concentrate and to obtain solid, not purifiedly be directly used in next step reaction. 1H?NMR(CDCl 3)d?8.0-6.8(9H,m),5.35(3H,s)。C) 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-propan-2-ol
With embodiment compound 4 (a) (0.4g 1mmol) is dissolved among the DMF (4mL), add N-methylmorpholine (0.3g, 0.35mL, 3mmol).(0.28g 1mmol), should react and stir 4 hours to add embodiment compound 4 (b) then.This reaction mixture of vacuum concentration obtains title compound through chromatography on silica gel then.MS(ESI):584.2(M+H) +。D) 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone
Method according to embodiment 2 (h); but replace anti--(3RS with 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-propan-2-ol; 4RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-4-hydroxyl-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine; the title compound (35mg, 70%) of preparation white solid.MS(ESI):582.5(M+H) +。
Embodiment 5 preparation N-[2-(2-benzyloxy phenyl) thiazoles-4-base carbonyl]-a) thiazolamine-4-carboxylic acid, ethyl ester hydrobromate of N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides
To the thiocarbamide that stirs (6.0g, add in ethanol 78.8mmol) (80mL) suspension ethyl bromide acetone (15.4g, 78.8mmol).At 45 ℃, the solution that obtains was heated 23 hours.With this solution be cooled to 0 ℃ 24 hours, filter to collect crystal then, obtain title compound (15.8g, 79%) with cold washing with alcohol. 1H?NMR(400MHz,CD 3OD)d?7.70(s,1H),4.41(q,2H),1.38(t,3H)。B) 2-bromo thiazole-4-carboxylic acid, ethyl ester
(12.15g is added dropwise to Sodium Nitrite (3.44g, aqueous solution 49.8mmol) (6mL) in the 16%HBr aqueous solution (150mL) suspension 4.8mmol) to being cooled to embodiment compound 5 (a) 0 ℃, that stir.Stir after 35 minutes, (7.83g is 54.6mmol) with the 16%HBr aqueous solution (60mL), at 70 ℃, with this mixed solution heating 1 hour to add cuprous bromide (I).This mixed solution is filtered, and filtrate is saturated with NaCl, uses ethyl acetate extraction (2 * 170mL) then.With the extracting solution drying (MgSO that merges 4), filter, be evaporated to dried.This residue and the solid that filters collection are for the first time merged, and reflux is 5 minutes in ethanol (500mL), filters then.The 48%HBr aqueous solution that adds 1.5mL in this filtrate with this vlil 16 hours, concentrates then again.With this residue at saturated NaHCO 3Distribute between the aqueous solution and the ethyl acetate.Organic layer is washed dry (MgSO with saturated brine 4), activated carbon decolorizing filters, and concentrates the title compound (7.46g, 75%) that obtains light yellow solid.MS(ESI):236.0(M+H) +。C) 2-benzyloxy phenyl-boron dihydroxide
To 2-benzyloxy bromobenzene compound-78 ℃, that stir (15.2g, be added dropwise in THF 57.8mmol) (100mL) solution n-Butyl Lithium (23.1mL, the hexane liquid of 2.5M, 57.8mmol).Under-78 ℃, this mixed solution was stirred 25 minutes, (54.4g is in THF 289mmol) (100mL) solution to join-78 ℃ of tri-isopropylborate that stir down by sleeve pipe.After being warmed to room temperature, stirred 3 hours, this mixed solution is poured among the 3N HCl (100mL), (3 * 200mL) extract with ethyl acetate.Merge organic layer, water and salt water washing in turn, dry (MgSO 4), filter, concentrate.This residue through column chromatography (silica gel, ethyl acetate/hexane) purifying obtain light yellow solid title compound (6.9g, 30.3mmol). 1H?NMR(400MHz,CDCl 3)d?7.90(d,1H),7.42(m,6H),7.07(t,1H),7.02(d,1H),6.05(s,2H),5.16(s,2H)。D) 2-(2-benzyloxy phenyl) thiazole-4-ethyl formate
To embodiment compound 5 (the b) (4.0g that stirs, 16.9mmol), embodiment compound 5 (d) (4.29g, 18.8mmol), four (triphenyl phosphine) palladium (0) (0.65g, 0.57mmol) glycol dimethyl ether (60mL) solution in add cesium fluoride (8.58g, 56.5mmol), under 85 ℃, with this mixed solution heating 16 hours.(0.65g 0.57mmol), under 85 ℃, continues heating 5 hours to add four (triphenyl phosphine) palladium (O).With this mixed solution water (60mL) dilution, (2 * 120mL) extract with ethyl acetate.The extracting solution that merges is washed dry (MgSO with saturated sodium bicarbonate aqueous solution and saturated brine 4), filter, concentrate.This residue obtains the title compound (3.22g, 56%) of white solid through flash chromatography on the 230-400 of 180g order silica gel with the hexane liquid wash-out purifying of 15% ethyl acetate.MS(ESI):340.3(M+H) +。E) 2-(2-benzyloxy phenyl) thiazole-4-carbonyl hydrazides
According to the method for embodiment 3 (d), but replace (1S)-1-benzyloxycarbonyl amino-1-(4-ethoxycarbonyl thiazol-2-yl)-3-methylbutane, the title compound of preparation white solid with 2-(2-benzyloxy phenyl) thiazole-4-carboxylic acid ethyl ester.MS(ESI):326.2(M+H) +。F) N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides
Method according to embodiment 3 (e)-3 (h), but with the 2-pyridyl methyl alcohol in the 3-pyridyl methyl alcohol replacement step (f), replace (1S)-1-benzyloxycarbonyl amino-1-(4-diazanyl carbonyl the thiazol-2-yl)-3-methylbutane in the step (h) with N-(3-pyridyl methoxycarbonyl)-L-leucine in place N-(2-pyridyl methoxycarbonyl)-L-leucine and with 2-(2-benzyloxy phenyl) thiazole-4-base carbonyl hydrazides, the title compound (93.8mg, 53%) of preparation white solid.MS(ESI):574.3(M+H) +。
Embodiment 6 preparation (1S)-N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyls] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides
According to the method for embodiment 3 (a)-3 (h), but replace 2-pyridyl methyl alcohol (f), the title compound (63mg, 42%) of preparation white solid with 3-pyridyl methyl alcohol.MS(ESI):611.5(M+H) +。
Embodiment 7 preparation 1-[N-(4-morpholino formamyl)-L-leucylaminos]-a) 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(4-phenoxyphenylsulfonyhalides base) amino-propan-2-ol of 3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone
According to the method for embodiment 4 (a)-4 (c), but, prepare title compound with the 2-benzyloxy bromobenzene in the 4-phenoxy group bromobenzene replacement step (a).MS(ESI):570.1(M+H +)。B) the amino propan-2-ol of 1-(L-leucylamino)-3-(4-phenoxyphenylsulfonyhalides base)
Feeding under the hydrogen, with embodiment compound 7 (a) (5.0g, 8.79mmol) and EtOH (140ml) solution stirring of 10%Pd/C (1.03g) 4 hours.Filter this reaction mixture by Celite, concentrate, be directly used in next step reaction without being further purified.MS(ESI):436(M+H) +。C) 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-propan-2-ol
With embodiment compound 7 (b) (0.24g, 0.5mmol), N-methylmorpholine (0.15g, 0.16mL, 1.5mmol) and morpholine-4-formyl chloride (J.Chem.Soc.1947; 307,313; 0.076g DMF 0.5mmol) (3ml) reaction mixture stirs and spends the night, and concentrates then.Chromatography (silica gel, 4: 1 EtOAc: hexane) obtain title compound.MS(ESI):549.4(M+H) +。D) 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone
Method according to embodiment 2 (h); but with 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-propan-2-ol replaces anti--(3RS; 4RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-4-hydroxyl-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine, the preparation title compound.MS(ESI):547.3(M+H) +。
Embodiment 8 preparation N-[2-(1-naphthyl) thiazoles-4-base carbonyl]-N '-[N-(4-pyridyl methoxycarbonyl)-L-leucyl] hydrazides
Method according to embodiment 5 (a)-5 (b) and 5 (d)-5 (f), but with 1-naphthyl boric acid replace in the step (d) 2-benzyloxy phenyl-boron dihydroxide and with the 3-pyridyl methyl alcohol in the 4-pyridyl methyl alcohol replacement step (f), the title compound (0.094g, 58%) of preparation white solid.MS(ESI):518.4(M+H) +
Embodiment 9 preparation N-[2-(2-benzyloxy phenyl) thiazoles-4-base carbonyl]-a) N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl of N '-(N-pyrazine carbonyl-L-leucyl) hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl) hydrazides
According to the method for embodiment 5 (a)-5 (f), but with the N-in N-tert-butoxycarbonyl-L-leucine in place step (f) (3-pyridyl methoxycarbonyl)-L-leucine, the title compound (1.015g, 94%) of preparation white solid.MS(ESI):539.1(M+H) +。B) N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(L-leucyl) hydrazides
(1.012g adds trifluoroacetic acid (2mL) in methylene dichloride 1.88mmol) (10mL) solution to the embodiment compound 9 (a) that stirs.Stir after 2 hours under the room temperature, with this solution concentration, residue is dissolved in the ethyl acetate.This solution is washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn.With organic layer drying (MgSO 4), filter, concentrate the title compound (0.766g, 93%) that obtains the white foam shape.MS(ESI):439.3(M+H) +。C) N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides
Method according to embodiment 1 (e); but with N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(L-leucyl) hydrazides replaces 2-[N-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide and replace N-benzyloxycarbonyl glycine with the pyrazine carboxylic acid; the title compound (0.146g, 94%) of preparation white solid.MS(ESI):545.4(M+H) +。
Embodiment 10 preparation N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-a) N-(N-tert-butoxycarbonyl-L-leucyl)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Method according to embodiment 5 (a)-5 (b) and 5 (d)-5 (f), but with 1-naphthyl boric acid replace in the step (d) 2-benzyloxy phenyl-boron dihydroxide and with the N-in N-tert-butoxycarbonyl-L-leucine in place step (f) (3-pyridyl methoxycarbonyl)-L-leucine, the title compound (2.2g, 96%) of preparation white solid.MS(ESI):483.2(M+H) +。B) N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Method according to embodiment 9 (b)-9 (c); but replace N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl in step (b) with N-(N-tert-butoxycarbonyl-L-leucyl)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl) hydrazides and with the pyrazine carboxylic acid in 1-benzyl-5-Methylimidazole-4-carboxylic acid replacement step (c); the title compound (0.115g, 75%) of preparation white solid.MS(ESI):581.1(M+H) +。
Embodiment 11 preparation (3RS)-3-[N-(3-benzyloxy benzoyl)-L-leucylaminos] a) anti--3-azido--4-hydroxyl tetrahydrofuran of tetrahydrofuran (THF)-4-ketone
With 3,4-epoxy tetrahydrofuran (THF) (9g, 105mmol) join stirring sodium azide (27g, 415mmol) and ammonium chloride (9g, methanol aqueous solution 159mmol) (95%, 200mL) in.Under 75 ℃, should react the heating and stirred 20 hours.Should react cooling, filter reduction vaporization.With the residue dilute with water, use ethyl acetate extraction, dry (MgSO 4), filtering, reduction vaporization obtains the title compound (10g, 74%) of colorless oil. 1H?NMR?d(CDCl 3)4.32(m,1H),4.09(dd,1H,J=4.8,9.9Hz),3.99(dd,1H,J=4.3,10.1Hz),3.94(m,1H),3.81(dd,1H,J=2.1,9.9Hz),3.73(dd,1H,J=1.8,10.1Hz),2.72(d,1H,J=4.6Hz)。B) anti--3-amino-4-hydroxy tetrahydrofuran (THF) hydrochloride
Under the logical hydrogen (35psi), with embodiment compound 11 (a) (10g, 77mmol) and ethanol (150mL) mixture of 10%Pd-C (1g) stirring 12 hours.This mixture is filtered, and the dealing with alcohol HCl processing with 100ml obtains title compound behind reduction vaporization, and it is brown solid (10.5g, 97% yield).m.p.132℃。 1H?NMR?d(d 6?DMSO)8.37(s,3H),4.13(m,1H),3.84(dd,1H,J=4.9,14.3),3.76(dd,1H,J=5.5,10.0Hz),3.58(dd,1H,J=2.7,10.0Hz),3.34(m,3H)。C) instead-(3RS, 4RS)-3-[N-(tert-butoxycarbonyl)-L-leucylamino]-the 4-hydroxyl tetrahydrofuran
(3.5ml, (7.3g, 31mmol) and N, (9ml is in methylene dichloride 52mmol) (200mL) solution for the N-diisopropylethylamine 29mmol) to join the N-tert-butoxycarbonyl-L-leucine of stirring with trimethyl-acetyl chloride.After 1 hour, (4g 28mmol), spends the night this mixture stirring to add embodiment compound 11 (b).This reaction mixture is poured in the water, used dichloromethane extraction.The organic layer that merges is washed dry (MgSO with 0.5N HCl, saturated sodium bicarbonate and saturated brine 4), filter.Reduction vaporization obtains title compound, and it is yellow foam (5g, 44%). 1H?NMR?d(CDCl 3)8.08(d,0.5H,J=4.8Hz),7.89(d,0.5H,J=7.4Hz),6.20(d,0.5H,J=8.3Hz),6.09(d,0.5H,J=8.7Hz),4.81(d,1H,J=16.0Hz),4.40(m,2H),4.20(m,2H),3.77(m,2H),1.60(m,3H),1.50(s,9H),0.92(m,6H)。D) instead-(3RS, 4RS)-3-(L-leucylamino)-4-hydroxyl tetrahydrofuran trifluoroacetate
Method according to embodiment 9 (b); but with anti--(3RS)-3-[N-(tert-butoxycarbonyl)-L-leucylamino]-the 4-hydroxyl tetrahydrofuran replaces N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl) hydrazides; the preparation title compound; it is white soup compound (2.6g, 100%). 1H NMR d (MeOD) 4.18 (m, 2H), 4.08 (m, 2H), 3.97 (m, 2H), 3.86 (apparent t, 2H, J=7.1Hz), 3.69 (dd, 2H, J=1.6,7.4Hz), 1.68 (m, 3H), 0.99 (d, 6H, J=2.1Hz).E) 3-benzyloxy methyl benzoate
To DMF (20mL) suspension of NaH (0.395g, 9.87mmol is in 60% Dormant oils) join the 3-methyl hydroxybenzoate (1.0g, 6.58mmol).Stir under the room temperature after 15 minutes, and the adding bromotoluene (1.1g, 6.58mmol).Stir after 3 hours under the room temperature, this solution is distributed between ethyl acetate and water.With the organic layer water (2 * 75mL), saturated sodium bicarbonate aqueous solution and salt water washing, subsequent drying (MgSO 4), filter, concentrate and obtain title compound, its be pale solid (1.013g, 4.2mmol). 1H?NMR(400MHz,CDCl 3)d?7.67(m,2H),7.48-7.34(m,6H),7.19(m,1H),5.12(s,2H),3.95(s,3H)。F) 3-benzyloxy phenylformic acid
To embodiment compound 11 (e) (0.400g, add in THF 1.65mmol) (2mL) and water (2mL) solution lithium hydroxide monohydrate (0.076g, 1.82mmol).Reflux and stir after 5 hours down, this solution is distributed between ethyl acetate and 3N HCl.With organic layer salt water washing, dry (MgSO 4), filter, concentrate obtain white solid (0.355g, 1.56mmol). 1H?NMR(400MHz,CD 3OD)d?7.58(m,2H),7.36-7.24(m,6H),7.10(m,1H),5.04(s,2H)。G) instead-(3RS, 4RS)-3-[N-(3-benzyloxy benzoyl)-L-leucylamino]-the 4-hydroxyl tetrahydrofuran
With embodiment compound 11 (f) (251mg, 1.0mmol) join embodiment compound 11 (the d) (329mg of stirring, 1.0mmol), diethyl phosphorocyanidate (0.16ml, 1.0mmol) and triethylamine (0.3ml is in methylene dichloride 2.1mmol) (5mL) solution.Should react and stir 1 hour, dilute with ether then.Organic layer is washed subsequent drying (MgSO with 1N hydrochloric acid, sodium bicarbonate and saturated brine 4), filter.Evaporating solvent obtains the title compound (302mg, 71%) of colorless oil. 1H NMR d (CDCl 3) 8.17 (d, 0.5H, J=5.1Hz), 8.03 (d, 0.5H, J=7.5Hz), 7.87 (d, 0.5H, J=7.8Hz), 7.56 (d, 0.5H, J=7.5Hz), and 7.46-6.80 (m, 9H), 5.08 (apparent d, 2H, J=10.1Hz), 5.07-4.70 (m, 1H), 4.45 (brs, 1H), 4.17 (brs, 1H), 4.12-3.80 (m, 4H), 3.70-3.50 (m, 4H), and 1.81-1.62 (m, 3H), 0.93-0.88 (m, 6H).MS(ESI):425(M+H) +。H) (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone
(500mg, (280mg is in methylene dichloride 0.7mmol) (10mL) solution 1.2mmol) to join the embodiment compound 11 (g) of stirring with Dress-Martin periodo alkane (periodinane).After 1 hour, add ether, then add Sulfothiorine (570mg, 3.6mmol).After 15 minutes, should react again with saturated sodium bicarbonate and saturated brine washing, dry (MgSO 4), filter.Evaporating solvent obtains the title compound (270mg, 93%) of white foam shape. 1H NMR d (CDCl 3) 7.92 (d, 0.5H, J=6.7Hz), 7.83 (d, 0.5H, J=6.7Hz), 7.48-7.04 (m, 10H), 5.04 (apparent d, 2H, J=4.2Hz), 4.99-4.81 (m, 1H), 4.48-3.68 (m, 5H), 1.81-1.62 (m, 3H), 0.93-0.84 (m, 6H).MS(ESI):423(M+H) +。
Embodiment 12 preparation N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base dress base]-a) N-cyclopropyl isobutylamine of N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides
With cyclopropylamine (12.0mL, 173mmol) and isobutyric aldehyde (15.8mL 173mmol) is dissolved in the methylene dichloride (50mL), stirs under the room temperature 1 hour.Subsequently this solution is cooled to 0 ℃, (73g 346mmol) adds with the 400mL methylene dichloride with sodium triacetoxy borohydride.This reaction mixture was stirred 4 hours, use sodium bicarbonate (5% aqueous solution) washing then.Organic phase is through MgSO 4Drying is filtered, and concentrates the title compound (14.0g, 71%) that obtains colourless liquid.MS(ESI):113.7(M+H) +。B) N-cyclopropyl-N-(2-methyl-propyl)-N '-benzoyl thiourea
With embodiment compound 12 (a) (14.0g 123mmol) is dissolved in the chloroform (100mL), add the benzoyl lsothiocyanates (20g, 123mmol, 18mL).Stir under the room temperature after 45 minutes, concentrate the title compound (29g, 85%) that this solution obtains yellow solid.MS(ESI):257.1(M+H) +。C) N-cyclopropyl-N-(2-methyl-propyl) thiocarbamide
(29g 105mmol) is dissolved in methyl alcohol (100mL) and the water (100mL), and (43g 315mmol), spends the night this vlil to add salt of wormwood with embodiment compound 12 (b).Concentrate this reaction mixture, be dissolved in again in the ethyl acetate, with sodium bicarbonate, water washing, through MgSO 4Drying is filtered, and concentrates the title compound (13.42g, 75%) that obtains yellow solid.MS(ESI):172.9(M+H) +。D) 2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-carboxylic acid ethyl ester
Under the heating, (13.42g 77.7mmol) is dissolved in the ethanol (30mL) with embodiment compound 12 (c).This solution is cooled to room temperature, and the adding ethyl bromide acetone (9.7mL, 77.7mmol).With this reaction mixture reflux 30 minutes, concentrate then residue is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.With the water ethyl acetate extraction, the organic phase that merges is washed dry (MgSO with saturated brine 4), filter, concentrate and obtain yellow oil.By silica gel, with ethyl acetate/hexane (1: 3) wash-out title compound, it is yellow oil (9.9g, 48%) with this crude product.MS(ESI):269.4(M+H) +。E) 2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl hydrazides
Method according to embodiment 3 (d), but with 2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-carboxylic acid ethyl ester replaces (1S)-1-benzyloxycarbonyl amino-1-(4-ethoxycarbonyl thiazol-2-yl)-3-methylbutane, the title compound (7.5g, 80%) of preparation white solid.MS(ESI):255.2(M+H) +。F) N '-(N-tert-butoxycarbonyl-L-leucyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides
Method according to embodiment 1 (e); but with 2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl hydrazides replacement 2-[N-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide and usefulness N-tert-butoxycarbonyl-L-leucine in place N-benzyloxycarbonyl glycine; the preparation title compound; it is white solid (7.5g, (100%)).MS(ESI):468.3(M+H) +。G) N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides
Method according to embodiment 9 (b)-9 (c); but use N '-(N-tert-butoxycarbonyl-L-leucyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl of step (b)]-N '-(N-tert-butoxycarbonyl-L-leucyl) hydrazides and replace the pyrazine carboxylic acid of step (c) with 5-methyl-2-Ben Ji oxazole-4-carboxylic acid; the preparation title compound, it is white solid (340mg).MS(ESI):553.4(M+H) +。
Embodiment 13 preparation 1-[3-(2-pyridyl) phenyl kharophens]-3-[N-(2-thiophene carbonyl)-L-leucylamino] a) 3-(trifluoromethyl sulfonyloxy) methyl phenylacetate of third-2-ketone
To logical argon gas, oven drying, sodium hydride is housed, and (2.54g, the dispersion liquid in 60% Dormant oils add anhydrous pentane (20mL) in flask 63.5mmol).This soup compound was stirred 5 minutes, place, remove most of pentane, add anhydrous THF (40mL).(9.99g, anhydrous THF (20mL) solution 60.1mmol) should react under the room temperature and stir 20 minutes to add 3-hydroxyl phenylacetic acid methyl esters in this suspension.(22.53g, anhydrous THF (40mL) solution 63.1mmol) stir this reaction solution and fall (1.5 hours) until the completely consumed of TLC analysis revealed raw material under the room temperature to add N-phenyl trifluoromethyl sulfimide then in this mixture.Add H 2O (10mL) quencher should be reacted, and was concentrated into half of original volume, used CHCl then 3(200mL) H is used in dilution 2The O washing.With the fresh CHCl of water layer 3(50mL) washing is with the organic layer 10%Na that merges 2CO 3, the washing of water and saturated brine, dry then (MgSO 4), filter, concentrate.Residue is through column chromatography (silica gel, 5: 95 EtOAc: hexane, 10: 90 EtOAc then: hexane) obtain the 17.47g title compound. 1H?NMR(400MHz,CDCl 3)7.42(m,1H),?7.31-7.19(m,3H),3.72(s,3H),3.68(s,2H)。B) 3-(2-pyridyl) methyl phenylacetate
To embodiment compound 13 (a) (6.86g, 23.0mmol) anhydrous dioxane (100mL) solution in add 2-pyridyl tributyl stannane (8.89g, 24.1mmol), LiCl (2.94g, 69.3mmol), 2,6 di tert butyl 4 methyl phenol (some crystallizations) and Pd (PPh 3) 4(632.1mg, 0.55mmol).Should react with protection of foil paper lucifuge and reflux and spend the night.This reaction is cooled to room temperature, concentrates.Residue is through column chromatography (silica gel, 1: 3 EtOAc: hexane, then 1: 2EtOAc: hexane) obtain the 3.85g title compound.MS(ESI):228.1(M+H) +。C) 3-(2-pyridyl) toluylic acid
(3.8g adds LiOHH in THF 16.7mmol) (50mL) solution to embodiment compound 13 (b) 2O (780.2mg, water 18.6mmol) (10mL) solution.Place this reaction solution under the room temperature and fall (2 hours) until the completely consumed of TLC analysis revealed raw material.This reaction mixture concentrated remove THF, add 1N HCl then and be neutralized to pH7,, use CHCl with salt solution (50mL) dilution 3(100mL) washing.By add 1N NaOH with the water layer re-adjustment to pH7, use fresh CHCl 3(100mL) washing.Again this process is repeated once, organic layer is merged, dry (MgSO 4), filter, concentrate and obtain the 3.79g title compound.MS(ESI):214.3(M+H) +。D) 1-[N-(tert-butoxycarbonyl)-L-leucylamino]-3[3-(2-pyridyl) phenyl kharophen] propan-2-ol
With 1, (5.61g 22.5mmol) is dissolved among the DMF (36mL) 3-diamino propan-2-ol.Add I-hydroxybenzotriazole hydrate (3.34g then, 24.75mmol), N-tert-butoxycarbonyl-L-leucine (5.61g, 22.5mmol) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide methiodide (4.73g, 24.75mmol), with this reaction mixture stirring 4 hours.Add embodiment compound 13 (c) (1.68g, 7.875mmol), then add the I-hydroxybenzotriazole hydrate (1.276g, 9.45mmol) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide methiodide (1.81g, 9.45mmol), should react again and stir 12 hours.With this reaction mixture vacuum concentration, obtain title compound through silica gel column chromatography then, it is white solid (1.70g, 43%).MS(ESI):499.3(M+H +)。E) 1-L-leucylamino-3[3-(2-pyridyl) phenyl kharophen] the propan-2-ol trifluoroacetate
Method according to embodiment 9 (b); but with 1-[N-(tert-butoxycarbonyl)-L-leucylamino]-3[3-(2-pyridyl) phenyl kharophen] propan-2-ol replacement N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl) hydrazides; the preparation title compound need not be further purified and be directly used in next step reaction.MS(ESI):399.2(M+H) +。F) 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] propan-2-ol
With 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide methiodide (0.138g, 0.722mmol) join embodiment compound 13 (e) (0.6mmol), N, N-diisopropylethylamine (0.23g, 0.315mL, 1.81mmol), I-hydroxybenzotriazole hydrate (0.097g, 0.722mmol) and 2-Thiophene Carboxylic Acid (0.077g is in DMF 0.6mmol) (10mL) solution.This reaction mixture stirring is spent the night, use saturated brine/EtOAc washing then.With the organic layer drying (MgSO that merges 4), filter, concentrate, obtain title compound through silica gel column chromatography, it is white foam shape thing (0.15g, 49%).MS(ESI):509.3(M+H +)。G) 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone
Method according to embodiment 11 (h); but with 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] propan-2-ol replaces anti--(3RS; 4RS)-3-[N-(3-benzyloxy benzoyl)-L-leucylamino]-the 4-hydroxyl tetrahydrofuran; the preparation title compound; it is white solid (70mg, 64%).MS(ESI):507.4(M+H) +。
Embodiment 14 preparation (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] a) N-benzyloxycarbonyl-L-alanyl brooethyl ketone of fourth-2-ketone
With isobutyl chlorocarbonate (2.90g, 21.2mmol 2.74mL) be added drop-wise to N-benzyloxycarbonyl-L-L-Ala under-40 ℃ (4.7g, 21.2mmol) and N-methylmorpholine (2.14g, 21.2mmol is in THF 2.32mL) (40mL) solution.Should react and stir 15 minutes, filter then, wash with ether.The diazomethane of ether (300mL) preparation of the 1-methyl-3-nitro-nitroso-group-guanidine of adding usefulness 12g and the 40%KOH of 36ml places refrigerator (0 ℃) to spend the night this reaction.In this crude product reaction mixture, drip 30%HBr/AcOH (14mL), stirred 5 minutes.With this solution with aqueous citric acid solution (2 * 50mL), saturated sodium bicarbonate aqueous solution (3 * 150mL), saturated brine (100mL) washs in turn.With the organic liquor drying (MgSO that merges 4), filtering, vacuum concentration obtains the solid title compound, is directly used in next step reaction without being further purified.MS(ESI):360.3(M+H +)。B) N-benzyloxycarbonyl-L-alanyl azido methyl ketone
With embodiment compound 14 (a) (1.5g 5mmol) is dissolved among the DMF (10mL), add then sodiumazide (0.39g, 6mmol) and Potassium monofluoride (0.58g 7.5mmol), should react to stir and spent the night.This is reflected between EtOAc and the water distributes organic extracting solution drying (MgSO that will merge then 4), filtering, vacuum concentration obtains title compound through chromatography (2-5% MeOH, methylene dichloride, silica gel) again, and it is white solid (0.5g, 38%).IR (membrane process): 2106.4cm -1C) (3S)-the amino fourth of 1-azido--3-benzyloxycarbonyl-2-alcohol
(0.5g 1.9mmol) is dissolved among the MeOH (10mL), and under 10 ℃, (0.144g 3.8mmol), should react and stir 15 minutes to add sodium borohydride with embodiment compound 14 (b).Should react water (10mL) quencher, and use EtOAc (25mL) to extract again.With the organic extracting solution drying (MgSO that merges 4), filter, concentrate and obtain title compound, be directly used in next step reaction (0.5g, 100%) without being further purified.D) (3S)-the amino fourth of 1-amino-3-benzyloxycarbonyl-2-alcohol
With embodiment compound 14 (c) (0.5g, 1.9mmol) be dissolved in MeOH (7.5mL) and triethylamine (0.72g, 7.1mmol, 1.0mL), add 1, the 3-dimercaptopropane (1.08g, 10mmol, 1.07mL), this reaction mixture stirring is spent the night, vacuum concentration obtains title compound with this white solid with hexane wash then, is directly used in next step reaction without being further purified.MS(ESI):239.3(M+H +)。E) (3S)-and 3-benzyloxycarbonyl amino-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-alcohol
With embodiment compound 14 (d) (0.452g, 1.9mmol) and embodiment compound 13 (c) (0.4g, 1.9mmol) be dissolved among the DMF (15mL), add I-hydroxybenzotriazole hydrate (0.27g, 2mmol) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide methiodide (0.38g, 2mmol), this reaction mixture stirring is spent the night.This is reflected between EtOAc and the 1N NaOH distributes, with the organic layer drying (MgSO that merges 4), filter, concentrate and obtain title compound (0.33g, 40%).MS(ESI):434.2(M+H +)。F) (3S)-and 3-amino-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-alcohol
Method according to embodiment 7 (b); but with (3S)-1-[3-(2-pyridyl) phenyl kharophen]-the amino fourth of 3-benzyloxycarbonyl-2-alcohol replacement 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(4-phenoxyphenylsulfonyhalides base) amino-propan-2-ol; the preparation title compound is directly used in next step reaction without being further purified.MS(ESI):300.3(M+H) +。G) (3S)-and 3-tert-butoxycarbonyl-L-leucylamino-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-alcohol
(0.28g 0.75mmol) is dissolved among the DMF (10mL) with embodiment compound 14 (f).Add HBTU (0.3g, 0.8mmol), N-tert-butoxycarbonyl-L-leucine (0.2g, 0.8mmol) and N-methylmorpholine (0.34g, 3.37mmol 0.37mL), spend the night this reaction mixture stirring.This reaction mixture of vacuum concentration obtains title compound through silica gel column chromatography then, and it is a white solid.MS(ESI):513.2(M+H) +。H) (3S)-and 3-(L-leucylamino)-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-alcohol
(2.0g 3.9mmol) is dissolved in the dioxane (85mL) of methylene dichloride (140mL) and 4M HCl, stirs 2 hours under the room temperature with embodiment compound 14 (g).Add toluene (100mL), this reaction mixture vacuum concentration is obtained title compound, be directly used in next step reaction without being further purified.MS(ESI):413.2(M+H) +。I) (3S)-and 3-(benzothiazole-6-base carbonyl-L-leucylamino)-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-alcohol
Method according to embodiment 14 (g), but with (3S)-3-(L-leucylamino)-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-alcohol replacement (3S)-3-amino-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-is pure and use benzothiazole-6-carboxylic acid to replace N-tert-butoxycarbonyl-L-leucine, the preparation title compound is directly used in next step reaction without being further purified.MS(ESI):574.3(M+H) +。J) (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone
Method according to embodiment 11 (h); but with (3S)-3-(benzothiazole-6-base carbonyl-L-leucylamino)-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-alcohol replaces anti--(3RS; 4RS)-3-[N-(3-benzyloxy benzoyl)-L-leucylamino]-the 4-hydroxyl tetrahydrofuran; the preparation title compound; it is white solid (30.1mg, 20%).MS(ESI):572.3(M+H) +。
Embodiment 15 preparation N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) (S)-2-(N-tert-butoxycarbonyl amino)-4-pentenoic acid of N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides
To 0 ℃, stir (S)-2-amino-4-pentenoic acid down (6.0g, 52.2mmol) 1, adding hydrogen-carbonate di tert butyl carbonate in 4-dioxane (105mL), water (53mL) and 1N NaOH (53mL) solution (12.5g, 57.4mmol).Under 0 ℃, should react and stir after 2 hours, this mixed solution is concentrated, in the residue water-soluble (75mL).Add one deck ethyl acetate, with water layer 0.3N KHSO 4Be acidified to pH3.Water layer is extracted with ethyl acetate (2x), organic layer is merged, water (2x) washing, subsequent drying (MgSO 4), filter, concentrate and obtain title compound, it is colorless oil (10.6g, 95%).MS(ESI):214.0(M+H +)。B) (S)-2-(N-tert-butoxycarbonyl amino)-3-cyclopropyl methyl propionate
(10.6g, ether 49.5mmol) (500mL) solution is cooled to 0 ℃ with embodiment compound 15 (a).Simultaneously, under the jolting, (36g slowly adds 40%NaOH (700mL) in ether 247mmol) (500mL) suspension to 1-methyl-3-nitro-nitroso-group-guanidine once in a while.After adding NaOH, this mixture was placed 20 minutes down at 0 ℃.Remove water layer then, in this acidic solution, drip this organic layer under the jolting.After being added dropwise to complete, under 0 ℃, with this solution stirring 20 minutes.After 20 minutes, add acid chloride (1.0g, 4.4mmol), with the mixture restir that obtains 15 minutes.Concentrate this mixture then, the residue repeating said steps obtains title compound, and it is brown oil (9.8g, 82%). 1H?NMR(400MHz,CDCl 3)d?5.17(d,1H),4.38(m,1H),3.72(s,3H),1.62(t,2H),1.42(s,9H),0.68(m,1H),0.42(m,2H),0.08(m,2H)。C) (S)-2-(N-tert-butoxycarbonyl amino)-3-cyclopropyl propionic acid
To the embodiment compound 15 (b) that stirs (7.5g, in THF 30.6mmol) (40mL) and water (40mL) solution, the adding lithium hydroxide monohydrate (1.4g, 33.7mmol).After the reflux 16 hours, concentrate this solution.Residue is dissolved in the ethyl acetate, with 1N HCl washing.With organic layer salt water washing, dry (MgSO 4), filter, concentrate and obtain title compound, it is brown oil (5.9g, 85%).MS(ESI):252.2(M+Na) +。D) N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides
Method according to embodiment 12 (f)-12 (g), but replace the N-tert-butoxycarbonyl-L-leucine in the step (f) and use 7-methoxyl group benzo furans-2-carboxylic acid to replace the 5-methyl-2-benzene base oxazole-4-carboxylic acid in the step (g) with (S)-2-(N-tert-butoxycarbonyl amino)-3-cyclopropyl propionic acid, the preparation title compound, it is white solid (0.120g, 74%).MS(ESI):540.3(M+H +)。
Embodiment 16 preparation 1-[N-(benzoxazole-5-base carbonyls)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone
According to the method for embodiment 13 (a)-13 (g), but, prepare title compound with the thiophene-2-carboxylic acid in benzoxazole-5-carboxylic acid replacement step (f).MS(ESI):542(M+H) +。
Embodiment 17 preparation 1-[N-[4-[2-(N, N-dimethylamino) oxyethyl groups] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone
According to the method for embodiment 13 (a)-13 (g), but with 4-[2-(N, N-dimethylamino) oxyethyl group] phenylformic acid (J.Med.Chem.27; 8; 1984; 1057-1066) the thiophene-2-carboxylic acid in the replacement step (f), the preparation title compound.MS(ESI):588(M+H) +。
Embodiment 18 preparation N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-b-cyclopropyl alanyl] a) 5-hydroxyl benzofuran-2-carboxylic acid, ethyl ester of hydrazides
Aluminum chloride under 0 ℃ (6.3g, 47.7mmol) and sulfur alcohol (4.5g, 72.9mmol, add in mixed solution 5.4mL) 5-methoxyl group benzo furans-2-carboxylic acid, ethyl ester (3.0g, 13.6mmol).Stir after 16 hours under the room temperature, this mixture is poured in the water,, use methylene dichloride (2x) to extract again with 3N HCl acidifying.Organic layer is merged, use the salt water washing, dry (MgSO 4), filter, concentrate.(silica gel: ethyl acetate/hexane) purifying obtains title compound to residue, and it is white solid (2.2g, 77%) through column chromatography. 1H?NMR(400MHz,CDCl 3)d?7.53(s,1H),7.30-7.18(m,2H),7.02(d,1H),5.26(sb,1H),4.43(q,2H),1.41(t,3H)。B) 5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-carboxylic acid, ethyl ester
To 0 ℃, embodiment compound 18 (a) (0.20g under stirring, 0.971mmol), N, N-dimethylethanolamine (0.122g, 1.26mmol, 0.127mL) and triphenylphosphine (0.331g, 1.26mmol) THF (3mL) solution in drip azo-2-carboxylic acid's diisopropyl ester (0.254g, 12.6mmol, 0.248mL).Stir after 16 hours under the room temperature, with this solution concentration, (silica gel: ethyl acetate/hexane) purifying obtains title compound to residue, and it is white solid (0.161g, 60%) through column chromatography.MS(ESI):278.2(M+H +)。C) 5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-carboxylic acid
Method according to embodiment 15 (c), but with 5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-carboxylic acid, ethyl ester replacement (S)-2-(N-tert-butoxycarbonyl amino)-3-cyclopropyl methyl propionate, the preparation title compound, it is white solid (0.139g, 96%). 1H?NMR(400MHz,MeOH-d)d?7.37(m,1H),7.12(m,2H),6.99(m,1H),4.31(t,2H),3.55(t,2H),2.96(s,6H)。D) N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-b-cyclopropyl alanyl] hydrazides
Method according to embodiment 12 (f)-12 (g), but replace the N-tert-butoxycarbonyl-L-leucine in the step (f) and use 5-[2-(N with (S)-2-(N-tert-butoxycarbonyl amino)-3-cyclopropyl propionic acid, the N-dimethylamino) oxyethyl group] cumarone-2-carboxylic acid replaces the 5-methyl-2-Ben Ji oxazole-4-carboxylic acid in the step (g), the preparation title compound, it is white solid (0.131g, 73%).MS(ESI):597.3(M+H +)。
More than explanation and embodiment disclose comprehensively and how to have prepared and use compound of the present invention.But the present invention is not limited to above-described specific embodiments, but comprises that the institute in the following claim scope changes.The periodical of the various references of being quoted, patent and other publication all comprise the present situation of this technical field herein, and its full content is attached among the present invention as a reference.

Claims (6)

1. use and be selected from the medicine that following compound is used to suppress L-Cysteine HCL Anhydrous: 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide; (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides; 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone; N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-is than pyridine ylmethoxy carbonyl)-L-leucyl] hydrazides; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides; N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides; 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone; (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides; 1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; 1-[N-[4-[2-(N, N-dimethylamino) oxyethyl group] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-β-cyclopropyl alanyl] hydrazides.
2. according to the application of claim 1, wherein this L-Cysteine HCL Anhydrous is falcipain.
3. use and be selected from the medicine that following compound is used for the treatment of the disease that is caused by parasitic infection, parasite is selected from: plasmodium falciparum, schizotrypanum cruzi, trypanosoma bocagei, leishmania mexicana, the pifanoi leishmania, leishmania major, Schistosoma mansoni, Onchocerca caecutiens, brugia pahangi, the entamoeba histolytica worm, the blue Bai Shi flagellate of intestines, worm, haemonchus contortus and liver fluke, the Vermes palace tapeworm that changes, trichinella, plate mouth nematode and roundworm and protozoa Cryptosporidium, Eimeria, toxoplasma gondii and receive and return worm, 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide; (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides; 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone; N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides; N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides; 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone; (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides; 1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; 1-[N-[4-[2-(N, N-dimethylamino) oxyethyl group] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-β-cyclopropyl alanyl] hydrazides.
4. according to the application of claim 2, wherein this disease is selected from: malaria, trypanosomiasis (nelavan, Chagas disease), leishmaniasis, schistosomicide, onchocerciasis (onchocerciasis) and giardiasis.
5. use and be selected from the medicine that following compound is used for the treatment of malaria: 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide; (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides; 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone; N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides; N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides; 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone; (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides; 1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; 1-[N-[4-[2-(N, N-dimethylamino) oxyethyl group] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-β-cyclopropyl alanyl] hydrazides.
6. medicinal compositions, it comprise be selected from following compound and pharmaceutically acceptable carrier, thinner or vehicle: 2-[N-(N-benzyloxycarbonyl glycyl)]-2 '-[N '-(N-benzyloxycarbonyl-L-leucyl)] carbohydrazide; (3RS)-and 1-(N-benzyloxycarbonyl-L-leucyl)-3-[N-(4-phenoxy group benzoyl) amino] tetramethyleneimine-4-ketone; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(2-pyridyl methoxycarbonyl)-L-leucyl)] hydrazides; 1-(N-benzyloxycarbonyl-L-leucylamino)-3-(2-benzyloxy benzenesulfonyl) amino-third-2-ketone; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; (1S)-and N-[2-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazole-4-base carbonyl]-N '-[N-(3-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; 1-[N-(4-morpholino formamyl)-L-leucylamino]-3-(4-phenoxyphenylsulfonyhalides base) amino-third-2-ketone; N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridyl methoxycarbonyl)-L-leucyl] hydrazides; N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(N-pyrazine carbonyl-L-leucyl) hydrazides; N-[N-(1-benzyl-5-Methylimidazole-4-base carbonyl)-L-leucyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; (3RS)-and 3-[N-(3-benzyloxy benzoyl)-L-leucylamino] tetrahydrofuran (THF)-4-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(5-methyl-2-Ben Ji oxazole-4-base carbonyl)-L-leucyl] hydrazides; 1-[3-(2-pyridyl) phenyl kharophen]-3-[N-(2-thiophene carbonyl)-L-leucylamino] third-2-ketone; (3S)-3-[N-(benzothiazole-6-base carbonyl)-L-leucylamino]-1-[3-(2-pyridyl) phenyl kharophen] fourth-2-ketone; N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(7-methoxyl group benzo furans-2-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides; 1-[N-(benzoxazole-5-base carbonyl)-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; 1-[N-[4-[2-(N, N-dimethylamino) oxyethyl group] benzoyl]-the L-leucylamino]-3-[3-(2-pyridyl) phenyl kharophen] third-2-ketone; With N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-[5-[2-(N, N-dimethylamino) oxyethyl group] cumarone-2-base carbonyl]-L-β-cyclopropyl alanyl] hydrazides.
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