CN102838523A - Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof - Google Patents
Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof Download PDFInfo
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- 0 *C(*)C(CC(CCN1)C1=O)NC(C(*)NC(*)=O)=O Chemical compound *C(*)C(CC(CCN1)C1=O)NC(C(*)NC(*)=O)=O 0.000 description 2
- HTQMBOWAEPNWLI-IENPIDJESA-N CC(C)(C)OC(NC(C[C@H](CCN1)C1=O)C(OC)=O)=O Chemical compound CC(C)(C)OC(NC(C[C@H](CCN1)C1=O)C(OC)=O)=O HTQMBOWAEPNWLI-IENPIDJESA-N 0.000 description 1
- VZHSIQLNVDTLKB-UHFFFAOYSA-N CNCC(CCN1)C1=O Chemical compound CNCC(CCN1)C1=O VZHSIQLNVDTLKB-UHFFFAOYSA-N 0.000 description 1
- JHUBMGXOINOWSQ-MXFDLHRLSA-N COC([C@H]([C@H](C[C@H](CCN1)C1=O)NC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O)O)=O Chemical compound COC([C@H]([C@H](C[C@H](CCN1)C1=O)NC([C@H](Cc1ccccc1)NC(/C=C/c1ccccc1)=O)=O)O)=O JHUBMGXOINOWSQ-MXFDLHRLSA-N 0.000 description 1
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Abstract
The invention relates to valerolactam enterovirus 71 (EV71) 3C protease inhibitors, wherein a structure general formula of the inhibitors is represented by a compound M, various variables in the structure is defined in an instruction, and EV71 replication is effectively inhibited or blocked with the compounds. The present invention relates to discoveries and applications of the compounds containing the structure represented by the formula (M), optical isomers, metabolites with pharmaceutical activities, pharmaceutically acceptable salts, solvates, and prodrugs thereof in preparations of anti-virus drugs for treatment of hand-foot-mouth disease infection. The present invention further relates to an intermediate of the structure compound represented by the formula (M) and a synthesis method thereof.
Description
Technical field
The invention relates to formula (M) compound, pharmaceutical composition that treatment enterovirus 71 (EV71) infects, and the compound method of this compounds, formulation method and be used for these synthetic compounds.Particularly, the present invention provides one type of Valerolactim compounds, contains the pharmaceutical composition of this compounds and the method that this compounds for treating EV71 infects.
Background of invention
(Hand-Foot-Mouth disease HFMD) has another name called dermexanthesis property blister stomatitis to hand foot mouth disease, is the global common transmittable disease that is caused by enterovirus, and all there is this sick popular report most of countries and regions, the world.This disease is mainly propagated through fecal oral route and respiratory tract, and infectivity by force, very easily causes popular or breaks out.Hand foot mouth disease is main with infant's morbidity, and the Most patients symptom is slight, is principal character with the fash or the bleb at positions such as heating and hand, foot, oral cavity.Small number of patients can concurrent aseptic meningitis, encephalitis, acute flaccid paralysis, respiratory tract infection and myocarditis etc., and indivedual severe infant disease progressions are fast, are prone to take place dead.Children infect the back with the adult and how not to fall ill, but can transmitted virus.Clinical manifestation is a main clinical characteristics with the fash at positions such as heating and hand, foot, oral cavity; Even more serious is; Virus can also be invaded patient breathing system, cns etc. and cause symptoms such as encephalitis, wet lung, flaccid paralysis, myocarditis, and disease progression is fast, takes place dead easily.South East Asia all is the hotspot of people brothers stomatosis with China all the time; Particularly in the last few years; Common influence along with multiple factors such as flow of personnel, virus variations; Great outburst has taken place in provinces such as China Shandong, Henan, Taiwan in this disease, has caused infant's death of thousands of examples, has brought huge economy and moral damage for infant family.
The enterovirus that causes hand foot mouth disease has kind more than 20; 16,4,5,9,10 types of enterovirns type 71 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 (EV 71) and coxsackie virus A 16-type (Cox A16).Virusology and EPDML research confirm; (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 paralysis multiple diseases relevant such as (poliomyelitis like paralysis) of aseptic meningitis (aseptic meningitis), BBE (brain stem encephalitis) and poliomyelitis appearance simultaneously with neural system.EV71 has caused repeatedly popular in recent years, discovers 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.Do not illustrate at present the concrete mechanism that EV71 virus forms viral persistence and causes hand foot mouth disease as yet; Still lack special, efficacious therapy medicine clinically; Can only take Chinese medicine or other antiviral drugs to treat; Research shows that considerable participant does not produce favourable effect to this treatment, constantly occurs death clinically.Therefore, need development to have the specific efficiently anti-EV71 virus formulation that is used for hand foot mouth disease.
EV71 is that people such as Schmit in 1969 separate from the infant faeces sample of suffering from central nervous system disease first and obtain, and belongs to the Picornaviridae enterovirus and belongs to, and virion is typical icosahedron structure.Its gene is made up of 7408 Nucleotide approximately; Belong to the sub-thread positive chain RNA virus; Only contain an opening code-reading frame (open-reading frame; ORF), the polyprotein (polyprotein) that 2194 amino acid of encoding constitute is 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) contains 2193 amino acid approximately.In infected cell, this polyprotein is hydrolyzed into and is P1, P2, three precursor proteins of P3.Further shear through the cell and the proteolytic enzyme of virus, P1 precursor protein further maturation is VP1, VP2, VP3 and four virus structural proteins of VP4, the assembling of responsible virion and stable; The then further maturation of P2 precursor protein is Nonstructural Protein (non-structural protein, nsp) 2A (specific protease), 2B and 2C; The P3 precursor protein then in order to form Nonstructural Protein 3A, 3B (VPg, 5 ' is terminal conjugated protein), 3C (specific protease) and 3D (RNA-dependent RNA polymerase, RdRp).
In seven Nonstructural Proteins, 3C proteolytic enzyme is considered to mainly exercise the function of specific protease, belongs to L-Cysteine HCL Anhydrous; Its active site is Cys147, His40, the catalysis triplet that Glu71 forms; Being responsible for each specifically that virus is coded protein cuts down from poly; Formation has the protein of standalone feature, in case thereby this proteic afunction, then virus is further transcribed and is duplicated and can't normally proceed.Therefore can be the effective means of treatment EV71 virus infection by the effect of the selectivity small molecules of specific recognition inhibition 3C proteolytic enzyme, 3C proteolytic enzyme becomes the important drugs target spot of treatment hand foot mouth disease.
The present invention is based on the crystal structure characteristic of EV71 3C proteolytic enzyme,, design a series of five membered lactams class 3C proteinase inhibitor that contain through combining the binding site of active region.
First advantage of the present invention is its Valerolactim class suppressor factor that provides, and can effectively suppress EV71 3C proteolytic enzyme.
The Valerolactim class suppressor factor that second advantage of the present invention provides can effectively suppress SARS virus master albumen Nsp5 proteolytic enzyme.
The 3rd advantage of the present invention is to be used for the preparation treatment L-Cysteine HCL Anhydrous medicine that induces an illness, like poliomyelitis, common cold etc.
Find compound I through biological activity test, II, XII, the EV71 virus during the XIV pair cell is cultivated has shown that extraordinary inhibition is active, has the excellent drug kinetic property in vivo.
Target of the present invention is to find especially effectively micromolecular compound of one type of anti-enterovirus 71, and is provided for said protease inhibitor compound synthetic midbody and these synthetic compound methods.
Summary of the invention:
The present invention is directed to the deficiency of the prior art of EV71 virus 3C proteinase inhibitor; A kind of formula (M) type EV71 virus 3C proteinase inhibitor that contains is provided, and another object of the present invention is the synthetic of the protease inhibitor compound midbody of describing will be provided and be used for these synthetic compound methods.
Valerolactim compounds and/or pharmacy acceptable salt and/or the hydrate preparation treatment enterovirus 71 (EV71) that the present invention relates to formula (M) application of medicine that catches.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; The administration simultaneously of immunomodulator or microbiotic) is used to suppress the viral 3C proteolytic enzyme of EV71, perhaps one of preventing/treating or multinomial EV71 virus infection symptom.
In particular, the present invention relates to the catch application of medicine of formula (M) compound and/or pharmacy acceptable salt and/or hydrate preparation treatment enterovirus 71 (EV71):
Wherein
R
1Expression-OH ,-SH, carbonyl ,-O-alkyl ,-O-naphthenic base ,-O-Heterocyclylalkyl ,-O-heterocyclic radical;-O-aryl ,-O-aralkyl ,-O-heteroaryl ,-O-heteroaralkyl ,-S-alkyl ,-S-naphthenic base;-S-Heterocyclylalkyl ,-S-heterocyclic radical ,-S-aryl ,-S-aralkyl ,-S-heteroaryl ,-S-heteroaralkyl;
R
2Expression-CN ,-CF
3,-C (O) R
5,-CO
2R
6,-C (O) NR
7R
8,-C (O) NR
7OR
8,-NO
2,-C (S) R
5,-CS
2R
6, C (S) NR
7R
8,-SO
2R
5,-SOR
5,-S (O)
2NR
7R
8,-S (O) NR
7OR
8,-SO
3R
5,-C (O) NR
7NR
8R
9,-C (S) NR
7NR
8R
9, R wherein
5, R
6, R
7, R
8And R
9Can be taken from following group :-H ,-NH independently
2,-OH, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryl alkenyl, heteroaryl thiazolinyl, acyl group or sulfonyl;
R
3Expression C1-6 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, C3-8 naphthenic base, aryl C1-6 alkyl; Heteroaryl C1-9 alkyl, aryl, heteroaryl, aryl C2-6 thiazolinyl; Heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, or optional can the replacement by 1 to 4 substituting group; Said 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
4The expression alkyl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, C1-6 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, C3-8 naphthenic base, aryl, heteroaryl, heterocyclic radical, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl.Perhaps replaced by optional one or more group;
The above aryl is a phenyl or naphthyl, and heteroaryl is to have 1,2 or 3 and be selected from N, O, heteroatomic five yuan or the hexa-atomic aromatic ring of S through what ring carbon atom or nitrogen-atoms connected; And heterocyclic radical is to have 1,2,3 or 4 and be selected from N, O through what ring carbon atom or nitrogen-atoms connected; The heteroatomic saturated or undersaturated non-aromaticity ring of S, aryl wherein, heteroaryl, heterocyclic radical; Naphthenic base, alkyl, cycloalkyloxy, alkoxyl group is optional can be replaced by 1 to 4 substituting group; Said 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 naphthenic base, cycloalkyloxy, aryl, two adjacent substituting groups on heteroaryl or the heterocyclic radical randomly form 0-3 together and contain O, N, heteroatomic three-six-ring of S.
The pharmaceutical composition that comprises in the scope of the invention, acceptable salt is gone up in formula (M) compound or its treatment that comprise anti-EV71 virus significant quantity, and is mixed with at pharmaceutically acceptable pharmaceutical carrier or auxiliary agent.
An importance of the present invention; Relate in Mammals the formula M compound of the content through this Mammals being given effective anti-EV71 virus, or its acceptable salt or ester in treatment; Or above-mentioned compsn, with the catch method of medicine of treatment enterovirus 71 (EV71).
Another importance of the present invention relates to through virus is exposed to and suppresses the viral formula (M) of EV71, or its acceptable salt or ester in treatment, under above-mentioned compsn, seeks the active drug of treatment hand foot mouth disease.
The pharmaceutical composition that other aspect relates to can comprise other anti-EV71 preparations in addition, also can comprise the suppressor factor of other targets of EV71 virus, like 3D proteinase inhibitor and VP1 protein inhibitor.
The detailed description of preferred version
Definition:
As described herein, only if mention separately, all be suitable for following definition:
When addressing each instance, (R) or (S) be used to indicate the absolute configuration of asymmetric center, this indicates is explanation rather than the independent substituent explanation that is used for entire compound.
When using " P1, P2, P3 " sign in this article; Mean C-end beginning from peptide analogs; And towards the position that N-holds the amino acid whose residue of extension, i.e. P1 representative is from first position of C end beginning, and P2 holds second position that begins (referring to Berger A.&Schechter I. from C; Transactions of the Royal Society London series B257,249-264 (1970)).
" halogen " used herein speech is meant halogenic substituent, promptly is selected from iodine, bromine, chlorine or fluorine.
" C1-6 alkyl " used herein speech; No matter when using separately or using with another substituting group combination, be meant 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 naphthenic base " used herein speech when using regardless of independent use or with another substituting group combination, is meant 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 speech; No matter when using separately or using with another substituting group combination, be meant 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 speech, when using separately or using with another substituting group combination, be meant 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 substituted hydrogen of bromine or iodine.
" C1-6 sulfenyl " used herein speech, when using separately or using with another substituting group combination, be meant acyclic, the straight or branched alkyl substituent, contain thiol group, for example thiopropyl.
" unsaturated non-aromatic ring " used herein speech means undersaturated naphthenic base, for example the substituting group cyclohexenyl.
" C3-8 cycloalkyloxy " used herein speech, no matter when using separately or using with another substituting group combination, mean substituting group comprise 3 to 8 carbon atoms-O-C
3-8Naphthenic base for example comprises-the O-cyclopropyl ,-O-cyclobutyl ,-O-cyclopentyl etc.
" C1-6 alkyl-carbonyl " used herein speech when using separately or using with another substituting group combination, is meant the C1-6 alkyl that connects through carbonyl, promptly-and C (O)-C
1-6Alkyl.
" aryl " used herein speech means the aromatic series single-loop system that contains 6 carbon atoms, or contains the aromatic series bicyclic system of 10 atoms, for example phenyl and naphthyl-loop systems.
" heteroaryl " used herein speech when using separately or using with another substituting group combination, means through what ring carbon atom or nitrogen-atoms connected and 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 deutero-unit price substituting group.Suitable heterocycle instance is like 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 speech, when using separately or using with another substituting group combination, be meant 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 speech; When using separately or using, mean the ester of compound (I), wherein any carboxyl-functional base or the hydroxyl-functional base of this molecule with another substituting group combination; Preferably carboxyl or hydroxy terminal, by carbalkoxy functional group or ester bond displacement:
R wherein, R ' part is to be selected from low-carbon alkyl (like methyl, ethyl, propyl group, butyl, hexyl); Alkoxyalkyl (like methoxyethyl); Alkoxy acyl (like acetoxy-methyl); Aralkyl (like benzyl); Aryloxyalkyl group (like benzene oxygen ethyl); Aryl (like phenyl).Can be optionally by halogen, C1-4 alkyl or C1-4 alkoxyl group replace.The prodrug ester that other are suitable lists among this paper it with for referencial use in.This type in mammalian body, is hydrolyzed the sour form that is converted into compound (M) usually at pharmaceutically acceptable ester.
About above-mentioned ester class, only if specify separately, the moieties of any existence all advantageously contains 1 to 6 carbon atom.Any aryl moiety that is present in this ester class all advantageously comprises phenyl group.
" pharmaceutically acceptable salt " speech is meant the salt of formula (M) compound among this paper, and it is applicable to that the tissue of people and animal contacts and nontoxicity nonirritant, no anaphylaxis etc. in normal therapeutic treatment.Generally be water-soluble or oil soluble, or easy dispersive, and on it uses, be effective.This speech comprises pharmaceutically acceptable acid salt and pharmaceutically acceptable base addition salt.
" pharmaceutically acceptable acid salt " speech is meant the character that keeps biological activity and free state alkali, and be abiotic go up or other aspects unwanted, itself and mineral acid such as sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, Hydrogen bromide, thionamic acid etc.; And organic acid such as acetic acid, trifluoracetic acid, Tricholroacetic Acid, styracin, Hydrocerol A, toxilic acid, hexanodioic acid, alginic acid; Xitix, aspartic acid, phenylformic acid, Phenylsulfonic acid, oxyacetic acid, oxysuccinic acid, lactic acid; Propanedioic acid, oxalic acid, nicotinic acid, Succinic Acid, Whitfield's ointment, Triple Pressed Stearic Acid, tartrate; Sulphanilic Acid, tri-methyl p-toluenesulfonate, p-methyl benzenesulfonic acid, racemic melic acid, YM 115H, TNP, formed salt such as propionic acid.
" pharmaceutically acceptable base addition salt " speech is meant the character that keeps biological activity and free state acid, and be abiotic go up or other aspects unwanted, its be with mineral alkali such as ammonia or ammonium or metallic cation like, sodium; Magnesium, copper, zinc, calcium; Potassium, the formed salt of the oxyhydroxide of aluminium etc. or carbonate particularly preferably is ammonium, potassium; Sodium, calcium, magnesium salts.Comprise primary amine by pharmaceutically acceptable organic atoxic alkali deutero-salt, secondary amine and tertiary amine, quaternary ammonium compound through substituted amine, comprises naturally in substituted amine, cyclammonium and basic ion exchange resin are like methylamine; Dimethyl amine, Trimethylamine, ethylamine, DIETHANOL AMINE, triethylamine, tripropylamine, isopropylamine; TBuA, thanomin, diethylolamine, dicyclohexylamine, Methionin, l-arginine, Histidine; Theine, choline, trimethyl-glycine, ethylene diamine, glycosamine, NMG, Theobromine; Piperazine, piperidines, purine, tetramethyl-ammonium compound, tetraethyl ammonium compound, pyridine; N, N xylidine, N-methyl piperidine, N-methylmorpholine, N, formed salt such as N-dibenzyl phenylethylamine.Preferred especially organic non-malicious alkali is isopropylamine, DIETHANOL AMINE, thanomin, Trimethylamine, dicyclohexylamine, choline, theine.
Preferred scheme
Preferred version of the present invention comprises formula (M) compound, and wherein Valerolactim partly is selected from two different isomer, the configuration that has (i) and (ii) represent:
Wherein preferably with the Valerolactim of the R configuration of structure (i) expression.
R
1: preferred version of the present invention comprises formula (M) compound, wherein R
1Preferred hydroxyl, carbonyl ,-O-alkyl ,-O-naphthenic base ,-O-Heterocyclylalkyl ,-O-heteroaryl, sulfonium base; C1-6 oxyalkyl more preferably, C3-6 oxygen naphthenic base or be selected from following heterocycle:
R most preferably
1Be hydroxyl.
R
2: preferred version of the present invention comprises formula (M) compound, wherein R
2Preferably-and CN ,-CF
3,-C (O) R
5,-NO
2,-C (S) R
5,-SO
2R
5R more preferably
5Be the C1-6 alkyl, C3-6 naphthenic base or be selected from following heterocycle:
Most preferred R
2For-CN ,-CF
3
R
3: preferred version of the present invention comprises formula (M) compound, wherein R
3C3-8 naphthenic base 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 replaced by 1 to 4 substituting group; Said 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
3For by the substituted styroyl of halogen.
R
4: preferred version of the present invention comprises formula (M) compound, wherein R
4Aryl C1-6 alkyl preferably, heteroaryl C1-9 alkyl, C3-8 naphthenic base; Aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl; Heteroaryl C2-6 alkynyl, or optionally replaced by 1 to 4 substituting group, said 1 to 4 substituting group preferentially is selected from halogen;-OH ,-SH, C1-8 alkoxyl group.
Most preferred R
4Be aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl.
Valerolactim 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 known with compound formed hydrate or form the method for solvate when in solution, concentrating during with the water freeze-drying with appropriate organic solvent.
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 like salt solution, BS, glucose, water, glycerine, ethanol and their binding substances.Carrier or vehicle can also comprise time lag material known in the art, like glyceryl monostearate or distearin, also can comprise wax, TKK 021, Vltra tears, methyl methacrylate or the like.If desired, 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-s, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional tamanori and carrier such as triglyceride.Oral prepns can comprise the mannitol of standard vector such as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate or the like.Preparation and deciding 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 that uses 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 the hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.The typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, Triple Pressed Stearic Acid or the like.Solid carrier can comprise that one or more maybe be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It goes back fourth to be encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents and the carrier with necessary compression property are with suitable mixed, with the shape and the size compression of needs in tablet.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-s in the liquid suspension of ampoule or bottle or non-water.Exemplary of liquid carriers comprises syrup, peanut oil, and sweet oil, water, or the like.Liquid vehicle is used to prepare solution, suspension-s, emulsion, syrup, the compsn of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier, the stable osmotic pressure-regulator 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 (comprising monohydroxy-alcohol and polyvalent alcohol, for example terepthaloyl moietie) and their verivate, and oils (for example fractionated coconut oil and peanut oil).The carrier that is used for administered parenterally can also be grease such as OE and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.The liquid vehicle that is used 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.Can use suitable dispersant or wetting agent (like Tween 80) and suspending agent to allocate this suspension based on the known technology of this area.But single pushes or injects perfusion in 30 minutes the passages through which vital energy circulates gradually during injection.This compound can also be with the form oral administration of liquid or solids compsn.Used parenteral one speech among this paper comprises in subcutaneous, intracutaneous, intramuscular, intravenously, intraarticular, the synovial membrane, in the breastbone, in the sheath and intralesional injection or infusion techn.
In order to obtain stable water miscible formulation, can compound or its pharmacy acceptable salt be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, the tart verivate can be dissolved in suitable basic soln.If can not get soluble form, can compound be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% TV, Ucar 35, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or glycerine hydroxy fatty acid ester or the like.
Pharmaceutical composition taking orally of the present invention, parenteral or holder administration through implanting, oral administration or preferred during through drug administration by injection.Various release systems are known and can be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, and injectable solution, the capsule in the liposome, particulate, microcapsule, or the like.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, the limit eyeball with (preferred usually) oral route.Compound can through any easily or other suitable administration; For example through injecting or bolus injection; Through epithelium or the mucous membrane circuit (for example; Oral mucosa, rectum and intestines mucosa, or the like) absorb or the support through carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.Be used 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 keep supplying other appropriate excipients or carrier that composite that literary composition mentions and compsn use, can in standard pharmacology textbook, find, for example at " Remington ' s Pharmaceutical Sciences ", in the 19th edition.In order to prevent and treat the hand foot mouth disease that EV71 virus causes; In single therapy; Described in this article 3C protease inhibitor compound is useful about 0.01 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 with about 1 to 5 time of administration every day, or the transfusion of an other successive.This type 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 contain has an appointment 5% to about 95% activeconstituents (w/w).Preferably, this type preparation contains 20% to about 80% the active compound of having an appointment.
This will understand the higher or lower dosage that possibly mention than preceding text to be familiar with this area.Given dose and processing mode to particular patient should be decided according to various factors; The activity that comprises employed specific compound; Patient's age, body weight, sex, as state of health, diet, time of administration, metabolic rate, the combination of medicine; And the seriousness that infects and process, patient handle doctor's judgement in addition to the tendency of infection.Generally speaking, with the low dose of begin treatment of the optimal dose that is lower than this compound in fact.Increase dosage through a spot of increase subsequently, till the effect that reaches the best in this case.Generally speaking, require being enough to producing effective antiviral result usually, do not give this compound but do not cause that any concentration content harmful or disadvantageous spinoff is thrown.
When compsn of the present invention comprises formula (M) compound and one or more other treatments or preventive combination; The amount of this compound and other preparation should provide with the dosage content between about 10 to 100%; More preferably about dosage of 10 to 80% gives with the single therapy method usually.
When these compounds or its in the pharmacy acceptable salt class with when pharmaceutically acceptable carrier is allocated, give Mammals in vivo with the compsn of gained, like the mankind, so that treatment or prevention EV71 virus infection.Also can use The compounds of this invention to mix, accomplish this type treatment with following series preparation, including, but not limited to: immunomodulator, like α, β, δ-Interferon, rabbit; Other anti-virus formulation, like acyclovir, ganciclovir; Other EV71 3C proteinase inhibitor; To the suppressor factor of other targets in EV71 life circulation, like 3D proteolytic enzyme, VP1 albumen; Or its compsn.Can other preparation be mixed with The compounds of this invention, to produce single dosage form.In addition, preparation that also can this type is other can be thrown respectively and give 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 through giving construction (M) compound, wherein substituting group such as again define, and suppresses the method for EV71 virus.
In preferred concrete scheme, these methods are useful in Mammals and reduce the EV71 replication.If pharmaceutical composition only comprises the The compounds of this invention as activeconstituents; These class methods can comprise in addition this Mammals is selected from immunomodulator; Antiviral agent; Other EV71 virus 3C proteinase inhibitor, or to other targets in the circulation of EV71 life, like 3D proteinase inhibitor and VP1 protein inhibitor.Can be before giving the present composition, simultaneously or afterwards, the preparation that this type is other gives Mammals.
Technical process
Formula of the present invention (M) compound can prepare with the inventive method effectively, comprises adopting following general compound method.R in these compound methods
1, R
2, R
3, R
4Definition as above.
Technical process I:
Midbody 1-4 obtains through the route of flow process I is synthetic; In this flow process; With L-glutamic acid 1-1 is raw material, at first carboxyl is carried out the esterification protection, subsequently its amino is carried out protective group and obtains its midbody 1-2; Usefulness, is introduced the cyanogen methyl group and is obtained midbody 1-3 compound 1-2 deprotonation with LiHMDS (or other strong basicity reagent) then.Then with the cyano reduction of midbody 1-3, and then the intramolecularly amidate action takes place, intramolecularly 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. (5mL) slowly is added dropwise in the methyl alcohol (100mL), stirred 5 minutes, (10.0g 67.9mmol), continues to stir and be heated to backflow, keeps reflux temperature reaction 2 hours to add L-glutamic acid then.Stopped reaction, removal of solvent under reduced pressure is used the ether recrystallization then.The oily matter that obtains is dissolved among the THF, and (28.5mL 203.7mmol), keeps 0 ℃ to stir 5 minutes, and (17.8g 81.5mmol), was stirred to room temperature reaction 2.5 hours to continue to drip the tert-Butyl dicarbonate that is dissolved among the THF (30mL) under 0 ℃ of condition, to drip TEA.After reaction finished, removal of solvent under reduced pressure after residue dissolves with DCM (200mL), added water (2 * 100mL) washing organic phases.Organic phase is used anhydrous sodium sulfate drying subsequently, concentrates then, and (PE: EA=5: 1) purifying obtains target compound (1-2) (17.8g, productive rate 95.2%) to the crude product that obtains through the flash chromatography post.
The preparation of step I-2 compound 2-t-butoxycarbonyl amino-4-cyanogen methyl-Methyl glutarate (1-3)
Will two (trimethyl silicon based) Lithamides (the THF solution of 78.5mL 1.0M, (10.0g in anhydrous THF (200mL) solution 36.4mmol), and stirs gained solution 30 minutes in this temperature 78.5mmol) to be added to-78 ℃ N-Boc-glutamic acid dimethyl ester (1-2).Slow then dripping bromine acetonitrile (3.4mL) continues reaction mixture to stir 2 hours at-78 ℃.After question response finishes, add saturated aqueous ammonium chloride (50mL) cancellation reaction, be stirred to room temperature.Removal of solvent under reduced pressure after residue water (100mL) dissolving, with DCM extraction (100mL * 3), merges organic phase.The organic phase that merges is used anhydrous sodium sulfate drying, concentrate then, (PE: EA=2: 1) purifying obtains target compound (1-3) (8.7g, productive rate 80.4%) to the crude product that obtains through the flash chromatography post.
The preparation of step I-3 compound 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate (1-4)
At 2-t-butoxycarbonyl amino-4-cyanogen methyl-Methyl glutarate (1-4) (5g; 15.9mmol) methyl alcohol (80mL) solution in add NSC 51149 hydrate (2g; 8mmol); Then under 0 ℃ of condition in resulting pink mixture gradation add Peng Qinghuana (6.0g, 159.5mmol), stirring at room 18 hours.The TLC monitoring reaction after question response finishes, adds saturated aqueous ammonium chloride (30mL) cancellation reaction, stirs 10 minutes.Suction filtration is removed solid impurity, removal of solvent under reduced pressure.After reaction finished, removal of solvent under reduced pressure after residue dissolves with DCM (100mL), added water (2 * 50mL) washing organic phases.The organic phase that merges is used anhydrous sodium sulfate drying, filters to steam to desolventize, and the crude product that obtains finally obtains key intermediate (1-4) (2.9g, productive rate 60.7%) through flash chromatography post (EA) purifying.
Flow process II
Structural unit 2-4 obtains through flow process II is synthetic, wherein R
3, R
4The group preceding text of expression are described.With compound 2-1 is raw material, at first carries out the carboxyl ester protection and obtains compound 2-2, carries out condensation with different organic acid 2-3 again and obtains midbody 2-4.
Flow process III
Formula among the present invention (M) compound is to carry out condensation by compound 1-4 deaminize protection base and compound 2-4 decarboxylize protection base, further carries out derivatize again and obtains.
Wherein, compound 3-1 is the R when formula (M) compound
1Be carbonyl, R
2Be low-carbon alkoxy, like methoxyl group.
Flow process IV
This flow process is the structure derivatize that carries out compound 3-1, has obtained R
1, R
2Be not isoplastic formula (M) compound.Wherein, formula of the present invention (M) compound R
1For-OH, R
2For-CN can be obtained by compound 3-1 derivatize through following synthetic route.
Step IV-1 compound 2-[2-R
4-amino-1-carbonyl-3-R
3] preparation of third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (4-1)
To 2-[2-R
4-amino-1-carbonyl-3-R
3] in the methanol solution (10mL) of third amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate (1equiv.) gradation add Peng Qinghuana (1equiv.), stirring at room 2 hours.Add saturated aqueous ammonium chloride (5mL) cancellation reaction, methyl alcohol is removed in decompression.(3 * 50mL) extract, and the organic phase of merging is used anhydrous sodium sulfate drying, concentrate then, and (DCM: MeOH=50: 1) purifying obtains target compound (4-1) (productive rate 85.8%) to the crude product that obtains through the flash chromatography post with DCM.
Step IV-2 compound 2-[2-R
4-amino-1-carbonyl-3-R
3] preparation of third amino-3-(2-carbonyl-3-tetramethyleneimine)-propionic aldehyde (4-2)
To 2-[2-R
4-amino-1-carbonyl-3-R
3] add DMP (3equiv.) in anhydrous DCM (10mL) solution of third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (1equiv.), stirred 2 hours.Add saturated sodium bicarbonate (2mL) cancellation reaction, add Sulfothiorine (2equiv.) simultaneously, be stirred to the organic phase clarification.(3 * 50mL) extract, and the organic phase of merging is used anhydrous sodium sulfate drying, concentrate then, and (DCM: MeOH=30: 1) purifying obtains target compound 4-2 (productive rate 80.2%) to the crude product that obtains through the flash chromatography post with DCM.
Step IV-3 compound 1-cyanic acid-2-[2-R
4-amino-1-carbonyl-3-R
3The preparation of]-third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (4-3)
To 2-[2-R
4-amino-1-carbonyl-3-R
3] add the saturated aqueous solution (0.1mL) (40%) of sodium sulfite anhy 96 (5equiv.) in DCM (1mL) solution of third amino-3-(2-carbonyl-3-tetramethyleneimine)-propionic aldehyde (1equiv.), stirred 30 minutes.Under 0 ℃ of condition, drip Potssium Cyanide (52.1mg, aqueous solution 0.8mmol) (0.5ml), room temperature reaction 24 hours then.(3 * 10mL) extract, and the organic phase of merging is used anhydrous sodium sulfate drying, concentrate then, and (DCM: MeOH=40: 1) purifying obtains target compound 4-3 (productive rate 52.3%) to the crude product that obtains through the flash chromatography post with DCM.
Instance
Through following unrestricted instance, illustrate in greater detail the present invention, but the present invention is not limited to following instance.With degree centigrade temperature is provided in the following instance.Only if statement separately, solution per-cent is represented the relation of weight to volume, and solution proportion is represented the relation of volume to volume.The structure of compound is confirmed in order to following a kind of or several different methods in the instance: nuclear magnetic resonance spectrometer, high resolution mass spectrum analysis, thin-layer chromatography.If structural formula and its chemical name of the expression compound that provides are not inconsistent, be as the criterion with structural formula.
Nuclear magnetic resonance spectrum (
1H NMR with
13C NMR) measures under the 400MHz field intensity with the Bruker400 spectrometer.Chemical shift use with respect to interior mark tetramethyl-silicomethane standard move down what 1,000,000/(ppm, δ) expression.
1The multiplicity at peak is represented as follows among the H-NMR: s=is unimodal; The d=doublet; The t=triplet; The m=multiplet.Coupling constant is represented with hertz.Solvent peak is with reference to the deuterated reagent of inside.Used commercialization reagent all is to obtain from their suppliers separately respectively there, if the condition handled of needing is arranged, explanation is arranged in addition in the literary composition.THF (THF) is to get through sodium-UVNUL MS-40 system distillation before use; Methylene dichloride (DCM) is to get from the hydrolith distillation before use.
This paper uses following abbreviation: Me: methyl; MeOH: methyl alcohol; Boc: uncle-butoxy carbonyl; TEA: triethylamine; EtOAc:DMP:Dess-martin reagent; ETHYLE ACETATE; PE: sherwood oil; Et2O: 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 spectrum analysis; MS: mass spectroscopy; HPLC: HPLC.
The instance of embodiment of the present invention is 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 the methyl alcohol (100mL), stirred 5 minutes, (10g 67.9mmol), continues to stir and be heated to backflow, keeps reflux temperature reaction 2 hours to add L-glutamic acid then.Stopped reaction, removal of solvent under reduced pressure is used the ether recrystallization.The oily matter that obtains is dissolved among the THF (150mL), under 0 ℃ of condition, drip TEA (28.5mL, 203.7mmol); Keep 0 ℃ to stir 5 minutes; (17.8g 81.5mmol), was stirred to room temperature reaction 2.5 hours to continue to drip the tert-Butyl dicarbonate that is dissolved among the THF (30mL).Reaction removes solvent under reduced pressure after finishing, and adds entry (200mL) in the residue; (2 * 200mL) from the aqueous phase extraction, and the organic phase of merging is used anhydrous sodium sulfate drying, concentrates then with DCM; The crude product that obtains 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 amino-4-cyanogen methyl-Methyl glutarate (1-3)
Under-78 ℃ condition; With two (trimethyl silicon based) Lithamide (THF solution of 78.5mL 1.0M; 78.5mmol) (10g in anhydrous THF (200mL) solution 36.4mmol), and stirs gained solution 30 minutes under this temperature slowly to be added drop-wise to N-Boc-L-(+)-glutamic acid dimethyl ester (1-2).Keep temperature-resistant then, slowly dripping bromine acetonitrile (3.4mL) continues reaction mixture to stir 2 hours under-78 ℃ condition.After question response finishes, add saturated aqueous ammonium chloride (50mL) cancellation reaction, be stirred to room temperature.Decompression is earlier revolved and is desolventized, and adds entry (200mL) then, with DCM (2 * 200mL) aqueous phase extracted; The organic phase that merges is used anhydrous sodium sulfate drying; Concentrate then, (PE: EA=2: 1) purifying obtains 2-t-butoxycarbonyl amino-4-cyanogen methyl-Methyl glutarate (8.7g to the crude product that obtains through the flash chromatography post; Productive rate 80.3%) is the pale yellow oily liquid body, TLC:R
f=0.5 (PE: EA=2: 1);
1H-NMR (400MHz, CDCl
3): δ 5.14 (d, J=6.0Hz, 1H), 4.38-4.40 (m, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 2.85-2.89 (m, 1H), 2.74-2.82 (m, 2H), 2.10-2.23 (m, 2H), 1.45 (s, 9H);
13C-NMR (100MHz, CDCl
3): δ 19.0,28.2, and 33.8,38.2,51.0,52.7 (2), 77.1 (3), 80.5,117.2,155.6,172.0.172.5.
The preparation of embodiment 3 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate (1-4)
To 2-t-butoxycarbonyl amino-4-cyanogen methyl-Methyl glutarate (1-4) (5g; 15.9mmol) methyl alcohol (80mL) solution in add NSC 51149 hydrate (2g; 7.9mmol); Then in resulting pink mixture, add several times under 0 ℃ of condition Peng Qinghuana (6g, 59.5mmol), stirring at room 18 hours.Add saturated aqueous ammonium chloride (30mL) cancellation reaction, stirred 10 minutes.Suction filtration is removed solid impurity, removes solvent under reduced pressure.Add entry (100mL); (3 * 100mL) from the aqueous phase extraction, and the organic phase of merging is used anhydrous sodium sulfate drying, concentrates then with DCM; The crude product that obtains is through flash chromatography post (EA) purifying; Obtaining 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate (2.8g, productive rate 60.5%) is white foam shape solid, TLC:R
f=0.2 (EA);
1H-NMR (400MHz, CDCl
3): δ 5.70-5.68 (m, 1H), 4.30-4.29 (m, 1H), 3.74 (s, 3H), 3.32-3.37 (t, 2H), 2.50-2.43 (m, 2H), 2.12-2.13 (m, 1H), 1.86-1.80 (m, 2H), 1.44 (s, 9H);
13C-NMR (100MHz, CDCl
3.): δ 179.9,172.9, and 155.8,79.8,52.3,52.2,40.4,38.2,34.0,28.2 (3), 28.0.
The preparation of embodiment 4 Chinese cassia tree carbonylamino-phenylalanine methyl esters (2-4)
Under 0 ℃ of condition to phenylalanine methyl ester (10g, in DCM 55.8mmol) (100mL) solution, add successively styracin (9.9g, 67.0mmol); EDC (16.1g, 83.8mmol), HOBt (11.3g, 83.8mmol); (35.2mL 251.4mmol), was stirred to room temperature 2 hours to drip TEA then.Remove solvent under reduced pressure, add entry (200mL), (2 * 200mL) extract from aqueous phase with DCM; The organic phase that merges is used anhydrous sodium sulfate drying; Concentrate then, (PE: EA=2: 1) purifying obtains Chinese cassia tree carbonylamino-phenylalanine methyl ester (13.8g to the crude product that obtains through the flash chromatography post; Productive rate 80.2%) is 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 carbonylamino-phenylalanine(Phe)s (2-5)
To Chinese cassia tree carbonylamino-phenylalanine methyl ester (2-4) (10g, methyl alcohol 32.3mmol) and water (100mL: 200mL) add in the solution Lithium Hydroxide MonoHydrate (2.0g, 48.5mmol), stirring at room 1.5 hours.Remove solvent under reduced pressure, add 1N hydrochloric acid pH is transferred to 3.(3 * 100mL) extractions merge organic phase, use anhydrous sodium sulfate drying, concentrate then, and obtaining Chinese cassia tree carbonylamino-phenylalanine(Phe) (8.6g, productive rate 90.6%) is white solid, TLC:R with ETHYLE ACETATE
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.
The preparation of embodiment 6 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate (3-1)
(drip TFA (13mL) among the 5g, anhydrous DCM (80mL) 16.6mmol), ice bath stirred 1.5 hours to 2-t-butoxycarbonyl amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate under 0 ℃ of condition.Remove solvent under reduced pressure, be dissolved in then among the DCM (100mL), under 0 ℃ of condition, add successively Chinese cassia tree carbonylamino-phenylalanine(Phe) (5.8g, 19.9mmol); EDC (4.7g, 24.9mmol), HOBt (3.4g, 24.9mmol); (10.5mL 74.7mmol), was stirred to room temperature 2 hours to drip TEA then.With DCM (2 * 200mL) extractions; The organic phase that merges is used anhydrous sodium sulfate drying; Concentrate then, (DCM: MeOH=80: 1) purifying obtains 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate (4.6g to the crude product that obtains through the flash chromatography post; 60.3%) is weak yellow foam shape solid, TLC:R
f=0.5 (DCM: MeOH=15: 1);
1H-NMR (400MHz, CDCl
3): δ 8.01 (1H, d), 7.61 (1H, d), 7.49-7.21 (11H, m), 6.85-6.45 (1H, d; J=16Hz), 5.12-4.98 (1H, m), 4.53-4.47 (1H, m), 3.73 (3H, s); 3.35-3.27 (2H, m), 3.21-3.13 (2H, m), 2.37-2.29 (1H, m), 2.20-2.14 (1H; M), 2.08 (1H, d), 1.92-1.88 (1H, m), 1.86-1.74 (1H, m);
13C-NMR (100MHz, CDCl
3.): δ 179.9,171.9, and 171.6,165.6,141.6,136.5,134.7,129.8,129.6 (2), 128.8 (2), 128.4 (2), 127.9 (2), 126.8,120.3,54.0,52.4,51.8,40.6,38.5,38.0,32.8,28.4.
The preparation of embodiment 7 1-cyanic acid-2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (3-2)
To 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-methyl propionate (3-1) (1g, add several times in methanol solution 2.2mmol) (10mL) Peng Qinghuana (0.8g, 21.6mmol), stirring at room 2 hours.Add saturated aqueous ammonium chloride (5mL) cancellation reaction, remove solvent under reduced pressure, with DCM (3 * 50mL) extractions; The organic phase that merges is used anhydrous sodium sulfate drying; Concentrate then, (DCM: MeOH=50: 1) purifying obtains 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (0.7g to the crude product that obtains through the flash chromatography post; Productive rate 80.2%) is white foam shape solid, TLC:R
f=0.2 (DCM: MeOH=15: 1);
1H-NMR (400MHz, CDCl
3): δ 8.30 (1H, d), 7.54 (2H, d), 7.55-7.26 (9H, m); 6.74-6.70 (1H, d, J=16Hz), 4.66-4.64 (1H, m), 3.78-3.75 (2H; M), and 3.30-3.01 (4H, m), 2.87-2.82 (1H, m), 2.20-2.12 (2H; M), and 1.74-1.61 (2H, m), 1.39-1.36 (1H, m);
13C-NMR (100MHz, CDCl
3): δ 181.0,172.3, and 166.0,141.4,136.8,134.7,129.5 (2), 128.8 (2), 128.5 (2), 127.9 (2), 126.8,126.2,120.5,65.1,54.8,52.7,40.6,32.1,31.9,31.5,29.7.
The preparation of embodiment 8 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propionic aldehyde (3-3)
(1g, (1.5g 3.4mmol), stirred 2 hours to add DMP in anhydrous DCM (10mL) solution 2.3mmol) to 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (3-2).Add saturated sodium bicarbonate (2.0mL) cancellation reaction, (1.1g 6.9mmol), is stirred to the organic phase clarification to add Sulfothiorine simultaneously.Add DCM (3 * 50mL) extractions; The organic phase that merges is used anhydrous sodium sulfate drying; Concentrate then, (DCM: MeOH=30: 1) purifying obtains 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propionic aldehyde (0.8g to the crude product that obtains through the flash chromatography post; Productive rate 80.6%) sees TLC:R for white foam shape solid
f=0.3 (DCM: MeOH=15: 1);
1H-NMR (400MHz, CDCl
3): δ 9.22 (1H, m), 8.44-8.42 (1H, m), 7.46-7.17 (11H, m), 6.80-6.47 (1H, d, J=16Hz), 4.33-4.25 (1H, m), 3.28-3.16 (4H, m), 2.31-2.17 (2H, m), 1.89-1.72 (3H, m);
13C-NMR (100MHz, CDCl
3): δ 200.0,180.1, and 172.3,165.9,141.6,136.4,134.7,129.8,129.5 (2), 128.8 (2), 128.5 (2), 127.9 (2), 127.0,120.3,57.7,54.3,40.6,38.8,38.0,37.4,29.6.
The preparation of embodiment 91-cyanic acid-2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (3-4)
To 2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propionic aldehyde (3-3) (100mg; 0.2mmol) DCM (1mL) solution in add sodium sulfite anhy 96 (84.2mg; 0.8mmol) saturated aqueous solution (0.1mL) (40%), stirred 30 minutes.Under 0 ℃ of condition, drip Potssium Cyanide (52.3mg, aqueous solution 0.8mmol) (0.5mL), room temperature reaction 24 hours then.With DCM (3 * 10mL) extractions; The organic phase that merges is used anhydrous sodium sulfate drying; Concentrate then, (DCM: MeOH=40: 1) purifying obtains 1-cyanic acid-2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (53.6mg to the crude product that obtains through the flash chromatography post; Productive rate 50.8%) is white foam shape solid, TLC:R
f=0.5 (DCM: MeOH=10: 1);
1H-NMR (400MHz, CDCl
3): δ 7.49-7.45 (1H, d, J=16Hz), 7.38-7.22 (10H, m), 6.67-6.63 (1H; D, J=16Hz), 4.78-4.74 (1H, m), 4.43-4.42 (1H, d); 4.20-4.17 (1H, m), 3.05-3.01 (1H, m), 2.56-2.49 (1H, m); 2.33-2.30 (1H, m), 2.13-2.06 (1H, m), 1.75-1.68 (2H, m)
13C-NMR (100MHz, CDCl
3): δ 182.2,174.4, and 168.5,142.3,138.4,136.2,131.0,130.3 (2), 130.0 (2), 129.6 (2), 129.0 (2), 127.9,121.4,120.3,64.8,56.5,51.8,41.5,39.2,38.9,30.8,28.9.
The preparation of embodiment 10 2-hydroxyl-3-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-4-(2-carbonyl-3-tetramethyleneimine)-methyl-butyrate (3-5)
(100mg, 0.2mmol) the middle methanol solution (1mL) that adds saturated hydrogenchloride is heated with stirring to backflow, reacts 19 hours to 1-cyanic acid-2-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-3-(2-carbonyl-3-tetramethyleneimine)-propyl alcohol (3-4).After reaction finished, methyl alcohol was removed in decompression, and the gained mixture is dissolved among the DCM (5mL); Add successively Chinese cassia tree carbonylamino-phenylalanine(Phe) (78.4mg, 0.3mmol), EDC (63.2mg; 0.4mmol), HOBt (45.1mg, 0.4mmol); (0.1mL 1.0mmol), was stirred to room temperature 2 hours to drip TEA then.With DCM (2 * 200mL) extractions; The organic phase that merges is used anhydrous sodium sulfate drying; Concentrate then, (DCM: MeOH=50: 1) purifying obtains 2-hydroxyl-3-[2-(Chinese cassia tree carbonyl)-amino-1-carbonyl-3-phenyl] third amino-4-(2-carbonyl-3-tetramethyleneimine)-methyl-butyrate (65.6mg to the crude product that obtains through the flash chromatography post; Productive rate 60.7%) is white foam shape solid, TLC:R
f=0.5 (DCM: MeOH=15: 1);
1H-NMR (400MHz, CDCl
3): δ 7.52-7.43 (1H, d, J=16Hz), 7.34-7.21 (10H, m), 6.67-6.63 (1H, d; J=16Hz), and 4.78-4.74 (1H, m), 4.43-4.42 (1H, d), 4.20-4.17 (1H, m); 3.73 (s, 3H), 3.05-3.01 (1H, m), 2.56-2.49 (1H, m); 2.33-2.30 (1H, m), 2.13-2.06 (1H, m), 1.75-1.68 (2H, m);
13C-NMR (400MHz, CDCl
3): δ 182.2,174.4, and 171.2,168.5,143.5,138.4,136.2,131.0,130.3 (2), 130.0 (2), 129.6 (2), 129.0 (2), 127.9,121.4,64.8,56.5,51.8,41.5,39.2,38.9,30.8,28.9.
Embodiment 11 EV71 3C proteinase inhibitor vitro enzyme are lived and are screened
Utilize FRET (fluorescence resonance energy transfer, FRET) technical measurement is lived to the enzyme of the suppressor factor of 3C proteolytic enzyme, according to 3C proteolytic enzyme recognition site design substrate: Dabcyl-RTATVQGPSLDFE-Edans, the suppressor factor 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 establishes 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 MEV71 3C albumen; The suppressor factor of 150 μ M fluorogenic substrates and different concns; 37 ℃ of reactions, through the ELIASA fluorescence intensity, the gained data utilize software GraphPad Prism 5 to handle the IC of the agent that is inhibited
50Observations shows, compound I, II, III, the IC of VI
50Be 5-50nM.
Embodiment 12 SARS main protease Nsp5 suppressor factor vitro enzyme are lived and are screened
Utilize FRET (fluorescence resonance energy transfer, FRET) technical measurement is lived to the enzyme of the suppressor factor of SARS Nsp5 proteolytic enzyme, according to Nsp5 proteolytic enzyme recognition site design substrate: MCA-AVLQSGFRL-L-Dnp, the suppressor factor 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 establishes negative control simultaneously.Utilizing 96 orifice plates to measure enzyme lives; 100 μ l reaction systems comprise: 50mM Tris-HCl pH7.3,1mMEDTA, 0.5 μ M SARS nsp5 albumen; The suppressor factor of 16uM fluorogenic substrate and different concns; 37 ℃ of reactions, through the ELIASA fluorescence intensity, the gained data utilize software GraphPad Prism 5 to handle the IC of the agent that is inhibited
50Observations shows, compound I I, the IC of IV.VIII
50Be 0.1-5 μ M.
Embodiment 13 cytopathic effects screening Cytopathic effect (CPE) assay:
Used clone is RD (human embryonic rhabdomyosarcoma) cell in the CPE experiment, and (titre is 100TCID to virus for the standard virus strain of EV71
50).Every hole adds 100 μ l RD cells (concentration is 3 * 10 in 96 orifice plates
4Individual/hole), let behind the cell attachment 1d, add the good suppressor factor of 50 μ l/ holes dilution, the suppressor factor 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 adds 50 μ l/ hole EV71 virus behind the 2h, observe behind the 2-3d cytopathic effect (cytopathic effect, CPE).The inhibition concentration of chemical combination I was 0.5 μ M-2.5 μ M when observations showed 50% cell survival.
Embodiment 14 virus replication inhibition abilities screening Cell-based immunodetection (CID) assay:
RD (human embryonic rhabdomyosarcoma) cell is diluted to 3 * 10 with the DMEM that contains 10%FBS and 1%PS (Dulbecco ' s Modified Eagle ' s Medium) substratum after trysinization in CID experiment
4Individual/ml, in 96 orifice plates, add 100 μ l/ hole RD cells, 37 ℃, 5%CO
2Overnight cultures added the good suppressor factor of 50 μ l/ holes dilution in second day, and 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.Add 50 μ l/ hole EV71 viruses (titre is 100TCID50), 37 ℃, 5%CO behind the 2h
2Cultivate, wash twice, 50 μ l/ hole anhydrous methanol fixed cell 10min with PBS behind the 30h; Wash twice back with PBS then and add 37 ℃ of sealings of 100 μ l/ hole PBS+0.5%Tween20+10%FBS 1h; Add anti-37 ℃ of effect 3h of 100 μ l/ holes (1: 500) dilution, clean plank 3 times, add two anti-anti-mouse immunoglobulin G of 100 μ l/ holes (1: 2500) dilution with 0.5%PBST; 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, (490nM) reads the fluorescent value in every hole on the ELISA determinator.More than repeat 3 times in 4 holes of experiment each concentration of suppressor factor.Calculate EC with GraphPad Prism 5
50Value.The EC of compounds X II
50Value is less than 1 μ M.
Claims (19)
1. a Valerolactim lopps enterovirus 71 (EV71) 3C proteinase inhibitor has compound or its various optical isomers of following general structure M, metabolite, pharmacologically acceptable salt, solvolyte or its prodrug of pharmaceutical activity:
Wherein
R
1Expression-OH ,-SH ,-NH
2, carbonyl ,-halogen ,-O-alkyl ,-O-the naphthenic base ,-O-alkyl of mixing ,-O-Heterocyclylalkyl ,-O-heterocyclic radical;-O-alkenyl ,-O-the cycloalkenyl group ,-O-thiazolinyl of mixing ,-O-heterocycloalkenyl ,-O-alkynyl group ,-O-the cycloalkynyl radical ,-O-alkynyl of mixing, the assorted alkynyl of-O-ring;-O-aryl ,-O-aralkyl ,-O-heteroaryl ,-O-heteroaralkyl ,-S-alkyl ,-S-the naphthenic base ,-S-alkyl of mixing ,-S-Heterocyclylalkyl;-S-heterocyclic radical ,-S-alkenyl ,-S-the cycloalkenyl group ,-S-thiazolinyl of mixing ,-S-heterocycloalkenyl ,-S-alkynyl group ,-S-the cycloalkynyl radical ,-S-alkynyl of mixing; The assorted alkynyl of-S-ring ,-S-aryl ,-S-aralkyl ,-S-heteroaryl ,-S-heteroaralkyl ,-N-alkyl ,-N-the naphthenic base ,-N-alkyl of mixing;-N-Heterocyclylalkyl ,-N-heterocyclic radical ,-N-alkenyl ,-N-the cycloalkenyl group ,-N-thiazolinyl of mixing ,-N-heterocycloalkenyl ,-N-alkynyl group;-N-the cycloalkynyl radical ,-N-alkynyl of mixing, the assorted alkynyl of-N-ring ,-N-aryl ,-N-aralkyl ,-N-heteroaryl ,-N-heteroaralkyl; Alkyl, naphthenic base, assorted alkyl, Heterocyclylalkyl, heterocyclic radical, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, aralkyl, heteroaryl, heteroaralkyl;
R
2Expression-H;-CN;-CF
3Alkyl, naphthenic base, assorted alkyl, Heterocyclylalkyl, heterocyclic radical, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, aralkyl, heteroaryl, heteroaralkyl;-C (O) R
5,-CO
2R
6,-C (O) NR
7R
8,-C (O) NR
7OR
8,-NO
2,-C (S) R
5,-CS
2R
6, C (S) NR
7R
8,-SO
2R
5,-SOR
5,-S (O)
2NR
7R
8,-S (O) NR
7OR
8,-SO
3R
5,-C (O) NR
7NR
8R
9,-C (S) NR
7NR
8R
9, R wherein
5, R
6, R
7, R
8And R
9Can be taken from following group :-H ,-NH independently
2,-OH, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryl alkenyl, heteroaryl thiazolinyl, acyl group or sulfonyl;
R
3Expression C1-6 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, C3-8 naphthenic base, aryl C1-6 alkyl; Heteroaryl C1-9 alkyl, aryl, heteroaryl, aryl C2-6 thiazolinyl; Heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, or optional can the replacement by 1 to 4 substituting group; Said 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
4The expression alkyl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, C1-6 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, C3-8 naphthenic base, aryl, heteroaryl, heterocyclic radical, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl.The above aryl is a phenyl or naphthyl, and heteroaryl is to have 1,2 or 3 and be selected from N, O, heteroatomic five yuan or the hexa-atomic aromatic ring of S through what ring carbon atom or nitrogen-atoms connected; And heterocyclic radical is to have 1,2,3 or 4 and be selected from N, O through what ring carbon atom or nitrogen-atoms connected; The heteroatomic saturated or undersaturated non-aromaticity ring of S, aryl wherein, heteroaryl, heterocyclic radical; Naphthenic base, alkyl, cycloalkyloxy, alkoxyl group is optional can be replaced by 1 to 4 substituting group; Said 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 naphthenic base, cycloalkyloxy, aryl, two adjacent substituting groups on heteroaryl or the heterocyclic radical randomly form 0-3 together and contain O, N, the first ring of the heteroatomic 3-6 of S.
2. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, R
1Be carbonyl ,-OH ,-SH, or oxyalkyl, oxygen ester group, sulfane base, thioester substrate.
3. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, R
2Can be-CN-CF
3, replacement or unsubstituted indoles, benzoglyoxaline, benzo oxygen azoles, triazole ,-NO
2,-C (O) R
5,-CO
2R
6,-C (O) NR
7R
8,-C (S) R
5,-CS
2R
6, C (S) NR
7R
8,-SO
2R
5,-SOR
5,-S (O)
2NR
7R
8,-S (O) NR
7OR
8,-SO
3R
5
4. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, the stereochemistry isomery of carbon atom position shown in the * can be R or S in the lactam nucleus.
The metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, R
1The stereochemistry isomery of carbon atom position shown in the adjacent * can be R or S.
The metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, the stereochemistry isomery of carbon atom position shown in the * can be R or S.
The metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, the stereochemistry isomery of carbon atom position shown in the * can be R or S.
5. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, wherein R
3And R
4Be respectively substituted or non-substituted alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryl alkenyl, heteroaryl thiazolinyl.
6. the metabolite of compound as claimed in claim 3, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, R
5, R
6, R
7, R
8Can be taken from-H-NH independently
2,-OH, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryl alkenyl, heteroaryl thiazolinyl.
7. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, wherein R
3And R
4Heteroaryl be five-, six-or the saturated or undersaturated heterocycle of seven-unit, 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.
8. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, halogen is F, Cl or Br.
9. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, prodrug or its optical isomer, alkyl and naphthenic base 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. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, 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.
11. the metabolite of compound as claimed in claim 1, pharmaceutical activity, pharmacologically acceptable salt, solvolyte, 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.
12. compound according to claim 1 is in the catch application of medicine of preparation treatment enterovirus 71 (EV71), wherein said compound comprises following instance but is not limited to this:
13. compound according to claim 1 is in the application of preparation treatment enterovirus infection disease medicament, wherein said enterovirus comprises following instance but is not limited to this: enterovirus 71 (EV71), poliovirus, CA, CB, Echo virus.
14. 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, IBV, human coronary virus 229E, TGE.
15. 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.
16. pharmaceutical composition; It comprises the metabolite of any one described compound, prodrug, pharmaceutical activity among the claim 1-12 of significant quantity or it is at pharmaceutically acceptable salt; With its at pharmaceutically acceptable mounting medium or auxiliary agent, in the catch application of antiviral of preparation treatment enterovirus 71 (EV71).
17. according to the pharmaceutical composition of claim 16, it further comprises and is selected from the EV71 antiviral agent, immunomodulator and anti-infectious second therapeutical agent are in the catch application of medicine of preparation treatment enterovirus 71 (EV71).
18. by claim 16,17 method, wherein said other anti-EV71 virus formulations are the anti-virus formulations that are selected from 3D proteinase inhibitor and VP1 protein inhibitor.
19. according to the pharmaceutical composition of claim 16, it is used to make the medicine that supplies the mammiferous EV71 virus infection of treatment.
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Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| WO2023137876A1 (en) * | 2022-01-20 | 2023-07-27 | 广州谷森制药有限公司 | Method for preparing intermediate for synthesizing new deuterated cyano compound |
| WO2023185763A1 (en) * | 2022-04-01 | 2023-10-05 | 中国科学院上海药物研究所 | Peptidomimetic compound, and preparation method, pharmaceutical composition and use therefor |
| WO2023198067A1 (en) * | 2022-04-11 | 2023-10-19 | 上海科技大学 | Compound and application thereof in preparation of medicine for treating enterovirus-related diseases |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1311793A (en) * | 1998-04-30 | 2001-09-05 | 阿格罗尼制药公司 | Antipicornaviral compounds, their prepn. and use |
| CN1372566A (en) * | 1999-08-04 | 2002-10-02 | 阿格罗尼制药公司 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
| US20050143319A1 (en) * | 2003-12-31 | 2005-06-30 | Taigen Biotechnology | Protease inhibitors |
| WO2005113580A1 (en) * | 2004-05-21 | 2005-12-01 | Pfizer Inc. | Anticoronviral compounds and compositions, their pharmaceutical uses and materials for their synthesis |
| WO2006061714A2 (en) * | 2004-12-09 | 2006-06-15 | Pfizer Inc. | Anticoronaviral compounds and compositions, their pharmaceutical uses and materials for their synthesis |
-
2011
- 2011-06-23 CN CN2011101705881A patent/CN102838523A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1311793A (en) * | 1998-04-30 | 2001-09-05 | 阿格罗尼制药公司 | Antipicornaviral compounds, their prepn. and use |
| CN1372566A (en) * | 1999-08-04 | 2002-10-02 | 阿格罗尼制药公司 | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
| US20050143319A1 (en) * | 2003-12-31 | 2005-06-30 | Taigen Biotechnology | Protease inhibitors |
| WO2005113580A1 (en) * | 2004-05-21 | 2005-12-01 | Pfizer Inc. | Anticoronviral compounds and compositions, their pharmaceutical uses and materials for their synthesis |
| WO2006061714A2 (en) * | 2004-12-09 | 2006-06-15 | Pfizer Inc. | Anticoronaviral compounds and compositions, their pharmaceutical uses and materials for their synthesis |
Non-Patent Citations (2)
| Title |
|---|
| CHIH-JUNG KUO 等: "Design, synthesis, and evaluation of 3C protease inhibitors as anti-enterovirus 71 agents", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 16, 13 June 2008 (2008-06-13), pages 7388 - 7398 * |
| KOK-CHUAN TIEW 等: "Design, synthesis, and evaluation of inhibitors of Norwalk virus 3C protease", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 21, 14 July 2011 (2011-07-14), pages 5315 - 5319, XP028326915, DOI: doi:10.1016/j.bmcl.2011.07.016 * |
Cited By (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10106580B2 (en) | 2011-03-30 | 2018-10-23 | Brown University | Enopeptins, uses thereof, and methods of synthesis thereto |
| CN104211666A (en) * | 2013-05-31 | 2014-12-17 | 中国人民解放军军事医学科学院毒物药物研究所 | 2,3-epoxy succinamide compound, preparation method and purpose thereof |
| JP2016520101A (en) * | 2013-05-31 | 2016-07-11 | インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ | 2,3-butanediamide epoxide compounds and methods for their preparation and use |
| US9630957B2 (en) | 2013-05-31 | 2017-04-25 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | 2,3-butanediamide epoxide compound and preparation method and use thereof |
| WO2014190899A1 (en) * | 2013-05-31 | 2014-12-04 | 中国人民解放军军事医学科学院毒物药物研究所 | 2,3-butanediamide epoxide compound and preparation method and use thereof |
| WO2016037072A3 (en) * | 2014-09-04 | 2016-08-18 | Brown University | Enopeptin analogs and methods of use thereof |
| WO2017085467A1 (en) * | 2015-11-17 | 2017-05-26 | Ucl Business Plc | Aminosulfonamide compounds |
| CN106928206B (en) * | 2015-12-31 | 2022-02-18 | 中国科学院上海药物研究所 | Aldehyde compound and its preparation method and use |
| WO2017114509A1 (en) * | 2015-12-31 | 2017-07-06 | 中国科学院上海药物研究所 | Aldehyde and preparation and application thereof |
| CN106928206A (en) * | 2015-12-31 | 2017-07-07 | 中国科学院上海药物研究所 | Aldehyde radical class compound and its preparation method and purposes |
| US11021514B2 (en) | 2016-06-01 | 2021-06-01 | Athira Pharma, Inc. | Compounds |
| CN107459511B (en) * | 2016-06-02 | 2020-05-29 | 南开大学 | Anti-enterovirus 71(EV71) 4-iminooxazolidine-2-ketone compound and preparation method and application thereof |
| CN107459511A (en) * | 2016-06-02 | 2017-12-12 | 南开大学 | Ketone compounds of 4 imino group oxazolidine of anti-enteric virus71 (EV71) 2 and its production and use |
| CN110354248A (en) * | 2019-04-26 | 2019-10-22 | 南开大学 | Application of the peptidomimetic aldehyde compound in preparation treatment swine fever virus (ASFV) infectious disease drug |
| WO2021151265A1 (en) * | 2020-01-29 | 2021-08-05 | 中国科学院上海药物研究所 | Pharmaceutical use of aldehyde-based compound |
| US11472793B2 (en) | 2020-04-17 | 2022-10-18 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| US11124497B1 (en) | 2020-04-17 | 2021-09-21 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| US11312704B2 (en) | 2020-04-17 | 2022-04-26 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| US11174231B1 (en) | 2020-06-09 | 2021-11-16 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| GB2595975B (en) * | 2020-06-09 | 2022-12-07 | Pardes Biosciences Inc | Inhibitors of cysteine proteases and methods of use thereof |
| GB2595975A (en) * | 2020-06-09 | 2021-12-15 | Pardes Biosciences Inc | Inhibitors of cysteine proteases and methods of use thereof |
| US11524940B1 (en) | 2020-06-09 | 2022-12-13 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| US11541034B2 (en) | 2020-09-03 | 2023-01-03 | Pfizer Inc. | Nitrile-containing antiviral compounds |
| US11452711B2 (en) | 2020-09-03 | 2022-09-27 | Pfizer Inc. | Nitrile-containing antiviral compounds |
| US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
| CN113087833A (en) * | 2021-03-31 | 2021-07-09 | 湖北大学 | Polymer-supported artificial catalysis triad catalyst and preparation method and application thereof |
| CN113087833B (en) * | 2021-03-31 | 2022-04-01 | 湖北大学 | Polymer-supported artificial catalysis triad catalyst and preparation method and application thereof |
| CN115403524A (en) * | 2021-05-26 | 2022-11-29 | 浙江省化工研究院有限公司 | Preparation method of 3-fluoro-pyrazole carboxylate and 3-fluoroalkyl-1-substituted pyrazole-4-carboxylic acid |
| WO2023137876A1 (en) * | 2022-01-20 | 2023-07-27 | 广州谷森制药有限公司 | Method for preparing intermediate for synthesizing new deuterated cyano compound |
| WO2023185763A1 (en) * | 2022-04-01 | 2023-10-05 | 中国科学院上海药物研究所 | Peptidomimetic compound, and preparation method, pharmaceutical composition and use therefor |
| WO2023198067A1 (en) * | 2022-04-11 | 2023-10-19 | 上海科技大学 | Compound and application thereof in preparation of medicine for treating enterovirus-related diseases |
| CN115322130A (en) * | 2022-08-02 | 2022-11-11 | 南京正济医药研究有限公司 | Preparation of (S) -2- (BOC-amino) -3- [ (S) -2-oxo-3-pyrrolidinyl ] propionic acid methyl ester |
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