Derivatives of 7-(2-amino-ethyl)benzothiazolone or their pharmaceutically acceptable salts, methods for their preparation, derivatives of n-[2-(4-hydroxy-2-oxo-3h-1,3-benzothiazol-7-yl) ethylamide]the pharmaceutical composition exhibiting agonistic activity against2-adrenoreceptor

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds exhibiting agonistic activity against2-adrenergic receptors. The essence of the invention: derivatives of 7-(2-amino-ethyl)benzothiazolone formula I

< / BR>
where X and Y independently denote-S(O)n- or-O-, n means 0,1 or 2, p, q and r independently denote 2 or 3, Z denotes phenyl, with the possible substitution by halogen, -OR1, NO2or NH2or Z represents a 5 - or 6-membered unsaturated heterocycle containing N or S, R1means hydrogen or alkyl (C1- C6or their pharmaceutically acceptable salts. Describes the methods for their preparation and the pharmaceutical compositions, as well as intermediate compounds for their receipt of the formula Va

< / BR>
where p, q and r, X, Y have the above meanings and Z is phenyl, optionally substituted by a halogen atom, NO2, NH2or or1where R1- H or C1- C6-alkyl. 4 C. and 7 C.p. f-crystals, 3 tables.

The invention relates to new compounds, methods for their preparation and pharmaceutical preparations, in which they enter and treatment options, based on their use.

In international patents and their activity as agonists2-adrenergic receptors and agonists of dopamine DA2.

Open group derived from 7-(2-amino-ethyl)-benzothiazolone, with considerable advantages over the known substances.

In accordance with the invention proposed compounds of General formula I

< / BR>
where

X and Y independently of one another denote-S(O)nor-O-,

n means 0, 1 or 2,

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

Z signifies phenyl, with the possible substitution by halogen, -OR1, -NO2or NR2R3or represents 5 - or 6 - membered heterocycle containing n, O or S, and R1, R2and R3independently from each other denote hydrogen or alkyl (C1-C6and farmatsevticheskii acceptable derivatives.

In addition, in accordance with the invention, a method for producing compounds of General formula I and their pharmaceutically acceptable derivatives, including:

a) alkylation of compounds of formula II, or its derivative

III

using alkylating compounds of General formula III,

L-(CH2)p-X-(CH2)q-Y-(CH2)r-Z

where

p, q, r, X, Y and Z have the above knowledge is soedineniya General formula IV

O=CH-(CH2)p-1-X-(CH2)q-Y-(CH2)-Z IV

where

p, q, r, X, Y and Z have the above meanings, in the presence of a reducing agent,

c) selective recovery of compounds of General formula V

< / BR>
where

p, q, X, Y and Z have the above values,

d) selective recovery of compounds of General formula Va,

< / BR>
where

p, q, r, X, Y and Z have the above values,

e) removing the protective group of the corresponding protected compounds of General formula I, in which is secured one or more functional groups, and if desired or necessary, converting the compounds of General formula I in a pharmaceutically acceptable derivative, or Vice versa.

At the step (a) ad hoc group, L represents either halogenlampe, for example chloride, bromide or iodide, or alkyl or arylsulfonate, such as methanesulfonamido or p-toluensulfonate. The reaction in the preferred case is carried out in the presence of a base, for example, inorganic bases such as sodium or potassium carbonate, or organic bases such as triethylamine, N,N-diisopropylethylamine or pyridine. The reaction is more conveniently carried out in a solvent tone; in amide with the substitution, for example in dimethylformamide, or in a chlorinated hydrocarbon, for example chloroform, at a temperature ranging from ambient temperature to the temperature of distillation of the solvent.

Alkylating a compound of General formula III can be obtained from the corresponding alcohol (i.e., compounds in which L is OH) by known methods. For example, the alcohol can be subjected to reaction with a halogenation agent, resulting in a compound of General formula III, where L is a halogen atom to an acceptable halogenation tools include, for example, triphenylphosphine-Tetrachloromethane additives (easy to get them in place, for example, by reaction of triphenylphosphine with tetrabromide carbon). The reaction can be carried out in the presence of a solvent, such as acetonitrile or a chlorinated hydrocarbon, for example dichloromethane, at a temperature of 0 - 30oC.

In step b) a reducing agent may be hydrogen in the presence of a catalyst, such as platinum, platinum oxide, palladium, palladium oxide, Raney Nickel or rhodium, on the basis of activated charcoal. As a solvent used alcohol, for example ethanol; esters such as ethyl acetate; plenumi or elevated. In addition, as a reducing agent can be used hydride such as DIBORANE or a metal hydride, for example sodium borohydride, sodium lambrogini or lithium-aluminum hydride. Selection of the solvent for this reaction depends on what hydride serves as a reducing agent; a solvent chosen from alcohols (methanol or ethanol) and ethers (diethyl ether, t-butyl methyl ether or tetrahydrofuran).

Alkylation with compounds of General formula IV can lead to the formation of the intermediate imine, the recovery of which the described conditions gives compound of General formula I.

The compounds of formula II and the General formula IV and the alcohols of General formula III are either known or can be obtained by known methods.

At stages c) and d) the reaction can be performed using traditional methods of recovery. The reducing agent may be electrophilic (e.g., DIBORANE) or nucleophilic (for example, a complex metal hydride such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride). In the preferred case of using a solvent in which the reaction conditions is inert. Preferred are appreticeship rasatura 0 - 100oC.

Compounds of General formula V and the General formula Va can be obtained by combining an amine with an acid or acid chloride by standard methods. For example, the connection is carried out in the presence of dicyclohexylcarbodiimide by way of Sigana and Hess (Sheehan and Hess, J. Am. Chem. Soc., 1955, 77, 1067) or 1,1-dicarbonitriles, as described in Staab (Staab, Angew. Chem. Int. Ed. Endl. , 1962, 1, 351). Amines necessary for carrying out this reaction, any known or can be obtained by known methods, for example as described in J. Med.Chem., 1987, 30, 1166.

Intermediate compounds of General formula Va are new, thus according to one aspect of the invention provides compounds of General formula Va

< / BR>
where

p, q, r, X, Y and Z have the above values.

The rest of the details of obtaining compounds of General formula I listed in the examples.

When carrying out the above processes may be necessary to protect functional groups in starting materials, for example, hydroxy - or amino groups, therefore, at the step e) may need to remove one or more protective groups. Acceptable protective groups and methods for their removal are described, for example, in "Protective Groups in Organic Synthesis", T the mi as phenylmethyl, diphenylmethyl or triphenylmethyl or derivatives tetragidrofurane.

Eligible groups for protecting amino groups include arylmethyl, such as benzyl, (R, S)- phenylethyl, diphenylmethyl, triphenylmethyl, and atilov: acetyl, trichloroacetyl or TRIFLUOROACETYL. You can use traditional methods of removing the protection. Allotrope group is removed, for example, by hydrogenolysis in the presence of a metal catalyst, for example palladium on charcoal. Tetrahydropyranyloxy groups were cleaved by hydrolysis in an acidic environment. Allowee group is removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, and groups such as trichloroacetyl, is removed by recovery, for example, zinc or acetic acid.

To pharmaceutically acceptable derivatives of compounds of General formula I include their pharmaceutically acceptable salts, esters and amides.

Suitable pharmaceutically acceptable salts of the compounds of General formula I include salts of organic and inorganic acids: hydrochloride, hydrobromide, sulfates, phosphates, maleate, tartratami, citrates, benzoate, 4-methoxybenzoate, 2 - or 4-hydroxybenzoate, 4-chlorobenzoate, benzols, diphenylacetate, trimeniaceae, adipate, fumarate, succinate, lactates, glutarate, gluconate, hydroxyethylmethacrylate, for example 1-hydroxy or 3-hydroxy-2-naphthaleneacetic or oleates. The aforementioned compounds can also form a salt with some reason. Such salts include salts of alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium. Compounds of General formula I can be obtained in the form of salts, including in the form of pharmaceutically acceptable salts. If necessary, these salts can be converted to the free base by conventional procedures. Pharmaceutically acceptable salt get in the reaction of compounds of General formula I with the appropriate acid or base in the presence of an appropriate solvent.

Suitable pharmaceutically acceptable esters of compounds of General formula I are alkyl (C1-C6-esters, such as ethyl ether. The esters can be obtained by conventional methods, for example by esterification or TRANS-esterification.

Suitable Amida are unsubstituted, and one - or disubstituted alkyl, C1-C6or phenylamide, her acid with ammonia or an appropriate amine.

The compounds of General formula I is characteristic of tautomery, they can also contain one or more asymmetric carbon, which involves optical and/or diastereomeric. The diastereomers separated by conventional methods, for example by chromatography or crystallization fractions. Various optical isomers produce by separation of racemic or other mixture of the compounds using conventional techniques, for example, crystallization fractions or liquid chromatography high pressure. On the other hand, the desired optical isomers receive as a result of the reaction between the starting materials with appropriate optical activity under conditions which do not cause racemization.

The term "alkyl" refers to straight, branched or cyclic saturated and unsaturated alkalemia group.

If Z denotes phenyl, containing as a substituent a halogen, -OR1, -NO2or-NR2R3we prefer that this Deputy was only one. The phenyl may be attached to the group -(CH2)p-X-(CH2)q-Y-(CH2)rin ortho-, meta - or paraprotein, but preferred are ortho - and paranil. However, we prefer compounds of General formula I in which Y represents phenyl.

Halogen-free, which might appear, is chlorine, bromine and fluorine. We prefer compounds of General formula I, in which Z denotes phenyl.

Preferred compounds of General formula I, in which at least one of the letters X and Y represents-O-.

Preferred compounds of General formula I, in which r is 2.

Preferred compounds of General formula I, in which p+q is equal to 5.

Groups, denoted by -(CH2)p-X-(CH2)q-Y-(CH2)rinclude the following:

-(CH2)3-S-(CH2)2-O-(CH2)2-

-(CH2)3-SO2-(CH2)2-O-(CH2)2-

-(CH2)3-O-(CH2)2-O-(CH2)2-

-(CH2)2-O-(CH2)3-O-(CH2)2-

-(CH2)2-O-(CH2)2-O-(CH2)2-

-(CH2)2-SO2-(CH2)3-O-(CH2)2< / BR>
-(CH2)2-S-(CH2)3-O-(CH2)2-

Compounds of General formula I useful to their pharmacological effects on animals. In particular, these compounds are agonists2and the I. G. Dougall, D. Harper, D. M. Jackson, P. Leff, Br. J. Pharmacol, 1991, 104, 1057. These compounds are agonists of dopamine DA2. The affinity of the test compounds to the binding sites DA2in the membranes of bovine pituitary gland can be determined by displacement of [3H]-N-n-propylnorapomorphine and [3H]-spiperone in the presence or in the absence of neytralinogo analogue guanosine-5'-triphosphate, respectively, as described in D. R. Sibley, A. DeLean, I. Creese, Anterior Pituitary Dopamine Receptors, Demonstration of Interconvertible High and Low Affinity States of the D-2 Dopamine Receptor, J. Biol. Chem, 1982, 257 (11), 6351-6361. Activity type DA2you can also demonstrate the functional screen, isolated ear artery of the rabbit, as described in Brown and O'connor, Br. J. Pharmacol., 1981, 73, 189P. In addition, these compounds give a good ratio of activity of DA2:2.

Compounds of General formula I are indicated for use in the treatment of several conditions known as reversible obstructive airway disease. Specialists expression "reversible obstructive airway disease should be well understood. It implies asthma, including bronchial asthma, allergic asthma, hereditary, acquired, dust asthma, particularly chronic or zastarela is of britanii N 2022078 and Br. J. Pharmacol, 1987, 24, 4983). Of particular interest is asthma. The term "treatment" herein is meant a prevention and relief of symptoms.

Thus, in accordance with one aspect of the invention proposes a method of prevention and treatment of reversible obstructive Airways disease, involving the administration to a patient suffering from the said disease or are sensitive to it, therapeutically effective amounts of compounds of General formula I or its pharmaceutically acceptable derivative.

Compounds of General formula I is also indicated for use for the treatment of various other conditions, such as inflammatory and allergic skin diseases, congestive heart failure and glaucoma.

When used in the above-mentioned purposes doses mentioned compounds depend on the composition of the used compound, the route of administration and expected result. However, as a rule, a satisfactory result can be achieved by applying a compound of General formula I, in a daily dose of about 1 μg to about 20 mg per 1 kg body weight of the animal, preferably in several stages 1-4 times a day or in a manner that provides long the form f, easy to use, contain 20 mcg - 1400 mg of the compound in a mixture with solid or liquid pharmaceutical diluent or carrier.

Compounds of General formula I can be used in pure form or in the composition of the corresponding pharmaceutical preparations topically, orally or parenterally.

Compositions, convenient for local application on the lungs include aerosols, such as powdered compositions in the package under pressure and without pressure; compositions suitable for oral administration include tablets, capsules and pills; compositions suitable for application to the skin, apply creams, for example, emulsions of the type oil-in-water or water-in-oil; compositions suitable for intravenous administration include injections and infusions; compositions, suitable for use on the eyes, apply drops and ointments.

In accordance with the invention also features a pharmaceutical preparation containing preferably not more than 80%, and more preferably not more than 50% by weight of compounds of General formula I, or its pharmaceutically acceptable derivative in a mixture with a pharmaceutically acceptable diluent or carrier.

Examples of such diluents and carriers are: for tablets and dragee - l is x parenteral, water, alcohols, glycerin, vegetable oil.

If a compound of General formula 1 is applied to the lungs, it can be inhaled in the form of powder, supplied under pressure and without pressure. Feeding powdered compounds of General formula 1 under pressure by compressed or liquefied gas. If the powder is fed without pressure, the finely ground active ingredient can be mixed with larger particles of the pharmaceutically acceptable carrier having a diameter of, for example, up to 100 μm. Suitable inert carriers include, for example, crystalline lactose.

Compounds of General formula 1 have the following in comparison with the known substances of similar composition: they are less toxic, more effective, are longer, have a broader range of actions are more powerful, fewer side effects, more easily absorbed and have other useful pharmacological properties.

The present invention can be illustrated by, but not limited to, the following examples, in which the temperature is measured in degrees Celsius. The reaction is conducted in an inert nitrogen or argon atmosphere. The selection of substances Prov is CLASS="ptx2">

Example 1. 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl]1,3-benzothiazol-2(3H)-she hydrochloride.

a) 3-[2-[2-Phenylethane]ethylthio]propanoic acid.

A solution of 2-[2-phenylethane]ethanthiol(2,13 g) in dry dimethylformamide (10 ml) was added dropwise to a cooled (0oC) stirred suspension of sodium hydride (0,60 g, 80% in oil) in dimethylformamide (DMF) (50 ml). The mixture was stirred at 0oC for 90 minutes Then dropwise added a solution of 3-bromopropane acid (3.15 g) in dry DMF (10 ml) and the reaction mixture was stirred at room temperature for 16 hours was Added water (250 ml) and the mixture was acidified to pH 2/3 using concentrated hydrochloric acid. Then the aqueous solution was extracted several times with ether and the combined ether layers were washed with water and brine, dried (MgSo4) and evaporated under reduced pressure. Obtained crude acid which was purified by chromatography on silica gel with a sharp pressure decrease with dichloromethane : ether in a ratio of 6 : 1 (1 drop of acetic acid/100 ml of eluent). Got mentioned in the subtitle compound (2.15 g).

1H-NMR (CDCl3) : 2,6 - 2,8 (m, 4H), of 2.81 (t, 2H), 2,89 (t, 2H), 3,6 is 3.76 (m, 4H), of 7.2 to 7.4 (m, 5H).

b) 3[2-[2SUP>) in water (50 ml) was added dropwise to a cooled (0oC) the solution of the substance obtained in step (a) (2.15 g) in methanol (50 ml). When the addition was complete, the ice bath was removed and stirred the reaction mixture at room temperature for 4 h and Then poured into water and three times was extracted with chloroform. The organic extracts were combined, washed with water, dried (MgSO4) and evaporated under reduced pressure, obtaining mentioned in the subtitle compound as a white solid (1,91 g, 79%).

Mass spectrum: derived El TMS 343 [(M-15)+];

1H-NMR (CDCl3) : was 2.76 (t, 2H), 2.91 in (t, 2H), 3,19 (m, 4H), and 3.72 (t, 2H), 3,86 (t, 2H), 7,15 - to 7.3 (m, 5H).

c) N-[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl]-3[2-[2 - phenylethane] ethylsulfanyl]propanamide.

To a stirred solution of 7-[2-amino-ethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrobromide (1,62 g) and substances obtained in stage b) (1.75 g) in DMF (25 ml) was added triethylamine (0,70 ml), 1-hydroxybenzotriazole hydrate (0,98 g) and, finally, dicyclohexylcarbodiimide (1,49 g). All this was stirred at room temperature for 16 hours was Added glacial acetic acid (0.1 ml) and stirred for another 15 minutes DMF was Removed under reduced pressure and the residue was diluted with ethyl acetate (50 ml). TOD is an atom, and dried (MgSO4). The solvent was removed under reduced pressure and the obtained residue was purified by chromatography column on silica gel with dichloromethane : ethanol in a ratio of 95 : 5. Have a substance specified in the subtitle (1.89 g, 71%).

So pl. 142 - 144oC.

Mass spectrum: FAB + ve 479 [(M+H)+];

1H-NMR (DMCO-d6) : 2,50 (m, 2H), 2,61 (t, 2H), of 2.81 (t, 2H), 3,2 - 3,4 (brm, 6H+D2O) to 3.64 (t, 2H, in), 3.75 (t, 2H), 6,70 (d, 1H), 6,80 (d, 1H), 7,15 - 7,30 (m, 5H), 8,14 (t, 1H), 10.0 g (brs, 1H), and 11.5 (s, 1H).

Analysis: found, %: C 55,03; H of 5.55; N 5,90; S 13,07.

C22H26N2O6S2< / BR>
Calculated, %: C 55,21; H 5,48; N 5,85; S 13,39.

d) 4-Hydroxy-7-[2-[3-[2-[2-phenylethane] ethylsulfanyl]Propylamine]ethyl] -1,3-benzothiazol-2-(3H)-she hydrochloride.

A solution of borane in tetrahydrofuran (1.0 M in THF, 15 ml) was added dropwise to a stirred solution of the product of step c) from 2.06 g) in dry tetrahydrofuran (100 ml). The reaction mixture was subjected to boiling in an inert atmosphere in the flask with reflux until thin layer chromatography showed that the source material anymore. The reaction mixture is cooled and added methanol (3.5 ml, CAUTION!). Then boiled in a flask with reflux condenser for 30 minutes the Solvents were removed when the item is. 1,18, 0.75 ml). It all boiled in a flask with reflux condenser for 30 minutes After cooling and removal under reduced pressure, methanol was obtained oily residue, which, after tretirovanie ether gave crude compound indicated in the title, in the form of a pale yellow solid. Portions indicated in the title compound was purified by preparatory reverse-phase liquid chromatography with methanol and 0.1% triperoxonane acid as eluent. And, finally, obtaining the hydrochloride by dissolving in a small amount of ethanol and processing of dry ether hydrochloric acid, followed by removal of solvents gave named the title compound as a white powder.

So pl. 201 - 203oC.

Mass spectrum: FAB + ve 465 [(M+H)+];

1H-NMR (DMCO-d6) : a 2.01 (m, 2H), 2,80 (m, 4H), 2,98 (brs, 2H), 3,10 (t, 4H), to 3.36 (t, 2h), 3,66 (t, 2H), of 3.77 (t, 2H), 6,77 (d, 1H), to 6.88 (d, 1H), 7,2 - to 7.35 (m, 5H), 8,98 (brs, 2H), 10,13 (brs, 1H), 11,77 (s, 1H).

Analysis: found, %: C 52,31; H of 5.85; N, 5,54; S 12,54; Cl of 7.48.

C22H28N2O5S2.HCl

Calculated,%: C 52,73; H Of 5.83; N 5,90; S 12,79; Cl 7,08.

Example 2. 4-hydroxy-7-[2-[2-[3-[2-phenylethane]propoxy]ethylamine]ethyl] -1,3-benzothiazole -2(3H)-she hydrochloride.

and) 2-[3-[2-�Boo, described in example 1A), using 3-[2-phenylethane]propanol (prepared from 2-phenylmethyl-1,3-dioxane according to the method described in Can. J. Chem., 1974, 52, 888).

1H-NMR(CDCl3) 1,89 (m, 2H), 2,90 (q, 2H), 3,49-of 3.60 (m, 6H), of 4.05 (s, 2H), 7,21-7,30 (m, 5H).

b) N-[2-[4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]-2-[3-[2-phenylethane] propoxy]ndimethylacetamide.

Specified in the subtitle compound was prepared according to the method described in example 1 (C).

So pl. 150 - 151oC.

Mass spectrum: FAB + ve 431[(M+H)+];

1H-NMR (DMCO-d6) : of 1.73 (m, 2H), 2.63 in (t, 2H), and 2.79 (t, 2H), 3,2-3,4 (brm, 6H+D2O) of 3.54 (t, 2H), 3,76 (brs, 2H), 6,69 (d, 1H), 6,79 (d, 1H), 7,16-7,29 (m, 5H), to 8.12 (t, 1H), 9,92 (s, 1H), of 11.61 (s, 1H).

Analysis: found, %: C 60,90; H of 6.02; N 6,40; S 6,91.

C22H26N2O5S

Calculated,%: C 61,37; H 6,09; N 6,51; S 7,45.

C) 4-Hydroxy-7-[2-[2-[3-[2-phenylethane] propoxy] ethylamine]ethyl]-1,3-benzothiazole -2(3H)-she hydrochloride.

Specified in the title compound was prepared according to the method described in example 1d).

So pl. 159 - 160oC.

Mass spectrum: FAB + ve 417 [(M+H)+;

1H-NMR (DMCO-d6) : of 1.75 (t, 2H), and 2.79 (t, 2H), 2,87 (t, 2H), 3,12 (m, 4H), of 3.45 (m, 4H+D2O) to 3.58 (m, 4H), 6,77 (d, 1H), 6,85 (d, 1H), 7.18 in-7,27 (m, 5H), 8,99 (brs, 2H), 10,16 (s, 1H), and 11.8 (brs, 1H)

Analysis: Nai is l 7,83.

Example 3. 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethoxy]Propylamine]ethyl] -1,3-benzothiazol-2 (3H)-she hydrochloride.

and) 3-[2-[-2-Phenylethane]ethoxy]propanenitrile.

A mixture of 3-(2-phenylethane) ethanol (8.0 g, prepared from 2-phenylmethyl 1,3-dioxolane according to the method described in Can. J. Chem., 1974, 52, 888), 3-bromopropionitrile (5.6 ml), sodium hydroxide (50 g) and tetrabutylammonium chloride (0.5 g) in dichloromethane (100 ml) and water (100 ml) was stirred at room temperature for 72 h the Mixture was diluted with water and separated the organic layer. The aqueous layer was extracted with a new portion of dichloromethane. The combined organic extracts washed with diluted aqueous hydrochloric acid and water, dried (MgSO4) and evaporated under reduced pressure. Got a crude product. The substance was purified by chromatography on silica gel with a sharp pressure decrease with ether : petroleum ether (so Kip. 60 - 80oC) in a ratio of 1 : 1 as eluent. Got mentioned in the subtitle compound as oil (9,84 g, 90%).

Mass spectrum: EI 219 (M+;

1H-NMR (CDCl3) to 2.55 (t, 2H), 2,90 (t, 2H), 3,61-3,74 (m, 8H), 7,18 and 7.36 (m, 5H).

b) 3-[2-[2-Phenylethane]ethoxy]propanal.

Diisobutylaluminum hydride (3.3 ml, 1.5 M in toluene) was added(step a)) in tetrahydrofuran. After 30 min the mixture was heated to room temperature and stirred 2 hours Carefully added water and 10% aqueous hydrochloric acid and stirred for another 5 minutes, the Reaction mixture was extracted several times with ether, the ether extracts combined, washed with saturated aqueous solution of sodium bicarbonate and brine, dried (MgSO4), was evaporated under reduced pressure and got mentioned in the subtitle compound as a yellow oil, which without purification was passed on to the next step.

c) 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethoxy]Propylamine]ethyl]-1,3-benzothiazol-2 (3H)-she hydrochloride.

Sodium cyanoborohydride (of 0.333 g) was added to a stirred solution of 3-[2-[2-phenylethane]ethoxy]propanal (stage b)) (2.2 g), 6% aqueous acetic acid (2 ml) and 7-[2 - amino-ethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrobromide (2,05 g) in methanol (180 ml). The reaction mixture was stirred 2 h at room temperature and by this time the chromatographic analysis showed that all starting material had been consumed. The reaction mixture was parselocale using concentrated ammonium hydroxide solution in water, removed the methanol under reduced pressure and the obtained crude product. Chromatographic purification of silica gel with constituent pressure from 0.1% water triperoxonane acid in methanol as eluent and cooking salt is hydrochloride gave specified in the title compound as a white solid.

So pl. 186 - 190oC.

Mass spectrum: FAB + ve 417 [(M+H)+];

1H-NMR (DMCO-d6) 1,80-of 1.88 (m, 2H) 2,78-of 2.86 (m, 4H), of 2.97 (t, 2H), to 3.09 (t, 2H), 3.46 in (t, 2H), 3,47-to 3.58 (m, 4H), of 3.60 (t, 2H), 6,76 (d, 1H), to 6.88 (d, 1H), 7,16-7,29 (m, 5H), to 8.70 (brs, 2H), 10,13 (s, 1H), 11,76 (brs, 1H).

Analysis: found,%: C 55,24; H 5,98; N Of 5.92; S 6,36; C of 17.35,

C22H28N2O4S. HCl.1,42 H2O

Calculated,%: C 55,20; H 6,41; N 5,88; S 6,70; Cl 7,41.

Example 4. 4-Hydroxy-7-[2-[2-[2-[2-phenylethane]ethoxy]ethylamine]ethyl]-1,3 - benzothiazol-2(3H)-she hydrochloride.

and) 2-[2-[-2-Phenylethane]ethoxy]acetic acid.

Sodium hydride (60% dispersion in oil, 0,86 g) repeatedly washed with petroleum ether and suspended in tetrahydrofuran (5 ml). To the suspension dropwise added a solution of 2-[2-phenylethane]ethanol (1.5 g prepared from 2-phenylmethyl-1,3-dioxolane according to the method described in Can. J. Chem., 1974, 52, 888) in tetrahydrofuran (10 ml) and the mixture was heated to 55oC for 15 min, and then 2 hours and stirred at room temperature. Added Chloroacetic acid (0.85 grams) in tetrahydrofuran (5 ml) and continued stirring for 17 h at room temperature. The tetrahydrofuran was removed under reduced pressure, and the residue was divided between saturated aqueous sodium bicarbonate, dietro which was extracted with diethyl ether. The organic extracts were washed with saturated salt solution, dried (MgSO4), was evaporated under reduced pressure and the obtained pale-brown oil (1.48 g). Chromatography on silica gel with ether : petroleum ether (so Kip. 60 - 80oC) 1 : 1 as eluent gave specified in the subtitle compound (1.07 g).

1H-NMR (CDCl3) : to 2.94 (t, 2H), 3,49-3,82 (m, 6H), to 4.16 (s, 2H), 7.18 in-7,34 (m, 5H).

b) N-[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl] ethyl] -2-[2- [2-phenylethane]ethyl]ndimethylacetamide.

Specified in the subtitle compound was prepared according to the procedure described in example 1c).

Mass spectrum: FAB + ve 417 [(M+H)+];

1H-NMR (DMCO-d6) : 2,61 (t, 2H), and 2.79 (t, 2H), and 3.31 (m, 6H), of 3.60 (t, 2H), 3,82 (s, 2H), 6,69 (d, 1H), 6,79 (d, 1H), 7,15-7,29 (m, 5H), 7,72 (t, 1H), to 9.91 (brs, 1H), of 11.61 (brs, 1H).

c) 4-Hydroxy-7-[2-[2-[2-[2-phenylethane] ethoxy] ethylamine] ethyl]- 1,3-benzothiazol-2(3H)-she hydrochloride

Specified in the title compound was prepared according to the method described in example 1d).

So pl. 123oC.

Mass spectrum: FAB + ve 403 [(M+H)+];

1H-NMR (DMCO-d6) : 2,78 (t, 2H), 2,85 (t, 2H), to 3.09 (m, 4H), of 3.56 (m, 6H), of 3.65 (t, 2H), 6,77 (d, 1H), 6,83 (d, 1H), 7,08-7,29 (m, 5H), of 9.00 (s, 2H), 10,15 (s, 1H), of 11.69 (s, 1H).

Analysis: found,%: C 56,62; H x 6.15; N To 6.43; Cl 9,40,

C21H

a) 3-Mercaptopropanol.

A solution of thiourea (36 g) in water (100 ml) was mixed with 3-bromopropane (33 ml) and boiled in a flask with reflux for 4 h Then the mixture was allowed to cool slightly and added a 10% aqueous solution of sodium hydroxide (190 ml). The mixture is again boiled in a flask with reflux for 3 h, then allowed it to cool and kept for 17 hours at room temperature. The mixture was acidified to pH 4 using concentrated sulfuric acid and was extracted with diethyl ether. The organic extracts were combined, dried (MgSO4), concentrated under reduced pressure and the obtained crude product as a yellow liquid. Distillation gave the connection specified in the subtitle (14,67 g).

Mass spectrum: EI 92 (M)+;

1H-NMR (CDCl3) : of 1.40 (m, 1H), 1.91 a (m, 3H), 2.63 in (q, 2H, in), 3.75 (t, 2H).

b) 2-Phenylmethyl-1,3-axation.

To a solution of thiol (14,67 g, step a)) in toluene (200 ml) was added p-toluensulfonate acid (1 g) and phenylacetaldehyde (18.3 ml). The reaction mixture was boiled in a flask with reflux condenser, using the unit Dean-stark. When they have collected the required amount of water, the mixture is cooled, washed with saturated sodium bicarbonate, saturated brine and Visu (19,65 g).

Mass spectrum: EI 194 (M)+;

1H-NMR (CDCl3) : of 1.66 (d, 1H), 1,95 (m, 1H), and 2.7 (m, 1H), equal to 2.94 (m, 2H), 3,10 (m, 1H), 3,53 (t, 1H), 4,14 (d, 1H), 4,90 (t, 1H), 6,69-to 7.32 (m, 5H).

c) 3-[2-Phenylethane]propandiol.

Calcium sawdust (3.5 g) was added in several stages to liquid ammonia (500 ml) and all this was intensively stirred for 10 minutes was Added dropwise thioacetal (step b), 10 g) in ether (7 ml) to a dark blue solution. Adding lasted 7 minutes, the Reaction mixture was 2 hours and stirred, then extinguished ammonium chloride until it stopped bubbling. The excess ammonia was evaporated in nitrogen under the hood during the night. The remaining solid was acidified to pH 1 to 2 using 10% aqueous hydrochloric acid and the product was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried (MgSO4), concentrated under reduced pressure and got the connection specified in the subtitle (8,29 g).

Mass spectrum: EI 196 (M)+;

1H-NMR (CDCl3) : of 1.29 (d, 1H), to 1.86 (m, 2H), has 2.56 (q, 2H), 2,87 (t, 2H), 3,49 (t, 2H), to 3.64 (t, 2H), 6,97-7,31 (m, 5H).

d) 2-[3-[2-Phenylethane]propylthio]acetic acid.

Sodium hydride (60%, to 3.38 g) was washed with petroleum ether and suspended in dimethylformamide (5 ml) at 0oC. was Added the - 8oC, and then added dropwise a solution of bromoxynil acid (5,88 g) in dimethylformamide (15 ml). Then, in order to facilitate stirring, was added dimethylformamide (20 ml). After 17 h at room temperature, the dimethylformamide was removed under reduced pressure. The remainder was divided between saturated aqueous sodium bicarbonate and diethyl ether (ether layer removed). The aqueous layer was acidified with hydrochloric acid to pH 1 to 2 and was extracted with diethyl ether. The ether extracts were combined, washed with water and brine, dried (MgSO4and boiled away under reduced pressure. Chromatography of the crude product on silica gel with petroleum ether (so Kip. 60 - 80oC) : ether in the ratio 1 : 1 as eluent gave specified in the subtitle compound (7,10 g).

1H-NMR (CDCl3) : to 1.86 (m, 2H), 2,70 (t, 2H), 2,87 (t, 2H), 3,21 (s, 2H), 3,51 (t, 2H), 3,63 (t, 2H), 7,17-7,30 (m, 5H), 9,74 (s, 1H).

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

Specified in the subtitle compound was prepared according to the method described in example 1c), from 7-[2-amino-ethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrobromide. After chromatography on silica gel with dichloromethane : ethanol in soothe 447 [(M+H)+];

1H-NMR (DMCO-d6) : to 1.70 (m, 2H), 2,65 (t, 2H), to 2.67 (t, 2H), 2,78 (t, 2H), 3,05 (s, 2H), or 3.28 (q, 2H), 3,41 (t, 2H), 3,53 (t, 2H), of 6.71 (d, 1H), 6,83 (d, 1H), 7,15-the 7.43 (m, 5H), with 8.05 (s, 1H), 9,9 (s, 1H), are 11.62 (s, 1H).

f) 4-Hydroxy-7-[2-[2-[3-[2-phenylethane]propylthio]ethylamine]ethyl] -1,3-benzothiazol-2(3H)-she hydrochloride.

Specified in the title substance was prepared as described in example 1d). The crude product was purified by reversed-phase liquid chromatography high pressure methanol in 0.1% aqueous triperoxonane acid as eluent.

So pl. 209 - 211oC

Mass spectrum FAB + ve 433 [(M + H)+];

1H-NMR (DMCO-d6) : is 1.82 (m, 2H)2,62 (m, 4H), 2,87 (m, 4H), of 2.93 (m, 2H), and 3.16 (m, 2H), 3,53 (t, 2H), the 3.65 (t, 2H), 6,83 (d, 1H), 6,94 (d, 1H) 7,26 - 7,37 (m, 5H), of 9.02 (s, 2H), of 10.21 (s, 1H), 11,83(s, 1H).

Analysis: found, %: C 55,36; H 6,35; N 6,12; S 13,30,

C22H28N2O3S2.HCl with excess 0.46 mol H2O

Calculated, %: C 55,36; H 6,32; N By 5.87; S 13,41.

Example 6. 4-Hydroxy-7-[2-[2-[3-[2-phenylethane]propylsulfonyl]ethylamine] ethyl] -1,3-benzothiazol-2(3H)-she hydrochloride.

a) 2-[3-[2-Phenylethane]propylsulfonyl]acetic acid.

Specified in the subtitle compound was prepared from 2-[3-[2 - phenylethane] property] acetic acid (example 5d)) according to the method described in, ,58 (t, 2H) to 3.67 (t, 2H), of 3.97 (s, 2H), 7,00 - the 7.43 (m, 5H), 8,79 (s, 1H).

b) N-[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl] ethyl] -2-[3-[2- phenylethane]propylsulfonyl]ndimethylacetamide.

Specified in the title compound was prepared according to the method described in example 1c). The crude product was purified by chromatography on silica gel with a sharp pressure decrease with dichloromethane-methanol in the ratio 9:1 as eluent.

Mass spectrum: FAB + ve 479 [(M + H)+];

1H-NMR (DMCO-d6) 1,92 (q, 2H), 2,62 (t, 2H), of 2.81 (t,2H), 3.27 to (m, 4H), 3,49 (t, 2H), to 3.58 (t, 2H), Android 4.04 (s, 2H), 6,70 (d, 1H), 6,83 (d, 1H), 7,17-7,29 (m, 5H), of 8.47 (t, 1H), 9,96 (s, 1H), 11,66 (d, 1H).

c) 4-Hydroxy-7-[2-[2-[3-[2-phenylethane]propylsulfonyl]ethylamine] ethyl] -1,3-benzothiazol-2(3H)-she hydrochloride.

Specified in the title substance was prepared as described in example 1d). The crude product was purified by reversed-phase liquid chromatography high pressure methanol in 0.1% aqueous triperoxonane acid as eluent.

So pl. 217 - 220oC.

Mass spectrum: FAB + ve 465 [(M + H)+];

1H-NMR (DMCO-d6) : 1,91 (quin, 2 H), of 2.81 (t, 2H), 2,87 (t, 2H), 3,20 (m, 4H), to 3.34 (t, 2H), 3,51 (t, 2H), 3,57 (q, 4H), 6,77 (d, 1H), 6,86 (d, 1H), 7,17 - 7,31 (m, 5H), 9,27 (s, 2H), 10,15 (s, 1H), 11,77 (s, 1H).

Analysis: found, %: C 52,57; H equal to 6.05; N 5,73; S 12,61 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylthio] Propylamine]ethyl] -1,3-benzothiazol-2(3H)-she hydrochloride.

a) N-[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl] ethyl] -3-[2-[2-phenylethane]ethylthio]propanamide.

Specified in the subtitle of the substance prepared by the method described in example 1c), with the use of the substance from example 1a).

Mass spectrum: FAB + ve 447 [(M + H)+;

1H-NMR (DMCO-d6) : of 2.26 is 2.33 (t, 2H), 2,54 - of 2.72 (m, 6H) 2,75 - and 2.83 (t, 2H), 3,19 of 3.28 (q, 2H), 3,50 - 3,63 (2xt, 4H), of 6.68 (d, 1H), 6,78 (d, 1H), 7,15 - to 7.3 (m, 5H), of 9.89 (s, 1H), 11,60 (brs, 1H).

b) 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylthio]Propylamine] ethyl]-1,3-benzothiazol-2(3H)-she hydrochloride.

Specified in the subtitle compound was prepared as described in example 1d).

So pl. 211 - 213oC.

Mass spectrum: FAB + ve 433 [(M + H)+];

1H-NMR (DMCO-d6) : of 1.85 (m, 2H), 2,59 (t, 2H), 2,65 (t, 2H), of 2.81 (t, 2H), 2,85 (t, 2H) 2,97 (t, 2H), is 3.08 (m, 2H), of 3.56 (t, 2H), 3,61 (t, 2H), 6,76 (d, 1H), 6.87 in (d, 1H), 7,17 - 7,30 (m, 5H), 8,9 (brs, 2H), 10,14 (s, 1H), 11,76 (s, 1H).

Analysis: found, %: C 56,49; H 6,40; N 6,12; S 13,78; Cl 7,98,

C22H28N2O3S2.HCl

Calculated, %: C 56,33; H 6,23; N 5,97; S 13,67; Cl 7,56.

Example 8. 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl]-1,3-benzothiazol-2(3H)-she 4-methylbenzenesulfonate.

a) 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl] -1,3-benzothiazol-2(3H)-it.

So pl. 69 - 70oC.

b) 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl] -1,3-benzothiazol-2(3H)-she 4-methylbenzenesulfonate

The portion of the free base was dissolved in methanol and added one molar equivalent of 4-methylbenzenesulfonic acid. The solution is boiled away under reduced pressure, and the collected solid was recrystallization (methanol/water). Got mentioned in the title compound as white needle crystals.

So pl. 170 - 171oC.

Example 9. 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl]-1,3-benzothiazol-2(3H)-she hemisuccinate.

Specified in the title compound was prepared according to the method described in example 8a) and b), using succinic acid.

So pl. 182 - 183oC, brilliant white plaques (recrystallization from methanol/water).

Example 10. 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl]-1,3-benzothiazol-2(3H)-she is using hexanoic acid.

So pl. 131 - 132oC, white needles (recrystallization from methanol/water).

Example 11. 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl]-1,3-benzothiazol-2(3H)-she tartrate.

Specified in the title compound was prepared according to the method described in example 8a) and b), using tartaric acid.

So pl. 158 - 162oC (recrystallization from methanol/water).

Example 12. 4-Hydroxy-7-[2-[3-[2-[2-phenylethane]ethylsulfanyl] Propylamine]ethyl]-1,3-benzothiazol-2(3H)-it 1-hydroxy-2-aftout (Xinafoate).

Specified in the title compound was prepared according to the method described in example 8a) and b), using 1-hydroxy-2-Naftowy acid.

So pl. 176 - 177oC, white needles (recrystallization from methanol/water).

Example 13. 4-Hydroxy-7-[2-[3-[2-[2-[2-AMINOPHENYL]ethoxy] ethylsulfanyl] Propylamine]ethyl]-1,3-benzothiazol-2(3H)-she dihydrochloride.

a) Methyl 3-[2-[2-[2-nitrophenyl]ethoxy]ethylsulfanyl]propanoate.

Concentrated nitric acid (at 3.25 ml) was added dropwise within half an hour to a stirred cooled (ice/salt) to a solution of methyl 3-[2-[2-phenylethane] ethylsulfanyl] propanoate (15,12 g) (prepared from the acid obtained by the procedure of p. during the night stirred, diluted with water and was extracted several times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. Got a crude mixture of isomeric methyl 3-[2-[2-[2-nitrophenyl]ethoxy]ethylsulfanyl] propanoate. Specified in the subtitle compound was separated from the other isomers by liquid chromatography high-pressure normal-phase with hexane : ethyl acetate in a ratio of 1 : 1 as eluent.

1H-NMR (CDCl3) : 2,80-2,84 (t, 2H), 3,17-3,24 (m, 4H), 3,32-to 3.36 (m, 2H), 3,71-of 3.78 (m, 2H), 3,84-a 3.87 (t, 2H), was 7.36-7,41 (m, 2H), 7,54 (t, 2H), to $ 7.91 (d, 1H).

b) 3-[2-[2-[2-Nitrophenyl]ethoxy]ethylsulfanyl]propanoic acid.

Metallic lithium (0,59 g) was dissolved in methanol (200 ml). Added water (100 ml), then cooled solution (ice/salt) dropwise added the compound obtained in stage a) (6,05 g) in methanol (50 ml). The reaction mixture was left to warm to room temperature, then stirred overnight. Removed under reduced pressure, the solvent and the residue was diluted with water. The basic aqueous solution was washed with ethyl acetate (who left), was acidified to pH 2 (concentrated hydrochloric acid) and extracted utilitly under reduced pressure. The resulting crude product was purified by chromatography on silica gel with a sharp pressure decrease with dichloromethane : ethanol in a ratio of 9 : 1 as eluent. Got mentioned in the subtitle compound.

Mass spectrum: TS 349 [(M+NH4)+].

c) N-[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]-3- [2-[2-[2-nitrophenyl]ethoxy]ethylsulfanyl]propanamide.

Specified in the subtitle compound was prepared as described in example 1c), from 7-[2-amino-ethyl]-4-hydroxy-1,3 Battiato-2(3H)-she hydrobromide and the product of step b). Specified in the subtitle compound was obtained after chromatography on silica gel with 6% ethanol in chloroform as eluent.

Mass spectrum FAB + ve 524 [(M+H)+];

1H-NMR (DMCO-d6) : 2,5 (m, 4H), 2,60 (t, 2H), to 3.09 (t, 2H), 3,24 (m, 4H), 3,68 (t, 2H), 3,74 (t, 2H), 6,70 (d, 1H), 6,80 (d, 1H), 7,47 (t, 1H), 7,55 (d, 1H), 7.62mm (t, 1H), to $ 7.91 (d, 2H), 8,14 (t, 1H), to 9.91 (s, 1H), are 11.62 (s, 1H).

d) N-[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl] ethyl]-3-[2- [2-[2-AMINOPHENYL]ethoxy]ethylsulfanyl]propanamide.

Hydrazine hydrate (10 ml) was dropwise added to a stirred suspension sieprath of Raney Nickel, the compound obtained in step c) (2,21 g), and ethanol (50 ml). When the reaction has ended, the Raney Nickel ATI and dichloromethane and the aqueous layer was extracted with new portions of dichloromethane. The extracts were combined, washed with water and brine, dried (MgSO4), boiled away under reduced pressure and the obtained crude product which was used without purification.

Mass spectrum FAB + ve 494 [(M+H)+];

1H-NMR (DMCO-d6) : 2.4 to 2.8 (t, 8H), 3,2-3,4 (m, 6H), to 3.58 (t, 2H), 3,76 (t, 2H), 6,46 (t, 1H), 6,59 (d, 1H), 6,70 (d, 1H), 6,80 (d, 1H), 6,86-6,93 (m, 2H), 8,16 (t, 1H), to 9.93 (brs, 1H), 11,63 (s, 1H).

e) 4-Hydroxy-7-[2-[3-[2-[2-[2-AMINOPHENYL] ethoxy]ethylsulfanyl] Propylamine]ethyl]-1,3-benzothiazol-2(3H)-she dihydrochloride.

Specified in the title compound was prepared as described in example 1d), using the product of step d). The crude product was purified by reversed-phase chromatography with 0.1% water triperoxonane acid in acetonitrile as eluent.

So pl. 65oC (softens).

Mass spectrum FAB + ve 480 [(M+H)+];

1H-NMR (DMCO-d6) : 2,00-of 2.08 (m, 4H), 2,8-3,3 (m, 10H), 3,39 is-3.45 (m, 2H), 3,71 (t, 2H), 3,81 (t, 2H), 4,5 (brs, 3H), 6,77 (d, 1H), 6.89 in (d, 1H), 7,28 and 7.36 (m, 4H), 9,04 (brs, 2H), 10,15 (s, 1H), and 11.6 (s, 1H).

Example 14. 4-Hydroxy-7-[2-[3-[2-[2-[4-nitrophenyl]ethoxy]ethylsulfanyl] Propylamine] ethyl]-1,3-benzothiazol-2(3H)-she hydrochloride.

a) N -[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl] ethyl]-3-[2-[2-[4- nitrophenyl]ethoxy]ethylsulfanyl]propanamide.

H)-she hydrobromide and 3-[2-[2-[4-nitrophenyl] ethoxy] -ethylsulfanyl] propanoic acid (example 13 (a)), gave specified in the subtitle compound (after chromatographic purification on silica gel with 8% ethanol in dichloromethane as eluent).

Mass spectrum: FAB + ve 524 [(M + H)+];

1H-NMR (DMCO-d6) : of 2.45 (t, 2H), 2,60 (t, 2H), 2,97 (t, 2H), 3,2-3,4(m, 6H), 3,69-of 3.77(m, 4H), 6,70 (d, 1H), 6,80 (d, 1H), 7,53 (d,2H), 8,12 (d, 3H), to 9.91 (brs, 1H), and 11.6 (brs, 1H).

b) 4-Hydroxy-7-[2-[3-[2-[2-[4-nitrophenyl] ethoxy] ethylsulfanyl]Propylamine] ethyl]-1,3-benzothiazol-2(3H)-she hydrochloride.

Specified in the title compound was prepared as described in example 1d). The crude reaction product was purified by reversed-phase chromatography with acetonitrile in 0.1% aqueous triperoxonane acid as eluent.

So pl. 75 - 78oC.

Mass spectrum: FAB + ve 510 [(M + H)+];

1H-NMR (DMCO-d6) : a 2.01 (quin, 2H), and 2.83 (t, 2H), 2,98 (t, 4H), of 3.12 (t, 4H), 3,39 (t, 2H), 3,70-with 3.79 (m, 4H), 6,76 (d, 1H), to 6.88 (d, 1H), 7,55 (d, 2H), 8,16 (d, 2H), 8,83 (brs, 2H), 10,13 (s, 1H), 11,76 (s, 1H).

Example 15. 7-[2-[2-[3-[2-[4-Forfinal]ethoxy]propylsulfonyl]ethylamine] ethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrochloride.

a) 2-[4-Forfinal]ethyl allyl ether.

2-[4-Forfinal] ethanol (7.0 g) was slowly added to a stirred suspension of sodium hydride (1.25 g, 60% in dispersion in oil, pre-washed Petro the NGO added allyl bromide (6.0 g) and all this was stirred over night. Water and ether, the layers were separated. The aqueous layer was extracted with a new portion of ether, the ether extracts combined, washed with water and dried (MgSO4). The ether was removed under reduced pressure and the obtained crude substance specified in the subtitle, in the form of a colorless oil (8.7 g, 96%).

Mass spectrum: El 180 (M)+;

1H-NMR (CDCl3) : or 2.9 (t, 2H), 3.6(t, 2H), 4,0 (t, 2H) 5,2 (m, 2H), 5,9 (m, 1H), 6,95 (m, 2H), 7,2 (m, 2H).

This reaction was successfully repeated in 5-fold scale.

b) 2-[3-[2-[4-Forfinal]ethoxy]propylthio]acetic acid.

The compound obtained in step a) (15 g), and thioglycolic acid (6.8 ml) was stirred at room temperature in a conical flask with air for 2 hours Then added another portion of thioglycolic (3.4 ml). Another half hour was mixed and thereafter the reaction was completed. The crude product was chromatographically on silica gel with dichloromethane:acetic acid in a ratio of 99 : 1 as eluent and got mentioned in the subtitle of the substance in the form of a colorless oil (19,69 g, 87%).

Mass spectrum: FAB + ve 273 [M + H)+];

1H-NMR (CDCl3) : to 1.87 (m, 2H), 2,71 (t, 2H), 2,85 (t, 2H), and 3.31 (d, 2H), 3,51 (t, 2H), the 3.65 (t, 2H), 6,98 (m, 2H), 7,18 (m, 2H).

c) 2-[3-[2-[4-Forfinal]ethoxy]propylsulfonyl]vesivehmaa acid mixture, obtained in step (b) (39.5 g), water (50 ml). Added a few tricks aqueous solution of OXONETM(278 g 400 ml) and the reaction was stirred overnight. Then added water (1 l) and all were extracted with ether (to remove sour materials). Then the aqueous layer was acidified using 20% aqueous sulfuric acid and three times was extracted with ether. The ether layers were combined, washed with water and brine, dried (MgSO4), concentrated under reduced pressure and the obtained pale-yellow oil (41.7 g). Otstavshie, oil gave a white solid residue. It was isolated by filtration and washed with small portions of ether : pentane in a 1 : 1 ratio. Got mentioned in the subtitle compound.

So pl. 47 - 48oC.

Mass spectrum: FAB + ve 305 [(M + H)+];

1H-NMR (CDCl3) : 2,12 (m, 2H), 2,84 (t, 2H), 3,32 (m, 2H), to 3.58 (t, 2H), the 3.65 (t, 2H), 4.00 points (s, 2H), 6,98 (m, 2H), 7,16 (m, 2H), 8,80 (brs, 1H).

d) N-[2-[4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl] ethyl] -2-[3-[2-[4- forfinal]ethoxy]propylsulfonyl]ndimethylacetamide.

Carbonyl-diimidazole (1,94 g) was added to a stirred solution of the acid (step c) (of 3.64 g) in DMF (15 ml) and stirred for another 40 min at room temperature. To this solution was added 7-[2-amino-ethyl]-4-hydroxy-1,3 benzothiazol-2(3H)-she hydrobromide (3,48 g), C is by a mixture of 10% aqueous hydrochloric acid and ether (each 100 ml). Gradually settled pale yellow solid, which was filtered, washed with pentane and dried in vacuum. Got mentioned in the subtitle compound yellow-brown color, which was used without purification.

Mass spectrum: FAB + ve 497 [(M + H)+];

1H-NMR (DMCO-d6) : at 1.91 (m, 2H), 2,61 (t, 2H), 2,80 (t, 2H), 3,30 (m, 4H), of 3.48 (t, 2H), of 3.56 (t, 2H), a 4.03 (s, 2H), 6,70 (d, 1H), PC 6.82 (d, 1H), 7,10 (t, 2H), 7,28 (m, 2H), 8,46 (t, 1H), 9,95 (s, 1H), 11,66 (s, 1H).

e) 7-[2-[2-[3-[2-[4-Forfinal] ethoxy]propylsulfonyl]ethylamine] ethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-she hydrochloride.

Specified in the title compound was prepared as described in example 1d), using the compound obtained in step d). The crude product was purified by chromatography with reversed phase with 35% tetrahydrofuran in 0.1% aqueous triperoxonane acid as eluent.

So pl. 240 - 245oC.

Mass spectrum: FAB + ve 483 [(M + H)+];

1H-NMR (DMCO-d6) : at 1.91 (m, 2H), 2,80 (t, 2H), 2,85 (t, 2H), 3,14-is 3.21 (m, 4H), 3,24(2H + D2O) to 3.49 (t, 2H), 3,54 (q, 4H), 6,76 (d, 1H), 6.87 in (d, 1H), 7,10 (t, 2H), 7,27 (t, 2H), 9,14 (s, 2H), 10,15 (s, 1H), 11,78 (s, 1H).

Analysis: found, %: C 50,58, H 5,62; N 5,61; S OF 12.26,

C22H27N2FO5S2.HCl;

Calculated, %: C 50,91; H 5,44; N 5,40; S 12,36.

Example 16. the asanee in the title substance was prepared, as described in example 15 using 2-trilateral, was not carried out only oxidation in example 15c). Except this was followed by the procedure of example 1b).

So pl. 220 - 221oC.

Mass spectrum: FAB + ve 471 [(M + H)+];

1H-NMR (DMCO-d6) : 1,90-to 1.98 (m, 2H); 2,53 (m, 2H), 2,85 (t, 2H), 3,03 (t, 2H), and 3.16 (m, 2H), 3,25 (m, 2H), 3,37 (m, 2H), 3,53 (m, 2H), 3,60 (t, 2H), 6,76 (d, 1H), to 6.88 (m, 2H), 6,94 (m, 1H), 7,33 (dd, 1H), which is 9.09 (brs, 2H), 10,14 (s, 1H), 11,78 (brs, 1H).

Analysis: found, %: C 46,67; H 5,51; N 5,68; S 18,42,

C20H26N2O5S3.HCl

Calculated, %: C Of 47.37; H Lower Than The 5.37; N 5,52; S 18,97.

Example 17. 4-Hydroxy-7-[2-[3-[2-[2-[2-pyridyl]ethoxy]ethylthio]Propylamine]ethyl]- 1,3-benzothiazol-2(3H)-she dihydrochloride.

a) 2-[2-[2-Brometalia]ethyl]-1,3-dioxolane.

To a stirred cooled (< 0oC) solution of 2-[2-[1,3-dioxolane-2-yl]-ethylthio]ethanol (13,6 g, prepared by condensation mercaptoethanol, 2-[2-bromacil] -1,3-dioxolane using sodium hydride) in dry acetonitrile (150 ml) was added triphenylphosphine (20 g) and carbon tetrabromide (38 g). The solution was stirred 4 h the Solvent was removed under reduced pressure and the residue was adsorbing silica gel. Substance chromatographically on silica gel with a sharp pressure decrease with 10% eTeacher oil (4,45 g), which without further purification was passed on to the next step.

b) 2-[2-[2-[2-[2-Pyridyl]ethoxy]ethylthio]ethyl]-1,3-dioxolane.

The substance obtained in step (a) (6,12 g), Tetra-n-butylamine the hydrosulfate (1 g) and 2-pyridylethyl (2,85 ml) was stirred with dichloromethane and 20% aqueous solution of sodium hydroxide (each 20 ml) until gas chromatography showed that the reaction was completed. The organic layer was separated, washed with water and dried (MgSO4). After removal of the solvents under reduced pressure left an oil. It was purified by chromatography on silica gel with a sharp pressure decrease with ethyl acetate : petroleum ether, so Kip. 60 - 80oC in the ratio of 4 : 1 as eluent. Got mentioned in the subtitle compound as a yellow oil (0,770 g).

1H-NMR (CDCl3) : of 1.92 (m, 2H), 2,65 (m, 4H), of 3.07 (t, 2H), 3,62 (t, 2H), 3,85 (m, 4H), 3,95 (m, 2H), 4,94 (t, 1H), 7,13 (m, 1H), 7,22 (d, 1H), 7,60 (td, 1H), 8,53 (d, 1H).

c) 3-[2-[2-[2-Pyridyl]ethoxy]ethylthio]propanal.

The product of step b) (0,850 g) was dissolved in 80% formic acid (10 ml) and left at room temperature for 22 hours, the Mixture was divided between ether and water. The layers were separated and the aqueous layer was extracted with ether. The ether extracts were combined, propylenediene in the form of oil (0,70 g).

1H-NMR (CDCl3) : 2,69 (m, 4H), 2,87 (t, 2H), 3,06 (t, 2H), to 3.64 (t, 2H), 3,85 (t, 2H), 7,13 (td, 1H), 7,21 (d, 1H), 7,60 (td, 1H), 8,53 (d, 1H), 9,74 (s, 1H).

d) 4-Hydroxy-7-[2-[3-[2-[2-[2-pyridyl]ethoxy]ethylthio]Propylamine]ethyl]- 1,3-benzothiazol-2(3H)-she dihydrochloride.

The product of step c) (0,700 g) was dissolved in methanol (20 ml). To this solution was added 7-[2-amino-ethyl] -4-hydroxy-1,3-benzothiazol-2(3H)-she hydrobromide (0,655 g), sodium cyanoborohydride (0,100 g) and aqueous 6% acetic acid (to bring the pH to 6). The solution was stirred over night at room temperature, then it was parselocale concentrated solution of ammonium hydroxide. The solvent was removed under reduced pressure and the residue was chromatographically in the column of silica gel with methanol in dichloromethane as eluent. The obtained fractions were combined and purified by reversed-phase chromatography with acetonitrile in 0.1% aqueous triperoxonane acid as eluent, and after preparation of the hydrochloride was released pure substance specified in the header.

So pl. 50 - 60oC (softens).

Mass spectrum : FAB + ve 434[(M + H)+];

1H-NMR (DMCO-d6) : to 1.86 (m, 2H), by 2.55 (t, 2H), 2,62 (t, 2H), 2,88 (m, 2H), 2.91 in (m, 2H), 2.95 and (m, 2H), or 3.28 (t, 2H), to 3.58 (t, 2H), 3,85 (t, 2H), 6,78 (d, 1H), to 6.88 (d, 1H), a 7.85 (t, 1H), of 7.96 (d, 11
H27N3O3S2.2HCl 1,5 H2O

Vicisano, %: C 47,27; H Equal To 6.05; N 7,88; S 12,02; Cl To 13.29.

Example 18. 4-Hydroxy-7-[2-[2-[3-[2-(4-hydroxyphenyl)ethoxy]propyl-sulfonyl] ethylamino]ethyl]-1,3-benzothiazol-2(3H) -, hydrochloride.

a) 4-(2-Propenyloxy)ethyl-1-(phenylmethoxy)benzene.

To a suspension free from oil of sodium hydride (1.6 g) in dry dimethylformamide under stirring in nitrogen atmosphere are added in several portions 2-[4-(phenylmethoxy)phenyl] ethanol. At the end of the addition the mixture is stirred for 4 hours, then added dropwise to propylbromide (7.98 g). The reaction mixture was stirred over night at room temperature, then poured with stirring into water (1.5 l). The mixture is extracted with ether, the extracts washed with brine, dried (MgSO4), filtered, the filtrate evaporated to dryness, get the oil, the yield of 15.3 g (86%).

Mass spectrum (electron impact): 268 (M).

Range PMR (360 MHz, CDCl3) , M. D.: 2,85 (2H, t), 3,62 (2H, t), 4,0 (2H, d), and 5.2 (2H, m) and 5.9 (1H, m), 7,0 (4H, HF), and 7.4 (5H, m).

b) 2-[3-[2-[4-(Phenylmethoxy)phenyl]ethoxy]propylthio] acetic acid.

A mixture of the product of stage a) of 15.3 g) combine with mercaptohexanol acid (of 5.82 g) and 2,2'-azobis(2-methylpropionitrile) (AlBN, 0.2 g) is heated in the UFC who I first isohexanol, containing ether (20%), then the mixture isohexane - ether (50:50), get the product as a colourless oil which slowly crystallizes (15.6 g, 76%).

Mass spectrum (electron impact): 360 (M).

Range PMR (360 MHz, CDCl3) , M. D.: of 1.85 (2H, m), 2,70 (2H, t), 2,80 (2H, t), 3,20 (2H, t), 3,51 (2H, t), 3,62 (2H, t), of 5.03 (2H, s) to 7.00 (4H, square), 7,40 (5H, m).

c) 3-[2-[4-(Phenylmethoxy)phenyl]ethoxy]propylsulfonyl acid.

To a solution of the sulfide from stage b) (15.2 g) in methanol (120 ml) under stirring at a temperature of 0oC in small portions, add a solution of OXONER(79 g) in water (300 ml). The resulting thick precipitate was stirred at room temperature for 4 hours, add a further quantity of water and the mixture extracted with chloroform. The extracts washed with brine, dried (MgSO4), filtered, the filtrate evaporated to dryness, get a solid white color, which crystallized from toluol, get a named connection in the form of white needle crystals (14.0 g, 84%) so pl. 105 - 107oC.

Mass spectrum (electron impact): 348 (M-CO2).

Range PMR (360 MHz, CDCl3+DMCO) , M. D.: 2,10 (2H, m), 2,80 (2H, t), 3,30 (2H, t), 3,60 (HN, t), of 3.95 (2H, s), 5,04 (2H, s) to 7.00 (4H, square), 7,40 (5H, m).

d) 2-[3-[2-(4-Hydroxyphenyl)ATOC is(10.0 g) in ethanol (250 ml) is stirred for 48 h, the catalyst is separated by filtration, the filtrate is evaporated to dryness. The solid residue is crystallized from ethanol, to obtain a named connection in the form of a solid white color (1.3 g, 34%), so pl. 172 - 2oC.

Mass spectrum (fast atom bombardment): 301 (M-H).

Range PMR (360 MHz, DMCO-d6) , M. D.: a 1.88 (2H, m) to 2.67 (2H, t), of 3.33 (2H, m), of 3.45 (4H, m) to 3.64 (2H, s), at 6.84 (4H, square), and 7.5 (1H, ush. C.).

e) N-[2-(4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]-2-[3- [2-(4-hydroxyphenyl)ethoxy]propylsulfonyl]ndimethylacetamide.

The acid solution from step d) (5,4 g) in dry dimethylformamide (100 ml) under nitrogen atmosphere is treated with 1,1'-carbonyl diimidazol (5.3g) and the mixture is stirred for 90 minutes, then add bromohydrin 7-(2-amino-ethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-she (5,28 g) and then triethylamine (1.8 g). The mixture is stirred at room temperature overnight and slowly with vigorous stirring add it to the mixture of diluted hydrochloric acid (200 ml) and ether (100 ml). The ether layer is separated, the aqueous phase is filtered, the filtrate is extracted with ethyl acetate. The extracts are evaporated to dryness, the residue combined with the filtered solid product was dissolved in ethanol and treated with activated carbon. The coal and solvent from the project factions get a connection in the form of a solid white color (2.5 g, 28%), so pl. 183 - 4oC.

Mass spectrum (fast atom bombardment): 495 (M+H).

Range PMR (360 MHz, DMCO-d6) , M. D.: 1,91 (2H, m), 2,65 (4H, m), 3,30 (4H, m), 3,47 (4H, m), Android 4.04 (2H, s), 6,77 (2H, square), 6,83 (4H, square), to 8.45 (1H, t) to 9.15 (1H, s), 9,96 (1H, s), of 11.61 (1H, s).

Elemental analysis: found, %: C 53,44, H 5,59, N 5,74, S 12,92. Brutto-formula C22H26N2O7S2. Calculated, %: C 53,43, 5,30 H, N 5,66, S 12,97.

f) 4-Hydroxy-7-[2-[2-[3-[2-(4-hydroxyphenyl)ethoxy-propylsulfonyl] -ethylamino] ethyl]1,3-benzothiazol-2(3H) -, hydrochloride.

To the amide from step e) (0,49 g) in tetrahydrofuran (20 ml) under nitrogen atmosphere with stirring was added 1 M solution of borane in tetrahydrofuran (3.5 ml) and boiled for 120 minutes the Mixture is cooled, the reaction is quenched by adding methanol and a few drops of concentrated hydrochloric acid. The mixture is evaporated to dryness, the residue purified flash chromatography on silica gel (eluent chloroform - ethanol, 9:1) get the fraction, which is then purified liquid chromatography high pressure (VGH). The resulting product is crystallized from dilute hydrochloric acid, get a named connection in the form of a solid white color (0,053 g, 10%), so pl. 167 - 8oC.

Mass spectrum (ESILoop): 481 (M+H).

Spec CLASS="ptx2">

Example 19. 4-Hydroxy-7-[2-[2-[3-[2-(4-methoxyphenyl)ethoxy]propylsulfonyl]ethylamino] ethyl]-1,3-benzothiazol-2(3H) -, hydrochloride.

and) 2-[3-[2-(4-Methoxyphenyl)ethoxy]propylsulfonyl]ethanol.

This connection can be produced from 2-(4-methoxyphenyl)ethanol with 2-mercaptoethanol in accordance with the above methods, stages a) and b) with subsequent oxidation of the intermediate sulfide hydrogen peroxide in aqueous acetonitrile.

Mass spectrum (ESI Loop: 303 (M+H).

Range PMR (360 MHz, CDCl3) , M. D.: of 2.08 (2H, m), 2,59 (1H, t), 2,82 (2H, t), is 3.10 (2H, t), 3,14 (2H, t), of 3.54 (2H, t), 3,61 (2H, t), with 3.79 (3H, t) 4,07 (2H, square), 6,97 (4H, square).

b) 2-[3-[2-(4-Methoxyphenyl)ethoxy] propylsulfonyl] ethyl ester of benzoic acid.

A solution of the product of stage a) (7.5 g) in methylene chloride (70 ml) is treated with triethylamine (4,2 ml), then added dropwise to the benzoyl chloride (3.5 ml). The mixture was stirred for 2 h, washed with diluted hydrochloric acid, dried (MgSO4), filtered, the filtrate is evaporated to dryness, get a named connection in the form of oil (11,0 g).

Mass spectrum (fast atom bombardment): 407 (M+H).

c) 1-[3-[2-(4-Methoxyphenyl)ethoxy]propylsulfonyl]ethylene.

Restaud additional 1 ml of DBu and the mixture is stirred over night. The reaction mass is washed with saturated aqueous sodium bicarbonate, water, brine and dried (MgSO4), filtered, the filtrate is evaporated to dryness, get the oil, which is purified by rapid chromatography on silica gel (eluent methylene chloride - ethyl acetate, 10 : 1) get a named connection in the form of oil (of 5.24 g).

Mass spectrum: 284 (M).

Range PMR (360 MHz, CDCl3) , M. D.: a 2.01 (2H, m), and 2.79 (2H, t), to 3.02 (2H, m), 3,51 (2H, t) to 3.58 (2H, t), with 3.79 (3H, t), 5,95 (1H, d), 6,14 (1H, d), 6,37 (1H, m), 6,7 (4H, HF).

d) 4-Hydroxy-7-[2-[2-[3-[-2-(4-methoxyphenyl)ethoxy] propylsulfonyl] ethylamino] ethyl]-1,3-benzothiazol-2(3H) -, hydrochloride.

The product from step c) (5,24 g) in methanol (10 ml) is treated with the hydrochloride of 7-(2-amino-ethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-she (5.0 g) and triethylamine (2,85 ml) and boiled for 2 hours, then cool and add hydrochloric acid (0.4 ml). The mixture is evaporated, the residue is purified flash chromatography on silica gel (eluent methylene chloride - methanol, 20 : 1). Product successively crystallized from methanol - HCl, methanol and water, get a named connection (0,474 g), so pl. 226oC.

Mass spectrum (ESI ammonium acetate): 481 (M+H), 479 (M-H).

Range PMR (360 MHz, DMCO-d6) , M. D.: 1,90 (2H, m), is 2.74 (2H, t), a-3.84 (2H, t), and 3.16 (2H, t), 3,22 (2 the fair analysis: found,%: C 49,22, H of 5.75, N, 5,44, S 11,44, Cl 6,64, Brutto-formula: C23H30N2O6S2. HCl with 2.4 mol of water, calculated,%: C 49,26, H 6.42 per, N 4,99, S 11,42, Cl 6,54.

Getting harmonistaion.

Dry powder ready preparative form containing a mixture of compounds of formula I and of a diluent, such as lactose, where the diluent is present in an amount up to 99% by weight of the finished formulation, for example 50 to 95% or from 75 to 95% by weight of the finished formulation.

An aqueous solution prepared formulation can contain just water or saline solution in which the concentration is in the range of 1.5 μg/ml to 3 mg/ml, preferably of 1.5 mg/ml 1.5 mg/ml, such as 0.5 mg/ml - 1.0 mg/ml. pH of the solution can be set by using HCl to a pH of about 3.5.

Examples of pharmaceutical compositions.

The compound obtained according to any one of examples 1 to 13, is mixed with the filler is lactose and finely pulverized with getting ready for the final form of the composition specified in the table. 1. An alternative to mixing the active component and the carrier, each of them finely chopped.

A predetermined quantity of compounds of examples 1 to 13 (for example, 150 mg) is dissolved in water for the. 3 and hereinafter the data on the biological activity concerning the measurement of agonism to2-adrenoreceptor and agonism to DA2the receptor dopamine.

Methods: beta2receptor analysis of the long-acting compounds on isolated preparation of the trachea of Guinea pigs.

Introduction: the trachea of Guinea pigs contain beta-adrenergic receptors, stimulation of which causes the relaxation of smooth muscle. This isolated tissue system is used to obtain quantitative information on the new long acting beta2-ligands.

Isolated tracheal rings Guinea pigs. Male Guinea-pigs-albino Dunkin-Hartley were killed by cervical displacement and deleted the entire trachea. After clearance from the adjacent connective tissue trachea was cut into six ring segments, each of width three cartilaginous beams, and then suspended in 20 ml bath for bodies containing Krebs solution.

The suspension was kept at 37oC and was continuously aziraphale oxygen containing 5% CO2. In the Krebs solution was added indomethacin (2,8 µm), cocaine (30 μm), corticosterone (10 μm), ascorbate (1 mm), CGP20712A (1 μm) and phentolamine (3 μm): income and corticosterone for inhibition of uptake 1 and uptake 2, respectively, ascorbate to prevent oxidation of the catecholamine and CGP20712A and phentolamine in order to avoid any confounding effects of activation of the beta1- and alpha-adrenergic receptors, respectively. Tracheal rings were suspended between two wire hooks (tungsten or stainless steel), one of them was attached to the gauge isometric force Ormed Beam, the other end to a stationary support in the tub for body. Changes in isometric force were recorded on a 2-channel flatbed recorders Advance Bryans.

The protocols of the experiment. At the beginning of each experiment to tissue exerted force of 1.0 g and this power was restored after a period of equilibration at 60 min until then, until it remained constant.

Tissue was then reduced to 3 μm methacholine, which is an agonist of muscarinic receptor. Once received sustained response for each tissue build cumulative curve (of 0.5 log unit increments): concentration of izoprenalin - effect (E/[A]). After washing poke was left for 60 min and then reduced to 3 μm methacholine. When he reached the stable response, adding 10 μm of the test compound or filler (the fact that atelectasia on test connection (or after 40 min, if relaxation is not observed), building E/[A] curve izoprenalin. Responses were recorded as relaxation in percentage reduction induced by methacholine.

Assuming that the compound causes relaxation and added that the concentration of the most effective, you can calculate its own (internal) activity () and efficiency () agonist. Internal activity is just a reaction caused by the test compound divided by the maximum relaxation induced by izoprenalin. The efficiency can be estimated, assuming that izoprenalin acts as a full agonist in this system, and thus using it to define the parameters of operational models Emand n (Leff et al., 1989). These parameters can then be used for comparative analysis of the test compounds, allowing to evaluate its effectiveness.

Set the affinity (PKAND) the test agonist receive, on the basis of the right shift control isoprenaline curve, which is obtained in the presence of the test agonist, i.e., the level of concentration, allowing you to set the affinity of the agonist in the Schild analysis.

Having set the affinity and eff is]).

Example. Izoprenalin (standard agonist).

p[A50] = p[ED50] = 7,14

m= 92,0 %

n = 1,18

Test connection (salmeterol).

Response to 10-5M = 41,3%.

Therefore internal activity () = 41,3/92,0 = 0,44. Since /Em= Gn/1 + Gnthen 0,44 = G1,18/1 + G1,18thus G (efficiency) = 0,82.

Isoprenaline control p[A50] = 7,1.

Izoprenalin in the presence of 10-5M of salmeterol on the list of p[A50] = 5,1.

Thus the concentration ratio (CR) = 100, and since CR - 1 = [A]KAthen pKA= 7,0

Having G and KAyou can set the activity (p[A50]) of the test compounds

[A50] = KA/(2+Gn)1/n-1)).

Thus using the above values, we get p[A50] = 7,14.

DA2receptor analysis on the drug isolated ear artery of the rabbit.

Introduction. The drug ear artery of the rabbit contains presynaptic dopamine receptors (DA2), the stimulation of which ingibiruet the secretion of norepinephrine from sympathetic neurons. This isolated tissue system is used to obtain quantitative Yemelianova on the site of the ear artery.

Male rabbits NZV (2.5 to 3.0 kg) were killed by an intravenous infusion pentobarbital-sodium (60 mg/kg). The ears were removed and the proximal part of the artery in the middle ear was exposed and was Coulibaly using polypropylene cannula (outer diameter 0.75 mm). After removal of artery cleaned of adhering connective tissue and got 6 rings (3 from each artery) width of 5 mm, keeping the surface of the circular layer of smooth muscle. Tissue was mounted on a thin hooks made of tungsten wire (diameter 0.25 mm) in the bath for the bodies of 20 ml containing Krebs solution of the following composition (mm): NaCl 117,56; NaHCO325,00; KCl Are 5.36; NaH2PO40,89; MgSO11,18; glucose 11,10 and CaCL22,55. In Krebs solution to block neuronal uptake and receptor included cocaine (30 μm) and propranolol (1 μm). This solution stood at 37oC and was continuously aziraphale a mixture of 95% O2and 5% CO2. The upper wire hook was attached to Ormed-sensor power offset, the lower hook was attached to a stationary support in the bathroom. Reduction of tissue caused by a stimulation site within 10 seconds every 2 minutes Used stimulation parameters were as follows: long lasting 0.5 MS, 5 Hz, 15 Century Changes in isometric sileage experiment for each tissue exerted force, 1.0, This power was restored during the stabilization period of 60 min until then, until it remained constant. At the end of this period began electrical stimulation. Reproducible response to the stimulation was established after approximately 60 minutes Curves the concentration of the agonist effect (E[a]) were constructed by cumulative additions agonist at 0.5 log10single increments. Responses were recorded as the percentage inhibition of stimulated twitches.

Quantification of agonist. As standard agonist took 58075AB (6,7 ADTN). After the response to electrical stimulation was stable, each fabric was exposed dose (300 μm) 58075AB, which can be observed visually. After reaching the maximal response of the agonist was washed. Then build curves E/[A] for the tested compounds. The reaction of compounds that cause agonism, expressed as a percentage of the response to the dose, the effect of which can be observed visually. By using high frequency (5 Hz) stimulation it is possible to identify compounds with lower efficiency than 58075AB.

The value for 580 with values significantly less than 1, it is possible to estimate values of efficiency. P-value[ED50], is a measure of agonist activity. It is the negative logarithm of the concentration of agonist that causes a reaction, corresponding to half of the maximum response. For compounds that have a value much smaller than 1, it is possible to calculate the magnitude of the affinity (affinity) from the measured values of p[ED50] and the set values of efficiency. These values of the affinity shown as pKa (negative logarithm of the concentration of agonist that binds half of the receptors).

Compounds that do not exhibit agonist, were studied as antagonists, incubare tissue with the highest possible concentration, and then build E/[A] curves 58075AB E/[A]. Degree offset to the right of these curves 58075AB compared with the control curves 58075AB allows you to set the affinity (affinity) of the tested compounds. Such assessments affinity is given in the form of values pA2(the negative logarithm of the concentration of antagonist that causes a 2-fold shift to the right of the control curve E[A]).

Comparative study of antagonists. (-)-Sulpiride was chosen as standardmaterial DA2-a receptor. The value of the equilibrium constant of dissociation (KV) is approximately 10 nm. In experiments using this antagonist, E/[A] curves antagonist was built for 60 min before incubation and after 60 min after incubation with 100 nm (-)-sulpiride. For selective DA2-agonists this concentration should cause an 11-fold parallel shift to the right of the control curve. Where it was possible to calculate these shifts, they are given as the ratio (CR). If qualified E/[A] curves cannot be obtained after the processing of (-)-sulpiride, agonism described only as (-)-sulpiride sensitive or (-)-sulpiride insensitive.

1. Derivatives of 7-(2-amino-ethyl)benzothiazolone General formula I

< / BR>
where the substituents X and Y independently of one another represent S(O)n- or-O-;

n takes on the values 0, 1 or 2;

p, q and r independently of each take the values 2 or 3;

Deputy Z represents a phenyl, optionally substituted by a halogen atom, NO2, NH2or or1where substituent R1- H or C1-C6-alkyl, or Deputy Z represents a 5 - or 6-membered unsaturated heterocycle containing N and CLASS="ptx2">

3. The compound of General formula I under item 1 or 2, where r = 2.

4. The compound of General formula I according to any one of paragraphs. 1 to 3, where p+q = 5.

5. The compound of General formula I according to any one of paragraphs. 1 to 4, where Y means o

6. The compound of General formula I according to any one of paragraphs. 1 - 5, where X represents-S - or-SO2-.

7. Derivative 7-(2-amino-ethyl)benzothiazolone General formula I, representing

4-hydroxy-7-[2-[3-[2-[2-phenylethane] ethylsulfanyl] Propylamine] ethyl]-1,3-benzothiazol-2(3H)-he,

4-hydroxy-7-[2-[2-[3-[2-phenylethane] propoxy] ethylamine] ethyl]-1,3-benzothiazol-2(3H)-he,

4-hydroxy-7-[2-[3-[2-[2-phenylethane] ethoxy] Propylamine] ethyl]-1,3-benzothiazol-2(3H)-he,

4-hydroxy-7-[2-[2-[2-[2-phenylethane] ethoxy] ethylamine] ethyl]-1,3-benzothiazol-2(3H)-he,

4-hydroxy-7-[2-[2-[3-[2-phenylethane]propylthio]ethylamine]ethyl]-1,3-benzothiazol-2(3H)-he,

4-hydroxy-7-[2-[2-[3-[2-phenylethane] propylsulfonyl] ethylamine] ethyl]-1,3-benzothiazol-2(3H)-he,

4-hydroxy-7-[2-[3-[2-[2-phenylethane]ethylthio]Propylamine]ethyl]-1,3-benzothiazol-2(3H)-he,

4-hydroxy-7-[2-[3-[2-[2-[2-AMINOPHENYL]ethoxy]ethylsulfanyl] Propylamine] ethyl]-1,3-benzothiazol-2-(3H)-he,

4-hydroxy-7-[2-[3-[2-[2-[4-nitrophenyl] ethoxy]ethylsulfanyl]Propylamine] ethyl]-1,3-benzothiazol-2-(3H)-he,

7-[2-[2-[3-[2-[4-forfinal] e is] propylthio] ethylamine] ethyl-1,3-benzothiazol-2(3H)-he or

4-hydroxy-7-[2-[3-[2-[2-[2-pyridyl] ethoxy] ethylthio]Propylamine] ethyl]-1,3-benzothiazol-2(3H)-he,

or pharmaceutically acceptable salt of any of them.

8. The pharmaceutical composition exhibiting agonistic activity against2-adrenergic receptors containing the active ingredient and pharmaceutically acceptable carrier or diluent, wherein the active component contains a compound I according to any one of paragraphs. 1 - 7 in an effective amount.

9. The method of obtaining derivatives of 7-(2-amino-ethyl)benzothiazolone formula I according to any one of paragraphs. 1 - 7 or their pharmaceutically acceptable salts, characterized in that carry out the alkylation of compounds of formula II

< / BR>
or its derivative compound of General formula IV

O=CH-(CH2)p-1-X-(CH2)q-Y-(CH2)r-Z

where p, q, r, X, Y and Z have the values listed in paragraph 1,

in the presence of a reducing agent.

10. The method of obtaining derivatives of 7-(2-amino-ethyl)benzothiazolone formula I according to any one of paragraphs. 1 to 7, characterized in that it includes selective recovery of compounds of General formula Va

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

11. Derivatives of N-[2-(4-hydroxy-2-oxo-- phenyl, optionally substituted by a halogen atom, NO2, NH2or or1where R1- H or C1-C6-alkyl.

 

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