Connection benzothiazolone, methods and intermediate compounds for their production, as well as containing pharmaceutical compositions

 

(57) Abstract:

The invention relates to new derivatives of benzothiazolone General formula I where X is-SO2NH - or-NS2-; p, q and r independently of one another represent 2 or 3; Y represents thienyl, optionally substituted C1-6by alkyl or halogen, or phenylthio or phenyl, optionally substituted C1-6by alkyl or halogen; each R independently represents H or C1-6alkyl; its optical isomers and pharmaceutically acceptable salts. The method of obtaining the compounds of formula I or its pharmaceutically acceptable salt by selective reductive alkylation of compounds of formula II with compound of formula III in the presence of a reducing agent or by selective reduction of compounds of formula IV. Amide of formula VI, the acid of formula V and the aldehyde of the formula III as intermediates for obtaining benzothiazolone formula I. the Pharmaceutical composition exhibiting agonistic activity against DA2receptors and2-adrenoretseptorov containing the compound of formula I or its pharmaceutically acceptable salt, dispersed in the propellant, optionally containing fillers, masiva the Cesky acceptable carrier. The technical result is to provide new compounds of benzothiazolone. 9 s and 9 C.p. f-crystals, 1 table.

The scope of the invention

The invention relates to new derivatives of benzothiazolone, namely to new derivatives of 7-(2-amino-ethyl)-benzothiazolone, and method of production thereof, pharmaceutical compositions containing them, and methods of treatment, which include their use. New compounds are agonists dopamine DA2-and receptor agonists2-adrenergic receptors.

Derivatives benzothiazolone known. For example, in international patent applications, publications WO 92/08708 and WO 92/23385 described biologically active amines, among them biologically active derivatives of aminoethylethanolamine, which are agonists2-adrenergic receptors and agonists dopamine DA2-receptor, and which are indicated in the treatment of obstructive diseases of the respiratory tract.

In WO 93/24473 described 7-(2-amino-ethyl)-benzothiazolone compounds that have the formula

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where X and Y are independently-S(O)n- or-O-, n is 0, 1 or 2; p, q and r are independently 2 or 3; Z is phenyl, optionally substituted with halogen, OR1, NO2or NR2R3; or Z I is Auda hydrogen or C1-6the alkyl. These compounds are agonists2-adrenergic receptors and agonists dopamine DA2-receptor and is indicated for the treatment of obstructive diseases of the respiratory tract.

The present invention relates to new derivatives of 7-(2-amino-ethyl)-benzothiazolone applicable as agonists dopamine DA2-and receptor agonists2-adrenergic receptors.

Description of the invention

Thus, in one aspect this invention relates to compounds of formula I, including their optical isomers

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where X represents-SO2NH - or-NHSO2-,

p, q and r independently from each other equal to 2 or 3,

Y represents thienyl, optionally substituted by alkyl or halogen, or phenylthio-, or phenyl, optionally substituted by alkyl or halogen; and

each R independently represents H or alkyl and pharmaceutically acceptable salts, esters and amides.

These compounds possess pharmacological activity. They demonstrate agonism as dopamine DA2-receptor, and so2-adrenergic receptors. They show a slight agonism or no1-adrenergic receptors. Link is positive, in formula I, q is 2, g is preferably equal to 2.

When Y is phenyl, substituted alkyl, the alkyl group preferably represents C1-6for example, C1or C2group, most preferred is methyl.

When Y is phenyl, substituted by halogen, halogen Deputy preferably is chlorine or fortuneteller.

The preferred compounds of this invention are the compounds of formula I in which X is SO2NH, p is 3, and q and r are each equal to 2. Other preferred compounds are the compounds of formula I in which X represents NHSO2, a and p, q, and r are all equal to 2.

Suitable pharmaceutically acceptable salts of compounds of formula I include acid additive salts derived from inorganic and organic acids. These compounds can also form salts with suitable bases. Examples of suitable salts include hydrochloride, citrate, D,L-lactate, polysulfate, polytetra, D-gluconate, methanesulfonate, p-toluensulfonate, profumata, benzoate, xinafoate, polosukhina, C-hydroxy-2-aftout, pouembout, polymaleic, D-camphorsulfonate, 10-undecanoate, mandelate, naphthalen-1-sulf suberate and diphenylacetate.

Suitable pharmaceutically acceptable esters of compounds of formula I include phenylalkylamine and alkalemia esters.

Suitable amides include unsubstituted or mono - or disubstituted by alkyl or phenylamide.

The most preferred compounds of this invention are:

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N- [2-(2-phenylethane)ethyl]propanesulfonate;

N-[2-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] ethyl]-2-(2-phenylethane)econsultant;

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N- [2-[2-(5-methyl-2-thienyl)ethoxy]ethyl]propanesulfonate;

N-[2-[2-(4-forfinal)ethoxy] ethyl] -3-[2-(4-hydroxy-2-oxo-3H - 1,3-benzothiazol-7-yl)ethylamino]propanesulfonate;

N-[2-[2-(4-chlorophenyl)ethoxy] ethyl] -3-[2-(4-hydroxy-2-oxo - 5H-1,3-benzothiazol-7-yl)ethylamino]propanesulfonate;

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] - N-[2-[2-(4-were)ethoxy]ethyl]propanesulfonate;

(R, S)-3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)- ethylamino]-N-[2-(2-phenyl-1-propoxy)ethyl]propanesulfonate;

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N-[2-[2-(2-were)ethoxy]ethyl]propanesulfonate and

3-[2-(4-hydroxy-2-oxo-3H-1,3-bendable preferably, in the form of hydrochloride.

This invention also relates to a method for producing compounds of formula I, which includes selective reductive alkylation of compounds of formula II

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the compound of the formula III

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in which p, q, r, R, X and Y have the meanings given above, in the presence of a reducing agent.

The reducing agent may be, for example, hydrogen in the presence of a catalyst, such as platinum, platinum oxide, palladium, palladium oxide, Raney Nickel or rhodium, on the media, such as charcoal, with the use of alcohol, such as ethanol or ether complex, for example, ethyl acetate or simply ether, e.g. tetrahydrofuran or water as a solvent for the reaction or a mixture of solvents, at normal or elevated temperature and pressure. The preferred temperature is room temperature. The preferred pressure of 1-3 atmospheres. Alternative reducing agent may be sodium borohydride or a metal hydride, for example, cyanoborohydride sodium. The selection of the suitable solvents for use with a hydride reducing agent will depend on the particular hydride used in this case, which is well known to specialists Its this reaction can be formed intermediate minovia connection which can be recovered under the above conditions to obtain compounds of formula I.

The compounds of formula II can be obtained by the known methods, for example, by the method described in J. Med.Chem., 1987, 30, 1116.

The aldehydes of the formula III can be obtained by many known methods, per se. For example, the dioxides of isothiazolinone (as in Example 1B, for example) can be recovered by using DIBAL in toluene; acetals (as in example 2B, for example) can hydrolyze 70% aqueous acetic acid; and esters (as in example 3G, for example), you can restore DIBAL in toluene. Specific synthesis of certain precursor compounds described in the examples and can be adapted for many different purposes.

The aldehydes of the formula III can also be obtained from the corresponding alcohols by partial oxidation using DMSO, DCC and anhydrous phosphoric acid; or using Chloramin pyridinium or pyridinium dichromate.

This invention also relates to an additional method of obtaining compounds of formula I, including selective recovery of the compounds of formula IV

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in which p, q, r, R, X and Y have the values listed above.

Suitable reducing agents include Elekter, complex metal hydrides, such as sodium bis(2-methoxyethoxy)aluminum hydride. The preferred reducing agent is DIBORANE. The solvent should be inert under the reaction conditions. Aprotic solvents are preferred, for example, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. The reaction can be conducted at a temperature of from about 0 to about 100oC, preferably at the boiling point.

The compounds of formula IV can be obtained by reaction of the amine of formula II with a suitable acid of formula V

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or with the corresponding acid chloride of the acid by standard methods. For example, the reaction can be carried out in the presence of dicyclohexylcarbodiimide using the method of Sheehan and Hess, J. Am. Chem. Soc., 1955, 77, 1067; or 1,1'- carbonyldiimidazole, as described in Staab, Angew. Chem. Int. Ed. Engl. , 1962, 1, 351; or patrimonialization of hexaflurophosphate in a solvent such as DMF as described in Example 1D. Acids which are necessary for this reaction, can be obtained from the corresponding esters by hydrolysis using lithium hydroxide in aqueous methanol according to the method of Example 16. In examples 1A, 2G, 3G, 4E, 5g, 6g, 7G, 8G and 9g describes specific methods for obtaining esters is that they react with amines of the formula II. The anhydrides of the acids can be obtained from acids, for example, by reaction with oxalylamino or thionyl chloride in toluene at a temperature in the range from room temperature to the boiling point.

The compounds of this invention can also be obtained by some other means.

One of such ways is the alkylation of compounds of formula II or its salts of ester or amide alkylating agent of the formula VI

< / BR>
in which p, q, r, R, X and Y have the meanings indicated above, a L designates easy leaving group, e.g. halogen, such as chlorine, bromine, or iodine, or alkyl - or arylsulfonate group, for example, methanesulfonate group.

The reaction can be conducted, for example, in the presence of a base, for example, inorganic bases such as sodium carbonate or potassium hydroxide, or organic bases such as triethylamine, N,N'- diisopropylethylamine or pyridine.

The reaction can be carried out in a solvent, for example, in a simple ether such as tetrahydrofuran or dioxane, a ketone such as butanone or methyl isobutyl ketone, substituted amide, for example, dimethylformamide, or in a chlorinated hydrocarbon, e.g. chloroform, at a temperature in internatnal temperature.

Alkylating agent of the formula VI can be obtained from the corresponding alcohol (i.e., compounds in which L represents a group HE), by methods known to experts in this field. For example, the alcohol can react with a halogenation agent to obtain compounds of formula VI in which L represents a halogen atom. Suitable halogenation agents include, for example, triphenylphosphoranylideneacetate adducts (traditionally produced in situ, for example, by the reaction of triphenylphosphine and tetrabromide carbon). The reaction can be carried out in the presence of a solvent, such as acetonitrile or chlorinated hydrocarbons, such as dichloromethane, for example, at a temperature in the range from 0 to 30oC.

Another method is the selective reduction of compound of formula VII

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in which p, q, r, R, X and Y have the values listed above.

Suitable reducing agents include electrophilic reducing agents, for example, DIBORANE and Alan (aluminum hydride) or nucleophilic reducing agents, for example, complex metal hydrides, such as sodium bis(2-methoxyethoxy)aluminum hydride. The preferred reducing agent is DIBORANE. The solvent should be inert under the conditions readysetauction. The reaction can be conducted at a temperature of from about 0 to about 100oC, preferably at the boiling point.

The compounds of formula VII can be obtained by the interaction between amines and acids or anhydrides of acids by standard methods. For example, the interaction can be performed in the presence of dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole or patrimonialization of hexaflurophosphate as described above in relation to compounds of formula IV. Amines required for the reaction, can be obtained by reaction of compounds of formula VI in which L is easily leaving group, e.g. halogen, such as chlorine or bromine, with phthalimide in the presence of a base. Received imides then you can handle hydrazinehydrate in ethanol to obtain compounds of the formula VI, in which the leaving group is replaced by an amino group.

In the above-described processes may be necessary to protect any functional groups, for example hydroxy - or amino-groups present in the source materials. Suitable protective groups and methods for their removal are described, for example, in "Protective Groups in Organic Synthesis" T. W. Greene and P. G. W. Wuts, John Wiley and Sons Inc., 1991.

Another way to get soedineniya or more functional groups are protected, and where it is desirable or necessary conversion of the compounds of formula I, its pharmaceutically acceptable salt, ester or amide or Vice versa.

Pharmaceutically acceptable salts can be obtained, for example, by reaction of compounds of formula I with an appropriate acid in the presence of a suitable solvent.

Pharmaceutically acceptable esters of compounds of formula I can be obtained using standard methods, for example, by reaction of esterification or interesterification.

Pharmaceutically acceptable amides of the compounds of formula I can be obtained using standard methods, for example, by reaction of compounds of formula I with an acid or acid chloride acid.

Intermediate compounds of formula IV are new, and thus, an additional aspect of the present invention are the compounds of formula IV

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in which p, q, r, R, X and Y have the values listed above.

Intermediate compounds of formula VII, as defined above, are new and, therefore, also presented in this invention.

In addition, the invention includes aldehydes of the formula III defined above and which are also new.

The compounds of formula I and their salts, esters and amides are dopamine agonists DA2-receptor. The affinity for binding of test compounds to the binding sites DA2receptors on the membranes of pituitary bull can be determined by substitution of [3N]-N-n-propylnorapomorphine and [3H]-spiperone, respectively, in the presence or absence of neytralinogo analogue of GTP, D. R. Sibley, A. DeLean and I. Greese, Anterior Pituitary Dopamione Receptors, Demonstration of Interconvertible High and Low Affinity States of Dopamine DA2-receptor, J. Biol. Chem., 1982, 257(11), 6351-6361. The activity of DA2the receptor can also be demonstrated in functional screening of the isolated ear artery of the rabbit, as described by Brown and O'connor, Br.J. Pharmacol. , 1981, 73, 189P. These compounds are agonists 2-adrenergic receptors. This activity can be displayed on the isolated trachea of the Guinea pig, as described I. G. Dougall, D. Harper., D. M. Jackson and P. Left, Br.J.Pharmacol., 1991, 104, 1057. Activity against 1the receptor can be analyzed using the screening of the isolated ear artery of the rabbit, as described below in Pharmacological example.

The compounds of formula I and their salts, esters and amides is shown for use in treating a number of respiratory diseases, including tandrea asthma and hypersensitivity of the respiratory tract); and bronchitis and the like (see , for example, UK Patent N 2022078 and Br.J.Pharmacol., 1987, 24, 4983).

The compounds of formula I and their salts, esters and amides are also shown for use in the treatment of various other painful conditions, such as inflammatory and allergic skin diseases, cancer, for example, small cell lung cancer, congestive heart failure and glaucoma.

The term "treatment" as used here includes both prevention and relief of symptoms.

Thus, an additional aspect of the present invention is the use of compounds of the formula I or their pharmaceutically acceptable salts, esters or amides for the treatment.

Further, the invention includes the use of compounds of the formula I or their pharmaceutically acceptable salts, esters or amides to obtain drugs for the treatment of obstructive diseases of the respiratory tract, particularly asthma or chronic bronchitis.

Besides, this invention relates to a method of treatment of diseases of the respiratory tract, which includes the introduction of a patient suffering from such disease or predisposed to it, terapeutiche and amides.

The usual daily single dose may be, for example, 1 μg to 10 mg for topical administration, preferably 10-500 μg, for example, is divided into two or three doses, or 10 μg to 100 mg for oral administration, preferably 100 μg to 10 mg, for example, is divided into two or three doses.

The compounds of formula I or their pharmaceutically acceptable salts, esters or amides can be used as such or as part of appropriate pharmaceutical compositions.

The introduction can be performed by using the inhalation and other routes, e.g. oral or intravenous.

Nasal or intra-lungs introduction can be performed using the appropriate inhalation device.

For example, dispensing inhalation device can be used for the introduction of compounds dispersed in a suitable propellant, and with or without additional excipients such as ethanol, surfactants, lubricants and stabilizers.

Suitable propellants include hydrocarbons, chlorofluorocarbons and hydrofluroalkane or any mixture of such propellants. Especially preferred propellants are P134a and P227, the active substances, and/or other fillers, for example, in combination with each other.

You can also use a sprayed aqueous suspension or, preferably, solutions, brought to the appropriate pH and/or toychest, or without it, in aerosol devices for single and repeated administration.

You can use powder inhalers for the administration of the drug, single or in combination with pharmaceutically acceptable carrier, in the latter case as in the form of finely ground powder, and in the form required mixture. Powder inhaler can be a single dose or mnogochasovym, and it can be used in powder or capsule containing the powder.

Dosing inhaler, aerosol or powder inhalers are well known, and there are many such devices.

The invention is illustrated by, but is not limited in any way by the following examples in which temperatures are indicated in degrees Celsius. If necessary, the reaction is carried out in an inert atmosphere of nitrogen or argon. When you have made a separation using preparative HPLC using column Novapak, Bondapak and Hypersil (registered trademark), SAPK 60, 35-70 microns.

Example 1

3-[2-(4-hydroxy-2-oxo-3H-1.3-benzothiazol-7 - yl)ethylamino] -N-[2-(2-phenylethane)ethyl]propanesulfinamide hydrochloride)

a) Methyl 3-[2-(2-phenylethane)ethylaminomethyl]propanoate

2-(2-phenylethane)ethanamine1(1.95 g) was stirred in dichloromethane at room temperature. Add triethylamine (3.36 ml) and then methyl-3-(chlorosulfonyl)-propanoate2and the mixture is stirred over night at room temperature. The mixture was diluted with additional amounts of dichloromethane, washed with diluted hydrochloric acid, then water, then dried (MgSO4). The solvent is removed in vacuo, resulting in a gain of pale yellow oil, which was then purified flash chromatography (eluent of 0.1% ethanol:dichloromethane) and get a connection named in the title, in the form of a pale yellow oil (1.68 g).

Mass spectrum: FAB 316 (M+H);

1H NMR (360 MHz, CDCl3) : 2.75 (2H, t), 2.85 (2H, t), 3.18-3.35 (4H, m), 3.46-3.57 (2H, m), 3.60-3.77 (5H, m), 4.44 (1H, Shir.t), 7.12-7.35 (5H, m).

1Chem. Weg., 1964, 97, 510-519.

2J. Am. Chem.Soc., 1950, 72, 128-132.

b) 3-[2-(2-phenylethane)ethylaminomethyl]propanoic acid

The product of stage (a) (1.68 g) was dissolved in ethanol (30 ml). Add a solution of lithium hydroxide (0.45 € ether. The aqueous layer was acidified with diluted hydrochloric acid and extracted with ether. The ether extract is washed with water, then saturated brine, then dried (MgSO4). The solvent is removed in vacuum to obtain the compound of the title in the form of a solid white mass (0.97 g), which was then used without further purification.

So pl. 80-82oC;

Mass spectrum: ESI 300 (M-H);

1H NMR (360 MHz, CDCl3) : 2.77-2.95 (4H, m), 3.20-3.47 (4H, m), 3.51-3.58 (2H, M), 3.69 (2H, t), 4.66 (1H, T), 7.18-7.38 (5H, m).

a) 2-[2-(2-phenylethane)ethyl]-3-isothiazoline-1,1'- dioxide

The product of stage b) (34 g) dissolved in dimethylformamide (200 ml). To this solution, which is stirred, add 1,1'- carbonyldiimidazole (20.12 g) and the mixture is stirred for 2 hours. Add triethylamine (15.7 ml) and the mixture stirred at room temperature for 60 hours. The mixture is then poured into diluted hydrochloric acid and extracted with ethyl acetate (3 times). The combined organic extracts washed with saturated sodium bicarbonate solution, then with saturated salt solution, dried (MgSO4) and the solvent is removed in vacuum to obtain a pale yellow oil, which was then purified flash chromatography (eluent of 50% ethyl acetate:petrol) and get soedinenii (2H, t), 2.99 (2H, t), 3.51 (2H, t), 3.64-3.68 (4H, m), 3.76 (2H, t), 7.18-7.43 (5H, m).

g) 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N-[2-(2-phenylethane)ethyl]propanesulfinamide hydrochloride

The product of stage C) (0.62 g) mechanically stirred in toluene (20 ml), then cooled to -70oC. Add the hydride diisobutylaluminum within 15 min keeping the temperature below -58oC. the Mixture is stirred for 10 min, after which TCX shows the absence of starting material. Carefully add ethyl acetate (9 ml), keeping the temperature below -60oC. the Mixture is allowed to warm to room temperature and add 10% solution of tartrate of potassium-sodium. After stirring for 1 hour the mixture is extracted with ethyl acetate (3 times). The combined organic extracts dried (MgSO4), then approximately 70% of the solvent is removed in vacuum. To the mixture is added methanol (20 ml) and again approximately 70% of the solvent is removed in vacuum, this procedure is repeated two more times. This solution was diluted with methanol (20 ml) and add 7-(2-amino-ethyl)-4-hydroxy-1,3 - benzothiazol-2(3H)-she hydrobromide (0.64 g). the pH was adjusted to 4 using glacial acetic acid. Add cyanoborohydride sodium (0.14 g), then sodium sulfate (50 mg) and the mixture is xida ammonium. Volatile products are removed under vacuum and the residue purified flash chromatography (eluent - 10-25% methanol in chloroform). The products are then purified HPLC with reversed phase (eluent to 25% methanol in 0.1% aqueous triperoxonane acid), resulting after transformation into a salt of hydrochloric acid to obtain the compound of the title in the form of a solid white mass (0.417 g).

So pl. 205-206oC;

Mass spectrum: FAB 408 (M+H);

1H NMR (360 MHz, d6DMSO) : 2.00 (2H, t), 2.73-2.92 (4H, m), 2.96-3.19 (8H, m), 3.44 (2H, t), 3.60 (2H, t), 6.75 (1H, d), 6.85 (1H, d), 7.13-7.35 (6H, m), 8.92 (2H, s), 10.41 (1H, s), 11.77 (1H, s).

Elemental analysis

Found: C, 51.48; H, 6.25; N, 8.41; S, 12.50%

Calculated for C22H29N3O5S2HCl: C, 51.20; H, 5.86; N, 8.14; S, 12.43%.

In an alternate method of the above stages a) and b) again, then hold stages d) and e), which are listed below:

d) N-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)-ethyl] - 3-[2-(2-phenylethane)ethylaminomethyl]propanamide

A solution of the product of stage b) (3,89 g) of the hydrochloride of 7- (2-amino-ethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-she (3.22 g), postreproductive hexaflurophosphate, PyBroP, (6.32 g) in dimethylformamide (50 ml) is cooled to -15oC and add diisopropylethylamine (9.0 ml) dropwise over 5 minutes Rav. After this mixture is added dropwise over 40 min in dilute hydrochloric acid (2N, 500 ml) and after stirring over the weekend particulate mass collected by filtration. This solid mass was dried under vacuum, resulting in the receive connection of subtitle (4.5 g).

Mass spectrum: FAB 492 (M-H).

e) 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N-[2-(2-phenylethane)ethyl]propanesulfinamide hydrochloride

To a solution of the product of stage d) (0.28 g) in tetrahydrofuran (2 ml) add balancetransfer (2.44 ml of 1M solution) for 5 minutes the Mixture is heated under reflux for 3 hours and after cooling, carefully add methanol (1 ml). Volatile products are removed under vacuum, the residue is re-dissolved in methanol (5 ml) and add concentrated hydrochloric acid (1 ml). Volatile products again removed in vacuo. The residue is divided between water and ethyl acetate, the aqueous layer was collected and again extracted with ethyl acetate. Then the aqueous layer was make basic with sodium bicarbonate and extracted four times with chloroform. The combined chloroform extracts are dried and volatile compounds are removed in vacuum to obtain after conversion into the hydrochloride joint is LaTeXe)acanalonia hydrochloride

a) 2-(2-phenylethane)acanaloniidae

Stir a suspension of 2-(2-phenylethane)ethanthiol (1.0 g) in water (40 ml) saturated with 5-10oC chlorine for 20 minutes the Mixture was washed with a strong jet of fluid under a stream of nitrogen to remove the excess chlorine. The mixture is then extracted with dichloromethane (2 times), the combined organic extracts washed with water and dried (CaCl2). The solvent is removed in vacuum to obtain an oil, which is then subjected to azeotropic distillation with toluene to obtain the compound of the title as a yellow oil (1.36 g), which is then used without further purification.

Mass spectrum: EI 248/250 (M);

1H NMR (360 MHz, CDCl3) : 2.90 (2H, t), 3.74 (2H, t), 3.88 (2H, t), 3.99 (2H, t), 7.13-7.36 (5H, m).

b) N-(2.2-dimethoxymethyl)-2-(2-phenylethane)econsultant

Stir a solution of the product of stage (a) (1.0 g) in dichloromethane (20 ml) and pyridine (0.358 ml) is treated by adding dropwise over 5 min a solution of dimethylacetal of aminoacetaldehyde (0.438 ml) in dichloromethane (5 ml). The mixture is stirred at room temperature for 2 days. The mixture is washed with water, then dried (CaCl2). Volatile products are removed under vacuum, resulting in a gain of orange oil, which then="ptx2">

Mass spectrum: 335 (M+NH4);

1H NMR (360 MHz, CDCl3) : 2.90 (2H, t), 3.13 (2H, t), 3.26 (2H, t), 3.38 (6H, s), 3.73 (2H, t), 3.85 (2H, t), 4.38 (1H, t), 4.46 (1H, t), 7.14-7.35 (5H, m).

in) N-[2-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7 - yl)ethylamino]ethyl] -2-(2-phenylethane)acanalonia hydrochloride

A solution of the product of stage b) (0.26 g) in 70% aqueous acetic acid (5 ml) is heated to 100oC for 2 hours, after which TCX showed absence of starting material. The solvent is removed in vacuum. The residue is collected in methanol (10 ml) and to this stirred solution was added 7- (2-amino-ethyl)- 4-hydroxy-1,3-benzothiazol-2(3H)-she hydrobromide (0.238 g) and cyanoborohydride sodium (0.038 g), and then acetic acid (1 drop). The mixture is stirred at room temperature for 24 hours. Mix make alkaline by addition of concentrated aqueous ammonium hydroxide solution. Volatile products are removed under vacuum and the residue purified flash chromatography (eluent - 17% ethanol in dichloromethane) to give a light yellow resin. The mass is then purified HPLC with reversed phase (eluent - 30-45% acetonitrile in 0.1% aqueous triperoxonane acid) to obtain after transformation into a salt of hydrochloric acid connection header in the form of a white powder (0.080 g).

Mass spectrum: 466 (M+H), .78 (1H, d), 6.87 (1H, d), 7.19-7.30 (5H, m), 7.43 (1H, t), 9.10 (2H, s), 10.16 (1H, s), 11.78 (1H, s).

Elemental analysis

Found: C, 49.35; H, 5.69; N, 8.30; S 14,94%

Calculated for C21H27N3O5S2HCl: C, 49.31; H, 5.67; N, 8.22; S 12.52%

In an alternative method, stage (a) is repeated with the subsequent carrying out steps (d) - (f) below.

g) Methyl-[2-(2-phenylethane)ethylsulfonyl]acetate

The suspension of the hydrochloride methylglycine (2.52 g) in dichloromethane (30 ml) was stirred at -18oC and add diisopropylethylamine (8 ml) for 10 minutes To this mixture is added dropwise to the product of stage (a) (2.64 g) in dichloromethane (10 ml) over 10 min, keeping the temperature below -5oC. the Cooling bath is removed and allow to stir the mixture to warm to room temperature. Over the next 50 min the mixture was washed with 5% aqueous potassium hydrosulfate and dried (Na2SO4), volatile products are removed under vacuum to obtain the compound of the title in the form of a brown oil (58.5 g).

Mass spectrum: FAB 302 (M+H);

1H NMR (360 MHz, CDCl3) : 2.90 (2H, t), 3.36 (2H, t), 3.72-3.85 (7H, m), 3.96 (2H, t), 4.70 (1H, Shir. s), 7.20-7.31 (5H, m).

d) 2-[(2-phenylethane)ethylsulfonyl]acetic acid

A solution of the product of the Oia (1.06 g) in water (7 ml) for 5 minutes. The ice bath is removed and the solution stirred for 16 hours. The mixture is acidified with concentrated hydrochloric acid (3 ml) and concentrated in vacuo to a volume of approximately 15 ml of the Residue is mixed with sodium bicarbonate and extracted with ether. Then the aqueous phase is again acidified with a saturated aqueous solution of potassium hydrosulfate and extracted with ether. This extract was dried (MgSO4) and volatile products are removed under vacuum to obtain a solid mass. Then the product is purified by recrystallization from a mixture of dichloroethane and toluene with getting the connection header in the form of weight crystalline solid (1.57 g).

Mass spectrum: FAB 288 (M+H);

1H NMR (360 MHz, CDCl3) : 2.90 (2H, t), 3.32 (2H, t), 3.74-3.78 (4H, m), 3.89 (2H, t), 4.66 (1H, t), 7.20-7.33 (5H, m), 8.07 (1H, Shir. C).

e) N-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)-ethyl] - 2-[2-(2-phenylethane)ethylsulfonyl]ndimethylacetamide

A solution of the product of stage (d) (70 g) in dimethylformamide (605 ml) is cooled to -10oC and add 1,1'-carbonyldiimidazole (39.5 g). The mixture is stirred for 119 minutes, then add 7-(2-amino-ethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrochloride (68.87 g), and then dropwise added triethylamine (34 ml) for 3 minutes, maintaining the temperature at -104). Volatile products are removed under vacuum to obtain the compound of the title in the form of foam (92.21 g).

Mass spectrum: FAB 480 (M+H);

1H NMR (360 MHz, d6DMSO) : 2.61 (2H, t), 2.81 (2H, t), 3.29-3.32 (4H, m, overlapped with water), 3.56 (2H, s), 3.61 (2H, t), 3.74 (2H, t), 6.70 (1H, d), 6.80 (1H, d), 7.16-7.53 (5H, m), 8.03 (1H, Shir. t).

W) N-[2-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7 - yl)ethylamino]ethyl] -2-(2-phenylethane)acanalonia hydrochloride

A solution of the product of stage (e) (38.7 g) in tetrahydrofuran (200 ml) cooled in an acetone bath/ice and add borohydride lithium (727 ml, 2M solution in tetrahydrofuran) for 30 minutes. After 15 minutes the cooling bath is removed and add trimethylsilane (205 ml) and stirred for 162 hours at room temperature. The mixture is cooled to -20oC and carefully add the methanol. After that add another 50 ml of methanol saturated with hydrogen chloride, and the mixture was allowed to warm to room temperature. One hour later, the mixture is heated with reverse holodilniki shake and after cooling in a bath of acetone/ice within 30 minutes the water is decanted. Add additional water (100 ml), the process is repeated. Semi-remaining mass is then dissolved in hot ethanol (40 ml), treated with activated charcoal (3 g) and stirred for 1 hour. The mixture is filtered and the solvent is removed in vacuum. The residue re-dissolved in hot ethanol (80 ml) and left to stand at room temperature for 16 hours. Then the precipitated crystals loosen and break up with a spatula, shaken and allowed to stand for a further 16 hours. Then the solid is collected by filtration and washed with ethanol, ether, then dried in vacuum to obtain the compound of the title (23 g).

Example 3

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7 - yl)ethylamino] -N-[2-[2-(5-methyl-2-thienyl)ethoxy]ethyl] propanesulfinamide hydrochloride

a) 2-[2-(5-methyl-2-thienyl)ethoxy]acetic acid

Sodium hydride (0.622 g) is suspended in anhydrous dimethylformamide (5 ml), treated by adding dropwise a solution of 2-(5-methyl-2-thienyl)ethanol (1.0 g) in anhydrous dimethylformamide (5 ml). The mixture is stirred at room temperature under nitrogen atmosphere for 2 hours, then add a solution of Chloroacetic acid (0.664 g) in anhydrous dimethylformamide (5 ml). The mixture was mechanically stirred at whom what lacerata. the pH of the aqueous layer was adjusted to 2 using dilute hydrochloric acid, and then extracted with ethyl acetate. The extract is washed with water, saturated salt solution, then dried (MgSO4). The solvent is removed in vacuum to obtain a brown oil (1.51 g), which is then used without further purification.

Mass spectrum: 200 (M);

1H NMR (360 MHz, CDCl3) : 2.45 (3H, s), 3.05-3.09 (2H, t), 3.75-3.83 (2H, t), 4.17 (2H, s), 6.56 (1H, d), 6.63 (1H, d).

b) 2-[2-(5-methyl-2-thienyl)ethoxy]ndimethylacetamide

The product of stage (a) (6.48 g) was dissolved in toluene (55 ml) and added dropwise to oxalicacid (2.877 ml) at room temperature under nitrogen atmosphere. Add a drop of dimethylformamide and the mixture is stirred for 3 hours, after which TCX showed absence of starting material. Volatile products are removed under vacuum to obtain a brown oil (6.7 g), which is then added dropwise to stirred concentrated ammonium hydroxide solution (50 ml) at 0oC. the Mixture was allowed to warm to room temperature and stirred for 4 hours. In the sediment falls brown solid. This solid is collected by filtration and washed with water, resulting in a receive connection header (2.02 g).

a) 2-[2-(5-methyl-2-thienyl)ethoxy]ethanamine

A solution of borane-tetrahydrofuran (1.0 M in THF, 21.7 ml) was added dropwise to stirred solution of the product of stage b) (1.25 g) in anhydrous tetrahydrofuran (100 ml). The reaction mixture is heated under reflux in an atmosphere of inert gas for 5 hours. The reaction mixture is cooled and carefully add methanol (10 ml). The solvents are removed in vacuo and the residue is dissolved in methanol (100 ml), to which is added concentrated hydrochloric acid (specific gravity 1.18, 0.45 ml). This solution was heated under reflux for 15 min, then the solvent was removed in vacuum. The residue was purified flash chromatography (eluent - dichloromethane:5% methanol) to give the named in the subtitle compound as a solid white mass (0.916 g).

Mass spectrum: 186 (M+H);

1H NMR (360 MHz, CDCl3) : 2.45 (3H, s), 3.04 (2H, t), 3.73 (2H, t), 3.97 (2H, s), 5.61 (2H, Shir.s), 6.57 (1H, d), 6.63 (1H, d).

d) Methyl 3-[2-[2-(5-methyl-2-thienyl)ethoxy]ethylaminomethyl] propanoate

The product of stage b) in the form of a hydrochloride (1.50 g) is stirred in dichloromethane (25 ml) under nitrogen atmosphere. Add triethylamine (2.21 ml) and then methyl-3-(chlorosulfonyl)propanoate (1.18 g). The mixture is mechanically lane and organic products are washed with diluted hydrochloric acid, then water, then dried (MgSO4). The mixture is filtered and the volatile products are removed under vacuum to obtain the compound of the title in the form of an oil (1.4 g).

Mass spectrum: 336 (M+H);

1H NMR (360 MHz, CDCl3) : 2.38 (3H, s), 2.80 (2H, t), 3.00 (2H, t), 3.26-3.36 (4H, m), 3.56 (2H, t), 3.64 (2H, t), 3.72 (3H, s), 4.71 (1H, t), 6.57 (1H, d), 6.60 (1H, d).

e) 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N-[2-[2-(5-methyl-2-thienyl)ethoxy]ethyl]propanesulfinamide hydrochloride

The product of stage d) (0.60 g) was dissolved in toluene (30 ml) under nitrogen atmosphere and cooled to -78oC. added dropwise diisobutylaluminium (1.5 M solution in toluene, 1.78 ml) and the mixture was kept at a temperature of -78oC 10 min. Reaction

stopped by the addition of ethyl acetate, then 10% aqueous solution of potassium tartrate sodium. The mixture is heated to room temperature and after stirring for 1 hour, extracted with toluene (3 times). The combined organic extracts washed with water, dried (MgSO4), then approximately 70% of the solvent is removed in vacuum. To the mixture is added methanol (20 ml) and again approximately 70% of the solvent is removed in vacuum, this procedure is repeated two more times. This solution was diluted with methanol (20 ml) and add 7-(2-amino-ethyl)-4-guide is anabolized sodium (0.114 g) and the mixture is stirred for 2 hours in nitrogen atmosphere. The mixture was doing basic by the addition of concentrated aqueous ammonium hydroxide solution. Volatile products are removed under vacuum and the residue purified flash chromatography (eluent - 15-20% methanol:dichloromethane). The product is then further purified HPLC with reversed phase (eluent - 25-85% methanol in 0.1% aqueous triperoxonane acid) to obtain after transformation into a salt of hydrochloric acid connection header in the form of a white solid (0.12 g).

So pl. 210-212oC;

Mass spectrum: FAB 500 (M+H);

1H NMR (360 MHz, d6DMSO) : 2.00 (2H, HF), 2.37 (3H, s), 2.85 (2H, t), 2.93 (2H, t), 3.01-3.17 (8H, m), 3.46 (2H, t), 3.58 (2H, t), 6.60 (1H, d), 6.65 (1H, d), 6.75-6.88 (2H, m), 7.31 (1H, t), 8.93 (2H, s), 10.15 (1H, s), 11.7 (1H, Shir. C).

Example 4

N-[2-[2-(4-forfinal)ethoxy] ethyl] -3-[2-(4- hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] propanesulfinamide hydrochloride

a) t-butyl 3-[2-(4-forfinal)ethoxy]propanoate

2-(4-forfinal)ethanol (20.5 g) and Triton-B (2.4 ml, 40% in methanol) are mixed with each other and the methanol removed in vacuo. Add tert-butyl acrylate (21.38 ml) and the solution is heated at a temperature of 50oC for 2 hours, then stirred at room temperature overnight. The solution was diluted with water and extracted with diethyl ether. United agencies is removed in vacuum to obtain the compound of the title (37.91 g), which is used without further purification.

1H NMR (360 MHz, CDCl3) : 1.46 (9H, s), 2.47 (2H, t), 2.84 (2H, t), 3.55-3.69 (4H, m), 6.93-6.98 (2H, m), 7.15-7.18 (2H, m).

b) 3-[2-(4-forfinal)ethoxy]propanoic acid

The product of stage (a) (37.91 g) dissolved in dichloromethane (50 ml) and add triperoxonane acid (50 ml). The solution was stirred at room temperature for 1 hour, then diluted with water and extracted with ethyl acetate (4 times). The combined organic extracts washed with water (4 times), then a saturated solution of salt, dried (MgSO4) and filtered. Volatile products are removed under vacuum, resulting in receive oil, this oil is collected in diethyl ether and extracted with aqueous sodium bicarbonate solution (3 times). The combined aqueous layers are acidified with concentrated hydrochloric acid, then extracted with diethyl ether (x 4). The combined organic extracts washed with saturated salt solution, dried (MgSO4) and filtered. Volatile products are removed under vacuum to obtain compound subtitle (19.95 g) which was used without further purification.

Mass spectrum: 212 (M);

1H NMR (360 MHz, CDCl3) : 2.62 (2H, t), 2.85 (2H, t), 3.66 (2H, t), 3.73 (2H, t), 6.94-6.99 (2H, m), 7.14-7.18 (m (11.2 ml) and diphenylphosphoryl (15.7 ml) was heated in toluene (150 ml) at 80oC for 5 hours in nitrogen atmosphere. Mixture is allowed to cool, then leave at room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate (3 times). The combined organic extracts washed with aqueous sodium bicarbonate solution, diluted hydrochloric acid, saturated brine, then dried (MgSO4) and filtered. Volatile products are removed under vacuum and the residue purified flash chromatography (eluent of 50% diethyl ether:isohexane) to obtain the compound of the title (5.54 g).

Mass spectrum: 209 (M);

1H NMR (360 MHz, CDCl3) : 2.89 (2H, t), 3.38 (2H, t), 3.56 (2H, t), 3.68 (2H, t), 6.95-7.01 (2H, m), 7.17-7.21 (2H, m).

d) Methyl N-[2-[2-(4-forfinal)ethoxy]ethyl]carbamate

The product of stage b) (9.0 g) was dissolved in methanol (300 ml) and to this stirred solution was added sodium methoxide (4.65 g). The mixture was mechanically stirred at room temperature for 3 hours. Volatile products are removed under vacuum and the residue extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4) and filtered. Volatile products are removed under vacuum and the part of the residue further purified flash chromatography (eluent - 60% diethyl ether:isohexane), resulting in a receive link is H, t), 3.63 (2H, t), 3.67 (3H, s), 6.95-7.00 (2H, m), 7.14-7.18 (2H, m).

Elemental analysis

Found: C, 59.1; H, 6.83; N, 5.83%

Calculated for C12H16FNO3: C, 59.74; H, 6.68; N, 5.81%.

d) 2-[2-(4-forfinal)ethoxy]ethanamine

The product of stage d) (8.0 g) is dissolved in ethylene glycol and to this add the potassium hydroxide (48 g) and hydrazinehydrate (8.3 ml). Stir the mixture heated to 140oC for 4 hours, then leave to cool to room temperature overnight. The mixture is diluted with water and extracted with diethyl ether (3 times). The combined organic extracts washed with brine, dried (MgSO4) and filtered. Volatile products are removed under vacuum, resulting in a receive connection header (5.36 g).

Mass spectrum: 184 (M+H);

1H NMR (360 MHz, CDCl3) : 2.82-2.88 (4H, m), 3.47 (2H, t), 3.64 (2H, t), 6.95-6.99 (2H, m), 7.16-7.20 (2H, m).

e) Methyl 3-[2-[2-(4-forfinal)ethoxy]ethylaminomethyl] propanoate

The connection header (8.32 g) receive, in accordance with the method of Example 3 g) using 2-[2-(4-forfinal)ethoxy] ethanamine (5.36 g), triethylamine (4.6 ml) and methyl-3- (chlorosulfonyl)propanoate (5.6 g) in diethyl ether (150 ml).

So pl. 49oC;

Mass spectrum: 184 (M+H);

1H NMR (36 is elementry analysis

Found: C, 50.52; H, 6.24; N, 4.16; S, 9.40%

Calculated for C14H20FNO5S: C, 50.44; H, 6.05; N, 4.20; S, 9.62%.

W) N-[2-[2-(4-forfinal)ethoxy] ethyl]-3-[2-(4-hydroxy - 2-oxo-3H-1.3-benzothiazol-7-yl)ethylamino]propanesulfinamide hydrochloride

The connection header (0.092 g) receive, in accordance with the method of Example 3D) using methyl 3-[2-[2-(4- forfinal)ethoxy]ethylaminomethyl] propanoate (1.0 g), diisobutylaluminium (1.5 M solution in toluene, 4 ml), 7-(2 - amino-ethyl)-4-hydroxy-1,3-benzothiazol-2-(3H)-she hydrochloride (0.875 g) and cyanoborohydride sodium (0.354 g).

So pl. 195-197oC;

Mass spectrum: FAB 498 (M+H);

1H NMR (360 MHz, d6DMSO) : 1.99 (2H, HF), 2.78-2.87 (4H, m), 3.04-3.16 (8H, m), 3.45 (2H, t), 3.59 (2H, t), 6.86 (1H, d), 6.85 (1H, d), 7.01 (2H, t), 7.26-7.31 (3H, m), 8.90 (2H, s), 10.15 (1H, s), 11.77 (1H, Shir. C).

Elemental analysis

Found: C, at 49.01; H, 5.74; N, 7.96; S, 11.50%

Calculated for C22H29NF3O5S2HCl 0.5 H2O: C, 49.48; H, 5.47; N, 7.87; S, 12.01%.

Example 5

N-[2-[2-(4-chlorophenyl)ethoxy] ethyl] -3-[2-(4- hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] propanesulfinamide hydrochloride

a) 2-[2-(4-chlorophenyl)ethoxy]acetic acid

2-(4-chlorophenyl)ethanol (10 g) is stirred in 50% aqueous sodium hydroxide (70 ml), dobavliay ml) and stirring is continued for 18 hours. Add water (50 ml) and after two hours the mixture is cooled on ice and acidified to pH 1 using concentrated hydrochloric acid. The organic layer is separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts washed with brine and dried (MgSO4). The solvent is removed in vacuo, resulting in a gain of pale yellow oil. This oil is dissolved in dichloromethane (100 ml) and add triperoxonane acid (100 ml), the mixture is heated under reflux for 1 hour. Volatile products are removed under vacuum and the residue is collected in a sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate, the ethyl acetate washed with water, dried (MgSO4) and volatile products are removed under vacuum, resulting in a receive connection header in the form of a solid light-brown substance (16.4 g), which is used without further purification.

Mass spectrum: EI 214/6 (M).

b) 2-[2-(4-chlorophenyl)ethoxy]ndimethylacetamide

The product of stage (a) (16.4 g) was dissolved in toluene (300 ml) and added dropwise to oxalicacid (13 ml) at room temperature under nitrogen atmosphere. The mixture is stirred for Glitte get what brown butter, which are added dropwise in a mixed solution of concentrated ammonium hydroxide (60 ml). Precipitated precipitated solid is collected by filtration, washed with water and isohexanol, resulting in a receive connection header (6.6 g).

So pl. 106-109oC;

Mass spectrum: FAB 214/6 (m+H);

1H NMR (360 MHz, CDCl3) : 2.89 (2H, t), 3.73 (2H, t), 3.93 (2H, s), 5.87 (1H, Shir. s), 6.22 (1H, Shir. s), 7.16 (2H, d), 7.28 (2H, d).

a) 2-[2-(4-chlorophenyl)ethoxy]ethanamine

The product of stage b) in small portions add to the mix a solution of balancetransfer (1.0 M in THF, 85 ml). The reaction mixture is heated under reflux in an atmosphere of inert gas for 3 hours. The reaction mixture is cooled and carefully add methanol (10 ml). The solvents are removed in vacuo, and the residue is dissolved in methanol (100 ml), to which is added concentrated hydrochloric acid (specific gravity 1.18, 4 ml). This solution is heated under reflux for 30 minutes, then the solvent is removed in vacuum. The residue is collected in water and washed with ether. Add sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The ethyl acetate washed with water, brine and dried (MgSO4). Volatile products from the without further purification.

Mass spectrum EI 200/2 (M+H).

d) Methyl 3-[2-[2-(4-chlorophenyl)ethoxy]ethylaminomethyl] propanoate

The product of stage b) (1.1 g) was stirred in dichloromethane (30 ml) under nitrogen atmosphere, add triethylamine (1.52 ml) and then methyl-3-(chlorosulfonyl)propanoate (2.04 g). The mixture is stirred at room temperature for 3 hours. Volatile products are removed under vacuum and the residue is purified flash chromatography on silica gel (eluent - 60% ether:petrol), resulting in a receive connection header (1.1 g) in the form of butter.

Mass spectrum: FAB 350/2 (m+H);

1H NMR (360 MHz, CDCl3) : 2.80 (2H, t), 2.82 (2H, t), 3.26 (2H, q), 3.33 (2H, t), 3.54 (2H, t), 3.67 (2H, t), 3.72 (2H, s), 4.63 (1H, t), 7.14 (2H, d), 7.27 (2H, d).

d) N-[2-[2-(4-chlorophenyl)ethoxy] ethyl]-3-[2-(4-hydroxy - 2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]propanesulfinamide hydrochloride

The product of stage d) (1.1 g) dissolved in toluene (50 ml) under nitrogen atmosphere and cooled to -78oC. added dropwise diisobutylaluminium (1.5 M solution in toluene, 2.6 ml) and the mixture was kept at a temperature of -78oC for 10 minutes. The reaction is stopped by adding 10% hydrochloric acid in ethanol and the mixture was allowed to warm to room temperature. The mixture is then poured into 10% hydrochloric acid and extracted with ether. United is uume. To the mixture is added methanol (20 ml) and again approximately 70% of the solvent is removed in vacuum, this procedure is repeated two more times. This solution was diluted with methanol (20 ml) and add 7-(2-amino-ethyl)- 4-hydroxy-1,3-benzothiazol-2(3H)-she hydrochloride (0.92 g). the pH was adjusted to 4 using glacial acetic acid. Add cyanoborohydride sodium (0.247 g) and the mixture is stirred for 2 hours in nitrogen atmosphere. The mixture was doing basic by the addition of concentrated aqueous ammonium hydroxide solution. Volatile products are removed under vacuum and the residue purified flash chromatography (eluent - 2.5-10% methanol: dichloromethane). The product is then purified by HPLC with reversed phase (eluent - 50-100% methanol in 0.1% aqueous triperoxonane acid), resulting after transformation into a salt of hydrochloric acid to obtain the compound of the title in the form of a white solid (0.089 g).

So pl. 190-193oC;

Mass spectrum: FAB 514/6 (M+H);

1H NMR (360 MHz, d6DMSO) : 1.99 (2H, m), 2.82 (4H, m), 3.12 (8H, m), 3.45 (2H, t), 3.60 (2H, t), 6.76 (1H, d), 6.87 (1H, d), 7.30 (5H, m), 8.87 (2H, Shir. C), 10,14 (1H, s), 11.77 (1H, Shir. C).

Elemental analysis

Found: C, 46.68; H, 5.55; N, 7.47; S, 10,86%

Calculated for C22H28N3O5S2HClH2O: C, 46.47; H, 5,50; N, 7.39; S, 11.28%.


a) 2-[2-(4-were)ethoxy]acetic acid

2-(4-were)ethanol (8.16 g) was stirred in 50% aqueous sodium hydroxide (25 ml), add t-butylbromide (9.05 ml) in toluene (30 ml) together with tetrabutylammonium (2.2 g) and the mixture is stirred for 18 hours. Add ice water (100 ml), then ether, the organic layer is separated and then the aqueous layer is acidified with hydrochloric acid. The acidified aqueous layer was extracted with ether, the extract washed with brine and dried (MgSO4). The solvent is removed in vacuo, resulting in a receive connection header in the form of a white solid (1.1 g), which is used without further purification.

1H NMR (360 MHz, CDCl3) : 2.32 (3H, s), 2.91 (2H, t), 3.77 (2H, t), 4.10 (2H, s), 7.11 (4H, m).

b) 2-[2-(4-were)ethoxy]ndimethylacetamide

The connection header (0.77 g) receive, in accordance with the method of Example 1, stage (b) using 2-[2-(4 - were)ethoxy]acetic acid (1.1 g), oxalicacid (1.44 g), concentrated ammonium hydroxide (20 ml) and toluene (40 ml).

So pl. 106-107oC;

Mass spectrum: FAB 194 (M+H, 100);

a) 2-[2-(4-were)ethoxy]ethanamine hydrochloride

The compound named in the heading, (6.25 g) gain with which tetrahydrofuran (1.0 M in THF, 75 ml) and tetrahydrofuran (40 ml).

Mass spectrum: FAB 180 (M+H, 100);

1H NMR (360 MHz, CDCl3) : 2.30 (3H, s), 2.87 (2H, t), 3.17 (2H, d), 3.65-3.73 (4H, m), 7.11 (4H, m), 8.30 (2H, Shir. C).

d) Methyl 3-[2-[2-(4-were)ethoxy]ethylaminomethyl] propanoate

The connection header (2.49 g) receive, in accordance with the method of Example 5, step (g) using 2- [2-(4-were)ethoxy]ethanamine hydrochloride (3.5 g), triethylamine (4.74 ml), methyl-3-(chlorosulfonyl)propanoate (3.08 g) and dichloromethane (80 ml).

Mass spectrum: FAB 330 (M+H, 119 (100));

e) 3-[2-(4-hydroxy-2-oxo-3H-1.3-benzothiazol-7-yl) ethylamino] -N-[2-[2-(4-were)ethoxy]ethyl]propanesulfinamide hydrochloride

Named the title compound (0.2 g) are obtained in accordance with the method of Example 5, step (d) using methyl-3-[2-[2-(4-were)ethoxy]ethylaminomethyl]propanoate (2.49 g), diisobutylaluminium (1.5 M solution in toluene, 7.5 ml), 7-(2-amino-ethyl)-4-hydroxy-1,3-benzothiazol - 2(3H)-she hydrochloride (2.2 g) and cyanoborohydride sodium (0.48 g).

So pl. 213-215oC;

Mass spectrum: FAB 494 (M+H);

1H NMR (360 MHz, d6DMSO) : 1.99 (2H, m), 2.25 (3H, s), 2.74-2.84 (4H, m), 3.06-3.15 (8H, m), 3.45 (2H, t), 3.57 (2H, t), 6.75 (1H, d), 6.87 (1H, d), 7.10 (4H, m), 7.30 (1H, t), 8.61 (2H, s), 10.11 (1H, s), 11.77 (1H, Shir. C).

1H NMR (360 MHz, CDCl3) : 1.32 (3H, d), 3.08 (1H, m), 3.67 (2H, t), 4.07 (2H, s), 7.23-7.34 (5H, m).

b) 2-(2-phenyl-1-propoxy)ndimethylacetamide

The connection header (4.39 g) receive, in accordance with the method of Example 5, step (b) using 2-(2-phenyl-1-propoxy)acetic acid (5.0 g), oxalicacid (4.5 ml), concentrated ammonium hydroxide (20 ml) and toluene (30 ml).

Mass spectrum: GC 134 (M-59);

1H NMR (360 MHz, CDCl3) : 1.31 (3H, d), 3.05 (1H, m), 3.61 (2H, m), 3.90 (2H, square), 7.22 (3H, m), 7.33 (2H, m).

a) 2-(2-phenyl-1-propoxy)ethanamine hydrochloride

The connection header (3.58 g) receive, in accordance with the method of Example 5, step C) using 2-(2-phenyl-1-propoxy)ndimethylacetamide (3.86 g), borane-tetrahydrofuran (1.0 M in THF, 50 ml) and tetrahydrofuran (40 ml).

Mass spectrum: GC 180 (M+H);

d) Methyl 3-[2-(2-phenyl-1-propoxy)ethylaminomethyl]- propanoate

The connection header (2.0 g) receive, in accordance with sposobami-3-(chlorosulfonyl)propanoate (3.73 g) and dichloromethane (70 ml).

Mass spectrum: GC 224 (M-105);

1H NMR (360 MHz, CDCl3) : 1.27 (3H, d), 2.75 (2H, t), 3.02 (1H, m), 3.20-3.29 (4H, m), 3.45-3.56 (4H, m), 3.72 (3H, s), 4.42 (1H, t), 7.21-7.34 (5H, m).

e) 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N-[2-(2-phenyl-1-propoxy)ethyl]propanesulfinamide hydrochloride

The connection header (0.164 g) receive, in accordance with the method of Example 5, step (d) using methyl 3-[2- (2-phenyl-1-propoxy)ethylaminomethyl] propanoate (1.01 g), diisobutylaluminium (1.5 M solution in toluene, 3 ml), 7-(2 - amino-ethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrochloride (0.89 g) and cyanoborohydride sodium (0.19 g).

So pl. 183-184oC;

Mass spectrum: FAB 494 (M+H);

Elemental analysis

Found: C, 52.42; H, 6.31; N, 8.28; S, 11.74%

Calculated for C23H31N3O5S2HCl: C, 52.11; H, 6.08; N, 7.93; S, 12.10%.

Example 8

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N- [2-[2-(2-were)ethoxy]ethyl]propanesulfinamide hydrochloride

a) 2-[2-(2-were)ethoxy] acetic acid

The connection of the subtitle (8.91 g) receive, in accordance with the method of Example 5, step (a) using 2-(2 - were)ethanol (5.0 g), tert-butylbromide (5.47 g), tetrabutylammonium (0.78 g), toluene (80 ml), 50% odgc, CDCl3) : 2.34 (3H, s), 2.97 (2H, t), 3.75 (2H, t), 4.13 (2H, s), 7.12-7.17 (4H, m), 8.14 (1H, Shir. C).

b) 2-[2-(2-were)ethoxy]ndimethylacetamide

The connection of the subtitle (5.02 g) receive, in accordance with the method of Example 5, step (b) using 2-[2-(2-were)ethoxy]acetic acid (6.726 g), oxalicacid (6.22 ml), concentrated ammonium hydroxide (60 ml) and toluene (60 ml).

Mass spectrum: FAB 194 (M+H);

1H NMR (360 MHz, CDCl3) : 2.22 (3H, s), 2.86 (2H, t), 3.60 (2H, t), 3.80 (2H, s), 7.06-7.19 (4H, m), 7.25 (2H, Shir. C).

a) 2-[2-(2-were)ethoxy]ethanamine hydrochloride

The connection of the subtitle (5.4 g) receive, in accordance with the method of Example 5, step (C) using 2-[2-(2 - were)ethoxy]ndimethylacetamide (5.13 g), a solution of borane-tetrahydrofuran (1.0 M in THF, 53.5 ml) and tetrahydrofuran (100 ml).

Mass spectrum: FAB 180 (M++H);

d) Methyl 3-[2-[2-(2-were)ethoxy]ethylaminomethyl] propanoate

The connection of the subtitle (5.4 g) receive, in accordance with the method of Example 5, step (g) using the hydrochloride of 2- [2-(2-were)ethoxy] ethanamine (5.4 g), triethylamine (8.73 ml), methyl 3-(chlorosulfonyl)propanoate (4.66 g) and dichloromethane (100 ml).

Mass spectrum: FAB 330 (M+H);

1H NMR (360 MHz, CDCl3) : 2.32 (3H, what-3H-1,3-benzothiazol-7-yl) ethylamino] -N-[2-[2-(2-were)ethoxy]ethyl]propanesulfinamide hydrochloride

The product of stage d) (2.0 g) dissolved in toluene (100 ml) under nitrogen atmosphere and cooled to -78oC. added dropwise diisobutylaluminium (1.5 M solution in toluene, 6.22 ml) and the mixture was kept at a temperature of -78oC for 10 minutes. The reaction is stopped by the addition of ethyl acetate, then 10% aqueous solution of potassium sodium tartrate. The reaction mixture is heated to room temperature and after stirring for 1 hour and extracted with toluene. The combined organic extracts washed with water, dried (MgSO4), then approximately 70% of the solvent is removed in vacuum. To the mixture was added methanol (50 ml) and again approximately 70% of the solvent is removed in vacuum, this procedure is repeated two more times. The solution was diluted with methanol (50 ml) and add 7-(2 - amino-ethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrochloride (1.8 g). the pH was adjusted to 4 using glacial acetic acid. Add cyanoborohydride sodium (0.114 g) and the mixture is stirred for 18 hours under nitrogen atmosphere. The mixture was doing basic by the addition of concentrated aqueous ammonium hydroxide solution. Volatile products are then removed in vacuum. The residue purified flash chromatography on silica (eluent of 1% methanol: dichloromethane). Then ATA which after transformation in Sol of hydrochloric acid to obtain the compound of the title in the form of a white solid (0.38 g).

So pl. 184-187oC;

Mass spectrum: FAB 494 (M+H);

1H NMR (360 MHz, d6DMSO) : 1.74-1.77 (2H, m), 1.99 (2H, t), 2.27 (3H, s), 2.79-2.85 (4H, m), 3.07-3.16 (6H, m), 3.45-3.48 (2H, m), 3.55-3.61 (2H, m), 6.74 (1H, d), 6.88 (1H, d), 7.08-7.17 (4H, m), 7.32 (1H, t), 8.81 (1H, s), 10.17 (1H, s), 11.77 (1H, Shir. C).

Example 9

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N- [2-(2-penilties)ethyl]propanesulfinamide hydrochloride

a) tert-butyl 2-(2-penilties)acetate

2-phenylthiourea (6.1 g), tert-butylbromide (7.9 ml), tetrabutylammonium (1.3 g), toluene (80 ml) and 75% aqueous sodium hydroxide (40 ml) is stirred together for a period of 72 hours. The organic layer is separated and the aqueous layer extracted with dichloromethane. The combined organic extracts washed with brine, dried (MgSO4) and the solvent is removed in vacuo, resulting in a receive connection header (12.07 g).

Mass spectrum: FAB 269 (M+H).

b) 2-(2-penilties)ndimethylacetamide

The product of stage (a) (12.07 g) dissolved in dichloromethane (50 ml) and add triperoxonane acid (50 ml), the mixture is stirred for 2 hours. Volatile products are removed under vacuum and the residue is collected in an aqueous solution of sodium bicarbonate and washed with ether. The aqueous layer was acidified with SUB>4) and volatile products are removed under vacuum. The residue is dissolved in toluene (50 ml) and added dropwise to oxalicacid (50 ml) at room temperature under nitrogen atmosphere. Added dropwise dimethylformamide (0.3 ml), the mixture is stirred for 45 minutes. Volatile products were removed and the crude acid chloride is added dropwise in a mixed solution of concentrated ammonium hydroxide (50 ml) at -10oC. Precipitated precipitated solid is collected by filtration, washed with water and ether, resulting in a receive connection header (3.53 g).

Mass spectrum: FAB 212 (M+H);

1H NMR (360 MHz, CDCl3) : 3.13 (2H, t), 3.72 (2H, t), 3.95 (2H, s), 5.58 (1H, Shir. s), 6.56 (1H, Shir. s), 7.20-7.39 (5H, m).

a) 2-(2-penilties)ethanamine hydrochloride

The connection header in the form of a salt of hydrochloric acid (6.0 g) receive, in accordance with the method of Example 5, step (C) using 2-(2-penilties)ndimethylacetamide (5.5 g), solution balancetransfer (1.0 M in THF, 60 ml) and tetrahydrofuran (60 ml).

d) Methyl 3-[2-(2-penilties)ethylaminomethyl]propanoate

The connection header (2.85 g) receive, in accordance with the method of Example 5, step (g) using 2-(2 - penilties)ethanamine hydrochloride (6. 348 (M+105).

e) 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N-[2-(2-penilties)ethyl]propanesulfinamide hydrochloride

The connection header (0.106 g) receive, in accordance with the method of Example 8, step (d) using methyl 3-[2- (2-penilties)ethylaminomethyl] propanoate (1.4 g), diisobutylaluminium (1.5 M solution in toluene, 3 ml), 7-(2-amino-ethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrochloride (1.2 g) and cyanoborohydride sodium (0.3 r).

So pl. 193-194oC;

Mass spectrum: FAB 512 (M+H);

1H NMR (360 MHz, d6DMSO) : 2.06 (2H, m), 2.85 (2H, m), 3.08 (6H, m), 3.15 (4H, m), 3.46 (2H, t), 3.59 (2H, t), 6.76 (1H, d), 7.19 (1H, m), 7.31-7.36 (4H, m), 9.06 (2H, s), 10.17 (1H, s), 11.78 (1H, Shir. C.).

Pharmacological example

The affinity of binding of the compounds of the examples above, the binding sites DA2receptors on the membranes of the pituitary gland of the ox is determined by the displacement of [3H] -N-n-propylnorapomorphine and [3H]-spiperone, respectively, in the presence or in the absence of neytralinogo analogue of GTP, D. R. Sibley, A. DeLean and I. Creese, Anterior Pituitaru Dopamione Receptors, Demonstration of Interconvertible High and Low Affinity States of the D-2 Dopamine Receptor, J. Biol. Chem., 1982, 257(11), 6351-6361.

Activity against DA2receptors demonstrate functional study understands that the research Institute2-adrenergic receptors has been shown in the isolated trachea of the Guinea pig, as described I. G. Dougall, D. Harper., D. M. Jackson and P. Leff, Br. J. Pharmacol., 1991, 104, 1057.

Activity against1receptors determined on isolated ear artery of the rabbit in the following way.

Isolated ear artery of the rabbit

Rabbits male NZW (2.5-3 kg) hammer intravenous injection pentobarbitone sodium (60 mg/kg). The ears are removed, the proximal part of the middle ear artery is isolated and introduced into it the cannula, using polypropylene cannula (outer diameter 0.75 mm). After removal of artery is cleaned from the adjacent connective tissue and dissect, receiving 6 rings width of 5 mm with retaining layer of circular smooth muscles. Tissue is placed on a thin hooks made of tungsten wire (diameter 0.25 mm) in 20 ml bath for bodies with Krebs solution of the following composition (mm): NaCl 117.56; NaHCO325.00; KCl 5.36; NaH2PO40.89; MgSO41.18; glucose 11.10 and CaCl22.55. The solution also include cocaine (30 μm) and propranolol (1 μm) to block neural capture and receptors, respectively. To prevent oxidation of the catecholamine also add ascorbate (100 μm). The temperature of this solution support is connected to a force sensor offset, Ormed, the lower hook is connected with a fixed substrate in the bath. Changes in isometric force recorded using Advance Bryans AB500 horizontal planar chart recorder.

Experimental part

General description

At the beginning of any experiment to each piece of cloth put a load of 1.0, Such a load is applied again two or three times during the stabilization period of approximately 60 min until then, until it becomes constant. At the same time, when you reinstall the load, bath wash. Curves the concentration-effect (E/[A] ) is built using the cumulative addition of the agonist in increments of 0.5 log10. Reaction (reduction) register as a percentage of the maximum response when using the standard agonist.

Quantitative determination of agonistic action

As standard agonist use phenylephrine. First build the curve E/[A] to phenylephrine. Then phenylephrine washed and build a curve E/[A] to test the connection. The reaction of compounds that cause agonism, expressed in percent of the maximum response to phenylephrine. The value of the asymptotes of the curve of the tested compounds unanimous 1).

The value of p[A50] is a measure of the activity (strength) agonist. It is the negative logarithm of the concentration of agonist causing half maximal response. For compounds whose activity is much smaller than 1, for example, 0.8, it is possible to calculate the efficiency values () and values of affinity (pKAusing the comparative analysis method. In this analysis it is assumed that the phenylephrine acts as a full agonist in this system, and therefore, it is used to determine the operating model parameters Emand n (Leff, et al., "Estimation of agonist affinity and efficacy by direct and operational model fitting. , " J. Pharmacol. Methods., 1989, 23, 225- 237). These parameters can then be used for comparative analysis of the tested compounds. Affinity is expressed as the pKA(the negative logarithm of the concentration of agonist, sufficient to take half of the receptors).

Quantitative determination of the antagonistic action

Compounds that did not show itself as agonists, researched antagonistic activity, incubare tissues with the highest concentrations of this compound, with the subsequent construction of curves E/[A] Veniaminovich curves. The degree of shift of the rotary test connection. This assessment affinity is expressed as the values pA2(the negative logarithm of this concentration of antagonist which gives twice the right shift control E/[A] curve).

Confirmation 1-mediated agonism

Prazosin was adopted as the standard 1antagonist. If under these conditions the test connection shows agonism, then when reaching asymptotes of the curve E/[A] test compounds add prazosin (1 μm) in order to check whether this reaction is reversible. If1antagonist eliminates the response to the test compound, then this implies that agonism is mediated1.

Activity

The table below includes data on agonistic activity2-adrenergic receptors and DA2-dopamine receptor of compounds 1-9 application.

Activity2-adrenergic receptors is illustrated in the study described Dougall et al. in Br.J.Pharmacol., 1991, 104, 1057 (see accompanying test page 11, lines 21-23 WO 97/10227). In this study, to obtain quantitative data on activity2-adrenoreceptor using isolated Guinea-pig trachea that contains2-adrenalize the izoprenalin, which is a full agonist of this system.

Agonistic concentration curves-action receive as a result of cumulatively adding the compounds to the preparation of the isolated trachea of the Guinea pig, and the answers are written as percentages of the response izoprenalin.

The value of pA50which is a measure of the effectiveness of agonist, is defined as the negative logarithm of the concentration of agonist that causes the response, which is the half of the maximum response.

If the investigational compound causes the relaxation of smooth muscles, may be specified by its true activity. The true activity is a response caused by the investigational compound, divided by the maximum response induced by izoprenalin.

The value of pA50and the true activity of each compound of examples are presented in the table below.

The activity of the receptor dopamine (DA2illustrated in a study described by Brown et al. in Br.J.Pharmacol., 1981, 73, 189P (see text corresponding to page 11, lines 19-21 WO 97/10227) and used as control compounds identified as "58075AB". Value pA50and the true activity of each is tx2">

As clearly shown by the data from the table, the compounds in accordance with this invention demonstrate good agonism against2-adrenergic receptors and DA2-dopamine receptor, providing a high applicability of these compounds in the treatment of respiratory diseases.

1. Connection benzothiazolone formula I

< / BR>
characterized in that

X represents-SO2NH - or-NHSO2-;

p, q and r independently of one another represent 2 or 3;

Y represents thienyl, optionally substituted C1-6by alkyl or halogen, or phenylthio or phenyl, optionally substituted C1-6by alkyl or halogen;

each R independently represents H or C1-6alkyl, its optical isomers and pharmaceutically acceptable salts.

2. Connection benzothiazolone under item 1, characterized in that q = 2.

3. Connection benzothiazolone under item 1, characterized in that r = 2.

4. Connection benzothiazolone under item 1, wherein Y is phenyl, substituted stands.

5. Connection benzothiazolone under item 1, wherein Y is phenyl, substituted by halogen selected from chlorine or fluorine.

6. Connection Bettona under item 1, characterized in that X = NHSO2and each of p, q and r = 2.

8. Connection benzothiazolone according to any one of the preceding paragraphs, characterized in that it is in the form of pharmaceutically acceptable salts are selected from salts of hydrochloride, citrate, D,L-lactate, polysulfate, polytetra, D-gluconate, methanesulfonate, p-toluensulfonate, profumata, benzoate, xinafoate, polyacrylate, 3-hydroxy-2-naphthoate, pouembout, premalatha, D-camphorsulfonate, 10-undecanoate, mandelate, naphthalen-1-sulfonate, naphthalen-2-sulfonate, 4-methoxybenzoate, 4-chlorobenzoate, 5-methyl salicylate, saharinata, monomethylfumarate, polusmerti and diphenylacetate.

9. Connection benzothiazolone under item 1, characterized in that it is chosen from the following compounds:

2-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N-[2-(2-phenylethane)ethyl]propanesulfonate;

N-[2-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)-ethylamino] ethyl]-2-(2-phenylethane)econsultant;

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N-[2-[2-(5-methyl-2-thienyl)ethoxy]ethyl]propanesulfonate;

N-[2-[2-(4-forfinal)ethoxy] ethyl] -3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]propanesulfonate;

N-[2-[2-(4-chlorophenyl)ethoxy] ethyl] -3-[2-(-7-Il)ethylamino]-N-[2-[-(4-were)ethoxy]ethyl]propanesulfonate;

(R, S)-3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-(2-phenyl-1-propoxy)ethyl]propanesulfonate;

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N-[2-[2-(2-were)ethoxy]ethyl]propanesulfonate; and

3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N[2-(2-penilties)ethyl]propanesulfonate.

10. Connection benzothiazolone under item 9, characterized in that it is in the form of hydrochloride salt.

11. The method of obtaining compounds of benzothiazolone formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 10, characterized in that the implement selective reductive alkylation of compounds of formula II

< / BR>
the compound of the formula III

< / BR>
in which p, q, r, R, X and Y have the values listed in paragraph 1, in the presence of a reducing agent.

12. The method of obtaining compounds of benzothiazolone formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 10, characterized in that conduct selective reduction of a compound of formula IV

< / BR>
in which p, q, r, R, X and Y have the values listed in paragraph 1.

13. Amide of formula IV

< / BR>
in which p, q, r, R, X and Y have the values listed in paragraph 1.

14. The aldehyde of formula III

< / BR>
in to the Y have the meanings specified in paragraph 1.

16. The pharmaceutical composition exhibiting agonistic activity against DA2receptors and2-intereception, including the connection of benzothiazolone formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1 - 10, dispergirovannoyj in the propellant, optionally containing fillers, lubricating agents or stabilizers.

17. The pharmaceutical composition exhibiting agonistic activity against DA2receptors and adrenergic receptors and including the connection of benzothiazolone formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 10, in the form of a sprayable aqueous slurry or solution.

18. The pharmaceutical composition exhibiting agonistic activity against DA2receptors and2-adrenoreceptor and including the connection of benzothiazolone formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 10, in the form of a dry powder for inhalation, optionally including a pharmaceutically acceptable carrier.

Priority points and features:

15.09.1995 under item 1, where X represents-SO2NH - or-NHSO2; p, q, r independently of one another represent 2 or 3; Y represents f is 4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N-[2-(2-phenylethane]ethyl]propanesulfonate; N-[2-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] ethyl]-2-(2-phenylethane)econsultant; 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(5-methyl-2-thienyl)ethoxy]ethyl]propanesulfonate;

on PP.2 - 8, 11 - 18;

10.07.1996 under item 1, where Y represents phenylthio, optionally substituted C1-6by alkyl;

under item 9, where connections are: N-[2-[2-(4-forfinal)ethoxy] ethyl]-3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]propanesulfonate; N-[2-[2-(4-chlorophenyl)ethoxy]ethyl]-3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] propanesulfonate; 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N-[2-(2-phenylethane)ethyl]propanesulfonate; (R,S)-3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-(2-phenyl-1-propoxy)ethyl] propanesulfonate; 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N[2-[2-(2-were)ethoxy]ethyl]propanesulfonate; 3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino] -N[2-(2-penilties)ethyl]propanesulfonate;

on p. 10;

12.09.1996 under item 1, where Y represents thienyl, optionally substituted C1-6by alkyl or halogen.

 

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< / BR>
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