CN103193770A - Substituted benzothiazole compound as well as preparation method and application thereof - Google Patents
Substituted benzothiazole compound as well as preparation method and application thereof Download PDFInfo
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- CN103193770A CN103193770A CN2013100907103A CN201310090710A CN103193770A CN 103193770 A CN103193770 A CN 103193770A CN 2013100907103 A CN2013100907103 A CN 2013100907103A CN 201310090710 A CN201310090710 A CN 201310090710A CN 103193770 A CN103193770 A CN 103193770A
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- JLUFNMPOZYZVFV-PDHZICCSSA-N CC(C)(C)OC(NC(CCC1)CC1C(N/C(/C)=C/C=C1/N=C(NC(C2CCCC2)=O)SC1=C)=O)=O Chemical compound CC(C)(C)OC(NC(CCC1)CC1C(N/C(/C)=C/C=C1/N=C(NC(C2CCCC2)=O)SC1=C)=O)=O JLUFNMPOZYZVFV-PDHZICCSSA-N 0.000 description 1
- 0 CNC(SC(*)=CC(NC(C(CCC1)CC1NC*)=N)=C)=C Chemical compound CNC(SC(*)=CC(NC(C(CCC1)CC1NC*)=N)=C)=C 0.000 description 1
- CYPMXPLUEFCSSF-UHFFFAOYSA-N NC(CCC1)CC1C(Nc1ccc2nc(NC(C3CCCC3)=O)[s]c2c1)=O Chemical compound NC(CCC1)CC1C(Nc1ccc2nc(NC(C3CCCC3)=O)[s]c2c1)=O CYPMXPLUEFCSSF-UHFFFAOYSA-N 0.000 description 1
- GPNAVOJCQIEKQF-UHFFFAOYSA-N Nc([s]c1c2)nc1ccc2[N+]([O-])=O Chemical compound Nc([s]c1c2)nc1ccc2[N+]([O-])=O GPNAVOJCQIEKQF-UHFFFAOYSA-N 0.000 description 1
- DNGLWSGKMNKZDF-UHFFFAOYSA-N Nc1ccc2nc(NC(C3CCCC3)=O)[s]c2c1 Chemical compound Nc1ccc2nc(NC(C3CCCC3)=O)[s]c2c1 DNGLWSGKMNKZDF-UHFFFAOYSA-N 0.000 description 1
- HLFXQKXAUWWWNI-UHFFFAOYSA-N [O-][N+](c(cc1)cc2c1nc(NC(C1CCCC1)=O)[s]2)=O Chemical compound [O-][N+](c(cc1)cc2c1nc(NC(C1CCCC1)=O)[s]2)=O HLFXQKXAUWWWNI-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the technical field of medicaments and provides a substituted benzothiazole compound and a pharmaceutically acceptable salt thereof. The structural formula of the substituted benzothiazole compound is as shown in formula I, wherein in formula I, R is a substituted naphthalene ring or a substituted aromatic heterocycle. The invention also provides the applications of the substituted benzothiazole compound and the pharmaceutically acceptable salt thereof to the preparation of medicaments for resisting fungi, tumors, viruses, high blood pressure and thrombus and topoisomerase inhibitors.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of new replacement benzothiazole compound---suitable-N-{2-[(pentamethylene base carbonyl) amino] benzothiazole-6-yl-3-[(replaces) amino] cyclohexyl Carbox amide and its esters and preparation method, and as the application of antifungal drug.
Background technology
In recent years, along with the widespread use for the treatment of meanss such as antibiotic, tumor chemoradiotherapy and organ transplantation, and sharply the rising of acquired immune deficiency syndrome (AIDS) morbidity, the ill colony of reading deep fungal infections such as bacterium, aspergillus fumigatus and cryptococcus neoformans in vain increases considerably.Therefore, deep fungal infection has now become the major cause that major diseases such as acquired immune deficiency syndrome (AIDS), tumour cause death.Yet desirable clinically anti-deep fungal medicine still very lacks, the following various problems of existing medicine ubiquity.Azole drug (for example fluconazole) is a kind of antifungal drug of being used widely that acts on lanosterol 14 α-demethylase (CYP51), but such medicine is owing to have restraining effect to human body cell cytochrome p 450 enzyme system, can cause tangible drug-drug interactions, and antimicrobial spectrum is limited, and is invalid to Resistant strain.Polyene antibiotics (for example amphotericin B) is the first-selected medicine of a class that acts on fungal cell's membrane lipid, but it is subjected to considerable restraint because toxic side effect makes application greatly.Lipopeptid class medicine (for example Caspofungin) is a class antifungal drug that acts on fungal cell wall β-1,3 glucan synthase, but its complex structure is expensive, and bioavailability is lower, and hemolytic toxicity is arranged.Therefore, except carry out the improvement of composition optimizes and preparation at above-mentioned main medicine, seek antifungal drug research New Policy and novel target spot and seem very urgent and necessary, to obtain the small-molecule drug with brand-new mechanism of action and brand new type.
N-mnyristoyl based transferase (NMT) is white growth and the necessary enzymes of surviving such as bacterium and Cryptococcus neoformans read, and being verified in recent years is the new target drone of antifungal drug effect.The part fungi NMT inhibitor of report demonstrates anti-mycotic activity preferably, is expected to develop into the novel anti fungi-medicine with brand-new mechanism of action.FTR1335 be at present report press down enzymic activity benzothiazole class NMT inhibitor preferably, structural formula is as follows.Yet, the FTR1335 antimicrobial spectrum is narrower, dialogue is read bacterium vitro inhibition effect (K.Yamazaki, Y.Kaneko, K.Suwa, S.Ebara, K.Nakazawa, K.Yasuno, Synthesis of potent and selective inhibitors of Candida albicans N-myristoyltransferase based on the benzothiazole structure, Bioorg Med Chem, 13 (2005) 2509-2522.), and still do not have bibliographical information at present and come the antimicrobial spectrum of spread F TR1335 and improve its anti-mycotic activity by structure of modification.
Summary of the invention
The object of the present invention is to provide a kind of replacement benzothiazole compound and its esters.Another object of the present invention is to provide the preparation method of described replacement benzothiazole compound and its esters.The 3rd purpose of the present invention is to provide described replacement benzothiazole compound and the application of its esters in preparation antifungal drug, topoisomerase enzyme inhibitor, antitumor drug, antiviral, antihypertensive drug or antithrombotic reagent.
Technical scheme of the present invention is: for the antimicrobial spectrum of spread F TR13335 with improve its anti-mycotic activity; the naphthalene nucleus that mainly concentrates on FTR13335 partly carries out structure of modification; obtain a class suitable-N-{2-[(pentamethylene base carbonyl) amino] benzothiazole-6-yl-3-[(replaces) amino] the cyclohexyl Carbox amide, can be used as the inhibitor of fungi N-mnyristoyl based transferase (NMT).
A first aspect of the present invention, provide a kind of replacement benzothiazole compound, i.e. suitable-N-{2-[(pentamethylene base carbonyl) amino] benzothiazole-6-yl }-3-[(replaces) amino] the cyclohexyl Carbox amide, and pharmacy acceptable salt, its general structure is shown in formula I:
In the formula I, R represents to replace naphthalene nucleus or substituted aroma heterocycle,
A) the various substituting group positions that replace in naphthalene nucleus or the substituted aroma heterocycle are to be positioned at other any position of removing link position, it can be single replacement, also can be polysubstituted, substituting group refers to: hydrogen, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group, nitro, cyano group, trifluoromethyl or halogen, and described halogen comprises F, Cl, Br, I;
B) the substituted aroma heterocycle is represented independently: quinoline, tetrahydroquinoline, isoquinoline 99.9, tetrahydroisoquinoline, pyridine, thiophene, thiazole, pyrazoles, furans, oxazole, isoxazole, pyridazine or pyrazine etc.
Formula I compound, R group preferably from:
(1) the R group is 1-bromo-2-naphthalene;
(2) the R group is 6-methoxyl group-2-naphthalene;
(3) the R group is the 1-naphthalene;
(4) the R group is 2-methoxyl group-1-naphthalene;
(5) the R group is 4-methoxyl group-1-naphthalene;
(6) the R group is 2-oxyethyl group-1-naphthalene;
(7) the R group is the 2-quinoline;
(8) the R group is the 3-quinoline;
(9) the R group is 2-chloro-3-quinoline;
(10) the R group is 1,2,3,4-tetrahydroquinoline-3-base;
(11) the R group is the 4-quinoline;
(12) the R group is the 6-quinoline;
(13) the R group is 1,2,3,4-tetrahydroquinoline-6-base;
(14) the R group is the 8-quinoline;
The part preferred compound is:
Suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(3-quinoline methyl) amino] cyclohexyl methane amide (8),
Suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(6-quinoline methyl) amino] cyclohexyl methane amide (12), or
Suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(1,2,3,4-tetrahydroquinoline-6-yl) methylamino-] cyclohexyl methane amide (13).
Above-mentioned benzothiazole compound can be according to the form of ordinary method preparation position pharmaceutical salts.Comprise its organic acid salt and inorganic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid etc., and organic acid includes, but is not limited to acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
A second aspect of the present invention provides a kind of preparation method who replaces benzothiazole compound and pharmacy acceptable salt thereof.
The building-up reactions flow process of The compounds of this invention is as follows:
Concrete steps are:
(A) preparation N-(6-nitrobenzene thiazole-2-yl) ring penta methane amide (II)
2-amino-6-nitrobenzene thiazole (I) and cyclopentane-carboxylic acid are in methylene dichloride, through 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 4-Dimethylamino pyridine condensation, stirring at room reaction 16 hours generates N-(6-nitrobenzene thiazole-2-yl) ring penta methane amide (II);
(B) preparation N-(6-aminobenzothiazole-2-yl) ring penta methane amide (III)
Compound N-(6-nitrobenzene thiazole-2-yl) ring penta methane amide (II) and tin protochloride are in ethanol, and heating reflux reaction 2 hours obtains N-(6-aminobenzothiazole-2-yl) ring penta methane amide (III);
(C) preparation tertiary butyl-N-suitable-the 3-[(2-[(cyclopentylcarbonyl) amino] benzothiazole-6-amino) carbonyl] cyclohexyl carbamate (IV)
N-(6-aminobenzothiazole-2-yl) ring penta methane amide (III) and suitable-3-(uncle's fourth oxygen carboxylic amino) hexahydrobenzoic acid are in methylene dichloride, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and I-hydroxybenzotriazole, stirring at room reaction 18 hours, obtain the tertiary butyl-N-suitable-the 3-[(2-[(cyclopentylcarbonyl) amino] benzothiazole-6-amino) carbonyl] cyclohexyl carbamate (IV);
(D) suitable-3-amino-N-[2-(cyclopentylcarbonyl) amino of preparation] benzothiazole-6-base-cyclohexyl methane amide (V)
The tertiary butyl-N-is suitable-the 3-[(2-[(cyclopentylcarbonyl) and amino] benzothiazole-6-amino) carbonyl] in cyclohexyl carbamate (IV) and the methylene dichloride, add trifluoroacetic acid, stirring at room reaction 1 hour obtains suitable-3-amino-N-[2-(cyclopentylcarbonyl) amino] benzothiazole-6-base-cyclohexyl methane amide (V);
(E) the preparation target compound suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl-3-[(replaces) amino] cyclohexyl methane amide (VI)
Compound is suitable-3-amino-N-[2-(cyclopentylcarbonyl) amino] benzothiazole-6-base-cyclohexyl methane amide (V) and replace naphthaldehyde or substd quinolines formaldehyde in methyl alcohol, mixed solution stirring at room reaction 2 hours; Add sodium cyanoborohydride and 3-5 and drip acetic acid, continued stirring reaction 10 hours, suitable-N-{2-[(cyclopentylcarbonyl that generation prepares target compound) amino] benzothiazole-6-yl }-the 3-[(replacement) amino] cyclohexyl methane amide (VI).
A third aspect of the present invention provides the application in preparation antifungal drug, topoisomerase enzyme inhibitor, antitumor drug, antiviral, antihypertensive drug or antithrombotic reagent of described replacement benzothiazole compound and pharmacy acceptable salt thereof.
Compound of the present invention is through external bacteriostatic experiment, the proof majority of compounds has anti-mycotic activity and wider antimicrobial spectrum preferably, especially the compound broad spectrum is greatly improved, and illustrates that this compounds can be used for preparing the medicine for the treatment of anti-fungal infection.
Compound of the present invention has been opened up new approach for furtheing investigate and develop new texture type antifungal drug.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples are only for explanation the present invention but not for limiting scope of the present invention.
The preparation of embodiment 1:N-(6-nitrobenzene thiazole-2-yl) ring penta methane amide (II)
Get 2-amino-6-nitrobenzene thiazole (4.00g, 0.02mol, 1equiv) and cyclopentane-carboxylic acid (2.28g, 0.02mol 1equiv) are dissolved in the 50mL methylene dichloride, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (5.75g, 0.03mol, 1.5equiv) with 4-Dimethylamino pyridine (0.40g, 2mmol, 0.1equiv), stirring at room reaction 16h.After reaction finishes, reaction solution with 5% salt pickling (3 * 30mL), 5% sodium bicarbonate wash (3 * 30mL), saturated nacl aqueous solution wash (3 * 30mL), use anhydrous Na
2SO
4Dry. filter, the evaporated under reduced pressure solvent, (developping agent: hexane:EtOAc=10:1 v/v), obtains faint yellow solid 5.66g, yield 97.3% to resistates through purification by silica gel column chromatography.
1H-NMR(300MHz,CDCl
3):9.15(brs,1H),8.76(d,1H,J=2.4Hz),8.34(dd,1H,J=9.0,2.4Hz),7.82(d,1H,J=9.0Hz),2.80-2.96(m,1H),1.90-2.11(m,2H),1.54-1.90(m,6H).ESI-MS(m/z):290[M-1].
The preparation of embodiment 2:N-(6-aminobenzothiazole-2-yl) ring penta methane amide (III)
Get compound ii (1.00g, 3.4mmol, 1equiv) and tin protochloride (2.30g, 10.2mmol 3equiv) are dissolved in the 50mL ethanol heating reflux reaction 2h.After reaction finished, the evaporate to dryness reaction solution added 5% sodium hydroxide solution 50mL and 100mL ethyl acetate and fully mixes vibration, and (2 * 100mL) extract water layer with ethyl acetate.Organic phase merges, with saturated nacl aqueous solution wash (3 * 30mL), anhydrous Na
2SO
4Dry.Filter, the evaporated under reduced pressure solvent, resistates obtains white solid 0.45g, yield 50.6% with ethyl acetate 20mL recrystallization.
1H-NMR(300MHz,DMSO-d
6):11.97(s,1H),7.37(d,1H,J=8.5Hz),6.97(d,1H,J=1.5),6.68(dd,1H,J=8.5,1.5Hz),5.14(s,2H),2.83-2.97(m,1H),1.78-1.95(m,2H),1.45-1.95(m,6H).ESI-MS(m/z):262[M+1].
Embodiment 3: the tertiary butyl-N-is suitable-and the 3-[(2-[(cyclopentylcarbonyl) amino] benzothiazole-6-amino) carbonyl] preparation of cyclohexyl carbamate (IV)
Get III (1.00g, 3.83mmol, 1equiv) and suitable-3-(uncle's fourth oxygen carboxylic amino) (0.93g, 3.83mmol 1equiv) are dissolved in the 25mL methylene dichloride hexahydrobenzoic acid, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.10g, 5.75mmol, 1.5equiv) and I-hydroxybenzotriazole (0.78g, 5.75mmol, 0.1equiv), stirring at room reaction 18h.Reaction filters out white depositions after finishing, and uses the 20mL washed with dichloromethane, obtains faint yellow solid 0.91g, yield 54.2%.1H-NMR(300MHz,DMSO-d6):12.45(s,1H),10.21(s,1H),8.50(d,1H,J=1.8Hz),7.83(d,1H,J=8.7Hz),7.68(dd,1H,J=8.7,1.8Hz),7.04(s,1H),3.07-3.22(m,1H),2.72-2.81(m,1H),2.55-2.66(m,1H),1.67-2.17(m,12H),1.57(s,9H),1.20-1.53(m,4H).ESI-MS(m/z):485[M-1].
Embodiment 4: suitable-3-amino-N-[2-(cyclopentylcarbonyl) amino] preparation of benzothiazole-6-base-cyclohexyl methane amide (V)
(0.35g, 0.72mmol 1equiv) are dissolved in the 3mL methylene dichloride, add trifluoroacetic acid 3mL, and stirring at room is reacted 1h, and the evaporated under reduced pressure solvent adds 5% aqueous sodium carbonate 30mL and ethyl acetate 50mL, fully mix vibration to get IV.(2 * 20mL) extract water layer with ethyl acetate.Merge organic phase, with saturated nacl aqueous solution wash (3 * 30mL), anhydrous Na
2SO
4Dry.Filter, the evaporated under reduced pressure solvent obtains white solid 0.27g, yield 92.59%.
1H-NMR(300MHz,DMSO-d
6):10.08(s,1H),8.41(s,1H),7.73(d,1H,J=8.7Hz),7.62(d,1H,J=8.7Hz),4.58-5.52(brs,2H),2.99-3.16(m,1H),2.43-2.69(m,2H),1.60-2.16(m,12H),0.99-1.60(m,4H).ESI-MS(m/z):385[M-1].
Embodiment 5: suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(1-bromo-2-menaphthyl) amino] preparation of cyclohexyl methane amide (compound 1 in the table)
(1equiv) (0.091g, 0.39mmol 1equiv) are dissolved among the methyl alcohol 10mL, mixed solution stirring at room reaction 2h with 1-bromo-2-naphthaldehyde for 0.15g, 0.39mmol along V to get compound.(0.025g, 0.39mmol 1equiv) drip acetic acid with 3-5, continue stirring reaction 10h to add sodium cyanoborohydride to reaction solution.After reaction finishes, the direct silica gel mixed sample of reaction solution, preparative chromatography purifying (developping agent: CH fast
2Cl
2-MeOH=10:1 v/v), obtains faint yellow solid 0.081g, yield 33.9%.
Embodiment 6: suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(3-quinoline methyl) amino] preparation of cyclohexyl methane amide (compound 8 in the table)
(1equiv) (0.061g, 0.39mmol 1equiv) are dissolved among the methyl alcohol 10mL, mixed solution stirring at room reaction 2h with the 3-quinoline aldehyde for 0.15g, 0.39mmol along V to get compound.(0.025g, 0.39mmol 1equiv) drip acetic acid with 3-5, continue stirring reaction 10h to add sodium cyanoborohydride to reaction solution.After reaction finishes, the direct silica gel mixed sample of reaction solution, preparative chromatography purifying (developping agent: CH fast
2Cl
2-MeOH=10:1 v/v), obtains faint yellow solid 0.015g, yield 7.14%.
13C-NMR(75MHz,CD
3OD):177.51,175.78,159.40,152.23,148.37,146.62,138.70,136.00,133.85,131.65,129.97,129.28,129.28,129.07,128.68,121.64,120.42,113.54,57.33,47.74,46.10,45.30,34.05,31.34,31.34,31.21,30.07,27.05,27.05,24.67.ESI-MS(m/z):528[M+1].HR?ESI-MS[M+1]:528.2443.
Embodiment 7: suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(6-quinoline methyl) amino] preparation of cyclohexyl methane amide (compound 12 in the table)
(1equiv) (0.061g, 0.39mmol 1equiv) are dissolved among the methyl alcohol 10mL, mixed solution stirring at room reaction 2h with the 6-quinoline aldehyde for 0.15g, 0.39mmol along V to get compound.(0.025g, 0.39mmol 1equiv) drip acetic acid with 3-5, continue stirring reaction 10h to add sodium cyanoborohydride to reaction solution.After reaction finishes, the direct silica gel mixed sample of reaction solution, preparative chromatography purifying (developping agent: CH fast
2Cl
2-MeOH=10:1 v/v), obtains faint yellow solid 0.022g, yield 10.59%.
13C-NMR(75MHz,CD
3OD):177.49,176.36,159.42,151.17,148.18,146.52,138.86,138.27,136.17,133.82,131.99,129.81,129.32,128.53,122.78,121.62,120.46,113.53,56.57,50.58,46.10,45.82,35.85,31.34,31.34,30.73,30.20,27.05,27.05,25.14.ESI-MS(m/z):528[M+1].HR?ESI-MS[M+1]:528.2443.
Embodiment 8: suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(1,2,3,4-tetrahydroquinoline-6-yl) methylamino-] preparation of cyclohexyl methane amide (compound 13 in the table)
(1equiv) (0.061g, 0.39mmol 1equiv) are dissolved among the methyl alcohol 10mL, mixed solution stirring at room reaction 2h with the 6-quinoline aldehyde for 0.15g, 0.39mmol along V to get compound.(0.025g, 0.39mmol 1equiv) drip acetic acid with 3-5, continue stirring reaction 10h to add sodium cyanoborohydride to reaction solution.After reaction finishes, the direct silica gel mixed sample of reaction solution, preparative chromatography purifying (developping agent: CH fast
2Cl
2-MeOH=10:1 v/v), obtains faint yellow solid 0.014g, yield 8.11%.Compound 13 is the by products that obtain in preparation compound 12 processes.
Agents useful for same is commercially available analytical pure among the embodiment.
Other compounds are synthesis material with different replacement naphthalene nucleus or quinoline ring in the table 1, and are listed as table 1, repeat the step among the embodiment 5, just can synthesize required replacement benzothiazole compound.
The chemical structure of table 1 preferred compound and
1H-NMR and MS data
Embodiment 9: amino suitable-N-{2-[(pentamethylene base carbonyl that the present invention synthesizes)] benzothiazole-6-yl }-3-[(replaces) amino] antifungic action of cyclohexyl Carbox amide
(1) experimental technique: adopt conventional external bacteriostatic experiment method (to see for details: Antimicrob Agents Chemother1995,39 (5): 1169)
1. materials and methods
(1) experimental strain
This experiment has selected for use following 6 kinds of important human body cause illness's standard fungal bacterial strains as the screening object, and fungal bacterial strain is provided by Changhai hospital of The 2nd Army Medical College Mycology Lab (or available from Chinese Academy of Sciences institute of materia medica).
1) Candida albicans (Candida albicans, type strain SC5314);
2) Candida parapsilosis (Candida parapsilosis, clinical strain 0306392);
3) Candida glabrata bacterium (Candida glabrata, type strain 537)
4) Cryptococcus neoformans (Cryptococcus neoformans, type strain BLS108);
5) trichophyton (Trichophyton rubrum, clinical strain 0501124);
6) gypsum shape sporidiole bacteria (Microsporum gypseum, clinical strain Cmccfmza).
(2) test method
The bacteria suspension preparation: a. Cryptococcus neoformans and candidiasis were cultivated 16 hours for 35 ℃ through the YEPD liquid nutrient medium, and twice activation with the blood cell counting plate counting, adjusted concentration to 1 * 10 with the RPM1640 liquid nutrient medium
3～5 * 10
3Individual/mL.B. thread fungus (trichophyton) is cultivated (35 ℃) one week and (28 ℃) two weeks respectively through the SDA inclined-plane, and twice activation adds the RPM1640 liquid nutrient medium and blow and beat with suction pipe, spore is free in the RPM1640 liquid, through four layers of filtered through gauze, counting is adjusted concentration to 1 * 10
3～5 * 10
3Individual/mL.
Soup preparation: get testing compound of the present invention and be dissolved in methyl-sulphoxide, be made into the medicine storage liquid of 3.2mg/mL, be diluted to 320 μ g/mL with RPM1640 before the experiment.
Inoculation: No. 1 hole of 96 orifice plates adds RPM1640200 μ l and makes blank, the 3-12 hole respectively adds bacteria suspension 100 μ l, No. 2 the hole adds bacteria suspension 180 μ l and soup 20 μ l, the drug level in 2-11 hole is made 9 grade of 2 doubling dilution, and each hole drug level is respectively 32,16,8,4,2,1,0.5,0.25,0.125 μ g/mL.No. 12 the hole does not add soup, makes positive control.
Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, and being lower than 80% lowest drug concentration with optical density value than positive control hole is minimal inhibitory concentration value (MIC).
(2) experimental result
External bacteriostatic experiment the results are shown in Table 2.
The external antimycotic minimal inhibitory concentration value (MIC of table 2 part selected objective target compound
80, μ g/mL)
Above-mentioned experimental result shows, compare with positive control drug, major part has anti-mycotic activity and wider antimicrobial spectrum preferably in the compound of the present invention, and especially the compound broad spectrum is greatly improved, and illustrates that this compounds can be used for preparing the medicine for the treatment of anti-fungal infection.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in above-described embodiment and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1. one kind replaces benzothiazole compound and pharmacy acceptable salt thereof, and its general structure is shown in formula I:
In the formula I, R represents to replace naphthalene nucleus or substituted aroma heterocycle,
A) the various substituting group positions that replace in naphthalene nucleus or the substituted aroma heterocycle are to be positioned at other any position of removing link position, it can be single replacement, also can be polysubstituted, substituting group is: hydrogen, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group, nitro, cyano group, trifluoromethyl or halogen, described halogen is F, Cl, Br, or I;
B) the substituted aroma heterocycle is represented independently: quinoline, tetrahydroquinoline, isoquinoline 99.9, tetrahydroisoquinoline, pyridine, thiophene, thiazole, pyrazoles, furans, oxazole, isoxazole, pyridazine, or pyrazine.
2. a kind of replacement benzothiazole compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that, in the formula I, R is selected from following group:
1-bromo-2-naphthalene, 6-methoxyl group-2-naphthalene, 1-naphthalene, 2-methoxyl group-1-naphthalene, 4-methoxyl group-1-naphthalene, 2-oxyethyl group-1-naphthalene, 2-quinoline, 3-quinoline, 2-chloro-3-quinoline, 1,2,3,4-tetrahydroquinoline-3-base, 4-quinoline, 6-quinoline, 1,2,3,4-tetrahydroquinoline-6-base, or 8-quinoline.
3. a kind of replacement benzothiazole compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that described benzothiazole compound is:
Suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(3-quinoline methyl) amino] the cyclohexyl methane amide,
Suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(6-quinoline methyl) amino] the cyclohexyl methane amide, or
Suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl }-3-[(1,2,3,4-tetrahydroquinoline-6-yl) methylamino-] the cyclohexyl methane amide.
4. according to claim 1,2 or 3 described a kind of replacement benzothiazole compound and pharmacy acceptable salts thereof, it is characterized in that described pharmacy acceptable salt is organic acid salt or inorganic acid salt.
5. a kind of replacement benzothiazole compound according to claim 4 and pharmacy acceptable salt thereof is characterized in that described mineral acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, or nitric acid; Organic acid comprises acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, or oxalic acid.
6. the preparation method of a replacement benzothiazole compound as claimed in claim 1 and pharmacy acceptable salt thereof is characterized in that the reaction process of this method is as follows:
Concrete steps are:
(A) preparation N-(6-nitrobenzene thiazole-2-yl) ring penta methane amide (II)
2-amino-6-nitrobenzene thiazole (I) and cyclopentane-carboxylic acid are in methylene dichloride, through 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 4-Dimethylamino pyridine condensation, stirring at room reaction 16 hours generates N-(6-nitrobenzene thiazole-2-yl) ring penta methane amide (II);
(B) preparation N-(6-aminobenzothiazole-2-yl) ring penta methane amide (III)
Compound N-(6-nitrobenzene thiazole-2-yl) ring penta methane amide (II) and tin protochloride are in ethanol, and heating reflux reaction 2 hours obtains N-(6-aminobenzothiazole-2-yl) ring penta methane amide (III);
(C) preparation tertiary butyl-N-suitable-the 3-[(2-[(cyclopentylcarbonyl) amino] benzothiazole-6-amino) carbonyl] cyclohexyl carbamate (IV)
N-(6-aminobenzothiazole-2-yl) ring penta methane amide (III) and suitable-3-(uncle's fourth oxygen carboxylic amino) hexahydrobenzoic acid are in methylene dichloride, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and I-hydroxybenzotriazole, stirring at room reaction 18 hours, obtain the tertiary butyl-N-suitable-the 3-[(2-[(cyclopentylcarbonyl) amino] benzothiazole-6-amino) carbonyl] cyclohexyl carbamate (IV);
(D) suitable-3-amino-N-[2-(cyclopentylcarbonyl) amino of preparation] benzothiazole-6-base-cyclohexyl methane amide (V)
The tertiary butyl-N-is suitable-the 3-[(2-[(cyclopentylcarbonyl) and amino] benzothiazole-6-amino) carbonyl] in cyclohexyl carbamate (IV) and the methylene dichloride, add trifluoroacetic acid, stirring at room reaction 1 hour obtains suitable-3-amino-N-[2-(cyclopentylcarbonyl) amino] benzothiazole-6-base-cyclohexyl methane amide (V);
(E) the preparation target compound suitable-the N-{2-[(cyclopentylcarbonyl) amino] benzothiazole-6-yl-3-[(replaces) amino] cyclohexyl methane amide (VI)
Compound is suitable-3-amino-N-[2-(cyclopentylcarbonyl) amino] benzothiazole-6-base-cyclohexyl methane amide (V) and replace naphthaldehyde or substd quinolines formaldehyde in methyl alcohol, mixed solution stirring at room reaction 2 hours; Add sodium cyanoborohydride and 3-5 and drip acetic acid, continued stirring reaction 10 hours, suitable-N-{2-[(cyclopentylcarbonyl that generation prepares target compound) amino] benzothiazole-6-yl }-the 3-[(replacement) amino] cyclohexyl methane amide (VI).
7. a replacement benzothiazole compound as claimed in claim 1 and pharmacy acceptable salt thereof the application in preparation antifungal drug, topoisomerase enzyme inhibitor, antitumor drug, antiviral, antihypertensive drug or antithrombotic reagent.
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Cited By (3)
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| JP2017515901A (en) * | 2014-05-09 | 2017-06-15 | キネタ・インコーポレイテッドＫｉｎｅｔａ， Ｉｎｃ． | Antiviral compounds, pharmaceutical compositions and methods of use thereof |
| CN107158385A (en) * | 2016-03-14 | 2017-09-15 | 苏州大学 | Purposes of the RIP3 inhibitor in antiplatelet thrombus medicine is prepared |
| CN112812111A (en) * | 2020-03-03 | 2021-05-18 | 中国药科大学 | Benzothiazole compound and medical application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017515901A (en) * | 2014-05-09 | 2017-06-15 | キネタ・インコーポレイテッドＫｉｎｅｔａ， Ｉｎｃ． | Antiviral compounds, pharmaceutical compositions and methods of use thereof |
| CN107158385A (en) * | 2016-03-14 | 2017-09-15 | 苏州大学 | Purposes of the RIP3 inhibitor in antiplatelet thrombus medicine is prepared |
| CN107158385B (en) * | 2016-03-14 | 2020-07-14 | 苏州大学 | Application of RIP3 inhibitor in preparation of anti-platelet thrombosis drugs |
| CN112812111A (en) * | 2020-03-03 | 2021-05-18 | 中国药科大学 | Benzothiazole compound and medical application thereof |
| WO2021175234A1 (en) * | 2020-03-03 | 2021-09-10 | 中国药科大学 | Benzothiazole compound and medical use |
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