CN110396090A - Imidazoles alcohols tetrahydro coptis oxime conjugate and its preparation method and application - Google Patents
Imidazoles alcohols tetrahydro coptis oxime conjugate and its preparation method and application Download PDFInfo
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- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract
The present invention relates to imidazoles alcohols tetrahydro coptis oxime conjugates and its preparation method and application, belong to chemosynthesis technical field, imidazoles alcohols tetrahydro coptis oxime conjugate is as shown in general formula I, such compound is to gram-positive bacteria, one of Gram-negative bacteria and fungi are a variety of with certain inhibitory activity, it can be used for preparing antibacterium and/or antifungal drug, it is more efficient to be provided for clinical antimicrobial treatment, the drug candidate of safety, facilitate the drug resistance for solving to be on the rise, the clinical treatments problem such as obstinate invasive organism and emerging harmful microorganism.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to imidazoles alcohols tetrahydro coptis oxime conjugate and its preparation side
Method and application.
Background technique
Natural berberine is a kind of quaternary ammonium morphinane alkaloid with polycyclic aromatic hydrocarbon structure, unique condensed ring virtue
Fragrant hydrocarbon structure and negative ions center are easy to through a variety of non-covalent bonding forces such as electrostatic, hydrogen bond, pi-pi accumulation, hydrophobic effect and life
The intracorporal a variety of enzymes of object, protein and other active sites are had an effect, thus show multiple biological activities.But due to the coptis
There is element biggish rigidity to make it solubility is small in water, cause its absorption difference, bioavilability be low, patient medication often,
The disadvantages of tolerance and weak curative effect, and then directly limit its application in clinic.Class of the tetrahydroberberine as berberine
Like object, molecular flexibility is improved to a certain extent, be conducive to improve solubility and then improves bioavilability, therefore in recent years
Huge Development volue and wide application prospect are shown in field of medicinal chemistry, so that more and more research work are endeavoured
In using tetrahydroberberine as the medicament research and development of basic framework, being included in antibacterium, antimycotic, antiviral, treating tuberculosis, anticancer, anti-
The many aspects such as diabetes, anti-inflammatory analgesic, anti-senile dementia disease are tried to explore.
Summary of the invention
In view of this, one of the objects of the present invention is to provide imidazoles alcohols tetrahydro coptis oxime conjugates and its pharmaceutically acceptable
Salt；The second purpose is to provide the preparation method of imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt；The third purpose exists
The answering in preparation antibacterium and/or antifungal drug in offer imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt
With；The fourth purpose is to provide the preparation of the imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt.
In order to achieve the above objectives, the invention provides the following technical scheme:
1, imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt, structure is as shown in general formula I:
In formula,
R1、R2And R3For hydrogen, halogen, alkyl, alkoxy, alkoxy carbonyl group, amino, hydroxyl, cyano, carboxyl or nitro；
R4For alkyl, naphthenic base, aryl, cyano, alkenyl, alkynyl, ester group, carboxyl, hydroxyl, sulfydryl or amino；
N is the integer of 0-18.
Preferably,
R1For hydrogen or methyl；
R2And R3For hydrogen or nitro；
R4For methyl, tert-butyl, alkenyl or aryl；
N is 0 or 1.
Preferably, it is any one of following compounds:
Preferably, the officinal salt is hydrochloride, sulfate, nitrate or acetate.
2, the preparation method of the imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt, the method includes such as
Lower step:
A, the preparation of intermediate II: obtaining berberrubine through demethylation reaction using berberine as starting material, will be described
Berberrubine obtains 9- hydroxy tetrahydro berberine through reduction reaction, and the 9- hydroxy tetrahydro berberine and hexamethylenetetramine are existed
It is reacted in trifluoroacetic acid up to intermediate II；
B, the preparation of intermediate III: intermediate II is dissolved in n,N-Dimethylformamide, alkali effect under with epoxy chlorine
Nucleophilic substitution occurs for propane up to intermediate III；
C, the preparation of intermediate compound IV: intermediate III is dissolved in n,N-Dimethylformamide, alkali effect under with 2- first
Base -5- nitroimidazole reacts up to intermediate compound IV；
D, the preparation of intermediate V: intermediate III is dissolved in n,N-Dimethylformamide, alkali effect under with 4- nitro
Imidazoles reacts up to intermediate V；
E, intermediate compound IV or V the preparation of imidazoles alcohols tetrahydro coptis oxime conjugate shown in general formula I: are dissolved in organic solvent
Afterwards, condensation reaction occurs to get imidazoles alcohols tetrahydro coptis oxime conjugate shown in general formula I with primary amine in the presence of alkali.
Preferably,
In step a, the temperature of the demethylation reaction is 190 DEG C；The reagent of the reduction reaction is sodium borohydride；Institute
Stating the ratio between amount of substance of 9- hydroxy tetrahydro berberine and hexamethylenetetramine is 1:1.2；
In step b, the ratio between the intermediate II, amount of substance of epoxychloropropane and alkali are 1:1.5:1.5, and the alkali is
Potassium carbonate；The nucleophilic substitution is specially to react 6h at 80 DEG C；
In step c, the ratio between the intermediate III, amount of substance of 2- 5-nitro imidazole and alkali 1:1:1.5 is described
Alkali is potassium carbonate；The reaction is specially to react 8h at 80 DEG C；
In step d, the ratio between the intermediate III, amount of substance of 4- nitroimidazole and alkali 1:1:1.5, the alkali are carbon
Sour potassium；The reaction is specially to react 8h at 80 DEG C；
In step e, the ratio between amount of substance of the intermediate compound IV or V and alkali and primary amine 1:1.5:1.5；The alkali is carbonic acid
Potassium；The organic solvent is acetonitrile；The condensation reaction is specially to react 6h at 80 DEG C.
3, the imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt are in preparation antibacterium and/or antifungal
Application in object.
Preferably, the bacterium is methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus, gold
Staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, K. pneumonia, Escherichia coli, copper
One of green pseudomonad, pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922 or Acinetobacter bauamnnii or
It is a variety of；The fungi is Candida albicans, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC 90023 or closely flat
One of sliding candidiasis ATCC 22019 or a variety of.
4, the preparation containing the imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt.
Preferably, the preparation be tablet, it is capsule, granule, injection, powder-injection, eye drops, liniment, suppository, soft
One of paste or aerosol.
The beneficial effects of the present invention are: the present invention provides imidazoles alcohols tetrahydro coptis oxime conjugates and preparation method thereof
And application, the present invention design principle of hybridization using drug, and oximes group is introduced on tetrahydroberberine 12, design synthesizes
A series of imidazoles alcohols tetrahydro coptis oxime conjugates, these compounds are through in vitro anti-microbial activity detection discovery to gram sun
Property bacterium (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus, staphylococcus aureus ATCC
25923, staphylococcus aureus ATCC 29213), (K. pneumonia, Escherichia coli, verdigris are false for Gram-negative bacteria
Monad, pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Acinetobacter bauamnnii) and fungi (Candida albicans
Bacterium, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC 90023, Candida parapsilosis bacterium ATCC 22019) all
There is certain inhibitory activity, can be used for preparing antibacterium and/or antifungal drug, to be provided more for clinical antimicrobial treatment
More efficient, safety drug candidates, facilitate the drug resistance for solving to be on the rise, obstinate invasive organism and new appearance
The clinical treatments problem such as harmful microorganism.
Other advantages, target and feature of the invention will be illustrated in the following description to a certain extent, and
And to a certain extent, based on will be apparent to those skilled in the art to investigating hereafter, Huo Zheke
To be instructed from the practice of the present invention.Target of the invention and other advantages can be realized by following specification and
It obtains.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.
The preparation of embodiment 1, intermediate II
Berberrubine is obtained through demethylation reaction at 190 DEG C using berberine as starting material, is also with sodium borohydride
Berberrubine is obtained 9- hydroxy tetrahydro berberine through reduction reaction by the reagent of original reaction, and 9- is added in 150mL round-bottomed flask
Hydroxy tetrahydro berberine (15g, 46mmol) and hexamethylenetetramine (7.710g, 55mmol) are made molten with trifluoroacetic acid (100mL)
Agent is stirred to react at 120 DEG C, and thin-layer chromatography, which tracks to reaction, to be terminated.It is hydrolyzed with the dilute sulfuric acid of mass fraction 10%, then with being saturated
Sodium bicarbonate solution tune pH is neutrality, is extracted with ethyl acetate solution, then concentrated, recrystallization, dry etc. post-process up in
Mesosome II (11.68g), yield 77.9%.
The preparation of embodiment 2, intermediate III
Bibliography " Sun H., Ansari M.F., Battini N., Bheemanaboina R.R.Y.and Zhou
C.H.,Novel potential artificial MRSA DNA intercalators:Synthesis and
biological evaluation of berberine-derived thiazolidinediones.Org.Chem.Fro
Nt., prepared by 2019,6,319 " the methods.
The preparation of embodiment 3, intermediate compound IV:
2- 5-nitro imidazole (155mg, 1.22mmol) and potassium carbonate (253mg, 1.83mmol) are in N, N- dimethyl
80 DEG C of stirring 1h in formamide (45mL).After being cooled to room temperature, intermediate III (500mg, 1.22mmol) is added in reaction solution
80 DEG C of reaction 8h.Reaction is extracted with dichloromethane after stopping, and organic phase is washed 2-3 times with saturated common salt, uses anhydrous slufuric acid later
Sodium is dry, is evaporated under reduced pressure out solvent.Crude product is obtained through silica gel chromatography (eluant, eluent: methylene chloride/methanol, 30:1, V/V)
To 282mg intermediate compound IV, yield: 43.2%.
The preparation of embodiment 4, intermediate V:
4- nitroimidazole (138mg, 1.22mmol) and potassium carbonate (253mg, 1.83mmol) are in N,N-dimethylformamide
80 DEG C of stirring 1h in (45mL).It is anti-by 80 DEG C in intermediate III (500mg, 1.22mmol) addition reaction solution after being cooled to room temperature
Answer 8h.Reaction is extracted with dichloromethane after stopping, and organic phase is washed 2-3 times with saturated common salt, dry with anhydrous sodium sulfate later,
It is evaporated under reduced pressure out solvent.Crude product obtains 383mg through silica gel chromatography (eluant, eluent: methylene chloride/methanol, 30:1, V/V)
Intermediate V, yield: 60.1%.
The preparation of embodiment 5, compound I-1:
Intermediate compound IV (400mg, 0.74mmol), methyl amine hydroxylamine hydrochloride (88mg, 1.11mmol) and potassium carbonate
(154mg, 1.11mmol) 80 DEG C of reaction 6h in acetonitrile (35mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product
91mg compound I-1 further is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), is produced
Rate: 21.6%.Fusing point: 152-153 DEG C；1H NMR(600MHz,DMSO-d6) δ 8.45 (s, 1H, CH=N-O), 8.28 (s, 1H,
), Imi-H 7.23 (s, 1H, Ber-11-H), 7.06 (s, 1H, Ber-1-H), 6.67 (s, 1H, Ber-4-H), 5.95 (d, J=
2.8Hz,2H,OCH2), O 5.50 (s, 1H, OH), 4.29-4.24 (m, 1H, Ber-8-H), 4.19 (t, J=16.8Hz, 1H,
), Ber-8-H 4.08 (t, J=11.2Hz, 2H, OCH2),4.01–3.99(m,1H,CHOH),3.90(s,3H,N-OCH3),3.82
(s,3H,OCH3),3.59–3.54(m,1H,Ber-13-H),3.40–3.36(m,2H,Imi-CH2),3.11–3.09(m,1H,
), Ber-13-H 2.90 (d, J=17.1Hz, 2H, Ber-5-H), 2.62 (d, J=15.3Hz, 1H, Ber-6-H), 2.45 (d, J
=9.1Hz, 2H, Ber-6-H), 2.42 (s, 3H, CH3)ppm.
The preparation of embodiment 6, compound I-2:
Intermediate compound IV (400mg, 0.74mmol), ethylhydroxyl amine hydrochloride (108mg, 1.11mmol)) and potassium carbonate
(154mg, 1.11mmol) 80 DEG C of reaction 6h in acetonitrile (35mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product
91mg compound I-2 further is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), is produced
Rate: 21.1%.Fusing point: 208-209 DEG C.1H NMR(600MHz,DMSO-d6) δ 8.45 (s, 1H, CH=N-O), 8.28 (s, 1H,
), Imi-H 7.23 (s, 1H, Ber-11-H), 7.06 (s, 1H, Ber-1-H), 6.67 (s, 1H, Ber-4-H), 5.95 (d, J=
2.8Hz,2H,OCH2), O 5.50 (s, 1H, OH), 4.29-4.24 (m, 1H, Ber-8-H), 4.19 (t, J=16.8Hz, 1H,
), Ber-8-H 4.08 (t, J=11.2Hz, 2H, OCH2),4.01–3.99(m,1H,Ber-14-H),3.93-3.92(m,1H,
CHOH),3.90(s,3H,N-OCH3),3.82(s,3H,OCH3),3.56–3.53(m,1H,Ber-13-H),3.40–3.36(m,
2H,Imi-CH2), 3.11-3.09 (m, 1H, Ber-13-H), 2.90 (d, J=17.1Hz, 2H, Ber-5-H), 2.62 (d, J=
15.3Hz, 1H, Ber-6-H), 2.45 (d, J=9.1Hz, 1H, Ber-6-H), 2.42 (s, 3H, CH3)ppm.
The preparation of embodiment 7, compound I-3:
Intermediate compound IV (400mg, 0.74mmol), t-butylhydroxylamine hydrochloride (140mg, 1.11mmol) and potassium carbonate
(154mg, 1.11mmol) 80 DEG C of reaction 6h in acetonitrile (35mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product
98mg compound I-3 further is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), is produced
Rate: 21.7%.Fusing point: 228-229 DEG C.1H NMR(400MHz,DMSO-d6) δ 8.34 (s, 1H, CH=N-O), 8.28 (s, 1H,
), Imi-H 7.23 (s, 1H, Ber-11-H), 7.01 (s, 1H, Ber-1-H), 6.67 (s, 1H, Ber-4-H), 5.95 (d, J=
6.2Hz,2H,OCH2), O 5.51 (s, 1H, OH), 4.30-4.17 (m, 2H, Ber-8-H), 4.10 (d, J=6.1Hz, 2H,
OCH2), 4.00 (d, J=5.2Hz, 1H, Ber-14-H), 3.94-3.89 (m, 1H, CHOH), 3.82 (s, 3H, OCH3),3.63–
3.58(m,1H,Ber-13-H),3.4-3.37(m,2H,Imi-CH2), 3.11 (d, J=8.6Hz, 1H, Ber-13-H), 2.95-
2.88 (m, 2H, Ber-5-H), 2.62 (d, J=15.6Hz, 1H, Ber-6-H), 2.46 (d, J=15.1Hz, 1H, Ber-6-
H),2.42(s,3H,CH3),1.32(s,9H,C(CH3)3)ppm.
The preparation of embodiment 8, compound I-4:
Intermediate compound IV (400mg, 0.74mmol), allyl hydroxylamine hydrochloride (121mg, 1.11mmol) and potassium carbonate
(154mg, 1.11mmol) 80 DEG C of reaction 6h in acetonitrile (35mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product
97mg compound I-4 further is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), is produced
Rate: 22.0%.Fusing point: 180-181 DEG C.1H NMR(600MHz,DMSO-d6) δ 8.49 (s, 1H, CH=N-O), 8.28 (s, 1H,
), Imi-H 7.22 (s, 1H, Ber-11-H), 7.04 (s, 1H, Ber-1-H), 6.67 (s, 1H, Ber-4-H), 6.04 (ddd, J=
22.4,10.7,5.6Hz,1H,CH2=CH-CH2), 5.95 (d, J=3.0Hz, 2H, OCH2O),5.49(s,1H,OH),5.35
(d, J=17.3Hz, 1H, CH2=CH), 5.24 (d, J=10.4Hz, 1H, CH2=CH), 4.64 (d, J=5.4Hz, 2H, CH2=
CH-CH2), 4.26 (dd, J=16.8,9.2Hz, 1H, Ber-8-H), 4.20 (t, J=16.8Hz, 1H, Ber-8-H), 4.10-
4.05(m,2H,OCH2), 4.00 (dd, J=9.7,4.7Hz, 1H, Ber-14-H), 3.94-3.90 (m, 1H, CHOH), 3.81
(s,3H,OCH3), 3.59-3.56 (m, 1H), 3.38 (dd, J=15.8,9.0Hz, 2H, Imi-CH2),3.11–3.10(m,1H),
2.90 (dd, J=14.6,7.6Hz, 1H, Ber-5-H), 2.62 (d, J=15.3Hz, 1H, Ber-6-H), 2.45 (d, J=
12.7Hz,1H,Ber-6-H),2.41(s,3H,CH3)ppm.
The preparation of embodiment 9, compound I-5:
Intermediate compound IV (400mg, 0.74mmol), benzyl hydroxylamine hydrochloride (154mg, 1.11mmol) and potassium carbonate
(154mg, 1.11mmol) 80 DEG C of reaction 6h in acetonitrile (35mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product
102mg compound I-5 further is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), is produced
Rate: 21.3%.Fusing point: 128-129 DEG C.1H NMR(600MHz,DMSO-d6) δ 8.52 (s, 1H, CH=N-O), 8.28 (s, 1H,
), Imi-H 7.42 (d, J=7.3Hz, 2H, Ph), 7.38 (t, J=7.4Hz, 2H, Ph), 7.32 (t, J=7.1Hz, 1H, Ph),
7.23 (s, 1H, Ber-11-H), 7.02 (s, 1H, Ber-1-H), 6.67 (s, 1H, Ber-4-H), 5.95 (d, J=5.8Hz, 2H,
OCH2O),5.50(s,1H,OH),5.17(s,2H,CH2), Ph 4.28-4.24 (m, 1H, Ber-8-H), 4.21 (d, J=
16.6Hz,1H,Ber-8-H),4.10–4.05(m,2H,OCH2), 4.00 (d, J=7.6Hz, 1H, Ber-14-H), 3.93-
3.90(m,1H,CHOH),3.81(s,3H,OCH3), 3.55 (d, J=13.8Hz, 1H, Ber-13-H), 3.40-3.36 (m, 2H,
Imi-CH2), 3.10 (d, J=4.8Hz, 1H, Ber-13-H), 2.90 (d, J=15.9Hz, 2H, Ber-5-H), 2.62 (d, J=
18.0Hz,1H,Ber-6-H),2.45(m,1H,Ber-6-H),2.41(s,3H,CH3)ppm.
The preparation of embodiment 10, compound I-6:
Intermediate V (300mg, 0.57mmol), benzyl hydroxylamine hydrochloride (137mg, 0.86mmol) and potassium carbonate (119mg,
0.86mmol) 80 DEG C of reaction 6h in acetonitrile (30mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product is further
79mg compound I-6 is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), yield:
21.9%.Fusing point: 148-149 DEG C.1H NMR(400MHz,DMSO-d6) δ 8.52 (s, 1H, CH=N-O), 8.39 (s, 1H, Imi-
5-H), 7.86 (s, 1H, Imi-2-H), 7.42 (d, J=7.1Hz, 2H, Ph), 7.38 (t, J=7.3Hz, 2H, Ph), 7.32 (t,
J=7.0Hz, 1H, Ph), 7.23 (s, 1H, Ber-11-H), 7.02 (s, 1H, Ber-1-H), 6.67 (s, 1H, Ber-4-H),
5.96 (d, J=3.7Hz, 2H, OCH2O),5.55(s,1H,OH),5.17(s,2H,PhCH2),4.39–4.34(m,1H,Ber-8-
H),4.19–4.14(m,3H,Ber-8-H,OCH2), 3.94 (dt, J=8.4,4.1Hz, 1H, Ber-14-H), 3.86 (dd, J=
10.5,4.9Hz,1H,CHOH),3.81(s,3H,OCH3), 3.54 (dd, J=16.4,3.3Hz, 1H, Ber-13-H), 3.37
(d, J=8.0Hz, 2H, Imi-CH2), 3.10 (d, J=8.5Hz, 1H, Ber-13-H), 2.94-2.87 (m, 2H, Ber-5-H),
2.61 (d, J=15.8Hz, 1H, Ber-6-H), 2.45 (d, J=11.5Hz, 1H, Ber-6-H) ppm.
The preparation of embodiment 11, compound I-7:
Intermediate V (400mg, 0.76mmol), methyl hydroxylamine hydrochloride (95mg, 1.14mmol) and potassium carbonate (158mg,
1.14mmol) 80 DEG C of reaction 6h in acetonitrile (35mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product is further
107mg compound I-7 is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), yield:
25.4%.Fusing point: 141-142 DEG C.1H NMR(600MHz,DMSO-d6) δ 8.45 (s, 1H, CH=N-O), 8.39 (s, 1H, Imi-
5-H),7.86(s,1H,Imi-2-H),7.22(s,1H,Ber-11-H),7.06(s,1H,Ber-1-H),6.67(s,1H,Ber-
4-H), 5.95 (d, J=3.4Hz, 2H, OCH2O),5.56(s,1H,OH),4.39–4.35(m,1H,Ber-8-H),4.19–
4.14(m,2H,OCH2), 4.11 (dd, J=11.2,8.1Hz, 1H Ber-8-H), 3.95-3.92 (m, 1H, Ber-14-H),
3.90(s,3H,N-OCH3),3.88–3.84(m,1H,CHOH),3.81(s,3H,OCH3), 3.55 (d, J=13.6Hz, 1H,
), Ber-13-H 3.37 (d, J=15.7Hz, 2H, Imi-CH2), 3.10 (d, J=5.4Hz, 1H, Ber-13-H), 2.90 (d, J
=16.6Hz, 2H, Ber-5-H), 2.62 (d, J=15.4Hz, 1H, Ber-6-H), 2.46 (dd, J=18.4,6.9Hz, 1H,
Ber-6-H)ppm.
The preparation of embodiment 12, compound I-8:
Intermediate V (400mg, 0.76mmol), ethylhydroxyl amine hydrochloride (111mg, 1.14mmol)) and potassium carbonate
(158mg, 1.14mmol) 80 DEG C of reaction 6h in acetonitrile (35mL).After reaction, it is evaporated under reduced pressure out solvent.Gained crude product
109mg compound I-8 further is obtained through silica gel chromatography (eluant, eluent: ethyl acetate/dichloromethane, 3/7, V/V), is produced
Rate: 25.3%.Fusing point: 212-213 DEG C.1H NMR(600MHz,DMSO-d6) δ 8.44 (s, 1H, CH=N-O), 8.39 (s, 1H,
Imi-5-H),7.86(s,1H,Imi-2-H),7.23(s,1H,Ber-11-H),7.06(s,1H,Ber-1-H),6.67(s,1H,
Ber-4-H),5.95(s,2H,OCH2), O 5.54 (s, 1H, OH), 4.37 (dd, J=18.3,7.1Hz, 1H, Ber-8-H),
4.20–4.13(m,5H,Ber-8-H,OCH2,OCH2CH3),3.95–3.92(m,1H,Ber-14-H),3.87–3.85(m,1H,
CHOH),3.81(s,3H,OCH3), 3.56 (d, J=15.2Hz, 1H, Ber-13-H), 3.37 (d, J=14.2Hz, 2H, Imi-
CH2), 3.11 (d, J=5.2Hz, 1H, Ber-13-H), 2.90 (t, J=11.1Hz, 2H, Ber-5-H), 2.62 (d, J=
15.5Hz, 1H, Ber-6-H), 2.45 (d, J=11.0Hz, 2H, Ber-6-H), 1.26 (t, J=7.0Hz, 3H, OCH2CH3)
ppm.
Note: DMSO is dimethyl sulfoxide, and Ber is benzene, and Imi is imidazoles, and Ph is phenyl ring.
The in vitro anti-microbial activity of embodiment 13, imidazoles alcohols tetrahydro coptis oxime conjugate
Using clinical trial standard (the Clinical and Laboratory for meeting United States National Committee's formulation
Standards Institute, CLSI) 96 hole micro-dilution methods, the imidazoles alcohols tetrahydro of detection embodiment 5-12 preparation is yellow
Even oxime conjugate is to gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus, gold
Staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213), Gram-negative bacteria (Krebs pneumonia bar
Bacterium, Escherichia coli, pseudomonas aeruginosa, pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Bao Man not lever
Bacterium) and fungi (Candida albicans, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC 90023, nearly smooth false silk
Saccharomycete ATCC 22019) minimum inhibitory concentration (MIC), a small amount of dimethyl sulfoxide of untested compound is dissolved, is added water dilute
Release the solution for being made that concentration is 1.28mg/mL, then be diluted to 128 μ g/mL with culture solution, 35 DEG C culture 24-72 hours, will cultivate
After sufficiently being shaken up on plate to oscillator, MIC is measured at wavelength 490nm, the results are shown in Table 1-3.
The external resisting gram-positive bacteria activity of imidazoles alcohols tetrahydro coptis oxime conjugate prepared by table 1, embodiment 5-12
Data (MIC, μ g/mL)
As it can be seen from table 1 compound shows certain inhibition work to the gram-positive bacteria tested in the present invention
With compound I-5 is to the very strong inhibitory activity of the display of tested gram-positive bacteria, especially to staphylococcus aureus
The MIC value of ATCC25923 is 16 μ g/mL, is 8 times (MIC=128 μ g/mL) of berberine respectively, 2 times of (MIC of Norfloxacin
=32 μ g/mL).
The external anti-Gram-negative bacteria activity of imidazoles alcohols tetrahydro coptis oxime conjugate prepared by table 2, embodiment 5-12
Data (MIC, μ g/mL)
From table 2 it can be seen that compound shows certain inhibition work to the Gram-negative bacteria tested in the present invention
With compound I-5 is to the very strong inhibitory activity of the display of tested Gram-negative bacteria, to K. pneumonia and verdigris
Pseudomonad MIC value is respectively 16 μ g/mL, hence it is evident that better than reference drug Norfloxacin, (MIC value is respectively 128 and 256 μ g/
mL).Compound I-7 and I-8 is the 4 of Norfloxacin respectively to the inhibitory activity of K. pneumonia and pseudomonas aeruginosa
Times and 8 times.
Table 3, embodiment 5-12 preparation imidazoles alcohols tetrahydro coptis oxime conjugate extracorporeal antifungal activity data (MIC,
μg/mL)
From table 3 it can be seen that compound shows certain inhibiting effect to the fungi tested in the present invention.Compound
I-5-I-7 is substantially better than reference drug Fluconazole to the inhibitory activity of Candida tropicalis.Compound I-3-I-4 and I-6-I-
The inhibitory activity of 8 pairs of aspergillus fumigatus is 8 times of reference drug Fluconazole respectively.
The pharmaceutical applications of embodiment 14, imidazoles alcohols tetrahydro coptis oxime conjugate
According to above-mentioned antimicrobial acivity testing result, imidazoles alcohols tetrahydro coptis oxime conjugate of the invention has preferable
Antibacterium, antifungal activity, antibacterium, antifungal drug can be made for clinical use.These drugs are either folk prescription
Preparation, such as be made of a kind of imidazoles alcohols tetrahydro coptis oxime conjugate of structure with pharmaceutically acceptable auxiliary material；It can also be with
Compound preparation, for example, by a kind of structure imidazoles alcohols tetrahydro coptis oxime conjugate and existing antibacterium, antifungal activity at
(such as sulfamethoxazole, Fluconazole, phosphorus Fluconazole, Itraconazole) and pharmaceutically acceptable auxiliary material is divided to be made, Huo Zheyou
Several imidazoles alcohols tetrahydro coptis oxime conjugates of different structure are made with pharmaceutically acceptable auxiliary material.The preparation type packet
Include but be not limited to tablet, capsule, powder, granule, pill, injection, powder-injection, solution, suspension, emulsion, bolt
The dosage forms such as agent, ointment, gelling agent, film, aerosol, percutaneous absorption patch and various slow-release controlled-release preparations and nanometer system
Agent.
1, the preparation of compound I-1 tablet
Prescription: compound I-1 10g, cornstarch 50g, lactose 187g, magnesium stearate 3.0g, concentration expressed in percentage by volume are
70% ethanol solution is appropriate, and 1000 are made altogether.
Preparation method: by cornstarch with 105 DEG C dry 5 hours it is spare；Compound I-1 is mixed with lactose, cornstarch
Even, with 70% ethanol solution softwood, be sieved wet granular processed, adds magnesium stearate, tabletting to get；Every slice weight 250mg,
Active component content is 10mg.
2, the preparation of compound I-3 capsule
Prescription: compound I-3 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low substitution
Hydroxypropylcellulose (100 mesh) 2.5g, talcum powder (100 mesh) 2.0g, sweetener 1.25g, orange essence 0.25g, appropriate pigment, water
In right amount, 1000 are made.
Preparation method: after the compound I-3 of recipe quantity is ground into superfine powder, with the modified starch of recipe quantity, micro-
Crystalline cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweetener, orange essence and pigment mix, with water softwood, 12-14 mesh
Sieve granulation, 40-50 DEG C of dryings, be sieved whole grain, be packed into capsulae vacuus to get；Every slice weight 50mg, active component content 25mg.
3, the preparation of compound I-5 granule
Prescription: compound I-5 26g, dextrin 120g, sucrose 280g.
Preparation method: compound I-5, dextrin, sucrose being uniformly mixed, wet granulation, 60 DEG C of dryings, packing to get.
4, the preparation of compound I-6 injection
Prescription: 1000mL is made in compound I-6 10g, propylene glycol 500mL, water for injection 500mL altogether.
Preparation method: propylene glycol and injection water, stirring and dissolving Weigh Compound I-6, is added, adds 1g active carbon, sufficiently stirs
15 minutes are stood after mixing, with 5 μm of stud filtering decarbonizations, then the miillpore filter refined filtration for being successively 0.45 μm and 0.22 μm with aperture,
Last encapsulating in 10mL ampoule, 100 DEG C of circulation steam sterilizations 45 minutes to get.
5, the preparation of compound I-2 powder-injection
Preparation method: -2 aseptic powdery of intermediate compound I aseptically dispense to get.
6, the preparation of compound I-4 eye drops
Prescription: compound I-4 3.78g, sodium chloride 0.9g, appropriate borate buffer solution, distilled water add to 1000mL.
Preparation method: Weigh Compound I-4, sodium chloride add in 500mL distilled water, with borate buffer solution tune after dissolution completely
PH to 6.5 is saved, adds distilled water to 1000mL, stirs evenly, filtering with microporous membrane is filling, sealing, 100 DEG C of circulation steam sterilizations 1
Hour to get.
7, the preparation of compound I-7 liniment
Prescription: compound I-7 4g, SOFT SOAP 7.5g, camphor 5g, distilled water add to 100mL.
Preparation method: the ethanol solution that camphor concentration expressed in percentage by volume is 95% is dissolved, spare；SOFT SOAP is heats liquefied,
Spare, potash fertilizer soap lye and camphor ethanol solution are added under constant stirring, then is gradually added into distilled water by Weigh Compound I-7, cream
Change completely after add distilled water to full dose to get.
8, the preparation of compound I-8 suppository
Prescription: compound I-8 4g, gelatin 14g, glycerol 70g, distilled water add to 100mL, and 100 pieces of metric system.
Preparation method: weighing gelatin and glycerol, adds distilled water to 100mL, and chemical combination is added when melting in the pasty state in 60 DEG C of heating of water-bath
Object I-8, stirs evenly, and when nearly solidification pours into vaginal plug mold, cooled and solidified to get.
9, the preparation of compound I-1 ointment
Prescription: compound I-1 0.5-2g, hexadecanol 6-8g, albolene 8-10g, atoleine 8-19g, monoglyceride 2-
5g, polyoxyethylene (40) stearate 2-5g, glycerol 5-10g, ethylparaben 0.1g, distilled water add to 100g.
Preparation method: hexadecanol, albolene, atoleine, monoglyceride and polyoxyethylene (40) stearate are heated complete
It is mixed after dissolving, keeps the temperature 80 DEG C, it is mutually spare as oil；It is molten by ethylparaben addition glycerol and distilled water, being heated to 85 DEG C
Solution, then oily phase is added under constant stirring, is added compound I-1 after emulsification, stirring it is cooling to get.
10, the preparation of compound I-5 and Fluconazole compound powder-injection
Prescription: compound I-5 50g, Fluconazole 50g, sodium benzoate 1g are made 100 bottles altogether.
Preparation method: taking compound I-5, Fluconazole and the sodium benzoate of recipe quantity, be uniformly mixed under aseptic conditions, packing
100 bottles to get.
11, the preparation of compound I-6 aerosol
Prescription: compound I-6 2.5g, Span20 3g, talcum powder (100 mesh) 4g, F-11 add in right amount.
Preparation method: compound I-6, Span20 and talcum powder are set into dry a few hours in vacuum oven respectively, set drier
It is inside cooled to room temperature, is ground into micro mist with airslide disintegrating mill, then mix by recipe quantity, pours into closed container, trichlorine one is added
Fluoromethane to specified amount to get.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of the technical program, should all be covered in the present invention
Scope of the claims in.
Claims (10)
1. imidazoles alcohols tetrahydro coptis oxime conjugate and its officinal salt, which is characterized in that structure is as shown in general formula I:
In formula,
R1、R2And R3For hydrogen, halogen, alkyl, alkoxy, alkoxy carbonyl group, amino, hydroxyl, cyano, carboxyl or nitro；
R4For alkyl, naphthenic base, aryl, cyano, alkenyl, alkynyl, ester group, carboxyl, hydroxyl, sulfydryl or amino；
N is the integer of 0-18.
2. imidazoles alcohols tetrahydro coptis oxime conjugate as described in claim 1 and its officinal salt, which is characterized in that
R1For hydrogen or methyl；
R2And R3For hydrogen or nitro；
R4For methyl, tert-butyl, alkenyl or aryl；
N is 0 or 1.
3. imidazoles alcohols tetrahydro coptis oxime conjugate as described in claim 1 and its officinal salt, which is characterized in that be following
Any one of compound:
4. imidazoles alcohols tetrahydro coptis oxime conjugate as described in claim 1 and its officinal salt, which is characterized in that it is described can
Pharmaceutical salts are hydrochloride, sulfate, nitrate or acetate.
5. the preparation method of the described in any item imidazoles alcohols tetrahydro coptis oxime conjugates of claim 1-4 and its officinal salt,
It is characterized in that, described method includes following steps:
A, the preparation of intermediate II: berberrubine is obtained through demethylation reaction using berberine as starting material, by the barberry
Red alkali obtains 9- hydroxy tetrahydro berberine through reduction reaction, by the 9- hydroxy tetrahydro berberine and hexamethylenetetramine in trifluoro
It is reacted in acetic acid up to intermediate II；
B, the preparation of intermediate III: intermediate II is dissolved in n,N-Dimethylformamide, alkali effect under with epoxychloropropane
Nucleophilic substitution occurs up to intermediate III；
C, the preparation of intermediate compound IV: intermediate III is dissolved in n,N-Dimethylformamide, alkali effect under with 2- methyl -5-
Nitroimidazole reacts up to intermediate compound IV；
D, the preparation of intermediate V: intermediate III is dissolved in n,N-Dimethylformamide, alkali effect under with 4- nitroimidazole
It reacts up to intermediate V；
E, the preparation of imidazoles alcohols tetrahydro coptis oxime conjugate shown in general formula I: after intermediate compound IV or V are dissolved in organic solvent,
Condensation reaction occurs with primary amine in the presence of alkali to get imidazoles alcohols tetrahydro coptis oxime conjugate shown in general formula I.
6. method as claimed in claim 5, which is characterized in that
In step a, the temperature of the demethylation reaction is 190 DEG C；The reagent of the reduction reaction is sodium borohydride；The 9-
The ratio between amount of substance of hydroxy tetrahydro berberine and hexamethylenetetramine is 1:1.2；
In step b, the ratio between the intermediate II, amount of substance of epoxychloropropane and alkali are 1:1.5:1.5, and the alkali is carbonic acid
Potassium；The nucleophilic substitution is specially to react 6h at 80 DEG C；
In step c, the ratio between the intermediate III, amount of substance of 2- 5-nitro imidazole and alkali 1:1:1.5, the alkali are
Potassium carbonate；The reaction is specially to react 8h at 80 DEG C；
In step d, the ratio between the intermediate III, amount of substance of 4- nitroimidazole and alkali 1:1:1.5, the alkali are potassium carbonate；
The reaction is specially to react 8h at 80 DEG C；
In step e, the ratio between amount of substance of the intermediate compound IV or V and alkali and primary amine 1:1.5:1.5；The alkali is potassium carbonate；
The organic solvent is acetonitrile；The condensation reaction is specially to react 6h at 80 DEG C.
7. the described in any item imidazoles alcohols tetrahydro coptis oxime conjugates of claim 1-4 and its officinal salt are in preparation antibacterium
And/or the application in antifungal drug.
8. the use as claimed in claim 7, which is characterized in that the bacterium is methicillin-resistant staphylococcus aureus, excrement
Enterococcus, staphylococcus aureus, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, Cray
Bai Shi pneumobacillus, Escherichia coli, pseudomonas aeruginosa, pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922
Or one of Acinetobacter bauamnnii or a variety of；The fungi is Candida albicans, Candida tropicalis, aspergillus fumigatus, white
One of color candida albicans ATCC 90023 or Candida parapsilosis bacterium ATCC 22019 or a variety of.
9. the preparation of the described in any item imidazoles alcohols tetrahydro coptis oxime conjugates of 1-4 containing claim and its officinal salt.
10. preparation as claimed in claim 9, which is characterized in that the preparation be tablet, capsule, granule, injection,
One of powder-injection, eye drops, liniment, suppository, ointment or aerosol.
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