Ethanol adduct derivatives chromane, method of its production, ethanol adduct derivatives chromane with bronchodilatory effect, and a pharmaceutical composition


(57) Abstract:

The invention relates to ethanol adducts of compounds of formula 1, are given in the description, their production, their use as tools for inhalation diseases, in particular asthma. 4 S. p. f-crystals.

The invention relates to ethanol adducts of compounds with formula 1

< / BR>
where R(1) phenyl which may be substituted by 1-2 methyl groups and/or chlorine,

R(2) and R(3) may be the same or different and are H, stands or stands, and

n number 3 and 4

m number 1 and 2, the method of their production and their use as tools for inhalation diseases.

The invention is concerned exclusively with optically active compounds, in which the lactam radical and a hydroxy group are 4R or 3S-configuration. In the case of asymmetric substitution of the C-2 atom in the system chromane the invention applies to both S and R-structured compounds.

Under the adducts of ethanol should be understood stable solvate of the compounds of formula 1 with ethanol, in the sense that ethanol is a solid component of the crystal lattice, determining the nature of the compounds in solid form.

Most prepost the Nile-6-phenolsulfonephthalein).

The main compounds of formula 1A

< / BR>
already known from European patent application [2] and their use for the treatment of various forms of asthma are described in European patent application EP 351 720. However, we are talking about ethanol adducts and not about not containing solvate compounds 1 and not on their hydrates. They offer the use of compounds 1A, in particular for the treatment of asthmatic phenomena, when the drugs are taken mainly by inhalation, concerns the transformation of solutions of substances in aerosols, such as spraying aqueous solutions. However, this application is limited to a certain degree of solubility of compounds 1A in the water. Much more effective would be the inhalation of powdered substances, either direct or in the form of suspensions, perchloromethane as a carrier gas, which would provide a higher or faster dispensing. To ensure a good passage of inhaled powdered substances to the lungs, in these cases ought to carry out the process of micronization. It turned out that the substances corresponding to European patent application [3] due to their adhesion in the process of inhalation, or not capable of mikronizirovannuu, or not fully m the th 1A. They were stable, well micronationalist and did not change the size of their particles when suspendirovanie in perchloromethane or other substances-carriers, in contrast to the substances known from [3] Thus we can say that the present invention in ethanol adducts have valuable physical properties that are suitable to use in their application as powdered funds for inhalation.

Similar in structure to the compounds and their solvents, preferably their hydrates, as well as their use for treatment of asthma are described, for example, in European patent application [1] however, the characteristics of the solvent, or even ethanol adduct to obtain a powdery funds for inhalation, and its receipt is not given.

Submitted according to the invention ethanol adducts or get in contact do not contain MES compounds of formula 1A or any other MES compounds 1A, for example, hydrate, ethanol, followed by recrystallization from ethanol.

Synthesis of starting materials required for this reaction, interaction, described in European patent application [4] or getting prowl as a means of inhalation of diseases associated with airway obstruction, such as asthma. Daily dose is depending on the severity of the disease of 0.1 µg/kg body weight, with the most preferred dose is from 1 to 10 µg/kg For use as tools for inhalation preferred micronized powder with a particle size in the range of 10 microns, optimally from 3 to 8 μm. This powder is inhaled either as such or with the addition of excipients, for example lactose, absorbed, inhaled, and for this purpose may be used the corresponding device. It can be used in conjunction with the substance carrier, for example in aerosol dispensers with the addition of surfactants or other auxiliary substances.

Example 1. Ethanol adduct (3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl) -6-phenylcarbonylamino.

Hemihydrate (3S, 4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl) -6-phenylcarbonylamino dissolved in boiling ethanol and cooled slowly to room temperature. The product is dried for 8 hours at a temperature of 80oC. T. pl. 118-120oC, IR/Br cm-1/1639, 1480, 1302, 1152, 732, 608, 577.

Analytically calculated for C21H23

of 13.2 g (0603 mole) of (2S, 4R)-4-(4-chloroethylamino)-3-hydroxy-2,2-dimethyl-6-phenylcarbonylamino dissolved in 100 ml of tetrahydrofuran and diluted with 4 g of finely ground solid NaOH. The reaction mixture is stirred for one hour at room temperature and adding 25 ml of H2O concentrated under vacuum. The residue is treated with ice water until the onset of crystallization. After recrystallization of pure methanol and subsequently from a mixture of methanol water (1:2) get polyhedrally adduct.

Yield 10.0 g

So pl. 121-123oC.

1H-NMR (270 Merz, CD Cl3): 1,25 (S, CH3), 2,00-to 2.18 (m, C (4')H2(2,47-2,70 (m, C (3') H2), 2,95 3,05 (m, C (5') H2), 3,18-3,30 (ps-dd, C (5')H2), of 3.13 (d, J 5,6, O-H), 3,71 (dd, J=10 Hz, C (3) H2), 5,31 (d, J 10 Hz, C (4)H2), 6,91 (d, J 8,4 Hz, C(6)H2), 7,45-7,60, 7,73, 7,9 (m, 7H, Ar-H), []2D0+41oC (C=1, ethanol), IR(KBr cm-1/ 1663, 1478, 1320, 939, 602.

Analytically calculated for C21H23NO50.5 H2O:

C TO 61.4; H 5,9; N 3,4

Found: C To 61.4; H 5,7; N 3,4.

Other preliminary stages.

(3S, 4R)-4-(4-chloroethylamino)-3-hydroxy-2,2-dimethyl-6-phenolsulfonephthalein 15,8 Osho stirred mixture of 3,26 g of NaOH in 80 ml of H2and 80 ml of CH2Cl2. After cooling to 5oC add 6,84 g (0,0485 mole) of 4-chlorobutyronitrile and stirred the mixture for 30 minutes at 5-10oC. After adding 100 ml of CH2Cl2(to enter into the solution already existing product), the organic phase is separated and twice washed first with 2N NaOH and then with water. After evaporation of the solvent the residue is treated with hot diisopropyl ether.

Output: 13,6 g, so pl. 178-180oC.

[]2D0-25oC (c=1, methanol).

Analytically calculated for C21H24ClNO5S

C AND 57.6; H 5,5; N 3,2;

Found: C 57,4; H 5,5; N 3,2.

(3S, 4R)-4-AMILO-3-hydroxy-2,2-dimethyl-6-phenolsulfonephthalein (+)-mandelate and free base.

198 g (0,59 moles) of racemic 4-amino-3-hydroxy-2,2-dimethyl-6-phenylcarbonylamino and 90,28 g (0,59 moles) of (+)-almond acid are dissolved in 4.5 l of hot (60oC) absolute ethanol. This was followed by cooling to room temperature for 2 hours. If spontaneous crystallization does not occur, inject a solution of 0.3 g of optically pure final product. Then stand the solution for 48 hours at room temperature is 1 DMF) again boiled with 1 liter of ethanol for one hour before phlegmy and after cooling was obtained (+)-mandelate in a single product.

Output: 81,

So pl. 203-204oC.

[]2D0+94oC (C=1, DMF).

Analytically calculated for C25H27NO7S:

C 61, 8MM; H 5,6; N 2,9;

Found: From 62.1; H 5,7; N 3,0.

The corresponding free base is obtained by the fact that Mandela was suspenderbelt specified in a mixture of 2-normal NaOH and CH2Cl2. So pl. []2D086o(C=1, dimethylformamide).


50 g (0,158) moles (4-amino-3-hydroxy-2,2-dimethyl-6-phenylcarbonylamino dissolved in 280 ml of ethanol was shaken in an autoclave at 70oC and a pressure of NH27 bar for 18 hours. After evaporation of the solvent the residue is recrystallized from isopropanol. Output: 39.9 g, so pl. 166-167oC.


To 100 ml of absolute dimethyl sulfoxide added 1.8 g (to 0.06 moles) of NaOH in 80% suspension in oil, and dropwise 20 g of 3,4-epoxy-2,2-dimethyl-6-phenylcarbonylamino dissolved in 80 ml of dimethyl sulfoxide at a temperature of 25-28oC. After 2 hours stirring at room temperature the mixture is poured with stirring into ice-cold water, and the image is tigerbunny coal sought further purification. After evaporation of the solvent the residue is treated with diisopropyl ether to start crystallization. Yield: 14.5 g, so pl. 103-105oC.


To 200 g of 4-nitrodiphenylamine (0,76 moles) and 140 ml (1.45 moles) of 2-methyl-3-butyn-3-ol in 1.4 l of dimethyl sulfoxide was added 100 g of solid formations NaOH. The mixture is stirred at room temperature for 5 hours, and adding 50 ml of 2-methyl-3-butyn-3-ol after 2 hour of mixing. The mixture is then poured with stirring into 1.5 liters of diisopropyl ether and 1 l of H2O. the Organic phase is separated and washed three times with water. After evaporation of the solvent remained the oil is reddish in color. By chromatography on kieselgel you can get a small sample of a pure substance: 2-methyl-3-(4-phenylsulfonyl) phenoxy-3-butyne with so pl. 58-60oC.

Analytically calculated for:


C TO 68.0; H 5,4;

Found: 67,5; H 5,8.

The main amount of this product without further purification was dissolved in 800 ml of 1,2-dichlorobenzene and boiled for 2 hours under reflux. After removal of the solvent under vacuum at 100oC get a dark oil, which by chrome is Analytically calculated for:


C TO 68.0; H 5,4;

Found: C 68,3; H 5,3.

The crude product obtained from this compound, dissolved in dimethyl sulfoxide and 10 ml of water and 15oC dilute of 100.2 g of N-bromosuccinimide, divided into small portions. The mixture is stirred for a total of over 5 hours, then poured into ice water. After extraction with the use of methyl tertiary butyl ether obtain crude 3-bromo-4-hydroxy-2,2-dimethyl-6-phenolsulfonephthalein, which is isolated in pure form by stirring in diisopropyl ether. Exit through the 3 stages to 105.3 g, so pl. 122-124oC.

Pharmacological data:

a) micronized

890 g (3 S, 4R)-3-hydroxy-2,2-dimethyl-4-/2-oxo-1-pyrrolidinyl/ -6-vinylsulfonylacetamido adduct micronized in the mill using an air jet. The particle size after micronisation is 10 μm to 50% of the particles. Using (3S, 4R)-3-hydroxy-2,2-dimethyl - 4-/2-oxo-1-pyrrolidinyl/-6-phenylcarbonylamino or (3S, 4R)-hydroxy - 2,2-dimethyl-4-/2-oxo-1-pyrrolidinyl/-6-phenolsulfonephthalein-hemihydrate under these conditions it is possible to do without grinding, because the products can stick with the introduction into the mill.

b) stable is ethyl-4-/2-oxo-1-pyrrolidinyl/-6-phenolsulfonephthalein - ethanol adduct does not change the size of their particles when suspendirovanie in the fluorocarbons within 8 days.

in) bronchodilator effect for anesthetized Guinea pigs.

Micronized in accordance with paragraph a) material (3S, 4R)-3-hydroxy - 2,2-dimethyl-4-/2-oxo-1-pyrrolidinyl/-6-phenolsulfonephthalein-ethanol adduct suspended in ftoruglevodorodnye and served in the dosing aerosol container. The concentration is chosen so that when one button of the spray can out of 0.1 mg or 1.0 mg of the substance together with 0.5 ml of perchloroethane. With the introduction of such a large number of substances Guinea pigs under anesthesia under the action of pentobarbital (introduction was carried out using the system for air injection method Konzett-Rossler), has been sustained reduction of bronchospasm caused by intravenous pressure of histamine, which amounted to 30 minutes n=2 or 40 minutes, n= 3. It should be noted that in the beginning there was a complete inhibition. Detailed description of the method is given in European patent application [3]

1. Ethanol adduct derivatives chromane General formula I

< / BR>
where R1phenyl;

R2and R3the same or different, are methyl or ethyl.

2. The method of obtaining compounds of General formula I, characterized in that the SOS MES subjected to contacting with ethanol followed by crystallization and purification of the target product.

3. The compound of General formula I, with bronchodilatory effect.

4. Pharmaceutical composition having bronchodilatory effect and containing as active principle derived chromane and pharmaceutical additives, characterized in that the active agent contains a compound of General formula I, in an effective amount.


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