CN103130710A - Anti-enterovirus 71 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof - Google Patents
Anti-enterovirus 71 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof Download PDFInfo
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- QPLOPNRBTYZIIG-DTIOYNMSSA-N CC(C)(C)OC(N[C@@H](CC(CCC#N)C(OC)=O)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CC(CCC#N)C(OC)=O)C(OC)=O)=O QPLOPNRBTYZIIG-DTIOYNMSSA-N 0.000 description 1
- QNSPKWUAZQIIGZ-QMMMGPOBSA-N CC(C)(C)OC(N[C@@H](CCC(OC)=O)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC(OC)=O)C(OC)=O)=O QNSPKWUAZQIIGZ-QMMMGPOBSA-N 0.000 description 1
- 0 CC(NC(*)C(NC(CC(CCCN1)C1=O)C=O)=O)=O Chemical compound CC(NC(*)C(NC(CC(CCCN1)C1=O)C=O)=O)=O 0.000 description 1
- OKRWEGGCEZPSQB-UJGDBWEASA-N COC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O Chemical compound COC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O OKRWEGGCEZPSQB-UJGDBWEASA-N 0.000 description 1
- AQTCMEVCOONKHH-OUQNNKQFSA-N COc1ccc(/C=C/C(N[C@@H](Cc2ccccc2)C(N[C@@H](CC(CCCN2)C2=O)C=O)=O)=O)cc1 Chemical compound COc1ccc(/C=C/C(N[C@@H](Cc2ccccc2)C(N[C@@H](CC(CCCN2)C2=O)C=O)=O)=O)cc1 AQTCMEVCOONKHH-OUQNNKQFSA-N 0.000 description 1
- YFHVCODMDZNZEA-PCUGXKRQSA-N OC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O Chemical compound OC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O YFHVCODMDZNZEA-PCUGXKRQSA-N 0.000 description 1
- MQTDBYCEECIZND-FJDHMSSLSA-N OC1NCCC[C@H]1CC(C=O)NC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O Chemical compound OC1NCCC[C@H]1CC(C=O)NC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O MQTDBYCEECIZND-FJDHMSSLSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
A structure general formula of a caprolactam aldehyde enterovirus 71 (EV 71) 3C protease inhibitor is as shown in chemical combination A, all variables in the structure are defined in an instruction book, and the compound effectively restrains or blocks the copy of the enterovirus 71. The invention relates to a compound with the structure as shown in formula (A), various types of optical isomers of the compound with the structure as shown in formula (A), drug active metabolites, officinal salt, solvate and discovery and application when the compound with the structure as shown in formula (A), the various kinds of optical isomers of the compound with the structure as shown in formula (A), the drug active metabolites and the officinal salt are used for preparing antiviral drugs for curing hand-foot-mouth virus infection diseases. The invention further relates to an intermediate and a synthetic method of preparing the compound with the structure as shown in formula (A).
Description
Technical field
The invention relates to formula (A) compound, pharmaceutical composition that treatment enteric virus71 (EV71) infects, and the synthetic method of this compounds, formulation method and the synthetic compound for these.Particularly, the invention provides a class hexanolactam aldehyde compound, the method that the pharmaceutical composition that contains this compounds and this compounds for treating EV71 infect.
Background of invention
Hand foot mouth disease (Hand-Foot-Mouth discasc, HFMD) has another name called dermexanthesis blister stomatitis, is the common transmittable disease caused by enterovirus, and all there is this sick popular report in world's most countries and area.This disease is mainly propagated by fecal-oral route and respiratory tract, and infectivity by force, very easily causes popular or breaks out.Hand foot mouth disease be take infant's morbidity as main, the Most patients symptom is slight, it is main clinical characteristics that the fash at the positions such as heating and hand, foot, oral cavity is take in clinical manifestation, more seriously, virus can also be invaded patient breathing system, central nervous system etc. and cause the symptoms such as encephalitis, pulmonary edema, flaccid paralysis, myocarditis, disease progression is fast, easily occurs dead.South East Asia and China are all the hotspots of people brothers stomatosis all the time, particularly in the last few years, joint effect along with many factors such as flow of personnel, virus variations, great outburst has occurred in provinces such as China Shandong, Henan, Taiwan in this disease, cause the Infant and child deaths case of thousands of examples, brought huge economy and moral damage to infant family.
The enterovirus that causes hand foot mouth disease has kind more than 20,16,4,5,9,10 types of enterovirus 7I type and CA group, 2,5 types of B group are the more common virus of hand foot mouth disease, and wherein modal is enterovirns type 71 (EV71) and coxsackie virus A 16-type (CoxA16).Virusology and EPDML studies confirm that, (Enterovirus 71 for human enterovirus 71, EV71) be the main pathogens of the people brothers stomatosis that breaks out in recent years, can also cause the multiple diseases relevant to neural system such as paralysis (polionyehtis hke paralysis) of aseptic meningitis (ascptic meningitis), BBE (brain stem encephalitis) and poliomyelitis sample simultaneously.EV71 has caused repeatedly popular in recent years, and research finds that the genotype of EV71 constantly changes in the air, and the transgenation in some site causes the pathogenic change of EV71, so the control of EV71 is faced with sizable pressure.The bright EV71 virus of current not yet lock forms viral persistence and causes the concrete mechanism of hand foot mouth disease, still lack clinically special, effective medicine, can only take Chinese medicine or other antiviral drugs to be treated, research shows, considerable participant does not produce favourable effect to this treatment, death constantly occurs clinically.Therefore, need development to there is the specific anti-EV71 virus formulation for hand foot mouth disease efficiently.
EV71 is that the people such as Schmit in 1969 separate first and obtain from the infant faeces sample of suffering from central nervous system disease, belongs to the Picornaviridae enterovirus and belongs to, and virion be typical positive two top body structures.Its gene approximately is comprised of 7408 Nucleotide, belong to single strand plus RNA virus, only contain an opening code-reading frame (open-reading frame, ORF), the polyprotein (polyprotein) of 2194 Amino acid profiles of coding, be respectively the 5 ' non-coding region (UTR) of 746bp and the 3 ' non-coding region of 83bp in the genome both sides.The polyprotein of EV71 genome encoding (polyprotein) is approximately containing 2193 amino acid.In infected cell, this polyprotein is hydrolyzed into as P1, P2, tri-precursor proteins of P3.Through cell and viral proteolytic enzyme, further shear, P1 precursor protein further maturation is VP1, VP2, VP3 and tetra-virus structural proteins of VP4, is responsible for the assembling of virion and stablizes; P2 precursor protein further maturation is Nonstructural Protein (non-structural protcm, nsp) 2A (specific protease), 2B and 2C; The P3 precursor protein is in order to form nonstructural protein 3A, 3B (VPg, 5 ' end is in conjunction with albumen), 3C (specific protease) and 3D (RNA-depcndcnt RNA polymcrase, RdRp).
In seven Nonstructural Proteins, HRV 3CP is considered to mainly exercise the function of specific protease, belong to L-Cysteine HCL Anhydrous, its active centre is Cys147, His40, the catalysis triplet that Glu71 forms, it is responsible that by virus, each coded protein cuts down from poly specifically, formation has the protein of standalone feature, once thereby the afunction of this albumen, virus is further transcribed and is copied and can't normally proceed.Therefore can be the effective means for the treatment of EV71 virus infection by the effect of the selectivity small molecules of specific recognition inhibition HRV 3CP, HRV 3CP becomes the important drugs target spot for the treatment of hand foot mouth disease.
The present invention is based on the crystal structure characteristic of EV713C proteolytic enzyme, by the binding site in conjunction with active region, design a series of HRV 3CP inhibitor containing the hexanolactam aldehyde structure.
First advantage of the present invention is its hexanolactam aldehydes inhibitor provided, and can effectively suppress EV713C proteolytic enzyme.
The hexanolactam aldehydes inhibitor that second advantage of the present invention is to provide, can effectively suppress SARS virus master albumen Nsp5 proteolytic enzyme.
In addition, the 3rd advantage of the present invention is can be for the preparation of the treatment L-Cysteine HCL Anhydrous medicine that induces an illness, as hand foot mouth disease, common cold, poliomyelitis etc.
Find Compound I by biological activity test, II, a plurality of compounds such as XIV have shown that to the EV71 virus in cell cultures extraordinary inhibition is active, have good pharmacokinetic property in vivo.
Target of the present invention is to find especially effectively micromolecular compound of the anti-enteric virus71 of a class, and is provided for the synthetic intermediate of described protease inhibitor compound and these synthetic synthetic methods.
Summary of the invention:
The present invention is directed to the deficiencies in the prior art of EV71 virus HRV 3CP inhibitor, provide a kind of containing formula (A) class EV71 virus HRV 3CP inhibitor, another object of the present invention is that synthesizing and the synthetic synthetic method for these of described protease inhibitor compound intermediate will be provided.
The present invention relates to the catch application of medicine of the hexanolactam aldehyde compound of formula (A) and/or pharmacy acceptable salt and/or hydrate preparation treatment enteric virus71 (EV71).These compounds are as its pharmacy acceptable salt and/or hydrate, perhaps as the pharmaceutical composition composition (no matter its whether with the antiviral agent of other treatment hand foot mouth disease, anti-infective, immunomodulator or microbiotic while administration) and for suppressing the HRV 3CP of EV71 virus, or the one or more EV71 virus infection of preventing/treating symptom.
In particular, the present invention relates to the catch application of medicine of formula (A) compound and/or pharmacy acceptable salt and/or hydrate preparation treatment enteric virus71 (EV71):
Wherein
R
1expression-H, the C1-12 alkyl, the C2-12 thiazolinyl, the C2-12 alkynyl, the C3-8 cycloalkyl, aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynes its,-O-alkyl,-O-cycloalkyl,-O-the alkyl of mixing,-O-Heterocyclylalkyl,-O-heterocyclic radical,-O-alkenyl,-O-cycloalkenyl group,-O-the thiazolinyl of mixing,-O-heterocycloalkenyl,-O-alkynyl group,-O-cycloalkynyl radical,-O-the alkynyl of mixing, the assorted alkynyl of-O-ring,-O-aryl,-O-aralkyl,-O-heteroaryl,-O-heteroaralkyl,-S-alkyl,-S-cycloalkyl,-S-the alkyl of mixing,-S-Heterocyclylalkyl,-S-heterocyclic radical,-S-alkenyl,-S-cycloalkenyl group,-S-the thiazolinyl of mixing,-S-heterocycloalkenyl,-S-alkynyl group,-S-cycloalkynyl radical,-S-the alkynyl of mixing, the assorted alkynyl of-S-ring,-S-aryl,-S-aralkyl,-S-heteroaryl,-S-heteroaralkyl,-N-alkyl,-N-cycloalkyl,-N-the alkyl of mixing,-N-Heterocyclylalkyl,-N-heterocyclic radical,-N-alkenyl,-N-cycloalkenyl group,-N-the thiazolinyl of mixing,-N-heterocycloalkenyl,-N-alkynyl group,-N-cycloalkynyl radical,-N-the alkynyl of mixing, the assorted alkynyl of-N-ring,-N-aryl,-N-aralkyl,-N-heteroaryl,-N-heteroaralkyl, or optionally can be replaced by 1 to 4 substituting group, described 1 to 4 substituting group is selected from halogen ,-OH ,-SH ,-NO
2,-CN, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-6 alkylthio, C1-8 carbalkoxy ,-CF
3,
R
2mean alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, heterocyclic radical, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl.The above aryl is phenyl or naphthyl, and heteroaryl is having 1,2 or 3 and being selected from N of connecting by ring carbon atom or nitrogen-atoms, O, heteroatomic five yuan or the hexa-atomic aromatic ring of S, and heterocyclic radical be by ring carbon atom or nitrogen-atoms, connect have 1,2,3 or 4 are selected from N, O, heteroatomic saturated or undersaturated nonaro-maticity ring, the wherein aryl of S, heteroaryl, heterocyclic radical, cycloalkyl, alkyl, cycloalkyloxy, alkoxyl group optionally can be replaced by 1 to 4 substituting group, and described 1 to 4 substituting group is selected from halogen ,-OH,-SH ,-NO
2,-CN, phenyl, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-6 alkylthio, C1-8 carbalkoxy ,-CF
3.The above cycloalkyl, cycloalkyloxy, aryl, assorted virtue or heterocyclic radical on two adjacent substituting groups optionally become together 0-3 to contain O, N, the heteroatomic 3-6 ring of S.
The above aryl is phenyl or naphthyl, and heteroaryl is having 1,2 or 3 and being selected from N of connecting by ring carbon atom or nitrogen-atoms, O, heteroatomic five yuan or the hexa-atomic aromatic ring of S, and heterocyclic radical be by ring carbon atom or nitrogen-atoms, connect have 1,2,3 or 4 are selected from N, O, heteroatomic saturated or undersaturated nonaro-maticity ring, the wherein aryl of S, heteroaryl, heterocyclic radical, cycloalkyl, alkyl, cycloalkyloxy, alkoxyl group optionally can be replaced by 1 to 4 substituting group, and described 1 to 4 substituting group is selected from halogen ,-OH,-SH ,-NO
2,-CN, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-6 alkylthio, C1-8 carbalkoxy, trifluoromethyl.The above cycloalkyl, cycloalkyloxy, aryl, the adjacent substituting group of the two-phase on heteroaryl or heterocyclic radical optionally forms together 0-3 and contains O, N, heteroatomic three-six-ring of S.
The pharmaceutical composition comprised in the scope of the invention, formula (A) compound that comprises anti-EV71 virus significant quantity or the upper acceptable salt of its treatment, and be mixed with pharmaceutically acceptable pharmaceutical carrier or auxiliary agent.
An importance of the present invention, relate in Mammals the formula A compound of the content by this Mammals being given to effective anti-EV71 virus, or its acceptable salt or ester in treatment, or above-mentioned composition, with the catch method of medicine for the treatment of enteric virus71 (EV71).
Another importance of the present invention, relate to formula (A) compound of facing upward EV71 virus processed by virus is exposed to, or its acceptable salt or ester in treatment, under composition described above, finds the active drug for the treatment of hand foot mouth disease.
The pharmaceutical composition that other aspect relates to, can comprise other anti-EV71 preparations in addition, also can comprise the inhibitor of other targets of EV71 virus, as 3D proteinase inhibitor and VP1 protein inhibitor.
The detailed description of preferred embodiment
Definition:
When for herein, unless mentioned separately all applicable following definition:
When addressing each example, (R) or, (S) for indicating the absolute configuration of asymmetric center, this indicates is explanation rather than the independent substituent explanation for whole compound.
" P1, P2, P3 " sign that this paper is used; mean from the C-end of peptide analogs; and the position of holding the amino acid whose residue extended towards N-, i.e. first position that P1 representative starts from the C end, P2 holds second position started (referring to BergerA.& from C; Schechtcr I, Transactions of the RoyalSociety London serics B257,249-264 (1970)).
" halogen " used herein word refers to halogenic substituent, is selected from iodine, bromine, chlorine or fluorine.
" C1-6 alkyl " used herein word, no matter when using separately or being used in combination with another substituting group, refer to the straight or branched alkyl substituent of acyclic, it comprises 1 to 6 carbon atom, comprise for example methyl, ethyl, propyl group, butyl, hexyl, 1-methylethyl, 1,1-dimethyl ethyl, 1-methyl-propyl and 2-methyl-propyl.
" C3-8 cycloalkyl " used herein word, no matter when using separately or being used in combination with another substituting group, refer to the straight or branched alkyl substituent of acyclic, it comprises 3 to 8 carbon atoms, comprises for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
" C1-8 alkoxyl group " used herein word, no matter when using separately or being used in combination with another substituting group, refer to the straight or branched alkoxy substituent of acyclic, it comprises 1 to 8 carbon atom, comprise for example methoxyl group, oxyethyl group, propoxy-, butoxy, hexyloxy, 1-methyl ethoxy, 2,2-dimethyl butoxy, 1-methyl hexyloxy and heptan the oxygen base.
" C1-8 alkylhalide group " used herein word, when using separately or being used in combination with another substituting group, refer to acyclic, the straight or branched alkyl substituent, it comprises 1 to 8 carbon atom, has one or more fluorine that are selected from, chlorine, the hydrogen that bromine or iodine replaces.
" C1-6 sulfenyl " used herein word, when using separately or being used in combination with another substituting group, refer to acyclic, the straight or branched alkyl substituent, contain thiol group, for example thiopropyl.
" unsaturated non-aromatic ring " used herein word, mean undersaturated cycloalkyl, for example the substituting group cyclohexenyl.
" C3-8 cycloalkyloxy " used herein word, no matter when using separately or being used in combination with another substituting group, mean substituting group comprise 3 to 8 carbon atoms-O-C
3-8cycloalkyl, for example comprise-O-cyclopropyl ,-O-cyclobutyl ,-O-cyclopentyl etc.
" C1-6 alkyl-carbonyl " used herein word, when using separately or being used in combination with another substituting group, refer to the C1-6 alkyl connected by carbonyl ,-C (O)-C
1-6alkyl.
" aryl " used herein word, mean the aromatic series single-loop system that contains 6 carbon atoms, or the aromatic series bicyclic system that contains 10 atoms, for example phenyl and naphthyl-loop systems.
" heteroaryl " used herein word, when using separately or being used in combination with another substituting group, what mean to connect by ring carbon atom or nitrogen-atoms has 1,2 or 3 are selected from N, O, heteroatomic five yuan of S, hexa-atomic or seven yuan of undersaturated heterocycles, remove hydrogen and derivative unit price substituting group.Suitable heterocycle example is as thiophene, furans, pyrroles, imidazoles, pyrazoles, thiazole ， oxazole ， isoxazole, 1,2,3-triazoles, 1,2-thiadiazoles, pyridine, pyrazine, pyrimidine, 1,2,4-triazine, benzoxazole, benzothiazole, quinoline.
" low-carbon alkyl, low-carbon (LC) thiazolinyl, low-carbon (LC) alkynyl " used herein word, when using separately or being used in combination with another substituting group, refer to the acyclic that comprises 1 to 6 carbon atom, the straight or branched alkyl, the alkenyl or alkynyl substituting group.
" the acceptable ester of pharmacy " used herein word, when using separately or being used in combination with another substituting group, mean the ester of compound formula (I), wherein any carboxyl-functional base or the hydroxyl-functional base of this molecule, preferably carboxyl or hydroxy terminal, by carbalkoxy functional group or ester bond, replaced:
R wherein, R ' part is to be selected from low-carbon alkyl (as methyl, ethyl, propyl group, butyl, hexyl); Alkoxyalkyl (as methoxyethyl); Alkoxy acyl (as acetoxy-methyl); Aralkyl (as benzyl); Aryloxyalkyl group (as benzene oxygen ethyl); Aryl (as phenyl).Can be optionally by halogen, C1-4 alkyl or C1-4 alkoxyl group replace.The prodrug ester that other are suitable, list it herein with for referencial use in.This class is acceptable ester pharmaceutically, usually, in mammalian body, is hydrolyzed the sour form that is converted into compound formula (A).
About above-mentioned ester class, unless otherwise specified, the moieties of any existence all advantageously contains 1 to 6 carbon atom.Any aryl moiety be present in this ester class, all advantageously comprise phenyl group.
" pharmaceutically acceptable salt " word refers to the salt of formula (A) compound herein, and it is applicable to the tissue contact of people and animal and nontoxicity in normal therapeutic treatment, and nonirritant, without anaphylaxis etc.Generally water-soluble or oil soluble, or easily disperse, and be effective on it uses.This word comprises pharmaceutically acceptable acid salt and pharmaceutically acceptable base addition salt.
" pharmaceutically acceptable acid salt " word refers to the character that keeps biological activity and free state alkali, and be abiotic upper or other aspects are unwanted, itself and mineral acid are as sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, Hydrogen bromide, thionamic acid etc., and organic acid is as acetic acid, trifluoracetic acid, Tricholroacetic Acid, styracin, citric acid, toxilic acid, hexanodioic acid, alginic acid, xitix, aspartic acid, phenylformic acid, the horizontal acid of benzene, oxyacetic acid, oxysuccinic acid, lactic acid, propanedioic acid, oxalic acid, nicotinic acid, succinic acid, Whitfield's ointment, stearic acid, tartrate, aniline sulfonic acid over the ground, tri-methyl p-toluenesulfonate, p-methyl benzenesulfonic acid, amygdalic acid, pectinic acid, picric acid, the formed salt such as propionic acid.
" pharmaceutically acceptable base addition salt " word refers to the character that keeps biological activity and free state acid, and is abiotic upper or other aspects are unwanted, its be with mineral alkali as ammonia or ammonium or metallicity ion as, sodium, magnesium, copper, zinc, calcium, potassium, the formed salt of the oxyhydroxide of aluminium etc. or carbonate, particularly preferably be ammonium, potassium, sodium, calcium, magnesium salts.Comprise primary amine by the derivative salt of pharmaceutically acceptable organic atoxic alkali, secondary amine and tertiary amine, quaternary ammonium compound, the amine be substituted, comprise natural being substituted and amine, cyclammonium and basic ion exchange resin, as methylamine, dimethyl amine, Trimethylamine, ethylamine, diethylamide, triethylamine, tripropylamine, isopropylamine, tributylamine, thanomin, diethanolamine, dicyclohexylamine, Methionin, arginine, Histidine, caffeine, choline, trimethyl-glycine, ethylene diamine, glycosamine, methylglucosamine, Theobromine, piperazine, piperidines, purine, the tetramethyl-ammonium compound, the tetraethyl ammonium compound, pyridine, N, the N xylidine, the N-methyl piperidine, N-methylmorpholine, N, the formed salt such as N-dibenzyl phenylethylamine.Particularly preferred organic non-malicious alkali is isopropylamine, diethylamide, thanomin, Trimethylamine, dicyclohexylamine, choline, caffeine.
Preferred scheme
Preferred version of the present invention comprises formula (A) compound, and wherein hexanolactam partly is selected from two different isomer, the configuration that has (i) and (ii) mean:
The hexanolactam of the R configuration wherein preferably meaned with structure (ii).
R
1: preferred version of the present invention comprises formula (A) compound, wherein R
1c3-8 cycloalkyl preferably, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, or optionally by 1 to 4 substituting group, replaced, described 1 to 4 substituting group preferentially is selected from halogen ,-OH ,-SH ,-NO
2,-CN, halogen C1-8 alkyl, C1-8 alkoxyl group.
Most preferred R
1for the styroyl replaced by halogen.
R
2: preferred version of the present invention comprises formula (A) compound, wherein R
2aryl C2-6 thiazolinyl preferably, heteroaryl C2-6 thiazolinyl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, the C3-8 cycloalkyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, or optionally by 1 to 4 substituting group, replaced, described 1 to 4 substituting group first is selected from halogen,-OH ,-SH, C1-8 alkoxyl group.
Most preferred R
2for aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl.
Hexanolactam compounds of the present invention can free form or is existed with salt form.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises such compound alkali and quaternary ammonium salt inorganic or that organic acid forms.
Compound of the present invention can form hydrate or solvate.Those skilled in the art are known to compound formed hydrate or form the method for solvate when concentrated with suitable organic solvent in solution during freeze-drying together with water.
The present invention comprises the medicine that contains the therapeutic dose the compounds of this invention, and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises as salt solution, buffer saline, glucose, water, glycerine, ethanol and their binding substances.Carrier or vehicle can also comprise time lag material known in the art, as glyceryl monostearate or distearin, also can comprise wax, ethyl cellulose, Vltra tears, methyl methacrylate etc.If necessary, said composition can also comprise wetting agent or emulsifying agent in a small amount, or the pH buffer reagent.Said composition can be liquid, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository as triglyceride with traditional tamanori and carrier.Oral preparations can comprise the mannitol of standard vector as the medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate etc.Preparation and determining optionally, preparation can design mixing, granulation and compression or solvent components.In another approach, said composition can be mixed with nano particle.
Pharmaceutical composition of the present invention can be with medicament forms administration miscellaneous.The pharmaceutical carrier used can be solid or liquid.
If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 10g.Typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Solid carrier can comprise that one or more may make sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent simultaneously; It can also be encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.In tablet, activeconstituents mixes with suitable ratio with the carrier with necessary compression property, with shape and the size compression of needs.Powder and tablet preferably comprise 99% activeconstituents at the most.
If the use liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injectable solution or suspension in the liquid suspension of ampoule or bottle or non-water.Typical liquid vehicle comprises syrup, peanut oil, and sweet oil, water, etc.Liquid vehicle is for the preparation of solution, suspension, emulsion, syrup, the composition of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premixs as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier, the stable osmotic pressure-conditioning agent that forms.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, and oils (for example fractionated coconut oil and peanut oil) ethylene glycol for example) and their derivative.Carrier for administered parenterally can also be for grease as ethyl oleate and sec.-propyl myristate.Aseptic liquid vehicle is for the aseptic fluid composition of administered parenterally.Liquid vehicle for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, for example, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.The known technology in field, used suitable dispersion agent or wetting agent (as tween 80) and suspension agent to allocate this suspension at all.During injection, but single pushes or injects gradually perfusion in the passages through which vital energy circulates of 30 minutes.This compound can also be with the form oral administration of liquid or solids composition.Parenteral word used herein, comprise in subcutaneous, intracutaneous, intramuscular, intravenously, intraarticular, synovial membrane, in breastbone, in sheath and intralesional injection or infusion techn.
In order to obtain stable water miscible formulation, compound or its pharmacy acceptable salt can be dissolved in to the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, acid derivative can be dissolved in suitable basic solution.If can not get soluble form, compound can be dissolved in to suitable cosolvent or their combination.The example of its suitable solvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, fatty alcohol or glycerine hydroxy fatty acid ester etc.
Pharmaceutical composition of the present invention can be oral, parenteral or by the holder administration of implanting, oral administration or preferred during by drug administration by injection.Various release systems are known and can be for the administrations of compound or other various preparations, and these preparations comprise tablet, capsule, and injectable solution, the capsule in liposome, particulate, microcapsule, etc.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (usually preferred) oral route.Compound can be by administration easily any or that other is suitable, for example, by injecting or bolus injection, by epithelium or the mucous membrane circuit (for example, oral mucosa, rectum and intestinal mucosa, etc.) absorb or the support by carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.For nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Can in standard pharmacology textbook, find for other suitable vehicle or the carrier of composite mentioned above and composition, for example, at " Remington ' s Pharmaccutical Sciences ", in the 19th edition.In order to prevent and treat the hand foot mouth disease that EV71 virus causes, in single therapy, described HRV 3CP inhibitor compound in this article, 0.01 be approximately useful to the dosage range of about 100mg/kg body weight between every day, and preferably 0.5 to the 75mg/kg body weight between every day.Usually, pharmaceutical composition of the present invention is by administration every day approximately 1 to 5 time, or other one continuous transfusion.This class medicine can be used as chronic or acute treatment.Can mix with carrier substance, produce the content of the activeconstituents of single dose form, can change according to the AD HOC of pending host and administration.Representational preparation will be containing having an appointment 5% to about 95% activeconstituents (w/w).Preferably, this class preparation is containing having an appointment 20% to about 80% active compound.
This will understand and may need than higher or lower dosage mentioned above to be familiar with this area.Given dose and processing mode to particular patient should be determined according to various factors, the activity that comprises used specific compound, the combination of the time of patient's age, body weight, sex, general state of health, diet, administration, metabolic rate, medicine, and the seriousness infected and process, the tendency of patient to infecting, process in addition doctor's judgement.Generally speaking, with in fact lower than the low dose of begin treatment of the optimal dose of this compound.Increase dosage by a small amount of increase subsequently, until reach in this case best effect.Generally speaking, require with normally to produce effective antiviral result, but do not cause that any harmful or concentration content disadvantageous side effect casts this compound.
When composition of the present invention comprises formula (A) compound and one or more other treatments or preventive combination, the amount of this compound and other preparation should provide with the about dosage content between 10 to 100%, more preferably about 10 to 80% dosage, give with the single therapy method usually.
When these compounds or its pharmaceutically acceptable salt when allocating together with acceptable carrier pharmaceutically, give Mammals in vivo by the composition of gained, as the mankind, so that treatment or prevention EV71 virus infection.Also can use the compounds of this invention to mix with lower series preparation, complete this class treatment, including, but not limited to: immunomodulator, as α, β, δ-Interferon, rabbit; Other anti-virus formulation, as acyclovir, ganciclovir; Other EV713C proteinase inhibitor; To the inhibitor of other targets in the EV71 Life Cycles, as 3D proteolytic enzyme, VP1 albumen; Or its composition.Other preparation can be mixed with the compounds of this invention, to produce single dosage form.In addition, preparation that also can this class is other can cast respectively Mammals, becomes the part of a plurality of dosage forms.Therefore, other concrete scheme of the present invention provides a kind of in Mammals, and by giving construction (M) compound, wherein substituting group, as above definition, suppresses the method for EV71 virus.
In preferred concrete scheme, these methods are useful on and reduce the EV71 replication in Mammals.If pharmaceutical composition only comprises the compounds of this invention as activeconstituents, these class methods can comprise in addition this Mammals is selected to immunomodulator, antiviral agent, other EV71 virus HRV 3CP inhibitor, or to other targets in the EV71 Life Cycles, as 3D proteinase inhibitor and VP1 protein inhibitor.Can be before giving the present composition, simultaneously or afterwards, the preparation that this class is other gives Mammals.
Technical process
Can effectively prepare by the inventive method by formula of the present invention (A) compound, comprise and adopt following general synthetic method.R in these synthetic methods
1, R
2as defined above.
Technical process I:
Intermediate 1-4 obtains through the route of flow process I is synthetic; in this flow process; take L-glutamic acid 1-1 as raw material; at first carboxyl is carried out to the esterification protection; subsequently its amino is carried out to protective group and obtain its intermediate 1-2; then with using LiHMDS (or other strong basic reagents) by compound 1-2 deprotonation, introduce the cyanoethyl group and obtain intermediate 1-3.Then by the cyano reduction of intermediate 1-3, and then the molecule lactamization reaction occurs, in molecule, Cheng Huan obtains key intermediate 1-4.
The preparation of step I-1 compound N-Boc-glutamic acid dimethyl ester (1-2)
Under 0 ℃ of condition, Acetyl Chloride 98Min. (5.0mL) slowly is added dropwise in methyl alcohol (100.0mL), stir 5 minutes, then add L-glutamic acid (10.0g, 67.9mmol), continue to stir and be heated to and reflux, keep reflux temperature reaction 2 hours.Stopped reaction, underpressure distillation is except desolventizing.The oily matter obtained is dissolved in THF, under 0 ℃ of condition, drips TFA (28.54mL, 203.7mmol), keep 0 ℃ to stir 5 minutes, continue dropping and be dissolved in the tert-Butyl dicarbonate (17.78g, 81.5mmol) in THF (30.0mL), be stirred to room temperature reaction 2.5 hours.After reaction finishes, removal of solvent under reduced pressure, after residue water (200.0mL) dissolves, adding citric acid solution is acidified to PH=4, adds DCM (2 * 100.0mL) extraction, merge organic phase, organic phase anhydrous sodium sulfate drying after the saturated common salt water washing for organic phase, then concentrated, the crude product obtained is through flash chromatography post (PE: EA=5: 1) purifying, obtain target compound (1-2) (17.8g, productive rate 95.2%).The preparation of step 1-2 compound 2-t-butoxycarbonyl amino-4-cyanoethyl-Methyl glutarate (1-3)
By two (trimethyl silicon based) Lithamide (THF solution of 78.5mL1.0M, 78.5mmol) be added to N-Boc-glutamic acid dimethyl ester (the 1-2) (10.0g of-78 ℃, 36.4mmol) anhydrous THF (200.0mL) solution in, and gained solution is stirred 30 minutes in this temperature.Then slowly drip bromopropionitrile (3.4mL), reaction mixture is continued under-78 ℃ stir 2 hours.After question response finishes, add Glacial acetic acid (5.0mL) cancellation reaction, be stirred to room temperature.Removal of solvent under reduced pressure, after residue water (100.0mL) dissolves, with DCM extraction (100.0mL * 3), merge organic phase, use the saturated common salt water washing, and by the organic phase anhydrous sodium sulfate drying, then concentrated, through the flash chromatography post, (E: EA=2: 1) purifying obtains target compound (1-3) (7.1g, productive rate 59.5%) to the thick thing obtained.
The preparation of step 1-3 compound 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-piperidines alkane)-methyl propionate (1-4)
At 2-t-butoxycarbonyl amino-4-cyanoethyl-Methyl glutarate (1-4) (5.0g, 15.9mmol) methyl alcohol (80.0mL) solution in add cobalt chloride hydrate (4.0g, 15.9mmol), then add sodium borohydride (6.0g to gradation in resulting pink solution under 0 ℃ of condition, 159.5mmol), stirring at room 18 hours.The TLC monitoring reaction, after question response, add saturated aqueous ammonium chloride (30.0mL) cancellation reaction, stirs 10 minutes.Suction filtration is removed solid impurity, and easy volatile solvent is removed in decompression, after DCM for residual liquid (100.0mL * 3) extraction, adds water (2 * 50.0mL) washing organic phase.The organic phase merged is washed with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying filters steaming and desolventizes, and the crude product obtained, through flash chromatography post (EA) purifying, finally obtains key intermediate (1-4) (2.9g, productive rate 60.7%).
Flow process II
Structural unit 2-4 obtains by flow process II is synthetic, wherein R
1, R
2its group meaned is above described.Take compound 2-1 as raw material, at first carry out the carboxyl ester protection and obtain compound 2-2, then carry out condensation from different organic acid 2-3 and obtain intermediate 2-4.
Flow process III
Formula in the present invention (A) compound is to slough the carbonyl-protection base by compound 1-4 deaminize protecting group and compound 2-4 to carry out condensation, more further carries out derivatize and obtain compound 3-1.
Flow process IV
This flow process is the structure derivatize that carries out compound 3-1, has obtained hexanamide aldehyde formula (A) compound.Wherein, formula of the present invention (A) compound can be obtained by compound 3-1 derivatize through following synthetic route.
Step IV-1 compound 2-[2-R
2-amino-1-carbonyl-3-R
1] preparation of the third amino-3-(2-carbonyl-3-piperidines alkane)-propyl alcohol (4-1)
To 2-[2-R
1-amino-1-carbonyl-3-R
3] in the methanol solution (10.0mL) of the third amino-3-(2-carbonyl-3-piperidines alkane)-methyl propionate (1.0equiv.) gradation add sodium borohydride (10.0equiv.), stirring at room 2 hours.Add saturated aqueous ammonium chloride (5.0mL) cancellation reaction, methyl alcohol is removed in decompression.With DCM (3 * 50.0ml), extract, the organic phase merged is washed with saturated nacl aqueous solution, and anhydrous sodium sulfate drying is then concentrated, through the flash chromatography post, (DCM: MeOH=50: 1) purifying obtains target compound (4-1) (productive rate 87.8%) to the crude product obtained.
Step IV-2 compound 2-[2-R
2-amino-1-carbonyl-3-R
1] preparation of the third amino-3-(2-carbonyl-3-piperidines alkane)-propionic aldehyde (4-2)
To 2-[2-R
4-amino-1-carbonyl-3-R
3] add DMP (1.0equiv.) in anhydrous DCM (10.0mL) solution of the third amino-3-(2-carbonyl-3-piperidines alkane)-propyl alcohol (1.0equiv.), stir 2 hours.Add saturated sodium bicarbonate (2.0mL) cancellation reaction, add Sulfothiorine (2.0equiv) simultaneously, be stirred to the organic phase clarification.With DCM (3 * 50.0mL) extraction, the organic phase anhydrous sodium sulfate drying of merging, then concentrated, through the flash chromatography post, (DCM: MeOH=30: 1) purifying obtains target compound 4-2 (productive rate 81.3%) to the crude product obtained.
Example
By following unrestricted example, illustrate in greater detail the present invention, but the present invention is not limited to following instance.Provide temperature with degree centigrade in following example.Unless statement separately, solution per-cent means the relation of weight to volume, and solution proportion means the relation of volume to volume.In example, the structure of compound is determined in order to lower a kind of or many clock method: nuclear magnetic resonance spectrometer, high resolution mass spectrum analysis, thin-layer chromatography.If structural formula and its chemical name of the expression compound provided are not inconsistent, with structural formula, be as the criterion.
Nuclear magnetic resonance spectrum (
1h NMR and
13c NMR) with the Bruker400 spectrometer, under the 400MHz field intensity, measure.Chemical shift is used with respect to interior mark tetramethyl-silicomethane standard and is moved down how many 1,000,000/(ppm, δ) expressions.
1in H-NMR, the multiplicity at peak is expressed as follows: s=is unimodal; The d=doublet; The t=triplet; The m=multiplet.Coupling constant means with hertz.Solvent peak is with reference to inner deuterated reagent.Commercialization reagent used is all that from them, supplier separately obtains there respectively, if having, needs the condition of processing, and in literary composition, is otherwise noted.Tetrahydrofuran (THF) (THF) is through sodium-benzophenone system distillation, to obtain before use; Methylene dichloride (DCM) is from the hydrolith distillation, to obtain before use.
This paper uses following abbreviation: Me: methyl; MeOH: methyl alcohol; Boc: uncle-butoxy carbonyl; TEA: triethylamine; EtOAc: ethyl acetate; DMP:Dess-martin reagent; PE: sherwood oil; Et
2o: ether; TFA: trifluoroacetic acid; EDC:1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride); HOBt:1-hydroxy benzo triazole hydrate.In addition, " L " represents naturally occurring amino acid.FBS: foetal calf serum; PBS solution: phosphoric acid buffer: PBST: phosphoric acid buffer adds Tween-20; ESMS: Electrospray Ionization Mass Spectrometry; MS: mass spectroscopy; HPLC: high performance liquid chromatography.
The example of embodiment of the present invention is as described below:
The preparation of embodiment 1 N-Boc-L-(+)-glutamic acid dimethyl ester (1-2)
Under 0 ℃ of condition, Acetyl Chloride 98Min. (5mL) slowly is added dropwise in methyl alcohol (100mL), stir 5 minutes, then add L-glutamic acid (10g, 67.9mmol), continue to stir and be heated to and reflux, keep reflux temperature reaction 2 hours.Stopped reaction, removal of solvent under reduced pressure, use the ether recrystallization.The oily matter obtained is dissolved in THF (150mL), drip TEA (28.5mL under 0 ℃ of condition, 203.7mmol), keep 0 ℃ to stir 5 minutes, continue to drip and be dissolved in the tert-Butyl dicarbonate (17.8g in THF (30mL), 81.5mmol), be stirred to room temperature reaction 2.5 hours.After reaction finishes, remove solvent under reduced pressure, add water (200mL) in residue, with DCM (2 * 200mL), from water, extract, the organic phase anhydrous sodium sulfate drying of merging, then concentrated, the crude product obtained is through flash chromatography post (PE: EA=5: 1) purifying, obtaining N-Boc-L-(+)-glutamic acid dimethyl ester (17.7g, productive rate 95.2%) is colourless oil liquid, TLC: R
f=0.5 (PE: EA=5: 1);
1h-NMR (400MHz, CDCl
3): δ 5.36 (m, 1H), 4.32 (m, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 2.43 (m, 2H), 2.19 (m, 1H), 1.96 (m, 1H), 1.440 (s, 9H);
13c-NMR (100MHz, CDCl
3): δ 173.0,172.6, and 155.3,79.7,52.7,52.2,51.6,30.0,28.1 (3), 27.5.
The preparation of embodiment 2 2-t-butoxycarbonyl aminos-4-cyanoethyl-Methyl glutarate (1-3)
Under the condition of-78 ℃, THF solution by two (trimethyl silicon based) Lithamide (78.5mL1.0) M, 78.5mmol) slowly be added drop-wise to N-Boc-L-(+)-glutamic acid dimethyl ester (1-2) (10g, 36.4mmol) anhydrous THF (200mL) solution in, and gained solution is stirred 30 minutes at this temperature.Then keep temperature-resistant, slowly drip bromopropionitrile (3.4mL), reaction mixture is continued under the condition of-78 ℃ stir 2 hours.After question response, add Glacial acetic acid (5mL) cancellation reaction, be stirred to room temperature.First decompression is revolved and is desolventized, then add water (200mL), by DCM (2 * 200mL) aqueous phase extracted, the organic phase anhydrous sodium sulfate drying merged, then concentrated, through the flash chromatography post, (PE: EA=2: 1) purifying obtains 2-t-butoxycarbonyl amino-4-cyanoethyl-Methyl glutarate (7.1g to the crude product obtained, productive rate 59.5%) be the pale yellow oily liquid body, TLC: R
f=0.4 (PE: EA=2: 1);
1h-NMR (400MHz, CDCl
3): δ 5.07 (d, J=8.8Hz, 1H), 4.36 (dd, J=12.4Hz, 1H), (3.75 s, 3H), 3.72 (s, 3H), 2.63 (m, 1H), (2.39 m, 2H), 1.96-2.06 (m, 4H), 1.45 (s, 9H);
13c-NMR (100MHz, CDCl
3): δ 174.38,172.34, and 155.37,118.67,80.33,52.56,52.17,51.56,40.78,34.46,28.26,27.32,15.15.
The preparation of embodiment 3 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-piperidines alkane)-methyl propionate (1-4)
To 2-t-butoxycarbonyl amino-4-cyanoethyl-Methyl glutarate (1-4) (5g, 15.9mmol) methyl alcohol (80mL) solution in add cobalt chloride hydrate (4g, 14.6mmol), then slowly add several times sodium borohydride (6g in resulting pink mixture under the 0C condition, 157.9mmol), stirring at room 18 hours.Add saturated aqueous ammonium chloride (30mL) cancellation reaction, stir 10 minutes.Suction filtration is removed solid impurity, removes easy volatile solvent under reduced pressure.With DCM (3 * 100mL), from water, extract, the organic phase anhydrous sodium sulfate drying merged, then concentrated, the crude product obtained is through flash chromatography post (EA) purifying, obtain 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-piperidines alkane)-methyl propionate (2.9g, productive rate 60.7%) be white foam shape solid, TLC: R
f=0.4 (EA);
1h-NMR (400MHz, CDCl
3): δ 6.007 (s, 1H), 5.60 (d, J=8.4Hz, 1H), 4.32 (m, 1H), 3.73 (s, 3H), 3.2 (t, J=3.2Hz, 2H), 2.32 (m, 1H), 1.60-1.90 (m, 4H), 1.44 (s, 9H);
13c-NMR (100MHz, CDCl
3.): δ 174.54,173.21, and 155.92,79.74,52.26,51.75,42.29,38.03,34.25,28.29,26.57,21.57.
The preparation of embodiment 4 Chinese cassia tree carbonyl phenylalanine methyl esters (2-4)
Under 0 ℃ of condition to phenylalanine methyl ester (10g, 55.8mmol) DCM (100mL) solution in, add successively styracin (9.9g, 67.0mmol), EDC (16.1g, 83.8mmol), HOBt (11.3g, 83.8mmol), then drip TEA (35.2mL, 251.4mmol), be stirred to room temperature 2 hours.Remove solvent under reduced pressure, add water (200mL), with DCM (2 * 200mL), from water, extract, the organic phase anhydrous sodium sulfate drying merged, then concentrated, through the flash chromatography post, (PE: EA2: 1) purifying obtains Chinese cassia tree carbonylamino-phenylalanine methyl ester (13.8g to the crude product obtained, productive rate 80.2%) be white solid, TLC: R
f=0.5 (PE: EA 2: 1):
1hNMR (400MHz, CDCl
3) δ 7.64-7.60 (d, 1H, J=16Hz), 7.47-7.11 (m, 10H), 6.42-6.38 (d, 1H, J=16Hz), 5.06-5.02 (m, 1H), 3.74 (s, 3H), 3.26-3.14 (m, 2H):
13c-NMR (100MHz, CDCl
3): δ 172.2,165.4, and 141.8,135.9,134.6,129.8,129.3 (2), 128.8 (2), 128.6 (2), 127.9 (2), 127.2,120.0,53.4,52.4,37.9.
The preparation of embodiment 5 Chinese cassia tree carbonyl phenylalanines (2-5)
Add lithium hydroxide (2.0g, 48.5mmol), stirring at room 1.5 hours in the methyl alcohol of Chinese cassia tree carbonylamino-phenylalanine methyl ester (2-4) (10g, 32.3mmol) and water (100mL:200mL) solution.Remove solvent under reduced pressure, add 1N hydrochloric acid that pH is adjusted to 3.With ethyl acetate (3 * 100mL) extraction, merge organic phase, use anhydrous sodium sulfate drying, then concentrated, obtaining Chinese cassia tree carbonylamino-phenylalanine (8.6g, productive rate 90.6%) is white solid, TLC:R
f=0.1 (PE: EA=2: 1);
1h-NMR (400MHz, CDCl
3): δ 7.65-7.61 (d, 1H, J=16Hz), 7.35-7.18 (m, 10H), 6.39-6.35 (d, 1H, J=16Hz), 5.02-5.00 (m, 1H), 3.30-3.20 (m, 2H);
13c-NMR (100MHz, CDCl
3): δ 166.4,142.6, and 135.7,134.4,130.1,129.4 (2), 128.9 (2), 128.6 (2), 128.8 (2), 128.0,127.3,119.4,53.7,53.7,37.2.
Implementation column 6 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] preparation of the third amino-3-(2-carbonyl-3-piperidines alkane)-methyl propionate (3-1)
Drip TFA (13mL) under 0 ℃ of condition in the anhydrous DCM (80mL) of 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-piperidines alkane)-methyl propionate (5g, 16.6mmol), ice bath stirs 1.5 hours.Remove solvent under reduced pressure, with triethylamine, adjust pH to neutral.Then be dissolved in DCM (100mL), add successively Chinese cassia tree carbonylamino-phenylalanine (5.8g under 0 ℃ of condition, 19.9mmol), EDC (4.7g, 24.9mmol), HOBt (3.4g, 24.9mmol), then drip TEA (10.5mL, 74.7mmol), be stirred to room temperature 2 hours.Water (3 * 50mL) washing, the organic phase anhydrous sodium sulfate drying, then concentrated, the crude product obtained is through flash chromatography post (DCM: MeOH=20: 1) purifying, obtain 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] the third amino-3-(2-carbonyl-3-piperidines)-methyl propionate (6.9g, 87.8%) be white foam shape solid, TLC:R
f0.5 (DCM: MeOH=20.1);
1h-NMR (400MHz, CDCl
3): δ 7.49 (d, J=16Hz, 1H), 7.21-7.35 (10H), (6.46 d, J=16Hz, 1H), 4.87 (q, J=3.2Hz, J=4Hz, 1H), 3.73 (s, 3H), 3.42 (m, 1H), 3.09-3.25 (m, 4H), 2.41 (m, 1H), 223 (m, 1H), 1.30-1.80 (6H);
13c-NMR (100MHz, CDCl
3): δ 172.05,165.26, and 141.89,135.83,134.63,129.89,128.85,128.63,127.92,127.19,119.96,53.31,52.42,37.91.
Embodiment 7 1-cyano group-2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] preparation of the third amino-3-(2-carbonyl-3-piperidines alkane)-propyl alcohol (3-2)
To 2[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] the third amino-3-(2-carbonyl-3-piperidines alkane)-methyl propionate (3-1) (1g, 2.2mmol) methanol solution (10mL) in add several times sodium borohydride (0.8g, 21.6mmol), stirring at room 2 hours.Add saturated aqueous ammonium chloride (5mL) cancellation reaction, remove easy volatile solvent under reduced pressure, with DCM (3 * 50mL), extract, the organic phase anhydrous sodium sulfate drying merged, then concentrated, the crude product obtained, through flash chromatography post (DCM: McOH=20: 1) purifying, obtains 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] the third amino-3-(2-carbonyl-3-piperidines alkane)-propyl alcohol (0.8g, productive rate 80.9%) for the white foam shape consolidates, TLC:R
f=0.4 (DCM: McOH 20: 1);
1h-NMR (400MHz, CDCl
3): δ 7.49 (d, J=16Hz, 1H), 7.21-7.35 (10H), (6.46 d, J=16Hz, 1H), 4.87 (q, J=3.2Hz, J=4Hz, 1H) .3.71 (m, 2H), 3.42 (m, 1H), (3.09-3.25 m, 4H), 2.41 (m, 1H), 2.23 (m, 1H) .1.30-1.80 (6H);
13c-NMR (100MHz, CDCl
3): δ 179.89,171.21, and 166.12,141.64,136.76,134.62,129.87,129.37,128.82,128.50,127.94,126.86,120.28,66.2,54.89,54.81,41.08,39.11,38.96,29.42,28.10,26.72.
Implementation column 8 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] preparation of the third amino-3-(2-carbonyl-3-piperidines alkane)-propionic aldehyde (3-3)
To 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] the third amino-3-(2-carbonyl-3-piperidines alkane)-propyl alcohol (3-2) (1g, 2.3mmol) anhydrous DCM (10mL) solution in add DMP (1.5g, 3.4mmol), stir 2 hours.Add saturated sodium bicarbonate (2.0mL) cancellation reaction, add Sulfothiorine (1.1g, 6.9mmol) simultaneously, be stirred to the organic phase clarification.Add DCM (3 * 50mL) extraction, the organic phase anhydrous sodium sulfate drying merged, then concentrated, the crude product obtained is through flash chromatography post (DCM: MeOH=30: 1) purifying, obtain 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] the third amino-3-(2-carbonyl-3-piperidines alkane)-propionic aldehyde (0.83g, productive rate 80.7%) see TLC:R for white foam shape solid
10.5 (DCM: MeOH=20: 1);
1h-NMR (400MHz, CDCl
3): δ 9.40 (s, 1H), 8.41 (d, J=6.4Hz), 7.58 (d, J=16Hz, 1H), 7.23 (10H), 6.49 (d, J=16Hz, 1H), 5.08 (m, 1H), 4.32 (m, 4H), 1.47-2.27 (7H);
13c-NMR (100MHz, CDCl
3): δ 200.20,175.09, and 172.29,165.80,141.51,136.46,134.72,129.79,129.49,128.81,128.53,127.91,126.97,120.38,57.09,54.38,42.19,38.82,37.18,30.74,27.06,21.1.
Embodiment 9 EV713C proteinase inhibitor vitro enzyme are lived and are screened
Utilize FRET (fluorescence resonance energy transfer) (fluorescence resonance energy transfer, FRET) technical measurement is lived for the enzyme of the inhibitor of HRV 3CP, according to HRV 3CP recognition site design substrate: Dabcyl-RTATVQGPSLDFE-Edans, the inhibitor ultimate density is respectively: 1mM, 500 μ M, 250 μ M, 125 μ M, 62.5 μ M, 31.25 μ M, 15.625 μ M, 7.8125 μ M, 3.9 μ M, 1.95 μ M, 976nM, 488nM, 244nM, 122nM, 61nM, 30.5nM, 15.3nM, 3.8nM, 1.9nM, 0.95nM, establish negative control simultaneously.Utilizing 96 orifice plates to measure enzyme lives, 100 μ l reaction systems comprise: 20mM MES pH6.5,10ug/ml BSA, 10 μ MEV713C albumen, the inhibitor of 150 μ M fluorogenic substrates and different concns, 37 ℃ of reactions, by the microplate reader fluorescence intensity, the data obtained utilizes software GraphPad Prism 5 to process the IC of the agent that is inhibited
50.Observations shows, Compound I I, the IC of VI
50for 5-50nM.
Embodiment 10 SARS main protease Nsp5 inhibitor vitro enzyme are lived and are screened
Before utilizing fluorescence resonance, amount shifts (fluoresccncc resonance energy transfer, FRET) technical measurement is lived for the enzyme of the inhibitor of SARS Nsp5 proteolytic enzyme, according to Nsp5 proteolytic enzyme recognition site design substrate: MCA-AVLQSGFR-L-Dnp, the inhibitor ultimate density is respectively 1mM, 500 μ M, 250 μ M, + 125 μ M, 62.5 μ M, 31.25 μ M, 15.625 μ M, 7.8125 μ M, 3.9 μ M, 1.95 μ M, 976nM, 488nM, 244nM, 122nM, 61nM, 30.5nM, 15.3 nM, 3.8nM, 1.9nM, 0.95nM, establish negative control simultaneously.Utilizing 96 orifice plates to measure enzyme lives, 100 μ l reaction systems comprise: 50mMTris-HCl pH7.3,1mMEDTA, 0.5 μ M SARS nsp5 albumen, the inhibitor of 16 μ M fluorogenic substrates and different concns, 37 ℃ of reactions, by the microplate reader fluorescence intensity, the data obtained utilizes software GraphPad Prism 5 to process the IC of the agent that is inhibited
50.Observations shows, Compound I, the IC of VIII
50for 0.1-5 μ M.
Embodiment 11 cytopathic effect screening Cytopathic effect (CPE) assay:
In the CPE experiment, cell used is RD (human cmbryonic rhabdomyosarcoma) cell, and for the standard virus strain of EV71, (titre is 100TCID to virus
50).In 96 orifice plates, every hole adds 100 μ l RD cells (concentration is 3 * 10
4individual/hole), allow after cell attachment 1d, the inhibitor that adds 50 μ l/ holes to dilute, the inhibitor final concentration is respectively: 100 μ M, 10 μ M, 5 μ M, 2.5 μ M, 1.25 μ M, 625nM, 312nM, 156nM, 78nM, 39nM, 19.5nM, 9.75nM, 3.9nM.4 holes of each concentration, triplicate, add 50 μ l/ hole EV71 viruses after 2h, observe cytopathic effect (cytopathic effect, CPE) after 2-3d.When observations shows 50% cell survival, the inhibition concentration of chemical combination I is 0.625 μ M-1.25 μ M.
Embodiment 12 virus replication inhibition ability screening Cell-based immunodetcction (CID) assay:
In CID experiment, RD (human embryonic rhabdomyosarcoma) cell is diluted to 3 * 10 with the DMEM containing 10%FBS phase 1%PS (Dulbecco ' s Modified Eagle's Medium) substratum after trysinization
4individual/ml adds 100 μ l/ hole RD cells in 96 orifice plates, and 37 ℃, 5%CO
2overnight incubation, the inhibitor that second day adds 50 μ l/ holes to dilute, final concentration is respectively: 25 μ M, 10 μ M, 5 μ M, 2.5 μ M, 1.5 μ M, 1.3 μ M, 1.1 μ M, 0.9 μ M, 0.7 μ M, 0.5 μ M, 0.166 μ M, 0.05 μ M.(titre is 100TClD to add 50 μ l/ hole EV71 viruses after 2h
50), 37 ℃, 5%CO
2cultivate, after 30h, with PBS, wash twice, 50 μ l/ hole anhydrous methanol fixed cell 10min, then add 37 ℃ of sealing 1h of 100 μ l/ hole PBS+0.5%Tween20+10%FBS after washing twice with PBS, the 37 ℃ of effect 3h of primary antibodie that add 100 μ l/ hole (1: 500) dilutions, clean plank 3 times with 0.5%PBST, the two anti-anti-mouse immunoglobulin G that add 100 μ l/ hole (1: 2500) dilutions, 37 ℃ of effect 1h, clean plank 3 times with 0.5%PBST, add 100 μ l/ hole OPD substrate color development at room temperature 5min, with 50 μ l/ hole 1M H
2sO
4termination reaction, on the ELISA determinator, (490nM) reads the fluorescent value in every hole.4 holes of each concentration of above experiment inhibitor, repeat 3 times.Calculate EC with GraphPad Prism 5
50value.The EC of compounds X IV
50value is less than 1 μ M.
Claims (17)
1. a hexanolactam aldehydes enteric virus71 (EV71) HRV 3CP inhibitor has metabolite, pharmacologically acceptable salt, solvate or its prodrug of the compound of following structure general formula A or its various optical isomers, pharmaceutical activity:
R
1expression-H, the C1-12 alkyl, the C2-12 thiazolinyl, the C2-12 alkynyl, the C3-8 cycloalkyl, aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl,-O-alkyl,-O-cycloalkyl,-O-the alkyl of mixing,-O-Heterocyclylalkyl,-O-heterocyclic radical,-O-alkenyl,-O-cycloalkenyl group,-O-the thiazolinyl of mixing,-O-heterocycloalkenyl,-O-alkynyl group,-O-cycloalkynyl radical,-O-the alkynyl of mixing, the assorted alkynyl of-O-ring,-O-aryl,-O-aralkyl,-O-heteroaryl,-O-heteroaralkyl,-S-alkyl,-S-cycloalkyl,-S-the alkyl of mixing,-S-Heterocyclylalkyl,-S-heterocyclic radical, the rare base of-S-chain,-S-cycloalkenyl group,-S-the thiazolinyl of mixing,-S-heterocycloalkenyl,-S-alkynyl group,-S-cycloalkynyl radical,-S-the alkynyl of mixing, the assorted alkynyl of-S-ring,-S-aryl,-S-aralkyl,-S-heteroaryl,-S-heteroaralkyl,-N-alkyl,-N-cycloalkyl,-N-the alkyl of mixing,-N-Heterocyclylalkyl,-N-heterocyclic radical,-N-alkenyl,-N-cycloalkenyl group,-N-the thiazolinyl of mixing,-N-heterocycloalkenyl,-N-alkynyl group,-N-cycloalkynyl radical,-N-the alkynyl of mixing, the assorted alkynyl of-N-ring,-N-aryl,-N-aralkyl,-N-heteroaryl,-N-heteroaralkyl, or optionally can be replaced by 1 to 4 substituting group, described 1 to 4 substituting group is selected from halogen ,-OH ,-SH ,-NO
2,-CN, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, O1-6 alkylthio, O1-8 carbalkoxy ,-CF
3,
R
2mean alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, heterocyclic radical, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynes of ring, aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl.The above aryl is phenyl or naphthyl, and heteroaryl is having 1,2 or 3 and being selected from N of connecting by ring carbon atom or nitrogen-atoms, O, heteroatomic five yuan or the hexa-atomic aromatic ring of S, and heterocyclic radical be by ring carbon atom or nitrogen-atoms, connect have 1,2,3 or 4 are selected from N, O, heteroatomic saturated or undersaturated nonaro-maticity ring, the wherein aryl of S, heteroaryl, heterocyclic radical, cycloalkyl, alkyl, cycloalkyloxy, alkoxyl group optionally can be replaced by 1 to 4 substituting group, and described 1 to 4 substituting group is selected from halogen ,-OH,-SH ,-NO
2,-CN, phenyl, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-6 alkylthio, C1-8 carbalkoxy ,-CF
3.The above cycloalkyl, cycloalkyloxy, aryl, two adjacent substituting groups on heteroaryl or heterocyclic radical optionally form together 0-3 and contain O, N, the heteroatomic 3-6 ring of S.
2. its optical isomer of the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or base, in the hexanolactam ring, the stereochemistry isomery of carbon atom position shown in * can be R or S.
The formula of compound as claimed in claim 1, pharmaceutical activity is thanked thing, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, and the stereochemistry isomery of carbon atom position shown in * can be R or S.
The metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, R
1the stereochemistry isomery of carbon atom position shown in adjacent * can be R or S.
3. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, R
1can be substituted or non-substituted C1-12 alkyl, C2-12 thiazolinyl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl.
4. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, R
2substituted or non-substituted aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl.
5. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, halogen is F, Cl or Br.
6. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, wherein R
1and R
2heteroaryl be five-, the saturated or undersaturated heterocycle of six or seven yuan, contain one to four and be selected from oxygen, the heteroatoms of nitrogen and sulphur.Comprise pyrryl, imidazolyl, pyrazolyl, thiazolyl ， oxazolyl ， isoxazolyl, 1,2,3-triazoles base, 1,2-thiadiazolyl group, pyridyl, pyrazinyl, pyrimidyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, quinolyl.
7. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, alkyl and cycloalkyl can be replaced by following optional one or more group: halogen ,-OH ,-NH
2, imido grpup, tertiary amine groups ,-SH ,-NO
2,-N
3, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-6 alkylthio, C1-8 carbalkoxy.
8. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, thiazolinyl and alkynyl can be replaced by following optional one or more group: halogen ,-OH ,-NH
2, imido grpup, tertiary amine groups ,-SH ,-NO
2,-N
3, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-6 alkylthio, C1-8 carbalkoxy.
9. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvate, prodrug or its optical isomer, aryl, heteroaryl or Heterocyclylalkyl can be replaced by following optional one or more group: halogen ,-OH ,-NH
2, imido grpup, tertiary amine groups ,-SH ,-NO
2,-N
3, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-6 alkylthio, C1-8 carbalkoxy.
10. compound according to claim 1 is in the catch application of medicine of preparation treatment enteric virus71 (EV71), and wherein said compound comprises following instance but is not limited to this:
11. compound according to claim 1 is in the application of a preparation treatment virus infection medicine, wherein said enterovirus comprises following instance but is not limited to this: poliovirus, CA, Coxsackie B virus, enteric virus71 (EV71), Echo virus.
12. compound according to claim 1 is in the application of preparation treatment coronavirus infection disease medicament, wherein said coronavirus comprises following instance but is not limited to this: SARS virus, infectious bronchitis virus, human coronary virus 229E, Transmissible gastroenteritis virus.
13. compound according to claim 1 is in the induce an illness application of medicine of preparation treatment L-Cysteine HCL Anhydrous, wherein said disease comprises following instance but is not limited to this: hand foot mouth disease, poliomyelitis, common cold, myocarditis, meningitis, hepatitis A.
A 14. pharmaceutical composition, it comprises the metabolite of any one described compound, prodrug, pharmaceutical activity in the claim 1-10 of significant quantity or it is at pharmaceutically acceptable salt, with its pharmaceutically acceptable carrier medium or auxiliary agent, in the catch application of antiviral of preparation treatment enteric virus71 (EV71).
15., according to the pharmaceutical composition of claim 14, it further comprises and is selected from the V71 antiviral agent, immunomodulator and anti-infectious the second therapeutical agent, in the catch application of medicine of preparation treatment enteric virus71 (EV71).
16., by claim 14,15 method, wherein said other anti-EV71 virus formulations are the anti-virus formulations that are selected from 3D proteinase inhibitor and VP1 protein inhibitor.
17., according to the pharmaceutical composition of claim 14, it is for making the medicine for the mammiferous EV71 virus infection for the treatment of.
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