CN102702298A - Glycyrrhetinic acid derivative and preparation method and medical application thereof - Google Patents

Glycyrrhetinic acid derivative and preparation method and medical application thereof Download PDF

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CN102702298A
CN102702298A CN2012101539212A CN201210153921A CN102702298A CN 102702298 A CN102702298 A CN 102702298A CN 2012101539212 A CN2012101539212 A CN 2012101539212A CN 201210153921 A CN201210153921 A CN 201210153921A CN 102702298 A CN102702298 A CN 102702298A
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volatile oil
oxo
triolefin
acid
iii
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CN102702298B (en
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赖宜生
龙文艳
赖忠辉
沙磊
季晖
游然
谭佳妮
洪浩
赖金娥
张奕华
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention relates to the medicine field, in particular to a glycyrrhetinic acid derivativeor pharmaceutically acceptable salt thereof, preparation methods of the glycyrrhetinic acid derivative and the salt of the glycyrrhetinic acid derivative thereof, a medical composition containing the glycyrrhetinic acid derivative, and medical application of the glycyrrhetinic acid derivatives and pharmaceutically acceptable salt thereof, wherein the glycyrrhetinic acid derivative and the pharmaceutically acceptable salt thereof are represented by formulas (I, II and III). Pharmacological experimental results show that the compound has excellent anti-inflammatory, anti-tumor and hypoglycemicactivity, and can be used for preparing medicines for treating inflammatory diseases, tumors and diabetes mellitus.

Description

A kind of Enoxolone derivative, its preparation method and medicinal use
Technical field
The present invention relates to pharmaceutical field; Be specifically related to a kind of Enoxolone derivative or its pharmacy acceptable salt; Its preparation method contains the medicinal compsns of these verivates and their medicinal use, particularly the application in the medicine of preparation treatment inflammatory disease, tumour and mellitus.
Background technology
Inflammation is that body is invaded a kind of complex physical and the pathologic reaction that is produced to tissue injury or virulence factor.The basic pathology variation of inflammation comprises going bad, ooze out and hyperplasia of local organization.These pathological changes take place according to certain sequencing in inflammatory process, and general early stage with rotten and ooze out and be changed to the master, the later stage is main with hyperplasia.It is generally acknowledged that acute inflammation mainly shows as lymphocytic infiltration and activation, have immunity and defense function, intrusion and infringement that can the prevention and control pathogenic agent.But, if the pro-inflammatory cytokine continuous action can cause chronic inflammatory diseases, produce the damage of cell and tissue, and then produce various diseases.Big quantity research shows that chronic inflammatory diseases is at the many major diseases of the mankind such as tumour (Immunobiology, 2009,214 (9-10): 761-777; Cell, 2010,140:883-899), cardiovascular and cerebrovascular diseases (Nat Rev Immunol; 2010,10 (1): 36-46), nerve degenerative diseases (Trends Mol Med, 2010; 16 (5): 238-246), allergic disease, mellitus (FEBS Lett, 2008,582 (1): 97-105; Mol CellEndocrinol, 2010,314 (1): 1-16) etc. play an important role in generation and the evolution.
Inflammatory mediator is one type of chemically reactive substance that under the pro-inflammatory cytokine effect, is produced and discharged, participate in or cause inflammation and react by local organization or blood plasma.The endogenous inflammatory mediator mainly comprises histamine, serotonin, prostaglandin(PG) (PGs), leukotriene (LTs), nitrogen protoxide (NO), lysosome composition, lymphokine, kinin system, complement system, blood coagulation system and fibrinolytic system etc.The endogenous inflammatory mediator is present in the body with its precursor or inactive state usually, under the effect of pro-inflammatory cytokine, be transformed into the also a large amount of releases of active substance, and the generation to some pathological change is brought into play important mediation with development in inflammatory process.
NO is the molecule of different physiological roles such as a kind of second messenger of having concurrently, neurotransmitter and effector molecule, participates in multiple physiology and pathologic process in the organism.In the inflammatory reaction process; Inducible nitric oxide synthase in the various kinds of cell such as scavenger cell, neutrophil leucocyte (iNOS) can be by various cytokines (like IFN-γ, TNF-α etc.) or abduction deliverings such as pro-inflammatory cytokine such as LPS; The NO that mediation produces high density plays the inflammatory mediator effect, promotes inflammatory reaction through effects such as vasodilation hyperemia, oedema, cytotoxicities.Increasing research confirms that the NO of the lasting high density that the iNOS mediation produces in the chronic inflammatory diseases has participated in the generation and the development of human diseasess such as some tumour, cardiovascular and cerebrovascular diseases, nerve degenerative diseases, allergic disease, mellitus.The NO generation of inhibition iNOS over-expresses and high density can be inflammation and relative disease provides an efficacious therapy method (NatRev Drug Discov, 2002,1 (12): 939-950; Expert Opin Ther Pat, 2011,21 (4): 537-560).
Prove that at present synthetic type oleanolic acid derivate CDDO and analogue thereof (comprise CDDO-Me, CDDO-Im; CDDO-MA; CDDO-EA is one type of iNOS suppressor factor efficiently Di-CDDO), can significantly suppress IFN-γ or lipopolysaccharide-induced mouse macrophage iNOS and express and the NO generation.Wherein, 2-cyanic acid-3,12-dioxy Oleanolic Acid-1; 9 (11)-diene-28-acid methyl esters (CDDO-Me) has been used to treat the relevant disease of multiple inflammation at present in clinical trial; Comprise cancer and diabetic nephropathy (NatRev Cancer, 2007,7 (5): 357-369).
Glycyrrhizic legume is important simply traditional Chinese medicine, and Ancient Times in China physician explains and claims that Radix Glycyrrhizae is " state is old ", and Japan medical science man analogy claims that Radix Glycyrrhizae is " an eastern medicine ".Theory of traditional Chinese medical science thinks, the flat flavor of Radix Glycyrrhizae property is sweet, has with middle emergency, moistening lung, detoxifies, eliminates the phlegm, effects such as cough-relieving, qualcomm meridian, sharp qi and blood, coordinating the actions of various ingredients in a prescription.Potenlini (glycyrrhizic acid) and aglycon glycyrrhetinic acid (glycyrrhetic acid) thereof are the main active ingredient of Radix Glycyrrhizae.Research shows, Potenlini and glycyrrhetinic acid have anti-inflammatory, antiulcer agent, antiviral, reducing blood-fat, removing radical, multiple biological activity (Phytother Res, 2008,22 (6): 709-724) such as antitumor.Yet, the biological activity of glycyrrhetinic acid generally a little less than, therefore and long-term or heavy dose of use can cause pseudohyperaldosteronism (Chem Pharm Bull, 1987,35 (5): 1910-1918), influenced its clinical application.
Summary of the invention
The invention discloses a kind of Enoxolone derivative, its preparation method and medicinal use.The pharmacological results shows that Enoxolone derivative of the present invention has good anti-inflammatory, antitumor and hypoglycemic activity, therefore can be used for preparing the medicine of treating inflammatory disease, tumour and mellitus.
The open general formula (I) of the present invention, (II) and (III) shown in Enoxolone derivative or its pharmacy acceptable salt:
Figure BSA00000718755600021
Wherein:
R 1Represent H, F, Cl, Br, I, CN, OH, OR 3Or OC (O) R 3
R 2Represent CN, CH 2OC (Ph) 3, CO 2H, CO 2R 4, CH 2OH, CH 2OC (O) R 4Or C (O) NR 5R 6
R 3Represent C 1-C 6Alkyl;
R 4Represent C 1-C 6Alkyl or C 6-C 10Aromatic base, wherein said aromatic base can be randomly be selected from following group and replace with one or more: F, Cl, Br, I, NO 2, CN, NH 2Or OH;
R 5And R 6Can be identical or different, represent H, C 1-C 6Alkyl or R 5And R 6Form 5-7 unit heterocyclic group with the nitrogen-atoms that connects with them; This heterocyclic group can randomly comprise other heteroatoms of one or more O of being selected from, S or N; And this heterocyclic group can randomly be replaced to five replacements by following identical or different substituting group list, and said substituting group comprises: F, Cl, Br, I, OH, NO 2, CN, NH 2, C 1-C 6Alkyl or C 1-C 6Alkoxyl group;
Wherein, except following formula (a-c) compound:
Figure BSA00000718755600022
Further, general formula (I), (II) and (III) shown in Enoxolone derivative or its pharmacy acceptable salt, it is characterized in that:
R 1Represent H, OH, Cl, Br, I, CN, OR 3Or OC (O) R 3
R 2Represent CN, CH 2OC (Ph) 3, CO 2H, CO 2R 4, CH 2OH, CH 2OC (O) R 4Or C (O) NR 5R 6
R 3Represent CH 3
R 4Represent CH 3Or C 2H 5
NR 5R 6Represent NH 2, piperazinyl or imidazolyl.
Specifically, general formula (I), (II) and (III) shown in Enoxolone derivative preferably from following compounds:
2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I a);
2-bromo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I B-1);
2-chloro-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I B-2);
2-methoxyl group-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I c);
2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I d);
2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-1);
2-bromo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-2);
2-chloro-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-3);
2-methoxyl group-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-4);
2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-5);
The 2-acetoxy-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-6);
3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides (I F-1);
2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides (I F-2);
N-methyl-2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides (I F-3);
2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acyl piperazine (I F-4);
3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I g);
2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I h);
2-cyanic acid-3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I i);
3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II a);
2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II b);
2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II c);
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II d);
2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylate methyl ester (II E-1);
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylate methyl ester (II E-2);
3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides (II F-1);
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides (II F-2);
N-methyl-2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides (II F-3);
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acyl imidazoles (II F-4);
3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II g);
2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II h);
2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II i);
2-hydroxyl-3-oxo-30-three benzyloxies-volatile oil-1,11,13 (18)-triolefin (II j);
2-hydroxyl-3-oxo-30-acetoxyl group-volatile oil-1,11,13 (18)-triolefin (II k);
2,30-dihydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefin (II l);
3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III a);
2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III b);
2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III c);
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III d);
3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-1);
2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-2);
2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-3);
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-4);
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides (III F-1);
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides (III F-2);
N-methyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides (III F-3);
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acyl imidazoles (III F-4);
3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III g);
2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III h);
2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III i).
The compound code name that relates in the following pharmacological evaluation is equal to the pairing compound of code name here.
Described compound comprise general formula (I), (II) and (III) shown in all conformers, optically active isomer and the racemic modification of compound, diastereomer and tautomer and steric isomer, and the mixtinite of any above-mentioned form.
Another object of the present invention is to provide general formula (I), (II) and (III) shown in the preparation method of compound, it is characterized in that:
A) work as R 2Be COOH, the preparation method of compound is shown in the general formula (I): with glycyrrhetinic acid (GA) is raw material, makes 3-acetoxyl group-11-oxo-18 β-volatile oil-12-alkene-30-acid (1) with acetic anhydride; 1 makes 3-acetoxyl group-11-oxo-volatile oil-12 with bromine reaction, 18-diene-30-acid (2), and 2 make 3 beta-hydroxies-11-oxo-volatile oil-12 through sodium hydroxide hydrolysis; 18-diene-30-acid (3), 3 generate 3,11-dioxo-volatile oil-1 with adjacent iodoxy phenylformic acid (IBX) heated oxide; 12; 18-triolefin-30-acid (a), a make 2-iodo-3,11-dioxo-volatile oil-1 with the elemental iodine reaction under pyridine catalysis; 12,18-triolefin-30-acid (I a); A makes 1 through hydrogen peroxide oxidation, 2-epoxy-3,10-dioxo-volatile oil-12,18-diene-30-acid (4), 4 with haloid acid (HX) or sodium alkyl alcohol (R 3ONa) reaction makes 2-halo-3 respectively, 10-dioxo-volatile oil-1,12,18-triolefin-30-acid (I b) and 2-alkoxyl group-3,10-dioxo-volatile oil-1,12,18-triolefin-30-acid (I c); 3 reacts under room temperature with IBX and to generate 3,10-dioxo-volatile oil-12, and 18-diene-30-acid (5), 5 make 2-hydroxyl-3,10-dioxo-volatile oil-1,12, the sour (I of 18-triolefin-30-through the potassium tert.-butoxide oxidation d); Its synthetic route is following:
Figure BSA00000718755600041
Wherein, X represents F, Cl, Br, R 3Definition as previously mentioned;
Compound is characterised in that shown in the preparation formula (a), and solvent is selected from DMSO 99.8MIN. (DMSO), N (DMF), N-Methyl pyrrolidone (NMP) or ETHYLE ACETATE; Temperature is 60-120 ℃; Reaction times is 4-24 hour;
B) work as R 2Be COOH, the preparation method of compound is shown in the general formula (II): with glycyrrhetinic acid (GA) is raw material, makes 3 β through sodium borohydride reduction; 11-dihydroxyl-18 β-glycyrrhetinic acid (6); 6 at room temperature make 3 beta-hydroxies-volatile oil-11,13 (18)-diene-30-acid (7) through 5% Hydrogen chloride dehydration, and 7 make 3-oxo-volatile oil-1 through the IBX heated oxide; 11,13 (18)-triolefins-30-acid (II a); II aUnder pyridine catalysis, make 2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II with the elemental iodine reaction b); II bMake 2-cyanic acid-3-oxo-volatile oil-1,11 with the cuprous cyanide reaction, 13 (18)-triolefins-30-acid (II c); 7 reacts under room temperature with IBX and to make 3-oxo-volatile oil-11,13 (18)-diene-30-acid (8), and 8 make 2-hydroxyl-3-oxo-volatile oil-1,11, the sour (II of 13 (18)-triolefins-30-through the potassium tert.-butoxide oxidation d); Its synthetic route is following:
Figure BSA00000718755600042
Preparation formula (II a) shown in compound be characterised in that solvent is selected from DMSO 99.8MIN. (DMSO), N (DMF), N-Methyl pyrrolidone (NMP) or ETHYLE ACETATE; Temperature is 60-120 ℃; Reaction times is 4-24 hour;
C) work as R 2Be COOH; The preparation method of compound is shown in the general formula (III): midbody (6) dewaters under the concentrated hydrochloric acid effect and makes 3 beta-hydroxies-18 β-volatile oil-9 (11); 12-diene-30-acid (9); 9 make 3-oxo-18 β-volatile oil-1,9 (11) through the IBX heated oxide, 12-triolefin-30-acid (III a); III aUnder pyridine catalysis, make 2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III with the elemental iodine reaction b); III bMake 2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11) with the cuprous cyanide reaction, 12-triolefin-30-acid (III c); 9 reacts under room temperature and make 3-oxo-18 β-volatile oil-9 (11) with IBX, 12-diene-30-acid (10), and 10 make 2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), the sour (III of 12-triolefin-30-through the potassium tert.-butoxide oxidation d); Its synthetic route is following:
Figure BSA00000718755600051
Preparation formula (III a) shown in compound be characterised in that solvent is selected from DMSO 99.8MIN. (DMSO), N (DMF), N-Methyl pyrrolidone (NMP) or ETHYLE ACETATE; Temperature is 60-120 ℃; Reaction times is 4-24 hour;
D) work as R 2Be CO 2R 4Or C (O) NR 5R 6The time, general formula (I), (II) and (III) shown in the preparation method of compound be: respectively with a, I A-d, II A-dAnd III A-dBe raw material, under the salt of wormwood effect with halohydrocarbon (R 4X) reaction, or generate behind the acyl chlorides again and aminated compounds (HNR with chloride reagent reaction 5R 6) reaction, make ester compound (I respectively e, II e, III e) and amides (I f, II f, III f); Its synthetic route is following:
Wherein, R 1, R 4, R 5, R 6Definition as previously mentioned;
Preparation formula (I f, II f, III f) shown in compound it is characterized in that chloride reagent is selected from oxalyl chloride, sulfur oxychloride or phosphorus trichloride;
E) work as R 2During for CN, general formula (I), (II) and (III) shown in the preparation method of compound be: with I F-1, II F-1And III F-1Be raw material, under the dehydrated reagent effect, make 3 respectively, 11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I g), 3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II g) and 3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III g); Under pyridine catalysis, I g, II gAnd III gMake 2-iodo-3 with Iod R respectively, 11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I h), 2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II h) and 2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III h); I h, II hAnd III hMake 2-cyanic acid-3 respectively, 11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I with the inferior reactive ketone of cyaniding separately again i), 2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II i) and 2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III i); Its synthetic route is following:
Figure BSA00000718755600061
Preparation formula (I g, II g, III g) time, dehydrated reagent is selected from trifluoroacetic anhydride, diacetyl oxide, POCl3 or phosphorus trichloride;
F) work as R 2Be CHOH, CH 2OC (Ph) 3Or CH 2OC (O) R 4The time; The preparation method of compound is shown in the general formula (II): GA generates 3 β, 11,30-trihydroxy--18 β-volatile oil-12-alkene (11) through the Lithium Aluminium Hydride reduction; 11 dewater under the Hydrogen chloride effect and are rearranged into 3 β; 30-dihydroxyl-volatile oil-11,13 (18)-diene (12), 12 with triphenylmethyl chloride (Ph 3CCl) reaction makes 3 beta-hydroxies-volatile oil-11; 13 (18)-diene-30-trityl ether (13); 13 make 3-oxo-volatile oil-11,13 (18)-diene-30-trityl ether (14) through IBX oxidation under room temperature, and 14 make 2-hydroxyl-3-oxo-30-three benzyloxies-volatile oil-1 through the potassium tert.-butoxide oxidation; 11,13 (18)-triolefin (II j); II jIn Glacial acetic acid min. 99.5, reflux and make 2-hydroxyl-3-oxo-30-acetoxyl group-volatile oil-1,11,13 (18)-triolefin (II k); II jReaction makes 2,30-dihydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefin (II under 50 ℃ in Glacial acetic acid min. 99.5 l); Its synthetic route is following:
Figure BSA00000718755600062
Further, preparation formula (a), (II a), (III a) be characterised in that solvent is DMSO; Temperature of reaction is 85 ℃; Reaction times is 8-12h; Preparation formula (I f, II f, III f) be characterised in that chloride reagent is an oxalyl chloride; Preparation formula (I g, II g, III g) be characterised in that dehydrated reagent is a trifluoroacetic anhydride.
Further purpose of the present invention is to provide a kind of pharmaceutical composition, is gone up in the claim 1,2 or 3 of significant quantity each compound or its pharmaceutically acceptable carrier or auxiliary material by treatment and forms.
Compound or its pharmacy acceptable salt that a purpose more of the present invention provides in the claim 1,2 or 3 each is used for treating the purposes of the medicine of inflammatory disease, tumour or mellitus in preparation.Wherein said inflammatory disease is dermatitis, inflammatory pain, neuropathic pain, osteoarthritis, rheumatic arthritis, rheumatoid arthritis or myocarditis.Wherein said tumour is liver cancer, cancer of the stomach, colorectal carcinoma, prostate cancer, carcinoma of the pancreas, mammary cancer, lung cancer, white blood disease.Wherein said mellitus are type i diabetes or type ii diabetes.
The compounds of this invention can with other antitumor drug for example alkylating agent (like endoxan or cis-platinum), antimetabolite (like 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (like NSC 94600), mitotic inhibitor (like taxol or vinealeucoblastine(VLB)), DNA intercalating agent (like Zorubicin) combined utilization, in addition can also with the radiotherapy combined utilization.These other antitumor drugs or radiotherapy can give with The compounds of this invention simultaneously or at different time.Thereby these combination therapys can produce synergy helps to improve result of treatment.
The pharmacological experimental method and the result of The compounds of this invention are following:
1. anti-inflammatory activity evaluation
Adopt LPS (LPS) inducing mouse scavenger cell (RAW 264.7) to discharge nitrogen protoxide (NO) model and carry out the anti-inflammatory activity evaluation of part of compounds of the present invention, active with Griess method test compounds to the inhibition that NO generates.Positive drug is a DEXAMETHASONE BP98.
1.1 medicine and reagent
Mouse macrophage RAW 264.7: draw Shanghai cell institute from the Chinese Academy of Sciences; LPS (E.coli 055:B5): available from Sigma company; Nitrogen protoxide detection kit: available from green skies biotechnology research institute; Dry powder DMEM substratum: available from GIBCO company; Foetal calf serum: available from people's marine life company; DMSO (analytical pure product): Shanghai Ling Feng chemical reagent ltd.
1.2 key instrument
CO 2Constant incubator: Thermo Electron company; XDS-1B laboratory inverted biologic microscope: Chongqing Photoelectric Instruments Corp.; The vertical steam sterilizer of YXQ-LS-50S II digital display: Medical Equipment Plant of Shanghai Boxun Industrial Co., Ltd.; 0412-1 table-type low-speed whizzer: Shanghai Medical Appliance (Group) Co., Ltd. Surgical Instruments Factory; Sartorius BS 224S electronic balance: Beijing Sai Duolisi instrument system ltd; The vertical self-controlled electric heating pressure steam sterilizer of LDZX-40C type: Shenan Medical Appliances Factory, Shanghai; BIO-RAD 1680 enzyme-linked immunosorbent assay instruments: Britain BIO-RAD company; TS-1QRBITAL SHAKER: its woods Bel instrument Manufacturing Co., Ltd of Haimen City.
1.3 experimental technique
(1) PBS solution: take by weighing NaCl 8g, KCl 0.2g, Na 2HPO 412H 2O 3.49g, KH 2PO 40.2g be dissolved in the tri-distilled water, stir constant volume 1L.Preserve subsequent use down in 4 ℃ behind the high-temperature sterilization.
(2) given the test agent mother liquor preparation: all prepare mother liquor with an amount of DMSO, with preceding substratum or PBS solution dilution to proper concn.
(3) cell cultures: the RAW264.7 cell is cultivated based on 37 ℃ with the DMEM that contains 10% serum, 5%CO 2Incubator is cultivated.
(4) after cell grows to logarithmic phase, with 3 * 10 5The density of individual/mL is seeded to 96 orifice plates, in incubator, cultivates; When cell proliferation to 80% was merged, pair cell carries out serum starvation to be handled, the compound pre-treatment of adding different concns 2 hours; The LPS that adds 100ng/mL induces; Carry out the NO assay with Griess method test kit after 24 hours, ELIASA 550nm surveys the OD value down.Press the public inhibiting rate that calculates, with the SPSS data processing software data are analyzed and obtained compound generates inhibition to RAW264.7NO IC 50The result is as shown in table 1.
Inhibiting rate (%)=(OD The LPS group-OD The administration group)/(OD The LPS group-OD The blank group) * 100%
Table 1 part of compounds of the present invention is active to the inhibition that lipopolysaccharide-induced RAW 264.7 cell NO generate
Experimental result shows: The compounds of this invention generates all to have to LPS inducing mouse scavenger cell (RAW 264.7) nitrogen protoxide and suppresses active, and the inhibition activity of The compounds of this invention all is better than the lead compound glycyrrhetinic acid.Wherein, I E-1, I i, II i, III cInhibition active suitable with the positive drug DEXAMETHASONE BP98; III iThe inhibition activity be better than DEXAMETHASONE BP98.
1.4 immunoblot experiment
Induce in the inflammatory model of scavenger cell RAW264.7 at LPS, iNOS is one of most representative effect protein, is the synthetic enzyme that the mediation excessive NO generates.Above-mentioned experiment shows that The compounds of this invention can significantly suppress LPS and induce scavenger cell RAW 264.7 nitrogen protoxides to generate, and this experiment adopts immunoblotting to investigate the influence that compound induces the iNOS of RAW264.7 cell to express to LPS.
Experimental technique: with the RAW264.7 cell with 4 * 10 6The density of individual/ware is incubated in the 60mm petridish, earlier with IIIc (final concentration is 3.08 μ mol/L), GA (final concentration is 187.88 μ mol/L) or contain the substratum pre-treatment 2 hours of equivalent DMSO, uses final concentration to induce 24 hours as the LPS of 100ng/mL again.Measure the iNOS protein level of each group through immunoblotting.Actin muscle is as last appearance contrast, experiment repetition 3 times.Experimental result is as shown in the figure. * *P＜0.001 (comparing) with the LPS group.
From figure, can know that LPS can significantly improve the iNOS protein expression of scavenger cell RAW264.7; Compare with the LPS group, The compounds of this invention IIIc is at IC 50Dosage under (3.08 μ mol/L) can reduce iNOS protein expression (p＜0.001) significantly.
2. external hypoglycemic activity evaluation
Select the HepG2 cell for use, adopt glucose oxidase method to carry out the glucose consumption experiment, carry out the external hypoglycemic activity evaluation of part of compounds of the present invention.The positive medicine of Walaphage.
2.1 medicine and reagent
Walaphage (Beijing JingFeng Pharmaceutical Co., Ltd, lot number: 101003); High sugared DMEM substratum (Invitrogen, lot number: 12800); Foetal calf serum (Invitrogen, lot number: 10099); Trypsin Beijing ancient cooking vessel state biotechnology limited liability Ltd, lot number: DH355-4); Glucose kit (ShangHai RongSheng Biology Pharmacy Co., Ltd, lot number: 20101001).
2.2 experiment is divided into groups
Blank group: substratum 100 μ L.
The normal control group: inoculating cell density is 10 3～10 4Individual cell/100 μ L does not contain organic solvent in the substratum.
Solvent control group: inoculating cell density is 10 3～10 4Individual cell/100 μ L contains 0.1% organic solvent in the substratum.
The positive drug group: inoculating cell density is 10 3～10 4Individual cell/100 μ L contains 0.1% organic solvent, positive drug concentration 10 in the substratum -5Mol/L.
Organized by examination: inoculating cell density is 10 3～10 4Individual cell/100 μ L contains 0.1% organic solvent in the substratum, set three concentration group, is respectively high density group (10 -4Mol/L), middle concentration group (10 -5Mol/L), low concentration group (10 -6Mol/L).Glycyrrhetinic acid concentration is 10 -4Mol/L.
2.3 experimental technique
(1) PBS damping fluid (0.01M, pH 7.4): take by weighing NaCl 8g, KCl 0.2g, Na 2HPO 412H 2O 3.63g, KH 2PO 40.24g, be dissolved in the 900mL distilled water, with hydrochloric acid adjust pH to 7.4, add water and be settled to 1L, high-temperature sterilization before using.
(2) 0.25% pancreatin: get pancreatin 0.125g, be dissolved in 50mL PBS (0.01M, pH 7.4), accent pH is 7.6-8.0, filters before using.
(3) high glucose medium: contain 90% high sugared DMEM, 10% foetal calf serum.
(4) preparation of testing compound: the PBS solution with containing 1%DMSO is made into 10 -2The mol/L storing solution is diluted to 10 respectively with high glucose medium again -4Mol/L, 10 -5Mol/L, 10 -6Mol/L solution (pastille substratum), subsequent use; The preparation of Walaphage: the PBS solution with containing 1%DMSO is mixed with 10 with Walaphage -2Mol/L solution is diluted to 10 with high glucose medium with strong solution again -5Mol/L (containing the positive drug substratum), subsequent use; The preparation of glycyrrhetinic acid (GA): the PBS solution with containing 1%DMSO is mixed with 10 with GA -2Mol/L solution is diluted to 10 with high glucose medium with strong solution again -4Mol/L (containing the GA substratum), subsequent use.
(5) HepG2 cell cultures: the HepG2 cell after the recovery with high glucose medium at 37 ℃, 5%CO 2Cultivate under the condition, the cell in the vegetative period of taking the logarithm is used 0.25% trypsin digestion cell, and add high glucose medium and prepare cell suspension, counting, the adjustment cell density is 10 4～10 5Individual cell/mL, absorption cell suspension 100 μ L put in 96 orifice plates and cultivated 12 hours.
(6) glucose consumption experiment: get the cell of cultivating in 96 orifice plates 12 hours; Be replaced with the pharmaceutical culture medium that contains different concns, cultivate after 24 hours, get 5 μ L substratum; Join in the 200 μ L glucose reagent; Adopt glucose oxidase method, measure glucose concn (each concentration is established 4 holes, repeats 3 times) with ELIASA.
2.4 data processing
Calculate the glucose consumption rate of given the test agent according to formula.
Figure BSA00000718755600091
2.5 statistical procedures
All data are all used means standard deviation
Figure BSA00000718755600092
expression.Adopt SPSS11.5 software to analyze, data relatively adopt one-way analysis of variance. *P＜0.05 expression has significant difference, *P＜0.01 expression has utmost point significant difference (comparing with the normal control group).Experimental result is shown in table 2-7.
Table 2 part of compounds of the present invention is to the influence (
Figure BSA00000718755600093
n=12) of HepG2 grape cell sugar consumption
Figure BSA00000718755600094
Table 3 part of compounds of the present invention is to the influence (
Figure BSA00000718755600095
n=12) of HepG2 grape cell sugar consumption
Figure BSA00000718755600096
Table 4 part of compounds of the present invention is to the influence (
Figure BSA00000718755600101
n=12) of HepG2 grape cell sugar consumption
Figure BSA00000718755600102
Table 5 part of compounds of the present invention is to the influence (
Figure BSA00000718755600103
n=12) of HepG2 grape cell sugar consumption
Figure BSA00000718755600104
Figure BSA00000718755600111
Table 6 part of compounds of the present invention is to the influence (
Figure BSA00000718755600112
n=12) of HepG2 grape cell sugar consumption
Figure BSA00000718755600113
Figure BSA00000718755600121
Table 7 part of compounds of the present invention is to the influence (
Figure BSA00000718755600122
n=12) of HepG2 grape cell sugar consumption
Figure BSA00000718755600123
Figure BSA00000718755600131
Experimental result shows: under lower concentration, middle concentration and high density, part of compounds of the present invention has hypoglycemic activity in various degree, and its hypoglycemic activity is superior to the lead compound glycyrrhetinic acid, wherein, and compound (I B-2, I c, I E-2, I E-3, I E-5, I E-6, I F-2, II a, II E-1, II F-2, II F-3, II k, III a, III E-1, III F-3, III F-4, III i) have a significant hypoglycemic activity; I B-2, II F-2, II F-3Hypoglycemic activity is superior to or is suitable with the positive control drug Walaphage.
3. anti-tumor activity evaluation
It is active to 8 kinds of human cancer cell strain inhibition of proliferation to adopt the tetramethyl-nitrogen blue colourimetry of azoles (MTT) to estimate part of compounds of the present invention.Mtt assay has been widely used in the responsive mensuration of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy etc.
Positive control drug: CDODA-Me and CDDO-Me.Wherein, CDODA-Me (2-cyanic acid-3,11-dioxo-18 β-volatile oil-1,12-diene-30-carboxylate methyl ester) is an Enoxolone derivative, has good antineoplastic activity (Bioorg Med Chem lett, 2008,18 (8): 2633-2639).CDDO-Me (2-cyanic acid-3; 12-dioxo-volatile oil-1,9 (11)-diene-28-carboxylate methyl ester) is oleanolic acid derivate, has good anti-inflammatory and anti-tumor activity; Be in the clinical development stage at present; Be used to treat tumour and diabetic nephropathy (Nat Rev Cancer, 2007,7 (5): 357-369).
Humanized's tumor cell line: hepatoma cell strain (HepG2), lung cancer cell line (A549), stomach cancer cell line (MGC-803), prostate cancer cell strain (PC-3), pancreatic cancer cell (BxPC-3), colon cancer cell line (HCT116), acute promyelocytic leukemia cell strain (HL-60), breast carcinoma cell strain (MCF-7).
Experimental technique: compound is dissolved with DMSO, be diluted to concentration with PBS and be respectively 1 * 10 -6, 1 * 10 -5, 1 * 10 -4Mol/L receives test solution.Get and be in one bottle of exponential phase of growth, growth conditions good cell, add 0.25% tryptic digestion, attached cell is come off, process every milliliter and contain 2 * 10 4-4 * 10 4The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L put constant temperature CO 2Cultivated 24 hours in the incubator.Change liquid, adding receives test solution, and every hole 20 μ L cultivated 48 hours.In the blue adding of tetramethyl-nitrogen azoles 96 orifice plates, every hole 20 μ L, reaction is 4 hours in the incubator.Supernatant is removed in suction, adds DMSO, every hole 150 μ L, and jolting is 5 minutes on the dull and stereotyped shaking table.Use enzyme-linked immunosorbent assay instrument in the optical density of wavelength, calculate cell proliferation inhibition rate as the every hole of mensuration, 570nm place.Establish 3 parallel holes for every group, and repeat 3 times.The result sees table 8.
Figure BSA00000718755600141
Table 8 part of compounds of the present invention is to tumor cell proliferation inhibition rate (%) (10 -4Mol/L)
Figure BSA00000718755600142
Figure BSA00000718755600151
The pharmacological results shows; The compounds of this invention has restraining effect in various degree to humanized's tumor cell proliferation, and wherein, the anti-tumor activity of majority of compounds is superior to the lead compound glycyrrhetinic acid; The activity of part of compounds is suitable with positive drug CDDO-Me, and is superior to CDODA-Me.
Description of drawings
Figure The compounds of this invention IIIc to LPS induce the iNOS protein expression of RAW264.7 influence ( * *P＜0.001vs LPS group).
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.The used glycyrrhetinic acid of the present invention is available from Xi'an Fu Jie Bioisystech Co., Ltd, content＞98%.
Embodiment 1
Figure BSA00000718755600152
The preparation of 3 β-acetoxyl group-18 β-glycyrrhetinic acid (1)
(0.5mg 1.06mmol) is dissolved in the 10mL diacetyl oxide glycyrrhetinic acid, and reflux 2h is cooled to room temperature, adds the aqueous solution (4mL HOAc, the 2mL H of Glacial acetic acid min. 99.5 2O), back flow reaction 30min postcooling adds water 50mL, suction filtration, drying, white powder 0.48mg, yield 88%, mp＞300 ℃.
3 β-acetoxyl group-11-oxo-volatile oil-12, the preparation of 18-diene-30-acid (2)
1 (0.2mg 0.39mmol) is dissolved in the 15mL Glacial acetic acid min. 99.5, slowly drips Br after being warming up to 80 ℃ 2(10min drips off for 0.125mg, Glacial acetic acid min. 99.5 1.17mmol) (4mL) solution; Under 80 ℃ of conditions, react 4h, cooling adds saturated sodium bisulfite solution (50mL); Suction filtration, oven dry, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 4 (V: V)]; Get pale yellow powder 140mg, yield 73%, 215～217 ℃ of mp.
3 beta-hydroxies-11-oxo-volatile oil-12, the preparation of 18-diene-30-acid (3)
2 (0.15mg 0.30mmol) is dissolved in the 10mL THF, adds methyl alcohol (5mL), 2M sodium hydroxide solution (5mL) successively, back flow reaction 5h; The most of solvent of pressure reducing and steaming with the neutralization of 5% hydrochloric acid soln, is separated out white solid; Suction filtration, oven dry, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 4 (V: V)]; Make white powder 130mg, yield 94.5%, 165～167 ℃ of mp.
3,11-dioxo-volatile oil-1,12, the preparation of 18-triolefin-30-acid (a)
3 (2.0g 4.2mmol) is dissolved among the 60mL DMSO, and adding IBX (4.70g, 16.8mmol); Be warming up to 85 ℃, reaction 12h adds water 200mL, ethyl acetate extraction (60mL * 3); Use 5% sodium hydrogencarbonate (50mL * 3) successively, saturated aqueous common salt (50mL * 3) washing, anhydrous sodium sulfate drying concentrates; Recrystallization from ethyl acetate/petroleum ether gets white powder solid 1.45g, yield 73.2%, 236～238 ℃ of mp.
2-iodo-3,11-oxo-volatile oil-1,12,18-triolefin-30-acid (I a) preparation
A (0.58mg 1.25mmol) is dissolved among the anhydrous THF of 20mL, add successively iodine (1.56g, 6.25mmol) and pyridine (0.487mg; 6.25mmol), back flow reaction 24h is cooled to room temperature, the most of solvent of pressure reducing and steaming; Add ETHYLE ACETATE (60mL), use 10% sodium sulfite solution (50mL * 3) successively, 5% hydrochloric acid soln (50mL * 3), saturated aqueous common salt (50mL * 3) washing; Anhydrous sodium sulfate drying concentrates, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 8 (V: V)]; Make white powder solid 0.45mg, yield 61%, 184～186 ℃ of mp.ESI-MS：545.2[M-CO 2H] -；IR(KBr，cm -1)v：3643，3127，2965，2925，2867，2812，1701，1655，1680，1641，1459，1400，1326，1241，1208，1154，1096，1032，960，868，790； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.793(s，3H，CH 3)，0.876(s，3H，CH 3)，1.107(s，6H，2×CH 3)，1.121(s，6H，2×CH 3)，1.154(s，3H，CH 3)，1.202(s，3H，CH 3)，1.412(s，3H，CH 3)，2.651(s，1H，C 9-H)，5.840(s，1H，C 19-H)，5.878(s，1H，C 12-H)，8.421(s，1H，C 1-H).
Embodiment 2
Figure BSA00000718755600161
1,2-epoxy-3,11-dioxo-volatile oil-12, the preparation of 18-diene-30-acid (4)
(100mg 0.21mmol) is dissolved among the 10mL THF a, adds the sodium hydroxide solution (1mL) of 2M, slowly drips 30%H 2O 2Methyl alcohol (1mL) (3mL) solution, stirring at room 18h, the most of solvent of pressure reducing and steaming; Regulate pH to neutral with 5% hydrochloric acid soln, separate out white solid, suction filtration; Oven dry, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 8 (V: V)], make white solid 70mg; Productive rate 67.9%, 219～221 ℃ of mp.ESI-MS：435.3[M-CO 2H] -，481.4[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.857(s，3H，CH 3)，0.992(s，3H，CH 3)，1.102(s，6H，2×CH 3)，1.286(s，6H，2×CH 3)，1.333(s，3H，CH 3)，1.492(s，3H，CH 3)，1.600(s，3H，CH 3)，2.868(s，1H，C 9-H)，3.398(d，1H，C 1-H，J＝3.9Hz)，4.401(d，1H，C 2-H，J＝4.47Hz)，5.899(s，1H，C 19-H)，5.945(s，1H，C 12-H).
2-bromo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I B-1) preparation
4 (200mg 0.41mmol) is dissolved in the 20mL Glacial acetic acid min. 99.5, drips 48% Hydrogen bromide (1mL) solution, under condition under the lucifuge; Stirring at room 40min adds water 50mL, separates out white solid; Suction filtration, oven dry, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 8 (V: V)]; Make white solid powder 130mg, productive rate 57.5%, 245～247 ℃ of mp.IR(KBr，m -1)v：3473，3133，2923，2852，1732，1682，1626，1607，1588，1458，1396，1385，1353，1329，1270，1245，1214，1152，1113，1040，1016，958，865，797，714，651；ESI-MS：497.4[M-CO 2H] -； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.879(s，3H，CH 3)，0.990(s，3H，CH 3)，1.178(s，6H，2×CH 3)，1.219(s，6H，2×CH 3)，1.254(s，3H，CH 3)，1.369(s，3H，CH 3)，1.618(s，3H，CH 3)，2.664(s，1H，C 9-H)，5.878(s，1H，C 19-H)，5.936(s，1H，C 12-H)，8.147(s，1H，C 1-H).
Embodiment 3
2-chloro-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I B-2) preparation
4 (300mg 0.63mmol) is dissolved in the 20mL Glacial acetic acid min. 99.5, drips concentrated hydrochloric acid (1mL); Stirring at room 30min adds water 30mL, separates out white solid; Suction filtration, oven dry, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 8 (V: V)]; Make white solid powder 170mg, productive rate 54.6%, 259～261 ℃ of mp.IR(KBr，cm -1)v：3439，3122，3963，2948，2858，1732，1685，1655，1627，1615，1597，1455，1385，1330，1353，1270，1246，1214，1198，1182，1153，1112，959，858；ESI-MS：454.4[M-CO 2H] -，499.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.879(s，3H，CH 3)，0.991(s，3H，CH 3)，1.174(s，6H，2×CH 3)，1.212(s，6H，2×CH 3)，1.254(s，3H，CH 3)，1.369(s，3H，CH 3)，1.617(s，3H，CH 3)，2.661(s，1H，C 9-H)，5.879(s，1H，C 19-H)，5.937(s，1H，C 12-H)，7.898(s，1H，C 1-H).
Embodiment 4
2-methoxyl group-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I c) preparation
Figure BSA00000718755600171
(230mg 10mmol) is dissolved under the room temperature in the 20mL methyl alcohol, adds 4 (100mg, methyl alcohol 0.21mmol) (10mL) solution with sodium Metal 99.5; Reflux 24h is cooled to room temperature, and most of solvent is removed in decompression, regulates pH to neutral with 5% hydrochloric acid soln; Separate out white solid, suction filtration, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 5 (V: V)]; Get white solid 60mg, productive rate 58.8%, 227～229 ℃ of mp.IR(KBr，cm -1)v：3482，3170，2969，2938，2865，1725，1685，1655，1637，1625，1614，1581，1457，1387，1357，1324，1254，1215，1191，1152，1140，1117，1099，1082，1034，977，931，877，867，843，816，675；ESI-MS：449.3[M-CO 2H] -，495.4[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.875(s，3H，CH 3)，0.996(s，3H，CH 3)，1.195(s，6H，2×CH 3)，1.234(s，6H，2×CH 3)，1.336(s，3H，CH 3)，1.442(s，3H，CH 3)，1.618(s，3H，CH 3)，2.652(s，1H，C 9-H)，3.556(s，3H，OCH 3)，5.861(s，1H，C 19-H)，5.896(s，1H，C 12-H)，6.678(s，1H，C 1-H).
Embodiment 5
Figure BSA00000718755600172
3,11-dioxo-volatile oil-12, the preparation of 18-diene-30-acid (5)
3 (1.0g 2.13mmol) is dissolved among the 40mL DMSO, and adding IBX (1.19g, 4.25mmol); Stirring at room reaction 8h adds water 100mL, and ethyl acetate extraction (50mL * 3) is used 5% sodium hydrogencarbonate (50mL * 3) successively; Saturated aqueous common salt (50mL * 3) washing, anhydrous sodium sulfate drying concentrates recrystallization from ethyl acetate/petroleum ether; Get white powder solid 0.78g, yield 78.3%, 203～205 ℃ of mp.2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid (I d) preparation
5 (0.15mg 0.32mmol) is dissolved in the 10mL trimethyl carbinol, be warming up to 45 ℃ after, add potassium tert.-butoxide (0.72mg; 6.24mmol), in 40～45 ℃ of about 50min of reaction, be cooled to room temperature, neutralize with 5% hydrochloric acid soln; Most of solvent is removed in decompression, suction filtration, oven dry; Column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 6 (V: V)], get white solid 64.9%, 246～248 ℃ of mp.IR(KBr，cm -1)v：3442，3142，2947，2855，2360，2342，1735，1664，1644，1594，1587，1476，1457，1401，1385，1362，1328，1278，1243，1220，1152，1117，1058，1032，1009，960，865，787，713，678；ESI-MS：435.4[M-CO 2H] -，481.4[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.820(s，3H，CH 3)，0.907(s，3H，CH 3)，1.194(s，6H，2×CH 3)，1.227(s，6H，2×CH 3)，1.361(s，3H，CH 3)，1.548(s，3H，CH 3)，1.589(s，3H，CH 3)，2.664(s，1H，C 9-H)，5.876(s，1H，C 19-H)，5.901(s，1H，C 12-H)，5.925(s，1H，C 1-H)，7.063(s，1H，C 2-OH).
Embodiment 6
2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-1) preparation
Figure BSA00000718755600173
I a(0.15mg 0.32mmol) is dissolved among the 20mL DMF, add Anhydrous potassium carbonate (53.4mg, 0.39mmol) and methyl iodide (55mg, 0.39mmol); Stirring at room 8h adds ammoniacal liquor (5mL), continues to stir 30min, adds water (60mL); Ethyl acetate extraction (30mL * 3), saturated common salt water washing (30mL * 3), anhydrous sodium sulfate drying concentrates; Column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 12 (V: V)], make white solid 110mg, productive rate 70.9%, 199～201 ℃ of mp.IR(KBr，cm -1)v：3448，3127，2969，2951，2858，1727，1679，1653，1587，1458，1400，1385，1327，1250，1207，1197，1151，1116，1096，1034，870，787，647；ESI-MS：604.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.835(s，3H，CH 3)，0.969(s，3H，CH 3)，1.117(s，6H，2×CH 3)，1.209(s，6H，2×CH 3)，1.317(s，3H，CH 3)，1.417(s，3H，CH 3)，1.552(s，3H，CH 3)，2.647(s，1H，C 9-H)，4.409(s，3H，CO 2CH 3)，5.857(s，1H，C 19-H)，5.902(s，1H，C 12-H)，8.430(s，1H，C 1-H).
Embodiment 7
2-bromo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-2) preparation
Figure BSA00000718755600181
With reference to I E-1The preparation method, by I B-1Make the white powder solid with iodomethane reaction, yield 83%, 192～194 ℃ of mp.IR(KBr，cm -1)v：3437，3127，2968，2869，1730，1686，1655，1605，1589，1458，1384，1329，1274，1246，1207，1196，1152，1115，1090，1032，967，931，868，797，761，720，650；ESI-MS：557.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.856(s，3H，CH 3)，0.973(s，3H，CH 3)，1.178(s，6H，2×CH 3)，1.220(s，6H，2×CH 3)，1.317(s，3H，CH 3)，1.431(s，3H，CH 3)，1.574(s，3H，CH 3)，2.657(s，1H，C 9-H)，3.705(s，3H，CO 2CH 3)，5.856(s，1H，C 19-H)，5.900(s，1H，C 12-H)，8.149(s，1H，C 1-H).
Embodiment 8
2-chloro-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-3) preparation
Figure BSA00000718755600182
With reference to I E-1The preparation method, by I B-2Make the white powder solid with iodomethane reaction, yield 87%, 225～227 ℃ of mp.IR(KBr，cm -1)v：3465，3133，2972，2948，2859，2362，2336，1729，1689，1655，1606，1458，1427，1385，1331，1247，1207，1196，1153，1119，1092，1032，971，958，880，864，851，810，761，661；ESI-MS：513.4[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.876(s，3H，CH 3)，0.972(s，3H，CH 3)，1.001(s，6H，2×CH 3)，1.220(s，6H，2×CH 3)，1.315(s，3H，CH 3)，1.331(s，3H，CH 3)，1.585(s，3H，CH 3)，2.684(s，1H，C 9-H)，3.705(s，3H，CO 2CH 3)，5.857(s，1H，C 19-H)，5.898(s，1H，C 12-H)，7.901(s，1H，C 1-H).
Embodiment 9
2-methoxyl group-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-4) preparation
Figure BSA00000718755600183
With reference to I E-1The preparation method is by I cMake white solid with iodomethane reaction, productive rate 79%, 118～120 ℃ of mp.IR(KBr，cm -1)v：3463，3127，2968，2868，1728，1684，1655，1618，1458，1399，1363，1326，1270，1247，1211，1197，1153，1117，1094；ESI-MS：509.4[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.875(s，3H，CH 3)，0.99(s，3H，CH 3)，1.19(s，6H，2×CH 3)，1.234(s，6H，2×CH 3)，1.336(s，3H，CH 3)，1.442(s，3H，CH 3)，1.618(s，3H，CH 3)，2.652(s，1H，C 9-H)，3.556(s，3H，OCH 3)，4.256(s，3H，CO 2CH 3)，5.861(s，1H，C 19-H)，5.896(s，1H，C 12-H)，6.678(s，1H，C 1-H).
Embodiment 10
2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-5) preparation
Figure BSA00000718755600191
With reference to I E-1The preparation method, by I dMake the white powder solid with iodomethane reaction, productive rate 79%, 207～209 ℃ of mp.IR(KB?r，cm -1)v：3449，3416，2972，2951，2868，1730，1663，1643，1633，1610，1587，1458，1427，1404，1384，1362，1323，1274，1244，1222，1196，1152，1133，1113，1054，985，957，882，864，784，769，704；ESI-MS：495.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.968(s，3H，CH 3)，0.148(s，3H，CH 3)，1.187(s，6H，2×CH 3)，1.225(s，6H，2×CH 3)，1.338(s，3H，CH 3)，1.542(s，3H，CH 3)，1.581(s，3H，CH 3)，2.651(s，1H，C 9-H)，3.791(s，3H，CO 2CH 3)，5.835(s，1H，C 19-H)，5.866(s，1H，C 12-H)，5.870(s，1H，C 1-H)，7.052(s，1H，C 2-OH).
Embodiment 11
The 2-acetoxy-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester (I E-6) preparation
Figure BSA00000718755600192
I E-5(0.15mg 0.31mmol) is dissolved in the 10mL diacetyl oxide, reflux 2h, and cooling adds entry, suction filtration, oven dry, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 10 (V: V)], make white solid 90mg, productive rate 54%, 212～214 ℃ of mp.IR(KBr，cm -1)v：3568，3448，3127，2977，2950，2855，1765，1728，1686，1655，1643，1400，1384，1366，1322，1203，1114，1039，1015，989，927，865；ESI-MS：537.4[M+1] +，554.3[M+NH 4] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.971(s，3H，CH 3)，0.115(s，3H，CH 3)，1.202(s，6H，2×CH 3)，1.224(s，6H，2×CH 3)，1.357(s，3H，CH 3)，1.557(s，3H，CH 3)，1.625(s，3H，CH 3)，2.192(s，3H，CH 3CO)，2.677(s，1H，C 9-H)，3.703(s，3H，CO 2CH 3)，5.835(s，1H，C 19-H)，5.879(s，1H，C 12-H)，7.356(s，1H，C 1-H).
Embodiment 12
3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides (I F-1) preparation
Figure BSA00000718755600193
A (0.25mg 0.25mmol) is dissolved in the 15mL anhydrous methylene chloride, drips methylene dichloride (5mL) solution of oxalyl chloride (0.5mL), dripped off in 30min minute, and stirring at room 4h, pressurization removes desolvates and excessive oxalyl chloride, and vacuum-drying gets the acyl chlorides midbody; It being dissolved in the 20mL anhydrous methylene chloride, feeding the exsiccant ammonia, is 11～12 up to pH value of solution; Stop to feed ammonia, continue stirring reaction 30min, concentrate; Column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 5 (V: V)]; Make white solid 150mg, productive rate 62%, 290～292 ℃ of mp.IR(KBr，cm -1)v：3464，3127，2971，2869，2361，2336，1656，1458，1400，1326，1276，1204，1159，1100，874，825，709，656；ESI-MS：464.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.019(s，3H，CH 3)，1.165(s，3H，CH 3)，1.217(s，1H，CH 3)，1.249(s，3H，CH 3)，1.249(s，3H，CH 3)，1.324(s，3H，CH 3)，1.492(s，3H，CH 3)，2.621(s，1H，C 9-H)，5.341(brs，H，NH)，5.515(brs，H，NH)，5.785(s，1H，C 19-H)，5.812(d，1H，C 2-H，J＝10.41Hz)，5.843(s，1H，C 12-H)，7.602(d，1H，C 1-H，J＝10.08Hz).
Embodiment 13
2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides (I F-2) preparation
Figure BSA00000718755600201
With reference to I F-1The preparation method, I E-5Get the white powder solid with ammonia gas react, productive rate 90%, 280～282 ℃ of mp.IR(KBr，cm -1)v：3469，3418，3355，3170，2955，2924，2869，1709，1655，1597，1456，1403，1386，1348，1327，1286，1243，1209，1161，1062，1003，872，790，707；ESI-MS：480.5[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.878(s，3H，CH 3)，1.013(s，3H，CH 3)，1.151(s，3H，CH 3)，1.204(s，9H，3×CH 3)，1.255(s，3H，CH 3)，2.666(s，1H，C 9-H)，5.358(brs，2H，NH 2)，5.817(s，1H，C 19-H)，5.875(s，1H，C 12-H)，5.924(s，1H，C 1-H)，7.022(s，1H，C 2-OH).
Embodiment 14
N-methyl-2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides (I F-3) preparation
Figure BSA00000718755600202
With reference to I F-1The preparation method, I E-5With methylamine react the white powder solid, productive rate 76%, 240～242 ℃ of mp.IR(KBr，cm -1)v：3420，3125，2970，2946，2864，2817，1660，1615，1517，1456，1401，1383，1326，1275，1205，1159，1133，1060，1008，975，952，868，787，714，621；ESI-MS：494.4[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.878(s，3H，CH 3)，0.995(s，3H，CH 3)，1.107(s，3H，CH 3)，1.304(s，9H，3×CH 3)，1.555(s，3H，CH 3)，2.671(s，1H，C 9-H)，2.807(brs，3H，NHCH 3)，5.508(brs，1H，NH)，5.784(s，1H，C 1-H)，5.828(s，1H，C 19-H)，5.895(s，1H，C 12-H)，7.023(s，1H，C 2-OH).
Embodiment 15
2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acyl piperazine (I F-4) preparation
Figure BSA00000718755600203
With reference to I F-1The preparation method, I E-5With piperazine react the white powder solid, productive rate 60%, mp＞300 ℃.IR(KBr，cm -1)v：3448，3127，2930，2857，2719，2362，2341，1655，1458，1399，1383，1325，1267，1242，1207，1133，1114，1058，1015，970，954，868，787，669；ESI-MS：549.4[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.854(s，3H，CH 3)，0.977(s，3H，CH 3)，1.146(s，3H，CH 3)，1.368(s，9H，3×CH 3)，1.544(s，3H，CH 3)，2.657(s，1H，C 9-H)，2.771(brs，1H，NH)，3.175(brs，4H，2×CH 2N)，3.744(brs，4H，2×CH 2NCO)，5.694(s，1H，C 1-H)，5.916(s，1H，C 19-H)，5.959(s，1H，C 12-H)，6.998(s，1H，C 2-OH).
Embodiment 16
3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I g) preparation
Figure BSA00000718755600204
I F-1(2.5g 5.3mmol) is dissolved in the 60mL anhydrous methylene chloride, drips trifluoroacetic anhydride (2.26g; 10.6mmol) methylene dichloride (10mL) solution, 10min dropwises, room temperature reaction 8h; Concentrate, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 8 (V: V)], make white solid 2g; Productive rate 80.6%, 280～284 ℃ of mp.IR(KBr，cm -1)v：3448，3127，2975，2940，2872，2362，2336，2233，1671，1649，1598，1458，1386，1364，1354，1325，1276，1258，1209，1159，1086，1026，863，827；ESI-MS：446.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.882(s，3H，CH 3)，1.033(s，3H，CH 3)，1.073(s，1H，CH 3)，1.169(s，3H，CH 3)，1.245(s，3H，CH 3)，1.334(s，3H，CH 3)，1.538(s，3H，CH 3)，2.592(s，1H，C 9-H)，5.503(s，1H，C 19-H)，5.808(d，1H，C 2-H，J＝10.11Hz)，5.899(s，1H，C 12-H)，7.608(d，1H，C1-H，J＝10.05Hz).
Embodiment 17
2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I h) preparation
Figure BSA00000718755600211
With reference to I aThe preparation method, by I gMake the white powder solid with Iod R, productive rate 70%, 316～318 ℃ of mp.IR(KBr，cm -1)v：3461，3129，2982，2919，2876，2230，1685，1669，1603，1451，1377，1365，1352，1328，1262，1208，1026，980，965，868，724，681，627，542；ESI-MS：572.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.052(s，3H，CH 3)，1.156(s，3H，CH 3)，1.232(s，1H，CH 3)，1.265(s，3H，CH 3)，1.377(s，3H，CH 3)，1.457(s，3H，CH 3)，1.520(s，3H，CH 3)，2.632(s，1H，C 9-H)，5.650(s，1H，C 19-H)，5.911(s，1H，C 12-H)，8.396(d，1H，C 1-H).
Embodiment 18
2-cyanic acid-3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I i) preparation
Figure BSA00000718755600212
I h(0.35mg 0.58mmol) is dissolved among the 20mL DMF, is warming up to backflow, and (104mg, 1.16mmol), back flow reaction 1h is cooled to room temperature, adds 10%FeCl to add CuCN 3The aqueous solution (30mL) is separated out gray solid, suction filtration, and oven dry, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 12 (V: V)], make white solid 150mg, productive rate 51.7%, 316～318 ℃ of mp.IR(KB?r，cm -1)v：3462，3127，2981，2929，2873，2230，1687，1659，1613，1451，1387，1355，1342，1331，1262，1208，1026，981，953，868，722，671，617，532；ESI-MS：471.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：1.032(s，3H，CH 3)，1.165(s，3H，CH 3)，1.213(s，1H，CH 3)，1.254(s，3H，CH 3)，1.381(s，3H，CH 3)，1.487(s，3H，CH 3)，1.520(s，3H，CH 3)，2.619(s，1H，C 9-H)，5.672(s，1H，C 19-H)，5.935(s，1H，C 12-H)，8.402(d，1H，C 1-H).
Embodiment 19
Figure BSA00000718755600213
3 β, the preparation of 11-dihydroxyl-18 β-volatile oil-12-alkene-30-acid (6)
(4.7g 10mmol) is dissolved among the 50mL THF GA, and (3.8g, (10min dropwises sodium hydroxide 100mmol) for 2.0g, 50mmol) solution 15mL, and backflow 24h is with reaction solution impouring 10%NaH to drip Peng Qinghuana 2PO 4In the aqueous solution (500mL), ethyl acetate extraction (150mL * 3), the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, and gets white powder 4.5g, yield 95.7%, 266～270 ℃ of mp.The preparation of 3 beta-hydroxies-volatile oil-11,13 (18)-diene-30-acid (7)
6 (4.82g 10mmol), is dissolved in the 60mL Glacial acetic acid min. 99.5, splashes into 5% Hydrogen chloride (2mL), separates out solid about 30min, continues reaction 1h, suction filtration, and washing, oven dry gets white solid 2.6g, yield 56%, 304～307 ℃ of mp.
3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II a) preparation
With reference to the preparation method of a, make white powder, yield 80%, 255～259 ℃ of mp with the IBX reaction by 6.IR(KB?r，cm -1)v：3042，2953，2862，1724，1653，1460，1384，1165，1101，818；ESI-MS：451.3[M+H] +，449.3[M-H] -； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.779(s，3H，CH 3)，0.987(s，3H，CH 3)，1.101(s，6H，2×CH 3)，1.122(s，6H，2×CH 3)，1.157(s，3H，CH 3)，5.743(d，1H，C 2-H，J＝10.5Hz)，5.879(s，1H，C 11-H，J＝8.3Hz)，6.494(d，1H，C 12-H，J＝8.9Hz)，7.260(d，1H，C 1-H，J＝10.3Hz).
Embodiment 20
2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II b) preparation
Figure BSA00000718755600221
With reference to I aThe preparation method, by II aMake the white powder solid with Iod R, productive rate 78%, 259～260 ℃ of mp.IR(KBr，cm -1)v：3468，2972，2933，2879，1686，1664，1657，1637，1629，1568，1543，1524，1468，1410，1327，1231，1126，1017，993，817；ESI-MS：577.3[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.891(s，9H，3×CH 3)，1.212(s，3H，CH 3)，1.369(s，3H，CH 3)，1.548(s，3H，CH 3)，1.630(s，3H，CH 3)，5.764(d，1H，C 11-H，J＝5.39Hz)，5.899(d，1H，C 12-H，J＝4.55Hz)，8.112(s，1H，C 1-H).
Embodiment 21
2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid (II c) preparation
Figure BSA00000718755600222
With reference to I iThe preparation method, by II bMake the white powder solid, productive rate 67%, 162～164 ℃ of mp with the CuCN reaction.IR(KBr，?cm -1)v：3463，2970，2933，2869，2364，2345，2233，1686，1654，1647，1637，1629，1560，1544，1534，1458，1400，1327，1231，1126，1016，993，816；ESI-MS：476.3[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.881(s，9H，3×CH 3)，1.202(s，3H，CH 3)，1.372(s，3H，CH 3)，1.538(s，3H，CH 3)，1.630(s，3H，CH 3)，5.754(d，1H，C 11-H，J＝5.49Hz)，5.897(d，1H，C 12-H，J＝5.55Hz)，8.130(s，1H，C 1-H).
Embodiment 22
3-oxo-volatile oil-1,11,13 (18)-diene-30-acid (8)
7 (2.27g 5mmol) is dissolved among the 40mLDMSO, and adding IBX (1.68g, 6mmol); Behind the stirring at room 6h, in reaction solution, add water (30mL), ethyl acetate extraction (40mL * 3) is used 5% sodium hydrogencarbonate (30mL * 3) successively; Saturated aqueous common salt (30mL * 3) washing, anhydrous sodium sulfate drying concentrates; Make white solid 2.1g, yield 92.1%, 340～342 ℃ of mp.
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II d) preparation
8 (0.20,0.29mmol) be dissolved in the 30mL trimethyl carbinol, be warming up to 45 ℃, add potassium tert.-butoxide (0.66g; 5.89mmol), in 40～45 ℃ of reaction 2.5h, cooling adds 5% hydrochloric acid and transfers pH to 4; The most of solvent of pressure reducing and steaming is separated out white solid, suction filtration; Dry white solid 110mg, yield 54.2%, 193～196 ℃ of mp.IR(KBr，cm -1)v：3431，3416，2957，2945，2866，1703，1462，1387，1233，1115，1040，897，673，554；ESI-MS：467.3[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.768(s，3H，CH 3)，0.972(s，3H，CH 3)，1.125(s，9H，3×CH 3)，1.214(s，3H，CH 3)，1.235(s，3H，CH 3)，2.701～2.791(m，2H，CH 2O)，5.715(d，1H，C 11-H，J＝8.4Hz)，5.990(s，1H，C 1-H)，6.484(d，1H，C 12-H，J＝8.1Hz)，6.582(s，1H，C 2-OH).
Embodiment 23
2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylate methyl ester (II E-1) preparation
Figure BSA00000718755600231
With reference to I E-1The preparation method, by II cMake the white powder solid with iodomethane reaction, productive rate 87%, 275～277 ℃ of mp.IR(KBr，cm -1)v：3456，3128，2977，2948，2237，1721，1682，1654，1637，1458，1400，1219，1195，1167，1081，1016，994；ESI-MS：490.3[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.843(s，3H，CH 3)，0.988(s，3H，CH 3)，1.140(s，3H，CH 3)，1.235(s，3H，CH 3)，1.307(s，3H，CH 3)，1.406(s，3H，CH 3)1.667(s，3H，CH 3)，3.629(s，3H，COCH 3)，5.732(d，1H，C 11-H，J＝4.92Hz)，5.897(d，1H，C 12-H，J＝5.46Hz)，8.134(s，1H，C 1-H).
Embodiment 24
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylate methyl ester (II E-2)
Figure BSA00000718755600232
With reference to I E-1The preparation method, by II dMake the white powder solid with iodomethane reaction, yield 80%, 109～111 ℃ of mp.IR(KB?r，cm-1)v：3414，2951，2868，1728，1668，1462，1385，1258，1240，1202，1155，1111，1055，1031，864，785，689，636，548；ESI-MS：481.3[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.884(s，3H，CH 3)，0.989(s，3H，CH 3)，1.147(s，3H，CH 3)，1.192(s，3H，CH 3)，1.215(s，3H，CH 3)，1.250(s，3H，CH 3)，1.453(s，3H，CH 3)，3.695(s，3H，OCH 3)，5.710(d，1H，C 11-H，J＝5.7Hz)，5.918(d，1H，C 12-H，J＝6.0Hz)，5.979(s，1H，C 2-OH)，6.730(s，1H，C 1-H).
Embodiment 25
3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides (II F-1)
Figure BSA00000718755600233
With reference to I F-1The preparation method, by II aMake the white powder solid with ammonia gas react, yield 60%.IR(KBr，cm -1)v：3561，3121，2979，2923，2878，2361，2341，1715，1664，1600，1469，1456，1400，1286，1253，1176，1153，1137，1079，1064，1010；ESI-MS：450.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.997(s，3H，CH 3)，0.134(s，3H，CH 3)，1.219(s，9H，3×CH 3)，1.640(s，6H，2×CH 3)，5.589(brs，2H，NH 2)，5.875(d，1H，C 11-H，J＝5.7Hz)，5.831(d，1H，C 1-H，J＝5.5Hz)，6.001(d，1H，C 12-H，J＝6.4Hz)，7.414(d，1H，C 2-H，J＝6.7Hz)
Embodiment 26
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides (II F-2)
Figure BSA00000718755600234
With reference to I F-1The preparation method, by II dMake the white powder solid with ammonia gas react, yield 58%, 175～177 ℃ of mp.IR(KBr，cm -1)v：3461，3131，2968，2924，2868，2360，2341，1716，1663，1604，1470，1456，1400，1286，1243，1186，1153，1137，1079，1054，1000；ESI-MS：466.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.987(s，3H，CH 3)，0.124(s，3H，CH 3)，1.419(s，9H，3×CH 3)，1.639(s，6H，2×CH 3)，5.688(brs，2H，NH 2)，5.795(d，1H，C 11-H，J＝5.6Hz)，5.831(s，1H，C 1-H)，6.003(d，1H，C 12-H，J＝6.3Hz)，6.724(s，1H，C 2-OH).
Embodiment 27
N-methyl-2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides (II F-3)
Figure BSA00000718755600241
With reference to I F-1The preparation method, by II dMake white solid, yield 62%, 236～238 ℃ of mp with the methylamine reaction.IR(KBr，cm -1)v：3463，3127，2972，2952，2861，2360，2341，1710，1629，1560，1523，1458，1400，1237，1114，916，823；ESI-MS：466.4[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.871(s，3H，CH 3)，0.988(s，3H，CH 3)，1.146(s，6H，2×CH 3)，1.163(s，3H，CH 3)，1.189(s，3H，CH 3)，1.450(s，3H，CH 3)，2.78(brs，3H，NHCH 3)，5.645(brs，1H，NHCH 3)，5.756(d，1H，C 11-H，J＝5.73Hz)，5.938(d，1H，C 12-H，J＝5.70Hz)，6.191(s，1H，C 1-H)，6.720(s，1H，C 2-OH).
Embodiment 28
2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acyl imidazoles (II F-4)
Figure BSA00000718755600242
With reference to I F-1The preparation method, by II dMake the white powder solid, yield 60%, 126～128 ℃ of mp with the imidazoles reaction.IR(KB?r，cm -1)v：3454，3134，2967，2867，2361，2338，1803，1718，1685，1669，1644，1463，1458，1400，1260，1246，1219，1065，1000，832，759；ESI-MS：517.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.853(s，3H，CH 3)，0.996(s，3H，CH 3)，1.144(s，3H，CH 3)，1.168(s，3H，CH 3)，1.249(s，3H，CH 3)，1.443(s，6H，2×CH 3)，5.581(d，1H，C 11-H，J＝7.65Hz)，5.832(d，1H，C 12-H，J＝5.73Hz)，5.971(s，1H，C 1-H)，6.711(s，1H，C 2-OH)，7.09(s，1H，N＝CH)，7.589(s，1H，N＝CH)，8.315(s，1H，N＝CH).
Embodiment 29
3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II g) preparation
Figure BSA00000718755600243
With reference to I gThe preparation method, by II F-1Make the white powder solid with the trifluoroacetic acid anhydride reactant, yield 78%, 201～203 ℃ of mp.IR(KBr，cm -1)v：3453，2970，2933，2879，2364，2345，2133，1686，1654，1647，1637，1629，1560，1544，1534，1458，1400，1327，1231，1126，1016，993，816；ESI-MS：432.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.913(s，3H，CH 3)，0.957(s，3H，CH 3)，1.122(s，3H，CH 3)，1.178(s，3H，CH 3)，1.252(s，3H，CH 3)，1.344(s，3H，CH 3)，1.462(s，3H，CH 3)，5.628(d，1H，C 11-H，J＝6.75Hz)，5.741(d，1H，C 12-H，J＝5.87Hz)，5.893(d，1H，C 2-H，J＝5.87Hz)，7.411(d，1H，C 1-H，J＝6.27Hz).
Embodiment 30
2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II h) preparation
Figure BSA00000718755600251
With reference to I hThe preparation method, by II gMake the white powder solid with Iod R, yield 70%, 211～213 ℃ of mp.IR(KBr，cm -1)v：3453，2980，2925，2869，2365，2235，2123，1676，1664，1637，1627，1629，1560，1564，1544，1458，1412，1327，1229，1136，1016，983；ESI-MS：558.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.973(s，3H，CH 3)，0.917(s，3H，CH 3)，1.142(s，3H，CH 3)，1.178(s，3H，CH 3)，1.232(s，3H，CH 3)，1.376(s，3H，CH 3)，1.482(s，3H，CH 3)，5.635(d，1H，C 11-H，J＝6.75Hz)，5.795(d，1H，C 12-H，J＝5.87Hz)，8.190(s，1H，C 1-H).
Embodiment 31
2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II i) preparation
Figure BSA00000718755600252
With reference to I iThe preparation method, by II hMake the white powder solid, yield 60%, 162～164 ℃ of mp with the CuCN reaction.IR(KBr，cm -1)v：3463，2970，2933，2869，2364，2345，2233，1686，1654，1647，1637，1629，1560，1544，1534，1458，1400，1327，1231，1126，1016，993，816；ESI-MS：457.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.853(s，3H，CH 3)，0.997(s，3H，CH 3)，1.122(s，3H，CH 3)，1.178(s，3H，CH 3)，1.232(s，3H，CH 3)，1.396(s，3H，CH 3)，1.462(s，3H，CH 3)，5.763(d，1H，C 11-H，J＝6.75Hz)，5.913(d，1H，C 12-H，J＝5.87Hz)，8.116(s，1H，C 1-H).
Embodiment 32
Figure BSA00000718755600253
3 beta-hydroxies-18 β-volatile oil-9 (11), 12-diene-30-acid (9)
6 (3g 6.36mmol) is dissolved among the anhydrous THF of 40mL, adds the concentrated hydrochloric acid (1d) of catalytic amount, behind the back flow reaction 8h; Be chilled to room temperature, ethyl acetate extraction (40mL * 3), saturated common salt water washing (20mL * 3) is behind the anhydrous sodium sulfate drying; Concentrate, get the white powder solid, recrystallizing methanol, drying; Get white powder solid 2.15g, yield 74.5%, 301～302 ℃ of mp.
3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III a)
With reference to the preparation method of a, make white solid by 9 with IBX reaction, yield 92%, mp＞300 ℃.IR(KBr，cm -1)v：3377，3221，3059，3028，2957，2624，2868，1726，1653，1462，1383，1254，1207，1146，1082，812，740，706，664，581；ESI-MS：449.3[M-H] -； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.891(s，3H，CH 3)，1.004(s，3H，CH 3)，1.127(s，3H，CH 3)，1.179(s，3H，CH 3)，1.196(s，3H，CH 3)，1.219(s，3H，CH 3)，5.727(d，1H，C 12-H，J＝5.7Hz)，5.883(d，1H，C 1-H，J＝10.1Hz)，5.889(d，1H，C 11-H，J＝6.4Hz)，7.418(d，1H，C 2-H，J＝10.4Hz).
Embodiment 33
2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III b)
Figure BSA00000718755600254
With reference to I aThe preparation method, by III aMake the white powder solid with Iod R, productive rate 60%, 229～231 ℃ of mp.IR(KB?r，cm -1)v：3469，2972，2932，2879，1676，1660，1654，1637，1621，1568，1543，1524，1468，1410，1327，1231，1116，1027，983，820；ESI-MS：577.3[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.891(s，9H，3×CH 3)，1.212(s，3H，CH 3)，1.369(s，3H，CH 3)，1.548(s，3H，CH 3)，1.630(s，3H，CH 3)，5.754(d，1H，C 11-H，J＝5.39Hz)，5.890(d，1H，C 12-H，J＝4.55Hz)，8.150(s，1H，C 1-H).
Embodiment 34
2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III c)
Figure BSA00000718755600261
With reference to I iThe preparation method, by III bMake the white powder solid, productive rate 60%, 168～170 ℃ of mp with the CuCN reaction.IR(KB?r，cm -1)v：3472，3132，2969，2949，2870，2360，2336，2234，1773，1691，1637，1466，1446，1400，1322，1259，1231，1179，1127，1016，993，950，836，817，737，674，591；ESI-MS：476.3[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.886(s，3H，CH 3)，0.998(s，3H，CH 3)，1.173(s，3H，CH 3)，1.203(s，3H，CH 3)，1.231(s，3H，CH 3)，1.4649(s，6H，2×CH 3)，5.755(d，1H，C 12-H，J＝5.54Hz)，5.897(d，1H，C 11-H，J＝5.40Hz)，8.134(s，1H，C 1-H).
Embodiment 35
Figure BSA00000718755600262
3-oxo-18 β-volatile oil-9 (11), 12-diene-30-acid (10)
Preparing method with reference to 5 makes white solid, yield 95%, 244～246 ℃ of mp by 9 with the IBX reaction.2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III d)
With reference to I dThe preparation method, make the white powder solid, yield 85%, 297～300 ℃ of mp by 10 with potassium tert.-butoxide reaction.IR(KBr，cm -1)v：3335，2970，2940，2862，1722，1651，1462，1400，1248，1233，1169，1057，795，714，667，624；ESI-MS：467.4[M+H] +；465.4[M-H] -； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.884(s，3H，CH 3)，0.989(s，3H，CH 3)，1.147(s，6H，2×CH 3)，1.192(s，3H，CH 3)，1.215(s，3H，CH 3)，1.250(s，3H，CH 3)，5.710(d，1H，C 11-H，J＝5.7Hz)，5.918(d，1H，C 12-H，J＝6.0Hz)，5.979(s，1H，C 1-H)，6.730(s，1H，C 2-OH).
Embodiment 36
3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-1)
Figure BSA00000718755600263
With reference to I E-1The preparation method, by III aMake the white powder solid with iodomethane reaction, yield 94%, 172～175 ℃ of mp.IR(KBr，cm -1)v：3431，3392，3040，2957，1728，1667，1460，1373，1316，1254，1217，1157，1111，1087，1026，988，930，827，766，664，584；ESI-MS：465.4[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.850(s，3H，CH 3)，1.070(s，3H，CH 3)，1.125(s，6H，2×CH 3)，1.176(s，3H，CH 3)，1.190(s，3H，CH 3)，1.402(s，3H，CH 3)，3.710(s，3H，OCH 3)，5.705(d，1H，C 11-H，J＝5.6Hz)，5.704(s，1H，C 12-H)，5.870(d，1H，C 12-H，J＝6.7Hz)，5.876(d，1H，C 11-H，J＝10.3Hz)，7.413(d，1H，C 1-H，J＝10.4Hz).
Embodiment 37
2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-2)
Figure BSA00000718755600271
With reference to I aThe preparation method, by III E-1Make the white powder solid with Iod R, yield 69%, 205～207 ℃ of mp.IR(KBr，cm -1)v：3448，2955，2367，1727，1676，1384，1191，820；ESI-MS：591.2[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.843(s，3H，CH 3)，1.009(s，3H，CH 3)，1.136(s，3H，CH 3)，1.179(s，6H，2×CH 3)，1.209(s，3H，CH 3)，1.415(s，3H，CH 3)，3.713(s，3H，OCH 3)，5.719(d，1H，C 11-H，J＝5.7Hz)，5.704(s，1H，C 12-H)，5.891(d，1H，C 12-H，J＝5.6Hz)，8.192(s，1H，C 1-H).
Embodiment 38
2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-3)
With reference to I iThe preparation method, by III E-2Make the white powder solid, yield 78%, 275～277 ℃ of mp with the CuCN reaction.IR(KBr，cm -1)v：3448，2924，2360，2343，1655，1384，671；ESI-MS：507.4[M+NH 4] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.844(s，3H，CH 3)，0.989(s，3H，CH 3)，1.140(s，3H，CH 3)，1.171(s，6H，2×CH 3)，1.197(s，3H，CH 3)，1.235(s，3H，CH 3)，1.253(s，3H，CH 3)，3.716(s，3H，OCH 3)，5.731(d，1H，C 11-H，J＝5.7Hz)，5.897(d，1H，C 12-H，J＝5.8Hz)，8.129(s，1H，C 1-H).
Embodiment 39
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester (III E-4)
Figure BSA00000718755600273
With reference to I E-1The preparation method, by III dMake the white powder solid with iodomethane reaction, yield 89%, 123～126 ℃ of mp.IR(KBr，cm -1)v：3398，2998，2945，2840，1735，1670，1635，1470，1396，1165，1079，986；ESI-MS：481.4[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.886(s，3H，CH 3)，0.987(s，3H，CH 3)，1.136(s，3H，CH 3)，1.194(s，3H，CH 3)，1.215(s，6H，2×CH 3)，1.250(s，3H，CH 3)，3.710(s，3H，OCH 3)，5.712(d，1H，C 11-H，J＝5.8Hz)，5.910(d，1H，C 12-H，J＝6.1Hz)，5.979(s，1H，C 1-H)，6.730(s，1H，C 2-OH)；
Embodiment 40
3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides (III F-1) preparation
Figure BSA00000718755600274
With reference to I F-1The preparation method, by III aMake white solid with ammonia gas react, yield 79%.IR(KBr，cm -1)v：3462，3126，2967，29252867，1663，1589，1462，1468，1410，1284，1242，1226，1187，1137，1081，1064，989，912，833，661，510；ESI-MS：450.4[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.872(s，3H，CH 3)，0.978(s，3H，CH 3)，1.145(s，6H，2×CH 3)，1.162(s，3H，CH 3)，1.199(s，3H，CH 3)，1.440(s，3H，CH 3)，5.525(brs，2H，NH 2)，5.646(d，1H，C 11-H，J＝5.73Hz)，5.828(d，1H，C 12-H，J＝5.70Hz)，5.981(s，1H，C 2-H，J＝4.73Hz)，7.419(s，1H，C 1-H，J＝5.03Hz).
Embodiment 41
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides (III F-2) preparation
Figure BSA00000718755600281
With reference to I F-1The preparation method, by III dMake the white powder solid with ammonia gas react, yield 89%, mp＞300 ℃.IR(KBr，cm -1)v：3461，3127，2969，2926，2868，1664，1599，1472，1458，1400，1285，1243，1216，1187，1137，1080，1054，999，918，834，662，511；ESI-MS：466.4[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.871(s，3H，CH 3)，0.988(s，3H，CH 3)，1.146(s，6H，2×CH 3)，1.163(s，3H，CH 3)，1.189(s，3H，CH 3)，1.450(s，3H，CH 3)，5.545(brs，2H，NH 2)，5.656(d，1H，C 11-H，J＝5.73Hz)，5.838(d，1H，C 12-H，J＝5.70Hz)，5.991(s，1H，C 1-H)，6.720(s，1H，C 2-OH).
Embodiment 42
N-methyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides (III F-3) preparation
Figure BSA00000718755600282
With reference to I F-1The preparation method, by III dMake the white powder solid, yield 80%, 159～161 ℃ of mp with the methylamine reaction.IR(KBr，cm -1)v：3431，3127，2964，2922，2867，2357，2328，1809，1800，1721，1701，1669，1650，1477，1460，1410，1384，1369，1258，1245，1220，1056，1000，898，875，853，822，781；ESI-MS：480.4[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.887(s，3H，CH 3)，0.976(s，3H，CH 3)，1.146(s，3H，CH 3)，1.190(s，3H，CH 3)，1.124(s，3H，CH 3)，1.128(s，3H，CH 3)，1.145(s，3H，CH 3)，3.256(s，3H，NCH 3)，5.718(d，1H，C 11-H，J＝5.28Hz)，5.856(d，1H，C 12-H，J＝5.79Hz)，5.963(s，1H，C 1-H)，6.716(s，1H，C 2-OH).
Embodiment 43
2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acyl imidazoles (III F-4) preparation
Figure BSA00000718755600283
With reference to I F-1The preparation method, by III dMake the white powder solid, yield 60%, 158～160 ℃ of mp with the imidazoles reaction.IR(KBr，cm -1)v：3461，3133，2969，2868，1720，1648，1458，1400，1219，1065，1001，830，754，659，541，518，489，468，403；ESI-MS：517.6[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.853(s，3H，CH 3)，0.996(s，3H，CH 3)，1.144(s，3H，CH 3)，1.168(s，3H，CH 3)，1.249(s，3H，CH 3)，1.443(s，6H，2×CH 3)，5.581(d，1H，C 11-H，J＝7.65Hz)，5.832(d，1H，C 12-H，J＝5.73Hz)，5.971(s，1H，C 1-H)，6.711(s，1H，C 2-OH)，7.09(s，1H，N＝CH)，7.589(s，1H，N＝CH)，8.315(s，1H，N＝CH).
Embodiment 44
3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III g) preparation
Figure BSA00000718755600284
With reference to I gThe preparation method, by III F-1Make the white powder solid with the trifluoroacetic acid anhydride reactant, yield 80%, 232～233 ℃ of mp.IR(KBr，cm -1)v：3553，2970，2943，2879，2354，2345，2133，1686，1654，1647，1637，1629，1560，1544，1534，1458，1440，1327，1231，1126，1016，993，816；ESI-MS：432.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.863(s，3H，CH 3)，0.917(s，3H，CH 3)，1.146(s，3H，CH 3)，1.188(s，3H，CH 3)，1.222(s，3H，CH 3)，1.386(s，3H，CH 3)，1.462(s，3H，CH 3)，5.648(d，1H，C 11-H，J＝6.75Hz)，5.7431(d，1H，C 12-H，J＝5.87Hz)，5.893(d，1H，C 2-H，J＝5.87Hz)，7.401(d，1H，C 1-H，J＝6.27Hz).
Embodiment 45
2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III h) preparation
With reference to I hThe preparation method, by III gMake the white powder solid with Iod R, yield 70%, 211～213 ℃ of mp.IR(KB?r，cm -1)v：3463，2970，2933，2879，2364，2245，2133，1686，1654，1647，1637，1629，1560，1564，1544，1458，1400，1327，1231，1126，1016，993，816；ESI-MS：558.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.973(s，3H，CH 3)，0.917(s，3H，CH 3)，1.142(s，3H，CH 3)，1.178(s，3H，CH 3)，1.232(s，3H，CH 3)，1.376(s，3H，CH 3)，1.482(s，3H，CH 3)，5.745(d，1H，C 11-H，J＝6.75Hz)，5.896(d，1H，C 12-H，J＝5.87Hz)，5.893(d，1H，C 2-H，J＝5.87Hz)，8.190(s，1H，C 1-H).
Embodiment 46
2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III i) preparation
Figure BSA00000718755600292
With reference to I iThe preparation method, by III hMake the white powder solid, yield 60%, 236～238 ℃ of mp with the CuCN reaction.IR(KBr，cm -1)v：3464，3149，2971，2933，2868，2232，1687，1637，1610，1457，1399，1386，1243，1129，1017，993，953，835，669，656，618；ESI-MS：457.3[M+1] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.853(s，3H，CH 3)，0.997(s，3H，CH 3)，1.122(s，3H，CH 3)，1.178(s，3H，CH 3)，1.232(s，3H，CH 3)，1.396(s，3H，CH 3)，1.462(s，3H，CH 3)，5.763(d，1H，C 11-H，J＝6.75Hz)，5.908(d，1H，C 12-H，J＝5.87Hz)，8.1064(s，1H，C 1-H).
Embodiment 47
3 β, 11, the preparation of 30-trihydroxy--18 β-volatile oil-12-alkene (11)
(2.4g 5mmol) is dissolved in the anhydrous THF of 40mL to GA, adds LiAlH in batches 4(1.52g 40mmol), slowly is warming up to backflow, and reaction 2h is chilled to room temperature; Add 5% Hydrogen chloride cancellation, ethyl acetate extraction (40mL * 3), saturated common salt water washing (20mL * 3), anhydrous sodium sulfate drying concentrates; Oven dry gets white solid 2.1g, yield 89.7%, 227～230 ℃ of mp.
3 β, the preparation of 30-dihydroxyl-volatile oil-11,13 (18)-diene (12)
Preparing method with reference to 7 makes the white powder solid, yield 63%, 228～230 ℃ of mp by 11 with the Glacial acetic acid min. 99.5 reaction.
The preparation of 3 beta-hydroxies-volatile oil-11,13 (18)-diene-30-trityl ether (13)
11 (0.80g 1.81mmol) is dissolved in the 60mL methylene dichloride, adds Triphenyl methane chloride 99 (2.5g successively; 9.05mmol), DMAP (0.23g, 1.89mmol), triethylamine (0.2mL), backflow 24h; Column chromatography [ETHYLE ACETATE: sherwood oil=1: 5 (V: V)]; Make white solid, yield 63%, 101～103 ℃ of mp. 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.716(s，3H，CH 3)，0.785(s，6H，2×CH 3)，0.894(s，3H，CH 3)，0.957(s，3H，CH 3)，0.991(s，3H，CH 3)，1.083(s，3H，CH 3)，2.386(d，1H，C 9-H，J＝14.3Hz)，2.810(s，2H，CH 2O)，3.244(dd，1H，C 3-H，J＝4.9，10.6Hz)，5.526(d，1H，C 11-H，J＝9.9Hz)，6.357(d，1H，C 12-H，J＝10.3Hz)，7.205～7.324(m，9H)，7.465(d，6H，J＝7.4Hz).
The preparation of 3-oxo-volatile oil-11,13 (18)-diene-30-trityl ether (14)
13 (3.34g 5mmol) is dissolved in 40mL DMSO, and adding IBX (1.68g, 6mmol); Stirring at room 6h adds water (30mL), and ethyl acetate extraction (40mL * 3) is used 5% sodium hydrogencarbonate (30mL * 3) successively; Saturated aqueous common salt (30mL * 3) washing, anhydrous sodium sulfate drying concentrates, oven dry; Get white solid 2.1g, yield 92.1%, 104～107 ℃ of mp. 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.755(s，3H，CH 3)，0.790(s，3H，CH 3)，0.968(s，3H，CH 3)，1.015(s，3H，CH 3)，1.042(s，3H，CH 3)，1.095(s，6H，2×CH 3)，2.391(d，1H，C 9-H，J＝14.5Hz)，2.541～2.618(m，2H，C 2-H)，2.817(s，2H，CH 2O)，5.511(d，1H，C 11-H，J＝10.1Hz)，6.390(d，1H，C 12-H，J＝10.3Hz)，7.207～7.326(m，9H)，7.466(d，6H，J＝7.4Hz).
2-hydroxyl-3-oxo-30-three benzyloxies-volatile oil-1,11,13 (18)-triolefin (II j) preparation
With reference to I dThe preparation method, make the white powder solid, yield 50%, 96～99 ℃ of mp by 14 with potassium tert.-butoxide reaction.IR(KBr，cm -1)v：3448，2920，2855，1655，1384，1033； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.767(s，3H，CH 3)，0.796(s，3H，CH 3)，0.954(s，3H，CH 3)，1.100(s，3H，CH 3)，1.126(s，3H，CH 3)，1.214(s，3H，CH 3)，1.252(s，3H，CH 3)，1.994(d，1H，C 18-H，J＝14.1Hz)，2.285(s，1H，C 9-H)，2.391(d，1H，C 18-H，J＝14.0Hz)，2.936(s，2H，CH 2O)，5.653(d，1H，C 11-H，J＝10.8Hz)，5.957(s，1H，C 1-H)，6.463(d，1H，C 12-H，J＝8.6Hz)，6.354(s，1H，C 1-H)，6.590(s，1H，C 2-OH)，7.239(m，9H)，7.471(d，6H).
Embodiment 48
2-hydroxyl-3-oxo-30-acetoxyl group-volatile oil-1,11,13 (18)-triolefin (II k) preparation
Figure BSA00000718755600301
II j(0.24mg 0.35mmol) is dissolved in the 20mL acetate, adds 5% Hydrogen chloride (3mL); Backflow 2h, ethyl acetate extraction (30mL * 3) is used 5% sodium hydrogen carbonate solution (20mL * 3), saturated aqueous common salt (20mL * 3) washing successively; Anhydrous sodium sulfate drying concentrates, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 8 (V: V)]; Make white powder solid 80mg, yield 50.6%, 57～61 ℃ of mp.IR(KBr，cm -1)v：3448，2926，2860，2354，1739，1648，1455，1384，1246，1035，760，710，637；ESI-MS：495.2[M+H] +； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.762(s，3H，CH 3)，0.960(s，3H，CH 3)，1.082(s，3H，CH 3)，1.127(s，3H，CH 3)，1.214(s，3H，CH 3)，1.238(s，6H，2×CH 3)，1.858(d，1H，C 18-H，J＝13.4Hz)，2.101(s，3H，COCH 3)，2.289(s，1H，C 9-H)，2.430(d，1H，C 18-H，J＝14.7Hz)，3.846(s，2H，CH 2O)，5.590(d，1H，C 11-H，J＝9.5Hz)，5.971(s，1H，C 1-H)，6.451(d，1H，C 12-H，J＝10.4Hz)，6.585(s，1H，C 2-OH).
Embodiment 49
2,30-dihydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefin (II l) preparation
Figure BSA00000718755600302
II j(380mg 0.546mmol) is dissolved in the 30mL Glacial acetic acid min. 99.5, adds 5% Hydrogen chloride (3mL), reacts 0.5h down in 50 ℃; Ethyl acetate extraction (30mL * 3) is used 5% sodium bicarbonate aqueous solution (20mL * 3), saturated aqueous common salt (20mL * 3) washing, anhydrous sodium sulfate drying successively; Concentrate, system sand, column chromatography for separation [ETHYLE ACETATE: sherwood oil=1: 5 (V: V)]; Make white powder solid 160mg, yield 64.5%, 76～80 ℃ of mp.ESI-MS：453.2[M+H] +；IR(KB?r，cm -1)v：3589，3448，2920，2860，2218，1655，1384； 1H-NMR(300MHz，CDCl 3)，δ(ppm)：0.728(s，3H，CH 3)，0.890(s，3H，CH 3)，1.014(s，3H，CH 3)，1.057(s，3H，CH 3)，1.140(s，3H，CH 3)，1.167(s，3H，CH 3)，1.183(s，6H，2×CH 3)，1.779(d，1H，C 18-H，J＝14.3Hz)，2.218(s，1H，C 9-H)，2.327(d，1H，C 18-H，J＝14.2Hz)，3.311(s，2H，CH 2O)，5.594(d，1H，C 11-H，J＝10.5Hz)，5.904(s，1H，C 1-H)，6.409(d，1H，C 12-H，J＝10.4Hz)，6.519(s，1H，C 2-OH)。

Claims (10)

  1. General formula (I), (II) and (III) shown in Enoxolone derivative or its pharmacy acceptable salt:
    Figure FSA00000718755500011
    Wherein:
    R 1Represent H, F, Cl, Br, I, CN, OH, OR 3Or OC (O) R 3
    R 2Represent CN, CH 2OC (Ph) 3, CO 2H, CO 2R 4, CH 2OH, CH 2OC (O) R 4Or C (O) NR 5R 6
    R 3Represent C 1-C 6Alkyl;
    R 4Represent C 1-C 6Alkyl or C 6-C 10Aromatic base, wherein said aromatic base can be randomly be selected from following group and replace with one or more: F, Cl, Br, I, NO 2, CN, NH 2Or OH;
    R 5And R 6Can be identical or different, represent H, C 1-C 6Alkyl or R 5And R 6Form 5-7 unit heterocyclic group with the nitrogen-atoms that connects with them; This heterocyclic group can randomly comprise other heteroatoms of one or more O of being selected from, S or N; And this heterocyclic group can randomly be replaced to five replacements by following identical or different substituting group list, and said substituting group comprises: F, Cl, Br, I, OH, NO 2, CN, NH 2, C 1-C 6Alkyl or C 1-C 6Alkoxyl group;
    Wherein, except following formula (a-c) compound:
    Figure FSA00000718755500012
  2. 2. Enoxolone derivative according to claim 1 or its pharmacy acceptable salt is characterized in that:
    R 1Represent H, OH, Cl, Br, I, CN, OR 3Or OC (O) R 3
    R 2Represent CN, CH 2OC (Ph) 3, CO 2H, CO 2R 4, CH 2OH, CH 2OC (O) R 4Or C (O) NR 5R 6
    R 3Represent CH 3
    R 4Represent CH 3Or C 2H 5
    NR 5R 6Represent NH 2, piperazinyl or imidazolyl.
  3. 3. Enoxolone derivative according to claim 1 or its pharmacy acceptable salt is characterized in that said compound is selected from:
    2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid;
    2-bromo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid;
    2-chloro-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid;
    2-methoxyl group-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid;
    2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-acid;
    2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester;
    2-bromo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester;
    2-chloro-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester;
    2-methoxyl group-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester;
    2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester;
    The 2-acetoxy-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylate methyl ester;
    2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides;
    N-methyl-2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides;
    2-hydroxyl-3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acyl piperazine;
    3,11-dioxo-volatile oil-1,12,18-triolefin-30-carboxylic acid amides;
    3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile;
    2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile;
    2-cyanic acid-3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile;
    3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid;
    2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid;
    2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid;
    2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid;
    2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylate methyl ester;
    2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylate methyl ester;
    3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides;
    2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides;
    N-methyl-2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acid amides;
    2-hydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-carboxylic acyl imidazoles;
    3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile;
    2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile;
    2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile;
    2-hydroxyl-3-oxo-30-three benzyloxies-volatile oil-1,11,13 (18)-triolefins;
    2-hydroxyl-3-oxo-30-acetoxyl group-volatile oil-1,11,13 (18)-triolefins;
    2,30-dihydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefins;
    3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid;
    2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid;
    2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid;
    2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid;
    3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester;
    2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester;
    2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester;
    2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylate methyl ester;
    3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides;
    2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides;
    N-methyl-2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acid amides;
    2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-carboxylic acyl imidazoles;
    3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile;
    2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile;
    2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile.
  4. 4. the preparation method of the described Enoxolone derivative of claim 1 is characterized in that:
    A) work as R 2Be COOH, the preparation method of compound is shown in the general formula (I): with glycyrrhetinic acid (GA) is raw material, makes 3 β-acetoxyl group-11-oxo-18 β-volatile oil-12-alkene-30-acid (1) with acetic anhydride; 1 makes 3 β-acetoxyl group-11-oxo-volatile oil-12 with bromine reaction, 18-diene-30-acid (2), and 2 make 3 beta-hydroxies-11-oxo-volatile oil-12 through sodium hydroxide hydrolysis; 18-diene-30-acid (3), 3 generate 3,11-dioxo-volatile oil-1 with adjacent iodoxy phenylformic acid (IBX) heated oxide; 12; 18-triolefin-30-acid (a), a make 2-iodo-3,11-dioxo-volatile oil-1 with the elemental iodine reaction under pyridine catalysis; 12,18-triolefin-30-acid (I a); A makes 1 through hydrogen peroxide oxidation, 2-epoxy-3,10-dioxo-volatile oil-12,18-diene-30-acid (4), 4 with haloid acid (HX) or sodium alkyl alcohol (R 3ONa) reaction makes 2-halo-3 respectively, 10-dioxo-volatile oil-1,12,18-triolefin-30-acid (I b) and 2-alkoxyl group-3,10-dioxo-volatile oil-1,12,18-triolefin-30-acid (I c); 3 reacts under room temperature with IBX and to generate 3,10-dioxo-volatile oil-12, and 18-diene-30-acid (5), 5 make 2-hydroxyl-3,10-dioxo-volatile oil-1,12, the sour (I of 18-triolefin-30-through the potassium tert.-butoxide oxidation d); Its synthetic route is following:
    Figure FSA00000718755500031
    Wherein, X represents F, Cl, Br, R 3Definition according to claim 1;
    Compound is characterised in that shown in the preparation formula (a), and solvent is selected from DMSO 99.8MIN. (DMSO), N (DMF), N-Methyl pyrrolidone (NMP) or ETHYLE ACETATE; Temperature is 60-120 ℃; Reaction times is 4-24 hour;
    B) work as R 2Be COOH, the preparation method of compound is shown in the general formula (II): with glycyrrhetinic acid (GA) is raw material, makes 3 β through sodium borohydride reduction; 11-dihydroxyl-18 β-glycyrrhetinic acid (6); 6 at room temperature make 3 beta-hydroxies-volatile oil-11,13 (18)-diene-30-acid (7) through 5% Hydrogen chloride dehydration, and 7 make 3-oxo-volatile oil-1 through the IBX heated oxide; 11,13 (18)-triolefins-30-acid (II a); II aUnder pyridine catalysis, make 2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-acid (II with the elemental iodine reaction b); II bMake 2-cyanic acid-3-oxo-volatile oil-1,11 with the cuprous cyanide reaction, 13 (18)-triolefins-30-acid (II c); 7 reacts under room temperature with IBX and to make 3-oxo-volatile oil-11,13 (18)-diene-30-acid (8), and 8 make 2-hydroxyl-3-oxo-volatile oil-1,11, the sour (II of 13 (18)-triolefins-30-through the potassium tert.-butoxide oxidation d); Its synthetic route is following:
    Figure FSA00000718755500032
    Preparation formula (II a) shown in compound be characterised in that solvent is selected from DMSO 99.8MIN. (DMSO), N (DMF), N-Methyl pyrrolidone (NMP) or ETHYLE ACETATE; Temperature is 60-120 ℃; Reaction times is 4-24 hour;
    C) work as R 2Be COOH; The preparation method of compound is shown in the general formula (III): midbody (6) dewaters under the concentrated hydrochloric acid effect and makes 3 beta-hydroxies-18 β-volatile oil-9 (11); 12-diene-30-acid (9); 9 make 3-oxo-18 β-volatile oil-1,9 (11) through the IBX heated oxide, 12-triolefin-30-acid (III a), III aUnder pyridine catalysis, make 2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-acid (III with the elemental iodine reaction b), III bMake 2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11) with the cuprous cyanide reaction, 12-triolefin-30-acid (III c); 9 reacts under room temperature and make 3-oxo-18 β-volatile oil-9 (11) with IBX, 12-diene-30-acid (10), and 10 make 2-hydroxyl-3-oxo-18 β-volatile oil-1,9 (11), the sour (III of 12-triolefin-30-through the potassium tert.-butoxide oxidation d); Its synthetic route is following:
    Figure FSA00000718755500041
    Preparation formula (III a) shown in compound be characterised in that solvent is selected from DMSO 99.8MIN. (DMSO), N (DMF), N-Methyl pyrrolidone (NMP) or ETHYLE ACETATE; Temperature is 60-120 ℃; Reaction times is 4-24 hour;
    D) work as R 2Be CO 2R 4Or C (O) NR 5R 6The time, general formula (I), (II) and (III) shown in the preparation method of compound be: respectively with a, I A-d, II A-dAnd III A-dBe raw material, under the salt of wormwood effect with halohydrocarbon (R 4X) reaction, or generate behind the acyl chlorides again and aminated compounds (HNR with chloride reagent reaction 5R 6) reaction, make ester compound (I respectively e, II e, III e) and amides (I f, II f, III f); Its synthetic route is following:
    Figure FSA00000718755500042
    Wherein, R 1, R 4, R 5, R 6Definition according to claim 1;
    Preparation formula (I f, II f, III f) shown in compound it is characterized in that chloride reagent is selected from oxalyl chloride, sulfur oxychloride or phosphorus trichloride;
    E) work as R 2During for CN, general formula (I), (II) and (III) shown in the preparation method of compound be: with I F-1, II F-1And III F-1Be raw material, under the dehydrated reagent effect, make 3 respectively, 11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I g), 3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II g) and 3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III g); Under pyridine catalysis, I g, II gAnd III gMake 2-iodo-3,11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I with the elemental iodine reaction respectively h), 2-iodo-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II h) and 2-iodo-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III h); I h, II hAnd III hMake 2-cyanic acid-3 respectively, 11-dioxo-volatile oil-1,12,18-triolefin-30-nitrile (I with the inferior reactive ketone of cyaniding separately again i), 2-cyanic acid-3-oxo-volatile oil-1,11,13 (18)-triolefins-30-nitrile (II i) and 2-cyanic acid-3-oxo-18 β-volatile oil-1,9 (11), 12-triolefin-30-nitrile (III i) its synthetic route is following:
    Figure FSA00000718755500051
    Preparation formula (I g, II g, III g) time, dehydrated reagent is selected from trifluoroacetic anhydride, diacetyl oxide, POCl3 or phosphorus trichloride;
    F) work as R 2Be CHOH, CH 2OC (Ph) 3Or CH 2OC (O) R 4The time; The preparation method of compound is shown in the general formula (II): GA generates 3,11,30-trihydroxy--18 β-volatile oil-12-alkene (11) through the Lithium Aluminium Hydride reduction; 11 dewater under the Hydrogen chloride effect and are rearranged into 3; 30-dihydroxyl-volatile oil-11,13 (18)-diene (12), 12 with triphenylmethyl chloride (Ph 3CCl) reaction makes 3-hydroxyl-volatile oil-11; 13 (18)-diene-30-trityl ether (13); 13 make 3-oxo-volatile oil-11,13 (18)-diene-30-trityl ether (14) through IBX oxidation under room temperature, and 14 make 2-hydroxyl-3-oxo-30-three benzyloxies-volatile oil-1 through the potassium tert.-butoxide oxidation; 11,13 (18)-triolefin (II j); II jIn Glacial acetic acid min. 99.5, reflux and make 2-hydroxyl-3-oxo-30-acetoxyl group-volatile oil-1,11,13 (18)-triolefin (II k); II jReaction makes 2,30-dihydroxyl-3-oxo-volatile oil-1,11,13 (18)-triolefin (II under 50 ℃ in Glacial acetic acid min. 99.5 l); Its synthetic route is following:
    Figure FSA00000718755500052
  5. 5. method according to claim 4, preparation formula (a), (II a), (III a) be characterised in that solvent is DMSO; Temperature of reaction is 85 ℃; Reaction times is 8-12h; Preparation formula (I f, II f, III f) be characterised in that chloride reagent is an oxalyl chloride; Preparation formula (I g, II g, III g) be characterised in that dehydrated reagent is a trifluoroacetic anhydride.
  6. 6. pharmaceutical composition is gone up in the claim 1,2 or 3 of significant quantity each compound or its pharmaceutically acceptable carrier or auxiliary material and is formed by treatment.
  7. 7. each compound or its pharmacy acceptable salt are used for treating the purposes of the medicine of inflammatory disease, tumour or mellitus among the claim 1-3 in preparation.
  8. 8. purposes according to claim 7, wherein said inflammatory disease are dermatitis, inflammatory pain, neuropathic pain, osteoarthritis, rheumatic arthritis, rheumatoid arthritis or myocarditis.
  9. 9. purposes according to claim 7, wherein said tumour are liver cancer, cancer of the stomach, colorectal carcinoma, prostate cancer, carcinoma of the pancreas, mammary cancer, lung cancer or white blood disease.
  10. 10. purposes according to claim 7, wherein said mellitus are type i diabetes or type ii diabetes.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232520A (en) * 2013-05-13 2013-08-07 中国药科大学 Spirosteroid compounds and preparation method and medical application thereof
CN104530176A (en) * 2015-01-05 2015-04-22 武汉华纳联合药业有限公司 GAOH derivative and medical application thereof
WO2017013410A1 (en) 2015-07-17 2017-01-26 Ucl Business Plc Selective inhibitors of i-nos for use against viral infection
CN110143995A (en) * 2019-06-03 2019-08-20 沈阳药科大学 Azacyclo- replaces 18 β-Enoxolone derivative and its preparation and application
CN111620924A (en) * 2020-06-04 2020-09-04 华中农业大学 Drug design method based on natural product, pentacyclic triterpenoid compound, preparation method and application thereof
CN114829577A (en) * 2019-10-17 2022-07-29 国立大学法人大阪大学 Glucuronic acid transferase, gene encoding the same, and method for using the same
CN115448973A (en) * 2022-09-05 2022-12-09 承德医学院 Glycyrrhetinic acid-azide compound with flexible bridge bond structure, preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101935334A (en) * 2010-01-14 2011-01-05 杭州市中医院 Berberine glycyrrhetinic acid enantiomeric salts and preparation method and application thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101935334A (en) * 2010-01-14 2011-01-05 杭州市中医院 Berberine glycyrrhetinic acid enantiomeric salts and preparation method and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FENG CAO, ET AL.: "Ethylene Glycol-Linked Amino Acid Diester Prodrugs of Oleanolic Acid for PepT1-Mediated Transport: Synthesis, Intestinal Permeability and Pharmacokinetics", 《MOL. PHARMACEUTICS》, vol. 9, 21 February 2012 (2012-02-21), pages 2127 - 2135 *
丁晔，等: "新型齐墩果酸衍生物的合成及抗肿瘤活性", 《中国药科大学学报》, vol. 42, no. 5, 31 December 2011 (2011-12-31), pages 385 - 391 *
申利红，等: "硝酸酯类甘草次酸衍生物的合成及肿瘤活性", 《中国药科大学学报》, vol. 39, no. 2, 31 December 2008 (2008-12-31), pages 103 - 107 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232520A (en) * 2013-05-13 2013-08-07 中国药科大学 Spirosteroid compounds and preparation method and medical application thereof
CN104530176A (en) * 2015-01-05 2015-04-22 武汉华纳联合药业有限公司 GAOH derivative and medical application thereof
CN104530176B (en) * 2015-01-05 2016-03-23 武汉华纳联合药业有限公司 GAOH derivative and medicinal use thereof
WO2017013410A1 (en) 2015-07-17 2017-01-26 Ucl Business Plc Selective inhibitors of i-nos for use against viral infection
CN110143995A (en) * 2019-06-03 2019-08-20 沈阳药科大学 Azacyclo- replaces 18 β-Enoxolone derivative and its preparation and application
CN110143995B (en) * 2019-06-03 2022-03-01 沈阳药科大学 Azacyclo-substituted 18 beta-glycyrrhetinic acid derivative and preparation and application thereof
CN114829577A (en) * 2019-10-17 2022-07-29 国立大学法人大阪大学 Glucuronic acid transferase, gene encoding the same, and method for using the same
CN111620924A (en) * 2020-06-04 2020-09-04 华中农业大学 Drug design method based on natural product, pentacyclic triterpenoid compound, preparation method and application thereof
CN115448973A (en) * 2022-09-05 2022-12-09 承德医学院 Glycyrrhetinic acid-azide compound with flexible bridge bond structure, preparation method and application thereof

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