CN104945320B - Alcaloid-derivatives and its application as drug - Google Patents

Alcaloid-derivatives and its application as drug Download PDF

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CN104945320B
CN104945320B CN201510150737.6A CN201510150737A CN104945320B CN 104945320 B CN104945320 B CN 104945320B CN 201510150737 A CN201510150737 A CN 201510150737A CN 104945320 B CN104945320 B CN 104945320B
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compound
formulas
alkyl
acceptable salt
stereoisomer
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CN104945320A (en
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陈敏
于跃
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Yangzhou Blue Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a kind of anti-active quinolinone alkaloid derivants of RSV and preparation method thereof, and in particular to -1 compound of Formulas I, its stereoisomer, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt and its application as antivirotic.Quinolinone alkaloid derivant provided by the invention has the characteristics that efficient, low toxicity, has the potentiality for being developed as antiviral drugs, is particularly useful for preventing and/or treating disease caused by rsv infection.

Description

Alcaloid-derivatives and its application as drug
Technical field
The present invention relates to a kind of quinolinone alkaloid derivants and preparation method thereof, and it is raw that the invention further relates to above-mentioned quinolinones Application of the alkaloids derivative in preparation antiviral drugs.More particularly to the Respiratory Syncytial Virus(RSV) of a kind of pair of Paramyxoviridae (RSV) with the quinolinone alkaloid derivant and the preparation method and application thereof of extremely strong inhibitory activity.
Background technique
(respiratory syncytial virus, abbreviation syncytial virus, RSV also belong to secondary viscous to Respiratory Syncytial Virus(RSV) Viraceae), it is a kind of RNA virus, belongs to Paramyxoviridae.Rsv infection can cause pneumonia and a variety of lower respiratory illness, annual complete The world at least 3,000,000 infants are admitted to hospital because of RSV virus infection, wherein at least there is that 160,000 people are dead, thus RSV also by Referred to as children killer (Science, 2013,342,546-547).Currently without the vaccine that can be applied to clinic, Ribavirin (three Ribavirin) it is unique chemotherapeutic agent (J.Med.Chem.2008,51,875-896) for being applied to clinic.In conclusion The drug of disease caused by exploitation prevention and/or treatment rsv infection becomes the task of top priority.
Summary of the invention
The present invention provides quinolinone alkaloid class compound, its stereoisomer, its geometrical isomerism of a kind of -1 structure of Formulas I Body, its solvate, its pharmaceutically acceptable salt or its salt solvate, it is characterised in that -1 compound of Formulas I have such as Flowering structure:
Wherein R1The amino acid residue of hydroxyl, R are taken off for c-terminus2For H, C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 Halogenated alkyl, C1-C4 alkyl acyl, C1-C4 halogenated alkyl acyl group, C3-C6 cycloalkanoyl, C2-C4 alkenyl, C7-C10 virtue Base alkyl, " --- -- " indicate singly-bound or to be not present,Indicate the key being directed toward in paperOr it is directed toward the key outside paperThe amino acid is alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), lysine (Lys), smart ammonia One of sour (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), wherein amino acid is configured as D type, L Type or DL type, the amino in amino acid is optionally by C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 halogenated alkyl or C1-C4 alkyl One or two of acyl group, C1-C4 alkoxy carbonyl replace, the alkylidene or aryl in amino acid optionally by C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 alkoxy, C1-C4 halogenated alkyl or C1-C4 alkyl acyl, hydroxyl, halogen, nitro, in cyano One or more replaces.
" alkyl " described herein preferably methyl, ethyl, propyl, normal-butyl, isobutyl group, tert-butyl；" halogenated alkyl " is excellent Select trifluoromethyl, difluoromethyl, pentafluoroethyl group, perfluoro butyl；" alkyl acyl " preferably acetyl group, propiono, positive bytyry, different Bytyry；" halogenated alkyl acyl group " preferably chloracetyl, acetyl bromide；" alkenyl " preferably allyl, acrylic, but-2-ene base； " naphthenic base " preferably cyclopropyl alkyl, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl；" cycloalkanoyl " preferred cyclopropyl Acyl group, ring bytyry, ring valeryl, cyclohexanoyl；" aryl alkyl " preferably benzyl, phenylethyl；" halogen " preferably fluorine, chlorine, Bromine, iodine.
Term " pharmaceutically acceptable salt " refers to the addition of atoxic inorganic or organic acid and/or alkali in the present invention Salt, reference can be made to " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.It is inorganic Or the preferred hydrochloric acid of organic acid, sulfuric acid, phosphoric acid, maleic acid, citric acid, fumaric acid, glucuronic acid, formic acid, acetic acid, ethanedioic acid, Succinic acid etc..
Term " solvate " refers to what formula I-1 compound or its salt and organic solvent or water were formed in the present invention Solvate, the preferred acetone of organic solvent, acetonitrile, methanol, ethyl alcohol, the solvate preferred formula I-1 compound or its salt of formation Monohydrate, dihydrate, trihydrate, an acetonitrile closes object, diacetonitrile closes object, an acetone closes object, diacetone closes object, half rich Horse hydrochloride-hydrate, fumarate dihydrate, one ethanolates of fumarate etc..
In the present invention term " geometric isomer " refer to when " --- -- " be singly-bound when, -1 compound of Formulas I include double bond be Z, The compound of two kinds of geometric configurations of E.
- 1 compound of Formulas I is selected from following compound, its stereoisomer, its geometric isomer, its solvate, its pharmacy The solvate of upper acceptable salt or its salt:
- 1 compound of Formulas I may not include compound 35.
- 1 compound of Formulas I may also include following compound, its stereoisomer, its geometric isomer, its solvate, its The solvate of pharmaceutically acceptable salt or its salt:
In another preferred example, R in -1 compound of Formulas I1、R2It is such as phase in above-mentioned particular compound 21-380,401-406 Answer the specific group of position.
It should be understood that above-mentioned preferred group can be combined with each other to form various preferred compounds of the invention, as space is limited, This does not tire out one by one states.
Another embodiment of the present invention provides a kind of antivirotic, it is characterised in that the antivirotic contains the change of Formulas I -1 Close the solvate of object, its stereoisomer, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Any one or more of be used as effective component.
Another embodiment of the present invention provides a kind of pharmaceutical composition, it is characterised in that the pharmaceutical composition includes Formulas I- 1 compound, its stereoisomer, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt solvent Any one or more of compound, and at least one pharmaceutically acceptable carrier, diluent or excipient.
Another embodiment of the present invention provides a kind of pharmaceutical composition, it is characterised in that comprising -1 compound of Formulas I, it is vertical Any one of body isomers, its geometric isomer, its solvate, its pharmaceutically acceptable salt or solvate of its salt Or it is several, and other at least one antiviral drugs.The pharmaceutical composition optimizing injection, oral preparation, freeze drying powder injection, Suspending agent etc..
Another embodiment of the present invention provides -1 compound of Formulas I, its stereoisomer, its geometric isomer, its solvent Purposes of the solvate of compound, its pharmaceutically acceptable salt or its salt in preparation antiviral drugs.
Another embodiment of the present invention provides -1 compound of Formulas I, its stereoisomer, its geometric isomer, its solvent The solvate of compound, its pharmaceutically acceptable salt or its salt is in the drug of preparation treatment and/or prevention respiratory disease Application.
Another embodiment of the present invention provides -1 compound of Formulas I, its stereoisomer, its geometric isomer, its solvent The medicine of the solvate of compound, its pharmaceutically acceptable salt or its salt disease as caused by RSV in preparation treatment and/or prevention Application in object.
Another embodiment of the present invention provides the preparation method of -1 compound of Formulas I, includes the following steps:
Method one:
(1) absolute configuration of compound 1 is determined first, and compound 1 is (by doctor Chen Min " Chinese Marine University in 2013 Ph.D. Dissertation " record method preparation) in CH3OH/CH3By after ester linkage hydrolyzing under the conditions of ONa, using cation exchange tree Rouge neutralizes, and obtains compound 2,3, and following compound 2 uses document J.Org.Chem.1969,34 (9), in 2543-2549 The Mosher analytic approach of record determines the absolute configuration of compound 2, warp1H NMR analyzes and determines out the absolute configuration of compound 2； Compound 3 uses document Amino Acids (2004) 27:231-247, Carlsberg Research Communications Marfey ' the s method recorded in January 1984, Volume 49, Issue 6, pp 591-596 is analyzed, determinization The absolute configuration of object 3 is closed, and then the absolute configuration of determining compound 1 is
(2) compound 1 obtains Formulas I -1-1 through alkylation reaction " compound, alkylation reaction condition is this field normal condition: being had In solvent, reacted under alkali, the effect of hydrocarbonylation reagent, wherein the preferred R of hydrocarbonylation reagent2X, wherein X be halogen, preferably chlorine, bromine, Iodine, R2For C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 halogenated alkyl, C2-C4 alkenyl, C7-C10 aryl alkyl；The preferred alkali of alkali Metal carbonate (such as Na2CO3、K2CO3)；
Or compound 1 obtains Formulas I -1-1 through acylation reaction " ' compound, acylation reaction condition is also this field conventional strip Part: it in organic solvent, is reacted under alkali, acylating reagent effect, wherein the preferred R ' COX (carboxylic acid halides) of acylating reagent, R ' COOCOR ' (acid anhydrides), wherein X is halogen, preferably chlorine, bromine, iodine, and R ' is C1-C3 alkyl, C1-C3 halogenated alkyl, C1-C4 alkyl, C3-C6 Naphthenic base, alkali preferred alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethyl benzene Amine etc.；The wherein preferred methylene chloride of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane Deng.
Or (3) Formulas I -1-1 " compound is in CH3OH/CH3Under the action of ONa, Formula II -2 is obtained.
(4) -2 compound of Formula II can be in H2Under effect, after reduction double bond obtains -3 compound of Formula II, optionally taken with various Condensation reaction occurs for the amino acid (corresponding to amino acid residue defined in Formulas I -1) in generation, and the preferred DCC/DAMP of condensation condition is obtained To Formulas I -1-1 compound；
Or condensation reaction occurs for the amino acid that II-2 compound is directly substituted or unsubstituted with various amino, is condensed item The preferred DCC/DAMP of part obtains Formulas I -1-1 compound；
Or the substituent group that obtained Formulas I -1-1 compound can further remove under suitable conditions on amino obtains formula I-1-2 compound.
Method two:
(1) Aflaquinolone A obtains -4 compound of Formula II through alkylation reaction or acylation reaction, and alkylation reaction condition is This field normal condition: it in organic solvent, is reacted under alkali, the effect of hydrocarbonylation reagent, wherein the preferred R of hydrocarbonylation reagent2X, wherein X be Halogen, preferably chlorine, bromine, iodine, R2For C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 halogenated alkyl, C2-C4 alkenyl, C7-C10 virtue Base alkyl；Alkali preferred alkali metal carbonate (such as Na2CO3、K2CO3)；Acylation reaction condition is also this field normal condition: organic In solvent, reacted under alkali, acylating reagent effect, wherein the preferred R ' COX (carboxylic acid halides) of acylating reagent, R ' COOCOR ' (acid anhydrides), Wherein X is halogen, preferably chlorine, bromine, iodine, and R ' is C1-C3 alkyl, C1-C3 halogenated alkyl, C1-C4 alkyl, C3-C6 naphthenic base, Alkali preferred alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline；Its The preferred methylene chloride of middle organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc..
(2) reduction of -4 compound of Formula II chosen property (can refer to CN1238327A, CN103012329A or The method that carbonyl reduction is α-OH by the selectivity J.Org.Chem. recorded in 2005,70,10732-10736) obtain Formula II- 2' compound, the wherein preferred aluminium isopropoxide of selective reduction reagent or NaBH4。
(3) Formula II -2' compound can obtain Formulas I -1-1', Formulas I -1-2' chemical combination by the scheme in one step of method (4) Object.
Method three:
(1) Aflaquinolone B obtains -5 compound of Formula II through alkylation reaction, and alkylation reaction condition is this field conventional strip Part: it in organic solvent, is reacted under alkali, the effect of hydrocarbonylation reagent, wherein the preferred R of hydrocarbonylation reagent2X, wherein X be halogen, preferably chlorine, Bromine, iodine, R2For C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 halogenated alkyl, C2-C4 alkenyl, C7-C10 aryl alkyl；Alkali is excellent Select alkali carbonate (such as Na2CO3、K2CO3)。
(2) -5 compound of Formula II can obtain Formulas I -1-3, Formulas I -1-4 compound by the scheme in one step of method (4).
Method four:
It is raw material by compound Aflaquinolone D, obtains Formulas I -1-5, Formulas I -1-6ization according to the scheme in method two Close object.
Method five:
It is raw material by compound Aflaquinolone C, obtains Formulas I -1-7, Formulas I -1-8ization according to the scheme in method two Close object.
Method six:
Formula II -7, II-10 compound can also be reduced to β-OH product Formula II -8', Formula II-under selective reduction agent effect After 11' (can refer to J.Org.Chem.1998,63,4438-4443, J.Org.Chem.2003,68,2572-2582 or The method that carbonyl reduction is β-OH by the selectivity Org.Lett. recorded in 2003,5,137-140), according still further to method four or Formulas I -1-5', Formulas I -1-6', Formulas I -1-7', Formulas I -1-8' compound are formed with the strategy of amino acid condensation in five, selectivity is also The former preferred NaBH of agent4/CeCl3·7H2O、LiAlH4/THF、(i-Bu)3Al。
Compound 1, Aflaquinolone A, Aflaquinolone D can be by Chen Minbo into method six for the above method one The method recorded in scholar 2013 " Chinese Marine University Ph.D. Dissertation " is prepared；Or Aflaquinolones A-D can also be by document J Nat Prod, and 2012,75 (3): the method recorded in 464-472 is prepared.
Give in above-mentioned synthetic method includes Formulas I -1-1, Formulas I -1-1', Formulas I -1- in -1 compound range of Formulas I 1 ", Formulas I -1-1 " ', Formulas I -1-2, Formulas I -1-2', Formulas I -1-3, Formulas I -1-4, Formulas I -1-5, Formulas I -1-6, Formulas I -1-7, Formulas I -1- 8, the synthetic method of I-1-5', Formulas I -1-6', Formulas I -1-7', Formulas I -1-8'.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and in below (eg embodiment) specifically Each technical characteristic of description can be combined with each other, to form a new or preferred technical solution.As space is limited, not another herein One tired states.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But It is that these embodiments are only not supposed to be a limitation to the present invention or implementation principle for better understanding invention, reality of the invention The mode of applying is not limited to the following contents.
Embodiment 1
500mg compound 1 is weighed, is dissolved in 20mL acetone, 150mg Na is added2CO3, after stirring half an hour at room temperature, add Enter 1.0mL MeI, after reacting 4h at 30 DEG C, TLC detection reaction raw materials almost disappear, and ethyl acetate is extracted twice, anhydrous Sodium sulphate dries organic layer, after concentration, through silica gel column chromatography (eluant, eluent is EtOAc/ petroleum ether=12:1~8:1), obtains light Yellow solid 472mg, as compound 37, yield 92%, ESI-MS m/z:565.3 [M+H]+, 587.3 [M+Na]+。
Embodiment 2
10mg compound 1 is weighed, is dissolved in 2mL methylene chloride, 3 μ L Ac are added2O, 50 μ L pyridines, stirs 2h at room temperature Afterwards, TLC detects reaction raw materials and almost disappears, and the dilution of 20mL methylene chloride, washing is added, and organic phase is done through anhydrous sodium sulfate It is dry, after concentration, through silica gel column chromatography (eluant, eluent is EtOAc/ petroleum ether=12:1~10:1), faint yellow solid 9.5mg is obtained, As compound 38, yield 88.2%, ESI-MS m/z:593.3 [M+H]+, 615.3 [M+Na]+。
Embodiment 3
Step (1): it weighs 400mg compound 37 and is dissolved in 15mL methanol, the CH of catalytic amount is added3ONa tune pH 9.0~ 10.0, after being stirred to react 2h at room temperature, cation exchange resin tune pH 7.0 is added, is filtered to remove cation exchange resin, it is dense Contract to obtain faint yellow solid 319mg, as compound 11, yield 99.7%, ESI-MS m/z:474.2 [M+ Na]+。
Step (2): weighing Boc-L- valine (300mg, 1.38mmol) and be dissolved in dry toluene (10mL), is added DCC (285mg, 1.38mmol), DMAP (7mg, 0.06mmol) are stirred 5 minutes at room temperature, addition compound 11 (27mg, 0.06mmol), after being heated to 65 DEG C of reactions 48 hours, after filtering, reduced pressure, through silica gel column chromatography (petroleum ether/EtOAc= 12/1) faint yellow solid 35mg, as compound 30, are obtained, yield 90%, ESI-MS (m/z): 651.3 [M+H]+, 673.4 [M+Na]+。
Embodiment 4
Step (1): weighing 10mg compound Aflaquinolone B, be dissolved in 3mL acetone, and 10mg K is added2CO3, room After temperature lower stirring half an hour, 20 μ L cyclopropane bromides are added, after reacting 10h at 50 DEG C, TLC detection reaction raw materials almost disappear It loses, ethyl acetate is extracted twice, and the dry organic layer of anhydrous sodium sulfate, after concentration, through silica gel column chromatography, (eluant, eluent is EtOAc/ stone Oily ether=12:1~8:1), obtain faint yellow solid 9.3mg, as compound 12, yield 85%, ESI-MS m/z:478.3 [M+H]+。
Step (2): it weighs Boc-D- asparagine (100mg, 0.43mmol) and is dissolved in dry toluene (10mL), add Enter DCC (89mg, 0.43mmol), DMAP (2mg, 0.0167mmol), stirs 5 minutes at room temperature, addition compound 12 (8mg, 0.0167mmol), after being heated to 65 DEG C of reactions 48 hours, after filtering, reduced pressure, through silica gel column chromatography (petroleum ether/EtOAc =8/1) faint yellow solid 10mg, as compound 182, are obtained, yield 86.3%, ESI-MS (m/z): 692.3 [M+H]+, 714.3[M+Na]+。
Compound 182 can be further subjected to step (3) and be converted into compound 401, remove the same of Boc in acid condition When, racemization occurs for D-Asn.
Step (3): it weighs 10mg compound 182 (0.01445mmol) and is dissolved in 2mL methylene chloride, be added dropwise 5 under ice bath μ L trifluoroacetic acid (TFA), is maintained under ice bath, and after reaction 0.5 hour, TLC detects raw material and disappears, and it is dilute that 20mL methylene chloride is added It releases, successively with saturation NaHCO3, saturation NaCl washing, anhydrous Na2SO4After drying, filtering, being concentrated under reduced pressure, through silica gel column chromatography (petroleum ether/EtOAc=3/1), obtains faint yellow solid 8mg, as compound 401, yield 93.5%, ESI-MS (m/z): 592.3[M+H]+, 614.3 [M+Na]+。
Embodiment 5
Step (1): weighing 200mg compound Aflaquinolone A, be dissolved in 20mL methylene chloride, and 63 μ L rings are added Propyl formyl chloride, 500 μ L pyridines, after stirring 1.5h at room temperature, TLC detection reaction raw materials almost disappear, and 50mL bis- is added Chloromethanes dilution, washing, organic phase is dried over anhydrous sodium sulfate, and after concentration, through silica gel column chromatography, (eluant, eluent is EtOAc/ petroleum Ether=12:1~10:1), obtain faint yellow solid 215mg, as compound 13, yield 93%, ESI-MS m/z:526.2 [M+ Na]+。
Step (2): weighing 20mg compound 13 and be dissolved in 20mL THF, and 15mg NaBH is added under ice bath4, anti-under ice bath After answering 2h, 2mL is added and is saturated NH4Cl terminates reaction, and after THF is evaporated off, ethyl acetate extraction, organic phase is done through anhydrous sodium sulfate It is dry, after concentration, through silica gel column chromatography (eluant, eluent is EtOAc/ petroleum ether=10:1~8:1), faint yellow solid 19mg is obtained, i.e., For compound 14, yield 95%, ESI-MS m/z:528.2 [M+Na]+。
Step (3): weighing L-PROLINE (230mg, 2mmol) and be dissolved in dry toluene (10mL), and DCC is added (413mg, 2mmol), DMAP (6mg, 0.05mmol) is stirred 5 minutes at room temperature, addition compound 14 (15mg, 0.03mmol), after being heated to 60 DEG C of reactions 48 hours, after filtering, reduced pressure, through silica gel column chromatography (petroleum ether/EtOAc= 10/1) faint yellow solid 17mg, as compound 74, are obtained, yield 94%, ESI-MS (m/z): 603.3 [M+H]+, 625.3 [M+Na]+。
Compound 74 can be further subjected to step (4) reduction and obtain compound 402.
Step (4): it weighs 10mg compound 74 (0.01659mmol) and is dissolved in 5mLCH3OH-CH2Cl2In (volume ratio 1:1), The Pd-C of catalytic amount is added, at room temperature in 1atm H2After the lower reaction 4h of effect, it is filtered to remove Pd-C, is concentrated to give faint yellow solid 10mg, as compound 402, yield 99.7%, ESI-MS (m/z): 605.3 [M+H]+, 627.3 [M+Na]+。
Embodiment 6
Step (1): it weighs 50mg compound Aflaquinolone D (0.1148mmol) and is dissolved in 10mL DMF, in room Temperature is lower to be added 100mg K2CO3, 28 μ L BnBr (0.2296mmol), after being stirred to react 4 hours at room temperature, TLC detection raw material disappears It loses, after reduced pressure, the dilution of 50mL ethyl acetate is added, successively washed with water, saturation NaCl, anhydrous Na2SO4Dry, filter, After reduced pressure, through silica gel column chromatography (petroleum ether/EtOAc=15/1), faint yellow solid 55mg, as compound 15 are obtained, Yield 91.7%, ESI-MS (m/z): 548.3 [M+Na]+。
Step (2): it weighs 50mg compound 15 (0.095mmol) and is dissolved in THF-CH3OH (volume ratio 5:2,10mL), in- 53mg CeCl is added at 70 DEG C3·7H2O (0.143mmol) and 5.5mg NaBH4(26mg, 0.143mmol) keeps this temperature, It is stirred to react after forty minutes, 2mL is added and is saturated NH4Cl terminates reaction, after organic solvent is evaporated off, ethyl acetate extraction, and organic phase It is dried over anhydrous sodium sulfate, after concentration, through silica gel column chromatography (eluant, eluent is EtOAc/ petroleum ether=10:1~8:1), obtains light Yellow solid 43mg, as compound 16, yield 85%, ESI-MS (m/z): 550.3 [M+Na]+。
Step (3): weighing Fmoc-N- methyl D-valine (707mg, 2mmol) and be dissolved in dry toluene (15mL), DCC (413mg, 2mmol), DMAP (6mg, 0.05mmol) is added, stirs 5 minutes at room temperature, addition compound 16 (20mg, 0.038mmol), after being heated to 60 DEG C of reactions 48 hours, filtering after being concentrated under reduced pressure, extracts, organic phase is through anhydrous through ethyl acetate Sodium sulphate is dry, and the product obtained after concentration is dissolved in 8mL morpholine, after being stirred at room temperature 1 hour, concentration, through silica gel column chromatography (eluant, eluent is EtOAc/ petroleum ether=10:1~6:1), obtains faint yellow solid 20mg, as compound 340, yield 82.3%, ESI-MS (m/z): 641.4 [M+H]+, 663.4 [M+Na]+。
Compound 340 can be further subjected to step (4) reduction double bond while remove benzyl and obtain compound 403.
Step (4): it weighs 10mg compound 340 (0.01561mmol) and is dissolved in 5mLCH3OH-CH2Cl2In (volume ratio 1: 1) Pd-C of catalytic amount, is added, at room temperature in 1atm H2After the lower reaction 6h of effect, it is filtered to remove Pd-C, is concentrated to give pale yellow colored solid Body 8mg, as compound 403, yield 92.7%, ESI-MS (m/z): 553.3 [M+H]+, 575.3 [M+Na]+。
Embodiment 7
Step (1): it weighs 50mg compound Aflaquinolone C (0.1148mmol) and is dissolved in 10mL DMF, in room Temperature is lower to be added 100mg K2CO3, 20 μ L allyl bromide, bromoallylenes (0.2296mmol), after being stirred to react 4 hours at room temperature, TLC detects raw material It disappears, after reduced pressure, the dilution of 50mL ethyl acetate is added, successively washed with water, saturation NaCl, anhydrous Na2SO4It is dry, mistake Filter after being concentrated under reduced pressure, through silica gel column chromatography (petroleum ether/EtOAc=12/1), obtains faint yellow solid 50mg, as compound 17, yield 91.6%, ESI-MS (m/z): 498.2 [M+Na]+。
Step (2): weighing 40mg compound 17 and be dissolved in 20mL THF, and 25mg NaBH is added under ice bath4, anti-under ice bath After answering 2h, 2mL is added and is saturated NH4Cl terminates reaction, and after THF is evaporated off, ethyl acetate extraction, organic phase is done through anhydrous sodium sulfate It is dry, after concentration, through silica gel column chromatography (eluant, eluent is EtOAc/ petroleum ether=10:1~8:1), faint yellow solid 36mg is obtained, i.e., For compound 18, yield 89.6%, ESI-MS m/z:500.2 [M+Na]+。
Step (3): weighing Fmoc-L- histidine (755mg, 2mmol) and be dissolved in dry toluene (15mL), and DCC is added (413mg, 2mmol), DMAP (6mg, 0.05mmol) is stirred 5 minutes at room temperature, addition compound 18 (20mg, 0.042mmol), after being heated to 60 DEG C of reactions 48 hours, filtering after being concentrated under reduced pressure, extracts, organic phase is through anhydrous through ethyl acetate Sodium sulphate is dry, and the product obtained after concentration is dissolved in 8mL morpholine, and after being stirred at room temperature 1 hour, concentration (is washed through silica gel column chromatography De- agent is EtOAc/ petroleum ether=6:1~3:1), obtain 20 mg of faint yellow solid, as compound 256, yield 77.7%, ESI-MS(m/z):615.3[M+H]+, 637.3 [M+Na]+。
Compound 256 can be further subjected to step (4) reduction double bond and obtain compound 404.
Step (4): it weighs 10mg compound 256 (0.01627mmol) and is dissolved in 5mLCH3OH-CH2Cl2In (volume ratio 1: 1) Pd-C of catalytic amount, is added, at room temperature in 1atm H2After the lower reaction 6h of effect, it is filtered to remove Pd-C, is concentrated to give pale yellow colored solid Body 9mg, as compound 404, yield 89.4%, ESI-MS (m/z): 619.3 [M+H]+, 641.3 [M+Na]+。
Embodiment 8
Compound 182,401 in embodiment 4 can be restored according to the reducing condition recorded in embodiment 5-7 step (4) To compound 405-406.
Embodiment 9
Using the preparation method recorded in embodiment any one of 1-8 or in the prior art similar to the reaction between reactive functionality Or carry out this field on its basis and routinely replace, compound 21-380,401-406, all of above compound can be prepared Pass through1HNMR, ESI-MS (being shown in Table 1) carry out structural identification, part of compounds through CD,1H-1H COSY、 HMQC、HMBC、NOESY Carry out structural identification.
Embodiment 10
The present invention tests all compounds to the inhibitory activity of Respiratory Syncytial Virus(RSV) (RSV), in order to which the present invention writes Convenience and understand the present invention convenient for more concise intuitive, only list the ESI-MS and respiratory tract of the compounds of this invention below The inhibitory activity data (being shown in Table 1) of syncytial virus (RSV).
The compounds of this invention tests the inhibitory activity of Respiratory Syncytial Virus(RSV) (RSV) according to following literature method: Zhang, Y.J.；Stein,D.A.；Fan,S.M.；Wang,K.Y.；Kroeker,A.D.；Meng,X.J.；Iversen, P.L.；Matson, D.O.Vet.Microbiol.2006,117(2-4),117-129；Or it can be according to other classes in the prior art It is tested like method reported in the literature.All compounds of the present invention (21-380,401-406) all have significantly RSV Inhibiting effect, medium effective concentration (EC50) 0.1 to 120ng/mL, and median toxic concentration (TC50) in 1-100 μ g/mL, Press down malicious index (TI)=TC50/EC50Up to 600, it is seen that the compounds of this invention or its stereoisomer, its geometric isomer, The solvate of its solvate, its pharmaceutically acceptable salt or its salt can be used for preparing the anti-rsv infection medicine of high-efficiency low-toxicity Object.
ESI-MS data of 1 the compounds of this invention of table (21-380,401-406) and its to Respiratory Syncytial Virus(RSV) (RSV) Inhibitory activity data.
" A " indicates that compound concentration is 0.1-2.0ng/mL in table 1, and " B " indicates that compound concentration is 10-25ng/mL, " C " indicates that compound concentration is 50-75ng/mL, and " D " indicates that compound concentration is 90-120ng/mL；" ++++" indicate LC50/ EC50Between 500-600, " +++ " indicates LC50/EC50Between 350-450, " ++ " indicates LC50/EC50200-300 it Between, "+" indicates LC50/EC50Between 50-150.
All references mentioned in the present invention is incorporated herein by reference document, just as each document quilt It is individually recited as with reference to such.In addition, it should also be understood that, after having read above content of the invention, those skilled in the art The present invention can be made various changes or modifications, such equivalent forms are equally fallen within defined by the application the appended claims Range.

Claims (10)

1. a kind of quinolinone alkaloid class compound of -1 structure of Formulas I, its stereoisomer, its geometric isomer or its pharmaceutically Acceptable salt, it is characterised in that -1 compound of Formulas I has the following structure:
Wherein R1The amino acid residue of hydroxyl, R are taken off for c-terminus2For H, C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 alkyl halide Base, C1-C4 alkyl acyl, C1-C4 halogenated alkyl acyl group, C3-C6 cycloalkanoyl, C2-C4 alkenyl, C7-C10 aryl alkyl, " --- -- " indicates singly-bound or is not present,Indicate the key being directed toward in paperOr it is directed toward the key outside paperInstitute Stating amino acid is alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylpropyl alcohol Propylhomoserin (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), half Guang ammonia Sour (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), lysine (Lys), arginine (Arg), group ammonia One of sour (His), aspartic acid (Asp), glutamic acid (Glu), wherein amino acid is configured as D type, L-type or DL type, ammonia Amino in base acid is optionally by C1-C4 alkyl, C3-C6 naphthenic base, C1-C4 halogenated alkyl or C1-C4 alkyl acyl, C1-C4 alkane One or two of Epoxide carbonyl replaces, the alkylidene or aryl in amino acid optionally by C1-C4 alkyl, C3-C6 naphthenic base, One or more of C1-C4 alkoxy, C1-C4 halogenated alkyl or C1-C4 alkyl acyl, hydroxyl, halogen, nitro, cyano take Generation；
It is excluded in -1 compound of Formulas I
2. -1 compound of Formulas I described in claim 1 is selected from following compound:
3. a kind of antivirotic, it is characterised in that the antivirotic contains described in any item -1 chemical combination of Formulas I of claim 1-2 Any one or more of object, its stereoisomer, its geometric isomer or its pharmaceutically acceptable salt are used as effective component.
4. a kind of pharmaceutical composition, it is characterised in that the pharmaceutical composition includes that the described in any item Formulas I -1 of claim 1-2 are changed Close any one or more of object, its stereoisomer, its geometric isomer or its pharmaceutically acceptable salt, and at least one Kind pharmaceutically acceptable carrier or excipient.
5. a kind of pharmaceutical composition, it is characterised in that the pharmaceutical composition includes that the described in any item Formulas I -1 of claim 1-2 are changed Close any one or more of object, its stereoisomer, its geometric isomer or its pharmaceutically acceptable salt, and at least one Kind pharmaceutically acceptable carrier or diluent.
6. a kind of pharmaceutical composition, it is characterised in that include described in any item -1 compounds of Formulas I of claim 1-2, its solid Any one or more of isomers, its geometric isomer or its pharmaceutically acceptable salt, and at least one other are disease-resistant Cytotoxic drug.
7. pharmaceutical composition as claimed in claim 6 is injection, oral preparation, freeze drying powder injection, suspending agent.
8. described in any item -1 compounds of Formulas I of claim 1-2, its stereoisomer, its geometric isomer or its pharmaceutically Purposes of the acceptable salt in preparation antiviral drugs.
9. described in any item -1 compounds of Formulas I of claim 1-2, its stereoisomer, its geometric isomer or its pharmaceutically Application of the acceptable salt in the drug of preparation treatment and/or prevention respiratory disease.
10. described in any item -1 compounds of Formulas I of claim 1-2, its stereoisomer, its geometric isomer or its pharmaceutically Application in the drug of acceptable salt disease as caused by RSV in preparation treatment and/or prevention.
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