CN104672249A - Podophyllotoxin derivative, preparation method thereof, medicinal composition and application thereof - Google Patents

Podophyllotoxin derivative, preparation method thereof, medicinal composition and application thereof Download PDF

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Publication number
CN104672249A
CN104672249A CN201410690846.2A CN201410690846A CN104672249A CN 104672249 A CN104672249 A CN 104672249A CN 201410690846 A CN201410690846 A CN 201410690846A CN 104672249 A CN104672249 A CN 104672249A
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formula
compound
amino
alkyl
halogen
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Inventor
肖旭华
孙亚飞
沈舜义
刘全海
肖璘
樊钱永
张志宏
任岩松
姚利霞
张锴婷
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention discloses a podophyllotoxin derivative shown by a general formula I, a preparation method thereof, a medicinal composition and an application thereof. In the podophyllotoxin derivative shown by the general formula I, X is oxygen or nitrogen, R1 is monosubstituted or polysubstituted, has arbitrary substitution positions, and is one or more of halogen, C1-C4 alkyl, C1-C4 alkoxy, amino group, nitro group and hydroxyl, and R2 is hydrogen or C1-C4 alkyl. The podophyllotoxin derivative disclosed by the invention has good tumor cell inhibitory activity, the antitumor activity of certain compounds is obviously superior to that of etoposide, and part of the compounds has relatively good inhibitory activity to human lung cancer cells in particular non-small cell lung cancer cell strains A549, thereby providing a new research and development direction for developing broad-spectrum, efficient and low-toxicity podophyllotoxin derivatives. Moreover, the podophyllotoxin derivative disclosed by the invention is simple in preparation method and has a good market development prospect.

Description

Podophyllotoxin derivative, its preparation method, pharmaceutical composition and application
Technical field
The present invention relates to a kind of podophyllotoxin derivative, its preparation method, pharmaceutical composition and application.
Background technology
Rely on ripple glycosides (Etoposide, VP-16) and teniposide (VM-26) be the podophyllotoxin derivative of clinical treatment tumour, Etoposide is normal and cisplatin combined is clinically used for the treatment of lung cancer and carcinoma of testis, and curative effect is better, also for lymphadenomatous treatment.Teniposide primary treatment He Jiejin and non Hodgkin lymphoma and have obvious effect, to brain tumor, children's Lymphocytic leukemia also has therapeutic action.But the tumor suppression spectrum of above-mentioned antitumor drug is narrow, simultaneously with serious bone marrow depression and gastrointestinal side effect etc.Podophyllotoxin derivative generally has good inhibited proliferation to human oral cavity epithelial cancer (KB) cell and to mouse lymphocyte leukemia cell (L1210), and inhibited proliferation or very poor is not had to people's lung cancer (non-small cell lung cancer cell strain A549) cell, therefore, this area is needed badly and is found the wide podophyllotoxin derivative of a kind of antitumor spectra, narrow effectively to solve podophyllotoxin analogue antitumor spectra, the defects such as toxic side effect is large.
Summary of the invention
Technical problem to be solved by this invention is that the tumor suppression spectrum in order to solve existing podophyllotoxin derivative is narrow, there are serious bone marrow depression and gastrointestinal side effect etc., and provide a kind of and the diverse podophyllotoxin derivative of prior art, its preparation method, pharmaceutical composition and application.It is active that podophyllotoxin derivative of the present invention has good inhibiting tumour cells, the anti-tumor activity of some compounds is obviously better than Etoposide, part of compounds has good inhibit activities to human lung carcinoma cell (non-small cell lung cancer cell strain A549), this is for expanding the antitumor spectra of podophyllotoxin analogue, and the podophyllotoxin derivative developing high-efficiency low-toxicity provides new R&D direction, and the preparation method of podophyllotoxin derivative of the present invention is simple, has the good prospect of marketing.
The invention provides podophyllotoxin derivative shown in following general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate;
Wherein, the carbon marked with No. * is α configuration chiral carbon or beta comfiguration chiral carbon;
X is oxygen or nitrogen;
R 1for monosubstituted or polysubstituted, the position of substitution is any, R 1for halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, amino, one or more in nitro and hydroxyl;
R 2for hydrogen or C 1~ C 4alkyl;
When X is O, and R 1for time monosubstituted, R 1be not 2-chlorine, 6-chlorine or 5-bromine;
When X is N, and R 1for time monosubstituted, R 1be not 2-chlorine or 6-chlorine;
When X is N, and R 1during for two replacement, R 1be not 4-chlorine and 6-methyl;
Work as R 2during for hydrogen, be beta comfiguration chiral carbon with the carbon of No. * mark; Work as R 2for C 1~ C 4alkyl time, with * mark carbon be α configuration chiral carbon.
R 1in, described halogen is preferably fluorine, chlorine, bromine or iodine.
R 1or R 2in, described C 1~ C 4alkyl be preferably methyl, ethyl, n-propyl, sec.-propyl or butyl.Described butyl is normal-butyl, isobutyl-or the tertiary butyl.
R 1in, described C 1~ C 4alkoxyl group be preferably methoxyl group, oxyethyl group, propoxy-or butoxy.Described propoxy-is preferably positive propoxy or isopropoxy.Described butoxy is preferably n-butoxy, isobutoxy or tert.-butoxy.
In compound of Formula I, R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.
In compound of Formula I, when X is oxygen, R 2during for hydrogen, R 1be preferably halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, one or more in amino and hydroxyl; R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.
In compound of Formula I, when X is oxygen, R 2during for hydrogen, R 1be preferably halogen, C 1~ C 4alkoxyl group and amino in one or more; R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.Work as R 1during for halogen and/or amino, R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.Work as R 1for C 1~ C 4alkoxyl group time, R 1the substituting group represented preferably is positioned at 6 of the carbon atom of pyridine ring.
In compound of Formula I, when X is oxygen, R 2for C 1~ C 4alkyl time, R 1be preferably halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, one or more in amino and hydroxyl; R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.
In compound of Formula I, when X is oxygen, R 2for C 1~ C 4alkyl time, R 1be preferably halogen, C 1~ C 4alkoxyl group and amino in one or more.Work as R 1during for halogen and/or amino, R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more; More preferably be positioned at 2 of the carbon atom of pyridine ring.Work as R 1for C 1~ C 4alkoxyl group time, R 1the substituting group represented preferably is positioned at 2 of the carbon atom of pyridine ring.
In compound of Formula I, when X is nitrogen, R 2during for hydrogen, R 1be preferably halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, one or more in amino and hydroxyl; R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.
In compound of Formula I, when X is nitrogen, R 2during for hydrogen, R 1be preferably halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group and amino in one or more.Work as R 1for C 1~ C 4alkyl and/or amino time, R 1the substituting group represented preferably is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more; More preferably be positioned at 2 and/or 6 of the carbon atom of pyridine ring.Work as R 1for C 1~ C 4alkoxyl group time, R 1the substituting group represented preferably is positioned at 6 of the carbon atom of pyridine ring.Work as R 1during for halogen, R 1be preferably monosubstituted; R 1the substituting group represented preferably is positioned at 5 of the carbon atom of pyridine ring.
In compound of Formula I, when X is oxygen or nitrogen, R 2during for hydrogen, R 1be preferably amino, amino 2 of being preferably positioned at the carbon atom of pyridine ring.
Podophyllotoxin derivative shown in described general formula I, its steric isomer, tautomer, its pharmacy acceptable salt, prodrug or solvate best, are following arbitrary compound:
Present invention also offers the podophyllotoxin derivative shown in described general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate for the preparation of the application in the medicine of Therapeutic cancer.Described cancer is preferably lung cancer, oral carcinoma, liver cancer or leukemia, especially lung cancer.Described lung cancer is preferably Non-small cell lung carcinoma.Described oral carcinoma is preferably human oral cavity epithelial cancer.The tumour cell of described cancer is preferably people's non-small cell lung cancer cell, human oral cancer epithelial cell, human liver cancer cell or mice sperm malformation test.Described Non-small cell lung carcinoma cell is preferably people's non-small cell lung cancer cell strain A549.Described human oral cancer cell is preferably human oral cancer epithelial cell strain KB.Described human liver cancer cell is preferably HepG2 cell lines.Described mice sperm malformation test is preferably mouse lymphocyte leukemia cell line L1210.
Present invention also offers a kind of pharmaceutical composition, it comprises one or more in podophyllotoxin derivative shown in above-mentioned general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug and solvate, and pharmaceutically acceptable vehicle.
According to therapeutic purpose, aforementioned pharmaceutical compositions can be made various types of administration unit dosage, such as: aqueous dispersant, liquid, Gel mile, syrup, elixir, medicine slurry, suspension, aerosol, control-released agent, quick-dissolving agent, effervescent, freeze-dried, tablet, powder, pill, sugar-coat are complete, capsule, delayed release agent, extend releasing agent, pulse control-released agent, multiparticulates agent or releasing agent immediately.
Present invention also offers the preparation method of podophyllotoxin derivative shown in a kind of described general formula I, it comprises the following step: in organic solvent, under the existence of alkali, under the effect of condensing agent, by such as formula the compound or its salt shown in A, carry out reaction as follows with such as formula the compound shown in B;
Wherein, R is hydroxyl (-OH) or amino (-NH 2); *, R 1and R 2definition all the same described in.
Wherein, the method for described reaction and condition can be the conventional method of this type of reaction of this area and condition.The present invention is following method and condition particularly preferably: in organic solvent, under the existence of alkali, under the effect of condensing agent and catalyzer, by such as formula the compound or its salt shown in A, reacts with such as formula the compound shown in B.
In the preparation method of the podophyllotoxin derivative shown in described general formula I, the described salt such as formula the compound shown in A refers to the salt that the acid such as formula the compound shown in A and this area routine is formed.The described salt such as formula the compound shown in A is preferably the hydrochloride such as formula the compound shown in A.Described organic solvent is preferably halogenated hydrocarbon solvent and/or amide solvent.Described halogenated hydrocarbon solvent is preferably methylene dichloride.Described amide solvent is preferably DMF (DMF).Described condensing agent is preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI), N, one or more in N '-dicyclohexylcarbodiimide (DCC) and diethyl phosphorocyanidate (DEPC), or, described condensing agent is preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI), N, one or more in N '-dicyclohexylcarbodiimide (DCC) and diethyl phosphorocyanidate (DEPC), with the mixture of 1-hydroxy benzo triazole (HOBt).Described mixture is preferably the mixture of 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) and 1-hydroxy benzo triazole (HOBt), wherein, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) is preferably 1:1 with the mol ratio of 1-hydroxy benzo triazole (HOBt).Described alkali is preferably organic bases, and described organic bases is preferably triethylamine.Described catalyzer is preferably DMAP (DMAP).Described alkali is preferably 1:1 ~ 3:1 with the mol ratio such as formula the compound or its salt shown in A.Described such as formula the compound or its salt shown in A, be preferably 1:1 ~ 1:1.5 with the mol ratio such as formula the compound shown in B.Described condensing agent is preferably 1:1 ~ 3:1 with the mol ratio such as formula the compound or its salt shown in A.Described catalyzer is preferably 0.05:1 ~ 0.1:1 with the mol ratio such as formula the compound or its salt shown in A.Described organic solvent is preferably 1mL/g ~ 10mL/g with the mass volume ratio such as formula the compound or its salt shown in A.The temperature of described reaction is preferably 0 ~ 30 DEG C.The process of described reaction can adopt the traditional test methods in this area (as TLC, HPLC or NMR) to monitor, and the reaction times is preferably 1 ~ 24 hour.
In the preparation method of the podophyllotoxin derivative shown in described general formula I, when X is O, preferably, by such as formula the compound shown in A with carry out esterification such as formula the compound shown in B; Described organic solvent is preferably halogenated hydrocarbon solvent; Described condensing agent is preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) and/or N, N '-dicyclohexylcarbodiimide (DCC); Or, described condensing agent is preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) and/or diethyl phosphorocyanidate (DEPC), with the mixture of 1-hydroxy benzo triazole (HOBt).Described mixture is preferably the mixture of 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) and 1-hydroxy benzo triazole (HOBt), wherein, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) is preferably 1:1 with the mol ratio of 1-hydroxy benzo triazole (HOBt).
In the preparation method of the podophyllotoxin derivative shown in described general formula I, when X is N, preferably, by such as formula the compound shown in A salt with carry out amidate action such as formula the compound shown in B; Described organic solvent is preferably halogenated hydrocarbon solvent and/or amide solvent; Described condensing agent is preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) and/or diethyl phosphorocyanidate (DEPC), is more preferably diethyl phosphorocyanidate (DEPC); Or, described condensing agent is preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) and/or diethyl phosphorocyanidate (DEPC), with the mixture of 1-hydroxy benzo triazole (HOBt).Described mixture is preferably the mixture of 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) and 1-hydroxy benzo triazole (HOBt), wherein, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (EDCI) is preferably 1:1 with the mol ratio of 1-hydroxy benzo triazole (HOBt).
After described reaction terminates, preferably, the operation of aftertreatment can also be comprised.The method of described aftertreatment and condition can be method and the condition of this area aftertreatment routine, preferably comprise the following step: when described organic solvent is halogenated hydrocarbon solvent, after above-mentioned reaction terminates, reaction solution unsaturated carbonate hydrogen aqueous ammonium is washed, washing, dry (such as using anhydrous sodium sulfate drying), except desolventizing, through column chromatography for separation (eluent is preferably dichloromethane/ethyl acetate, methylene dichloride/acetone, methylene chloride/methanol, cyclohexane/ethyl acetate, petrol ether/ethyl acetate); When described organic solvent is amide solvent, after above-mentioned reaction terminates, extraction (as ethyl acetate), pickling (such as massfraction is the aqueous hydrochloric acid of 5%), saturated sodium bicarbonate aqueous solution is washed, washing, after obtaining organic phase, removing organic solvent.In the present invention, the preparation method of the pharmacy acceptable salt of the podophyllotoxin derivative shown in described general formula I and condition also can according to the ordinary method of this area salt-forming reaction and condition preparations.
In the present invention, described room temperature all refers to 10 ~ 30 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is:
It is active that podophyllotoxin derivative of the present invention has good inhibiting tumour cells, the anti-tumor activity of some compounds is obviously better than Etoposide, part of compounds is to human lung carcinoma cell, especially non-small cell lung cancer cell strain A549 has good inhibit activities, this podophyllotoxin derivative for exploitation high-efficiency low-toxicity provides new R&D direction, and the preparation method of podophyllotoxin derivative of the present invention is simple, has the good prospect of marketing.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Room temperature in following embodiment all refers to 10 ~ 35 DEG C; Ice bath all refers to 0 DEG C.
Embodiment 1
4 β-chloroacetyl amido-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin
Under room temperature, by 4 '-demethyl epipodophyllotoxin (10g, 25mmol) be added in chloromethyl cyanide (15mL, 250mmol), drip 0.15mL 98% vitriol oil, stir, can see that insolubles dissolves and adularescent solid generates rapidly, add 50mL isopropanol solid, suction filtration, filter cake continuation 100mL Virahol divides washes 2 times, after wash with water to neutrality.Place the dry 40 DEG C of dry 4h of vacuum drying oven, obtain white solid powder 10g, yield: 84%.
ESI-MS：476(M+H +)，493(M+H 3O +).
1hNMR (DMSO): 8.60 (1H, dd, NH), 8.20 (exchanges of 1H, d, OH heavy water), 6.89 (1H, d, 5H), 6.52 (1H, d, 8H), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o), 5.19 (1H, dd, H-4), 4.5 (1H, d, H-1), 4.34 (1H, t, H-11 α), 3.79 (1H, t, H-11 β), 3.89 (6H, S, 2 ', 6 '-O-CH 3), 3.21 (1H, dd, s, H-1), 3.15 (1H, m, 3H).
Embodiment 2
4 beta-amino-4-deoxidations-4 ' preparation of-demethyl epipodophyllotoxin hydrochloride
By 4 β-ChloroacetYl-4 '-demethyl epipodophyllotoxin (10g, 21mmol) be added in 50mL Glacial acetic acid, be warming up to 80 DEG C, add thiocarbamide (2.4g, 31mmol), can see in about 10min that reaction solution has muddiness to become clarification, maintain 80 DEG C and stir 2.5h, adularescent solid generates, to precipitating not regeneration, stopped reaction, continue to add 50mL Glacial acetic acid, dilution solid, suction filtration, filter cake anhydrous diethyl ether 150mL washs three times, be transferred in vacuum drying oven dry, 4 beta-aminos-4 '-demethyl epipodophyllotoxin hydrochloride 6.85g yield: 84%.
ESI-MS：400(M+H +).
1hNMR (DMSO): 8.60 (2H, s ,-NH2 heavy water exchanges and disappears), 8.20 (1H, s, OH heavy water exchanges and disappears), 7.20 (1H, d, 5H), 6.80 (1H, d, 8H), 6.19 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o), 4.78 (1H, d, H-4), 4.57 (1H, d, H-1), 4.34 (2H, m, H-11 α, β), 3.60 (6H, s, 2 ', 6 '-O-CH 3), 3.08 (1H, m, H-3).
Embodiment 3
4 β-(2-methoxyl group niacinamide)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 1)
Under room temperature, by 2-methoxyl group nicotinic acid (229mg, 1.5mmol), HOBt (204mg, 1.5mmol) EDCI (396mg, 2mmol) drops in 6mL methylene dichloride, stirs 2h, by 4 beta-aminos-4 ' hydrochloride (435mg of-demethyl epipodophyllotoxin, 1mmol) add reaction solution, drip 0.5mL triethylamine, continue reaction 2h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: dichloromethane/ethyl acetate gradient elution) purifying, obtains white solid 212mg, yield: 38%.
ESI-MS：535(M+H +)557(M+Na +).
1hNMR (DMSO): 8.6 (1H, d, 4-pyridine-H), 8.25 (2H, d, N-H ,-OH heavy hydrogen exchanges and disappears), 8.00 (1H, d, 6-pyridine-H), 7.08 (1H, dd, 3-pyridine-H), 6.89 (1H, d, H-5), 6.52 (1H, d, H-8), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH2O-), 5.49 (1H, dd, H-4), 4.5 (1H, d, H-1), 4.54 (1H, t, H-11 α), 3.99 (1H, t, H-11 β), 3.99 (6H, s, 3 ', 5 '-O-CH 3), 3.80 (3H, s, 2-pyridine-OCH 3), 3.36 (2H, d, s, H-1, NH), 3.15 (1H, m, H-3).
Embodiment 4
4 β-(6-methylnicotinamide)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 2)
Under room temperature, by 6-methylnicotinic acid (196mg, 1.6mmol), HOBt (253mg, 1.5mmol) EDCI (305mg, 1.5mmol) drops in 6mL methylene dichloride, stirs 2h, by 4 beta-aminos-4 ' hydrochloride (540mg of-demethyl epipodophyllotoxin, 1.25mmol) add reaction solution, drip 0.5mL triethylamine, continue reaction 2h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: dichloromethane/ethyl acetate gradient elution) purifying, obtains white solid 212mg, yield: 38%.
ESI-MS：519(M+H +)，541(M+Na +).
1hNMR (DMSO): 8.99 (1H, s, 2-pyridine-H), 8.80 (1H, d,-NH), 8.20 (1H, s, OH, heavy water exchanges), 8.19 (1H, dd, 4-pyridine-H), 7.35 (1H, d, 5-pyridine-H), 6.89 (1H, s, H-5), 6.52 (1H, s, H-8), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.45 (1H, dd, H-4), 4.79-4.70 (1H, m, 11a-H), 4.52 (1H, d, H-1), 4.45 (1H, t, H-11 α), 3.80 (1H, t, H-11 β), 3.69 (6H, s, 3 ', 5 '-OCH 3), 3.5 (1H, dd, 2-H), 3.15 (1H, m, H-3), 2.60 (3H, s, 6-pyridine-CH 3).
Embodiment 5
4 β-(2-methylnicotinamide)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 3)
Under room temperature, by 2-methylnicotinic acid (275mg, 1.6mmol), HOBt (270mg, 1.6mmol) EDCI (380mg, 1.6mmol) drops in 6mL methylene dichloride, stirs 2h, by 4 beta-aminos-4 ' hydrochloride (540mg of-demethyl epipodophyllotoxin, 1.25mmol) add reaction solution, drip 0.5mL triethylamine, continue reaction 2h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: dichloromethane/ethyl acetate gradient elution) purifying, obtains white solid 212mg, yield: 33%.
ESI-MS：519(M+H +)，541(M+Na +).
1hNMR (DMSO): 8.60 (1H, d, 4-pyridine-H), 7.61 (1H, d, 6-pyridine-H), 7.19 (1H, m, OH, heavy water exchanges 5-pyridine-H, 6.82 (1H, s, H-5), 6.57 (1H, s, H-8), 6.25 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.45 (1H, dd, H-4), 4.60 (1H, d, H-1), 4.58 (1H, d, H-11 α), 4.00 (1H, t, H-11 β), 3.80 (6H, s, 3 ', 5 '-OCH 3), 3.20 (1H, dd, 2-H), 3.85 (1H, m, H-3), 2.65 (3H, s, 2-pyridine-CH 3).
Embodiment 6
4 β-(6-methoxyl group nicotinoyl amido)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 4)
Under room temperature, by 2-methylnicotinic acid (184mg, 1.6mmol), HOBt (270mg, 1.6mmol) EDCI (380mg, 1.6mmol) drops in 6mL methylene dichloride, stirs 2h, by 4 beta-aminos-4 ' hydrochloride (540mg of-demethyl epipodophyllotoxin, 1.25mmol) add reaction solution, drip 0.5mL triethylamine, continue reaction 2h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: methylene dichloride/acetone gradient elution) purifying, obtains white solid 212mg, yield: 38%.
ESI-MS：535(M+H +)，557(M+Na +).
1hNMR (DMSO): 8.79 (1H, s, 2-pyridine-H), 8.75 (1H, d,-NH), 8.20 (1H, s, OH, heavy water exchanges), 8.19 (1H, dd, 4-pyridine-H), 6.98 (1H, d, 5-pyridine-H), 6.97 (1H, s, H-5), 6.52 (1H, s, H-8), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.45 (1H, dd, H-4), 4.52 (1H, d, H-1), 4.35 (1H, t, H-11 α), 3.90 (6-pyridine-OCH 3), 3.80 (1H, t, H-11 β), 3.69 (6H, s, 3 ', 5 '-OCH 3), 3.08 (1H, m, H-3).
Embodiment 7
4 β-(2-methoxyl group nicotinylsalicylic oxygen)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 5)
Under room temperature, by 2-methoxyl group nicotinic acid (202mg, 1.5mmol), DCC (309mg, 1.5mmol), DMAP (catalytic amount) drops in 6mL methylene dichloride, stirs 15min, by 4 '-demethyl epipodophyllotoxin (414mg, 1mmol) add reaction solution, continue reaction 24h, TLC detection reaction no longer to carry out, stopped reaction.Aftertreatment: suction filtration, filtrate decompression is steamed and is desolventized, and gained crude product, through column chromatography purification (eluent: dichloromethane/ethyl acetate wash-out) purifying, obtains white solid 139mg, yield: 26%.
ESI-MS：536(M+H +)，558(M+Na +).
1hNMR (CDCl 3): 8.25 (1H, dd, 4-pyridine-H), 8.00 (1H, d, 6-pyridine-H), 7.00 (1H, s, H-5), 6.99 (1H, dd, 5-pyridine-H), 6.52 (1H, s, H-8), 6.30 (1H, d, H-4), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.50 (1H, s ,-OH), 4.56 (1H, d, H-1), 4.30 (1H, t, H-11 α), 4.02 (1H, t, H-11 β), 3.90 (3H, s, 2-pyridine-OCH 3), 3.69 (6H, s, 3 ', 5 '-OCH 3), 3.30 (1H, dd, 2), 3.00 (1H, m, H-3).
Embodiment 8
4 β-(6-methylnictotinyl oxygen base)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 6)
Under room temperature, by 6-methylnicotinic acid (184mg, 1.6mmol), HOBt (270mg, 1.6mmol) EDCI (380mg, 1.6mmol) drops in 6mL methylene dichloride, stirs 2h, by 4 '-demethyl epipodophyllotoxin (500mg, 1.25mmol) add reaction solution, drip 0.5mL triethylamine, continue reaction 2h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: methylene dichloride/acetone gradient elution) purifying, obtains white solid 197mg, yield: 38%.
ESI-MS：520(M+H +)，542(M+Na +).
1hNMR (CDCl 3): 9.20 (1H, s, 2-pyridine-H), 8.25 (1H, dd, 4-pyridine-H), 7.23 (1H, d, 5-pyridine-H), 6.99 (1H, s, H-5), 6.58 (1H, s, H-8), 6.28 (2H, s, H-2 ', 6 '), 5.99 (2H, d ,-OCH 2o-), 4.80 (1H, d, H-4), 4.64 (1H, d, H-1), 4.38 (2H, m, 11-α, β-H), 3.64 (6H, s, 3 ', 5 '-OCH 3), 3.23 (1H, dd, 2-H), 2.82 (1H, m, H-3), 2.60 (3H, s, 6-pyridine-CH 3).
Embodiment 9
4 β-(2-methylnictotinyl oxygen base)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 7)
Under room temperature, by 2-methylnicotinic acid (184mg, 1.6mmol), HOBt (270mg, 1.6mmol) EDCI (380mg, 1.6mmol) drops in 6mL methylene dichloride, stirs 2h, by 4 '-demethyl epipodophyllotoxin (500mg, 1.25mmol) add reaction solution, drip 0.5mL triethylamine, continue reaction 2h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: methylene dichloride/acetone gradient elution) purifying, obtains white solid 223mg, yield: 47%.
ESI-MS：552(M+Na +).
1hNMR (DMSO): 8.69 (1H, d, 4-pyridine-H), 8.25 (1H, d, 6-pyridine-H), 7.48 (1H, dd, 5-pyridine-H), 7.00 (1H, s, H-5), 6.60 (1H, s, H-8), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.69 (1H, s ,-OH, heavy water exchanges and disappears), 4.58 (1H, d, H-1), 4.69 (1H, d, H-4), 4.48 (1H, t, H-11 α), 4.23 (1H, t, H-11 β), 3.69 (9H, s, 3 ', 5 '-O-CH 3), 3.20 (2H, d, H-1), 2.89 (1H, m, H-3), 3.71 (3H, s, 2-pyridine-CH 3).
Embodiment 10
4 β-(2,6-bis-chloro-5-fluorine nicotinylsalicylic oxygen)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 8)
Under room temperature, by fluoro-for chloro-for 2,6-bis-5-nicotinic acid (420mg, 2mmol), 4 '-demethyl epipodophyllotoxin (400mg, 1mmol), DMAP (catalytic amount) drops in 4mL methylene dichloride, and instill two triethylamines, stir 0.5h, by EDCI (380,1.25mmol) add reaction solution, after 4.5h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: methylene chloride/methanol gradient elution) purifying, obtains white solid 211mg, yield: 36%.
ESI-MS：592(M+H +).
1hNMR (DMSO-d6): 8.79 (1H, s, 2-pyridine-H), 6.97 (1H, s, H-5), 6.52 (1H, s, H-8), 6.39 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.45 (1H, dd ,-OH, heavy water exchanges and disappears), 4.80 (4H, dd, H-4), 4.40 (1H, d, H-1), 4.20 (1H, t, H-11 α), 3.80 (1H, t, H-11 β), 3.69 (6H, s, 3 ', 5 '-OCH 3), 3.38 (1H, dd, 2-H), 3.08 (1H, m, H-3).
Embodiment 11
4 β-(6-methoxyl group nicotinylsalicylic oxygen)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 9)
At 0 DEG C, by 6-methoxyl group nicotinic acid (765mg, 5mmol), HOBt (1.043g, 7.5mmol), EDCI (1.437g, 7.5mmol) drops in 7mL methylene dichloride, stir 2h, 4 '-demethyl epipodophyllotoxin (1.2g, 3mmol) is added reaction solution, drips 0.5mL triethylamine, continue reaction 3h, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: methylene dichloride/acetone gradient elution) purifying, obtains white solid 203mg, yield: 38%.
ESI-MS：536(M+H +)，558(M+Na +).
1hNMR (DMSO-d 6): 8.90 (1H, s, 2-pyridine-H), 8.25 (1H, dd, 4-pyridine-H), 8.20 (1H, s, OH, heavy water exchanges), 7.00 (1H, s, H-5), 6.98 (1H, d, 5-pyridine-H), 6.52 (1H, s, H-8), 6.35 (1H, d, H-4), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.45 (1H, dd, H-4), 4.62 (1H, d, H-1), 4.35 (1H, t, H-11 α), 3.90 (1H, t, H-11 β), 3.80 (3H, s, 6-pyridine-OCH 3), 3.62 (6H, s, 3 ', 5 '-OCH 3), 3.58 (1H, dd, 2-H), 3.10 (1H, m, H-3).
Embodiment 12
The preparation of 4 α-(2-methoxyl group nicotinylsalicylic oxygen)-4-deoxidation-podophyllotoxin (compound 10)
Use podophyllotoxin (76mg, 0.18mmol) with 2-methoxyl group nicotinic acid (22mg, 0.27mmol) under room temperature, 2-methoxyl group nicotinic acid: EDCI:HOBt (1.5:1.5:1.5) is added in methylene dichloride (methylene dichloride is 5:1 with the volume mass ratio of epipodophyllotoxin), after stirring 2h, epipodophyllotoxin (1eq) and triethylamine (2eq) is added in reaction solution, when TLC detection reaction is no longer carried out, stopped reaction.Reaction solution saturated sodium bicarbonate, washing, anhydrous sodium sulfate drying, revolves and steams except desolventizing, gained solid column chromatographic isolation and purification.Eluent is methylene dichloride and acetone, obtained target compound I-960mg, yield: 63%.
ESI-MS:550 (M+H +), 572 (M+Na +), 397,282,209 (fragment peak).
1hNMR (DMSO-d 6): 8.42 (1H, d, 4-pyridine-H), 8.25 (1H, d, 6-pyridine-H), 7.08 (1H, dd, 5-pyridine-H), 6.60 (1H, s, 5H), 6.60 (1H, s, 8H), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.49 (1H, dd, H-4), 4.58 (1H, d, H-1), 4.54 (1H, t, H-11 α), 4.23 (1H, t, H-11 β), 3.99 (3H, s, 2-pyridine-OCH 3), 3.60 (9H, s, 3 ', 4 ', 5 '-O-CH 3), 3.36 (1H, d, 2-H), 3.15 (1H, m, H-3).
Embodiment 13
The preparation of 4 α-(6-methoxyl group nicotinylsalicylic oxygen)-4-deoxidation-podophyllotoxin (compound 11)
Under room temperature, by 6-methoxyl group nicotinic acid (230mg, 1.5mmol), HOBt (202mg, 1.5mmol) EDCI (288mg, 1.5mmol) drops in 6mL methylene dichloride, stirs 2h, by podophyllotoxin (460mg, 1mmol) add reaction solution, drip 0.5mL triethylamine, continue reaction 2h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filters, remove solvent under reduced pressure, gained crude product, through column chromatography purification (eluent: cyclohexane/ethyl acetate gradient elution) purifying, obtains white solid 312mg, yield: 57%.
MS：550(M+H +)，572(M+Na +).
1hNMR (CDCl 3): 8.82 (1H, s, 2-pyridine-H), 8.19 (1H, d, 4-pyridine-H), 6.83 (1H, s, H-5), 6.80 (1H, d, 5-pyridine-H), 6.60 (1H, s, H-8), 6.43 (2H, s, H-2 ', 6 '), 6.14 (1H, dd, H-4), 6.00 (2H, d ,-OCH 2o-), 4.62 (1H, d, H-1), 4.54 (1H, t, H-11 α), 4.23 (1H, t, H-11 β), 3.99 (3H, s, 2-pyridine-OCH 3), 3.78 (9H, S, 3 ', 4 ', 5 '-O-CH 3), 3.00 (2H, m, H-2, H-3).
Embodiment 14
The preparation of 4 α-(6-methylnictotinyl oxygen base)-4-deoxidation-podophyllotoxin (compound 12)
Under room temperature, by 6-methylnicotinic acid (202mg, 1.5mmol), DCC (309mg, 1.5mmol) DMAP (catalytic amount) drops in 6mL anhydrous tetrahydro furan (THF), stir 15min, podophyllotoxin (414mg, 1mmol) is added reaction solution, and add 2mL methylene dichloride (increasing the meltage of podophyllotoxin), continue reaction 24h, TLC detection reaction no longer to carry out, stopped reaction.Aftertreatment: suction filtration, filtrate decompression is steamed and is desolventized, and gained crude product, through column chromatography purification (eluent: dichloromethane/ethyl acetate wash-out) purifying, obtains white solid 277mg, yield: 57%.
MS：534(M+H +).
1hNMR (CDCl 3): 9.19 (1H, s, 2-pyridine-H), 8.25 (1H, dd, 4-pyridine-H), 7.29 (1H, d, 5-pyridine-H), 7.00 (1H, s, H-5), 6.52 (1H, s, H-8), 6.23 (2H, s, H-2 ', 6 '), 6.12 (1H, d, H-4), 6.00 (2H, d ,-OCH 2o-), 4.62 (1H, d, H-1), 4.35 (1H, t, H-11 α), 3.90 (1H, t, H-11 β), 3.80 (3H, s, 4 '-OCH 3), 3.62 (6H, s, 3 ', 5 ' ,-OCH 3), 3.00 (2H, dd, 2-H, H-3), 2.69 (3H, s, 6 pyridine-CH 3).
Embodiment 15
The preparation of 4 α-(2-hydroxyl nicotinylsalicylic oxygen)-4-deoxidation-podophyllotoxin (compound 13)
With 2-hydroxy niacin 417mg, under room temperature, 2-hydroxy niacin: EDCI:HOBt (1.5:1.5:1.5) is added in methylene dichloride (DCM is 5:1 with the volume mass ratio of podophyllotoxin), after stirring 2h, podophyllotoxin (1eq) and triethylamine (2eq) is added in reaction solution, when TLC detection reaction is no longer carried out, stopped reaction.Reaction solution saturated sodium bicarbonate, washing, anhydrous sodium sulfate drying, revolves and steams except desolventizing, gained solid column chromatographic isolation and purification.Eluent is methylene dichloride and ethyl acetate, obtains white object compound 800mg, yield: 72%.
MS：558(M+Na +)，574(M+K +).
1hNMR (DMSO-d 6): 12 (1H, s, 2-pyridine-OH), 8.19 (1H, d, 4-pyridine-H), 7.68 (1H, d, 6-pyridine-H), 7.00 (1H, s, H-5), 6.58 (1H, s, H-8), 6.40 (2H, s, H-2 ', 6 '), 6.23 (1H, t, 5-pyridine-H), 6.04 (1H, d, H-4), 6.00 (2H, d ,-OCH 2o-), 4.62 (1H, d, H-1), 4.35 (1H, t, H-11 α), 3.90 (1H, t, H-11 β), 3.68 (9H, s, 3 ', 4 ', 5 '-OCH 3), 3.40 (1H, dd, 2-H), 2.89 (1H, m, H-3).
Embodiment 16
4 β-(6-hydroxyl nicotinylsalicylic oxygen)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 14)
Use the 6-hydroxy niacin of 208mg, under room temperature, 6-hydroxy niacin: 4 '-demethyl epipodophyllotoxin: DMAP: triethylamine (1.5:1:0.1:2) is fed in methylene dichloride (volume mass of methylene dichloride and 4 '-demethyl epipodophyllotoxin is than being 5:1), and instill two triethylamines, stir 0.5h, by EDCI (380,1.25mmol) add reaction solution, after 4.5h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, gained crude product is through column chromatography purification.Eluent is methylene dichloride and methyl alcohol, obtains white object compound 170mg, yield: 33.7%.
ESI-MS：522(M+H +)，544(M+Na +).
1h-NMR (DMSO-d 6): 12.17 (1H, s, OH), 8.18 (1H, s, 2-pyridine-H), 7.86 (1H, d, 4-pyridine-H), 6.96 (1H, s, 5H), 6.55 (1H, s, 8H), 6.42 (1H, d, 5-pyridine-H), 6.36 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH2O-), 5.43 (1H, s, H-4), 4.76 (1H, s, H-1), 4.62 (1H, s, H-2), 4.19-4.39 (2H, t, 11-α, β-H), 3.60 (9H, s, 3 ', 5 '-O-CH3), 2.83 (1H, m, H-3).
Embodiment 17
4 β-(2-amino nicotinylsalicylic oxygen)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 15)
138mg 2-amino-nicotinic acid, under room temperature, 2-amido nicotinic acid: 4 '-demethyl epipodophyllotoxin: DMAP: triethylamine (1.5:1:0.1:2) is fed in methylene dichloride (volume mass of methylene dichloride and 4 '-demethyl epipodophyllotoxin is than being 5:1), and instill two triethylamines, stir 0.5h, by EDCI (380,1.25mmol) add reaction solution, after 4.5h, TLC detection reaction is complete, stopped reaction.Aftertreatment: use saturated sodium bicarbonate aqueous solution, washing successively, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, gained crude product is through column chromatography purification.Eluent is methylene dichloride and methyl alcohol, obtains white object compound 200mg, yield: 77%.
ESI-MS：521(M+H +)，543(M+Na +).
1h-NMR (CDCl 3): 8.35 (1H, dd, 6-pyridine-H), 8.25 (1H, dd, 4-pyridine-H), 6.83 (1H, s, H-5), 6.72 (1H, m, 5-pyridine-H), 6.58 (1H, s, H-8), 6.37 (3H, s ,-NH 2with H-2 ', 6 '), 5.99 (2H, d ,-OCH 2o-), 4.80 (1H, d, J=3.2HZ, H-4), 4.33 (2H, m, 11-α, β-H), 3.68 (6H, s, 3 ', 5 '-OCH 3), 3.31 (1H, dd, 2-H), 2.82 (1H, m, H-3).
Embodiment 18
4 β-(2,6-bis-chloro-5-fluorine nicotinoyl amido)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 16)
With 2 of 104mg, the chloro-5-fluorine nicotinic acid of 6-bis-, under ice bath, by 2, the volume mass of the chloro-5-fluorine nicotinic acid of 6-bis-: 4 beta-amino-4-deoxidations-4 '-demethyl epipodophyllotoxin hydrochloride (1:1) drop in DMF (DMF) (DMF and 4 beta-amino-4-deoxidations-4 '-demethyl epipodophyllotoxin hydrochloride is than being 1:1), after stirring 2h under ice bath, add diethyl phosphorocyanidate (DEPC, 1eq) and triethylamine (Et successively 3n, 2eq), under ice bath, (0 DEG C) continues reaction, after TLC detection reaction is complete, 5 times of volume water are added in reaction solution, and be extracted with ethyl acetate, use the aqueous hydrochloric acid of 5% successively, saturated sodium bicarbonate aqueous solution and water washing ethyl acetate layer, removing ethyl acetate, obtain target compound crude product, obtain white solid 105mg, yield: 35.5%.
1H-NMR(400MHz,DMSO-d 6)δ9.09(d,J＝7.9Hz,1H),8.42(d,J＝7.8Hz,1H),8.18(s,1H),6.92(s,1H),6.54(s,1H),6.27(s,2H),6.01(d,J＝8.9Hz,2H),5.34(dd,J＝7.8,4.2Hz,1H),4.51(d,J＝4.8Hz,1H),4.39(t,J＝7.9Hz,1H),4.05(t,J＝9.5Hz,1H),3.65(s,6H),3.14(dd,J＝14.4,4.9Hz,1H),3.10-2.99(m,1H).
Embodiment 19
4 β-(2-aminonicotinamide base)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 17)
With 2-amino-nicotinic acid, under room temperature, 2-amino-nicotinic acid: HOBt:EDCI to add in appropriate methylene dichloride (DCM and 4 beta-amino-4-deoxidations-4 ' volume mass of-demethyl epipodophyllotoxin hydrochloride than being 10:1) according to the feed ratio of 1.5:1.5:1.5, stir 2h, 4 beta-aminos-4 by 1eq '-demethyl epipodophyllotoxin hydrochloride adds reaction solution, drips the triethylamine of 2eq, continues reaction, when TLC detection reaction is completely or reaction no longer carries out, stopped reaction.Aftertreatment: wash with saturated sodium bicarbonate aqueous solution, washing, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, gained crude product is through column chromatography purification, and dichloromethane/ethyl acetate gradient elution (3:1 ~ 1:3, v/v), purifying, obtains target compound.100mg, yield: 19.2%.
ESI-MS：520(M+H +)，542(M+Na +).
1h-NMR (CDCl 3): 8.19 (1H, dd, N-H), 7.55 (1H, dd, pyridine-H), 6.80 (1H, s, H-5), 6.57 (2H, m, pyridine-H, H-8), 6.40 (2H, S ,-NH 2), 6.32 (2H, s, H-2 ', 6 '), 6.00 (2H, d, OCH2O), 6.23 (2H, s, H-2 ', 6 '), 6.00 (2H, d ,-OCH 2o-), 5.38 (1H, dd, H-4), 4.48 (1H, m, H-1), 4.46 (1H, t, H-11 α), 3.87 (1H, t, H-11 β), 3.78 (6H, s, 3 ', 5 '-OCH 3), 3.08 (2H, m, H-3, H-2).
Embodiment 20
4 β-(2-hydroxyl-5-bromine nicotinoyl amido)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 18)
2-hydroxyl-5-bromo-nicotinic acid (56mg, 0.25mmol), under ice bath, by 2-hydroxyl-5-bromo-nicotinic acid: 4 beta-amino-4-deoxidations-4 '-demethyl epipodophyllotoxin hydrochloride (1:1) is added to appropriate N, in dinethylformamide (DMF) (DMF and 4 beta-amino-4-deoxidations-4 ' volume mass of-demethyl epipodophyllotoxin hydrochloride than for 1:1), after stirring 2h under ice bath, add diethyl phosphorocyanidate (DEPC, 1eq) and triethylamine (Et successively 3n, 2eq), under ice bath, (0 DEG C) continues reaction, after TLC detection reaction is complete, adds 5 times of volume water in reaction solution, and be extracted with ethyl acetate, use the aqueous hydrochloric acid of 5% successively, saturated sodium bicarbonate aqueous solution and water washing ethyl acetate layer, removing ethyl acetate, obtain white solid 68mg, yield: 45%.
ESI-MS:600 (M+H +), 601 (M+H +, isotopic peak).
1H-NMR(400MHz,DMSO-d 6)δ11.35(s,1H),8.18(s,1H),8.07(t,J＝8.7Hz,1H),7.90(d,J＝3.1Hz,1H),6.84(s,1H),6.53(s,1H),6.25(d,J＝23.5Hz,2H),5.99(d,J＝12.0Hz,2H),5.34(dd,J＝7.8,4.4Hz,1H),4.57(d,J＝4.9Hz,1H),4.39-4.28(m,1H),3.72(dd,J＝18.1,8.2Hz,2H),3.65(s,6H),3.08-2.88(m,3H).
Embodiment 21
4 β-(the fluoro-nicotinoyl amido of 5-)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 19)
Use 71mg5-fluorine nicotinic acid, under ice bath, by 5-fluorine nicotinic acid: 4 beta-amino-4-deoxidations-4 '-demethyl epipodophyllotoxin hydrochloride (1:1) is added to appropriate N, in dinethylformamide (DMF) (DMF is 2:1 with the volume mass ratio of 4 beta-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin hydrochlorides), after stirring 2h under ice bath, add diethyl phosphorocyanidate (DEPC, 1eq) and triethylamine (Et successively 3n, 2eq), under ice bath, (0 DEG C) continues reaction, after TLC detection reaction is complete, 5 times of volume water are added in reaction solution, and be extracted with ethyl acetate, use the aqueous hydrochloric acid of 5% successively, saturated sodium bicarbonate aqueous solution and water washing ethyl acetate layer, removing ethyl acetate, obtain white solid 154mg, yield: 59%, fusing point 188-189 DEG C.
ESI-MS：545(M+Na +).
1H-NMR(400MHz,DMSO-d 6)δ8.95(s,1H),8.93(d,J＝1.7Hz,1H),8.73(d,J＝2.7Hz,1H),8.22–8.15(m,2H),6.88(s,1H),6.58(s,1H),6.30(s,2H),6.00(d,J＝12.0Hz,2H),5.44(dd,J＝7.9,4.7Hz,1H),4.54(d,J＝5.2Hz,1H),4.35(t,J＝8.0Hz,1H),3.85(dd,J＝10.8,8.7Hz,1H),3.66(s,5H),3.38(dd,J＝14.4,5.3Hz,1H),3.10–2.99(m,1H).
Embodiment 22
4 β-(the bromo-nicotinoyl amido of 5-)-4-deoxidation-4 ' preparation of-demethyl epipodophyllotoxin (compound 20)
With 52mg 5-bromo-nicotinic acid, under ice bath, by 5-bromo-nicotinic acid: 4 beta-amino-4-deoxidations-4 '-demethyl epipodophyllotoxin hydrochloride (1:1) is added to appropriate N, in dinethylformamide (DMF) (DMF is 5:1 with the volume mass ratio of 4 beta-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin hydrochlorides), after stirring 2h under ice bath, add diethyl phosphorocyanidate (DEPC, 1eq) and triethylamine (Et successively 3n, 2eq), under ice bath, (0 DEG C) continues reaction, after TLC detection reaction is complete, 5 times of volume water are added in reaction solution, and be extracted with ethyl acetate, use the aqueous hydrochloric acid of 5% successively, saturated sodium bicarbonate aqueous solution and water washing ethyl acetate layer, removing ethyl acetate, obtain white solid 70mg, yield: 48%, fusing point: 188-181 DEG C.
ESI-MS：524(M+H +)，546(M+Na +).
1H-NMR(400MHz,DMSO-d 6)δ9.10–8.89(m,2H),8.84(s,1H),8.51(s,1H),8.17(s,1H),6.88(s,1H),6.57(s,1H),6.29(s,2H),5.99(d,J＝11.7Hz,2H),5.42(s,1H),4.54(s,1H),4.33(s,1H),3.91-3.80(m,1H),3.66(s,6H),3.45-3.33(m,1H),3.12-2.95(m,1H).
Effect example:
The activity experiment of the part of compounds inhibition tumor cell in the present invention
One, experiment material
1, test compound: the compound 1 ~ 20 prepared by the various embodiments described above.
2, control compound: Etoposide (etoposide, VP-16), cis-platinum (Cisplatin, CDDP).
3, cell strain: Non-small cell lung carcinoma (A549) cell strain, human oral cancer epithelium (KB) cell strain, people's liver cancer (HepG2) cell strain and mouse lymphocyte leukemia (L1210) cell strain.
Two, test method
(1) cell cultures: by A549 cell strain, HepG2 cell strain, KB cell strain and L1210 cell strain take out from liquid nitrogen, thaw rapidly in 37 DEG C of water-baths, cell moves in 10mL sterile centrifugation tube and adds 6mLDMEM cell culture medium in aseptic operating platform, 1000 revs/min of centrifugal 5min.Abandoning supernatant, add 5 ~ 6mLDMEM cell culture medium in precipitation, move in Tissue Culture Flask after dropper piping and druming makes it suspend, put in 37 DEG C of cell culture incubators, next day, in incubator, take out cell, discard the DMEM cell culture medium in cell bottle, add 5 ~ 6mL, next day takes out cell in incubator, discard DMEM cell culture medium in cell bottle, add 5 ~ 6mLDMEM cell culture medium, put in 37 DEG C of cell culture incubators.The next day, in incubator, take out cell, discard DMEM cell culture medium in cell bottle, add PBS (PH7.4) 2 ~ 3mL and rock cleaning, repeat again after outwelling PBS solution once to clean.In culturing bottle, add 3 ~ 5 0.25% trypsin solutions rocks evenly, add a cover and to be placed in 37 DEG C of cell culture incubators about 3 minutes, find that cell departs from culturing bottle wall in basis of microscopic observation, add DMEM cell culture medium 2mL, after dropper piping and druming makes cell depart from bottle wall completely, move in 2 clean culturing bottles respectively, add DMEM cell culture medium 5 ~ 6mL and blow and beat evenly, be placed in 37 DEG C of cell culture incubators.In whole culturing process, cell does not allow growth overstocked.
(2) sample preparation: sample (compound 1 ~ 20) is dissolved in methyl-sulphoxide, obtains the solution that concentration is 10mg/mL.Make gradient dilution with PBS again, obtain the dilute sample that concentration is respectively 1000 μ g/mL, 100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL.
Prepared by reference substance: be dissolved in by cis-platinum in PBS, obtain the solution that concentration is 1mg/mL.Make gradient dilution with PBS again, obtain the dilution reference substance that concentration is respectively 1000 μ g/mL, 100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL.
(3) sample diluted is added in flat 96 orifice plates, every hole 10uL, make two parallel testings at often.By corresponding for DMSO make gradient dilution after add in plate, in contrast.
(4) get the cell being in logarithmic phase, cell is suspended in the DMEM substratum containing 10% calf serum after trysinization also washing, through trypan blu e dyeing exclusive method meter viable count, and regulates cell suspending liquid density to 2 × 10 5cell/mL.
(5) in flat 96 orifice plates, every hole adds 90 microlitres of cells, in 37 DEG C, 5%CO 2overnight incubation in cell culture incubator.
(6) flat 96 orifice plates of cell will be added at 37 DEG C, 5%CO 2cultivate 48 hours in cell culture incubator.
(7) add 20uL5mg/mLMTT solution in every hole, continue to be incubated 3 ~ 4 hours in incubator.
(8) every hole adds 100uL lysate, continues incubated overnight in incubator, generation Jia Za crystal is fully dissolved.Measure 492nm absorbance value.
(9) according to comparative survival rate of cells after absorbance value calculating compound treatment.Calculation formula is as follows:
(10) by the IC of computed in software compound to each tumour cell 50.
Three, experimental result
The inhibiting pharmacological datum of the in-vitro multiplication of podophyllotoxin derivative of the present invention to each cell strain is as shown in table 1.
Table 1
Cytoactive shows: say on the whole, the anti-tumor activity of amides is better than the anti-tumor activity of ester compound.
In ester compound, for podophyllotoxin derivative, when the substituting group on pyridine ring is C 1~ C 4methoxyl group time, 6 replace activity comparatively 2-position replace active good; On pyridine ring, halogen substiuted can increase the inhibit activities of compound on tumor cell, and 2,5 and 6 of pyridine ring when having a halogenic substituent (such as the compounds of this invention 8) simultaneously, better to the inhibit activities of tumour cell.For Etoposide chlorins compound, when the substituting group on pyridine ring is C 1~ C 4methoxyl group time, 2 replace active replace compared with 6 active good.
In amides, when the substituting group on pyridine ring is monosubstituted, and when being methoxyl group, 6 replacements are active active good compared with 2 replacements.When the substituting group on pyridine ring be monosubstituted and for F time, better to the inhibit activities of tumour cell, but when 2,6 of pyridine ring are Cl, and 5 when being F, antitumor activity of compound poor (such as the compounds of this invention 16).
When the 2-amino of pyridine ring replaces, no matter be acid amides or ester compound, all better to the inhibit activities of four kinds of tumour cells, especially to the inhibit activities of A549 cell strain, IC50 value is all at 10 below μ g/mL.
The 6-position of pyridine ring be methyl should active all same compared with the 2-position group of methoxy substitution replace activity will; 2-position replaces, and methyl is active active higher than methoxyl group, when inferring that this position replaces, active relevant with group size.

Claims (17)

1. podophyllotoxin derivative, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate shown in a general formula I;
Wherein, the carbon marked with No. * is α configuration chiral carbon or beta comfiguration chiral carbon;
X is oxygen or nitrogen;
R 1for monosubstituted or polysubstituted, the position of substitution is any, R 1for halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, amino, one or more in nitro and hydroxyl; R 2for hydrogen or C 1~ C 4alkyl;
When X is O, and R 1for time monosubstituted, R 1be not 2-chlorine, 6-chlorine or 5-bromine;
When X is N, and R 1for time monosubstituted, R 1be not 2-chlorine or 6-chlorine;
When X is N, and R 1during for two replacement, R 1be not 4-chlorine and 6-methyl;
Work as R 2during for hydrogen, be beta comfiguration chiral carbon with the carbon of No. * mark; Work as R 2for C 1~ C 4alkyl time, with * mark carbon be α configuration chiral carbon.
2. the podophyllotoxin derivative shown in general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate as claimed in claim 1, is characterized in that,
R 1in, described halogen is fluorine, chlorine, bromine or iodine;
And/or, R 1or R 2in, described C 1~ C 4alkyl be methyl, ethyl, n-propyl, sec.-propyl or butyl;
And/or, R 1in, described C 1~ C 4alkoxyl group be methoxyl group, oxyethyl group, propoxy-or butoxy.
3. the podophyllotoxin derivative shown in general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate as claimed in claim 1, is characterized in that, R 1the substituting group represented is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.
4. the podophyllotoxin derivative shown in general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate as claimed in claim 1, is characterized in that,
When X is oxygen, R 2during for hydrogen, R 1for halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, one or more in amino and hydroxyl; R 1the substituting group represented is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more;
When X is oxygen, R 2for C 1~ C 4alkyl time, R 1for halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, one or more in amino and hydroxyl; R 1the substituting group represented is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more;
When X is nitrogen, R 2during for hydrogen, R 1for halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group, one or more in amino and hydroxyl; R 1the substituting group represented is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more.
5. the podophyllotoxin derivative shown in general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate as claimed in claim 4, is characterized in that,
When X is oxygen, R 2during for hydrogen, R 1for halogen, C 1~ C 4alkoxyl group and amino in one or more; Work as R 1during for halogen and/or amino, R 1the substituting group represented is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more; Work as R 1for C 1~ C 4alkoxyl group time, R 1the substituting group represented is positioned at 6 of the carbon atom of pyridine ring;
When X is oxygen, R 2for C 1~ C 4alkyl time, R 1for halogen, C 1~ C 4alkoxyl group and amino in one or more; Work as R 1during for halogen and/or amino, R 1the substituting group represented is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more; Work as R 1for C 1~ C 4alkoxyl group time, R 1the substituting group represented is positioned at 2 of the carbon atom of pyridine ring;
When X is nitrogen, R 2during for hydrogen, R 1for halogen, C 1~ C 4alkyl, C 1~ C 4alkoxyl group and amino in one or more; Work as R 1for C 1~ C 4alkyl and/or amino time, R 1the substituting group represented is arranged in 2,5 of the carbon atom of pyridine ring and 6 one or more; Work as R 1for C 1~ C 4alkoxyl group time, R 1the substituting group represented is positioned at 6 of the carbon atom of pyridine ring; Work as R 1during for halogen, R 1for monosubstituted; R 1the substituting group represented is positioned at 5 of the carbon atom of pyridine ring.
6. the podophyllotoxin derivative shown in general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate as claimed in claim 1, it is characterized in that, X is oxygen or nitrogen, R 2for hydrogen, R 1for amino.
7. the podophyllotoxin derivative shown in general formula I, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate as claimed in claim 1, it is characterized in that, it is following arbitrary compound:
8. the podophyllotoxin derivative shown in a general formula I as claimed in claim 1, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate are for the preparation of the application in Therapeutic cancer medicine.
9. apply as claimed in claim 8, it is characterized in that, described cancer is lung cancer, oral carcinoma, liver cancer or leukemia.
10. apply as claimed in claim 9, it is characterized in that, described lung cancer is Non-small cell lung carcinoma; And/or described oral carcinoma is human oral cavity epithelial cancer.
11. apply as claimed in claim 10, it is characterized in that, the tumour cell behaviour non-small cell lung cancer cell of described cancer, human oral cancer epithelial cell, human liver cancer cell or mice sperm malformation test.
12. apply as claimed in claim 11, it is characterized in that, described Non-small cell lung carcinoma cell behaviour non-small cell lung cancer cell strain A549; And/or described human oral cancer cell is human oral cancer epithelial cell strain KB; And/or described human liver cancer cell is HepG2 cell lines; And/or described mice sperm malformation test is mouse lymphocyte leukemia cell line L1210.
13. 1 kinds of pharmaceutical compositions, it is characterized in that, it comprises one or more in the podophyllotoxin derivative shown in general formula I as claimed in claim 1, its steric isomer, tautomer, pharmacy acceptable salt, prodrug or solvate, and pharmaceutically acceptable vehicle.
The preparation method of podophyllotoxin derivative shown in 14. general formula Is as claimed in claim 1, it is characterized in that, it comprises the following step: in organic solvent, under the existence of alkali, under the effect of condensing agent, by such as formula the compound or its salt shown in A, carry out reaction as follows with such as formula the compound shown in B;
Wherein, R is hydroxyl or amino; *, the definition of R1 and R2 is as described in any one of claim 1 ~ 6.
15. preparation methods as claimed in claim 14, is characterized in that, in organic solvent, under the existence of alkali, under the effect of condensing agent and catalyzer, by such as formula the compound or its salt shown in A, react with such as formula the compound shown in B.
16. preparation methods as claimed in claim 15, is characterized in that,
The described salt such as formula the compound shown in A is the hydrochloride such as formula the compound shown in A;
And/or described organic solvent is halogenated hydrocarbon solvent and/or amide solvent;
And/or described condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride, N, N ' one or more in-dicyclohexylcarbodiimide and diethyl phosphorocyanidate; Or described condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride, N, N ' one or more in-dicyclohexylcarbodiimide and diethyl phosphorocyanidate, with the mixture of 1-hydroxy benzo triazole; Described mixture is preferably the mixture of 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride and 1-hydroxy benzo triazole; Wherein, the mol ratio of 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride and 1-hydroxy benzo triazole is preferably 1:1;
And/or described alkali is organic bases;
And/or described catalyzer is DMAP;
And/or described alkali is 1:1 ~ 3:1 with the mol ratio such as formula the compound or its salt shown in A;
And/or, described such as formula the compound or its salt shown in A, be 1:1 ~ 1:1.5 with the mol ratio such as formula the compound shown in B;
And/or described condensing agent is 1:1 ~ 3:1 with the mol ratio such as formula the compound or its salt shown in A;
And/or described catalyzer is 0.05:1 ~ 0.1:1 with the mol ratio such as formula the compound or its salt shown in A;
And/or described organic solvent is 1mL/g ~ 10mL/g with the mass volume ratio such as formula the compound or its salt shown in A;
And/or the temperature of described reaction is 0 ~ 30 DEG C.
17. preparation methods as claimed in claim 16, is characterized in that,
When X is O, by such as formula the compound shown in A with carry out esterification such as formula the compound shown in B; Described organic solvent is halogenated hydrocarbon solvent; Described condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride and/or N, N '-dicyclohexylcarbodiimide; Or described condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride and/or N, N '-dicyclohexylcarbodiimide, with the mixture of 1-hydroxy benzo triazole;
When X is N, by such as formula the compound shown in A salt with carry out amidate action such as formula the compound shown in B; Described organic solvent is halogenated hydrocarbon solvent and/or amide solvent; Described condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride and/or diethyl phosphorocyanidate; Or described condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride and/or diethyl phosphorocyanidate, with the mixture of 1-hydroxy benzo triazole.
CN201410690846.2A 2013-11-26 2014-11-25 Podophyllotoxin derivative, preparation method thereof, medicinal composition and application thereof Pending CN104672249A (en)

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CN107652300A (en) * 2017-09-20 2018-02-02 辽宁大学 Podophyllotoxin analogue and its application containing 1,2,4 triazinone structures
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CN105801592A (en) * 2016-03-25 2016-07-27 遵义医学院 Preparation method of podophyllotoxin picolinic formic ether derivative and application of derivative to anti-leukemia drug
CN106008540A (en) * 2016-05-19 2016-10-12 遵义医学院 Heterocyclic aromatic acid ester type podophyllotoxin derivatives with anti-tumor activity as well as preparation method and application
CN107652300A (en) * 2017-09-20 2018-02-02 辽宁大学 Podophyllotoxin analogue and its application containing 1,2,4 triazinone structures
CN107652300B (en) * 2017-09-20 2019-08-09 辽宁大学 The podophyllotoxin analogue of the structure of triazinone containing 1,2,4- and its application
CN112125916A (en) * 2020-09-28 2020-12-25 杭州仁者生物科技有限公司 Novel small molecule inhibitors of insulin-like growth factor-1receptor and uses thereof
CN114028580A (en) * 2021-09-30 2022-02-11 成都理工大学 Preparation method of podophyllotoxin twin drug nanoparticles
CN114028580B (en) * 2021-09-30 2023-08-08 成都理工大学 Preparation method of podophyllotoxin twin drug nanoparticles

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