CN1080289A - 3-(1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one contains the pharmaceutical composition and the preparation thereof of this compound - Google Patents

3-(1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one contains the pharmaceutical composition and the preparation thereof of this compound Download PDF

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CN1080289A
CN1080289A CN93102959.7A CN93102959A CN1080289A CN 1080289 A CN1080289 A CN 1080289A CN 93102959 A CN93102959 A CN 93102959A CN 1080289 A CN1080289 A CN 1080289A
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compound
tetrazolium
alkyl
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acid
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I·赫梅茨
J·辛泊斯
L·瓦萨里·尼·德布雷塞
Z·卡普
A·霍瓦施
M·巴洛格
G·克雷姿特里
K·博尔
A·帕乔
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Chinoin Private Co Ltd
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Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The present invention relates to 3-shown in the new general formula of part (I) (1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one and pharmacy acceptable salt and/or hydrate and their preparation.These compounds have significant antianaphylaxis and antiulcer activity.
The present invention also relates to the preparation method of general formula (I) compound and pharmacy acceptable salt and/or hydrate, comprising 3-shown in the cyclization general formula (II) (2-pyridine amino) in acidic medium-2-(1H-tetrazolium-5-yl) vinyl cyanide, and general formula (I) compound changed into its pharmacy acceptable salt, perhaps, from its salt alkali that dissociates, or be converted into another kind of salt with known method itself.

Description

3-(1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one contains the pharmaceutical composition and the preparation thereof of this compound
The present invention relates to the new 3-(1H-tetrazolium-5-yl of part shown in the logical formula I)-4H-pyrido [1,2-a] pyrimidin-4-one and pharmacy acceptable salt and/or hydrate and their preparation method.These compounds have significant antianaphylaxis or antiulcer activity.
3-(1H-tetrazolium-5-yl shown in the logical formula I)-4H-pyrido [1,2-a] pyrimidin-4-one, when R is hydrogen atom, is described in US-PS Nos.4122274 and 4209620 as anti-allergic agent, and in US-PSNo.4457932, is described as anti ulcer agent.
Yet, raw material that above-mentioned patent specification provides and method are that the preparation of logical formula I compound of hydrogen is not most suitable for R, because they cause low-down productive rate, even also low than shown in describing, and/or used reactant with hazardness, as 1: 3 mixture of the aluminum chloride-sodiumazide in the tetrahydrofuran (THF).
Reactant that US-PS No.4474953 provides and reaction conditions are more favourable, but the productive rate of the 60-70% that provides among the embodiment does not relate to the logical formula I compound that pure wherein R is a hydrogen (1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one.After repeating its method, we identify and separated product, a kind ofly contain 3-(2-ethyl-tetrazolium-5-yl shown in the logical formula III) 3-(1-ethyl-tetrazolium-5-yl shown in derivative and the logical formula IV) tautomers mixture of derivative, productive rate about 30%.These isomer can separate by crystallization process.Can identify compound shown in the logical formula IV by the x-ray diffraction method.The formation of these compounds can by ethyl shown in the Tripyrophosphoric acid formula of (V)-[3-(2-pyridyl/amino)-2-(1H-tetrazolium-5-yl) the alcoholic acid ethylation reaction that produced of acrylate ring-closure reaction, the cyclization product, promptly R is that the alkylation of the logical formula I compound of hydrogen illustrates.Thereby, compare with logical formula I compound, also obtained a large amount of logical formula III and (IV) compound.
Basis of the present invention is to find that unexpectedly vinyl cyanide shown in the logical formula II can plain mode, and good yield does not produce by product and is transformed into pyrido [1,2-a] pyrimidine shown in the logical formula I.
Of the present inventionly theme as logical formula I
Shown compound and pharmacy acceptable salt thereof and/or hydrate, wherein
R represents hydrogen atom, C 1-4Alkyl, or C 6-10Aryl;
R 1Represent hydrogen atom, C 1-4Alkyl, halogen atom, hydroxyl, nitro, carboxyl, C 2-5Carbalkoxy or C 7-12Aralkoxy;
R 2Represent hydrogen atom, C 1-4Alkyl, or halogen atom;
And preparation method thereof.
Here used term " C 1-4Alkyl "-itself or its residue, as in alkoxyl group-the expression straight or branched have a sturated aliphatic hydrocarbon base (as methyl, ethyl, the n-propyl and the tertiary butyl) to four carbon atom.Used term " C 6-10Aryl " expression optionally has a C 1-4The phenyl of alkyl or bitter edible plant base.
Logical formula I compound can obtain and general formula (I A) compound equilibrated mixture by mode A.
Figure 931029597_IMG6
The present invention also relates to the preparation method of logical formula I compound and pharmacy acceptable salt and/or hydrate, comprising 3-(2-pyridine amino shown in the logical formula II of cyclisation in acidic medium)-2-(1H-tetrazolium-5-yl) vinyl cyanide
Figure 931029597_IMG7
(R wherein, R 1And R 2As defined above)
And the logical formula I compound that will so obtain be transformed into its pharmacy acceptable salt or, if desired,, perhaps be converted into its another kind of salt by known method own from its salt alkali that dissociates.
Logical formula II compound is meant general formula (II A) compound (R wherein, the R that is made of (square formula B) the tautomeric equilibrium mixture of logical formula II compound 1And R 2As defined above) and the tetrazole ring tautomer of logical formula II and (II A) compound and the E-Z geometrical isomer of logical formula II compound.
As acid reagent, organic and mineral acid all can be employed.If desired.Reaction can preferably be carried out in the presence of water in the presence of solvent.
Can use paraffinic acid and aryl sulfonic acid as organic acid.For mineral acid, preferably can use hydrohalogen, the various acid of sulfonic acid and phosphorus.Reaction can be finished under heating up if desired.Temperature can be selected according to the character of acid reagent, carries out if be reflected under the solvent existence, then can be according to the character selective reaction temperature of solvent.Preferably, be reflected under the temperature that is different from room temperature and carry out.
Dilute with water or reaction mixture PH transferred to neutrality after, can from the reaction precipitation of reaction mixture, obtain logical formula I compound, also can obtain by for example filtering.
If desired, can under the effect of acid or alkali, be transformed into its pharmacy acceptable salt and/or hydrate with leading to the formula I compound.If desired, also can be from their salt alkali be separated out and is transformed into their another kind of salt.According to the method, use example hydrochloric acid, Hydrogen bromide, sulfuric acid, acetate, citric acids etc. can be made acid salt easily, and can be made into sodium, potassium and calcium salt.
On the therapeutics, logical formula I compound or it pharmaceutically can be used as the pharmaceutical compositions that contains with mixed this active ingredient of inert non-toxic solid or liquid diluent and carrier by the salt that is subjected to.
These pharmaceutical compositions can solid (tablet, capsule, dragee) or the preparation of liquid (solution, suspension, emulsion) form.
For carrier, can use general material (as talcum, lime carbonate, Magnesium Stearate, water, poly-(ethylene glycol).
If desired, can contain supplementary material such as emulsifying agent in the preparation, or dissolved material.
Form tautomeric equilibrium mixture (square formula B)
Logical formula II and (II A) shown in raw material can be by handling with ammonium azide from propane dinitrile (malonitriles) preparation shown in the logical formula VI, (R wherein, R 1And R 2As preceding definition), logical formula VI compound can obtain the tautomeric equilibrium mixture with 3-cyano group shown in the general formula (VI A)-4-imino--4H-pyrido [1,2-a] pyrimidine.(square formula C)
Mode C
Compound shown in logical formula VI and (the VI A) can be by document [Journal of Organic Chemistry, 1986,51,2988] as can be known simple method in, by the 2-amino-pyridine, propane dinitrile and ortho ester available on the market reaction come synthetic.
Figure 931029597_IMG10
Following non-restrictive example explains the present invention.
Embodiment
Embodiment 1
Under the reflux conditions with 53.3g(0.25mol) 3-(2-pyridine amino)-2-(1H-tetrazolium-5-yl)-vinyl cyanide heated 1 hour in the 500ml concentrated hydrochloric acid.Heat after 10-15 minute, the mother crystal dissolving, and the crystallization of product occurs.With the suspension cooling that produces, dilute with 1000ml water, and neutralize with 25% ammonia soln.Collect crystallization, wash with water.Product: 41.48g(87.9%) 3-(1H-tetrazolium-5-yl)-4-oxygen-4H-pyrido [1,2-a] pyrimidine.
MP:316 ℃ (decomposition)
To C 9H 6N 6O analyzes
Calculated value: C 50.47%; H 2.82%; N 39.24%;
Measured value: C 49.73%; H 2.77%; N 39.48%.
Embodiment 2
Under the reflux conditions with 23.7g(0.1mol) 3-[(3-methyl-2-pyridyl) amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide heated 1 hour in the 200ml concentrated hydrochloric acid.Heat mother crystal dissolving after 10-15 minute, the crystallization of product occurs.With gained suspension cooling, with the dilution of 400ml water, and with 25% ammonia soln neutralize (PH=6.5).Collect crystallization, wash with water.
Product: 19.57g(85.76%) 3-(1H-tetrazolium-5-yl)-9-methyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine.
MP:312 ℃ (dimethyl formamide)
To C 10H 8N 6O analyzes
Calculated value: C 52.62%; H 3.53%; N 36.83%;
Measured value: C 52.66%; H 3.44%; N 37.27%.
Embodiment 3
Under 60 ℃ of stirrings with 13.3g(0.059mol) 3-[(6-methyl-2-pyridyl) amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 70g Tripyrophosphoric acid.Reaction mixture heated in 130-140 ℃ of oil bath and stirred 2 hours, it is cooled to 30-40 ℃ then, carefully with the dilution of 210ml water and ice-cooled down with 75ml25% ammonia soln neutralization (PH=6.5-7).The crystallization that collecting precipitation goes out washes with water.Product: 12.7g(94.8%) 3-(1H-tetrazolium-5-yl)-6-methyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine.
MP:286 ℃ of decomposition (dimethyl formamide)
To C 10H 8N 6O analyzes
Calculated value: C 52.62%; H 3.53%; N 36.83%;
Measured value: C 52.80%; H 3.48%; N 3701%.
Embodiment 4
Under 60 ℃ of stirrings with 2.41g(0.01mol) 3-methyl-3-[(6-methyl-2-pyridyl)-amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 20g Tripyrophosphoric acid.Reaction mixture heated in 130-140 ℃ of oil bath and stirred 4 hours, it is cooled to 50-60 ℃ then, with 28ml water dilute carefully and ice-cooled down with 28ml25% ammonia soln neutralization (PH=7).The crystallization that collecting precipitation goes out washes with water
Product: 1.47g(60.8%) 3-(1H-tetrazolium-5-yl)-2,6-dimethyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine.
MP:258-260 ℃ of decomposition (dimethyl formamide)
To C 11M 10N 6O analyzes
Calculated value: C 54.54%; H 4.16%; N 34.70%;
Measured value: C 54.58%; H 4.12%; N 34.33%
Embodiment 5
Under 60 ℃ of stirrings with 2.47g(0.01ml) 3-[(5-chloro-2-pyridyl)-amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 12g Tripyrophosphoric acid.In 130-140 ℃ of oil bath, with reaction mixture heating and stirred 1 hour, it is cooled to 50-60 ℃ then, carefully with the dilution of 50ml water and ice-cooled down with the ammonia soln neutralization (PH=6.5-7) of 25ml25%.Collect the heavy crystallization of making, wash with water.Product: 1.7g(68.6%) 3-(1H-tetrazolium-5-yl)-7-chloro-4-oxygen-4H-pyrido [1,2-a] pyrimidine.
MP:304 ℃ of decomposition
To C 9H 5N 6OCl analyzes
Calculated value: C 43.48%; H 2.03%; N 33.80%; Cl14.26%;
Measured value: C 43.71%; H 2.50%; N 33.53%; Cl14.60%.
Embodiment 6
Under 60 ℃ of stirrings with 2.27g(0.01mol) 3-[(5-methyl-2-pyridyl)-amino]-2-(1H-tetrazolium-5-yl)-vinyl cyanide adds in the 12g Tripyrophosphoric acid, in 140 ℃ of oil baths, with reaction mixture heated and stirred 1 hour, with its cool to room temperature, neutralize with the 20ml25% ammonia soln down with the dilution of 50ml water and ice-cooled carefully then.The crystallization that collecting precipitation goes out washes with water.
Product: 2.3g(93.5%) 3-(1H-tetrazolium-5-yl)-7-methyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine-hydrate, MP:297 ℃ of decomposition.
To C 10H 8N 6OH 2O analyzes
Calculated value: C 48.78%; H 4.09%; N 34.13%;
Measured value: C 49.34%; H 4.18%; N 34.57%.
Embodiment 7
Under 60 ℃ of stirrings with 2.27g(0.01mol) 3-[(4-methyl-2-pyridyl)-amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 20g Tripyrophosphoric acid.In 140 ℃ of oil baths,, then it is cooled to room temperature with reaction mixture heated and stirred 1 hour, carefully with the dilution of 60ml water and ice-cooled down with 28ml25% ammonia soln neutralization (PH=6.5-7).The crystallization that collecting precipitation goes out washes with water.
Product: 2.24g(94.5%) 3-(1H-tetrazolium-5-yl)-8-methyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine semihydrate.MP:288 ℃ of decomposition.
To C 10H 8N 6O1/2H 2O analyzes
Calculated value: C 50.63%; H 3.82%; N 35.42%;
Measured value: C 50.26%; H 3.90%; N 35.38%.
Embodiment 8
Under 60 ℃ of stirrings with 2.41g(0.01mol) 3-[(4,6-dimethyl-2-pyridyl)-amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 12g Tripyrophosphoric acid.With reaction mixture heated and stirred 1 hour in 140 ° of oil baths, then it is cooled to room temperature, carefully with the dilution of 50ml water and ice-cooled down with the neutralization of 18ml25% ammonia soln.The crystallization that collecting precipitation goes out washes with water.Product: 1.43g(59.1%) 3-(1H-tetrazolium-5-yl)-6,8-dimethyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine.
MP:350 ℃ of decomposition
To C 11H 10N 6O analyzes
Calculated value: C 54.54%; H 4.16%; N 34.69%;
Measured value: C 54.35%; H 4.21%; N 33.94%.
Embodiment 9
Under the reflux conditions with 2.3g(0.01mol) 3-[(3-hydroxyl-2-pyridyl) amino]-2-(1H-tetrazolium-5-yl)-vinyl cyanide heated 1 hour in the 20ml concentrated hydrochloric acid.With the reaction mixture cool to room temperature and pour in the 30ml water, PH is adjusted to 6.5 with the 10ml25% ammonia soln.Collect crystallization, wash with water.Product: 2.4g(90.2%) 3-(1H-tetrazolium-5-yl)-9-hydroxyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine hydrochloride.
MP:324 ℃ of decomposition
To C 9H 6N 6O 2HCl analyzes
Calculated value: C 40.54%; H 2.65%; N 31.52%;
Measured value: C 40.82%; H 2.78%; N 31.26%.
Embodiment 10
Under 60 ℃ of stirrings with 1.1g(0.004mol) 3-[(3,5-two chloro-2-pyridyl)-amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 12g Tripyrophosphoric acid.With reaction mixture heated and stirred 30 minutes in 130-140 ℃ of oil bath, it is cooled to 60 ℃ then, carefully with the dilution of 50ml water and ice-cooled down with 15ml25% ammonia soln neutralization (PH=7).The crystallization that collecting precipitation goes out washes with water.Product :-two chloro-4-oxygen-4H-pyrido [1,2-a] pyrimidines 1.04g(90.4%) 3-(1H-tetrazolium-5-yl).
MP:291 ℃ of decomposition (dimethyl formamide)
To C 9H 4N 6Cl 2O analyzes
Calculated value: C 38.19%; H 1.42%; N 29.69%; Cl25.05%;
Measured value: C 37.80%; H 1.58%; N 29.77%; Cl25.02%.
Embodiment 11
Under the reflux conditions with 1.25g(4mmol) 3-(5-bromo-2-pyridine amino)-2-(1H-tetrazolium-5-yl) vinyl cyanide heated 1 hour in the 10ml concentrated hydrochloric acid.Reaction mixture is cooled to room temperature and pours in the 30ml water usefulness 10ml25% ammonia soln neutralization (PH=7) into.Collect crystallization, wash with water.
Product: 1.25%(99.0%) 3-(1H-tetrazolium-5-yl)-7-bromine 4-oxygen-4H-pyrido [1,2-a] pyrimidine.MP:298-300 ℃ of decomposition
To C 9H 5N 6BrO analyzes
Calculated value: C 36.88%; H 1.72%; N 28.67%; Br27.26%;
Measured value: C 36.76%; H 1.62%; N 28.86%; Br27.13%.
Embodiment 12
Under 60 ℃ of stirrings with 1.41g(4.6mmol) 3-phenyl-[(6-methyl-2-pyridyl)-amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 12g Tripyrophosphoric acid.Reaction mixture heated in 130-140 ℃ of oil bath and stirred 1 hour, it is cooled to 60 ℃ then, carefully with the dilution of 60ml water, and ice-cooled down with 14ml25% ammonia soln neutralization (PH=7).The crystallization that collecting precipitation goes out washes with water.
Product: 1.05g(75.0%) 3-(1H-tetrazolium-5-yl)-2-phenyl-6-methyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine.
MP:280 ℃ of decomposition (dimethyl formamide)
To C 16H 12N 6O analyzes
Calculated value: C 63.15%; H 3.97%; N 27.62%;
Measured value: C 63.39%; H 3.66%; N 27.72%.
Embodiment 13
Under the reflux conditions with 0.65g(2.5mmol) 3-(3-nitro-2-pyridine amino)-2-(1H-tetrazolium-5-yl) vinyl cyanide heated 1 hour in the 10ml concentrated hydrochloric acid.Reaction mixture is cooled to room temperature and pours in the 35ml water usefulness 9ml25% ammonia soln neutralization (PH=7) into.Collect crystallization, wash with water.
Product: 0.49g(75.0%) 3-(1H-tetrazolium-5-yl)-9-nitro-4-oxygen-4H-pyrido [1,2-a] pyrimidine.MP:283-285 ℃ of decomposition
To C 9H 5N 7O 3Analyze
Calculated value: C 41.71%; H 1.94%; N 37.83%;
Measured value: C 41.20%; H 2.30%; N 38.20%.
Embodiment 14
Under 60 ℃ of stirrings with 1.4g(0.005mol) 3-[(3-ethoxycarbonyl-2-pyridyl) amino]-2-(1H-tetrazolium-5-yl) vinyl cyanide adds in the 12g Tripyrophosphoric acid.With reaction mixture heated and stirred 1 hour in 130-140 ℃ of oil bath, it is cooled to 60 ℃ then, carefully with the dilution of 50ml water and ice-cooled down with 16ml25% ammonia soln neutralization (PH=7), the crystallization that collecting precipitation goes out washes with water.Product: 3-(1H-tetrazolium-5-yl)-9-ethoxycarbonyl-6-methyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine.MP:247-250 ℃ of decomposition
To C 12H 10N 6O analyzes
Calculated value: C 50.35%; H 3.52%; N 29.36%;
Measured value: C 50.12%; H 3.45%; N 29.87%.
Embodiment 15
50,100,200 and the preparation of 400mg tablet.
With 750mg3-(1H-tetrazolium-5-yl)-2,6-dimethyl-4-oxygen-4H-pyrido [1,2-a] pyrimidine sylvite and 1050g crystalline cellulose and 15g pectin (amidopectine) stir evenly.
Down auxiliary at 150g amino methyl vinylformic acid-methacrylic acid-methyl terpolymer (Eudragit-lac) solution, with this granulating mixture, lay equal stress on 40 ℃ of following dryings then and newly granulate.With its with contain the powdered mixture mixing of 20g talcum and 20g Magnesium Stearate, by known method itself,, it is pressed into 50,100 then, 200 and the 400mg tablet with suitable compressing tablet instrument.

Claims (7)

1, the compound shown in the logical formula I
Or its pharmacy acceptable salt and/or hydrate, wherein
R represents hydrogen, C 1-4Alkyl or C 6-10Aryl;
R 1Represent hydrogen, C 1-4Alkyl, halogen, hydroxyl, nitro, carboxyl, C 2-5Carbalkoxy or C 7-12Aralkoxy,
R 2Represent hydrogen, C 1-4Alkyl or halogen
Restricted condition is
If R represents hydrogen, R 1Can not be hydrogen, C 1-4Alkyl or halogen.
2, contain logical formula I compound or its pharmacy acceptable salt and/or medicinal compound of hydrate, R wherein, R as active ingredient 1And R 2Define identical with claim 1.
3, the logical formula I compound of preparation
Figure 931029597_IMG3
Or the method for its pharmacy acceptable salt and/or hydrate, wherein
R represents hydrogen, C 1-4Alkyl or C 6-10Aryl;
R 1Represent hydrogen, C 1-4Alkyl, halogen, hydroxyl, nitro, carboxyl, C 2-5Carbalkoxy or C 7-12Aralkoxy,
R 2Represent hydrogen, C 1-4Alkyl or halogen
This method is included in the 3-(2-pyridine amino of the logical formula II of cyclisation in the acidic medium)-2-(1H-tetrazolium-5-yl) R of vinyl cyanide-wherein, R 1And R 2As defined above, and will lead to the formula I compound and be transformed into its pharmacy acceptable salt and/or hydrate, perhaps from salt dissociate alkali and it is transformed into another kind of salt by known method itself.
4, according to the method for claim 3, comprising the organic or inorganic acid of using as acidic medium, as paraffinic acid, aryl sulfonic acid, hydrohalogen, sulfuric acid or phosphoric acid.
5, according to the method for claim 3, comprising the cyclisation of in the presence of solvent, leading to the formula II compound
Figure 931029597_IMG4
R wherein, R 1And R 2Define identical with claim 1.
6, according to the method for claim 3, comprising water as solvent.
7, according to the method for claim 1-4, carry out at 25-50 ℃ comprising cyclic action.
CN93102959.7A 1992-02-13 1993-02-13 3-(1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one contains the pharmaceutical composition and the preparation thereof of this compound Pending CN1080289A (en)

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HU9200432A HUT64064A (en) 1992-02-13 1992-02-13 Process for producing puyrido/1,2-a/pyrimidine derivatives and pharmaceutical compositions comprising same as active ingredient

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WO2016183063A1 (en) 2015-05-11 2016-11-17 Incyte Corporation Crystalline forms of a pi3k inhibitor

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