RU2172313C2 - Benzothiazolone compounds, methods and intermediate compounds for their synthesis and pharmaceutical composition containing thereof - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to novel derivatives of benzothiazolone of the general formula (I) β₂- where X means

or -SO₂NH-; p, q and r = 2 or 3 being independently each of other; Y means thienyl optionally substituted with -NHSO₂--alkyl or halogen atom or phenylthio-group or phenyl optionally substituted with C_1-6-alkyl or halogen atom; each of R means independently H or C_1-6-alkyl, its optical isomers and pharmaceutically acceptable salts. Method of synthesis of compound of the formula (I) or its pharmaceutically acceptable salt involves selective reductive alkylation of compound of the formula (II) C_1-6 with compound of the formula (III)

in the presence of reducing agent or by selective reduction of compound of the formula (IV)

. Amide of the formula (VI)

, acid of the formula (V)

and aldehyde of the formula (III) are used as intermediate compounds for synthesis of benzothiazolone of the formula (I). Invention relates to also a pharmaceutical composition eliciting agonistic effect with respect to DA₂-receptors and β₂-adrenoreceptors and containing compound of the formula (I) or its pharmaceutically acceptable salt dispersed in propellant optionally containing vehicle, lubricating agents or stabilizing agents or as dry powder for inhalation optionally including pharmaceutically acceptable carrier. EFFECT: new derivatives of benzothiazolone indicated above, improved methods of synthesis, valuable pharmacological properties. 18 cl, 9 ex

Description

Field of Invention
The invention relates to new derivatives of benzothiazolone, namely to new derivatives of 7- (2-aminoethyl) -benzothiazolone, and to a method for their preparation, pharmaceutical compositions containing them, and treatment methods that include their use. The new compounds are dopamine DA ₂ receptor agonists and β ₂ adrenoreceptor agonists.

Derivatives of benzothiazolone are known. For example, in international patent applications, publication numbers WO 92/08708 and WO 92/23385, biologically active amines are described, among them biologically active derivatives of aminoethylbenzothiazolone, which are β ₂ -adrenoreceptor agonists and dopamine DA ₂ receptor agonists, and which are shown in treatment of obstructive airways diseases.

где X и Y независимо являются -S(O)_n- или -О-, n равно 0, 1 или 2; p, q и r независимо равны 2 или 3; Z является фенилом, необязательно замещенным галогеном, OR¹, NO₂ или NR²R³; или Z является пяти- или шестичленным гетероциклом, содержащим N, O или S; и R¹, R² и R³ независимо являются водородом или C_1-6 алкилом. Данные соединения являются агонистами β₂-адренорецептора и агонистами допаминового DA₂-рецептора и показаны при лечении обструктивных заболеваний дыхательных путей.WO 93/24473 describes 7- (2-aminoethyl) benzothiazolone compounds which have the formula

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, OR ¹ , NO ₂ or NR ² R ³ ; or Z is a five- or six-membered heterocycle containing N, O or S; and R ¹ , R ² and R ³ are independently hydrogen or C _1-6 alkyl. These compounds are β ₂ -adrenoreceptor agonists and dopamine DA ₂ receptor agonists and are indicated in the treatment of obstructive airways diseases.

The present invention relates to a group of new derivatives of 7- (2-aminoethyl) -benzothiazolone, which are applicable as agonists of the dopamine DA ₂ receptor and agonists of β ₂ -adrenoreceptor.

где X представляет -SO₂NH- или -NHSO₂-,
p, q и r независимо друг от друга равны 2 или 3,
Y представляет тиенил, необязательно замещенный алкилом или галогеном, или фенилтио-, или фенил, необязательно замещенный алкилом или галогеном; и
каждый R независимо представляет H или алкил и его фармацевтически приемлемые соли, сложные эфиры и амиды.Description of the invention
Thus, in one aspect, this invention relates to compounds of formula I, including their optical isomers

where X is —SO ₂ NH— or —NHSO ₂ -,
p, q and r are independently 2 or 3,
Y represents thienyl optionally substituted with alkyl or halogen, or phenylthio or phenyl optionally substituted with alkyl or halogen; and
each R independently represents H or alkyl and its pharmaceutically acceptable salts, esters and amides.

These compounds have pharmacological activity. They demonstrate agonism for both the dopamine DA ₂ receptor and the β ₂ adrenoreceptor. They show little or no agonism towards the α ₁ -adrenoreceptor. The compounds have a preferred duration of action and a DA ₂ / B ₂ ratio.

 Preferably, in formula I q is 2, g is preferably 2.

When Y is phenyl substituted with alkyl, the alkyl group is preferably C _1-6 , for example a C ₁ or C ₂ group, methyl is most preferred.

 When Y is phenyl substituted with halogen, the halogen substituent is preferably a chloro or fluoro substituent.

Preferred compounds of this invention are compounds of formula I in which X is SO ₂ NH, p is 3, and q and r are each equal to 2. Other preferred compounds are compounds of formula I in which X is NHSO ₂ , a and p, and q , and r are all equal to 2.

 Suitable pharmaceutically acceptable salts of the compounds of formula I include acid addition salts prepared with inorganic and organic acids. These compounds may also form salts with suitable bases. Examples of suitable salts include hydrochloride, citrate, D, L-lactate, hemi sulfate, hemi-sulfate, D-gluconate, methanesulfonate, p-toluenesulfonate, semi-fumarate, benzoate, xinafoate, half-succinate, 3-hydroxy-2-naphthoate, half-embonate, D-male camphorsulfonate, 10-undecanoate, mandelate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, 4-methoxybenzoate, 4-chlorobenzoate, 5-methylsalicylate, saccharinate, monomethyl sulfate, hemisuberate and diphenyl acetate.

 Suitable pharmaceutically acceptable esters of the compounds of formula I include phenylalkyl and alkyl esters.

 Suitable amides include unsubstituted or mono- or disubstituted alkyl or phenylamides.

The most preferred compounds of this invention are:
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylethoxy) ethyl] propanesulfonamide;
N- [2- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] ethyl] -2- (2-phenylethoxy) ethanesulfonamide;
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (5-methyl-2-thienyl) ethoxy] ethyl] propanesulfonamide;
N- [2- [2- (4-fluorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] propanesulfonamide;
N- [2- [2- (4-chlorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-5H-1,3-benzothiazol-7-yl) ethylamino] propanesulfonamide;
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] - N- [2- [2- (4-methylphenyl) ethoxy] ethyl] propanesulfonamide;
(R, S) -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenyl-1-propoxy) ethyl] propanesulfonamide;
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (2-methylphenyl) ethoxy] ethyl] propanesulfonamide and
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2-phenylthioethoxy) ethyl] propanesulfonamide;
preferably in the form of salts, and most preferably in the form of hydrochloride.

соединением формулы III

в которой p, q, r, R, X и Y имеют значения, определенные выше, в присутствии восстановителя.This invention also relates to a method for producing compounds of formula I, which comprises selective reductive alkylation of a compound of formula II

compound of formula III

in which p, q, r, R, X and Y are as defined 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 a support, for example charcoal, using an alcohol, for example ethanol or an ester, for example ethyl acetate or an ether, for example tetrahydrofuran or water, as a solvent for the reaction or mixture of solvents, at normal or elevated temperature and pressure. The preferred temperature is room temperature. The preferred pressure is 1-3 atmospheres. An alternative reducing agent may be sodium borohydride or a metal hydride, for example sodium cyanoborohydride. The selection of suitable solvents for use with a hydride reducing agent will depend on the particular hydride used in this case, as is well known to those skilled in the art. Suitable solvents include alcohols, for example ethanol or methanol.

 During this reaction, intermediate imine compounds may be formed which can be reduced under the conditions described above to give compounds of formula I.

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

 The aldehydes of formula III can be obtained by many known methods, per se. For example, isothiazolidine dioxides (as in Example 1B, for example) can be reduced using DIBAL in toluene; acetals (as in example 2b, for example) can be hydrolyzed with 70% aqueous acetic acid; and esters (as in Example 3g, for example), DIBAL can be reduced in toluene. The specific synthesis of certain precursors of the compounds is described in the examples and can be adapted for many different purposes.

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

в которой p, q, r, R, X и Y имеют значения, указанные выше.The present invention also relates to an additional method for preparing compounds of formula I, comprising selectively reducing a compound of formula IV

in which p, q, r, R, X and Y have the meanings indicated 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. A 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 carried out at a temperature of from about 0 to about 100 ^° C., preferably at a boiling point.

или с соответствующим хлорангидридом кислоты стандартными методами. Например, реакция может быть проведена в присутствии дициклогексилкарбодиимида с использованием метода Sheehan и Hess, J. Am. Chem. Soc., 1955, 77, 1067; или 1,1'- карбонилдиимидазола, как описано в Staab, Angew. Chem. Int. Ed. Engl. , 1962, 1, 351; или бромтрипирролидинфосфония гексафторфосфата в таком растворителе, как ДМФ, как описано в Примере 1д. Кислоты, которые необходимы для этой реакции, можно получить из соответствующих сложных эфиров гидролизом, используя гидроксид лития в водном метаноле по методу Примера 16. В примерах 1а, 2г, 3г, 4е, 5г, 6г, 7г, 8г и 9г описаны конкретные способы получения сложных эфиров, и эти способы можно адаптировать для получения других сложных эфиров для дальнейшего получения кислот, которые реагируют с аминами формулы II. Хлорангидриды кислот можно получить из кислот, например, реакцией с оксалилхлоридом или тионилхлоридом в толуоле при температуре в интервале от комнатной температуры до температуры кипения.Compounds of formula IV can be prepared by reacting an amine of formula II with a suitable acid of formula V

or with the appropriate acid chloride 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 bromotripyrrolidine phosphonium hexafluorophosphate in a solvent such as DMF, as described in Example 1e. Acids that 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. Examples 1a, 2g, 3g, 4e, 5g, 6g, 7g, 8g and 9g describe specific methods of preparation esters, and these methods can be adapted to obtain other esters for the further production of acids that react with amines of the formula II. Acid chlorides can be obtained from acids, for example by reaction with oxalyl chloride or thionyl chloride in toluene at a temperature in the range from room temperature to boiling point.

 The compounds of this invention can also be obtained in several other ways.

в которой p, q, r, R, X и Y имеют значения, указанные выше, a L обозначает легко уходящую группу, например, галоген, такой как хлор, бром, или йод, или алкил- или арилсульфонилокси группу, например, метансульфонилокси группу.One such method is the alkylation of a compound of formula II or its salt, ester or amide with an alkylating agent of formula VI

in which p, q, r, R, X and Y are as defined above, a L is an easily leaving group, for example, a halogen such as chlorine, bromine, or iodine, or an alkyl or arylsulfonyloxy group, for example a methanesulfonyloxy group .

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

 The reaction can be carried out in a solvent, for example, in an ether, such as tetrahydrofuran or dioxane, in a ketone, such as butanone or methyl isobutyl ketone, in a substituted amide, for example dimethylformamide, or in a chlorinated hydrocarbon, for example, chloroform, at a temperature in the range from room temperature temperature to the boiling point of the solvent. Preferably, the reaction is carried out at room temperature.

An alkylating agent of formula VI can be obtained from the corresponding alcohol (i.e., a compound in which L represents an OH group) by methods known to those skilled in the art. For example, an alcohol may react with a halogenating agent to give a compound of formula VI in which L represents a halogen atom. Suitable halogenating agents include, for example, triphenylphosphine tetrahalogenomethane adducts (conventionally prepared in situ, for example by reaction of triphenylphosphine and carbon tetrabromide). The reaction can take place in the presence of a solvent, such as acetonitrile or a chlorinated hydrocarbon, such as dichloromethane, for example, at a temperature in the range from 0 to 30 ^o C.

в которой p, q, r, R, X и Y имеют значения, указанные выше.Another method is the selective reduction of the compounds of formula VII

in which p, q, r, R, X and Y have the meanings indicated 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. A 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 carried out at a temperature of from about 0 to about 100 ^° C., preferably at a boiling point.

 Compounds of formula VII can be prepared by reacting amines and acids or acid chlorides by standard methods. For example, the interaction can be carried out in the presence of dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole or bromotripyrrolidine phosphonium hexafluorophosphate, as described above with respect to compounds of formula IV. Amines necessary for the reaction can be obtained by reacting compounds of formula VI in which L is an easily leaving group, for example, a halogen such as chlorine or bromine, with phthalimide in the presence of a base. The resulting imides can then be treated with hydrazine hydrate in ethanol to give compounds of formula VI in which the leaving group is replaced by an amino group.

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

 Another method for preparing compounds of formula I involves the removal of protecting groups from a corresponding protected compound of formula I in which one or more functional groups are protected, and where it is desirable or necessary to convert the resulting compound of formula I to its pharmaceutically acceptable salt, ester or amide, or vice versa.

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

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

 Pharmaceutically acceptable amides of the compounds of formula I can be prepared using standard methods, for example, by reacting a compound of formula I with an acid or acid chloride.

в которой p, q, r, R, X и Y имеют значения, указанные выше.Intermediate compounds of formula IV are new, and thus, an additional aspect of the present invention are compounds of formula IV

in which p, q, r, R, X and Y have the meanings indicated above.

 The intermediates of formula VII as defined above are also new and are thus also provided in this invention.

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

 In addition, this invention includes acids of formula V and the corresponding acid chlorides, which are new.

The compounds of formula I and their salts, esters and amides are agonists of the dopamine DA ₂ receptor. The affinity for binding of the test compounds to DA ₂ receptor binding sites on bovine pituitary membranes can be determined by the substitution of [ ³ H] -Nn-propyl-rapomorphine and [ ³ H] -spiperone, respectively, in the presence or absence of a non-hydrolyzable GTP analog, DR Sibley, A DeLean and I. Greese, Anterior Pituitary Dopamione Receptors, Demonstration of Interconvertible High and Low Affinity States of Dopamine DA ₂ -receptor, J. Biol. Chem., 1982, 257 (11), 6351-6361. DA ₂ receptor activity can also be demonstrated by functional screening on an isolated rabbit ear artery, as described by Brown and O'Connor, Br.J. Pharmacol 1981, 73, 189P. These compounds are also β ₂ -adrenoreceptor agonists. This activity can be shown on an isolated guinea pig trachea, as described by IGDougall, D. Harper., DMJackson and P. Left, Br.J. Pharmacol., 1991, 104, 1057. Activity on the α ₁ receptor can be analyzed using screening rabbit isolated ear artery, as described below in the Pharmacological Example.

 The compounds of formula I and their salts, esters and amides are indicated for use in the treatment of a number of respiratory diseases, including conditions such as asthma, including bronchial asthma, allergic asthma, hereditary asthma (eg, late 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 indicated for use in the treatment of various other painful conditions, for example, inflammatory and allergic skin diseases, cancers, for example small cell lung cancer, congestive heart failure and glaucoma.

 The term "treatment", as used here, includes both prevention and alleviation of the symptoms of the disease.

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

 The invention further includes the use of compounds of formula I or their pharmaceutically acceptable salts, esters or amides for the manufacture of medicaments for the treatment of obstructive airways diseases, especially for the treatment of asthma or chronic bronchitis.

 Furthermore, the present invention relates to a method for treating respiratory tract diseases, which comprises administering to a patient suffering from or predisposed to such a disease, a therapeutically effective amount of a compound of formula I or its pharmaceutically acceptable salts, esters or amides.

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

 The compounds of formula I or their pharmaceutically acceptable salts, esters or amides can be used as such or in the composition of the respective pharmaceutical compositions.

 The introduction can be carried out by inhalation and in other ways, for example, by oral or intravenous administration.

 Nasal or intrapulmonary administration can be carried out using appropriate inhalation devices.

 For example, metered-dose inhalation devices can be used to administer a compound dispersed in a suitable propellant, with or without the addition of additional excipients such as ethanol, surfactants, lubricants, and stabilizers.

 Suitable propellants include hydrocarbons, chlorofluorocarbons and hydrofluoroalkanes, or mixtures of any such propellants. Particularly preferred propellants are P134a and P227, each of which can be used alone or in combination with other propellants and / or surfactants and / or other excipients, for example, in combination with each other.

 Sprayable aqueous suspensions or, preferably, solutions adjusted to or without appropriate pH and / or tonicity can also be used in aerosol devices for both single and multiple administration.

 Powder inhalers can be used to administer the drug, alone or in combination with a pharmaceutically acceptable carrier, in the latter case as a finely divided powder or as a necessary mixture. A powder inhaler may be single dose or multi-dose, and a powder or capsule containing the powder may be used in it.

 A metered dose inhaler, aerosol or powder inhaler is well known, and many such devices are available.

 The invention is illustrated, but not limited in any way by the following examples, in which the temperature is given in degrees Celsius. If necessary, the reaction is carried out in an inert atmosphere of nitrogen or argon. When necessary, preparative HPLC separation was performed using Novapak, Bondapak and Hypersil columns (registered trademarks) filled with BDSC-18, reverse phase silica. Flash chromatography was performed using silica Fisher Matrix 60, 35-70 microns.

Example 1
3- [2- (4-hydroxy-2-oxo-3H-1.3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylethoxy) ethyl] propanesulfonamide hydrochloride)
a) Methyl 3- [2- (2-phenylethoxy) ethylaminosulfonyl] propanoate
2- (2-phenylethoxy) ethanamine ¹ (1.95 g) was stirred in dichloromethane at room temperature. Triethylamine (3.36 ml) was added, then methyl 3- (chlorosulfonyl) propanoate ² and the mixture was stirred overnight at room temperature. The mixture was diluted with an additional volume of dichloromethane, washed with dilute hydrochloric acid, then with water, then dried (MgSO ₄ ). The solvent was removed in vacuo, whereby a pale yellow oil was obtained, which was then purified by flash chromatography (eluent — 0.1% ethanol: dichloromethane) to give the title compound as a pale yellow oil (1.68 g).

Mass spectrum: FAB 316 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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, br t), 7.12-7.35 (5H, m).

¹ Chem. Veg., 1964, 97, 510-519.

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

b) 3- [2- (2-phenylethoxy) ethylaminosulfonyl] propanoic acid
The product of step a) (1.68 g) was dissolved in ethanol (30 ml). A solution of lithium hydroxide (0.45 g) in water (30 ml) was added and the mixture was stirred overnight at room temperature. Water was added and the mixture was washed with ether. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ether. The ether extract was washed with water, then with brine, and then dried (MgSO ₄ ). The solvent was removed in vacuo to give the title compound as a white solid (0.97 g), which was then used without further purification.

Mp 80-82 ^o C;
Mass spectrum: ESI 300 (MH);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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).

c) 2- [2- (2-phenylethoxy) ethyl] -3-isothiazolidinone-1,1'-dioxide
The product of step b) (34 g) was dissolved in dimethylformamide (200 ml). To this solution, which was stirred, 1,1'-carbonyldiimidazole (20.12 g) was added and the mixture was stirred for 2 hours. Triethylamine (15.7 ml) was added and the mixture was stirred at room temperature for 60 hours. The mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate (3 times). The combined organic extracts were washed with saturated sodium bicarbonate solution, then with brine, dried (MgSO ₄ ), and the solvent was removed in vacuo to give a pale yellow oil, which was then purified by flash chromatography (eluent 50% ethyl acetate: gasoline) to give the title compound as an oil (27.4 g).

Mass spectrum: ESI 301 (M + NH ₄ );
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.87 (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).

d) 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylethoxy) ethyl] propanesulfonamide hydrochloride
The product of step c) (0.62 g) was mechanically stirred in toluene (20 ml), then cooled to -70 ^° C. Diisobutylaluminum hydride was added, keeping the temperature below -58 ^° C for 15 minutes. The mixture was stirred for 10 minutes, after which TCX shows the lack of source material. Ethyl acetate (9 ml) was carefully added while maintaining the temperature below -60 ^° C. The mixture was allowed to warm to room temperature and 10% potassium sodium tartrate solution was added. After stirring for 1 hour, the mixture was extracted with ethyl acetate (3 times). The combined organic extracts were dried (MgSO ₄ ), then approximately 70% of the solvent was removed in vacuo. Methanol (20 ml) was added to the mixture and again about 70% of the solvent was removed in vacuo, this procedure was repeated two more times. This solution was diluted with methanol (20 ml) and 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrobromide (0.64 g) was added. The pH was adjusted to 4 with glacial acetic acid. Sodium cyanoborohydride (0.14 g) was added, then sodium sulfate (50 mg) and the mixture was stirred for 72 hours. The mixture is made basic by the addition of a concentrated aqueous solution of ammonium hydroxide. Volatile products are removed in vacuo and the precipitate is purified by flash chromatography (eluent 10-25% methanol in chloroform). The products are then purified by reverse phase HPLC (eluent 25% methanol in 0.1% aqueous trifluoroacetic acid), whereby after conversion to the hydrochloric acid salt, the title compound is obtained in the form of a white solid (0.417 g).

Mp 205-206 ^o C;
Mass spectrum: FAB 408 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 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 C ₂₂ H ₂₉ N ₃ O ₅ S ₂ • HCl: C, 51.20; H, 5.86; N, 8.14; S, 12.43%.

In an alternative method, the above steps a) and b) are repeated, then steps d) and e) are carried out, which are given below:
d) N- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethyl] - 3- [2- (2-phenylethoxy) ethylaminosulfonyl] propanamide
A solution of the product of stage b) (3.89 g), 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (3.22 g), bromotripyrrolidine phosphonium hexafluorophosphate, PyBroP, (6.32 g ) in dimethylformamide (50 ml) was cooled to -15 ^° C and diisopropylethylamine (9.0 ml) was added dropwise over 5 minutes. The solution was stirred at -15 ^° C for 5 minutes, after which it was allowed to warm to 13 ^° C for more than 4 hours. After this, the mixture was added dropwise over 40 minutes to dilute hydrochloric acid (2N, 500 ml) and, after stirring over the weekend, the solid mass was collected by filtration. This solid mass was dried in vacuo, whereby a subtitle compound (4.5 g) was obtained.

 Mass spectrum: FAB 492 (M-H).

e) 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylethoxy) ethyl] propanesulfonamide hydrochloride
To a solution of the product of stage d) (0.28 g) in tetrahydrofuran (2 ml), borantetrahydrofuran (2.44 ml of a 1M solution) is added over 5 minutes. The mixture was refluxed for 3 hours and, after cooling, methanol (1 ml) was carefully added. Volatiles were removed in vacuo, the residue was redissolved in methanol (5 ml) and concentrated hydrochloric acid (1 ml) was added. Volatile products are again removed in vacuo. The residue was partitioned between water and ethyl acetate, the aqueous layer was collected and extracted again with ethyl acetate. Then the aqueous layer is made basic with sodium bicarbonate and extracted four times with chloroform. The combined chloroform extracts were dried and the volatiles removed in vacuo to give the title compound (0.070 g) after conversion to the hydrochloride salt.

Example 2
N- [2- [2- (4-hydroxy-2-oxo-3H-1.3-benzothiazol-7-yl) ethylamino] ethyl] -2- (2-phenylethoxy) ethanesulfonamide hydrochloride
a) 2- (2-phenylethoxy) ethanesulfonyl chloride
A stirred suspension of 2- (2-phenylethoxy) ethanethiol (1.0 g) in water (40 ml) was saturated at 5-10 ^° C with chlorine for 20 minutes. The mixture is washed with a strong stream of liquid under a stream of nitrogen to remove excess chlorine. The mixture was then extracted with dichloromethane (2 times), the combined organic extracts were washed with water and dried (CaCl ₂ ). The solvent was removed in vacuo to give an oil, which was then azeotroped with toluene to give the title compound as a yellow oil (1.36 g), which was then used without further purification.

Mass spectrum: EI 248/250 (M);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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-dimethoxyethyl) -2- (2-phenylethoxy) ethanesulfonamide
A stirred solution of the product of stage a) (1.0 g) in dichloromethane (20 ml) and pyridine (0.358 ml) are treated by adding dropwise a solution of dimethyl acetal aminoacetaldehyde (0.438 ml) in dichloromethane (5 ml) over 5 minutes. The mixture was stirred at room temperature for 2 days. The mixture was washed with water, then dried (CaCl ₂ ). Volatiles were removed in vacuo to give an orange oil, which was then purified by flash chromatography (eluent-ether) to give the title compound as a yellow oil (0.42 g).

Mass spectrum: 335 (M + NH ₄ );
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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).

c) N- [2- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] ethyl] -2- (2-phenylethoxy) ethanesulfonamide hydrochloride
A solution of the product of step b) (0.26 g) in 70% aqueous acetic acid (5 ml) was heated to 100 ^° C. for 2 hours, after which TCX showed no starting material. The solvent is removed in vacuo. The residue was taken up in methanol (10 ml) and 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrobromide (0.238 g) and sodium cyanoborohydride (0.038 g) were added to this stirred solution. and then acetic acid (1 drop). The mixture was stirred at room temperature for 24 hours. The mixture is made alkaline by the addition of a concentrated aqueous solution of ammonium hydroxide. Volatiles were removed in vacuo and the residue was purified by flash chromatography (eluent 17% ethanol in dichloromethane) to give a pale yellow gum. The mass was then purified by reverse phase HPLC (eluent 30-45% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give the title compound as a white powder (0.080 g) after conversion to hydrochloric acid salt.

Mass spectrum: 466 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 2.81-2.90 (4H, m), 3.04-3.09 (4H, broad d), 3.26-3.28 (2H, m), 3.24 (2H + H ₂ O) , 3.63 (2H, s), 3.74 (2H, t), 6.78 (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 C ₂₁ H ₂₇ N ₃ O ₅ S ₂ • HCl: C, 49.31; H, 5.67; N, 8.22; S, 12.52%
In an alternative method, step (a) is repeated, followed by steps (g) to (g) below.

g) Methyl [2- (2-phenylethoxy) ethylsulfonylamino] acetate
A suspension of methyl glycinate hydrochloride (2.52 g) in dichloromethane (30 ml) was stirred at -18 ^° C and diisopropylethylamine (8 ml) was added over 10 minutes. To this mixture was added the product of step (a) (2.64 g) in dichloromethane (10 ml) dropwise over 10 minutes, keeping the temperature below -5 ^° C. The cooling bath was removed and the stirred mixture was allowed to warm to room temperature. After a further 50 minutes, the mixture was washed with 5% aqueous potassium hydrogen sulfate and dried (Na ₂ SO ₄ ), the volatiles were removed in vacuo to give the title compound as a brown oil (58.5 g).

Mass spectrum: FAB 302 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.90 (2H, t), 3.36 (2H, t), 3.72-3.85 (7H, m), 3.96 (2H, t), 4.70 (1H, br s) 7.20-7.31 (5H, m).

d) 2 - [(2-phenylethoxy) ethylsulfonylamino] acetic acid
A solution of the product of step (g) (3.2 g) in methanol (30 ml) is cooled in an ice bath and treated with a solution of lithium hydroxide hydrate (1.06 g) in water (7 ml) for 5 minutes. The ice bath was removed and the solution was stirred for 16 hours. The mixture was acidified with concentrated hydrochloric acid (3 ml) and concentrated in vacuo to a volume of approximately 15 ml. The residue was mixed with sodium bicarbonate and extracted with ether. Then, the aqueous phase is again acidified with a saturated aqueous solution of potassium hydrogen sulfate and extracted with ether. This extract was dried (MgSO ₄ ) and the volatiles removed in vacuo to give a solid mass. The product is then purified by recrystallization from a mixture of dichloroethane and toluene to give the title compound as a mass of crystalline solid (1.57 g).

Mass spectrum: FAB 288 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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, br s).

e) N- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethyl] - 2- [2- (2-phenylethoxy) ethylsulfonylamino] acetamide
A solution of the product of step (d) (70 g) in dimethylformamide (605 ml) was cooled to -10 ^° C and 1,1'-carbomoyldiimidazole (39.5 g) was added. The mixture was stirred for 119 minutes, then 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (68.87 g) was added, and then triethylamine (34 ml) was added dropwise over 3 minutes, maintaining the temperature at -10 ^o C. After the next 10 minutes at a temperature of -10 ^o C, the mixture was allowed to warm to room temperature and stirred for 24 hours. This mixture was then added dropwise to dilute hydrochloric acid (2N, 1870 ml) and the aqueous mixture was extracted with ethyl acetate. Then the organic products are washed with dilute hydrochloric acid, aqueous sodium bicarbonate and then dried (MgSO ₄ ). Volatiles were removed in vacuo to give the title compound as a foam (92.21 g).

Mass spectrum: FAB 480 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 2.61 (2H, t), 2.81 (2H, t), 3.29-3.32 (4H, m, overlapping 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, br t).

g) N- [2- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] ethyl] -2- (2-phenylethoxy) ethanesulfonamide hydrochloride
A solution of the product of step (e) (38.7 g) in tetrahydrofuran (200 ml) was cooled in an acetone / ice bath and lithium borohydride (727 ml, 2M solution in tetrahydrofuran) was added over 30 minutes. After 15 minutes, the cooling bath was removed and trimethylsilyl chloride (205 ml) was added and stirred for 162 hours at room temperature. The mixture was cooled to -20 ^° C and methanol was carefully added. Then add another 50 ml of methanol saturated with hydrogen chloride, and the mixture is allowed to warm to room temperature. One hour later, the mixture was refluxed for 30 minutes, then cooled and the volatiles removed in vacuo. Water (400 ml) was added, the flask was shaken vigorously and after cooling in an acetone / ice bath for 30 minutes, the water was decanted. An additional amount of water (100 ml) is added, the process is repeated. The semi-solid remaining mass is then dissolved in hot ethanol (40 ml), treated with activated carbon (3 g) and stirred for 1 hour. The mixture was filtered and the solvent was removed in vacuo. The residue was redissolved in hot ethanol (80 ml) and allowed to stand at room temperature for 16 hours. Then the precipitated crystals are loosened and broken with a spatula, shaken and left to stand for another 16 hours. Then the solid was collected by filtration and washed with ethanol, ether, then dried in vacuo to give the title compound (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] propanesulfonamide hydrochloride
a) 2- [2- (5-methyl-2-thienyl) ethoxy] acetic acid
Sodium hydride (0.622 g) was suspended in anhydrous dimethylformamide (5 ml), treated by dropwise adding a solution of 2- (5-methyl-2-thienyl) ethanol (1.0 g) in anhydrous dimethylformamide (5 ml). The mixture was stirred at room temperature under nitrogen for 2 hours, then a solution of chloroacetic acid (0.664 g) in anhydrous dimethylformamide (5 ml) was added. The mixture was mechanically stirred at room temperature overnight. Volatiles were removed in vacuo, the residue was quenched with water and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to a value of 2 using dilute hydrochloric acid, and then extracted with ethyl acetate. This extract was washed with water, brine, then dried (MgSO ₄ ). The solvent was removed in vacuo to give a brown oil (1.51 g), which was then used without further purification.

Mass spectrum: 200 (M);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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] acetamide
The product of step a) (6.48 g) was dissolved in toluene (55 ml) and oxalyl chloride (2.877 ml) was added dropwise at room temperature under a nitrogen atmosphere. A drop of dimethylformamide was added and the mixture was stirred for 3 hours, after which TCX showed no starting material. Volatiles were removed in vacuo to give a brown oil (6.7 g), which was then added dropwise to a stirred concentrated solution of ammonium hydroxide (50 ml) at 0 ^° C. The mixture was allowed to warm to room temperature and was stirred for 4 hours. A brown solid precipitated. This solid was collected by filtration and washed with water, whereby a title compound (2.02 g) was obtained.

Mass spectrum: 200 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.45 (3H, s), 3.04 (2H, t), 3.73 (2H, t), 3.97 (2H, s), 5.61 (2H, br s), 6.57 (1H, d), 6.63 (1H, d).

c) 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 a stirred solution of the product of stage b) (1.25 g) in anhydrous tetrahydrofuran (100 ml). The reaction mixture was refluxed under an inert gas atmosphere for 5 hours. The reaction mixture was cooled and methanol (10 ml) was carefully added. The solvents were removed in vacuo and the residue was dissolved in methanol (100 ml), to which concentrated hydrochloric acid was added (specific gravity 1.18, 0.45 ml). This solution was heated under reflux for 15 minutes, then the solvent was removed in vacuo. The residue was purified by flash chromatography (eluent: dichloromethane: 5% methanol) to obtain the subtitled compound as a white solid (0.916 g).

Mass spectrum: 186 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.45 (3H, s), 3.04 (2H, t), 3.73 (2H, t), 3.97 (2H, s), 5.61 (2H, br s), 6.57 (1H, d), 6.63 (1H, d).

d) Methyl 3- [2- [2- (5-methyl-2-thienyl) ethoxy] ethylaminosulfonyl] propanoate
The product of step c) in the form of hydrochloride (1.50 g) is stirred in dichloromethane (25 ml) under nitrogen. Triethylamine (2.21 ml) was added, followed by methyl 3- (chlorosulfonyl) propanoate (1.18 g). The mixture was mechanically stirred at room temperature overnight. The solution was diluted with an additional volume of dichloromethane and the organic products were washed with diluted hydrochloric acid, then with water, then dried (MgSO ₄ ). The mixture was filtered and the volatiles removed in vacuo to give the title compound as an oil (1.4 g).

Mass spectrum: 336 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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).

d) 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (5-methyl-2-thienyl) ethoxy] ethyl] propanesulfonamide hydrochloride
The product of step g) (0.60 g) is dissolved in toluene (30 ml) in a nitrogen atmosphere and cooled to -78 ^° C. Diisobutylaluminium hydride (1.5 M solution in toluene, 1.78 ml) is added dropwise and the mixture is kept at a temperature of -78 ^° C 10 min Reaction
stopped by adding ethyl acetate, then 10% aqueous potassium tartrate sodium. The mixture was warmed to room temperature and after stirring for 1 hour, extracted with toluene (3 times). The combined organic extracts were washed with water, dried (MgSO ₄ ), then approximately 70% of the solvent was removed in vacuo. Methanol (20 ml) was added to the mixture, and again approximately 70% of the solvent was removed in vacuo, this procedure was repeated two more times. This solution was diluted with methanol (20 ml) and 7- (2-amino-ethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (0.516 g) was added. The pH was adjusted to 4 with glacial acetic acid. Sodium cyanoborohydride (0.114 g) was added and the mixture was stirred for 2 hours under nitrogen. The mixture is made basic by the addition of a concentrated aqueous solution of ammonium hydroxide. Volatile products are removed in vacuo and the residue purified by flash chromatography (eluent 15-20% methanol: dichloromethane). The product is then further purified by reverse phase HPLC (eluent 25-85% methanol in 0.1% aqueous trifluoroacetic acid) to give the title compound as a white solid (0.12 g) after conversion to the hydrochloric acid salt.

Mp 210-212 ^o C;
Mass spectrum: FAB 500 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 2.00 (2H, q), 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, br s).

Example 4
N- [2- [2- (4-fluorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] propanesulfonamide hydrochloride
a) t-butyl-3- [2- (4-fluorophenyl) ethoxy] propanoate
2- (4-fluorophenyl) ethanol (20.5 g) and Triton-B (2.4 ml, 40% in methanol) were mixed together and the methanol was removed in vacuo. Tert-butyl acrylate (21.38 ml) was added and the solution was heated at 50 ^° C. for 2 hours, then stirred at room temperature overnight. The solution was diluted with water and extracted with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO ₄ ) and filtered. Volatiles were removed in vacuo to give the title compound (37.91 g), which was used without further purification.

¹ H NMR (360 MHz, CDCl ₃ ) δ: 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-fluorophenyl) ethoxy] propanoic acid
The product of step a) (37.91 g) was dissolved in dichloromethane (50 ml) and trifluoroacetic acid (50 ml) was added. 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 were washed with water (4 times), then with brine, dried (MgSO ₄ ) and filtered. Volatile products are removed in vacuo, resulting in an oil, this oil is collected in diethyl ether and extracted with aqueous sodium bicarbonate (3 times). The combined aqueous layers were acidified with concentrated hydrochloric acid, then extracted with diethyl ether (x 4). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and filtered. Volatile products are removed in vacuo to give a subtitle compound (19.95 g), which was used without further purification.

Mass spectrum: 212 (M);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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 (2H, m), 7.37 (1H, br s).

c) 2- [2- (4-fluorophenyl) ethoxy] ethyl isocyanate
The product of step b) (15.49 g), triethylamine (11.2 ml) and diphenylphosphoryl azide (15.7 ml) are heated in toluene (150 ml) at 80 ^° C. for 5 hours under a nitrogen atmosphere. The mixture was allowed to cool, then left at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic extracts were washed with aqueous sodium bicarbonate, diluted with hydrochloric acid, saturated brine, then dried (MgSO ₄ ) and filtered. Volatiles were removed in vacuo and the residue was purified by flash chromatography (eluent 50% diethyl ether: isohexane) to give the title compound (5.54 g).

Mass spectrum: 209 (M);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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-fluorophenyl) ethoxy] ethyl] carbamate
The product of step c) (9.0 g) was dissolved in methanol (300 ml) and sodium methoxide (4.65 g) was added to this stirred solution. The mixture was mechanically stirred at room temperature for 3 hours. Volatiles were removed in vacuo and the residue was extracted with ethyl acetate. This ethyl acetate was washed with brine, dried (MgSO ₄ ) and filtered. Volatiles were removed in vacuo and a portion of the residue was further purified by flash chromatography (eluent 60% diethyl ether: isohexane) to give the title compound (0.375 g).

Mass spectrum: FAB 242 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.84 (2H, t), 3.34 (2H, t), 3.49 (2H, 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 C ₁₂ H ₁₆ FNO ₃ : C, 59.74; H, 6.68; N, 5.81%.

d) 2- [2- (4-fluorophenyl) ethoxy] ethanamine
The product of step g) (8.0 g) was dissolved in ethylene glycol and potassium hydroxide (48 g) and hydrazine hydrate (8.3 ml) were added to this. The stirred mixture was heated to 140 ^° C. for 4 hours, then allowed to cool to room temperature overnight. The mixture was diluted with water and extracted with diethyl ether (3 times). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and filtered. Volatiles were removed in vacuo to give the title compound (5.36 g).

Mass spectrum: 184 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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-fluorophenyl) ethoxy] ethylaminosulfonyl] propanoate
The title compound (8.32 g) was obtained according to the method of Example 3 g) using 2- [2- (4-fluorophenyl) ethoxy] ethanamine (5.36 g), triethylamine (4.6 ml) and methyl 3- (chlorosulfonyl) propanoate ( 5.6 g) in diethyl ether (150 ml).

Mp 49 ^o C;
Mass spectrum: 184 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.78-2.87 (4H, m), 3.24-3.28 (2H, m), 3.34 (2H, t), 3.51-3.56 (2H, t), 3.65 (2H, t), 3.73 (3H, s), 6.97-7.01 (2H, m), 7.15-7.19 (2H, m).

Elemental analysis
Found: C, 50.52; H, 6.24; N, 4.16; S, 9.40%
Calculated for C ₁₄ H ₂₀ FNO ₅ S: C, 50.44; H, 6.05; N, 4.20; S, 9.62%.

g) N- [2- [2- (4-fluorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-3H-1.3-benzothiazol-7-yl) ethylamino] propanesulfonamide hydrochloride
The title compound (0.092 g) was prepared according to the method of Example 3e) using methyl 3- [2- [2- (4-fluorophenyl) ethoxy] ethylaminosulfonyl] propanoate (1.0 g), diisobutylaluminum hydride (1.5 M solution in toluene, 4 ml ), 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2- (3H) -one hydrochloride (0.875 g) and sodium cyanoborohydride (0.354 g).

Mp 195-197 ^o C;
Mass spectrum: FAB 498 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 1.99 (2H, q), 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, s).

Elemental analysis
Found: C, 49.01; H, 5.74; N, 7.96; S, 11.50%
Calculated for C ₂₂ H ₂₉ NF ₃ O ₅ S ₂ • HCl • 0.5H ₂ O: 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] propanesulfonamide hydrochloride
a) 2- [2- (4-chlorophenyl) ethoxy] acetic acid
2- (4-chlorophenyl) ethanol (10 g) was stirred in 50% aqueous sodium hydroxide (70 ml), tetrabutylammonium bromide (1.4 g) was added and the mixture was stirred for 1 hour. Tert-butyl bromoacetate (28.6 ml) in toluene (140 ml) was added and stirring was continued for 18 hours. Water (50 ml) was added and after two hours the mixture was cooled on ice and acidified to pH 1 with concentrated hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO ₄ ). The solvent was removed in vacuo to give a pale yellow oil. This oil was dissolved in dichloromethane (100 ml) and trifluoroacetic acid (100 ml) was added, the mixture was heated under reflux for 1 hour. Volatile products are removed in vacuo, and the residue is collected in sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate, this ethyl acetate was washed with water, dried (MgSO ₄ ) and the volatiles removed in vacuo to give the title compound as a light tan solid (16.4 g), which was used without further purification .

 Mass spectrum: EI 214/6 (M).

b) 2- [2- (4-chlorophenyl) ethoxy] acetamide
The product of step a) (16.4 g) was dissolved in toluene (300 ml) and oxalyl chloride (13 ml) was added dropwise at room temperature under a nitrogen atmosphere. The mixture was stirred for 1 hour, then dimethylformamide (0.3 ml) was added. After 2 hours, volatiles were removed in vacuo to give a brown oil, which was added dropwise to a stirred solution of concentrated ammonium hydroxide (60 ml). The precipitated solid was collected by filtration, washed with water and isohexane, whereby the title compound (6.6 g) was obtained.

Mp 106-109 ^o C;
Mass spectrum: FAB 214/6 (m + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.89 (2H, t), 3.73 (2H, t), 3.93 (2H, s), 5.87 (1H, br s), 6.22 (1H, br s) 7.16 (2H, d); 7.28 (2H, d).

c) 2- [2- (4-chlorophenyl) ethoxy] ethanamine
The product of stage b) is added in small portions to a stirred solution of borantetrahydrofuran (1.0 M in THF, 85 ml). The reaction mixture was refluxed under an inert gas atmosphere for 3 hours. The reaction mixture was cooled and methanol (10 ml) was carefully added. The solvents were removed in vacuo and the residue was dissolved in methanol (100 ml), to which concentrated hydrochloric acid was added (specific gravity 1.18, 4 ml). This solution was heated under reflux for 30 minutes, then the solvent was removed in vacuo. The residue was taken up in water and washed with ether. Sodium bicarbonate was added and the aqueous layer was extracted with ethyl acetate. This ethyl acetate was washed with water, brine and dried (MgSO ₄ ). Volatiles were removed in vacuo to give the title compound as an oil (5.5 g), which was then used without further purification.

 Mass spectrum EI 200/2 (M + H).

d) Methyl 3- [2- [2- (4-chlorophenyl) ethoxy] ethylaminosulfonyl] propanoate
The product of step c) (1.1 g) was stirred in dichloromethane (30 ml) under nitrogen, triethylamine (1.52 ml) was added, followed by methyl 3- (chlorosulfonyl) propanoate (2.04 g). The mixture was stirred at room temperature for 3 hours. Volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (eluent 60% ether: gasoline) to give the title compound (1.1 g) as an oil.

Mass spectrum: FAB 350/2 (m + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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] propanesulfonamide hydrochloride
The product of step g) (1.1 g) is dissolved in toluene (50 ml) in a nitrogen atmosphere and cooled to -78 ^° C. Diisobutylaluminum hydride (1.5 M solution in toluene 2.6 ml) is added dropwise and the mixture is kept at -78 ^° C for 10 minutes. . The reaction was stopped by the addition of 10% hydrochloric acid in ethanol and the mixture was allowed to warm to room temperature. The mixture was poured into 10% hydrochloric acid and extracted with ether. The combined organic extracts were washed with water, dried (MgSO ₄ ), then approximately 70% of the solvent was removed in vacuo. Methanol (20 ml) was added to the mixture, and again approximately 70% of the solvent was removed in vacuo, this procedure was repeated two more times. This solution was diluted with methanol (20 ml) and 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (0.92 g) was added. The pH was adjusted to 4 with glacial acetic acid. Sodium cyanoborohydride (0.247 g) was added and the mixture was stirred for 2 hours under nitrogen. The mixture is made basic by the addition of a concentrated aqueous solution of ammonium hydroxide. Volatile products are removed in vacuo and the residue purified by flash chromatography (eluent 2.5-10% methanol: dichloromethane). The product is then purified by reverse phase HPLC (eluent 50-100% methanol in 0.1% aqueous trifluoroacetic acid), whereby after conversion to the hydrochloric acid salt, the title compound is obtained in the form of a white solid (0.089 g).

T. pl. 190-193 ^o C;
Mass spectrum: FAB 514/6 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 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, br s), 10.14 (1H, s), 11.77 (1H, br s).

Elemental analysis
Found: C, 46.68; H, 5.55; N, 7.47; S, 10.86%
Calculated for C ₂₂ H ₂₈ N ₃ O ₅ S ₂ • HCl • H ₂ O: C, 46.47; H, 5.50; N, 7.39; S, 11.28%.

Example 6
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (4-methylphenyl) ethoxy] ethyl] propanesulfonamide hydrochloride
a) 2- [2- (4-methylphenyl) ethoxy] acetic acid
2- (4-methylphenyl) ethanol (8.16 g) was stirred in 50% aqueous sodium hydroxide (25 ml), t-butyl bromoacetate (9.05 ml) in toluene (30 ml) was added together with tetrabutylammonium bromide (2.2 g) and the mixture was stirred for 18 hours. Ice water (100 ml) was added, then ether, the organic layer was separated and then the aqueous layer was acidified with hydrochloric acid. The acidified aqueous layer was extracted with ether, this extract was washed with brine and dried (MgSO ₄ ). The solvent was removed in vacuo to give the title compound as a white solid (1.1 g), which was used without further purification.

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

b) 2- [2- (4-methylphenyl) ethoxy] acetamide
The title compound (0.77 g) was obtained according to the method of Example 1, step (b) using 2- [2- (4-methylphenyl) ethoxy] acetic acid (1.1 g), oxalyl chloride (1.44 g), concentrated ammonium hydroxide (20 ml) and toluene (40 ml).

T. pl. 106-107 ^o C;
Mass spectrum: FAB 194 (M + H, 100);
c) 2- [2- (4-methylphenyl) ethoxy] ethanamine hydrochloride
The title compound (6.25 g) was obtained according to the method of Example 5, step (c) using 2- [2- (4-methylphenyl) ethoxy] acetamide (5.79 g), borane tetrahydrofuran (1.0 M in THF , 75 ml) and tetrahydrofuran (40 ml).

Mass spectrum: FAB 180 (M + H, 100);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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, broad s).

d) Methyl 3- [2- [2- (4-methylphenyl) ethoxy] ethylaminosulfonyl] propanoate
The title compound (2.49 g) was obtained according to the method of Example 5, step (g) using 2- [2- (4-methylphenyl) 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));
d) 3- [2- (4-hydroxy-2-oxo-3H-1.3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (4-methylphenyl) ethoxy] ethyl] propanesulfonamide hydrochloride
The title compound (0.2 g) was obtained according to the method of Example 5, step (e) using methyl 3- [2- [2- (4-methylphenyl) ethoxy] ethylaminosulfonyl] propanoate (2.49 g), diisobutylaluminium hydride (1.5 M solution in toluene, 7.5 ml), 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (2.2 g) and sodium cyanoborohydride (0.48 g).

T. pl. 213-215 ^o C;
Mass spectrum: FAB 494 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 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, br s).

Example 7
3- [2- (4-hydroxy-2-oxo-3H-1.3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenyl-1-propoxy) ethyl] propanesulfonamide hydrochloride
a) 2- (2-phenyl-1-propoxy) acetic acid
The title compound (14.95 g) was obtained according to the method of Example 6, step (a) using 2-phenyl-1-propanol (13.6 g), tert-butyl bromoacetate (19.5 g), tetrabutylammonium bromide (3.2 g), toluene ( 70 ml) and 50% aqueous sodium hydroxide (25 ml).

¹ H NMR (360 MHz, CDCl ₃ ) δ: 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) acetamide
The title compound (4.39 g) was obtained according to the method of Example 5, step (b) using 2- (2-phenyl-1-propoxy) acetic acid (5.0 g), oxalyl chloride (4.5 ml), concentrated ammonium hydroxide (20 ml ) and toluene (30 ml).

Mass spectrum: GC 134 (M-59);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 1.31 (3H, d), 3.05 (1H, m), 3.61 (2H, m), 3.90 (2H, q), 7.22 (3H, m), 7.33 ( 2H, m).

c) 2- (2-phenyl-1-propoxy) ethanamine hydrochloride
The title compound (3.58 g) was obtained according to the method of Example 5, step c) using 2- (2-phenyl-1-propoxy) acetamide (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) ethylaminosulfonyl] - propanoate
The title compound (2.0 g) was obtained according to the method of Example 5, step (g) using 2- (2-phenyl-1-propoxy) ethanamine hydrochloride (3.58 g), triethylamine (5.65 ml), methyl 3- (chlorosulfonyl ) propanoate (3.73 g) and dichloromethane (70 ml).

Mass spectrum: GC 224 (M-105);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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).

d) 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenyl-1-propoxy) ethyl] propanesulfonamide hydrochloride
The title compound (0.164 g) was obtained according to the method of Example 5, step (e) using methyl 3- [2- (2-phenyl-1-propoxy) ethylaminosulfonyl] propanoate (1.01 g), diisobutylaluminum hydride (1.5 M solution in toluene 3 ml), 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (0.89 g) and sodium cyanoborohydride (0.19 g).

T. pl. 183-184 ^o C;
Mass spectrum: FAB 494 (M + H);
Elemental analysis
Found: C, 52.42; H, 6.31; N, 8.28; S, 11.74%
Calculated for C ₂₃ H ₃₁ N ₃ O ₅ S ₂ • HCl: 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-methylphenyl) ethoxy] ethyl] propanesulfonamide hydrochloride
a) 2- [2- (2-methylphenyl) ethoxy] acetic acid
The subtitle compound (8.91 g) was obtained according to the method of Example 5, step (a) using 2- (2-methylphenyl) ethanol (5.0 g), tert-butyl bromoacetate (5.47 g), tetrabutylammonium bromide (0.78 g), toluene (80 ml), 50% aqueous sodium hydroxide (40 ml), trifluoroacetic acid (20 ml) and dichloromethane (20 ml).

¹ H NMR (360 MHz, CDCl ₃ ) δ: 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, br s).

b) 2- [2- (2-methylphenyl) ethoxy] acetamide
The subtitle compound (5.02 g) was prepared according to the method of Example 5, step (b) using 2- [2- (2-methylphenyl) ethoxy] acetic acid (6.726 g), oxalyl chloride (6.22 ml), concentrated ammonium hydroxide (60 ml) and toluene (60 ml).

Mass spectrum: FAB 194 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 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, broad s).

c) 2- [2- (2-methylphenyl) ethoxy] ethanamine hydrochloride
The subtitle compound (5.4 g) was obtained according to the method of Example 5, step (c) using 2- [2- (2-methylphenyl) ethoxy] acetamide (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-methylphenyl) ethoxy] ethylaminosulfonyl] propanoate
The subtitle compound (5.4 g) was prepared according to the method of Example 5, step (g) using 2- [2- (2-methylphenyl) ethoxy] ethanamine hydrochloride (5.4 g), triethylamine (8.73 ml), methyl 3- (chlorosulfonyl ) propanoate (4.66 g) and dichloromethane (100 ml).

Mass spectrum: FAB 330 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 2.32 (3H, s), 2.71 (2H, t), 2.91 (2H, t), 3.24 (2H, t), 3.34 (2H, t), 3.53 (2H , m), 3.62 (2H, t), 3.70 (3H, s), 4.64 (1H, t), 7.14 (4H, m).

d) 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (2-methylphenyl) ethoxy] ethyl] propanesulfonamide hydrochloride
The product of step g) (2.0 g) was dissolved in toluene (100 ml) under nitrogen and cooled to -78 ^° C. Diisobutylaluminum hydride (1.5 M solution in toluene, 6.22 ml) was added dropwise and the mixture was kept at -78 ^° C in for 10 minutes. The reaction is stopped by the addition of ethyl acetate, then a 10% aqueous solution of potassium sodium tartrate. The reaction mixture was warmed to room temperature and after stirring for 1 hour, extracted with toluene. The combined organic extracts were washed with water, dried (MgSO ₄ ), then approximately 70% of the solvent was removed in vacuo. Methanol (50 ml) was added to the mixture and again approximately 70% of the solvent was removed in vacuo, this procedure was repeated two more times. The solution was diluted with methanol (50 ml) and 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (1.8 g) was added. The pH was adjusted to 4 with glacial acetic acid. Sodium cyanoborohydride (0.114 g) was added and the mixture was stirred for 18 hours under nitrogen. The mixture is made basic by the addition of a concentrated aqueous solution of ammonium hydroxide. Volatile products are then removed in vacuo. The precipitate was purified by flash chromatography on silica (eluent 1% methanol: dichloromethane). The material was then purified by reverse phase HPLC (eluent 35-85% methanol in 0.1% aqueous trifluoroacetic acid), whereby after conversion to the hydrochloric acid salt, the title compound was obtained as a white solid (0.38 g).

T. pl. 184-187 ^o C;
Mass spectrum: FAB 494 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 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, br s).

Example 9
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylthioethoxy) ethyl] propanesulfonamide hydrochloride
a) tert-butyl 2- (2-phenylthioethoxy) acetate
2-phenylthioethanol (6.1 g), tert-butyl bromoacetate (7.9 ml), tetrabutylammonium bromide (1.3 g), toluene (80 ml) and 75% aqueous sodium hydroxide (40 ml) were stirred together for 72 hours. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, dried (MgSO ₄ ) and the solvent was removed in vacuo to give the title compound (12.07 g).

 Mass spectrum: FAB 269 (M + H).

b) 2- (2-phenylthioethoxy) acetamide
The product of step a) (12.07 g) was dissolved in dichloromethane (50 ml) and trifluoroacetic acid (50 ml) was added, the mixture was stirred for 2 hours. Volatile products are removed in vacuo, and the residue is collected in an aqueous solution of sodium bicarbonate and washed with ether. The aqueous layer was acidified with concentrated hydrochloric acid, then extracted with ethyl acetate. Ethyl acetate was washed with brine, dried (MgSO ₄ ) and the volatiles removed in vacuo. The residue was dissolved in toluene (50 ml) and oxalyl chloride (50 ml) was added dropwise at room temperature under a nitrogen atmosphere. Dimethylformamide (0.3 ml) was added dropwise, and the mixture was stirred for 45 minutes. Volatiles were removed and the crude acid chloride was added dropwise to a stirred solution of concentrated ammonium hydroxide (50 ml) at -10 ^° C. The precipitated solid was collected by filtration, washed with water and ether, to give the title compound (3.53 g).

Mass spectrum: FAB 212 (M + H);
¹ H NMR (360 MHz, CDCl ₃ ) δ: 3.13 (2H, t), 3.72 (2H, t), 3.95 (2H, s), 5.58 (1H, br s), 6.56 (1H, br s) 7.20-7.39 (5H, m).

c) 2- (2-phenylthioethoxy) ethanamine hydrochloride
The title compound in the form of a hydrochloric acid salt (6.0 g) was obtained according to the method of Example 5, step (c) using 2- (2-phenylthioethoxy) acetamide (5.5 g), a solution of borantetrahydrofuran (1.0 M in THF, 60 ml) and tetrahydrofuran (60 ml).

d) Methyl 3- [2- (2-phenylthioethoxy) ethylaminosulfonyl] propanoate
The title compound (2.85 g) was obtained according to the method of Example 5, step (g) using 2- (2-phenylthioethoxy) ethanamine hydrochloride (6.0 g), triethylamine (4 ml), methyl 3- (chlorosulfonyl) propanoate (5.8 g) and dichloromethane (50 ml).

 Mass spectrum: FAB 348 (M + 105).

d) 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylthioethoxy) ethyl] propanesulfonamide hydrochloride
The title compound (0.106 g) was obtained according to the method of Example 8, step (e) using methyl 3- [2- (2-phenylthioethoxy) ethylaminosulfonyl] propanoate (1.4 g), diisobutylaluminum hydride (1.5 M solution in toluene, 3 ml ), 7- (2-aminoethyl) -4-hydroxy-1,3-benzothiazole-2 (3H) -one hydrochloride (1.2 g) and sodium cyanoborohydride (0.3 r).

T. pl. 193-194 ^o C;
Mass spectrum: FAB 512 (M + H);
¹ H NMR (360 MHz, d ₆ DMSO) δ: 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, br s. )

Pharmacological Example
The affinity of the binding of the compounds of the examples described above to the binding sites of DA ₂ receptors on the pituitary membranes of the bull is determined by the displacement of [ ³ H] -N-n-propylnano-pomorphine and [ ³ H] -spiperone, respectively, in the presence or absence of a non-hydrolyzable GTP analog , DR 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 DA ₂ receptors is demonstrated in a functional study on an isolated rabbit ear artery as described by Brown and O 'Connor, Br. J. Pharmacol., 1981, 73, 189P.

Β ₂ -adrenoreceptor activity was shown on the isolated guinea pig trachea as described by IG Dougall, D. Harper., DM Jackson and P. Leff, Br. J. Pharmacol., 1991, 104, 1057.

Activity against α ₁ receptors is determined on an isolated rabbit ear artery in the following manner.

Rabbit's isolated ear artery
Male NZW rabbits (2.5-3 kg) are sacrificed by intravenous injection of sodium pentobarbitonate (60 mg / kg). The ears are removed, the proximal part of the middle ear artery is isolated and a cannula is inserted into it using a polypropylene cannula (external diameter 0.75 mm). After removal, the artery is cleaned of adjacent connective tissue and dissected, receiving 6 rings 5 mm wide with preservation of a layer of circular smooth muscles. Tissues are placed on thin tungsten wire hooks (diameter 0.25 mm) in a 20 ml organ bath with a Krebs solution of the following composition (mm): NaCl 117.56; NaHCO ₃ 25.00; KCl 5.36; NaH ₂ PO ₄ 0.89; MgSO ₄ 1.18; glucose 11.10 and CaCl ₂ 2.55. Cocaine (30 μM) and propanolol (1 μM) are also included in the solution in order to block neuronal uptake and β receptors, respectively. Ascorbate (100 μM) is also added to prevent catecholamine oxidation. The temperature of this solution was maintained at 37 ^° C. and 95% O ₂ and 5% CO _{2 were} continuously passed through it. The upper wire hook is connected to the Ormed displacement force sensor, the lower hook is connected to a fixed substrate in the bath. Changes in isometric force are recorded with an Advance Bryans AB500 horizontal plane recorder.

experimental part
general description
At the beginning of which experiment, a load of 1.0 g is applied to each piece of tissue. This load is applied repeatedly two or three times during a stabilization period of approximately 60 minutes until it becomes constant. At the same time, when the load is reinstalled, the baths are washed. The concentration-action curves (E / [A]) are plotted using the cumulative addition of an agonist in 0.5 log ₁₀ increments. Reactions (reductions) are recorded as a percentage of the maximum response when using a standard agonist.

Quantification of agonist action
Phenylephrine is used as a standard agonist. First, the E / [A] curve for phenylephrine is constructed. Then phenylephrine is washed and the E / [A] curve is plotted for the test compound. Agonism causing compounds are expressed as a percentage of the maximum phenylephrine response. The asymptotic value of the curve of the test compound relative to phenylephrine shows the intrinsic activity of the compound. Phenylephrine's own activity is taken as 1).

The value of p [A ₅₀ ] is a measure of the activity (strength) of the agonist. This is the negative logarithm of the agonist concentration causing half the maximum response. For compounds whose intrinsic activity is significantly less than 1, for example, ≅0.8, it is possible to calculate the efficacy values (τ) and affinity values (pK _A ) using the comparative analysis method. In such an analysis, it is assumed that phenylephrine acts as a complete agonist in this system, and therefore, it is used to determine the operational model parameters E _m and 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 to perform a comparative analysis of the test compounds. The affinity is expressed as pK _A (negative logarithm of an agonist concentration sufficient to occupy half of the receptors).

Quantification of antagonistic effects
Compounds that did not manifest themselves as agonists were tested for antagonistic activity by incubating tissues with the highest concentrations of this compound, followed by the construction of E / [A] curves, phenylephrine curves. The degree of rightward shift of such phenylephrine curves is compared with the phenylephrine control curves, which allows one to evaluate the affinity of the test compound. This affinity score is expressed in pA ₂ values (the negative logarithm of the antagonist concentration that gives a double shift to the right of the control E / [A] curve).

Confirmation of α ₁ -mediated agonism
Prazosin was accepted as the standard α ₁ antagonist. If, under these conditions, the test compound exhibits agonism, then when the asymptote of the E / [A] curve of the test compound is reached, prazosin (1 μM) is added to check if this reaction is reversible. If the α ₁ antagonist eliminates the response to the test compound, then this suggests that agonism is mediated by α ₁ .

Activity Data
The table below includes data on the agonistic activity of the β ₂ -adrenoreceptor and DA ₂ -receptor of dopamine compounds 1-9 of the application.

Β ₂ -adrenoreceptor activity is illustrated in a study described by Dougall et al. in Br.J. Pharmacol., 1991, 104, 1057 (see test corresponding to page 11, lines 21-23 of WO 97/10227). In this study, to obtain quantitative data on the activity of β ₂ -adrenoreceptors, an isolated guinea pig trachea containing β ₂ -adrenoreceptors is used, which, when stimulated, leads to relaxation of smooth muscles. Isoprenaline, which is considered a complete agonist of this system, is used as a control.

 Agonistic concentration-action curves are obtained by cumulative addition of the test compound to a preparation from an isolated guinea pig trachea, and the responses are recorded as a percentage of the response of isoprenaline.

The value of pA _50, which is a measure of the effectiveness of the agonist, is defined as the negative logarithm of the concentration of the agonist causing the response, which is half the maximum response.

 If the test compound causes relaxation of smooth muscle, then its true activity can be determined. True activity is the response elicited by the test compound, divided by the maximum response elicited by isoprenaline.

The pA ₅₀ value and the true activity of each compound of the examples are presented in the table below.

Dopamine receptor activity (DA ₂ ) is illustrated in a study described by Brown et al. in Br.J. Pharmacol., 1981, 73, 189P (see text corresponding to p. 11, lines 19-21 of WO 97/10227), using, as a control, a compound identified as “58075AB”. The pA ₅₀ values and the true activity of each compound of the examples are included in the table along with the results of the study of β ₂ -adrenoreceptor.

As the data in the table clearly show, the compounds in accordance with this invention show good agonism with respect to the β ₂ -adrenoreceptor and DA ₂ -receptor of dopamine, providing high applicability of these compounds in the treatment of respiratory diseases.

Claims (18)

1. The benzothiazolone compound of formula I

characterized in that
X is —SO ₂ NH— or —NHSO ₂ -;
p, q and r independently represent 2 or 3;
Y represents thienyl optionally substituted with C _1-6 alkyl or halogen, or phenylthio or phenyl optionally substituted with C _1-6 alkyl or halogen;
each of R independently represents H or C _1-6 alkyl, its optical isomers and its pharmaceutically acceptable salts.  2. The benzothiazolone compound according to claim 1, characterized in that q = 2.  3. The benzothiazolone compound according to claim 1, characterized in that r = 2.  4. The benzothiazolone compound according to claim 1, characterized in that Y is phenyl substituted with methyl.  5. The benzothiazolone compound according to claim 1, characterized in that Y is phenyl substituted with a halogen selected from chlorine or fluorine. 6. The benzothiazolone compound according to claim 1, characterized in that X = SO ₂ NH, p = 3, and each of r and q = 2. 7. The benzothiazolone compound according to claim 1, characterized in that X = NHSO ₂ , and each of p, q and r = 2.  8. The benzothiazolone compound according to any one of the preceding paragraphs, characterized in that it is in the form of a pharmaceutically acceptable salt selected from salts of hydrochloride, citrate, D, L-lactate, hemi sulfate, hemi-sulfate, D-gluconate, methanesulfonate, p-toluenesulfonate, semi-fumarate , benzoate, xinafoate, hemisuccinate, 3-hydroxy-2-naphthoate, half embonate, semimaleate, D-camphorsulfonate, 10-undecanoate, mandelate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, 4-methoxybenzoate, 4-chlorobenzoate -methyl salicylate, saccharinate, monomethyl suberate, usuberata and diphenylacetates. 9. The benzothiazolone compound according to claim 1, characterized in that it is selected from the following compounds:
2- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylethoxy) ethyl] propanesulfonamide;
N- [2- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] ethyl] -2- (2-phenylethoxy) ethanesulfonamide;
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (5-methyl-2-thienyl) ethoxy] ethyl] propanesulfonamide;
N- [2- [2- (4-fluorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] propanesulfonamide;
N- [2- [2- (4-chlorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] propanesulfonamide;
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2 - [- (4-methylphenyl) ethoxy] ethyl] propanesulfonamide;
(R, S) -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenyl-1-propoxy) ethyl ] propanesulfonamide;
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (2-methylphenyl) ethoxy] ethyl] propanesulfonamide; and
3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N [2- (2-phenylthioethoxy) ethyl] propanesulfonamide.  10. The benzothiazolone compound according to claim 9, characterized in that it is in the form of a hydrochloride salt. 11. A method of producing a benzothiazolone compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that selective reductive alkylation of the compound of formula II is carried out

compound of formula III

in which p, q, r, R, X and Y have the meanings indicated in claim 1, in the presence of a reducing agent. 12. A method of obtaining a compound of benzothiazolone of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that the selective recovery of the compounds of formula IV is carried out

in which p, q, r, R, X and Y have the meanings indicated in claim 1. 13. The amide of formula IV

in which p, q, r, R, X and Y have the meanings indicated in claim 1. 14. The aldehyde of the formula III

in which p, q, r, R, X and Y have the meanings indicated in claim 1. 15. The acid of the formula V

in which p, q, r, R, X and Y have the meanings indicated in claim 1. 16. A pharmaceutical composition exhibiting an agonistic effect on DA ₂ receptors and β ₂ andro receptors, comprising a benzothiazolone compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims. 1-10 dispersed in a propellant, optionally including fillers, lubricants or stabilizers. 17. A pharmaceutical composition exhibiting an agonistic effect on DA ₂ receptors and

adrenergic receptors and comprising a benzothiazolone compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, in the form of a sprayable aqueous suspension or solution. 18. A pharmaceutical composition exhibiting an agonistic effect on DA ₂ receptors and β ₂ adrenoreceptors and comprising a benzothiazolone compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, in the form of a dry powder for inhalation, optionally including a pharmaceutically acceptable carrier. Priority on points and signs:
09/15/1995 according to claim 1, where X is —SO ₂ NH— or —NHSO ₂ ; p, q, r independently represent 2 or 3; Y represents phenyl optionally substituted with halogen; R represents H;
according to claim 9, wherein the compounds are: 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylethoxy] ethyl ] propanesulfonamide; N- [2- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] ethyl] -2- (2-phenylethoxy) ethanesulfonamide; 3- [2 - (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- [2- (5-methyl-2-thienyl) ethoxy] ethyl] propanesulfonamide;
according to claims 2 to 8, 11 to 18;
07/10/1996 according to claim 1, where Y is phenylthio, optionally substituted with C _1-6 alkyl;
according to claim 9, wherein the compounds are: N- [2- [2- (4-fluorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl) ethylamino] propanesulfonamide; N- [2- [2- (4-chlorophenyl) ethoxy] ethyl] -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] propanesulfonamide; 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenylethoxy) ethyl] propanesulfonamide; (R, S) -3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [2- (2-phenyl-1-propoxy) ethyl ] propanesulfonamide; 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N [2- [2- (2-methylphenyl) ethoxy] ethyl] propanesulfonamide; 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N [2- (2-phenylthioethoxy) ethyl] propanesulfonamide;
according to claim 10;
09/12/1996 according to claim 1, where Y is thienyl, optionally substituted with C _1-6 alkyl or halogen.

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