CN110590748A - Aromatic amino benzyl piperazine nitrogen oxide and composition and application thereof - Google Patents
Aromatic amino benzyl piperazine nitrogen oxide and composition and application thereof Download PDFInfo
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- 125000003118 aryl group Chemical group 0.000 title description 2
- -1 aromatic aminobenzyl piperazine nitroxide Chemical class 0.000 claims abstract description 35
- 239000000419 plant extract Substances 0.000 claims abstract description 32
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000001769 aryl amino group Chemical group 0.000 claims abstract description 9
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/79—Schisandraceae (Schisandra family)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9062—Alpinia, e.g. red ginger or galangal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Medical Informatics (AREA)
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- Engineering & Computer Science (AREA)
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- Oncology (AREA)
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Abstract
The invention provides an aryl amino benzyl piperazine nitrogen oxide, which is defined in the specification. The present invention further provides a composition comprising the aromatic aminobenzyl piperazine nitroxide, and more particularly, a composition comprising a mixture of a first aromatic aminobenzyl piperazine nitroxide and a second aromatic aminobenzyl piperazine nitroxide which are different from each other, the mixture being capable of enhancing the antibacterial effect of various plant extracts by a synergistic effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an aryl aminobenzyl piperazine oxynitride, and a composition and application thereof.
Background
Nosocomial infections are a significant problem affecting hospital medical quality. With the continuous development and progress of modern medical technology, a large amount of antibacterial drugs are used, and the drug-resistant strains of clinical pathogenic bacteria are continuously increased. Therefore, the improvement of the antibacterial activity of the existing drugs can help to improve the treatment effect of the patients with bacterial infection.
CN08939081A discloses an antibacterial composition comprising metformin and an aromatic aminobenzylpiperazine nitroxide of the formula i, and discloses the antibacterial activity of this compound when administered alone.
The plant extract is rich in a plurality of components with antibacterial activity, for example, the extracts of plants such as the populus nymphs and the like (the report of tropical biology, 2019,10(03): 226;) 230. the extracts of the plants such as the blumea riparia, the rhinestone, the illicium verum, the aeolian milkvetch root, the sinoacutus hexapetalus mongholicus, the kadsura longipedunculata, the anoectochilus roxburghii, the typhonium giganteum, the rhynchophyllum giganteum, the stringy euphorbia root, the typhonium giganteum, the fraxinellus pallidus, the cudrania cochinchinensis, and the like have certain antibacterial activity.
It is well known that the therapeutic effects of Chinese herbs are manifested by the synergistic action of a series of compounds (effective components) with similar structures. Therefore, a compound group which can generate synergistic action with the plant extract is searched, and a new way is provided for treating difficult and complicated diseases by combining Chinese and western medicine.
Disclosure of Invention
The invention aims to provide an aryl amino benzyl piperazine nitrogen oxide, and the aryl amino benzyl piperazine nitrogen oxide or a mixture of two of the aryl amino benzyl piperazine nitrogen oxides can generate a synergistic antibacterial effect with extracts of plants such as radix sileris, rhinestone, illicium verum, and ledebouriella root.
In order to achieve the above object, the present invention provides an aryl aminobenzyl piperazine nitroxide, which is characterized in that the aryl aminobenzyl piperazine nitroxide is one selected from the following compounds 1 to 11:
in another aspect of the present invention, there is provided a composition containing an arylaminobenzyl piperazine nitroxide, wherein the arylaminobenzyl piperazine nitroxide is one selected from the group consisting of the compounds 1 to 11 and the following compounds 12 to 13:
in one aspect, the composition of the present invention preferably comprises a mixture of a first arylaminobenzyl piperazine nitroxide and a second arylaminobenzyl piperazine nitroxide which are different from each other and selected from the compounds 1 to 13.
Further preferably, the mass ratio of the first arylaminobenzyl piperazine nitrogen oxide to the second arylaminobenzyl piperazine nitrogen oxide in the composition is 0.01: 1-100: 1.
In another aspect, the composition of the present invention preferably further comprises a plant extract.
Further preferably, the plant extract of the present invention is an extract of one selected from the group consisting of jatropha curcas, rhubard, illicium simonsii, and ledebouriella sessilifolia.
More preferably, the ratio of the mass of the mixture of the first aryl amino benzyl piperazine nitrogen oxide and the second aryl amino benzyl piperazine nitrogen oxide in the composition to the mass of the plant extract is between 0.01:1 and 100: 1.
In another aspect, the composition of the present invention can be prepared into oral solid preparation.
More preferably, the oral solid preparation of the present invention is one selected from the group consisting of tablets, capsules and capsules.
In another aspect, the invention provides the use of a compound or composition as hereinbefore described in the manufacture of a medicament for the treatment of a bacterial infectious disease.
Preferably, the bacterial infectious disease of the present invention is a disease caused by infection with one bacterium selected from the group consisting of Citrobacter freundii, Propionibacterium acnes, Serratia liquidescens, Aerococcus viridis, Staphylococcus pini, Kukeria clarkii, Neisseria meningitidis, Micrococcus luteus, Corynebacterium glutamicum, Leuconostoc decarboxylatum, Alcaligenes xyloxidans, Chlamydia trachomatis, Staphylococcus intermedia, Achromobacter xylosoxidans, and Streptococcus mitis.
In vitro test results show that the mixture of the aryl amino benzyl piperazine nitrogen oxides can generate synergistic antibacterial action with extracts of various plants such as anemone rivularis, rhinestone, illicium verum, leprosum and the like
Detailed Description
The following description of the embodiments is only intended to aid in the understanding of the method of the invention and its core ideas. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The following description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.
Preparation example 1 preparation of N-oxide of aryl aminobenzylpiperazine
The invention relates to a method disclosed in Chinese medicine industry journal 2011, 42(10):728, which takes commercially available aryl aminobenzyl piperazine as a raw material and adopts different oxidation conditions for oxidation to prepare the aryl aminobenzyl piperazine nitrogen oxide.
Preparation example 1.1 preparation and Structure confirmation of Compound 1
Dissolving 4mmol of compound 1s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and stirring for reaction at room temperature. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.8:0.1) showed substantial disappearance of starting material (about 28h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.8:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 225-227 ℃.1H-NMR(CDCl3)δ：1H-NMR(CDCl3)δ：9.24(s，2H)，8.71(d，2H)，8.54(d，2H)，8.41(d，2H)，7.86(d，4H)，7.56(dd，2H)，7.36～7.35(m，6H)，7.26(s，2H)，7.21(d，2H)，7.13(d，2H)，4.49(s，4H)，3.67(t，8H)，2.16(s，6H)。
For comparison, of Compound 1s1H-NMR(CDCl3)δ：9.24(s，2H)，8.71(d，2H)，8.55(d，2H)，8.40(d，2H)，7.93(d，4H)，7.56(dd，2H)，7.38(d，2H)，7.35(d，4H)，7.25(s，2H)，7.20(d，2H)，7.16(d，2H)，3.67(s，4H)，2.46(t，8H)，2.13(s，6H)。
Preparation example 1.2 preparation and Structure confirmation of Compound 2
Dissolving 4mmol of compound 2s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 8h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 187-188 ℃.1H-NMR(CDCl3)δ：9.23(s，1H)，8.70(d，1H)，8.56(d，1H)，8.42(d，1H)，7.94(s，1H)，7.90(d，1H)，7.59～7.56(m，2H)，7.46(dd，1H)，7.36(d，1H)，7.25(s，1H)，7.21(d，1H)，7.13(d，1H)，3.66(s，2H)，3.34(t，4H)，3.31(s，3H)，2.79(t，4H)，2.12(s，3H)。
For comparison, of Compound 2s1H-NMR(CDCl3)δ：9.23(s，1H)，8.71(d，1H)，8.55(d，1H)，8.41(d，1H)，7.94～7.93(m，2H)，7.58～7.56(m，2H)，7.47(dd，1H)，7.37(d，1H)，7.27～7.22(m，2H)，7.13(d，1H)，3.66(s，2H)，2.48(t，4H)，2.35(t，4H)，2.16(s，3H)，2.11(s，3H)。
Preparation example 1.3 preparation and Structure confirmation of Compound 3
Dissolving 4mmol of compound 3s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 8h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 202-204 ℃.1H-NMR(CDCl3)δ：9.23(s，1H)，8.95(d，1H)，8.69(d，1H)，8.44(d，1H)，7.95(d，1H)，7.90(d，2H)，7.72(s，1H)，7.58(dd，1H)，7.36(d，1H)，7.33(d，2H)，7.30(d，1H)，3.67(s，2H)，3.35(t，4H)，3.29(s，3H)，2.80(t，4H)，2.10(s，3H)，2.07(s，3H)
For comparison, of Compound 3s1H-NMR(CDCl3)δ：9.24(s，1H)，8.93(d，1H)，8.70(d，1H)，8.42(d，1H)，7.93～7.91(m，3H)，7.73(s，1H)，7.57(dd，1H)，7.35～7.31(m，4H)，3.64(s，2H)，2.47(t，4H)，2.34(t，4H)，2.15(s，3H)，2.13(s，3H)，2.06(s，3H)。
Preparation example 1.4 preparation and Structure confirmation of Compound 4
4mmol of compound 4s is taken and dissolved in 40mL of DMF, 2mL of 30 percent hydrogen peroxide is added at one time under the stirring at room temperature, and the reaction is carried out under the stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 8h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 211-213 ℃.1H-NMR(CDCl3)δ：9.26(s，1H)，8.68(d，1H)，8.41(d，1H)，7.91(d，2H)，7.58～7.57(m，2H)，7.33(d，2H)，7.26(s，1H)，7.21(d，1H)，7.16(d，1H)，3.66(s，2H)，3.34(t，4H)，3.32(s，3H)，2.80(t，4H)，2.47(s，3H)，2.13(s，3H)。
For comparison, of Compound 4s1H-NMR(CDCl3)δ：9.23(s，1H)，8.69(d，1H)，8.41(d，1H)，7.92(d，2H)，7.58(s，1H)，7.56(dd，1H)，7.35(d，2H)，7.25～7.24(m，2H)，7.14(d，1H)，3.68(s，2H)，2.48(t，4H)，2.46(s，3H)，2.33(t，4H)，2.15(s，3H)，2.13(s，3H)。
Preparation example 1.5 preparation and Structure confirmation of Compound 5
Dissolving 4mmol of compound 5s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 8h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 226-228 ℃.1H-NMR(CDCl3)δ：9.24(s，1H)，8.69(d，1H)，8.63(d，1H)，8.41(d，1H)，7.93(d，4H)，7.70(s，1H)，7.57(dd，1H)，7.34～7.33(m，6H)，3.64(s，4H)，3.35(t，8H)，3.30(s，6H)，2.79(t，8H)，2.11(s，3H)。
For comparison, of Compound 5s1H-NMR(CDCl3)δ：9.25(s，1H)，8.70(d，1H)，8.65(d，1H)，8.43(d，1H)，7.95(d，1H)，7.92(d，4H)，7.59～7.58(dd，2H)，7.34(d，4H)，7.34(s，1H)，7.30(d，1H)，7.11(d，1H)，3.68(s，4H)，2.53～2.50(m，8H)，2.36～2.34(m，8H)，2.13(s，6H)，2.10(s，3H)。
Preparation example 1.6 preparation and Structure confirmation of Compound 6
Dissolving 4mmol of compound 6s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and stirring for reaction at room temperature. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 27h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 256-257 ℃.1H-NMR(CDCl3)δ：9.23(s，1H)，8.68(d，1H)，8.56(d，1H)，8.43(d，1H)，7.83(d，2H)，7.56(dd，1H)，7.36～7.35(m，3H)，7.24～7.23(m，2H)，7.12(d，1H)，4.50(s，2H)，3.37(t，4H)，3.00(t，4H)，2.13(s，3H)。
For comparison, of Compound 6s1H-NMR(CDCl3)δ：9.23(s，1H)，8.72(d，1H)，8.55(d，1H)，8.42(d，1H)，7.93(d，2H)，7.58(dd，1H)，7.37～7.35(m，2H)，7.24～7.23(m，2H)，7.13(d，1H)，3.66(s，2H)，2.63(t，4H)，2.33(t，4H)，2.13(s，3H)。
Preparation example 1.7 preparation and Structure confirmation of Compound 7
Dissolving 4mmol of compound 7s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 8h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 219-221 ℃.1H-NMR(CDCl3)δ：9.24(s，1H)，8.71(d，1H)，8.58(d，1H)，8.41(d，1H)，7.93(d，4H)，7.57(dd，1H)，7.37～7.36(m，5H)，7.25(s，1H)，7.21(d，1H)，7.13(d，1H)，3.69(s，2H)，3.67(s，2H)，3.44(t，4H)，3.33(t，4H)，3.30(s，3H)，2.81(t，4H)，2.50(t，4H)，2.14(s，3H)。
For comparison, of Compound 7s1H-NMR(CDCl3)δ：9.24(s，1H)，8.71(d，1H)，8.54(d，1H)，8.42(d，1H)，7.93(d，4H)，7.56(dd，1H)，7.34～7.33(m，5H)，7.26(s，1H)，7.21(d，1H)，7.16(d，1H)，3.68(s，2H)，3.65(s，2H)，3.43(t，4H)，2.53(t，4H)，2.48(t，4H)，2.34(t，4H)，2.14(s，3H)，2.12(s，3H)。
Preparation example 1.8 preparation and Structure confirmation of Compound 8
Dissolving 4mmol of compound 8s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 6.5h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 208-210 ℃.1H-NMR(CDCl3)δ：9.25(s，1H)，8.71(d，1H)，8.55(d，1H)，8.41(d，1H)，7.82(d，2H)，7.56(dd，1H)，7.35～7.34(m，3H)，7.26(s，1H)，7.24(d，1H)，7.12(d，1H)，4.51(s，2H)，3.43(d，1H)，3.37～3.35(m，3H)，3.19(d，1H)，3.06(t，1H)，2.92(t，1H)，2.12(s，3H)，1.12(d，3H)。
For comparison, of Compound 8s1H-NMR(CDCl3)δ：9.23(s，1H)，8.70(d，1H)，8.56(d，1H)，8.41(d，1H)，7.91(d，2H)，7.57(dd，1H)，7.37～7.34(m，3H)，7.26(s，1H)，7.22(d，1H)，7.14(d，1H)，3.60(s，2H)，2.75～2.71(m，2H)，2.69～2.67(m，2H)，2.60(t，1H)，2.56(d，1H)，2.28(d，1H)，2.14(s，3H)，1.11(d，3H)。
Preparation example 1.9 preparation and Structure confirmation of Compound 9
Dissolving 4mmol of compound 9s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 7.5h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 215-217 ℃.1H-NMR(CDCl3)δ：9.22(s，1H)，8.69(d，1H)，8.55(d，1H)，8.42(d，1H)，7.92(d，2H)，7.59(dd，1H)，7.37～7.35(m，3H)，7.24～7.23(m，2H)，6.96(d，1H)，3.90(s，3H)，3.67(s，2H)，3.36(t，4H)，3.30(s，3H)，2.79(t，4H)，2.12(s，3H)。
For comparison, of Compound 9s1H-NMR(CDCl3)δ：9.24(s，1H)，8.69(d，1H)，8.56(d，1H)，8.40(d，1H)，7.90(d，2H)，7.58(dd，1H)，7.37～7.34(m，3H)，7.27(s，1H)，7.23(d，1H)，6.97(d，1H)，3.91(s，3H)，3.65(s，2H)，2.49(t，4H)，2.34(t，4H)，2.12(s，6H)。
Preparation example 1.10 preparation and Structure confirmation of (Compound 10)
Dissolving 4mmol of compound 10s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 7h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, vacuum filtering, subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) to obtain yellowish solid, and vacuum drying. The melting point is 268-270 ℃.1H-NMR(CDCl3)δ：9.25(s，1H)，8.68(d，1H)，8.55(d，1H)，8.42(d，1H)，7.92(d，4H)，7.56(dd，1H)，7.36～7.35(m，5H)，7.24～7.23(m，3H)，6.92(d，1H)，3.67(s，4H)，3.35(t，8H)，3.31(s，6H)，2.80(t，8H)，2.11(s，3H)。
For comparison, of Compound 10s1H-NMR(CDCl3)δ：9.22(s，1H)，8.69(d，1H)，8.57(d，1H)，8.42(d，1H)，7.91(d，4H)，7.56(dd，1H)，7.37～7.35(m，5H)，7.27(s，1H)，7.20(d，1H)，6.92(d，1H)，3.68(s，4H)，2.48(t，8H)，2.36(t，8H)，2.16(s，6H)，2.13(s，3H)。
Preparation example 1.11 preparation and Structure confirmation of Compound 11
Dissolving 4mmol of compound 11s in 40mL of DMF, adding 2mL of 30% hydrogen peroxide at one time under stirring at room temperature, and reacting under stirring at 45 ℃. TLC (developing solvent: dichloromethane-methanol-triethylamine, 1:0.6:0.1) showed substantial disappearance of starting material (about 8h) and was concentrated to dryness under reduced pressure, and 15mL of ethyl acetate was added to the residue, which was heated to 80 ℃ and stirred for 1 h. Drying over anhydrous magnesium sulfate, suction filtering, and subjecting the filter cake to column chromatography (eluent: dichloromethane-methanol-Triethylamine, 1:0.6:0.1) to obtain a yellowish solid, and drying in vacuum. The melting point is 244-246 ℃.1H-NMR(CDCl3)δ：9.23(s，1H)，8.68(d，1H)，8.55(d，1H)，8.43(d，1H)，7.91(d，4H)，7.57(dd，1H)，7.37(d，1H)，7.33(d，4H)，7.24(d，1H)，7.23(s，1H)，6.93(d，1H)，3.81(s，2H)，3.66(s，2H)，3.36(t，4H)，3.30(s，3H)，2.80(t，4H)，2.66(t，4H)，2.33(t，4H)，2.14(s，3H)。
For comparison, of Compound 11s1H-NMR(CDCl3)δ：9.26(s，1H)，8.70(d，1H)，8.56(d，1H)，8.42(d，1H)，7.92(d，4H)，7.59(dd，1H)，7.36～7.34(m，5H)，7.26(s，1H)，7.22(d，1H)，6.93(d，1H)，3.65(s，4H)，2.65(t，4H)，2.49(t，4H)，2.34～2.33(m，8H)，2.14(s，3H)。
Preparation example 2 preparation of plant extract
Drying the dried plant material at 40 deg.C by ultrasonic extraction, pulverizing, sieving with 40 mesh sieve, and placing into self-sealing bag. Before the test, 50g of dry plant powder is weighed, acetone is added for ultrasonic extraction, 60min is carried out each time, and the extraction is repeated for 3 times. Filtering, concentrating, and storing in refrigerator at 4 deg.C.
The plant material is one selected from the group consisting of Pachyrhizus (PGF), Gekko Swinhonis (BZ), Illicium verum (SBJ), and Largehead anemone (LJF).
Test example 1 Effect of mixture of N-oxides of arylaminobenzylpiperazine on the antibacterial Activity of plant extracts
(1) The tested drugs are: mixing an aromatic amino benzyl piperazine nitrogen oxide compound X and Y (X, Y is selected from 1-23, and X is not equal to Y) in a specific mass ratio of 1, and marking as a mixture X-Y; ② the Plant Extract (PE) obtained in preparation example 2; and the mixture formed by the test substances of the third and fourth (2) in the mass ratio is marked as a mixture X-Y-PE (PE is selected from one of PGF, BZ, SBJ and LJF).
(2) Test method
Preparing a sample solution: taking a certain amount of a test object, using DMF as a solvent, and preparing test sample solutions with 6 concentrations by adopting a specific multiple continuous dilution method.
② fungus suspensionLiquid preparation, the activated strain is inoculated into a liquid culture medium (agar is not added), and shaking table culture is carried out. Bacteria colony count is calculated by plate dilution method, and bacteria suspension concentration is adjusted to 10 by sterile physiological saline7CFU/mL。
Step three, determining the bacteriostatic activity by agar-hole diffusion: and cooling the sterilization culture medium to 50 ℃, adding 5mL of bacterial suspension, uniformly mixing, pouring into culture dishes with the diameter of 9cm, and standing for 40min, wherein each culture dish is 20 mL. The solidified medium was uniformly perforated with a sterile punch (7 mm diameter), and marked. Add 40. mu.L of test sample solution to each well, DMF as a blank. The bacteria were cultured at 37 ℃ for 24 hours, and the Inhibition Ratio (IR) to the test strain was calculated by measuring and recording the diameter (mm) of the zone of inhibition at each concentration, repeating 3 times, and taking the average as the measurement result according to the following formula.
For mixtures X-Y and PE, the IR is plotted against the logarithm (log (c)) of the total concentration of mixture X-Y and the test concentration (ng/mL) of PE, and the concentration of each test substance at which inhibition of specific fa occurs is calculated from the linear regression equation and is reported as ICfa(A)And ICfa(PE). For mixture X-Y-PE, the concentration of mixture X-Y in mixture X-Y-F at which inhibition of a particular fa occurs is calculated from a linear regression equation using IR plotted against the logarithm of mixture X-Y (ng/mL) against IR, and is reported as ICfa(mixA)Then, the concentration of PE in the mixture X-Y-PE at which the inhibition rate of specific fa occurred was calculated from the mass ratio and recorded as ICfa(mixPE)。
The Combination Index (CI) at which a specific fa inhibitory rate is produced is calculated according to the following formula.
When CI <1, it means that there is synergism, the smaller the CI, the stronger the synergism.
TABLE 1.1 Effect of a mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of Citrobacter freundii by plant extracts (fa ═ 30.99%)
Table 1.2 effect of mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of propionibacterium acnes by plant extracts (fa ═ 30.15%)
Table 1.3 effect of mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of serratia liquefaciens by plant extracts (fa ═ 30.02%)
Table 1.4 effect of mixture of aryl aminobenzylpiperazine nitroxides on inhibition of p.viridis by plant extracts (fa ═ 30.16%)
Table 1.5 effect of mixture of aryl aminobenzylpiperazine nitroxides on inhibition of staphylococcus squirrel by plant extracts (fa ═ 30.37%)
Table 1.6 effect of mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of kucuria krebsiella inhibition by plant extracts (fa 31.40%)
TABLE 1.7 Effect of a mixture of N-oxides of arylaminobenzylpiperazine on Neisseria meningitidis inhibition by plant extracts (fa ═ 30.10%)
Table 1.8 effect of mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of micrococcus luteus by plant extracts (fa ═ 30.21%)
TABLE 1.9 Effect of a mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of Corynebacterium glutamicum by plant extracts (fa 30.09%)
TABLE 1.10 Effect of the mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of Nodecarboxylic Leckera effect of plant extracts (fa ═ 31.15%)
TABLE 1.11 Effect of a mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of Xyloxigenic bacteria by plant extracts (fa 30.63%)
Table 1.12 effect of mixture of aryl aminobenzylpiperazine nitroxides on the chlamydia trachomatis inhibition by plant extracts (fa ═ 30.15%)
TABLE 1.13 Effect of a mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of Staphylococcus intermedia by plant extracts (fa ═ 32.68%)
TABLE 1.14 Effect of mixtures of aryl aminobenzylpiperazine nitroxides on the inhibition of Achromobacter xylosoxidans by plant extracts (fa ═ 31.34%)
TABLE 1.15 Effect of a mixture of aryl aminobenzylpiperazine nitroxides on the inhibition of Streptococcus mitis by plant extracts (fa ═ 30.91%)
Example 1 oral solid preparation containing N-oxide of aryl aminobenzylpiperazine and method for preparing the same
Prescription (1500 unit dose)
Preparation method
Taking the mixture X-Y-PE and auxiliary materials according to the prescription amount, and sieving the mixture and the auxiliary materials with a 100-mesh sieve. Mixing the mixture X-Y-PE, lactose, microcrystalline cellulose, crospovidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Granulating with 16 mesh sieve, adding prescription amount of silica gel micropowder and magnesium stearate, mixing, and encapsulating to obtain capsule;
taking the mixture X-Y-PE and auxiliary materials according to the prescription amount, and sieving the mixture and the auxiliary materials with a 100-mesh sieve. Mixing the mixture X-Y-PE, lactose, microcrystalline cellulose, crospovidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Sieving with 16 mesh sieve, adding silica gel micropowder and magnesium stearate, mixing, and packaging to obtain granule;
taking the mixture X-Y-PE and auxiliary materials according to the prescription amount, and sieving the mixture and the auxiliary materials with a 100-mesh sieve. Mixing the mixture X-Y-PE, lactose, microcrystalline cellulose, crospovidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. And (4) granulating by using a 16-mesh sieve, adding the superfine silica powder and the magnesium stearate according to the prescription amount, mixing uniformly, and tabletting to obtain the tablet.
Claims (10)
1. The aryl amino benzyl piperazine nitrogen oxide is characterized in that the aryl amino benzyl piperazine nitrogen oxide is one of the following compounds 1-11:
2. a composition comprising an aryl aminobenzyl piperazine nitroxide according to claim 1 or an aryl aminobenzyl piperazine nitroxide selected from the group consisting of compounds 12 to 13 shown below.
3. The composition according to claim 2, wherein the composition comprises a mixture of a first and a second aromatic aminobenzyl piperazine nitroxide selected from compounds 1 to 13 and different from each other.
4. The composition according to claim 3, wherein the mass ratio of the first arylaminobenzyl piperazine nitroxide to the second arylaminobenzyl piperazine nitroxide is between 0.01:1 and 100: 1.
5. The composition according to any one of claims 2 to 4, wherein said composition further comprises a plant extract.
6. The composition of claim 5, wherein said plant extract is an extract of a plant selected from the group consisting of Kaschin-Beck, Michelia alba, Illicium verum, and Largehead Atractylodes.
7. The composition according to any one of claims 2 to 4, wherein the composition is formulated as an oral solid preparation.
8. The composition of claim 7, wherein said oral solid dosage form is one selected from the group consisting of a tablet, a capsule and a capsule.
9. Use of a compound according to claim 1 or a composition according to any one of claims 2 to 4 in the preparation of a medicament for the treatment of bacterial infectious diseases.
10. Use according to claim 9, characterized in that said bacterial infectious disease is a disease caused by a bacterial infection selected from the group consisting of Citrobacter freundii, Propionibacterium acnes, Serratia liquefaciens, Aerococcus viridis, Staphylococcus squirrel, Kurkia kefir, Neisseria meningitidis, Micrococcus luteus, Corynebacterium parvum, Leuconostoc decarboxylases, Alcaligenes xylosoxidans, Chlamydia trachomatis, Staphylococcus intermedius, Achromobacter xylosoxidans, Streptococcus mitis, Staphylococcus pasteurii and Staphylococcus capricae.
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| CN1662538A (en) * | 2002-06-21 | 2005-08-31 | 苏文生命科学有限公司 | Arylalkyl indoles having sertonin receptor affinity useful as therapeutic agents, process for their preparation and pharmaceutical compositions containing them |
| CN101443322A (en) * | 2006-03-10 | 2009-05-27 | 小野药品工业株式会社 | Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient |
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Application publication date: 20191220 |