CN116969981A - Dihydroquinoline compound and preparation method, pharmaceutical composition and application thereof - Google Patents
Dihydroquinoline compound and preparation method, pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN116969981A CN116969981A CN202310747289.2A CN202310747289A CN116969981A CN 116969981 A CN116969981 A CN 116969981A CN 202310747289 A CN202310747289 A CN 202310747289A CN 116969981 A CN116969981 A CN 116969981A
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- CN
- China
- Prior art keywords
- acid
- compound
- dihydroquinoline
- pharmaceutically acceptable
- dihydroquinoline compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Dihydroquinoline compound Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
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- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000003068 molecular probe Substances 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000007850 fluorescent dye Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000000523 sample Substances 0.000 claims description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
The invention discloses a dihydroquinoline compound, a preparation method, a pharmaceutical composition and application thereof, wherein the structure of the compound is shown as a formula I, and the compound also comprises pharmaceutically acceptable salts thereof. The compound has good affinity and selectivity with Abeta 42 oligomer; meanwhile, the polypeptide has proper fat solubility, can penetrate through a blood brain barrier in vivo, is stable in metabolism and can screen out pathological characteristics of AD; in addition, the imaging characteristic of the near infrared fluorescence molecular probe is also provided, and the kit can be used for early diagnosis of Alzheimer's disease.
Description
Technical Field
The invention relates to a dihydroquinoline compound, a preparation method, a pharmaceutical composition and application thereof, in particular to a dihydroquinoline compound which can be prepared into a near infrared fluorescent probe, and a preparation method, a pharmaceutical composition and application thereof.
Background
Patients with Alzheimer's Disease (AD) have reduced cognitive function, reduced ability to survive daily life, and are associated with various neuropsychiatric symptoms and behavioral disorders. In the brain of humans suffering from Alzheimer's disease, two toxic proteins, β -amyloid (which forms plaques) and tau (which forms tangles) are generally found. The development of AD disease is divided into three phases: preclinical, mild cognitive impairment and dementia. In preclinical stages, cerebral neuronal lesions are relatively mild and patients have essentially no obvious symptoms. By the time of mild cognitive impairment and dementia, many neurons have been apoptotic and disease treatment is difficult when clinical symptoms appear. Therefore, the diagnosis of AD patients in time in the preclinical stage will win a time window for treatment, and is very critical for slowing down or reversing the development of the disease.
Currently, the main methods clinically used to diagnose AD patients are: neuropsychological clinical profile assessment, magnetic Resonance Imaging (MRI), computed Tomography (CT), positron emission computed tomography (PET), and toxic protein tracers. The neuropsychological clinical characteristics are evaluated by using AD rating scale cognition part (ADAS-cog), clinical dementia rating scale (CDR-SB), simple mental scale (MMSE) and the like to evaluate the abnormal conditions of memory, thinking skill damage and behaviors and characters of the patient. Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) acquire cross-sectional images of the brain and analyze the extent of lesions based on the atrophic changes in brain volume. Positron emission computed tomography (PET) recognizes brain regions of reduced glucose metabolism as Fluorodeoxyglucose (FDG). The tracer is used for tracking beta-amyloid and tau protein, and the decrease of beta-amyloid monomer 42 (Abeta 42) and the increase of tau protein concentration in cerebrospinal fluid are detected to be used as diagnosis indexes of AD.
However, most of the above diagnostic methods are applicable to the diagnosis of patients in mild cognitive impairment and dementia, but lack effective means for finding pre-clinical patients. Neuropsychological characterization is the core evidence of clinically judged dementia, but by the time dementia, cognitive and mental symptoms are found, the patient is already in the middle and late stages of the disease. Also, when structural lesions of the brain are diagnosed by imaging, the volumes of the hippocampus, cortex and amygdala in the brain are reduced, the number of neurons is greatly reduced, and the therapeutic effect of the disease is limited. Diagnostic techniques that can find AD patients in preclinical stages remain a clinical urgent need.
Disclosure of Invention
The invention aims to: the first object of the invention is to provide a dihydroquinoline compound, the second object is to provide a preparation method of the compound, the third object is to provide a pharmaceutical composition containing the compound, and the fourth object is to provide an application of the compound and the pharmaceutical composition thereof in preparation of near infrared fluorescent probes.
The technical scheme is as follows: the dihydroquinoline compound disclosed by the invention has a structure shown in a formula I and further comprises pharmaceutically acceptable salts thereof:
wherein:
r is selected from unsubstituted or substituted C1-C6 alkyl, 3-6 membered cycloalkyl, phenyl, said substituents being selected from halogen, hydroxy, nitro, cyano, amino, mercapto, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl.
Preferably, in the structure:
r is selected from unsubstituted or substituted C1-C4 alkyl and 3-5 membered cycloalkyl, and the substituent is selected from halogen and hydroxy.
Further preferably, in the structure:
r is selected from unsubstituted or substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, and the substituent is selected from hydroxy.
Still more preferably, in the structure:
r is selected from unsubstituted or substituted ethyl, n-propyl, cyclopropyl, cyclobutyl, and the substituent is selected from hydroxy.
Preferably, the number of substituents is selected from 1,2, 3.
Specifically, the dihydroquinoline compound is selected from any one of the following compounds:
wherein the pharmaceutically acceptable salt is a salt of the compound with an acid selected from any one of the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.
The maximum emission wavelength of near-infrared (NIR) fluorescent imaging probes is 600-1700 nm. In this region, the fluorescence background of the biological tissue is weak, and the probe has high sensitivity. After the NIR probe is combined with the target protein, fluorescence characteristics (such as fluorescence intensity, emission wavelength and quantum yield) are changed remarkably, and interaction with the target protein can be detected directly without connecting a reporter group, so that the NIR small molecular probe becomes a very efficient method for researching AD diagnosis.
Before the occurrence of mild cognitive impairment symptoms of cognitive impairment, the balance of beta-amyloid (aβ) monomer production is broken, aβ42, aβ40 misfolded in the brains of AD patients, aggregating into aβ oligomers (aβ oligomers, aβo) which are neurotoxic substances, leading to synaptic damage and neuronal apoptosis, aβo being related to the severity of the disease. Therefore, the Abeta O is selected as a biomarker, sensitive and specific active small molecules are developed, and further, a novel diagnostic reagent is developed, so that the method has important significance for timely finding and treating AD patients.
The invention designs a near infrared fluorescent probe with a novel structure and a derivative thereof, which can generate enhanced near infrared fluorescence by targeting amyloid oligomers appearing in early stage of Alzheimer's disease and can be used for early screening of diseases in vitro and in vivo.
The preparation method of the dihydroquinoline compound comprises the following steps:
under the catalysis of alkali, in an organic solvent, carrying out condensation reaction on a compound of a formula II and a compound of a formula III to obtain the compound of the formula I;
wherein R is as defined above;
and salifying the corresponding acid with the compound I prepared by the method to obtain the pharmaceutically acceptable salt.
In particular, the organic solvent may be an organic solvent conventional in such reactions in the art, preferably acetonitrile, ethanol, benzene solvents; preferably, the volume molar ratio of the compound of formula II to the compound of formula III is 1:1.
The base may be a base conventional in such reactions in the art, preferably tetrahydroisoquinoline (i.e., 1,2,3, 4-tetrahydroisoquinoline); the amount of the base is generally catalytic, and the molar ratio of the base to the compounds of the formulae II and III is preferably from (0.1 to 1): 1, more preferably from (0.1 to 0.2): 1.
The condensation reaction temperature may be from 0 to 100 ℃, preferably from 20 to 70 ℃, as is conventional in such reactions in the art; the progress of the reaction may be monitored by conventional detection methods for organic synthesis reactions in the art, such as TLC, GC, HPLC or NMR, etc.; the reaction time is preferably 2 to 24 hours, for example 10 hours.
Further preferred, the process for the preparation of the compound of formula III is as follows:
the pharmaceutical composition comprises the dihydroquinoline compound and a pharmaceutically acceptable carrier, and is prepared into common pharmaceutical preparations such as pills, paste, tablets, capsules, syrups, suspensions, oral liquid or injection (subcutaneous injection, intravenous injection and the like) by adding common pharmaceutical excipients such as perfume, sweetener, liquid/solid filler, diluent and the like.
The dihydroquinoline compound and the pharmaceutical composition thereof are applied to preparation of near infrared fluorescent probes, in particular to active molecular probes of targeted amyloid oligomers, and are used as early detection tracers of Alzheimer's disease.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
1. the compound has good affinity and selectivity with neurotoxic Abeta 42 oligomer, and the fluorescence intensity after combination is higher than 10 times compared with the affinity of nontoxic Abeta monomer; the logP value is 2.91, has proper fat solubility and can penetrate the blood brain barrier in vivo; the maximum excitation wavelength is 540nm, the maximum emission wavelength is 610nm, and the imaging near infrared fluorescent molecular probe has the characteristic of imaging; the in vivo metabolism is stable, near infrared fluorescence imaging can be carried out, and AD pathological characteristics can be screened out;
2. as near infrared fluorescent probes, the imaging of the Abeta oligomer which is closely related to the generation and development of AD is particularly targeted, and can be used for early diagnosis of Alzheimer's disease.
Drawings
FIG. 1 is a fluorescence emission spectrum of monomers, oligomers, protein fibers, PBS of compounds P1 and Abeta 42;
FIG. 2 shows the binding constants of compound P1 and Abeta 42 oligomer;
FIG. 3 is a near infrared imaging of compound P1 in mice;
FIG. 4 is a synthetic scheme for compound P1;
FIG. 5 is a diagram of compound P1 1 H NMR spectrum.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1: preparation of 2- (3, 4-dihydroquinolin-1 (2H) -yl) ethanol
Tetrahydroquinoline (1.59 g/1.5mL,12 mmol), 2-bromoethanol (2.25 g/1.28mL,18 mmol), sodium bicarbonate (1.3 g,15.6 mmol), and a condenser were added to a 50mL eggplant-shaped bottle, and the reaction was monitored by spotting after 26h of reaction at 60 ℃. Post-treatment: cooling the reaction solution to room temperature, and suction filteringThe filter cake was washed with DCM and the filtrate was collected. The organic phase was collected by extraction with water. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. And (3) separating and purifying by column chromatography, wherein the eluting agents are PE, EA=15:1, 10:1 and 8:1 in sequence. Finally, 2g of pale yellow oily liquid are obtained, yield: 95%. 1 H NMR(300MHz,Chloroform-d)δ7.13–7.03(m,1H),6.99(dd,J＝7.4,1.6Hz,1H),6.72(d,J＝8.2Hz,1H),6.64(td,J＝7.3,1.1Hz,1H),3.84(t,J＝5.8Hz,2H),3.47(t,J＝5.8Hz,2H),3.41–3.31(m,2H),2.81(t,J＝6.4Hz,2H),2.04–1.92(m,2H),1.87(s,1H).
Example 2: preparation of ethyl 2- (3, 4-dihydroquinolin-1 (2H) -acetate
3-1 (1.9 g,10.71 mmol) was dissolved in 120mL DCM and EDCI (6.16 g,32.2 mmol), DMAP (254 mg,5.36 mmol), acetic acid (1.61 g/1.53mL,26.8 mmol) was added and reacted at room temperature for 4h, TLC thin layer plate monitored the reaction. Developer PE, ea=6:1. Post-treatment: the reaction solution was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography, eluent PE: ea=20:1, to give 2.27g of colorless oily liquid, yield: 97%. 1 H NMR(300MHz,Chloroform-d)δ7.09–6.99(m,1H),6.94(d,J＝7.3Hz,1H),6.60(dd,J＝16.0,8.6Hz,2H),4.26(t,J＝6.3Hz,2H),3.52(t,J＝6.3Hz,2H),3.43–3.24(m,2H),2.75(t,J＝6.4Hz,2H),2.04(s,3H),1.94(p,J＝6.3Hz,2H).
Example 3: preparation of ethyl 2- (6-formyl-3, 4-dihydroquinolin-1 (2H) -acetate
After the nitrogen replacement of the three-necked bottle, 0.75mL of DMF is added into a syringe, the syringe is precooled in an ice bath, phosphorus oxychloride (0.17 mL,1.82 mmol) is added dropwise, and the mixture is stirred at room temperature for 30min; the reaction solution was again pre-cooled in an ice bath, 3-2 (200 mg,0.91 mmol) dissolved in 1.5mL of DMF was added dropwise and stirred at room temperature for 2h. Post-treatment: pouring the reaction solution into crushed ice, and adjusting pH to 2N NaOHAlkaline, EA extraction, combined organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, column chromatography separation and purification, eluent PE: ea=3:1, afforded 190mg of milky white liquid, yield: 84.4%. 1 H NMR(300MHz,Chloroform-d)δ9.71(s,1H),7.59(dd,J＝8.6,2.1Hz,1H),7.51(s,1H),6.71(d,J＝8.6Hz,1H),4.33(t,J＝6.1Hz,2H),3.67(t,J＝6.1Hz,2H),3.56–3.40(m,2H),2.83(t,J＝6.3Hz,2H),2.07(s,3H),2.05–1.96(m,2H).
Example 4: preparation of 1- (2-hydroxyethyl) -1,2,3, 4-tetrahydroquinoline-6-carbaldehyde
After dissolving W-3 (190 mg,0.77 mol) in 8mL of methanol, naOH (50 mg,1.25 mmol) dissolved in 1mL of water was added dropwise, and the mixture was stirred at room temperature for 30min. Post-treatment: the reaction solution was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography, eluent PE: ea=3:1, to give 120mg of pale yellow oily liquid, yield: 92%. 1 H NMR(300MHz,Chloroform-d)δ9.69(s,1H),7.57(dd,J＝8.6,2.1Hz,1H),7.50(s,1H),6.75(s,1H),3.94(t,J＝5.8Hz,2H),3.61(t,J＝5.8Hz,2H),3.57–3.48(m,2H),2.85(t,J＝6.3Hz,2H),2.05–1.98(m,2H).
Example 5: (E) -2- (6- (2- (6-ethyl-5- (4-ethylphenyl) -2, 2-difluoro-2H-1λ3,3,2λ4-dioxoborane-4-yl) vinyl) -3, 4-dihydroquinolin-1 (2H) -yl) ethan-1-ol (P1)
Y-2 (260 mg,0.974 mmol) and W-4 (200 mg,0.974 mmol) were used as reaction materials, the preparation and experimental methods of Y-2 were as described in CN110615808A, and the polarity of the developing agent used in the monitoring reaction was PE: EA=2:1. Separating and purifying by column chromatography, wherein the polarity of mobile phase is PE: EA: DCM=6:1:0.5 (a small amount of DCM is added to improve solubility, prevent the product from precipitating and adhering on a silica gel column in the process of passing through the column), collecting the product point, concentrating by spin-removing solvent, pulping with petroleum ether to obtain 77mg of dark red solid with the yield of 17%.
1 H NMR(300MHz,Chloroform-d)δ8.05(d,J＝15.1Hz,1H),7.35(s,2H),7.23–7.15(m,3H),7.07(s,1H),6.66(d,J＝8.8Hz,1H),6.15(d,J＝15.1Hz,1H),3.91(t,J＝5.6Hz,2H),3.58(t,J＝5.7Hz,2H),3.52(t,J＝5.7Hz,2H),2.78(dt,J＝12.1,6.6Hz,4H),2.37(q,J＝7.5Hz,2H),1.99(t,J＝5.9Hz,2H),1.37(t,J＝7.6Hz,3H),1.18(t,J＝7.5Hz,3H).
HRMS(ESI)C 26 H 30 BF 2 NO 3 ,[M+Na] + calculated＝476.2185；found＝476.2175.
Example 6: determination of the wavelength of Compound P1
Excitation wavelength measurement: 10. Mu.M of Compound P1 in DMSO. When an ultraviolet spectrophotometer (scanning wavelength range is 300-900 nm) is used, firstly, solvent DMSO is added into a cuvette to balance a base line, and after the base line is stable, the solution to be measured is added into the cuvette for full-band scanning measurement. If the obtained picture is normal in peak type and has no plateau phase, the picture is the optimal measurement concentration. The maximum absorption wavelength of ultraviolet spectrophotometry is selected as the excitation wavelength of fluorescence spectrophotometry to be 540nm.
Measuring the maximum emission wavelength: the four-sided light-transmitting cuvette containing the solution to be measured was placed in a fluorescence spectrophotometer to measure the emission wavelength to 610nm.
Example 7: (E) Fluorescence study of the binding of 2- (6- (2- (6-ethyl-5- (4-ethylphenyl) -2, 2-difluoro-2H-1λ3,3,2λ4-dioxoborane-4-yl) vinyl) -3, 4-dihydroquinolin-1 (2H) -yl) ethan-1-ol to amyloid fibers, oligomers and monomers
1. Experimental method
Probe concentration in the test solution: protein concentration = 250nm:750nm; adding 960 mu L of PBS into the four-sided light-transmitting cuvette, uniformly mixing, and measuring an emission spectrum to serve as a blank control; then 10 mu L of 25 mu M DMSO solution of the compound P1 is stirred uniformly, and then the emission spectrum is measured; 30. Mu.L of 25. Mu. M A. Beta.42 HFIP solution was added, gently stirred, and the emission spectrum was measured.
The compound P1 is respectively combined with the Abeta 42 oligomer and the fiber by a fluorescence detection method.
2. Experimental results
TABLE 1 wavelength of Compound P1 and selectivity for Abeta protein
Note that: i is the fluorescence intensity of P1 itself, I M For the fluorescence intensity of P1 combined with Abeta monomer, I A For P1 and Abeta polymer binding fluorescence intensity, I O Fluorescence intensity for P1 binding to Abeta oligomer, deltaI O /ΔI M For the ratio of fluorescence intensity of oligomer to monomer binding, ΔI O /ΔI A Is the ratio of fluorescence intensity of oligomer to polymer binding.
As can be seen from table 1 and fig. 1, compound P1 has good affinity and selectivity for neurotoxic aβ42 oligomer, and fluorescence intensity after binding is more than 10-fold higher than that of nontoxic aβ monomer.
Example 8: study of binding constant of Compound P1 and Abeta 42 oligomer
1. Experimental method
The concentration of immobilized protein was 500nM, the concentration of the compound solution was changed to give compound concentrations of 10, 25, 50, 100, 200nM (corresponding to compound concentrations of 1, 2.5, 5, 10, 20. Mu.M, respectively) in the cuvette solution at the final measurement, and the maximum fluorescence intensities at the different compound concentrations were measured. The Kd values were calculated by processing the data with GraphPad Prism 8.0.1, with the compound concentration as the abscissa and the fluorescence intensities obtained at the different compound concentrations as the ordinate.
2. Experimental results
The binding constant of compound P1 to the Abeta 42 oligomer was 43.99nM (FIG. 2).
Example 9: near infrared imaging Property study of Compound P1 in vivo
1. Experimental method
Compound P1 solution (4 mg/kg) was prepared: a mixed solution of 15% DMSO+15% polyoxyethylated castor oil+70% PBS was stabilized at 25℃for 20min and then injected into the tail vein. APP/P3 to 6 months of ageS1 mice and 3 littermates (WT mice). Each mouse was injected with 100 μl of the above solution; all data were measured using an IVIS Spectrum animal imaging system (Caliper LifeSciences, perkin Elmer, hopkitton, mass.). Fluorescent signal intensity analysis application4.2.1 software, all mice were selected with ROI (Region of interest) of the same size.
2. Experimental results
The results of in vivo imaging of 6 month old AD mice showed near infrared fluorescence imaging to distinguish 6 month old AD mice from normal mice (FIG. 3).
In FIG. 3, A is a fluorescent representation of WT mice, B is a fluorescent imaging of APP/PS1 mice, and C is a fluorescent signal intensity graph.
Claims (10)
1. A dihydroquinoline compound characterized by having the structure of formula I, further comprising a pharmaceutically acceptable salt thereof:
wherein:
r is selected from unsubstituted or substituted C1-C6 alkyl, 3-6 membered cycloalkyl, phenyl, said substituents being selected from halogen, hydroxy, nitro, cyano, amino, mercapto, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl.
2. The dihydroquinoline compound according to claim 1, wherein in the structure:
r is selected from unsubstituted or substituted C1-C4 alkyl and 3-5 membered cycloalkyl, and the substituent is selected from halogen and hydroxy.
3. The dihydroquinolines of claim 2 wherein in the structure:
r is selected from unsubstituted or substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, and the substituent is selected from hydroxy.
4. A dihydroquinoline compound according to any one of claims 1-3, wherein the number of substituents is selected from 1,2, 3.
5. The dihydroquinoline compound according to claim 1, wherein the dihydroquinoline compound is selected from any one of the following compounds:
6. the dihydroquinoline compound according to claim 1, wherein the pharmaceutically acceptable salt is a salt of the compound with an acid selected from any one of the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.
7. A process for the preparation of dihydroquinolines as claimed in claim 1 comprising the steps of:
under the catalysis of alkali, in an organic solvent, carrying out condensation reaction on a compound of a formula II and a compound of a formula III to obtain the compound of the formula I;
wherein R is as defined in any one of claims 1 to 5;
and salifying the corresponding acid with the compound I prepared by the method to obtain the pharmaceutically acceptable salt.
8. A pharmaceutical composition comprising the dihydroquinoline compound of claim 1 and a pharmaceutically acceptable carrier.
9. Use of the dihydroquinoline compound of claim 1 or the pharmaceutical composition of claim 8 for preparing a near infrared fluorescent probe.
10. The use according to claim 9, wherein the probe is an active molecular probe targeting amyloid oligomers.
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