CN102267929A

CN102267929A - Preparation of novel N-amino acid substituted azulene sulfamide medicine and anti-gastric ulcer actions thereof

Info

Publication number: CN102267929A
Application number: CN2011101647994A
Authority: CN
Inventors: 杨芳; 石万棋; 张露昀; 张萍; 李颖; 尹述凡
Original assignee: Sichuan Guokang Pharmaceutical Co Ltd
Current assignee: Sichuan Guokang Pharmaceutical Co Ltd
Priority date: 2011-06-20
Filing date: 2011-06-20
Publication date: 2011-12-07
Anticipated expiration: 2031-06-20
Also published as: CN102267929B

Abstract

The invention discloses a sodium azulene sulfonate derivative, particularly novel N-amino acid substituted kessazulen-1-sulfamides of which the structural formula is disclosed in the specification, wherein R2 is hydrogen or methoxyformoxyl group; R3 is hydrogen, methyl propyl group, benzyl group, indolyl-3-methyl group, methyl group or methoxyformoxyl methyl group; R4 is hydrogen, 2-methyl propyl group or indolyl-3-methyl group; R5 is hydrogen or indolyl-3-methyl group; and R6 is 2-thienyl group or 4-trifluoromethyl phenyl group. The compounds have obvious anti-gastric ulcer activity. The preparation method comprises the following steps: (1) preparing sodium 3,8-dimethyl-5-isopropyl azulene-1-sulfonate; (2) preparing glycine methyl ester hydrochloride; and (3) preparing the N-amino acid substituted kessazulen-1-sulfamides (Parts A, B, C and D), and the like.

Description

The preparation and the anti-gastric-ulcer effect of novel N-aminoacid replacement Azulene sulphonamide medicine

Technical field

The present invention relates to more to create the derivative of blue hydrocarbon Azulene, more create the preparation method of blue hydrocarbon azulene derivatives and more create the purposes of blue hydrocarbon azulene derivatives.

Background technology

More create blue hydrocarbon Azulene (Guaiazulene, promptly 1,4-dimethyl-7-sec.-propyl Azulene, 1,4-dimethyl-7-isopropylazulene) be the effective constituent of foreign chrysanthemum, its structural formula is as follows:

More creating blue hydrocarbon Azulene is a kind of active material of anti-gastric-ulcer that has, to antianaphylaxis, and anti-inflammatory, antiulcer agent, antipepsin have the obvious treatment effect, have been subject to the people's attention since coming out, and many people study it, have developed a series of medicines.For example, publication number is in the patent application of CN1984898, has reported a kind of Na ⁺The cotransport production method of Azulene analog derivative of body inhibitor of-glucose; Publication number is in the patent application of CN101062005, has invented a kind of toothpaste that contains sodium azulenesulfonate, and this toothpaste has good preventing and result of treatment to common oral disease; Publication number is in the patent application of CN101200438, has introduced a kind of new type water-solubility azulene derivatives and preparation method thereof, and this compounds can be used as the medicine of treatment gastritis and peptide ulceration; Publication number is in the patent application of CN1803768, and a kind of synthesis technique with sodium azulenesulfonate of stability is provided; Publication number is in the patent application of CN101591228, has invented a kind of novel Azulene analog derivative, reasonable effect is arranged aspect disease that this compounds causes because of hypoimmunity in treatment and anti-ageing the waiting for a long time.This shows that the Azulene analog derivative that contains azulene structure often shows certain biological activity, therefore, the research of novel Azulene analog derivative is had potential for the research and development of new drug be worth and positive meaning.

Summary of the invention

The objective of the invention is more to create blue hydrocarbon Azulene is lead compound, synthesizes and more creates blue hydrocarbon azulene derivatives, so that the anti-gastric-ulcer class medicine with better pharmacologically active that exploitation makes new advances.

Of the present invention more to create blue hydrocarbon azulene derivatives be that N-replaces and more to create blue hydrocarbon Azulene-1-sulphonamide, and its structural formula is as follows:

In the described structural formula, R ₂Be hydrogen or methoxycarbonyl base, R ₃Be hydrogen or 2-methyl-propyl or benzyl or indoles-3-methyl or methyl or methoxycarbonyl methyl; R ₄Be hydrogen or 2-methyl-propyl or indoles-3-methyl; R ₅Be hydrogen or indoles-3-methyl; R ₆Be 2-thienyl or 4-trifluoromethyl.

The present invention proves (seeing embodiment 17) by experiment, and the N-replacement is more created blue hydrocarbon Azulene-1-sulphonamide and compared with model group, and significant difference is arranged, and the anti-gastric-ulcer activity is stronger, can be used as the active pharmaceutical ingredients of medicament for anti-gastric ulcer, develops the better new drug of drug effect.

N-of the present invention replaces that more to create blue hydrocarbon Azulene-1-sulphonamide preparation method be to be basic substance more to create blue hydrocarbon Azulene, after sulfonation, make sodium azulenesulfonate with the NaOH neutralization, again its-(4a～4h) sulfoamido has been introduced in condensation, successfully synthesizes derivative (5a～5h) by SULPHURYL CHLORIDE and amino acid methyl ester hydrochloride on the 1-position; In order further to probe into the character of its derivative, we are with 5a, 5c, the 5d hydrolysis has obtained carboxylic derivative (6a～6c), in addition with 5a, 5d and hydrazine hydrate condensation make hydrazide derivative, and (7a～7b), and then with 7a, 7b and aromatic aldehyde condensation must contain the derivative (8a～8b) of acylhydrazone class formation.To sum up, having obtained 15 kinds does not see that the blue hydrocarbon azulene derivatives N-of more creating of bibliographical information replaces and more creates blue hydrocarbon Azulene-1-sulphonamide.Its reaction formula is following sees Scheme1,2,3:

In the above-mentioned reaction formula:

1: more create blue hydrocarbon Azulene (1,4-dimethyl-7-sec.-propyl Azulene)

2:3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate (sodium azulenesulfonate)

3a: glycine

4a: glycine methyl ester hydrochloride

5a:N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

6a:N-2-carboxyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

7a:N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

8a:N-(2-carbonyl-2-(2-(2-thienyl methene) ethyl)-3-', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

The 3b:L-leucine

4b:L-leucine methyl ester hydrochloride

5b:N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

6b:N-2-(2-methyl-propyl)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

7b:N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

8b:N-(3-(1H-3-indyl)-1-carbonyl-1-(2-(4-trifluoromethyl) benzyl) diazanyl)-2-propyl group)-3 ', 8 ' dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

The 3c:L-phenylalanine

The 4c:L-phenylalanine methyl ester hydrochloride

5c:N-2-phenmethyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

6c:N-2-(3-skatole)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

The 3d:L-tryptophane

4d:L-tryptophan methyl ester hydrochloride

5d:N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

The 3e:L-L-Ala

4e:L-alanine methyl ester hydrochloride

5e:N-2-methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

The 3f:L-aspartic acid

4f:L-aspartic acid methyl ester hydrochloride

5f:N-2-methoxycarbonyl methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

The 3g:L-proline(Pro)

The 4g:L-proline methyl ester hydrochloride

5g:N-(2-methoxycarbonyl)-1-pyrryl-3 ', 8-' dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

3h: beta-amino L-Ala

4h: beta-amino alanine methyl ester hydrochloride

5h:N-3-methoxycarbonyl ethyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

From above-mentioned reaction formula as can be seen, have following processing step:

The preparation of (1) 3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate

Raw material and prescription thereof: 4mmol more creates blue hydrocarbon Azulene, the dense H of 2mL ₂SO ₄, an amount of NaOH.

Solvent orange 2 A c ₂O 4mL;

Processing step:

Under normal pressure, ice bath, in 25mL pyriform bottle, add 4mmol successively and more create blue hydrocarbon Azulene, 2mLAc ₂O by constant pressure funnel (top adds drying tube), stirs down the slowly dense H of adding 1mL ₂SO ₄And 2mLAc ₂The mixed solution of O, after dropwising, the about 2h of stirring at room, TLC follow the tracks of to react to raw material point and disappear.Mixed solution is poured in the 4mL water, slowly dripped NaOH solution again and transfer pH=8～9, mixed solution is iced to solid separates out, suction filtration is used cold water successively, petroleum ether, drying, claim 1 is described 3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate;

(2) preparation of amino acid methyl ester hydrochloride

Raw material and prescription thereof: 8mmol amino acid, 4mL SOCl ₂, NaOH solution, 2% ethanol solution of ninhydrin.

Solvent: methyl alcohol 60mL.

Processing step:

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) down in stirring ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol amino acid, stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of and reacts to the disappearance of raw material point, steams solvent and promptly gets the described amino acid methyl ester hydrochloride of claim 2.

(3) N-replaces the preparation of more creating blue hydrocarbon Azulene-1-sulphonamide (A part).

Raw material and prescription thereof: 2mmol sodium azulenesulfonate, 5mmol (COCl) ₂, 2.5mmol amino acid methyl ester hydrochloride, 0.8mL DMF, 1.8mL Py, 3mL Et ₃N, rare HCl.

Solvent: CH ₂Cl ₂.

Processing step:

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol amino acid methyl ester hydrochloride in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates gets the described N-replacement of claim 3 by silica gel column chromatography separating purification and more creates blue hydrocarbon Azulene-1-sulphonamide (A part).

N-replaces the preparation of more creating blue hydrocarbon Azulene-1-sulphonamide (B part).

Raw material and prescription thereof: blue hydrocarbon Azulene-1-sulphonamide (N-methoxycarbonyl methyl-3 ' is more created in 1mmol N-replacement, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5_ sec.-propyl Azulene-1 '-sulphonamide 5b, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d), 0.8mL 5%NaOH, rare HCl, CH ₂Cl ₂

Solvent: methyl alcohol 5mL, water 15mL.

Processing step:

Blue hydrocarbon Azulene-1-sulphonamide (N-methoxycarbonyl methyl-3 ' is more created in 1mmol N-replacement, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5b, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d) product is dissolved in 5mL methyl alcohol and the 15mL water, toward wherein adding 5%NaOH solution 0.8mL, use CH ₂Cl ₂Extract three times, stay water layer.In water layer, slowly add rare HCl to pH=5～6, use CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates gets the described N-replacement of claim 3 by silica gel column chromatography separating purification and more creates blue hydrocarbon Azulene-1-sulphonamide (B part).

N-replaces the preparation of more creating blue hydrocarbon Azulene-1-sulphonamide (C part).

Raw material and prescription thereof: blue hydrocarbon Azulene-1-sulphonamide (N-methoxycarbonyl methyl-3 ' is more created in 1mmol N-replacement, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d), 3mmol 80% hydrazine hydrate.

Solvent: dehydrated alcohol 60mL.

Processing step:

In the 100mL round-bottomed flask, add 1mmol N-replacement successively and more create blue hydrocarbon Azulene-1-sulphonamide (N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d), the 60mL dehydrated alcohol, the 3mmol80% hydrazine hydrate, 80 ℃ of about 8h of following back flow reaction, after TLC detects the disappearance of raw material point, steam solvent, resistates gets the described N-replacement of claim 3 by the silicagel column separation and purification and more creates blue hydrocarbon Azulene-1-sulphonamide (C part).

N-replaces the preparation of more creating blue hydrocarbon Azulene-1-sulphonamide (D part).

Raw material and prescription thereof: blue hydrocarbon Azulene-1-sulphonamide (N-(2-diazanyl-2-oxygen ethyl)-3 ' is more created in 0.5mmol N-replacement, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7a, N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7b), 0.6mmol aromatic aldehyde.

Solvent: dehydrated alcohol 15mL.

Processing step:

In 25mL pyriform bottle, add 0.5mmol N-replacement and more create blue hydrocarbon Azulene-1-sulphonamide (N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7a, N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8-' dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7b), the 15mL dehydrated alcohol, 0.6mmol aromatic aldehyde, room temperature or 35 ℃ of following stirrings are spent the night, TLC follows the tracks of to react to raw material point and disappears, steam solvent, resistates gets the described N-replacement of claim 3 by the silicagel column separation and purification and more creates blue hydrocarbon Azulene-1-sulphonamide (D part).

In the aforesaid method:

In the preparation of amino acid methyl ester hydrochloride, be characterised in that amino acid methyl ester hydrochloric acid is a kind of in glycine methyl ester hydrochloride, L-leucine methyl ester hydrochloride, L-phenylalanine methyl ester hydrochloride, L-tryptophan methyl ester hydrochloride, L-alanine methyl ester hydrochloride, L-aspartic acid methyl ester hydrochloride, L-proline methyl ester hydrochloride, the beta-amino alanine methyl ester hydrochloride.

Described N-replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (A part), it is characterized in that product is a N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-phenmethyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-methoxycarbonyl methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-(2-methoxycarbonyl)-1-pyrryl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-3-methoxycarbonyl ethyl-3 ', a kind of in 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide.

Described N-replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (B part), it is characterized in that product is a N-2-carboxyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(2-methyl-propyl)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(3-skatole)-2-carboxyl methylene radical-3 ', a kind of in 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide.

Described N-replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (C part), it is characterized in that product is N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', a kind of in 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide.

Described N-replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (D part), it is characterized in that aromatic aldehyde is a 2 thiophene carboxaldehyde, a kind of in the trifluoromethylated benzaldehyde.

In the aforesaid method, the preparation of described (1) 3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate; (2) preparation of glycine methyl ester hydrochloride; (3) N-replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (A, B, C, D four parts).It is characterized in that preparing 3, during 8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate, solvent for use is Ac ₂O; During the preparation of glycine methyl ester hydrochloride, solvent for use is an anhydrous methanol; N-replaces when more creating the preparation of blue hydrocarbon Azulene-1-sulphonamide (A part), and solvent for use is CH ₂Cl ₂N-replaces when more creating the preparation of blue hydrocarbon Azulene-1-sulphonamide (B part), and solvent for use is the first alcohol and water; N-replaces when more creating the preparation of blue hydrocarbon Azulene-1-sulphonamide (C, D part), and solvent for use is a dehydrated alcohol.

The present invention has following beneficial effect:

1. N-replacement of the present invention is more created blue hydrocarbon Azulene-1-sulphonamide and is compared with model group, have significant difference, the anti-gastric-ulcer activity is stronger, thereby is active pharmaceutical ingredients with it, can develop the multiple medicament for anti-gastric ulcer of better efficacy, have obvious social and economic benefit.

2. the method for the invention operational path is simple, and cost is lower, can be suitable for industrialization and enlarge the needs of producing.

Embodiment

Below by embodiment blue hydrocarbon Azulene-1-sulphonamide and preparation method thereof more being created in N-replacement of the present invention is described further.

Embodiment 1: present embodiment prepares N-methoxycarbonyl methyl-3,8-dimethyl-5-sec.-propyl Azulene-1-sulphonamide (being called for short 5a), and its structural formula is as follows:

The processing step of present embodiment is as follows:

The preparation of (1) 3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate (being called for short 2)

Under the ice bath, in 25mL pyriform bottle, add 4mmol successively and more create blue hydrocarbon Azulene, 2mLAc ₂O slowly adds the dense H of 1mL by constant pressure funnel (top adds drying tube) ₂SO ₄And 2mLAc ₂The mixed solution of O, after dropwising, the about 2h of stirring at room, TLC follow the tracks of to react to raw material point and disappear.Mixed solution is poured in the 4mL water, slowly dripped NaOH solution again and transfer pH=8～9, mixed solution is iced to solid separates out, suction filtration is used cold water successively, petroleum ether, drying, blue solid 1.05g, yield 87.5%, m.p.106～107 ℃.

(2) preparation of glycine methyl ester hydrochloride (being called for short 4a)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol glycine (3a), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of and reacts to the disappearance of raw material point, steams solvent and promptly gets glycine methyl ester hydrochloride (4a), productive rate 100%.

(3) N-methoxycarbonyl methyl-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5a)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol glycine methyl ester hydrochloride (4a) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mLPy, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) be eluent] obtain N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (5a), purple powder, yield 28%, m.p.70-72 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.28 (s, 1H), 8.11 (s, 1H), 7.59 (d, J=11.0Hz, 1H), 7.39 (d, J=11.4Hz, 1H), 5.17 (t, J=10.3Hz, 1H), 3.84 (d, J=5.3Hz, 2H), 3.67 (s, 3H), 3.38 (s, 3H), 3.13 (dd, J=6.9Hz, 6.9Hz, 1H), 2.57 (s, 3H), 1.38 (d, J=7.0Hz, 6H) .IR (KBr) v:3315 (NH), 1735 (C=O), 1370 (as, S=O), 1155 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₁₈H ₂₃NO ₄S[M+H] ⁺350.1421 found 350.1429; [M+Na] ⁺372.1240 found372.1226; [M+K] ⁺388.0979 found 388.0989.

Embodiment 2: present embodiment prepares N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5b), and its structural formula is as follows:

The processing step of present embodiment is as follows:

(2) preparation of L-leucine methyl ester hydrochloride (being called for short 4b)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol L-leucine (3b), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get L-leucine methyl ester hydrochloride (being called for short 4b), productive rate 100%.

(3) N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5b)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-leucine methyl ester hydrochloride (4b) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5b), purple crystals, yield 21%, m.p.68-70 ℃; ¹HNMR (CDCl ₃, 400MHz) δ: 8.26 (s, 1H), 8.14 (s, 1H), 7.58 (d, J=11.2Hz, 1H), 7.39 (d, J=11.2Hz, 1H), 5.13 (d, J=10.0Hz, 1H), 3.97～3.90 (m, 1H), 3.43 (s, 3H), 3.38 (s, 3H), 3.13 (dd, J=7.1Hz, 6.8Hz, 1H), 2.56 (s, 3H), 1.74～1.67 (m, 1H), 1.50～1.40 ((m, 2H), 1.37 (d, J=6.8Hz, 6H), 0.84 (d, J=6.6Hz, 3H), 0.69 (d, J=6.6Hz, 3H) .IR (KBr) v:3308 (NH), 1746 (C=O), 1370 (as, S=O), 1155 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₂H ₃₁NO ₄S[M+H] ⁺406.2047 found406.2048; [M+K] ⁺444.1605 found 444.1652.

Embodiment 3: present embodiment prepares N-2-phenmethyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5c), and its structural formula is as follows:

The processing step of present embodiment is as follows:

(2) preparation of L-phenylalanine methyl ester hydrochloride (being called for short 4c)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol L-phenylalanine (3c), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get L-phenylalanine methyl ester hydrochloride (being called for short 4c), productive rate 100%.

(3) N-2-phenmethyl-2-methoxycarbonyl methylene radical-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5c)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-phenylalanine methyl ester hydrochloride (4c) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-2-phenmethyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5c), purple crystals, yield 17%, m.p.100-102 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.24 (s, 1H), 7.99 (s, 1H), 7.56 (d, J=11.4Hz, 1H), 7.31 (d, J=11.2Hz, 1H), 7.14～7.11 (m, 1H), 7.10 (d, J=1.5Hz, 2H), 7.00 (t, J=3.6Hz, 4.5Hz, 2H), 5.18 (d, J=9.2Hz, 1H), 4.25～4.20 (m, 1H), 3.57 (s, 3H), 3.22 (s, 3H), 3.16～3.05 (m, 2H), 2.97 (dd, J=6.7Hz, 6.7Hz, 1H), 2.53 (s, 3H), 1.38 (d .J=6.8Hz, 6H) .IR (KBr) v:3369 (NH), 1741 (C=O), 1369 (as, S=O), 1155 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₅H ₂₉NO ₄S[M+H] ⁺440.1890 found 440.1897:[M+K] ⁺478.1449 found 478.1503.

Embodiment 4: present embodiment prepares N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d), and its structural formula is as follows:

The processing step of present embodiment is as follows:

(2) preparation of L-tryptophan methyl ester hydrochloride (being called for short 4d)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmolL-tryptophane (3d), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get L-tryptophan methyl ester hydrochloride (being called for short 4d), productive rate 100%.

(3) N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-tryptophan methyl ester hydrochloride (abbreviation 4d) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d), purple crystals, yield 20%, m.p.178-180 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.19 (s, 1H), 7.99 (s, 2H), 7.52 (d, J=11.6Hz, 1H), 7.38 (d, J=7.9Hz, 1H), 7.25 (d, J=4.7Hz, 1H), 7.23 (d, J=8.1Hz, 1H), 7.09 (t, J=7.2Hz, 8.1Hz, 1H), 6.98 (dd, J=4.4Hz, 8.4Hz, 2H), 5.28 (d, J=8.9Hz, 1H), 4.32～4.27,3.30～3.26 (m, 3H), 3.51 (s, 3H), 3.21 (s, 3H), 3.19～3.08 (m, 1H), 2.47 (s, 3H), 1.37 (d, J=6.9Hz, 6H) .IR (KBr) v:3304 (NH), 1744 (C=O), 1370 (as, S=O), 1145 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₇H ₃₀N ₂O ₄S[M+H] ⁺479.1999 found 479.1990; [M+Na] ⁺501.1818found 501.1837; [M+K] ⁺517.1558 found 517.1551.

Embodiment 5: present embodiment prepares N-2-methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5e), and its structural formula is as follows:

The processing step of present embodiment is as follows:

(2) preparation of L-alanine methyl ester hydrochloride (being called for short 4e)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmolL-L-Ala (3e), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get L-alanine methyl ester hydrochloride (being called for short 4e), productive rate 100%.

(3) N-2-methyl-2-methoxycarbonyl methylene radical-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5e)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-alanine methyl ester hydrochloride (abbreviation 4e) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-2-methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5e), purple crystals, yield 25%, m.p.77-78 ℃; ¹HNMR (CDCl ₃, 400MHz) δ: 8.27 (s, 1H), 8.12 (s, 1H), 7.58 (d, J=11.3Hz, 1H), 7.39 (d, J=10.9Hz, 1H), 5.32 (d, .J=7.9Hz, 1H), 4.08～4.01 (m, 1H), 3.57 (s, 3H), 3.38 (s, 3H), 3.16～3.09 (m, 1H), 2.57 (s, 3H), 1.38 (t, J=5.0Hz, 6.8Hz, 9H) .IR (KBr) v:3363 (NH), 1733 (C=O), 1369 (as, S=O), 1158 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₁₉H ₂₅NO ₄S[M+H] ⁺364.1577 found 364.1574; [M+Na] ⁺386.1397 found 386.1390; [M+K] ⁺402.1136 found 402.1132.

Embodiment 6: present embodiment prepares N-2-methoxycarbonyl methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5f), and its structural formula is as follows:

The processing step of present embodiment is as follows:

(2) preparation of L-alanine methyl ester hydrochloride (being called for short 4f)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol L-aspartic acid (3f), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get L-aspartic acid methyl ester hydrochloride (being called for short 4f), productive rate 100%.

(3) N-2-methoxycarbonyl methyl-2-methoxycarbonyl methylene radical-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5f)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-aspartic acid methyl ester hydrochloride (abbreviation 4f) in the mixed solution slowly splashes into 3mLEt by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) be eluent] obtain N-2-methoxycarbonyl methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (5f), purple crystals, yield 15%, m.p.122-124 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.27 (s, 1H), 8.15 (s, 1H), 7.59 (d, J=11.3Hz, 1H), 7.39 (d, J=11.3Hz, 1H), 5.74 (d, J=7.4Hz, 1H), 4.23～4.19 (m, 1H), 3.64 (s, 3H), 3.57 (s, 3H), 3.39 (s, 3H), 3.17～3.10 (m, 1H), 2.97～2.84 (m, 2H), 2.57 (s, 3H), 1.37 (d, J=6.9Hz, 6H) .IR (KBr) v:3307 (NH), 1735 (C=O), 1370 (as, S=O), 1165 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₁H ₂₇NO ₆S[M+H] ⁺422.1632 found 422.1641; [M+Na] ⁺444.1451 found 444.1471; [M+K] ⁺460.1191found 460.1244.

Embodiment 7: present embodiment prepares N-(2-methoxycarbonyl)-1-pyrryl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5g), and its structural formula is as follows:

The processing step of present embodiment is as follows:

(2) preparation of L-proline methyl ester hydrochloride (being called for short 4g)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol L-proline(Pro) (3g), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get L-proline methyl ester hydrochloride (being called for short 4g), productive rate 100%.

(3) N-(2-methoxycarbonyl)-1-pyrryl-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5g)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-proline methyl ester hydrochloride (abbreviation 4g) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-(2-methoxycarbonyl)-1-pyrryl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5g), purple powder, yield 22%, m.p.72-73 ℃; ¹HNMR (CDCl ₃, 400MHz) δ: 8.25 (s, 1H), 8.14 (s, 1H), 7.57 (d, J=11.2Hz, 1H), 7.40 (d, J=11.3Hz, 1H), 4.49 (dd, J=3.7Hz, 2.5Hz, 1H), 3.72 (dd, J=7.1Hz, 7.1Hz, 2H), 3.68～3.62 (m, 1H), 3.49～3.43 (m, 1H), 3.38 (s, 3H), 3.31 (s, 3H), 3.16～3.09 (m, 1H), 2.57 (s, 3H), 2.35～2.24 (m, 1H), 2.17 (s, 1H), 1.37 (d, J=6.9Hz, 6H) .IR (KBr) v:1735 (C=O), 1370 (as, S=O), 1150 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₁H ₂₇NO ₄S[M+H] ⁺390.1734 found 390.1736; [M+Na] ⁺412.1553 found 412.1516; [M+K] ⁺428.1292found 428.1281.

Embodiment 8: present embodiment prepares N-3-methoxycarbonyl ethyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5h), and its structural formula is as follows:

The processing step of present embodiment is as follows:

Under the ice bath, in 25mL pyriform bottle, add 4mmol successively and more create blue hydrocarbon Azulene, 2mLAc ₂O slowly adds the dense H of 1mL by constant pressure funnel (top adds drying tube) ₂SO ₄And 2mLAc ₂The mixed solution of O, after dropwising, the about 2h of stirring at room, TLC follow the tracks of to react to raw material point and disappear.Mixed solution is poured in the 4mL water, slowly dripped NaOt solution again and transfer pH=8～9, mixed solution is iced to solid separates out, suction filtration is used cold water successively, petroleum ether, drying, blue solid 1.05g, yield 87.5%, m.p.106～107 ℃.

(2) preparation of Beta-alanine methyl ester hydrochloride (being called for short 4h)

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol Beta-alanine (3h), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get Beta-alanine methyl ester hydrochloride (being called for short 4h), productive rate 100%.

(3) N-3-methoxycarbonyl ethyl-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5h)

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol Beta-alanine methyl ester hydrochloride (abbreviation 4h) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-3-methoxycarbonyl ethyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5h), purple crystals, yield 23%, m.p.94-96 ℃; ¹H NMR (CDC ₃, 400MHz) δ: 8.27 (s, 1H), 8.10 (s, 1H), 7.58 (d, J=11.8Hz, 1H), 7.37 (d, J=11.0Hz, 1H), 5.28 (t, J=8.4Hz, 7.5Hz, 1H), 3.65 (s, 3H), 3.36 (s, 3H), 3.30 (dd, J=6.3Hz, 6.1Hz, 2H), 3.16～3.09 (m, 1H), 2.59～2.56 (m, 2H), 2.58 (s, 3H), 1.37 (d, J=6.8Hz, 6H) .IR (KBr) v:3314 (NH), 1728 (C=O), 1370 (as, S=O), 1154 (s, S=0) cm ^-1.HRMS (ESI) calcd for C ₁₉H ₂₅NO ₄S[M+H] ⁺364.1577 found 364.1583; [M+Na] ⁺386.1397 found 386.1405; [M+K] ⁺402.1136 found 402.1151.

Embodiment 9: present embodiment prepares N-2-carboxyl methyl-3 ', and synthetic (being called for short 6a) of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, its structural formula is as follows:

The processing step of present embodiment is as follows:

Under the ice bath, in 25mL pyriform bottle, add 4mmol successively and more create blue hydrocarbon Azulene, 2mLAc ₂O slowly adds the dense H of 1mL by constant pressure funnel (top adds drying tube) ₂SO ₄And 2mLAc ₂The elder brother of O closes liquid, and after dropwising, the about 2h of stirring at room, TLC follow the tracks of to react to raw material point and disappear.Mixed solution is poured in the 4mL water, slowly dripped NaOH solution again and transfer pH=8～9, mixed solution is iced to solid separates out, suction filtration is used cold water successively, petroleum ether, drying, blue solid 1.05g, yield 87.5%, m.p.106～107 ℃.

(3) N-methoxycarbonyl methyl-3 ' under the preparation ice bath of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5a), adds the 2mmol sodium azulenesulfonate, 0.8mL DMF, 5mL CH successively in 25mL pyriform bottle ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol glycine methyl ester hydrochloride (4a) in the mixed solution slowly splashes into 3mLEt by constant pressure funnel again ₃N and 1mLPy, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) be eluent] obtain N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (5a), purple powder, yield 28%, m.p.70-72 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.28 (s, 1H), 8.11 (s, 1H), 7.59 (d, J=11.0Hz, 1H), 7.39 (d, J=11.4Hz, 1H), 5.17 (t, J=10.3Hz, 1H), 3.84 (d, J=5.3Hz, 2H), 3.67 (s, 3H), 3.38 (s, 3H), 3.13 (dd, J=6.9Hz, 6.9Hz, 1H), 2.57 (s, 3H), 1.38 (d, J=7.0Hz, 6H) .IR (KBr) v:3315 (NH), 1735 (C=O), 1370 (as, S=O), 1155 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₁₈H ₂₃NO ₄S[M+H] ⁺350.1421 found 350.1429; [M+Na] ⁺372.1240 found372.1226; [M+K] ⁺388.0979 found 388.0989.

(4) N-2-carboxyl methyl-3 ', the preparation of synthetic (being called for short 6a) of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

With 1mmol N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5a) is dissolved in 5mL methyl alcohol and the 15mL water, toward wherein adding 5%NaOH solution 0.8mL, uses CH ₂Cl ₂Extract three times, stay water layer.In water layer, slowly add rare HCl to pH=5～6, use CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Eluent: petroleum ether-ethyl acetate (V: V=4: 1)] obtain N-2-carboxyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 6a), purple crystals, yield 97%, m.p.128-129 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.32 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.73 (d, J=10.8Hz, 1H), 7.43 (d, J=10.8Hz, 1H), 3.67 (s, 1H), 3.28 (s, 3H), 2.56 (s, 3H), 2.51 (s, 2H), 1.33 (d, J=6.7Hz, 6H) .IR (KBr) v:3449 (OH), 3316 (NH), 1711 (C=O), 1382 (as, S=O), 1147 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₁₇H ₂₁NO ₄S[M+H] ⁺336.1264 found 336.1267; [M+Na] ⁺358.1083 found 358.1081.

Embodiment 10: present embodiment prepares N-2-(2-methyl-propyl)-2-carboxyl methylene radical-3 ', 8 ' dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 6b), and its structural formula is as follows:

The processing step of present embodiment is as follows:

(4) N-2-(2-methyl-propyl)-2-carboxyl methylene radical-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 6b)

With 1mmol N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5b) is dissolved in 5mL methyl alcohol and the 15mL water, toward wherein adding 5%NaOH solution 0.8mL, uses CH ₂Cl ₂Extract three times, stay water layer.In water layer, slowly add rare HCl to pH=5～6, use CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Eluent: petroleum ether-ethyl acetate (V: V=4: 1)] obtain N-2-(2-methyl-propyl)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 6b), purple crystals, yield 95%, m.p.44-46 ℃: ¹H NMR (DMSO-d ₆, 400MHz) δ: 10.80 (s, 1H), 10.52 (s, 1H), 10.39 (d, J=9.4Hz, 1H), 10.22 (d, J=10.9Hz, 1H), 9.93 (d, J=11.4Hz, 1H), 6.13～6.07 (m, 1H), 5.79 (s, 3H), 5.71～5.64 (m, 1H), 5.03 (s, 3H), 4.14～3.99 (m, 2H), 3.87～3.84 (m, 1H), 3.82 (d, J=6.9Hz, 6H), 3.28 (d, J=6.4Hz, 3H), 3.06 (d, J=6.4Hz, 3H) .IR (KBr) v:3329 (NH), 1726 (C=O), 1372 (as, S=O), 1151 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₁H ₂₉NO ₄S[M+H] ⁺392.1890 found392.1898; [M+Na] ⁺414.1710found 414.1723; [M+K] ⁺430.1449 found430.1467.

Embodiment 11: present embodiment prepares N-2-(3-skatole)-2-carboxyl methylene radical-3 ', 8 ' dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 6c), and its structural formula is as follows:

The processing step of present embodiment is as follows:

Cryosel is bathed down, adds 60mL methyl alcohol in the 100mL round-bottomed flask, slowly adds 4mL SOCl by constant pressure funnel (top connects drying tube) ₂, with NaOH solution absorption tail gas.After stirring 1h, add 8mmol L-tryptophane (3d), stirring at room 30min, again at 66 ℃ of following backflow 6h, the ethanol solution of ninhydrin colour developing with 2%, TLC follows the tracks of to react to raw material point and disappears, steam solvent and promptly get L-tryptophan methyl ester hydrochloride (being called for short 4d), productive rate 100%.

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-tryptophan methyl ester hydrochloride (abbreviation 4d) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders: petroleum ether-ethyl acetate (V: V=4: 1) be eluent] by silica gel column chromatography and obtains N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d), purple crystals, yield 20%, m.p.178-180 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.19 (s, 1H), 7.99 (s, 2H), 7.52 (d, J=11.6Hz, 1H), 7.38 (d, J=7.9Hz, 1H), 7.25 (d, J=4.7Hz, 1H), 7.23 (d, J=8.1Hz, 1H), 7.09 (t, J=7.2Hz, 8.1Hz, 1H), 6.98 (dd, J=4.4Hz, 8.4Hz, 2H), 5.28 (d, J=8.9Hz, 1H), 4.32～4.27,3.30～3.26 (m, 3H), 3.51 (s, 3H), 3.21 (s, 3H), 3.19～3.08 (m, 1H), 2.47 (s, 3H), 1.37 (d, J=6.9Hz, 6H) .IR (KBr) v:3304 (NH), 1744 (C=O), 1370 (as, S=O), 1145 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₇H ₃₀N ₂O ₄S[M+H] ⁺479.1999found 479.1990; [M+Na] ⁺501.1818found 501.1837; [M+K] ⁺517.1558found 517.1551.

(4) N-2-(3-skatole)-2-carboxyl methylene radical-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 6c)

With 1mmol N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d) is dissolved in 5mL methyl alcohol and the 15mL water, toward wherein adding 5%NaOH solution 0.8mL, uses CH ₂Cl ₂Extract three times, stay water layer.In water layer, slowly add rare HCl to pH=5～6, use CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders: eluent: petroleum ether-ethyl acetate (V: V=4: 1)] by silica gel column chromatography and obtains N-2-(3-skatole)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 6c), purple crystals, yield 98%, m.p.107-108 ℃; ¹H NMR (DMSO-d ₆, 400MHz) δ: 13.35 (s, 1H), 10.69 (s, 1H), 10.52 (d, J=8.4Hz, 1H), 10.00 (s, 1H), 9.81 (dd, J=11.2Hz, 8.1Hz, 2H), 9.74 (d, J=7.9Hz, 1H), 9.68 (s, 1H), 9.50 (t, J=7.4Hz, 7.6Hz, 1H), 9.36 (t, J=7.6Hz, 1H), 6.43～6.37 (m, 1H), 5.66 (s, 3H), 5.61 (dd, J=6.4Hz, 6.1Hz, 2H), 5.51 (dd, J=8.4Hz, 8.3Hz, 1H), 5.00 (s, 3H), 3.81 (d, J=7.0Hz, 6H) .IR (KBr) v:3409 (NH), 1736 (C=O), 1378 (as, S=O), 1146 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₆H ₂₈N ₂O ₄S[M+H] ⁺465.1843 found 465.1841; [M+Na] ⁺487.1662 found 487.1672; [M+K] ⁺503.1401 found 503.1414.

Embodiment 12: present embodiment prepares N-(2-diazanyl-2-oxygen ethyl)-3 ', and synthetic (being called for short 7a) of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, its structural formula is as follows:

The processing step of present embodiment is as follows:

(4) N-(2-diazanyl-2-oxygen ethyl)-3 ', the preparation of synthetic (being called for short 7a) of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

In the 100mL round-bottomed flask, add 1mmol N-methoxycarbonyl methyl-3 ' successively, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5a), the 60mL dehydrated alcohol, 3mmol 80% hydrazine hydrate, 80 ℃ of about 8h of following back flow reaction, TLC steams solvent after detecting the disappearance of raw material point, and resistates separates [silica gel: 300～400 orders by silicagel column; Eluent: petroleum ether-ethyl acetate-ethanol (V: V: V=4: 1: 0.5)] obtain N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (7a), purple powder, yield 80.5%, m.p.71-73 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.28 (s, 1H), 8.02 (s, 1H), 7.61 (d, J=11.40Hz, 1H), 7.56～7.52 (m, 1H), 7.39 (d, J=10.9Hz, 1H), 5.68～5.60 (m, 1H), 3.40 (t, J=4.32Hz, 3.61Hz, 1H), 3.33 (s, 3H), 2.56 (s, 3H), 3.13 (dd, J=6.92Hz, 2H), 2.04～1.96 (m, 2H), 1.38 (d, J=6.93Hz, 6H) .IR (KBr) v:3281 (NH ₂), 1660 (C=O), 1543 (C-N), 1375 (as, S=O), 1253 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₁₇H ₂₃N ₃O ₃S[M-H] ^-348.1382 found 348.1392.

Embodiment 13: present embodiment prepares N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 7b), and its structural formula is as follows:

The processing step of present embodiment is as follows:

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol L-tryptophan methyl ester hydrochloride (abbreviation 4d) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d), purple crystals, yield 20%, m.p.178-180 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.19 (s, 1H), 7.99 (s, 2H), 7.52 (d, J=11.6Hz, 1H), 7.38 (d, J=7.9Hz, 1H), 7.25 (d, J=4.7Hz, 1H), 7.23 (d, J=8.1Hz, 1H), 7.09 (t, J=7.2Hz, 8.1Hz, 1H), 6.98 (dd, J=4.4Hz, 8.4Hz, 2H), 5.28 (d, J=8.9Hz, 1H), 4.32～4.27,3.30～3.26 (m, 3H), 3.51 (s, 3H), 3.21 (s, 3H), 3.19～3.08 (m, 1H), 2.47 (s, 3H), 1.37 (d, J=6.9Hz, 6H) .IR (KBr) v:3304 (NH), 1744 (C=O), 1370 (as, S=O), 1145 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₇H ₃₀N ₂O ₄S[M+H] ⁺479.1999 found 479.1990; [M+Na] ⁺501.1818found 501.1837:[M+K] ⁺517.1558 found 517.1551.

(4) N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 7b)

In the 100mL round-bottomed flask, add 1mmol N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ' successively, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d), the 60mL dehydrated alcohol, the 3mmol80% hydrazine hydrate, 80 ℃ of about 8h of following back flow reaction, TLC steams solvent after detecting the disappearance of raw material point, and resistates separates [silica gel: 300～400 orders by silicagel column; Eluent: petroleum ether-ethyl acetate-ethanol (V: V: V=4: 1: 0.5)] obtain N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 7b), purple crystals, yield 88.1%, m.p.200-202 ℃: ¹H NMR (DMSO-d ₆, 400MHz) δ: 10.79 (s, 1H), 9.09 (s, 1H), 8.17 (s, 1H), 7.76 (d, J=8.5Hz, 1H), 7.64 (d, J=11.0Hz, 1H), 7.49 (s, 1H), 7.32 (d, J=5.2Hz, 1H), 7.27 (dd, J=8.7Hz, 8.1Hz, 2H), 7.14 (d, J=1.9Hz, 1H), 6.98 (t, J=7.1Hz, 8.0Hz, 1H), 6.84 (t, J=7.2Hz, 7.6Hz, 1H), 3.94 (dd, J=8.2Hz, 7.7Hz, 1H), 3.16～3.09 (m, 1H), 3.12 (s, 3H), 3.03～2.91 (m, 2H), 2.50 (s, 3H), 1.92～1.77 (m, 2H), 1.30 (d, J=6.9Hz, 6H) .IR (KBr) v:3294 (NH ₂), 1654 (C=O), 1545 (C-N), 1378 (as, S=O), 1147 (s, S=O) cm ^-1.HRMS (ESI) calcdfor C ₂₆H ₃₀N ₄O ₃S[M-H] ^-477.1960found 477.1951.

Embodiment 14: present embodiment prepare N-(synthetic (being called for short 8a) of 2-carbonyl-2-(2-(2-thienyl methene) ethyl)-3 ', 8 ' dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, its structural formula is as follows:

The processing step of present embodiment is as follows:

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmol glycine methyl ester hydrochloride (4a) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mLPy, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) be eluent] obtain N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (5a), purple powder, yield 28%, m.p.70-72 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.28 (s, 1H), 8.11 (s, 1H), 7.59 (d, J=11.0Hz, 1H), 7.39 (d, J=11.4Hz, 1H), 5.17 (t, J=10.3Hz, 1H), 3.84 (d, J=5.3Hz, 2H), 3.67 (s, 3H), 3.38 (s, 3H), 3.13 (dd, J=6.9Hz, 6.9Hz, 1H), 2.57 (s, 3H), 1.38 (d, J=7.0Hz, 6H) .IR (KBr) v:3315 (NH), 1735 (C=O), 1370 (as, S=O), 1155 (s, S=O) cm ^-1, HRMS (ESI) calcd for C ₁₈H ₂₃NO ₄S[M+H] ⁺350.1421 found 350.1429; [M+Na] ⁺372.1240 found372.1226; [M+K] ⁺388.0979 found 388.0989.

(5) N-(2-carbonyl-2-(2-(2-thienyl methene) ethyl)-3 ', the preparation of synthetic (being called for short 8a) of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide

In 25mL pyriform bottle, add 0.5mmol N-(2-diazanyl-2-oxygen ethyl)-3 ', synthetic (being called for short 7a) of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, the 15mL dehydrated alcohol, 0.6mmol 2-thiophene phenol formaldehyde, stir under 35 ℃ and spend the night, TLC follows the tracks of and reacts to the disappearance of raw material point, steams solvent, and resistates separates [silica gel: 300～400 orders by silicagel column; Eluent: petroleum ether-ethyl acetate-ethanol (V: V: V=4: 1: 0.5)] obtain N-(2-carbonyl-2-(2-(2-thienyl methene) ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (8a), the purple powder, yield 78%, m.p.69-70 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 9.66 (s, 1H), 8.25 (d, J=2.10Hz, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=11.32Hz, 1H), 7.40～7.34 (d, J=3.27Hz, 2H), 7.24 (d, J=3.63Hz, 1H), 7.03 (dd, J=3.55Hz, 3.55Hz, 1H), 5.67 (t, J=4.34Hz, 4.77Hz, 1H), 4.27 (d, J=4.86Hz, 2H), 3.41 (s, 3H), 3.11 (dd, J=7.22Hz, 7.02Hz, 1H), 2.56 (s, 3H), 1.36 (d, J=6.89Hz, 6H) .IR (KBr) v:3396 (NH), 1685 (C=O), 1546 (C=N), 1381 (as, S=O), 1153 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₂H ₂₅N ₃O ₃S ₂[M-H] ^-442.1259 found 442.1250.

Embodiment 15: present embodiment prepares N-(3-(1H-3-indyl)-1-carbonyl-1-(2-(4-trifluoromethyl) benzyl) diazanyl)-2-propyl group)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 8b), its structural formula is as follows:

The processing step of present embodiment is as follows:

Under the ice bath, in 25mL pyriform bottle, add the 2mmol sodium azulenesulfonate successively, 0.8mL DMF, 5mL CH ₂Cl ₂, 0.8mL Py slowly adds 5mmol (COCl) by constant pressure funnel ₂With 2.5mL CH ₂Cl ₂Mixed solution, with the acyl chlorides that Tri N-Propyl Amine check generates, TLC follow the tracks of react disappear to raw material point after, adding 2.5mmolL-tryptophan methyl ester hydrochloride (abbreviation 4d) in the mixed solution slowly splashes into 3mL Et by constant pressure funnel again ₃N and 1mL Py, after dropwising, stirred overnight at room temperature.Reaction solution is poured in the small beaker that fills 15mL water, added among an amount of rare HCl and excessive Et ₃N and Py transfer pH=5～6, CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates separates [silica gel: 300～400 orders by silica gel column chromatography; Petroleum ether-ethyl acetate (V: V=4: 1) for eluent] obtain N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d), purple crystals, yield 20%, m.p.178-180 ℃; ¹H NMR (CDCl ₃, 400MHz) δ: 8.19 (s, 1H), 7.99 (s, 2H), 7.52 (d, J=11.6Hz, 1H), 7.38 (d, J=7.9Hz, 1H), 7.25 (d, J=4.7Hz, 1H), 7.23 (d, J=8.1Hz, 1H), 7.09 (t, J=7.2Hz, 8.1Hz, 1H), 6.98 (dd, J=4.4Hz, 8.4Hz, 2H), 5.28 (d, J=8.9Hz, 1H), 4.32～4.27,3.30～3.26 (m, 3H), 3.51 (s, 3H), 3.21 (s, 3H), 3.19～3.08 (m, 1H), 2.47 (s, 3H), 1.37 (d, J=6.9Hz, 6H) .IR (KBr) v:3304 (NH), 1744 (C=O), 1370 (as, S=O), 1145 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₂₇H ₃₀N ₂O ₄S[M+H] ⁺479.1999 found 479.1990; [M+Na] ⁺501.1818found 501.1837; [M+K] ⁺517.1558 found 517.1551.

In the 100mL round-bottomed flask, add 1mmol N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ' successively, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 5d), the 60mL dehydrated alcohol, the 3mmol80% hydrazine hydrate, 80 ℃ of about 8h of following back flow reaction, TLC steams solvent after detecting the disappearance of raw material point, and resistates separates [silica gel: 300～400 orders by silicagel column; Eluent: petroleum ether-ethyl acetate-ethanol (V: V: V=4: 1: 0.5)] obtain N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 7b), purple crystals, yield 88.1%, m.p.200-202 ℃; ¹H NMR (DMSO-d ₆, 400MHz) δ: 10.79 (s, 1H), 9.09 (s, 1H), 8.17 (s, 1H), 7.76 (d, J=8.5Hz, 1H), 7.64 (d, J=11.0Hz, 1H), 7.49 (s, 1H), 7.32 (d, J=5.2Hz, 1H), 7.27 (dd, J=8.7Hz, 8.1Hz, 2H), 7.14 (d, J=1.9Hz, 1H), 6.98 (t, J=7.1Hz, 8.0Hz, 1H), 6.84 (t, J=7.2Hz, 7.6Hz, 1H), 3.94 (dd, J=8.2Hz, 7.7Hz, 1H), 3.16～3.09 (m, 1H), 3.12 (s, 3H), 3.03～2.91 (m, 2H), 2.50 (s, 3H), 1.92～1.77 (m, 2H), 1.30 (d, J=6.9Hz, 6H) .IR (KBr) v:3294 (NH ₂), 1654 (C=O), 1545 (C-N), 1378 (as, S=O), 1147 (s, S=O) cm ^-1.HRMS (ESI) calcdfor C ₂₆H ₃₀N ₄O ₃S[M-H] ^-477.1960 found 477.1951.

(5) N-(3-(1H-3-indyl)-1-carbonyl-1-(2-(4-trifluoromethyl) benzyl) diazanyl)-2-propyl group)-3 ', the preparation of 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 8b)

In 25mL pyriform bottle, add 0.5mmol N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5_ sec.-propyl Azulene-1 '-sulphonamide (being called for short 7b), the 15mL dehydrated alcohol, 0.6mmol to trifluoromethylated benzaldehyde, the about 30min of stirring at room, TLC follow the tracks of to react to raw material point and disappear, steam solvent, resistates separates [silica gel: 300～400 orders by silicagel column; Eluent: petroleum ether-ethyl acetate-ethanol (V: V: V=4: 1: 0.5)] obtain N-(3-(1H-3-indyl)-1-carbonyl-1-(2-(4-trifluoromethyl) benzyl) diazanyl)-2-propyl group)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (being called for short 8b), the purple powder, yield 98%, m.p.215-216 ℃; ¹H NMR (DMSO-d ₆, 400MHz) δ: 11.40 (s, 1H), 10.72 (d, J=2.14Hz, 1H), 8.09 (s, 1H), 8.06～7.99 (m, 1H), 7.83～7.76 (m, 1H), 7.78 (s, 1H), 7.63 (t, J=8.2Hz, 12.3Hz, 2H), 7.58 (d, J=3.9Hz, 1H), 7.51 (s, 1H), 7.50～7.42 (m, 1H), 7.33～7.28 (m, 1H), 7.24 (d, J=9.2Hz, 1H), 7.22 (d, J=4.3Hz, 1H), 7.15 (t, J=8.1Hz, 10.0Hz, 1H), 7.04～6.74 (m, 1H), 6.90 (dd, J=7.3Hz, 7.1Hz, 1H), 5.16 (dd, J=7.8Hz, 8.6Hz, 1H), 3.15 (s, 3H), 3.09 (dd, J=7.0Hz, 7.3Hz, 2H), 3.04～2.98 (m, 1H), 2.16 (s, 3H), 1.30 (d, J=6.8Hz, 6H) .IR (KBr) v:3273 (NH), 1679 (C=O), 1540 (C=N), 1369 (as, S=O), 1153 (s, S=O) cm ^-1.HRMS (ESI) calcd for C ₃₄H ₃₃F ₃N ₄O ₃S[M-H] ^-633.2147 found 633.2133.

Embodiment 16: present embodiment preparation 3, and 8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate (being called for short 2), its structural formula is as follows:

The processing step of present embodiment is as follows:

3, the preparation of 8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate (being called for short 2)

Embodiment 17: biological activity test

1. experimental drug

Be subjected to reagent:

(1) embodiment 1～embodiment 15 preparation more create blue hydrocarbon azulene derivatives: 5a～5h, 6a～6c, 7a～7b, 8a～8b.

5a:N-methoxycarbonyl methyl-3,8-dimethyl-5-sec.-propyl Azulene-1-sulphonamide (embodiment 1 preparation)

5b:N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 2 preparations)

5c:N-2-phenmethyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 3 preparations)

5d:N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 4 preparations)

5e:N-2-methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 5 preparations)

5f:N-2-methoxycarbonyl methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 6 preparations)

5g:N-(2-methoxycarbonyl)-1-pyrryl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 7 preparations)

5h:N-3-methoxycarbonyl ethyl-3 ', 8 '-dimethyl-5 '-propyl group Azulene-1 '-sulphonamide (embodiment 8 preparations)

6a:N-2-carboxyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 9 preparations)

6b:N-2-(2-methyl-propyl)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 10 preparations)

6c:N-2-(3-skatole)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 11 preparations)

7a:N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 12 preparations)

7b:N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 13 preparations)

8a:N-(2-carbonyl-2-(2-(2-thienyl methene) ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 14 preparations)

8b:N-(3-(1H-3-indyl)-1-carbonyl-1-(2-(4-trifluoromethyl) benzyl) diazanyl)-2-propyl group)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide (embodiment 15 preparations)

(2) sodium azulenesulfonate: 3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate (embodiment 16 preparations).

(3) Xylo-Mucine (CMC): Tianjin recovery fine chemistry industry institute produces.

2. laboratory animal

Kunming mouse, body weight 24～29g, male and female half and half, Sichuan University's Experimental Animal Center provides, animal rank: one-level.

3. laboratory apparatus

(1) electronic balance, the two outstanding fraternal company limiteds of the U.S., model: T-1000, Max=1000g, d=0.1g;

(2) analytical balance, Beijing Sai Duolisi balance company limited, model: BS210S, Max=210g, d=0.1mg.

4. medicine preparation

Sodium azulenesulfonate (embodiment 16) and embodiment 1～embodiment 15 preparations are more created blue hydrocarbon azulene derivatives 5a～5h, 6a～6c, 7a～7b, 8a～8b use mass concentration 0.5% Xylo-Mucine (CMC) liquid to be mixed with the suspension confession experiment usefulness that concentration is 0.5 μ mol/mL respectively.

5. experimental technique

With sodium azulenesulfonate and target compound 5a～5h, 6a～6c, 7a～7b, 8a～8b are mixed with the suspension that concentration is 0.5 μ mol/mL with 0.5%CMC-Na respectively, and do blank (model group) and positive control respectively with 0.5%CMC-Na, omeprazole liquid (0.67mg/mL).Concrete experimental technique is: get Kunming mouse, and by the body weight random packet, 8 every group, male and female half and half.Model group gavages 0.5%CMC-Na liquid 0.4ml/20g; The omeprazole group gavages omeprazole liquid 0.4ml/20g; Sodium azulenesulfonate group and target compound group gavage soup 0.4ml/20g separately respectively.Below respectively organize mouse, be administered once every day, successive administration five days, and behind last administration 0.5h, each organizes mouse gavaging dehydrated alcohol 0.5ml, behind the 1h, puts to death mouse, dissects and gets stomach, cleans, and keeps the score according to the degree of pathology.What contrafluxion was rubescent is 1 minute, and petechial hemorrhage or erosion respectively are 1 minute, and rotten to the corn 1 of wire is 3 minutes.And carry out statistical study, calculate stomach ulcer mark and ulcer inhibition rate [ulcer inhibition rate=(model group stomach ulcer mark-administration group stomach ulcer mark)/model group stomach ulcer mark], and organize a significance difference relatively.Experimental result sees Table 1 and table 2.

(5a～5h is 6a) to the active influence of mouse gastric ulcer for table 1 target compound

^dEach administration group and model group are relatively; * P＜0.05.

Table 2 target compound (6b～6c, 7a～7b, 8a～8b) to the active d that influences of mouse gastric ulcer

^dEach administration group and model group are relatively; * P＜0.05.

From the data of table 1 and table 2 as can be seen, this type of of embodiment 1～embodiment 15 preparations more created blue hydrocarbon azulene derivatives 5a～5h, 6a～6c, 7a～7b, 8a～8b overwhelming majority has certain anti-gastric-ulcer activity, 5d wherein, 5h, 6b, 6c, 8a anti-gastric-ulcer ability is stronger more remarkable, with the model group contrast significant difference is arranged.

Experimental result shows, provided by the present inventionly more creates blue hydrocarbon azulene derivatives and can develop the anti-gastric-ulcer newtype drug with stronger pharmacologically active that makes new advances.

Claims

1. blue hydrocarbon Azulene-1-sulphonamide is more created in novel N-replacement, it is characterized in that structural formula is as follows:

2. novel N-replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide, it is characterized in that processing step is as follows:

The preparation of (1) 3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate

Raw material and prescription thereof:

4mmol more creates blue hydrocarbon Azulene, the dense H of 2mL ₂SO ₄, an amount of NaOH.

Solvent orange 2 A c ₂O 4mL;

Processing step:

(2) preparation of amino acid methyl ester hydrochloride

Raw material and prescription thereof:

8mmol amino acid, 4mL SOCl ₂, NaOH solution, 2% ethanol solution of ninhydrin.

Solvent: methyl alcohol 60mL.

Processing step:

Raw material and prescription thereof:

The 2mmol sodium azulenesulfonate, 5mmol (COCl) ₂, 2.5mmol amino acid methyl ester hydrochloride, 0.8mL DMF, 1.8mL Py, 3mL Et ₃N, rare HCl.

Solvent: CH ₂Cl ₂.

Processing step:

Raw material and prescription thereof:

Blue hydrocarbon Azulene-1-sulphonamide (product N-methoxycarbonyl methyl-3 ' in the A part is more created in 1mmol N-replacement, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5b, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d), 0.8mL 5%NaOH, rare HCl, CH ₂Cl _2.,

Solvent: methyl alcohol 5mL, water 15mL.

Processing step:

Blue hydrocarbon Azulene-1-sulphonamide (N-methoxycarbonyl methyl-3 ' is more created in 1mmol N-replacement, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5b, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d) is dissolved in 5mL methyl alcohol and the 15mL water,, uses CH toward wherein adding 5%NaOH solution 0.8mL ₂Cl ₂Extract three times, stay water layer.In water layer, slowly add rare HCl to pH=5～6, use CH ₂Cl ₂Extract three times, merge organic layer, steam solvent, resistates gets the described N-replacement of claim 3 by silica gel column chromatography separating purification and more creates blue hydrocarbon Azulene-1-sulphonamide (B part).

Raw material and prescription thereof:

Blue hydrocarbon Azulene-1-sulphonamide (N-methoxycarbonyl methyl-3 ' is more created in 1mmol N-replacement, 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d), 3mmol 80% hydrazine hydrate.

Solvent: dehydrated alcohol 60mL.

Processing step:

In the 100mL round-bottomed flask, add 1mmol N-replacement successively and more create blue hydrocarbon Azulene-1-sulphonamide (N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5a, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 5d), the 60mL dehydrated alcohol, 3mmol 80% hydrazine hydrate, 80 ℃ of about 8h of following back flow reaction, after TLC detects the disappearance of raw material point, steam solvent, resistates gets the described N-replacement of claim 3 by the silicagel column separation and purification and more creates blue hydrocarbon Azulene-1-sulphonamide (C part).

Raw material and prescription thereof:

0.5mmol replacing, N-more creates blue hydrocarbon Azulene-1-sulphonamide (N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7a, N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7b), 0.6mmol aromatic aldehyde.

Solvent: dehydrated alcohol 15mL.

Processing step:

In 25mL pyriform bottle, add 0.5mmol N-replacement and more create blue hydrocarbon Azulene-1-sulphonamide (N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7a, N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide 7b), the 15mL dehydrated alcohol, 0.6mmol aromatic aldehyde, room temperature or 35 ℃ of following stirrings are spent the night, TLC follows the tracks of to react to raw material point and disappears, steam solvent, resistates gets the described N-replacement of claim 3 by the silicagel column separation and purification and more creates blue hydrocarbon Azulene-1-sulphonamide (D part).

3. N-according to claim 2 replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (A part), it is characterized in that product is a N-methoxycarbonyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(2-methyl-propyl)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-phenmethyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(3-skatole)-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-methoxycarbonyl methyl-2-methoxycarbonyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-(2-methoxycarbonyl)-1-pyrryl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-3-methoxycarbonyl ethyl-3 ', in 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide-kind.

N-according to claim 2 replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (B part), it is characterized in that product is a N-2-carboxyl methyl-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(2-methyl-propyl)-2-carboxyl methylene radical-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-2-(3-skatole)-2-carboxyl methylene radical-3 ', a kind of in 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide.

N-according to claim 2 replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (C part), it is characterized in that product is N-(2-diazanyl-2-oxygen ethyl)-3 ', 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide, N-(1-diazanyl-3-(1H-3-indyl)-1-propionyl-2-yl)-3 ', a kind of in 8 '-dimethyl-5 '-sec.-propyl Azulene-1 '-sulphonamide.

N-according to claim 2 replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (D part), it is characterized in that aromatic aldehyde is a 2 thiophene carboxaldehyde, a kind of in the trifluoromethylated benzaldehyde.

4. according to the preparation of claim 2 or 3 described (1) 3,8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonates; (2) N-replaces the preparation method who more creates blue hydrocarbon Azulene-1-sulphonamide (A, B, C, D four parts).It is characterized in that preparing 3, during 8-dimethyl-5-sec.-propyl Azulene-1-sodium sulfonate, solvent for use is Ac ₂O; N-replaces when more creating the preparation of blue hydrocarbon Azulene-1-sulphonamide (A part), and solvent for use is CH ₂Cl ₂N-replaces when more creating the preparation of blue hydrocarbon Azulene-1-sulphonamide (B part), and solvent for use is the first alcohol and water; N-replaces when more creating the preparation of blue hydrocarbon Azulene-1-sulphonamide (C, D part), and solvent for use is a dehydrated alcohol.

5. the application of blue hydrocarbon Azulene-1-sulphonamide in the preparation medicament for anti-gastric ulcer more created in the described N-replacement of arbitrary claim in the claim 1 to 4.Comprise by its tablet that is prepared from, pill, granule, capsule and injection or other clinical acceptable suitable dosage forms.