CN109851560A - Biphenyl diazole analog derivative and its preparation method and application - Google Patents

Biphenyl diazole analog derivative and its preparation method and application Download PDF

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CN109851560A
CN109851560A CN201910018160.1A CN201910018160A CN109851560A CN 109851560 A CN109851560 A CN 109851560A CN 201910018160 A CN201910018160 A CN 201910018160A CN 109851560 A CN109851560 A CN 109851560A
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base
imidazoles
propyl
xenyl
biphenyl
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CN109851560B (en
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谢建中
刘超
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Xintiandi Pharmaceutical Co ltd
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Henan Newland Pharmaceutical Co Ltd
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Abstract

The invention belongs to pharmaceutical chemistry to synthesize field more particularly to a kind of biphenyl diazole analog derivative and preparation method thereof, and the invention further relates to application of the diazole analog derivative in the drug of preparation treatment various diseases due to caused by fungi or bacterium infection.The biphenyl diazole analog derivative that the present invention limits is tested through antibacterial activity in vitro, show that such compound has stronger antimycotic and antibacterial activity, compared with existing antibacterials, have many advantages, such as structure novel, efficient, wide spectrum, therefore the biphenyl diazole analog derivative that the present invention limits has a good application prospect.

Description

Biphenyl diazole analog derivative and its preparation method and application
Technical field
The invention belongs to pharmaceutical synthesis field more particularly to a kind of biphenyl diazole analog derivative and preparation method thereof, this hairs The bright application for further relating to diazole analog derivative in the drug of preparation treatment various diseases due to caused by fungi or bacterium infection.
Background technique
Fungal infection is a kind of common disease, can be divided into mycotic infection of superficial part and deep fungal according to the difference of infection site Infection.Wherein, the disease incidence of mycotic infection of superficial part is higher, can cause the infection of skin, nail, mucous membrane etc., but generally will not Lead to serious consequence；Mycotic infection of superficial part main pathogenic bacteria is trichophyta, Epidermophyton etc..Deep fungal infection is also known as System property fungal infection, in recent years with immunosuppressor, a large amount of uses, the chemicotherapy of cancer patient and the AIDS of broad-spectrum antibiotic Patient's is increasing, seriously compromises the normal immunological function of human body, so that the disease incidence of deep fungal infection is increasingly It is high；Candida albicans, cryptococcus and aspergillus fumigatus are the three big main pathogenic bacterias for leading to deep fungal infection；Furthermore, it has been reported that in conjunction with bacterium, Sickle-like bacteria and hyphomycete also can result in deep fungal infection.Clinically, the drug for treating mycotic infection of superficial part is relatively more, and Deep fungal infection drug is treated than relatively limited, only amphotericin B and azole (Fluconazole, Itraconazole etc.) antibacterials. Moreover, because fungal cell and human cell belong to eukaryocyte, the similitude of the two is higher, so that antifungal drug shortage pair The selectivity of human body cell leads to stronger toxic side effect, it is difficult to meet clinical Treatment need.Such as: although amphotericin B There is stronger antifungal activity, but can only be injected intravenously and renal toxicity is larger, seriously limits its clinical application；Ketoconazole is made Stopped in 2015 in China for first oral broad-spectrum antifungal drug due to stronger liver renal toxicity and gastrointestinal reaction Only production and sales use；Widely used Itraconazole is able to suppress Cytochrome P450 3A4, simultaneously with other drugs Serious interaction can be generated when medication；5-flurocytosine antimicrobial spectrum is relatively narrow, and is relatively also easy to produce drug resistance；Equally, spy compares naphthalene Fragrant antimicrobial spectrum is also relatively narrow, is only used for mycotic infection of superficial part.In addition, being widely used due to antifungal drug, leads to the resistance to of fungi Pharmacological property problem also becomes to be on the rise.Therefore, it needs to find safe and efficient, less toxic, wide spectrum antifungal drug to have become and grind The hot spot studied carefully.
Bacterium infection is that clinically another common disease, usual pathogenic bacteria invade growth and breeding in blood circulation, generates toxin With acute systemic infection caused by other metabolites, clinically with shiver with cold, high fever, fash, arthralgia and hepatosplenomegaly It is characterized, infectious shock and venereal disease stove partially can be migrated.Clinically some patientss are it may also occur that agitation, peripheral coldness and purple The thin speed of dark purple, arteries and veins, tachypnea, blood pressure decline etc..Especially old man, children, have chronic disease or immunologic hypofunction person, treatment not Complications are had in time, can be developed as septicemia or septicopyemia.Bacterium is the pathogen of many diseases, including lung knot The diseases such as core, stranguria syndrome, anthracnose, syphilis, the plague, sand holes are caused by bacterium.For example, several gram-positive species are made At human diseases, the most common organism includes staphylococcus, streptococcus, enterococcus spp, fusobacterium, Bacillus, rodlike Bacillus and listeria；Clinically the example of intractable drug-resistant bacteria includes methicillin-resistant staphylococcus aureus (MRSA), penicillin resistance pneumococcus (PRSP) and vancomycin-resistant enterococcus (VRE).Although the use of antibiotic makes one The many serious bacterial infection diseases of class are effectively controlled, but the increasing for also resulting in antibody-resistant bacterium is widely used in antibiotic Add, reduces the antimicrobial efficiency of existing antibiotic.But since bacterium has generated drug resistance, high toxicity to existing antibiotic The propagation of bacterial strain and no available more effective antibacterial agent, the treatment of bacterial infectious disease become more difficult and high It is expensive.It is now recognized that most promising therapeutic strategy should be not lethal pathogen cell and only weaken the pathogenic toxicity of pathogen, it should Strategy does not threaten the existence of pathogen itself without causing drug resistance problems.It is recent the study found that pathogen it is pathogenic It is to be regulated and controled by a kind of intervention school-based (QS) of Density dependence, intervention school-based is by mediating the expression of Disease-causing gene with reality Now its is pathogenic.When pathogenic strain density reaches a certain level, pathogenic bacteria itself synthesis discharges certain signaling molecule, Neng Gouqi The expression of dynamic related gene, regulates and controls a variety of biobehaviorals of pathogenic bacteria, and such as bioluminescence generates toxin, forms biomembrane, produces Raw antibiotic etc..
Although clinically having the effect that many antibacterials can have both anti-fungal infection, bacterial-infection resisting, There are problems that single antibacterial effect significantly limits to, such as azole drug has irreplaceable role, but such in clinic Drug exposes more and more deficiencies, such as narrow antimicrobial spectrum, drug resistance, toxic side effect, drug interaction single using dosage form Deng, develop novel wide spectrum, efficiently, low toxicity, the diversified antibacterials of administration mode be always the area research important class Topic.It urgently finds a kind of novel antibacterials, the common fungal infection of immunotherapy targeted autoantibody but also bacterium can be inhibited well Infection, and can not inhibit pathogenic bacteria grow under the premise of, weaken cause a disease mushroom toxin substance, for treat fungoid or Bacterial infection disease avoids the increase of antibody-resistant bacterium.
Summary of the invention
In view of the problems of the existing technology, the present invention provides a kind of biphenyl diazole analog derivative and preparation method thereof and answers With；The biphenyl diazole analog derivative is tested through antibacterial activity in vitro, is shown that such compound has stronger antibacterial activity, is being controlled Treating has biggish researching value in fungal infection or bacterial-infection resisting disease.
To achieve the goals above, the present invention provides biphenyl diazole analog derivative shown in general formula I is as follows.
X in the general formula is C or N, preferably C.
Y in the general formula is carbonyl or methylene.
R in the general formula1For hydrogen-based, halogen, amino, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynes Base, (C1-C6) alkoxy, (C1-C6) alkyl sulfenyl, or (the C being optionally substituted by halogen1-C6) alkyl or (C1-C6) alkoxy；It is preferred that hydrogen Base, halogen, (C1-C6) alkyl or (C1-C6) alkoxy.
The halogen is fluorine, chlorine, bromine or iodine generation；The alkyl is the alkyl of linear chain or branched chain.
R in the general formula2For hydrogen-based, halogen, amino, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynes Base, (C1-C6) alkoxy, (C1-C6) alkyl sulfenyl, or (the C being optionally substituted by halogen1-C6) alkyl or (C1-C6) alkoxy；It is preferred that hydrogen Base, halogen, (C1-C6) alkyl or (C1-C6) alkoxy.
The halogen is fluorine, chlorine, bromine or iodine generation；The alkyl is the alkyl of linear chain or branched chain.
The preferably following compound of general formula I derivative of the present invention, but these compounds are not meant to of the invention any Limitation:
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl]-(1,1 '-xenyl) -4- formamide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-fluoro- (1,1 '-xenyl) -4- formyl Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-chloro- (1,1 '-xenyl) -4- formyl Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-methyl-(1,1 '-xenyl) -4- first Amide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-fluoro- (1,1 '-xenyl) -4- formyl Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-methyl-(1,1 '-xenyl) -4- first Amide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-trifluoromethyl-(1,1 '-xenyl) - 4- formamide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-cyano-(1,1 '-xenyl) -4- first Amide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 ', 4 '-two fluoro- (1,1 '-xenyls) - 4- formamide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] fluoro- (1,1 '-xenyl) -4- formyl of -2- Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] chloro- (1,1 '-xenyl) -4- formyl of -3- Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 1 base of 1H-1,2,4- triazole) propyl- 2- yl]-(1,1 '-xenyl) -4- first Amide.
N- [(1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- amine.
N- [4 '-fluoro- (1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- Amine.
N- [4 '-chloro- (1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- Amine.
In order to realize that another object of the present invention, the preparation method of general formula I derivative of the invention are specific as follows.
The first situation: when Y is carbonyl:
The synthesis of step 1, intermediate biphenyl acid.
Using parabromobenzoic acid and various substituted phenyl boric acids as raw material, in Pd (PPh3)4Effect is lower to occur Suzuki coupling instead It should obtain various substituted diphenic acids.Its synthetic route is such as.
Reagent and condition: (a) Pd (PPh3)4,K2CO3,reflux,5h。
The synthesis of step 2, target compound.
It is starting material with histidinol 4, with intermediate biphenyl acid 3 through obtaining amide under condensation reagent EDCI and HOBt effect Intermediate 5, intermediate 5 occur substitution reaction with imidazoles under CDI effect and obtain target compound 6.Specific synthetic route such as institute Show.
Reagent and condition: (a) EDCI, HOBt, DIEA, r.t., 7h；(b)CDI,imidazole,CH3CN,reflux, 7h。
When X is N, synthetic route is as follows.
Be raw material with intermediate 5, first under thionyl chloride effect, chlorination occur and obtains intermediate 7, then with triazole Substitution reaction occurs and obtains triazole class compounds.
Reagent and condition: (a) SOCl2,DMF,r.t.,2h；(b)1H-1,2,4-triazole,Triethylamine, DMF,r.t.10h.
Second situation: when Y is-CH2When.
Using p-bromobenzaldehyde and various substituted phenyl boric acids as raw material, in Pd (PPh3)4Effect is lower to occur Suzuki coupling instead It should obtain various substituted biphenyl aldehyde.Its synthetic route is such as.
Reagent and condition: (a) Pd (PPh3)4,K2CO3,reflux,5h。
The synthesis of step 2, target compound.
It is starting material with histidinol 4, obtains intermediate 11 through reduction amination with intermediate biphenyl aldehyde 10, intermediate 11 exists CDI effect is lower and imidazoles occurs substitution reaction and obtains target compound 12.Specific synthetic route is as shown.
Reagent and condition: (a) Na2SO4,NaBH(OAc)3；(b)CDI,imidazole,CH3CN,reflux,7h。
Remarkable result of the invention.
Diazoles compound designed by the present inventor shows to have preferable anti-true by extracorporeal antifungal activity experiment Bacterium activity, therefore the present invention can be used for preparing the various antimycotic drugs for the treatment of, such as anti-candidiasis, Candida albicans, Trichophyton rubrum, red saccharomycete, neogenesis cryptococcus, Shen kirschner pityrosporion ovale, the mucor that grows thickly, gypsum sample trichophyta, head mold The drugs such as bacterium, aspergillus fumigatus.In addition, showing that there is stronger antibacterial activity, this change by ill vitro antibacterial activity research experiment Close the object standard bacterial infectious disease to be directed to staphylococcus, streptococcus as caused by gram-positive bacterium, enterococcus spp, Fusobacterium, Bacillus, corynebacterium and listeria；It can be clinically used for treatment bacterial infectious disease, such as papule, bone Marrow inflammation brain abscess, urinary tract infections, meningitis, osteomyelitis, bronchitis, rhinitis, tetanus, diarrhea, pseudomembranous colitis, poisoning Property Hirschsprung's disease；Systemic infection (such as bacteremia, septicemia)；Infection and Lung infection in abdomen (such as become with Cystic fiber Lung infection in the patient of property) etc. specifically infected as caused by gramnegative bacterium.
The compound that the present invention limits has preferable antimycotic and antibacterial activity, compared with existing antibacterials, Have many advantages, such as structure novel, efficient, wide spectrum, therefore this class compound has a good application prospect.
Specific embodiment
The present invention is described in detail With reference to embodiment.
Embodiment 1N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl]-(1,1 '-xenyl) -4- first Amide.
The preparation of step 1 1,1'- diphenic acid (intermediate 3).
Under protection of argon gas, by 4- bromobenzoic acid 2.75g (13.8mmol), phenyl boric acid 2g (16.4mmol), K2CO3 2.71g (27.3mmol), four triphenyl phosphorus palladium 0.2g are added in dioxane solvent/water (10:1) of 40mL, are warming up to 75 DEG C, TLC monitors fully reacting after 5h.Cooling reaction solution, filters, and adjusts pH value to 2-3, has a large amount of white solids to generate, filter To white solid 2.30g, yield 84.9%.MS[M+H]+(m/z): 199.2.
The preparation of step 2 intermediate 5.
By intermediate 3 (2g, 10.1mmol), EDCHCl 2.13g (11.1mmol) and HOBt 1.50g (11.1mmol) It is dissolved in 40mL DMF, after stirring 1h at room temperature, histidinol hydrochloride 1.82g (11.1mmol) and DIEA2.61g is added (26.2mmol) stirs 8h at room temperature, and TLC monitors fully reacting, and 30mL water, ethyl acetate extraction, saturated common salt washing is added Wash organic layer, Na2SO4It is dried overnight.Desiccant is filtered out, brown oil 2.88g, yield 88.8% are concentrated under reduced pressure to give.ESI- MS[M+H]+(m/z):322.4。
Step 3N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl]-(1,1 '-xenyl) -4- formyl The preparation of amine.
Intermediate 5 (1.00g, 3.11mmol), CDI 0.76g (4.67mmol) and imidazoles 0.42g (6.22mmol) is molten Solution reacts 5h in 30mL acetonitrile at 70 DEG C, and TLC monitors fully reacting.Pressurize concentration of reaction solution, dissolves the residue in acetic acid Ethyl ester, washing, saturated common salt water washing are washed, Na2SO4It is dried overnight.Desiccant is filtered out, rufous grease is concentrated under reduced pressure to give, Column chromatographs to obtain off-white powder 0.75g, yield 64.9%.
LC-MS m/z[M+H]+372.2.1H-NMR(400MHz,DMSO-d6) δ 13.23 (s, 1H), 9.01 (d, J= 7.9Hz, 1H), 8.70 (s, 1H), 7.92 (d, J=8.3Hz, 2H), 7.82 (d, J=8.3Hz, 2H), 7.76 (s, 1H), 7.70 (d, J=7.3Hz, 2H), 7.65 (s, 1H), 7.52 (t, J=7.5Hz, 2H), 7.42 (t, J=7.3Hz, 1H), 7.25 (s, 1H), 6.86 (s, 1H), 4.95 (m, J=18.7Hz, 1H), 4.77-4.37 (m, 2H), 2.94-2.64 (m, 2H)
According to the method for embodiment 1, using the diphenic acid replaced respectively is raw material, is waited through coupling, condensation, substitution reaction Embodiment 2-11 is prepared in journey.
2 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-fluoro- (1,1 '-biphenyl Base) -4- formamide
LC-MS m/z[M+H]+390.2.1H-NMR(600MHz,DMSO-d6) δ 13.24 (s, 1H), 9.04 (d, J= 8.0Hz, 1H), 8.76 (s, 1H), 7.90 (d, J=8.4Hz, 2H), 7.80 (s, 1H), 7.68-7.65 (m, 2H), 7.63 (s, 1H), 7.60 (td, J=7.9,1.5Hz, 1H), 7.51-7.43 (m, 1H), 7.36-7.33 (m, 2H), 7.23 (s, 1H), 6.87 (s, 1H), 4.88 (ddd, J=9.9,8.1,4.7Hz, 1H), 4.57 (dd, J=14.1,4.7Hz, 1H), 4.42 (dd, J= 14.1,10.0Hz,1H),2.96-2.63(m,2H).
3 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-chloro- (1,1 '-biphenyl Base) -4- formamide
LC-MS m/z[M+H]+406.2.1H-NMR(400MHz,DMSO-d6) δ 13.15 (s, 1H), 9.01 (d, J= 7.9Hz, 1H), 8.74 (s, 1H), 7.85 (d, J=8.3Hz, 2H), 7.76 (s, 1H), 7.64 (s, 1H), 7.62-7.58 (m, 1H), 7.55 (d, J=8.4Hz, 2H), 7.49-7.41 (m, 3H), 7.23 (s, 1H), 6.86 (s, 1H), 5.02-4.90 (m, 1H), 4.79-4.74 (m, 1H), 4.41 (dd, J=14.0,9.9Hz, 1H), 2.95-2.64 (m, 2H)
4 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-methyl-(1,1 '-biphenyl Base) -4- formamide
LC-MS m/z[M+H]+386.1.1H-NMR(400MHz,DMSO-d6) δ 13.13 (s, 1H), 8.99 (d, J= 7.9Hz, 1H), 8.70 (s, 1H), 7.81 (d, J=8.4Hz, 2H), 7.74 (s, 1H), 7.72 (d, J=1.0Hz, 1H), 7.64 (s, 1H), 7.43 (d, J=8.4Hz, 2H), 7.34-7.25 (m, 3H), 7.23 (s, 1H), 6.87 (s, 1H), 4.99-4.93 (m, 1H), 4.82-4.73 (m, 1H), 4.39 (dd, J=14.1,9.8Hz, 1H), 2.94-2.64 (m, 2H), 2.24 (s, 3H),
5 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-fluoro- (1,1 '-biphenyl Base) -4- formamide
LC-MS m/z[M+H]+390.2.1H-NMR(400MHz,DMSO-d6)δ13.15(s,1H),9.02(s,1H), 8.76 (s, 1H), 7.91 (d, J=8.4Hz, 2H), 7.76 (s, 1H), 7.69-7.68 (m, 2H), 7.66 (d, J=7.7Hz, 1H),7.57(s,1H),7.50-7.35(m,3H),7.13(s,1H),6.86(s,1H),4.99–4.95(m,1H),4.55– 4.37(m,2H),2.94-2.64(m,2H).
6 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-methyl-(1,1 '-biphenyl Base) -4- formamide
LC-MS m/z[M+H]+386.2.1H-NMR(400MHz,DMSO-d6) δ (ppm): 13.05 (s, 1H), 8.96 (d, J =7.9Hz, 1H), 8.76 (s, 1H), 7.98 (d, J=8.4Hz, 2H), 7.89 (d, J=8.4Hz, 2H), 7.81 (s, 1H), 7.76(m,2H),7.67-7.63(m,3H),7.22(s,1H),6.86(s,1H),4.99–4.94(m,1H),4.54–4.37(m, 2H),2.94-2.64(m,2H),2.52(s,3H),.
7 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-trifluoromethyls-(1,1 ' - Xenyl) -4- formamide
LC-MS m/z[M+H]+340.2.1H-NMR(400MHz,DMSO-d6) δ 13.23 (s, 1H), 9.03 (d, J= 7.9Hz,1H),8.75(s,1H),8.00–7.82(m,8H),7.76(s,1H),7.64(s,1H),7.22(s,1H),6.85(s, 1H), 4.99-4.93 (m, 1H), 4.52 (dd, J=14.0,5.0Hz, 1H), 4.40 (dd, J=14.0,9.8Hz, 1H), 2.94- 2.64(m,2H).
8 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-cyano-(1,1 '-biphenyl Base) -4- formamide
LC-MS m/z[M+H]+397.2.1H-NMR(400MHz,DMSO-d6) δ 13.23 (s, 1H), 9.02 (d, J= 7.9Hz, 1H), 8.73 (s, 1H), 8.22 (s, 1H), 8.08 (d, J=8.4Hz, 1H), 7.75 (s, 1H), 7.93-7.87 (m, 5H), 7.72 (t, J=7.8Hz, 1H), 7.67 (s, 1H), 7.24 (s, 1H), 6.85 (s, 1H), 5.00-4.91 (m, 1H), 4.82-4.74 (m, 1H), 4.43 (dd, J=14.0,9.8Hz, 1H), 2.94-2.62 (m, 2H)
9 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 ', 4 '-two fluoro- (1,1 ' - Xenyl) -4- formamide
LC-MS m/z[M+H]+408.2.1H-NMR(400MHz,DMSO-d6) δ 13.24 (s, 1H), 9.02 (d, J= 7.9Hz, 1H), 8.75 (s, 1H), 7.89 (d, J=8.3Hz, 2H), 7.76-7.54 (m, 5H), 7.48-7.35 (m, 1H), 7.28-7.18 (m, 2H), 6.85 (s, 1H), 4.99-4.92 (m, 1H), 4.80-4.74 (m, 1H), 4.39 (dd, J=14.0, 9.9Hz,1H),2.94-2.64(m,2H).
10 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] fluoro- (1,1 '-biphenyl of -2- Base) -4- formamide
LC-MS m/z[M+H]+390.1.1H-NMR(400MHz,DMSO-d6) δ 13.23 (s, 1H), 9.02 (d, J= 7.9Hz, 1H), 8.77 (s, 1H), 7.74 (s, 1H), 7.71-7.65 (m, 3H), 7.63 (s, 1H), 7.60 (d, J=8.4Hz, 2H), 7.51 (t, J=7.4Hz, 2H), 7.43 (d, J=7.2Hz, 1H), 7.22 (s, 1H), 6.86 (s, 1H), 4.95 (dt, J= 12.5,6.2Hz, 1H), 4.84-4.71 (m, 1H), 4.44 (dd, J=14.0,9.8Hz, 1H), 2.93-2.61 (m, 2H)
11 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] chloro- (1,1 '-biphenyl of -3- Base) -4- formamide
LC-MS m/z[M+H]+406.2.1H-NMR(600MHz,DMSO-d6) δ 13.08 (s, 1H), 9.01 (d, J= 7.9Hz, 1H), 8.77 (s, 1H), 7.79 (d, J=1.7Hz, 1H), 7.76-7.69 (m, 4H), 7.63 (s, 1H), 7.50 (t, J =7.4Hz, 2H), 7.44 (d, J=7.4Hz, 1H), 7.35 (d, J=7.9Hz, 1H), 7.24 (s, 1H), 6.90 (s, 1H), 5.05-4.93 (m, 1H), 4.78-4.69 (m, 1H), 4.35 (dd, J=14.1,9.7Hz, 1H), 2.86-2.59 (m, 2H)
12 N- of embodiment [1- (- 1 base of 1H- imidazoles) -3- (- 1 base of 1H-1,2,4- triazole) propyl- 2- yl]-(1,1 '-connection Phenyl) -4- formamide
Intermediate 51.0g (3.11mmol) is dissolved in dry DMF, then thionyl chloride 1.11g is slowly added dropwise at 0 DEG C (9.33mmol).After reacting at room temperature 2h, 1H-1,2,4- triazole 0.64g (9.33mmol) and triethylamine 0.94g is added (9.99mmol) continues to react at room temperature 8h, and TLC detection reaction is completed, and 40mL water, ethyl acetate extraction, saturation food is then added Salt water washing organic layer, Na2SO4It is dried overnight.Desiccant, evaporating solvent under reduced pressure are filtered out, residue is purified by silica gel column chromatography, Obtain white solid 0.52g, yield 44.8%.
LC-MS m/z[M+H]+373.2.1H-NMR(600MHz,DMSO-d6) δ 13.13 (s, 1H), 8.98 (d, J= 7.8Hz, 1H), 8.76 (s, 1H), 8.52 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=8.5Hz, 2H), 7.79 (d, J= 8.5Hz,2H),7.76–7.70(m,3H),7.54–7.47(m,2H),7.45–7.41(m,1H),4.99–4.92(m,1H), 4.87-4.81 (m, 1H), 4.65 (dd, J=14.0,8.9Hz, 1H), 2.94-2.64 (m, 2H)
13 N- of embodiment [(1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- amine
The preparation of step 1 1,1'- biphenylcarboxaldehyde (intermediate 10)
Under protection of argon gas, by 4- bromobenzaldehyde 2.55g (13.8mmol), phenyl boric acid 2g (16.4mmol), K2CO3 2.71g (27.3mmol), four triphenyl phosphorus palladium 0.2g are added in dioxane solvent/water (10:1) of 40mL, are warming up to 75 DEG C, TLC monitors fully reacting after 5h.Cooling reaction solution, filters, and adjusts pH value to 2-3, has a large amount of white solids to generate, filter To white solid 2.24g, yield 89.1%.MS[M+H]+(m/z): 183.2.
The preparation of step 2 intermediate 11.
Intermediate 10 (2g, 11.0mmol) and histidinol hydrochloride 1.80g (11.0mmol) are dissolved in dehydrated alcohol, then It is added anhydrous sodium sulfate (2.61g, 21.9mmol), stirs 2 hours at room temperature, triacetyl is then being added into reaction system Base sodium borohydride (2.79g, 13.2mmol) continues to react at room temperature 8h, and TLC monitors fully reacting, and saturated ammonium chloride is added and stops instead It answers, is extracted with ethyl acetate, saturated common salt water washing organic layer, Na2SO4It is dried overnight.Desiccant is filtered out, is concentrated under reduced pressure to give Brown oil 2.76g, yield 81.8%.ESI-MS[M+H]+(m/z):308.4。
Step 3 N- [(1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- amine Preparation.
Intermediate 11 (1.00g, 3.25mmol), CDI 0.79g (4.88mmol) and imidazoles 0.44g (6.51mmol) is molten Solution reacts 5h in 30mL acetonitrile at 70 DEG C, and TLC monitors fully reacting.Pressurize concentration of reaction solution, dissolves the residue in acetic acid Ethyl ester, washing, saturated common salt water washing are washed, Na2SO4It is dried overnight.Desiccant is filtered out, rufous grease is concentrated under reduced pressure to give, Column chromatographs to obtain off-white powder 0.73g, yield 62.8%.LC-MS m/z[M+H]+358.4.1H-NMR(400MHz,DMSO- d6) δ 13.21 (s, 1H), 9.01 (d, J=7.9Hz, 1H), 8.70 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.64 (d, J =8.3Hz, 2H), 7.52 (d, J=8.3Hz, 2H), 7.46 (d, J=7.3Hz, 2H), 7.41 (t, J=7.5Hz, 2H), 7.35 (t, J=7.3Hz, 1H), 7.25 (s, 1H), 6.86 (s, 1H), 4.77-4.37 (m, 2H), 4.15 (m, 1H), 3.82-3.80 (m, 2H),2.94-2.64(m,2H).
According to the method for embodiment 13, the use of the biphenyl aldehyde replaced is respectively raw material, through coupling, reduction amination, replaces instead It should wait processes that embodiment 14 and 15 is prepared.
14 N- of embodiment [4 '-fluoro- (1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (1H- imidazoles -4 Base) propyl- 2- amine
LC-MS m/z[M+H]+376.4.1H-NMR(400MHz,DMSO-d6) δ 13.21 (s, 1H), 9.01 (d, J= 7.9Hz, 1H), 8.70 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.61 (d, J=8.3Hz, 2H), 7.47 (d, J= 7.3Hz, 2H), 7.41 (d, J=7.3Hz, 2H), 7.25 (s, 1H), 7.13 (t, J=8.5Hz, 2H), 6.86 (s, 1H), 4.47- 4.21(m,2H),4.18(m,1H),3.84-3.81(m,2H),2.90-2.74(m,2H).
15 N- of embodiment [4 '-chloro- (1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (1H- imidazoles -4 Base) propyl- 2- amine
LC-MS m/z[M+H]+392.9.1H-NMR(400MHz,DMSO-d6) δ 13.21 (s, 1H), 9.01 (d, J= 7.9Hz, 1H), 8.70 (s, 1H), 8.01 (d, J=8.3Hz, 2H), 7.76 (s, 1H), 7.65 (s, 1H), 7.63 (t, J= 8.5Hz, 2H), 7.45 (d, J=7.3Hz, 2H), 7.39 (d, J=7.3Hz, 2H), 7.25 (s, 1H), 6.86 (s, 1H), 4.73- 4.31(m,2H),4.11(m,1H),3.80-3.74(m,2H),2.95-2.62(m,2H).
One, extracorporeal antifungal activity is tested.
Experimental method is as follows: positive control drug: Fluconazole and Itraconazole；For trying strain: being respectively as follows: the torrid zone for examination fungi Candidiasis, Candida albicans, Trichophyton rubrum, red saccharomycete, neogenesis cryptococcus, gypsum sample trichophyta, rhizopus, Dark brown Aspergillus.
1, filamentous fungi susceptibility test methods are (referring to the American National Clinical Laboratory Standard committee (NCCLS) The version filamentous fungi drug sensitive test schemes in 2003 announced, culture and dilution use PDA culture medium with culture medium).
(1) preparation of antifungal drug dilution: susceptibility detection is carried out using disposable sterile 96 orifice plate；For Every kind of test fungal uses the potato dextrose agar (PDA) without antifungal drug to cultivate datum hole as growth control hole； Diluent used is drawn first, and the storing liquid of drug is added in the first pipe, successively carries out 2 doubling dilutions.
(2) preparation of fungi inoculation liquid: most of fungies must be at 35 DEG C with potato dextrose agar (PDA) culture medium The 0.85% salt water 1ml containing 0.01ml polysorbas20 is added on the bacterium colony for be incubated for 7 days, prepares suspension for activation 7 days.With light splitting Photometer adjusts bacteria suspension concentration；The A value (OD value) of Aspergillus is adjusted to 0.10；Rhizopus A value (OD value) adjustment To 0.15；The inoculation suspension of 2 times of final concentrations is obtained after 50 doubling dilutions.
(3) cultivate: 96 orifice plates observe result stationary incubation 24-72 hours in 35 DEG C of aerobic environments.
2, yeast-like fungi susceptibility test methods are (public referring to the American National Clinical Laboratory Standard committee (NCCLS) SDA culture medium is used in the saccharomycete drug sensitive test scheme of cloth, culture and dilution with culture medium).
(1) it the preparation of antifungal drug dilution: is tested with the sterile test tube of 13 × 100mm；In control tube containing only There are husky Borrow's agar glucose (SDA) medium liquid culture medium and strain subject and is free of antifungal drug.
(2) preparation of bacterium inoculation liquid: all strain subjects at least Ying Sha Borrow agar glucose (SDA) fluid nutrient medium Upper transferred species 2 times, to ensure its purity and fertility, cultivation temperature should be 35 DEG C from beginning to end.It should select through culture in 24 hours The diameter of candida albicans is greater than bacterium colony 5 of 1mm, and suspension is made with 0.85% salt water in it.Its concentration is adjusted to 1 × 106-5 ×106Cell/mL.It is used to husky Borrow agar glucose (SDA) culture medium, culture medium dilutes 2000 times, finally when inoculation Bacteria concentration is 1.0 × 103-2.0×103Cell/mL.
(3) the gradient dilution liquid of the antifungal drug of 0.1mL the inoculation of fluid nutrient medium: is divided in numbered test tube In, in growth control pipe, the dilution of 0.1mL is only added without drug containing；After mixing up bacterium inoculation liquid, by 0.9mL's Bacterium inoculation liquid is added in corresponding test tube and is shaken up, and so that the antifungal drug of each gradient is diluted 10 times, culture medium is dilute Release 1.11 times.
(4) it cultivates: test tube being cultivated 24-72 hours in 35 DEG C of aerobic environments, observed result.Experimental result is shown in Table 1.
The antifungal activity test result of compound in 1 embodiment of the present invention of table.
Derivative 1-15 defined by the embodiment of the present invention shows different degrees of external suppression to the fungi tested System activity, wherein there is part of compounds to survey the external inhibitory activity of fungi to part and be better than positive control drug (Itraconazole, fluorine Health azoles) or it is suitable with it.
Two, ill vitro antibacterial activity is tested
Test strain: staphylococcus aureus, Escherichia coli, streptococcus pneumonia.
(1) the compound of the present invention is tested to staphylococcus aureus, Escherichia coli, pneumonia by broth microdilution antifungal susceptibility test Streptococcic antibacterial activity.
Open 96 orifice plates of bacterium of having gone out under aseptic condition, the 1st hole is added the M-H meat soup of 200 μ L drug containing, and final concentration of 32 μg/mL.100 μ L blank cultures are added in remaining 11 holes.100 μ L are accurately drawn from the 1st hole with liquid-transfering gun, the second hole is added, blow It beats and mixes, then draw 100 μ L to the 3rd hole from the 2nd hole again, and so on, until the 10th hole, 100 μ L are inhaled after mixing and are discarded.This When every hole drug concentration be 64,32,16,8,4,2,1,0.5 μ g/mL.Last 2 hole not drug containing, one is used as bacterial growth Control, one is used as negative control.
In above-mentioned 96 orifice plate, the 0.5 μ L of bacteria suspension of 108CFU/mL is added in preceding 11 hole, makes the final inoculum concentration be about 105CFU/mL.Add bacterium speed will as quickly as possible, in order to avoid overlong time, causes every hole bacterial growth Time Inconsistency and influence result Judgement.Each bacterial strain does 3 parallel tests simultaneously.It is completed by the superclean bench alcolhol burner of whole process after sterilization.Carefully Operation, prevents from polluting.Inoculated 96 orifice plate is put into 37 DEG C of constant incubator culture 16-20h, then observes and record knot Fruit.
After the completion of culture, 96 orifice plates are taken out from insulating box, bacterial growth situation in peep hole.Determine result it Before, result is just significant when the bacterium normal growth that determine growth control hole, negative control hole are without bacterial growth.Naked eyes are seen Examine MIC of the drug concentration in the not hole of bacterial growth as the drug to the bacterium.If there is hole phenomenon is jumped, then weight is needed Retrial is verified.Bacteriostatic activity test result is shown in Table 2.
The anti-Conventional bacteria active testing result of 2 the compounds of this invention of table (MIC, μ g/mL).
Three, mouse sub-acute toxicity test.
Any compound of 1-15 of the embodiment of the present invention is suspended in the concentration of 10ml/kg containing 0.5% methylcellulose Aqueous base-material in, and be used for sub-acute toxicity test, (male, surrounding is big, and weight is 25g left to ICR mouse in the experiment It is right), stomach-filling is given by the 1mL syringe equipped with detector with the suspension that compound concentration is 10mg/kg to 50mg/kg, Once a day, continuous gavage two weeks；Until when minimum oral dose 10mg/kg, observe survival condition and internal organs in two weeks, The indexs such as liver enzyme and liver weight variation, do not detect signs of toxicity.It can be seen that the compound poison that the present invention limits is secondary It acts on very low.

Claims (9)

1. biphenyl diazole analog derivative, which is characterized in that the diazole analog derivative is as shown in general formula I
X in the general formula is C or N；
Y in the general formula is carbonyl or methylene；
R in the general formula is hydrogen-based, halogen, amino, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1- C6) alkoxy, (C1-C6) alkyl sulfenyl, or (the C being optionally substituted by halogen1-C6) alkyl or (C1-C6) alkoxy；
R in the general formula2For hydrogen-based, halogen, amino, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1- C6) alkoxy, (C1-C6) alkyl sulfenyl, or (the C being optionally substituted by halogen1-C6) alkyl or (C1-C6) alkoxy.
2. biphenyl diazole analog derivative as described in claim 1, which is characterized in that the preferred C of X in the general formula.
3. biphenyl diazole analog derivative as described in claim 1, which is characterized in that the R in the general formula1For hydrogen-based, halogen, (C1-C6) alkyl or (C1-C6) alkoxy.
4. biphenyl diazole analog derivative as described in claim 1, which is characterized in that the R in the general formula2For hydrogen-based, halogen, (C1-C6) alkyl or (C1-C6) alkoxy.
5. biphenyl diazole analog derivative as described in claim 1, which is characterized in that the halogen is fluorine, chlorine, bromine or iodine generation； The alkyl is the alkyl of straight chain and branch.
6. biphenyl diazole analog derivative as described in claim 1, which is characterized in that the derivative is selected from:
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl]-(1,1 '-xenyl) -4- formamide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-fluoro- (1,1 '-xenyl) -4- formamide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-chloro- (1,1 '-xenyl) -4- formamide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 '-methyl-(1,1 '-xenyl) -4- formyl Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-fluoro- (1,1 '-xenyl) -4- formamide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-methyl-(1,1 '-xenyl) -4- formyl Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-trifluoromethyl-(1,1 '-xenyl) -4- first Amide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -4 '-cyano-(1,1 '-xenyl) -4- formyl Amine；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] -2 ', 4 '-two fluoro- (1,1 '-xenyl) -4- first Amide；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] fluoro- (1,1 '-xenyl) -4- formamide of -2-；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- yl] chloro- (1,1 '-xenyl) -4- formamide of -3-；
N- [1- (- 1 base of 1H- imidazoles) -3- (- 1 base of 1H-1,2,4- triazole) propyl- 2- yl]-(1,1 '-xenyl) -4- formyl Amine；
N- [(1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- amine；
N- [4 '-fluoro- (1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- amine；
N- [4 '-chloro- (1,1 '-xenyl) -4- methyl] -1- (- 1 base of 1H- imidazoles) -3- (- 4 base of 1H- imidazoles) propyl- 2- amine.
7. the biphenyl diazole analog derivative as described in claim 1-6 is used to prepare antimycotic or anti-bacterial drug.
8. the use as claimed in claim 7, which is characterized in that the fungi includes candidiasis, Candida albicans, red Color trichophyta, red saccharomycete, neogenesis cryptococcus, gypsum sample trichophyta, rhizopus or aspergillus fumigatus.
9. application as claimed in claim 8, which is characterized in that the bacterium is gram-positive bacterium.
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CN111533693A (en) * 2020-05-08 2020-08-14 张建蒙 Cinnamic acid amide diazole derivative and application thereof in antifungal drugs
CN113912534A (en) * 2021-11-10 2022-01-11 江苏科技大学 Biphenyl heterocyclic compound, and synthesis method and application thereof

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CN104530038A (en) * 2014-12-10 2015-04-22 沈阳药科大学 Amide imidazole derivative and application thereof

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WO2003045381A1 (en) * 2001-11-27 2003-06-05 Molecular Skincare Limited Aminoalkylimidazole derivatives and their use in medicine
CN104530038A (en) * 2014-12-10 2015-04-22 沈阳药科大学 Amide imidazole derivative and application thereof
CN105541828A (en) * 2014-12-10 2016-05-04 沈阳药科大学 Acylaminoimidazole derivative and use thereof

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CN111533693A (en) * 2020-05-08 2020-08-14 张建蒙 Cinnamic acid amide diazole derivative and application thereof in antifungal drugs
CN113912534A (en) * 2021-11-10 2022-01-11 江苏科技大学 Biphenyl heterocyclic compound, and synthesis method and application thereof
CN113912534B (en) * 2021-11-10 2023-07-25 江苏科技大学 Biphenyl heterocyclic compound, synthesis method and application thereof

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