CN105367558B - Andrographolidume derivative and its preparation method and application - Google Patents
Andrographolidume derivative and its preparation method and application Download PDFInfo
- Publication number
- CN105367558B CN105367558B CN201510535244.4A CN201510535244A CN105367558B CN 105367558 B CN105367558 B CN 105367558B CN 201510535244 A CN201510535244 A CN 201510535244A CN 105367558 B CN105367558 B CN 105367558B
- Authority
- CN
- China
- Prior art keywords
- dehydrogenation
- dihydroxy
- deoxyandrographolides
- compound
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 *CC(CCO1)C1=O Chemical compound *CC(CCO1)C1=O 0.000 description 1
- BDUDWASRDLQDTE-SOEJABDUSA-N C[C@H](C1[C@@](C)(CC2)C(CCC3=CCOC3=O)=C(CS)CC1)[C@@H]2O Chemical compound C[C@H](C1[C@@](C)(CC2)C(CCC3=CCOC3=O)=C(CS)CC1)[C@@H]2O BDUDWASRDLQDTE-SOEJABDUSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/58—One oxygen atom, e.g. butenolide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Andrographolidume derivative and its preparation method and application.The invention belongs to pharmaceutical technology fields, are related to a kind of new compound, its isomers or its pharmaceutically acceptable salt with preventing respiratory viruses activity and pharmaceutical composition and preparation method containing the compound.And application of these compounds in the drug infected caused by treating and/or preventing Respirovirus.The compound and its isomers or its pharmaceutically acceptable salt such as general formula（I）It is shown, wherein R1, R2, R3As described in claims and specification.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to that a kind of new compound with preventing respiratory viruses activity, its is different
Structure body or its pharmaceutically acceptable salt and pharmaceutical composition and preparation method containing the compound.And these chemical combination
Application of the object in the drug infected caused by treating and/or preventing Respirovirus.
Background technology
Respirovirus is can to invade the respiratory tract of the mankind and cause respiratory tract local patholoic change or only using respiratory tract to invade
Introduction householder will cause the virus of the outer histoorgan lesion of respiratory tract.According to statistics, more than 90% acute respiratory infection is by disease
Poison causes, especially using the infection of the upper respiratory tract as common disease and frequently-occurring disease clinically.Viral respiratory infection easily passes through the mankind's
Normal activity causes the propagation of large area, has the characteristics that prevalence is wide, infectiousness is strong, incidence is high, virus variation is big.Example
Such as, the SARS in China's sprawling in 2003, inland of China and Hong Kong, Taiwan add up case up to 7747, dead 829 people；And
The Influenza A H1N1 to have swept the globe in 2009 by January, 2010, causes global 208 countries and regions to report 250,000
Case, wherein 12799 people are dead.Respiratory virus infection serious threat the health of the public, and is currently available that antiviral agent
Article kind is limited, lacks specificity.How to be effectively prevented and treated viral respiratory infection diseases is that international the world of medicine is common
It faces and key subjects urgently to be resolved hurrily.
It can be found that it is clinically very limited for treating the medication amount of viral respiratory infection at present, also far from full
The clinical needs of foot.And the extensive use due to existing drug clinically so that virus morphs, and is produced to these drugs
Different degrees of drug resistance is given birth to.Although immunologic develop into the method for we providing and effectively preventing certain virus infection,
But since many viruses are no or are difficult to find that suitable vaccine, novel strain are constantly found, virus variation comparatively fast makes former epidemic disease
The reasons such as seedling failure so that find new, effective preventing respiratory viruses drug and its lead compound seem it is more important and
It is urgent.
Invention content
The purpose of the present invention is find and develop the compound with good antiviral activity.Available for prepare treatment/or
Prevent the drug of respiratory viral infection disease.
The specific technical solution of the present invention is as follows：
The present invention provides a kind of logical formula (I) compound represented and its isomers or its pharmaceutically acceptable salt：
Wherein, R1For 5-10 members aryl, 5-10 circle heterocyclic rings aryl, 5-10 circle heterocyclic ring bases, X-R4,
The aryl, heterocycle and heteroaryl can be optionally by 1-3 identical or different R5Substitution, it is the aryl, miscellaneous
The hetero atom that ring group and heteroaryl optionally can be selected from N, O and S containing 1-4；
X be O, S or N atom, R4It is independent hydrogen, C1-C10 alkyl, the C1-C10 alkanoyls of linear chain or branch chain, C5-C6
Cycloalkanoyl, 5-10 members aroyl and 4-hetaroylpyrazol；
R5For hydrogen, C1-C4 alkyl, hydroxyl, amino and fluorine, chlorine or bromine atom.
R2、R3Can be identical or different, it is independent hydrogen, the C1-C10 alkanoyls of linear chain or branch chain, C5-C6 cycloalkanoyls,
5-10 members aroyl and 4-hetaroylpyrazol.
The present invention is preferably such as the compound of lower structure and its isomers or its pharmaceutically acceptable salt：
Wherein, R1For 5-10 members aryl, 5-10 circle heterocyclic rings aryl, 5-10 circle heterocyclic ring bases, X-R4,
The aryl, heterocycle and heteroaryl can be optionally by 1-3 identical or different R5Substitution, it is the aryl, miscellaneous
The hetero atom that ring group and heteroaryl optionally can be selected from N, O and S containing 1-4；
X be O, S or N atom, R4It is independent hydrogen, C1-C4 alkyl；
R5For hydrogen.
The present invention is preferably such as the compound of lower structure and its isomers or its pharmaceutically acceptable salt：
Wherein, R1For 5-10 members aryl, 5-10 circle heterocyclic rings aryl, 5-10 circle heterocyclic ring bases, X-R4,
The hetero atom that the aryl, heterocycle and heteroaryl optionally can be selected from N, O and S containing 1-4；
X be O, S or N atom, R4It is independent hydrogen, C1-C4 alkyl；
R5For hydrogen.
In a preferred embodiment of the invention,
R1For phenyl, naphthalene, 1- imidazole radicals, 1- triazol radicals, 1- uracil bases, 3- uracil bases, 1- cytimidines base, 1-
Thymine base, 3- thymine bases, 7- adenyls, 9- adenyls, 7- guanyl-s, 9-guanine base, 1- β-D- furans
Mutter ribosyl -1H-1,2,4- triazole -3- carboxylic acid amides, N- piperidyls, N- morpholinyls, N- nafoxidines base,-X-R4, wherein X
For O, S or N atom, R4It is independent hydrogen, methyl, ethyl, isopropyl, benzyl, phenethyl, cyclopenta, cyclohexyl, 1- Buddha's warrior attendants
Alkyl or adamantane methyl, formoxyl, acetyl group, ring valeryl, cyclohexanoyl, benzoyl, 4- picolinoyls, 3- pyridines
Formoxyl, 2- furanylcarbonyls, 2- Thenoyls, 2- pyrroyl groups, maleoyl and sulphur caprylyl；
R2、R3Can be identical or different, it is independent hydrogen, formoxyl, acetyl group, ring valeryl, cyclohexanoyl, benzoyl
Base, 4- picolinoyls, 3- picolinoyls, 2- furanylcarbonyls, 2- Thenoyls, 2- pyrroyl groups, maleoyl
And sulphur caprylyl.
In second preferred embodiment of the present invention,
R1For 1- imidazole radicals, 1- triazol radicals, 3- uracil bases, 1- cytimidines base, 9- adenyls, 9-guanine base,
N- morpholinyls or-X-R4Segment, wherein X be O, S or N atom, R4It is independent hydrogen, benzyl, 1- adamantyls or adamantane
Methyl, acetyl group；
R2、R3Can be identical or different, it is independent hydrogen, acetyl group, benzoyl, 4- picolinoyls.
In order to which preparation needs, the present invention also needs to further protect the pharmaceutical salt of above compound, and acceptable salt is
Acylate, inorganic acid salt, organic alkali salt or inorganic base salts, wherein organic acid include acetic acid, methanesulfonic acid, citric acid, fumaric acid,
Maleic acid, glycolic, lactic acid, salicylic acid, succinic acid, p-methyl benzenesulfonic acid, tartaric acid, methanesulfonic acid, malonic acid, lipoic acid；It is inorganic
Acid includes, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid；Organic base includes meglumine, Glucosamine；Inorganic base includes alkali gold
Belong to the alkali compounds of sodium, potassium, barium, calcium, magnesium, zinc.
The chemical name and structural formula of particularly preferred compound are as follows：
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (3- thymine bases) -14 deoxyandrographolides：
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (3- ureas pyrimidine radicals) -14 deoxyandrographolides：
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (1- cytimidines base) -14 deoxyandrographolides：
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (1- triazol radicals) -14 deoxyandrographolides：
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (N- adamantane amido) -14 deoxyandrographolides：
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (N- morpholinyls) -14 deoxyandrographolides：
3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (N- benzamido groups) -14 deoxyandrographolides：
3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (1- imidazole radicals) -14 deoxyandrographolides：
- 14 deoxyandrographolide of two dehydrogenation -17- sulfydryls of 3 α, 19- dihydroxy -8,9-：
- 14 deoxyandrographolide of two dehydrogenation -17- amino of 3 α, 19- dihydroxy -8,9-：
Invention further provides the preparation method of above-mentioned part of compounds, but it is not limited only to following preparation methods：
Using andrographolide as raw material, with lewis acid, such as：AlCl3, ZnCl2, BF3·Et2O is catalyst, in 20-
Esterification occurs with aceticanhydride under the conditions of 100 DEG C, reacts 1-5 hours.After reaction, reaction system is cooled to room temperature, and
Reaction solution is poured into ice water, washes out white precipitate.It filters, filter cake is washed with water to neutrality.After to be dried, with proper amount of methanol or
Ethyl alcohol makes it completely dissolved, and reducing agent NaBH4 or LiBH4 are disposably added in into this solution, and reaction temperature is controlled at 40-80 DEG C
Reaction 40 minutes~2 hours.Then reaction solution is poured into ice water, white solid is precipitated, filtered.After drying, gained is produced
Product are dissolved in dichloromethane or chloroform, add in N-methylmorpholine-N oxides and selenium dioxide thereto, in the lower reaction 5-10 of reflux
Hour.Washed reaction liquid twice, concentrates after dry, obtained material open silica gel chromatography (expansion system：Chloroform：Third
Ketone=100:1).Gained intermediate is dissolved in tetrahydrofuran, paratoluensulfonyl chloride and pyridine are instilled simultaneously at 0-10 DEG C, is dripped
Finish, back flow reaction 2-4 hours.Without purifying, electrophilic reagent is directly added in thereto, such as：It is imidazoles sylvite, triazole sylvite, each
Kind base sylvite, amantadine and Rimantadine and benzylamine.Add in appropriate potassium hydroxide, back flow reaction 4-10 in ethanol later
Hour, removing acetyl group is to get the compounds of this invention.
The present invention also provides a kind of pharmaceutical compositions, are the compound or its pharmaceutically acceptable salt of more than formula (I)
As active constituent.The compound of the present invention can be mixed with pharmaceutically acceptable diluent, adjuvant and/or carrier faces
The Pharmaceutical composition needed on bed.When the pharmaceutical composition of the present invention is applied to clinical, several dosage form can be configured to,
Such as:Oral preparation (such as tablet, capsule, pastille, solution or suspension)；(solution of such as injectable is mixed for the preparation of injectable
The dried powder of suspension or injectable, adding in water for injection before the injection can use immediately)；Topical formulations (such as ointment or
Solution).Carrier for the pharmaceutical composition of the present invention is the available common vector of pharmaceutical field, including：Oral preparation is used
Adhesive, lubricant, disintegrant, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent etc.；Injectable formulation
Preservative, solubilizer, stabilizer etc.；Matrix, diluent, lubricant, preservative of topical formulations etc..Pharmaceutical preparation can
With by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) administration, if some drugs are in stomach condition
Under be unstable, enteric coated tablets can be configured to.
The compound of the present invention has the following advantages compared with the immediate prior art：
(1) a kind of new antiviral compound, its isomers or its pharmaceutically acceptable salt are provided for the first time, it is disease-resistant
Cytotoxic activity is stronger, drug resistance is more preferable, is worth in clinical promotion and application.
(2) present invention has further carried out Antiviral breeding to part of compounds, including cellulotoxic experiment and external disease-resistant
Poison experiment, the experimental results showed that the compounds of this invention, to having good inhibiting effect for examination H3N2, part of compounds is due to sun
Property comparison medicine virazole, and do not show overt toxicity to cell, good therapeutic index is shown, the results are shown in Table 1.
(3) preparation process of above compound of the present invention is simple, and drug purity height, high income, stable quality are easy to carry out
Large-scale production.
Specific embodiment
The specific embodiment of form by the following examples does further specifically the above of the present invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
Embodiment 1：The preparation of the compounds of this invention
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (3- thymine bases) -14 deoxyandrographolides (abbreviation compound
1) preparation：
Using andrographolide as raw material, in the presence of the anhydrous ZnCl2 of 4g, by andrographolide (10g, 28.55mmol) and
40ml aceticanhydrides are heated to reflux, and the reaction was continued until reaction solution is clarified.Reaction solution is poured into ice water, is vigorously stirred, is filtered, is used
Water washing filter cake to neutrality, filter cake recrystallization obtains 3 α, 14,19- triacetyl andrographolide fine work 12.5g, yield
91.8%.20ml methanol is dissolved in, disposably adds in 0.4g NaBH at room temperature4, the reaction was continued 5 hours.Reaction solution is poured into
It in ice water, is vigorously stirred, filters, filter cake vacuum drying is recrystallized to give 3 α, -14 deoxyandrographolide of 19- diacetyls
6.5g, yield 65%.
By 3 α of 10g, -14 deoxyandrographolide of 19- diacetyls, 5g N-methylmorpholine-N oxides and 3.8g dioxies
Change selenium to be dissolved in 20mL dichloromethane, back flow reaction 10 hours, washed reaction liquid twice, concentrates after dry, and obtained material is with opening
It puts silica gel chromatography and obtains 3 α, -14 deoxyandrographolide of two dehydrogenation -17- hydroxyls of 19- diacetyls -8,9-.By 0.5g
It is dissolved in 20mL tetrahydrofurans the said goods, and room temperature instills 2mL paratoluensulfonyl chlorides and 4mL pyridines simultaneously, and drop finishes, in this temperature
Degree is lower, and the reaction was continued 2 hours.Without purifying, 0.5 gram of 3- thymidines sylvite and NaI 69mg are directly added into, is reacted at 65 DEG C
24 hours.After reaction, it is cooled to room temperature, 10mL washings are primary, and water layer is extracted 2 times with 1,2- dichloroethanes (5mL), merge
Organic phase, 10mL saturated nacl aqueous solutions are washed once, and open silica gel chromatography obtains light yellow solid, yield 78%.1H-
NMR(600MHz,DMSO-d6)δ(ppm)：3.120 (1H, dd, J=10.2,4.8Hz, H-3), 7.549 (1H, brt, J=
6.0Hz, H-14), 4.825 (2H, brs, H-15), 3.265 (1H, d, J=10.8Hz, H-17a), 3.815 (1H, d, J=
11.4Hz, H-17b), 0.932 (3H, s, H-18), 4.255 (1H, d, J=15.0Hz, H-19a), 4.306 (1H, d, J=
15.0Hz,H-19b)、1.062(3H,s,H-20)、7.265(1H,brt,H-4’)、1.742(3H,s,H-7’)、11.207(1H,
s,N-H)。
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (3- ureas pyrimidine radicals) -14 deoxyandrographolides (abbreviation compound 2)
Preparation：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, bis- dehydrogenation -17- of 19- dihydroxy 8,9- (3- ureas pyrimidine radicals) -14 deoxyandrographolides.1H-NMR
(600MHz,DMSO-d6)δ(ppm)：3.195 (1H, dd, J=10.8,5.4Hz, H-3), 7.550 (1H, brt, J=6.0Hz,
H-14), 4.825 (2H, brs, H-15), 3.268 (1H, d, J=10.2Hz, H-17a), 3.810 (1H, d, J=10.8Hz, H-
17b), 0.933 (3H, s, H-18), 4.727 (1H, d, J=15.0Hz, H-19a), 4.333 (1H, d, J=14.4Hz, H-
19b), 1.054 (3H, s, H-20), 5.550 (1H, d, J=7.8Hz, H-4 '), 7.392 (1H, d, J=7.8Hz, H-5 ').
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (1- cytimidines base) -14 deoxyandrographolides (abbreviation compound 3)
Preparation：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, bis- dehydrogenation -17- of 19- dihydroxy 8,9- (1- cytimidines base) -14 deoxyandrographolides.1H-NMR
(600MHz,DMSO-d6)δ(ppm)：3.919 (1H, dd, J=10.8,5.4Hz, H-3), 7.547 (1H, brt, J=6.0Hz,
H-14), 4.818 (2H, s, H-15), 4.298 (1H, d, J=15.0Hz, H-17a), 4.260 (1H, d, J=14.4Hz, H-
17b), 0.925 (3H, s, H-18), 3.810 (1H, d, J=11.4Hz, H-19a), 3.254 (1H, d, J=10.8Hz, H-
19b), 1.053 (3H, s, H-20), 7.346 (1H, s, J=7.2Hz, H-5 '), 5.691 (1H, s, J=6.6Hz, H-3 ').
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (1- triazol radicals) -14 deoxyandrographolides (abbreviation compound 4)
Preparation：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (1- triazol radicals) -14 deoxyandrographolides.1H-NMR
(600MHz,DMSO-d6)δ(ppm)：3.198 (1H, dd, J=10.8,5.4Hz, H-3), 7.568 (1H, brt, J=6.0Hz,
H-14), 4.828 (2H, s, H-15), 4.841 (1H, d, J=15.0Hz, H-17a), 4.753 (1H, d, J=14.4Hz, H-
17b), 0.934 (3H, s, H-18), 3.810 (1H, d, J=11.4Hz, H-19a), 3.260 (1H, d, J=10.8Hz, H-
19b)、1.045(3H,s,H-20)、8.485(1H,s,H-5’)、7.939(1H,s,H-3’)。
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (N- adamantane amido) -14 deoxyandrographolides (abbreviation compound
5) preparation：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, bis- dehydrogenation -17- of 19- dihydroxy 8,9- (N- adamantane amido) -14 deoxyandrographolides.1H-NMR
(600MHz,DMSO-d6)δ(ppm)：3.203 (1H, dd, J=10.8,5.4Hz, H-3), 7.498 (1H, brt, J=6.0Hz,
H-14), 4.813 (2H, s, H-15), 3.844 (1H, d, J=10.8Hz, H-17a), 3.258 (1H, d, J=11.4Hz, H-
17b), 0.910 (3H, s, H-18), 2.941 (1H, d, J=12.6Hz, H-19a), 2.747 (1H, d, J=13.2Hz, H-
19b)、1.077(3H,s,H-20)。
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (N- morpholinyls) -14 deoxyandrographolides (abbreviation compound 6)
It prepares：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (N- morpholinyls) -14 deoxyandrographolides.1H-NMR
(600MHz,DMSO-d6)δ(ppm)：3.182 (1H, dd, J=10.8,5.4Hz, H-3), 7.617 (1H, brt, J=6.0Hz,
H-14), 4.846 (2H, s, H-15), 3.774 (1H, d, J=16.8Hz, H-17a), 3.889 (1H, d, J=16.8Hz, H-
17b), 0.942 (3H, s, H-18), 3.812 (1H, d, J=10.8Hz, H-19a), 3.273 (1H, d, J=10.8Hz, H-
19b)、1.079(3H,s,H-20)、3.392(4H,brs,H-3’,5’)、3.088(4H,brs,H-2’,6’)
3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (N- benzamido groups) -14 deoxyandrographolides (abbreviation compound 7)
It prepares：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (N- benzamido groups) -14 deoxyandrographolides.1H-NMR
(600MHz,DMSO-d6)δ(ppm)：3.188 (1H, dd, J=10.8,5.4Hz, H-3), 7.624 (1H, brt, J=6.0Hz,
H-14), 4.785 (2H, s, H-15), 3.841 (1H, d, J=10.8Hz, H-17a), 3.256 (1H, d, J=10.8Hz, H-
17b), 0.894 (3H, s, H-18), 3.128 (1H, d, J=12.0Hz, H-19a), 2.949 (1H, d, J=12.6Hz, H-
19b), 1.077 (3H, s, H-20), 7.311 (2H, dd, J=7.2Hz, H-3 ', 5 '), 7.266 (2H, dd, J=7.2Hz, H-
2’,6’)、7.204(1H,m,H-4’)、3.663(2H)。
3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (1- imidazole radicals) -14 deoxyandrographolides (abbreviation compound 8)
It prepares：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (1- imidazole radicals) -14 deoxyandrographolides.1H-NMR
(600MHz,DMSO-d6)δ(ppm)：3.19 (1H, dd, J=10.8,5.4Hz, H-3), 7.57 (1H, brt, J=6.0Hz, H-
14), 4.83 (2H, s, H-15), 4.82 (1H, d, J=15.0Hz, H-17a), 4.72 (1H, d, J=14.4Hz, H-17b),
0.91 (3H, s, H-18), 3.82 (1H, d, J=11.4Hz, H-19a), 3.26 (1H, d, J=10.8Hz, H-19b), 1.04
(3H,s,H-20)、8.19(1H,s,H-5’)、7.939(1H,brs,H-3’)、7.79(1H,brs,H-4’)。
The preparation of -14 deoxyandrographolide (abbreviation compound 9) of two dehydrogenation -17- sulfydryls of 3 α, 19- dihydroxy -8,9-：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, -14 deoxyandrographolide of two dehydrogenation -17- sulfydryls of 19- dihydroxy -8,9-.1H-NMR(600MHz,
pyridine-d5)δ(ppm)：7.21 (1H, brs, H-14), 4.76 (2H, brs, H-15), 4.60 (1H, d, J=11.8Hz, H-
17), 4.40 (1H, d, J=11.8Hz, H-17), 4.53 (1H, d, J=10.6Hz, H-19), 3.70 (1H, d, J=10.6Hz,
H-19), 3.67 (1H, o, H-3), 1.56 (3H, s), 1.05 (3H, s).
The preparation of -14 deoxyandrographolide (abbreviation compound 10) of two dehydrogenation -17- amino of 3 α, 19- dihydroxy -8,9-：
Concrete operations and the preparation for matching reference compound 1.
Obtain 3 α, -14 deoxyandrographolide of two dehydrogenation -17- amino of 19- dihydroxy -8,9-.1H-NMR(600MHz,
pyridine-d5)δ(ppm)：7.24 (1H, brs, H-14), 4.69 (2H, brs, H-15), 4.71 (1H, d, J=11.8Hz, H-
17), 4.52 (1H, d, J=11.8Hz, H-17), 4.43 (1H, d, J=10.6Hz, H-19), 3.75 (1H, d, J=10.6Hz,
H-19), 3.64 (1H, o, H-3), 1.53 (3H, s), 1.15 (3H, s).
The preventing respiratory viruses research of 2 product of the present invention of embodiment
First, material
Strain：Influenza A virus (A3/ capital section/30/95), by Shanghai City, health and epidemic prevention station provides, and through Shanghai, Fudan University is big
The passage of antiviral study room is learned to preserve.
Cell model：Dog kidney cells mdck cell (is passed on through Fudan University in Shanghai antiviral study room and is preserved).
2nd, drug cytotoxicity is tested
Toxotest：Mdck cell is in 37 DEG C of 96 well culture plate monolayer cultivation, 5%CO2Supernatant is abandoned in culture 24 hours, suction
Liquid was separately added into various concentration liquid, each a concentration of 4 hole, through 72 hours observation toxicity.
3rd, cell phenotype conversion
Mdck cell is in 37 DEG C of 96 well culture plate monolayer cultivation, 5%CO2Supernatant is abandoned in culture 24 hours, suction, and cell is through dilute
Liquid washing is released, inhales and abandons cleaning solution, addition 30TCID50 virus liquids, 37 DEG C, 5%CO2Absorption 2 hours sucks virus, adds in 5
Concentration liquid, each a concentration of 4 hole, through 37 DEG C, 5%CO2Culture 72 hours, observation CPE (lesion), if cell controls group, disease
Malicious control group, positive controls (Ribavirin) and medicine group, while CPE is observed, calculate IC50(half effective inhibition concentration).
1 part of compounds antiviral activity of table
Claims (7)
1. with compound or its pharmaceutically acceptable salt described in general formula (I)：
Wherein,
R1For phenyl, naphthalene, 1- imidazole radicals, 1- triazol radicals, 1- uracil bases, 3- uracil bases, 1- cytimidines base, 1- thymus gland
Pyrimidine radicals, 3- thymine bases, 7- adenyls, 9- adenyls, 7- guanyl-s, 9-guanine base or-X-R4, wherein X
For S, R4For hydrogen, benzyl, phenethyl, 1- adamantyls or adamantane methyl；
R2、R3For hydrogen.
2. following compound or its pharmaceutically acceptable salt, are selected from：
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (3- thymine bases) -14 deoxyandrographolides
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (3- uracil bases) -14 deoxyandrographolides
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (1- cytimidines base) -14 deoxyandrographolides
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (1- triazol radicals) -14 deoxyandrographolides
Bis- dehydrogenation -17- of 3 α, 19- dihydroxy 8,9- (N- adamantane amido) -14 deoxyandrographolides
3 α, 19- dihydroxy 8,9- bis- dehydrogenation -17- (N- morpholinyls) -14 deoxyandrographolides
3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (N- benzamido groups) -14 deoxyandrographolides
3 α, 19- dihydroxy -8,9- two dehydrogenation -17- (1- imidazole radicals) -14 deoxyandrographolides
- 14 deoxyandrographolide of two dehydrogenation -17- sulfydryls of 3 α, 19- dihydroxy -8,9-
- 14 deoxyandrographolide of two dehydrogenation -17- amino of 3 α, 19- dihydroxy -8,9-.
3. compound or its pharmaceutically acceptable salt described in claim 1-2 any one, wherein, described pharmaceutically may be used
The salt of receiving is acylate or inorganic acid salt.
4. a kind of pharmaceutical composition includes the compound or its pharmaceutically acceptable salt described in claim 1-2 any one
With one or more pharmaceutical carriers and/or diluent.
5. a kind of pharmaceutical preparation, comprising the compound described in claim 1-2 any one or its pharmaceutically acceptable salt or
Pharmaceutical composition described in right 4.
6. the medicine described in compound or its pharmaceutically acceptable salt or claim 4 described in claim 1-2 any one
Pharmaceutical preparation described in compositions or claim 5 is in the medicine for preparing treatment and/or prevention respiratory viral infection disease
Application in object.
7. the medicine described in compound or its pharmaceutically acceptable salt or claim 4 described in claim 1-2 any one
Application of the pharmaceutical preparation in treatment and/or prevention influenza A virus medicament is prepared described in compositions or claim 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510535244.4A CN105367558B (en) | 2015-08-27 | 2015-08-27 | Andrographolidume derivative and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510535244.4A CN105367558B (en) | 2015-08-27 | 2015-08-27 | Andrographolidume derivative and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105367558A CN105367558A (en) | 2016-03-02 |
| CN105367558B true CN105367558B (en) | 2018-07-03 |
Family
ID=55370244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510535244.4A Active CN105367558B (en) | 2015-08-27 | 2015-08-27 | Andrographolidume derivative and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105367558B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2955294T3 (en) | 2017-05-24 | 2023-11-29 | Heilongjiang zhenbaodao pharmaceutical co ltd | Saline and crystalline form of modified andrographolide compound and method of preparation thereof |
| CN110092777B (en) * | 2019-05-29 | 2020-07-14 | 江西省中医药研究院 | Dehydroandrographolide derivative and preparation method and application thereof |
| CN113264909A (en) * | 2020-02-16 | 2021-08-17 | 沈阳药科大学 | Andrographolide derivative and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101190912A (en) * | 2006-12-01 | 2008-06-04 | 黄振华 | Antiviral compound and preparation method thereof |
| CN101376651A (en) * | 2007-08-28 | 2009-03-04 | 北京美倍他药物研究有限公司 | Andrographolide and water-soluble aminoacid ester derivative of dewatered andrographolide |
| CN101531649A (en) * | 2008-03-12 | 2009-09-16 | 北京天恒永康医药科技有限责任公司 | Method for preparing andrographolide derivatives and preparation thereof |
| CN101570524A (en) * | 2009-06-16 | 2009-11-04 | 南京工业大学 | Substituted andrographolide derivative and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006008115A1 (en) * | 2004-07-16 | 2006-01-26 | Universidad Austral De Chile | Diterpenic labdans as immunostimulants for treating infectious diseases |
-
2015
- 2015-08-27 CN CN201510535244.4A patent/CN105367558B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101190912A (en) * | 2006-12-01 | 2008-06-04 | 黄振华 | Antiviral compound and preparation method thereof |
| CN101376651A (en) * | 2007-08-28 | 2009-03-04 | 北京美倍他药物研究有限公司 | Andrographolide and water-soluble aminoacid ester derivative of dewatered andrographolide |
| CN101531649A (en) * | 2008-03-12 | 2009-09-16 | 北京天恒永康医药科技有限责任公司 | Method for preparing andrographolide derivatives and preparation thereof |
| CN101570524A (en) * | 2009-06-16 | 2009-11-04 | 南京工业大学 | Substituted andrographolide derivative and preparation method and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| Microbial transformation of 14-deoxy-11, 12-didehydroandrographolide and 14-deoxyandrographolide and inhibitory effects on nitric oxide production of the transformation products;Li-Xia Chen et al.;《Journal of Molecular Catalysis B: Enzymatic》;20110625;第72卷;第248-255页 * |
| Microbial transformation of deoxyandrographolide and their inhibitory activity on LPS-induced NO production in RAW 264.7 macrophages;Sa Deng et al.;《Bioorganic & Medicinal Chemistry Letters》;20120104;第22卷;第1615-1618页 * |
| Microbial transformation of neoandrographolide by Mucor spinosus (AS 3.2450);Yixiong Wang et al.;《Journal of Molecular Catalysis B: Enzymatic》;20101023;第68卷;第83-88页 * |
| Synthesis and Cytotoxic Activity of 12-Methyleneurea-14-deoxyandrographolide Derivatives;Xu Chong et al.;《Chinese Journal of Natural Medicines》;20110120;第9卷(第1期);第0046-0050页 * |
| 穿心莲二萜内酯类化学成分的研究;陈丽霞 等;《中国中药杂志》;20061031;第31卷(第19期);第1594-1597页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105367558A (en) | 2016-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103961340B (en) | A kind of LSD1 inhibitor and its application | |
| CN113181339B (en) | Medicinal application of aldehyde compound | |
| CN105849100A (en) | Inhibitors of influenza viruses replication | |
| WO2008116385A1 (en) | Caffeoyl quinic acid derivatives containing nitrogen, and preparation method, pharmaceutically composition and usage thereof | |
| CN105367558B (en) | Andrographolidume derivative and its preparation method and application | |
| JP4654187B2 (en) | Isoflavone derivatives of tectorigenin, their preparation, and antiviral agents containing them as active ingredients | |
| CN106946760A (en) | Derivatives of indirubin or pharmaceutically receptible salt are used for antineoplastic and preparation method | |
| CN100361975C (en) | Novel 5-hydroxy-3-carboxylate indoles derivant and method for preparing the same | |
| CN101190912A (en) | Antiviral compound and preparation method thereof | |
| CN107459496A (en) | Application of the novel thiazole analog derivative in treatment virus infection | |
| CN112771048B (en) | Inhibitors of influenza virus replication and intermediates and uses thereof | |
| CN108129366B (en) | Antiviral compounds, methods of preparation and uses thereof | |
| CN103864642B (en) | Rhein derivatives and preparation method and use thereof | |
| CN106632133B (en) | Thiazole derivative and the preparation method and application thereof | |
| CN104447481B (en) | Benzoic acid Thiourea resisiting influenza virus compound and its production and use | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN103450184A (en) | Salt of scoulerine derivatives | |
| CN101541717A (en) | A trans-cinnamic acid derivative, its preparation method and the use | |
| TWI599571B (en) | Process for prepararing intermediate compound of ixazomib citrate, and ixazomib citrate made thereby | |
| CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
| CN111670191A (en) | Crystal form of pyridone derivative, preparation method and application | |
| CN112939864B (en) | Spiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3-ones | |
| CN100357284C (en) | Compounds against influenza virus and their preparing process and application | |
| CN113398125B (en) | Tezonite pharmaceutical composition and medical application thereof | |
| CN115804764B (en) | Application of secoisolariciresinol diglucoside compound in preparation of medicine with respiratory syncytial virus resisting effect |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |