CN113912603B - Preparation method and application of isofraxine analogue from ciprofloxacin to isofraxine analogue - Google Patents
Preparation method and application of isofraxine analogue from ciprofloxacin to isofraxine analogue Download PDFInfo
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Abstract
The invention provides an isopulegol analogue, a preparation method and application of the isopulegol analogue from ciprofloxacin to isopulegol analogue, which are used for solving the technical problem of how to design an indoloquinoline antitubercular drug with a novel structure by taking the isopulegol alkaloid as a lead and an atomic economic strategy. The invention selects ciprofloxacin to prepare the isoleukophylline analogue, realizes the effective chemical construction from the fluoroquinolone structure to the indoloquinoline skeleton, expands a new structure modification way of the isoleukophylline, and achieves the complementation of the dominant structures of the fluoroquinolone medicine and the natural indoloquinoline alkaloid. The in vitro antituberculosis activity test result shows that the compound has better growth inhibition activity on test tuberculosis strains, the activity of part of the compound is equivalent to that of control isoniazid, and the compound has drug resistance and lower cytotoxicity, and can be further developed and prepared as antituberculosis drugs with brand-new structures.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry related to organic synthesis and new drug development, in particular to an isopulegol analogue, and also relates to a preparation method of the isopulegol analogue from ciprofloxacin to isopulegol analogue and application of the isopulegol analogue in preparation of antituberculosis drugs.
Background
Tuberculosis is a chronic infectious disease with high incidence rate caused by tubercle bacillus, and is currently an urgent public health and social problem facing the world due to the lack of effective therapeutic drugs. Meanwhile, in addition to the fact that the tubercle bacillus is easy to generate drug resistance to the existing drugs, especially the generation of multi-drug resistance, new challenges are presented to the development of anti-tubercular drugs, so that no novel compound is available for the treatment of tuberculosis for more than half a century since the discovery of the anti-tubercular drugs of rifampicin. Therefore, the development of antitubercular drugs is a complex intellectual innovation project with high time consumption and high investment. The method takes the active ingredients of natural medicines as the lead, optimizes and modifies the structure of the lead, and is the most economical and effective strategy for finding new medicines. In the research and development of various natural active ingredients, it is found that the sinomenine alkaloid taking indoloquinoline as a structural characteristic framework, such as sinomenine (cryptamine, A), isopsorptamine (B), neophacoline (C) and the like,
the structure is unique, and the compound has better anti-plasmodium and anti-tumor activities, which are of interest in research, but reports on anti-tuberculosis activity are few. However, due to the difficult source of the white vine alkaloid and the poor water solubility, the bioavailability is low, and the like, the clinical application is limited. Therefore, how to design indoloquinoline antitubercular drugs with novel structures by using white She Tenglei alkaloid as a precursor and using an atomic economic strategy is very important. On the one hand, fluoroquinolone-based medicines are not only clinically important antibacterial medicines, but also clinical second-line antitubercular medicines, for example, the dominant structures of the sinomenine alkaloids and fluoroquinolones are spliced, the respective pharmacophore advantages are exerted, and the design and discovery of novel indoloquinoline antitubercular medicines are possible; on the other hand, by introducing effective substituent groups in fluoroquinolone drug molecules, the pharmacodynamics and pharmacokinetics properties of the fluoroquinolone drug molecules are further improved so as to overcome the defects of the existing alkaloids and promote the patentability development of novel indoloquinoline antituberculosis drugs.
Disclosure of Invention
Aiming at the technical problem of how to design an indoloquinoline antitubercular drug with a novel structure by taking a white leaf vine alkaloid as a lead and using an atomic economic strategy, the invention provides an isopsoralen analogue, and also relates to a preparation method of the isopsoralen analogue from ciprofloxacin to isopsoralen analogue and application of the isopsoralen analogue in preparation of antitubercular drugs. The invention takes the fluoroquinolone drug ciprofloxacin (II) purchased from commercial industry as a raw material, deacidifies into quinolinone (6-fluoro-1-cyclopropyl-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one, III), and then successfully constructs an isoborneol analogue with phenylhydrazine by a Fischer indole synthesis method; the isostephanine (B) in the stephanine alkaloid is selected as a lead, indolo [3,2-c ] quinoline is taken as a dominant skeleton, hydrophilic alkaline piperazinyl in a fluoroquinolone drug structure is introduced to increase water solubility and improve bioavailability, and meanwhile, the introduction of fluorine atoms can increase the permeability of drug molecules to improve the bioactivity.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
the chemical structural general formula of the isogamboge analogue is shown in formula I:
the substituent R in the formula I can be independently a hydrogen atom-H or methoxy-OCH 3 methyl-CH 3 Fluorine atom-F, chlorine atom-Cl or xantho-amido-SO 2 NH 2 。
Preferably, the chemical structural formula of the isofraxine analog is:
a method for preparing an analogue from ciprofloxacin to isobegonine, comprising the following steps:
s1, performing reduction decarboxylation reaction on ciprofloxacin shown in a formula II serving as a raw material and potassium borohydride to obtain 2, 3-dihydroquinolin-4-one shown in a formula III;
s2, preparing a sinomenine alkaloid with the structural characteristics of the mother nucleus of the indoloquinoline by using the 2, 3-dihydroquinolin-4-one and phenylhydrazine obtained in the step S1 through Fischer indole synthesis;
s3, carrying out post-treatment on the sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus obtained in the step S2 to obtain the iso-sinomenine analogue as in claim 1 or 2.
Preferably, the 6-fluoro-1-cyclopropyl-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one of formula III is prepared from ciprofloxacin of formula II, which is commercially available as a starting material, by reductive decarboxylation with sodium borohydride, a commercially available analytical chemical reagent, in a similar manner to the preparation method reference (Kondo H, sakamoto F, et al, studio procugs.7. Synthesis and antimicrobial activity of 3-formylquinolone derivatives, J Med Chem,1988,31 (1): 221-225.).
As a further improvement, potassium borohydride which is low in price, not easy to absorb moisture and mild in reaction is used for replacing sodium borohydride in the literature.
The step S1 specifically comprises the following steps:
mixing ciprofloxacin with a solvent to prepare a suspension, slowly adding potassium borohydride into the suspension under stirring at normal temperature, heating the mixed reactant in a water bath, and stirring and refluxing until the ciprofloxacin disappears to obtain a mixed solution;
y2, placing the mixed solution obtained in the step Y1 to room temperature, and evaporating the solvent in the mixed solution by using an evaporator to obtain a remainder;
y3, adding the residues obtained in the step Y2 into deionized water, mixing, adjusting the pH to be approximately equal to 2 by using concentrated hydrochloric acid, adding activated carbon for decolorization, adjusting the pH to be approximately equal to 10 by using sodium hydroxide with the mass concentration of 30%, and standing to precipitate solids;
and Y4, recrystallizing the solid precipitated in the step Y3 by hot water and recrystallizing by normal hexane to obtain 2, 3-dihydroquinolin-4-one.
Preferably, the step S2 specifically includes the following steps:
t1, dissolving the 2, 3-dihydroquinolin-4-one obtained in the step S1 in absolute ethyl alcohol, adding phenylhydrazines, and stirring at normal temperature until the 2, 3-dihydroquinolin-4-one disappears to obtain a mixed solution;
and T2, dropwise adding a cyclization catalyst into the mixed solution obtained in the step T1, carrying out heating reflux reaction, standing to room temperature, and filtering and collecting the produced sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus.
Preferably, the step S3 specifically includes the following steps:
z1, dissolving the sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus obtained in the step S3 in deionized water, adding active carbon for reflux decoloration, adding concentrated ammonia water to adjust the PH to be approximately equal to 10, and filtering and collecting the generated solid;
and Z2, recrystallizing the solid obtained in the step T3 by using an absolute ethyl alcohol-ethyl acetate mixed solvent to obtain the pale yellow crystalline isopulegol analogue.
Preferably, the solvent in the step Y1 is absolute methanol, absolute ethanol or 95% ethanol, and the molar ratio of ciprofloxacin to potassium borohydride is 1 (1-3).
Preferably, the molar ratio of the 2, 3-dihydroquinolin-4-one to the phenylhydrazine in the step T1 is 1 (1-2), the phenylhydrazine is phenylhydrazine, p-methylphenylhydrazine, m-methylphenylhydrazine, o-methylphenylhydrazine, p-fluorophenylhydrazine, m-fluorophenylhydrazine or m-fluorosulfonylamino phenylhydrazine, the cyclization catalyst in the step T2 is concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, glacial acetic acid or trifluoroacetic acid, and the reflux reaction time is 10-24 hours.
Application of isofraserin analog in preparing antitubercular medicine is provided.
Preferably, the isopulegol analogs are used for preparing medicaments for inhibiting mycobacterium tuberculosis, and the mycobacterium tuberculosis is H 37 Ra or H 37 Rv。
The invention has the beneficial effects that:
1. the isowhite leaf vine alkaloid analogue disclosed by the invention retains the dominant skeleton of isowhite leaf vine alkaloid, namely the indoloquinoline mother nucleus, has the characteristic structure of fluoroquinolone medicaments, namely a quinoline ring, and is particularly used as an effective modification group of fluoroquinolone medicaments, and the hydrophilic alkaline piperazine group is used as the modification group of the indoloquinoline mother nucleus, so that the water solubility of the isowhite leaf vine alkaloid can be effectively improved, the bioavailability is improved, the development of medicament formation is facilitated, and meanwhile, the introduction of fluorine atoms can increase the permeation effect of medicaments, and the effects of synergism, toxicity reduction and medicament resistance are realized.
2. The indoloquinoline mother nucleus and the quinoline ring in the isowhite phylline analogue realize complementation and activity superposition of pharmacophores with different structures, and an in-vitro antitubercular activity test result in experimental examples shows that the compound has better growth inhibition activity on a test tuberculosis strain, has the activity of partial compounds being equivalent to that of a control isoniazid, has drug resistance and lower cytotoxicity, has excellent in-vitro antitubercular bacillus growth inhibition activity, and can be further developed as a novel antitubercular drug with the structural characteristics of indoloquinoline.
3. The preparation method of the invention prepares 2, 3-dihydroquinolin-4-one by using ciprofloxacin through reduction decarboxylation reaction and potassium borohydride, and then prepares the isoleukophylline analogue by using 2, 3-dihydroquinolin-4-one and phenylhydrazine through a Fischer indole synthesis method, thereby realizing effective chemical construction from a fluoroquinolone structure to an indoloquinoline skeleton, expanding a novel structure modification way of the isoleukophylline, and achieving complementation of the dominant structures of fluoroquinolone drugs and natural indoloquinoline alkaloids.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without any inventive effort, are intended to be within the scope of the invention.
Example 1
The chemical structural general formula of the isogamboge analogue is shown in formula I:
in this embodiment, the substituent R in formula I is an H atom, and the chemical structural formula of the isopulegol analog, i.e., 2-fluoro-3-piperazin-1-yl-5-cyclopropyl-5H-indolo [3,2-c ] quinoline, is:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-1), which comprises the following steps:
s1, performing reduction decarboxylation reaction on ciprofloxacin shown in a formula II serving as a raw material and potassium borohydride to obtain 2, 3-dihydroquinolin-4-one shown in a formula III.
Specifically, the method comprises the following steps: mixing ciprofloxacin with a solvent to prepare a suspension, slowly adding potassium borohydride into the suspension under stirring at normal temperature, heating the mixed reactant in a water bath, and stirring and refluxing until the ciprofloxacin disappears to obtain a mixed solution; y2, placing the mixed solution obtained in the step Y1 to room temperature, and evaporating the solvent in the mixed solution by using an evaporator to obtain a remainder; y3, adding the residues obtained in the step Y2 into deionized water, mixing, adjusting the pH to be approximately equal to 2 by using concentrated hydrochloric acid, adding activated carbon for decolorization, adjusting the pH to be approximately equal to 10 by using sodium hydroxide with the mass concentration of 30%, and standing to precipitate solids; and Y4, recrystallizing the solid precipitated in the step Y3 by hot water and recrystallizing by normal hexane to obtain 2, 3-dihydroquinolin-4-one.
In this embodiment, the method specifically includes: cyclopropyle Sha Xing 18.0.0 g (55.0 mmol) is suspended in 500mL absolute methanol, 7.4g (138.0 mmol) of potassium borohydride is slowly added in portions under stirring at normal temperature, the mixed reactant is heated in a water bath, and the stirring reflux reaction is carried out until the raw material II disappears. The mixture was left at room temperature, and the solvent was distilled off under reduced pressure using a rotary evaporator. Adding deionized 500mL into the residue, adjusting pH to about 2.0 with concentrated hydrochloric acid, decolorizing with appropriate amount of active carbon, and filtering to obtain filtrateThe pH of the sodium hydroxide solution with the concentration of 30% is regulated to be approximately 10.0, and the solid is deposited. The crude product is recrystallized by hot water and normal hexane in sequence to obtain 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one with a yield of 51.4% and m.p.112-114 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:7.56 (1H, d, 5-H), 6.76 (1H, d, 5-H), 3.15 to 3.62 (10H, m,2-H and piperazine-H), 2.51 to 2.57 (3H, m,3-H and CH), 1.87 (1H, m, NH), 0.84 to 0.97 (4H, m, cyclopropyl CH) 2 CH 2 )；MS(m/z)：290[M+H] + Calculation (C) 16 H 20 FN 3 O)：289.36。
S2, preparing the sinomenine alkaloid with the structural characteristics of the mother nucleus of the indoloquinoline by using the 2, 3-dihydroquinolin-4-one and phenylhydrazine obtained in the step S1 through Fischer indole synthesis. Specifically, the method comprises the following steps: t1, dissolving the 2, 3-dihydroquinolin-4-one obtained in the step S1 in a solvent, adding phenylhydrazines, and stirring at normal temperature until the 2, 3-dihydroquinolin-4-one disappears to obtain a mixed solution; and T2, dropwise adding a cyclization catalyst into the mixed solution obtained in the step T1, carrying out heating reflux reaction, standing to room temperature, and filtering and collecting the produced sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus.
In this embodiment, the method specifically includes: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one III is dissolved in 15mL of absolute ethanol, 0.50g (4.6 mmol) of phenylhydrazine is added, and the mixture is stirred at room temperature to react for 16 hours, thereby generating a large amount of precipitate. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was reacted under reflux for 16h and left overnight. The resulting solids were collected by filtration. The solid is the sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus.
S3, performing post-treatment on the sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus obtained in the step S2 to obtain the iso-sinomenine analogue as claimed in claim 1 or 2. Specifically, the method comprises the following steps: z1, dissolving the sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus obtained in the step S3 in deionized water, adding active carbon for reflux decoloration, adding concentrated ammonia water to adjust the PH to be approximately equal to 10, and filtering and collecting the generated solid; and Z2, recrystallizing the solid obtained in the step T3 by using an absolute ethyl alcohol-ethyl acetate mixed solvent to obtain the pale yellow crystalline isopulegol analogue.
In this embodiment, the method specifically includes: the solid was dissolved with 50mL deionized water, and an appropriate amount of activated carbon was added to decolorize under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give the title compound of formula I-1 as pale yellow crystals in a yield of 60.4%, m.p.235-237 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.14 to 1.28 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.15 to 3.26 (4H, m, piperazine-H), 3.37 (1H, br, NH), 3.57 to 3.86 (5H, m, piperazine-H and cyclopropyl CH), 7.14 to 8.04 (6H, m,1-H, 4-H and Ph-H), 8.75 (1H, s, 6-H); MS (m/z): 361[ M+H ]] + Calculation (C) 22 H 21 FN 4 )：360.44。
Example 2
The difference between the present embodiment and the embodiment 1 is that the substituent R in the formula I is methoxy, and the chemical structural formula of the isogambogine analog, namely 2-fluoro-5-cyclopropyl-8-methoxy-3-piperazin-1-yl-5H-indolo [3,2-c ] quinoline, is as follows:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-2), which comprises the following steps: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is taken and dissolved in 15mL of absolute ethanol, 0.62g (4.5 mmol) of p-methoxyphenylhydrazine is added, and the mixture is stirred at normal temperature to react overnight, so that a significant precipitate is formed. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was reacted under reflux for 20h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried, and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give pale yellow crystalsThe target compound has the formula I-2, the yield is 52.4%, and the m.p.238-240 ℃. 1 H NMR(400MHz, CD 3 Cl) δ:1.17 to 1.36 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.16 to 3.28 (4H, m, piperazine-H), 3.40 (1H, br, NH), 3.62 to 3.91 (8H, m, piperazine-H, OCH) 3 And cyclopropyl CH), 7.35 to 8.12 (5H, m,1-H, 4-H and Ph-H), 8.84 (1H, s, 6-H); MS (m/z): 391[ M+H ]] + Calculation (C) 23 H 23 FN 4 O)： 390.46。
It is to be noted that, in this example, the process for preparing 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is substantially identical to that of example 1, except that in this example, the molar ratio of ciprofloxacin to potassium borohydride is set to 1:2, the absolute methanol used in example 1 was replaced with absolute ethanol as a solvent.
Example 3
The difference between the present embodiment and the embodiment 1 is that the substituent R in the formula I is methoxy, and the chemical structural formula of the isogambogine analog, namely 2-fluoro-5-cyclopropyl-3-piperazin-1-yl-9-methoxy-5H-indolo [3,2-c ] quinoline, is as follows:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-3), which comprises the following steps: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is taken and dissolved in 15mL of absolute ethanol, 0.83g (6.0 mmol) of m-methoxyphenylhydrazine is added, and the mixture is stirred at normal temperature to react for 20 hours, wherein obvious precipitate formation occurs. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was reacted under reflux for 16h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried, and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give the title compound of formula I-3 as pale yellow crystals in 42.7% yield，m.p.232～234℃。 1 H NMR(400 MHz,CD 3 Cl) δ:1.14 to 1.42 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.18 to 3.32 (4H, m, piperazine-H), 3.42 (1H, br, NH), 3.66 to 3.90 (8H, m, piperazine-H, OCH) 3 And cyclopropyl CH), 7.42 to 8.16 (5H, m,1-H, 4-H and Ph-H), 8.86 (1H, s, 6-H); MS (m/z): 391[ M+H ]] + Calculation (C) 23 H 23 FN 4 O)：390.46。
It is to be noted that, in this example, the process for preparing 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is substantially identical to that of example 1, except that in this example, the molar ratio of ciprofloxacin to potassium borohydride is set to 1:1, the anhydrous methanol used in example 1 was replaced with 95% ethanol as a solvent.
Example 4
The difference between the present embodiment and the embodiment 1 is that the substituent R in the formula I is methoxy, and the chemical structural formula of the isogambogine analogue, namely 2-fluoro-5-cyclopropyl-3-piperazin-1-yl-10-methoxy-5H-indolo [3,2-c ] quinoline, is as follows:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-4), which comprises the following steps: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is dissolved in 15mL of absolute ethanol, 0.72g (5.0 mmol) of o-methoxyphenylhydrazine is added, and the mixture is stirred at normal temperature to react for 24 hours to form a precipitate. Concentrated hydrochloric acid (0.50, mL) was added, and the mixture was refluxed for 15h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give the title compound of formula I-4 as pale yellow crystals in 40.2% yield, m.p.230-232 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.15 to 1.38 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.23 to 3.36 (4H, m, piperazine-H), 3.40 (1H, br, NH), 3.68 to 3.92 (8H, m, piperazine-H, OCH) 3 And cyclopropyl CH), 7.46 to 8.24 (5H, m,1-H, 4-H and Ph-H), 8.87 (1H, s, 6-H); MS (m/z): 391[ M+H ]] + Calculation (C) 23 H 23 FN 4 O)： 390.46。
It is to be noted that, in this example, the process for preparing 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is substantially identical to that of example 1, except that in this example, the molar ratio of ciprofloxacin to potassium borohydride is set to 1:2, the anhydrous methanol used in example 1 was replaced with 95% ethanol as a solvent.
Example 5
An isopulegol analog, which differs from example 1 in that the substituent R in formula I is methyl, is 2-fluoro-3-piperazin-1-yl-5-cyclopropyl-8-methyl-5H-indolo [3,2-c ] quinoline of the formula:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-5), which comprises the following steps: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one of formula III was dissolved in 15mL of absolute ethanol, and 0.70g (5.7 mmol) of p-methylphenylhydrazine was added thereto, followed by stirring at room temperature and reacting overnight to give a precipitate. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was refluxed for 22h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=3:1) to give the title compound of formula I-5 as pale yellow crystals in 45.0% yield, m.p.235-237 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.07 to 1.35 (4H, m, cyclopropyl CH) 2 CH 2 )，2.23(3H，s， Ph-CH 3 ) 3.12 to 3.30 (4H, m, piperazine-H), 3.38 (1H, br, NH), 3.65 to 3.87 (5H, m, piperazine-H and cyclopropyl CH), 7.28 to 8.06 (5H, m,1-H, 4-H and Ph-H), 8.82 (1H, s, 6-H); MS (m/z): 375[ M+H ]] + Calculation (C) 23 H 23 FN 4 )：374.46。
It is to be noted that, in this example, the process for preparing 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is substantially identical to that of example 1, except that in this example, the molar ratio of ciprofloxacin to potassium borohydride is set to 1:3, the absolute methanol used in example 1 was replaced with absolute ethanol as solvent.
Example 6
An isopulegol analog, which differs from example 1 in that the substituent R in formula I is F atom, is 2, 8-difluoro-3-piperazin-1-yl-5-cyclopropyl-5H-indolo [3,2-c ] quinoline of the formula:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-6), which comprises the following steps: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is dissolved in 15mL of absolute ethanol, 0.60g (4.8 mmol) of p-fluorobenzenehydrazine is added, and the mixture is stirred at normal temperature to react for 24 hours, thereby generating a large amount of precipitate. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was reacted under reflux for 16h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give the title compound of formula I-6 as pale yellow crystals in 58.7% yield, m.p.241-243 ℃. 1 H NMR(400MHz, CD 3 Cl) δ:1.21 to 1.46 (4H, m, cyclopropyl)CH 2 CH 2 ) 3.21 to 3.36 (4H, m, piperazine-H), 3.45 (1H, br, NH), 3.72 to 3.94 (5H, m, piperazine-H and cyclopropyl CH), 7.52 to 8.23 (5H, m,1-H, 4-H and Ph-H), 8.87 (1H, s, 6-H); MS (m/z): 379[ M+H ]] + Calculation (C) 22 H 20 F 2 N 4 )： 378.43。
Example 7
An isopulegol analog, which differs from example 1 in that the substituent R in formula I is F atom, is 2, 9-difluoro-3-piperazin-1-yl-5-cyclopropyl-5H-indolo [3,2-c ] quinoline of the formula:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-7), which comprises the following steps: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is taken and dissolved in 15mL of absolute ethyl alcohol, 0.66g (5.2 mmol) of m-fluorobenzenehydrazine is added, and the mixture is stirred at normal temperature to react for 24 hours, so that obvious precipitate is formed. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was reacted under reflux for 16h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give the title compound of formula I-7 as pale yellow crystals in 45.2% yield, m.p.236-238 ℃. 1 H NMR(400MHz, CD 3 Cl) δ:1.22 to 1.48 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.26 to 3.37 (4H, m, piperazine-H), 3.46 (1H, br, NH), 3.75 to 3.92 (5H, m, piperazine-H and cyclopropyl CH), 7.48 to 8.24 (5H, m,1-H, 4-H and Ph-H), 8.86 (1H, s, 6-H); MS (m/z): 379[ M+H ]] + Calculation (C) 22 H 20 F 2 N 4 )： 378.43。
Example 8
The difference between the present embodiment and the embodiment 1 is that the substituent R in the formula I is chlorine atom, and the chemical structural formula of the isogambogine analogue, namely 2-fluoro-8-chloro-3-piperazin-1-yl-5-cyclopropyl-5H-indolo [3,2-c ] quinoline, is as follows:
the present example used a method for preparing an isopulellin analogue from ciprofloxacin to isopulellin analogue (I-8), comprising the steps of: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is dissolved in 15mL of absolute ethanol, 0.74g (5.2 mmol) of p-chlorophenylhydrazine is added, and the mixture is stirred at normal temperature to react for 24 hours, thereby generating a large amount of precipitate. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was reacted under reflux for 16h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give the title compound of formula I-8 as pale yellow crystals in 52.6% yield, m.p.228-230 ℃. 1 H NMR(400MHz, CD 3 Cl) δ:1.16 to 1.43 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.22 to 3.35 (4H, m, piperazine-H), 3.42 (1H, br, NH), 3.68 to 3.87 (5H, m, piperazine-H and cyclopropyl CH), 7.42 to 8.21 (5H, m,1-H, 4-H and Ph-H), 8.87 (1H, s, 6-H); MS (m/z): 395 (Cl) 35 )[M+H] + ，397(Cl 37 )[M+H] + Calculation (C) 22 H 20 ClFN 4 )：394.88。
Example 9
An isopulegol analog, which differs from example 1 in that the substituent R in formula I is a chlorine atom, is 2-fluoro-9-chloro-3-piperazin-1-yl-5-cyclopropyl-5H-indolo [3,2-c ] quinoline of the formula:
the present example used a method for preparing an isopulellin analogue from ciprofloxacin to isopulellin analogue (I-9), comprising the steps of: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one is taken and dissolved in 15mL of absolute ethyl alcohol, 0.70g (5.0 mmol) of m-chlorophenylhydrazine is added, and the mixture is stirred at normal temperature to react for 24 hours, so that obvious precipitate is formed. Concentrated hydrochloric acid (0.50 mL) was added and the mixture was reacted under reflux for 24h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=5:1) to give the title compound of formula I-9 as pale yellow crystals in 42.6% yield, m.p. 232-234 ℃. 1 H NMR(400MHz, CD 3 Cl) δ:1.12 to 1.40 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.26 to 3.38 (4H, m, piperazine-H), 3.40 (1H, br, NH), 3.70 to 3.88 (5H, m, piperazine-H and cyclopropyl CH), 7.46 to 8.22 (5H, m,1-H, 4-H and Ph-H), 8.88 (1H, s, 6-H); MS (m/z): 395 (Cl) 35 )[M+H] + ，397(Cl 37 )[M+H] + Calculation (C) 22 H 20 ClFN 4 )：394.88。
Example 10
The difference between the present embodiment and the embodiment 1 is that the substituent R in the formula I is a sulfonamide group, and the chemical structural formula of the isogambogine analog, namely 2-fluoro-8-sulfonamide group-3-piperazin-1-yl-5-cyclopropyl-5H-indolo [3,2-c ] quinoline, is as follows:
the present example uses a method for preparing an isopulegol analog from ciprofloxacin to isopulegol analog for preparing the isopulegol analog (I-10), which comprises the following steps: 1.0g (3.5 mmol) of 1-cyclopropyl-6-fluoro-7-piperazin-1-yl-2, 3-dihydro-quinolin-4 (1H) -one (1) was dissolved in 15mL of absolute ethanol and p-chlorosulfonyl was added0.67g (3.6 mmol) of amino phenylhydrazine is stirred at normal temperature for reaction for 24 hours, and a large amount of precipitate is formed. Concentrated hydrochloric acid (0.50 mL) was added, and the mixture was reacted under reflux for 15h and left overnight. The resulting solid was collected by filtration, dissolved in 50mL of deionized water, added with an appropriate amount of activated carbon, and decolorized under reflux for 1h. The filtrate was filtered hot and the pH of the filtrate was adjusted to approximately 10.0 with ammonia. The resulting solid was collected by filtration, dried and recrystallized from an absolute ethanol-ethyl acetate mixed solvent (v: v=8:1) to give the title compound of formula I-10 as pale yellow crystals in 58.6% yield, m.p.246-248 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.21 to 1.47 (4H, m, cyclopropyl CH) 2 CH 2 ) 3.37 to 3.42 (4H, m, piperazine-H), 3.52 (1H, br, NH), 3.76 to 4.12 (5H, m, piperazine-H and cyclopropyl CH), 7.35 to 8.36 (7H, m,1-H, 4-H, ph-H and NH) 2 )，8.92(1H，s，6-H)；MS(m/z)：440[M+H] + Calculation (C) 22 H 22 FN 5 O 2 S)：439.52。
The invention also provides application of the isostephanine analogue in preparing antitubercular medicaments, in particular to application of the isostephanine analogue in preparing medicaments for inhibiting mycobacterium tuberculosis, wherein the mycobacterium tuberculosis is H 37 Ra or H 37 Rv, the following experimental examples of the use of isoeuonymus alatus analogues in the preparation of antitubercular drugs are described in detail.
Experimental example
1. In vitro anti-tubercular Activity assay of Isobanchamine analogues provided in examples 1-10
1. Experimental reagent
Positive controls Isoniazid (INH) and ciprofloxacin were purchased from the food and drug institute of the Henan province; 7H9 liquid medium was purchased from Difco, inc. of America. Under aseptic condition, the positive control and the test samples of examples I-1 to I-10 are prepared into 4mg/mL solution by using dimethyl sulfoxide (DMSO), after ultrasonic dissolution, the solution is filtered by using a 0.22 mu m filter membrane, and the filtrate is stored as a stock solution at-20 ℃ for standby (when in use, in order to avoid the influence of DMSO on experimental results, the concentration of DMSO in the culture solution is less than 0.5%).
2. Tuberculosis strain
The experimental tubercle strains are respectively mycobacterium tuberculosis standard strains H 37 Ra(ATCC25177)、 H 37 Rv (ATCC 27294) and 3 clinically isolated drug-resistant mycobacterium tuberculosis numbers H6, H7 and H10, respectively, were provided by the disease prevention control center in henna and provided for the determination of experimental data. Wherein, H6 and H7 are multi-drug resistant strains to isoniazid, rifampin, ethambutol, streptomycin and ofloxacin, and H10 is a drug resistant strain to isoniazid and rifampin.
3. Experimental method
1) Preparation of strain suspension: taking out the tubercle bacillus to be tested cultured for 2-3 weeks, inoculating to a sterilized small bottle, mixing to be milky, diluting with physiological saline, preparing bacterial liquid into bacterial liquid of 1mg/mL by turbidimetric tube with No.1 McPhellinus standard, and diluting with physiological saline to 1×10 5 CFU is ready for use.
2) On a 96-well plate, 200. Mu.mL of a solution of the test compound at an appropriate concentration (the test compound was diluted to 200. Mu.g/mL with a sterile 7H9 liquid culture solution) was added, and then the test compound was diluted again as needed (the doubling ratio was diluted to 50, 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.195, 0.097, 0.048, 0.024, 0.012. Mu.g/mL), and a drug-free control well was set.
3) Adding the diluted bacterial liquid into all detection holes and drug-free facing holes, placing the plates into a constant temperature incubator at 37deg.C and 5% CO per plate 2 Culturing under the condition for 21 days. The lowest concentration at which no strain grows is observed by a microscope of 40 x, namely the lowest inhibitory concentration (MIC) of the drug. Meanwhile, isoniazid and ciprofloxacin are used as positive control, and DMSO and a culture solution without any compound are used as negative control. Each data was measured in triplicate and averaged, and the experimental results are shown in table 1.
TABLE 1 in vitro antitubercular Activity (MIC) of test samples
The results in Table 1 show that of the compounds provided in examples 1 to 10, examples1. Example 4, example 6, example 7 and example 10 vs H 37 Ra and H 37 The MIC values of the two mycobacterium tuberculosis standard strains of Rv are lower than that of the control ciprofloxacin, and the activity of the two mycobacterium tuberculosis standard strains of example 4, example 6, example 7 and example 10 is equivalent to that of isoniazid, so that the two mycobacterium tuberculosis standard strains of Rv have better in-vitro antituberculosis activity. Meanwhile, the MIC values of most of the compounds provided in examples 1-10 for 3 clinically isolated drug-resistant strains H6, H7 and H10 are far lower than those of control ciprofloxacin or isoniazid, and the compounds show better drug-resistant activity.
2. In vitro cytotoxicity assays of examples 1-10
1. Experimental reagent
Positive controls Isoniazide (INH) and ciprofloxacin were purchased from the food and drug laboratory in henna province; the normal cells were VERO, a strain of VERO cells, purchased from Shanghai general derivative technologies, inc. RPMI, trypsin (TRGPSIN) and fetal bovine serum were purchased from holly bioengineering materials limited, hangzhou; brominated- (4, 5) -dimethyl-2-thiazole-2, 5-diphenyltetrazole (MTT, ameresco split); sodium Dodecyl Sulfate (SDS), sodium dihydrogen phosphate was purchased from the Tianjin chemical reagent development center; disodium ethylenediamine tetraacetate (EDTA) and dimethyl sulfoxide (DMSO) were purchased from the company of the tendril chemical formula.
2. Preparation of experimental test solution
Under aseptic condition, the positive control and the samples of examples 1-10 are prepared into 1.0X10 by using dimethyl sulfoxide (DMSO) -4 mol·L -1 12 stock solutions at concentration, and then the stock solution was diluted to have 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0. Mu. Mol.L) with RPMI-1640 medium of calf serum at a concentration of 10% by mass -1 ) After being fully dissolved by ultrasonic, the working solution is filtered by a filter membrane with the thickness of 0.22 mu m, and the filtrate is taken as a test solution to be preserved at the temperature of minus 20 ℃ for standby.
3. Experimental method (MTT method)
Taking VERO African green monkey kidney cell strain in logarithmic growth phase, inoculating 6000 cells per well into 96-well plate, adding the above 12 samples of working solution with 5 concentration gradients, respectively, adding 5 g.L per well after 48 hr –1 10. Mu.L of MTT (thiazole blue) solution was further cultured for 4 hours, and then 100. Mu.L of 10% strength by mass Sodium Dodecyl Sulfate (SDS) solution was added. After incubation for 24 hours, absorbance (OD) values were measured at 570nm using a microplate reader. The cell proliferation inhibition rate was calculated according to the formula:
inhibition ratio = [ (1-experimental group OD value)/control group OD value ] ×100%
Then, linear regression is performed on the VERO cell inhibition rate corresponding to each concentration by the logarithmic value of each concentration of each sample to obtain a dose-effect equation, and the half Inhibition Concentration (IC) of each sample to the experimental VERO cell is calculated from the obtained dose-effect equation 50 ) The method comprises the steps of carrying out a first treatment on the surface of the Each data was measured in triplicate and averaged, and the results are shown in table 2.
TABLE 2 in vitro VERO cytotoxicity assay (IC) of test samples 50 )
Table 2 shows that the compounds provided in examples 1 to 10 have half-growth inhibitory concentrations (IC 50 ) The positive control ciprofloxacin showed relatively low cytotoxicity, and at the same time, the compounds IC provided in examples 1 to 10 50 IC higher than positive isoniazid 50 The values indicate that the compounds provided in examples 1-10 are less cytotoxic than the positive control isoniazid.
In summary, the compounds provided in examples 1 to 10 not only have better anti-tubercle bacillus activity in vitro, but also have potential anti-drug resistance activity, and show lower cytotoxicity. Based on the law of new medicine research, the ciprofloxacin to isobaiphylline analogues are hopeful to develop high-efficiency low-toxicity antitubercular medicines.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (10)
1. The isogamboge analogue is characterized in that the chemical structural general formula is shown in formula I:
the substituent R in the formula I can be independently a hydrogen atom-H or methoxy-OCH 3 methyl-CH 3 Fluorine atom-F, chlorine atom-Cl or sulfonamide group-SO 2 NH 2 。
2. The isopsorine analog of claim 1, wherein the isopsorine analog has the chemical formula:
3. a method for preparing an analogue from ciprofloxacin to isobaiphylline, which is characterized by comprising the following steps:
s1, taking ciprofloxacin shown in a formula II as a raw material and carrying out reduction decarboxylation reaction with potassium borohydride to prepare 2, 3-dihydroquinolin-4-one shown in a formula III;
s2, preparing the isowhite sinomenine alkaloid with the structural characteristics of the mother nucleus of the indoloquinoline by using the 2, 3-dihydroquinolin-4-one and phenylhydrazine obtained in the step S1 through the Fischer indole synthesis method shown below;
s3, carrying out post-treatment on the isostephanine alkaloid with the structural characteristics of the indoloquinoline mother nucleus obtained in the step S2 to obtain the isostephanine analogue as claimed in claim 1 or 2.
4. A process for the preparation of an analogue from ciprofloxacin to isofraxinus according to claim 3, wherein step S1 comprises the steps of:
mixing ciprofloxacin with a solvent to prepare a suspension, slowly adding potassium borohydride into the suspension under stirring at normal temperature, heating the mixed reactant in a water bath, and stirring and refluxing until the ciprofloxacin disappears to obtain a mixed solution;
y2, placing the mixed solution obtained in the step Y1 to room temperature, and evaporating the solvent in the mixed solution by using an evaporator to obtain a remainder;
y3, adding the residues obtained in the step Y2 into deionized water, mixing, adjusting the pH to be 2 by using concentrated hydrochloric acid, adding activated carbon for decolorization, adjusting the pH to be 10 by using sodium hydroxide with the mass concentration of 30%, and standing to precipitate a solid;
and Y4, recrystallizing the solid precipitated in the step Y3 by hot water and recrystallizing by normal hexane to obtain 2, 3-dihydroquinolin-4-one.
5. A process for the preparation of an analogue from ciprofloxacin to isofraxinus according to claim 3, wherein step S2 comprises the steps of:
t1, dissolving the 2, 3-dihydroquinolin-4-one obtained in the step S1 in absolute ethyl alcohol, adding phenylhydrazines, and stirring at normal temperature until the 2, 3-dihydroquinolin-4-one disappears to obtain a mixed solution;
and T2, dropwise adding a cyclization catalyst into the mixed solution obtained in the step T1, carrying out heating reflux reaction, standing to room temperature, and filtering and collecting the produced isofraxine alkaloid with the structural characteristics of the indoloquinoline mother nucleus.
6. The method for preparing the analogue from ciprofloxacin to isofraxinus according to claim 3, wherein the step S3 specifically comprises the following steps:
z1, dissolving the sinomenine alkaloid with the structural characteristics of the indoloquinoline mother nucleus obtained in the step S2 in deionized water, adding active carbon for reflux decoloration, adding concentrated ammonia water to adjust the pH value to be 10, and filtering and collecting the generated solid;
and Z2, recrystallizing the solid obtained in the step Z1 by using an absolute ethyl alcohol-ethyl acetate mixed solvent to obtain the pale yellow crystalline isopulegol analogue.
7. The method for preparing an analogue from ciprofloxacin to isobai foline according to claim 4, wherein the solvent in the step Y1 is anhydrous methanol, anhydrous ethanol or 95% ethanol, and the molar ratio of ciprofloxacin to potassium borohydride is 1 (1-3).
8. The method for preparing the analogue from ciprofloxacin to isopulegol according to claim 5, wherein the molar ratio of the 2, 3-dihydroquinolin-4-one to the phenylhydrazine in the step T1 is 1 (1-2), the phenylhydrazine is phenylhydrazine, p-methylphenylhydrazine, m-methylphenylhydrazine, o-methylphenylhydrazine, p-fluorophenylhydrazine or m-fluorophenylhydrazine, the cyclization catalyst in the step T2 is concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, glacial acetic acid or trifluoroacetic acid, and the reflux reaction time is 10-24 h.
9. Use of an isopulegol analogue according to any one of claims 1, 2, 4 to 8 in the preparation of an antitubercular drug.
10. The use of an isopulegol analog according to claim 9 for the preparation of an antitubercular drug, wherein the isopulegol analog is used for the preparation of a drug for inhibiting mycobacterium tuberculosis, which is H 37 Ra or H 37 Rv。
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