CN101223177A水溶性青蒿素衍生物｜CN101223177A: Water-Soluble Derivatives of Artemisinin

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CN101223177A水溶性青蒿素衍生物

CN101223177A: Water-Soluble Derivatives of Artemisinin

水溶性青蒿素衍生物、制法、药物组合物及用途

本发明公开了一类水溶性青蒿素衍生物、制备方法、药物组合物及它的用途。该类衍生物的结构如右，经药理试验证明该类化合物及药物组合物具有明显的免疫抑制活性作用，可开发成为治疗人体免疫功能亢进引起的疾病(红斑狼疮、类风湿关节炎，多发性硬化症等自身免疫性疾病)，以及细胞器官移植后抗移植物排斥反应的新型免疫抑制药物。

PCT国内申请，说明书已公开。

Water-soluble arteannuin derivant, production method, medicine composition and usage

Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions containing them and the use thereof are disclosed. The artemisinin derivatives have the structure as following: These compounds and compositions have immuno-suppressive activities which has been proved by pharmacological test, and may be used to prepare novel immuno-suppressants for treating the diseases caused by hypofunction of human immunity( e. g. auto-immune diseases such as lupus erythematosus, rheumatoid arthritis, multiple sclerosis and the like), and may be useful as anti-rejection agentsin organ transplantation.

Water-soluble arteannuin derivant, preparation method, pharmaceutical composition and purposes

Ice dissolubility artemisinin derivative, preparation method, pharmaceutical composition and purposes

Technical field

The present invention relates to the chemical synthesis of terpenoid and its immunosuppressive action, and in particular to new artemisine compounds and preparation method thereof and the pharmaceutical composition as immunodepressant.Background technology

Qinghaosu is from Chinese medicine sweet wormwood（Plant Artemisia annua Artemisia a draw a L.) the antimalarial active ingredient that extracts, a kind of rare sesquiterpene lactone containing peroxy-radical.It not only has remarkable anti-Zuo effects, it was found that have immunosuppressive action.Its derivative Artesunate has stronger immunosuppressive action, can treat lupus erythematosus and some skin diseases, obtains good therapeutic effect [remaining its refined etc., Artesunate lupus hung classes 56, Chinese journal of dermatology, 1997,39： 51；Chen Hua etc., Artesunate eczema-dermatitis and light sensitive dermatoses clinical observation, institute of Bengbu Medical College report, 1991,16： 251].But patient needs long-term intravenous to inject, the sodium-salt aqueous solution of Artesunate will be in prepared before use, using being inconvenient.Present clinical is often expensive and toxic to kidney, liver with immune suppressive cyclosporin A, causes some patients to adhere to medication.Therefore, present inventor expands the research for finding more efficient, safer immunodepressant.

Qinghaosu Artesunate present inventor, which once studies, finds that the artemisinin derivative that a class contains carboxylic acid functional has stronger immunosuppressive action（Chinese invention patent, application number： 200510023824.1 ).But theirs is water-soluble small, and possible bioavilability is undesirable.Thus continually look for more preferably immunodepressant.

It is an object of the invention to provide a class water-soluble arteannuin derivant for the content of the invention.

Another object of the present invention is to provide the preparation method of the analog derivative. It is yet another object of the invention to provide the purposes of the analog derivative.

It is a further object to provide the pharmaceutical composition of the analog derivative.The present invention provides such as following formula（1) compound shown in, its isomers and pharmaceutical salts:

(1)

Formula（1) in

As n=0, X=Y=H, Z=NH₂

As n=l, X=OH, Y=H, Z=NH₂, NHMe, NHEt, NHPr(n), NHBu, As n=l, X=OH, Y=CH₃, phenyl etc.

Z - NH₂, NHR (R = d-C₄Alkyl), NHCH₂CH₂OH, NR,₂(R ,=d-C₄Alkyl,

NH(CH₂)₂.₃NMe₂ NQ -CH, ³

Formula（L) isomers of compound shown in includes but is not limited to stereoisomer and optical isomer.

Formula（1) pharmaceutical salts of compound shown in include but is not limited to the addition salts with hydrochloric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, oxalic acid, tartaric acid, citric acid etc..

The formula of the present invention（1) it is preferably such as following formula in compound（1) compound, wherein,

n = 0, X = Y=H,Z = NH₂;

n= l;X Offer formula α of the present invention) shown in compound, its isomers and pharmaceutical salts.They are with dihydroartemisinine（2) it is raw material, is reacted under acid catalysed conditions with substituted alcohols.Such as substituted alcohols are halohydrin, then and then with amine react, generate target compound（1, η=0).Such as substituted alcohols are dihydric alcohol, then first generate hydroxyl qinghaosu ether, are then translated into p-methyl benzenesulfonic acid ester, then are reacted with amine, generate target compound（1, η=0 such as substituted alcohols are epoxy prapanol, and obtained sweet wormwood glycidyl ethers react with amine, generate target compound（1, η=1).As substituted alcohols are propenyls, it is necessary to be further oxidized to sweet wormwood glycidyl ethers；Reacted again with amine, generate target compound（1, η=1).In the organic solvents such as alcohol with inorganic acid or organic acid corresponding salt can be made in target compound containing unhindered amina.Formula obtained by the inventive method（1) compound can be refined with conventional technique.

Some specific preparation methods can refer to the patent of present inventor（12454.9) and the paper J. Med. Chem. 2000,43 (8) that have delivered ZL 89 1 09562.4, ZL 93 1:1635-1640 includes the formula in safely, effectively dosage range the present invention further provides a kind of pharmaceutical composition with immunosuppressive action, described pharmaceutical composition（1) compound or pharmaceutically acceptable salt thereof shown in and pharmaceutically acceptable carrier.

" safely, effectively dosage " is referred to：The amount of compound is enough to be obviously improved the state of an illness, and is unlikely to produce serious side effect.The safely, effectively dosage of compound is determined according to concrete conditions such as treatment target Elderly, body weight, treatment indication, method of administration, the course for the treatment of and any related treatments.Adult generally 10 mg/ days to 800 mg/ days, in single or divided doses.Children are cut down according to the circumstance.

Substituted amino qinghaosu ether（By weight percentage） 1-55 %

Excipient（By weight percentage） 15-40%

Adjuvant（By weight percentage） 20-65%

The composition of the present invention can be used for oral, parenteral, intranasal, is administered through tongue, through eye, through respiratory tract or per rectum, especially tablet or enteric coated pill, liquid drugs injection, sublingual tablets, patch, suppository, creme, ointment, skin gel etc..

" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solid or liquid fillers or excipient, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity.In " compatibility " referred to herein as composition each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmaceutically acceptable carrier part example has sugar（Such as glucose, sucrose, lactose）, starch（Such as cornstarch, farina）, cellulose and its derivates（Such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate, microcrystalline cellulose）, polyethylene glycol, gelatin, talcum powder, stearic acid, magnesium stearate, calcium sulfate, Plant gentry（Such as soya-bean oil, sesame oil, peanut oil, olive oil）.It can also be emulsifying agent（Such as tween), wetting agent (such as 12 protective embankment base sodium sulphate）, colouring agent, flavor enhancement, stabilizer, preservative, apirogen water etc..Selection of the composition of the present invention to carrier depends on the administering mode of compound.

Present inventor uses following method, and the screening and research of the immunosuppressive activity of in vitro and in vivo have been carried out to compound of the invention.（Reference book：Modern pharmacology experimental method, Zhang Juntian chief editors, Beijing Medical University/combined publication society of China Concord Medical Science University publishes for 1998）.One, experiment material experimental animals:It is sheerly Balb/c male mices, 6-8 week old.

RPMI- 1640 culture mediums (Gibco, pH7.2) add 10% hyclone (FBS), 100'U/ml penicillin, lOO g/ml streptomysins, 10mM HEPES, the and-Μ Ε of 50 μ Μ 2.Stimulant：ConA（), ConA bacteria lipopolysaccharide（LPS, Lai Zi ＆ceric sCbJ/055:B5), suitable concn is diluted to RPMI- 1640 culture mediums before use.Two, experimental methods

[one] lymphocytotoxicity is tested

1. vertebra puts to death mouse, sterile to take its spleen, grind and single cell suspension is made, use MTT lysates（10%SDS, 50% dimethylformamide；PH7.2) remove after red blood cell, cell concentration is tuned into 5xl0 with the RPMI-1640 nutrient solutions containing 10%FBS⁶/ml。 .

80 μ 1 cell suspension, 40 u 1 sample, 40 nutrient solutions of the μ 1 containing 10%FBS are added in 2.96 well culture plates；Control plus the nutrient solutions of 80 μ 1, cumulative volume are 160 μ 1.And set blank control.

3. it is put into 37 °C, 5% C0₂Cultivated 48 hours in incubator.6-7 hours before culture is terminated, add the μ 1 of 5mg/ml MTT 16 per hole.

4. terminate culture, add the MTT lysates of 80 μ 1 per hole（10%SDS, 50% dimethylformamide；PH7.2), after being placed 6-7 hours in incubator, 0D is determined at 570nm with ELIASA₅₇.Value.

[two] lymphocyte proliferation assay

1. de- vertebra puts to death mouse, sterile to take spleen that single cell suspension is made, cell concentration is tuned into 4xl07ml with the nutrient solutions of RPMI- 1640 containing 10%FBS. 2. adding 100 μ 1 cell suspension in 96 orifice plates, 50 μ 1 sample solution, ConA the or LPS solution of 50 μ 1, control wells add 50 nutrient solutions of the μ 1 containing 10%FBS.Cumulative volume is 200 μ 1.

3. in 37 °C, 5% C0₂Cultivated 48 hours in incubator.7-8 hours before culture is terminated, add 0. 5 Ci []-thymidine per hole（The holes of 25 μ 1/）.

4. terminating culture, cell collector is used（HARVESTER96, Τ Ο Μ Τ Ε Ο collect cell on glass fibre membrane, add scintillation solution, with liquid scintillation numeration instrument（MicroBeta Trilux, PerkinElmer) detection cell DNA in []-thymidine incorporation, reflect cell proliferative conditions.

[three] Allogeneic Mixed Lymphocyte breeder reaction (MLR)

1. de- vertebra puts to death C57BL/6 and Balb/c mouse, sterile to take its spleen, grind and single cell suspension is made, remove after red blood cell, cell concentration is tuned into 6xl0 with the RPMI-1640 nutrient solutions containing 10% calf serum⁶/ml。

2. C57BL/6 splenocytes are reacting cells, Balb/c splenocytes（Irradiated through Co 60,3000 rads) to stimulate cell, two kinds of cells are mixed in equal volume.

3. the μ 1 of cell mixture 100, the μ 1 of sample 100 are added in 96 orifice plates, the nutrient solution of control plus 100 μ 1 containing 10% serum.And do the independent culture control of two kinds of cells.

4. 37 °C, 5% C0₂Cultivated in incubator 3,4,5 days.Terminate first 1 day of culture, add (that is, 3. 8xl0 of 25 μ of dilution 1^1DBq []-thymidine）.

5. terminate culture, culture plate is frozen in -20 °C of refrigerators.

6. cell collector（HARVESTER96, T0MTEC cell) is collected on glass fibre membrane, incorporations of numeration instrument (MicroBeta Trilux, PerkinElmer) the detection DNA to []-thymidine is dodged with liquid, reflects cell proliferative conditions.

[four] delayed type hypersensitivity, DTH animal model（DTH)

1. DayO, Balb/c mouse（Female, 6-8 weeks Elderly）Every group ten, every rear foot is with 20 1 0. 5% DNFB sensitization.Next day is strengthened.（DNFB is dissolved in [acetone：Olive oil=4:1] in finish）；

2. each DNFB of 10 μ 1 0. 4% are attacked inside and outside Day (7-9), mouse auris dextra；

3. the preceding 1 day abdominal cavity gavage of attack is once, attacks preceding abdominal cavity gavage once, after 24 hours, then be administered once； 4. 30-48 hours after attack, detect each index.

[five] the mouse arthritis animal model ox II Collagen Type VIs of ox II Collagen Type VIs induction（CII, Collagen Research Center, Tokyo, Japan) 0. IN acetums are dissolved in, in 4 °C of refrigerator overnights.Experimental day is by the strain of tuberculosis containing Mycobacterium H37Rv CFA (Walco Pure Chemical industries Ltd., Osaka, Japan) with CII it is isometric it is fully emulsified hook, (the μ containing CII 125 of 25 μ of emulsifying agent 1 are subcutaneously injected in DBA/1 mouse tails_§) sensitization is carried out, it is immunized again in afterbody with the emulsifying agent of same dose after 3 weeks, this time adjuvant uses IFA.Begin to be administered second of immune the previous day Jian（Intraperitoneal injection or gavage）, successive administration 2 weeks to 3 months.Using rank scores method. 0:Without redness； 1 :Toe joint slightly swells； 2：Toe joint and pedal swelling； 3 :Sufficient pawl swelling below ankle-joint； 4:Whole sufficient pawl swellings including ankle-joint.The summation of every animal foot scoring represents the CIA order of severity.

Three, experimental results

[one] the effect performance of lymphopoiesis and toxicity test immune response process is mainly made up of the humoral immune reaction of cell immune response and the B cell mediation mediated with T cell.The activated dissociation of cell and cell is directly stimulated to breed to evaluate the inhibitory activity of medicine lymphproliferation response with T cell mitogen ConA and B cell mitogen LPS in vitro；Screening repeatedly has been carried out on 10 μ Μ, Ι μ Μ, 0. 1 concentration of μ Μ tri- first.Wherein three compounds with obvious immunosuppressive activity are embodiment 1, embodiment 11, embodiment 14, and they are not having cytotoxic concentration, breed the inhibiting rate of (Con A) to Τ cells respectively up to 65%, 48%, 52%；To B cell proliferation（LPS inhibiting rate) is respectively up to 73%, 99%, 81%；Embodiment 2, embodiment 3, embodiment 12 are not having cytotoxic concentration, T cell is bred the inhibiting rate of (Con A) respectively up to 48%, 47%, 47 °/., to B cell proliferation（LPS inhibiting rate) is respectively up to 48%, 51%, 47%；Embodiment 8, embodiment 16, embodiment 17, embodiment 18 are not having cytotoxic concentration, and T cell is bred（Con A) inhibiting rate be 13%, 0%, 6%, 9% respectively, to B cell proliferation（LPS as a result inhibiting rate) shows that this four compounds are stronger to the inhibitory activity of B cell proliferation respectively up to 42%, 51%, 24%, 26%, but has in no cytotoxicity seldom or without inhibitory action to T cell.Based on the above results, embodiment 1, embodiment 11, embodiment 14 are selected in vivo and external its immunosupress pharmacology of further inspection Check is active.

[two] Allogeneic Mixed Lymphocyte breeder reaction (MLR) alloantigen is the main cause for causing body rejection after blood transfusion, organ transplant.When response lymphocyte and the co-cultivation of heterologous lymphocyte, the alloantigen on heterologous lymphocyte, mainly histocompatibility antigen are expressed MHC- 1, MHC- II molecules, stimulation responses T cell trigger immunoproliferation reaction.Medicine is evaluated to the pharmacological action closer to physiological immune system response to MLR effect by medicine.As illustrated, embodiment 1, embodiment 11, embodiment 14 significantly inhibit the propagation of response lymphocyte in MLR, their EC50 is respectively： 3. 48 ±0. 72 μ Μ 、 0. 59 ±0. 066 μ Μ、 0. 67±0. 012 μ Μ.

[three] delayed type hypersensitivity, DTH animal model（DTH)

- Wei Jin mono- Walk check embodiment 1, embodiment 11, the immunopharmacological activity of embodiment 14 in vivo, show that embodiment 1, embodiment 11, embodiment 14 respectively can significantly suppress mice ear degree in oral 50mg/kg, 100mg/kg, 50mg/kg from classical mouse DTH reaction model results（P<0. 01) the inhibiting rate difference 56. 5% compared with control group, is 50. 5%, 52. 2%, with ciclosporin A (CsA) 5mg/kg 40. 6 ° of inhibiting rate/.Pharmacological activity is suitable.

[four] mouse arthritis animal model

Embodiment 1 and embodiment 14 further examine its immunopharmacological activity of Check on mouse arthritis animal model.As a result show that embodiment 1 and embodiment 14 can significantly suppress mouse arthroncus degree (P in oral lmg/kg, 0. 5mg/kg respectively<05) 0. illustrate

Fig. 1 is that to significantly reduce DTH mice ears thickness chart 2 be that auricle weight difference embodiment 1, embodiment 11, embodiment 14 significantly reduce DTH mouse swelling auricle weight for ear swelling thickness difference embodiment 1, embodiment 11, embodiment 14

Fig. 3 is the arthritis score of embodiment 1.

The mouse arthritis of the preventing and treating ox Type Ⅱ collagen induction of embodiment 11, suppress morbidity arthroncus

Fig. 4 is the arthritis score of embodiment 14.

The mouse arthritis of the preventing and treating ox Type Ⅱ collagen induction of embodiment 14, suppress morbidity arthroncus embodiment

With reference to embodiment, the present invention is further elaborated, but these embodiments are definitely not any limitation of the invention.（Composition is by weight percentage in the following example） Qinghaosu parent nucleus is represented with Q in the examples below that

(Q) wave molding（One）Represent β substitution or/and α substitution ' straight line（One "¹) represent β substitutions

Dotted line（) represent α substitution embodiments 12 ,-amino arteether（β types） With maleic acid into salt.White crystals.Fusing point： 139— 141°C.Elementary analysis（C₂₁H₃₃N0₉)_:

Calculated value：The N3.16 measured values of 56.87 H of C 7.50：3'- amino -2'- hydroxyl wormwood artemisia the propyl ether of 56.84 H of C, 7.59 N3.10. embodiments 2（β types）

Q-0-C-C-C-NH.

Η Shang H_Q 2 OH ²With maleic acid into salt.White crystals.Fusing point： 146— 147°C.Elementary analysis (C₂₂H₃₅O₁₀N):

Calculated value：The measured values of 55.80 H of C, 7.45 N 2.96：The light base wormwood artemisia propyl ether of 3'- methylaminos -2'- of 55.92 H of C, 7.43 N 2.94. embodiments 3（β types）

Q-0-C-C-C

H I I

2 OHNHMe and maleic acid are into salt.White crystals.Fusing point： 145— 146°C.Elementary analysis（C₂₃H₃₇O₁₀N): Calculated value：The measured values of 56.66 H of C, 7.65 N 2.87：3'- methylamino -2'- hydroxyl wormwood artemisia the butyl ether of 56.67 H of C, 7.63 N 2.89. embodiments 4（β types）

Η Η

Q-0-C-C-C-Me H I I

2 OH NHMe and maleic acid are into salt.White amorphous solid.

Elementary analysis（C₂₄H₃₉ O₁₀N)_:

Calculated value：3'- amino -2'- hydroxyl wormwood artemisia the butyl ether of 7.66 N 2.67. embodiments of C 57.47 H, 7.84 N, 2.79 measured value C, 57.72 H 5（β types） With maleic acid into salt.White amorphous solid.

Elementary analysis（C₂₃ H₃₇0₁₍₎N)_:

Calculated value：The measured values of 56.66 H of C, 7.65 N 2.87：3'- hydroxyethylamino -2'- hydroxyl wormwood artemisia the propyl ether of 56.64 H of C, 7.74 N 2.71. embodiments 6（β types）

With maleic acid into salt.White amorphous solid.

Elementary analysis（C₂₄ H₃₉ O_uN)_:

Calculated value：The measured values of 55.70 H of C, 7.59 N 2.71：3'- phenyl -3'- methylamino -2'- hydroxyl wormwood artemisia the propyl ether of 55.69 H of C, 7.89 N 2.58. embodiments 7（β types）

It is sour into salt with horse Come.White amorphous solid Elementary analysis (C₂9l-l4iO₁₀N):

Calculated value：The measured values of 61.80 H of C, 7.33 N 2.49：3'- phenyl -3'- amino -2'- hydroxyl wormwood artemisia the propyl ether of 61.64 H of C, 7.41 N 2.48. embodiments 8（β types) It is sour into salt with horse Come.White amorphous solid.

Elementary analysis（C₂₈H₃₉0₁₍₎N)_:

Calculated value：The N measured values of 61.19 H of C 7.15：3'- hydroxyethylamino -2'- hydroxyls the third butyl ether of wormwood artemisia of 61.29 H of C, 7.23 N embodiments 9（β types) With maleic acid into salt.White amorphous solid.

Elementary analysis (C₂₅H₄₁O_nN):

Calculated value：The N measured values of 56.49 H of C 7.77：3'- dimethylamino -2'- hydroxyl wormwood artemisia the butyl ether of 56.21 H of C, 7.94 N embodiments 10（β types） With maleic acid into salt.White amorphous solid.

Elementary analysis（C₂₅H₄₁0₁₍₎N)_:

Calculated value：The measured values of 58.24 H of C 8.02： C 58.06 H 7.99 The 3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether types of embodiment 11）

With maleic acid into salt.White crystals.Fusing point： 158- 160 °Co (J. Med. Chem. 2000, 43 (8):1635-1640 reports that the melting point compound is 148-152 °C)

Elementary analysis（C₂₆H₄₁0₁₍₎N)_:

Calculated value： C 59.19 H 7.83 N 2.65

Measured value： C 59.14 H 7.86 N 2.66.

3'- piperidyl -2'- hydroxyl wormwood artemisia the propyl ether of embodiment 12（β types）

With maleic acid into salt.White crystals.Fusing point： 157— 159 °C.

Elementary analysis（C₂₇H₄₃(½N)_:

Calculated value： C 59.87 H 8.00 N 2.59

Measured value： C 59.86 H 8.02 N 2.58.

Light base wormwood artemisia butyl ether (the α types of the 3'- methylaminos -2'- of embodiment 13）

With maleic acid into salt.White amorphous solid.

Elementary analysis（C₂₄H₃₉ O₁₀N)_:

Calculated value： C 57.47 H 7.84 N 2.79

Measured value： C 57.62 H 7.51 N 2.61.

The 3'- tert-butylamine base -2'- hydroxyl wormwood artemisia propyl ether of embodiment 14（β types）

With maleic acid into salt.White crystals.Fusing point： 171— 173 °C.

Elementary analysis（C₂₆H₄₃0₁₍₎N)_:

Calculated value： C 58.96 H 8.18 N 2.64

Measured value： C 58.92 H 7.91 N 2.59. 3'- phenyl -3'- nafoxidine base -2'- hydroxyl wormwood artemisia the propyl ether of embodiment 15（β types)

With maleic acid into salt.White amorphous solid.

Elementary analysis (C₃₂H₄₅O₁₀N):

Calculated value：The measured values of 63.67 H of C, 7.51 N 2.32：3'- phenyl -3'- piperidyl -2'- hydroxyl wormwood artemisia the propyl ether of 63.36 H of C, 7.09 N 2.04. embodiments 16（β types）

With maleic acid into salt.White crystals.Fusing point： 163— 165 °C.Elementary analysis（C₃₃H₄₇O₁₀N)_:

Calculated value：The measured values of 64.16 H of C, 7.67 N 2.27：The light base wormwood artemisia propyl ether of 3'- phenyl -3'- dimethylaminos -2'- of 64.43 H of C, 7.68 N 2.18. embodiments 17（6 types）

It is sour into salt with horse Come.White crystals.Fusing point： 166— 168 °C.Elementary analysis（C^i^C QN):

Calculated value：The measured values of 62.38 H of C, 7.50 N 2.42：The tertiary fourth amino -2'- hydroxyls wormwood artemisia propyl ether of 3'- phenyl -3'- diformazans of 62.05 H of C, 7.68 N 2.41. embodiments 18（β types)

With maleic acid into salt.White crystals.Fusing point： 167— 169 °C.Elementary analysis (C₃₂H₄₇O₁₀N):

Calculated value： C 63.45 H 7.82 N 2.31 Measured value：The N embodiments 19 2 of 63.70 H of C 7.83 ,-amino arteether ^ types) maleate tablet formulation is as follows：

2'- amino arteethers（β types) 35 % starch of maleate, 25 % sodium cellulose glycolates 30 % starch slurries (10 %) 9 % stearic acid 1 % active component is crushed, 100 mesh sieve, mixed with sodium cellulose glycolate, 10% starch slurry, pelletize, dry, add dried starch, lubricant to mix, tabletting.

The 3'- tert-butylamine base -2'- hydroxyl wormwood artemisia propyl ether of embodiment 20（β types）Maleate tablet

Prescription is as follows：

3'- tert-butylamine base -2'- hydroxyl wormwood artemisia propyl ether（β types） 30 %

The % of Macrogol 4000 5 of the % of microcrystalline cellulose 65 micronizings crushes active component, sieves, with microcrystalline cellulose, the uniform rear direct tablet compressing of mix lubricant.Embodiment 21 2 ,-amino arteether（β types) citrate casing piece

Prescription is as follows：

2 ,-amino arteether type) 35% starch of citrate, 20 % dried starch 35 % starch slurries (10 %) 8 % talcum powder, 2 % Active component and starch are well mixed, plus softwood is made in 10 % starch slurries, pelletizes, and dries, whole grain, adds dried starch, talcum powder and mixes, tabletting is enteric coated.

The light base wormwood artemisia propyl ether of 3'- nafoxidine bases -2'- of embodiment 22（β types）The ebonite Nang of oxalates

Prescription is as follows：

3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether（β types）The % of 50% microcrystalline cellulose of oxalates, 30% polyethylene glycol 1500 20 is sufficiently mixed active component and auxiliary material uniformly, is fitted into capsulae vacuus.The 3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether types of embodiment 23）Gel ' prescription is as follows：

3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether（β types）The % of 35 %-polyethylene glycol 65 is by Liquid Macrogol and polyethylene glycol 1500 (1：1) agitating and heating, after fusion, adds the active component of grinding sieving, is sufficiently stirred for into gel.The 2'- amino arteethers of embodiment 24（β types) maleate liquid drugs injection dissolves active component water for injection, filters, embedding, sterilizing.

Claim

1st, a class has water-soluble arteannuin derivant, stereoisomer and the optical isomer and pharmaceutically acceptable salt of following structural formula

(1)

Wherein：

As n=0, X=Y=H, Z=NH2

' as n=1, X=OH, Y=H, Z=NH2, NHMe, NHEt, NHPr(n), NHBu, As n=l, X=OH, Y=C, phenyl,

Z = N¾, NHR (R = Ci-C4Protective embankment base), NHCH2CH2OH, NR'2(R ,=C C4Alkyl),

2nd, water-soluble arteannuin derivant according to claim 1, it is characterised in that

As n=0, X=Y=H, Z=N is 2 ,-amino arteether（β types) and its can hyoscine acid-addition salts. 3rd, water-soluble arteannuin according to claim 1 derives plain thing, it is characterised in that

As n=l, X=OH, Y=H, Z=NH2, NHMe, NHEt, NHPr(n), NHBu,

Particularly 3'- tert-butylamines base -2'- hydroxyls wormwood artemisia propyl ether（β types) and its can hyoscine acid-addition salts and 3'- nafoxidine base -2'- footpaths base wormwood artemisia propyl ether type）And its can hyoscine acid-addition salts.

4th, water-soluble arteannuin derivant according to claim 1, it is characterised in that

As n=l, X=OH, Y=CH3)Phenyl,

Z = NH2, NHR (R=C C alkyl), NHCH2CH2OH, NR'2(R ,=d-C4Alkyl),

5th, the preparation method of water-soluble arteannuin derivant as claimed in claim 1, comprises the following steps：A. dihydroartemisinine is that raw material is halohydrin reaction, gained compound and aminated compounds reaction generation target compound with substituted alcohols in acid condition（1, n=0);

B. dihydroartemisinine is that raw material is in acid condition diol reaction with substituted alcohols, then first generates hydroxyl qinghaosu ether, be then then converted to p-methyl benzenesulfonic acid ester, finally with amine reaction generation target compound（1, n=0);

C. dihydroartemisinine is raw material when being epoxy prapanol reaction with substituted alcohols in acid condition, and obtained qinghaosu reacts with amine, generates target compound（1, n=l);

D. dihydroartemisinine be raw material be with substituted alcohols in acid condition propenyl reaction when, be first oxidized to qinghaosu glycidyl ethers, then with amine reaction generation target compound（1, n=l).

6th, the composition of water-soluble arteannuin derivant as claimed in claim 1, it is characterised in that be made up of following composition（By weight percentage）：

Substituted amino qinghaosu ether 1-55%

Excipient 15-40%

Adjuvant 20-65%.

7th, the composition of water-soluble arteannuin derivant according to claim 6, it is characterised in that pharmaceutically acceptable excipient is sugar（Glucose, sucrose, lactose), starch（Cornstarch, farina), cellulose and its derivates（Sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate, microcrystalline cellulose）, it is poly- ^ glycol, bright Glue, talcum powder, stearic acid, magnesium stearate, calcium sulfate, vegetable oil（Soya-bean oil, sesame oil, peanut oil, olive oil）；It can also be emulsifying agent（Tween), wetting agent（Lauryl sodium sulfate）, colouring agent, flavor enhancement, stabilizer, preservative, apirogen water.

8th, the purposes of water-soluble arteannuin derivant as claimed in claim 1, prepare prevention, treat because of immune function of human body it is hyperfunction caused by apply in disease, including the medicine of autoimmune disease such as lupus erythematosus, rheumatoid arthritis, multiple sclerosis.

9th, the purposes of water-soluble arteannuin derivant according to claim 11, it is characterised in that applied in the immunosuppressive drug of anti-rejection after preparing organelle transplanting.