CN102079724B - Ethylene sulfonyl chloride azole compounds with anti-microbial activity as well as preparation method and medical use thereof - Google Patents
Ethylene sulfonyl chloride azole compounds with anti-microbial activity as well as preparation method and medical use thereof Download PDFInfo
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Abstract
The invention relates to ethylene sulfonyl chloride azole compounds with anti-microbial activity, and preparation of pharmaceutically acceptable salts thereof; and the invention further relates to an application of novel ethylene sulfonyl chloride azole compounds and salts thereof in the aspect of anti-infection medicaments. The ethylene sulfonyl chloride azole compounds show very valuable pharmacological activity in antibacterial and antifungal activity aspects. The general molecular formulas of the novel ethylene sulfonyl chloride azole compounds are as shown in I-X disclosed in the specification, wherein Ar, R, X, M, Im1 and Im2 are defined in the claims.
Description
Technical field
The present invention relates to novel SULPHURYL CHLORIDE ethene azole compounds and pharmaceutically preparation, the biological activity of acceptable salt.The invention still further relates to the medicinal use of novel SULPHURYL CHLORIDE ethene azole compounds.
Background technology
Sulfa drugs is the synthetic anti-infectives of a class, is mainly anti-bacteria breeding, and generally without germicidal action, antimicrobial spectrum is wider, and multiple gram-positive microorganism and Gram-negative bacteria are had to good anti-microbial activity.But the generally use along with disulfonamide thing, has produced several drug resistance bacterial strain.Therefore the pharmacophoric group that in recent years research of sulfamido antimicrobial compounds has been conceived to introduce other is to improve anti-microbial activity.
Azole compounds is the very important nitrogen heteroaromatic compounds of a class, azole compounds extensively appears in various types of medicines, demonstrate different pharmacologically actives, as anticancer, antibacterial, antimycotic, antiviral, parasiticide, anti-carbonic anhydrase, anti-HIV, anti-cyclooxygenase, antagonism Histamine Receptors etc., wherein a lot of azole compounds have been applied to clinical.It is because this class heterocycle structure is containing N heteroatoms that azole compounds is widely used in field of medicaments, easily produces in vivo multiple non-covalent interaction, as hydrogen bond, π-π effect or and Zn
2+, Fe
2+thereby etc. metallic ion coordination, suppress the activity of organism endoenzyme etc.Azole group still much has the good bioisostere of bioactive molecule, and if imidazole ring is the biological isostere of pyrazoles, benzoglyoxaline is used as the biological isostere of the guanine fragment in DNA.Azole compounds as antibacterial, antifungal drug existing be much applied to clinical, if fluconazole is the wide spectrum of clinical use, the antifungal drug of efficient, low toxicity.In recent years, research showed that vinylchlorid azole compounds showed very valuable pharmacologically active aspect antibacterial, anti-mycotic activity, and some ethene azole compounds are for disinfectant use in agriculture.
Research shows azoles ring, sulfonamide structure to introduce for clinical medicines structure as pharmacophore, can improve its biological activity, and the effect of increase and target spot, improves its physico-chemical property.The compound activity that obtains is obviously better than material medicine.But for containing azoles ring structure the research in sulfonamides compound biological activity field also less, this field also has the space of many worth explorations.
Given this, the present invention is first by the sulfuryl amine group key chain vinylchlorid azole compounds that anti-microbial activity is played an important role, and invented the SULPHURYL CHLORIDE ethene azole compounds of novel many target spots, efficient, broad-spectrum anti-microbial activity and acceptable salt pharmaceutically thereof.This compounds is expected to develop into the anti-infective with broad-spectrum antibacterial action.
Summary of the invention
The object of this invention is to provide a SULPHURYL CHLORIDE ethene azole compounds class new texture, that there is Effective Anti microbial process:
Im in formula
1and Im
2be respectively azole group, it is 1 of 1 replacement, 2,4-triazole, benzotriazole, imidazoles, glyoxal ethyline, 2-5-nitro imidazole, 4-nitroimidazole, 2-phenylimidazole, benzoglyoxaline, 2-tolimidazole, 2-methyl-5-nitro benzoglyoxaline or 5,6-dimethylbenzimidazole group;
R is hydroxyethyl, alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl group;
X is chlorine atom, bromine atoms; M is sodium atom and potassium atom;
Ar is benzene and substituted benzene, naphthalene and replacement naphthalene thereof, anthracene and replacement anthracene thereof;
Another object of the present invention is to provide the pharmaceutically preparation of acceptable salt of SULPHURYL CHLORIDE ethene azole compounds (I～X), as the preparation method of its hydrochloride, nitrate salt, acetate.
The present invention also aims to provide SULPHURYL CHLORIDE ethene azole compounds (I～X) and pharmaceutically acceptable salt for the preparation of the purposes of the infectious disease medicaments such as antibacterium, fungi.
The invention allows for SULPHURYL CHLORIDE ethene azole compounds and the synthetic method of acceptable salt pharmaceutically thereof, with substituted aromatics, chloroacetyl chloride is starting raw material synthetic intermediate 2-chlorine aryl methyl ketone, 2-chlorine aryl methyl ketone reacts with a series of azole compounds and obtains 2-azoles aryl methyl ketone again, react with chlorsulfonic acid again and obtain chlorine SULPHURYL CHLORIDE vinyl azole compounds, then from a series of different ammoniacal liquor, primary amine, secondary amine, azole is reacted to obtain SULPHURYL CHLORIDE ethene azole compounds, finally again SULPHURYL CHLORIDE vinyl azole compounds is changed into nitrate, hydrochloride or acetate.
The concrete synthetic route of the present invention and method are as follows:
(1) 2-chlorine aryl methyl ketone compound (XI) is synthetic
Under Catalyzed by Anhydrous Aluminium Chloride condition; aromatic ring or replacement aromatic ring and chloroacetyl chloride pass through Friedel-Crafts acylation reaction in organic solvent; temperature control-50～100 ℃; react 4～12 hours; after reaction finishes; adopt column chromatography, recrystallization, the conventional separation and purification means such as dry, make 2-chlorine aryl methyl ketone intermediate.
(2) 2-azoles aryl methyl ketone compound (XII) is synthetic
In organic solvent, drop into azole compounds and alkali normal-temperature reaction 0.5～2.5 hour, then drop into 2-chlorine aryl methyl ketone (XI), 0～100 ℃ of temperature control, reacts 2～10 hours, makes 2-azoles aryl methyl ketone intermediate (XII).
(3) chlorine SULPHURYL CHLORIDE ethene azole compounds (I) is synthetic
In carbon tetrachloride solvent, add chlorsulfonic acid, drop into 2-azoles aryl methyl ketone (XII) in batches, first temperature control 25～4O ℃, reacts 1～8 hour, then is warmed up to 60～100 ℃, react 12～72 hours, thin-layer chromatography tracks to reaction to be finished, and adopts concentrated, extraction, column chromatography, recrystallization, the conventional separation and purification means such as dry, makes chlorine SULPHURYL CHLORIDE ethene azole derivative (I).
(4) preparation of sulphonamide vinylchlorid azole compounds (II～VII)
Control temperature of reaction is room temperature to 100 ℃, input strong aqua, primary amine, azole compounds, diethanolamine react 2～72 hours with chlorine SULPHURYL CHLORIDE vinyl azole (I) respectively, thin-layer chromatography tracks to reaction to be finished, adopt concentrated, extraction, column chromatography, recrystallization, the conventional separation and purification means such as dry, preparing corresponding general formula is (II～V) sulphonamide vinylchlorid azole derivative.Compound (V) carries out halogenation with halogenation sulfoxide or Phosphorates phosphorus Halides and makes sulphonamide vinylchlorid azoles (VI), and compound (VI) reacts with azole compounds and makes sulphonamide vinylchlorid azoles (VII).
(5) preparation of SULPHURYL CHLORIDE ethene azole compounds (VIII～X)
Control temperature of reaction is room temperature to 100 ℃, and chlorine SULPHURYL CHLORIDE vinyl azole (I) hydrolysis reaction 2～72 hours in 1～5M sodium hydroxide or 1～5M potassium hydroxide dilute alkaline soln, makes SULPHURYL CHLORIDE vinyl azole (VIII); Compound (VIII) reacts and within 1～24 hour, makes SULPHURYL CHLORIDE vinyl azole (IX) with 2～10M sodium hydroxide or potassium hydroxide.
(6) SULPHURYL CHLORIDE ethene azole compounds (I～X) hydrochloride, nitrate or acetate is synthetic
The synthetic SULPHURYL CHLORIDE ethene azole compounds (I～X) of above-mentioned steps is dissolved in respectively in ether or tetrahydrofuran (THF) to (SULPHURYL CHLORIDE ethene azole compounds is in ether, tetrahydrofuran (THF) or ethanol during poor solubility, can add chloroform hydrotropy), slowly drip hydrochloric acid, nitric acid, aqueous acetic acid, till generating without white precipitate, then with dry after ether or tetrahydrofuran (THF) washing solid, prepare general formula (I～X) SULPHURYL CHLORIDE ethene azole derivative hydrochloride, nitrate or acetate;
Or the synthetic SULPHURYL CHLORIDE ethene azole compounds of above-mentioned steps is dissolved in organic solvent, stirring at room, and then add excessive hydrochloric acid, nitric acid, aqueous acetic acid, 0～50 ℃ of temperature control, react 1248 hours, after reaction finishes, adopt concentrated, recrystallization, the conventional separation and purification means such as dry, prepare general formula (I～X) SULPHURYL CHLORIDE ethene azole derivative hydrochloride, nitrate or acetate.
The present invention adopts said synthesis route and method, obtains target compound of the present invention and simple synthetic method, and raw material is easy to get, and cost is low.
Adopt the synthetic SULPHURYL CHLORIDE ethene azole compounds of aforesaid method or its pharmaceutically acceptable salt expection can prepare antimicrobial acivity pharmaceutical composition, the SULPHURYL CHLORIDE ethene azole compounds that this pharmaceutical composition contains physiology significant quantity or its medically acceptable salt, their consumption weight ratios in composition are 0.1%～90%.
SULPHURYL CHLORIDE ethene azole compounds of the present invention or its pharmacy acceptable salt can be with unit dosage form administrations, and route of administration can be enteron aisle and non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity etc.
The SULPHURYL CHLORIDE ethene azole compounds of the present invention's invention or the route of administration of its pharmacy acceptable salt can be intravenously administrable.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and acupoint injection therapy etc.
The form of administration of SULPHURYL CHLORIDE ethene azole compounds of the present invention or its pharmacy acceptable salt can be the drug forms such as tablet, capsule, aerosol, dispersible tablet, oral liquid, suppository, pill, infusion solutions, little pin, freeze-dried powder, ointment or liniment, comprise the now conventional preparation of generally acknowledged pharmaceutics general knowledge of employing and various slowly-releasings, controlled release form or nanometer formulation.
Embodiment
Below by the embodiment of the synthetic example of some particular compound is described in further detail foregoing of the present invention again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.The simple modifications that essence according to the present invention is carried out the present invention all belongs to protection scope of the present invention.
The preparation of the chloro-1-of embodiment 1:2-(2,4-dimethyl-chloro-phenyl-) ethyl ketone (be called for short compounds X I1, compound 1):
M-xylene 10.62g (0.1mol) and aluminum chloride 13.38g (0.1mol) are joined in 100mL three-necked bottle, then under stirring at room, by constant pressure funnel, drip chloroacetyl chloride 11.14g (0.9mol).Add and with TLC, follow the tracks of reaction afterwards, developping agent is CH
2cl
2, after reaction finishes, reactant is poured in frozen water, with dichloromethane extraction, successively water, 2% sodium hydroxide solution and water wash respectively, and anhydrous sodium sulfate drying obtains product 14.63g solid, productive rate 86.8% after solvent evaporated; 52～54 ℃ of fusing points.MS(m/z)：183[M+]，205[M+Na]
+.
The preparation of the chloro-acetonaphthone of embodiment 2:2-(be called for short compounds X I2, compound 2):
6.128g (0.048mol) naphthalene is added to 6.332g (0.048mol) aluminum chloride, use dithiocarbonic anhydride to make solvent, stir the lower 5.828g (0.0516mol) of dropping chloroacetyl chloride, react stopped reaction after 3 hours, pour separatory extraction in frozen water into, successively water, 2% sodium hydroxide solution, water wash, anhydrous sodium sulfate drying, evaporate to dryness.Obtain 9.47g product, productive rate 82%.MS(m/z)：205[M+]，227[M+Na]
+.
The preparation of embodiment 3:1-(4-fluorophenyl)-2-(2-methyl-5-nitro-1H-imidazoles) ethyl ketone (be called for short compounds X II1, compound 3):
By 6.36g (0.05mol) 2-5-nitro imidazole, 7.60g (0.055mol) K
2cO
3, 50mL acetonitrile, be placed in the 250mL tri-neck round-bottomed flasks with condensation reflux unit, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 1 hour.Add the chloro-1-of 9.49g (0.055mol) compound 2-(4-fluorophenyl) ethyl ketone, 40 ℃ of stirrings of oil bath temperature control 3 hours.After reaction stops, decompression steams acetonitrile, filters, and filter cake respectively water, chloroform respectively washs 5～6 times, after being dried, obtains white solid 12.11g, productive rate: 92%, and fusing point: 206～208 ℃.IR(KBr)v：3139.3(Ar-H)，2990.4，2942.9(CH
3，CH
2)，1685.0(C＝O)，1598.8，1540.9，1504.6(aromatic?frame)，1392.0，1328.7，1293.1，1235.0，1160.1，991.0，835.9cm
-1；
1H?NMR(300MHz，DMSO-d
6)δ：8.22(s，1H，Im-H)，8.15(s，2H，Ph?2，6-H)，7.48(t，2H，J＝7.8Hz，Ph?3，5-H)，5.83(s，2H，CH
2)，2.27(s，3H，Im-CH
3)ppm；
13C?NMR(300MHz，DMSO-d
6)δ：191.1(C＝O)，167.5(Ph?4-C)，164.2(Im?2-C)，146.4(Im?5-C)，145.5，131.5，123.4，116.3(Ar-C)，53.3(CH
2)，12.6(Im-CH
3)ppm；MS(m/z)：264[M]
+.
The preparation of embodiment 4:1-(4-chloro-phenyl-)-2-(2-methyl-5-nitro-1H-imidazoles) ethyl ketone (be called for short compounds X II2, compound 4):
By 6.36g (0.05mol) 2-5-nitro imidazole, 8.29g (0.06mol) K
2cO
3, 50mL acetonitrile, be placed in the 250mL tri-neck round-bottomed flasks with condensation reflux unit, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 1 hour.Add the chloro-1-of 10.40g (0.055mol) compound 2-(4-chloro-phenyl-) ethyl ketone, 40 ℃ of stirrings of oil bath temperature control 3 hours.After reaction stops, decompression steams acetonitrile, filters, and filter cake respectively water, chloroform respectively washs 5～6 times, after being dried, obtains white solid 12.22g, productive rate: 87.4%, and fusing point: 248～249 ℃.IR(KBr)v：3122.5(Ar-H)，2992.2，2959.2(CH
3，CH
2)，1685.4(C＝O)，1593.2，1540.1，1500.4(aromatic?frame)，1394.9，1331.8，1298.1，1234.7，1095.7，991.3，824.9cm
-1；
1H?NMR(300MHz，DMSO-d
6)δ：8.21(s，1H，Im-H)，8.07(d，2H，J＝7.9Hz，Ph?2，6-H)，7.74(d，2H，J＝7.8Hz，Ph?3，5-H)，5.82(s，2H，CH
2)，2.26(s，3H，Im-CH
3)ppm；
13C?NMR(300MHz，DMSO-d
6)δ：191.6(CO)，146.4(Im?2-C)，145.4(Im?4-C)，139.4，132.9，130.3(Ph?2，6-C)，129.3(Ph?3，5-C)，123.4，53.2(CH
2)，12.6(Im-CH
3)ppm；MS(m/z)：280[M]
+.
The preparation of embodiment 5:1-(4-fluorophenyl)-2-(4-nitro-1H-imidazoles) ethyl ketone (be called for short compounds X II3, compound 5):
In dry round-bottomed flask, drop into 1.04g (0.009mol) 4-nitroimidazole and 1.15g (0.008mol) salt of wormwood, add appropriate acetonitrile to make solvent, under stirring, add the chloro-1-of 1.13g (0.006mol) 2-(4-fluorophenyl) ethyl ketone.React stopped reaction after 15 hours, by solvent evaporate to dryness.Add water and chloroform to cook solvating agent extraction, saturated ammonium chloride solution, distilled water wash for organic phase.Anhydrous sodium sulfate drying.Solvent evaporate to dryness is obtained to 1.44g product later, and productive rate is 85.4%; Fusing point: 171～172 ℃.MS(m/z)：250[M+]，272[M+Na]
+.
The preparation of embodiment 6:1-(4-chloro-phenyl-)-2-(4-nitro-1H-imidazoles) ethyl ketone (be called for short compounds X II4, compound 6):
In dry round-bottomed flask, drop into 1.2g (0.011mol) 4-nitroimidazole and 1.47g (0.011mol) salt of wormwood, add appropriate acetonitrile to make solvent, under stirring, add the chloro-1-of 2.18g 2-(4-chloro-phenyl-) ethyl ketone.React stopped reaction after 15 hours, by solvent evaporate to dryness.Add water and chloroform to cook solvating agent extraction, saturated ammonium chloride solution, distilled water wash for organic phase.Anhydrous sodium sulfate drying.Solvent evaporate to dryness is obtained to 2.04g product later, and productive rate is 65%; Fusing point: 181～183 ℃.MS(m/z)：266[M+]，288[M+Na]
+.
The preparation of embodiment 7:1-(naphthyl)-2-(4-nitro-1H-imidazoles) ethyl ketone (be called for short compounds X II5, compound 7):
In dry round-bottomed flask, drop into 1.141g (0.01mol) 4-nitroimidazole and 1.39g (0.01mol) Anhydrous potassium carbonate, add appropriate acetonitrile to make solvent, under stirring, add the chloro-1-of 1.52g (0.007mol) 2-(naphthyl) ethyl ketone.React stopped reaction after 15 hours, by solvent evaporate to dryness.Add water and chloroform to cook solvating agent extraction, saturated ammonium chloride solution, distilled water wash for organic phase.Anhydrous sodium sulfate drying.Solvent evaporate to dryness is obtained to 2.0g product later, and productive rate is 86.2%; Fusing point: 166～167 ℃.MS(m/z)：282[M+]，304[M+Na]
+.
The preparation of embodiment 8:1-(2,4-3,5-dimethylphenyl)-2-(4-nitro-1H-imidazoles) ethyl ketone (be called for short compounds X II6, compound 8):
In dry round-bottomed flask, drop into 1.36g (0.012mol) 4-nitroimidazole and 1.67g (0.01mol) Anhydrous potassium carbonate, add appropriate acetonitrile to make solvent, under stirring, add the chloro-1-of 2.0g (0.01mol) 1.52g 2-(2,4-3,5-dimethylphenyl) ethyl ketone.React stopped reaction after 15 hours, by solvent evaporate to dryness.Add water and chloroform to cook solvating agent extraction, saturated ammonium chloride solution, distilled water wash for organic phase.Anhydrous sodium sulfate drying.Solvent evaporate to dryness is obtained to 2.15g product later, and productive rate is 86.2%; Fusing point: 172～174 ℃.MS(m/z)：260[M+]，282[M+Na]
+.
The preparation of embodiment 9:1-(phenyl)-2-(4-nitro-1H-imidazoles) ethyl ketone (be called for short compounds X II7, compound 9):
In dry round-bottomed flask, drop into 1.13g (0.01mol) 4-nitroimidazole and 1.38g (0.01mol) Anhydrous potassium carbonate, add appropriate acetonitrile to make solvent, under stirring, add the chloro-1-of 1.28g (8.3mmol) 2-(phenyl) ethyl ketone.React stopped reaction after 15 hours, by solvent evaporate to dryness.Add water and chloroform to cook solvating agent extraction, saturated ammonium chloride solution, distilled water wash for organic phase.Anhydrous sodium sulfate drying.Solvent evaporate to dryness is obtained to 1.52g product later, and productive rate is 70%; Fusing point: 155～157 ℃.MS(m/z)：264[M+]，286[M+Na
+]
+.
The preparation of embodiment 10::5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-fluorobenzene-1-SULPHURYL CHLORIDE (be called for short Compound I 1, compound 10):
By 11.65g (0.1mol) chlorsulfonic acid, 30mLCCl
4be placed in the 100mL tri-neck round-bottomed flasks with prolong, drying tube, device for absorbing tail gas, under room temperature vigorous stirring, 5.26g (0.02mol) compound 1-(4-fluorophenyl)-2-(2-methyl-5-nitro-1H-imidazoles) ethyl ketone is added in batches, adding rear 30 ℃ of constant temperature stirs 3 hours, then be slowly warming up to 75 ℃, at this temperature, react after 12 hours and add 1g NaCl, after 2 hours, add again 1g NaCl, react stopped reaction after 2 hours.Reaction system is cooled to room temperature and pours in frozen water, have a large amount of white solids to generate, when the white cigarette of nothing generates, filter, distilled water wash solid 5～8 times, the dry rear white solid 6.00g that obtains, productive rate: 83%, fusing point: 162 ℃.IR(KBr)v：3142.5(Ar-H)，3068.9(＝C-H)，2815.9(CH
3)，1600.96，1552.2，1513.1(aromatic?frame)，1380.8，1166.1，822.9cm
-1；
1H?NMR(300MHz，CDCl
3)δ：8.19～8.16(m，1H，Ph?6-H)，8.14(s，1H，Im-H)，8.03～7.98(m，1H，Ph?4-H)，7.43(d，1H，J＝8.8Hz，Ph?3-H)，7.22(s，1H，＝CH)，2.45(s，3H，Im-CH
3)ppm；
13C?NMR(300MHz，DMSO)δ：1614(Im?2-C)，157.8(Ph?2-C)，147.2(Im?5-C)，145.6(Ph?4-C)，136.0(Ph?5-C)，132.6(Im?4-C)，131.8(Ph?1-C)，130.1(Ph?6-C)，120.5(Ph-CCl＝)，119.5(Ph3-C)，118.9(＝CH-Im)，13.8(Im-CH
3)ppm；MS(m/z)：380[M]
+.
The preparation of embodiment 11:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-chlorobenzene-1-SULPHURYL CHLORIDE (be called for short Compound I 2, compound 11):
By 8.74g (0.075mol) chlorsulfonic acid, 20mLCCl
4be placed in the 100mL tri-neck round-bottomed flasks with prolong, drying tube, device for absorbing tail gas, under room temperature vigorous stirring, 4.20g (0.015mol) compound 1-(4-chloro-phenyl-)-2-(2-methyl-5-nitro-1H-imidazoles) ethyl ketone is added in batches, add rear 30 ℃ of constant temperature and stir 3h, then be slowly warming up to 75 ℃, at this temperature, react after 12 hours and add 1g NaCl, after 2 hours, add again 1g NaCl, react stopped reaction after 2 hours.Reaction system is cooled to room temperature and pours in frozen water, have a large amount of white solids to generate, when the white cigarette of nothing generates, filter, distilled water wash solid 5～8 times, the dry rear white solid 3.70g that obtains, productive rate: 65.2%, fusing point: 185 ℃.IR(KBr)v：3152.8(Ar-H)，3084.9(＝C-H)，2825.9(CH
3)，1591.5，1542.5，1499.1(aromatic?frame)，1375.7，1179.9，813.4cm
-1；
1H?NMR(400MHz，CD
3COCD
3)δ：8.39(d，1H，J＝2.4Hz，Ph?6-H)，8.22(s，1H，Im-H)，7.96(dd，1H，Ph4-H)，7.79(d，1H，J＝8Hz，Ph?3-H)，7.32(s，1H，＝CH)，2.53(s，3H，Im-CH
3)ppm；
13CNMR(300MHz，DMSO)δ：147.1(Im?2-C)，145.6(Ph?1-C)，141.8(Im?5-C)，135.0(Ph5-C)，134.2(Ph?2-C)，133.8(Ph?4-C)，133.7(Ph?3-C)，129.9(PhCCl)，128.5(Ph?6-C)，120.7(CH-Im)119.0(Im?4-C)，13.7(Im-CH
3)pm；MS(m/z)：398[M]
+.
The preparation of embodiment 12:5-(the chloro-2-of 1-(4-nitro-1H-imidazoles) vinyl)-2-toluene-1-SULPHURYL CHLORIDE (be called for short Compound I 3, compound 12)
By 1.165g (10.00mmol) chlorsulfonic acid, 20mLCCl
4be placed in prolong, drying tube, in the 100mL round-bottomed flask of device for absorbing tail gas, under room temperature vigorous stirring, 0.490g (2.00mmol) compound 1-(4-aminomethyl phenyl)-(4-nitro-1H-imidazoles) ethyl ketone is added in batches, adding rear 30 ℃ of constant temperature stirs 15 hours, then be slowly warming up to 60 ℃, react 24 hours, again be warmed up to 70 ℃ of reactions 24 hours, with thin-layer chromatography (TLC), follow the tracks of reaction (developping agent: chloroform/methanol, 40/1, V/V), add 0.500g NaCl, reaction system is cooled to room temperature to be poured in frozen water, there are a large amount of faint yellow solids to generate, when generating without white cigarette, filter, distilled water wash solid 5～8 times, 60～90 ℃ of petroleum ether 5～8 times, 30～60 ℃ of petroleum ether 2 times, by column chromatography, purify and obtain single-point (developping agent, chloroform/methanol, 40/1, V/V), concentrated, with acetone recrystallization, must be dried rear acquisition faint yellow solid 0.480g, productive rate: 66.7%,
1hNMR (300MHz, CDCl
3, J in Hz) and δ: 8.34 (s, 1H, Im 2-H), 8.31 (s, 1H, Ph 6-H), 7.91 (s, 1H, Ph 4-H), 7.89 (s, 1H, Ph 3-H), 7.58～7.55 (d, 1H, J=9.0Hz, Im 5-H), 7.45 (s, 1H ,=CH), 2.86 (s, 3H, Ph-CH
3) ppm.
The preparation of embodiment 13:5-(the chloro-2-of 1-(1,2,4-triazole) vinyl)-2-toluene-1-SULPHURYL CHLORIDE (be called for short Compound I 4, compound 13)
By 1.165g (10.00mmol) chlorsulfonic acid, 20mL CCl
4be placed in prolong, drying tube, in the 100mL round-bottomed flask of device for absorbing tail gas, under room temperature vigorous stirring, by 0.402g (2.00mmol) compound 1-(2-tolyl)-2-(1, 2, 4-triazole) add in batches, adding rear 30 ℃ of constant temperature stirs 8 hours, then be slowly warming up to 60 ℃ of reactions 18 hours, with thin-layer chromatography (TLC), follow the tracks of reaction (developping agent, chloroform/methanol, 20/1, V/V), add 0.50g NaCl, reaction system is cooled to room temperature to add in frozen water, there are a large amount of brown solids to generate, when generating without white cigarette, suction filtration, distilled water wash solid 5～8 times, 60～90 ℃ of petroleum ether 5～8 times, 30～60 ℃ of petroleum ether 2 times, with acetone recrystallization, obtain brown solid 0.410g, productive rate: 65.3%, 168 ℃ of fusing points,
1h NMR (300MHz, CDCl
3, J inHz) and δ: 9.10 (s, 1H, Im 4-H), 8.34 (s, 1H, Im 2-H), 8.09 (s, 1H, Ph 6-H), 7.90～7.87 (d, 1H, J=9.0Hz, Ph 4-H), 7.76 (s, 1H,=CH), 7.54～7.52 (d, 1H, J=6.0Hz, Ph 3-H), 2.84 (s, 3H, Ph-CH
3) ppm.
Embodiment 14:5-(the chloro-2-of 1-(4-nitro-1H-imidazoles) vinyl)-2, the preparation of 4-dimethylbenzene-1-SULPHURYL CHLORIDE (be called for short Compound I 5, compound 14)
By 0.583g (5.00mmol) chlorsulfonic acid, 20mLCCl
4be placed in prolong, drying tube, in the 100mL round-bottomed flask of device for absorbing tail gas, under room temperature vigorous stirring, by 0.259g (1.00mmol) 1-(2, 4-3,5-dimethylphenyl)-(4-nitro-1H-imidazoles) ethyl ketone adds in batches, adding rear 30 ℃ of constant temperature stirs 15 hours, then be slowly warming up to 60 ℃, react 24 hours, again be warmed up to 70 ℃ of reactions 24 hours, with thin-layer chromatography (TLC), follow the tracks of reaction to finishing (developping agent: chloroform/methanol, 40/1, V/V), add 0.500g NaCl, reaction system is cooled to room temperature to add in frozen water, there are a large amount of brown color solids to generate, when generating without white cigarette, suction filtration, distilled water wash solid 5～8 times, 60～90 ℃ of petroleum ether 5～8 times, 30～60 ℃ of petroleum ether 2 times, by column chromatography, purify (eluent, ethyl acetate/petroleum ether, 1/2, V/V), concentrated faint yellow solid 0.300g, productive rate: 79.9%, fusing point: 172 ℃.
1H?NMR(300MHz，CDCl
3，J?in?Hz)δ：8.38(s，1H，Im?2-H)，8.02(s，1H，ph?6-H)，7.88(s，1H，Ph?3-H)，7.37(s，1H，Im?5-H)，7.10(s，1H，＝CH)，2.80(s，3H，Ph?2-CH
3)，2.53(s，3H，Ph?4-CH
3)ppm.
Embodiment 15:1-(5-(the chloro-2-of 1-(1H-1,2,4-triazole-1-) vinyl)-2-tolylsulfonyl)-1H-1, the preparation of 2,4-triazole (be called for short compound IV 1, compound 15)
By 0.069g (1.00mmol) 1,2,4-triazole, 0.170g (1.20mmol) K
2cO
3, 15mL acetonitrile, be placed in the 100mL tri-neck round-bottomed flasks with return stirring device, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 40min.Compound 5-1-(the chloro-2-of 1-(1,2,4-triazole) the vinyl)-2-toluene-1-SULPHURYL CHLORIDE that adds 0.191g (0.60mmol), 40 ℃ of stirrings of oil bath temperature control 1.5 hours.Cooling rear decompression steams acetonitrile, and adding distil water 20mL all dissolves solid, uses CH
2cl
2(3 * 15mL) extraction, column chromatography is separated, and concentrating under reduced pressure obtains white solid 0.160g, productive rate: 76%, 260 ℃ of fusing point: >,
1hNMR (300MHz, CDCl
3, J in Hz) and δ: 9.09 (s, 1H, Ph6-H), 8.84 (s, 1H, O
2s-Im 4-H), 8.48 (s, 1H, CH-Im 4-H), 8.09 (s, 1H, CH-Im 2-H), 8.06 (s, 1H, SO
2-Im 2-H), 7.89～7.87 (d, 1H, J=6Hz, Ph 3-H), 7.76 (s, 1H ,=CH), 7.47～7.45 (d, 1H, J=6Hz, Ph 4-H), 2.68 (s, 3H, Ph-CH
3) ppm.
The preparation of embodiment 16:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-fluorobenzene sulphonamide (be called for short Compound I I 1, compound 16)
0.36g (1mmol) compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-fluorobenzene-1-SULPHURYL CHLORIDE is placed in to 100mL round-bottomed flask, add THF to make its dissolving, then under stirring at room, add wherein 10mL strong aqua, TLC tracks to raw material and disappears.After decompression steams THF, filter, with distilled water and chloroform, wash 3 times respectively, after being dried, obtain Off-white solid 0.27g, productive rate: 80%, fusing point: 261～263 ℃.IR (KBr) v:3426.2 (NH
2), 3156.3 (Ar-H), 3087.8 (=C-H), 1601.8,1542.0,1495.1 (aromatic ring frame) cm
-1;
1h NMR (400MHz, CD
3cOCD
3) δ: 8.41 (s, 1H, Im-H), 8.23 (dd, 1H, Ph 6-H), 8.12 (m, 1H, Ph3-H), 7.87 (s, 1H ,=CH), 7.53 (t, 1H, J=9.2Hz, Ph 4-H), 2.48 (s, 1H, Im-CH
3) ppm; MS (m/z): 361[M]
+.
The preparation of embodiment 17:5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-chlorobenzene sulfonamide (be called for short Compound I I2, compound 17):
0.12g (0.3mmol) compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-chlorobenzene-1-SULPHURYL CHLORIDE is placed in to 100mL round-bottomed flask, add 5mL THF to make its dissolving, then under stirring at room, add wherein 10mL strong aqua, TLC tracks to raw material and disappears.After decompression steams THF, filter, with distilled water and chloroform, wash 3 times respectively, after being dried, obtain Off-white solid 0.11g, productive rate: 82.5%, 250 ℃ of fusing point: >.IR(KBr)v：3327.4(NH
2)，3149.6(Ar-H)，3090.7(＝C-H)，2985.6，2956.1(CH
3)，1588.3，1545.0，1499.5(aromatic?frame)，1469.8，1379.6，1164.4，1037.6，831.1cm
-1；
1H?NMR(300MHz，CDCl
3)δ：ppm；
1H?NMR(300MHz，DMSO-d
6)δ：8.62(s，1H，Im-H)，8.28(d，1H，J＝15.7Hz，Ph?6-H)，8.02(d，J＝7.1Hz，1H，Ph?3-H)，7.95(s，1H，＝CH)，7.82(d，1H，J＝8.3Hz，Ph?4-H)，2.41(s，1H，Im-CH
3)ppm；MS(m/z)：377[M]
+
The preparation of embodiment 18:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl) the fluoro-N-of-2-(2-hydroxyethyl) benzsulfamide (be called for short compound III 1, compound 18)
In 100mL round-bottomed flask, with 20mL acetone, 0.66g (1.8mmol) compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-fluorobenzene-1-SULPHURYL CHLORIDE is dissolved, then under stirring, room temperature (15 ℃) dropwise adds wherein 0.37g (6mmol) thanomin, have a large amount of white solids to generate, TLC tracks to raw material and disappears.After decompression steams acetone, filter, distilled water wash 5 times, obtains light green solid 0.45g, productive rate after being dried: 84.2%, and fusing point: 200～201 ℃.IR (KBr) v:3317.0 (NH), 3156.7 (Ar-H), 3072.2 (=C-H), 2949.6,28735.3 (CH
3), 1598.8,1554.7,1513.9 (aromatic ring frame) cm
-1;
1h NMR (300MHz, DMSO-d
6) δ: 8.61 (s, 1H, Im-H), 8.29 (s, 1H, Ph 6-H), 8.02 (s, 1H, Ph 3-H), 7.93 (s, 1H ,=CH), 7.65 (t, 1H, J=7.9Hz, Ph 4-H), 3.40 (s, 2H, NCH
2), 2.97 (s, 2H, CH
2oH), 2.43 (s, 1H, Im-CH
3) ppm; MS (m/z): 405[M]
+.
The preparation of embodiment 19:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl) the chloro-N-of-2-(2-hydroxyethyl) benzsulfamide (be called for short compound III 1, compound 19):
In 100mL round-bottomed flask, with 20mL acetone, 0.38g (1mmol) 0.66g compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-chlorobenzene-1-SULPHURYL CHLORIDE is dissolved, then under stirring, room temperature (15 ℃) dropwise adds wherein 0.12g (2mmol) thanomin, have a large amount of white solids to generate, TLC tracks to raw material and disappears.After decompression steams acetone, filter, distilled water wash 5 times, obtains light green solid 0.24g, productive rate after being dried: 81%, and fusing point: 241～242 ℃.IR(KBr)v：3324.2(NH)，3158.9(Ar-H)，3083.9(＝C-H)，1590.8，1553.6，1512.4(aromatic?frame)，1386.0，1327.1.1297.6，1153.4，1035.9，820.4cm
-1；
1H?NMR(300MHz，DMSO-d
6)δ：8.63(s，1H，Im-H)，8.32(s，1H，Ph?6-H)，8.05(d，1H，J＝7.5Hz，Ph?3-H)，7.99(s，1H，＝CH)，7.85(d，1H，J＝7.6Hz，Ph?4-H)，3.39(s，2H，NCH
2)，2.95(s，2H，CH
2OH)，2.43(s，1H，Im-CH
3)ppm；MS(m/z)：421[M]
+。
Embodiment 20:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl) the chloro-N of-2-, the preparation of N-bis-(2-hydroxyethyl) benzsulfamide (be called for short compound V1, compound 20):
By 0.13g (1.2mmol) diethanolamine, 0.28g (2mmol) K
2cO
3, 15mL acetonitrile, be placed in the 100mL tri-neck round-bottomed flasks with return stirring device, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 40min.Add 0.26g (0.6mmol) compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-chlorobenzene-1-SULPHURYL CHLORIDE, 40 ℃ of stirrings of oil bath temperature control 4 hours.Cooling decompression steams acetonitrile, and adding distil water filters, and by distilled water and chloroform washing solid several times, dries and obtains faint yellow solid 0.16g, productive rate: 52%, and fusing point: 162～165 ℃.IR(KBr)v：3350.4(OH)，3193.0(Ar-H)，3092.6(＝C-H)，2952.3，2894.3，2849.3(CH
3，CH
2)，1590.9，1547.3，1500.8(aromaticframe)，1377.5，1150.6(PhSO
2-N)，824.1cm
-1；
1H?NMR(300MHz，CDCl
3)δ：8.39(s，1H，Im-H)，8.19(s，1H，Ph?6-H)，7.81(t，1H，J＝4.7Hz，Ph?3-H)，7.66(t，1H，J＝8.3Hz，Ph4-H)，7.31(s，1H，＝CH)，3.89(t，4H，J＝4.7Hz，NCH
2)，3.53(t，4H，J＝6.1Hz，CH
2OH)，2.51(s，1H，Im-CH
3)ppm；MS(m/z)：465[M]
+.
Embodiment 21:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl) the fluoro-N of-2-, the preparation of N-bis-(2-hydroxyethyl) benzsulfamide (be called for short compound V2, compound 21)
By 0.13g (1.2mmol) diethanolamine, 0.28g (2mmol) K
2cO
3, 15mL acetonitrile, be placed in the 100mL tri-neck round-bottomed flasks with return stirring device, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 40min.Add 0.38g (1mmol) compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-fluorobenzene-1-SULPHURYL CHLORIDE, 40 ℃ of stirrings of oil bath temperature control 4 hours.Cooling decompression steams acetonitrile, and adding distil water filters, and by distilled water and chloroform washing solid several times, dries and obtains oyster white crystal 0.23g, productive rate: 82.1%, and fusing point: 165～166 ℃.IR (KBr) v:3350.4 (OH), 3191.2 (Ar-H), 3082.6 (=C-H), 2946.0,2895.7 (CH
3, CH
2), 1597.6,1553.5,1506.2 (aromatic ring frame) cm
-1;
1h NMR (400MHz, CD
3cOCD
3) δ: 8.40 (s, 1H, Im-H), 8.27 (dd, 1H, Ph 6-H), 8.14 (m, 1H, Ph 3-H), 7.87 (s, 1H ,=CH), 7.55 (t, 1H, J=9.2Hz, Ph 4-H), 3.73 (t, 4H, J=5.6Hz, NCH
2), 3.47 (t, 4H, J=6Hz, CH
2oH), 2.47 (s, 1H, Im-CH
3) ppm; MS (m/z): 449[M]
+.
Embodiment 22:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-N, the preparation of N-bis-(2-chloroethyl)-2-fluorobenzene sulphonamide (be called for short compound VI 1, compound 22):
By 0.36g (1mmol) mustine hydrochlcride, 0.55g (4mmol) K
2cO
3, 15mL acetonitrile, be placed in the 100mL tri-neck round-bottomed flasks with return stirring device, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 40min.Add 0.38g (1mmol) compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-fluorobenzene-1-SULPHURYL CHLORIDE, 40 ℃ of stirrings of oil bath temperature control 4 hours.Cooling decompression steams acetonitrile, and adding distil water filters, and by distilled water and chloroform washing solid several times, dries and obtains white solid 0.27g, productive rate: 56.3%, and fusing point: 173～175 ℃.IR(KBr)v：3131.6(Ar-H)，3042.9(＝C-H)，2970.9，2866.7(CH
3，CH
2)，1597.6，1542.8，1504.6(aromatic?frame?)，1373.1，1156.9，816.0cm
-1；
1H?NMR(300MHz，CDCl
3)δ：8.10(t，1H，J＝4.7Hz，Ph?6-H)，7.96(s，1H，Im-H)，7.76～7.73(m，1H，Ph?3-H)，7.52(s，1H，＝CH)，7.29(t，1H，J＝9.6Hz，Ph?4-H)，3.77～3.62(m，8H，CH
2)，2.63(s，1H，Im-CH
3)ppm；MS(m/z)：485[M]
+.
Embodiment 23:5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-N, the preparation of N-bis-(2-chloroethyl)-2-chlorobenzene sulfonamide (be called for short compound VI 2, compound 23):
By 0.36g (1mmol) mustine hydrochlcride, 0.55g (4mmol) K
2cO
3, 15mL acetonitrile, be placed in the 100mL tri-neck round-bottomed flasks with return stirring device, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 40min.Add 0.38g (1mmol) compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) vinyl)-2-chlorobenzene-1-SULPHURYL CHLORIDE, 40 ℃ of stirrings of oil bath temperature control 4 hours.Cooling decompression steams acetonitrile, and adding distil water filters, and by distilled water and chloroform washing solid several times, dries and obtains white solid 0.33g, productive rate: 65%, and 250 ℃ of fusing point: >.IR(KBr)v：3146.2(Ar-H)，3066.3(＝C-H)，2969.2(CH
3)，1590.3，1542.8，1509.6(aromatic?frame)，1380.1，1295.0，1200.7，1068.2，826.7cm
-1；
1H?NMR(300MHz，DMSO)δ：8.61(s，1H，Im-H)，8.27(s，1H，Ph?6-H)，7.86(s，1H，＝CH)，7.75(d，J＝7.8Hz，1H，Ph?3-H)，7.57(d，1H，J＝7.3Hz，Ph?4-H)，3.86～3.71(m，8H，CH
2)，2.29(s，1H，Im-CH
3)ppm；MS(m/z)：503[M]
+.
Embodiment 24:1-(5-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles-1-) vinyl)-2-fluorobenzene sulphonyl)-1H-1, the preparation of 2,4-triazolium salt hydrochlorate (be called for short compound IV 4HCl, compound 24)
By 0.07g (1mmol) 1,2,4-triazole, 0.17g (1.2mmol) K
2cO
3, 15mL acetonitrile, be placed in the 100mL tri-neck round-bottomed flasks with return stirring device, thermometer and drying tube, 40 ℃ of oil bath temperature controls stir 40min.Compound 5-1-(the chloro-2-of 1-(2-methyl-5-nitro-1H-imidazoles) the vinyl)-2-fluorobenzene-1-SULPHURYL CHLORIDE that adds 0.23g (0.6mmol), oil bath temperature control 40C stirs 3 hours.Cooling rear decompression steams acetonitrile, and adding distil water 20mL all dissolves solid, with dilute hydrochloric acid, is adjusted to pH=2～3, be placed with white solid and separate out, with dilute hydrochloric acid washing 3～4 times, obtain white crystal 0.15g, productive rate: 61%, 270 ℃ of fusing point: >.IR (KBr) v:3150.2,3100.9 (Ar-H), 3075.4 (=C-H), 2985.0,2886.6 (CH
3), 2819.5,2766.3,2671.6,2594.1,1595.7,1549.4,1512.7 (aromatic ring frame) cm
-1;
1h NMR (300MHz, CDCl
3) δ: 8.69 (s, 1H, triazole 4-H), 8.42 (s, 1H, triazole 2-H), 8.41 (s, 1H, Im-H), 8.13 (s, 1H, Ph 6-H), 7.65 (t, 1H, J=9.6Hz, Ph 3-H), 7.51 (s, 1H,=CH), 7.34 (t, 1H, J=9.2Hz, Ph 4-H), 2.41 (s, 1H, Im-CH
3) ppm; MS (m/z): 411[M]
+.
SULPHURYL CHLORIDE ethene azole compounds of the present invention and pharmacy acceptable salt expection thereof can be combined use as fluconazole, phosphorus fluconazole, itraconazole, Sulfamethoxazole, Ciprofloxacin etc. with antimycotic, the antibacterials of now having gone on the market, and preparation has the pharmaceutical composition of fungi, bacterial growth inhibition activity or antibacterium, fungi infestation.Such pharmaceutical composition can adopt the drug forms such as tablet, capsule, aerosol, dispersible tablet, oral liquid, suppository, pill, infusion solutions, little pin, freeze-dried powder, ointment or liniment, comprise the now conventional preparation of generally acknowledged pharmaceutics general knowledge of employing and various slowly-releasings, controlled release form, nanometer formulation etc.
For better, understand essence of the present invention, the inhibiting the pharmacological results to two kinds of fungies and eight kinds of bacterial growths with compound respectively, illustrates that these compounds exist potential purposes at pharmaceutical field below.Pharmacology embodiment has provided the part activity data of part of compounds.Mandatory declaration, pharmacology embodiment of the present invention is for the present invention rather than limitation of the present invention are described.The simple modifications that essence according to the present invention is carried out the present invention all belongs to protection scope of the present invention.
Embodiment 25: in vitro anti-microbial activity experiment
Test method:
The compounds of this invention is used coubling dilution and standard microtiter technique, for fungi, Gram-negative and gram-positive microorganism, tests.Experimental result is with the judgement of minimum inhibitory concentration (MIC) value.
The test of minimum inhibitory concentration adopts clinical experiment standard (the National Committee for Clinical Laboratory Standards that meets United States National Committee's formulations in 1993, NCCLS) 96 hole micro-dilution methods, by methyl-sulphoxide (DMSO) sample dissolution, it is 1.28mgmL that water dilution is made into concentration
-1, with nutrient solution, be diluted to 128 μ gmL
-1.At 35 ℃, cultivate 24～72 hours.After culture plate is fully stirred evenly on vibrator, the turbidity of group is measured MIC in spectrophotometer 490nm place per sample
50.
Test-results:
The preliminary antimicrobial acivity of compound 10～24 the results are shown in Table 1.
The antimicrobial acivity data of table 1 compound 10～24
Aspect antimycotic, compound 22,23,24 all can significantly suppress the growth of Candida albicans, and the activity of the antimycotic Candida albicans of compound 10～21 is low.With with reference to medicine fluconazole, compare, compound 22,23,24 likely develops into the new medicine with antifungic action and treatment fungi infestation disease.
Aspect antibacterium, compound 10～24 (except compound 12,14,24) has general restraining effect to aspergillus fumigatus, and wherein 10,16,18 pairs of aspergillus fumigatus performances of compound are significant suppresses active.In 22,23,24 pairs of gram-positive microorganism streptococcus aureus performances of compound, wait until significant a kind of activity.Compound 12,13,15,20～24 can significantly suppress the growth of Pseudomonas aeruginosa.Compound 10,11,14,15,17,22,23 can significantly suppress Bacillus proteus and colibacillary multiplication capacity, and these compounds likely develop into the novel medicine with anti-microbial effect and treatment bacterial infective diseases
Embodiment 26: the preparation method of institute's invention compound 16 tablets
Prescription:
Method for making: preparation 4% is through propyl methocel (E-30) solution, standby.Take 10g starch put 105 ℃ dry 5 hours standby.The institute's invention compound 16, the Microcrystalline Cellulose that take 20g starch and recipe quantity, mix, and pulverized 80 mesh sieves.With 4% through propyl methocel (E-30) solution by material softwood processed, with 20 mesh sieves, granulate, in 50 ℃～60 ℃ moisture content 3% left and right that are dried in particle.Cross the whole grain of 20 mesh sieves, add dry starch (105 ℃ are dried 5 hours), the Magnesium Stearate of recipe quantity, mixed eventually, survey intermediate content, stator weight; Compressing tablet.
Embodiment 27: the preparation method of institute's invention compound 16 injection liquids
Prescription:
Method for making: take institute's invention compound 16 and the propylene glycol of recipe quantity, inject water 500ml, stirring and dissolving; In above-mentioned solution, add 0.1% gac, stir, places 15 minutes, 5 microns of de-charcoals of titanium rod, then through smart filter of millipore filtration of 0.45 micron of filter cartridge and 0.22 micron; Embedding in 10ml ampoule, 100 ℃ of flowing steam sterilizings 45 minutes, obtain the injection liquid of invention compound 16.
Claims (5)
1. a class SULPHURYL CHLORIDE ethene azole compounds and at the acceptable salt of pharmaceutical field, is characterized in that the general molecular formula of compound represents with (I～VII):
Im in formula
1and Im
2being respectively azole group, is 1,2,4-triazol-1-yl, imidazoles, 2-Methylimidazole, 2-5-nitro imidazole, 4-nitroimidazole;
R is hydroxyethyl;
X is chlorine atom, bromine atoms;
Ar is benzene;
Described salt is hydrochloride, nitrate, acetate.
2. the preparation method of the SULPHURYL CHLORIDE ethene azole compounds described in claim 1, is characterized in that: take benzene as starting raw material is through the synthetic SULPHURYL CHLORIDE ethene azole compounds of series reaction and acceptable salt pharmaceutically thereof, comprise the steps:
Step 1: the preparation of the 2-chlorine aryl methyl ketone intermediate of structure shown in general formula (XI)
Under Catalyzed by Anhydrous Aluminium Chloride condition, benzene and chloroacetyl chloride pass through Friedel-Crafts acylation reaction in organic solvent, temperature control-50～100 ℃, react 4～12 hours, after reaction finishes, adopt column chromatography, recrystallization, dry conventional separation and purification means, i.e. 2-chlorine aryl methyl ketone intermediate shown in preparation (XI);
Organic solvent refers to a kind of in following organism: chloroform, methylene dichloride, dithiocarbonic anhydride;
Benzene: the mol ratio of aluminum chloride is 1.0: 1.0～6.0;
Step 2: the preparation of the 2-azoles aryl methyl ketone intermediate of structure shown in general formula (XII)
In organic solvent, drop into azole compounds and alkali normal-temperature reaction 0.5～2.5 hour, drop into again the 2-chlorine aryl methyl ketone that step 1 makes, 0～100 ℃ of temperature control, react 2～10 hours, thin-layer chromatography tracks to reaction to be finished, and adopts concentrated, column chromatography, recrystallization, dry conventional separation and purification means, prepares the 2-azoles aryl methyl ketone intermediate shown in general formula (XII);
Azole compounds refers to a kind of in following compound: 1,2,4-triazole, imidazoles, 2-Methylimidazole, 2-5-nitro imidazole, 4-nitroimidazole;
Described solvent refers to a kind of in following: acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide, N, N-dimethyl formamide;
Described alkali refers to a kind of in following: salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride;
Step 3: the preparation of the chlorine SULPHURYL CHLORIDE ethene azole compounds of structure shown in general formula (I)
In carbon tetrachloride solvent, add chlorsulfonic acid, drop into 2-azoles aryl methyl ketone (XII), 25～40 ℃ of first temperature controls, react 1～8 hour in batches, be warmed up to again 60～100 ℃, react 12～72 hours, thin-layer chromatography tracks to reaction to be finished, and adopts concentrated, extraction, column chromatography, recrystallization, dry conventional separation and purification means, prepare general formula (I) chlorine SULPHURYL CHLORIDE ethene azole derivative
2-azoles aryl methyl ketone: the mol ratio of chlorsulfonic acid is 1.0: 4.0～8.0,
Step 4: the preparation of the sulphonamide vinylchlorid azole compounds of structure shown in general formula (II～VII)
Control temperature of reaction is room temperature to 100 ℃, drop into strong aqua, ethylol amine, azole compounds, diethanolamine reacts 2～72 hours with chlorine SULPHURYL CHLORIDE vinyl azole (I) respectively, thin-layer chromatography tracks to reaction to be finished, adopt concentrated, extraction, column chromatography, recrystallization, dry conventional separation and purification means, preparing corresponding general formula is (II～V) sulphonamide vinylchlorid azole derivative, compound (V) carries out halogenation with halogenation sulfoxide or Phosphorates phosphorus Halides and makes sulphonamide vinylchlorid azoles (VI), compound (VI) reacts with azole compounds and makes sulphonamide vinylchlorid azoles (VII),
Azole compounds refers to a kind of in following compound: 1,2,4-triazole, imidazoles, 2-Methylimidazole, 2-5-nitro imidazole, 4-nitroimidazole;
Halogenation sulfoxide refers to sulfur oxychloride, thionyl bromide;
Phosphorates phosphorus Halides refers to phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide;
Step 5: the preparation of the SULPHURYL CHLORIDE ethene azole compounds hydrochloride of structure shown in general formula (I～VII)
I?～?VII·nHCl
The SULPHURYL CHLORIDE ethene azole compounds (I～VII) that above-mentioned steps is synthetic is dissolved in respectively in ether or tetrahydrofuran (THF), slowly drip aqueous hydrochloric acid, till generating without white precipitate, then with dry after ether or tetrahydrofuran (THF) washing solid, prepare general formula (I～VII) SULPHURYL CHLORIDE ethene azole derivative hydrochloride; N=0.5～5;
Described solvent refers to a kind of in following solvents: chloroform, acetone, methyl alcohol, acetonitrile,
Step 6: the preparation of the azole compounds of structure SULPHURYL CHLORIDE ethene shown in general formula (I～VII) nitrate
I?～VII·n?HNO3
By above-mentioned steps five methods, with the aqueous nitric acid Instead of Hydrochloric aqueous solution, prepare general formula (I～VII) SULPHURYL CHLORIDE ethene azole derivative nitrate; N is 0.5～5;
Step 7: the preparation of the SULPHURYL CHLORIDE ethene azole compounds acetate of structure shown in general formula (I～VII)
I?～VII·n?HOAc
By above-mentioned steps five methods, with the aqueous acetic acid Instead of Hydrochloric aqueous solution, prepare the acetate of general formula (I～VII) SULPHURYL CHLORIDE ethene azole derivative, n is 0.5～5.
3. the SULPHURYL CHLORIDE ethene azole compounds (I～VII) described in claim 1 or the application of their pharmacologically acceptable salt in preparing antifungal drug.
4. the pharmaceutical composition that prepared by the SULPHURYL CHLORIDE ethene azole compounds described in claim 1 or its pharmacy acceptable salt, the SULPHURYL CHLORIDE ethene azole compounds that this pharmaceutical composition contains physiology significant quantity or its pharmacy acceptable salt, their consumption weight ratios in composition are 0.1%～90%; Composition exists with following pharmaceutically acceptable dosage form: tablet, capsule, oral liquid, infusion solutions, little pin, freeze-dried powder, ointment, liniment and suppository, comprise the now conventional preparation of generally acknowledged pharmaceutics general knowledge of employing and various slowly-releasings, controlled release form or nanometer formulation.
5. the application of the compound described in claim 1 on the medicine of preparation treatment infectious diseases.
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| 磺酰类苯并咪唑化合物的合成及抗微生物活性研究;宋春泽等;《第五届全国化学生物学学术会议论文摘要集》;20070813;第208页 * |
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