CN108354928A - Mostly thio gibberellic acid ester type compound application in preparation of anti-tumor drugs - Google Patents

Mostly thio gibberellic acid ester type compound application in preparation of anti-tumor drugs Download PDF

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CN108354928A
CN108354928A CN201810131532.7A CN201810131532A CN108354928A CN 108354928 A CN108354928 A CN 108354928A CN 201810131532 A CN201810131532 A CN 201810131532A CN 108354928 A CN108354928 A CN 108354928A
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gibberellic acid
dioxies
ester
dioxy
methyl
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陈静波
张洪彬
赵玉祥
飞鹏
隋迎春
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Yunnan University YNU
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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
    • A61K31/365—Lactones
    • 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

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Abstract

The present invention discloses a kind of how thio gibberellic acid ester type compound application in preparation of anti-tumor drugs, the especially application in the drug for preparing treatment leukaemia, liver cancer, lung cancer, breast cancer, colon cancer, melanoma.Shown in the how thio gibberellic acid esters compound structure such as general formula (I) of the present invention, with gibberellic acid basic skeleton structure, the identical alkylthio radicals of 1 and 17 connection, the group of 13 connections is that chlorine, hydroxyl, acetoxyl group or 13 and 1,17 are all connected with identical alkylthio radicals.Such compound shows good inhibitory activity in anti-tumor experiment to a variety of human tumor cell lines in vitro.

Description

Mostly thio gibberellic acid ester type compound application in preparation of anti-tumor drugs
Technical field：
The invention belongs to chemistry and field of medicaments, more particularly to a kind of how thio gibberellic acid ester type compound prepare it is antitumor Application in drug.
Background technology：
Malignant tumour is just seriously threatening the life and health of the mankind, with factors such as Chinese population aging and environment Influence, tumor incidence and lethality all show the trend of rising.Tumor therapeuticing method mainly has operative treatment, radiation at present Treatment and drug therapy (i.e. chemotherapy).Malignant tumour is whole body rather than localized diseases, can act on the drug therapy of whole body and be Current most important therapy, occupies irreplaceable position in the treatment of tumour.Common chemotherapeutics is mostly because serious Toxic side effect and limit its application, find with novel targets, new construction, high activity, less toxic side effect chemotherapeutics As an important and urgent task.
Gibberellin, a kind of natural tetracyclic diterpene compound, most important physiological function are to promote growth and development of plants, Promote seed to sprout, improve setting percentage, reduce withering and falling for plant organ, changes plant male and female ratio etc., be applied primarily to agriculture Industry produces.Due to more than the functional group in its molecular structure and concentrating, there are a variety of possibilities in the transformation of chemical constitution.
In gibberellin structure of modification and bioactivity research, we have been approved two patents of invention (Zhang Hongbin, Chen Jing Wave, Liu Jianping, minister in ancient times's morning .3,15- dicarbonyl gibberellic acid class compound and its ester and salt [P] .ZL200410021939.2；Zhang Hong Refined, Chen Jingbo, new shoots of bamboo from the old stump are first, minister in ancient times's morning, Liu Jianping, Zeng Xianghui, Zhang Yanli .13- halo-3,15-dioxygibberellic acid esters and its system Preparation Method [P] ZL200810058297.1.), with gibberellin GA3For starting material, structure of modification is carried out to it, obtains one Class A rings have α, alpha, beta-unsaturated ketone structure, and D rings have the michael reaction receptor class gibberellic acid of alpha-methylene cyclopentanone structure Derivative finds that such compound has good antitumor activity and multiple target point Anticancer Effect and Mechanism, moreover it is possible to apparent to reverse The multidrug resistance of tumour cell.GA3The side of the gibberellic acid derivatives containing double alpha, beta-unsaturated ketone structures is prepared by structure of modification Method is as shown in Fig. 2.
On the basis of previous work, the present invention continues to contain double α, and the gibberellic acid derivatives of alpha, beta-unsaturated ketone structure are original Material, designed and synthesized how thio gibberellic acid ester type compound of the present invention, anti tumor activity in vitro the experimental results showed that： Most of such compounds have preferable inhibitory activity to a variety of human tumor cells pearls.
Invention content：
The purpose of the present invention is to provide the how thio gibberellic acid ester type compounds that one kind had not been reported in the prior art And using it as the pharmaceutical composition application in preparation of anti-tumor drugs of active constituent.
In order to realize the above-mentioned purpose of the present invention, the present invention provides the following technical solutions：
Present invention firstly provides a kind of gibberellic acid esters compound or pharmaceutically acceptable salt thereofs how thio as shown in general formula (I) to make Application in standby antitumor drug, the how thio gibberellic acid ester type compound are：Three alkane sulphur of 3,15- dioxies -1,13,17- Base gibberellic acid ester or chloro- 3,15- dioxies -1,17-, the bis- alkylthio group gibberellic acid esters of 13- or 13- hydroxyl -3,15- dioxies -1,17- Two alkylthio group gibberellic acid esters or 13- acetoxy-3s, bis- alkylthio group gibberellic acid ester of 15- dioxies -1,17-, structure feature are： The identical alkylthio radicals of 1- and 17- connections；13- connection groups be chlorine, hydroxyl, acetoxyl group or 13- and 1-, 17- are all connected with identical alkylthio radicals；7- carboxylates are Arrcostab, benzyl ester, to methoxybenzyl base ester,
In general formula (I), R1For C1~C8Alkyl, 2- hydroxyethyls, phenyl, p-methylphenyl；R2For S R1, chlorine, hydroxyl, second Acyloxy；R3For C1~C8Alkyl, benzyl or to methoxy-benzyl.
Above-mentioned how thio gibberellic acid ester type compound, including but not limited to following compound：
Three methyl mercapto Methyl gibberellates of 3,15- dioxies -1,13,17-, three ethylmercapto group gibberellic acid of 3,15- dioxies -1,13,17- Methyl esters, three rosickyite base Methyl gibberellates of 3,15- dioxies -1,13,17-, three isopropyisulfanyl gibberellic acid of 3,15- dioxies -1,13,17- Methyl esters, three butylthio Methyl gibberellates of 3,15- dioxies -1,13,17-, three secondary butylthio gibberellic acid of 3,15- dioxies -1,13,17- Methyl esters, three tertiary butylthio Methyl gibberellates of 3,15- dioxies -1,13,17-, 3,15- dioxy -1,13,17- tricyclic penta sulfenyls are red mould Sour methyl esters, three cyclohexylthio Methyl gibberellates of 3,15- dioxies -1,13,17-, (the 2- hydroxyl second of 3,15- dioxies -1,13,17- three Sulfenyl) Methyl gibberellate, three methyl mercapto gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, three second sulphur of 3,15- dioxies -1,13,17- Base gibberellic acid benzyl ester, three rosickyite base gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, three isopropyl sulphur of 3,15- dioxies -1,13,17- Base gibberellic acid benzyl ester, three butylthio gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, three Zhong Ding sulphur of 3,15- dioxies -1,13,17- Base gibberellic acid benzyl ester, three tertiary butylthio gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, 3,15- dioxy -1,13,17- tricyclics penta Sulfenyl gibberellic acid benzyl ester, three cyclohexylthio gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, 3,15- dioxies -1,13,17- three (2- hydroxyeththylthios) gibberellic acid benzyl ester, three methyl mercapto gibberellic acid of 3,15- dioxies -1,13,17- are to methoxybenzyl base ester, 3,15- Three ethylmercapto group gibberellic acid of dioxy -1,13,17- is to methoxybenzyl base ester, three rosickyite base gibberellic acid pair of 3,15- dioxies -1,13,17- Methoxybenzyl base ester, three isopropyisulfanyl gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester, dioxy -1,13 3,15-, Tri- butylthio gibberellic acid of 17- is to methoxybenzyl base ester, three secondary butylthio gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl Base ester, three tertiary butylthio gibberellic acid of 3,15- dioxies -1,13,17- are to methoxybenzyl base ester, 3,15- dioxy -1,13,17- tricyclics Penta sulfenyl gibberellic acid to methoxybenzyl base ester, three cyclohexylthio gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester, (2- hydroxyeththylthios) gibberellic acid of 3,15- dioxies -1,13,17- three is to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- of 13- The chloro- 3,15- of the chloro- 3,15- dioxies -1,17- diethyls sulfenyl Methyl gibberellate of dimethyl sulfenyl Methyl gibberellate, 13-, 13- bis- Oxygen -1,17- dipropyl sulfenyls Methyl gibberellate, the chloro- 3,15- dioxies -1,17- diisopropyls sulfenyl Methyl gibberellates of 13-, 13- are chloro- 3,15- dioxy -1,17- dibutyl sulfide bases Methyl gibberellate, the chloro- 3,15- dioxies -1,17- di-secondary butylthio Methyl gibberellates of 13-, The chloro- two tertiary butylthio Methyl gibberellates of 3,15- dioxies -1,17- of 13-, the chloro- two ring penta sulfenyls of 3,15- dioxies -1,17- of 13- are red The chloro- 3,15- dioxies -1,17- of mould acid methyl esters, the chloro- two cyclohexylthio Methyl gibberellates of 3,15- dioxies -1,17- of 13-, 13- two (2- hydroxyeththylthios) Methyl gibberellate, the chloro- 3,15- dioxies -1,17- dimethyl sulfenyl gibberellic acid benzyl esters of 13-, 13- chloro- 3, 15- dioxy -1,17- diethyl sulfenyl gibberellic acid benzyl ester, the chloro- 3,15- dioxies -1,17- dipropyls sulfenyl gibberellic acid benzyl esters of 13-, 13- Chloro- 3,15- dioxies -1,17- diisopropyl sulfenyl gibberellic acid benzyl ester, the chloro- 3,15- dioxies -1,17- dibutyl sulfides base gibberellic acid benzyls of 13- Chloro- two tertiary butylthios of 3,15- dioxies -1,17- of the chloro- 3,15- dioxies -1,17- di-secondary butylthio gibberellic acid benzyl ester of ester, 13-, 13- The chloro- 3,15- dioxies -1,17- of the chloro- two ring penta sulfenyl gibberellic acid benzyl esters of 3,15- dioxies -1,17- of gibberellic acid benzyl ester, 13-, 13- two Chloro- two (2- hydroxyeththylthios) the gibberellic acid benzyl esters of 3,15- dioxies -1,17- of cyclohexylthio gibberellic acid benzyl ester, 13-, 13- chloro- 3, 15- dioxy -1,17- dimethyl sulfenyl gibberellic acid is red mould to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- diethyl sulfenyls of 13- Acid to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- dipropyls sulfenyl gibberellic acid of 13- to methoxybenzyl base ester, 13- chloro- 3, 15- dioxy -1,17- diisopropyl sulfenyl gibberellic acid is red mould to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- dibutyl sulfide bases of 13- Acid is chloro- to methoxybenzyl base ester, 13- to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- di-secondary butylthio gibberellic acid of 13- Two tertiary butylthio gibberellic acid of 3,15- dioxies -1,17- is to methoxybenzyl base ester, the chloro- two ring penta sulfenyls of 3,15- dioxies -1,17- of 13- Gibberellic acid is to methoxybenzyl base ester, the chloro- two cyclohexylthio gibberellic acid of 3,15- dioxies -1,17- of 13- to methoxybenzyl base ester, 13- Chloro- 3,15- dioxies -1,17- two (2- hydroxyeththylthios) gibberellic acid is to methoxybenzyl base ester；Dioxy -1 13- hydroxyl -3,15-, 17- dimethyl sulfenyls Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- diethyl sulfenyls Methyl gibberellate, hydroxyl -3 13-, 15- dioxy -1,17- dipropyl sulfenyls Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- diisopropyl sulfenyls Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- dibutyl sulfide bases Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- di-secondary butylthios are red Mould acid methyl esters, two tertiary butylthio Methyl gibberellates of 13- hydroxyl -3,15- dioxies -1,17-, 13- hydroxyl -3,15- dioxies -1,17- Two ring penta sulfenyl Methyl gibberellates, two cyclohexylthio Methyl gibberellates of 13- hydroxyl -3,15- dioxies -1,17-, hydroxyl -3 13-, 15- dioxies -1,17- two (2- hydroxyeththylthios) Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- dimethyl sulfenyls are red Mould acid benzyl ester, 13- hydroxyl -3,15- dioxy -1,17- diethyl sulfenyl gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxies -1,17- two Rosickyite base gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxy -1,17- diisopropyl sulfenyl gibberellic acid benzyl ester, 13- hydroxyls -3,15- two Oxygen -1,17- dibutyl sulfide base gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxy -1,17- di-secondary butylthio gibberellic acid benzyl ester, 13- hydroxyls Two tertiary butylthio gibberellic acid benzyl esters of base -3,15- dioxies -1,17-, 13- hydroxyl -3,15- dioxies two ring penta sulfenyls of -1,17- are red mould Acid benzyl ester, two cyclohexylthio gibberellic acid benzyl esters of 13- hydroxyl -3,15- dioxies -1,17-, 13- hydroxyl -3,15- dioxies -1,17- two (2- hydroxyeththylthios) gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxy -1,17- dimethyl sulfenyl gibberellic acid are to methoxy-benzyl Ester, 13- hydroxyl -3,15- dioxy -1,17- diethyl sulfenyl gibberellic acid to methoxybenzyl base ester, dioxy -1 13- hydroxyl -3,15-, 17- dipropyl sulfenyl gibberellic acid is to methoxybenzyl base ester, 13- hydroxyl -3,15- dioxy -1,17- diisopropyl sulfenyl gibberellic acid to methoxy Base benzyl ester, 13- hydroxyl -3,15- dioxy -1,17- dibutyl sulfide base gibberellic acid are to methoxybenzyl base ester, 13- hydroxyls -3,15- two Oxygen -1,17- di-secondary butylthio gibberellic acid is red mould to methoxybenzyl base ester, 13- hydroxyl -3,15- dioxies two tertiary butylthios of -1,17- Acid is to methoxybenzyl base ester, two ring penta sulfenyl gibberellic acid of 13- hydroxyl -3,15- dioxies -1,17- to methoxybenzyl base ester, 13- hydroxyls Two cyclohexylthio gibberellic acid of base -3,15- dioxies -1,17- is to methoxybenzyl base ester, two (2- of 13- hydroxyl -3,15- dioxies -1,17- Hydroxyeththylthio) gibberellic acid is to methoxybenzyl base ester；13- acetoxy-3s, 15- dioxy -1,17- dimethyl sulfenyl gibberellic acid first Ester, 13- acetoxy-3s, 15- dioxy -1,17- diethyl sulfenyls Methyl gibberellate, 13- acetoxy-3s, 15- dioxies -1,17- Dipropyl sulfenyl Methyl gibberellate, 13- acetoxy-3s, 15- dioxy -1,17- diisopropyl sulfenyls Methyl gibberellate, 13- acetyl oxygen Base -3,15- dioxy -1,17- dibutyl sulfide bases Methyl gibberellate, 13- acetoxy-3s, 15- dioxy -1,17- di-secondary butylthios are red Mould acid methyl esters, 13- acetoxy-3s, two tertiary butylthio Methyl gibberellates of 15- dioxies -1,17-, 13- acetoxy-3s, 15- bis- Two ring penta sulfenyl Methyl gibberellates of oxygen -1,17-, 13- acetoxy-3s, two cyclohexylthio gibberellic acid first of 15- dioxies -1,17- Ester, 13- acetoxy-3s, 15- dioxies -1,17- two (2- hydroxyeththylthios) Methyl gibberellate, 13- acetoxy-3s, 15- bis- Oxygen -1,17- dimethyl sulfenyl gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- diethyl sulfenyl gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- dipropyl sulfenyl gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxies -1,17- two Isopropyisulfanyl gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- dibutyl sulfide base gibberellic acid benzyl ester, 13- acetoxyl groups - 3,15- dioxy -1,17- di-secondary butylthio gibberellic acid benzyl ester, 13- acetoxy-3s, two tertiary butylthios of 15- dioxies -1,17- are red mould Acid benzyl ester, 13- acetoxy-3s, two ring penta sulfenyl gibberellic acid benzyl esters of 15- dioxies -1,17-, 13- acetoxy-3s, 15- dioxies - Bis- cyclohexylthio gibberellic acid benzyl esters of 1,17-, 13- acetoxy-3s, 15- dioxies -1,17- two (2- hydroxyeththylthios) gibberellic acid Benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- dimethyl sulfenyl gibberellic acid to methoxybenzyl base ester, 13- acetoxy-3s, 15- dioxy -1,17- diethyl sulfenyl gibberellic acid is to methoxybenzyl base ester, 13- acetoxy-3s, 15- dioxy -1,17- dipropyl sulfenyls Gibberellic acid is to methoxybenzyl base ester, 13- acetoxy-3s, and 15- dioxy -1,17- diisopropyl sulfenyl gibberellic acid is to methoxy-benzyl Ester, 13- acetoxy-3s, 15- dioxy -1,17- dibutyl sulfide base gibberellic acid is to methoxybenzyl base ester, 13- acetoxy-3s, 15- Dioxy -1,17- di-secondary butylthio gibberellic acid is to methoxybenzyl base ester, 13- acetoxy-3s, two tertiary fourth sulphur of 15- dioxies -1,17- Base gibberellic acid is to methoxybenzyl base ester, 13- acetoxy-3s, and two ring penta sulfenyl gibberellic acid of 15- dioxies -1,17- is to methoxybenzyl Base ester, 13- acetoxy-3s, two cyclohexylthio gibberellic acid of 15- dioxies -1,17- to methoxybenzyl base ester, 13- acetoxy-3s, (2- hydroxyeththylthios) gibberellic acid of 15- dioxies -1,17- two to methoxybenzyl base ester,
The corresponding chemical constitution of above compound is respectively：
In the above structural formula：Me is methyl, and Et is ethyl, and Pr is propyl,iPr is isopropyl, and Bu is butyl,sBu is Zhong Ding Base,tBu is tertiary butyl,cPent is cyclopenta,cHex is cyclohexyl, and Bn is benzyl, and PMB is to methoxy-benzyl, and Ac is acetyl Base
Refer to that can pharmaceutically connect according to the pharmaceutical salts of how thio gibberellic acid ester type compound shown in the general formula (I) The salt received is that the carboxylic how thio gibberellic acid ester type compound involved in the present invention is aoxidized with alkali or alkaline earth metal The carboxylate that object, hydroxide, methoxyl group compound, ethoxylate or carbonate reaction are converted to, including lithium salts, sodium salt, potassium Salt, magnesium salts, calcium salt, strontium salt, bismuth salt.
Antineoplastic is being prepared according to how thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof shown in the general formula (I) Application in object, the tumour are leukaemia, liver cancer, lung cancer, breast cancer, colon cancer, melanoma.
The present invention additionally provides the how thio gibberellic acid esters as claimed in claim 1 or 2 containing therapeutically effective amount simultaneously The mixture of any type of compound or two kinds or more or the pharmaceutical composition of its pharmaceutical salts and pharmaceutically acceptable carrier Object and the pharmaceutical composition application in preparation of anti-tumor drugs.The wherein described tumour be leukaemia, liver cancer, Lung cancer, breast cancer, colon cancer, melanoma.
Purposes invention furthermore provides above-mentioned how thio gibberellic acid esters compound or its salt as prodrug.Described Prodrug, which refers to above-mentioned thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof itself, may have weaker activity or even without work Property, but upon administration, corresponding biologically active form is converted by metabolism or other modes in physiological conditions.
Gibberellin is one of five big plant hormones, and agricultural production, main life have just been put into early in the 1970s Reason function is to promote growth and development of plants, and seed is promoted to sprout, and improves setting percentage, reduces withering and falling for plant organ, changes plant Male and female ratio etc..Gibberellin belongs to tetracyclic diterpene compound, since there are more functional groups in molecular structure, to be change The transformation for learning structure provides a variety of possibility.Early stage is the study found that have α, alpha, beta-unsaturated ketone or alpha-methylene cyclopentanone structure The terpenoid of unit has antitumor activity mostly.Gibberellic acid GA3Commercialization fermenting and producing, the A in molecule are realized Ring can oxidized reaction build a α, alpha, beta-unsaturated ketone structure, while D rings also there is the item for transforming alpha-methylene cyclopentanone as Part.The present invention is with gibberellic acid GA3For starting material, structure of modification is carried out to it, obtains and is stepped shown in a collection of following structural formula Ke Er reacts receptor class gibberellic acid derivatives, it is found that such compound has good antitumor activity and the antitumor work of multiple target point Use machine
System, moreover it is possible to which the multidrug resistance of apparent reversing tumor cell obtains two Chinese invention patents (ZL200410021939.2；ZL200810058297.1. it) authorizes.
In follow-up study, the present invention designs and method as shown in Figure 3 has synthesized shown in general formula according to the present invention (I) How thio gibberellic acid ester type compound, anti tumor activity in vitro the experimental results showed that：Most of such compounds are to a variety of people The proliferation of tumour cell pearl has apparent inhibiting effect.
How thio gibberellic acid ester type compound provided by the invention is the present inventor in the antitumor research of gibberellic acid derivatives On the basis of previous work, a kind of compound obtained through structure optimization, stability is good, has because of itself or as prodrug Preferable antitumor activity provides new thinking and selection to provide a kind of antitumor drug.
When the how thio gibberellic acid ester type compound of the present invention is used as drug, can directly it use, or with pharmaceutical composition The form of object uses.The form that compound can also be formed with other drugs uses, which contain 0.1~99%, excellent It is selected as 0.5~90% the compounds of this invention, remaining is pharmaceutically acceptable, nontoxic to humans and animals and inert drug The common pharmaceutical carrier of preparation and/or excipient.The pharmaceutical composition of the present invention is used in the form of per weight dose. Different pharmaceutic adjuvants can be used, solid pharmaceutical preparation (tablet, capsule, granule, powder etc.) or injection is made.
Drug of the present invention can include how thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof and one kind or more The pharmaceutical diluent or carrier of kind.Pharmaceutical acceptable carrier include but not limited to lecithin, vitamin E, polyethylene glycol, propylene glycol, Glycerine, the surfactant of tween or other drugs preparation, aluminium oxide, aluminum stearate, ion exchange material, buffer substance Such as phosphate, sorbic acid, polyvinyl pyrrolidone, cellulosic material, polyvinyl alcohol, sodium carboxymethylcellulose, lanolin, cyclodextrin Etc. the carrier that can be used for promoting compound, its pharmaceutical salts or prodrugs thereof of the present invention to transmit.
Drug of the present invention can include how thio gibberellic acid ester type compound or its pharmaceutically acceptable salt with And other pharmaceutically acceptable auxiliaries.Pharmaceutically acceptable auxiliaries include but not limited to：Disintegrant such as sodium carboxymethyl starch, cross-linked carboxymethyl cellulose Sodium, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, sodium alginate etc., adhesive such as PVP K30, crystallite are fine Tie up element, sodium alginate etc., filler such as Lactis Anhydrous, starch, glucose, lactose bead etc., lubricant such as dodecyl sulphate Magnesium, magnesium stearate etc. and other excipient, solubilizer, flavouring agent, colorant etc..
The pharmaceutical dosage form that compound of the present invention can be made into includes tablet, capsule, granule, powder, liniment, soft Paste, injection etc..
Description of the drawings
Fig. 1 is the how thio gibberellic acid esters compound structure schematic diagram of the present invention.
Fig. 2 is GA3The method flow of the gibberellic acid derivatives containing double alpha, beta-unsaturated ketone structures is prepared by structure of modification Figure.
Fig. 3 is the method flow of how thio gibberellic acid ester type compound shown in synthesis general formula (I) according to the present invention Figure.
Specific implementation mode：
Below in conjunction with the accompanying drawings, the essentiality content further illustrated the present invention with the embodiment of the present invention, but not with This limits the present invention.
Embodiment 1：
The preparation of three ethylmercapto group Methyl gibberellates (SG0101) of 3,15- dioxies -1,13,17- and structured data：
Chloro- 3, the 15- dioxies Methyl gibberellates (391mg, 1.0mmol) of 13- are dissolved in dichloromethane (10mL), are then added Ethyl mercaptan (0.24mL, 0.86g/mL, 3.3mmol, 3.3eq.) and triethylamine (0.042mL, 0.73g/mL, 0.3mmol, 0.3eq.), reaction 2 hours is stirred at room temperature.After completion of the reaction through TLC detections, evaporated under reduced pressure solvent.Residue is through silica gel column chromatography (petrol ether/ethyl acetate=6:1) white solid 488mg, yield are obtained：90.2%.
1H-NMR(300MHz,CDCl3):δ=3.64 (3H, s), 3.46 (2H, t), 3.06 (1H, dd, J=17.1, 7.5Hz), 2.88-2.82 (3H, m), 2.80-2.54 (9H, m), 2.17 (1H, d, J=11.7Hz), 2.03-1.89 (2H, m), 1.83-1.62(2H, m),1.32-1.25(10H,m),1.21(3H,s)；
13C-NMR(75MHz,CDCl3):δ=214.79,197.90,173.67,170.33,95.32,64.32,60.27, 60.05, 53.17,52.45,50.46,48.91,45.85,42.98,42.72,40.70,27.71,27.62,26.87, 26.59,22.44,17.44, 14.67,14.59,14.29,10.42；
HRMS(ESI):m/z[M+Na]+calcd for C26H36O6S3:563.1566；found:563.1567.
Embodiment 2：
The preparation of three rosickyite base Methyl gibberellates (SG0102) of 3,15- dioxies -1,13,17- and structured data：
Chloro- 3, the 15- dioxies Methyl gibberellates (391mg, 1.0mmol) of 13- are dissolved in dichloromethane (10mL), are then added Propanethiol (0.30mL, 0.84g/mL, 3.3mmol, 3.3eq.) and triethylamine (0.042mL, 0.73g/mL, 0.3mmol, 0.3eq.), it is stirred at room temperature 2 hours.After completion of the reaction through TLC detections, evaporated under reduced pressure solvent.Residue is through silica gel column chromatography (stone Oily ether/ethyl acetate=6:1) white solid 525mg, yield are obtained：90.1%.
1H-NMR(300MHz,CDCl3):δ=3.63 (3H, s), 3.43 (2H, t), 3.03 (1H, dd, J=17.1, 7.5Hz), 2.83-2.77(2H,m),2.66-2.52(8H,m),2.28(1H,t),2.16(1H,t),2.03-1.85(2H, m),1.65-1.54(7H, m),1.31-1.21(2H,m),1.19(3H,s),1.06-0.94(9H,m),0.87(1H,t)；
13C-NMR(75MHz,CDCl3):δ=214.83,197.94,173.77,170.40,95.44,64.39,60.32, 60.20, 53.18,52.48,50.54,48.84,45.90,43.36,42.80,40.79,35.94,34.93,30.45, 29.22,27.75,26.98, 22.84,22.84,17.56,13.98,13.61,13.44,10.46；
HRMS(ESI):m/z[M+Na]+calcd for C29H42O6S3:605.2036；found:605.2034.
Embodiment 3
The preparation of three tertiary butylthio Methyl gibberellates (SG0103) of 3,15- dioxies -1,13,17- and structured data：
Chloro- 3, the 15- dioxies Methyl gibberellates (391mg, 1.0mmol) of 13- are dissolved in dichloromethane (10mL), are then added Tert-butyl mercaptan (0.39mL, 0.80g/mL, 3.3mmol, 3.3eq.) and triethylamine (0.083mL, 0.73g/mL, 0.6mmol, 0.6eq.), it is stirred at room temperature 2 hours.After completion of the reaction through TLC detections, evaporated under reduced pressure solvent.Silica gel column chromatography (petroleum ether/acetic acid Ethyl ester=6:1) white solid 555mg, yield are obtained：88.8%.
1H-NMR(300MHz,CDCl3):δ=3.62 (3H, s), 3.40 (1H, d, J=7.2Hz), 3.26-3.15 (2H, M), 3.01 (1H, q), 2.85-2.78 (3H, m), 2.71-2.65 (3H, m), 2.35 (1H, d, J=11.7Hz), 2.21-2.18 (1H,m),1.50 (9H,s),1.40-1.20(21H,m),0.85(3H,s)；
13C-NMR(75MHz,CDCl3):δ=213.67,198.06,173.91,170.26,95.62,64.15,62.29, 60.15, 53.74,52.31,51.38,50.43,47.09,45.71,45.11,45.04,43.08,42.23,40.55, 33.24,33.24,33.24, 31.06,31.06,31.06,30.62,30.62,30.62,29.24,23.02,17.28, 10.29；
HRMS(ESI):m/z[M+Na]+calcd for C32H48O6S3:647.2505；found:647.2507.
Embodiment 4
Preparation and structure number of the three ethylmercapto group gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester (SG0104) According to：
The chloro- 3,15- dioxies gibberellic acid of 13- is dissolved in dichloromethane (10mL) to methoxybenzyl base ester (497mg, 1.0mmol) In, then be added ethyl mercaptan (0.24mL, 0.86g/mL, 3.3mmol, 3.3eq.) and triethylamine (0.084mL, 0.73g/mL, 0.6mmol, 0.6eq.), it is stirred at room temperature 2 hours.After completion of the reaction through TLC detections, evaporated under reduced pressure solvent.Silica gel column chromatography (stone Oily ether/ethyl acetate=4:1) white solid 541mg, yield are obtained：83.6%.
1H-NMR(300MHz,CDCl3):δ=7.24 (2H, d, J=8.7Hz), 6.88 (2H, d, J=8.7Hz), 5.00 (2H, q), 3.81 (3H, s), 3.45 (2H, d, J=9.6Hz), 3.06 (1H, q), 2.85-2.55 (9H, m), 2.45 (1H, d, J =11.7Hz), 2.36 (1H, m), 2.71 (1H, t), 2.07 (1H, d, J=12.0Hz), 1.98-1.62 (5H, m), 1.31- 1.17(12H,m)；
13C-NMR(75MHz,CDCl3):δ=214.83,197.89,173.65,169.63,159.90,130.72, 126.94, 114.08,95.22,67.40,64.31,60.24,58.84,55.29,53.03,50.26,48.80,45.87, 42.93,42.63,40.07, 27.77,27.56,26.78,26.58,22.18,17.24,14.59,14.52,14.23, 10.46；
HRMS(ESI):m/z[M+Na]+calcd for C33H42O7S3:669.1985；found:669.1988.
Embodiment 5：
Preparation and structure of the three isopropyisulfanyl gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester (SG0105) Data：
For preparation method with embodiment 4, isopropyl mercaptan dosage is (0.31mL, 0.82g/mL, 3.3mmol, 3.3eq.), other Reactant, catalyst, the dosage of solvent and operating process obtain white solid 593mg, yield with embodiment 4：87.6%.
1H-NMR(300MHz,CDCl3):δ=7.18 (2H, d, J=8.4Hz), 6.82 (2H, d, J=8.7Hz), 4.92 (1H, d, J=11.7Hz), 4.83 (1H, d, J=11.7Hz), 3.74 (3H, s), 3.39 (1H, d, J=7.2Hz), 3.35 (1H, d, J=9.6Hz), 3.00 (1H, dd, J=7.5,7.5Hz), 2.93-2.52 (8H, m), 2.41 (1H, d, J= 11.4Hz), 2.22 (1H, t), 2.03 (1H, d, J=11.7Hz), 1.81 (1H, q), 1.69-1.65 (3H, m), 1.24-1.14 (21H,m)；
13C-NMR(75MHz,CDCl3):δ=214.64,197.94,173.74,169.65,159.88,130.80, 126.95, 114.07,95.25,67.41,64.31,60.28,59.32,55.25,53.17,50.26,49.60,45.58, 43.34,41.70,40.85, 36.73,36.18,33.26,28.12,26.01,25.39,25.35,23.48,23.34, 23.27,23.18,17.14,10.45；
HRMS(ESI):m/z[M+Na]+calcd for C36H48O7S3:711.2454；found:711.2451.
Embodiment 6
Preparation and structure number of the three butylthio gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester (SG0106) According to：
For preparation method with embodiment 4, butyl mercaptan dosage is (0.36mL, 0.84g/mL, 3.3mmol, 3.3eq.), other are anti- It answers object, catalyst, the dosage of solvent and operating process with embodiment 4, obtains white solid 590mg, yield：80.7%.
1H-NMR(300MHz,CDCl3):δ=7.16 (2H, d, J=8.7Hz), 6.81 (2H, d, J=8.7Hz), 4.88 (2H, q), 3.73 (3H, s), 3.39 (1H, d, J=9.9Hz), 3.34 (1H, s), 2.95 (1H, q), 2.78-2.48 (9H, m), 2.36 (1H, d, J=12.0Hz), 2.26-2.19 (3H, m), 1.99 (1H, d, J=11.4Hz), 1.69-1.56 (16H, m), 1.31(3H,s),0.88-0.81 (9H,m)；
13C-NMR(75MHz,CDCl3):δ=214.85,197.90,173.65,169.66,159.88,130.70, 126.90, 114.07,95.28,67.39,64.31,60.22,58.81,55.21,52.98,50.28,48.66,45.93, 43.28,42.65,39.97, 33.67,32.53,31.58,31.34,31.14,27.73,27.65,26.96,22.25, 22.06,21.84,17.28,13.77,13.71, 13.61,10.45；
HRMS(ESI):m/z[M+Na]+calcd for C39H54O7S3:753.2924；found:753.2925.
Embodiment 7：
Preparation and structure of the three tertiary butylthio gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester (SG0107) Data：
For preparation method with embodiment 4, tert-butyl mercaptan dosage is (0.39mL, 0.80g/mL, 3.3mmol, 3.3eq.), other Reactant, catalyst, the dosage of solvent and operating process obtain faint yellow solid 516mg, yield with embodiment 4：70.5%.
1H-NMR(300MHz,CDCl3):δ=7.14 (2H, d, J=8.7Hz), 6.79 (2H, d, J=8.7Hz), 5.00 (1H, d, J=11.4Hz), 4.81 (1H, d, J=11.7Hz), 3.74 (3H, s), 3.30 (1H, d, J=7.2Hz), 3.24 (1H, s), 3.18 (1H, d, J=9.3Hz), 3.10 (1H, q), 2.93 (1H, dd, J=4.2,4.2Hz), 2.82-2.72 (2H, M), 2.63 (1H, d, J=9.3Hz), 2.44 (1H, t), 2.38 (1H, d, J=7.5Hz), 2.19 (1H, dd, J=3.9, 3.6Hz),2.10-2.06(1H,m),1.98(1H,t), 1.85(2H,q),1.78-1.41(5H,m),1.27-1.18(22H, m),1.12(3H,s)；
13C-NMR(75MHz,CDCl3):δ=213.19,197.06,172.62,168.70,158.82,129.61, 125.95, 112.96,94.21,75.17,66.12,63.12,60.18,57.80,54.20,52.92,48.64,44.59, 44.29,44.05,42.44, 39.52,39.23,29.98,29.66,28.47,27.36,23.08,15.98,9.32；
HRMS(ESI):m/z[M+Na]+calcd for C39H54O7S3:753.2924；found:753.2920.
Embodiment 8：
Preparation and structure of the three cyclohexylthio gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester (SG0108) Data：
For preparation method with embodiment 4, cyclohexylmercaptan dosage is (0.40mL, 0.95g/mL, 3.3mmol, 3.3eq.), other Reactant, catalyst, the dosage of solvent and operating process obtain white solid 668mg, yield with embodiment 4：82.6%.
1H-NMR(300MHz,CDCl3):δ=7.18 (2H, d, J=8.4Hz), 6.82 (2H, d, J=8.4Hz), 4.87 (2H, q), 3.73 (3H, s), 3.42 (1H, d, J=7.2Hz), 3.35 (1H, d, J=9.6Hz), 3.04 (1H, d, J= 10.7Hz), 2.99 (1H, dd, J=7.5,7.2Hz), 2.84-2.55 (6H, m), 2.39 (1H, d, J=11.7Hz), 2.31- 2.23(2H,m),2.01-1.56(22H,m), 1.30-1.22(14H,m),1.09(3H,s)；
13C-NMR(75MHz,CDCl3):δ=214.72,198.01,173.79,169.74,159.85,130.77, 126.94, 114.12,95.34,77.50,77.08,76.65,67.40,64.30,60.23,59.60,55.19,53.16, 50.34,49.58,45.73, 45.31,44.62,43.60,41.28,41.18,41.06,36.31,35.26,33.66, 33.49,33.39,28.27,26.07,25.88, 25.79,25.55,25.40,24.90,17.10,10.42；
HRMS(ESI):m/z[M+Na]+calcd for C45H60O7S3:831.3393；found:831.3391.
Embodiment 9：
The preparation of 13- hydroxyl -3,15- dioxy -1,17- diethyl sulfenyl Methyl gibberellates (SG0109) and structured data：
13- hydroxyl -3,15- dioxy Methyl gibberellates (373mg, 1.0mmol) are dissolved in chloroform (10mL), are then added Enter ethyl mercaptan (0.24mL, 0.86g/mL, 3.3mmol, 3.3eq.) and diisopropyl ethyl amine (0.050mL, 0.78g/mL, 0.3mmol, 0.3eq.), reaction 2 hours is stirred at room temperature.After completion of the reaction through TLC detections, evaporated under reduced pressure solvent.Residue passes through Silica gel column chromatography (petrol ether/ethyl acetate=3:1) white solid 380mg, yield are obtained：76.4%.
1H-NMR(300MHz,CDCl3):δ=3.64 (3H, s), 3.45 (3H, t), 3.12-3.03 (2H, m), 2.79- 2.49 (10H, m), 2.16 (2H, d, J=11.4Hz), 1.99-1.95 (2H, q), 1.32-1.24 (7H, q), 1.21 (3H, s)；
13C-NMR(75MHz,CDCl3):δ=214.72,197.96,173.56,170.46,95.02,76.36,64.32, 61.52, 57.97,53.42,52.47,49.74,45.59,43.02,42.65,40.57,29.28,27.37,26.79, 26.41,17.01,14.58, 14.58,10.46；
HRMS(ESI):m/z[M+Na]+calcd for C24H32O7S2:519.1482；found:519.1482.
Embodiment 10：
The preparation of 13- hydroxyl -3,15- dioxy -1,17- dipropyl sulfenyl Methyl gibberellates (SG0110) and structured data：
For preparation method with embodiment 9, propanethiol dosage is (0.20mL, 0.84g/mL, 2.2mmol, 2.2eq.), other are anti- It answers object, catalyst, the dosage of solvent and operating process with embodiment 9, obtains white solid 486mg, yield：92.5%.
1H-NMR(300MHz,CDCl3):δ=3.64 (3H, s), 3.44 (3H, t), 3.10-3.02 (2H, m), 2.85- 2.49 (10H, m), 2.16 (2H, d, J=11.1Hz), 1.97 (2H, t), 1.68-1.58 (5H, m), 1.21 (3H, s), 1.03- 0.96(6H,m)；
13C-NMR(75MHz,CDCl3):δ=214.64,197.96,173.55,170.46,95.06,76.35,64.31, 61.52, 57.98,53.36,52.44,49.71,45.57,43.36,42.71,40.55,34.81,34.53,29.29, 27.76,22.77,22.68, 17.05,13.46,13.38,10.45；
HRMS(ESI):m/z[M+Na]+calcd for C26H36O7S2:547.1795；found:547.1795.
Embodiment 11：
The preparation of 13- hydroxyl -3,15- dioxy -1,17- diisopropyl sulfenyl Methyl gibberellates (SG0113) and structured data：
For preparation method with embodiment 9, isopropyl mercaptan dosage is (0.21mL, 0.81g/mL, 2.2mmol, 2.2eq.), other Reactant, catalyst, the dosage of solvent and operating process obtain white solid 481mg, yield with embodiment 9：91.6%.
1H-NMR(300MHz,CDCl3):δ=3.64 (3H, s), 3.47 (1H, d, J=6.9Hz), 3.38 (2H, d, J= 11.1Hz), 3.13-2.94 (4H, m), 2.83-2.70 (3H, m), 2.61-2.49 (3H, q), 2.15 (2H, d, J= 11.4Hz),1.96(2H,m), 1.67-1.62(1H,q),1.32-1.26(12H,m),1.20(3H,s)；
13C-NMR(75MHz,CDCl3):δ=214.52,198.02,173.58,170.44,95.01,76.27,64.25, 61.45, 58.34,53.52,52.42,49.69,45.37,43.33,41.74,40.54,36.22,35.76,29.29, 26.22,23.51,23.28, 23.28,23.21,16.92,10.41；
HRMS(ESI):m/z[M+Na]+calcd for C26H36O7S2:547.1795；found:547.1799.
Embodiment 12：
The preparation of 13- hydroxyl -3,15- dioxy -1,17- dibutyl sulfide base Methyl gibberellates (SG0114) and structured data：
For preparation method with embodiment 9, butyl mercaptan dosage is (0.24mL, 0.84g/mL, 2.2mmol, 2.2eq.), other are anti- It answers object, catalyst, the dosage of solvent and operating process with embodiment 9, obtains white solid 471mg, yield：85.2%.
1H-NMR(300MHz,CDCl3):δ=3.64 (3H, s), 3.44 (2H, t), 3.11-3.01 (2H, m), 2.84- 2.49 (10H, m), 2.16 (2H, d, J=11.4Hz), 1.96 (2H, m), 1.68-1.52 (6H, m), 1.45-1.34 (4H, m), 1.21(3H,s), 0.95-0.90(6H,m)；
13C-NMR(75MHz,CDCl3):δ=214.72,197.98,173.60,170.49,95.09,76.42,64.37, 61.54, 57.88,53.41,52.49,49.77,45.62,43.44,42.70,40.53,32.58,32.23,31.43, 31.43,29.34,27.90, 22.04,21.93,17.10,13.74,13.69,10.50；
HRMS(ESI):m/z[M+Na]+calcd for C28H40O7S2:575.2108；found:575.2111.
Embodiment 13：
The preparation of two tertiary butylthio Methyl gibberellates (SG0115) of 13- hydroxyl -3,15- dioxies -1,17- and structured data：
For preparation method with embodiment 9, tert-butyl mercaptan dosage is (0.26mL, 0.80g/mL, 2.2mmol, 2.2eq.), other Reactant, catalyst, the dosage of solvent and operating process obtain white solid 490mg, yield with embodiment 9：88.6%.
1H NMR(300MHz,CDCl3):δ=3.64 (3H, s), 3.38 (1H, d, J=7.2Hz), 3.25-3.11 (3H, M), 2.91-2.83 (2H, m), 2.70 (1H, d, J=9.3Hz), 2.55-2.48 (2H, m), 2.19-2.12 (2H, m), 1.98- 1.92 (2H, m), 1.68-1.61 (1H, q), 1.36 (18H, d, J=9.9Hz), 1.28 (1H, s), 1.20 (3H, s)；
13C NMR(75MHz,CDCl3):δ=214.06,198.15,173.72,170.46,95.36,76.28,64.24, 61.60, 58.92,54.06,52.46,49.71,45.74,45.21,45.06,43.59,40.71,40.51,31.14, 31.14,31.14,30.79, 30.79,30.79,29.59,24.37,17.16,10.41；
HRMS(ESI):m/z[M+Na]+calcd for C28H40O7S2:575.2108；found:575.2109.
Embodiment 14：
The preparation of two cyclohexylthio Methyl gibberellates (SG0116) of 13- hydroxyl -3,15- dioxies -1,17- and structured data：
For preparation method with embodiment 9, cyclohexylmercaptan dosage is (0.28mL, 0.95g/mL, 2.2mmol, 2.2eq.), other Reactant, catalyst, the dosage of solvent and operating process obtain white solid 451mg, yield with embodiment 9：74.5%.
1H-NMR(300MHz,CDCl3):δ=3.64 (3H, s), 3.50 (2H, d, J=8.4Hz), 3.37 (1H, d, J= 9.6Hz), 3.14-3.04 (2H, m), 2.82-2.67 (5H, m), 2.56 (2H, d, J=10.5Hz), 2.48 (2H, d, J= 11.4Hz),2.15(2H, m),2.04-1.61(13H,m),1.33-1.25(10H,m),1.20(3H,s)；
13C-NMR(75MHz,CDCl3):δ=214.40,198.03,173.54,170.41,95.04,76.21,64.19, 61.42, 58.39,53.42,52.34,49.61,45.23,44.66,44.21,43.57,41.25,40.47,33.65, 33.52,33.52,33.38, 33.38,29.29,25.98,25.98,25.85,25.85,25.63,25.50,16.88, 10.36；
HRMS(ESI):m/z[M+Na]+calcd for C32H44O7S2:627.2421；found:627.2418.
Embodiment 15：
The preparation of 13- hydroxyl -3,15- dioxy -1,17- hexichol sulfenyl Methyl gibberellates (SG0117) and structured data：
13- hydroxyl -3,15- dioxy Methyl gibberellates (372mg, 1.0mmol) are dissolved in chloroform (10mL), are then added Enter benzenethiol (0.22mL, 1.07g/mL, 2.2mmol, 2.2eq.), reaction 2 hours is stirred at room temperature.It is finished through TLC detection reactions Afterwards, evaporated under reduced pressure solvent.Residue is through silica gel column chromatography (petrol ether/ethyl acetate=3:1) white solid 555mg, yield are obtained： 93.6%.
1H-NMR(300MHz,CDCl3):δ=7.40-7.26 (10H, m), 3.90 (1H, d, J=8.1Hz), 3.65 (1H, D, J=9.6Hz), 3.61 (3H, s), 3.42 (2H, dd, J=13.2,3.6Hz), 3.11-3.04 (2H, m), 2.84-2.58 (4H,m),2.44 (2H,t),2.14-2.02(2H,m),1.84(1H,t),1.68-1.63(1H,m),1.28-1.21(4H, m)；
13C-NMR(75MHz,CDCl3):δ=214.15,197.49,173.25,170.35,134.55,132.96, 132.96, 132.90,129.97,129.97,129.62,129.62,129.29,129.29,128.69,127.09,95.24, 76.22,64.35, 61.46,57.72,52.67,52.37,49.36,46.49,45.65,41.58,40.35,30.25, 29.13,16.84,10.43；
HRMS(ESI):m/z[M+Na]+calcd for C32H32O7S2:615.1482；found:615.1485.
Embodiment 16：
Preparation and knot of the 13- hydroxyl -3,15- dioxy -1,17- hexichol sulfenyl gibberellic acid to methoxybenzyl base ester (SG0118) Structure data：
The preparation method is the same as that of Example 1 5,13- hydroxyls -3,15- dioxies gibberellic acid be to methoxybenzyl base ester dosage (479mg, 1.0 mmol), other reactants, catalyst, the dosage of solvent and operating process obtain faint yellow solid 650mg with embodiment 17, Yield：93.0%.
1H-NMR(300MHz,CDCl3):δ=7.40-7.26 (10H, m), 7.17 (2H, d, J=8.7Hz), 6.83 (2H, D, J=8.7Hz), 4.00 (1H, d, J=8.1Hz), 3.78 (3H, s), 3.33-2.78 (4H, m), 2.58 (1H, d, J= 9.2Hz), 2.55-2.50 (2H, m), 2.30 (1H, d, J=9.2Hz), 1.84 (2H, t), 1.21 (3H, s)；
13C-NMR(75MHz,CDCl3):δ=197.34,192.16,173.35,169.77,159.78,145.35, 133.28, 131.21,130.33,129.71,128.92,127.62,114.03,95.75,72.20,67.28,63.90, 60.43,57.19,55.29, 52.96,52.24,46.75,45.20,41.76,41.61,31.63,18.86,14.22, 10.29；
HRMS(ESI):m/z[M+Na]+calcd for C39H38O8S2:721.1900；found:721.1898.
Embodiment 17：
Preparation and knot of the 13- hydroxyl -3,15- dioxy -1,17- diethyl sulfenyl gibberellic acid to methoxybenzyl base ester (SG0119) Structure data：
Preparation method with embodiment 9,13- hydroxyls -3,15- dioxies gibberellic acid to methoxybenzyl base ester dosage be (479mg, 1.0 mmol), ethyl mercaptan dosage is (0.16mL, 0.86g/mL, 2.2mmol, 2.2eq.), other reactants, catalyst, solvent Dosage and operating process with embodiment 9, silica gel column chromatography condition is (petrol ether/ethyl acetate=3:1) it, obtains faint yellow sticky Solid 541mg, yield：89.7%.
1H-NMR(300MHz,CDCl3):δ=7.14 (2H, d, J=8.7Hz), 6.79 (2H, d, J=8.7Hz), 5.00 (1H, d, J=11.7Hz), 4.80 (1H, d, J=11.4Hz), 3.73 (3H, s), 3.36 (2H, q), 3.01 (1H, dd, J= ), 7.5,7.5Hz 2.88 (1H, dd, J=4.5,4.5Hz), 2.73 (1H, s), 2.66 (1H, d, J=9.6Hz), 2.63-2.37 (6H, m), 2.21 (1H, dd, J=3.9,4.2Hz), 2.07-2.05 (1H, m), 1.98 (1H, d, J=10.8Hz), 1.84- 1.78(2H,m),1.54(1H,t), 1.20-1.15(6H,m),1.12(3H,s)；
13C-NMR(75MHz,CDCl3):δ=214.87,197.94,173.52,169.77,159.83,130.63, 127.00, 113.96,95.00,76.31,67.14,64.26,61.20,57.88,55.22,53.35,49.74,45.91, 42.89,42.56,40.44, 29.16,27.09,26.67,26.22,16.88,14.48,14.43,10.38；
HRMS(ESI):m/z[M+Na]+calcd for C31H38O8S2:625.1900；found:625.1902.
Embodiment 18：
13- hydroxyl -3,15- dioxy -1,17- diisopropyl sulfenyl gibberellic acid to the preparation of methoxybenzyl base ester (SG0120) and Structured data：
Preparation method with embodiment 9,13- hydroxyl -3,15- dioxy gibberellic acid be to methoxybenzyl base ester dosage (479mg, 1.0 mmol), isopropyl mercaptan dosage is (0.21mL, 0.81g/mL, 2.2mmol, 2.2eq.), other reactants, catalyst, molten With embodiment 9, silica gel column chromatography condition is (petrol ether/ethyl acetate=3 for the dosage of agent and operating process:1) white solid, is obtained 590mg, yield：93.5%.
1H-NMR(300MHz,CDCl3):δ=7.21 (2H, d, J=8.4Hz), 6.87 (2H, d, J=8.4Hz), 5.06 (1H, d, J=11.4Hz), 4.88 (1H, d, J=11.7Hz), 3.80 (3H, s), 3.47 (2H, d, J=7.5Hz), 3.39 (1H, d, J=9.9Hz), 3.11-2.68 (7H, m), 2.53 (2H, q), 2.46 (1H, d, J=11.4Hz), 2.29 (1H, dd, J =4.2,4.2Hz), 2.20-2.11 (1H, m), 2.05 (1H, d, J=9.3Hz), 1.92-1.86 (1H, m), 1.64 (1H, t), 1.32-1.23(12H,m),1.15(3H,s)；
13C-NMR(75MHz,CDCl3):δ=214.65,198.01,173.53,169.78,159.81,130.59, 126.99, 113.94,94.97,76.22,67.10,64.21,61.19,58.37,55.23,53.50,49.72,45.69, 43.30,41.68,40.49, 36.16,35.58,29.25,25.95,23.46,23.24,23.18,16.86,10.40；
HRMS(ESI):m/z[M+Na]+calcd for C33H42O8S2:653.2213；found:653.2210.
Embodiment 19：
Preparation and knot of the 13- hydroxyl -3,15- dioxy -1,17- dibutyl sulfide base gibberellic acid to methoxybenzyl base ester (SG0121) Structure data：
Preparation method with embodiment 9,13- hydroxyls -3,15- dioxies gibberellic acid to methoxybenzyl base ester dosage be (479mg, 1.0 mmol), butyl mercaptan dosage is (0.24mL, 0.84g/mL, 2.2mmol, 2.2eq.), other reactants, catalyst, solvent Dosage and operating process with embodiment 9, silica gel column chromatography condition is (petrol ether/ethyl acetate=3:1) it is solid, to obtain thick white Body 593mg, yield：90.0%.
1H-NMR(300MHz,CDCl3):δ=7.17 (2H, d, J=8.7Hz), 6.83 (2H, d, J=8.7Hz), 5.03 (1H, d, J=11.7Hz), 4.85 (1H, d, J=11.4Hz), 3.77 (3H, s), 3.39 (3H, q), 2.99 (1H, q), 2.91 (1H, dd, J=4.2,4.5Hz), 2.68 (1H, d, J=9.6Hz), 2.62 (1H, t), 2.55-2.40 (6H, m), 2.27 (1H, Dd, J=4.2,4.2Hz), 2.04-3.22 (15H, m), 1.15 (3H, s), 0.89 (3H, m)
13C-NMR(75MHz,CDCl3):δ=214.78,197.86,173.48,169.74,159.88,130.63, 127.05, 113.98,95.00,76.33,67.14,64.29,61.21,57.80,55.23,53.32,49.80,45.93, 43.32,42.59,40.42, 32.45,32.13,31.35,31.29,29.25,27.69,21.90,21.81,16.97, 13.65,13.57,10.42；
HRMS(ESI):m/z[M+Na]+calcd for C35H46O8S2:681.2526；found:681.2530.
Embodiment 20：
13- hydroxyl -3,15- dioxy -1,17- di-secondary butylthio gibberellic acid to the preparation of methoxybenzyl base ester (SG0122) and Structured data：
Preparation method with embodiment 9,13- hydroxyls -3,15- dioxies gibberellic acid to methoxybenzyl base ester dosage be (479mg, 1.0 mmol), sec-butyl thioalcohol dosage is (0.24mL, 0.83g/mL, 2.2mmol, 2.2eq.), other reactants, catalyst, molten With embodiment 9, silica gel column chromatography condition is (petrol ether/ethyl acetate=3 for the dosage of agent and operating process:1) thick white, is obtained Solid 606mg, yield：92.0%.
1H-NMR(300MHz,CDCl3):δ=7.21 (2H, d, J=8.7Hz), 6.87 (2H, d, J=8.7Hz), 5.07 (1H, d, J=11.7Hz), 4.89 (1H, d, J=11.7Hz), 3.81 (3H, s), 3.44-3.41 (2H, m), 2.96-3.07 (2H,m),2.82-2.67 (5H,m),2.31-2.13(7H,m),1.65-1.49(5H,m),1.35(6H,q),1.13(3H, s),0.97(6H,m)；
13C-NMR(75MHz,CDCl3):δ=214.64,197.90,173.56,169.76,159.86,130.59, 127.05, 113.97,95.00,76.27,67.13,64.27,61.20,58.01,55.24,53.48,49.71,45.66, 43.55,43.09,42.72, 41.57,40.32,29.73,29.57,29.33,26.13,21.24,20.66,16.87, 11.07,10.42；
HRMS(ESI):m/z[M+Na]+calcd for C35H46O8S2:681.2526；found:681.2525.
Embodiment 21：
Two tertiary butylthio gibberellic acid of 13- hydroxyl -3,15- dioxies -1,17- to the preparation of methoxybenzyl base ester (SG0123) and Structured data：
Preparation method with embodiment 9,13- hydroxyl -3,15- dioxy gibberellic acid be to methoxybenzyl base ester dosage (479mg, 1.0 mmol), tert-butyl mercaptan dosage is (0.26mL, 0.80g/mL, 2.2mmol, 2.2eq.), other reactants, catalyst, molten With embodiment 9, silica gel column chromatography condition is (petrol ether/ethyl acetate=3 for the dosage of agent and operating process:1) white solid, is obtained 616mg, yield：93.5%.
1H-NMR(300MHz,CDCl3):δ=7.21 (2H, d, J=8.4Hz), 6.86 (2H, d, J=8.4Hz), 5.07 (1H, d, J=11.7Hz), 4.88 (1H, d, J=11.7Hz), 3.81 (3H, s), 3.37 (1H, d, J=7.2Hz), 3.28- 3.23 (2H, m), 3.16 (1H, dd, J=7.5,7.5Hz), 3.03-2.79 (2H, m), 2.10 (1H, d, J=9.3Hz), 2.55-2.44 (2H, m), 2.27 (1H, dd, J=3.9,3.6Hz), 2.17 (1H, q), 2.04 (1H, t), 1.96-1.79 (4H, m),1.39-1.20(14H,m),1.18(3H,s)；
13C-NMR(75MHz,CDCl3):δ=214.12,198.02,173.61,169.71,159.88,130.61, 127.05, 114.02,95.24,76.21,67.14,64.16,61.25,58.89,55.22,53.97,49.71,45.63, 45.34,45.06,43.43, 40.59,40.35,31.03,30.69,29.53,24.12,17.02,10.33；
HRMS(ESI):m/z[M+Na]+calcd for C35H46O8S2:681.2526；found:681.2528.
Embodiment 22：
Two cyclohexylthio gibberellic acid of 13- hydroxyl -3,15- dioxies -1,17- to the preparation of methoxybenzyl base ester (SG0124) and Structured data：
Preparation method with embodiment 9,13- hydroxyls -3,15- dioxies gibberellic acid to methoxybenzyl base ester dosage be (479mg, 1.0 mmol), cyclohexylmercaptan dosage is (0.27mL, 0.95g/mL, 2.2mmol, 2.2eq.), other reactants, catalyst, molten With embodiment 9, silica gel column chromatography condition is (petrol ether/ethyl acetate=3 for the dosage of agent and operating process:1) white solid, is obtained 611mg, yield：85.9%.
1H-NMR(300MHz,CDCl3):δ=7.21 (2H, d, J=8.4Hz), 6.87 (2H, d, J=8.7Hz), 5.04 (1H, d, J=11.7Hz), 4.90 (1H, d, J=11.7Hz), 3.81 (3H, s), 3.49 (1H, d, J=6.9Hz), 4.40 (1H, d, J=9.6Hz), 3.09-2.99 (2H, m), 2.81-2.66 (5H, m), 2.52 (1H, q), 2.46 (1H, d, J= 8.7Hz), 2.33 (1H, dd, J=3.9,3.9Hz), 2.07-1.60 (14H, m), 1.49-1.19 (11H, m), 1.16 (3H, s)；
13C-NMR(75MHz,CDCl3):δ=214.60,198.03,173.56,169.79,159.81,130.54, 127.01, 113.93,95.02,76.24,67.10,64.21,61.18,58.38,55.22,53.43,49.74,45.62, 44.60,44.16,43.53, 41.19,40.40,33.63,33.53,33.34,29.29,25.93,25.78,25.67, 25.51,16.84,10.39；
HRMS(ESI):m/z[M+Na]+calcd for C39H50O8S2:733.2839；found:733.2840.
Embodiment 23：
The preparation of the chloro- 3,15- dioxies -1,17- hexichol sulfenyl Methyl gibberellates (SG0125) of 13- and structured data：
Chloro- 3, the 15- dioxies Methyl gibberellates (390mg, 1.0mmol) of 13- are dissolved in dichloromethane (10mL), are then added Reaction 2 hours is stirred at room temperature in benzenethiol (0.22mL, 1.07g/mL, 2.2mmol, 2.2eq.).After completion of the reaction through TLC detections, Evaporated under reduced pressure solvent.Residue is through silica gel column chromatography (petrol ether/ethyl acetate=3:1) white solid 438mg, yield are obtained： 71.7%.
1H-NMR(300MHz,CDCl3):δ=7.47-7.23 (10H, m), 3.63 (3H, s), 3.23-2.93 (3H, m), 2.87-2.79(4H,m),2.74-2.34(3H,m),2.22-2.04(3H,m),1.28-1.25(5H,m)；
13C-NMR(75MHz,CDCl3):δ=212.07,197.18,173.06,169.92,137.03,133.07, 133.07, 132.72,129.72,129.72,129.07,129.07,128.80,127.55,127.55,126.66,95.18, 66.13,64.30, 61.31,60.88,52.48,52.48,49.48,46.42,45.05,43.29,41.58,30.89, 29.47,17.09,10.42；
HRMS(ESI):m/z[M+Na]+calcd for C32H31ClO6S2:633.1143；found:633.1142.
Pharmacodynamic experiment part
One, cell growth inhibition assay
1. experiment reagent
MTS(3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- Sulfophenyl) -2H-tetra zolium), DMSO be purchased from Sigma Co., USA；DMEM, RPMI-1640, penicillin/chain Mycin is purchased from HyClone companies；Trypsase is purchased from Bioind companies；CellTiterAQueous One Solution Cell Proliferation Assay kit are purchased from Promega companies.Compound according to the present invention is by this laboratory Voluntarily it is synthetically prepared.
Used cell A549, SMMC-7721, HL-60, MCF-7, SW480, A-375 are purchased from Chinese section in experiment Institute's Shanghai cell bank.
PBS buffer solution (pH 7.4,10 × storage liquid) is prepared：NaCl 80g, KH2PO42.4g, Na2HPO4·12H2O 35.8 g, KCl 2g adjust pH to 7.4, are settled to 1L, and when use is diluted to 1 × buffer solution.
2. experimental method
MTS methods detect cell survival rate：CellTiterAQueousOne Solution cell proliferation detecting kits The living cells quantity in the experiments such as cell Proliferation and cytotoxicity is detected with colorimetric method.The reagent includes a kind of novel tetrazolium Compound (3- (4,5-Dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4- Sulfophenyl) -2H-tetrazolium, inner salt, MTS) and a kind of electron coupling agent (phenazine ethosulfate,PES).PES can enhance chemical stability, this enables it to mix with MTS, form a stable solution. MTS is reduced into coloured formazans product by a variety of dehydrogenases in cell, can be directly dissolved in culture solution, is examined at 490nm It is directly proportional to the quantity of living cells in culture to measure formazan product light absorption values.
It is as follows：
(1) concentration of cell suspension is adjusted to 5 × 10 with the culture solution containing 10% fetal calf serum4A/mL is thin by 100 μ L 96 orifice plates are added in born of the same parents' suspension, i.e., 5000 cells are inoculated with per hole, microwell plate 200 μ L aqua sterilisas of lateral opening middle addition are with balancing micro vents plate Humidity reduces edge effect.
(2) culture plate is placed in 37 DEG C, 5%CO216-24h is cultivated in incubator, reaches exponential phase after cell is adherent The processing of Shi Kejia compounds.
(3) untested compound that maximum concentration is 80 μM is prepared with culture solution, by 5 times of progress gradient dilutions, prepares 5 altogether Concentration, i.e., respectively 80 μM, 16 μM, 3.2 μM, 0.64 μM and 0.128 μM.
(4) the various concentration compound after 100 μ L dilutions is added in 96 orifice plates, each detectable concentration is all provided with 3 multiple holes.
(5) cell is placed in 37 DEG C, 5%CO2After being incubated 48h in incubator, stop culture, removes the culture in 96 orifice plates 120 μ L MTS dilution (MTS dilutions, i.e. culture solution are added in liquid:CellTiterAQueousOne Solution reagents =5:1).
(6) blank control is arranged：Due to CellTiterAQueousAfter One Solution are incubated with cell culture medium There can be the absorption light of micro spontaneous generation, it is therefore desirable to which the blank control wells (acellular) of 3 repetitions are set in 490nm.It should Control wells contain the cell culture medium and CellTiter isometric with experimental portAQueous One Solution Reagent, the light absorption value of experimental port subtract the light absorption value of " acellular " blank control wells, you can the light absorption value corrected.
(7) culture plate is placed in 37 DEG C, 5%CO2After incubator is incubated 1-4h, culture plate is placed in low speed on oscillator and is shaken 5min is swung, the light absorption value in each hole is detected at enzyme-linked immunosorbent assay instrument 490nm.Record OD values simultaneously calculate various concentration compound The lower survival rate of cell of processing and the IC of each untested compound50Value.
3. experimental result
More than 1 thio gibberellic acid class compound antitumor proliferation function of table
The present invention how thio gibberellic acid ester type compound to leukemia HL-60, liver cancer SMMC-7721, lung cancer A-549, Totally six human tumor cell lines have carried out cell in vitro Proliferation Ability by breast cancer MCF-7, colon cancer SW480, melanoma A-375 Experiment, using cis-platinum as positive control medicine, the results showed that how thio gibberellic acid ester type compound shown in most of general formulas (I) There are good inhibiting effect, partial data to see the above table 1 the proliferation of above-mentioned tumour cell.
Embodiment 26：
The preparation of tablet：
The compounds of this invention is made by the method for embodiment 1-35, takes the mixing of one of which compound or several compounds Object is 1 by itself and excipient weight ratio:5-1:Excipient, pelletizing press sheet is added in 10 ratio.
Embodiment 27：
The preparation of oral liquid formulations：
The compounds of this invention is made by the method for embodiment 1-5, takes the mixing of one of which compound or several compounds Object, routinely oral solution preparation method oral solution is made.
Embodiment 28：
The preparation of capsule, granule or electuary：
The compounds of this invention is made by the method for embodiment 1-5, takes the mixing of one of which compound or several compounds Object is 5 by itself and excipient weight ratio:Excipient is added in 1 ratio, and capsule or granule or electuary is made.

Claims (8)

1. the answering in the preparation of antitumor drugs of how thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof shown in the following general formula (I) With,
The how thio gibberellic acid ester type compound is:3,15- dioxies -1,13, tri- alkylthio group gibberellic acid esters of 17- or 13- Bis- alkylthio group gibberellic acid ester of bis- alkylthio group gibberellic acid ester of chloro- 3,15- dioxies -1,17- or 13- hydroxyls -3,15- dioxy -1,17-, Or 13- acetoxy-3s, two alkylthio group gibberellic acid esters of 15- dioxies -1,17-.Its structure feature is：1- and 17- connection phases Same alkylthio radicals；The group of 13- connections is chlorine, hydroxyl, acetoxyl group or 13- and is all connected with phase with 1-, 17- Same alkylthio radicals；7- carboxylates are for Arrcostab, benzyl ester or to methoxybenzyl base ester.
2. how thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof according to claim 1 is in the preparation of antitumor drugs It answers, it is characterised in that the how thio gibberellic acid ester type compound is following compound：
Three methyl mercapto Methyl gibberellates of 3,15- dioxies -1,13,17-, three ethylmercapto group gibberellic acid first of 3,15- dioxies -1,13,17- Ester, three rosickyite base Methyl gibberellates of 3,15- dioxies -1,13,17-, three isopropyisulfanyl gibberellic acid first of 3,15- dioxies -1,13,17- Ester, three butylthio Methyl gibberellates of 3,15- dioxies -1,13,17-, three secondary butylthio gibberellic acid first of 3,15- dioxies -1,13,17- Ester, three tertiary butylthio Methyl gibberellates of 3,15- dioxies -1,13,17-, 3,15- dioxy -1,13,17- tricyclic penta sulfenyl gibberellic acid Methyl esters, three cyclohexylthio Methyl gibberellates of 3,15- dioxies -1,13,17-, (the 2- hydroxyl second sulphur of 3,15- dioxies -1,13,17- three Base) Methyl gibberellate, three methyl mercapto gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, three ethylmercapto groups of 3,15- dioxies -1,13,17- Gibberellic acid benzyl ester, three rosickyite base gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, three isopropyisulfanyls of 3,15- dioxies -1,13,17- Gibberellic acid benzyl ester, three butylthio gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, three secondary butylthios of 3,15- dioxies -1,13,17- Gibberellic acid benzyl ester, three tertiary butylthio gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, penta sulphur of 3,15- dioxy -1,13,17- tricyclics Base gibberellic acid benzyl ester, three cyclohexylthio gibberellic acid benzyl esters of 3,15- dioxies -1,13,17-, three (2- hydroxyls of 3,15- dioxies -1,13,17- Base ethylmercapto group) gibberellic acid benzyl ester, three methyl mercapto gibberellic acid of 3,15- dioxies -1,13,17- is to methoxybenzyl base ester, 3,15- dioxies - Tri- ethylmercapto group gibberellic acid of 1,13,17- is to methoxybenzyl base ester, three rosickyite base gibberellic acid of 3,15- dioxies -1,13,17- to methoxyl group Benzyl ester, three isopropyisulfanyl gibberellic acid of 3,15- dioxies -1,13,17- are to methoxybenzyl base ester, 3,15- dioxies -1,13,17- three Butylthio gibberellic acid to methoxybenzyl base ester, three secondary butylthio gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester, Three tertiary butylthio gibberellic acid of 3,15- dioxies -1,13,17- is to methoxybenzyl base ester, 3,15- dioxy -1,13,17- tricyclic penta sulfenyls Gibberellic acid is to methoxybenzyl base ester, three cyclohexylthio gibberellic acid of 3,15- dioxies -1,13,17- to methoxybenzyl base ester, 3,15- bis- (2- hydroxyeththylthios) gibberellic acid of oxygen -1,13,17- three is to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- dimethyl disulfides of 13- The chloro- 3,15- dioxies -1,17- of the chloro- 3,15- dioxies -1,17- diethyls sulfenyl Methyl gibberellate of base Methyl gibberellate, 13-, 13- two The chloro- 3,15- dioxies -1,17- diisopropyls sulfenyl Methyl gibberellate of rosickyite base Methyl gibberellate, 13-, chloro- dioxy -1 3,15- 13-, The chloro- 3,15- of 17- dibutyl sulfide bases Methyl gibberellate, the chloro- 3,15- dioxies -1,17- di-secondary butylthio Methyl gibberellates of 13-, 13- bis- The chloro- two ring penta sulfenyl Methyl gibberellates of 3,15- dioxies -1,17- of two tertiary butylthio Methyl gibberellates of oxygen -1,17-, 13-, 13- are chloro- The chloro- 3,15- dioxies -1,17- two (2- hydroxyeththylthios) of two cyclohexylthio Methyl gibberellates of 3,15- dioxies -1,17-, 13- is red mould The chloro- 3,15- dioxies -1,17- diethyl sulfide of the chloro- 3,15- dioxies -1,17- dimethyl sulfenyl gibberellic acid benzyl ester of sour methyl esters, 13-, 13- The chloro- 3,15- dioxies -1,17- of the chloro- 3,15- dioxies -1,17- dipropyls sulfenyl gibberellic acid benzyl ester of base gibberellic acid benzyl ester, 13-, 13- two The chloro- 3,15- dioxies -1,17- dibutyl sulfides base gibberellic acid benzyl ester of isopropyisulfanyl gibberellic acid benzyl ester, 13-, chloro- dioxy -1 3,15- 13-, The chloro- two tertiary butylthio gibberellic acid benzyl esters of 3,15- dioxies -1,17- of 17- di-secondary butylthio gibberellic acid benzyl ester, 13-, the chloro- 3,15- of 13- The chloro- two cyclohexylthio gibberellic acid benzyl esters of 3,15- dioxies -1,17- of two ring penta sulfenyl gibberellic acid benzyl esters of dioxy -1,17-, 13-, 13- Chloro- 3,15- dioxies -1,17- two (2- hydroxyeththylthios) gibberellic acid benzyl ester, the chloro- 3,15- dioxies -1,17- dimethyl sulfenyls of 13- Gibberellic acid is chloro- to methoxybenzyl base ester, 13- to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- diethyls sulfenyl gibberellic acid of 13- 3,15- dioxy -1,17- dipropyl sulfenyl gibberellic acid is red to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- diisopropyl sulfenyls of 13- Mould acid to methoxybenzyl base ester, the chloro- 3,15- dioxies -1,17- dibutyl sulfides base gibberellic acid of 13- to methoxybenzyl base ester, 13- chloro- 3, 15- dioxy -1,17- di-secondary butylthio gibberellic acid is red to methoxybenzyl base ester, chloro- two tertiary butylthios of 3,15- dioxies -1,17- of 13- Mould acid is chloro- to methoxybenzyl base ester, 13- to methoxybenzyl base ester, the chloro- two ring penta sulfenyl gibberellic acid of 3,15- dioxies -1,17- of 13- Two cyclohexylthio gibberellic acid of 3,15- dioxies -1,17- is to methoxybenzyl base ester, chloro- two (the 2- hydroxyls of 3,15- dioxies -1,17- of 13- Ethylmercapto group) gibberellic acid is to methoxybenzyl base ester；13- hydroxyl -3,15- dioxy -1,17- dimethyl sulfenyls Methyl gibberellate, 13- hydroxyls Base -3,15- dioxy -1,17- diethyl sulfenyls Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- dipropyl sulfenyl gibberellic acid first Ester, 13- hydroxyl -3,15- dioxy -1,17- diisopropyl sulfenyls Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- dibutyl sulfides Base Methyl gibberellate, 13- hydroxyl -3,15- dioxy -1,17- di-secondary butylthios Methyl gibberellate, dioxy -1 13- hydroxyl -3,15-, Bis- tertiary butylthio Methyl gibberellates of 17-, two ring penta sulfenyl Methyl gibberellates of 13- hydroxyl -3,15- dioxies -1,17-, 13- hydroxyls - Two cyclohexylthio Methyl gibberellates of 3,15- dioxies -1,17-, 13- hydroxyl -3,15- dioxies two (2- hydroxyeththylthios) of -1,17- are red Mould acid methyl esters, 13- hydroxyl -3,15- dioxy -1,17- dimethyl sulfenyl gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxies -1,17- Diethyl sulfenyl gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxy -1,17- dipropyl sulfenyl gibberellic acid benzyl ester, 13- hydroxyls -3,15- two Oxygen -1,17- diisopropyl sulfenyl gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxy -1,17- dibutyl sulfide base gibberellic acid benzyl ester, 13- hydroxyls Base -3,15- dioxy -1,17- di-secondary butylthio gibberellic acid benzyl ester, 13- hydroxyl -3,15- dioxies two tertiary butylthios of -1,17- are red mould Acid benzyl ester, two ring penta sulfenyl gibberellic acid benzyl esters of 13- hydroxyl -3,15- dioxies -1,17-, 13- hydroxyl -3,15- dioxies -1,17- two Cyclohexylthio gibberellic acid benzyl ester, two (2- hydroxyeththylthios) gibberellic acid benzyl esters of 13- hydroxyl -3,15- dioxies -1,17-, 13- hydroxyls - 3,15- dioxy -1,17- dimethyl sulfenyl gibberellic acid is to methoxybenzyl base ester, 13- hydroxyl -3,15- dioxy -1,17- diethyl sulfenyls Gibberellic acid is to methoxybenzyl base ester, 13- hydroxyl -3,15- dioxy -1,17- dipropyl sulfenyl gibberellic acid to methoxybenzyl base ester, 13- Hydroxyl -3,15- dioxy -1,17- diisopropyl sulfenyl gibberellic acid is to methoxybenzyl base ester, 13- hydroxyl -3,15- dioxies -1,17- two Butylthio gibberellic acid is to methoxybenzyl base ester, 13- hydroxyl -3,15- dioxy -1,17- di-secondary butylthio gibberellic acid to methoxybenzyl Base ester, two tertiary butylthio gibberellic acid of 13- hydroxyl -3,15- dioxies -1,17- are to methoxybenzyl base ester, 13- hydroxyl -3,15- dioxies - Bis- ring penta sulfenyl gibberellic acid of 1,17- is to methoxybenzyl base ester, two cyclohexylthio gibberellic acid pair of 13- hydroxyl -3,15- dioxies -1,17- Methoxybenzyl base ester, two (2- hydroxyeththylthios) gibberellic acid of 13- hydroxyl -3,15- dioxies -1,17- are to methoxybenzyl base ester；13- Acetoxy-3,15- dioxy -1,17- dimethyl sulfenyls Methyl gibberellate, 13- acetoxy-3s, 15- dioxy -1,17- diethyls Sulfenyl Methyl gibberellate, 13- acetoxy-3s, 15- dioxy -1,17- dipropyl sulfenyls Methyl gibberellate, 13- acetoxy-3s, 15- dioxy -1,17- diisopropyl sulfenyls Methyl gibberellate, 13- acetoxy-3s, 15- dioxy -1,17- dibutyl sulfides Ji Chimeisuanjia Ester, 13- acetoxy-3s, 15- dioxy -1,17- di-secondary butylthios Methyl gibberellate, 13- acetoxy-3s, dioxy -1 15-, Bis- tertiary butylthio Methyl gibberellates of 17-, 13- acetoxy-3s, two ring penta sulfenyl Methyl gibberellates of 15- dioxies -1,17-, 13- second Two cyclohexylthio Methyl gibberellates of acyloxy -3,15- dioxies -1,17-, 13- acetoxy-3s, two (2- hydroxyls of 15- dioxies -1,17- Base ethylmercapto group) Methyl gibberellate, 13- acetoxy-3s, 15- dioxy -1,17- dimethyl sulfenyl gibberellic acid benzyl ester, 13- acetyl oxygen Base -3,15- dioxy -1,17- diethyl sulfenyl gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- dipropyl sulfenyls are red mould Acid benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- diisopropyl sulfenyl gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxies - 1,17- dibutyl sulfide base gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- di-secondary butylthio gibberellic acid benzyl ester, 13- second Two tertiary butylthio gibberellic acid benzyl esters of acyloxy -3,15- dioxies -1,17-, 13- acetoxy-3s, two rings penta of 15- dioxies -1,17- Sulfenyl gibberellic acid benzyl ester, 13- acetoxy-3s, two cyclohexylthio gibberellic acid benzyl esters of 15- dioxies -1,17-, 13- acetoxy-3s, 15- dioxies -1,17- two (2- hydroxyeththylthios) gibberellic acid benzyl ester, 13- acetoxy-3s, 15- dioxy -1,17- dimethyl sulfenyls Gibberellic acid to methoxybenzyl base ester, 13- acetoxy-3s, 15- dioxy -1,17- diethyl sulfenyl gibberellic acid to methoxybenzyl base ester, 13- acetoxy-3s, 15- dioxy -1,17- dipropyl sulfenyl gibberellic acid is to methoxybenzyl base ester, 13- acetoxy-3s, 15- bis- For oxygen -1,17- diisopropyl sulfenyl gibberellic acid to methoxybenzyl base ester, 13- acetoxy-3s, 15- dioxy -1,17- dibutyl sulfide bases are red Mould acid to methoxybenzyl base ester, 13- acetoxy-3s, 15- dioxy -1,17- di-secondary butylthio gibberellic acid to methoxybenzyl base ester, 13- acetoxy-3s, two tertiary butylthio gibberellic acid of 15- dioxies -1,17- is to methoxybenzyl base ester, 13- acetoxy-3s, 15- bis- Two ring penta sulfenyl gibberellic acid of oxygen -1,17- is to methoxybenzyl base ester, 13- acetoxy-3s, two cyclohexylthios of 15- dioxies -1,17- Gibberellic acid is to methoxybenzyl base ester, 13- acetoxy-3s, and 15- dioxies -1,17- two (2- hydroxyeththylthios) gibberellic acid is to methoxy Base benzyl ester；
The corresponding chemical constitution of above compound is respectively：
In the above structural formula：Me is methyl, and Et is ethyl, and Pr is propyl,iPr is isopropyl, and Bu is butyl,sBu is sec-butyl,tBu is tertiary butyl,cPent is cyclopenta,cHex is cyclohexyl, and Bn is benzyl, and PMB is to methoxy-benzyl, and Ac is acetyl group.
3. how thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof is being made shown in general formula (I) according to claim 1 or 2 Application in standby antitumor drug, it is characterised in that the pharmaceutical salts refer to pharmaceutically acceptable salt, are carboxylic more Thio gibberellic acid ester type compound and alkali or alkaline earth metal oxide, hydroxide, methoxyl group compound, ethoxylate or The carboxylate that carbonate reaction is converted to, including lithium salts, sodium salt, sylvite, magnesium salts, calcium salt, strontium salt, bismuth salt.
4. how thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof is being made shown in general formula (I) according to claim 1 or 2 Application in standby antitumor drug, it is characterised in that the tumour is：It is leukaemia, liver cancer, lung cancer, breast cancer, colon cancer, black Melanoma.
5. how thio gibberellic acid esters compound or pharmaceutically acceptable salt thereof shown in general formula (I) as claimed in claim 1 or 2 be anti-in preparation Application in tumour prodrug, it is characterised in that the prodrug refers to how thio gibberellic acid ester type compound shown in general formula (I) Or its pharmaceutical salts itself have weaker activity or even without activity, but upon administration, in physiological conditions, by metabolism or Other modes are converted into corresponding biologically active form.
6. any type or two of the how thio gibberellic acid ester type compound as claimed in claim 1 or 2 containing therapeutically effective amount Kind or more mixture or its pharmaceutical salts and pharmaceutically acceptable carrier pharmaceutical composition.
7. the pharmaceutical composition application in preparation of anti-tumor drugs described in claim 6.
8. pharmaceutical composition application in preparation of anti-tumor drugs according to claim 7, it is characterised in that described Tumour is leukaemia, liver cancer, lung cancer, breast cancer, colon cancer, melanoma.
CN201810131532.7A 2018-02-09 2018-02-09 Mostly thio gibberellic acid ester type compound application in preparation of anti-tumor drugs Pending CN108354928A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101260095A (en) * 2008-04-18 2008-09-10 云南大学 13-halo-3,15-dioxygibberellic acid ester and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101260095A (en) * 2008-04-18 2008-09-10 云南大学 13-halo-3,15-dioxygibberellic acid ester and preparation method thereof

Non-Patent Citations (2)

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Title
飞鹏: "迈克尔受体类赤霉素衍生物的合成与活性研究", 《中国优秀硕士学位论文数据库 医药卫生科技辑》 *
马维维: "抗肿瘤干细胞脱半萜内酯类化合物的结构修饰", 《万方硕士学位论文数据库》 *

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