CN109438344A - The synthesis and application of quinoline -2 (1H) ketone piperazine compounds - Google Patents

The synthesis and application of quinoline -2 (1H) ketone piperazine compounds Download PDF

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CN109438344A
CN109438344A CN201811499420.3A CN201811499420A CN109438344A CN 109438344 A CN109438344 A CN 109438344A CN 201811499420 A CN201811499420 A CN 201811499420A CN 109438344 A CN109438344 A CN 109438344A
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quinolin
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quinoline
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吉庆刚
邓乔
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Southwest University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention discloses a kind of novel quinolines -2 (1H) ketone piperazine compounds design synthesis and its antimicrobial aspect application, the structure of the compound is as shown in general formula Ι:R1,R2Group is respectively as follows: the naphthenic base and heterocycle, aromatic radical of hydrogen, the straight chain of 1-5 carbon atom or branch key alkyl, 3-8 carbon atom composition；Or 5-8 circle heterocyclic ring or heteroaromatic etc. are formed with N atom.Compound synthesized by the present invention through biological activity test experiments have shown that, part of compounds is obvious to chitin synthesis enzyme inhibition activity, part of compounds shows preferable inhibitory activity to Candida albicans, Aspergillus flavus, Cryptococcus neoformans and aspergillus fumigatus, can be used for preparing the drug of resisting pathogenic microbes.

Description

The synthesis and application of quinoline -2 (1H) ketone piperazine compounds
Technical field
The invention belongs to field of medicaments, are related to novel quinoline -2 (1H) ketone piperazine compounds design synthesis and its it is micro- resisting The application of biological aspect.
Background technique
Since quinolone compounds have excellent antibacterial activity, thousands of Carbostyril derivative has been synthesized.Quinoline A part of Nuo Tongshi quinoline alkaloid family is a kind of important heterocyclic compound, is represent a kind of living with broad-spectrum biological The compound of property, such as in anticancer, antibacterium, antimycotic, antimalarial, antiviral]Etc. to people's printing it is deep.Quinoline -2- (1H) structure of ketone is present in many synthesis compounds and natural products, there is extensive pharmaceutical activity.
Piperazine and its substitutive derivative are using one of more successful drug effect segment, this is by the medicine of current clinical use Object is proved, in general, there is compound piperazine moiety can show certain pharmacological activity, such as antibacterial agent, antidepressants, is resisted The research article of tumour, anticonvulsive drug, antiviral, anti-malarial and potential antipsychotics, this kind of compound is visible:Bioorg. Med. Chem.2006, 14: 2859-2868；Arch. Pharm. Chem. Life. Sci. 2009, 342: 405-411；Bioorg. Med. Chem. Lett.2013,23: 3225-3229；J. Med. Chem.2010, 53: 7076-7094；J. Nat. Prod.2005, 6: 1397-1399；Curr. Med. Chem. 2001, 8: 371- 384；Med. Chem.2011, 19: 7281-7298。
These documents do not cover or the structure including new compound according to the present invention, preparation method and use. The present invention has designed and synthesized a kind of quinoline -2 (1H) ketone piperazine compounds, is control with Polyoxin B, determines such change Object is closed to the inhibiting effect of chitin synthetase, and determines it in activity antimycotic, in terms of antibacterium, has expanded quinolone Application range.Up to the present, new compound according to the present invention in terms of inhibiting chitin synthesis enzymatic activity also not It appears in the newspapers, is the health of the mankind so can develop as the inhibitor of chitin synthetase into novel antifungal preparation It contributes.
Summary of the invention
In conclusion it is an object of the invention to design a new class of quinoline -2 (1H) the ketone piperazine compounds of synthesis, from In filter out chitin synthesis enzyme inhibition activity and the preferable compound of antifungal activity, and it is simple and easy to provide these compounds Preparation method and its application in antimicrobial field.
Particular content of the invention is as follows:
Quinoline -2 (1H) ketone piperazine compounds, shown in the general structure I of the compound:
Wherein, R1,R2Group is respectively as follows: hydrogen, the straight chain or branch key alkyl of 1-5 carbon atom；The cycloalkanes of 3-8 carbon atom composition Base and heterocycle；Aromatic radical；Or 5-8 circle heterocyclic ring or heteroaromatic etc. are formed with N atom, above-mentioned substance is to respectively correspond a knot The particular compound of structure formula, this is well known to those skilled in the art.
It further illustrates, R in I compound represented of general formula1,R2For any one in hydrogen and following radicals:
Or R1,R2Following groups are formed with N:
But it is not limited to given example.
The synthetic method of above compound, is performed as follows, as shown in Scheme 1
Scheme 1: the synthetic route of compound 1
Above-mentioned Scheme1 reaction condition is as follows:
A) 5- amino -3,4- dihydroquinoline -2 (1H) ketone (compound 2) and diethanol amine or two-(2- bromoethyl) amine hydrogen bromines Hydrochlorate solution in potassium hydroxide reacts 3 hours in heating obtains compound 3;
B) by compound 3 and potassium iodide, tetra-tert amine bromide is dissolved in sodium hydrate aqueous solution, adds epoxy chloropropionate Alkane reacts 4 hours, after reacting and carrying out completely, obtains creamy white solid, is crystallized with ethyl acetate, filters, dry, obtains white Pulverulent solids, i.e. compound 4;
C) it by various amino-compounds described in compound 4, general formula 1, is heated to after mixing in molten, stirring is anti- It answers 0.5 hour.It is cooling, it crosses column and obtains colourless oil liquid.Grease is after concentrated hydrochloric acid is acidified, with methanol-acetone mixed solvent weight Crystallization, obtains 1a ~ 1w.
Specifically
In step a, compound 2 is 1:1-3 with the molar ratio of diethanol amine or two-(2- bromoethyl) amine salt, optimum Ratio is 1:1-1.4, and heating temperature is 50-100 DEG C, and preferably 75-85 DEG C, potassium hydroxide solution concentration is 10-15%, and dosage is 2-3 times of compound 2.
In stepb, reaction temperature is 20-50 DEG C, preferably 25-30 DEG C.
In step c, reaction temperature is molten condition, does not have to additional addition solvent.
Corresponding compound can be made by preparation method disclosed above in those of ordinary skill in the art.
Above compound can be used as chitin synthetase inhibitor application, also can be used as anti-pathogenic microorganism medicine application. The microorganism is pathogenetic bacteria or disease fungus, such as Escherichia coli, staphylococcus aureus, methicillin-resistant staphylococcus grape Coccus, hay bacillus, proteus, pseudomonas aeruginosa；Candida albicans, Cryptococcus neoformans, Aspergillus flavus, aspergillus fumigatus Deng.
Specific embodiment
In order to deepen the understanding of the present invention, the present invention will be described in further detail with reference to the examples below, the embodiment For explaining only the invention, it is not intended to limit the scope of the present invention., those skilled in the art is according to the present invention Some nonessential modifications and adaptations that above content is made all belong to the scope of protection of the present invention.
All reagents used are all that commercially available analysis is pure or chemical pure, without specially treated if undeclared. Extent of reaction is monitored by thin-layer chromatography, is developed the color at 254 nm of ultraviolet lamp, is partially developed the color with iodine and the concentrated sulfuric acid.Fusing point uses X- The measurement of 6 melting point detectors.Nuclear magnetic resonance spectroscopy and carbon spectrum use 300 nmr determination of Bruker AV, and what is used is deuterated Reagent has DMSO-d6, CDCl3And D2O includes internal standard substance TMS.Chemical shift δ unit is ppm, and coupling constant J unit is Hz, s, d, t, q, m respectively indicate unimodal, double peak, triplet, quartet and multiplet.Mass spectrum uses Shimadzu LC-MS- 2010A/EV test.
Embodiment one
5- (sending piperazine -1- base) -3,4- dihydroquinoline -2 (1H) ketone (2)
5- amino -3,4- dihydroquinoline -2 (1 is successively added into 40 ml waterH) ketone 7 (5.00 g, 30.83 mmol), two- (2- bromoethyl) amine hydrobromate (50.57 g, 33.91 mmol), stirring are warming up to 80 °C, hydrogen are added dropwise in half an hour in three batches The aqueous solution of potassium oxide (1.90 g, 33.91 mmol, 10 ml).Reaction is warming up to 100 °C after adding, then is kept the temperature anti- It answers 3 hours.To after completion of the reaction, be cooled to room temperature, filtering, filtrate is 10 with the potassium hydroxide aqueous solution tune PH of 10 %, is precipitated A large amount of white solids.It filters, it is dry with appropriate water washing, obtain white powdery solids 8(6.4 g, yield 61%, Mp 235- 237 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.01 (s, 1H, quinolin, -CONH-), 7.07 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.65 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.58 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.94 (s, 1H, NH), 2.82-2.94 (m, 4H, quinolin-H4 and -CH2-), 2.67-2.84 (m, 6H, -CH2-), 2.35 (t, J = 7.3 Hz, 2H, quinolin-H3); 13C NMR (75 MHz, DMSO-d6) δ: 170.59, 150.18, 139.44, 127.33, 117.62, 112.55, 110.18, 51.34, 46.73, 30.16, 20.38; LC-MS (ESI): m/z 232 [M+ H]+.
Embodiment two
5- (4- (ethylene oxide -2- base-methyl) sends piperazine -1- base) -3,4- dihydroquinoline -2 (1H) ketone (3)
5- (sending piperazine -1- base) -3,4- two is successively added into sodium hydrate aqueous solution (1.4 g, 34.88 mmol, 26 ml) Hydrogen quinoline -2 (1H) ketone 8 (6.2 g, 29.07 mmol), potassium iodide (0.12 g, 0.73 mmol), tetra-tert amine bromide (0.24 g, 0.73 mmol) is stirred at room temperature to dissolution completely, adds epoxychloropropane (5.38 g, 58.14 mmol), White gummy solid is precipitated in stir about after ten minutes.Reaction 4 hours is stirred at room temperature, after reacting and carrying out completely, obtains creamy white It is low that solid is sunken to bottle.Upper aqueous layer is removed, ethyl acetate crystallization is added, filters, it is dry, white powdery solids 9(5.3 g is obtained, Yield 64%, Mp 184-186 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.02 (s, 1H, quinolin, -CONH-), 7.08 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.69 (d, J = 7.9 Hz, 1H, quinolin-H8), 6.60 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.05 (m, 1H, CH), 2.76- 2.87 (m, 6H, -CH2-), 2.52-2.74 (m, 6H, -CH2-), 2.47 (m, 1H,-CH2-), 2.36 (t, J = 7.3 Hz, 2H quinolin-H3), 2.26 (m, 1H,-CH2-); 13C NMR (75 MHz, CDCl3) δ: 172.74, 150.86, 138.28, 127.67, 117.86, 113.95, 111.31, 61.03, 53.91, 51.61, 50.23, 44.88, 30.51, 20.59; LC-MS (ESI): m/z 288 [M+H]+.
Embodiment three
5- (4- (2- hydroxyl -3- ((4- anisyl) amino) propyl) piperazine -1- base) -2- oxo -1,2,3,4- tetrahydroquinoline Hydrochloride (1a)
By 5- (4- (ethylene oxide -2- base-methyl) sends piperazine -1- base) -3,4- dihydroquinoline -2 (1H) ketone 9 (0.20 g, 0.7 Mmol), P-nethoxyaniline (0.17 g, 1.4 mmol) is heated to 90 °C to reaction in molten, stirring after mixing Reaction 0.5 hour.It is cooling, it crosses column and obtains colourless oil liquid.Grease uses methanol-acetone mixed solvent after concentrated hydrochloric acid is acidified Recrystallization, obtains white powdery solids 10a(yield 75%, Mp 258-261 °C);1H NMR (300 MHz, CDCl3) δ: 7.99 (s, 1H, quinolin, -CONH-), 7.17 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.80 (m, 3H, quinolin-H8 and Ar-H2, H6), 6.65 (d, J = 8.8 Hz, 2H, Ar-H3, H5), 6.55 (d, J = 7.8 Hz, 1H, quinolin-H6), 4.05 (m, 1H, NH), 3.77 (s, 3H, CH3O-), 3.17- 3.34 (m, 1H, CH), 2.78-3.14 (m, 10H, -CH2-), 2.36-2.76 (m, 6H, -CH2-); 13C NMR (75 MHz, DMSO-d6) δ: 170.53, 150.66, 143.28, 139.15, 127.28, 117.33, 114.59, 113.19, 112.79, 111.01, 110.66, 66.42, 62.69, 55.30, 53.89, 51.53, 49.18, 30.26, 20.32; LC-MS (ESI): m/z 411 [M+H]+.
According to the identical method of experimental example three, the various compounds of 1b-1w can be prepared:
1b;(yield 69%, Mp 261-263 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.09 (s, 1H, quinolin, -CONH-), 7.11 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.92-7.05 (m, 2H, Ar-H4, H5), 6.82-6.93 (m, 2H, Ar-H3, H6), 6.69 (d, J = 8.2 Hz, 1H, quinolin- H8), 6.65 (d, J = 8.0 Hz, 1H, quinolin-H6), 4.38 (m, 1H, NH), 3.82 (s, 3H, CH3O-), 3.62-3.74 (m, 1H, CH), 2.99-3.59 (m, 12H, -CH2-), 2.82 (t, J = 7.3 Hz, 2H, quinolin-H4), 2.36 (t, J = 7.3 Hz, 2H, quinolin-H3); 13C NMR (75 MHz, DMSO-d6) δ: 170.37, 149.60, 149.11, 139.36, 137.23, 127.48, 121.02, 119.54, 117.35, 112.78, 111.61, 111.50, 110.17, 62.73, 59.24, 55.91, 51.83, 50.54, 48.06, 30.11, 20.16; LC-MS (ESI): m/z 411 [M+H]+.
1c;(yield 72%, Mp 223-225 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.10 (s, 1H, quinolin, -CONH-), 7.22-7.43(m, 4H, Ar-H3, H4, H5 and quinolin-H7), 7.11 (m, 2H, Ar-H2, H6), 6.67 (t, J = 7.1 Hz, 2H, quinolin-H6, H8), 4.44 (s, 1H, NH), 2.96-3.83 (m, 13H, -CH2-), 2.82 (t, J = 7.1 Hz, 2H, quinolin-H4), 2.36 (t, J = 7.0 Hz, 2H, quinolin-H3); 13C NMR (75 MHz, DMSO-d6) δ: 170.36, 149.11, 140.77, 139.37, 129.51, 127.49, 124.20, 119.25, 117.57, 112.91, 111.52, 62.48, 59.15, 52.82, 51.88, 48.04, 30.11, 20.16; LC-MS (ESI): m/z 381 [M+H]+.
1d;(yield 70%, Mp 241-243 °C);1H NMR (300 MHz, CDCl3) δ: 9.51 (s, 1H, quinolin, -CONH-), 7.14 (t, J = 7.9 Hz, 1H, quinolin-H7), 7.01 (d, J = 7.4 Hz, 2H, Ar-H3, H5), 6.84 (t, J = 7.4 Hz, 1H, Ar- H4), 6.76 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.64 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.89-4.01 (m, 1H, NH), 3.70 (m, 2H, CH and OH), 2.74-3.11 (m, 10H, -CH2-), 2.40-2.70 (m, 6H, -CH2-), 2.34 (s, 6H, -CH3); 13C NMR (75 MHz, CDCl3) δ: 172.40, 150.39, 145.48, 137.92, 129.27, 128.43, 127.34, 121.59, 117.50, 113.61, 111.06, 65.76, 61.06, 53.27, 51.56, 51.43, 30.15, 20.25, 18.09; LC-MS (ESI): m/z 409 [M+H]+.
1e;(yield 68%, Mp 261-264 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.10 (s, 1H, quinolin, -CONH-), 7.34 (d, J = 7.6 Hz, 2H, Ar-H3, H5), 7.24 (d, J = 7.9 Hz, 2H, Ar-H2, H6), 7.10 (t, J = 7.8 Hz, 1H, quinolin-H7), 6.67 (t, J = 6.9 Hz, 2H, quinolin-H6, H8), 4.46 (s, 1H, NH), 3.00-3.75 (m, 13H, -CH2- and CH), 2.82 (t, J = 6.9 Hz, 2H, quinolin-H4), 2.35 (t, J = 6.9 Hz, 2H, quinolin-H3), 2.28 (s, 3H, -CH3); 13C NMR (75 MHz, DMSO-d6) δ: 170.37, 149.10, 139.36, 135.87, 130.06, 127.49, 123.40, 121.24, 117.56, 112.89, 111.52, 61.92, 58.93, 53.22, 51.89, 48.02, 30.11, 20.53, 20.15; LC-MS (ESI): m/z 395 [M+H]+.
1f;(yield 62%, Mp 259-262 °C);1H NMR (300 MHz, CDCl3) δ: 9.15 (s, 1H, quinolin, -CONH-), 7.14 (m, 2H, Ar-H3, and quinolin-H7), 7.07 (d, J = 7.2 Hz, 1H, Ar-H6), 6.77 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.69 (t, J = 7.5 Hz, 1H, Ar-H4), 6.63 (m, 2H, Ar-H5, and quinolin-H6), 3.99-4.19 (m, 1H, NH), 3.62 (s, 2H, -CH2-), 3.27-3.41 (m, 1H, CH), 3.14 (dd, J = 12.4, 6.4 Hz, 1H, -CH2-), 2.74-3.02 (m, 8H, -CH2-), 2.45-2.72 (m, 6H, -CH2-), 2.18 (s, 3H, -CH3); 13C NMR (75 MHz, CDCl3) δ: 172.19, 150.38, 145.85, 137.86, 129.75, 127.36, 126.68, 122.18, 117.53, 116.85, 113.64, 111.00, 109.52, 64.89, 61.37, 53.21, 51.40, 47.29, 30.14, 20.25, 17.19; LC-MS (ESI): m/z 395 [M+H]+.
1g;(yield 59%, Mp 191-194 °C);1H NMR (300 MHz, CDCl3) δ: 8.98 (s, 1H, quinolin, -CONH-), 7.97-7.86 (m, 1H, naphthalen-H8), 7.75-7.83 (m, 1H, naphthalen-H5), 7.40-7.49 (m, 2H, naphthalen- H4, H7), 7.35 (t, J = 7.8 Hz, 1H, quinolin-H7), 7.26 (d, J = 8.1 Hz, 1H, naphthalen-H2), 7.15 (t, J = 8.0 Hz, 1H, naphthalen-H3), 6.77 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.56-6.65 (m, 2H, quinolin-H6 and naphthalen-H6), 4.26 (s, 1H, NH), 2.97-3.73 (m, 13H, - CH2-), 2.85 (t, J = 7.1 Hz, 2H, quinolin-H4), 2.33 (t, J = 7.0 Hz, 2H, quinolin-H3); 13C NMR (75 MHz, CDCl3) δ: 172.19, 150.26, 143.19, 137.75, 133.89, 128.18, 127.40, 126.12, 125.39, 124.34, 123.37, 119.83, 117.55, 117.30, 113.74, 111.06, 104.14, 64.79, 61.51, 53.23, 51.15, 47.51, 30.08, 20.19; LC-MS (ESI): m/z 431 [M+H]+.
1h;(yield 65%, Mp 193-195 °C);1H NMR (300 MHz, CDCl3) δ: 8.87 (s, 1H, quinolin, -CONH-), 7.24 (d, J = 8.6 Hz, 2H, Ar- H3, H5), 7.14 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.76 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.59 (d, J = 7.8 Hz, 1H, quinolin-H6), 6.51 (d, J = 8.6 Hz, 2H, Ar- H2, H6), 4.25 (s, 1H, NH), 4.00 (m, 1H, CH), 2.98-3.25 (m, 10H, -CH2-), 2.39-2.68 (m, 6H, -CH2-); 13C NMR (75 MHz, CDCl3) δ: 172.00, 150.38, 146.94, 137.81, 131.49, 127.36, 117.54, 114.25, 113.64, 110.92, 108.72, 64.73, 61.07, 52.17, 51.42, 47.13, 30.12, 20.24; LC-MS (ESI): m/z 459 [M+H]+.
1i ;(yield 63%, Mp 221-223 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.09 (s, 1H, quinolin, -CONH-), 7.23 (d, J = 8.5 Hz, 2H, Ar-H3, H5), 7.10 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.94 (d, J = 8.6 Hz, 2H, Ar-H2, H6), 6.67 (m, 2H, quinolin- H6, H8), 4.32 (s, 1H, NH), 2.97-3.80 (m, 13H, -CH2- and CH), 2.81 (t, J = 6.9 Hz, 2H, quinolin-H4), 2.35 (t, J = 6.9 Hz, 2H, quinolin-H3); 13C NMR (75 MHz, DMSO-d6) δ: 170.38, 149.07, 142.97, 139.34, 129.03, 127.48, 124.45, 118.00, 117.54, 112.90, 111.52, 63.00, 59.33, 52.77, 51.76, 48.03, 30.10, 20.15; LC- MS (ESI): m/z 415 [M+H]+.
1j;(yield 67%, Mp 175-177 °C);1H NMR (300 MHz, CDCl3) δ: 9.03 (s, 1H, quinolin, -CONH-), 7.25 (d, J = 7.3 Hz, 1H, Ar-H3), 7.14 (t, J = 7.7 Hz, 2H, quinolin-H7 and Ar-H5), 6.76 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.69 (d, J = 8.7 Hz, 1H, quinolin-H6), 6.51-6.65 (m, 2H Ar-H4, H6), 4.79 (s, 1H, NH), 3.97- 4.31(m, 1H, OH), 3.25-3.40 (m, 1H, -CH2-), 3.09-3.23 (m, 1H, -CH2-), 2.73-3.03 (m, 9H, -CH2-), 2.43-2.72 (m, 6H, -CH2-); 13C NMR (75 MHz, CDCl3) δ: 172.13, 150.38, 143.72, 137.82, 131.41, 128.80, 127.36, 122.39, 119.14, 117.52, 117.03, 113.66, 110.97, 64.84, 61.28, 53.24, 51.39, 46.98, 30.13, 20.23; LC- MS (ESI): m/z 415 [M+H]+.
1k;(yield 53 %, Mp 177-180 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.12 (s, 1H, quinolin, -CONH-), 9.21 (s, 1H, imidazol-H2), 7.74 (d, J = 36.9 Hz, 2H, imidazol-H4, H5), 7.08 (t, J = 7.5 Hz, 1H, quinolin-H7), 6.48-6.74 (m, 2H, quinolin-H6, H8), 4.49 (m, 2H, -CH2-), 4.27 (m, 1H, CH), 2.94-3.74 (m, 11H, - CH2-), 2.80 (t, J = 6.9 Hz, 2H, quinolin-H4), 2.33 (t, J = 6.9 Hz, 2H, quinolin-H3); 13C NMR (75 MHz, DMSO-d6) δ: 170.38, 149.04, 139.33, 135.79, 127.46, 122.75, 119.39, 117.56, 112.91, 111.56, 64.01, 58.36, 52.51, 51.90, 48.02, 30.09, 20.14; LC-MS (ESI): m/z 356 [M+H]+.
1l(yield 42%, Mp 192-195 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.01 (s, 1H, quinolin, -CONH-), 8.42 (s, 1H, triazol-H2), 7.93 (s, 1H, triazol-H5), 7.05 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.66 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.59 (d, J = 7.8 Hz, 1H, quinolin-H6), 4.24-4.37 (m, 1H, CH), 4.05-4.18 (m, 1H, OH), 3.91-4.04 (m, 2H, -CH2-), 2.67-2.88 (m, 6H, -CH2- and quinolin-H4), 2.49- 2.66 (m, 4H, -CH2-), 2.22-2.42 (m, 4H, quinolin-H3 and -CH2-); 13C NMR (75 MHz, DMSO-d6) δ: 170.58, 151.08, 150.61, 144.74, 139.11, 127.29, 117.33, 112.80, 110.70, 66.35, 61.61, 53.73, 53.47, 51.42, 30.23, 20.29; LC-MS (ESI): m/z 357 [M+H]+.
1m;(yield 75%, Mp 240-243 °C);1H NMR (300 MHz, D2O) δ: 7.03 (t, J = 8.0 Hz, 1H, quinolin-H7), 6.71 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.48 (d, J = 7.8 Hz, 1H, quinolin-H6), 4.33 (t, J = 9.1 Hz, 1H, CH), 3.58 (m, 2H, -CH2-), 2.81- 3.41 (m, 11H, -CH2-), 2.62 (t, J = 7.3 Hz, 2H, quinolin-H4), 2.20 (t, J = 7.3 Hz, 2H, quinolin-H3), 1.24 (s, 9H, -CH3); 13C NMR (75 MHz, D2O) δ: 174.12, 147.98, 136.95, 127.61, 117.84, 114.23, 112.10, 61.24, 58.27, 57.43, 53.57, 47.78, 43.91, 28.72, 24.26, 19.16; LC-MS (ESI): m/z 361 [M+H]+.
1n;(yield 72%, Mp 265-268 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.10 (s, 1H, quinolin, -CONH-), 7.11 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.67 (t, J = 8.1 Hz, 2H, quinolin-H6, H8), 4.52 (m, 1H, CH), 2.90-3.76 (m, 16H, -CH2-, NH and OH), 2.73-2.85 (m, 2H, quinolin-H4), 2.36 (t, J = 7.1 Hz, 2H, quinolin-H3), 1.63 (m, 2H, -CH2-), 1.31 (m, 2H, -CH2-), 0.87 (t, J = 7.3 Hz, 3H, -CH3); 13C NMR (75 MHz, DMSO-d6) δ: 170.37, 149.12, 139.36, 127.49, 117.56, 112.90, 111.51, 61.39, 58.76, 52.72, 50.03, 48.02, 46.76, 30.11, 27.26, 20.15, 19.39, 13.59; LC-MS (ESI): m/z 361 [M+H]+.
1o;(yield 82%, Mp 228-230 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.01 (s, 1H, quinolin, -CONH-), 7.05 (t, J = 7.8 Hz, 1H, quinolin-H7), 6.66 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.58 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.69 (m, 1H, CH), 2.78 (m, 6H, -CH2-), 2.10-2.66 (m, 14H, -CH2-), 0.92 (t, J = 6.9 Hz, 6H, - CH3); 13C NMR (75 MHz, DMSO-d6) δ: 170.50, 150.68, 139.15, 127.25, 117.31, 112.73, 110.65, 66.13, 62.81, 57.72, 53.85, 51.54, 47.13, 30.26, 20.31, 11.87; LC-MS (ESI): m/z 361 [M+H]+.
1p;(yield 82%, Mp 228-230 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.01 (s, 1H, quinolin, -CONH-), 7.05 (t, J = 7.8 Hz, 1H, quinolin-H7), 6.66 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.58 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.69 (m, 1H, CH), 2.78 (m, 6H, -CH2-), 2.10-2.66 (m, 14H, -CH2-), 0.92 (t, J = 6.9 Hz, 6H, - CH3); 13C NMR (75 MHz, DMSO-d6) δ: 170.50, 150.68, 139.15, 127.25, 117.31, 112.73, 110.65, 66.13, 62.81, 57.72, 53.85, 51.54, 47.13, 30.26, 20.31, 11.87; LC-MS (ESI): m/z 361 [M+H]+.
1q ;(yield 66%, Mp 280-283 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.11 (s, 1H, quinolin, -CONH-), 7.25 (d, J = 8.5 Hz, 2H, Ar-H3, H5,), 7.12 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.87 (d, J = 8.4 Hz, 2H, Ar-H2, H6), 6.72 (d, J = 7.8 Hz, 1H, quinolin-H8), 6.59 (d, J = 7.8 Hz, 1H, quinolin-H6), 4.51 (s, 1H, OH), 4.14 (s, 2H, Ar-CH2-), 3.34-3.77 (m, 7H, -CH2- and CH), 2.71-3.09 (m, 7H, - CH2-), 2.87 (t, J = 7.2 Hz, 2H, quinolin-H4), 2.31 (t, J = 7.2 Hz, 2H, quinolin-H3); 13C NMR (75 MHz, DMSO-d6) δ: 170.74, 150.36, 139.44, 137.21, 133.61, 129.56, 128.44, 127.58, 117.69, 112.17, 110.33, 60.47, 58.51, 51.82, 49.44, 48.62, 47.38, 30.18, 20.23; LC-MS (ESI): m/z 429 [M+H]+.
1r;(yield 75%, Mp 258-261 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.02 (s, 1H, quinolin, -CONH-), 7.08 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.68 (d, J = 7.9 Hz, 1H, quinolin-H8), 6.60 (d, J = 7.8 Hz, 1H, quinolin-H6), 4.31 (s, 1H, OH), 3.82 (m, 1H, CH), 3.27-3.67 (m, 5H, -CH2-), 2.80 (m, 6H, -CH2-), 2.59 (m, 3H, -CH2-), 2.11-2.47 (m, 10H, -CH2-); 13C NMR (75 MHz, DMSO-d6) δ: 170.51, 150.66, 139.14, 127.27, 117.32, 112.77, 110.65, 66.27, 65.15, 63.37, 62.86, 54.02, 53.77, 51.48, 30.25, 20.31; LC-MS (ESI): m/z 375 [M+H]+.
1s;(yield 71%, Mp 229-232 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.09 (s, 1H, quinolin, -CONH-), 7.09 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.70 (d, J = 8.0 Hz, 1H, quinolin-H8), 6.62 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.81 (m, 1H, CH), 3.39-3.76 (m, 8H, -CH2- and OH), 2.75-2.90 (m, 6H, -CH2-), 2.69 (d, J = 3.9 Hz, 4H, -CH2-), 2.27-2.48 (m, 8H, -CH2- and NH); 13C NMR (75 MHz, DMSO-d6) δ: 170.56, 150.67, 139.13, 127.26, 117.31, 112.77, 110.66, 65.07, 63.72, 62.96, 54.60, 53.78, 51.50, 45.44, 30.25, 20.31; LC-MS (ESI): m/z 374 [M+H]+.
1t;(yield 64%, Mp 221-223 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.02 (s, 1H, quinolin, -CONH-), 7.08 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.68 (d, J = 7.9 Hz, 1H, quinolin-H8), 6.60 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.81 (m, 1H, CH), 3.25-3.72 (m, 2H, -CH2-), 2.70-2.90 (m, 6H, -CH2-), 2.18-2.70 (m, 13H, -CH2- and OH), 1.43-1.56 (m, 4H, piperidine-H3, H5), 1.31-1.42 (m, 2H, piperidine- H4); 13C NMR (75 MHz, DMSO-d6) δ: 170.49, 150.67, 139.14, 127.26, 117.32, 112.76, 110.66, 65.06, 63.53, 62.95, 54.62, 53.79, 51.51, 30.26, 25.51, 23.90, 20.32; LC-MS (ESI): m/z 373 [M+H]+.
1u;(yield 75%, Mp 255-258 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.03 (s, 1H, quinolin, -CONH-), 7.08 (t, J = 7.8 Hz, 1H, quinolin-H7), 6.68 (d, J = 7.9 Hz, 1H, quinolin-H8), 6.61 (d, J = 7.7 Hz, 1H, quinolin-H6), 3.65-3.83 (m, 1H, CH), 2.75-2.96 (m, 6H, -CH2-), 2.65-2.75 (m, 4H, -CH2-), 2.18-2.64 (m, 11H, - CH2-), 1.46-1.67 (m, 8H, azepane-H3, H4, H5, H6); 13C NMR (75 MHz, DMSO-d6) δ: 170.48, 150.66, 139.14, 127.25, 117.30, 112.74, 110.66, 65.81, 62.76, 62.13, 55.37, 53.84, 51.51, 30.26, 27.56, 26.61, 20.32; LC-MS (ESI): m/z 387 [M+H]+.
1v;(yield 54%, Mp 189-192 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.01 (s, 1H, quinolin, -CONH-), 7.08 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.69 (d, J = 7.9 Hz, 1H, quinolin-H8), 6.60 (d, J = 7.8 Hz, 1H, quinolin-H6), 4.42 (s, 3H, OH), 3.63-3.77 (m, 1H, CH), 3.29-3.54 (m, 5H, -CH2-), 2.71-289 (m, 6H, -CH2-), 2.51-2.70 (m, 8H, -CH2-), 2.19-2.45 (m, 5H, -CH2-); 13C NMR (75 MHz, DMSO-d6) δ: 170.52, 150.68, 139.13, 127.27, 117.32, 112.76, 110.63, 66.31, 62.44, 60.08, 59.22, 57.55, 53.88, 51.44, 30.25, 20.31; LC-MS (ESI): m/z 393 [M+H]+.
1w;(yield 65%, Mp 233-236 °C);1H NMR (300 MHz, DMSO-d6) δ: 10.102 (s, 1H, quinolin, -CONH-), 7.13 (t, J = 7.9 Hz, 1H, quinolin-H7), 6.71 (d, J = 7.9 Hz, 1H, quinolin-H8), 6.63 (d, J = 7.8 Hz, 1H, quinolin-H6), 3.79 (m, 1H, CH), 3.19-3.68 (m, 2H, -CH2-), 2.72-2.85 (m, 6H, -CH2-), 2.19-2.66 (m, 13H, -CH2- and OH), 1.52-1.64 (m, 4H, piperidine-H3, H4), 1.31-1.42 (m, 2H, piperidine- H4); 13C NMR (75 MHz, DMSO-d6) δ: 170.43, 150.43, 138.72, 127.24, 117.47, 112.77, 110.79, 65.15, 63.44, 62.61, 54.68, 53.49, 51.27, 30.16, 26.53, 20.03; LC-MS (ESI): m/z 359 [M+H]+.
Example IV, the experiment of chitin synthesis inhibition of enzyme activity
Chitin synthetase derives from beer yeast cells film, enzyme-to-substrate incubation together on microwell plate, generation it is several Coated WGA is combined together and is fixed on Ding Zhiyu plate, is then added WGA-HRP, WGA-HRP can with it is fixed onboard Chitin combines, and extra reagent is washed off with distilled water, then using the activity of tmb substrate solution detection HRP, uses 2M's Sulfuric acid detects its OD after terminating reaction at 450 nm, calculates the IC of compound50Value.
Compound 1a-1w has carried out chitin synthesis enzyme inhibition activity primary dcreening operation, and the highest drug concentration of primary dcreening operation is 300 μ G/ml, inhibiting rate (IP, inhibition percentage) are inhibiting rate of the highest drug concentration to chitin synthetase, Its IC is further tested to the preferable compound of chitin synthesis enzyme inhibition activity50Value, primary dcreening operation result and IC50Value is such as 1 institute of table Show.
The IC of CHS inhibiting rate and part of compounds when the surveyed compound medicine concentration of table 1 is 300 μ g/ml50Value
Table 1 The CHS inhibition percentage and IC50 values of the test compounds
Embodiment five, the antimycotic experiment of compound
After the compound of the present invention is dissolved with DMSO, solution for standby is made with autoclaved distilled water, by 96 orifice plates, XiLin Bottle, pipette tips and other items high pressure sterilization pipettes the bacterium solution solution 100uL diluted with liquid-transfering gun into 96 orifice plates, with Ofloxacin, Streptomysin；Fluconazole, Polyoxin B is as control comparisons.
Target compound 1a-1w has carried out extracorporeal antifungal activity screening, and data are shown in Table 2.
The extracorporeal antifungal activity data of 2. compound 1a-w of table
Table 2 In vitro Antifungal activity of compounds 1a-1w
Embodiment six, the experiment of compound antibacterium
Target compound 1a ~ 1w of all synthesis has carried out ill vitro antibacterial activity screening, and data are shown in Table 3.
The ill vitro antibacterial activity data of 3 compound 1a ~ 1w of table
Table 3 In vitro Antibacterial activity of compounds 1a-1w

Claims (9)

  1. Quinoline -2 1. (1H) ketone piperazine compounds, shown in the general structure I of the compound:
    。
  2. 2. quinoline -2 (1H) ketone compounds as described in claim one, it is characterised in that: a nitrogen-atoms and quinoline for piperazine ring Quinoline ketone 5- are connected, another nitrogen-atoms is connected by the carbochain of 3 carbon atoms with another nitrogenous segment.
  3. 3. as described in claim one, wherein R1,R2Group is respectively as follows: hydrogen, the straight chain or branch key alkyl of 1-5 carbon atom；3-8 The naphthenic base and heterocycle of a carbon atom composition；Aromatic radical；Or 5-8 circle heterocyclic ring or heteroaromatic etc. are formed with N atom, further Illustrate, R in I compound represented of general formula1,R2For any one in hydrogen and following radicals:
    Or R1,R2Following groups are formed with N:
    。
  4. 4. compound described in claim one can be synthesized by following route, as shown in Scheme 1
    Scheme 1: the synthetic route of compound 1.
  5. 5. compound 2 is 1 with the molar ratio of diethanol amine or two-(2- bromoethyl) amine salt in the step a of claim 4: 1-3, optimum ratio are 1:1-1.4, and heating temperature is 50-100 DEG C, and preferably 75-85 DEG C, potassium hydroxide solution concentration is 10-15%, dosage are 2-3 times of compound 2.
  6. 6. reaction temperature is 20-50 DEG C, preferably 25-30 DEG C in the step b of claim 4.
  7. 7. reaction temperature is molten condition in the step c of claim 4, additional addition solvent is not had to.
  8. 8. above compound can be used as chitin synthetase inhibitor application, anti-pathogenic microorganism medicine application also can be used as.
  9. 9. the microorganism is pathogenetic bacteria or disease fungus, as Escherichia coli, staphylococcus aureus, methicillin-resistant are golden yellow Color staphylococcus, hay bacillus, proteus, pseudomonas aeruginosa；Candida albicans, Cryptococcus neoformans, Aspergillus flavus, cigarette Aspergillus etc..
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110713459A (en) * 2019-12-04 2020-01-21 西南大学 Design synthesis and application of quinolinone fumaramide derivatives
CN114751873A (en) * 2022-04-25 2022-07-15 扬州市普林斯医药科技有限公司 Preparation method of 1- (2, 3-dichlorophenyl) piperazine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
邓乔: "几丁质合成酶抑制剂喹啉-2(1H)酮类新化合物设计合成与生物活性研究", 《中国优秀硕士学位论文全文数据库工程科技I辑》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110713459A (en) * 2019-12-04 2020-01-21 西南大学 Design synthesis and application of quinolinone fumaramide derivatives
CN114751873A (en) * 2022-04-25 2022-07-15 扬州市普林斯医药科技有限公司 Preparation method of 1- (2, 3-dichlorophenyl) piperazine

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