CN101367800A - Synthesis of tubercle bacillus resistant medicament 3-alkoxyl-8-alkyl -12-R3-jatrorrhizine salt and uses thereof - Google Patents
Synthesis of tubercle bacillus resistant medicament 3-alkoxyl-8-alkyl -12-R3-jatrorrhizine salt and uses thereof Download PDFInfo
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Abstract
The present invention relates to a novel chemical substance, 3-alkoxyl-8-alkyl-12-R3-jatrorrhizine salt. The 3-alkoxyl-8-alkyl-12-R3-jatrorrhizine salt has a molecular structural formula as shown on the right, wherein, X is F<->, Cl<->, Br<->, I<->, SO4<2->, NO3<->, PO4<3->, lemon acid radical, radical vinegar or lactic acid radical; R1 is CnH2n+1 with n between 2 and 10; R2 is CnH2n+1 with n between 2 and 10; and R3 is H, F, Cl, Br or I. The present invention has obvious activity for anti-mycobacterium tuberculosis, which is 100 to 5,000 times higher than berberine and jatrorrhizine, and the present invention is a novel compound which has promising medical value for anti-mycobacterium tuberculosis, and the like.
Description
Technical field
The present invention relates to a class new compound and a medicinal use thereof, be specifically related to the new chemical substance of a class, 3-alkoxyl group-8-alkyl-12-R
3-jateorhizine salt derivative.
Background technology
Berberine (Berberine) claims berberine again, is a kind of traditional natural antibacterial active substance that extracts from the coptis, is mainly used in the medicine for treatment that the intestinal bacteria sexuality is dyed clinically.In recent years pharmacological research finds that berberine hydrochloride and some structural derivative thereof have antibiotic, and anti-inflammatory is antitumor, multiple pharmacologically actives such as hypoglycemic and reducing blood-fat.Therefore, further investigation and the structure of modification work to the berberine hydrochloride pharmacological action excites wide spread interest.Structure activity study result to Berberine shows that at 8 introducing alkyl (methane is to octane) of Berberine molecule, its anti-microbial activity increases.Applicant's early-stage Study result shows that behind 8 introducing chain alkyls (ethane is to 12 alkyl), its anti-microbial activity increases, and during to 8 alkyl berberines, the anti-microbial activity maximum descends then; Behind 3 introducing alkoxyl groups of jateorhizine (Berberine analogue), the variation of the anti-microbial activity of the 3-alkoxyl group jateorhizine of formation and 8-alkyl berberine all fours; Introduce the research work that alkyl forms aspect 3-alkoxyl group-8-alkyl jateorhizine salt simultaneously 3 and 8 of jateorhizine and do not appear in the newspapers as yet, especially any report is not seen in the research work of this compounds aspect anti-mycobacterium tuberculosis.
Summary of the invention
The objective of the invention is to propose 3-alkoxyl group-8-alkyl-12-R
3-jateorhizine salt derivative discloses the purposes of bacterium aspects such as its anti-mycobacterium tuberculosis, and the tubercle bacillus resistant activity of this compounds is apparently higher than berberine hydrochloride and jateorhizine salt.
The present invention relates to the new chemical substance of a class, 3-alkoxyl group-8-alkyl-12-R
3-jateorhizine salt, its molecular structural formula is as follows:
Wherein, X=F
-, Cl
-, Br
-, I
-, SO
4 2-, NO
3 -, PO
4 3-, citrate, acetate or lactate; R
1=C
nH2n+1, n=2～10; R
2=C
nH2n+1, n=2～10; R
3=H or F or Cl or Br or I.
3-alkoxyl group-8-alkyl-12-R
3The synthetic method of-jateorhizine salt is as follows:
(1), be reaction solvent with DMF, jateorhizine is joined among the DMF, after the rising temperature for dissolving, add the haloalkane of 1～10 times of mol ratio, after mixing, back flow reaction 2～5 hours;
(2), after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-alkoxyl group jateorhizine salt crude product, after the DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-alkoxyl group jateorhizine salt;
(3) be reaction solvent with anhydrous tetrahydro furan, ether or dioxane, under nitrogen protection, press (X-C with magnesium chips and haloalkane
nH2n+1, n=2～10; X=F
-, Cl
-, Br
-, I) mol ratio of 1～1.5:1 prepares corresponding Grignard reagent, 5～100:1 of solvent (anhydrous tetrahydro furan, ether or dioxane) and the weightmeasurement ratio of haloalkane;
(4) in 3-alkoxyl group jateorhizine salt, add anhydrous tetrahydro furan or ether or dioxane (3-alkoxyl group jateorhizine salt is 1:5～50 with the ratio of solvent), make into and under nitrogen protection, carry out ice bath behind the 3-alkoxyl group jateorhizine salt suspension and cool to-20～20 ℃;
(5) under nitrogen protection and ice bath, (3) step synthetic Grignard reagent is added in the 3-alkoxyl group jateorhizine salt suspension of (4) preparation, stir simultaneously, remove ice bath after adding, reflux finishes its reaction;
(6) separate the acquisition supernatant liquor, vacuum concentration is used methanol crystallization after becoming solid, obtains 3-alkoxyl group-8-alkyl dihydro jateorhizine intermediate;
(7) 3-alkoxyl group-8-alkyl dihydro jateorhizine intermediate is used the halogen oxidation in acetic acid, the mol ratio of 3-alkoxyl group-8-alkyl dihydro jateorhizine intermediate and halogen is 1:1～2, obtains 3-alkoxyl group-8-alkyl jateorhizine halate product;
(8) 3-alkoxyl group-8-alkyl jateorhizine halate is dissolved in the acetic acid, adds the halogen reaction, and the mol ratio of the two is 1:1～20, obtains 3-alkoxyl group-8-alkyl-12-R
3-jateorhizine halate product.
The structural characterization result of the 3-octyloxy of above-mentioned acquisition-8-butyl jateorhizine salt is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, R
f=0.34, yield: 64.0%.m.p.＝143-147℃；UV(CH
3OH)λmax：438,350,243(nm)；IR(KBr)v：3071(CH
Ar)、2929?and?2856(CH)、1605(Ar)、1520(C＝N)、1463?and?1352(CH)、1283--1016(C-O)、730((-CH
2-)n，n≧4)cm
-1；
1H?NMR?δ(ppm)：0.87(s，J＝7.2Hz，3H，-CH
3)、1.03(t，3H，-CH
3)、1.28～1.34(m，8H，-CH
2-)、1.62(m，2H，-CH
2-)、1.76(m，2H，-O-C-CH
2-)、1.80(m，2H，-CH
2-)、3.17(t，J＝6.0Hz，2H，5-CH
2-)、3.80(m，2H，-CH
2-)；3.93(s，3H，2-OCH
3)、4.05(t，J＝6.6Hz，2H，O-CH
2-)、4.07(s，3H，-OCH
3)、4.07(s，3H，-OCH
3)、4.82(t，J＝6.0Hz，2H，6-CH
2-)、7.11(s，1H，4-Ar-H)、7.63(s，1H，1-Ar-H)、8.05((d，J＝9.0Hz，1H，12-Ar-H)、8.20(d，J＝9.0Hz，1H，11-Ar-H)、8.88(s，1H，13-Ar-H)；
13CNMRδ(ppm)：160.9、152.2、150.7、148.6、145.4、137.9、132.6、128.7、125.0、124.5、121.0、119.7、119.6、111.2、109.1、68.3、61.4、56.9、56.1、49.6、32.0、31.2、29.8、28.7、28.6、28.5、26.2、25.4、22.5、22.0、13.9、13.6；Anal.calcd?for?C
32H
44NClO
4：C?70.91％，H?8.13％，N?2.59％，Cl?6.56％；found?C?70.92％，H?8.12％，N?2.58％，Cl?6.57％.
The structural characterization data of contrast 3-octyloxy jateorhizine hydrochloride and 3-octyloxy-8-butyl jateorhizine salt find that in the jateorhizine molecule after the modification, 8 protons disappear in 3-octyloxy jateorhizine hydrochloride molecule, the corresponding peak of alkyl newly occurs.Show that synthetic is 3-octyloxy-8-butyl jateorhizine salt really.
Utilize same spectroscopic data, can prove the 3-alkoxyl group-8-alkyl jateorhizine salt that can synthesize other according to the method described above.
The structural characterization result of 3-octyloxy of above-mentioned acquisition-8-butyl-12-Br-jateorhizine bromate is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, R
f=0.54, yield: 58.0%.m.p.＝146-149℃；UV(CH
3OH)λmax：441,352,245(nm)；IR(KBr)v：3070(CH
Ar)、2931?and?2858(CH)、1604(Ar)、1520(C＝N)、1465?and?1351(CH)、1283--1016(C-O)、730((-CH
2-)n，n≧4)cm
-1；
1H?NMRδ(ppm)：0.87(s，J＝7.2Hz，3H，-CH
3)、1.03(t，3H，-CH
3)、1.28～1.34(m，8H，-CH
2-)、1.62(m，2H，-CH
2-)、1.76(m，2H，-O-C-CH
2-)、1.80(m，2H，-CH
2-)、3.17(t，J＝6.0Hz，2H，5-CH
2-)、3.80(m，2H，-CH
2-)；3.93(s，3H，2-OCH
3)、4.05(t，J＝6.6Hz，2H，O-CH
2-)、4.07(s，3H，-OCH
3)、4.07(s，3H，-OCH
3)、4.82(t，J＝6.0Hz，2H，6-CH
2-)、7.11(s，1H，4-Ar-H)、7.63(s，1H，1-Ar-H)、8.20(d，J＝9.0Hz，1H，11-Ar-H)、8.88(s，1H，13-Ar-H)；
13C?NMRδ(ppm)：160.9、152.2、150.7、148.6、145.4、137.9、132.6、128.7、125.0、124.5、121.0、119.7、119.6、111.2、109.1、68.3、61.4、56.9、56.1、49.6、32.0、31.2、29.8、28.7、28.6、28.5、26.2、25.4、22.5、22.0、13.9、13.6；Anal.calcd?for?C
32H
44NClO
4：C?70.91％，H?8.13％，N?2.59％，Br?8.66％；found?C?70.92％，H?8.12％，N?2.58％，Cl?6.57％.
The structural characterization data of contrast 3-octyloxy-8-butyl jateorhizine salt and 3-octyloxy-8-butyl-12-Br-jateorhizine salt find that in the molecule after the modification, 12 protons disappear in 3-octyloxy-8-butyl jateorhizine molecules of salt.Show that synthetic is 3-octyloxy-8-butyl-12-Br-jateorhizine salt really.
Utilize same spectroscopic data, can prove the 3-alkoxyl group-8-alkyl-12-R3-jateorhizine salt that can synthesize other according to the method described above.
This compounds has following characteristics:
1,3-alkoxyl group-8-alkyl-12-R
3-jateorhizine salt is the synthetic novel substance first time.
2, to 3-alkoxyl group-8-alkyl-12-R
3-jateorhizine salt is along with the alkyl chain length increase of derivative, its anti-mycobacterium tuberculosis etc.
Anti-microbial activity increases earlier, descends then.
3, to 3-octyloxy-8-alkyl-jateorhizine salt, along with the alkyl chain length increase of derivative, anti-microbial activities such as its anti-mycobacterium tuberculosis increase earlier; After the length of alkyl chain was greater than 4, its tubercle bacillus resistant activity descended.
4, this compound yield height, price is low, has fabulous value of exploiting and utilizing.
Berberine and jateorhizine are the main anti-microbial activity compositions in the coptis, have anti-microbial activity widely, and traditional Chinese medicine is used for antisepsis and anti-inflammation.The present invention finds, 3-alkoxyl group-8-alkyl-12-R
3The anti-microbial activity of-jateorhizine salt is apparently higher than berberine salt and jateorhizine, therefore, and with 3-alkoxyl group-8-alkyl-12-R
3-jateorhizine salt is made the formulations such as medicinal tablet of anti-mycobacterium tuberculosis and is used separately, perhaps uses simultaneously with other anti-mycobacterium tuberculosis medicines, perhaps uses simultaneously with other Chinese medicines and Chinese patent medicine, and it treats phthisical effect will be better.So 3-alkoxyl group-8-alkyl-12-R
3-jateorhizine salt can be used as the phthisical new raw material medicine development and use of a kind of treatment.
The compounds of this invention can composition form be used for the patient of relative disease by the mode of administrations such as oral, injection or external application.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc., make liquid preparation such as water oil-suspending agent or syrup etc.; When being used for drug administration by injection, can be made into injection solution or oil-suspending agent etc.; Be used for external application and can make emplastrum or liniment.More than various formulations can be according to the conventional production method preparation of pharmaceutical field.
The amount of application of The compounds of this invention can be according to variations such as the type of route of administration, patient's age, body weight, the disease for the treatment of and severity.
Embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention with this.
Embodiment 1:3-octyloxy-8-butyl jateorhizine bromate
The preparation method is as follows:
1., 0.1 mole of jateorhizine is dissolved among 100 milliliters of DMF, be warmed up to 80 ℃, stir the n-octane bromide that slowly adds 1 mole down, after adding, back flow reaction 3 hours;
2., after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-octyloxy jateorhizine bromate crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-octyloxy jateorhizine bromate.
3., dry all reaction glassware, take by weighing dried magnesium chips 0.12mol and put in the 250mL three-necked flask, be reaction solvent with anhydrous diethyl ether 100mL, under nitrogen protection, add the bromination of n-butane of 0.06mol, prepare corresponding Grignard reagent.
4., drying 3-octyloxy jateorhizine bromate of taking by weighing 0.03mol places the 500mL three-necked flask, adds the 100mL anhydrous diethyl ether, makes into behind 3-octyloxy jateorhizine bromate suspension under nitrogen protection ice bath to 0 ℃.
5., the Grignard reagent with preparation under nitrogen protection and ice bath slowly joins in 3-octyloxy jateorhizine bromate suspension, stirs simultaneously, the removal ice bath makes and gets back to room temperature adding after, reflux 2h afterreaction finishes.
6., reaction solution is centrifugal, get supernatant liquor after, add ether extraction again, repeated multiple times, with the extraction situation of thin-layer method monitoring reaction product, to raw material point very little till.The centrifuged supernatant vacuum concentration is used methanol crystallization after becoming solid, and crystal is 3-octyloxy-8-butyl dihydro jateorhizine.
7., measure 0.015mol Br with transfer pipet
2Dissolve in the 10mL Glacial acetic acid, take by weighing and two liquid are mixed reflux 1h after 0.01mol 3-octyloxy-8-butyl dihydro jateorhizine dissolves in the 100mL Glacial acetic acid.
8., the reaction solution cooled and filtered, precipitation is with 10% Na
2S
2O
5Solution washing, last water washing and precipitating, precipitation methanol crystallization, i.e. 3-octyloxy-8-butyl jateorhizine bromate.
Embodiment 2:3-butoxy-8-decyl jateorhizine hydrochloride
The preparation method is as follows:
1., 0.1 mole of jateorhizine is dissolved among 100 milliliters of DMF, be warmed up to 80 ℃, stir the n-propylcarbinyl chloride that slowly adds 5 moles down, after adding, back flow reaction 3 hours;
2., after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-butoxy jateorhizine hydrochloride crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-butoxy jateorhizine hydrochloride.
3., dry all reaction glassware, take by weighing dried magnesium chips 0.12mol and put in the 250mL three-necked flask, be reaction solvent with anhydrous diethyl ether 100mL, under nitrogen protection, add the chloro n-decane of 0.06mol, prepare corresponding Grignard reagent.
4., drying 3-butoxy jateorhizine hydrochloride of taking by weighing 0.03mol places the 500mL three-necked flask, adds the 100mL anhydrous diethyl ether, makes into behind 3-butoxy jateorhizine hydrochloride suspension under nitrogen protection ice bath to 0 ℃.
5., the Grignard reagent with preparation under nitrogen protection and ice bath slowly joins in 3-butoxy jateorhizine hydrochloride suspension, stirs simultaneously, the removal ice bath makes and gets back to room temperature adding after, reflux 2h afterreaction finishes.
6., reaction solution is centrifugal, get supernatant liquor after, add ether extraction again, repeated multiple times, with the extraction situation of thin-layer method monitoring reaction product, to raw material point very little till.The centrifuged supernatant vacuum concentration is used methanol crystallization after becoming solid, and crystal is 3-butoxy-8-decyl dihydro jateorhizine.
7., measure 0.015mol Br with transfer pipet
2Dissolve in the 10mL Glacial acetic acid, take by weighing and two liquid are mixed reflux 1h after 0.01mol 3-butoxy-8-decyl dihydro jateorhizine dissolves in the 100mL Glacial acetic acid.
8., the reaction solution cooled and filtered, precipitation is with 10% Na
2S
2O
5Solution washing, last water washing and precipitating, precipitation methanol crystallization, i.e. 3-butoxy-8-decyl jateorhizine.
Embodiment 3:3-butoxy-8-ethyl jateorhizine iodate
The preparation method is as follows:
1., 0.1 mole of jateorhizine is dissolved among 100 milliliters of DMF, be warmed up to 80 ℃, stir the n-propylcarbinyl chloride that slowly adds 5 moles down, after adding, back flow reaction 3 hours;
2., after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-butoxy jateorhizine hydrochloride crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-butoxy jateorhizine hydrochloride.
3., dry all reaction glassware, take by weighing dried magnesium chips 0.12mol and put in the 250mL three-necked flask, be reaction solvent with anhydrous diethyl ether 50mL, under nitrogen protection, add the iodo hexane of 0.08mol, prepare corresponding Grignard reagent.
4., drying 3-butoxy jateorhizine hydrochloride of taking by weighing 0.03mol places the 500mL three-necked flask, adds the 50mL anhydrous diethyl ether, makes into behind 3-butoxy jateorhizine hydrochloride suspension under nitrogen protection ice bath to 0 ℃.
5., the Grignard reagent with preparation under nitrogen protection and ice bath slowly joins in 3-butoxy jateorhizine hydrochloride suspension, stirs simultaneously, the removal ice bath makes and gets back to room temperature adding after, reflux 2h afterreaction finishes.
6., reaction solution is centrifugal, get supernatant liquor after, add ether extraction again, repeated multiple times, with the extraction situation of thin-layer method monitoring reaction product, to raw material point very little till.The centrifuged supernatant vacuum concentration is used methanol crystallization after becoming solid, and crystal is 3-butoxy-8-ethyl dihydro jateorhizine.
7., measure 0.015mol Br with transfer pipet
2Dissolve in the 15mL Glacial acetic acid, take by weighing and two liquid are mixed reflux 1h after 0.01mol 3-butoxy-8-ethyl dihydro jateorhizine dissolves in the 100mL Glacial acetic acid.
8., the reaction solution cooled and filtered, precipitation is with 10% Na
2S
2O
5Solution washing, last water washing and precipitating, precipitation methanol crystallization, i.e. 3-butoxy-8-ethyl jateorhizine.
Embodiment 4:3-octyloxy-8-butyl-12-bromo jateorhizine bromate
The preparation method:
0.1 mole of 3-octyloxy-8-butyl jateorhizine bromate is dissolved in 100 milliliters of acetic acid, adds 0.6 mole bromine, reaction is 30 minutes under the room temperature, is cooled to 10 ℃, filters; Precipitation is dissolved in that recrystallization once obtains 3-octyloxy-8-butyl-12-bromo jateorhizine bromate product in the ethanol.
Embodiment 5:3-butoxy-8-hexyl-12-iodo jateorhizine iodate
The preparation method:
0.1 mole of 3-butoxy-8-hexyl-jateorhizine iodate is dissolved in 100 milliliters of acetic acid, adds 1 mole of iodine, reaction is 30 minutes under the room temperature, is cooled to 10 ℃, filters; Precipitation is dissolved in that recrystallization once obtains 3-butoxy-8-hexyl-12-iodo jateorhizine iodate product in the ethanol.
Embodiment 6:3-oxyethyl group-8-ethyl-12-fluoro jateorhizine fluorate
The preparation method:
0.1 mole of 3-oxyethyl group-8-ethyl-jateorhizine fluorate is dissolved in 100 milliliters of acetic acid, adds 0.2 mole of fluorine, reaction is 30 minutes under the room temperature, is cooled to 10 ℃, filters; Precipitation is dissolved in that recrystallization once obtains 3-oxyethyl group-8-ethyl-12-fluoro jateorhizine fluorate product in the ethanol.
The anti-mycobacterium tuberculosis medicinal tablet of embodiment 7:3-octyloxy-8-butyl jateorhizine bromate:
Get 10 gram 3-octyloxy-8-butyl jateorhizine bromates (medicine), add spherulitic lactose (auxiliary material) 70 grams, Magnesium Stearate (auxiliary material) 15 grams, Microcrystalline Cellulose (auxiliary material) 5 grams, be suppressed into the tablet of 0.5 gram a slice after mixing.Be every pastille 50mg.Oral, promptly can be used as the medicine of anti-mycobacterium tuberculosis.
The antibacterials tablet of embodiment 8:3-octyloxy-8-butyl-12-bromo jateorhizine bromate:
Get 10 gram 3-octyloxy-8-butyl-12-bromo jateorhizine bromates (medicine), add spherulitic lactose (auxiliary material) 80 grams, Magnesium Stearate (auxiliary material) 5 grams, Microcrystalline Cellulose (auxiliary material) 5 grams, be suppressed into the tablet of 0.5 gram a slice after mixing.Be every pastille 50mg.Oral, promptly can be used as antibacterials.
The antimicrobial oral liquid of embodiment 9:3-hexyloxy-8-hexyl jateorhizine iodate:
Get 10 gram 3-hexyloxy-8-hexyl jateorhizine iodates (medicine), add Tween-80 (emulsifying agent auxiliary material) 5 grams, stevioside (sweeting agent auxiliary material) 1 gram, mix back constant volume to 1000 milliliter, filter with sterilization back can and become 5 milliliters one oral liquid, every pastille 50mg.Oral, promptly can be used as antibacterials.
The antimicrobial oral liquid of embodiment 10:3-hexyloxy-8-hexyl-12-chloro jateorhizine hydrochloride:
Get 10 gram 3-hexyloxy-8-hexyl-12-chloro jateorhizine hydrochlorides (medicine), add Tween-80 (emulsifying agent auxiliary material) 10 grams, stevioside (sweeting agent auxiliary material) 1 gram, mix back constant volume to 2000 milliliter, filter with sterilization back can and become 10 milliliters one oral liquid, every pastille 50mg.Oral, promptly can be used as antibacterials.
The antibacterial effect of embodiment 11:3-alkoxyl group-8-alkyl-12-R3-jateorhizine hydrochloride:
1., experiment material.Investigational agent: berberine salt (positive control), jateorhizine salt (positive control), 3-octyloxy-8-ethyl jateorhizine salt, 3-octyloxy-8-butyl jateorhizine salt, 3-octyloxy-8-hexyl jateorhizine salt, 3-octyloxy-8-octyl group jateorhizine salt, 3-octyloxy-8-decyl jateorhizine salt, 3-octyloxy-8-butyl-12-bromo jateorhizine bromate are formulated as 1000ppm/ml.
2., bacterial classification: tubercule bacillus, streptococcus aureus (reference culture, ATCC25923), streptococcus aureus (resistant organism, MR), intestinal bacteria, helicobacter pylori.
3., substratum: MH meat soup, MH agar is the product of selling.
4., qualitative test (employing paper disk method): the preparation of bacterium liquid: after cultivations such as tubercule bacillus 24 hours (mycobacterium abscessus was cultivated 2 days), wash with NS, turbidimetry is made into 10
8Cfu/ml bacterium liquid.Scraps of paper preparations: the scraps of paper of the about 6mm of diameter are soaked in soup, and every agreement that contracts a film or TV play to an actor or actress 10 μ l preserve after putting the refrigerator drying.Test: test organisms liquid evenly is applied on the MH agar plate, puts drug paper disk, streptococcus aureus is observed after cultivating 24h, writes down the straight warp of antibacterial ring.
5., quantitative test (adopt liquid nutrient medium serial dilution): with meat soup with each investigational agent sesquialter dilution be 1:2,1:4,1:8: 1:16,1:32,1:64,1:128,1:256,1:512,1:1024,1:2048,1:4096,1:8192, other establishes the positive control pipe that does not add investigational agent; Every developmental tube adds test organisms liquid 0.05ml (10
8Cfu/ml), mixing is cultivated the 24h observations for rearmounted 37 ℃.
Qualitative experiment the results are shown in Table 1, and quantitative experiment the results are shown in Table 2.
Table 1, qualitative bacteriostatic experiment result
| Bacterial classification | Berberine hydrochloride | The jateorhizine hydrochloride | 3-octyloxy-8-ethyl jateorhizine salt | 3-octyloxy-8-butyl jateorhizine salt | 3-octyloxy-8-hexyl jateorhizine salt | 3-octyloxy-8-octyl group jateorhizine salt | 3-octyloxy-8-decyl jateorhizine salt | 3-octyloxy-8-butyl-12-bromo jateorhizine salt |
| Tubercule bacillus | 0.85 | 0.88 | 2.26 | 3.05 | 2.64 | 2.02 | 1.63 | 3.43 |
| Streptococcus aureus | 0.65 | 0.67 | 1.81 | 2.55 | 2.23 | 2.08 | 1.98 | 2.88 |
| Intestinal bacteria | 0.66 | 0.66 | 1.98 | 2.67 | 2.17 | 1.76 | 1.44 | 2.94 |
| The resistance gold-coloured staphylococci | 0.78 | 0.81 | 1.96 | 2.25 | 2.05 | 1.55 | 1.29 | 2.69 |
| Helicobacter pylori | 0.55 | 0.56 | 1.78 | 2.21 | 1.86 | 1.53 | 1.22 | 2.53 |
The anti-bacterial result (the MIC of table 2, jateorhizine and modified compound thereof; Drug level: μ g/ml)
| Bacterial classification | Berberine hydrochloride | The jateorhizine hydrochloride | 3-octyloxy-8-ethyl jateorhizine salt | 3-octyloxy-8-butyl jateorhizine salt | 3-octyloxy-8-hexyl jateorhizine salt | 3-octyloxy-8-octyl group jateorhizine salt | 3-octyloxy-8-decyl jateorhizine salt | 3-octyloxy-8-butyl-12-bromo jateorhizine salt |
| Tubercule bacillus | 250 | 500 | 0.98 | 0.24 | 0.48 | 0.98 | 3.9 | 0.12 |
| Streptococcus aureus | 250 | 500 | 1.96 | 0.48 | 0.48 | 1.98 | 7.8 | 0.24 |
Can see from above-mentioned experimental result, the specific activity jateorhizine and the Berberine of the anti-mycobacterium tuberculosis of 3-octyloxy-8-ethyl jateorhizine salt be high 1041 times～and 2083 times; The anti-mycobacterium tuberculosis effect of 3-octyloxy-8-butyl-12-bromo jateorhizine salt is best, than jateorhizine and Berberine high 2083 times～4166 times.
Claims (3)
1.3-alkoxyl group-8-alkyl-12-R3-jateorhizine salt, its molecular structural formula is as follows:
Wherein, X=F
-, Cl
-, Br
-, I
-, SO
4 2-, NO
3 -, PO
4 3-, citrate, acetate or lactate; R
1=C
nH2n+1, n=2～10; R
2=C
nH2n+1, n=2～10; R
3=H or F or Cl or Br or I.
2. the described 3-alkoxyl group of claim 1-8-alkyl-12-R
3The synthetic method of-jateorhizine salt is characterized in that step is as follows:
(1), be reaction solvent with DMF, jateorhizine is joined among the DMF, after the rising temperature for dissolving, add the haloalkane of 1～10 times of mol ratio, after mixing, back flow reaction 2～5 hours;
(2), after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-alkoxyl group jateorhizine salt crude product, after the DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-alkoxyl group jateorhizine salt;
(3) be reaction solvent with anhydrous tetrahydro furan, ether or dioxane, under nitrogen protection, press (X-C with magnesium chips and haloalkane
nH2n+1, n=2～10; X=F
-, Cl
-, Br
-, I) mol ratio of 1～1.5:1 prepares corresponding Grignard reagent, 5～100:1 of the weightmeasurement ratio of reaction solvent and haloalkane;
(4) volume ratio 1:5～50 add anhydrous tetrahydro furan or ether or dioxane in 3-alkoxyl group jateorhizine salt by weight, make into to carry out ice bath behind the 3-alkoxyl group jateorhizine salt suspension under nitrogen protection and cool to-20～20 ℃;
(5) under nitrogen protection and ice bath, (3) step synthetic Grignard reagent is added in the 3-alkoxyl group jateorhizine salt suspension of (4) preparation, stir simultaneously, remove ice bath after adding, reflux finishes its reaction;
(6) separate the acquisition supernatant liquor, vacuum concentration is used methanol crystallization after becoming solid, obtains 3-alkoxyl group-8-alkyl dihydro jateorhizine intermediate;
(7) 3-alkoxyl group-8-alkyl dihydro jateorhizine intermediate is used the halogen oxidation in acetic acid, the mol ratio of 3-alkoxyl group-8-alkyl dihydro jateorhizine intermediate and halogen is 1:1～2, obtains 3-alkoxyl group-8-alkyl jateorhizine halate product;
(8) 3-alkoxyl group-8-alkyl jateorhizine halate is dissolved in the acetic acid, adds the halogen reaction, and the mol ratio of the two is 1:1～20, obtains 3-alkoxyl group-8-alkyl-12-R3-jateorhizine halate product.
3. claim 1 or 2 described 3-alkoxyl group-8-alkyl-12-R
3The application of-jateorhizine salt aspect anti-mycobacterium tuberculosis.
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|---|---|---|---|
| CNA2008102328373A CN101367800A (en) | 2008-10-09 | 2008-10-09 | Synthesis of tubercle bacillus resistant medicament 3-alkoxyl-8-alkyl -12-R3-jatrorrhizine salt and uses thereof |
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|---|---|---|---|
| CNA2008102328373A CN101367800A (en) | 2008-10-09 | 2008-10-09 | Synthesis of tubercle bacillus resistant medicament 3-alkoxyl-8-alkyl -12-R3-jatrorrhizine salt and uses thereof |
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|---|---|
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018853A (en) * | 2019-12-27 | 2020-04-17 | 西南大学 | Phenol berberine benzimidazole compound and preparation method and application thereof |
| CN111686109A (en) * | 2020-07-09 | 2020-09-22 | 西南大学 | Application of 8-octyl berberine salt in preparation of anti-helicobacter pylori infection medicine |
| CN115215858A (en) * | 2022-07-08 | 2022-10-21 | 哈尔滨医科大学 | 2,3-disubstituted berberine derivatives, and preparation method and application thereof |
| CN116425741A (en) * | 2023-03-12 | 2023-07-14 | 西南大学 | Jatrorrhizine derivative with antibacterial activity, synthesis method and application |
-
2008
- 2008-10-09 CN CNA2008102328373A patent/CN101367800A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018853A (en) * | 2019-12-27 | 2020-04-17 | 西南大学 | Phenol berberine benzimidazole compound and preparation method and application thereof |
| CN111686109A (en) * | 2020-07-09 | 2020-09-22 | 西南大学 | Application of 8-octyl berberine salt in preparation of anti-helicobacter pylori infection medicine |
| CN115215858A (en) * | 2022-07-08 | 2022-10-21 | 哈尔滨医科大学 | 2,3-disubstituted berberine derivatives, and preparation method and application thereof |
| CN115215858B (en) * | 2022-07-08 | 2023-08-11 | 哈尔滨医科大学 | 2, 3-disubstituted berberine derivative, and preparation method and application thereof |
| CN116425741A (en) * | 2023-03-12 | 2023-07-14 | 西南大学 | Jatrorrhizine derivative with antibacterial activity, synthesis method and application |
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