CN101337948A - 1,5-benzothiazepines compounds, preparation method and application thereof - Google Patents
1,5-benzothiazepines compounds, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1, 5-benzothiazepine compound which has the structure shown in a formula (1) or a formula (2), a preparation method and the application thereof. The structure thereof is shown in a figure, and in the formula, G stands for hydrogen or halogen, R1 stands for hydrogen, alkyl or aryl, R2 stands for alkyl or aryl, and R3 stands for hydrogen, metallic ions, alkyl or benzyl; in the formula (1), when the R3 is hydrogen or the metallic ions, n stands for 1, 2, 3, 4, 5 or 6; when the R3 is alkyl or benzyl, the n stands for 0, 1, 2, 3, 4, 5 or 6; in the formula (2), the n stands for 0, 1, 2, 3, 4, 5 or 6. The 1, 5-benzothiazepine compound has very good inhibition effect to epiphyte.
Description
Technical field
The present invention relates to a kind of 1,5-benzothiazepines compounds and its production and application, especially a kind of 1 of carbalkoxy, carboxyl and carboxylate salt functional group thereof, 5-benzothiazepines compounds and its production and application of containing.
Background technology
1, the 5-benzothiazepines is the important seven member ring heterocyclic compounds thing of a class, has multiple potential biological activity.For many years, design and synthesized multiple compound, carried out screening active ingredients widely around its germ resistance people.As, synthesized and closed a series of 1 of indole ring, 5-benzothiazepines derivative, finding that it has gram-positive bacteria suppresses effect preferably; Discovery contains 1 of pyrimidine ring, and 5-benzothiazepines derivative has the effect of AIDS virus resisting, and its activity is active close with two new drugs that are in the clinical evaluation stage.Studies show that in a large number the benzothiazepines compound with seven yuan of parent nucleus features of sulphur nitrogen generally presents better antibacterial activity to various bacteria such as streptococcus aureus, Staphylococcus albus, and fungies such as Candida albicans are also had certain fungistatic effect.But, up to the present found 1, therefore 5-benzothiazepines derivative is not high to the bacteriostatic activity of fungi, when having only large usage quantity, just presents biocidal property, does not possess good patent medicine prospect.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of 1 of carbalkoxy, carboxyl and carboxylate salt functional group thereof, 5-benzothiazepines compounds of containing;
Another technical problem that will solve of the present invention provides a kind of 1 of carbalkoxy, carboxyl and carboxylate salt functional group thereof, preparation method of 5-benzothiazepines compounds of containing;
The another technical problem that will solve of the present invention provides a kind of 1 of carbalkoxy, carboxyl and carboxylate salt functional group thereof of containing, the application of 5-benzothiazepines compounds aspect the inhibition fungi.
For solving the problems of the technologies described above, The compounds of this invention has structure shown in general formula (I) or the general formula (II):
In the formula,
G represents hydrogen or halogen,
R
1Expression hydrogen, alkyl or aryl,
R
2The expression alkyl or aryl,
R
3Expression hydrogen, metal ion, alkyl or Bian Ji,
In general formula (I), work as R
3When getting hydrogen or metal ion, n represents 1,2,3,4,5 or 6; Work as R
3Get alkyl or Bian Jishi, n represents 0,1,2,3,4,5 or 6,
N represents 0,1,2,3,4,5 or 6 in general formula (II).
The preparation method that the present invention has the compound of general formula (I) structure adopts following processing step:
(1), ester group replaces 1, synthesizing of 5-benzothiazepines: being selected from solvent is anhydrous methanol, dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride or chloroform, under the condition that controlled temperature is 0～50 ℃, the α that near amino thiophenols that near amino thiophenols or halogen replace and carbalkoxy or alkoxycarbonyl alkyl replace, the alpha, beta-unsaturated ketone reaction obtains intermediate product; Then intermediate product is dissolved in the above-mentioned selected solvent, ring-closure reaction takes place, make target compound 3 of the present invention, 4-dialkyl-1,5-benzothiazepines-2-fatty acid ester;
(2), 1, synthesizing of 5-benzothiazepines-2-soap: being selected from solvent is anhydrous methanol, dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride or chloroform, with above-mentioned 3,4-dialkyl-1,5-benzothiazepines-2-fatty acid ester is dissolved in the above-mentioned solvent, adds the aqueous solution of sodium hydroxide or potassium hydroxide, hydrolysis, obtain target compound 3 of the present invention, 4-dialkyl-1,5-benzothiazepines-2-soap;
(3), 1,5-benzothiazepines-2-lipid acid synthetic: with above-mentioned 3,4-dialkyl-1, the 5-benzothiazepines-2-soap is with acetic acid or hcl acidifying, obtain target compound 3 of the present invention, 4-dialkyl-1, the 5-benzothiazepines-2-lipid acid.
The preparation method that the present invention has the compound of general formula (II) structure adopts following processing step:
(1), ester group replaces 1, synthesizing of 5-benzothiazepines: solvent is selected from and is dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, methyl alcohol, ethanol or substituted benzene, control reaction temperature-15～50 ℃, the α that near amino thiophenols that near amino thiophenols or halogen replace and carbalkoxy or alkoxycarbonyl alkyl replace, the alpha, beta-unsaturated ketone reaction, obtain intermediate product, then intermediate product is dissolved in the above-mentioned selected solvent, ring-closure reaction takes place, make target compound 2 of the present invention, 4-dialkyl-1,5-benzothiazepines-3-fatty acid ester;
(2), 1, synthesizing of 5-benzothiazepines-3-soap: solvent is selected from and is dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, methyl alcohol, ethanol or substituted benzene, with obtain 2,4-dialkyl-1,5-benzothiazepines-3-fatty acid ester is dissolved in the above-mentioned solvent, adds the aqueous solution of sodium hydroxide or potassium hydroxide, hydrolysis, obtain target compound 2 of the present invention, 4-dialkyl-1,5-benzothiazepines-3-soap;
(3), 1,5-benzothiazepines-3-lipid acid is synthetic: will obtain 2,4-dialkyl-1, the 5-benzothiazepines-3-soap is with acetic acid or hcl acidifying, obtain target compound 2 of the present invention, 4-dialkyl-1, the 5-benzothiazepines-3-lipid acid.
The invention also discloses have general formula (I) or (II) structure 1, the application of 5-benzothiazepines compounds in mycocide.
General formula of the present invention (I) and general formula (II) are for having unitary 1 of carbalkoxy, carboxyl and the carboxylate salt functional group thereof of containing of common primary structure, the 5-benzothiazepines compounds, the composition principle of the two is identical, and all has the restraining effect to fungi, belongs to same compounds.
The novel cpd that the present invention finds has very strong germ resistance to Candida albicans, and fungies such as cryptococcus neoformans are also had certain restraining effect, belong to the extremely sensitive compound of a class fungi, and the toxicity of pair cell is less, has a good application prospect.
Carbalkoxy compounds in the general formula wherein of the present invention (I) has very high restraining effect to Candida albicans, and other pathomycete is also had stronger germicidal action; Carboxylic acid (salt) compounds described in the general formula (I) also has high restraining effect to Candida albicans, and other pathomycete is also had stronger germicidal action, and antibacterial circle diameter is reducing and reduce gradually with concentration basically.
Compound in the general formula wherein of the present invention (II) has the obvious suppression effect to fungies such as Candida albicanss.It is worthy of note that because most compounds has restraining effect to Candida albicans (fungi), antifungal medicament is fewer clinically, so this work has the assorted tall and erect class medicine of anti-mycotic activity with significant for finding.
Description of drawings
The present invention is further detailed explanation below in conjunction with the drawings and specific embodiments.
Fig. 1 is the infrared spectra (IR) of the embodiment of the invention 1;
Fig. 2 is the proton nmr spectra (HNMR) of the embodiment of the invention 1;
Fig. 3 is mass spectrum (MS) figure of the embodiment of the invention 1.
Embodiment
Have structure 1 shown in the general formula (I), the 5-benzothiazepines compounds:
In the formula,
G represents hydrogen or halogen; R
1Expression hydrogen, alkyl or aryl; R
2The expression alkyl or aryl; R
3Expression hydrogen, metal ion, alkyl or Bian Ji.
Work as R
3When getting hydrogen or metal ion, n represents 1,2,3,4,5 or 6; Work as R
3Get alkyl or Bian Jishi, n represents 0,1,2,3,4,5 or 6,
Wherein said halogen is a fluorine or chlorine; R
1Described in alkyl be methyl, ethyl or propyl group; R
1Described in aryl be phenyl, fluoro phenyl, chlorophenyl, bromo phenyl, ethylphenyl, nitrophenyl, p-methoxy-phenyl or aminomethyl phenyl; R
2Described in alkyl be methyl, ethyl or propyl group; R
2Described in aryl be phenyl, fluoro phenyl, chlorophenyl, bromo phenyl, nitrophenyl, p-methoxy-phenyl, aminomethyl phenyl or ethylphenyl; R
3Described in alkyl be methyl, ethyl or propyl group; R
3Described in metal ion be sodium ion or potassium ion.
Has 1 of structure shown in the general formula (I), the preparation method of 5-benzothiazepines compounds: the α that carbalkoxy or alkoxycarbonyl alkyl replace, alpha, beta-unsaturated ketone and near amino thiophenols or the reaction of replacement near amino thiophenols, hydrolysis reaction, acidification reaction, a series of target compounds of the present invention have been obtained, promptly contain 1 of carbalkoxy, carboxyl and carboxylate salt functional group thereof, the 5-benzothiazepines compounds.
Concrete steps are as follows: solvent is selected from anhydrous methanol, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride or chloroform, the α that near amino thiophenols that near amino thiophenols or halogen replace and carbalkoxy or alkoxycarbonyl alkyl replace, the alpha, beta-unsaturated ketone reaction, controlled temperature 0-50 ℃, reacted 10-30 hour.Stopped reaction leaves standstill, suction filtration gets crude product, and recrystallization gets series compound 3 of the present invention, 4-dialkyl-1,5-benzothiazepines-2-fatty acid ester.
Solvent is selected from anhydrous methanol, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride or chloroform, with the above-mentioned compound that obtains 3,4-dialkyl-1,5-benzothiazepines-2-fatty acid ester is dissolved in the above-mentioned solvent, the aqueous solution that adds sodium hydroxide or potassium hydroxide again, room temperature reaction 1-6 hour.Organic solvent is removed in underpressure distillation, and water layer transfers to neutrality with dilute hydrochloric acid, and freeze-drying afterwards gets target compound 3,4-dialkyl-1,5-benzothiazepines-2-soap compounds.
With obtain 3,4-dialkyl-1,5-benzothiazepines-2-soap to pH＜3, obtains target compound 3 of the present invention, 4-dialkyl-1,5-benzothiazepines-2-lipid acid with acetic acid or hcl acidifying.
Below for having 1 of general formula (I) structure, the synthetic route of 5-benzothiazepines compounds:
Have structure 1 shown in the general formula (II), the 5-benzothiazepines compounds:
In the formula,
G represents hydrogen or halogen,
R
1Expression hydrogen, alkyl or aryl,
R
2The expression alkyl or aryl,
R
3Expression hydrogen, metal ion, alkyl or Bian Ji,
N represents 0,1,2,3,4,5 or 6.
Wherein said halogen is a fluorine or chlorine; R
1Described in alkyl be methyl, ethyl or propyl group; R
1Described in aryl be phenyl, fluoro phenyl, chlorophenyl, bromo phenyl, ethylphenyl, nitrophenyl, p-methoxy-phenyl or aminomethyl phenyl; R
2Described in alkyl be methyl, ethyl or propyl group; R
2Described in aryl be phenyl, fluoro phenyl, chlorophenyl, bromo phenyl, nitrophenyl, p-methoxy-phenyl, aminomethyl phenyl or ethylphenyl; R
3Described in alkyl be methyl, ethyl or propyl group; R
3Described in metal ion be sodium ion or potassium ion.
Has structure 1 shown in the general formula (II), the preparation method of 5-benzothiazepines compounds: the α that carbalkoxy or alkoxycarbonyl alkyl replace, alpha, beta-unsaturated ketone and near amino thiophenols or the reaction of replacement near amino thiophenols, hydrolysis reaction, acidification reaction, a series of target compounds of the present invention have been obtained, promptly contain 1 of carbalkoxy, carboxyl and carboxylate salt functional group thereof, the 5-benzothiazepines compounds.
Concrete steps are as follows: solvent is selected from and is dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, methyl alcohol, ethanol or substituted benzene, near amino thiophenols or replace the α of near amino thiophenols and carbalkoxy or alkoxycarbonyl alkyl replacement, the alpha, beta-unsaturated ketone reaction, controlled temperature-20～50 ℃, reacted 0.5-8 hour, and obtained intermediate product.Intermediate product is dissolved in the above-mentioned selected solvent, ring-closure reaction takes place obtain crude product, and the recrystallization crude product obtains target compound 2 of the present invention, 4-dialkyl-1,5-benzothiazepines-3-fatty acid ester.
Solvent is selected from and is dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, methyl alcohol, ethanol or substituted benzene, with obtain 2,4-dialkyl-1,5-benzothiazepines-3-fatty acid ester is dissolved in the above-mentioned solvent, the aqueous hydrolysis that adds sodium hydroxide or potassium hydroxide, obtain target compound 2 of the present invention, 4-dialkyl-1,5-benzothiazepines 3-soap.
With obtain 2,4-dialkyl-1, the 5-benzothiazepines-3-soap to pH＜3, obtains target compound 2 of the present invention with acetic acid or hcl acidifying, 4-dialkyl-1, the 5-benzothiazepines-3-lipid acid.
Below for having 1 of general formula (II) structure, the synthetic route of 5-benzothiazepines compounds:
Below be specific embodiments of the invention:
Embodiment 1:2-ethoxy carbonyl-4-phenyl-1, the preparation of 5-benzothiazepines
Add γ-phenyl-α, β-unsaturated methylene acetone acetoacetic ester 2.0g (10.0mmol) and 15mL anhydrous methanol added o-amino thiophenol 1.1mL (10.0mmol) again, 0 ℃ of reaction 12 hours.Stopped reaction leaves standstill, and suction filtration gets solids, gets light yellow solid 2.4g with the above-mentioned solids of anhydrous methanol recrystallization, m.p:90～92 ℃, and productive rate 77.6%, this solid is 2-ethoxy carbonyl-4-phenyl-1 after measured, the 5-benzothiazepines.
Its characterization data: as Figure 1-3, Yield 77.6%; MS[M+H
+]: 312; IR KBr (v cm
-1) 1726 (C=O), 1610 (C=N);
1H NMR (400MHz, DMSO-d
6), δ (ppm): 7.08-8.03 (9H, m), 4.30-4.35 (1H, dd), 3.19-3.23 (1H, dd), 3.09-3.14 (1H, dd), 4.18-4.23 (2H, q), 1.27-1.30 (3H, t).
Embodiment 2:2-ethoxy carbonyl-4-rubigan-1, the preparation of 5-benzothiazepines
Carry out with embodiment 1 identical method, different is to get γ-rubigan-α, β-unsaturated methylene acetone acetoacetic ester replaces γ-phenyl-α, β-unsaturated methylene acetone acetoacetic ester, and need reacting the back concentrating under reduced pressure, residuum carries out column chromatography for separation, and rotary evaporation gets solids, this solid is 2-ethoxy carbonyl-4-rubigan-1 after measured, the 5-benzothiazepines.
Embodiment 3:2-ethoxy carbonyl-4-is to fluorophenyl-1, the preparation of 5-benzothiazepines
Carry out with embodiment 1 identical method, different is gets γ-to fluorophenyl-α, β-unsaturated methylene acetone acetoacetic ester replaces γ-phenyl-α, β-unsaturated methylene acetone acetoacetic ester, and need reacting the back concentrating under reduced pressure, residuum carries out column chromatography for separation, and rotary evaporation gets solids, after measured this solid be 2-ethoxy carbonyl-4-to fluorophenyl-1, the 5-benzothiazepines.
Embodiment 4:2-ethoxy carbonyl-4-p-methoxyphenyl-1, the preparation of 5-benzothiazepines
Carry out with embodiment 1 identical method, different is to get γ-p-methoxyphenyl-α, β-unsaturated methylene acetone acetoacetic ester replaces γ-phenyl-α, β-unsaturated methylene acetone acetoacetic ester, and need reacting the back concentrating under reduced pressure, residuum carries out column chromatography for separation, and rotary evaporation gets solids, this solid is 2-ethoxy carbonyl-4-p-methoxyphenyl-1 after measured, the 5-benzothiazepines.
Embodiment 5:4-phenyl-1, the preparation of 5-benzothiazepines-2-formic acid sodium salt
Add 0.3g (1.0mmol) 2-ethoxy carbonyl-4-phenyl-1,5-benzothiazepines solid and 40mL dehydrated alcohol add the 5mL aqueous solution of 0.2g (5.0mmol) sodium hydroxide, again 50 ℃ of reactions 10 hours.Add 20mL water then, concentrating under reduced pressure steams ethanol, and water layer is transferred pH=7～8 with dilute hydrochloric acid, and freeze-drying afterwards gets solids, and this solids is a 4-phenyl-1 after measured, 5-benzothiazepines-2-formic acid sodium salt.
Its characterization data is: Yield 73.5%; MS[M+H
+]: 283; IR KBr (vcm
-1), 1600 (C=N), 1570 (COO
-), 1416 (COO
-);
1H NMR (400MHz, DMSO-d
6), δ (ppm): 7.11-8.009H, m), 4.31-4.34 (1H, dd), 3.16-3.181H, dd), 3.11-3.13 (1H, dd).
Embodiment 6:4-phenyl-1, the preparation of 5-benzothiazepines-2-formic acid
Add 0.1mmol 4-phenyl-1,5-benzothiazepines-2-formic acid sodium salt, the 10mL dissolve with methanol, add 25mL acetic acid then, stirring at room 2 hours has left standstill solid and has separated out, filter light yellow solid, productive rate is 78.1%, and this solid chemical compound is a 4-phenyl-1 after measured, 5-benzothiazepines-2-formic acid.
Its characterization data is: Yield 78.1%; MS[M-1]: 282; IR KBr (v cm
-1) 3000 (COOH), 1712 (C=O), 1652 (C=N);
1H NMR (400MHz, DMSO-d
6), δ (ppm): 13.1 (1H, s), 7.05-8.12 (9H, m), 4.25-4.30 (1H, dd), 3.15-3.17 (1H, dd), 3.12-3.14 (1H, dd).
Embodiment 7:4-rubigan-1, the preparation of 5-benzothiazepines-2-formic acid sodium salt
Carry out with embodiment 5 identical methods, different is 2-ethoxy carbonyl-4-rubigan-1, the 5-benzothiazepines replaces 2-ethoxy carbonyl-4-phenyl-1, the 5-benzothiazepines, get faint yellow solid, this solid is a 4-rubigan-1 after measured, 5-benzothiazepines-2-formic acid sodium salt.
Embodiment 8:2-p-hydroxybenzene-3-ethoxycarbonyl methylene radical-4-methyl isophthalic acid, the preparation of 5-benzothiazepines
Add 3-ethanoyl-4-p-hydroxybenzene-3-butenoic acid ethyl (25mmol); near amino thiophenols 3.1g (25mmol); the 30mL anhydrous methanol; 0 ℃ was reacted 1 hour down; separate out a large amount of solids, filter; obtain solids, this solids is dissolved in the 30mL anhydrous methanol; dropwise add acetic acid; make PH=4-6, stirred overnight at room temperature is put into refrigerator and cooled and is frozen; filter; solid anhydrous methanol recrystallization gets the light yellow solid compound, productive rate 49%; this solid chemical compound is 2-p-hydroxybenzene-3-ethoxycarbonyl methylene radical-4-methyl isophthalic acid after measured, the 5-benzothiazepines.
Its characterization data is: Yield 49.5%; MS[M+H
+]: 356; IR KBr (v cm
-1) 1718 (C=O), 1637 (C=N);
1H NMR (400MHz, DMSO-d
6), δ (ppm): 6.63-7.52 (8H, m), 5.20-5.23 (1H, d), 4.54 (1H, s), 4.17 (2H, d), 3.90-3.92 (2H, q), 3.70-3.72 (1H, m), 2.29 (3H, s), 0.96-0.99 (3H, t).
Embodiment 9:2-p-hydroxybenzene-4-methyl isophthalic acid, the preparation of 5-benzothiazepines-3-acetic acid sodium salt
Add 0.36g (1mmol) 2-p-hydroxybenzene-3-ethoxycarbonyl methylene radical-4-methyl isophthalic acid, 5-benzothiazepines solid and 30mL anhydrous methanol add the 5mL aqueous solution of 0.2g (5mmol) sodium hydroxide again, 30 ℃ of reactions 10 hours.Add 20mL water, concentrating under reduced pressure steams methyl alcohol, and water layer is transferred pH=8-9 with dilute hydrochloric acid, and freeze-drying afterwards gets solids, and this solids is 2-p-hydroxybenzene-4-methyl isophthalic acid after measured, 5-benzothiazepines-3-acetic acid sodium salt.
Its characterization data is: Yield 70.2%; MS[M+H
+]: 327; IR KBr (v cm
-1), 1633 (C=N), 1578 (COO
-), 1412 (COO
-);
1H NMR (400MHz, DMSO-d
6), δ (ppm): 6.60-7.54 (8H, m), 5.21-5.23 (1H, d), 4.52 (1H, s), 4.15 (2H, d), 3.70-3.72 (1H, m), 2.29 (3H, s).
Embodiment 10:2-p-hydroxybenzene-4-methyl isophthalic acid, the preparation of 5-benzothiazepines-3-acetate
Add 0.1mmol 2-p-hydroxybenzene-4-methyl isophthalic acid, 5-benzothiazepines-3-acetic acid sodium salt, the 10mL dissolve with methanol, add 50mL acetic acid then, 50 ℃ were stirred 3 hours, and had left standstill solid and separated out, suction filtration gets white solid, productive rate 65.1%, this solid chemical compound is 2-p-hydroxybenzene-4-methyl isophthalic acid after measured, 5-benzothiazepines-3-acetate.
Its characterization data is: Yield 65.1%; MS[M-1]: 326; IR KBr (v cm
-1) 3050 (COOH), 1675 (C=O), 1633 (C=N);
1H NMR (400MHz, DMSO-d
6), δ (ppm): 12.8 (1H, s), 6.61-7.50 (8H, m), 5.20-5.23 (1H, d), 4.54 (1H, s), 4.16 (2H, d), 3.70-3.72 (1H, m), 2.29 (3H, s).
Embodiment 11:2-p-nitrophenyl-3-ethoxycarbonyl methylene radical-4-methyl isophthalic acid, the preparation of 5-benzothiazepines
Carry out with embodiment 8 identical methods; different is that 3-ethanoyl-4-p-nitrophenyl-3-butenoic acid ethyl replaces 3-ethanoyl-4-p-hydroxybenzene-3-butenoic acid ethyl; get faint yellow solid; this solid chemical compound is 2-p-nitrophenyl-3-ethoxycarbonyl methylene radical-4-methyl isophthalic acid after measured, the 5-benzothiazepines.
Bacteriostatic activity experiment of the present invention:
Experimental technique: (1), test sample (the foregoing description preparation finished product) is made into the solution of different concns with DMSO, with micro sample adding appliance it is added on the filter paper, make every to contain sample size and be respectively 200 μ g, 100 μ g, 50 μ g, 25 μ g, 12.5 μ g, it is standby that room temperature is placed to DMSO volatilization back.The control drug fluconazole is made into different concns solution with physiological saline, it is added on the filter paper, make every content of dispersion be respectively 10 μ g, 5 μ g, 2.5 μ g, 1.5 μ g, 0.250 μ g, 0.125 μ g, 0.0625 μ g with micro sample adding appliance.
(2), the bacterial classification with logarithmic phase is diluted to 10 with Regulox (MH) liquid nutrient medium
6CFU/mL dips in aseptic cotton carrier and to get bacterium liquid, is uniformly coated on the MH agar plate, then the pastille scraps of paper is attached on the substratum, cultivates 48 hours observationss in 37 ℃.Experimental strain: Candida albicans (C.albicans) and cryptococcus neoformans (C.neoformans).
(3), experiment repeats twice, The anti-bacterial result is averaged.
As follows in order to last method to the result that The compounds of this invention carries out determination of activity:
Annotate: the compound fungistatic effect is remarkable in the test, asepsis growth on the whole watch-glass, and the result is with "+" expression, and compound does not have obvious fungistatic effect (antibacterial circle diameter＜6mm), the result is with "-" expression in the test.
By above-mentioned bacteriostatic activity experiment of the present invention as can be seen, have general formula (I) or (II) structure 1, the 5-benzothiazepines compounds has the good restraining effect to fungi, can be used for killing the antifungal drug of fungi such as Candida albicans.
Claims (11)
1, a kind of 1, the 5-benzothiazepines compounds is characterized in that this compound has structure shown in general formula (I) or the general formula (II):
In the formula,
G represents hydrogen or halogen,
R
1Expression hydrogen, alkyl or aryl,
R
2The expression alkyl or aryl,
R
3Expression hydrogen, metal ion, alkyl or Bian Ji,
In general formula (I), work as R
3When getting hydrogen or metal ion, n represents 1,2,3,4,5 or 6; Work as R
3Get alkyl or Bian Jishi, n represents 0,1,2,3,4,5 or 6,
N represents 0,1,2,3,4,5 or 6 in general formula (II).
2, according to claim 11, the 5-benzothiazepines compounds is characterized in that described halogen is a fluorine or chlorine.
3, according to claim 11, the 5-benzothiazepines compounds is characterized in that R
1Described in alkyl be methyl, ethyl or propyl group.
4, according to claim 11, the 5-benzothiazepines compounds is characterized in that R
1Described in aryl be phenyl, fluoro phenyl, chlorophenyl, bromo phenyl, ethylphenyl, nitrophenyl, p-methoxy-phenyl or aminomethyl phenyl.
5, according to claim 11, the 5-benzothiazepines compounds is characterized in that R
2Described in alkyl be methyl, ethyl or propyl group.
6, according to claim 11, the 5-benzothiazepines compounds is characterized in that R
2Described in aryl be phenyl, fluoro phenyl, chlorophenyl, bromo phenyl, nitrophenyl, p-methoxy-phenyl, aminomethyl phenyl or ethylphenyl.
7, according to claim 11, the 5-benzothiazepines compounds is characterized in that R
3Described in alkyl be methyl, ethyl or propyl group.
8, according to claim 11, the 5-benzothiazepines compounds is characterized in that R
3Described in metal ion be sodium ion or potassium ion.
9, a kind of have 1 of general formula (I) structure, and the preparation method of 5-benzothiazepines compounds is characterized in that this method adopts following processing step:
(1), ester group replaces 1, synthesizing of 5-benzothiazepines: being selected from solvent is anhydrous methanol, dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride or chloroform, under the condition that controlled temperature is 0～50 ℃, the α that near amino thiophenols that near amino thiophenols or halogen replace and carbalkoxy or alkoxycarbonyl alkyl replace, the alpha, beta-unsaturated ketone reaction obtains intermediate product; Then intermediate product is dissolved in the above-mentioned selected solvent, ring-closure reaction takes place, make target compound 3,4-dialkyl-1,5-benzothiazepines-2-fatty acid ester;
(2), 1, synthesizing of 5-benzothiazepines-2-soap: being selected from solvent is anhydrous methanol, dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride or chloroform, with above-mentioned 3,4-dialkyl-1,5-benzothiazepines-2-fatty acid ester is dissolved in the above-mentioned solvent, adds the aqueous solution of sodium hydroxide or potassium hydroxide, hydrolysis, obtain target compound 3,4-dialkyl-1,5-benzothiazepines-2-soap;
(3), 1,5-benzothiazepines-2-lipid acid synthetic: with above-mentioned 3,4-dialkyl-1, the 5-benzothiazepines-2-soap is with acetic acid or hcl acidifying, obtains target compound 3,4-dialkyl-1, the 5-benzothiazepines-2-lipid acid.
10, a kind of have 1 of general formula (II) structure, and the preparation method of 5-benzothiazepines compounds is characterized in that this method adopts following processing step:
(1), ester group replaces 1, synthesizing of 5-benzothiazepines: solvent is selected from and is dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, methyl alcohol, ethanol or substituted benzene, control reaction temperature-15～50 ℃, the α that near amino thiophenols that near amino thiophenols or halogen replace and carbalkoxy or alkoxycarbonyl alkyl replace, the alpha, beta-unsaturated ketone reaction, obtain intermediate product, then intermediate product is dissolved in the above-mentioned selected solvent, ring-closure reaction takes place, make target compound 2,4-dialkyl-1,5-benzothiazepines-3-fatty acid ester;
(2), 1, synthesizing of 5-benzothiazepines-3-soap: solvent is selected from and is dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, methyl alcohol, ethanol or substituted benzene, with obtain 2,4-dialkyl-1,5-benzothiazepines-3-fatty acid ester is dissolved in the above-mentioned solvent, adds the aqueous solution of sodium hydroxide or potassium hydroxide, hydrolysis, obtain target compound 2,4-two hydrocarbon-1,5-benzothiazepines-3-soap;
(3), 1,5-benzothiazepines-3-lipid acid is synthetic: will obtain 2,4-dialkyl-1, the 5-benzothiazepines-3-soap is with acetic acid or hcl acidifying, obtains target compound 2,4-dialkyl-1, the 5-benzothiazepines-3-lipid acid.
11, have general formula (I) or (II) structure 1, the 5-benzothiazepines compounds is in the application of killing aspect the fungi.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103965185A (en) * | 2014-03-28 | 2014-08-06 | 河北师范大学 | 1, 5-benzodiazepine compound containing thiazolyl and ester and application of compound |
| CN105837564A (en) * | 2016-03-30 | 2016-08-10 | 贵州大学 | Pyridine-containing benzothiazepine derivatives, and preparation method and application thereof |
| CN107857767A (en) * | 2017-06-07 | 2018-03-30 | 河北师范大学 | 1,5 benzodiazepine compounds of five-membered ring lactone fusion |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103965185A (en) * | 2014-03-28 | 2014-08-06 | 河北师范大学 | 1, 5-benzodiazepine compound containing thiazolyl and ester and application of compound |
| CN103965185B (en) * | 2014-03-28 | 2016-06-29 | 河北师范大学 | 1,5-benzodiazepine compound containing thiazolyl and ester group and application thereof |
| CN105837564A (en) * | 2016-03-30 | 2016-08-10 | 贵州大学 | Pyridine-containing benzothiazepine derivatives, and preparation method and application thereof |
| CN105837564B (en) * | 2016-03-30 | 2019-02-05 | 贵州大学 | One kind benzothiazepines containing pyridine derivative, preparation method and the usage |
| CN107857767A (en) * | 2017-06-07 | 2018-03-30 | 河北师范大学 | 1,5 benzodiazepine compounds of five-membered ring lactone fusion |
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