CN104945320A - Quinolinone alkaloid derivatives with anti-RSV activity and preparation method thereof - Google Patents

Quinolinone alkaloid derivatives with anti-RSV activity and preparation method thereof Download PDF

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CN104945320A
CN104945320A CN201510150737.6A CN201510150737A CN104945320A CN 104945320 A CN104945320 A CN 104945320A CN 201510150737 A CN201510150737 A CN 201510150737A CN 104945320 A CN104945320 A CN 104945320A
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compound
solvate
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salt
isomer
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CN104945320B (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 invention relates to quinolinone alkaloid derivatives with anti-RSV activity and a preparation method thereof and particularly relates to compounds shown in the formula I-1, stereisomers, stereomers, solvates and pharmaceutically acceptable salts of the compounds, or solvates of the pharmaceutically acceptable salts of the compounds, and application of the compounds, the stereisomers, stereomers, solvates and pharmaceutically acceptable salts of the compounds or the solvates of the pharmaceutically acceptable salts of the compounds as antiviral agents. The provided quinolinone alkaloid derivatives have the characteristics of high efficiency and low toxicity, have a potential to be developed into antiviral drugs and especially can be used for preventing and/or treating diseases caused by RSV infection.

Description

Quinolinone alkaloid derivant of a kind of anti-RSV activity and preparation method thereof
Technical field
The present invention relates to a kind of quinolinone alkaloid derivant and preparation method thereof, the invention still further relates to the application of above-mentioned quinolinone alkaloid derivant in preparation antiviral.Particularly relate to a kind of respiratory syncytial virus to Paramyxoviridae (RSV) and there is quinolinone alkaloid derivant of extremely strong inhibit activities and preparation method thereof and application.
Background technology
Respiratory syncytial virus (respiratory syncytial virus pneumonia, be called for short syncytial virus, RSV, also belongs to Paramyxoviridae), is a kind of RNA viruses, belongs to Paramyxoviridae.Rsv infection can cause pneumonia and multiple lower respiratory illness, and the annual whole world has at least 3,000,000 infants to be admitted to hospital because of RSV virus infection, wherein has at least 160,000 people dead, therefore RSV is also referred to as children killer (Science, 2013,342,546-547).Not can be applicable to clinical vaccine at present, ribavirin (ribavirin) is uniquely applied to clinical chemotherapeutic agent (J.Med.Chem.2008,51,875 – 896).In sum, develop the medicine preventing and/or treating the disease that rsv infection causes and become the task of top priority.
Summary of the invention
The invention provides the solvate of a kind of quinolinone alkaloid compounds of formula I-1 structure, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt, it is characterized in that formula I-1 compound has following structure:
Wherein R 1for carboxyl terminal takes off the amino-acid residue of hydroxyl, R 2for H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkyl acyl, C1-C4 haloalkyl acyl group, C3-C6 cycloalkanoyl, C2-C4 thiazolinyl, C7-C10 arylalkyl, "-----" represents singly-bound or does not exist, represent the key pointed in paper or the key outside sensing paper described amino acid is L-Ala (Ala), α-amino-isovaleric acid (Val), leucine (Leu), Isoleucine (Ile), proline(Pro) (Pro), phenylalanine (Phe), tryptophane (Trp), methionine(Met) (Met), glycine (Gly), Serine (Ser), Threonine (Thr), halfcystine (Cys), tyrosine (Tyr), l-asparagine (Asn), glutamine (Gln), Methionin (Lys), arginine (Arg), Histidine (His), aspartic acid (Asp), one in L-glutamic acid (Glu), is wherein amino acid whosely configured as D type, L-type, or DL type, the amino in amino acid is optionally by C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl or C1-C4 alkyl acyl, one or two in C1-C4 alkoxy carbonyl replaces, and the alkylidene group in amino acid or aryl are optionally by C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxyl group, C1-C4 haloalkyl or C1-C4 alkyl acyl, hydroxyl, halogen, nitro, one or more replacements in cyano group.
Described " alkyl " preferable methyl, ethyl, propyl group, normal-butyl, isobutyl-, the tertiary butyl herein; " haloalkyl " be trifluoromethyl, difluoromethyl, pentafluoroethyl group, perfluoro butyl preferably; " alkyl acyl " be ethanoyl, propionyl, positive butyryl radicals, isobutyryl preferably; " haloalkyl acyl group " be chloracetyl, acetyl bromide preferably; " thiazolinyl " be allyl group, propenyl, but-2-ene base preferably; " cycloalkyl " be cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base preferably; " cycloalkanoyl " be ring propionyl, ring butyryl radicals, ring pentanoyl, cyclohexanoyl preferably; " arylalkyl " be benzyl, phenylethyl preferably; " halogen " be fluorine, chlorine, bromine, iodine preferably.
In the present invention, term " pharmacy acceptable salt " refers to the additive salt of atoxic inorganic or organic acid and/or alkali, can see " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201 – 217.The preferred hydrochloric acid of inorganic or organic acid, sulfuric acid, phosphoric acid, toxilic acid, citric acid, fumaric acid, glucuronic acid, formic acid, acetic acid, oxalic acid, succinic acid etc.
In the present invention, term " solvate " refers to the solvate that formula I-1 compound or its salt and organic solvent or water are formed, the preferred acetone of organic solvent, acetonitrile, methyl alcohol, ethanol, the monohydrate, dihydrate, trihydrate, an acetonitrile compound, diacetonitrile compound, an acetone compound, two acetone compounds, hemifumarate monohydrate, fumarate dihydrate, fumarate one ethanolates etc. of the solvate preferred formula I-1 compound or its salt of formation.
In the present invention, term " geometrical isomer " refers to that formula I-1 compound comprises the compound that double bond is Z, E two kinds of geometric configurations when "-----" is for singly-bound.
Formula I-1 compound is selected from the solvate of following compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt:
Formula I-1 compound can not comprise compound 35.
Formula I-1 compound also can comprise the solvate of following compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt:
In another preference, R in formula I-1 compound 1, R 2it is the concrete group as corresponding position in above-mentioned particular compound 21-380,401-406.
Should be understood that above-mentioned preferred group can combine to form various preferred compound of the present invention mutually, as space is limited, do not tire out one by one at this and state.
Another embodiment of the present invention provides a kind of antiviral agent, it is characterized in that this antiviral agent contains any one or several in the solvate of formula I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt as effective constituent.
Another embodiment of the present invention provides a kind of pharmaceutical composition, it is characterized in that any one or several in the solvate of the contained I-1 compound of this pharmaceutical composition, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt, and the pharmaceutically acceptable carrier of at least one, thinner or vehicle.
Another embodiment of the present invention provides a kind of pharmaceutical composition, it is characterized in that any one or several in the solvate of contained I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt, and other antiviral of at least one.These pharmaceutical composition optimizing injection, oral preparations, lyophilized injectable powder, suspension agent etc.
Another embodiment of the present invention provides the purposes of the solvate of formula I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt in preparation antiviral.
Another embodiment of the present invention provides the solvate of formula I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt preparing the application treated and/or prevented in the medicine of respiratory tract disease.
Another embodiment of the present invention provides the solvate of formula I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt preparing the application treated and/or prevented in the medicine of the disease caused by RSV.
Another embodiment of the present invention provides the preparation method of formula I-1 compound, comprises the steps:
Method one:
(1) absolute configuration of first deterministic compound 1, compound 1 (the method preparation recorded by doctor Chen Min " the Chinese Marine University Ph.D. Dissertation " of 2013) is at CH 3oH/CH 3by after ester linkage hydrolyzing under ONa condition, adopt Zeo-karb neutralization, obtain compound 2,3, following compound 2 adopts document J.Org.Chem.1969, the Mosher analytical method recorded in 34 (9), 2543-2549, the absolute configuration of deterministic compound 2, warp 1h NMR analyzes the absolute configuration judging compound 2; Compound 3 adopts document Amino Acids (2004) 27:231 – 247, Carlsberg Research Communications January 1984, Volume 49, Issue 6, Marfey ' the s method recorded in pp 591-596 is analyzed, the absolute configuration of deterministic compound 3, and then the absolute configuration of deterministic compound 1 is
(2) compound 1 obtains formula I-1-1 through alkylation reaction " compound, alkylation reaction condition is this area normal condition: in organic solvent, reacts, wherein the preferred R of hydrocarbonylation reagent under alkali, the effect of hydrocarbonylation reagent 2x, wherein X is halogen, preferred chlorine, bromine, iodine, R 2for C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 thiazolinyl, C7-C10 arylalkyl; Alkali preferred alkali metal carbonate is (as Na 2cO 3, K 2cO 3);
Or compound 1 obtains formula I-1-1 through acylation reaction " ' compound; acylation reaction condition is also this area normal condition: in organic solvent; react under alkali, acylating reagent effect; the wherein preferred R ' COX of acylating reagent (carboxylic acid halides), R ' COOCOR ' (acid anhydrides); wherein X is halogen; preferably chlorine, bromine, iodine, R ' is C1-C3 alkyl, C1-C3 haloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, alkali preferred alkali metal hydroxide (as NaOH, KOH), triethylamine, pyridine, sodium-acetate, quinoline, imidazoles, xylidine etc.; The wherein preferred methylene dichloride of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc.
Or (3) formula I-1-1 " compound is at CH 3oH/CH 3under the effect of ONa, obtain formula II-2.
(4) formula II-2 compound can at H 2under effect, after reduction double bond obtains formula II-3 compound, with the various amino acid (amino-acid residue corresponding to defining in formula I-1) be optionally substituted, condensation reaction occurs, the preferred DCC/DAMP of condensation condition, obtains formula I-1-1 compound;
Or II-2 compound is directly substituted or unsubstituted amino acid generation condensation reaction with various amino, and the preferred DCC/DAMP of condensation condition, obtains formula I-1-1 compound;
Or the formula I-1-1 compound obtained can obtain formula I-1-2 compound by the substituting group removed under suitable conditions on amino further.
Method two:
(1) Aflaquinolone A obtains formula II-4 compound through alkylation reaction or acylation reaction, and alkylation reaction condition is this area normal condition: in organic solvent, reacts, wherein the preferred R of hydrocarbonylation reagent under alkali, the effect of hydrocarbonylation reagent 2x, wherein X is halogen, preferred chlorine, bromine, iodine, R 2for C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 thiazolinyl, C7-C10 arylalkyl; Alkali preferred alkali metal carbonate is (as Na 2cO 3, K 2cO 3); Acylation reaction condition is also this area normal condition: in organic solvent, react under alkali, acylating reagent effect, the wherein preferred R ' COX of acylating reagent (carboxylic acid halides), R ' COOCOR ' (acid anhydrides), wherein X is halogen, preferred chlorine, bromine, iodine, R ' is C1-C3 alkyl, C1-C3 haloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, alkali preferred alkali metal hydroxide (as NaOH, KOH), triethylamine, pyridine, sodium-acetate, quinoline, imidazoles, xylidine etc.; The wherein preferred methylene dichloride of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc.
(2) formula II-4 compound (can refer to CN1238327A, CN103012329A or J.Org.Chem.2005 through selective reduction, 70, carbonyl reduction is the method for α-OH by the selectivity recorded in 10732-10736) obtain formula II-2' compound, the wherein preferred aluminum isopropylate of selective reduction reagent or NaBH 4.
(3) formula II-2' compound by the scheme in method one step (4), can obtain formula I-1-1', formula I-1-2' compound.
Method three:
(1) Aflaquinolone B obtains formula II-5 compound through alkylation reaction, and alkylation reaction condition is this area normal condition: in organic solvent, reacts, wherein the preferred R of hydrocarbonylation reagent under alkali, the effect of hydrocarbonylation reagent 2x, wherein X is halogen, preferred chlorine, bromine, iodine, R 2for C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 thiazolinyl, C7-C10 arylalkyl; Alkali preferred alkali metal carbonate is (as Na 2cO 3, K 2cO 3).
(2) formula II-5 compound by the scheme in method one step (4), can obtain formula I-1-3, formula I-1-4 compound.
Method four:
Be raw material by compd A flaquinolone D, obtain formula I-1-5, formula I-1-6 compound according to the scheme in method two.
Method five:
Be raw material by compd A flaquinolone C, obtain formula I-1-7, formula I-1-8 compound according to the scheme in method two.
Method six:
Formula II-7, II-10 compound (can refer to J.Org.Chem.1998 after also can being reduced to β-OH product formula II-8', formula II-11' under selective reduction agent effect, 63,4438-4443, J.Org.Chem.2003,68,2572-2582 or Org.Lett.2003,5, carbonyl reduction is the method for β-OH by the selectivity recorded in 137-140), formula I-1-5', formula I-1-6', formula I-1-7', formula I-1-8' compound is formed with the strategy of amino acid condensation again, the preferred NaBH of selective reduction agent according in method four or five 4/ CeCl 37H 2o, LiAlH 4/ THF, (i-Bu) 3al.
In aforesaid method one to method six, compound 1, Aflaquinolone A, Aflaquinolone D can be prepared by the method recorded in doctor Chen Min " the Chinese Marine University Ph.D. Dissertation " of 2013; Or Aflaquinolones A-D also can by document J Nat Prod, and the method recorded in 2012,75 (3): 464 – 472 prepares.
Give the formula I-1-1, formula I-1-1', the formula I-1-1 that are included in formula I-1 compound range in above-mentioned synthetic method ", formula I-1-1 " ', the synthetic method of formula I-1-2, formula I-1-2', formula I-1-3, formula I-1-4, formula I-1-5, formula I-1-6, formula I-1-7, formula I-1-8, I-1-5', formula I-1-6', formula I-1-7', formula I-1-8'.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and in below (eg embodiment) specifically described each technical characteristic can combine mutually, thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
For the ease of a further understanding of the present invention, the embodiment provided below has done more detailed description to it.But these embodiments only are not used for limiting scope of the present invention or implementation principle for better understanding invention, embodiments of the present invention are not limited to following content.
Embodiment 1
Take 500mg compound 1, be dissolved in 20mL acetone, add 150mg Na 2cO 3, after stirred at ambient temperature half an hour, add 1.0mL MeI, after reacting 4h at 30 DEG C, the almost completely dissolve of TLC detection reaction raw material, extraction into ethyl acetate twice, anhydrous sodium sulfate drying organic layer, after concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=12:1 ~ 8:1), obtains faint yellow solid 472mg, be compound 37, productive rate 92%, ESI-MS m/z:565.3 [M+H] +, 587.3 [M+Na] +.
Embodiment 2
Take 10mg compound 1, be dissolved in 2mL methylene dichloride, add 3 μ L Ac 2o, 50 μ L pyridines, after stirred at ambient temperature 2h, the almost completely dissolve of TLC detection reaction raw material, add 20mL dchloromethane, washing, organic phase is through anhydrous sodium sulfate drying, after concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=12:1 ~ 10:1), obtains faint yellow solid 9.5mg, be compound 38, productive rate 88.2%, ESI-MS m/z:593.3 [M+H] +, 615.3 [M+Na] +.
Embodiment 3
Step (1): take 400mg compound 37 and be dissolved in 15mL methyl alcohol, add the CH of catalytic amount 3oNa adjusts pH9.0 ~ 10.0, after stirred at ambient temperature reaction 2h, adds Zeo-karb and adjusts pH 7.0, filter decationize exchange resin, concentrate to obtain faint yellow solid 319mg, be compound 11, productive rate 99.7%, ESI-MS m/z:474.2 [M+Na] +.
Step (2): take Boc-L-α-amino-isovaleric acid (300mg, 1.38mmol) be dissolved in dry toluene (10mL), add DCC (285mg, 1.38mmol), DMAP (7mg, 0.06mmol), stirred at ambient temperature 5 minutes, add compound 11 (27mg, 0.06mmol), be heated to 65 DEG C of reactions after 48 hours, after filtration, concentrating under reduced pressure, through silica gel column chromatography (sherwood oil/EtOAc=12/1), obtain faint yellow solid 35mg, be compound 30, productive rate 90%, ESI-MS (m/z): 651.3 [M+H] +, 673.4 [M+Na] +.
Embodiment 4
Step (1): take 10mg compd A flaquinolone B, be dissolved in 3mL acetone, add 10mg K 2cO 3, after stirred at ambient temperature half an hour, add 20 μ L cyclopropane bromides, after reacting 10h at 50 DEG C, the almost completely dissolve of TLC detection reaction raw material, extraction into ethyl acetate twice, anhydrous sodium sulfate drying organic layer, after concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=12:1 ~ 8:1), obtains faint yellow solid 9.3mg, be compound 12, productive rate 85%, ESI-MS m/z:478.3 [M+H] +.
Step (2): take Boc-D-l-asparagine (100mg, 0.43mmol) be dissolved in dry toluene (10mL), add DCC (89mg, 0.43mmol), DMAP (2mg, 0.0167mmol), stirred at ambient temperature 5 minutes, add compound 12 (8mg, 0.0167mmol), be heated to 65 DEG C of reactions after 48 hours, after filtration, concentrating under reduced pressure, through silica gel column chromatography (sherwood oil/EtOAc=8/1), obtain faint yellow solid 10mg, be compound 182, productive rate 86.3%, ESI-MS (m/z): 692.3 [M+H] +, 714.3 [M+Na] +.
Compound 182 can experience step (3) further and be converted into compound 401, while removing Boc in acid condition, and D-Asn generation racemization.
Step (3): take 10mg compound 182 (0.01445mmol) and be dissolved in 2mL methylene dichloride, 5 μ L trifluoroacetic acids (TFA) are dripped under ice bath, under remaining on ice bath, react after 0.5 hour, TLC detects raw material and disappears, add 20mL dchloromethane, use saturated NaHCO successively 3, saturated NaCl washing, anhydrous Na 2sO 4drying, after filtration, concentrating under reduced pressure, through silica gel column chromatography (sherwood oil/EtOAc=3/1), obtains faint yellow solid 8mg, is compound 401, productive rate 93.5%, ESI-MS (m/z): 592.3 [M+H] +, 614.3 [M+Na] +.
Embodiment 5
Step (1): take 200mg compd A flaquinolone A, be dissolved in 20mL methylene dichloride, add 63 μ L Cyclopropyl carbonyl chloride, 500 μ L pyridines, after stirred at ambient temperature 1.5h, the almost completely dissolve of TLC detection reaction raw material, add 50mL dchloromethane, washing, organic phase is through anhydrous sodium sulfate drying, after concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=12:1 ~ 10:1), obtains faint yellow solid 215mg, be compound 13, productive rate 93%, ESI-MS m/z:526.2 [M+Na] +.
Step (2): take 20mg compound 13 and be dissolved in 20mL THF, add 15mg NaBH under ice bath 4, after reacting 2h under ice bath, add the saturated NH of 2mL 4cl termination reaction, steam except after THF, extraction into ethyl acetate, organic phase through anhydrous sodium sulfate drying, after concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=10:1 ~ 8:1), obtain faint yellow solid 19mg, be compound 14, productive rate 95%, ESI-MS m/z:528.2 [M+Na] +.
Step (3): take L-PROLINE (230mg, 2mmol) be dissolved in dry toluene (10mL), add DCC (413mg, 2mmol), DMAP (6mg, 0.05mmol), stirred at ambient temperature 5 minutes, add compound 14 (15mg, 0.03mmol), be heated to 60 DEG C of reactions after 48 hours, after filtration, concentrating under reduced pressure, through silica gel column chromatography (sherwood oil/EtOAc=10/1), obtain faint yellow solid 17mg, be compound 74, productive rate 94%, ESI-MS (m/z): 603.3 [M+H] +, 625.3 [M+Na] +.
Compound 74 can experience step (4) reduction further and obtain compound 402.
Step (4): take 10mg compound 74 (0.01659mmol) and be dissolved in 5mLCH 3oH-CH 2cl 2in (volume ratio 1:1), add the Pd-C of catalytic amount, in 1atm H under room temperature 2after effect lower reaction 4h, cross and filter Pd-C, concentrate to obtain faint yellow solid 10mg, be compound 402, productive rate 99.7%, ESI-MS (m/z): 605.3 [M+H] +, 627.3 [M+Na] +.
Embodiment 6
Step (1): take 50mg compd A flaquinolone D (0.1148mmol) and be dissolved in 10mL DMF, add 100mg K under room temperature 2cO 3, 28 μ L BnBr (0.2296mmol), after stirred at ambient temperature reacts 4 hours, TLC detects raw material and disappears, and after concentrating under reduced pressure, adds 50mL diluted ethyl acetate, washs successively, anhydrous Na with water, saturated NaCl 2sO 4drying, after filtration, concentrating under reduced pressure, through silica gel column chromatography (sherwood oil/EtOAc=15/1), obtains faint yellow solid 55mg, is compound 15, productive rate 91.7%, ESI-MS (m/z): 548.3 [M+Na] +.
Step (2): take 50mg compound 15 (0.095mmol) and be dissolved in THF-CH 3oH (volume ratio 5:2,10mL), adds 53mg CeCl at-70 DEG C 37H 2o (0.143mmol) and 5.5mg NaBH 4(26mg, 0.143mmol), keeps this temperature, and stirring reaction, after 40 minutes, adds the saturated NH of 2mL 4cl termination reaction, steam except after organic solvent, extraction into ethyl acetate, organic phase through anhydrous sodium sulfate drying, after concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=10:1 ~ 8:1), obtain faint yellow solid 43mg, be compound 16, productive rate 85%, ESI-MS (m/z): 550.3 [M+Na] +.
Step (3): take Fmoc-N-methyl D-α-amino-isovaleric acid (707mg, 2mmol) be dissolved in dry toluene (15mL), add DCC (413mg, 2mmol), DMAP (6mg, 0.05mmol), stirred at ambient temperature 5 minutes, add compound 16 (20mg, 0.038mmol), be heated to 60 DEG C of reactions after 48 hours, filter, after concentrating under reduced pressure, through extraction into ethyl acetate, organic phase is through anhydrous sodium sulfate drying, the product obtained after concentrated is dissolved in 8mL morpholine, stirring at room temperature is after 1 hour, concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=10:1 ~ 6:1), obtain faint yellow solid 20mg, be compound 340, productive rate 82.3%, ESI-MS (m/z): 641.4 [M+H] +, 663.4 [M+Na] +.
Compound 340 can experience step (4) reduction double bond further and remove benzyl simultaneously and obtain compound 403.
Step (4): take 10mg compound 340 (0.01561mmol) and be dissolved in 5mLCH 3oH-CH 2cl 2in (volume ratio 1:1), add the Pd-C of catalytic amount, in 1atm H under room temperature 2after effect lower reaction 6h, cross and filter Pd-C, concentrate to obtain faint yellow solid 8mg, be compound 403, productive rate 92.7%, ESI-MS (m/z): 553.3 [M+H] +, 575.3 [M+Na] +.
Embodiment 7
Step (1): take 50mg compd A flaquinolone C (0.1148mmol) and be dissolved in 10mL DMF, add 100mg K under room temperature 2cO 3, 20 μ L allyl bromide 98s (0.2296mmol), after stirred at ambient temperature reacts 4 hours, TLC detects raw material and disappears, and after concentrating under reduced pressure, adds 50mL diluted ethyl acetate, washs successively, anhydrous Na with water, saturated NaCl 2sO 4drying, after filtration, concentrating under reduced pressure, through silica gel column chromatography (sherwood oil/EtOAc=12/1), obtains faint yellow solid 50mg, is compound 17, productive rate 91.6%, ESI-MS (m/z): 498.2 [M+Na] +.
Step (2): take 40mg compound 17 and be dissolved in 20mL THF, add 25mg NaBH under ice bath 4, after reacting 2h under ice bath, add the saturated NH of 2mL 4cl termination reaction, steam except after THF, extraction into ethyl acetate, organic phase through anhydrous sodium sulfate drying, after concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=10:1 ~ 8:1), obtain faint yellow solid 36mg, be compound 18, productive rate 89.6%, ESI-MS m/z:500.2 [M+Na] +.
Step (3): take Fmoc-L-Histidine (755mg, 2mmol) be dissolved in dry toluene (15mL), add DCC (413mg, 2mmol), DMAP (6mg, 0.05mmol), stirred at ambient temperature 5 minutes, add compound 18 (20mg, 0.042mmol), be heated to 60 DEG C of reactions after 48 hours, filter, after concentrating under reduced pressure, through extraction into ethyl acetate, organic phase is through anhydrous sodium sulfate drying, the product obtained after concentrated is dissolved in 8mL morpholine, stirring at room temperature is after 1 hour, concentrated, through silica gel column chromatography (eluent is EtOAc/ sherwood oil=6:1 ~ 3:1), obtain faint yellow solid 20mg, be compound 256, productive rate 77.7%, ESI-MS (m/z): 615.3 [M+H] +, 637.3 [M+Na] +.
Compound 256 can experience step (4) reduction double bond further and obtain compound 404.
Step (4): take 10mg compound 256 (0.01627mmol) and be dissolved in 5mLCH 3oH-CH 2cl 2in (volume ratio 1:1), add the Pd-C of catalytic amount, in 1atm H under room temperature 2after effect lower reaction 6h, cross and filter Pd-C, concentrate to obtain faint yellow solid 9mg, be compound 404, productive rate 89.4%, ESI-MS (m/z): 619.3 [M+H] +, 641.3 [M+Na] +.
Embodiment 8
Compound 182,401 in embodiment 4 can according to the reductive condition recorded in embodiment 5-7 step (4), and reduction obtains compound 405-406.
Embodiment 9
Adopt the reaction in the preparation method or prior art recorded in any one of embodiment 1-8 between similar reactive functionality or carry out this area routine on its basis and replace, compound 21-380,401-406 can be prepared, the equal warp of above all compounds 1hNMR, ESI-MS (see 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 the inhibit activities of all compounds to respiratory syncytial virus (RSV), the convenience of writing in order to the present invention and be convenient to more concisely understand the present invention intuitively, only lists the ESI-MS of the compounds of this invention and the inhibit activities data (see table 1) of respiratory syncytial virus (RSV) below.
The inhibit activities of the compounds of this invention to respiratory syncytial virus (RSV) is tested 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 can conventionally in the method reported in other similar documents test.The all compounds of the present invention (21-380,401-406) all have significant restraining effect to RSV, its medium effective concentration (EC 50) at 0.1 to 120ng/mL, and median toxic concentration (TC 50) at 1-100 μ g/mL, press down malicious index (TI)=TC 50/ EC 50be up to 600, the solvate of visible the compounds of this invention or its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt can be used for the anti-rsv infection medicine preparing high-efficiency low-toxicity.
The ESI-MS data of table 1 the compounds of this invention (21-380,401-406) and the inhibit activities data to respiratory syncytial virus (RSV) thereof.
In table 1, " A " represents that compound concentration is 0.1-2.0ng/mL, and " B " represents that compound concentration is 10-25ng/mL, and " C " represents that compound concentration is 50-75ng/mL, and " D " represents that compound concentration is 90-120ng/mL; " ++++" represent LC 50/ EC 50between 500-600, " +++ " represents LC 50/ EC 50between 350-450, " ++ " represents LC 50/ EC 50between 200-300, "+" represents LC 50/ EC 50between 50-150.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read foregoing of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

1. a solvate for the quinolinone alkaloid derivant of formula I-1 structure, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt, is characterized in that formula I-1 compound has following structure:
Wherein R 1for carboxyl terminal takes off the amino-acid residue of hydroxyl, R 2for H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkyl acyl, C1-C4 haloalkyl acyl group, C3-C6 cycloalkanoyl, C2-C4 thiazolinyl, C7-C10 arylalkyl, "-----" represents singly-bound or does not exist, represent the key pointed in paper or the key outside sensing paper described amino acid is L-Ala (Ala), α-amino-isovaleric acid (Val), leucine (Leu), Isoleucine (Ile), proline(Pro) (Pro), phenylalanine (Phe), tryptophane (Trp), methionine(Met) (Met), glycine (Gly), Serine (Ser), Threonine (Thr), halfcystine (Cys), tyrosine (Tyr), l-asparagine (Asn), glutamine (Gln), Methionin (Lys), arginine (Arg), Histidine (His), aspartic acid (Asp), one in L-glutamic acid (Glu), is wherein amino acid whosely configured as D type, L-type, or DL type, the amino in amino acid is optionally by C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl or C1-C4 alkyl acyl, one or two in C1-C4 alkoxy carbonyl replaces, and the alkylidene group in amino acid or aryl are optionally by C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxyl group, C1-C4 haloalkyl or C1-C4 alkyl acyl, hydroxyl, halogen, nitro, one or more replacements in cyano group.
2. formula I-1 compound according to claim 1 is selected from following compound:
3. an antiviral agent, is characterized in that this antiviral agent contains any one or several in the solvate of formula I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt described in any one of claim 1-2 as effective constituent.
4. a pharmaceutical composition, it is characterized in that any one or several that this pharmaceutical composition comprises in the solvate of formula I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt described in any one of claim 1-2, and the pharmaceutically acceptable carrier of at least one, thinner or vehicle.
5. a pharmaceutical composition, it is characterized in that any one or several in the solvate of formula I-1 compound, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt comprised described in any one of claim 1-2, and other antiviral of at least one.
6. pharmaceutical composition according to claim 5 is injection, oral preparations, lyophilized injectable powder, suspension agent.
7. the purposes of solvate in preparation antiviral of the formula I-1 compound described in any one of claim 1-2, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt.
8. the solvate of the formula I-1 compound described in any one of claim 1-2, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt is preparing the application treated and/or prevented in the medicine of respiratory tract disease.
9. the solvate of the formula I-1 compound described in any one of claim 1-2, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt is preparing the application treated and/or prevented in the medicine of the disease caused by RSV.
10. the preparation method of the solvate of the formula I-1 compound described in any one of claim 1-2, its steric isomer, its geometrical isomer, its solvate, its pharmacy acceptable salt or its salt, to is characterized in that adopting in present specification in method one to six any one method or adopts any one method in embodiment 1-9.
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CN106496202A (en) * 2015-09-06 2017-03-15 中国海洋大学 A kind of alkaloid compound and preparation method thereof and the application as I type viral agent of anti-herpes simplex
CN106496202B (en) * 2015-09-06 2019-08-06 中国海洋大学 A kind of alkaloid compound and preparation method thereof and the application as I type viral agent of anti-herpes simplex
CN107602614A (en) * 2016-05-09 2018-01-19 桂林医学院 A kind of quinolinone phosphate derivative and its synthetic method and application
CN107602612A (en) * 2016-05-09 2018-01-19 桂林医学院 Quinolinone phosphate derivative and its synthetic method and application
CN107602615A (en) * 2016-05-09 2018-01-19 桂林医学院 Quinolinone phosphate derivative and its preparation method and application
CN107602615B (en) * 2016-05-09 2019-05-03 桂林医学院 Quinolinone phosphate derivative and its preparation method and application
CN107602612B (en) * 2016-05-09 2019-05-03 桂林医学院 Quinolinone phosphate derivative and its synthetic method and application
WO2018177296A1 (en) * 2017-03-28 2018-10-04 中国海洋大学 Lactam compound, and preparation method therefor and use thereof
US10993938B2 (en) 2017-03-28 2021-05-04 Ocean University Of China Lactam compound, preparation method and use thereof

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