CN105669519B - Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine - Google Patents

Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine Download PDF

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CN105669519B
CN105669519B CN201610002989.9A CN201610002989A CN105669519B CN 105669519 B CN105669519 B CN 105669519B CN 201610002989 A CN201610002989 A CN 201610002989A CN 105669519 B CN105669519 B CN 105669519B
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methoxycarbonyl group
indoles
methylene
indolecarboxaldehydes
dihydro
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CN105669519A (en
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洪伟
王昊
常喆
李京洋
杨延辉
王瑜
谭晓丽
欧阳溢凡
杨浩
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North Minzu University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pest Control & Pesticides (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Provide the medical usage of a kind of below formula Benzazole compounds and its salt, preparation method and such corresponding compound and its salt and medicine and disinfectant containing such compound and its salt.By there is good antibacterial and bactericidal activity to MRSA (resistant Staphylococcus aureus), MDR K.Pneumonia (resistance Klebsiella Pneumoniae), MDR A.Baumanii (resistance Acinetobacter bauamnnii) experimental results demonstrate such compound and its salt.

Description

Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine
Technical field
It is particularly a kind of containing indoles, aminoguanidine or hydrazine ketone the present invention relates to chemistry and compound field of medical application Benzazole compounds and its salt, the preparation method and medical applications as drug-resistance bacteria medicine.
Background technology
In recent years, various antibiotic continually develop listing and clinical practice, particularly some medical institutions and medical people Based under the quick requirement for eliminating infection sufferer, heavy dose of and excess is abnormal more and more tighter using antibiotic by member and patient Weight.These phenomenons so that also develop evolution rapidly for the drug-fast bacteria of antibiotic preparation：Methicillin-resistant staphylococcus aureus (MRSA), clinical antibacterial and anti-infectious treatment band are given in the appearance to the staphylococcus aureus (MSSA) of methicillin-sensitivity etc. Puzzlement is newly carried out.
But the cause pathogeny imcrobe infection such as bacterium is always one of important diseases for threatening human health.Due to fluoquinolone Class medicine antibacterial spectrum is wide, and antibacterial activity is strong, and clinical practice is extensive, in recent years, resistance phenomenon of the bacterium to FQNS It is increasingly tight, the propagation of drug-fast bacteria in addition, force the medicine that medical research personnel study and medical worker's urgent need development and application is new Thing come overcome this increasingly severe drug resistance the problem of.Wherein staphylococcus aureus be most commonly seen initiation it is iatrogenic and doctor Treat one of bacterium of utensil infection：Such as the medicament-resistant mutation such as emerging MRSA bacterial strain is resistance to extreme to existing antibacterials By；Kerekou pneumonia bacterium and primary Acinetobacter bauamnnii are a kind of typical iatrogenic or conditioned pathogens, and kerekou pneumonia bacterium can cause The disease such as pneumonia and meningitis；Primary Acinetobacter bauamnnii can trigger bacteremia, urinary infection, Secondary cases meningitis, Surgery Position infection and Ventilator Associated Pneumonia etc..
Due to the appearance of above-mentioned drug-fast bacteria, the conventional infection disease for making necessarily to be controlled originally becomes getting worse, And clinical and microorganism scholar serious concern is caused.Current new drug development is made slow progress, and existing medicine can not be controlled again Drug-fast bacteria is treated, has been further exacerbated by above mentioned problem.The exploitation of the drug molecule of the antimicrobial agent of new structure is that solve this hardly possible The breach of topic.
The content of the invention
The present invention proposes that it provides a kind of Benzazole compounds and its salt, preparation in order to solve the above problems The medical usage of method and such corresponding compound and its salt and medicine and disinfectant containing such compound and its salt.Hair A person of good sense passes through that experimental results demonstrate such compound and its salt to MRSA (resistant Staphylococcus aureus), MDR K.Pneumonia (resistance Klebsiella Pneumoniae), MDR A.Baumanii (resistance Acinetobacter bauamnnii) have well antibacterial And bactericidal activity.
A kind of Benzazole compounds provided by the invention, chemical structure of general formula are as follows：
Wherein,
X is methylene, carbonyl or sulfonyl；
R1 is fluorine, chlorine, bromine, methoxy acyl group, nitro or hydrogen；
R2 is methoxy acyl group, (to methoxy acyl group) phenyl, (to trifluoro epoxide) phenyl, (fluorine-based to three) phenyl, (a methoxy Acyl group) phenyl, (a trifluoro epoxide) phenyl, (to fluorine m-chloro) phenyl or hydrogen.
Benzazole compounds provided by the invention, in order to obtain more preferable antibacterial and bactericidal effect, R therein1Preferably To chloro, to bromo, to it is fluorine-based, to methoxy acyl group, p-nitrophenyl methyl, a methoxy acyl group, a nitro.
Benzazole compounds provided by the invention, in order to obtain more preferable antibacterial and bactericidal effect, R therein2Preferably 5- methoxies acyl group, 6- methoxies acyl group, 5- (to methoxy acyl group) phenyl, 5- (to trifluoro epoxide) phenyl, 5- (fluorine-based to three) phenyl, 5- (a methoxy acyl group) phenyl, 5- (a trifluoro epoxide) phenyl, 5- (to fluorine m-chloro) phenyl.
The Benzazole compounds of the offer of the present invention, its corresponding X, R1、R2With with Compound numbers such as table 1 below, the institute of table 2 Show.
The compound of Formula I of table 1
Above-mentioned formula I Benzazole compounds are entitled：
Compound 1：2- [(1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 2：2- [(1- is to benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 3：2- [(1- is to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 4：2- [(methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidine；
Compound 5：2- [(1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 6：2- [(1- m-nitro methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 7：2- [(1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 8：2- [(1- is to benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 9：2- [(1- is to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 10：2- [(methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidine；
Compound 11：2- [(1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 12：2- [(1- m-nitro methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 13：2- [(1- benzoyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 14：2- [(1- benzoyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
Compound 15：2- [(1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidine；
Compound 16：2- [(1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidine；
Compound 17：2- [(1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidine；
Compound 18：2- [(1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidine；
Compound 19：2- [(1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indoles) methylene] aminoguanidine；
Compound 20：2- [(1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indoles) methylene] aminoguanidine.
The Compounds of formula II of table 2
Above-mentioned formula II Benzazole compounds are entitled：
Compound 21：1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone；
Compound 22：1- is to benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone；
Compound 23：1- to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone；
Compound 24：Methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone；
Compound 25：1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone；
Compound 26：1- m-nitro methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone；
Compound 27：1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone；
Compound 28：1- is to benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone；
Compound 29：1- to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone；
Compound 30：Methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone；
Compound 31：1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone；
Compound 32：1- m-nitro methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone；
Compound 33：1- benzoyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone；
Compound 34：1- benzoyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone；
Compound 35：1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone；
Compound 36：1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone；
Compound 37：1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- miaows Azoles -2- bases) hydrazine ketone；
Compound 38：1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- miaows Azoles -2- bases) hydrazine ketone；
Compound 39：1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone；
Compound 40：1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- Base) hydrazine ketone.
The present invention also provides a kind of salt of Benzazole compounds, it is characterised in that：
The salt is salt of the Benzazole compounds of above-mentioned middle any one obtained by with inorganic acid or organic acid reaction (III, IV), its structure are shown as：
Wherein, HA is inorganic acid or the strong organic acid of partially acidic；
And X, R1, R2Described in as defined above i.e.：
X is methylene, carbonyl or sulfonyl；
R1 is fluorine, chlorine, bromine, methoxy acyl group, nitro or hydrogen；
R2 is methoxy acyl group, (to methoxy acyl group) phenyl, (to trifluoro epoxide) phenyl, (fluorine-based to three) phenyl, (a methoxy Acyl group) phenyl, (a trifluoro epoxide) phenyl, (to fluorine m-chloro) phenyl or hydrogen.
Further in order to obtain more preferable antibacterial and bactericidal effect, R therein1Preferably to chloro, to bromo, to fluorine Base, to methoxy acyl group, p-nitrophenyl methyl, a methoxy acyl group, a nitro.
Further in order to obtain more preferable antibacterial and bactericidal effect, R therein2Preferably 5- methoxies acyl group, 6- methoxies Acyl group, 5- (to methoxy acyl group) phenyl, 5- (to trifluoro epoxide) phenyl, 5- (fluorine-based to three) phenyl, 5- (a methoxy acyl group) benzene Base, 5- (a trifluoro epoxide) phenyl, 5- (to fluorine m-chloro) phenyl.
Further for production process and using effect, inorganic acid is any in sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid One kind, the organic acid are sulfonic acid.
The salt of the Benzazole compounds of the offer of the present invention, preferably hydrochloride or hydrogen bromide salt, its corresponding X, R1、R2 With with Compound numbers such as table 3 below, shown in table 4.
The compound of formula III of table 3
The salt of above-mentioned general formula III Benzazole compounds is entitled：
Compound 41：2- [(1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 42：2- [(1- is to benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 43：2- [(1- is to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine hydrochloric acid Salt；
Compound 44：2- [(methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidine hydrochloric acid Salt；
Compound 45：2- [(1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 46：2- [(1- m-nitro methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 47：2- [(1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 48：2- [(1- is to benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 49：2- [(1- is to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine hydrochloric acid Salt；
Compound 50：2- [(methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidine hydrochloric acid Salt；
Compound 51：2- [(1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 52：2- [(1- m-nitro methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 53：2- [(1- benzoyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 54：2- [(1- benzoyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
Compound 55：2- [(1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidine hydrochloric acid Salt；
Compound 56：2- [(1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidine hydrochloric acid Salt；
Compound 57：2- [(1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidine hydrochloric acid Salt；
Compound 58：2- [(1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidine hydrochloric acid Salt；
Compound 59：2- [(1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indoles) methylene] aminoguanidine hydrochloric acid Salt；
Compound 60：2- [(1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indoles) methylene] aminoguanidinium salts hydrochlorate.
The compound of Formula IV of table 4
The salt of above-mentioned formula IV Benzazole compounds is entitled：
Compound 61：1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone hydrogen bromide salt；
Compound 62：1- is to benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone hydrogen bromide salt；
Compound 63：1- to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone hydrogen bromide salt；
Compound 64：Methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone hydrogen bromide salt；
Compound 65：1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone hydrogen bromide salt；
Compound 66：1- m-nitro methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone hydrogen bromide salt；
Compound 67：1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone hydrogen bromide salt；
Compound 68：1- is to benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine Ketone hydrogen bromide salt；
Compound 69：1- to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone hydrogen bromide salt；
Compound 70：Methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone hydrogen bromide salt；
Compound 71：1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone hydrogen bromide salt；
Compound 72：1- m-nitro methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) Hydrazine ketone hydrogen bromide salt；
Compound 73：1- benzoyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone Hydrogen bromide salt；
Compound 74：1- benzoyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone Hydrogen bromide salt；
Compound 75：1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone hydrogen bromide salt；
Compound 76：1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone hydrogen bromide salt；
Compound 77：1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- miaows Azoles -2- bases) hydrazine ketone hydrogen bromide salt；
Compound 78：1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- miaows Azoles -2- bases) hydrazine ketone hydrogen bromide salt；
Compound 79：1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles - 2- yls) hydrazine ketone hydrogen bromide salt；
Compound 80：1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- Base) hydrazine ketone hydrogen bromide salt.
The present invention also provides a kind of drug-resistance bacteria medicine composition, it is characterised in that：
Wherein, described pharmaceutical composition contains above-mentioned formula I, II Benzazole compounds or above-mentioned general formula III, IV indoles The salt of compound and pharmaceutically useful auxiliary material, auxiliary material includes excipient, diluent, stabilizer and flavouring etc., according to pharmacy Conventional method mixes, and the liquid dosage form such as the solid dosage forms such as tablet, capsule, granule, powder and syrup, oral liquid is made.
Compound I, II and its salt III, IV dosage are with differences such as patient age, sex, the state of an illness without same.Typically into The dosage of people can be 0.01-5000mg/ days, preferably 1-1000mg/ days, more preferably 5-500mg/ days.
The present invention also provides a kind of disinfectant, for medical apparatus or human hand disinfection, it is characterised in that：
Wherein, described pharmaceutical composition contains above-mentioned formula I, II Benzazole compounds or above-mentioned general formula III, IV indoles The salt of compound and solvent that can be appropriate, such as water, ethanol or its mixed solvent.
The concentration of compound I, II and its salt III, IV in disinfectant is related to the requirement of disinfection, general surgical device Tool sterilization is mass concentration 0.05%-2.0%, more preferably preferably 0.1%-1.0%, 0.5%-1.0%.
Above-mentioned formula I, II Benzazole compounds or above-mentioned general formula III, the salt of IV Benzazole compounds are preparing overriding resistance Application in mushroom medicine.
The method for preparing the salt of the Benzazole compounds of above-mentioned formula (III, IV), it is characterised in that including that will have formula (V) and logical formula (VI) compound in the anhydrous polar solvent of drying hybrid reaction i.e. obtain formula (III, IV) indoles The salt of compound；And by the salt of the Benzazole compounds of formula (III, IV) by adding alkali alkalization to can obtain formula (I, II) indoles Compound
Wherein,
X, R1, R2, HA implications are the same as above-mentioned；
I.e. when the X differences in logical formula (V),
When X is methylene, intermediate 1- (3- or the benzyl of 4- substitutions) -3- formoxyls -5 (or 6)-methoxy carbonyl are prepared Base indoles (3), reaction scheme is as follows：
When X is carboxyl, (or 6)-methoxycarbonyl indole (4) of intermediate 1- benzoyl -3- formoxyls -5 is prepared, is reacted Route is as follows：
When X is sulfonyl, intermediate 1- benzenesulfonyl -3- formoxyls -5- (3- or the phenyl of 4- substitutions) indoles is prepared (8), reaction scheme is as follows：
It is reacted to obtain formula with the compound of logical formula (VI) respectively after obtaining above-mentioned intermediate 3,4,8 (i.e. formula V) Compound in (III, I)
Alkalization using NaOH solution alkalized to pH be more than 10 after；
It similarly can obtain the compound in formula (IV, II).
Prepare the salt of the Benzazole compounds of above-mentioned formula (I, II) and the Benzazole compounds of above-mentioned formula (III, IV) Method, wherein, the polar solvent is preferably any one or its in methanol, ethanol, acetonitrile, DMF Mixed solvent.
Prepare the salt of the Benzazole compounds of above-mentioned formula (I, II) and the Benzazole compounds of above-mentioned formula (III, IV) Method, wherein, the temperature of the hybrid reaction is preferably room temperature or reflux temperature.
The pharmacological evaluation of the compounds of this invention
(1) experimental manipulation
Minimal inhibitory concentration (MIC) is obtained using 96 hole Microdilution plate method measure In Vitro Bacteriostatics, is coated with using blood plate Method measure minimum bactericidal concentration (MBC).
(1) experimental strain
This experiment has selected following 4 kinds of common human body cause illness's bacterial strains as test object：
Staphylococcus aureus, resistant Staphylococcus aureus, resistance Klebsiella Pneumoniae, resistance Acinetobacter bauamnnii
(2) experimental method：The antibacterial activity in vitro measure of compound
The culture of strain：Choose the single bacterium colony grown on trypticase soy broth (TSB) flat board and be inoculated in liquid 37 DEG C in TSB, 200rpm. culture 18h, microbial strain culture is obtained in case subsequent measurements antibacterial activity.
Determination of Antibacterial Activity method is：The Determination of Antibacterial Activity of compound is carried out using sterile 96 orifice plate.All bacterial strains Initial screening is all to obtain initial antibacterial activity from each compound with the parallel 3 hole sizer choosing of 100 μ g/ml concentration.It is chosen at The compound with antibacterial activity further carries out minimal inhibitory concentration (MIC) measure under 100 μ g/ml concentration.Each hole point The medicine that Jia Ru do not diluted with 2 times of concentration cultures (trypticase soy broth, TSB).Synthesize obtained each positiveization The first solution of debita spissitudo is made in compound, and two times of concentration of each compound used therefor, every kind of positiveization are diluted to culture medium (2 ×) Each 12 gradients of compound, 96 orifice plates add 200 μ l per hole, and each positive compound is final concentration of：100.0、50.0、25.0、12.5、 6.3rd, 3.1,1.6,0.8,0.4,0.2,0.1 and 0.05 μ g/ml.The final concentration difference of 12 gradients of comparison medicine lavo-ofloxacin For：64.0th, 32.0,16.0,8.0,4.0,2.0,1.0,0.5,0.25,0.125,0.063,0.031 and 0.016 μ g/ml.Then A kind of bacterium S.aureus (ATCC 29213), MRSA, MDR K.pneumoniae and MDR A.baumanii are added, is surveyed respectively MIC of the fixed every kind of bacterium to every kind of compound.100 μ l are inoculated with per hole, are about 1 × 10 per pore fungi amount5Cfu, it is per hole final volume 200μl.2 growth Positive control wells without antimicrobial are all provided with per plate and two growths with distilled water substitutive medium are negative Control wells, surrounding is sealed with adhesive tape after 96 orifice plates are capped, and is placed in 37 DEG C of quiescent cultures of wet box.Each hole is determined with ELIASA Absorbance at the 600nm of different time points, the selection at time point is 0,24h and 48h respectively.It is after 48h it will be observed that positive raw The hole that long control wells and negative growth control wells have clear and definite difference is coated on blood agar plate, and control is used as using 1% DMSO. So as to determine the sterilization conditions of medicine, minimum bactericidal concentration (MBC) is obtained.
(2) experimental result
Antibacterial experiment in vitro the results are shown in Table 5.
The target compound In Vitro Bacteriostasis Cmin value (MIC, unit μ g/mL) of the part of table 5.
Table 5
Note：S.aureus：Staphylococcus aureus；MRSA：Resistant Staphylococcus aureus；MDR K.pneumonia：It is resistance to Medicine Klebsiella Pneumoniae；MDR A.baumanii：Resistance Acinetobacter bauamnnii；levofloxacin：Lavo-ofloxacin； Vancomycin：Vancomycin；-：Do not tested
Table 6 is that part of compounds In Vitro Bacteriostasis and sterilization Cmin value contrast (MIC and MBC, unit μ g/mL).
Table 6
Note：MRSA：Resistant Staphylococcus aureus；MDR K.pneumonia：Resistance Klebsiella Pneumoniae；MDR A.baumanii：Resistance Acinetobacter bauamnnii；Vancomycin：Vancomycin；＞：More than or equal to 100 μ g/ml；-：No Tested
Invention effect and effect
From table 5 and 6, the salt (hydrochloride, hydrogen bromide salt) of new indole class compound of the invention has well The activity of antimicrobial agent, wherein compound 41,47,55,56,57,58,61,68,75,77,78,79 pairs of the external of drug-fast bacteria resist Bacterium activity is much better than lavo-ofloxacin, particularly compound 41, and 47,61 is also motionless to resistance Klebsiella Pneumoniae and resistance Bao Man Bacillus equally has superior antibacterial activity.Therefore the compound of the present invention and its esters can be used for preparing overriding resistance golden yellow Portugal The medicine of the drug-fast bacterias such as grape coccus and the disinfectant of medical apparatus.
Embodiment
In order that the technical means, the inventive features, the objects and the advantages of the present invention are easy to understand, it is real below Apply example and detailed introduction is done with pharmaceutical dosage form to the compound of the present invention, the preparation of compound salt and medicinal usage.
The general formula III of embodiment one, the preparation of I
Prepare intermediate 1- (3- or the benzyl of 4- substitutions) -3- formoxyls -5 (or 6)-methoxycarbonyl group Yin in formula V Diindyl 3
Prepare (or 6)-methoxycarbonyl indole (2) of 3- formoxyls -5
5 (or 6)-methoxycarbonyl indoles (1) respectively with POCl3 (POCl3) in dry N, the bar of N- dimethyl sulfoxide (DMSO)s (or 6)-methoxycarbonyl indole (2) of Vilsmeier-Hack reaction generation 3- formoxyls -5 occurs under part
Prepare (or 6)-methoxycarbonyl indole (2) of 3- formoxyls -5 and manipulate example
Prepare 3- formoxyl -5- methoxycarbonyl indoles
Under nitrogen protection, indole -5-carboxylic acid methyl esters 5.00g (28.57mmol) is added into super dry DMF20mL, and 0 DEG C is cooled to, POCl3 3.62mL (38.86mol) is then slowly added dropwise.After 0 DEG C is reacted 10min, 3h is reacted at room temperature.Will After reaction solution is cooled to 0 DEG C, water 60mL quenching reactions are added, then reaction solution pH to 10 is adjusted with the 2M NaOH aqueous solution, continues After stirring 5min, 70 DEG C of reaction 30min are heated to.Reaction solution is cooled to room temperature, and decompression is filtered, and filter cake is washed with water and methanol respectively Wash to obtain pale pink solid, yield 89%, m.p.231.4-233.0 DEG C；1H-NMR (400MHz, DMSO)：12.44 (brs, 1H, NH), 9.98 (s, 1H, CHO), 8.77 (d, J=1.2,1H, Ar-H), 8.44 (s, 1H, Ar-H), 7.88 (dd, J1=8.4, J2=1.6,1H, Ar-H), 7.61 (d, J=8.8,1H, Ar-H), 3.87 (s, 3H, CH3)；ES-MS 204.1(M+H)+。
3- formoxyls -5 (or 6)-methoxycarbonyl indole (2) reacts life with substituted benzyl bromine in the presence of sodium hydride respectively Into (3)
Prepare 1- (3- or the benzyl of 4- substitutions) -3- formoxyls -5 (or 6)-methoxycarbonyl indole (3) and manipulate example
1- is prepared to chlorophenylmethyl -3- formoxyl -5- methoxycarbonyl indoles
Under nitrogen protection, 3- formoxyl -5- methoxycarbonyl indoles 0.50g (2.46mmol) are added to super dry DMSO In 8mL, sodium hydride 0.11g (2.71mmol) is then added, in room temperature reaction 1h.Bromine chloride 0.56g (2.71mmol) will be added Enter to reaction solution, and in room temperature reaction 10h.After reaction terminates, saturated ammonium chloride solution 20mL is added to reaction solution, and with two Chloromethanes extracts (150mL × 3), and organic layer uses saturated sodium-chloride water solution and water washing, anhydrous sodium sulfate drying, revolving respectively Crude product is concentrated to give, through column chromatography, eluant, eluent is dichloromethane, obtains white solid 0.42g, yield 52%, m.p.160.2-160.7℃；1H-NMR (400MHz, CDCl3)：10.06 (s, 1H, CHO), 9.03 (s, 1H, Ar-H), 8.02 (dd, J1=8.4, J2=1.6,1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.35 (d, J=8.4,2H, Ar-H), 7.33 (d, J= 8.4,1H, Ar-H), 7.10-7.12 (d, J=8.4,2H, Ar-H), 5.37 (s, 2H, CH2), 3.95 (s, 3H, CH3)；ES-MS 328.1(M+H)+。
Different R1, the intermediate 3 of R2 substituents can similarly be prepared：
3- formoxyl -5- methoxycarbonyl indoles are used when preparing 1- to benzyl -3- formoxyl -5- methoxycarbonyl indoles Be raw material to fluorobenzyl bromide, method is same as above.Yield is 96%, m.p.153.3-153.9 DEG C；1H-NMR (400MHz, CDCl3)： 10.05 (s, 1H, CHO), 9.02 (s, 1H, Ar-H), 8.03 (dd, J1=8.8, J2=1.6,1H, Ar-H), 7.77 (s, 1H, Ar- H), 7.35 (d, J=8.4,1H, Ar-H), 7.17 (dd, J1=8.8, J2=5.2,2H, Ar-H), 7.06 (t, J=8.8,2H, Ar-H), 5.36 (s, 2H, CH2), 3.94 (s, 3H, CH3)；ES-MS312.1(M+H)+。
3- formoxyl -5- methoxy carbonyls are used when preparing 1- to methoxycarbonyl group benzyl -3- formoxyl -5- methoxycarbonyl indoles Base indoles and be raw material to methoxycarbonyl group benzyl bromine, method is same as above.Yield is 92%, m.p.203.6-204.0 DEG C；1H-NMR (400MHz, CDCl3)：δ 10.06 (s, 1H, CHO), 9.03 (d, J=1.2,1H, Ar-H), 8.03 (d, J=8.4,2H, Ar- H), 8.00 (dd, J1=8.8, J2=1.6,1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.30 (d, J=8.8,1H, Ar-H), 7.21 (d, J=8.4,2H, Ar-H), 5.46 (s, 2H, CH2), 3.94 (s, 3H, CH3), 3.91 (s, 3H, CH3)；ES-MS 352.1(M+H)+。
Between preparation 1- 3- formoxyl -5- methoxy carbonyls are used during methoxycarbonyl group benzyl -3- formoxyl -5- methoxycarbonyl indoles Base indoles and a methoxycarbonyl group benzyl bromine are raw material, and method is same as above.Yield is 91%, m.p.148.6-149.3 DEG C；1H-NMR (400MHz, CDCl3)：10.06 (s, 1H, CHO), 9.03 (d, J=1.2,1H, Ar-H), 8.02 (dd, J1=8.8, J2=1.2, 2H, Ar-H), 7.94 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.44 (t, J=8.0,1H, Ar-H), 7.34 (d, J= 8.8,1H, Ar-H), 7.31 (d, J=8.0,1H, Ar-H), 5.44 (s, 2H, CH2), 3.94 (s, 3H, CH3), 3.91 (s, 3H, CH3)；ES-MS 352.1(M+H)+。
3- formoxyl -5- methoxycarbonyl groups Yin is used when preparing 1- p-nitrophenyl methyl -3- formoxyl -5- methoxycarbonyl indoles Diindyl and be raw material to nitrobenzyl bromine, method is same as above.Yield is 86%, m.p.219.2-219.6 DEG C；1H-NMR (400MHz, DMSO)：10.01 (s, 1H, CHO), 8.80 (d, J=1.2,1H, Ar-H), 8.66 (s, 1H, Ar-H), 8.21 (d, J=8.8, 2H, Ar-H), 7.88 (dd, J1=8.4, J2=1.6,1H, Ar-H), 7.69 (d, J=8.4,1H, Ar-H), 7.51 (d, J= 8.8,2H, Ar-H), 5.79 (s, 2H, CH2), 3.87 (s, 3H, CH3)；ES-MS 339.1(M+H)+。
3- formoxyl -5- methoxycarbonyl groups Yin is used when preparing 1- m-nitro methyl -3- formoxyl -5- methoxycarbonyl indoles Diindyl and a nitrobenzyl bromine are raw material, and method is same as above.Yield is 71%, m.p.190.9-193.9 DEG C；1H-NMR (400MHz, CDCl3)：10.09 (s, 1H, CHO), 9.04 (s, 1H, Ar-H), 8.21 (d, J=8.4,1H, Ar-H), 8.11 (s, 1H, Ar- H), 8.03 (dd, J1=8.8, J2=1.6,1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.55 (t, J=8.0,1H, Ar-H), 7.41 (d, J=8.0,1H, Ar-H), 7.30 (d, J=8.8Hz, 1H, Ar-H), 5.52 (s, 2H, CH2), 3.95 (s, 3H, CH3)； ES-MS 339.1(M+H)+。
3- formoxyl -6- methoxycarbonyl indoles are used when preparing 1- to chlorophenylmethyl -3- formoxyl -6- methoxycarbonyl indoles Be raw material to bromine chloride, method is same as above.Yield is 64%, m.p.153.1-154.2 DEG C；1H-NMR (400MHz, CDCl3)： 10.03 (s, 1H, CHO), 8.36 (d, J=8.0,1H, Ar-H), 8.09 (s, 1H, Ar-H), 8.02 (dd, J1=8.4, J2= 1.6,1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.35 (d, J=8.4,2H, Ar-H), 7.12-7.14 (d, J=8.4,2H, Ar- H), 5.40 (s, 2H, CH2), 3.94 (s, 3H, CH3)；ES-MS328.1(M+H)+。
3- formoxyl -6- methoxycarbonyl indoles are used when preparing 1- to benzyl -3- formoxyl -6- methoxycarbonyl indoles Be raw material to fluorobenzyl bromide, method is same as above.Yield is 56%, m.p.155.6-155.7 DEG C；1H-NMR (400MHz, CDCl3)： 10.03 (s, 1H, CHO), 8.35 (d, J=8.4,1H, Ar-H), 8.11 (s, 1H, Ar-H), 8.01 (dd, J1=8.4, J2= 1.6,1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.20 (dd, J1=8.8, J2=5.2,2H, Ar-H), 7.07 (t, J=8.4, 2H, Ar-H), 5.40 (s, 2H, CH2), 3.94 (s, 3H, CH3)；ES-MS 312.1(M+H)+。
3- formoxyl -6- methoxy carbonyls are used when preparing 1- to methoxycarbonyl group benzyl -3- formoxyl -6- methoxycarbonyl indoles Base indoles and be raw material to methoxycarbonyl group benzyl bromine, method is same as above.Yield is 58%, m.p.169.9-171.1 DEG C；1H-NMR (400MHz, CDCl3)：10.05 (s, 1H, CHO), 8.37 (d, J=8.0,1H, Ar-H), 8.07 (s, 1H, Ar-H), 8.03 (d, J=8.4,2H, Ar-H), 8.01-8.03 (dd, J1=8.4, J2=1.2,1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.23 (d, J =8.4Hz, 2H, Ar-H), 5.50 (s, 2H, CH2), 3.93 (s, 3H, CH3), 3.91 (s, 3H, CH3)；ES-MS 352.1(M+H )+。
Between preparation 1- 3- formoxyl -6- methoxy carbonyls are used during methoxycarbonyl group benzyl -3- formoxyl -6- methoxycarbonyl indoles Base indoles and a methoxycarbonyl group benzyl bromine are raw material, and method is same as above.Yield is 56%, m.p.141.2-141.7 DEG C；1H-NMR (400MHz, CDCl3)：10.03 (s, 1H, CHO), 8.36 (d, J=8.0,1H, Ar-H), 8.10 (s, 1H, Ar-H), 8.02 (d, J=8.0,1H, Ar-H), 8.01 (dd, J1=8.0, J2=1.6,1H, Ar-H), 7.94 (s, 1H, Ar-H), 7.84 (s, 1H, Ar- H), 7.45 (t, J=7.6,1H, Ar-H), 7.34 (d, J=7.6,1H, Ar-H), 5.47 (s, 2H, CH2), 3.93 (s, 3H, CH3), 3.91 (s, 3H, CH3)；ES-MS 352.1(M+H)+。
3- formoxyl -6- methoxycarbonyl groups Yin is used when preparing 1- p-nitrophenyl methyl -3- formoxyl -6- methoxycarbonyl indoles Diindyl and be raw material to nitrobenzyl bromine, method is same as above.Yield is 80%, m.p.184.5-184.9 DEG C；1H-NMR (400MHz, CDCl3)：10.08 (s, 1H, CHO), 8.39 (d, J=8.0,1H, Ar-H), 8.22 (d, J=8.8,2H, Ar-H), 8.02- 8.04 (m, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.30 (d, J=8.8,2H, Ar-H), 5.56 (s, 2H, CH2), 3.93 (s, 3H, CH3)；ES-MS 339.1(M+H)+。
3- formoxyl -6- methoxycarbonyl groups Yin is used when preparing 1- m-nitro methyl -3- formoxyl -6- methoxycarbonyl indoles Diindyl and a nitrobenzyl bromine are raw material, and method is same as above.Yield is 70%, m.p.153.8-155.3 DEG C；1H-NMR (400MHz, CDCl3)：10.07 (s, 1H, CHO), 8.38 (d, J=8.4,1H, Ar-H), 8.21 (dd, J1=8.4, J2=1.2,1H, Ar- H), 8.10 (s, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 8.03 (dd, J1=8.4, J2=1.2,1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.55 (t, J=8.0,1H, Ar-H), 7.42-7.44 (d, J=8.0,1H, Ar-H), 5.55 (s, 2H, CH2), 3.93 (s, 3H, CH3)；ES-MS 339.1(M+H)+。
Prepare (or 6)-methoxycarbonyl indole of intermediate 1- benzoyl -3- formoxyls -5 i.e. intermediate 4 in formula V
3- formoxyls -5 (or 6)-methoxycarbonyl indole (2) reacts with chlorobenzoyl chloride in the presence of sodium hydride in DMF respectively Generate (or 6)-methoxycarbonyl indole (4) of 1- benzoyl -3- formoxyls -5
Prepare (or 6)-methoxycarbonyl indole (4) of 1- benzoyl -3- formoxyls -5 and manipulate example
Prepare 1- benzoyl -3- formoxyl -5- methoxycarbonyl indoles
Under argon gas protection, 3- formoxyl -5- methoxycarbonyl indoles 0.10g (0.49mmol) are added into super dry DMF 2mL In, and sodium hydride 0.02g (0.54mmol) is added after being cooled to 0 DEG C, react at room temperature 1h.Then reaction solution is cooled to 0 again DEG C, chlorobenzoyl chloride 0.07mL (0.54mmol) is added dropwise, room temperature reaction is overnight.After reaction terminates, reaction solution is poured into 100mL water Stand, decompression suction filtration obtains crude product, and through column chromatography, eluant, eluent is ethyl acetate: petroleum ether=1: 8 (V: V), obtains white solid 0.11g, yield 71%.m.p.172.7-173.3℃；1H-NMR (400MHz, CDCl3)：10.10 (s, 1H, CHO), 9.00 (d, J=1.2,1H, Ar-H), 8.35 (d, J=8.8,1H, Ar-H), 8.18 (dd, J1=8.8, J2=1.6,1H, Ar-H), 8.03 (s, 1H, Ar-H), 7.81-7.79 (m, 2H, Ar-H), 7.71 (t, J=7.6,1H, Ar-H), 7.61 (t, J=7.6,2H, Ar-H), 3.98 (s, 3H, CH3)；ES-MS 308.1(M+H)+。
Different R1, the intermediate 4 of R2 substituents can similarly be prepared：
Prepare 1- benzoyl -3- formoxyl -6- methoxycarbonyl indoles when use 3- formoxyl -6- methoxycarbonyl indoles for Raw material, method are same as above.Yield is 66%, m.p.176.1-176.4 DEG C；1H-NMR (400MHz, CDCl3)：10.09 (s, 1H, CHO), 9.00 (s, 1H, Ar-H), 8.38 (d, J=8.0,1H, Ar-H), 8.15 (dd, J1=8.4, J2=1.2,1H, Ar-H), 8.08 (s, 1H, Ar-H), 7.81-7.79 (m, 2H, Ar-H), 7.73 (t, J=7.6,1H, Ar-H), 7.62 (t, J=7.6,2H, Ar-H), 3.97 (s, 3H, CH3)；ES-MS 308.1(M+H)+。
Intermediate 1- benzenesulfonyl -3- formoxyls -5- (3- or the phenyl of the 4- substitutions) indoles prepared in formula V is i.e. middle Body (8)
Prepare 3- formoxyl -5- bromo indoles (6)
5- bromo indoles (5) and POCl3 (POCl3) occur under conditions of dry N, N- dimethyl sulfoxide (DMSO)s Vilsmeier-Hack reaction generation 3- formoxyl -5- bromo indoles (6)
Prepare 3- formoxyl -5- bromo indoles (6) and manipulate example
Under nitrogen protection, 5- bromo indoles 5.00g (25.5mmol) is added into super dry DMF (20ml), and is cooled to 0 DEG C, POCl3 3.22ml (34.68mol) is then slowly added dropwise.After 0 DEG C is reacted 10min, turn room temperature reaction 3h.Will reaction After liquid is cooled to 0 DEG C, water (100ml) quenching reaction is added, then reaction solution pH to 8-9 is adjusted with the 2M NaOH aqueous solution, continues After stirring 5min, 70 DEG C of reaction 30min are heated to.Reaction solution is cooled to room temperature, and decompression filters, and obtains filter cake, is obtained after drying white Solid 5.19g, yield 99%.m.p.203.5-204.3℃；1H-NMR (400MHz, DMSO)：12.28 (s, 1H, NH), 9.93 (s, 1H, CHO), 8.35 (s, 1H, Ar-H), 8.21 (d, J=2.0,1H, Ar-H), 7.49 (d, J=8.4,1H, Ar-H), 7.43 (dd, J1=8.8, J2=2.0,1H, Ar-H)；ES-MS 225.1(M+H)+。
Prepare 1- benzenesulfonyl -3- formoxyl -5- bromo indoles (7)
3- formoxyl -5- bromo indoles (6) react generation 1- benzenesulfonyl -3- first with benzene sulfonyl chloride in the presence of sodium hydride Acyl group -5- bromo indoles (7)
Prepare 1- benzenesulfonyl -3- formoxyl -5- bromo indoles (7) and manipulate example
Under nitrogen protection, 3- formoxyl -5- methoxycarbonyl indoles 2.00g (8.8807mmol) are added to super dry DMSO In 15ml, sodium hydride 0.392g (9.7706mmol) is then added, in room temperature reaction 1h.By benzene sulfonyl chloride 1.883g (10.664mmol) is added to reaction solution, and in room temperature reaction 18h.After reaction terminates, saturated ammonium chloride solution 100ml is added Extracted (200ml × 3) to reaction solution, and with dichloromethane, organic layer uses saturated sodium-chloride water solution and water washing respectively, anhydrous Sodium sulphate is dried, and concentrated by rotary evaporation obtains crude product, after acetone/n-hexane recrystallization, obtains white solid 2.675g, yield is 83%.m.p.235.2-239.3℃；1H-NMR (400MHz, DMSO)：10.06 (s, 1H, CHO), 8.96 (s, 1H, Ar-H), 8.22 (d, J=2.0,1H, Ar-H), 8.14-8.12 (m, 2H, Ar-H), 7.95 (d, J=8.8,1H, Ar-H), 7.81-7.77 (m, 1H, Ar-H), 7.69-7.65 (m, 2H, Ar-H), 7.62 (dd, J1=8.8, J2=2.0,1H, Ar-H)；ES-MS 365.2 (M+H)+。
Prepare 1- benzenesulfonyl -3- formoxyls -5- (3- or the phenyl of 4- substitutions) indoles i.e. intermediate (8)
1- benzenesulfonyl -3- formoxyl -5- bromo indoles (7) are respectively with substituted phenyl boric acid in [1,1 '-bis- (diphenylphosphines) Ferrocene] palladium chloride (Pd (dppf) Cl2) catalysis under Suzuki reaction generations 1- benzenesulfonyl -3- formoxyls -5- occurs (3- or the phenyl of 4- substitutions) indoles (8)
Prepare 1- benzenesulfonyl -3- formoxyls -5- (3- or the phenyl of 4- substitutions) indoles (8) and manipulate example
1- benzenesulfonyl -3- formoxyl -5- are prepared to methoxycarbonyl group phenyl indoles
1- benzenesulfonyl -3- formoxyl -5- bromo indoles 0.5g (1.37mmol) are added in 10mlTHF and 10ml water, so After sequentially add potassium carbonate 0.28g (2.055mmol), pmethoxycarbonylphenylboronic acid 0.24g (1.64mmol), 1,1 '-bis- (two Tert-butyl group phosphine) ferrocene dichloro conjunction palladium 8.9mg (0.0137mmol), heat up 60 DEG C of stirring reaction 8h.After reaction terminates, acetic acid is used Ethyl ester extracts (100ml × 3), and anhydrous sodium sulfate drying, concentrated by rotary evaporation obtains crude product, and through column chromatography, eluant, eluent is ethyl acetate/stone Oily ether, obtain white solid 0.62g, yield 86%.m.p.166.5-166.8℃；1H-NMR (400MHz, CDCl3)：10.13 (s, 1H, CHO), 8.52 (d, J=2.0,1H, Ar-H), 8.27 (s, 1H, Ar-H), 8.11 (d, J=8.4,2H, Ar-H), 8.04 (d, J=8.8,1H, Ar-H), 8.02-7.99 (m, 2H, Ar-H), 7.70-7.63 (m, 4H, Ar-H), 7.57-7.53 (m, 2H, Ar-H), 3.94 (s, 3H, OCH3)；ES-MS 420.5(M+H)+。
Different R1, the intermediate 8 of R2 substituents can similarly be prepared：
Methoxycarbonyl group phenyl indoles is to use 1- benzenesulfonyl -3- formyls between preparing 1- benzenesulfonyl -3- formoxyls -5- Base -5- bromo indoles are raw material, and method is same as above, yield 53%.m.p.186.8-187.1℃；1H NMR (400MHz, CDCl3)： 10.13 (s, 1H, CHO), 8.50 (d, J=1.6,1H, Ar-H), 8.28-8.27 (m, 2H, Ar-H), 8.05-7.99 (m, 4H, Ar-H), 7.83-7.80 (m, 1H, Ar-H), 7.69 (dd, J1=8.8, J2=2.0,1H, Ar-H), 7.66-7.63 (m, 1H, Ar- H), 7.57-7.50 (m, 3H, Ar-H), 3.95 (s, 3H, OCH3)；ES-MS 420.5(M+H)+。
Prepare 1- benzenesulfonyl -3- formoxyl -5- to trifluoro oxygen Phenylindole be using 1- benzenesulfonyl -3- formoxyls - 5- bromo indoles are raw material, and method is same as above, yield 89%.m.p.180.4-181.3℃；1H NMR (400MHz, DMSO)： 10.12 (s, 1H, CHO), 8.98 (s, 1H, Ar-H), 8.34 (d, J=1.6,1H, Ar-H), 8.18-8.16 (m, 2H, Ar-H), 8.07 (d, J=8.8,1H, Ar-H), 7.80-7.75 (m, 2H, Ar-H), 7.69-7.65 (m, 3H, Ar-H), 7.61-7.57 (m, 2H, Ar-H), 7.37 (d, J=8.4,1H, Ar-H)；ES-MS 446.4(M+H)+。
Prepare trifluoro oxygen Phenylindole between 1- benzenesulfonyl -3- formoxyls -5- be using 1- benzenesulfonyl -3- formoxyls - 5- bromo indoles are raw material, and method is same as above, yield 74%.m.p.150.4-151.0℃；1H-NMR (400MHz, DMSO)：δ 10.12 (s, 1H, CHO), 8.98 (s, 1H, Ar-H), 8.33 (d, J=1.6,1H, Ar-H), 8.18-8.16 (m, 2H, Ar-H), 8.07 (d, J=8.8,1H, Ar-H), 7.78-7.74 (m, 4H, Ar-H), 7.70-7.66 (m, 2H, Ar-H), 7.45 (d, J= 8.0,2H, Ar-H)；ES-MS 446.4(M+H)+。
It is to use 1- benzenesulfonyl -3- formoxyls -5- to trifluorophenyl indoles to prepare 1- benzenesulfonyl -3- formoxyl -5- Bromo indole is raw material, and method is same as above, yield 67%.m.p.216.5-216.8℃；1H-NMR (400MHz, CDCl3)：10.13 (s, 1H, CHO), 8.50 (d, J=1.6,1H, Ar-H), 8.28 (s, 1H, Ar-H), 8.05 (d, J=8.8,1H, Ar-H), 8.03-8.00 (m, 2H, Ar-H), 7.74-7.68 (m, 4H, Ar-H), 7.68-7.63 (m, 2H, Ar-H), 7.58-7.53 (m, 2H, Ar-H)；ES-MS 430.4(M+H)+。
Prepare 1- benzenesulfonyl -3- formoxyl -5- to fluorine m-chloro Phenylindole be using 1- benzenesulfonyl -3- formoxyls - 5- bromo indoles are raw material, and method is same as above, yield 83%.m.p.171.1-171.6℃；1H NMR (400MHz, CDCl3)：δ 10.12 (s, 1H, CHO), 8.41 (d, J=1.6,1H, Ar-H), 8.27 (s, 1H, Ar-H), 8.03-7.99 (m, 3H, Ar-H), 7.67-7.62 (m, 2H, Ar-H), 7.58-7.53 (m, 3H, Ar-H), 7.46 (ddd, J1=8.6, J2=4.4, J3=2.41H, Ar-H), 7.21 (t, J=8.6,1H, Ar-H)；ES-MS 414.9(M+H)+。
After above-mentioned intermediate 3,4,8 is prepared for can respectively with the reactant salt in formula VI
Prepare target compound III
Intermediate (3) or (4) or (8) react at room temperature generation target with aminoguanidinium salts hydrochlorate VI in dry methanol respectively Compound III
Prepare 2- [(1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate (chemical combination in table 7 Thing 41) manipulate example
1- is added to absolute methanol to chlorophenylmethyl -3- formoxyl -5- methoxycarbonyl indoles 0.20g (0.61mmol) In 5mL, aminoguanidinium salts hydrochlorate 0.07g (0.61mmol) is then added, and it is 3-4 to adjust reaction solution pH with concentrated hydrochloric acid at room temperature Afterwards, 80min is reacted at room temperature.The backward reaction solution of reaction end, which adds diethyl ether to stand, separates out solid, and decompression is filtered, and filter cake is washed with ether After obtain Off-white solid 0.22g, yield 87%.Compound 41 and other compounds 42-60 experimental datas see attached list 7.
Using intermediate (3) when in table 7 prepared by compound 42-52, method is same as above for raw material.
Compound 53 in table 7,54 use intermediate (4) when preparing, and for raw material, method is same as above.
Using intermediate (8) when in table 7 prepared by compound 55-60, method is same as above for raw material.
Prepare target compound I
The ice-cold NaOH for obtained target compound (III) 0.5-1.0g powder being dissolved or being suspended in 5%-10% is molten In liquid, then it is molten to upper strata aqueous phase to be stirred vigorously 10-30 minutes for the dichloromethane DCM solvents of 1 times of amount of addition NaOH solution volume Liquid pH value (can be properly added granular NaOH solids) when being more than 10, stratification, and the DCM solvent extractions of 0.5 times of amount are organic Phase, it is concentrated under reduced pressure at 30 degrees Celsius of temperature and dry obtains target compound I.
Table 7 is target compound III R1, R2 and X group collocation, yield and nucleus magnetic hydrogen spectrum data, sees attached list 7.
Similarly such manipulation, aminoguanidinium salts hydrochlorate is only changed into sulfate, phosphate, hydrobromate or sulfonic acid Salt, same reaction dissolvent are that ethanol, acetonitrile, DMF DMF or its mixed solvent can obtain corresponding mesh Mark compound III corresponding sulfate, phosphate, hydrobromate or sulfonate.
The beneficial effect and effect of the present embodiment
Target compound I, III that the present embodiment provides synthetic method, step is easy, anti-under normal temperature or counterflow condition Should, it is separated by filtration and is easy to purify, high income, be easy to manipulate, is adapted to following industrialized production.
Embodiment two-way formula IV, the preparation of II compounds
Prepare target compound IV
Intermediate (3) or (4) or (8) are flowed back with 4,5- glyoxalidine -2- hydrazine hydrogen bromide VI in dry methanol respectively React target compound IV；
1- is prepared to chlorophenylmethyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromine Change hydrogen salt (compound 61 in table 8) and manipulate example
1- is added to absolute methanol to chlorophenylmethyl -3- formoxyl -6- methoxycarbonyl indoles 0.05g (0.15mmol) In 2mL, then 4,5- glyoxalidine -2- hydrazine hydrogen bromide 0.03g (0.15mmol) are added in reaction solution, are heated to 75 DEG C instead Should.After reaction terminates, reaction solution is cooled to room temperature, ether is added and stands precipitation solid, decompression is filtered, and filter cake is washed with ether After obtain Off-white solid 0.07g, yield 87%.Compound 61 and other compounds 62-80 experimental datas see attached list 8.
Using intermediate (3) when in table 8 prepared by compound 62-72, method is same as above for raw material.
Compound 73 in table 8,74 use intermediate (4) when preparing, and for raw material, method is same as above.
Using intermediate (8) when in table 8 prepared by compound 75-80, method is same as above for raw material.
Prepare target compound II
Obtained target compound IV0.5-1.0g powder is dissolved or is suspended in 5%-10% ice-cold NaOH solution In, the dichloromethane DCM solvents for then adding 1 times of amount of NaOH solution volume are stirred vigorously 10-30 minutes to upper strata aqueous phase solution PH value (can be properly added granular NaOH solids) when being more than 10, stratification, the DCM solvent extraction organic phases of 0.5 times of amount, It is concentrated under reduced pressure at 30 degrees Celsius of temperature and dry obtains target compound II.
Table 8 is target chemical combination IV R1, and R2 and X group collocation, yield and nucleus magnetic hydrogen spectrum data see attached list 8.
Similarly such manipulation, aminoguanidinium salts hydrochlorate is only changed into sulfate, phosphate, hydrobromate or sulfonic acid Salt, same reaction dissolvent are that ethanol, acetonitrile, DMF DMF or its mixed solvent can obtain corresponding mesh Mark compound IV corresponding sulfate, phosphate, hydrobromate or sulfonate.
The beneficial effect and effect of the present embodiment
Target compound II, IV that the present embodiment provides synthetic method, step is easy, anti-under normal temperature or counterflow condition Should, high income, product is easy to extract and purified, and is easy to manipulate, and is adapted to following industrialized production.
The preparation of the compounds of this invention aseptic powder injection of embodiment three
1st, prescription：
Prescription 1：
Any one 250g in compound III or IV (in terms of compound)
1000 are prepared altogether
Prescription 2：
Any one 500g in compound III or IV (in terms of compound)
1000 are prepared altogether
Prescription 3：
Any one 1000g in compound III or IV (in terms of compound)
1000 are prepared altogether
Prescription 4：
Any one 2000g in compound III or IV (in terms of compound)
1000 are prepared altogether
2nd, preparation technology：
(1) antibiotic glass bottle used, plug etc. will be prepared and carries out aseptic process；
(2) raw material (being fed intake after conversion) is weighed by prescription, aseptic powdery is placed in racking machine and dispensed, at any time detection dress Amount；
(3) jump a queue, gland, finished product full inspection, packaging and storage.
The preparation of the aseptic freeze-dried powder pin of example IV the compounds of this invention
1st, prescription：
Prescription 1：
2nd, preparation technology：
(1) container prepares, and will prepare antibiotic cillin bottle used, plug etc. and carries out aseptic process；
(2) solution is prepared, weighs raw material (being fed intake after conversion) by prescription, using 500-800ml waters for injection in a reservoir Stirring and dissolving, while use 10% hydrochloric acid regulation solubility and pH value；
(3) filtering after above-mentioned solution filtering, dispenses, and partly jump a queue to partly jumping a queue；
(4) freeze and jump a queue, gland, finished product full inspection, packaging and storage.
The preparation of the compounds of this invention tablet of embodiment five
1st, prescription：
Prescription 1：
Prescription 2：
2nd, preparation technology：
(1) raw material be crushed into 100 mesh sieves, remaining auxiliary material crosses 100 mesh sieves respectively, standby；
(2) raw material and auxiliary material are weighed according to recipe quantity；
(3) by hydroxypropyl methylcellulose it is soluble in water be made 2% the aqueous solution it is standby；
(4) by any one in the compounds of this invention I or II or III or IV or B, pregelatinized starch, low substituted hydroxy-propyl Cellulose, microcrystalline cellulose are well mixed, and the addition 2%HPMC aqueous solution is appropriate, stirs, suitable softwood is made；
(5) pelleting of 20 mesh sieves is crossed；
(6) particle is dried under conditions of 60 DEG C；
(7) dried particle adds magnesium stearate, superfine silica gel powder and carboxyrnethyl starch sodium, crosses 18 mesh sieve whole grains, and mixing is equal It is even；
(8) sample, semi-finished product chemical examination；
(9) the piece weight piece determined according to chemical examination；
(10) finished product full inspection, packaging and storage.
The preparation of the compounds of this invention disinfectant of embodiment six
Above-mentioned compound I or II or III or IV is prepared as 0.5%-1.0% concentration with the dissolving of ethanol water mixed solvent Solution, while add appropriate preservative, stabilizer (ethylene glycol, mannitol etc.), which dispenses, to be produced.
The beneficial effect and effect of the present embodiment
Target compound I, II, III, IV that the present embodiment provides disinfectant are readily produced manufacture, can be widely used for curing The disinfection of institute's operating theater instruments etc..
Annex
The target compound III of table 7 R1, R2 and X group collocation, yield, fusing point, nucleus magnetic hydrogen spectrum and mass spectrometric data
The target compound IV of table 8 R1, R2 and X group collocation, yield, fusing point, nucleus magnetic hydrogen spectrum and mass spectrometric data

Claims (10)

1. a kind of Benzazole compounds, chemical structure of general formula are as follows：
Wherein,
X is methylene, carbonyl or sulfonyl；
R1For fluorine, chlorine, bromine, methoxy acyl group, nitro or hydrogen；
R2For methoxy acyl group, (to methoxy acyl group) phenyl, (to trifluoro epoxide) phenyl, (fluorine-based to three) phenyl, (a methoxy acyl group) Phenyl, (a trifluoro epoxide) phenyl, (to fluorine m-chloro) phenyl or hydrogen.
2. Benzazole compounds according to claim 1, it is characterised in that：
Wherein, R1For to chloro, to bromo, to it is fluorine-based, to methoxy acyl group, to nitro, a methoxy acyl group, a nitro.
3. Benzazole compounds according to claim 1, it is characterised in that：
Wherein, R2It is (right for 5- methoxies acyl group, 6- methoxies acyl group, 5- (to methoxy acyl group) phenyl, 5- (to trifluoro epoxide) phenyl, 5- Three is fluorine-based) phenyl, 5- (a methoxy acyl group) phenyl, 5- (a trifluoro epoxide) phenyl, 5- (to fluorine m-chloro) phenyl.
4. Benzazole compounds according to claim 1, it is characterised in that：
Described compound is selected from：
2- [(1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- is to benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- is to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidine；
2- [(1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- m-nitro methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- is to benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- is to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidine；
2- [(1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- m-nitro methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- benzoyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- benzoyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidine；
2- [(1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidine；
2- [(1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidine；
2- [(1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidine；
2- [(1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidine；
2- [(1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indoles) methylene] aminoguanidine；
2- [(1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indoles) methylene] aminoguanidine；
1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- is to benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- is to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
Methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- m-nitro methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- is to benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- is to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
Methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- m-nitro methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzoyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzoyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone；
1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone.
A kind of 5. salt of Benzazole compounds, it is characterised in that：
The salt is the Benzazole compounds of any one in claim 1-4 with obtained by inorganic acid or organic acid reaction Salt (III, IV), its structure is shown as：
Wherein,
X is methylene, carbonyl or sulfonyl；
R1For fluorine, chlorine, bromine, methoxy acyl group, nitro or hydrogen；
R2For methoxy acyl group, (to methoxy acyl group) phenyl, (to trifluoro epoxide) phenyl, (fluorine-based to three) phenyl, (a methoxy acyl group) Phenyl, (a trifluoro epoxide) phenyl, (to fluorine m-chloro) phenyl or hydrogen；
HA is inorganic acid or the strong organic acid of partially acidic.
6. the salt of Benzazole compounds according to claim 5, it is characterised in that：
Wherein, the inorganic acid is any one in sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, and the organic acid is sulfonic acid.
7. the salt of Benzazole compounds according to claim 5, it is characterised in that：
It is selected from：
2- [(1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- is to benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- is to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- m-nitro methyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- is to benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- is to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indoles between 1-) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- m-nitro methyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzoyl -5- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzoyl -6- methoxycarbonyl group -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
2- [(1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indoles) methylene] aminoguanidinium salts hydrochlorate；
1- is to chlorophenylmethyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- is to benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- is to methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromination Hydrogen salt；
Methoxycarbonyl group benzyl -5- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromination Hydrogen salt；
1- p-nitrophenyl methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- m-nitro methyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- is to chlorophenylmethyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- is to benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- is to methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromination Hydrogen salt；
Methoxycarbonyl group benzyl -6- methoxycarbonyl group -3- indolecarboxaldehydes between 1-, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromination Hydrogen salt；
1- p-nitrophenyl methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- m-nitro methyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- benzoyl -5- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- benzoyl -6- methoxycarbonyl group -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide salt；
1- benzenesulfonyls -5- (4- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromination Hydrogen salt；
1- benzenesulfonyls -5- (3- methoxycarbonyl groups phenyl) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromination Hydrogen salt；
1- benzenesulfonyls -5- (4- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromine Change hydrogen salt；
1- benzenesulfonyls -5- (3- Trifluoromethoxyphen-ls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromine Change hydrogen salt；
1- benzenesulfonyls -5- (4- trifluoromethyls) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone bromination Hydrogen salt；
1- benzenesulfonyls -5- (the fluoro- 3- chlorphenyls of 4-) -3- indolecarboxaldehydes, (4,5- dihydro -1H- imidazoles -2- bases) hydrazine ketone hydrogen bromide Salt.
8. the salt and claim 1-4 that prepare the Benzazole compounds of the formula (III, IV) described in claim 5-7 any one are appointed The method of the Benzazole compounds of formula (I, II) described in meaning one, it is characterised in that including that will have formula (V) and formula (VI) compound hybrid reaction in the anhydrous polar solvent of drying, that is, the salt of the Benzazole compounds of formula (III, IV) is obtained； And the salt of the Benzazole compounds of formula (III, IV) be can obtain into formula (I, II) Benzazole compounds by adding alkali alkalization,
Wherein,
X is methylene, carbonyl or sulfonyl；
R1For fluorine, chlorine, bromine, methoxy acyl group, nitro or hydrogen；
R2For methoxy acyl group, (to methoxy acyl group) phenyl, (to trifluoro epoxide) phenyl, (fluorine-based to three) phenyl, (a methoxy acyl group) Phenyl, (a trifluoro epoxide) phenyl, (to fluorine m-chloro) phenyl or hydrogen；
HA is inorganic acid or the strong organic acid of partially acidic.
9. the Benzazole compounds according to claim 8 for preparing the formula (III, IV) described in claim 5-7 any one Salt and claim 1-4 any one described in formula (I, II) Benzazole compounds method, it is characterised in that：
Wherein, the polar solvent is that methanol, ethanol, acetonitrile, any one or its mixing in DMF are molten Agent,
The temperature of the hybrid reaction is room temperature or reflux temperature.
10. a kind of drug-resistance bacteria medicine composition or disinfectant, it is characterised in that：
Wherein, described pharmaceutical composition or disinfectant contain the Benzazole compounds described in claim any one of 1-4 or 5-7 The salt of Benzazole compounds described in one.
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