CN105566262B - Alkyl amine compound of benzofuran 7 and application thereof - Google Patents

Alkyl amine compound of benzofuran 7 and application thereof Download PDF

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Publication number
CN105566262B
CN105566262B CN201610013304.0A CN201610013304A CN105566262B CN 105566262 B CN105566262 B CN 105566262B CN 201610013304 A CN201610013304 A CN 201610013304A CN 105566262 B CN105566262 B CN 105566262B
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benzofuran
amine
bases
compound
methyl
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CN105566262A (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

Abstract

The present inventor designs and has synthesized a kind of alkyl amine compound of benzofuran 7 with brand new.Test indicate that：Majority of compounds has potent inhibitory activity to golden yellow pigment synthesis in the alkyl amine compound of benzofuran 7 disclosed by the invention, some of which compound is to drug-fast bacteria (S.aureus USA400 MW2, USA300 LAC, Mu50) pigment inhibitory activity is extremely strong, in vitro the significantly killing of enhancing hydrogen peroxide and enhancing human blood killing.In vivo for sensitive strain (S.aureus Newman) and two plants of antibody-resistant bacterium (S.aureus USA400 MW2, Mu50) in the animal model of infection, bacterium can be significantly reduced to be colonized in mice viscera (kidney, the heart and liver).The present invention has established architecture basics further to design and develop new bacterial-infection resisting medicine from now on.

Description

Benzofuran -7- alkyl amine compounds and application thereof
Technical field
The present invention relates to a kind of benzofuran -7- alkyl amine compounds and its production and use, belong to medicine Learn and pharmacotherapeutics field.
Background technology
Staphylococcus aureus (Staphylococcus aureus, SA) is to cause health care related in world wide Most common pathogen is infected, from discovery so far, SA infection is almost extended over the entire globe.As the representative of gram-positive bacteria, it It is to cause most common pathogen in mankind's suppurative infection, local suppurative infection, pneumonia, pseudomembranous enteritis, the heart can be directly resulted in The general infections such as Bao Yan, meningitis, septicemia, pyemia.SA infection can divide hospital acquired infections and Community-acquired sense Dye, the possibility that the discovery of the latter further increases the potential biohazardous of this pathogenic bacteria and causes infection to break out.At present not Only it is found that staphylococcus aureus (the Methicillin-resistant Staphylococcus of methicillin-resistant Aureus, MRSA), it have also appeared the MRSA of high drug resistance (XDR) and complete drug resistance (TDR)；Even occur in that mould through the ages Plain intermediate-resistant staphylococcus aureus (Vancomycin-intermediate Staphylococcus aureus, VISA), staphylococcus aureus (Glycopeptide-intermediate of glycopeptide antibiotics intermediate-resistant Staphylococcus aureus, GISA) and characteristic of vancomycin-resistant Staphylococcus aureus (Vancomycin-resistant Staphylococcus aureus,VRSA).MRSA from evolve within 1961 come after with surprising rapidity in world's scope spreading, Have passed over two continents.2011, the U.S. had more than 80,000 people and suffers from MRSA infection, and 11285 people die from relevant disease (National Action Plan For Combating Antibiotic-Resistant Bacteria,2015,US).Have been reported that MRSA Infection, AIDS and hepatitis B are listed in the big infectious diseases in the world three, seriously threaten the health of the mankind, have caused complete The great attention of ball medical field.
In face of MRSA, the mankind remain with always it is now recognized that maximally effective " trump card ", that is, it is a kind of it is entitled " through the ages The antibiotic of mycin ".The side effect of vancomycin is very strong, has and seriously causes deaf property and renal toxicity, is clinically rarely employed.But it is existing When other antibiotic are all invalid to pathogen, vancomycin is re-enabled.However, being occurred in that in the U.S. within 2002 pair The staphylococcus aureus (VRSA) of vancomycin height resistance, its appearance makes the infection of staphylococcus aureus turn into again Very intractable clinical problem.
With the development of life science and medical science, it has been found that pathogen include staphylococcus aureus and have pathogenic be Because they by producing various virulence factors (Virulence factor) to help the field planting of bacterium, it is adhesion, thin Cellular toxicity, immune evasion etc. are so that bacterium successfully implements infection.At present, the effect machine of the antibiotic clinically used System is not the pathogenic link of directed toward bacteria, but suppresses bacterium by directly suppressing the most basic vital movement of pathogen Growth or directly kill bacterium, the bacterial antibiotic drug resistance thus triggered has become the bottle of antibiotic clinical practice Neck problem.Appearance just because of various drug-resistant bacterias and spread, the medicine (Anti-virulence of antibacterium virulence Drugs) turn into new bacterial-infection resisting medicine and study focus of interest.The medicine of current antibacterium virulence mainly passes through 5 kinds of approach play a role：(1) the toxin expression of containment object bacteria；(2) quorum sensing between bacterium is blocked；(3) toxin is suppressed Secretion and transmission；(4) links of bacterial adhesion are blocked；(5) suppress bacterial immune to escape.Any one has above-mentioned 5 kinds The medicine of one of effect can reduce the pathogenic of bacterium, effectively prevent and treat multi-infection disease.
It is emphasized that because the medicine of antibacterium virulence does not directly affect the living or death of thalline, but cut down bacterium It is pathogenic or release its arms, help the immune system effectively bacteria removal, selection pressure of the medicine to bacterium of human body It is smaller.Scientists predict that it can effectively reduce the generation of bacterial drug resistance, propagate and popular, and to the normal flora of human body (Normal flora) has less influence, can cooperate with and use with other conventional antibiotics, make up existing conventional antibiotic Weak point.On the other hand, the medicine of antibacterium virulence may be effective to having produced the bacterial strain of resistance, because no matter resisting For the bacterial strain of raw element resistance or sensitive strain, they are similar in terms of pathogenic molecule mechanism, in general.
2005, Univ California-San Diego USA (UCSD) Victor professors Nizet had found Staphylococcus aureus The golden yellow pigment (Staphyloxanthin) of bacterium, which has, helps staphylococcus aureus to escape the generation of human body innate immune system Active oxygen murder ability, be key factor for determining bacterium pathogenecity.University of Illinois of U.S. champagne school district Eric professors Oldfield etc. successfully have found that a known inhibitors of cholesterol synthesis BPH-652 can suppress golden yellow grape The formation of golden yellow pigment in coccus, so as to cut down pathogenecity of the staphylococcus aureus in Mice Body.Also some grind Study carefully report, golden yellow pigment can increase resistivity of the bacterium to oleic acid, in mouse subcutaneous infection model experiment, it is impossible to produce The abscess region that the plain mutant strain that adds lustre to triggers is significantly reduced compared with wild-type strain, implies that pigment can be by improving bacterium antioxygen The ability of change is so as to increase the virulence of bacterium.Thus, golden yellow pigment is determine staphylococcus aureus pathogenecity one Key factor.These existing Preliminary Studies confirm that the golden yellow pigment synthesis of the virulence factor for suppressing staphylococcus aureus is 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 thereby resulted in is particularly Prominent, some bacteriums being clinically separated have been occupied first place in the world to the drug resistance of some antibiotic.In face of severe bacteria antibiotic Drug resistance, we need the new antibacterials action target spot of discovery and new bacterial-infection resisting medicine badly.Therefore, research and develop The antibacterials of anti-golden yellow pigment synthesis have important practical significance and scientific value.
The content of the invention
The present inventor designs and has synthesized a kind of benzofuran -7- alkyl amine chemical combination with brand new Thing.Test indicate that：The majority of compounds of the present invention has potent inhibitory activity to golden yellow pigment synthesis (with golden yellow color Crucial enzyme CrtN is action target in plain building-up process), some of which compound is to drug-fast bacteria (S.aureus USA400MW2, USA300LAC, Mu50) pigment inhibitory activity is extremely strong, significantly the killing of enhancing hydrogen peroxide and strengthens in vitro Human blood is killed.In vivo for sensitive strain (S.aureus Newman) and two plants of antibody-resistant bacterium (S.aureus USA400 MW2, Mu50) infection animal model in, bacterium can be significantly reduced and be colonized in the mice viscera (kidney, the heart and liver), be to enter from now on One step designs and develops new bacterial-infection resisting medicine and has established architecture basics.
A purpose of the invention is that there is provided a kind of novel benzofuran -7- alkyl amine compounds of structure.
Benzofuran -7- alkyl amine compounds of the present invention, be compound shown in Formulas I or its pharmaceutically may be used The salt of receiving：
In Formulas I, R1For hydrogen (H) or C1~C3Straight or branched alkyl, R2For C1~C6Aliphatic group or substituted C1~C6Fat hydrocarbon Base, n is 1~3 integer；
Wherein, the substituted C1~C6The substituent of aliphatic group is selected from：3~6 yuan of cyclic hydrocarbon radical or oxygen-containing (O) heterocyclic radical, It is a kind of in 3~6 yuan of the cyclic hydrocarbon radical or naphthyl of substitution；
The substituent of 3~6 yuan substituted of the cyclic hydrocarbon radical is selected from：C1~C4Straight or branched alkyl, fluorine-containing C1~C3 Straight or branched alkyl, C1~C3Straight or branched alkoxyl, halogen (F, Cl, Br or I, similarly hereinafter), phenyl, nitro (NO2) or(R3For C1~C3Straight or branched alkyl) in it is a kind of or two kinds, substituent number is 1 or 2.
Another object of the present invention is, discloses above-mentioned benzofuran -7- alkyl amines compound (chemical combination shown in Formulas I Thing or its pharmaceutically acceptable salt) a kind of purposes, i.e., shown in Formulas I compound or its pharmaceutically acceptable salt exist Prepare the application in the golden yellow pigment synthesis inhibitor class antibacterials of staphylococcus aureus.Or,
Compound shown in Formulas I or its pharmaceutically key of acceptable salt during golden yellow pigment synthesis is prepared Application in enzyme CrtN inhibitor.
Brief description of the drawings
Fig. 1 are the compounds of this invention IA- 6 suppress the final photograph of golden yellow pigment synthesis；
Wherein, I from left to rightA- 6 concentration is followed successively by 50 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0 μM.
Fig. 2 are the compounds of this invention IC- 1 suppresses the final photograph of golden yellow pigment synthesis；
Wherein, I from left to rightC- 1 concentration is followed successively by 50 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0 μM.
Fig. 3 are compound IAThe golden yellow pigment of -6 pairs of drug-fast bacteria USA400MW2 (A), USA300LAC (B) and Mu50 (C) Inhibitory activity data (the IC of synthesis50, nM)；
Fig. 4 are compound IA- 6 pairs of enhancing Newman (A, survival 36.2%vs 1.2%), USA400MW2 (B, Survival 11.7%vs 0.6%), USA300LAC (C, survival 14.2%vs 0.7%) and Mu50 (D, Survival 25.3%vs 4.3%) hydrogen peroxide killing experiments result.
Fig. 5 are compound IA- 6 pairs of enhancing Newman (A, survival 26.7%vs 0.8%), USA400MW2 (B, Survival 10.2%vs 1.3%), USA300LAC (C, survival 12.1%vs 1.2%) and Mu50 (D, Survival 16.1%vs 3.0%) human blood killing experiments result.
Fig. 6 are the compounds of this invention IA- 6 reduction staphylococcus aureus Newman depositing in mouse kidney and heart Motility rate result.
Fig. 7 are the compounds of this invention IA- 6 reduction staphylococcus aureus USA400MW2 are in mouse liver and kidney Survival results.
Fig. 8 are the compounds of this invention IASurvivals of -6 reduction staphylococcus aureus Mu50 in mouse liver and kidney Rate result.
Embodiment
In a preferred technical scheme of the invention, R2For C1~C6Aliphatic group or substituted C1~C6Aliphatic group；
The substituted C1~C6The substituent of aliphatic group is selected from：3~6 yuan of cycloalkyl, 3~6 yuan of substituted cycloalkyl, 5~ It is a kind of in 6 yuan of aromatic ring yls or oxygen-containing (O) aromatic heterocyclic, 5~6 yuan of substituted aromatic ring yls or oxygen-containing (O) aromatic heterocyclic or naphthyl；
The substituent of 3~6 yuan of substituted cycloalkyl is phenyl,
The substituent of 5~6 yuan of substituted aromatic ring yls or oxygen-containing (O) aromatic heterocyclic is selected from：C1~C4Straight or branched alkane Base, fluorine-containing C1~C3Straight or branched alkyl, C1~C3Straight or branched alkoxyl, halogen, nitro (NO2) or(R3For C1~C3Straight or branched alkyl) in it is a kind of.
In further optimal technical scheme, R2For C1~C6Aliphatic group or substituted C1~C6Aliphatic group；
The substituted C1~C6The substituent of aliphatic group is selected from：Cyclopenta, cyclohexyl, the cyclopropyl of phenyl substitution, furans It is a kind of in base, phenyl, substituted-phenyl or naphthyl；
The substituent of the substituted-phenyl is selected from：C1~C4Straight or branched alkyl (such as methyl, ethyl or the tert-butyl group), The C of perfluor1~C3Straight or branched alkyl (such as trifluoromethyl, pentafluoroethyl group or heptafluoropropyl), C1~C3Straight or branched alkane Epoxide (such as methoxyl group, ethyoxyl or propoxyl group), halogen, nitro (NO2) or(R3For methyl, ethyl or propyl group) in one Kind.
In further optimal technical scheme, R2For one kind in following groups：
The method that the present invention also provides compound shown in a kind of synthesis type I, exemplified by synthesizing the compound that n is 1, it is synthesized Strategy is as follows：
Specifically include following steps：
1) 2- iodophenols are dissolved in DMF, add sodium hydride to bubble-free and produce, add 2- bromo- 1, 1- diethoxyethane, is stayed overnight in stirring reaction at 90 DEG C.Room temperature is cooled to, water is added into reaction system, ethyl acetate is used Extraction three times, saturated common salt washing, anhydrous magnesium sulfate is dried, and is filtered, and concentration, residue obtains 1- (2,2- through column chromatography for separation Diethoxy ethyoxyl) -2- iodobenzenes (intermediate II)；
2) intermediate II and polyphosphoric acids are added in toluene, heated overnight at reflux.After reaction terminates, while hot by reactant System is poured into the sodium hydrate aqueous solution of saturation, is extracted with ethyl acetate three times, and saturated common salt washing, anhydrous magnesium sulfate is dried, Filtering, concentration, residue obtains 7- iodos benzofuran (intermediate III) through column chromatography for separation；
3) by intermediate III, cuprous cyanide is added in DMF, is heated to reflux 10~20 hours.It is cold But to room temperature, concentrated ammonia liquor is added into system, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous magnesium sulfate is dried, mistake Filter, concentration, residue obtains benzofuran -7- formonitrile HCNs (intermediate compound IV) through column chromatography for separation；
4) anhydrous tetrahydrofuran solution of intermediate compound IV is slowly dropped to lithium aluminium hydride reduction under subzero 78 DEG C, nitrogen protection Anhydrous tetrahydro furan suspension in, 20 DEG C~30 DEG C reactions are stayed overnight after completion of dropping, and water is sequentially added into reaction system, 15% sodium hydrate aqueous solution, water quenching is gone out reaction, and anhydrous sodium sulfate drying is directly added in reaction system, is filtered, is concentrated to give (benzofuran -7- bases) methylamine (intermediate V)；
5) intermediate V is dissolved in tetrahydrofuran, adds sodium hydroxide and stir 5~10 minutes, two are slowly added under ice bath The tetrahydrofuran solution of dimethyl dicarbonate butyl ester.0 DEG C~30 DEG C stirring reactions 1~3 hour.Filtering, concentration, residue is through column chromatography Separation, obtains N- [(benzofuran -7- bases) methylene]-t-butyl carbamate (intermediate VI)；
6) intermediate VI anhydrous tetrahydrofuran solution is slowly dropped to the nothing of lithium aluminium hydride reduction under 0 DEG C, nitrogen protection In water tetrahydrofuran suspension, heating reflux reaction 10~20 hours, water is sequentially added into reaction system after completion of dropping, 15% sodium hydrate aqueous solution, water quenching is gone out reaction, and anhydrous sodium sulfate drying is directly added in reaction system, is filtered, is concentrated to give N- [(benzofuran -7- bases) methylene]-methylamine (intermediate VII)；
7) (E) -2- substitutions -3- substitutions-methacrylaldehyde is dissolved in methanol, sodium borohydride is added portionwise under ice bath, room temperature is anti- Answer 10~30 minutes.Water is added in concentration, residue, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous magnesium sulfate is done Dry, filtering is concentrated to give (E) -2- substitutions -3- substitutions-propenyl (intermediate VIII)；
8) intermediate VIII is dissolved in absolute ether, under nitrogen protection ice bath, adds phosphorus tribromide, 20~30 DEG C of reactions 10~20 hours, in the saturated sodium bicarbonate solution that reaction system is poured into ice, three times, saturated aqueous common salt are extracted with ethyl acetate Wash, anhydrous magnesium sulfate is dried, filtering, 30 DEG C are concentrated to give (E) -2- substitutions -3- substitutions-propylene bromine (intermediate compound I X)；
9) by intermediate VII, intermediate compound I X, potassium carbonate is added in DMF, 20 DEG C~30 DEG C reactions 10~20 hours, water is added into reaction system, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous sodium sulfate drying, Filtering, concentration, residue through column chromatography for separation, obtain compound (E)-N- methyl-N- [(benzofuran -7- bases) methylene] - 2- substitutions -3- substitutions -propyl- 2- alkene -1- amine (object IA)。
Or
The step of synthetic intermediate VII (i.e. step 1)~6)) with it is described previously identical；
7) by substituted carboxylic acid, thionyl chloride is added in ethanol solution, is heated to reflux 1~3 hour.It is dense after reaction terminates Contracting, washing, obtains substituted carboxylic acid ethyl ester (intermediate X I)；
8) intermediate X I is dissolved in anhydrous tetrahydro furan, nitrogen is protected and is slowly added to diisobutyl aluminium hydride at 0 DEG C Toluene solution, 20 DEG C~30 DEG C are reacted 10~20 hours, add methanol and reaction is quenched, filter, concentration, and residue is through column chromatography point From, obtain substitution methanol (intermediate X II)；
9) intermediate X II is dissolved in absolute ether, under nitrogen protection ice bath, adds phosphorus tribromide, 20 DEG C~30 DEG C anti- Answer 10~20 hours, in the saturated sodium bicarbonate solution that reaction system is poured into ice, three times, saturated common salt are extracted with ethyl acetate Washing, anhydrous magnesium sulfate is dried, filtering, and 30 DEG C are concentrated to give substitution bromomethane (intermediate X III)；
10) by intermediate VII, intermediate X III, potassium carbonate is added in DMF, and 20 DEG C~30 DEG C anti- Answer 10~20 hours.After reaction terminates, water is added into reaction system, is extracted with ethyl acetate three times, saturated common salt washing, nothing Aqueous sodium persulfate is dried, and is filtered, and concentration, residue obtains compound N-methy-N- [(benzofuran -7- bases) through column chromatography for separation Methylene]-substitution-methylamine (object IC)。
Or,
The step of synthetic intermediate VII (i.e. step 1)~6)) with it is described previously identical；
7) replace 3- -propyl- 2- alkynes -1- alcohol is dissolved in absolute ether, under nitrogen protection ice bath, adds phosphorus tribromide, 20 DEG C~30 DEG C react 10~20 hours.In the saturated sodium bicarbonate solution that reaction system is poured into ice, three are extracted with ethyl acetate Secondary, saturated common salt washing, anhydrous magnesium sulfate is dried, filtering, and 30 DEG C are concentrated to give the bromo- 1- substitutions of 3- -propyl- 1- alkynes (intermediates XIV)；
8) by intermediate VII, intermediate X IV, potassium carbonate is added in DMF, 20~30 DEG C of reactions 10 ~20 hours.Water is added into reaction system, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous sodium sulfate drying, mistake Filter, concentration, residue through column chromatography for separation, obtain compound N-methy-N- [(benzofuran -7- bases) methylene] -3- substitution - Propyl- 2- alkynes -1- amine (object ID)。
Or,
The step of synthetic intermediate VII (i.e. step 1)~6)) with it is described previously identical；
7) by intermediate VII, 3- substitution -1- N-Propyl Bromides, potassium carbonate is added in DMF, and 20 DEG C~30 DEG C reaction 10~20 hours.Water is added into reaction system, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous slufuric acid Sodium is dried, and is filtered, and concentration, residue obtains compound N-methy-N- [(benzofuran -7- bases) methylenes through column chromatography for separation Base] -3- substitutions -propyl- 1- amine (object IE)。
Or,
The step of synthetic intermediate V (i.e. step 1)~4)) with it is described previously identical；
5) by intermediate V, E-3- substitutions-methacrylaldehyde, molecular sieve is added in dichloromethane, heating reflux reaction 15~30 Hour, room temperature is cooled to, is filtered, concentration, residue obtains (E, E)-N- (3- substitutions -propyl- 2- alkene -1- forks through column chromatography for separation Base)-N- (benzofuran -7- bases) methylamine (intermediate X)；
6) intermediate X is dissolved in methanol, under condition of ice bath, sodium borohydride is added portionwise, reacts at room temperature 10~30 minutes, Water is added in concentration, residue, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous sodium sulfate drying is filtered, concentration Obtain intermediate (E)-N- [(benzofuran -7- bases) methylene] -3- substitutions -propyl- 2- alkene -1- amine (object IBa)；
7) by object IBaIt is dissolved in anhydrous DMF, under condition of ice bath, sodium hydride is added portionwise, stirs Reaction 10~30 minutes, adds idoalkane, and nitrogen protects 20~30 DEG C to react 10~20 hours, water is added into reaction system, Be extracted with ethyl acetate three times, saturated common salt washing, anhydrous sodium sulfate drying, filter, concentration, residue through column chromatography for separation, Obtain compound (E)-N-R1- N- [(benzofuran -7- bases) methylene] -3- substitutions -propyl- 2- alkene -1- amine (object IBb)。
Wherein, R1And R2Definition with it is described previously identical.
According to the teaching of above-mentioned synthetic method, those skilled in the art are without creative work, you can obtain Formulas I and included All compounds.
The present invention will be further illustrated below in an example.These embodiments are merely to illustrate the present invention, no Limit the scope of the invention in any way.All parameters and remaining explanation in embodiment, unless otherwise indicated, All it is for unit with quality (gram).
Embodiment 1
The preparation of 1- (2,2- diethoxies ethyoxyl) -2- iodobenzenes (intermediate II)：
30 grams of 2- iodophenols are dissolved in 200 milliliters of DMFs, 6 grams of sodium hydrides to bubble-free is added and produces It is raw, bromo- 1, the 1- diethoxyethane of 31 milliliters of 2- is added, is stayed overnight in stirring reaction at 90 DEG C.Room temperature is cooled to, to reaction system Middle addition water, is extracted with ethyl acetate three times, and saturated common salt washing, anhydrous magnesium sulfate is dried, and is filtered, concentration, and residue is through silicon Plastic column chromatography separates (ethyl acetate/petroleum ether=1:25) title compound, 42.8 grams of colorless oils, yield 93% are obtained.
1H-NMR(400MHz,CDCl3) δ 7.77 (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- iodos benzofuran (intermediate III)：
42.8 grams of intermediate IIs and 85 grams of polyphosphoric acids are added in 200 milliliters of toluene, heated overnight at reflux.Reaction terminates Afterwards, reaction system is poured into the sodium hydrate aqueous solution of saturation while hot, be extracted with ethyl acetate three times, saturated common salt washing, Anhydrous magnesium sulfate is dried, and is filtered, and concentration, residue separates (petroleum ether) through silica gel column chromatography and obtains title compound, 17 grams of nothings Color oil, yield 55%.
1H-NMR (400MHz, Acetone) δ 7.95 (s, 1H), 7.70 (dd, J=17.8,7.5Hz, 2H), 7.09 (d, J =9.0Hz, 2H).
Embodiment 3
The preparation of benzofuran -7- formonitrile HCNs (intermediate compound IV)：
By 17 grams of intermediate IIIs, 12.5 grams of cuprous cyanides are added in 150 milliliters of DMFs, heated back Flow through night.After intermediate III reaction completely, room temperature is cooled to, concentrated ammonia liquor to solution is added into system and is clarified, ethyl acetate is used Extraction three times, saturated common salt washing, anhydrous magnesium sulfate is dried, and is filtered, and concentration, residue separates (acetic acid second through silica gel column chromatography Ester/petroleum ether=1:25) title compound, 9 grams of white solids, yield 90%, are obtained.
1H-NMR(400MHz,CDCl3) δ 7.84 (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 benzofuran -7- base methylamines (intermediate V)：
By 100 milliliters of anhydrous tetrahydrofuran solutions of 9 grams of intermediate compound IVs, it is slowly added dropwise under subzero 78 DEG C, nitrogen protection Into 100 milliliters of anhydrous tetrahydro furan suspensions of 9 grams of lithium aluminium hydride reductions, room temperature reaction is stayed overnight after completion of dropping.To reaction system In sequentially add 9 milliliters of water, 9 milliliter of 15% sodium hydrate aqueous solution, 9 milliliters of water quenchings are gone out reaction, directly in reaction system plus Enter anhydrous sodium sulfate drying, filter, be concentrated to give 9 grams of pale yellowish oil title compounds, yield 97%.
1H-NMR (400MHz, MeOD) δ 7.77 (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- (benzofuran -7- ylmethyls)-t-butyl carbamate (intermediate VI)：
9 grams of intermediate V are dissolved in 100 milliliters of tetrahydrofuran solutions, 4.6 grams of sodium hydroxides is added and stirs 5 minutes, ice bath Under be slowly added to 100 milliliters of tetrahydrofuran solutions dissolved with 21 milliliters of di-tert-butyl dicarbonates.Reaction 1 hour is stirred at room temperature.Cross Filter, concentration, residue separates (ethyl acetate/petroleum ether=1 through silica gel column chromatography:25) title compound, is obtained, 12.5 grams shallow Yellow solid, yield 83%
1H-NMR(400MHz,CDCl3) δ 7.64 (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- (benzofuran -7- bases)-N- methyl methylamines (intermediate VII)：
12.6 grams of intermediate VI 100 milliliters of anhydrous tetrahydrofuran solutions are slowly dropped under 0 DEG C, nitrogen protection In 50 milliliters of anhydrous tetrahydro furan suspensions of 7.7 grams of lithium aluminium hydride reductions, heating reflux reaction 12 hours after completion of dropping.Reaction knot Shu Hou, sequentially adds 8 milliliters of water, 8 milliliter of 15% sodium hydrate aqueous solution into reaction system, and 8 milliliters of water quenchings are gone out reaction, directly Anhydrous sodium sulfate drying is added in reaction system, filters, is concentrated to give title compound, 7.8 grams of yellow oils, yield 95%.
1H-NMR(400MHz,CDCl3) δ 7.63 (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- tolyls) -propyl- 2- alkene -1- alcohol (intermediate VIII-1)：
100 milligrams of (E) -3- (4- tolyls)-methacrylaldehyde are dissolved in 10 ml methanols, 26 milligrams are added portionwise under ice bath Sodium borohydride, is reacted at room temperature 15 minutes.Water is added in concentration, residue, is extracted with ethyl acetate three times, saturated common salt washing, Anhydrous magnesium sulfate is dried, filtering, is concentrated to give title compound, 99 milligrams of oil directly cast single step reaction, yield 98%.
Embodiment 8
(E) preparation of the bromo- propylene (intermediate compound I X-1) of -1- (4- tolyls) -3-：
370 milligrams of intermediate VIII-1 are dissolved in 20 milliliters of absolute ethers, under nitrogen protection ice bath, 85 microlitre three are added Phosphonium bromide, room temperature reaction is stayed overnight.After reaction terminates, in the saturated sodium bicarbonate solution that reaction system is poured into ice, acetic acid second is used Ester is extracted three times, and saturated common salt washing, anhydrous magnesium sulfate is dried, filtering, and 30 DEG C are concentrated to give title compound, 395 milligrams of whites Solid, yield 85%.
1H-NMR(400MHz,CDCl3) δ 7.27 (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- [(benzofuran -7- bases) methylene] -3- (4- tolyls) propyl- 2- alkene -1- amine (compounds IA- 1) preparation.
By 120 milligrams of intermediate VII, 148 milligrams of intermediate compound I X-1,116 milligrams of potassium carbonate are added to 10 milliliters of N, N- bis- In NMF, room temperature reaction is stayed overnight.After reaction terminates, water is added into reaction system, is extracted with ethyl acetate three times, satisfied With salt washing, anhydrous sodium sulfate drying is filtered, concentration, residue separate through silica gel column chromatography (ethyl acetate/petroleum ether= 1:5) title compound, 145 milligrams of colorless oils, yield 67%, are obtained.
In order to be purified, compound is entered to be dissolved in 1 milliliter of ethyl acetate, one minute hydrogen chloride gas is passed through, by it Hydrochloride is made, solvent evaporated, the petrol ether/ethyl acetate mixed solvent of addition 1/100 separates out white hydrochloride salt solid, taken out Filter, washing, obtains compound IA- 1 hydrochloride.1H-NMR is its hydrochloride form data.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C20H22NO(M+H)+ 292.1701,found292.1707。
Embodiment 10
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- 2-methyl-2-phenylpropanes base) propyl- 2- alkene -1- amine (chemical combination Thing IA- 2) preparation：
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (4- 2-methyl-2-phenylpropanes base)-methacrylaldehyde, remaining institute Raw material, reagent and preparation method be the same as Example 7-9 are needed, 122 milligrams of title compound as oil are obtained, yield is 49%.The chemical combination Thing hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C23H28NO(M+H)+334.2171,found 334.2172。
Embodiment 11
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (naphthalene -2- bases) propyl- 2- alkene -1- amine (compounds IA- 3) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (naphthalene -2- bases)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 116 milligrams of colorless oil title compounds, yield is 47%.The chemical combination Thing hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 8.00-7.85 (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/z calcd for C23H22NO(M+H)+328.1701,found 328.1701。
Embodiment 12
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (naphthalene -1- bases) propyl- 2- alkene -1- amine (compounds IA- 4) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (naphthalene -1- bases)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 144 milligrams of colorless oil title compounds, yield is 59%.The chemical combination Thing hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 8.20 (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/z calcd for C23H22NO(M+H)+328.1701,found 328.1698。
Embodiment 13
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (2,4 dichloro benzene base) propyl- 2- alkene -1- amine (is changed Compound IA- 5) preparation.
Except (E) -3- (4- tolyls)-methacrylaldehyde is changed into outside (E) -3- (2,4- dichlorophenyl)-methacrylaldehyde, remaining Required raw material, reagent and preparation method be the same as Example 7-9, obtain 146 milligrams of title compound as oil, and yield is 57%.The change Compound hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.90 (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/z calcd for C19H18Cl2NO(M+H)+346.0765,found 346.0750。
Embodiment 14
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- trifluoromethyls) propyl- 2- alkene -1- amine (compound IA- 6) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (4- trifluoromethyls)-methacrylaldehyde, its Raw material, reagent and preparation method be the same as Example 7-9 needed for remaining, obtain 111 milligrams of title compound as oil, yield is 43%.Should Compound hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.94 (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/z calcd for C20H19F3NO(M+H)+346.1419,found 346.1406。
Embodiment 15
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- fluorophenyls) propyl- 2- alkene -1- amine (compounds IA- 7) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (4- fluorophenyls)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 120 milligrams of colorless oil title compounds, yield is 50%.The chemical combination Thing hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.90 (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/z calcd for C19H19FNO(M+H)+296.1451,found 296.1449。
Embodiment 16
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- bromophenyls) propyl- 2- alkene -1- amine (compounds IA- 8) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (4- bromophenyls)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 122 milligrams of colorless oil title compounds, yield is 46%.The chemical combination Thing hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C19H19BrNO(M+H)+356.0650,found 358.0634。
Embodiment 17
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- chlorphenyls) propyl- 2- alkene -1- amine (compounds IA- 9) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (4- chlorphenyls)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 143 milligrams of colorless oil title compounds, yield is 61%.The chemical combination Thing hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.90 (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/z calcd for C19H19ClNO(M+H)+312.1155,found 312.1148。
Embodiment 18
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- methoxyphenyls) propyl- 2- alkene -1- amine (is changed Compound IA- 10) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (4- methoxyphenyls)-methacrylaldehyde, remaining institute Raw material, reagent and preparation method be the same as Example 7-9 are needed, 113 milligrams of colorless oil title compounds are obtained, yield is 49%.Should Compound hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C20H22NO2(M+H)+ 308.1651,found 308.1653。
Embodiment 19
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- nitrobenzophenones) propyl- 2- alkene -1- amine (chemical combination Thing IA- 11) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (4- nitrobenzophenones)-methacrylaldehyde, needed for remaining Raw material, reagent and preparation method be the same as Example 7-9, obtain 143 milligrams of title compound as yellow oil, and yield is 59%.The change Compound hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 8.28 (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/z calcd for C19H19N2O3(M+H)+323.1396,found 323.1393。
Embodiment 20
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (2- nitrobenzophenones) propyl- 2- alkene -1- amine (chemical combination Thing IA- 12) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (2- nitrobenzophenones)-methacrylaldehyde, needed for remaining Raw material, reagent and preparation method be the same as Example 7-9, obtain 178 milligrams of title compound as yellow oil, and yield is 74%.The change Compound hydrochloride is yellow solid.
1H-NMR (400MHz, MeOD) δ 8.06 (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/z calcd for C19H19N2O3(M+H)+323.1396,found 323.1393。
Embodiment 21
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (2- fluorophenyls) propyl- 2- alkene -1- amine (compounds IA- 13) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (2- fluorophenyls)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 117 milligrams of colorless oil title compounds, yield is 53%.The chemical combination Thing hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C19H19FNO(M+H)+296.1451,found 296.1452。
Embodiment 22
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- methyl formates phenyl) propyl- 2- alkene -1- amine (compound IA- 14) preparation.
In addition to intermediate VIII-1 to be changed into intermediate (E) -4- phenyl-but-2-ene -1- alcohol, remaining required raw material, examination Agent and preparation method be the same as Example 8-9, obtain 212 milligrams of colorless oil title compounds, and yield is 85%.The compound hydrochloric acid Salt is yellow oil.
1H-NMR (400MHz, MeOD) δ 8.05 (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/z calcd for C21H22NO3(M+H)+336.1600,found 336.1597。
Embodiment 23
(2E, 4E)-N- methyl-N- [(benzofuran -7- bases) methylene] -5- phenyl-amyl- 2,4- diene -1- amine (chemical combination Thing IA- 15) preparation.
Except intermediate VIII-1 is changed into outside intermediate (2E, 4E) -5- phenyl-amyl- 2,4- diene -1- alcohol, remaining institute Raw material, reagent and preparation method be the same as Example 8-9 are needed, 73 milligrams of colorless oil title compounds are obtained, yield is 42%.The change Compound hydrochloride is yellow oil.
1H-NMR (400MHz, MeOD) δ 7.92 (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/z calcd for C21H22NO(M+H)+304.1701,found 304.1695。。
Embodiment 24
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- cyclohexyl -propyl- 2- alkene -1- amine (compound IA- 16) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (cyclohexyl)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 89 milligrams of colorless oil title compounds, yield is 42%.The compound Hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.94 (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/z calcd for C19H26NO(M+H)+284.2014,found 284.2008。
Embodiment 25
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- cyclopenta -propyl- 2- alkene -1- amine (compound IA- 17) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (cyclopenta)-methacrylaldehyde, original needed for remaining Material, reagent and preparation method be the same as Example 7-9, obtain 78 milligrams of colorless oil title compounds, yield is 39%.The compound Hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C18H24NO(M+H)+270.1858,found 270.1862。
Embodiment 26
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (furans -2- bases) -propyl- 2- alkene -1- amine (chemical combination Thing IA- 18) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -3- (furans -2- bases)-methacrylaldehyde, needed for remaining Raw material, reagent and preparation method be the same as Example 7-9, obtain 116 milligrams of pale yellowish oil title compounds, and yield is 58%.Should Compound hydrochloride is light yellow oil.
1H-NMR (400MHz, MeOD) δ 7.90 (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/z calcd for C17H18NO2(M+H)+268.1338,found 268.1334。
Embodiment 27
(E)-N, 2- dimethyl-N-[(benzofuran -7- bases) methylene] -3- phenyl -propyl- 2- alkene -1- amine (compounds IA- 19) preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E) -2- methyl -3- phenyl-propenals, needed for remaining Raw material, reagent and preparation method be the same as Example 7-9, obtain 150 milligrams of colorless oil title compounds, and yield is 67%.The change Compound hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.92 (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/z calcd for C20H22NO(M+H)+292.1701,found 292.1607。
Embodiment 28
(E)-N- methyl-N- [(benzofuran -7- bases) methylene]-but-2-ene -1- amine (compound IA- 20) preparation.
In addition to changing the bromo- propylene of (E) -1- (4- tolyls) -3- into 2- butylene bromides, remaining required raw material, reagent and Preparation method be the same as Example 9, obtains 81 milligrams of colorless oil title compounds, and yield is 50%.The compound hydrochloride is Huang Color grease.
1H-NMR (400MHz, MeOD) δ 7.94 (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/z calcd for C14H18NO(M+H)+216.1388,found 216.1383。
Embodiment 29
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- phenyl -propyl- 2- alkene -1- amine (compound IA-21) Preparation.
In addition to changing (E) -3- (4- tolyls)-methacrylaldehyde into (E)-cinnamic acid, remaining required raw material, reagent and preparation Method be the same as Example 7-9, obtains 115 milligrams of colorless oil title compounds, and yield is 56%.The compound hydrochloride is white Solid.
1H-NMR (400MHz, MeOD) δ 7.94 (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/z calcd for C19H20NO(M+H)+278.1545,found 278.1539.
Embodiment 30
(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -4- phenyl-butyl- 3- alkene -1- amine (compound IA-22) Preparation.
In addition to intermediate VIII-1 to be changed into intermediate (E) -4- phenyl-butyl- 3- alkene -1- alcohol, remaining required raw material, examination Agent and preparation method be the same as Example 8-9, obtain 90 milligrams of colorless oil title compounds, and yield is 42%.The compound hydrochloric acid Salt is yellow oil.
1H-NMR (400MHz, MeOD) δ 7.90 (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/z calcd for C20H22NO(M+H)+292.1701,found 292.1695.
Embodiment 31
(E, E)-N- (3- phenyl -propyl- 2- alkene -1- forks base)-(6,7,8,9- tetrahydrochysene -5H- benzos [7] annulene -1- bases) first The preparation of amine (intermediate X -1).
By 294 milligrams of intermediate V, 264 milligrams of trans-cinnamic aldehydes, 1 gram molecule sieve is added to 25 milliliters of dichloromethane solutions In, heating reflux reaction 17 hours.After reaction terminates, room temperature is cooled to, is filtered, concentration directly casts one without isolating and purifying Step.
Embodiment 32
(E)-N- [(benzofuran -7- bases) methylene] -3- phenyl -propyl- 2- alkene -1- amine (compound IB- 1) preparation.
Intermediate X is dissolved in methanol, 76 milligrams of sodium borohydrides are added portionwise under ice bath, is reacted at room temperature 10~30 minutes. Water is added in concentration, residue, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous sodium sulfate drying, filtering is obtained 97 milligrams of title compound as yellow oil, yield is 96%.The compound hydrochloride is yellow solid.
1H-NMR (400MHz, MeOD) δ 7.92 (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/z calcd for C18H18NO(M+H)+264.1388, found264.1383。
Embodiment 33
(E)-N- ethyls-N- [(benzofuran -7- bases) methylene] -3- phenyl -propyl- 2- alkene -1- amine (compound IB-2) Preparation.
By 360 milligrams of IB- 1 is dissolved in 10 milliliters of anhydrous DMFs, and 56 milligrams of hydrogen are added portionwise under ice bath Change sodium, stirring reaction 15 minutes.0.6 milliliter of iodoethane is subsequently added, the lower room temperature reaction of nitrogen protection is stayed overnight.After reaction terminates, Water is added into reaction system, is extracted with ethyl acetate three times, saturated common salt washing, anhydrous sodium sulfate drying is filtered, concentration, Residue separates (ethyl acetate/petroleum ether=1 through silica gel column chromatography:5) title compound, is obtained, 200 milligrams of grease are received Rate 50%.The compound hydrochloride is tan solid.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C20H22NO(M+H)+292.1701,found 292.1700。
Embodiment 34
(E)-N- isopropyls-N- [(benzofuran -7- bases) methylene] -3- phenyl -propyl- 2- alkene -1- amine (compound IB- 3) preparation.
In addition to changing iodoethane into 2- iodopropanes, remaining required raw material, reagent and preparation method be the same as Example 32 are obtained 210 milligrams of title compound as yellow oil, yield is 50%.The compound hydrochloride is light yellow solid.
1H-NMR (400MHz, MeOD) δ 7.92 (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/z calcd for C21H24NO(M+H)+306.1858, found 306.1862。
Embodiment 35
The preparation of (1S, 2S)-ethyl -2- cyclo-propane carboxylic acid, ethyl esters (intermediate X I-1).
By 1 gram of (1S, 2S) -2- cyclo-propane carboxylic acid, 1 milliliter of thionyl chloride is added in 10 milliliters of ethanol solutions, plus Heat backflow 2 hours.After reaction terminates, concentrate, washing obtains title compound, 1.1 grams of colorless oils, yield 98%.
1H-NMR(400MHz,CDCl3) δ 7.33-7.09 (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- phenycyclopropyls) methanol (intermediate X II-1).
549 milligrams of intermediate X I-1 are dissolved in 25 milliliters of anhydrous tetrahydro furans, nitrogen is protected and is slowly added to 3.9 at 0 DEG C The diisobutyl aluminium hydride toluene solution of 1.5 moles every liter of milliliter, is stirred at room temperature reaction and stays overnight.After reaction terminates, methanol is added Reaction is quenched, filters, concentration, residue separates (ethyl acetate/petroleum ether=1 through silica gel column chromatography:10) title compound, is obtained Thing, 304 milligrams of colorless chromogenic grease, yield 71%.
1H-NMR(400MHz,CDCl3) δ 7.32-7.22 (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- (bromomethyl) cyclopropyl) benzene (intermediate X III-1).
In addition to changing intermediate VIII-1 into intermediate X II-1, remaining required raw material, reagent and preparation method are with implementation Example 8, obtains 300 milligrams of title compound as yellow oil, and yield is 57%.
1H-NMR(400MHz,CDCl3) δ 7.31-7.23 (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- [(benzofuran -7- bases) methylene] -1- [(1S, 2S) -2- phenycyclopropyls]-methylamine (compound IC- 1) preparation.
Except changing intermediate compound I X-1 into intermediate X III-1, remaining required raw material, reagent and preparation method be the same as Example 9,112 milligrams of title compound as yellow oil are obtained, yield is 52%.The compound hydrochloride is yellow oil.
1H-NMR (400MHz, MeOD) δ 7.86 (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/z calcd for C20H22NO(M+H)+292.1701,found 292.1704。
Embodiment 39
The preparation of 1- phenyl -3- propargyl bromides (intermediate X IV-1).
In addition to intermediate VIII-1 to be changed into 3- phenyl -propyl- 2- alkynes -1- alcohol, remaining required raw material, reagent and preparation side Method be the same as Example 8, obtains 211 milligrams of title compound as yellow oil, and yield is 84%.
1H-NMR(400MHz,CDCl3) (s, the 2H) of δ 7.44 (d, J=4.5Hz, 2H), 7.32 (s, 3H), 4.16
Embodiment 40
N- methyl-N- [(6,7,8,9- tetrahydrochysene -5H- benzos [7] annulene -2- bases) methyl] -3- phenyl -propyl- 2- alkynes -1- amine (compound ID- 1) preparation.
In addition to changing intermediate compound I X-1 into intermediate X IV-1, remaining required raw material, reagent and preparation method be the same as Example 9,120 milligrams of colorless oil title compounds are obtained, yield is 59%.The compound hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.93 (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/z calcd for C19H18NO(M+H)+ 276.1388,found276.1388。
Embodiment 41
N- methyl-N- [(6,7,8,9- tetrahydrochysene -5H- benzos [7] annulene -2- bases) methylene] -3- phenyl -propyl- 1- amine (is changed Compound IE- 1) preparation.
In addition to intermediate compound I X-1 to be changed into (3- bromopropyls) benzene, remaining required raw material, reagent and preparation method are with implementation Example 9, obtains 126 milligrams of colorless oil title compounds, and yield is 60%.The compound hydrochloride is white solid.
1H-NMR (400MHz, MeOD) δ 7.91 (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/z calcd for C19H22NO(M+H)+ 280.1701,found 280.1704。
Embodiment 42
The compounds of this invention suppresses the active initial screening experiments of golden yellow pigment synthesis.
Experiment bacterial strain：Staphylococcus aureus Newman wild strains (the Staphylococcus aureus of fresh activation Subsp.aureus str.Newman) and its homologous crtN insertion mutations strain (without golden yellow pigment synthesis).Experiment is cultivated Base：Pancreas peptone soybean broth culture medium (Tryptone Soy broth, TSB), Britain's Oxid Products, plus single water that steams are matched somebody with somebody System, it is 121 DEG C, standby after sterilizing in 15 minutes.
Primary dcreening operation experimental method：(1) preparation of compound：The compounds of this invention dimethyl sulfoxide (DMSO) (DMSO) is dissolved, matched somebody with somebody It is set to the mother liquor that concentration is 10mM.Take 100 μ L mother liquors plus 400 μ L DMSO to be diluted to concentration for 2mM, 250 μ L are taken after mixing (2mM) solution continues plus equivalent DMSO carries out 2 times of dilutions, until solution concentration is 0.0625mM, it is stand-by.(2) culture of bacterial strain： From picking Newman bacterial strains monoclonal on TSA flat boards to dress with the test tube of the sterile TSB culture mediums of 4mL, 37 DEG C, 250rpm is cultivated It is standby after 12 hours.(3) the compounds of this invention suppresses the primary dcreening operation of golden yellow pigment synthesis ability in staphylococcus aureus：Take Sterile test tube, the μ L of TSB culture mediums 3980 of fresh sterilizing are added into every test tube.Then, 20 μ L are separately added into test tube The concentration prepared is 10mM, and 2mM, 1mM, 0.5mM, 0.25mM, 0.125mM, 0.0625mM compound solution send out this Bright final compound concentration is respectively 50 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM.Meanwhile, to another In test tube, (final concentration of 0.5%) is used as the negative control without compound to 20 μ L of addition DMSO solution.Into every test tube, It is separately added into the bacterium solution (inoculum concentration that 40 μ L are cultivated 12 hours：Culture medium=1：100), and in 37 DEG C, 250rpm is cultivated 24 hours Afterwards, bacterium solution 1.5mL is taken out, after 14000g is centrifuged 2 minutes, supernatant is removed, observation bacterial strain is adding the chemical combination of the present invention of certain concentration After thing, whether the golden yellow pigment of synthesis significantly reduces compared with negative control.Referring specifically to Fig. 1 and Fig. 2.
Embodiment 43
The compounds of this invention suppresses the IC of golden yellow pigment synthesis activity50Determination experiment method
The selection of compound concentration：According to primary dcreening operation result, the ability that each compound suppresses golden yellow pigment synthesis is determined. The more strongly active compound for having, such as its in primary dcreening operation least concentration still can strong inhibition pigment generation, then can be by primary dcreening operation Similar approach continues to test, until compound can not suppress the generation of golden yellow pigment substantially.According to experimental result, for each 11 different concentration gradients of compound design, make its ability for suppressing pigment synthesis include 0%~100% substantially.Bacterial strain Culture：The test tube of the sterile TSB culture mediums of 4mL is used to dress from picking Newman bacterial strains on TSA flat boards and crtN mutant strains monoclonal In, it is 37 DEG C, standby after 250rpm is cultivated 12 hours.IC50Measure：Sterile test tube is taken, fresh sterilizing is added into every test tube The μ L of TSB culture mediums 3980.Then, the chemical combination of the present invention for 11 concentration gradients that 20 μ L have been prepared is separately added into test tube Thing.Meanwhile, into another two test tubes, 20 μ L DMSO solution (final concentration 0.5%) is separately added into, pair without compound is used as According to.The Newman (negative control) and crtN that 40 μ L cultures 12 hours are separately added into two test tubes for adding DMSO solution dash forward Mutant (positive control).Remaining adds and the Newman bacterial strains that 40 μ L are cultivated 12 hours is separately added into the test tube of compound.It is all Test tube is in 37 DEG C, and 250rpm shifts to 30 DEG C after cultivating 12 hours, 250rpm continues to cultivate the accumulation to increase pigment in 36 hours.It is complete Into after culture, 3mL bacterium solutions are taken in 2mL EP pipes, after 14000g is centrifuged 2 minutes, are removed supernatant, are washed twice with PBS After (each 1mL), 300 μ L methanol solutions are added, spiral is mixed extracts pigment in 3 minutes after heating in 55 DEG C of water-baths.Then 14000g is centrifuged 2 minutes, is drawn methanol extract liquid and is managed in 1.5mLEP, adds equivalent methanol solution, is repeated to extract twice, is closed And the pigment of three extractions.Using the methanol extract liquid in crtN mutant as blank control, each sample under 450nm wavelength is determined Absorbance, and determine the absorbance without compound negative control.The compounds of this invention at various concentrations, the phase of pigment synthesis To level=A450 (sample)/A450 (negative control) × 100%.Using the molar concentration of compound as abscissa, closed with pigment Into relative level be ordinate, in the softwares of Graphpad prism 5.0 carry out inhibitor concentration-inhibiting rate (log (inhibitor) vs response) curve matching, and by software according to fitting result calculate compound suppress pigment synthesis IC50。
To the benzofuran -7- alkyl amine compounds of synthesis, staphylococcus aureus is chosen, carries out suppressing golden yellow color The IC of plain synthesizing activity50Test, activity data is as shown in table 1.：
Inhibitory activity data (IC of the benzofuran -7- alkyl amines compound of table 1. to golden yellow pigment synthesis50, nM)
As can be seen from Table 1,14 the compounds of this invention there are potent activities to suppressing golden yellow pigment synthesis, wherein half The effective inhibition concentration IC of number50<10nM reactive compound has 5, half effective inhibition concentration 10nM<IC50<100nM activity Compound has 7, half effective inhibition concentration 100nM<IC50<1000nM reactive compound has 4.
Therefore, the benzofuran -7- alkyl amines compounds main with general structure I of the invention has very strong right The inhibitory activity of golden yellow pigment synthesis, new, targeting Staphylococcus aureus can be developed into by illustrating the compound of the present invention The antibacterials of bacterium virulence factor golden yellow pigment synthesis.
Embodiment 44
The compounds of this invention IA- 6 suppress the IC of the golden yellow pigment synthesis activity of drug-fast bacteria50Determination experiment method and result.
In addition to changing staphylococcus aureus Newman into USA400MW2, USA300LAC and Mu50, remaining method Be the same as Example 42. and embodiment 43..As a result Fig. 3 are seen.
As seen from Figure 3, compound I of the inventionA- 6, the synthesis for the golden yellow pigment of staphylococcus aureus presses down System is not limited to Newman bacterial strains, while having potent inhibitory action to antibody-resistant bacterium USA400MW2, USA300LAC and Mu50.
Embodiment 45
The compounds of this invention IA-5、IA-6、IA-8、IA-9、IA- 10 and IAIt is crucial during -15 pairs of golden yellow pigment synthesis The IC of enzyme CrtN inhibitory activity50Determination experiment method and result.
1) preparation of substrate diapophytoene emulsions
The pet28a of incubated overnight::CrtM/E.coli (DE3) presses 1：100 (bacterium solutions：Culture medium) ratio be forwarded to The LB+ kanamycins kanamycin (final concentrations of 50ml fresh steriles：50 μ g/ml) in culture medium, 37 DEG C, under the conditions of 250rpm After culture 24 hours, thalline is collected by centrifugation in 8000g, 4min, and is washed twice with PBS.20ml third is added into thalline Ketone liquid, is vortexed and mixes to extract pigment and its intermediate product, and adds 10ml n-hexanes and 10ml NaCl in backward extract solution (10%, mass/volume) solution, and acutely vibrate to remove the lubricant component in extract solution, then collection is containing pigment and wherein Between product hexane layer, and add 10ml n-hexanes, repeat the extraction process once.Merge hexane extract solution twice, and Add anhydrous MgSO4It is dried and weighs.The diapophytoene of acquisition and phosphatidyl choline are pressed 1:3 ratio is dissolved in In 200 μ l chloroforms, and it is concentrated in vacuo to drying.Added per 8mg diapophytoene with 24mg phosphatidyl choline mixtures 2ml 0.02M HEPES buffer (20mM HEPES, pH=7.5；500mM NaCl), it is then ultrasonic until shape in frozen water Into homogeneous latex emulsion.
2) CrtN enzyme activity is analyzed
Related Component mother liquor is configured in reaction system：FAD 10mM, glucose 200mM, glucose oxidase 2000U/ml, Catalase, 20000U/ml is dissolved as with diapophytoene emulsions.Above-mentioned solution uses 0.02M HEPES buffer Configuration.
Whole reaction system is 700 μ l, is carried out in 2mlEP pipes.Reaction system includes following component：50μl Diapophytoene emulsions (contain catalase), 70 μ l various concentrations compounds (distilled water configuration) or distilled water, 262.5 μ L 0.02M HEPES buffer, 3.5 μ lFAD solution, 7 μ l glucose solutions, 7 μ l glucose oxidase solutions finally Jia 300 μl pet28a::CrtN/E.coli (DE3) is complete, and cell pyrolysis liquid (~1.41mg CrtN albumen) starts reaction.Reaction is at 37 DEG C Carried out 14 hours in shaking table, shaking table revolution 250rpm/min.
3) reaction product is extracted and detection
After the completion of reaction, 500 μ l methanol terminating reactions are added, and reaction solution is transferred in 15ml centrifuge tubes.Reaction solution 700 μ l chloroforms of middle addition, fully shaking is vortexed to extract the pigment of reaction, then 7000rpm, centrifuges within 3 minutes, carefully draws chlorine Imitative layer.Reaction product is extracted in 500 μ l chloroforms of addition in residual reaction liquid, and merges reaction extract solution in a vacuum It is concentrated to dryness.Enriched product adds 200 μ l chloroforms and dissolved, and sucks in the microwell plate of 96- holes, then at 450 nm Its absorbance is determined, for quantifying for CrtN products diaponeurosporene.IC50It is defined as under experiment condition, suppresses CrtN The concentration of corresponding compound during active half, being plotted in Graphpad 5.0 for CrtN enzyme activity amount effect relation curves is carried out.
Benzofuran -7- alkyl amines the compound of table 2. is to CrtN enzyme inhibition activity data (IC50, μM)
As can be seen from Table 2, compound I of the inventionA-5、IA-6、IA-8、IA-9、IA- 10 and IA- 15 be potent gold Key enzyme CrtN inhibitor in xanthein building-up process.
Embodiment 46
The compounds of this invention IAFour kinds of staphylococcus aureuses of -6 pairs of enhancings (Newman, USA400MW2, USA300LAC and Mu50) hydrogen peroxide killing experiments method and result.
The compound of certain concentration is added into sterile test tube makes final concentration of 1 μM, and by inoculum concentration：Culture medium=1： 100 ratio adds four kinds of staphylococcus aureus bacterium solutions of incubated overnight.In 37 DEG C, after 250rpm is cultivated about 24 hours, inhale 500 μ l medium centrifugals are taken, thalline are collected, and washed twice with PBS buffer.Then, plus the 500 abundant whirlpools of μ l PBS solutions Rotation, thalline is resuspended, and is drawn in 15 μ l bacterium solutions addition, 1500 μ l PBS buffer, is fully vortexed and is mixed (OD=~0.1). Take bacterium solution after 250 μ l mixings in 2ml EP pipes, to add 10 μ l about 37% peroxidating Hydrogen solution, make hydrogen peroxide in bacterium solution whole Concentration is 1.5%.Add after hydrogen peroxide, the effective sealed membranes of EP are covered, and be positioned over 37 DEG C, 30 are incubated under the conditions of 250rpm Minute, killed.It is another to take bacterium solution after 250 μ l mixings to add the sterile PBS buffer of 10 μ l, it is used as control.After the completion of reaction, Add the catalase (mother liquor configured：20000U/ml, PBS buffer are configured) solution 5 μ l and mixings that be vortexed, with decomposition Remaining hydrogen peroxide.And take in the sterile PBS buffer of 100 μ l reaction solutions to 900 μ l, 10 times of dilutions are carried out, by that analogy, Until dilution 106Times.And above-mentioned dilution is put to 10 μ l respectively on TSA flat boards, overnight incubation meter is survived in 37 DEG C of incubators Clump count.Survival probability of bacteria calculates the=(bacterial population × dilution grown after the killing of sample hydrogen peroxide after hydrogen peroxide killing Multiple)/(bacterial population × extension rate of control group bacterial growth) × 100%.As a result Fig. 4 are seen.
As seen from Figure 4, compound I of the inventionA- 6 can significantly strengthen hydrogen peroxide to four kinds of golden yellow Portugals The killing of grape coccus, is greatly lowered survival rate.
Embodiment 47
The compounds of this invention IAFour kinds of staphylococcus aureuses of -6 pairs of enhancings (Newman, USA400MW2, USA300LAC and Mu50) human blood killing experiments method and result.
The compound of certain concentration is added into sterile test tube makes final concentration of 1 μM, and by inoculum concentration：Culture medium=1： 100 ratio adds four kinds of staphylococcus aureus bacterium solutions of incubated overnight.In 37 DEG C, 250rpm is drawn after cultivating about 24 hours 500 μ l medium centrifugals, collect thalline, and washed twice with PBS buffer.Then, plus 500 μ l PBS solutions are fully vortexed, Thalline is resuspended, and draws 15 μ l bacterium solutions and is added in 1500 μ l PBS buffer, being fully vortexed mixes (OD=~0.1).Then 150 μ lOD=0.1 bacterium solution is taken, adds in the sterile PBS buffer of 850 μ l, makes OD=~0.015, it is standby.Use BD VACUTAINER PT pipes collect healthy human body fresh venous, take one, sterile glass test tube, and 360 μ l are successively added thereto New blood and the bacterium solution of 40 μ l OD=~0.015, and after 37 DEG C, after 250rpm is incubated 6 hours, and take 50 μ l reaction solutions Into the sterile PBS buffer of 450 μ l, 10 times of dilutions are carried out, by that analogy, until dilution 106Times.Separately take OD=~0.015 Bacterium solution carries out 10 times of dilutions as control, until dilution 106Times.And above-mentioned dilution is put to 10 μ l respectively on TSA flat boards, The clump count that overnight incubation meter is survived in 37 DEG C of incubators.Survival probability of bacteria is calculated=(grown after the killing of sample blood after blood killing Bacterial population × extension rate)/(bacterial population × extension rate/10 of control group bacterial growth) × 100%.As a result Fig. 5 is seen.
As seen from Figure 5, compound I of the inventionA- 6 can significantly strengthen human blood to four kinds of Staphylococcus aureus The killing of bacterium, is greatly lowered survival rate.
Embodiment 48
The compounds of this invention IA- 6 resist in Mice Body three kinds of staphylococcus aureuses (Newman, USA400MW2 and Mu50) activity test method and result.
Experiment is bought with SPF grades of female BAl BIc/c mouse from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, sterile bar Raised under part to 6-8 week old.The staphylococcus aureus strains of incubated overnight are transferred to fresh sterile Triptic soya meat In soup culture medium (Tryptone Soy broth, TSB), and 3 hours are persistently cultivated extremely in 37 DEG C, under the conditions of 250rpm is per minute Exponential phase of growth.After being washed twice with PBS, it is suspended in standby in PBS.In mouse infection experiment, mouse is divided at random Group, every group 15.All mouse are anaesthetized by the way that yellow Jackets (80mg/kg) are injected intraperitoneally, and 100 μ l are then injected after eye socket not With bacterium amount infecting mouse (as described below).For the compounds for treating group of Newman infection models, IA- 6 dosages are set to 200mg/kg, for the compounds for treating group of drug-fast bacteria (USA400MW2 and Mu50) infection model, set 200mg/kg and Two I of 50mg/kgA- 6 dosage control groups, first time drug injection is noted altogether 12 hours before bacterium infection in metainfective 4 days Penetrate 8 times (2 times a day, being spaced 12 hours, totally 9 times).After experiment terminates, mouse is by sucking CO2It is condemned to death.The heart of mouse, Kidney and liver are removed, and uniformly crush the sterile PBS buffer (containing 0.01%tritonX-100) in 1mL.Broken liquid is connected Continuous dilution, takes 10 μ L various concentrations dilutions to drop on TSA flat boards, and measuring and calculating bacterium CFU is counted.Number of the bacterium in Different Organs Bacterial population × extension rate under=specific extension rate.And in the softwares of Graphpad 5.0, using Mann-Whitney Test (two-tailed) carries out statistical analysis.Infective dose：Newman:1×107CFU；USA400MW:4×107CFU； Mu50:1.6×108CFU.In drug-fast bacteria (USA400MW2 and Mu50) infection model, BPH-652 is set to be used as positive control. As a result Fig. 6, Fig. 7 and Fig. 8 are seen.
As seen from Figure 6, the compounds of this invention IA- 6 can conspicuousness reduction Newman bacterial strains in mouse kidney and liver Field planting in dirty.In kidney, bacteria clearance is up to 85.9%.In heart, bacteria clearance is up to 90.2%.
As seen from Figure 7, the compounds of this invention IA- 6 can conspicuousness reduction USA400MW2 bacterial strains in mouse liver and Field planting in kidney, and therapeutic effect is better than positive control BPH-652.In liver, high dose group bacteria clearance is up to 99.6%, low dose group bacteria clearance is up to 80.5%.In kidney, high dose group bacteria clearance is up to 96.6%, low dose Amount group bacteria clearance is up to 83.3%.
As seen from Figure 8, the compounds of this invention IA- 6 can conspicuousness reduction Mu50 bacterial strains in mouse liver and kidney In field planting, and therapeutic effect is better than positive control BPH-652.In liver, high dose group bacteria clearance is up to 99.97%, low dose group bacteria clearance is up to 99.9%.In kidney, high dose group bacteria clearance is up to 92.3%, low dose Amount group bacteria clearance is up to 79.2%.
Benzofuran -7- alkyl amine the molecular structure of compounds of the present invention is relatively simple, and preparation technology is succinct, is produced into This is low, and stronger suppression is shown in pair golden yellow pigment synthesis Inhibition test for having substantial connection with the pathogenic link of bacterium System activity.The compound of the present invention presents the potent CrtN inhibitory activity of comparison, especially compound I simultaneouslyA- 6, in body Outside, the potent golden yellow pigment synthesis for suppressing drug-fast bacteria USA400MW2, USA300LAC and Mu50, while peroxide can be significantly increased Change the killing ability of hydrogen and human blood for four kinds of staphylococcus aureuses.In vivo, IA- 6 can the golden yellow Portugal of conspicuousness reduction Grape coccus Newman, USA400MW2 and Mu50 are colonized in mouse kidney, heart and liver.Therefore, the series compound is not only It is expected to develop into the antibacterials of new single drug mode, but also can develops into existing antibiotic combinations to prescription The antibacterials of formula.

Claims (4)

  1. It is compound shown in Formulas I or its pharmaceutically acceptable salt 1. a kind of benzofuran -7- alkyl amine compounds：
    In Formulas I, R1For hydrogen or C1~C3Straight or branched alkyl, n is 1~3 integer, R2For one kind in following groups：
  2. 2. benzofuran -7- alkyl amine compounds as claimed in claim 1, it is characterised in that described benzofuran -7- Alkyl amine compound is：(E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3-1 (4- tolyls) propyl- 2- alkene -1- Amine, (E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- 2-methyl-2-phenylpropanes base) propyl- 2- alkene -1- amine, (E)-N- first Base-N- [(benzofuran -7- bases) methylene] -3- (naphthalene -2- bases) propyl- 2- alkene -1- amine, (E)-N- methyl-N- [(benzofuran - 7- yls) methylene] -3- (2,4- dichlorophenyl) propyl- 2- alkene -1- amine, (E)-N- methyl-N- [(benzofuran -7- bases) methylenes Base] -3- (4- trifluoromethyls) propyl- 2- alkene -1- amine, (E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- Fluorophenyl) propyl- 2- alkene -1- amine, (E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- bromophenyls) propyl- 2- alkene - 1- amine, (E)-N- methyl-N- [(benzofuran -7- bases) methylene] -3- (4- chlorphenyls) propyl- 2- alkene -1- amine, (E)-N- first Base-N- [(benzofuran -7- bases) methylene] -3- (4- methoxyphenyls) propyl- 2- alkene -1- amine, (E)-N- methyl-N- [(benzos Furans -7- bases) methylene] -3- (4- nitrobenzophenones) propyl- 2- alkene -1- amine, [(benzofuran -7- bases) is sub- by (E)-N- methyl-N- Methyl] -3- (4- methyl formates phenyl) propyl- 2- alkene -1- amine, or (2E, 4E)-N- methyl-N- [(benzofuran -7- bases) methylenes Base] -5- phenyl-amyl- 2,4- diene -1- amine.
  3. 3. benzofuran -7- alkyl amines compound as claimed in claim 1 or 2 is during golden yellow pigment synthesis is prepared Application in key enzyme CrtN inhibitor.
  4. 4. benzofuran -7- alkyl amines compound as claimed in claim 1 or 2 is preparing staphylococcus aureus golden yellow Application in pigment synthesis inhibitor class antibacterials.
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