CN1827634B - Nitrate derivatives of glycyrrhetic acid and glycyrrhetinic acid and pharmaceutical use thereof - Google Patents

Abstract

Disclosed are nitrate derivant of glycyrrhizic acid or glycor represented by formula Ia and Ib and its nontoxic salt which can be accepted in the sphere of pharmacy, their precoss for preparing, and components and usage of the drugs which contain these compounds.Thereinto, R1, R2 and R3 stand for hydroxyl or -X-L-oxo-oxonitryl (X stands for oxygen,imino; L stands for alkyl with 2-6 of canbon atoms, substituted alkyl or cycloalkyl, hydroxyl amino acid residue or N,N'-disubstituted piperazine); R3 stands for hydrogen, oxonitryl or carbonyl -L'oxo-oxonitryl (L'stands for alkyl with 1-6 of canbonatoms, substituted alkyl or cycloalkyl, aralkyl, N,N'-disubstituted piperazine); in formula Ib, R1, R2 and R3 may be the same or different, but in which at least one of them contains -X-L-oxo-oxonitryl; in formula Ib, at least one of R3 or R4 must contain oxonitryl. In formula Ia and Ib, hydrogen of 18-carbon can be alpha-isomer or beta-isomer.

Description

The nitrate derivatives of Potenlini and glycyrrhetinic acid and medicinal use thereof

Technical field

The present invention relates to the nitrate derivatives and the atoxic pharmacy acceptable salt thereof of Potenlini and glycyrrhetinic acid and contain these compounds as the pharmaceutical composition of activeconstituents and in the application for preparing aspects such as hepatitis treatment medicine and ulcer treatment medicine; The invention still further relates to the preparation method of the nitrate derivatives and the atoxic pharmacy acceptable salt thereof of Potenlini and glycyrrhetinic acid.

Background technology

The present invention relates to the nitrate derivatives and the atoxic pharmacy acceptable salt thereof of Potenlini and glycyrrhetinic acid, and their preparation method, and the medicine composition that contains these compounds, and Potenlini or the nitrate derivatives of glycyrrhetinic acid and the method for atoxic pharmacy acceptable salt treatment hepatitis and peptide ulceration etc. thereof by awarding effective therapeutic dose.

Potenlini (Glycyrrhizic acid, GA), claim glycyrrhizin (Glycyrrhizin again, GL), chemical name 3-O-(2 '-beta d glucopyranosiduronic acid base)-beta d glucopyranosiduronic acid glycosides 3 beta-hydroxies-11-carbonyl oxygen-18 β volatile oil-12-alkene-30-carboxylic acid (English chemical name: 3-O-(2 '-β-D-glucuronopyranosyl)-β-D-glucuronopyranoside 3 β-hydroxy-11-oxo-18 β olean-12-en-30-oic acid), be the effective constituent of separation and Extraction from Radix Glycyrrhizae.Natural isolating Potenlini is 18 beta isomers, and 18 beta isomers can be converted into 18 αYi Goutis by ad hoc approach.Its chemical structure is as follows:

Potenlini beta isomer Potenlini αYi Gouti

Carboxyl in the Potenlini molecule can become single salt, two salt or three salt with various positively charged ions such as sodium ion, potassium ion, ammonium ion, zine ion, magnesium ion etc.Studies show that Potenlini has anti-inflammatory, antiviral and effects such as protecting liver and detoxication and raise immunity, clinically be widely used in treating various acute, chronic hepatitis.What clinical application was more is beta isomer mono-ammonium (commodity are called potenlin) and αYi Gouti di-ammonium salts (commodity are called Glycyrrhizic acid,diammonium salt, chief editors such as Chen Xinqian, new pharmacology, the 15th edition, People's Health Publisher, 2004, the 472 pages); Formulation has injection liquid or capsule, respectively by injection administration or oral administration; These preparations have and significantly fall enzyme, anti-inflammatory and hepatoprotective effect.

Potenlini is that (glycyrrhetinic acid is the active metabolite of Potenlini for GlycyrrhetinicAcid, GLA) performance pharmacological action by being converted into its aglycon glycyrrhetinic acid in vivo; External, can Potenlini be converted into glycyrrhetinic acid by hydrolysis.The chemical structure of glycyrrhetinic acid is as follows:

Glycyrrhetinic acid beta isomer glycyrrhetinic acid αYi Gouti

The preparation that contains Potenlini or glycyrrhetinic acid and derivative thereof also has Radix Glycyrrhizae fluidextract or FUFANG GANCAO PIAN to be used for the cough-relieving what is said or talked about of dispelling, treatment upper respiratory tract infection and bronchitis (chief editor such as Chen Xinqian, new pharmacology, the 15th edition, the People's Health Publisher, 2004, the 421 pages); Zinc glycyrrhizate and liver Meticortene Solu-Delta-cortef are used for the treatment of peptide ulceration (chief editor such as Chen Xinqian, new pharmacology, the 15th edition, People's Health Publisher, 2004, the 440,442 pages).

But, also there are some untoward reactions in Potenlini or glycyrrhetinic acid and derivative thereof in clinical application, mainly contain and receive poor, nauseating, vomiting, abdominal distension, skin pruritus, urticaria, dry, edema, dizziness, uncomfortable in chest, palpitaition, blood pressure and increase, side effect (the chief editor such as Chen Xinqian who also has some steroid samples, new pharmacology, the 15th edition, the People's Health Publisher, 2004, the 421,440,442 and 472 pages).Therefore need more effective and side effect glycyrrhizin derivative still less, to be used for the treatment of diseases such as hepatitis, peptide ulceration and virus infection.

Summary of the invention

The invention provides respectively nitrate derivatives and atoxic pharmacy acceptable salt thereof by Potenlini shown in structural formula Ia and the Ib or glycyrrhetinic acid, and their preparation method, and the medicine composition that contains these compounds, and Potenlini or the nitrate derivatives of glycyrrhetinic acid and the method for atoxic pharmacy acceptable salt treatment hepatitis and peptide ulceration etc. thereof by awarding effective therapeutic dose.

Potenlini nitric ether glycyrrhetinic acid nitric ether

Ia Ib

In formula Ia, R ₁, R ₂And R ₃Representative-OH or-X-L-ONO ₂(wherein X represents O, NH; It is saturated or undersaturated alkyl, the substituted alkyl of 2-6 that L represents carbonatoms, and carbonatoms is the cycloalkyl of 3-6, the amino-acid residue of hydroxyl, N, N ' disubstituted piperazine); R ₁, R ₂And R ₃Identical or different, but wherein must have one to be-X-L-ONO at least ₂Hydroxyl in the formula Ia molecule can be made the prodrug of monoesters or polyester, and the hydrogen that carbon is 18 can be αYi Gouti or beta isomer.

In formula Ib, R ₃Be OH or X-L-ONO ₂(wherein X represents O, NH; It is saturated or undersaturated alkyl, the substituted alkyl of 2-6 that L represents carbonatoms, and carbonatoms is the cycloalkyl of 3-6, the amino-acid residue of hydroxyl, N, N ' disubstituted piperazine); The hydrogen that carbon is 18 can be αYi Gouti or beta isomer; R ₄Represent H, NO ₂Or CO-L ' ONO ₂(wherein to represent carbonatoms be saturated or undersaturated alkyl, the substituted alkyl of 1-6 to L ', and carbonatoms is the cycloalkyl of 3-6, the aromatic alkyl of aromatic alkyl or replacement, N, N ' disubstituted piperazine); R ₃Or R ₄In must have at least one to contain nitrooxy; The hydrogen that carbon is 18 can be αYi Gouti or beta isomer.

The present invention also provides formula II _aThe nitrate derivatives of shown Potenlini, wherein R ₁, R ₂And R ₃Representative-OH or-X-L ₁'-ONO ₂, X represents O, NH; L ₁' to represent carbonatoms be that saturated or undersaturated alkyl, substituted alkyl or the carbonatoms of 2-6 is the cycloalkyl of 3-6; R ₁, R ₂And R ₃Identical or different, but wherein must have one to be-X-L at least ₁' ONO ₂, work as R ₁, R ₂And R ₃In have at least one be-during OH, the carboxyl in the molecule can become single salt, two salt with various positively charged ions such as sodium ion, potassium ion, ammonium ion, zine ion, magnesium ion etc.Hydroxyl in the molecule can be made the prodrug of monoesters or polyester.

The present invention also provides formula II _aThe nitrate derivatives of shown Potenlini and non-toxicity pharmacy acceptable salt, wherein R ₁, R ₂And R ₃Representative-OH or L ₂Shown group:

Formula L ₂Middle A is the amino-acid residue such as the serine residue of hydroxyl, threonine residues; These amino acid can be D type or L type, also can be racemies; A can also be 3-Hydroxyproline residue or 4-Hydroxyproline residue, and said hydroxyl dried meat hydrochloric acid can be cis or transconfiguration; R ₁, R ₂And R ₃Identical or different, but wherein must have one to be L at least ₂Carboxyl in the molecule can become single salt, two salt with various positively charged ions such as sodium ion, potassium ion, ammonium ion, zine ion, magnesium ion etc.Hydroxyl in the molecule can be made the prodrug of monoesters or polyester.

The present invention also provides formula II _aThe nitrate derivatives of shown Potenlini and non-toxicity pharmacy acceptable salt, wherein R ₁, R ₂And R ₃Representative-OH or L ₃Shown group:

Formula L ₃Middle X represents O, NH; Y, Z are carbonyl or methylene radical, and Y, Z are identical or different; L ₃', L ₃" represent saturated or undersaturated alkyl, the substituted alkyl of 2-6, L ₃', L ₃" identical or different; R ₁, R ₂And R ₃Identical or different, but wherein must have one to be L at least ₂Work as R ₁, R ₂And R ₃In have at least one be-during OH, the carboxyl in the molecule can become single salt, two salt with various positively charged ions such as sodium ion, potassium ion, ammonium ion, zine ion, magnesium ion etc.Alkaline N atom in the molecule on the piperazine can become single salt or many salt with the pharmaceutically acceptable mineral acid example hydrochloric acid of non-toxicity, sulfuric acid etc. or organic acid such as methylsulfonic acid, toxilic acid, oxysuccinic acid etc.Hydroxyl in the molecule can be made the prodrug of monoesters or polyester.

The present invention also provides formula II _bThe nitrate derivatives of shown glycyrrhetinic acid, wherein R ₄Be H, R ₃Representative-X-L ₁'-ONO ₂, wherein X represents O, NH; L ₁' to represent carbonatoms be that saturated or undersaturated alkyl, substituted alkyl or the carbonatoms of 2-6 is the cycloalkyl of 3-6.Hydroxyl in the molecule can be made the prodrug of ester.

The present invention also provides formula II _bThe nitrate derivatives of shown glycyrrhetinic acid and non-toxicity pharmacy acceptable salt, wherein R ₄Be H, R ₃Representative-OH or L ₂Shown group:

Formula L ₂Middle A is the amino-acid residue such as the serine residue of hydroxyl, threonine residues; These amino acid can be D type or L type, also can be racemies; A can also be 3-Hydroxyproline residue or 4-Hydroxyproline residue, and said hydroxyl dried meat hydrochloric acid can be cis or transconfiguration.Carboxyl in the molecule can with salifies such as various positively charged ions such as sodium ion, potassium ion, ammonium ion, zine ion, magnesium ion.

The present invention also provides formula II _bThe nitrate derivatives of shown glycyrrhetinic acid and non-toxicity pharmacy acceptable salt, wherein R ₄Be H, R ₃Representative-OH or L ₃Shown group:

Formula L ₃Middle X represents O, NH; Y, Z are carbonyl or methylene radical, and Y, Z are identical or different; L ₃', L ₃" to represent carbonatoms be saturated or undersaturated alkyl, the substituted alkyl of 2-6, carbonatoms is the cycloalkyl of 3-6, L ₃', L ₃" identical or different.Alkaline N atom in the molecule on the piperazine can with salifies such as the pharmaceutically acceptable mineral acid example hydrochloric acid of non-toxicity, sulfuric acid etc. or organic acid such as methylsulfonic acid, toxilic acid, oxysuccinic acid.

The present invention also provides formula II _bThe nitrate derivatives of shown glycyrrhetinic acid and non-toxicity pharmacy acceptable salt, wherein R ₃For-OH or carbonatoms are the alkoxyl group of 1-3, R ₄Represent CO-L '-ONO ₂, wherein to represent carbonatoms be saturated or undersaturated alkyl, the substituted alkyl of 1-6 carbonatoms to L ', carbonatoms is the cycloalkyl of 3-6, the aromatic alkyl of aromatic alkyl or replacement.Work as R ₃During for OH, the carboxyl in the molecule can with salifies such as various positively charged ions such as sodium ion, potassium ion, ammonium ion, zine ion, magnesium ion.

The present invention also provides formula II _bThe nitrate derivatives of shown glycyrrhetinic acid and non-toxicity pharmacy acceptable salt thereof, wherein, R ₃Representing OH or carbonatoms is the alkoxyl group of 1-3, R ₄Represent L ₄Shown group:

Formula L ₃Middle Y, Z are carbonyl or methylene radical, and Y, Z are identical or different; L ₄', L ₄" to represent carbonatoms be saturated or undersaturated alkyl, the substituted alkyl of 2-6, carbonatoms is the cycloalkyl of 3-6, L ₄', L ₄" identical or different.Alkaline N atom in the molecule on the piperazine can with salifies such as the pharmaceutically acceptable mineral acid example hydrochloric acid of non-toxicity, sulfuric acid etc. or organic acid such as methylsulfonic acid, toxilic acid, oxysuccinic acid.

The present invention also provides formula II _bThe nitrate derivatives of shown glycyrrhetinic acid and non-toxicity pharmacy acceptable salt, wherein R ₃Representing OH or carbonatoms is the alkoxyl group of 1-3, R ₄For-NO ₂Work as R ₃During for OH, the carboxyl in the molecule can with salifies such as various positively charged ions such as sodium ion, potassium ion, ammonium ion, zine ion, magnesium ion.

The present invention also provides formula II on the other hand _aOr II _bThe preparation method of the Potenlini of representative or the nitrate derivatives of glycyrrhetinic acid and atoxic pharmacy acceptable salt thereof.

The present invention also provides pharmaceutical composition on the other hand, and these pharmaceutical compositions contain formula II _aOr II _bThe Potenlini of representative or the nitrate derivatives of glycyrrhetinic acid and atoxic pharmacy acceptable salt thereof are as activeconstituents and suitable excipient.These pharmaceutical compositions can be solution, tablet, capsule or injection; These pharmaceutical compositions can pass through injection administration or oral administration.

The present invention also provides on the other hand and uses II _aOr II _bThe method of the Potenlini of representative or the nitrate derivatives of glycyrrhetinic acid and atoxic pharmacy acceptable salt treatment hepatitis thereof.

The present invention also provides on the other hand and uses II _aOr II _bThe method of the Potenlini of representative or the nitrate derivatives of glycyrrhetinic acid and atoxic pharmacy acceptable salt treatment digestive ulcer medicament thereof.

Embodiment

Can further describe the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.

Compound I I _1-7Can prepare according to following synthetic route:

With 18 α trisodium glycyrrhetinates is raw material, is reacted into the bromo alkyl ester with the dibromo alkane substitute, makes the nitrate derivatives of corresponding 18 α Potenlinis again with the Silver Nitrate reaction; Same, be raw material with 18 β trisodium glycyrrhetinates, can make the nitrate derivatives of corresponding 18 β Potenlinis.

Embodiment 1 18 α Radix Glycyrrhizae acyl-three (2-nitrooxy-ethyl)-ester (II ₁) preparation 1a, 18 α Radix Glycyrrhizae acyls-three (2-bromo-ethyl)-ester

18 α trisodium glycyrrhetinates, 1.78 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.5 gram (8mmol) glycol dibromides, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.86 gram 18 α Radix Glycyrrhizae acyls-three (2-bromo-ethyl)-esters.1b, 18 α Radix Glycyrrhizae acyl-three (2-nitrooxy-ethyl)-ester (II ₁) preparation

Respectively 1.86 gram (1.63mmol) 18 α Radix Glycyrrhizae acyls-three (2-bromo-ethyl)-esters are dissolved in 10 milliliters of acetonitriles, 1.1 gram (6.52mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-three (2-bromo-ethyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.56 gram II ₁High resolution mass spectrum: calculated value C ₄₈H ₇₂N ₃O ₂₅(MH ⁺) 1090.4455, measured value 1090.4453.

Embodiment 2 18 α Radix Glycyrrhizae acyl-three (4-nitrooxy-butyl)-ester (II ₂) preparation 2a, 18 α Radix Glycyrrhizae acyls-three (4-bromo-butyl)-ester

18 α trisodium glycyrrhetinates, 1.78 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,4-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.37 gram 18 α Radix Glycyrrhizae acyls-three (4-bromo-butyl)-esters.2b, 18 α Radix Glycyrrhizae acyl-three (4-nitrooxy-butyl)-ester (II ₂) preparation

Respectively 1.37 gram (1.21mmol) 18 α Radix Glycyrrhizae acyls-three (4-bromo-butyl)-esters are dissolved in 10 milliliters of acetonitriles, 0.82 gram (4.84mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-three (4-bromo-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.38 gram I ₂High resolution mass spectrum: calculated value C ₅₄H ₈₄N ₃O ₂₅(MH ⁺) 1174.5394, measured value 1174.5392.

Embodiment 3 18 α Radix Glycyrrhizae acyls-three (3-nitrooxy-3-methyl-propyl group)-ester (II ₃) preparation

3a, 18 α Radix Glycyrrhizae acyls-three (3-bromo-3-methyl-propyl group)-ester

18 α trisodium glycyrrhetinates, 1.78 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,3-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.20 gram 18 α Radix Glycyrrhizae acyls-three (3-bromo-3-methyl-propyl group)-esters.

3b, 18 α Radix Glycyrrhizae acyls-three (3-nitrooxy-3-methyl-propyl group)-ester (II ₃) preparation

Respectively 1.20 gram (1.06mmol) 18 α Radix Glycyrrhizae acyls-three (3-bromo-3-methyl-propyl group)-esters are dissolved in 10 milliliters of acetonitriles, 0.72 gram (4.24mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-three (3-bromo-3-methyl-propyl group)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.29 gram II ₃High resolution mass spectrum: calculated value C ₅₄H ₈₄N ₃O ₂₅(MH ⁺) 1174.5394, measured value 1174.5394.

Embodiment 4 18 α Radix Glycyrrhizae acyls-three (4-nitrooxy-trans-2-butene base)-ester (II ₄) preparation

4a, 18 α Radix Glycyrrhizae acyls-three (4-bromo-trans-2-butene base)-ester

18 α trisodium glycyrrhetinates, 1.78 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.72 gram (8mmol) 1,4-two bromo-trans-2-butenes, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.65 gram 18 α Potenlinis three (4-bromo-trans-2-butene base)-esters.

4b, 18 α Radix Glycyrrhizae acyls-three (4-nitrooxy-trans-2-butene base)-ester (II ₄) preparation

Respectively 1.65 gram (1.46mmol) 18 α Radix Glycyrrhizae acyls-three (4-bromo-trans-2-butene base)-esters are dissolved in 10 milliliters of acetonitriles, 1.0 gram (5.84mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-three (4-bromo-trans-2-butene base)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.77 gram II ₄High resolution mass spectrum: calculated value C ₅₄H ₇₈N ₃O ₂₅(MH ⁺) 1168.4924, measured value 1168.4925.

Embodiment 5 18 α Radix Glycyrrhizae acyls-three (4-nitrooxy-3-hydroxyl-butyl)-ester (II ₅) preparation

5a, 18 α Radix Glycyrrhizae acyls-three (4-bromo-3-hydroxyl-butyl)-ester

18 α trisodium glycyrrhetinates, 1.78 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.86 gram (8mmol) 1,4-two bromo-2-butanols, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.02 gram 18 α Radix Glycyrrhizae acyls-three (4-bromo-3-hydroxyl-butyl)-esters.

5b, 18 α Radix Glycyrrhizae acyls-three (4-nitrooxy-3-hydroxyl-butyl)-ester (II ₅) preparation

Respectively 1.02 gram (0.8mmol) 18 α Radix Glycyrrhizae acyls-three (4-bromo-3-hydroxyl-butyl)-esters are dissolved in 10 milliliters of acetonitriles, 0.55 gram (3.2mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-three (4-bromo-3-hydroxyl-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.34 gram II ₅High resolution mass spectrum: calculated value C ₅₄H ₈₄N ₃O ₂₈(MH ⁺) 1222.5241, measured value 1222.5240.

Embodiment 6 18 α Radix Glycyrrhizae acyl-three (2-nitrooxy-cyclohexyl)-ester (II ₆) preparation 6a, 18 α Radix Glycyrrhizae acyls-three (2-bromo-cyclohexyl)-ester

18 α trisodium glycyrrhetinates, 1.78 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.94 gram (8mmol) 1,2-dibromo-cyclohexane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 0.90 gram 18 α Radix Glycyrrhizae acyls-three (2-bromo-cyclohexyl)-ester.6b, 18 α Radix Glycyrrhizae acyl-three (2-nitrooxy-cyclohexyl)-ester (II ₆) preparation

Respectively 0.90 gram (0.69mmol) 18 α Radix Glycyrrhizae acyls-three (2-bromo-cyclohexyl)-ester is dissolved in 10 milliliters of acetonitriles, 0.47 gram (2.76mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-three (2-bromo-cyclohexyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.27 gram II ₆High resolution mass spectrum: calculated value C ₆₀H ₉₀N ₃O ₂₅(MH ⁺) 1252.5863, measured value 1252.5860.

Embodiment 7 18 β Radix Glycyrrhizae acyl-three (4-nitrooxy-butyl)-ester (II ₇) preparation 7a, 18 β Radix Glycyrrhizae acyls-three (4-bromo-butyl)-ester

18 β trisodium glycyrrhetinates, 1.78 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,4-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.02 gram 18 β Radix Glycyrrhizae acyls-three (4-bromo-butyl)-esters.

7b, 18 β Radix Glycyrrhizae acyl-three (4-nitrooxy-butyl)-ester (II ₇) preparation

Respectively 1.02 gram (0.9mmol) 18 β Radix Glycyrrhizae acyls-three (4-bromo-butyl)-esters are dissolved in 10 milliliters of acetonitriles, 0.61 gram (3.6mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 β Radix Glycyrrhizae acyls-three (4-bromo-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.31 gram II ₇High resolution mass spectrum: calculated value C ₅₄H ₈₄N ₃O ₂₅(MH ⁺) 1174.5394, measured value 1174.5391.

Compound I I ₈Can prepare according to following synthetic route:

With 18 α Potenlinis is raw material, forms mixed acid anhydride with isobutyl chlorocarbonate earlier, is reacted into the bromo alkylamide with the bromo alkylamine then, makes the nitrate derivatives of corresponding 18 α Potenlinis again with the Silver Nitrate reaction; Same, be raw material with 18 β trisodium glycyrrhetinates, can make the nitrate derivatives of corresponding 18 β Potenlinis.

Embodiment 8 18 α Radix Glycyrrhizae acyl-three (3-nitrooxy-propyl group)-acid amides (II ₈) preparation 8a, 18 β Radix Glycyrrhizae acyls-three (3-bromo-propyl group)-acid amides

3.94 gram (18mmol) 3-propantheline bromide hydrobromides are dissolved in 18 milliliters of 2N sodium hydroxide solutions, mixed solution is cooled to 5 ℃.Get 18 α Potenlinis, 3.29 grams (4mmol) and be dissolved in 15 milliliters of tetrahydrofuran (THF)s, be cooled to-15 ℃ under cryosel is bathed, add 0.5 gram (5mmol) N-methylmorpholine, 0.7 gram (5mmol) isobutyl chlorocarbonate successively, reaction is 10 minutes under cryosel is bathed; Drip the sodium hydroxide solution of 3-propantheline bromide hydrobromide in reaction solution, ice bath stirred 1.5 hours down.Reaction is finished, and regulates the pH value to 3-4 with dilute hydrochloric acid, uses n-butanol extraction 3 times, and united extraction liquid with saturated sodium bicarbonate solution and saturated common salt washing, spends the night with anhydrous sodium sulfate drying successively.Filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 18 β Radix Glycyrrhizae acyls-three (3-bromo-propyl group)-acid amides 1.46 grams.

8b, 18 α Radix Glycyrrhizae acyl-three (3-nitrooxy-propyl group)-acid amides (II ₈) preparation

Respectively 1.46 gram (1.3mmol) 18 β Radix Glycyrrhizae acyls-three (3-bromo-propyl group)-acid amides are dissolved in 5 milliliters of acetonitriles, 0.9 gram (5.28mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 β Radix Glycyrrhizae acyls-three (3-bromo-propyl group)-acid amides, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.58 gram II ₈High resolution mass spectrum: calculated value C ₅₁H ₈₁N ₆O ₂₂(MH ⁺) 1129.5404, measured value 1129.5403.

Compound I I ₉Can prepare according to following synthetic route:

With 18 β Rizinsan K2 A2s is raw material, is reacted into the bromo alkyl ester with the dibromo alkane substitute, makes the nitrate derivatives of corresponding 18 β Potenlinis again with the Silver Nitrate reaction; Same, be raw material with 18 α Rizinsan K2 A2s, can make the nitrate derivatives of corresponding α 18 Potenlinis.

Embodiment 9 18 β Radix Glycyrrhizae acyl-two (4-nitrooxy-butyl)-ester (II ₉) preparation

9a, 18 β Radix Glycyrrhizae acyls-two (4-bromo-butyl)-ester

18 β Rizinsan K2 A2s, 1.8 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,4-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 0.65 gram 18 β Radix Glycyrrhizae acyls-two (4-bromo-butyl)-ester.

9b, 18 β Radix Glycyrrhizae acyl-two (4-nitrooxy-butyl)-ester (II ₉) preparation

Respectively 0.65 gram (0.6mmol) 18 β Radix Glycyrrhizae acyls-two (4-bromo-butyl)-ester is dissolved in 5 milliliters of acetonitriles, 0.4 gram (2.4mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-two (4-bromo-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.28 gram II ₉High resolution mass spectrum: calculated value C ₅₀H ₇₇N ₂O ₂₂(MH ⁺) 1057.4968, measured value 1057.4965.

Compound I I ₁₀Can prepare according to following synthetic route:

With 18 β monoammonium glycyrrhizinates is raw material, is reacted into the bromo alkyl ester with the dibromo alkane substitute, makes the nitrate derivatives II of corresponding 18 β Potenlinis again with the Silver Nitrate reaction ₁₀Same, be raw material with 18 α glycyrrhizic acid monoammoniums, can make the nitrate derivatives of corresponding α 18 Potenlinis.

Embodiment 10 18 β Radix Glycyrrhizae acyl-list (4-nitrooxy-butyl)-ester (II ₁₀) preparation

10a, 18 β Radix Glycyrrhizae acyl-lists (4-bromo-butyl)-ester

18 β monoammonium glycyrrhizinates, 1.8 grams (2mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,4-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethanol/methylene (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 0.65 gram 18 β Radix Glycyrrhizae acyl-lists (4-bromo-butyl)-ester.

10b, 18 β Radix Glycyrrhizae acyl-list (4-nitrooxy-butyl)-ester (II ₁₀) preparation

Respectively 0.65 gram (0.6mmol) 18 β Radix Glycyrrhizae acyl-lists (4-bromo-butyl)-ester is dissolved in 5 milliliters of acetonitriles, 0.4 gram (2.4mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae acyl-list (4-bromo-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.28 gram II ₁₀High resolution mass spectrum: calculated value C ₄₆H ₇₀NO ₁₉(MH ⁺) 940.4542, measured value 940.4540.

Compound III _1-4Can prepare according to following synthetic route:

With the amino acid nitration of hydroxyl, make nitrate derivatives earlier; 18 α Potenlinis and isobutyl chlorocarbonate form mixed acid anhydride, and the reaction of the amino acid derivative of nitration promptly gets the nitrate derivatives of 18 α Potenlinis then; Same, be raw material with 18 β Potenlinis, can make the nitrate derivatives of corresponding 18 β Potenlinis.

Embodiment 11 N ^α-18 α Radix Glycyrrhizae acyls three (O-nitro-L-Serine) (III ₁) preparation

11a, O-nitro-L-Serine nitrate

In there-necked flask, add 25 milliliters of nitrosonitric acids, bathe with cryosel and be cooled to-5 to-10 ℃; 5 gram L-Serines are joined in the reaction solution in batches, and the control reacting liquid temperature is lower than 0 ℃.After adding, stir reaction down 30 minutes.Reaction is finished, and reaction solution is splashed in 100 milliliters of ether, separates out precipitation, the leaching precipitation, and the ether thorough washing, the white solid 4.3 that gets O-nitro-L-Serine nitrate after the drying restrains, and is directly used in the next step.

11b, N ^α-18 α Radix Glycyrrhizae acyls three (O-nitro-L-Serine) (III ₁) preparation

3.84 gram (18mmol) O-nitro-L-Serine nitrate are dissolved in 18 milliliters of 2N sodium hydroxide solutions, mixed solution is cooled to 5 ℃.Get 18 α Potenlinis, 3.29 grams (4mmol) and be dissolved in 15 milliliters of tetrahydrofuran (THF)s, be cooled to-15 ℃ under cryosel is bathed, add 0.5 gram (5mmol) N-methylmorpholine, 0.7 gram (5mmol) isobutyl chlorocarbonate successively, reaction is 10 minutes under cryosel is bathed; Drip the sodium hydroxide solution of O-nitro-L-Serine nitrate in reaction solution, ice bath stirred 1.5 hours down.Reaction is finished, and regulates the pH value to 3-4 with dilute hydrochloric acid, uses n-butanol extraction 3 times, and united extraction liquid with saturated sodium bicarbonate solution and saturated common salt washing, spends the night with anhydrous sodium sulfate drying successively.Filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethanol/methylene (1: 2) wash-out, collect required component, evaporated under reduced pressure gets III ₁1.06 gram.High resolution mass spectrum: calculated value C ₅₁H ₇₅N ₆O ₂₈(MH ⁺) 1219.4629, measured value 1219.4628.

Embodiment 12 N ^α-18 α Radix Glycyrrhizae acyls three (O-nitro-D-Serine) (III ₂) preparation

With reference to the method for embodiment 11a, 11b, replace the L-Serine with the D-Serine, can make III ₂0.82 gram.High resolution mass spectrum: calculated value C ₅₁H ₇₅N ₆O ₂₈(MH ⁺) 1219.4629, measured value 1219.4626.

Embodiment 13 N ^α-18 α Radix Glycyrrhizae acyls three (O-nitro-L-Threonine) (III ₃) preparation

With reference to the method for embodiment 11a, 11b, replace the L-Serine with the L-Threonine, can make III ₃0.82 gram.High resolution mass spectrum: calculated value C ₅₄H ₈₁N ₆O ₂₈(MH ⁺) 1261.5099, measured value 1261.5100.

Embodiment 14 N ^α-18 α Radix Glycyrrhizae acyls three (O-nitro-L-oxyproline) (III ₄) preparation

With reference to the method for embodiment 11a, 11b, replace the L-Serine with the L-oxyproline, can make III ₄0.82 gram.High resolution mass spectrum: calculated value C ₅₇H ₈₁N ₆O ₂₈(MH ⁺) 1297.5099, measured value 1297.5096.

Compound IV ₁Can prepare according to following synthetic route:

With 18 α trisodium glycyrrhetinates is raw material, is reacted into the tribromo substituted alkyl ester of Potenlini with the dibromo alkane substitute, reacts with piperazine again; Free NH on the piperazine molecule again with dibromo alkane substitute reaction, reaction product is last reacts the nitrate derivatives IV that makes corresponding 18 α Potenlinis with Silver Nitrate ₁Same, be raw material with 18 β trisodium glycyrrhetinates, can make the nitrate derivatives of corresponding 18 β Potenlinis.

Embodiment 15 18 α Radix Glycyrrhizae acyls-three 4-[4-(4-nitrooxy-butyl)-piperazine]-1-base-butyl }-ester (IV ₁) preparation

Prepare 18 α Radix Glycyrrhizae acyls-three (4-bromo-butyl ester) with reference to embodiment 1a.

15a, 18 α Radix Glycyrrhizae acyls-three [4-(piperazine-1-yl)-butyl]-ester

Getting 18 α Radix Glycyrrhizae acyls-three (4-bromo-butyl)-ester 10 grams (8.83mmol) is dissolved in 50 milliliters of tetrahydrofuran (THF)s, add triethylamine 2.7 grams (26.5mmol), stir and add 3.8 gram (44mmol) Piperazine anhydrous down, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness, with residue elimination solid, residue is separated with silica gel column chromatography,, collect required component with ethanol/methylene/triethylamine (1: 1: 0.01) mixed solvent wash-out, evaporated under reduced pressure gets 6.14 gram 18 α Radix Glycyrrhizae acyls-three [4-(piperazine-1-yl)-butyl]-esters.

15b, 18 α Radix Glycyrrhizae acyls-three 4-[4-(4-bromo-butyl)-piperazine]-1-base-butyl }-ester

Getting 18 α Radix Glycyrrhizae acyls-three [4-(piperazine-1-yl)-butyl]-ester 6.14 grams (5.33mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1.7 grams (16.6mmol), stir and add 4.8 gram (22mmol) 1 down, the 4-dibromobutane, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness,, residue is separated with silica gel column chromatography residue elimination solid, with ethanol/methylene/triethylamine (1: 1: 0.01) mixed solvent wash-out, collect required component, evaporated under reduced pressure, 2.84 gram 18 α Radix Glycyrrhizae acyls-three { 4-[4-(4-bromo-butyl)-piperazine]-1-base-butyl }-esters.

15c, 18 α Radix Glycyrrhizae acyls-three 4-[4-(4-nitrooxy-butyl)-piperazine]-1-base-butyl }-ester (IV ₁) preparation

Respectively 2.84 gram (1.8mmol) 18 α Radix Glycyrrhizae acyls-three { 4-[4-(4-bromo-butyl)-piperazine]-1-base-butyl }-esters are dissolved in 10 milliliters of acetonitriles, 1.22 gram (7.2mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizae acyls-three { 4-[4-(4-bromo-butyl)-piperazine]-1-base-butyl }-ester, lucifuge stirring at room 48 hours, filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography,, collect required component with ethanol/methylene/triethylamine (1: 2: 0.02) wash-out, evaporated under reduced pressure gets 1.18 gram IV ₁High resolution mass spectrum: calculated value C ₇₈H ₁₃₂N ₉O ₂₅(MH ⁺) 1594.9334, measured value 1594.9334.

Compound IV ₂Can prepare according to following synthetic route:

With 18 α trisodium glycyrrhetinates is raw material, is reacted into the tribromo substituted alkyl ester of Potenlini with the dibromo alkane substitute, reacts with piperazine again; Free NH on the piperazine molecule again with bromo alkyl acyl chloride reaction, reaction product is last reacts the nitrate derivatives IV that makes corresponding 18 α Potenlinis with Silver Nitrate ₂Same, be raw material with 18 β trisodium glycyrrhetinates, can make the nitrate derivatives of corresponding 18 β Potenlinis.

Embodiment 16 18 α Radix Glycyrrhizae acyls-three 4-[4-(4-nitrooxy-butyryl radicals)-piperazine-1-yl]-butyl }-ester (IV ₂) preparation

Method with reference to embodiment 15a prepares 18 α Radix Glycyrrhizae acyls-three [4-(piperazine-1-yl)-butyl]-ester.

16a, 18 α Radix Glycyrrhizae acyls-three 4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-ester

Getting 18 α Radix Glycyrrhizae acyls-three [4-(4-piperazine-1-yl)-butyl]-ester 6.14 grams (5.33mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s; add triethylamine 1.7 grams (16.6mmol); stir and drip 3 gram (16mmol) 4-bromobutanoylchlorides down; stirring at room reaction 10 hours; cooling is placed and is spent the night; filter; with the filtrate decompression evaporate to dryness; with residue elimination solid; residue is separated with silica gel column chromatography,, collect required component with ethanol/methylene/triethylamine (1: 1: 0.01) mixed solvent wash-out; evaporated under reduced pressure, 3.16 gram 18 α Radix Glycyrrhizae acyls-three { 4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-esters.

16b, 18 α Radix Glycyrrhizae acyls-three 4-[4-(4-nitrooxy-butyryl radicals)-piperazine-1-yl]-butyl }-ester (IV ₂) preparation

Respectively 3.16 gram (2mmol) 18 α Radix Glycyrrhizae acyls-three { 4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-esters are dissolved in 10 milliliters of acetonitriles, 1.36 gram (8mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizae acyls-three { 4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-ester; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethanol/methylene/triethylamine (1: 2: 0.02) wash-out; evaporated under reduced pressure gets 1.18 gram IV ₂High resolution mass spectrum: calculated value C ₇₈H ₁₂₆N ₉O ₂₈(MH ⁺) 1636.8712, measured value 1636.8710.

Compound IV ₃Can prepare according to following synthetic route:

Piperazine elder generation and bromo alkyl acyl chloride reaction generate the single bromo alkyl of N-acyl piperazine, are reacted into ester with 18 α trisodium glycyrrhetinates again; Free NH and dibromo alkane substitute reaction in the piperazine molecule, reaction product is last reacts the nitrate derivatives IV that makes corresponding 18 α Potenlinis with Silver Nitrate ₃Same, be raw material with 18 β trisodium glycyrrhetinates, can make the nitrate derivatives of corresponding 18 β Potenlinis.

Embodiment 17 18 α Radix Glycyrrhizae acyls-three 3-[4-(4-nitrooxy-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester (IV ₃) preparation

17a, 4-bromo butyryl radicals-piperazine

Piperazine anhydrous 17.2 grams (200mmol) are dissolved in 200 milliliters of tetrahydrofuran (THF)s; add triethylamine 10 grams (100mmol); stir and drip 18.5 gram (100mmol) 4-bromobutanoylchlorides down; stirring at room reaction 10 hours; cooling is placed and is spent the night; filter; with the filtrate decompression evaporate to dryness; with residue elimination solid; residue is separated with silica gel column chromatography,, collect required component with sherwood oil/methylene dichloride/triethylamine (1: 1: 0.05) mixed solvent wash-out; evaporated under reduced pressure gets 13.2 gram 4-bromo butyryl radicals-piperazines.

17b, 18 α Radix Glycyrrhizae acyls-three [3-(piperazine-1-base-carbonyl)-propyl diester]

Trisodium glycyrrhetinate 3.56 grams (4mmol) are suspended among 15 milliliters of DMF; drip 3.76 gram (16mmol) 4-bromo butyryl radicals-piperazines; room temperature reaction 22 hours filters, and removes Sodium Bromide; with the filtrate decompression evaporate to dryness; residue is separated with silica gel column chromatography,, collect required component with ethanol/methylene/triethylamine (1: 1: 0.02) wash-out; evaporated under reduced pressure gets 2.4 gram 18 α Radix Glycyrrhizae acyls-three [3-(piperazine-1-base-carbonyl)-propyl diester].

17c, 18 α Radix Glycyrrhizae acyls-three 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester

Getting 18 α Radix Glycyrrhizae acyls-three [3-(piperazine-1-base-carbonyl)-propyl diester], 2.4 grams (2mmol) is dissolved in 20 milliliters of tetrahydrofuran (THF)s, add triethylamine 0.8 gram (8mmol), stir and drip 1.73 gram (8mmol) 1 down, the 4-dibromobutane, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness,, residue is separated with silica gel column chromatography residue elimination solid, with ethanol/methylene/triethylamine (1: 1: 0.01) mixed solvent wash-out, collect required component, evaporated under reduced pressure, 1.05 gram 18 α Radix Glycyrrhizae acyls-three { 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-esters.

17d 18 α Radix Glycyrrhizae acyls-three 3-[4-(4-nitrooxy-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester (IV ₃) preparation

Respectively 1.05 gram (0.65mmol) 18 α Radix Glycyrrhizae acyls-three { 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-esters are dissolved in 5 milliliters of acetonitriles, 0.45 gram (2.6mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizae acyls-three { 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester, lucifuge stirring at room 48 hours, filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography,, collect required component with ethanol/methylene/triethylamine (1: 2: 0.02) wash-out, evaporated under reduced pressure gets 0.43 gram IV ₃High resolution mass spectrum: calculated value C ₇₈H ₁₂₆N ₉O ₂₈(MH ⁺) 1636.8712, measured value 1636.8710.

Compound V _1-6Can prepare according to following synthetic route:

With 18 α glycyrrhetinic acids is raw material, makes sodium salt earlier, is reacted into the bromo alkyl ester with the dibromo alkane substitute then, makes the nitrate derivatives of corresponding 18 α glycyrrhetinic acids again with the Silver Nitrate reaction; Same, be raw material with 18 β glycyrrhetinic acids, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids.

Embodiment 18 18 α Radix Glycyrrhizaes time acyl-(2-nitrooxy-ethyl)-ester (V ₁) preparation 18a, 18 α Sodium glycyrrhetinates

Get 2.3 gram (100mmol) sodium and add in 500 ml methanol in batches, be stirred to dissolving; Add 47 gram (100mmol) 18 α glycyrrhetinic acids then in batches, stirred evaporated under reduced pressure 25 minutes; In residue, add 500 milliliters of exsiccant toluene, evaporated under reduced pressure; Add 500 milliliters of exsiccant toluene again, evaporated under reduced pressure obtains 18 α Sodium glycyrrhetinates.

18b, 18 α Radix Glycyrrhizaes time acyl-(2-bromo-ethyl)-ester

Sodium glycyrrhetinate 2 grams (4mmol) are suspended among 10 milliliters of DMF, drip 1.5 gram (8mmol) glycol dibromides, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.48 grams, 18 α Radix Glycyrrhizaes time acyl-(2-bromo-ethyl)-ester.

18c, 18 α Radix Glycyrrhizaes time acyl-(2-nitrooxy-ethyl)-ester (V ₁) preparation

Respectively 1.48 gram (2.47mmol) 18 α Radix Glycyrrhizaes time acyl-(2-bromo-ethyl)-esters are dissolved in 10 milliliters of acetonitriles, 0.5 gram (3mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae time acyl-(2-bromo-ethyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 0.76 gram V ₁ ¹H?NMR(400MHz，CDCl ₃)：δ5.61(s，1H)；4.62(t，2H)；4.17(t，2H)；3.22(m，1H)；2.78(m.1H)；2.31(s，1H)；2.12(t，1H)；1.36(s，3H)；1.15(s，3H)；1.14(s，3H)；1.11(s，3H)；1.03(s，3H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₂H ₅₀NO ₇(MH ⁺) 560.3587, measured value 560.3586.

Embodiment 19 18 α Radix Glycyrrhizaes time acyl-(4-nitrooxy-butyl)-ester (V ₂) preparation 19a, 18 α Radix Glycyrrhizaes acyl-(4-bromo-butyl)-ester

Sodium glycyrrhetinate 2 grams (4mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,4-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.59 grams, 18 α Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-ester.

19b, 18 α Radix Glycyrrhizaes time acyl-(4-nitrooxy-butyl)-ester (V ₂) preparation

Respectively 1.59 gram (2.53mmol) 18 α Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-esters are dissolved in 10 milliliters of acetonitriles, 0.82 gram (4.84mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae time acyl-(4-bromo-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 0.85 gram V ₂, fusing point 62-65 ℃. ¹H?NMR(400MHz，CDCl ₃)：δ5.62(s，1H)；4.50(t，2H)；4.14(t，2H)；3.23(m，1H)；2.80(m，1H)；2.34(s，1H)；2.14(t，1H)；1.74(m，4H)；1.36(s，3H)；1.15(s，3H)；1.14(s，3H)；1.12(s，3H)；0.98(s，3H)；0.80(s，6H)。High resolution mass spectrum: calculated value C ₃₄H ₅₄NO ₇(MH ⁺) 588.3900, measured value 588.3898.

Embodiment 20 18 α Radix Glycyrrhizaes time acyl-(3-nitrooxy-3-methyl-propyl group)-ester (V ₃) preparation

20a, 18 α Radix Glycyrrhizaes time acyl-(3-bromo-3-methyl-propyl group)-ester

Sodium glycyrrhetinate 2 grams (4mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,3-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.14 grams, 18 α Radix Glycyrrhizaes time acyl-(3-bromo-3-methyl-propyl group)-ester.

20b, 18 α Radix Glycyrrhizaes time acyl-(3-nitrooxy-3-methyl-propyl group)-ester (V ₃) preparation

Respectively 1.14 gram (1.82mmol) 18 α Radix Glycyrrhizaes time acyl-(3-bromo-3-methyl-propyl group)-esters are dissolved in 10 milliliters of acetonitriles, 0.72 gram (4.24mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae time acyl-(3-bromo-3-methyl-propyl group)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.79 gram V ₃ ¹H?NMR(400MHz，CDCl ₃)：δ5.54(s，1H)；4.41(m，1H)；4.21(t，2H)；3.22(m，1H)；2.80(m，1H)；2.30(s，1H)；2.14(t，H)；1.76(m，2H)；1.71(d，3H)；1.35(s，3H)；1.15(s，3H)；1.14(s，3H)；1.11(s，3H)；1.10(s，3H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₄H ₅₄NO ₇(MH ⁺) 588.3900, measured value 588.3897.

Embodiment 21 18 α Radix Glycyrrhizaes time acyl-(4-nitrooxy-trans-2-butene base)-ester (V ₄) preparation

21a, 18 α Radix Glycyrrhizaes time acyl-(4-bromo-trans-2-butene) base-ester

Sodium glycyrrhetinate 2 grams (4mmol) are suspended among 10 milliliters of DMF, drip 1.72 gram (8mmol) 1,4-two bromo-trans-2-butenes, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.42 gram 18 α glycyrrhetinic acids-(4-bromo-trans-2-butene base)-esters.

21b, 18 α Radix Glycyrrhizaes time acyl-(4-nitrooxy-trans-2-butene base)-ester (V ₄) preparation

Respectively 1.42 gram (2.27mmol) 18 α Radix Glycyrrhizaes time acyl-(4-bromo-trans-2-butene base)-esters are dissolved in 10 milliliters of acetonitriles, 1.0 gram (5.84mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae time acyl-(4-bromo-trans-2-butene base)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.67 gram V ₄ ¹H?NMR(400MHz，CDCl ₃)：δ5.58(s，1H)；5.22(m，1H)；5.16(m，1H)；4.65(d，2H)；4.32(d，2H)；3.22(m，1H)；；2.80-2.72(m，1H)；2.30(s，1H)；2.18(t，1H)；1.32(s，3H)；1.12(s，3H)；1.06(s，3H)；1.03(s，3H)；0.96(s，3H)；0.77(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₄H ₅₂NO ₇(MH ⁺) 586.3744, measured value 586.3743.

Embodiment 22 18 α Radix Glycyrrhizaes time acyl-(4-nitrooxy-3-hydroxyl-butyl)-ester (V ₅) preparation

22a, 18 α Radix Glycyrrhizaes time acyl-(4-bromo-3-hydroxyl-butyl)-ester

Sodium glycyrrhetinate 2 grams (4mmol) are suspended among 10 milliliters of DMF, drip 1.86 gram (8mmol) 1,4-two bromo-2-butanols, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.47 grams, 18 α Radix Glycyrrhizaes time acyl-(4-bromo-3-hydroxyl-butyl)-ester.

22b, 18 α Radix Glycyrrhizaes time acyl-(4-nitrooxy-3-hydroxyl-butyl)-ester (V ₅) preparation

Respectively 1.47 gram (2.3mmol) 18 α Radix Glycyrrhizaes time acyl-(4-bromo-3-hydroxyl-butyl)-esters are dissolved in 10 milliliters of acetonitriles, 0.55 gram (3.2mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of Radix Glycyrrhizae time acyl-(4-bromo-3-hydroxyl-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.68 gram V ₅ ¹H?NMR(400MHz，CDCl ₃)：δ5.54(s，1H)；5.42(s，1H)；4.51(m，1H)；4.46(d，2H)；4.20(t，2H)；3.22(m，1H)；2.30(s，1H)；2.14(t，1H)；1.73(m，2H)；1.33(s，3H)；1.10(s，3H)；1.03(s，3H)；1.01(s，3H)；0.96(s，3H)；0.75(s，3H)；0.72(s，3H)。High resolution mass spectrum: calculated value C ₃₄H ₅₄NO ₈(MH ⁺) 604.3849, measured value 640.3846.

Embodiment 23 18 β Radix Glycyrrhizaes time acyl-(4-nitrooxy-butyl)-ester (V ₆) preparation

23a, 18 β Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-ester

Sodium glycyrrhetinate 2 grams (4mmol) are suspended among 10 milliliters of DMF, drip 1.73 gram (8mmol) 1,4-dibromobutane, room temperature reaction 22 hours, filter, remove Sodium Bromide,, residue is separated with silica gel column chromatography the filtrate decompression evaporate to dryness, with ethyl acetate/petroleum ether (1: 1) wash-out, collect required component, evaporated under reduced pressure gets 1.42 grams, 18 β Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-ester.

23b, 18 β Radix Glycyrrhizaes time acyl-(4-nitrooxy-butyl)-ester (V ₆) preparation

Respectively 1.42 gram (2.26mmol) 18 β Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-esters are dissolved in 10 milliliters of acetonitriles, 0.61 gram (3.6mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 β Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-ester, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.71 gram V ₆, ¹H NMR (400MHz, CDCl ₃): δ 5.62 (s, 1H); 4.50 (t, 2H); 4.14 (t, 2H); 3.23 (m, 1H); 2.80 (m, 1H); 2.34 (s, 1H); 2.14 (t, 1H); 1.74 (m, 4H); 1.36 (s, 3H); 1.15 (s, 3H); 1.14 (s, 3H); 1.12 (s, 3H); 0.98 (s, 3H); 0.80 (s, 6H).High resolution mass spectrum: calculated value C ₃₄H ₅₄NO ₇(MH ⁺) 588.3900, measured value 588.3902.

Compound V ₇Can prepare according to following synthetic route:

With 18 α glycyrrhetinic acids is raw material, forms mixed acid anhydride with isobutyl chlorocarbonate earlier, is reacted into the bromo alkylamide with the bromo alkylamine then, makes the nitrate derivatives V of corresponding 18 α glycyrrhetinic acids again with the Silver Nitrate reaction ₇Same, be raw material with 18 β glycyrrhetinic acids, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids.

Embodiment 24 18 α Radix Glycyrrhizaes time acyl-N-(3-nitrooxy-propyl group)-acid amides (V ₇) preparation

24a, 18 α Radix Glycyrrhizaes time acyl-N-(3-bromo-propyl group)-acid amides

1.97 gram (9mmol) 3-propantheline bromide hydrobromides are dissolved in 9 milliliters of 2N sodium hydroxide solutions, mixed solution is cooled to 5 ℃.Get 18 α glycyrrhetinic acids, 3.76 grams (8mmol) and be dissolved in 15 milliliters of tetrahydrofuran (THF)s, be cooled to-15 ℃ under cryosel is bathed, add 1.0 gram (10mmol) N-methylmorpholines, 1.4 gram (10mmol) isobutyl chlorocarbonates successively, reaction is 10 minutes under cryosel is bathed; Drip the sodium hydroxide solution of 3-propantheline bromide hydrobromide in reaction solution, ice bath stirred 1.5 hours down.Reaction is finished, and regulates the pH value to 3-4 with dilute hydrochloric acid, uses n-butanol extraction 3 times, and united extraction liquid with saturated sodium bicarbonate solution and saturated common salt washing, spends the night with anhydrous sodium sulfate drying successively.Filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 18 α Radix Glycyrrhizaes time acyl-(3-bromo-propyl group)-acid amides 1.83 grams.

24b, 18 α Radix Glycyrrhizaes time acyl-N-(3-nitrooxy-propyl group)-acid amides (V ₇) preparation

Respectively 1.83 gram (3.1mmol) 18 α Radix Glycyrrhizaes time acyl-(3-bromo-propyl group)-acid amides are dissolved in 10 milliliters of acetonitriles, 0.9 gram (5.28mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizaes time acyl-(3-bromo-propyl group)-acid amides, lucifuge stirring at room 48 hours is filtered, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 2) wash-out, collect required component, evaporated under reduced pressure gets 0.78 gram V ₇ ¹H?NMR(400MHz，CDCl ₃)： ¹H?NMR(400MHz，CDCl ₃)：δ6.01(m，1H)；5.54(s，1H)；4.38(t，2H)；3.35(m，2H)；3.22(m，1H)；2.62(m，2H)；2.30(s，1H)；2.14(t，4H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₃H ₅₃N ₂O ₆(MH ⁺) 573.3904, measured value 573.3903.

Compound VI _1-4Can prepare according to following synthetic route:

With the amino acid nitration of hydroxyl, make nitrate derivatives earlier; 18 α glycyrrhetinic acids and isobutyl chlorocarbonate form mixed acid anhydride, and the reaction of the amino acid derivative of nitration promptly gets the nitrate derivatives of 18 α glycyrrhetinic acids then; Same, be raw material with 18 β glycyrrhetinic acids, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids.

Embodiment 25 N ^α-18 α Radix Glycyrrhizaes time acyl (O-nitro-L-Serine) (VI ₁) preparation

With reference to the method for embodiment 11a, preparation O-nitro-L-Serine nitrate.

25a, N ^α-18 α Radix Glycyrrhizaes time acyl (O-nitro-L-Serine) (VI ₁) preparation

1.92 gram (9mmol) O-nitro-L-Serine nitrate are dissolved in 9 milliliters of 2N sodium hydroxide solutions, mixed solution is cooled to 5 ℃.Get 18 α glycyrrhetinic acids, 3.76 grams (8mmol) and be dissolved in 15 milliliters of tetrahydrofuran (THF)s, under cryosel is bathed, be cooled to-15 ℃, add 1.0 gram (10mmol) N-methylmorpholines, 1.4 gram (10mmol) isobutyl chlorocarbonates successively,, reaction is 10 minutes under cryosel is bathed; Drip the sodium hydroxide solution of O-nitro-L-Serine nitrate in reaction solution, ice bath stirred 1.5 hours down.Reaction is finished, and regulates the pH value to 3-4 with dilute hydrochloric acid, uses n-butanol extraction 3 times, and united extraction liquid with saturated sodium bicarbonate solution and saturated common salt washing, spends the night with anhydrous sodium sulfate drying successively.Filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography, with ethyl acetate/petroleum ether (1: 2) wash-out, collect required component, evaporated under reduced pressure gets VI ₁1.88 gram. ¹H?NMR(400MHz，CDCl ₃)：δ10.8(s，1H)；6.63(d，1H)；5.54(s，1H)；4.41(d，2H)；3.22(m，1H)；2.8(m，1H)；2.30(s，1H)；2.14(t，1H)；1.68(m，6H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.06(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₃H ₅₁N ₂O ₈(MH ⁺) 603.3645, measured value 603.3644.

Embodiment 26 N ^α-18 α Radix Glycyrrhizaes time acyl (O-nitro-D-Serine) (VI ₂) preparation

With reference to the method for embodiment 25, replace the L-Serine with the D-Serine, make VI ₂0.98 gram. ¹H?NMR(400MHz，CDCl ₃)：δ10.8(s，1H)；6.63(d，1H)；5.54(s，1H)；4.41(d，2H)；3.22(m，1H)；2.8(m，1H)；2.30(s，1H)；2.14(t，1H)；1.68(m，6H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.06(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₃H ₅₁N ₂O ₈(MH ⁺) 603.3645, measured value 603.3643.

Embodiment 27 N ^α-18 α Radix Glycyrrhizaes time acyl (O-nitro-L-Threonine) (VI ₃) preparation

With reference to the method for embodiment 28, replace the L-Serine with the L-Threonine, make VI ₃1.42 gram. ¹H?NMR(400MHz，CDCl ₃)：δ11.2(s，1H)；6.59(s，1H)；5.54(s，1H)；4.48(m，1H)；3.34(m，1H)；3.22(m，1H)；2.8(m，1H)；2.30(s，1H)；2.14(t，1H)；1.68(m，6H)；1.37(d，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.06(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₄H ₅₃N ₂O ₈(MH ⁺) 617.3802, measured value 617.3801.

Embodiment 28 N ^α-18 α Radix Glycyrrhizaes time acyl (O-nitro-L-oxyproline) (VI ₄) preparation

With reference to the method for embodiment 11a, 11b, replace the L-Serine with the L-oxyproline, make VI ₄1.28 gram. ¹H?NMR(400MHz，D ₆-DMSO)：δ11.4(s，1H)；5.54(s，1H)；4.48(m，1H)；4.15(t，1H)；3.22(m，1H)；2.8(d，2H)；2.30(s，1H)；2.14(m，4H)；1.68(m，6H)；1.62(s，3H)；1.42(m，2H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₆H ₅₃N ₂O ₈(MH ⁺) 641.3802, measured value 641.3800.

Compound VI I _1-2Can prepare according to following synthetic route:

Earlier 18 α glycyrrhetinic acids are made sodium salt, be reacted into the bromo alkyl ester of glycyrrhetinic acid, react with piperazine again with the dibromo alkane substitute; Free NH on the piperazine molecule again with dibromo alkane substitute reaction, reaction product is last reacts the nitrate derivatives VII that makes corresponding 18 α glycyrrhetinic acids with Silver Nitrate ₁Same, be raw material with 18 β glycyrrhetinic acids, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids.

Embodiment 29 18 α Radix Glycyrrhizaes time acyl-2-[4-(2-nitrooxy-ethyl)-piperazine]-1-base-ethyl }-ester (VII ₁) preparation

Method with reference to embodiment 18a prepares 18 α Radix Glycyrrhizaes time acyl-(2-bromo-ethyl)-ester.

29a, 18 α Radix Glycyrrhizaes time acyl-[2-(piperazine-1-yl)-ethyl]-ester

Getting 18 α Radix Glycyrrhizaes time acyl-(2-bromo-ethyl)-ester 10 grams (16.7mmol) is dissolved in 50 milliliters of tetrahydrofuran (THF)s, add triethylamine 1.70 grams (16.7mmol), stir and add 2.76 gram (32mmol) Piperazine anhydrous down, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness, residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out, evaporated under reduced pressure gets 6.35 grams, 18 α Radix Glycyrrhizaes time acyl-[2-(piperazine-1-yl)-ethyl]-ester.

29b, 18 α Radix Glycyrrhizaes acyl-2-[4-(2-bromo-ethyl)-piperazine]-1-base-ethyl }-ester

Getting 18 α Radix Glycyrrhizaes time acyl-[2-(piperazine-1-yl)-ethyl]-ester 6.35 grams (10.5mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1.08 grams (10.6mmol), stir and add 4.8 gram (22mmol) 1 down, the 4-dibromobutane, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness,, residue is separated with silica gel column chromatography, with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out, collect required component, evaporated under reduced pressure, 3.04 grams, 18 α Radix Glycyrrhizaes time acyl-{ 2-[4-(2-bromo-ethyl)-piperazine]-1-base-ethyl }-ester.

29c, 18 α Radix Glycyrrhizaes acyl-2-[4-(2-nitrooxy-ethyl)-piperazine]-1-base-ethyl }-ester (VII ₁) preparation

Respectively 3.04 gram (4.28mmol) 18 α Radix Glycyrrhizaes time acyls-{ 2-[4-(2-bromo-ethyl)-piperazine]-1-base-ethyl }-ester is dissolved in 15 milliliters of acetonitriles, 1.22 gram (7.2mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizaes time acyl-{ 2-[4-(2-bromo-ethyl)-piperazine]-1-base-ethyl }-ester, lucifuge stirring at room 48 hours, filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 2: 0.02) wash-out, evaporated under reduced pressure gets 1.58 gram VII ₁ ¹H?NMR(400MHz，CDCl ₃)：δ5.54(s，1H)；4.56(t，2H)；4.13(t，2H)；3.22(m，1H)；2.49(m，4H)；2.36(m，4H)；2.30(s，1H)；2.14(m，4H)；1.75(m，8H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₄₀H ₆₆N ₃O ₇(MH ⁺) 700.4901, measured value 700.44998.

Embodiment 30 18 α Radix Glycyrrhizaes time acyl-4-[1-(4-nitrooxy-butyl)-piperazine]-4-base-butyl }-ester (VII ₂) preparation

Method with reference to embodiment 19a prepares 18 α Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-ester.

30a, 18 α Radix Glycyrrhizaes time acyl-[4-(piperazine-1-yl)-butyl]-ester

Getting 18 α Radix Glycyrrhizaes time acyl-(4-bromo-butyl)-ester 10 grams (16mmol) is dissolved in 50 milliliters of tetrahydrofuran (THF)s, add triethylamine 1.63 grams (16mmol), stir and add 2.76 gram (32mmol) Piperazine anhydrous down, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness, residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out, evaporated under reduced pressure gets 6.72 grams, 18 α Radix Glycyrrhizaes time acyl-[4-(piperazine-1-yl)-butyl]-ester.

30b, 18 α Radix Glycyrrhizaes acyl-4-[1-(4-bromo-butyl)-piperazine]-4-base-butyl }-ester

Getting 18 α Radix Glycyrrhizaes time acyl-[4-(piperazine-1-yl)-butyl]-ester 6.72 grams (10.6mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1.08 grams (10.6mmol), stir and add 4.8 gram (22mmol) 1 down, the 4-dibromobutane, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness,, residue is separated with silica gel column chromatography, with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out, collect required component, evaporated under reduced pressure, 3.29 grams, 18 α Radix Glycyrrhizaes time acyl-{ 4-[1-(4-bromo-butyl)-piperazine]-4-base-butyl }-ester.

30c, 18 α Radix Glycyrrhizaes acyl-4-[1-(4-nitrooxy-butyl)-piperazine]-4-base-butyl }-ester (VII ₂) preparation

Respectively 3.29 gram (4.29mmol) 18 α Radix Glycyrrhizaes time acyls-{ 4-[1-(4-bromo-butyl)-piperazine]-4-base-butyl }-ester is dissolved in 15 milliliters of acetonitriles, 1.22 gram (7.2mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizaes time acyl-{ 1-[4-(4-bromo-butyl)-piperazine]-4-base-butyl }-ester, lucifuge stirring at room 48 hours, filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 2: 0.02) wash-out, evaporated under reduced pressure gets 1.74 gram VII ₂ ¹H?NMR(400MHz，CDCl ₃)：δ5.54(s，1H)；4.46(t，2H)；4.06(t，2H)；3.22(m，1H)；2.48(m，4H)；2.42-2.35(m，6H)；2.34(t，2H)；2.30(s，1H)；2.14(m，4H)；1.75(m，8H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₄₂H ₇₀N ₃O ₇(MH ⁺) 728.5214, measured value 728.5212.

Compound VI I ₃Can prepare according to following synthetic route:

18 α glycyrrhetinic acids are made sodium salt earlier, be reacted into the bromo alkyl ester of glycyrrhetinic acid, react with piperazine again with the dibromo alkane substitute; Free NH on the piperazine molecule again with bromo alkyl acyl chloride reaction, reaction product is last reacts the nitrate derivatives VII that makes corresponding 18 α glycyrrhetinic acids with Silver Nitrate ₃Same, be raw material with 18 β glycyrrhetinic acids, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids.

Embodiment 31 18 α Radix Glycyrrhizaes time acyl-4-[4-(4-nitrooxy-butyryl radicals)-piperazine-1-yl]-butyl }-ester (VII ₃) preparation

Method with reference to embodiment 33a prepares 18 α Radix Glycyrrhizaes time acyl-[4-(piperazine-1-yl)-butyl]-ester.

31a, 18 α Radix Glycyrrhizaes acyl-4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-ester

Getting 18 α Radix Glycyrrhizaes time acyl-[4-(piperazine-1-yl)-butyl]-ester 6 grams (9.5mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1 gram (9.5mmol), stir and drip 1.78 gram (9.5mmol) 4-bromobutanoylchlorides down, stirring at room reaction 10 hours, cooling is placed and is spent the night, filter, with the filtrate decompression evaporate to dryness.With the residue acetic acid ethyl dissolution; water and saturated common salt washing in succession; use anhydrous sodium sulfate drying; evaporated under reduced pressure; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out; evaporated under reduced pressure, 3.47 grams, 18 α Radix Glycyrrhizaes time acyl-{ 4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-ester.

31b, 18 α Radix Glycyrrhizaes acyl-4-[4-(4-nitrooxy-butyryl radicals)-piperazine-1-yl]-butyl }-ester (VII ₃) preparation

Respectively 3.47 gram (4.44mmol) 18 α Radix Glycyrrhizaes time acyls-{ 4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-ester is dissolved in 10 milliliters of acetonitriles, 1.36 gram (8mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizaes time acyl-{ 4-[4-(4-bromo-butyryl radicals)-piperazine-1-yl]-butyl }-ester; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 2: 0.02) wash-out; evaporated under reduced pressure gets 1.36 gram VII ₃ ¹H?NMR(400MHz，CDCl ₃)：δ5.54(s，1H)；3.41(t，4H)；3.36(t，4H)；3.22(m，1H)；2.64(t，2H)；2.44(m，4H)；2.35(m，4H)；2.30(s，1H)；2.14(m，4H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.33(m，2H)；1.30(m，4H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。

High resolution mass spectrum: calculated value C ₄₂H ₆₈N ₃O ₈(MH ⁺) 742.5006, measured value 742.5003.

Compound VI I ₄Can prepare according to following synthetic route:

Piperazine elder generation and bromo alkyl acyl chloride reaction generate the single bromo alkyl of N-acyl piperazine, are reacted into ester with 18 α Sodium glycyrrhetinates again; Free NH and dibromo alkane substitute reaction in the piperazine molecule, reaction product is last reacts the nitrate derivatives VII that makes corresponding 18 α glycyrrhetinic acids with Silver Nitrate ₄Same, be raw material with 18 β Sodium glycyrrhetinates, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids.

Embodiment 32 18 α Radix Glycyrrhizaes time acyl-and 3-[4-(4-nitrooxy-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester (VII ₄) preparation

Method with reference to embodiment 17a prepares 4-bromo butyryl radicals-piperazine.

32a, 18 α Radix Glycyrrhizaes time acyl-three [3-(piperazine-1-base-carbonyl)-propyl diester]

Sodium glycyrrhetinate 3.94 grams (8mmol) are suspended among 15 milliliters of DMF; drip 2.82 gram (12mmol) 4-bromo butyryl radicals-piperazines; room temperature reaction 22 hours filters, and removes Sodium Bromide; with the filtrate decompression evaporate to dryness; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.02) wash-out; evaporated under reduced pressure gets 2.65 grams, 18 α Radix Glycyrrhizaes time acyl-[3-(piperazine-1-base-carbonyl)-propyl diester].

32b, 18 α Radix Glycyrrhizaes acyl-and 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester

Getting 18 α Radix Glycyrrhizaes time acyl-[3-(piperazine-1-base-carbonyl)-propyl diester], 2.65 grams (4.10mmol) is dissolved in 15 milliliters of tetrahydrofuran (THF)s, add triethylamine 0.41 gram (4.10mmol), stir and drip 1.73 gram (8mmol) 1 down, the 4-dibromobutane, heating reflux reaction 10 hours, being cooled to the room temperature placement spends the night, filter, with the filtrate decompression evaporate to dryness, residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out, evaporated under reduced pressure, 1.35 grams, 18 α Radix Glycyrrhizaes time acyl-{ 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester.

32c 18 α Radix Glycyrrhizaes time acyl-and 3-[4-(4-nitrooxy-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester (VII ₄) preparation

Respectively 1.35 gram (1.73mmol) 18 α Radix Glycyrrhizaes time acyls-{ 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester is dissolved in 5 milliliters of acetonitriles, 0.45 gram (2.6mmol) AgNO ₃Be dissolved in 2 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 18 α Radix Glycyrrhizaes time acyl-{ 3-[4-(4-bromo-butyl)-piperazine-1-yl] carbonyl-propyl group }-ester, lucifuge stirring at room 48 hours, filter, with the filtrate decompression evaporate to dryness, separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 2: 0.02) wash-out, evaporated under reduced pressure gets 0.31 gram VII ₄ ¹H?NMR(400MHz，CDCl ₃)：δ5.53(s，1H)；3.20(m，1H)；2.65(t，2H)；3.44(m，4H)；3.32(m，4H)；2.30(s，1H)；2.12(m，4H)；1.70(m，6H)；1.61(s，3H)；1.35(s，3H)；1.34(m，2H)；1.30(m，4H)；1.12(s，3H)；1.09(s，3H)；1.07(s，3H)；1.02(m，2H)；0.78(s，3H)；0.71(s，3H)。High resolution mass spectrum: calculated value C ₄₂H ₆₈N ₃O ₈(MH ⁺) 742.5006, measured value 742.5004.

Compound VIII _1-5Can prepare according to following synthetic route:

18 α glycyrrhetinic acids or glycyrrhetinic acid ester and bromo alkyl acyl chloride or bromo aralkyl acyl chloride reaction, reaction product make the nitrate derivatives VIII of corresponding 18 α glycyrrhetinic acids or glycyrrhetinic acid ester again with the Silver Nitrate reaction _1-5Same, be raw material with 18 β glycyrrhetinic acids or glycyrrhetinic acid ester, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids or glycyrrhetinic acid ester.

Embodiment 33 3 β-(2-nitrooxy-ethanoyl)-Oxy-1 8 α glycyrrhetinic acid (VIII ₁) preparation

33a, 3 β-(2-bromo-ethanoyl)-Oxy-1 8 α glycyrrhetinic acids

Getting 18 α glycyrrhetinic acids 3.76 grams (8mmol) is dissolved in 15 milliliters of tetrahydrofuran (THF)s in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1 gram (9.5mmol), stir and drip 1.49 gram (9.5mmol) 2-bromoacetyl chlorides down, stirring at room reaction 10 hours, cooling is placed and is spent the night, filter, with the filtrate decompression evaporate to dryness.With the residue acetic acid ethyl dissolution; water and saturated common salt washing in succession; use anhydrous sodium sulfate drying; evaporated under reduced pressure; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 1) mixed solvent wash-out; evaporated under reduced pressure gets 3.18 gram 3 β-(2-bromo-ethanoyl)-Oxy-1 8 α glycyrrhetinic acids.

33b, 3 β-(2-nitrooxy-ethanoyl)-Oxy-1 8 α glycyrrhetinic acid (VIII ₁) preparation

Get 3.18 gram (5.38mmol) 3 β-(2-bromo-ethanoyl)-Oxy-1 8 α glycyrrhetinic acids and be dissolved in 10 milliliters of acetonitriles, 1.8 gram (10.4mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-(2-bromo-ethanoyl)-Oxy-1 8 α glycyrrhetinic acids; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 2) wash-out; evaporated under reduced pressure gets 1.39 gram VIII ₁ ¹H?NMR(400MHz，CDCl ₃)：δ12.22(s?1H)；5.54(s，1H)；5.34(s，2H)；3.22(m，1H)；2.30(s，1H)；2.14(m，4H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₂H ₄₈NO ₈(MH ⁺) 574.3380, measured value 574.3382.

Embodiment 34 3 β-(4-nitrooxy-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid (VIII ₂) preparation

34a, 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acids

Getting 18 α glycyrrhetinic acids 3.76 grams (8mmol) is dissolved in 15 milliliters of tetrahydrofuran (THF)s in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1 gram (9.5mmol), stir and drip 1.78 gram (9.5mmol) 4-bromobutanoylchlorides down, stirring at room reaction 10 hours, cooling is placed and is spent the night, filter, with the filtrate decompression evaporate to dryness.With the residue acetic acid ethyl dissolution; water and saturated common salt washing in succession; use anhydrous sodium sulfate drying; evaporated under reduced pressure; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 1) mixed solvent wash-out; evaporated under reduced pressure gets 2.96 gram 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acids.

34b, 3 β-(4-nitrooxy-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid (VIII ₂) preparation

Get 2.96 gram (4.78mmol) 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acids and be dissolved in 10 milliliters of acetonitriles, 1.8 gram (10.4mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acids; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 2) wash-out; evaporated under reduced pressure gets 1.39 gram VIII ₂ ¹H?NMR(400MHz，CDCl ₃)：δ12.21(s，1H)；5.41(s，1H，)；4.54(t，2H)；4.46(m，1H)；2.80-2.60(m，1H)；2.46-2.43(t，2H)；2.33-2.27(s，1H)；2.18(t，1H)；2.05-1.92(m，4H)；1.32(s，3H)；1.10(s，3H)；1.06(s，3H)；1.05(s，3H)；0.94(s，3H)；0.75(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₄H ₅₂NO ₈(MH ⁺) 602.3693, measured value 602.3690.

Embodiment 35 3 β-(4-nitrooxy-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid methyl esters (VIII ₃) preparation

35a, 18 α glycyrrhetinic acid methyl esters

Sodium glycyrrhetinate 4 grams (8mmol) are suspended among 20 milliliters of DMF, drip 1.42 gram (10mmol) methyl iodide, room temperature reaction 12 hours filters, and removes sodium iodide, with the filtrate decompression evaporate to dryness, residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 1) wash-out, evaporated under reduced pressure gets 2.94 grams, 18 α glycyrrhetinic acid methyl esters.

35b, 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid methyl esters

2.94 gram (6mmol) 18 α glycyrrhetinic acid methyl esters are dissolved in 15 milliliters of tetrahydrofuran (THF)s in 20 milliliters of tetrahydrofuran (THF)s, add triethylamine 0.8 gram (8mmol), stir and drip 1.5 gram (8mmol) 4-bromobutanoylchlorides down, stirring at room reaction 10 hours, cooling is placed and is spent the night, filter, with the filtrate decompression evaporate to dryness.With the residue acetic acid ethyl dissolution; water and saturated common salt washing in succession; use anhydrous sodium sulfate drying; evaporated under reduced pressure; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 1) mixed solvent wash-out; evaporated under reduced pressure gets 1.54 gram 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid methyl esters.

35c, 3 β-(4-nitrooxy-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid methyl esters (VIII ₃) preparation

Get 1.54 gram (2.43mmol) 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid methyl esters and be dissolved in 10 milliliters of acetonitriles, 0.9 gram (5.2mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acid methyl esters; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 2) wash-out; evaporated under reduced pressure gets 0.68 gram VIII ₃, fusing point: 223-228 ℃. ¹H?NMR(400MHz，CDCl ₃)：δ5.54(s，1H)；4.46(t，2H)；3.69(s，3H)；3.22(m，1H)；2.49(t，2H)；2.30(s，1H)；2.14(m，4H)；1.75(m，4H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₄H ₅₁NO ₈(MH ⁺) 601.3615, measured value 601.3615.

Embodiment 36 3 β-(4-nitrooxy methyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acid (VIII ₄) preparation

36a, 3 β-(4-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids

Getting 18 α glycyrrhetinic acids 3.76 grams (8mmol) is dissolved in 15 milliliters of tetrahydrofuran (THF)s in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1 gram (9.5mmol), stir and drip 1.8 gram (9.5mmol) 4-chloromethyl-Benzoyl chlorides down, stirring at room reaction 10 hours, cooling is placed and is spent the night, filter, with the filtrate decompression evaporate to dryness.With the residue acetic acid ethyl dissolution; water and saturated common salt washing in succession; use anhydrous sodium sulfate drying; evaporated under reduced pressure; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 1) mixed solvent wash-out; evaporated under reduced pressure gets 2.52 gram 3 β-(4-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids.

36b, 3 β-(4-nitrooxy methyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acid (VIII ₄) preparation

Get 2.52 gram (3.78mmol) 3 β-(4-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids and be dissolved in 10 milliliters of acetonitriles, 0.9 gram (5.2mmol) AgNO ₃Be dissolved in 3 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-(4-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids; 50 ℃ of lucifuges stirred 24 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 2) wash-out; evaporated under reduced pressure gets 1.47 gram VIII ₄

¹H?NMR(400MHz，CDCl ₃)：δ12.21(s?1H)；8.04(d，2H)；7.63(d，2H)；5.68(s，2H)；5.54(s，1H)；3.22(m，1H)；2.30(s，1H)；2.14(m，4H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。High resolution mass spectrum: calculated value C ₃₈H ₅₁NO ₈(MH ⁺) 649.3615, measured value 649.3613.

Embodiment 37 3 β-(3-nitrooxy methyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acid (VIII ₅) preparation

37a, 3 β-(3-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids

Getting 18 α glycyrrhetinic acids 3.76 grams (8mmol) is dissolved in 15 milliliters of tetrahydrofuran (THF)s in 30 milliliters of tetrahydrofuran (THF)s, add triethylamine 1 gram (9.5mmol), stir and drip 1.8 gram (9.5mmol) 3-chloromethyl-Benzoyl chlorides down, stirring at room reaction 10 hours, cooling is placed and is spent the night, filter, with the filtrate decompression evaporate to dryness.With the residue acetic acid ethyl dissolution; water and saturated common salt washing in succession; use anhydrous sodium sulfate drying; evaporated under reduced pressure; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 1) mixed solvent wash-out; evaporated under reduced pressure gets 2.66 gram 3 β-(4-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids.

37b, 3 β-(3-nitrooxy methyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acid (VIII ₅) preparation

Get 2.52 gram (3.78mmol) 3 β-(4-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids and be dissolved in 10 milliliters of acetonitriles, 0.9 gram (5.2mmol) AgNO ₃Be dissolved in 3 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-(4-brooethyl-benzoyl)-Oxy-1 8 α glycyrrhetinic acids; 50 ℃ of lucifuges stirred 24 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether (1: 2) wash-out; evaporated under reduced pressure gets 1.05 gram VIII ₄

¹H?NMR(400MHz，CDCl ₃)：δ12.21(s?1H)；8.10(s，1H)；8.05(d，1H)；7.76(d，1H)；7.65(t，1H)；5.67(s，2H)；5.54(s，1H)；3.22(m，1H)；2.30(s，1H)；2.14(m，4H)；1.68(m，6H)；1.62(s，3H)；1.35(s，3H)；1.32(m，8H)；1.15(s，3H)；1.11(s，3H)；1.10(s，3H)；1.02(m，2H)；0.79(s，3H)；0.73(s，3H)。

High resolution mass spectrum: calculated value C ₃₈H ₅₁NO ₈(MH ⁺) 649.3615, measured value 649.3612.

Compound I X _1-3Can prepare according to following synthetic route:

18 α glycyrrhetinic acids or glycyrrhetinic acid ester and bromo alkyl acyl chloride, reaction product react with piperazine again; Free NH on the piperazine molecule and two bromo alkane reactions, reaction product is last reacts the nitrate derivatives that makes corresponding 18 α glycyrrhetinic acids or glycyrrhetinic acid ester with Silver Nitrate; Same, be raw material with 18 β glycyrrhetinic acids or glycyrrhetinic acid ester, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids or glycyrrhetinic acid ester.

Embodiment 38 3 β-2-[1-(2-nitrooxy-ethyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acid (IX ₁) preparation

Method according to embodiment 33a prepares 3 β-(2-bromo-ethanoyl)-Oxy-1 8 α glycyrrhetinic acids.

38a 3 β-[2-(piperazine-1-yl)-ethanoyl]-Oxy-1 8 α glycyrrhetinic acids

Getting 3 β-(2-bromo-ethanoyl)-Oxy-1 8 α glycyrrhetinic acids 10 grams (16.9mmol) is dissolved in 50 milliliters of tetrahydrofuran (THF)s; add triethylamine 1.70 grams (16.9mmol); stir and add 2.76 gram (32mmol) Piperazine anhydrous down; heating reflux reaction 10 hours; being cooled to the room temperature placement spends the night; filter; with the filtrate decompression evaporate to dryness; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out; evaporated under reduced pressure gets 6.20 gram 3 β-[2-(piperazine-1-yl)-ethanoyl]-Oxy-1 8 α glycyrrhetinic acids.

38b, 3 β-2-[1-(2-bromo-ethyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids

Getting 3 β-[2-(piperazine-1-yl)-ethanoyl]-Oxy-1 8 α glycyrrhetinic acids 6.20 grams (10.4mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s; add triethylamine 1.08 grams (10.6mmol); stir and add 4.1 gram (22mmol) 1 down; the 2-ethylene dibromide; heating reflux reaction 10 hours; being cooled to the room temperature placement spends the night; filter; with the filtrate decompression evaporate to dryness,, residue is separated with silica gel column chromatography; with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out; collect required component, evaporated under reduced pressure, 3.70 gram 3 β-{ 2-[1-(2-bromo-ethyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids.

38c, 3 β-2-[1-(2-nitrooxy-ethyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acid (IX ₁) preparation

Respectively 3.70 gram (5.26mmol) 3 β-{ 2-[1-(2-bromo-ethyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids are dissolved in 15 milliliters of acetonitriles, 1.22 gram (7.2mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-{ 2-[1-(2-bromo-ethyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 2: 0.02) wash-out; evaporated under reduced pressure gets 1.56 gram IX ₁High resolution mass spectrum: calculated value C ₃₈H ₅₉N ₃O ₈(M ⁺) 685.4302, measured value 685.4300.

Embodiment 39 3 β-2-[1-(4-nitrooxy-butyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acid (IX ₂) preparation

Method according to embodiment 38a prepares 3 β-[2-(piperazine-1-yl)-ethanoyl]-Oxy-1 8 α glycyrrhetinic acids.

39 α, 3 β-2-[1-(4-bromo-butyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids

Getting 3 β-[2-(piperazine-1-yl)-ethanoyl]-Oxy-1 8 α glycyrrhetinic acids 6.20 grams (10.4mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s; add triethylamine 1.08 grams (10.6mmol); stir and add 4.75 gram (22mmol) 1 down; the 4-dibromobutane; heating reflux reaction 10 hours; being cooled to the room temperature placement spends the night; filter; with the filtrate decompression evaporate to dryness,, residue is separated with silica gel column chromatography; with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out; collect required component, evaporated under reduced pressure, 4.12 gram 3 β-{ 2-[1-(4-bromo-butyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids.

39c, 3 β-2-[1-(4-nitrooxy-butyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acid (IX ₂) preparation

Respectively 4.12 gram (5.64mmol) 3 β-{ 2-[1-(4-bromo-butyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids are dissolved in 15 milliliters of acetonitriles, 1.22 gram (7.2mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-{ 2-[1-(4-bromo-butyl)-piperazine]-4-base-ethanoyl }-Oxy-1 8 α glycyrrhetinic acids; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 2: 0.02) wash-out; evaporated under reduced pressure gets 1.27 gram IX ₂High resolution mass spectrum: calculated value C ₄₀H ₆₄N ₃O ₈(MH ⁺) 714.4693, measured value 714.4690.

Embodiment 40 3 β-4-[1-(4-nitrooxy-butyl)-piperazine]-4-base-butyryl radicals }-Oxy-1 8 α glycyrrhetinic acid (IX ₃) preparation

Method according to embodiment 34a prepares 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acids.

40a, 3 β-[4-(piperazine-1-yl)-butyryl radicals]-Oxy-1 8 α glycyrrhetinic acids

Getting 3 β-(4-bromo-butyryl radicals)-Oxy-1 8 α glycyrrhetinic acids 10 grams (16.2mmol) is dissolved in 50 milliliters of tetrahydrofuran (THF)s; add triethylamine 1.70 grams (16.9mmol); stir and add 2.76 gram (32mmol) Piperazine anhydrous down; heating reflux reaction 10 hours; being cooled to the room temperature placement spends the night; filter; with the filtrate decompression evaporate to dryness; residue is separated with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out; evaporated under reduced pressure gets 5.13 gram 3 β-[4-(piperazine-1-yl)-butyryl radicals]-Oxy-1 8 α glycyrrhetinic acids.

40b, 3 β-4-[1-(4-bromo-butyl)-piperazine]-4-base-butyryl radicals }-Oxy-1 8 α glycyrrhetinic acids

Getting 3 β-[4-(piperazine-1-yl)-butyryl radicals]-Oxy-1 8 α glycyrrhetinic acids 5.13 grams (8.2mmol) is dissolved in 30 milliliters of tetrahydrofuran (THF)s; add triethylamine 1.08 grams (10.6mmol); stir and add 4.75 gram (22mmol) 1 down; the 4-dibromobutane; heating reflux reaction 10 hours; being cooled to the room temperature placement spends the night; filter; with the filtrate decompression evaporate to dryness,, residue is separated with silica gel column chromatography; with ethyl acetate/petroleum ether/triethylamine (1: 1: 0.01) mixed solvent wash-out; collect required component, evaporated under reduced pressure, 3.08 gram 3 β-{ 4-[1-(4-bromo-butyl)-piperazine]-4-base-butyryl radicals }-Oxy-1 8 α glycyrrhetinic acids.

40c, 3 β-4-[1-(4-nitrooxy-butyl)-piperazine]-4-base-butyryl radicals }-Oxy-1 8 α glycyrrhetinic acid (IX ₃) preparation

Respectively 3.08 gram (4.21mmol) 3 β-{ 4-[1-(4-bromo-butyl)-piperazine]-4-base-butyryl radicals }-Oxy-1 8 α glycyrrhetinic acids are dissolved in 15 milliliters of acetonitriles, 1.22 gram (7.2mmol) AgNO ₃Be dissolved in 5 milliliters of acetonitriles.With AgNO ₃Acetonitrile solution be added drop-wise in the solution of 3 β-{ 4-[1-(4-bromo-butyl)-piperazine]-4-base-butyryl radicals }-Oxy-1 8 α glycyrrhetinic acids; lucifuge stirring at room 48 hours; filter; with the filtrate decompression evaporate to dryness; separate with silica gel column chromatography,, collect required component with ethyl acetate/petroleum ether/triethylamine (1: 2: 0.02) wash-out; evaporated under reduced pressure gets 0.83 gram IX ₃High resolution mass spectrum: calculated value C ₄₂H ₆₈N ₃O ₈(MH ⁺) 742.5006, measured value 742.5003.

Compounds X _1-2Can prepare according to following synthetic route:

18 α glycyrrhetinic acids or glycyrrhetinic acid ester and nitrosonitric acid react, and make the nitrate derivatives of corresponding 18 α glycyrrhetinic acids or glycyrrhetinic acid ester; Same, be raw material with 18 β glycyrrhetinic acids or glycyrrhetinic acid ester, can make the nitrate derivatives of corresponding 18 β glycyrrhetinic acids.

Embodiment 41 3 β-nitrooxy-18 α glycyrrhetinic acid (X ₁) preparation

In there-necked flask, add 25 milliliters of nitrosonitric acids, bathe with cryosel and be cooled to-5 to-10 ℃; 4.7 gram (10mmol) 18 α glycyrrhetinic acids are joined in the reaction solution in batches, and the control reacting liquid temperature is lower than 0 ℃.After adding, stir reaction down 30 minutes.Reaction is finished, and reaction solution is splashed in 100 milliliters of ether, separates out precipitation, the leaching precipitation, and the ether thorough washing gets X after the drying ₁2.3 gram, fusing point: 212-220 ℃ decomposition. ¹H?NMR(400MHz，CDCl ₃)：δ12.22(s，1H)；5.42(s，1H)；4.78(m，1H)；2.71(m，1H)；2.43(s，1H)；2.12(t，2H)；1.34(s，3H)；1.10(s，3H)；1.07(s，3H)；1.05(s，3H)；0.98(s，3H)；0.83(s，3H)；0.76(s，3H)。

Embodiment 42 3 β-nitrooxy-18 α glycyrrhetinic acid methyl esters (X ₂) preparation

Method according to embodiment 35a prepares 18 α glycyrrhetinic acid methyl esters.

In there-necked flask, add 25 milliliters of nitrosonitric acids, bathe with cryosel and be cooled to-5 to-10 ℃; 4.84 gram (10mmol) 18 α glycyrrhetinic acids are joined in the reaction solution in batches, and the control reacting liquid temperature is lower than 0 ℃.After adding, stir reaction down 30 minutes.Reaction is finished, and reaction solution is splashed in 100 milliliters of ether, separates out precipitation, the leaching precipitation, and the ether thorough washing gets X after the drying ₂1.6 gram. ¹H?NMR(400MH2，CDCl ₃)：5.46(s，1H)；4.76(m，1H)；3.68(s，3H)；2.72(m，1H)；2.40(s，1H)；2.12(t，2H)；1.35(s，3H)；1.08(s，3H)；1.06(s，3H)；1.05(s，3H；0.99(s，3H)；0.81(s，3H)；0.75(s，3H)。

Embodiment 43 anti-CCl ₄The pharmacodynamics evaluation of poisoning induced mice liver injury

Get the Baclb/c mouse of the about 20-25g of quality, random packet, every group of 5 mouse.Testing compound by the orally give various dose; Behind the 1h, according to the dosage of 10mL/kg, the CCl of subcutaneous injection 100mL/L% ₄, the preparation liver injury model; Subcutaneous injection physiological saline is as the normal control group.After the modeling after 12 hours, the testing compound of orally give various dose once more.After the administration 24 hours for the second time, put to death animal, leave and take serum specimen, unified with full automatic biochemical apparatus for the ALT in the serum, the AST level detects.Evaluation result sees Table 1.

The pharmacodynamics evaluation of embodiment 44 anti-paracetamol induced mice liver injuries

Get the Baclb/c mouse of the about 20-25g of quality, random packet, every group of 5 mouse.Testing compound by the orally give various dose; Behind the 1h, prepare liver injury model with the paracetamol subcutaneous injection of 100mL/kg, subcutaneous injection physiological saline is as the normal control group.Behind the modeling 1h, by the oral testing compound that gives various dose once more.After the administration 24 hours for the second time, put to death animal, leave and take serum specimen, unified with full automatic biochemical apparatus for the ALT in the serum, the AST level detects.Evaluation result sees Table 2.

The pharmacological evaluation of rat gastric ulcer due to embodiment 45 anti-hydrochloric acid/ethanol

With reference to reported method such as Takeuchi (The Journal Pharmacology andExperimental Therapeutics 1998; 286:115-121.) measure the antiulcer activity of compound.Get the male Sprague-Dawley rat of the about 200-230g of quality, random packet, every group of 5 animals.Before the experiment, fasting 18 hours.The oral testing compound of animal is after 30 minutes, 1 milliliter of oral hydrochloride/alcohol mixed solution (60% ethanol is in the hydrochloric acid of 150mM).After 1 hour, putting to death animal, get stomach, measure damaged area, is 100% with physiological saline group damaged area, relatively antiulcer activity.Evaluation result sees Table 3.

Table 1, anti-CCl ₄The therapeutic action of poisoning induced mice liver injury

The therapeutic action of table 2, the liver injury of anti-paracetamol induced mice

Table 3 antiulcer activity

Claims (3)

1. by the nitrate derivatives and the atoxic pharmacy acceptable salt thereof of Potenlini shown in structural formula Ia and the Ib or glycyrrhetinic acid:

Potenlini nitric ether glycyrrhetinic acid nitric ether

Ia Ib

In formula Ia, R ₁, R ₂And R ₃Representative-OH or-X-L-ONO ₂, wherein X represents O or NH, and it is that alkyl, the carbonatoms of 2-6 is the cycloalkyl of 3-6 that L represents carbonatoms, R ₁, R ₂And R ₃Identical or different, but wherein must have one to be-X-L-ONO at least ₂, the hydrogen that carbon is 18 can be αYi Gouti or beta isomer; In formula Ib, R ₃Be OH or X-L-ONO ₂, wherein X represents O or NH, and it is that alkyl, the carbonatoms of 2-6 is the cycloalkyl of 3-6 that L represents carbonatoms, R ₄Represent H, NO ₂Or CO-L '-ONO ₂, wherein to represent carbonatoms be that alkyl, the carbonatoms of 1-6 is the cycloalkyl of 3-6 to L ', R ₃Or R ₄In must have at least one to contain nitrooxy, the hydrogen that carbon is 18 can be αYi Gouti or beta isomer.

2. the nitrate derivatives of described Potenlini of claim 1 or glycyrrhetinic acid and atoxic pharmacy acceptable salt thereof are as the pharmaceutical composition of activeconstituents.

3. the nitrate derivatives of described Potenlini of claim 1 or glycyrrhetinic acid and atoxic pharmacy acceptable salt thereof the purposes in preparation hepatitis and peptic ulcer medicine.