CN105566262A - Benzofuran-7-alkylamine compounds and applications thereof - Google Patents

Benzofuran-7-alkylamine compounds and applications thereof Download PDF

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CN105566262A
CN105566262A CN201610013304.0A CN201610013304A CN105566262A CN 105566262 A CN105566262 A CN 105566262A CN 201610013304 A CN201610013304 A CN 201610013304A CN 105566262 A CN105566262 A CN 105566262A
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cumarone
base
amine
methyl
alkene
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CN105566262B (en
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李剑
蓝乐夫
王友鑫
陈菲菲
狄红霞
魏汉文
蒋华良
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

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Abstract

The inventor designs and synthesizes benzofuran-7-alkylamine compounds with a novel structure. The test results show that most of the disclosed benzofuran-7-alkylamine compounds have a strong activity on inhibiting the synthesis of golden yellow pigment, and some compounds have an extremely strong inhibiting activity on pigments of drug resistant bacteria (S.aureus USA400 MW2, USA300 LAC, Mu50), and prominently enhance the hydrogen peroxide killing and human blood killing in vitro. In vivo, for the animal model infected by sensitive strain (S.aureus Newman) and two drug resistant strains (S.aureus USA400 MW2, Mu50), the planting of bacteria in internal organs (kidney, heart, and liver) of mice is prominently reduced. The benzofuran-7-alkylamine compounds are advantageously used for producing novel anti-bacterium drugs.

Description

Cumarone-7-alkyl amine compound and uses thereof
Technical field
The present invention relates to a kind of cumarone-7-alkyl amine compound and its production and use, belong to pharmaceutical chemistry and pharmacotherapeutics field.
Background technology
Streptococcus aureus (Staphylococcusaureus, SA) causes the modal pathogenic agent of healthcare associated infections in world wide, from discovery so far, and the infection almost extend over the entire globe of SA.As the representative of gram-positive microorganism, it causes modal pathogenic bacteria in mankind's suppurative infection, directly can cause the systemic infections such as local suppurative infection, pneumonia, pseudomembranous enteritis, pericarditis, meningitis, septicemia, Sepsis.The infection of SA can divide hospital acquired infections and Community Acquired Infections, and the discovery of the latter further increases the potential biohazardous of this pathogenic bacterium and causes the possibility infecting outburst.Not only find methicillin resistant staphylococcus aureus (Methicillin-resistantStaphylococcusaureus at present, MRSA), have also appeared the MRSA of high resistance (XDR) and complete resistance (TDR); Even there is the streptococcus aureus (Vancomycin-intermediateStaphylococcusaureus of vancomycin intermediate resistance, VISA), the streptococcus aureus (Glycopeptide-intermediateStaphylococcusaureus of glycopeptide antibiotics intermediate-resistant, and characteristic of vancomycin-resistant Staphylococcus aureus (Vancomycin-resistantStaphylococcusaureus, VRSA) GISA).MRSA with surprising rapidity at world's scope spreading, has crossed over two continents after evolution out in 1961.2011, the U.S. has suffered from MRSA infection more than 80,000 people, and 11285 people die from relative disease (NationalActionPlanForCombatingAntibiotic-ResistantBacter ia, 2015, US).Have report that MRSA infection, acquired immune deficiency syndrome (AIDS) and hepatitis B are listed in the large infectious diseases in the world three, the health of the mankind in serious threat, has caused the great attention of global medical circle.
In face of MRSA, the mankind remain with always and think at present the most effectively " trump card ", namely the microbiotic of a kind of " vancomycin " by name.The side effect of vancomycin is very strong, has and seriously causes deaf property and renal toxicity, seldom use clinically.But now, when other microbiotic are all invalid to pathogenic bacteria, vancomycin is re-enabled.But, within 2002, there is the streptococcus aureus (VRSA) to vancomycin height resistance in the U.S., the clinical problem that its appearance makes the infection of streptococcus aureus again become very thorny.
Along with the development of life science and medical science, it is found that and comprise streptococcus aureus by pathogenic bacteria to have pathogenic be because they are by producing various virulence factor (Virulencefactor) to help the field planting of bacterium, adhesion, cytotoxicity, immune evasion etc. thus to make bacterium successfully implement infection.At present, the antibiotic mechanism of action used clinically is not the pathogenic link of directed toward bacteria, but by directly suppressing the most basic vital movement of pathogenic bacteria carry out the growth of anti-bacteria or directly kill bacterium, the bacterial antibiotic resistance caused thus has become the bottleneck problem of microbiotic clinical application.Just because of various drug-resistant bacteria appearance and spread, the medicine (Anti-virulencedrugs) of antibacterium virulence is becoming the focus that novel bacterial-infection resisting medicine institute pays close attention to.The medicine of current antibacterium virulence plays a role mainly through 5 kinds of approach: the toxin of (1) containment object bacteria is expressed; (2) quorum sensing between bacterium is blocked; (3) toxin secretion and transmission is suppressed; (4) links of bacterial adhesion is blocked; (5) anti-bacteria immune evasion.The medicine that any one has one of above-mentioned 5 kinds of effects can reduce the pathogenic of bacterium, effectively prevention and therapy multi-infection disease.
It is emphasized that the medicine due to antibacterium virulence does not directly affect the living or death of thalline, but cut down the pathogenic of bacterium or remove its arms, help the immunity system bacteria removal effectively of human body, the selection pressure of medicine to bacterium is less.Scientists prediction it effectively can reduce the generation of bacterial drug resistance, propagation and popular, and on the normal microflora (Normalflora) of human body, there is less impact, can use with other conventional antibiotic is collaborative, make up the weak point of existing conventional antibiotic.On the other hand, the medicine of antibacterium virulence may effectively to the bacterial strain producing resistance, because no matter for bacterial strain or the sensitive strain of antibiotics resistance, they are in pathogenic molecule mechanism, are in general similar.
2005, what Univ California-San Diego USA (UCSD) professor VictorNizet found that the golden yellow pigment (Staphyloxanthin) of streptococcus aureus has help streptococcus aureus a to escape active oxygen that human body innate immune system produces murders ability, is the key factor determining bacterium pathogenecity.Champagne school district, University of Illinois of U.S. professors EricOldfield etc. successfully find that a known cholesterol synthesis inhibitor BPH-652 can suppress the formation of golden yellow pigment in streptococcus aureus, thus the pathogenecity of abatement streptococcus aureus in Mice Body.Also some research reports are had, golden yellow pigment can increase the resistivity of bacterium to oleic acid, in the model experiment of mouse subcutaneous infection, can not the chromatogenous mutant strain abscess region of causing comparatively wild type strain obviously reduce, hint pigment can by improving the oxidation resistant ability of bacterium thus increasing the virulence of bacterium.Thus, golden yellow pigment is the key factor determining streptococcus aureus pathogenecity.These existing Preliminary Studies confirm to suppress the golden yellow pigment synthesis of the virulence factor of streptococcus aureus to be new, effective antibacterials strategy.
China is one of the most serious country of abuse of antibiotics in the world, and the bacterial resistance sex chromosome mosaicism caused thus is particularly outstanding, and some bacteriums of clinical separation are occupied first place in the world to some antibiotic resistance.In the face of severe bacteria antibiotic resistance, we need badly and find novel antibacterials action target spot and novel bacterial-infection resisting medicine.Therefore, the antibacterials researching and developing anti-golden yellow pigment synthesis have important practical significance and scientific value.
Summary of the invention
The present inventor designs and has synthesized a kind of cumarone-7-alkyl amine compound with brand new.Show after tested: majority of compounds of the present invention has potent inhibit activities (with enzyme CrtN crucial in golden yellow pigment synthesis process for action target) to golden yellow pigment synthesis, wherein some compound is to resistant organism (S.aureusUSA400MW2, USA300LAC, Mu50) pigment inhibit activities is extremely strong, strengthens hydrogen peroxide in vitro significantly and kills and wounds and strengthen human blood and kill and wound.In vivo for sensitive strain (S.aureusNewman) and two strain Resistant strain (S.aureusUSA400MW2, Mu50) in the animal model infected, significantly can reduce bacterium at mice viscera (kidney, the heart and liver) middle field planting, establish architecture basics for designing and developing novel bacterial-infection resisting medicine from now on further.
The present invention's object is, provides a kind of cumarone-7-alkyl amine compound of novel structure.
Cumarone-7-alkyl amine compound of the present invention is compound shown in formula I or its pharmaceutically acceptable salt:
In formula I, R 1for hydrogen (H) or C 1~ C 3straight or branched alkyl, R 2for C 1~ C 6the C of aliphatic radical or replacement 1~ C 6aliphatic radical, n is the integer of 1 ~ 3;
Wherein, the C of described replacement 1~ C 6the substituting group of aliphatic radical is selected from: the cyclic hydrocarbon radical of 3 ~ 6 yuan or containing oxygen (O) heterocyclic radical, a kind of in the cyclic hydrocarbon radical of 3 ~ 6 yuan of replacement or naphthyl;
The substituting group of the cyclic hydrocarbon radical of 3 ~ 6 yuan of described replacement is selected from: C 1~ C 4straight or branched alkyl, fluorine-containing C 1~ C 3straight or branched alkyl, C 1~ C 3straight or branched alkoxyl group, halogen (F, Cl, Br or I, lower same), phenyl, nitro (NO 2) or (R 3for C 1~ C 3straight or branched alkyl) in a kind of or two kinds, substituting group number is 1 or 2.
Another object of the present invention is, disclose a kind of purposes of above-mentioned cumarone-7-alkyl amine compound (compound shown in formula I or its pharmaceutically acceptable salt), i.e. compound shown in formula I or its pharmaceutically application of acceptable salt in preparation streptococcus aureus golden yellow pigment synthesis inhibitor class antibacterials.Or,
Compound shown in formula I or its pharmaceutically application of acceptable salt in the inhibitor preparing the key enzyme CrtN in golden yellow pigment synthesis process.
Accompanying drawing explanation
Fig. 1. be the compounds of this invention I athe final photograph of the golden yellow pigment synthesis of-6 suppression;
Wherein, I from left to right athe concentration of-6 is followed successively by 50 μMs, 10 μMs, 5 μMs, 2.5 μMs, 1.25 μMs, 0.625 μM, 0.3125 μM, 0 μM.
Fig. 2. be the compounds of this invention I cthe final photograph of the golden yellow pigment synthesis of-1 suppression;
Wherein, I from left to right cthe concentration of-1 is followed successively by 50 μMs, 10 μMs, 5 μMs, 2.5 μMs, 1.25 μMs, 0.625 μM, 0.3125 μM, 0 μM.
Fig. 3. be Compound I ainhibit activities data (the IC of-6 pairs of resistant organism USA400MW2 (A), USA300LAC (B) and Mu50 (C) golden yellow pigment synthesis 50, nM);
Fig. 4. be Compound I a-6 to enhancing Newman (A, survival36.2%vs1.2%), USA400MW2 (B, survival11.7%vs0.6%), USA300LAC (C, and Mu50 (D, survival25.3%vs4.3%) hydrogen peroxide killing experiments result survival14.2%vs0.7%).
Fig. 5. be Compound I a-6 to enhancing Newman (A, survival26.7%vs0.8%), USA400MW2 (B, survival10.2%vs1.3%), USA300LAC (C, and Mu50 (D, survival16.1%vs3.0%) human blood killing experiments result survival12.1%vs1.2%).
Fig. 6. be the compounds of this invention I a-6 reduce the survival results of streptococcus aureus Newman in mouse kidney and heart.
Fig. 7. be the compounds of this invention I a-6 reduce the survival results of streptococcus aureus USA400MW2 in mouse liver and kidney.
Fig. 8. be the compounds of this invention I a-6 reduce the survival results of streptococcus aureus Mu50 in mouse liver and kidney.
Embodiment
In the present invention's preferred technical scheme, R 2for C 1~ C 6the C of aliphatic radical or replacement 1~ C 6aliphatic radical;
The C of described replacement 1~ C 6the substituting group of aliphatic radical is selected from: 3 ~ 6 yuan of cycloalkyl, 3 ~ 6 yuan of cycloalkyl of replacement, 5 ~ 6 yuan of aromatic ring yls or containing oxygen (O) aromatic heterocyclic, 5 ~ 6 yuan of aromatic ring yls of replacement or containing a kind of in oxygen (O) aromatic heterocyclic or naphthyl;
The substituting group of 3 ~ 6 yuan of cycloalkyl of described replacement is phenyl,
5 ~ 6 yuan of aromatic ring yls of described replacement or be selected from containing the substituting group of oxygen (O) aromatic heterocyclic: C 1~ C 4straight or branched alkyl, fluorine-containing C 1~ C 3straight or branched alkyl, C 1~ C 3straight or branched alkoxyl group, halogen, nitro (NO 2) or (R 3for C 1~ C 3straight or branched alkyl) middle a kind of.
In further optimal technical scheme, R 2for C 1~ C 6the C of aliphatic radical or replacement 1~ C 6aliphatic radical;
The C of described replacement 1~ C 6the substituting group of aliphatic radical is selected from: cyclopentyl, cyclohexyl, the cyclopropyl that phenyl replaces, furyl, phenyl, a kind of in substituted-phenyl or naphthyl;
The substituting group of described substituted-phenyl is selected from: C 1~ C 4straight or branched alkyl (as methyl, ethyl or the tertiary butyl etc.), the C of perfluor 1~ C 3straight or branched alkyl (as trifluoromethyl, pentafluoroethyl group or seven fluoropropyls etc.), C 1~ C 3straight or branched alkoxyl group (as methoxyl group, oxyethyl group or propoxy-etc.), halogen, nitro (NO 2) or (R 3for methyl, ethyl or propyl group) middle a kind of.
In further optimal technical scheme, R 2for a kind of in following groups:
The present invention also provides the method for compound shown in a kind of synthesis type I, and to synthesize the compound that n is 1, its synthesis strategy is as follows:
Specifically comprise the steps:
1) be dissolved in DMF by 2-iodophenol, add sodium hydride and produce to bubble-free, add bromo-1, the 1-diethoxyethane of 2-, at 90 DEG C, stirring reaction spends the night.Be cooled to room temperature, in reaction system, add water, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, concentrated, resistates, through column chromatography for separation, obtains 1-(2,2-diethoxy oxyethyl group)-2-iodobenzene (intermediate II);
2) intermediate II and polyphosphoric acid are added in toluene, heated overnight at reflux.After reaction terminates, while hot reaction system is poured in saturated aqueous sodium hydroxide solution, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, concentrated, resistates, through column chromatography for separation, obtains 7-iodo cumarone (intermediate III);
3) by intermediate III, cuprous cyanide joins in DMF, reflux 10 ~ 20 hours.Be cooled to room temperature, in system, add strong aqua, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, and concentrated, resistates, through column chromatography for separation, obtains cumarone-7-formonitrile HCN (intermediate compound IV);
4) by the anhydrous tetrahydrofuran solution of intermediate compound IV subzero 78 DEG C, be slowly added drop-wise in the anhydrous tetrahydro furan suspension of lithium aluminum hydride under nitrogen protection, dropwise rear 20 DEG C ~ 30 DEG C reactions to spend the night, water is added successively in reaction system, 15% aqueous sodium hydroxide solution, shrend is gone out reaction, directly in reaction system, add anhydrous sodium sulfate drying, filter, concentrate to obtain (cumarone-7-base) methylamine (intermediate V);
5) intermediate V is dissolved in tetrahydrofuran (THF), adds sodium hydroxide and stir 5 ~ 10 minutes, under ice bath, slowly add the tetrahydrofuran solution of tert-Butyl dicarbonate.0 DEG C ~ 30 DEG C stirring reactions 1 ~ 3 hour.Filter, concentrated, resistates, through column chromatography for separation, obtains N-[(cumarone-7-base) methylene radical]-t-butyl carbamate (intermediate VI);
6) by the anhydrous tetrahydrofuran solution of intermediate VI 0 DEG C, be slowly added drop-wise in the anhydrous tetrahydro furan suspension of lithium aluminum hydride under nitrogen protection, dropwise post-heating back flow reaction 10 ~ 20 hours, water is added successively in reaction system, 15% aqueous sodium hydroxide solution, shrend is gone out reaction, directly in reaction system, add anhydrous sodium sulfate drying, filter, concentrate to obtain N-[(cumarone-7-base) methylene radical]-methylamine (intermediate VII);
7) (E)-2-being replaced-3-replacement-propenal is dissolved in methyl alcohol, adds sodium borohydride, room temperature reaction 10 ~ 30 minutes under ice bath in batches.Concentrated, add water in resistates, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, concentrated that (E)-2-replaces-3-replacement-vinylcarbinol (intermediate VIII);
8) intermediate VIII is dissolved in anhydrous diethyl ether, under nitrogen protection ice bath, add phosphorus tribromide, 20 ~ 30 DEG C are reacted 10 ~ 20 hours, reaction system are poured in the saturated sodium bicarbonate solution of ice, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, and 30 DEG C concentrated that (E)-2-replaces-3-replacement-propylene bromine (intermediate compound I X);
9) by intermediate VII, intermediate compound I X, salt of wormwood joins N, in dinethylformamide, 20 DEG C ~ 30 DEG C are reacted 10 ~ 20 hours, add water, be extracted with ethyl acetate three times in reaction system, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrated, resistates, through column chromatography for separation, obtains compound (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-2-and replaces-3-replacement-propyl-2-alkene-1-amine (target compound I a).
Or
The step (i.e. step 1) ~ 6 of synthetic intermediate VII)) with described identical above;
7) by substituted carboxylic acid, thionyl chloride joins in ethanolic soln, reflux 1 ~ 3 hour.After reaction terminates, concentrated, washing, obtains substituted carboxylic acid ethyl ester (intermediate X I);
8) intermediate X I is dissolved in anhydrous tetrahydro furan, the toluene solution of diisobutyl aluminium hydride is slowly added at nitrogen protection 0 DEG C, 20 DEG C ~ 30 DEG C are reacted 10 ~ 20 hours, add methyl alcohol cancellation reaction, filter, concentrated, resistates, through column chromatography for separation, obtains replacing methyl alcohol (intermediate X II);
9) intermediate X II is dissolved in anhydrous diethyl ether, under nitrogen protection ice bath, add phosphorus tribromide, 20 DEG C ~ 30 DEG C are reacted 10 ~ 20 hours, reaction system are poured in the saturated sodium bicarbonate solution of ice, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, and 30 DEG C so concentrated that to replace monobromethane (intermediate X III);
10) by intermediate VII, intermediate X III, salt of wormwood joins in DMF, and 20 DEG C ~ 30 DEG C are reacted 10 ~ 20 hours.After reaction terminates, water is added in reaction system, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrated, resistates, through column chromatography for separation, obtains compound N-methy-N-[(cumarone-7-base) methylene radical]-replacement-methylamine (target compound I c).
Or,
The step (i.e. step 1) ~ 6 of synthetic intermediate VII)) with described identical above;
7) be dissolved in anhydrous diethyl ether by 3-replacement-propyl-2-alkynes-1-alcohol, under nitrogen protection ice bath, add phosphorus tribromide, 20 DEG C ~ 30 DEG C are reacted 10 ~ 20 hours.Reaction system poured in the saturated sodium bicarbonate solution of ice, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, and 30 DEG C concentrated obtains 3-bromo-1-replacement-propyl-1-alkynes (intermediate X IV);
8) by intermediate VII, intermediate X IV, salt of wormwood joins in DMF, and 20 ~ 30 DEG C are reacted 10 ~ 20 hours.Water is added in reaction system, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated, resistates, through column chromatography for separation, obtains compound N-methy-N-[(cumarone-7-base) methylene radical]-3-replacement-propyl-2-alkynes-1-amine (target compound I d).
Or,
The step (i.e. step 1) ~ 6 of synthetic intermediate VII)) with described identical above;
7) intermediate VII, 3-are replaced-1-N-PROPYLE BROMIDE, salt of wormwood joins in DMF, and 20 DEG C ~ 30 DEG C are reacted 10 ~ 20 hours.In reaction system, add water, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrated, resistates, through column chromatography for separation, obtains compound N-methy-N-[(cumarone-7-base) methylene radical]-3-replacement-propyl-1-amine (target compound I e).
Or,
The step (i.e. step 1) ~ 4 of synthetic intermediate V)) with described identical above;
5) by intermediate V, E-3-replacement-propenal, molecular sieve joins in methylene dichloride, heating reflux reaction 15 ~ 30 hours, is cooled to room temperature, filters, concentrated, resistates, through column chromatography for separation, obtains (E, E)-N-(3-replacement-propyl-2-alkene-1-pitches base)-N-(cumarone-7-base) methylamine (intermediate X);
6) intermediate X is dissolved in methyl alcohol, under condition of ice bath, add sodium borohydride, room temperature reaction 10 ~ 30 minutes in batches, concentrated, water is added in resistates, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrate to obtain intermediate (E)-N-[(cumarone-7-base) methylene radical]-3-replacement-propyl-2-alkene-1-amine (target compound I ba);
7) by target compound I babe dissolved in anhydrous DMF, under condition of ice bath; add sodium hydride, stirring reaction 10 ~ 30 minutes, adds idoalkane in batches; nitrogen protection 20 ~ 30 DEG C reaction 10 ~ 20 hours, adds water, is extracted with ethyl acetate three times in reaction system; saturated common salt is washed; anhydrous sodium sulfate drying, filters, concentrated; resistates, through column chromatography for separation, obtains compound (E)-N-R 1-N-[(cumarone-7-base) methylene radical]-3-replacement-propyl-2-alkene-1-amine (target compound I bb).
Wherein, R 1and R 2definition with described identical above.
According to the instruction of above-mentioned synthetic method, those skilled in the art, without the need to creative work, can obtain all compounds that formula I comprises.
The present invention will be illustrated further below in an example.These embodiments only for illustration of the present invention, the protection domain do not limited the present invention in any way.All parameters in embodiment and remaining explanation unless otherwise indicated, are all for unit with quality (gram).
Embodiment 1
The preparation of 1-(2,2-diethoxy oxyethyl group)-2-iodobenzene (intermediate II):
Be dissolved in 200 milliliters of DMFs by 30 grams of 2-iodophenols, add 6 grams of sodium hydrides and produce to bubble-free, add 31 milliliters of bromo-1,1-diethoxyethane of 2-, at 90 DEG C, stirring reaction spends the night.Be cooled to room temperature, in reaction system, add water, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, concentrated, residue by silicagel column chromatographic separation (ethyl acetate/petroleum ether=1:25) obtains title compound, 42.8 grams of water white oils, yield 93%.
1H-NMR(400MHz,CDCl 3)δ7.77(dd,J＝7.8,1.4Hz,1H),7.29(dd,J＝11.7,4.4Hz,1H),6.86–6.78(m,1H),6.72(td,J＝7.7,1.2Hz,1H),4.90(t,J＝5.2Hz,1H),4.04(d,J＝5.2Hz,2H),3.82(tt,J＝14.1,7.1Hz,2H),3.77–3.69(m,2H),1.28–1.23(m,6H)。
Embodiment 2
The preparation of 7-iodo cumarone (intermediate III):
42.8 grams of intermediate II and 85 grams of polyphosphoric acid are added in 200 milliliters of toluene, heated overnight at reflux.After reaction terminates, while hot reaction system is poured in saturated aqueous sodium hydroxide solution, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, concentrated, residue by silicagel column chromatographic separation (sherwood oil) obtains title compound, 17 grams of water white oils, yield 55%.
1H-NMR(400MHz,Acetone)δ7.95(s,1H),7.70(dd,J＝17.8,7.5Hz,2H),7.09(d,J＝9.0Hz,2H)。
Embodiment 3
The preparation of cumarone-7-formonitrile HCN (intermediate compound IV):
By 17 grams of intermediate III, 12.5 grams of cuprous cyanides join in 150 milliliters of DMFs, heated overnight at reflux.After intermediate III reacts completely, be cooled to room temperature, in system, add strong aqua clarify to solution, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, concentrated, residue by silicagel column chromatographic separation (ethyl acetate/petroleum ether=1:25), obtain title compound, 9 grams of white solids, yield 90%.
1H-NMR(400MHz,CDCl 3)δ7.84(t,J＝11.2Hz,1H),7.77(s,1H),7.61(d,J＝7.5Hz,1H),7.33(t,J＝7.7Hz,1H),6.88(s,1H)。
Embodiment 4
The preparation of cumarone-7-base methylamine (intermediate V):
By 100 of 9 grams of intermediate compound IV milliliters of anhydrous tetrahydrofuran solutions, subzero 78 DEG C, be slowly added drop-wise in 100 milliliters of anhydrous tetrahydro furan suspensions of 9 grams of lithium aluminum hydrides under nitrogen protection, dropwise rear room temperature reaction and spend the night.In reaction system, add 9 ml waters successively, 9 milliliter of 15% aqueous sodium hydroxide solution, 9 ml water cancellation reactions, directly add anhydrous sodium sulfate drying, filter, concentrate to obtain 9 grams of pale yellowish oil title compounds, yield 97% in reaction system.
1H-NMR(400MHz,MeOD)δ7.77(d,J＝1.9Hz,1H),7.40(t,J＝8.6Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(d,J＝7.3Hz,1H),7.00(s,1H),4.05(s,2H)。
Embodiment 5
The preparation of N-(cumarone-7-ylmethyl)-t-butyl carbamate (intermediate VI):
9 grams of intermediate V are dissolved in 100 milliliters of tetrahydrofuran solutions, add 4.6 grams of sodium hydroxide and stir 5 minutes, under ice bath, slowly add the 100 milliliters of tetrahydrofuran solutions being dissolved with 21 milliliters of tert-Butyl dicarbonates.Stirring at room temperature reacts 1 hour.Filter, concentrated, residue by silicagel column chromatographic separation (ethyl acetate/petroleum ether=1:25), obtains title compound, 12.5 grams of light yellow solids, yield 83%
1H-NMR(400MHz,CDCl 3)δ7.64(d,J＝1.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.37–7.10(m,2H),6.78(d,J＝2.1Hz,1H),4.63(s,2H),1.57–1.29(m,9H)。
Embodiment 6
The preparation of 1-(cumarone-7-base)-N-methyl methylamine (intermediate VII):
By 100 of 12.6 grams of intermediate VI milliliters of anhydrous tetrahydrofuran solutions 0 DEG C, be slowly added drop-wise in 50 milliliters of anhydrous tetrahydro furan suspensions of 7.7 grams of lithium aluminum hydrides under nitrogen protection, dropwise post-heating back flow reaction 12 hours.After reaction terminates, in reaction system, add 8 ml waters successively, 8 milliliter of 15% aqueous sodium hydroxide solution, 8 ml water cancellation reactions, directly add anhydrous sodium sulfate drying, filter in reaction system, concentrate to obtain title compound, 7.8 grams of yellow oil, yield 95%.
1H-NMR(400MHz,CDCl 3)δ7.63(d,J＝2.0Hz,1H),7.51(dt,J＝10.5,5.2Hz,1H),7.32–7.14(m,2H),6.78(d,J＝2.1Hz,1H),4.07(s,2H),2.48(s,3H)。
Embodiment 7
(E) preparation of-3-(4-tolyl)-propyl-2-alkene-1-alcohol (intermediate VIII-1):
100 milligrams of (E)-3-(4-tolyl)-propenal are dissolved in 10 ml methanol, add 26 milligrams of sodium borohydrides under ice bath, room temperature reaction 15 minutes in batches.Concentrated, add water in resistates, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, and concentrate to obtain title compound, 99 milligrams of oil, directly cast single step reaction, yield 98%.
Embodiment 8
(E) the preparation of-1-bromo-propylene of (4-tolyl)-3-(intermediate compound I X-1):
Be dissolved in by 370 milligrams of intermediate VIII-1 in 20 milliliters of anhydrous diethyl ethers, under nitrogen protection ice bath, add 85 microlitre phosphorus tribromides, room temperature reaction spends the night.After reaction terminates, reaction system poured in the saturated sodium bicarbonate solution of ice, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous magnesium sulfate drying, filters, and 30 DEG C concentrate to obtain title compound, 395 milligrams of white solids, yield 85%.
1H-NMR(400MHz,CDCl 3)δ7.27(t,J＝7.4Hz,2H),7.13(d,J＝7.4Hz,2H),6.61(d,J＝15.6Hz,1H),6.34(dt,J＝15.6,7.8Hz,1H),4.16(d,J＝7.7Hz,2H),2.34(s,3H)。
Embodiment 9
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-tolyl) third-2-alkene-1-amine (Compound I a-1) preparation.
By 120 milligrams of intermediate VII, 148 milligrams of intermediate compound I X-1,116 milligrams of salt of wormwood join in 10 milliliters of DMFs, and room temperature reaction spends the night.After reaction terminates, water is added in reaction system, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated, residue by silicagel column chromatographic separation (ethyl acetate/petroleum ether=1:5), obtains title compound, 145 milligrams of colorless oil, yield 67%.
In order to be purified, compound be entered to be dissolved in 1 milliliter of ethyl acetate, pass into one minute hydrogen chloride gas, being made hydrochloride, solvent evaporated, adds the petrol ether/ethyl acetate mixed solvent of 1/100, separates out white hydrochloride salt solid, suction filtration, washing, obtains Compound I a-1 hydrochloride. 1h-NMR is its hydrochloride form data.
1H-NMR(400MHz,MeOD)δ7.93(s,1H),7.82(d,J＝7.7Hz,1H),7.51(d,J＝7.3Hz,1H),7.41(t,J＝10.2Hz,3H),7.22(d,J＝7.3Hz,2H),7.01(s,1H),6.92(d,J＝15.6Hz,1H),6.41–6.28(m,1H),4.83(d,J＝13.5Hz,1H),4.62(d,J＝13.1Hz,1H),4.18–4.07(m,1H),4.04–3.89(m,1H),2.86(s,3H),2.37(s,3H)；HRMS(ESI)m/zcalcdforC 20H 22NO(M+H) +292.1701,found292.1707。
Embodiment 10
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-trimethylphenylmethane base) third-2-alkene-1-amine (Compound I a-2) preparation:
Except (E)-3-(4-tolyl)-propenal being changed into except (E)-3-(4-trimethylphenylmethane base)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 122 milligrams of title compound as oil, yield is 49%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.93(s,1H),7.81(t,J＝11.2Hz,1H),7.59–7.35(m,6H),7.01(s,1H),6.93(d,J＝15.9Hz,1H),6.45–6.27(m,1H),4.84(d,J＝13.4Hz,1H),4.62(d,J＝13.3Hz,1H),4.17–4.07(m,1H),4.07–3.92(m,1H),2.86(s,3H),1.34(s,9H)；HRMS(ESI)m/zcalcdforC 23H 28NO(M+H) +334.2171,found334.2172。
Embodiment 11
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(naphthalene-2-base) third-2-alkene-1-amine (Compound I a-3) preparation.
Except (E)-3-(4-tolyl)-propenal being changed into except (E)-3-(naphthalene-2-base)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 116 milligrams of colorless oil title compounds, yield is 47%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ8.00–7.85(m,5H),7.83(d,J＝7.6Hz,1H),7.75(d,J＝8.5Hz,1H),7.53(s,3H),7.41(t,J＝7.4Hz,1H),7.13(d,J＝15.6Hz,1H),7.01(s,1H),6.62–6.47(m,1H),4.86(d,J＝13.4Hz,1H),4.66(d,J＝13.4Hz,1H),4.28–4.14(m,1H),4.14–3.98(m,1H),2.91(s,3H)；HRMS(ESI)m/zcalcdforC 23H 22NO(M+H) +328.1701,found328.1701。
Embodiment 12
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(naphthalene-1-base) third-2-alkene-1-amine (Compound I a-4) preparation.
Except (E)-3-(4-tolyl)-propenal being changed into except (E)-3-(naphthalene-1-base)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 144 milligrams of colorless oil title compounds, yield is 59%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ8.20(d,J＝8.1Hz,1H),7.93(s,3H),7.89–7.71(m,3H),7.66–7.48(m,4H),7.42(t,J＝7.5Hz,1H),7.02(s,1H),6.55–6.39(m,1H),4.92(d,J＝13.2Hz,1H),4.69(d,J＝13.2Hz,1H),4.35–4.22(m,1H),4.20–4.06(m,1H),2.94(s,3H)；HRMS(ESI)m/zcalcdforC 23H 22NO(M+H) +328.1701,found328.1698。
Embodiment 13
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(2,4 dichloro benzene base) third-2-alkene-1-amine (Compound I a-5) preparation.
Except changing (E)-3-(4-tolyl)-propenal into (E)-3-(2,4-dichlorophenyl) outside-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, and obtain 146 milligrams of title compound as oil, yield is 57%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.90(s,1H),7.78(d,J＝7.5Hz,1H),7.69(d,J＝7.7Hz,1H),7.50(s,2H),7.36(d,J＝7.2Hz,2H),7.24(d,J＝15.9Hz,1H),6.97(s,1H),6.54–6.33(m,1H),4.80(d,J＝12.8Hz,1H),4.63(d,J＝12.8Hz,1H),4.17–3.95(m,2H),2.81(s,3H)；HRMS(ESI)m/zcalcdforC 19H 18Cl 2NO(M+H) +346.0765,found346.0750。
Embodiment 14
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-trifluoromethyl) third-2-alkene-1-amine (Compound I a-6) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(4-trifluoromethyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 111 milligrams of title compound as oil, yield is 43%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.94(s,1H),7.82(d,J＝7.8Hz,1H),7.72(s,4H),7.53(d,J＝7.4Hz,1H),7.41(t,J＝7.6Hz,1H),7.03(d,J＝15.8Hz,2H),6.64–6.49(m,1H),4.86(d,J＝13.7Hz,1H),4.66(d,J＝12.9Hz,1H),4.24–4.12(m,1H),4.09–3.97(m,1H),2.93(s,3H)；HRMS(ESI)m/zcalcdforC 20H 19F 3NO(M+H) +346.1419,found346.1406。
Embodiment 15
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-fluorophenyl) third-2-alkene-1-amine (Compound I a-7) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(4-fluorophenyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 120 milligrams of colorless oil title compounds, yield is 50%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.90(s,1H),7.79(d,J＝7.6Hz,1H),7.55(d,J＝5.6Hz,2H),7.48(d,J＝7.2Hz,1H),7.37(t,J＝7.5Hz,1H),7.11(t,J＝8.3Hz,2H),6.98(s,1H),6.91(d,J＝15.8Hz,1H),6.41–6.25(m,1H),4.80(d,J＝13.2Hz,1H),4.60(d,J＝12.9Hz,1H),4.15–4.02(m,1H),4.02–3.87(m,1H),2.84(s,3H)；HRMS(ESI)m/zcalcdforC 19H 19FNO(M+H) +296.1451,found296.1449。
Embodiment 16
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-bromophenyl) third-2-alkene-1-amine (Compound I a-8) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(4-bromophenyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 122 milligrams of colorless oil title compounds, yield is 46%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.93(s,1H),7.81(t,J＝10.5Hz,1H),7.66–7.24(m,6H),6.98(d,J＝20.3Hz,1H),6.92(d,J＝15.8Hz,1H),6.57–6.33(m,1H),4.84(d,J＝13.4Hz,1H),4.63(d,J＝13.2Hz,1H),4.21–4.07(m,1H),4.06–3.89(m,1H),2.87(s,3H)；HRMS(ESI)m/zcalcdforC 19H 19BrNO(M+H) +356.0650,found358.0634。
Embodiment 17
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-chloro-phenyl-) third-2-alkene-1-amine (Compound I a-9) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(4-chloro-phenyl-)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 143 milligrams of colorless oil title compounds, yield is 61%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.90(s,1H),7.79(d,J＝7.7Hz,1H),7.50(d,J＝8.3Hz,3H),7.38(d,J＝7.1Hz,3H),6.96(d,J＝14.9Hz,1H),6.91(d,J＝15.7Hz,1H),6.47–6.32(m,1H),4.81(d,J＝13.2Hz,1H),4.61(d,J＝13.4Hz,1H),4.18–4.04(m,1H),4.03–3.89(m,1H),2.84(s,3H)；HRMS(ESI)m/zcalcdforC 19H 19ClNO(M+H) +312.1155,found312.1148。
Embodiment 18
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-p-methoxy-phenyl) third-2-alkene-1-amine (Compound I a-10) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(4-p-methoxy-phenyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 113 milligrams of colorless oil title compounds, yield is 49%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.93(s,1H),7.82(d,J＝7.6Hz,1H),7.49(t,J＝9.2Hz,3H),7.40(t,J＝7.4Hz,1H),7.04–6.93(m,3H),6.90(d,J＝15.8Hz,1H),6.25(dt,J＝15.2,7.5Hz,1H),4.83(d,J＝13.3Hz,1H),4.61(d,J＝13.3Hz,1H),4.14–4.05(m,1H),4.02–3.90(m,1H),3.83(s,3H),2.94–2.81(m,3H)；HRMS(ESI)m/zcalcdforC 20H 22NO 2(M+H) +308.1651,found308.1653。
Embodiment 19
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-nitrophenyl) third-2-alkene-1-amine (Compound I a-11) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(4-nitrophenyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 143 milligrams of title compound as yellow oil, yield is 59%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ8.28(d,J＝8.4Hz,2H),7.94(s,1H),7.80(dd,J＝21.2,8.0Hz,3H),7.53(d,J＝7.3Hz,1H),7.41(t,J＝7.6Hz,1H),7.14–6.96(m,2H),6.71–6.55(m,1H),4.86(d,J＝13.3Hz,1H),4.67(d,J＝13.3Hz,1H),4.27–4.13(m,1H),4.15–3.90(m,1H),2.94(s,3H)；HRMS(ESI)m/zcalcdforC 19H 19N 2O 3(M+H) +323.1396,found323.1393。
Embodiment 20
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(2-nitrophenyl) third-2-alkene-1-amine (Compound I a-12) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(2-nitrophenyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 178 milligrams of title compound as yellow oil, yield is 74%.This compound hydrochloride is yellow solid.
1H-NMR(400MHz,MeOD)δ8.06(d,J＝8.2Hz,1H),7.94(s,1H),7.85–7.71(m,3H),7.66–7.51(m,2H),7.40(dd,J＝15.2,7.2Hz,2H),7.01(s,1H),6.50–6.27(m,1H),4.87(d,J＝13.3Hz,1H),4.68(d,J＝13.3Hz,1H),4.25–4.15(m,1H),4.14–3.99(m,1H),2.95(s,3H)；HRMS(ESI)m/zcalcdforC 19H 19N 2O 3(M+H) +323.1396,found323.1393。
Embodiment 21
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(2-fluorophenyl) third-2-alkene-1-amine (Compound I a-13) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(2-fluorophenyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 117 milligrams of colorless oil title compounds, yield is 53%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.93(s,1H),7.82(d,J＝7.7Hz,1H),7.64(dd,J＝17.1,9.5Hz,1H),7.53(d,J＝7.3Hz,1H),7.39(dd,J＝14.8,7.3Hz,2H),7.23(t,J＝7.5Hz,1H),7.12(dd,J＝19.1,12.9Hz,2H),7.04–6.94(m,1H),6.60–6.47(m,1H),4.84(d,J＝13.4Hz,1H),4.65(d,J＝13.2Hz,1H),4.22–4.10(m,1H),4.08–3.98(m,1H),2.91(s,3H)；HRMS(ESI)m/zcalcdforC 19H 19FNO(M+H) +296.1451,found296.1452。
Embodiment 22
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-methyl-formiate phenyl) third-2-alkene-1-amine (Compound I a-14) preparation.
Except intermediate VIII-1 being changed into intermediate (E)-4-phenyl-but-2-ene-1-alcohol, all the other desired raw materials, reagent and preparation method are with embodiment 8-9, and obtain 212 milligrams of colorless oil title compounds, yield is 85%.This compound hydrochloride is yellow oil.
1H-NMR(400MHz,MeOD)δ8.05(d,J＝7.8Hz,2H),7.94(s,1H),7.82(d,J＝7.7Hz,1H),7.65(d,J＝7.8Hz,2H),7.52(d,J＝7.4Hz,1H),7.41(t,J＝7.6Hz,1H),7.02(d,J＝12.1Hz,2H),6.62–6.49(m,1H),4.85(d,J＝13.2Hz,1H),4.65(d,J＝13.4Hz,1H),4.22–4.12(m,1H),4.10–3.98(m,1H),3.93(s,3H),2.89(s,3H)；HRMS(ESI)m/zcalcdforC 21H 22NO 3(M+H) +336.1600,found336.1597。
Embodiment 23
(2E, 4E)-N-methyl-N-[(cumarone-7-base) methylene radical]-5-phenyl-penta-2,4-diene-1-amine (Compound I a-15) preparation.
Outside intermediate VIII-1 being changed into intermediate (2E, 4E)-5-phenyl-penta-2,4-diene-1-alcohol, all the other desired raw materials, reagent and preparation method are with embodiment 8-9, and obtain 73 milligrams of colorless oil title compounds, yield is 42%.This compound hydrochloride is yellow oil.
1H-NMR(400MHz,MeOD)δ7.92(s,1H),7.78(d,J＝10.8Hz,1H),7.48(d,J＝6.7Hz,3H),7.43–7.31(m,3H),7.30–7.20(m,1H),7.04–6.90(m,2H),6.83–6.65(m,2H),5.96(dt,J＝14.9,7.4Hz,1H),4.78(d,J＝13.3Hz,1H),4.57(d,J＝13.3Hz,1H),4.10-3.98(m,1H),3.95–3.85(m,1H),2.81(s,3H)；HRMS(ESI)m/zcalcdforC 21H 22NO(M+H) +304.1701,found304.1695。。
Embodiment 24
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-cyclohexyl-propyl-2-alkene-1-amine (Compound I a-16) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(cyclohexyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 89 milligrams of colorless oil title compounds, yield is 42%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.94(d,J＝2.2Hz,1H),7.87–7.79(m,1H),7.48(d,J＝6.9Hz,1H),7.44–7.34(m,1H),7.01(d,J＝2.2Hz,1H),6.06(dd,J＝15.3,7.8Hz,1H),5.63(dt,J＝14.9,7.3Hz,1H),4.76(d,J＝13.3Hz,1H),4.56(d,J＝13.4Hz,1H),3.99(m,1H),3.76(m,1H),2.87(s,3H),2.3(m,1H),1.88–1.58(m,6H),1.41–1.28(m,4H)；HRMS(ESI)m/zcalcdforC 19H 26NO(M+H) +284.2014,found284.2008。
Embodiment 25
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-cyclopentyl-propyl-2-alkene-1-amine (Compound I a-17) preparation.
Except (E)-3-(4-tolyl)-propenal is changed into except (E)-3-(cyclopentyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 78 milligrams of colorless oil title compounds, yield is 39%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.93(d,J＝2.2Hz,1H),7.83–7.80(m,1H),7.48(d,J＝6.9Hz,1H),7.44–7.34(m,1H),7.01(d,J＝2.2Hz,1H),6.10(dd,J＝15.3,7.8Hz,1H),5.66(dt,J＝14.9,7.3Hz,1H),4.75(d,J＝13.3Hz,1H),4.53(d,J＝13.2Hz,1H),3.90(m,1H),3.76(m,1H),2.80(s,3H),2.61(m,1H),1.99–1.83(m,2H),1.84–1.53(m,4H),1.49–1.30(m,2H)；HRMS(ESI)m/zcalcdforC 18H 24NO(M+H) +270.1858,found270.1862。
Embodiment 26
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(furans-2-base)-propyl-2-alkene-1-amine (Compound I a-18) preparation.
Except (E)-3-(4-tolyl)-propenal being changed into except (E)-3-(furans-2-base)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 116 milligrams of pale yellowish oil title compounds, yield is 58%.This compound hydrochloride is light yellow oil.
1H-NMR(400MHz,MeOD)δ7.90(d,J＝2.4Hz,1H),7.79(dd,J＝7.8,1.1Hz,1H),7.53(d,J＝1.6Hz,1H),7.48(t,J＝5.6Hz,1H),7.37(td,J＝7.4,3.0Hz,1H),6.97(t,J＝2.7Hz,1H),6.78(d,J＝15.6Hz,1H),6.52(d,J＝3.3Hz,1H),6.51–6.44(m,1H),6.28–6.13(m,1H),4.78(d,J＝13.3Hz,1H),4.58(d,J＝13.3Hz,1H),4.15–4.01(m,1H),3.89–3.97(m,1H),2.84(s,3H)；HRMS(ESI)m/zcalcdforC 17H 18NO 2(M+H) +268.1338,found268.1334。
Embodiment 27
(E)-N, 2-dimethyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine (Compound I a-19) preparation.
Except (E)-3-(4-tolyl)-propenal being changed into (E)-2-methyl-3-phenyl-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, obtain 150 milligrams of colorless oil title compounds, yield is 67%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.92(s,1H),7.81(d,J＝7.8Hz,1H),7.52(d,J＝7.4Hz,1H),7.40-7.22(m,6H),6.97(d,J＝18.2Hz,1H),6.86(s,1H),4.85(d,J＝13.3Hz,1H),4.56(d,J＝13.3Hz,1H),4.11–4.05(m,1H),3.98(d,J＝12.7Hz,1H),2.91(s,3H),2.04(s,3H)；HRMS(ESI)m/zcalcdforC 20H 22NO(M+H) +292.1701,found292.1607。
Embodiment 28
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-but-2-ene-1-amine (Compound I a-20) preparation.
Except changing into except crotyl bromine by the bromo-propylene of (E)-1-(4-tolyl)-3-, all the other desired raw materials, reagent and preparation method are with embodiment 9, and obtain 81 milligrams of colorless oil title compounds, yield is 50%.This compound hydrochloride is yellow oil.
1H-NMR(400MHz,MeOD)δ7.94(s,1H),7.77(dd,J＝34.7,14.0Hz,1H),7.49(d,J＝7.4Hz,1H),7.38(dd,J＝18.9,11.4Hz,1H),7.05–6.91(m,1H),6.14(dd,J＝14.8,6.7Hz,1H),5.81–5.63(m,1H),4.73(d,J＝17.1Hz,1H),4.52(d,J＝17.1Hz,1H),3.94–3.86(m,1H),3.80–3.71(m,1H),2.81(s,3H),1.84(t,J＝16.1Hz,3H)；HRMS(ESI)m/zcalcdforC 14H 18NO(M+H) +216.1388,found216.1383。
Embodiment 29
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine (Compound I a-21) preparation.
Except changing into except (E)-phenylacrolein by (E)-3-(4-tolyl)-propenal, all the other desired raw materials, reagent and preparation method are with embodiment 7-9, and obtain 115 milligrams of colorless oil title compounds, yield is 56%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.94(s,1H),7.83(d,J＝7.7Hz,1H),7.58–7.47(m,3H),7.38(dt,J＝14.2,7.4Hz,4H),7.00(d,J＝10.8Hz,1H),6.95(s,1H),6.48–6.32(m,1H),4.82(s,1H),4.65(s,1H),4.07(d,J＝38.8Hz,2H),2.90(s,3H)；HRMS(ESI)m/zcalcdforC 19H 20NO(M+H) +278.1545,found278.1539.
Embodiment 30
(E)-N-methyl-N-[(cumarone-7-base) methylene radical]-4-phenyl-Ding-3-alkene-1-amine (Compound I a-22) preparation.
Except intermediate VIII-1 being changed into intermediate (E)-4-phenyl-Ding-3-alkene-1-alcohol, all the other desired raw materials, reagent and preparation method are with embodiment 8-9, and obtain 90 milligrams of colorless oil title compounds, yield is 42%.This compound hydrochloride is yellow oil.
1H-NMR(400MHz,MeOD)δ7.90(s,1H),7.83(d,J＝7.5Hz,1H),7.50(d,J＝7.2Hz,1H),7.42(s,3H),7.33(t,J＝7.1Hz,2H),7.26(d,J＝5.8Hz,1H),7.00(s,1H),6.66(d,J＝16.3Hz,1H),6.28–6.12(m,1H),4.85(d,J＝13.7Hz,1H),4.63(d,J＝13.7Hz,1H),3.68-3.59(m,1H),3.51-3.41(m,1H),2.93(s,3H),2.85–2.77(m,2H)；HRMS(ESI)m/zcalcdforC 20H 22NO(M+H) +292.1701,found292.1695.
Embodiment 31
The preparation of (E, E)-N-(3-phenyl-propyl-2-alkene-1-pitches base)-(6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-1-base) methylamine (intermediate X-1).
By 294 milligrams of intermediate V, 264 milligrams of trans-Cinnamylaldehydes, 1 mol sieve joins in 25 milliliters of dichloromethane solutions, heating reflux reaction 17 hours.After reaction terminates, be cooled to room temperature, filter, concentrated, directly throw next step without separation and purification.
Embodiment 32
(E)-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine (Compound I b-1) preparation.
Intermediate X is dissolved in methyl alcohol, under ice bath, adds 76 milligrams of sodium borohydrides in batches, room temperature reaction 10 ~ 30 minutes.Concentrated, add water in resistates, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous sodium sulfate drying, and filter, obtain 97 milligrams of title compound as yellow oil, yield is 96%.This compound hydrochloride is yellow solid.
1H-NMR(400MHz,MeOD)δ7.92(s,1H),7.77(d,J＝7.7Hz,1H),7.49(t,J＝9.3Hz,3H),7.43–7.29(m,4H),6.99(d,J＝1.8Hz,1H),6.92(d,J＝15.8Hz,1H),6.43–6.30(m,1H),4.60(s,2H),3.94(d,J＝7.2Hz,2H)；HRMS(ESI)m/zcalcdforC 18H 18NO(M+H) +264.1388,found264.1383。
Embodiment 33
(E)-N-ethyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine (Compound I b-2) preparation.
By 360 milligrams of I b-1 is dissolved in 10 milliliters of anhydrous DMFs, adds 56 milligrams of sodium hydrides, stirring reaction 15 minutes under ice bath in batches.Add 0.6 milliliter of iodoethane subsequently, under nitrogen protection, room temperature reaction spends the night.After reaction terminates, water is added in reaction system, be extracted with ethyl acetate three times, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated, residue by silicagel column chromatographic separation (ethyl acetate/petroleum ether=1:5), obtains title compound, 200 milligrams of oily matter, yield 50%.This compound hydrochloride is tan solid.
1H-NMR(400MHz,MeOD)δ7.93(d,J＝1.8Hz,1H),7.82(d,J＝7.8Hz,1H),7.53(d,J＝7.4Hz,3H),7.44–7.32(m,4H),7.01(d,J＝1.9Hz,1H),6.95(d,J＝15.8Hz,1H),6.46–6.32(m,1H),4.75(s,2H),4.03(dd,J＝17.7,10.4Hz,2H),3.39–3.34(m,2H),1.49(t,J＝7.2Hz,3H).HRMS(ESI)m/zcalcdforC 20H 22NO(M+H) +292.1701,found292.1700。
Embodiment 34
(E)-N-sec.-propyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine (Compound I b-3) preparation.
Except changing into except 2-iodopropane by iodoethane, all the other desired raw materials, reagent and preparation method are with embodiment 32, and obtain 210 milligrams of title compound as yellow oil, yield is 50%.This compound hydrochloride is light yellow solid.
1H-NMR(400MHz,MeOD)δ7.92(d,J＝1.8Hz,1H),7.79(d,J＝7.7Hz,1H),7.52(t,J＝7.2Hz,2H),7.44(d,J＝6.9Hz,2H),7.37(d,J＝6.2Hz,3H),6.99(s,1H),6.90(d,J＝16.3Hz,1H),6.30–6.18(m,1H),4.85(d,J＝13.7Hz,1H),4.57(d,J＝13.7Hz,1H),4.14(d,J＝12.9Hz,1H),4.04(dd,J＝13.6,7.2Hz,1H),3.85(dt,J＝13.3,6.6Hz,1H),1.60(d,J＝6.6Hz,3H),1.52(d,J＝6.6Hz,3H)；HRMS(ESI)m/zcalcdforC 21H 24NO(M+H) +306.1858,found306.1862。
Embodiment 35
The preparation of (1S, 2S)-ethyl-2-cyclo-propane carboxylic acid, ethyl ester (intermediate X I-1).
By 1 gram of (1S, 2S)-2-cyclo-propane carboxylic acid, 1 milliliter of thionyl chloride joins in 10 milliliters of ethanolic solns, reflux 2 hours.After reaction terminates, concentrated, washing, obtains title compound, 1.1 grams of colorless oil, yield 98%.
1H-NMR(400MHz,CDCl 3)δ7.33–7.09(m,5H),4.19(q,J＝7.2Hz,2H),2.59–2.48(m,1H),1.98–1.84(m,1H),1.67–1.56(m,1H),1.38-1.30(m,1H),1.29(t,J＝7.2Hz,3H)。
Embodiment 36
The preparation of ((1S, 2S)-2-phenycyclopropyl) methyl alcohol (intermediate X II-1).
Be dissolved in by 549 milligrams of intermediate X I-1 in 25 milliliters of anhydrous tetrahydro furans, slowly add the diisobutyl aluminium hydride toluene solution of 3.9 milliliters 1.5 moles often liter at nitrogen protection 0 DEG C, stirring at room temperature reaction is spent the night.After reaction terminates, add methyl alcohol cancellation reaction, filter, concentrated, residue by silicagel column chromatographic separation (ethyl acetate/petroleum ether=1:10), obtains title compound, 304 milligrams of colorless chromogenic oily matter, yield 71%.
1H-NMR(400MHz,CDCl 3)δ7.32–7.22(m,2H),7.14(dd,J＝17.4,10.1Hz,1H),7.06(dd,J＝14.9,7.8Hz,2H),3.68–3.56(m,2H),1.50–1.39(m,1H),1.29–1.21(m,1H),1.03–0.88(m,2H).
Embodiment 37
The preparation of ((1S, 2S)-2-(brooethyl) cyclopropyl) benzene (intermediate X III-1).
Except changing into except intermediate X II-1 by intermediate VIII-1, all the other desired raw materials, reagent and preparation method are with embodiment 8, and obtain 300 milligrams of title compound as yellow oil, yield is 57%.
1H-NMR(400MHz,CDCl 3)δ7.31–7.23(m,2H),7.16(dd,J＝16.9,10.0Hz,1H),7.08(t,J＝12.2Hz,2H),3.52(t,J＝8.7Hz,1H),3.42(t,J＝8.9Hz,1H),1.95(d,J＝4.2Hz,1H),1.60(d,J＝4.6Hz,1H),1.37–1.13(m,2H).
Embodiment 38
N-methyl-N-[(cumarone-7-base) methylene radical]-1-[(1S, 2S)-2-phenycyclopropyl]-methylamine (Compound I c-1) preparation.
Except changing intermediate compound I X-1 into intermediate X III-1, all the other desired raw materials, reagent and preparation method are with embodiment 9, and obtain 112 milligrams of title compound as yellow oil, yield is 52%.This compound hydrochloride is yellow oil.
1H-NMR(400MHz,MeOD)δ7.86(t,J＝4.1Hz,1H),7.83–7.75(m,1H),7.53–7.43(m,1H),7.42–7.31(m,1H),7.28(td,J＝7.5,1.7Hz,2H),7.22–7.11(m,3H),6.97(td,J＝5.3,2.2Hz,1H),4.85(dd,J＝16.5,6.5Hz,1H),4.58(dd,J＝13.3,5.0Hz,1H),3.52-3.45(m,1H),3.29–3.15(m,1H),2.90(d,J＝7.3Hz,3H),2.13–2.03(m,1H),1.62–1.49(m,1H),1.18–1.06(m,1H),0.94–0.81(m,1H).HRMS(ESI)m/zcalcdforC 20H 22NO(M+H) +292.1701,found292.1704。
Embodiment 39
The preparation of 1-phenyl-3-propargyl bromide (intermediate X IV-1).
Except intermediate VIII-1 being changed into 3-phenyl-propyl-2-alkynes-1-alcohol, all the other desired raw materials, reagent and preparation method are with embodiment 8, and obtain 211 milligrams of title compound as yellow oil, yield is 84%.
1H-NMR(400MHz,CDCl 3)δ7.44(d,J＝4.5Hz,2H),7.32(s,3H),4.16(s,2H).
Embodiment 40
N-methyl-N-[(6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-2-base) methyl]-3-phenyl-propyl-2-alkynes-1-amine (Compound I d-1) preparation.
Except changing into except intermediate X IV-1 by intermediate compound I X-1, all the other desired raw materials, reagent and preparation method are with embodiment 9, and obtain 120 milligrams of colorless oil title compounds, yield is 59%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.93(s,1H),7.84(d,J＝7.7Hz,1H),7.56(dd,J＝14.6,7.2Hz,3H),7.52–7.37(m,4H),7.02(s,1H),4.89(d,J＝13.3Hz,1H),4.78(d,J＝13.3Hz,1H),4.41(d,J＝11.6Hz,2H),3.05(s,3H).HRMS(ESI)m/zcalcdforC 19H 18NO(M+H) +276.1388,found276.1388。
Embodiment 41
N-methyl-N-[(6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-2-base) methylene radical]-3-phenyl-propyl-1-amine (Compound I e-1) preparation.
Except intermediate compound I X-1 being changed into (3-bromopropyl) benzene, all the other desired raw materials, reagent and preparation method are with embodiment 9, and obtain 126 milligrams of colorless oil title compounds, yield is 60%.This compound hydrochloride is white solid.
1H-NMR(400MHz,MeOD)δ7.91(s,1H),7.80(d,J＝7.6Hz,1H),7.44(t,J＝8.0Hz,1H),7.36(t,J＝7.5Hz,1H),7.28(d,J＝7.1Hz,2H),7.22(s,4H),7.0(s,1H),4.76(d,J＝13.3Hz,1H),4.59(d,J＝13.3Hz,1H),3.31–3.23(m,1H),3.21-3.10(m,1H),2.88(s,3H),2.72(t,J＝7.1Hz,2H),2.17(d,J＝5.6Hz,2H).HRMS(ESI)m/zcalcdforC 19H 22NO(M+H) +280.1701,found280.1704。
Embodiment 42
The compounds of this invention suppresses the active initial screening experiments of golden yellow pigment synthesis.
Experiment bacterial strain: the streptococcus aureus Newman wild strain (Staphylococcusaureussubsp.aureusstr.Newman) of fresh activation and the crtN insertion mutation strain (without golden yellow pigment synthesis) of homology thereof.Experiment substratum: pancreas peptone soybean broth substratum (TryptoneSoybroth, TSB), Britain Oxid Products, adds single water that steams and prepares, 121 DEG C, after sterilizing in 15 minutes, for subsequent use.
Primary dcreening operation experimental technique: the preparation of (1) compound: the compounds of this invention dimethyl sulfoxide (DMSO) (DMSO) is dissolved, is configured to the mother liquor that concentration is 10mM.Getting DMSO that 100 μ L mother liquors add 400 μ L, to be diluted to concentration be 2mM, gets 250 μ L (2mM) solution and continue to add equivalent DMSO and carry out 2 times of dilutions after mixing, until strength of solution is 0.0625mM, stand-by.(2) cultivation of bacterial strain: picking Newman bacterial strain mono-clonal is in the test tube of the aseptic TSB substratum of dress 4mL from TSA flat board, 37 DEG C, after 250rpm cultivates 12 hours, for subsequent use.(3) the compounds of this invention suppresses the primary dcreening operation of golden yellow pigment synthesis ability in streptococcus aureus: get sterile test tube, to often propping up in test tube the TSB substratum 3980 μ L adding fresh sterilizing.Subsequently, in test tube, add the concentration that 20 μ L have prepared is respectively 10mM, 2mM, 1mM, 0.5mM, the compound solution of 0.25mM, 0.125mM, 0.0625mM, makes the compounds of this invention final concentration be respectively 50 μMs, 10 μMs, 5 μMs, 2.5 μMs, 1.25 μMs, 0.625 μM, 0.3125 μM.Meanwhile, in another test tube, add the DMSO solution (final concentration is 0.5%) of 20 μ L, as the negative control without compound.To often propping up in test tube, add the bacterium liquid (inoculum size: substratum=1:100) that 40 μ L cultivate 12 hours respectively, and in 37 DEG C, after 250rpm cultivates 24 hours, take out bacterium liquid 1.5mL, 14000g, after centrifugal 2 minutes, removes supernatant, observe bacterial strain after adding the compounds of this invention of certain concentration, whether the golden yellow pigment of synthesis has obvious minimizing compared with negative control.Specifically see Fig. 1 and Fig. 2..
Embodiment 43
The compounds of this invention suppresses the IC of golden yellow pigment synthesis activity 50determination experiment method
The selection of compound concentration: according to primary dcreening operation result, determines that each compound suppresses the ability of golden yellow pigment synthesis.For there being comparatively strong active compound, as it still can the generation of strongly inhibited pigment when primary dcreening operation minimum concentration, then experiment can be continued, until compound can not suppress the generation of golden yellow pigment substantially by primary dcreening operation similar approach.Experimentally result, for the concentration gradient that each compound design 11 is different, makes it suppress the ability of pigment synthesis substantially to comprise 0% ~ 100%.The cultivation of bacterial strain: in from picking Newman bacterial strain TSA flat board and crtN mutant strain mono-clonal to the test tube of the aseptic TSB substratum of dress 4mL, 37 DEG C, after 250rpm cultivates 12 hours, for subsequent use.IC 50mensuration: get sterile test tube, to often propping up in test tube the TSB substratum 3980 μ L adding fresh sterilizing.Subsequently, in test tube, add the compounds of this invention of 11 concentration gradients that 20 μ L have prepared respectively.Meanwhile, in another two test tubes, add the DMSO solution (final concentration 0.5%) of 20 μ L respectively, as the contrast without compound.Newman (negative control) and crtN mutant strain (positive control) that 40 μ L cultivate 12 hours is added respectively in two test tubes adding DMSO solution.All the other add in the test tube of compound the Newman bacterial strain adding 40 μ L respectively and cultivate 12 hours.All test tubes are in 37 DEG C, and 250rpm changes after cultivating 12 hours to 30 DEG C, and 250rpm continues cultivation 36 hours to increase the accumulation of pigment.After completing cultivation, get 3mL bacterium liquid in 2mLEP pipe, 14000g, after centrifugal 2 minutes, removes supernatant, after PBS buffer solution twice (each 1mL), adds 300 μ L methanol solutions, heats and extract pigment in 3 minutes after spiral mixing in 55 DEG C of water-baths.Centrifugal 2 minutes of 14000g subsequently, draws methanol extract liquid and manages in 1.5mLEP, then add equivalent methanol solution, repeat extraction twice, merges the pigment extracted for three times.With the methanol extract liquid in crtN mutant for blank, the absorbance of each sample under mensuration 450nm wavelength, and measure the absorbance without compound negative control.The compounds of this invention at various concentrations, relative level=A450 (the sample)/A450 (negative control) × 100% of pigment synthesis.With the volumetric molar concentration of compound for abscissa, with the relative level of pigment synthesis for ordinate, in Graphpadprism5.0 software, carry out the fitting of a curve of inhibitor concentration-inhibiting rate (log (inhibitor) vsresponse), and suppress the IC of pigment synthesis according to fitting result computerized compound by software 50.
To the cumarone-7-alkyl amine compound of synthesis, choose streptococcus aureus, carry out the IC suppressing golden yellow pigment synthesis activity 50test, activity data is as shown in table 1.:
Table 1. cumarone-7-alkyl amine compound is to the inhibit activities data (IC of golden yellow pigment synthesis 50, nM)
As can be seen from Table 1,14 the compounds of this invention are had to have potent activities, wherein half effective inhibition concentration IC to the golden yellow pigment synthesis of suppression 50the active compound of <10nM has 5, half effective inhibition concentration 10nM<IC 50the active compound of <100nM has 7, half effective inhibition concentration 100nM<IC 50the active compound of <1000nM has 4.
Therefore, cumarone-7-alkyl amine the compounds main with general structure I of the present invention has the very strong inhibit activities to golden yellow pigment synthesis, illustrates that compound of the present invention can develop into antibacterials that are novel, the golden yellow pigment synthesis of target streptococcus aureus virulence factor.
Embodiment 44
The compounds of this invention I athe IC of the golden yellow pigment synthesis activity of-6 suppression resistant organism 50determination experiment method and result.
Except changing into except USA400MW2, USA300LAC and Mu50 by streptococcus aureus Newman, all the other methods are with embodiment 42. and embodiment 43..The results are shown in Figure 3..
As seen from Figure 3, Compound I of the present invention a-6, the synthesis for the golden yellow pigment of streptococcus aureus suppresses to be not limited to Newman bacterial strain, has potent restraining effect to Resistant strain USA400MW2, USA300LAC and Mu50 simultaneously.
Embodiment 45
The compounds of this invention I a-5, I a-6, I a-8, I a-9, I a-10 and I a-15 IC to key enzyme CrtN inhibit activities in golden yellow pigment synthesis process 50determination experiment method and result.
1) preparation of substrate diapophytoene emulsion
The pet28a::crtM/E.coli (DE3) of incubated overnight is forwarded in LB+ kantlex kanamycin (final concentration: the 50 μ g/ml) substratum of 50ml fresh sterile in the ratio of 1:100 (bacterium liquid: substratum), 37 DEG C, cultivate under 250rpm condition after 24 hours, 8000g, 4min collected by centrifugation thalline, and with PBS buffer solution twice.20ml acetone solution is added in thalline, vortex mixing is to extract pigment and intermediate product thereof, and in backward extracting solution, add 10ml normal hexane and 10mlNaCl (10%, mass/volume) solution, and thermal agitation is to remove the lubricant component in extracting solution, then collect the hexane layer containing pigment and intermediate product thereof, and add 10ml normal hexane again, repeat this leaching process once.Merge the hexane extraction liquid of twice, and add anhydrous MgSO 4carry out drying and weigh.The diapophytoene of acquisition and phosphatidylcholine are dissolved in 200 μ l chloroforms in the ratio of 1:3, and vacuum concentration is to dry.Every 8mgdiapophytoene adds 2ml0.02MHEPESbuffer (20mMHEPES, pH=7.5 with in 24mg phosphatidylcholine mixture; 500mMNaCl), then ultrasonic until form homogeneous latex emulsion in frozen water.
2) CrtN enzyme is lived and is analyzed
Related Component mother liquor configuration in reaction system: FAD10mM, glucose 200mM, glucose oxidase 2000U/ml, catalase, is dissolved as 20000U/ml by diapophytoene emulsion.Above-mentioned solution all configures with 0.02MHEPESbuffer.
Whole reaction system is 700 μ l, carries out in 2mlEP pipe.Reaction system comprises following composition: 50 μ ldiapophytoene emulsions (containing catalase), 70 μ l different concns compound (distilled water configuration) or distilled water, 262.5 μ l0.02MHEPESbuffer, 3.5 μ lFAD solution, 7 μ l glucose solutions, 7 μ l glucose oxidase solutions, finally add the full cell pyrolysis liquid (~ 1.41mgCrtN albumen) of 300 μ lpet28a::crtN/E.coli (DE3) and start reaction.Reaction carries out 14 hours, shaking table revolution 250rpm/min in 37 DEG C of shaking tables.
3) reaction product is extracted and is detected
After having reacted, add 500 μ l methyl alcohol termination reactions, and reaction solution is transferred in 15ml centrifuge tube.Add 700 μ l chloroforms in reaction solution, fully concussion vortex is with the pigment of abstraction reaction, then 7000rpm, and 3 minutes centrifugal, carefully draws chloroform layer.Reaction product is extracted adding 500 μ l chloroforms in residual reaction liquid, and merge reaction extracting solution and carry out being concentrated into dry in a vacuum.Enriched product adds 200 μ l chloroforms and dissolves, and sucks in the microwell plate of 96-hole, measures its absorbancy at 450 nm subsequently, quantitative for CrtN product diaponeurosporene.IC 50under being defined as experiment condition, suppress the concentration of the compound that the active half of CrtN is corresponding, CrtN enzyme being plotted in Graphpad5.0 of amount effect relation curve alive is carried out.
Table 2. cumarone-7-alkyl amine compound is to CrtN enzyme inhibition activity data (IC 50, μM)
As can be seen from Table 2, Compound I of the present invention a-5, I a-6, I a-8, I a-9, I a-10 and I a-15 is the inhibitor of key enzyme CrtN in potent golden yellow pigment synthesis process.
Embodiment 46
The compounds of this invention I a-6 to enhancing four kinds of streptococcus aureus (Newman, USA400MW2, USA300LAC and Mu50) hydrogen peroxide killing experiments methods and result.
The compound adding certain concentration in sterile test tube makes final concentration be 1 μM, and in inoculum size: the ratio of substratum=1:100 adds four kinds of streptococcus aureus bacterium liquid of incubated overnight.In 37 DEG C, 250rpm cultivated after about 24 hours, drew 500 μ l medium centrifugals, collected thalline, and washed twice with PBSbuffer.Then, add the abundant vortex of 500 μ lPBS solution, thalline is resuspended, and draw 15 μ l bacterium liquid and add in 1500 μ lPBSbuffer, abundant vortex mixing (OD=~ 0.1).Get 250 μ l and mix rear bacterium liquid in 2mlEP pipe, add the peroxidation Hydrogen solution of 10 μ l about 37%, make hydrogen peroxide final concentration in bacterium liquid be 1.5%.After adding hydrogen peroxide, by effective for EP sealed membrane capping, and be positioned over 37 DEG C, hatch 30 minutes under 250rpm condition, kill and wound.After separately getting 250 μ l mixings, bacterium liquid adds the aseptic PBSbuffer of 10 μ l, in contrast.After having reacted, add catalase (mother liquor: 20000U/ml, PBSbuffer configure) the solution 5 μ l vortex mixing that configure, to decompose remaining hydrogen peroxide.And get in the aseptic PBSbuffer of 100 μ l reaction solution to 900 μ l, carry out 10 times of dilutions, by that analogy, until dilution 10 6doubly.And above-mentioned diluent is put respectively 10 μ l on TSA flat board, the colony number of overnight incubation meter survival in 37 DEG C of incubators.Hydrogen peroxide kills and wounds rear Survival probability of bacteria calculating=(sample hydrogen peroxide kills and wounds the bacterial count × extension rate of rear growth)/(bacterial count × extension rate of control group bacterial growth) × 100%.The results are shown in Figure 4..
As seen from Figure 4, Compound I of the present invention a-6 can strengthen hydrogen peroxide killing and wounding four kinds of streptococcus aureuses significantly, and survival rate is significantly reduced.
Embodiment 47
The compounds of this invention I a-6 to enhancing four kinds of streptococcus aureus (Newman, USA400MW2, USA300LAC and Mu50) human blood killing experiments methods and result.
The compound adding certain concentration in sterile test tube makes final concentration be 1 μM, and in inoculum size: the ratio of substratum=1:100 adds four kinds of streptococcus aureus bacterium liquid of incubated overnight.In 37 DEG C, 250rpm cultivates after about 24 hours and draws 500 μ l medium centrifugals, collects thalline, and washes twice with PBSbuffer.Then, add the abundant vortex of 500 μ lPBS solution, thalline is resuspended, and draw 15 μ l bacterium liquid and add in 1500 μ lPBSbuffer, abundant vortex mixing (OD=~ 0.1).Then get the bacterium liquid of 150 μ lOD=0.1, add in the aseptic PBSbuffer of 850 μ l, make OD=~ 0.015, for subsequent use.Healthy human body fresh venous is collected with BDVACUTAINERPT pipe, get one, sterile glass test tube, successively add the bacterium liquid of 360 μ l fresh bloods and 40 μ lOD=~ 0.015 wherein, then in 37 DEG C, after 250rpm hatches 6 hours, and get in the aseptic PBSbuffer of 50 μ l reaction solution to 450 μ l, carry out 10 times of dilutions, by that analogy, until dilution 10 6doubly.The bacterium liquid separately getting OD=~ 0.015 in contrast, carries out 10 times of dilutions, until dilution 10 6doubly.And above-mentioned diluent is put respectively 10 μ l on TSA flat board, the colony number of overnight incubation meter survival in 37 DEG C of incubators.Blood kills and wounds rear Survival probability of bacteria calculating=(sample blood kills and wounds the bacterial count × extension rate of rear growth)/(bacterial count × extension rate/10 of control group bacterial growth) × 100%.The results are shown in Figure 5.
As seen from Figure 5, Compound I of the present invention a-6 can strengthen human blood killing and wounding four kinds of streptococcus aureuses significantly, and survival rate is significantly reduced.
Embodiment 48
The compounds of this invention I a-6 resist three kinds of streptococcus aureus (Newman, USA400MW2 and Mu50) activity test methods and result in Mice Body.
Experiment SPF level female BAl BIc/c mouse from Shanghai western pul-Bi Kai laboratory animal company limited buy, kept under sterile conditions to 6-8 week age.The staphylococcus aureus strains of incubated overnight is transferred in fresh sterile pancreas peptone soybean broth substratum (TryptoneSoybroth, TSB), and in 37 DEG C, continues cultivation 3 little of exponential phase of growth under 250rpm per minute condition.After PBS buffer solution twice, be suspended in PBS for subsequent use.In mouse infection experiment, mouse is randomized, and often organizes 15.All mouse, by abdominal injection vetanarcol (80mg/kg) anesthesia, then inject different bacterium amount infecting mouse (referring to following) of 100 μ l after eye socket.For the compounds for treating group of Newman infection model, I a-6 dosages are set to 200mg/kg, for the compounds for treating group of resistant organism (USA400MW2 and Mu50) infection model, arrange 200mg/kg and 50mg/kg two I a-6 dosage control groups, first time drug injection at bacteriological infection first 12 hours, inject altogether in metainfective 4 days 8 times (every day 2 times, 12 hours, interval, totally 9 times).After experiment terminates, mouse is by sucking CO 2be condemned to death.The heart of mouse, kidney and liver are removed, evenly the broken sterile PBS buffer (containing 0.01%tritonX-100) at 1mL.Broken liquid, by serial dilution, is got 10 μ L different concns diluents and is dropped on TSA flat board, measuring and calculating bacterium CFU counting.Bacterial count × the extension rate of bacterium under the number=specific extension rate of Different Organs.And in Graphpad5.0 software, adopt Mann-WhitneyTest (two-tailed) to carry out statistical analysis.Infective dose: Newman:1 × 10 7cFU; USA400MW:4 × 10 7cFU; Mu50:1.6 × 10 8cFU.In resistant organism (USA400MW2 and Mu50) infection model, BPH-652 is set as positive control.The results are shown in Figure 6., Fig. 7. and Fig. 8.
As seen from Figure 6, the compounds of this invention I a-6 can the field planting of reduction Newman bacterial strain in mouse kidney and liver of significance.In kidney, bacteria clearance reaches 85.9%.In heart, bacteria clearance reaches 90.2%.
As seen from Figure 7, the compounds of this invention I a-6 can the field planting of reduction USA400MW2 bacterial strain in mouse liver and kidney of significance, and result for the treatment of is better than positive control BPH-652.In liver, high dose group bacteria clearance is up to 99.6%, and low dose group bacteria clearance reaches 80.5%.In kidney, high dose group bacteria clearance is up to 96.6%, and low dose group bacteria clearance reaches 83.3%.
As seen from Figure 8, the compounds of this invention I a-6 can the field planting of reduction Mu50 bacterial strain in mouse liver and kidney of significance, and result for the treatment of is better than positive control BPH-652.In liver, high dose group bacteria clearance is up to 99.97%, and low dose group bacteria clearance reaches 99.9%.In kidney, high dose group bacteria clearance is up to 92.3%, and low dose group bacteria clearance reaches 79.2%.
Cumarone-7-alkyl amine molecular structure of compounds of the present invention is comparatively simple, and preparation technology is succinct, and production cost is low, in the golden yellow pigment synthesis Inhibition test pathogenic link with bacterium being had to substantial connection, all demonstrate stronger inhibit activities.Compound of the present invention presents more potent CrtN inhibit activities simultaneously, especially Compound I a-6, in vitro, the golden yellow pigment synthesis of potent suppression resistant organism USA400MW2, USA300LAC and Mu50, significantly can strengthen hydrogen peroxide and the human blood kill capability for four kinds of streptococcus aureuses simultaneously.In vivo, I a-6 significancees can reduce streptococcus aureus Newman, USA400MW2 and Mu50 at mouse kidney, field planting in heart and liver.Therefore, this series compound is not only expected to the antibacterials being developed to novel single drug mode, but also can be developed to the antibacterials with existing antibiotic combinations administering mode.

Claims (7)

1. a cumarone-7-alkyl amine compound is compound shown in formula I or its pharmaceutically acceptable salt:
In formula I, R 1for hydrogen or C 1~ C 3straight or branched alkyl, R 2for C 1~ C 6the C of aliphatic radical or replacement 1~ C 6aliphatic radical, n is the integer of 1 ~ 3;
Wherein, the C of described replacement 1~ C 6the substituting group of aliphatic radical is selected from: the cyclic hydrocarbon radical of 3 ~ 6 yuan or oxygen containing heterocyclic radical, a kind of in the cyclic hydrocarbon radical of 3 ~ 6 yuan of replacement or naphthyl;
The substituting group of the cyclic hydrocarbon radical of 3 ~ 6 yuan of described replacement is selected from: C 1~ C 4straight or branched alkyl, fluorine-containing C 1~ C 3straight or branched alkyl, C 1~ C 3straight or branched alkoxyl group, halogen, phenyl, nitro or middle one or two kinds, substituting group number is 1 or 2;
R 3for C 1~ C 3straight or branched alkyl.
2. cumarone-7-alkyl amine compound as claimed in claim 1, is characterized in that, wherein R 2for C 1~ C 6the C of aliphatic radical or replacement 1~ C 6aliphatic radical;
The C of described replacement 1~ C 6the substituting group of aliphatic radical is selected from: 3 ~ 6 yuan of cycloalkyl, 3 ~ 6 yuan of cycloalkyl of replacement, 5 ~ 6 yuan of aromatic ring yls or oxygen containing aromatic heterocyclic, a kind of in 5 ~ 6 yuan of aromatic ring yls of replacement or oxygen containing aromatic heterocyclic or naphthyl;
The substituting group of 3 ~ 6 yuan of cycloalkyl of described replacement is phenyl,
5 ~ 6 yuan of aromatic ring yls of described replacement or the substituting group of oxygen containing aromatic heterocyclic are selected from: C 1~ C 4straight or branched alkyl, fluorine-containing C 1~ C 3straight or branched alkyl, C 1~ C 3straight or branched alkoxyl group, halogen, nitro or middle one, R 3for C 1~ C 3straight or branched alkyl.
3. cumarone-7-alkyl amine compound as claimed in claim 2, is characterized in that, wherein R 2for C 1~ C 6the C of aliphatic radical or replacement 1~ C 6aliphatic radical;
The C of described replacement 1~ C 6the substituting group of aliphatic radical is selected from: cyclopentyl, cyclohexyl, the cyclopropyl that phenyl replaces, furyl, phenyl, a kind of in substituted-phenyl or naphthyl;
The substituting group of described substituted-phenyl is selected from: C 1~ C 4straight or branched alkyl, the C of perfluor 1~ C 3straight or branched alkyl, C 1~ C 3straight or branched alkoxyl group, halogen, nitro or middle one, R 3for C 1~ C 3straight or branched alkyl.
4. cumarone-7-alkyl amine compound as claimed in claim 3, is characterized in that, wherein R 2for a kind of in following groups:
5. cumarone-7-alkyl amine the compound as described in claim 1 or 4, it is characterized in that, described cumarone-7-alkyl amine compound is: (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-tolyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-trimethylphenylmethane base) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(naphthalene-2-base) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(naphthalene-1-base) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(2,4 dichloro benzene base) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-trifluoromethyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-fluorophenyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-bromophenyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-chloro-phenyl-) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-p-methoxy-phenyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-nitrophenyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(2-nitrophenyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(2-fluorophenyl) third-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(4-methyl-formiate phenyl) third-2-alkene-1-amine; (2E, 4E)-N-methyl-N-[(cumarone-7-base) methylene radical]-5-phenyl-penta-2,4-diene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-cyclohexyl-propyl-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-cyclopentyl-propyl-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-(furans-2-base)-propyl-2-alkene-1-amine; (E)-N, 2-dimethyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-but-2-ene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine; (E)-N-methyl-N-[(cumarone-7-base) methylene radical]-4-phenyl-Ding-3-alkene-1-amine; (E)-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine; (E)-N-ethyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine; (E)-N-sec.-propyl-N-[(cumarone-7-base) methylene radical]-3-phenyl-propyl-2-alkene-1-amine; N-methyl-N-[(cumarone-7-base) methylene radical]-1-[(1S, 2S)-2-phenycyclopropyl]-methylamine; N-methyl-N-[(6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-2-base) methyl]-3-phenyl-propyl-2-alkynes-1-amine or N-methyl-N-[(6,7,8,9-tetrahydrochysene-5H-benzo [7] annulene-2-base) methylene radical]-3-phenyl-propyl-1-amine.
6. as the application in the inhibitor of the key enzyme CrtN in the golden yellow pigment synthesis process of preparation of the cumarone-7-alkyl amine compound in Claims 1 to 5 as described in any one.
7. as the application of the cumarone-7-alkyl amine compound in Claims 1 to 5 as described in any one in preparation streptococcus aureus golden yellow pigment synthesis inhibitor class antibacterials.
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