CH642057A5 - Benzenesulphonamide and benzamide derivatives and their preparation - Google Patents

Description

60 The invention relates to new benzenesulfonamide and benzenecarboxamide derivatives, their preparation and medicaments containing these compounds.

It has been found that certain benzenesulfonamide and benzenecarboxamide derivatives are suitable for the treatment of kar-65 diovascular disorders, such as angina and high pressure, because of their ability to block β-adrenoreceptors. A number of these compounds additionally have a usable blocking effect on a-adrenore-

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receptors. The combined α and β blocking activity of these compounds makes them particularly well suited for the treatment of high pressure. The compounds can also be used to treat peripheral vascular diseases,

e.g. B. Raynaud's disease, and used to treat cardiac arrhythmias.

The invention relates to compounds of the general formula:

'-fr

R

CH-CH2-NH-CH (CH ^) CH2 X

(I)

OH

wherein

Rj represents a halogen or the group NR2R3; R2 and R3, which may be the same or different, represent hydrogen or straight-chain or branched (Cj-QO-alkyl), or where R2 and R3 together with the nitrogen atom can form a 5- or membered heterocyclic ring which is a further heteroatom from the group can contain O, N or S, or where R2 is hydrogen and R3 is the group R4CO or R4S02, where R4 is hydrogen or (C1_4) alkyl;

R5 represents hydrogen or one or more halogen atoms or hydroxy or (C] _4) alkoxy groups;

X is CH2.0 or the group NR6, in which Re is hydrogen or (CM) alkyl, and

Y stands for S02NH2 or CONH2,

and the acid addition salts with organic or inorganic acids thereof.

Preferred compounds according to the invention are those in which R 1 is chlorine, fluorine or an amino, (C, 4) -alkylamino or (C 1-4 -dialkylamino group, in particular a dimethylamino group. Rs is preferably hydrogen or halogen and in particular fluorine If R5 is halogen, this substituent can be in the para or meta position, X is preferably CH2.

A particularly preferred group of compounds contains the following compounds. These compounds in particular show the ability to block both α and β adoreceptors.

2-fluoro-5- [l-hydroxy-2 - [[3- (4-fluorophenyl) -l-methylpropyl] -

amino] ethyl] benzenesulfonamide. 2-fluoro-5- [l-hydroxy-2 [(l-methyl-3-phenylpropyl) amino] -

ethyl] -benzenesulfonamide.

2-dimethylamino-5- [l-hydroxy-2 - [(1-methyl-3-phenyl-

propyl) amino] ethyl] benzenesulfonamide. 2-amino-5- [l-hydroxy-2 - [(l-methyl-3-phenylpropyl) -ami-

no] -ethyl] -benzoisulfonamide. 5- [l-Hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] -

ethyl] -2-methylaminobenzenesulfonamide. 2-dimethylamino-5- [l-hydroxy-2- [N- (l-methyl-3-phe-

nylpropyl) amino] ethyl] benzamide. 2- (butylmethylamino) -5- [l-hydroxy-2 - [(l-methyl-3-phe-

nylpropyl) amino] ethyl] benzenesulfonamide.

2-fluoro-5- [l -hydroxy-2 - [[3- (3-fluorophenyl) -1 -methyl-

propyl] amino] ethyl] benzenesulfonamide. 2- (ethylmethylamino) -5- [l-hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] benzene sulfonamide. The compounds according to the invention include all possible diastereoisomers and optical enantio-morphs as well as mixtures thereof. The acid addition salts with inorganic or organic acids can e.g. the hydrochlorides, maleates, tartrates, etc.

The blocking effects on the a- and ß-adreno-receptors were demonstrated in a bilaterally vagotomized anesthetized dog. The compounds were administered by injection into a cannulated femoral vein. The β-blocking activities of the compounds were determined for their ability to antagonize increases in heart rate induced by intravenous administration of (-) - isoprenaline. The DR10 values for each antagonist were calculated from the values obtained. The DR10 value is the dose of the antagonist required to cause the agonist dose-response curve to shift 10 times to the right for increases in heart rate. 20 The a-blocking activities of the compounds were determined by their ability to prevent increases in diastolic blood pressure caused by intravenous administration of phenylephrine. The a-blocking activity was quantified as the DR10-25 value as described above.

A process for the preparation of the benzenesulfonamide and benzenecarboxamide derivatives according to the invention is characterized in that a compound of the general formula:

CO-CH2-NR7Rq

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or the corresponding alcohol thereof, where Y and Ri have the meanings given in claim 1 and R7 is benzyl and Rg is hydrogen or benzyl, 40 with a ketone of the general formula:

O-C-CH I

ch-

wherein R5 and X have the meanings given in claim 1, reductively alkylated.

So in particular you can use a ketone of the general formula:

55

coch,

(ii)

wherein Y and Rj have the meanings given above, 60 with a halogen, preferably bromine, to halogen ketones of the formula:

rl "ö-

COCHgHal (III)

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4th

react and then with an amine NHR7R8, where R is benzyl or the group R, where R is a "group of the general formula:

ch-

l 3

- gh - chn - x r «

and R8 represents hydrogen or benzyl, to aminoketones of the general formula:

COCH2NR7Rq (V)

\ /

r

'"ö" i oh chch2nr? r8 (vi)

\ /

chch0nhr0 (vii)

L

This can be accomplished by reducing the compounds of formula VI, in which R7 is a benzyl group and Rg has the meaning given above, with a suitable ketone, e.g. one of the formula:

(iv)

10th

c -

i

CH3

ch2x

■ - Rc

(viii)

reductively alkylated in the presence of hydrogen and a suitable catalyst, such as platinum on charcoal or palladium on charcoal.

An amine of the general formula:

wherein R7 and R8 have the meanings given above, condense.

The ketone group in the compound of formula V can then be converted to a CHOH group with a suitable reducing agent, such as a complex metal hydride, e.g. As sodium borohydride, can be reduced, whereby a compound VI:

20th

\ /

chch2nh2 oh

(IX)

with a suitable ketone that provides a group R, e.g. condense one with formula VIII and then reduce the product obtained either by catalytic hydrogenation or with a reducing agent such as sodium 30 borohydride to a compound of formula I according to the invention.

The reductive alkylation can also be carried out directly using a ketone of the formula:

wherein R7 and R8 have the meanings given above, is obtained. The compounds of the formula VI in which R7 represents a group R and R8 represent hydrogen are compounds according to the invention.

Alternatively, the reduction of the compound of formula V can also be accomplished by catalytic hydrogenation in the presence of a noble metal catalyst, e.g. of platinum or palladium or mixtures thereof, whereby 1-phenyl-2-aminoethanol derivatives of the general formula:

h / v el v_V ~ 'C0CH2 \

(x)

8th

wherein R8 has the meaning given above, whereby compounds of formula I according to 45 of the invention are obtained.

In an alternative process for the preparation of compounds according to the invention, a glyoxal of the general formula:

so wherein R9 is hydrogen or the group R can be obtained. The compounds of formula VII in which R9 represents the radical R are compounds according to the invention.

If a non-catalytic reduction is used to reduce the aminoketone V, then the benzyl groups in the molecule are not attacked. In order to convert such benzyl groups into hydrogen atoms, a subsequent catalytic hydrogenolysis can be carried out in order to obtain compounds according to the invention. Catalytic hydrogenolysis can be carried out using hydrogen and a palladium oxide catalyst.

In order to convert compounds of the formula VI in which R7 is benzyl and compounds of the formula VII in which R9 is hydrogen into compounds according to the invention, it is necessary to introduce an R group.

55

c0ch0 (xi)

where Rx has the meaning given above, can be used as starting material. When condensing with an amine of the formula:

H.N - ck - ch „- X 2, 2

65

ch,

the glyoxal provides an intermediate azomethine of the general formula:

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GOCH «N - CH - CH0 -

l 2

CH,

(XIII)

which is then reduced, for example with a complex metal hydride such as sodium borohydride, or hydrogen and a noble metal catalyst. In this way, a compound of formula I is obtained.

CHCHöHal i 8

(XIV)

In another process for the preparation of compounds according to the invention, a halohydrin of the formula XIV or an epoxide of the formula XV can be:

CH - CHf in which Y and Rt have the meanings given above and Hai represents a halogen atom, react with an amine of the formula XII.

It is possible that the group in the Y position is a group that can be converted into a group -CONH2. This group can be converted to the -CONH2 group at any suitable stage in the reaction. Examples of groups which can be converted into a -CONH2 group in a suitable stage are the groups -CN and -CÖOR10, where R10 represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms. The cyano group can be converted by hydrolysis or by treatment with hydroperoxide under basic conditions. The carboxylic acid or ester group can be converted by reaction with ammonia in a suitable solvent, such as ethanol.

If R! represents a halogen atom, it is generally expedient that this is present in the starting materials. If Rx is a group NR2R3, then this can suitably be introduced so that compounds of the formulas II and X, in which Rt is halogen, are treated with ammonia or an amine HNR2R3 in a solvent, preferably ethanol. In the preparation of compounds of the formula I in which R2 is hydrogen and R3 has a meaning other than hydrogen, an amine HN (R3) CH2Ph can be used, with subsequent removal of the benzyl group being provided.

The compounds according to the invention can be isolated as such or in the form of their acid addition salts with organic or inorganic acids.

The compounds according to the invention can be formulated for use in human or veterinary medicine for therapeutic or prophylactic purposes. The invention therefore also includes pharmaceutical compositions which contain at least one compound of the general formula I or a physiologically acceptable addition salt thereof as the active ingredient. As already stated, preferred salts are e.g. the hydrochloride, maleate, tartrate, etc. Such drugs can be presented in a conventional manner with the aid of carriers or excipients and formulation aids as required, and with or without supplemental drugs. Such drugs are e.g. B. solid or liquid preparations for oral administration, suppositories and injectable preparations. Oral administration is most conveniently in the form of tablets which are manufactured by conventional methods and which, if desired, can have a coating. Injectable preparations can be formulated with the aid of physiologically acceptable carriers and agents in the form of solutions, suspensions or as dry products for reconstitution before use. The doses of the active ingredient that can be used generally vary within a wide range. Suitable dosage units are generally in the range from 5 to 1000 mg, preferably 20 to 200 mg. A suitable daily dose is e.g. in the range 35 from 300 to 3000 mg orally, depending on the age and weight of the patient and the severity of the disease. The invention is illustrated in the examples.

example 1

40 2-chloro-5- [1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] benzene sulfonamide hydrochloride:

(a) 5- (2-bromoacetyl) -2-chlorobenzenesulfonamide:

A solution of 5-acetyl-2-chlorobenzenesulfonamide (4.7 g) in glacial acetic acid (100 ml) was treated with bromine (3.2 g) in glacial 45 sig (20 ml), dropwise at 50 ° C with vigorous stirring was treated. After an initial induction period of 5 minutes, the color of the bromine disappeared. The addition took 30 minutes. The resulting solution was stirred for 15 minutes before the acetic acid was removed under reduced pressure. The resulting white solid was dissolved in acetone (30 ml), diluted with benzene (250 ml) and the solution was concentrated until the volume of the solution was 150 ml. After cooling, white crystals separated, 4.1 g, mp 55 168 to 172 ° C.

(b) 2-Chloro-5- [l-hydroxy-2- [N- (l-methyl-3-phenylpropyl) -N- (phenylmethyl) amino] ethyl] -benzenesulfonamide: a mixture of 5- (2nd ~ Bromoacetyl) -2-chlorobenzenesulfone-

60 amide (3.13 g) in butanone (50 ml) and N- (l-methyl-3-phenylpropyl) -N- (phenylmethyl) amine (4.8 g) was refluxed for 30 min. The solvent was removed under reduced pressure and the residue was stirred with dry ether and filtered. The ether solution was evaporated to dryness and the product was dissolved in ethanol (50 ml) and treated with sodium borohydride (0.3 g). The mixture was stirred for 30 minutes. Another aliquot of sodium borohydride (0.3 g) was added

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puts. The reaction mixture was acidified with 2N hydrochloric acid and the ethanol was removed under reduced pressure. The concentrate was made alkaline with 5N sodium hydroxide solution and the mixture was extracted with ethyl acetate (2 x 50 ml). The extracts were washed with water (2 x 50 ml), dried (MgSO4) and evaporated to dryness to give the product as a yellow oil, 4.6 g. This oil was purified by chromatography on preparative chromatographic plates (silica, CHCl3 / 5% MeOH) and converted into the hydrochloride salt, mp 120 to 125 ° C.

(c) 2-Chloro-5- [l -hydroxy-2 - [(1 -methyl-3-phenylpropyl) amino] ethyl] benzenesulfonamide hydrochloride:

A solution of 2-chloro-5- [l-hydroxy-2- [N- (l-methyl-3-phenylpropyl) -N- (phenylmethyl) amino] ethyl] benzene sulfonamide (0.5 g) was hydrogenated over palladium oxide (0.05 g) for 18 h (64 ml of hydrogen were taken up; theoretical value 48 ml). The catalyst was filtered off, washed with ethanol and the resulting solution was evaporated to dryness under reduced pressure to give the product as a white foam, 0.3 g, mp 88-94 ° C.

Example 2

2-fluoro-5- [l-hydroxy-2 - [[3- (4-fluorophenyl) -1-methyl-propyl] -amino] ethyl] -benzenesulfonamide hydrochloride:

(a) 5- (2-bromoacetyl) -2-fluorobenzenesulfonamide:

A solution of 5-acetyl-2-fluorobenzenesulfonamide (1.0 g) in acetic acid (30 ml) was added dropwise with a solution of bromine (0.736 g) in acetic acid (4.5 ml) at 50 ° C in the presence of a few drops treated by 48% hydrogen bromide in acetic acid. After stirring for 15 to 20 minutes, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and washed with 8% sodium bicarbonate solution (50 ml) and water (50 ml). The organic layer was then dried (MgSO4) and concentrated to give a light brown oil which crystallized from benzene / acetone, 1.2 g, mp 129-132 ° C.

(b) 2-Fluoro-5 - [[bis- (phenylmethyl) amino] acetyl] benzenesulfonamide hydrochloride:

Dibenzylamine (1.94 ml) in butanone (5 ml) was added dropwise to a stirred solution of 5- (bromoacetyl) -2-fluorobenzenesulfonamide (1.0 g) in butanone (60 ml). The stirring was continued for 3 hours at room temperature. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was converted to the hydrochloride salt, 1.01 g, mp 198 to 200 ° C.

(c) 2-Fluoro-5- [l -hydroxy-2 - [[3- (4-fluorophenyl) -l-methy] propy]] - amino] -ethyl] -benzenesulfonamide hydrochloride:

A mixture of 2-fluoro-5 - [[bis- (phenylmethyl) amino] acetyl] benzene sulfonamide (2.2 g) and 4- [4-fluorophenyl] butan-2-one (3.48 g) in ethanol (50 ml) was hydrogenated at room temperature and pressure in the presence of pre-reduced 10% palladium oxide on carbon (0.42 g) and 5% platinum oxide on carbon (0.42 g) until the hydrogen uptake had ceased . The catalyst and the solvent were removed and the residue was dissolved in ethyl acetate and precipitated with petroleum ether (bp 60 to 80 ° C.). The crude product was chromatographed on silica (Merck 210 to 63 [im, 35 g) and eluted with ethyl acetate, which contained 10 drops of ammonium hydroxide per 250 ml.

The first fraction (300 ml) was discarded. Evaporation of the second fraction (375 ml), however, provided a colorless oil (0.8 g) which was converted to the hydrochloride salt, 0.85 g, mp 95-105 ° C.

Similarly, 2-fluor-5 - [[bis- (phenylmethyl) amino] acetyl] benzenesulfonamide (2.5 g) and 4-phenylbutan-2-one (5 g) in 2-fluoro 5- [l-hydroxy-2- [l-methyl-3-phenylpropyl) amino] ethyl] -benzenesulfonamide hydrochloride, 0.4 g, mp 80 to 95 * C, converted.

Example 3

2-Dimethylamino-5- [l-hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] benzenesulfonamide dihydrochloride:

(a) 5-acetyl-2-dimethylaminobenzenesulfonamide:

A mixture of 5-acetyl-2-chlorobenzenesulfonamide (0.5 g) in ethanol (10 ml) and dimethylamine in ethanol (33%, 5 ml) was heated in a closed vessel on a steam bath for 16 h. The solvents were removed under reduced pressure and the residue was crystallized from ethanol to give the product, 0.31 g, mp 184-185 ° C.

(b) 5-bromoacetyl-2-dimethylaminobenzenesulfonamide:

A solution of 5-acetyl-2-

Dimethylaminobenzenesulfonamide (1 g) in chloroform (70 ml) was treated dropwise with bromine (0.75 g) in chloroform (10 ml) and with hydrogen bromide in acetic acid (48%, 2 ml). The mixture was stirred for 3 hours and filtered. The product, a light yellow solid (2.04 g), quickly discolored in sunlight. The compound was partitioned between ethyl acetate (100 ml) and sodium carbonate (100 ml). The organic layer was separated, washed with water, dried (MgS04) and evaporated to dryness. The residue was recrystallized from ethyl acetate to give the bromoacetyl compound, 1.1 g, mp 142-143 ° C.

(c) 2-Dimethylamino-5- [l-hydroxy-2- [bis- (phenyl-methyl) -amino] ethyl] -benzenesulfonamide hydrochloride: a solution of 5-bromoacetyl-2-dimethylaminobenzene-

sulfonamide (2.4 g) in butanone (100 ml) was treated with dibenzylamine (1.5 ml) and propylene oxide (10 ml). The mixture was refluxed for 4.5 hours before the solvent was removed under reduced pressure. The resulting yellow oil was dissolved in absolute ethanol and treated with sodium borohydride (1.2 g) for 1 h before the mixture was acidified with dilute hydrochloric acid and the ethanol was removed under reduced pressure. The product was extracted into ethyl acetate (3 x 150 ml) and the organic layer was washed with sodium bicarbonate solution (100 ml), water (100 ml) and then dried (MgSO4) and evaporated to dryness. The residue was converted into the hydrochloride salt, 1.5 g, mp 180 to 183 ° C. (dec.).

(d) 2-Dimethylamino-5- [l-hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] benzenesulfonamide dihydrochloride:

A solution of 2-dimethylamino-5- [l-hydroxy-2- [bis- (phenylmethyl) amino] ethyl] benzene sulfonamide (4.4 g) in absolute ethanol (300 ml) was over palladium on charcoal (0 , 5 g) and platinum on charcoal (0.5 g) with 4-phenylbutan-2-one at 3.52 kg / cm 2 and room temperature for 18 hours in a Cook hydrogenation device. The catalyst was filtered off and the solvent was removed under reduced pressure. The remaining oil was dissolved in ethyl acetate (10 ml) and precipitated from petroleum ether (bp 60 to 80 ° C.) (400 ml). The resulting

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Oil was chromatographed on silica (Merck, 30 g) and eluted with ethyl acetate containing 10 drops of 0.88 ammonia solution per 200 ml. The compound mentioned was isolated as a foam and converted into the hydrochloride salt, 2.6 g, mp 120 to 130 ° C.

Similarly, 2-dimethylamino-5- [1-hydroxy-2- [bis- (phenylmethyl) amino] ethyl] benzenesulfonamide (Compound A) was converted to the following compounds by reductive alkylation with the corresponding ketone :

2-Dimethylamino-5- [l-hydroxy-2 - [(l-methyl-2-phenoxyethyl) amino] ethyl] benzenesulfonamide dihydrochloride hydrate (1.2 g), mp 120 to 130 ° C , from compound A (2.2 g) and l-phenoxypropan-2-one (2.7 g). 2-Dimethylamino-5- [l-hydroxy-2 - [[l-methyl-2- (methylphenyl) amino) ethyl] amino] ethyl] benzenesulfonamide trihydrochloride (2.6 g), mp 130 to 140 ° C, from Compound A (hydrochloride) (4.45 g) and 1- (methylphenylamino) -2-propanone (7.4 g).

2-dimethylamino-5- [l -hydroxy-2 - [(4-fluorophenyl) -1-methyl-propyl] -amino] ethyl] -benzenesulfonamide dihydrochloride (2.0 g), mp 126 to 134 ° C., from compound A (hydrochloride) (3.9 g) and 4-fluorobenzyl acetone (6.6 g). In the latter case, the hydrogenation took place in 65 hours instead of 18 hours.

Example 4

5- [l-Hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] -2- (1-piperidinyl) benzenesulfonamide dihydrochloride monohydrate:

(a) 5-acetyl-2- (l-piperidinyl) benzenesulfonamide:

A solution of 5-acetyl-2-fluorobenzenesulfonamide (1 g) and piperidine (0.98 g) in ethanol (50 ml) was heated under reflux for 3.5 hours. The solvent was removed and the residue was dissolved in ethyl acetate (100 ml) and washed with water (2 x 100 ml). The organic phase was dried (MgSO4.) And concentrated. The product was crystallized from isopropanol, 0.92 g, mp 130.5 to 131.5 ° C.

(b) 5- (2-bromoacetyl) -2- (1-piperidinyl) benzene sulfonamide hydrobromide:

A solution of bromine (1.13 g) in chloroform (23 ml) was added dropwise to a refluxing suspension of 5-acetyl-2- (l-piperidinyl) benzenesulfonamide (2 g) in chloroform (100 ml) and 48% Added hydrogen bromide to acetic acid (2.3 g). The suspension was then stirred for 1 hour and the chloroform was decanted. The residue was recrystallized from ethanol / ethyl acetate, whereby the hydrobromide salt, mp 185 to 189 ° C. (dec.), Was obtained.

(c) 5- [l-Hydroxy-2- [bis- (phenylmethyl) amino] ethyl] -2- (l-piperidinyl) benzenesulfonamide:

A solution of dibenzylamine (3.34 g) in butanone (10 ml) was added to a vigorously stirred suspension of 5- (2-bromoacetyl) -2- (l-piperidinyl) benzenesulfonamide hydrobromide (2.5 g) added to butanone (100 ml). After 3 h the mixture was filtered and the filtrate concentrated to a yellow oil. This oil was dissolved in ethanol (100 ml) and treated with sodium borohydride (0.42 g) at room temperature. After 1 h, excess borohydride was destroyed with 2N hydrochloric acid. Ethanol was removed and the residue was made alkaline with 8% sodium bicarbonate solution and extracted with ethyl acetate (3 x 100 ml). The extracts were washed with water (100 ml), dried and concentrated to give a light yellow oil (2.7 g). This was chromatographed on Merck silica gel 60 (50 g)

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tographed, whereby the product was obtained as a white solid, 2 g, mp 133 to 142 ° C.

(d) 5- [l-Hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] -2- (1-piperidinyl) benzenesulfonamide dihydrochloride monohydrate.

A solution of 4-phenylbutan-2-one (1.73 g) and 5- [l-hydroxy-2- [bis- (phenylmethyl) amino] ethyl] -2- (l-piperidinyl) benzenesulfonamide (1.4 g) in ethanol (200 ml) was over a mixture of 10% palladium on charcoal (0.28 g) and 5% palladium on charcoal (0.28 g) in a Cook hydrogenator at a pressure of 2 , 81 kg / cm2 hydrogenated for 24 h. The catalyst and solvent were removed and the remaining oil was dissolved in ethyl acetate (5 ml) and precipitated from petroleum ether (bp 60-80 ° C.) (300 ml). This oil was chromatographed on silica (Merck) (30 g) and eluted with ethyl acetate containing 10 drops of 0.88 ammonia solution per 200 ml. The compound mentioned was isolated as a foam and converted into the hydrochloride salt, 800 mg, mp poorly defined, but> 114 ° C.

Found:

theoretical values for C23H33N303S ■ 2HC1 ■ H20: C 52.4 H 6.7 N 8.0%

C 52.8 H 7.1 N 8.05%

Example 5

2-Diethylamino-5- [l-hydroxy-2 - [(l-methyl-3-phenyl-propyl) -amino] ethyl] -benzenesulfonamide dihydrochloride:

(a) 5-Acetyl-2-diethylaminobenzenesulfonamide.

A solution of 5-acetyl-2-fluorobenzenesulfonamide (6.5 g), diethylamine (7.0 ml) and absolute ethanol (200 ml) was refluxed for 22 hours. The solution was concentrated to a gum under reduced pressure and partitioned between ethyl acetate (100 ml) and water (120 ml). The organic phase was separated and evaporated to dryness. Trituration of the residue with aqueous isopropanol gave the diethylamine compound as cream-colored crystals, 5.9 g, mp 103-105 ° C.

(b) 5-bromoacetyl-2-diethylaminobenzenesulfonamide hydrobromide:

A stirred mixture of 5-acetyl-2-diethylamino-benzenesulfonamide (5.5 g), chloroform (275 ml) and 48% hydrogen bromide in acetic acid (13.75 ml) was treated with bromine (1.19 ml) in chloroform ( 110 ml) treated dropwise over the course of 2 h. The reaction mixture was then stirred at room temperature for 1 hour. The chloroform was decanted from the precipitated semi-solid, which was then washed with chloroform (300 ml) and then with ethyl acetate (400 ml). In this way, the bromoketone hydrobromide was obtained as a white crystalline solid (8.4 g), mp 135 to 138 ° C (from ethanol / ethyl acetate).

(c) 2-Diethylamino-5- [l -hydroxy-2- (dibenzylamino) ethylj-benzenesulfonamide:

A solution of 5-bromoacetyl-2-diethylaminobenzene sulfonamide hydrobromide (4.5 g), dibenzylamine (2.5 ml), propylene oxide (22.5 ml) and butanone (250 ml) was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in absolute ethanol (150 ml). Sodium borohydride (0.7 g) was added and the solution was stirred overnight at room temperature. The solution was evaporated to dryness under reduced pressure, acidified (2N hydrochloric acid) and then made alkaline (sodium

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hydrogen carbonate) and then extracted with ethyl acetate. The extracts were evaporated and the residue (6.2 g) was dissolved in ethanol and treated with ethereal hydrogen chloride solution. The mixture was then evaporated to dryness under reduced pressure. The solid obtained was triturated with ethyl acetate to give the crude hydrochloride salt, 5.02 g, mp 230-240 ° C (from ethanol / ethyl acetate).

The salt (5.02 g) was dissolved in hot water, filtered and made alkaline with sodium bicarbonate. The cooled solution was extracted with ethyl acetate (4 x 50 ml). Removal of the solvent provided the free base as an off-white solid, 2.17 g, mp 133-135 ° C.

(d) 2-DiethyIamino-5- [l-hydroxy-2 - [(l-methyl-3-phenyIpropyl) amino] ethyl] -benzenesulfonamide dihydrochloride:

A mixture of 2-diethylamino-5- [l-hydroxy-2- (dibenzylamino) ethyl] benzene sulfonamide (1.17 g), 10% palladium oxide on carbon (0.2 g), 5% platinum oxide on carbon (0 , 2 g), 4-phenylbutan-2-one (1.48 g) and absolute ethanol (500 ml) were hydrogenated overnight at room temperature and a pressure of 3.52 kg / cm 2 in a Cook hydrogenation device. The catalyst and solvent were removed to give a mobile oil (2.0 g). This material was chromatographed on a column with silica (35 g, 210 to 63 pm, Merck). Elution with ethyl acetate containing 0.88 ammonium hydroxide (10 drops of ammonium hydroxide per 250 ml of ethyl acetate) provided a first 200 ml fraction which was discarded, and then a 270 ml fraction which concentrated under reduced pressure leaving a colorless oil (1.0 g). This oil was converted to the hydrochloride salt, 0.7 g, mp 140-150 ° C.

Similarly, the reductive alkylation of 2-diethylamino-5- [l -hydroxy-2- (dibenzylamino) ethyl] benzenesulfonamide (Compound B) with the corresponding ketone provided the following compounds:

2-diethylamino-5- [l-hydroxy-2 - [[l-methyl-2- (methylphenylamino) ethyl] amino] benzenesulfonamide trihydrochloride (0.87 g), mp 140 to 150 ° C ( Dec.), From Compound B (2.25 g) and 1- (methylphenylamino) -2-propanone (3.25 g).

2-diethylamino-5- [l-hydroxy-2 - [[l-methyl-3- (4-fluorophenyl) propyl] amino] ethyl] benzenesulfonamide (0.5 g), mp 106 to 110 ° C, from compound B (1.9 g) and 4-fluoro-benzylacetone (4.02 g).

The catalyst in the latter two reactions was only 10% palladium oxide on carbon.

Example 6

2-Amino-5- [l-hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] benzenesulfonamide dihydrochloride:

(a) 5-Acetyl-2-aminobenzenesulfonamide:

A solution of 5-acetyl-2-fluorobenzenesulfonamide (0.5 g) in ethanol (40 ml) saturated with ammonia was heated to 100 ° C overnight in a bomb. Concentration of the resulting solution provided a yellow crystalline solid, 0.4 g, mp 263-264 ° C (from ethanol).

(b) 2-Amino-5- [2-bromoacetyl) benzenesulfonamide:

A suspension of 2-amino-5-acetylbenzenesulfonamide (0.25 g) and copper (I) bromide (0.523 g) in ethyl acetate (15 ml) and chloroform (15 ml) was refluxed overnight. The copper (I) bromide was filtered off and the filtrate was concentrated in ethyl acetate (20 ml)

dissolved and washed with water (2 x 20 ml). The organic phase was then dried and concentrated to give a colorless solid (0.3 g).

NMR spectroscopy showed that it was a 3: 1 mixture of bromoketone and starting material. This was used without further cleaning.

(c) 2-Amino-5- [l-hydroxy-2- [N- (l-methyl-3-phenylpropyl) -N- (phenylmethyl) amino] ethyl] -benzenesulfonamide:

A solution of 2-amino-5- (2-bromoacetyl) benzenesulfonamide (0.5 g), N- (l-methyl-3-phenylpropyl) -N- (phenylmethyl) amine (0.45 g) and propylene oxide (2.5 ml) in

2-butanone (30 ml) was refluxed for 3 hours. The solution was then concentrated to a red-brown oil (0.7 g), which was dissolved in absolute ethanol (30 ml) and treated with sodium borohydride (258 mg) at room temperature for 2 hours. Excess borohydride was then destroyed with 2N hydrochloric acid and the ethanol was removed under reduced pressure. The residue was made alkaline with 8% sodium bicarbonate solution and extracted with ethyl acetate (3 x 50 ml). The extracts were washed with water (100 ml), dried and concentrated to an orange oil (0.63 g). The oil was dissolved in acetone (10 ml) and reprecipitated as an orange solid (340 mg) by adding petroleum ether (bp 60 to 80 ° C). Chromatographic purification of this solid on silica plates [Merck STI7, elution with chloroform: methanol (5: 1)] and conversion of the product to the hydrochloride salt provided the compound mentioned, 0.2 g, mp 133 to 136 ° C.

(d) 2-Amino-5- [l-hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] benzenesulfonamide dihydrochloride:

A solution of 2-amino-5- [l-hydroxy-2- [N- (l-methyl-

3-phenylpropyl) -N- (p_henylmethyl) amino] ethyl] benzene sulfonamide (0.2 g) in ethyl acetate (50 ml) and acetic acid

(1 ml) was hydrogenated over 10% palladium oxide on charcoal (200 g). The hydrogen uptake over the course of 80 min was 13.5 ml (theoretical uptake 10.6 ml). The catalyst was filtered off and the filtrate was diluted with dry ether (150 ml). The hydrochloride salt was precipitated by adding ethereal hydrochloric acid. 130 mg, mp 129 to 136 ° C (dec.).

Example 7

2-ethylamino-5- [l-hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] benzenesulfonamide sesquihydrochloride:

(a) 5-acetyl-2-ethyaminobenzenesulfonamide:

A solution of 5-acetyl-2-fluorobenzenesulfonamide (6.0 g) and ethylamine (70% solution in water, 25 ml) in absolute ethanol (100 ml) was heated to 100 ° C. in a bomb for 16 h. The resulting yellow solution was evaporated to a small volume, whereby the compound mentioned was obtained as a gray-white crystalline solid, 6.0 g, mp 201 to 204 ° C. (from ethanol).

(b) 5- (bromoacetyl) -2-ethylaminobenzenesulfonamide:

A solution of 5-acetyl-2-ethylaminobenzenesulfona-mid (2.4 g) in ethyl acetate (100 ml) and chloroform (100 ml) was under 18 h in the presence of copper (I) bromide (4.4 g) Stir heated to reflux. The precipitate was filtered off and the solvent was removed under reduced pressure. The resulting brown solid was dissolved in ethyl acetate (200 ml) and washed with water (2 x 10 ml), dried and evaporated to dryness. The residue was recrystallized twice from chloroform, where8

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by the compound mentioned as a gray-white crystalline solid, 1.6 g, mp 156 to 157 = C, was obtained.

(c) 2-Ethylamino-5- [l-hydroxy-2 - [(l-methyl-3-phenyl-propyl) -amino] ethyl] -benzenesulfonamide sesquihydrochloride:

A solution of 5-bromoacetyl-2-ethylaminobenzenesulfonamide (0.96 g) and N- (l-methyl-3-phenylpropyl) -N- (phenylmethyl) amine (1.4 g) and propylene oxide (5 ml) in butanone (70 ml) was heated to reflux for 4.5 h. The solvent was removed under reduced pressure to give a light yellow oil which was added dropwise to petroleum ether (bp 60-80 ° C) (200 ml). A gummy solid was thus obtained. This material was dissolved in ethyl acetate (100 ml) without further purification and hydrogenated over palladium on charcoal (0.3 g) and platinum on charcoal (0.3 g) in the presence of acetic acid (2 ml) for 18 hours. The catalyst was filtered off and the resulting colorless solution was treated with ethereal hydrogen chloride to give the hydrochloride salt, 1.0 g, mp 120-125 ° C.

Example 8

5- [l-Hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] -2-methylaminobenzenesulfonamide dihydrochloride.

(a) 5-Acetyl-2- [N-methyl-N- (phenylmethyl) amino] benzenesulfonamide:

A solution of 5-acetyl-2-chlorobenzenesulfonamide (0.7 g) and benzylmethylamine (1.1 g) in ethanol (40 ml) was heated in a bomb at 120 ° C for 3 days. The resulting red solution was evaporated to a small volume, whereby the named compound was deposited as light yellow crystals. The crystals were recrystallized twice from absolute ethanol to give a gray-white crystalline solid, 0.4 g, mp 159-161 ° C.

(b) 5-bromoacetyl-2-methylaminobenzenesulfonamide:

A solution of 5-acetyl-2- (N-methyl-N-phenylmethylamino) benzenesulfonamide (0.96 g) in chloroform (40 ml) was stirred to give a suspension of copper (I) bromide (1 , 4 g) in refluxing ethyl acetate (50 ml) over a period of 30 min. The resulting mixture was stirred at reflux for an additional 16 h. The precipitated copper (I) bromide was filtered off and the solution was evaporated to dryness. The resulting dark oil was dissolved in chloroform (50 ml), filtered through diatomaceous earth and evaporated to dryness to give a yellow foam (0.9 g). This material was recrystallized twice from chloroform to give the title compound, 0.6 g, mp 170-172 ° C (dec.).

(c) 5- [l -hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] -2-methylaminobenzenesulfonamide dihydrochloride:

A solution of 5-bromoacetyl-2-methylaminobenzene sulfonamide (1.0 g) and N-benzyl-2-amino-4-phenylbutane (1.2 g) in butanone (70 ml) was treated with propylene oxide for 4.5 hours (5 ml) heated to reflux. The solvent was removed under reduced pressure to give a light yellow oil which was added dropwise to petroleum ether (bp 60-80 ° C, 100 ml) to give a gummy solid. Without further purification, this material was dissolved in ethyl acetate (100 ml) and acetic acid (2 ml) and hydrogenated over palladium on charcoal (0.3 g) and platinum on charcoal (0.3 g) for 18 hours. The hydrogen uptake was 200 ml. The theoretical uptake

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is 145 ml. The catalyst was filtered off and the resulting colorless solution was treated with ethereal hydrogen chloride to precipitate a white solid which turned pink after several minutes. The solid was filtered off and dried in vacuo to give the named compound as a brown solid, 1.0 g, mp 115-125 ° C.

Example 9

2-Dimethylamino-5- [l-hydroxy-2- [N- (l-methyl-3-phenylpropyl) amino] ethyl] benzamide dihydrochloride:

(a) Methyl 5-acetyl-2-dimethylaminobenzoate:

Powdered anhydrous aluminum chloride (3.8 g) was added to a solution of N, N-dimethylmethylanthranilate (5.0 g) in ethylene dichloride (50 ml), which was stirred on an ice bath, to give a dark greenish-yellow solution . After stirring for 10 minutes, a solution of anhydrous aluminum chloride (4.2 g) and acetyl chloride (2.42 g) in ethylene dichloride (25 ml) was added dropwise over 5 minutes. After 15 minutes, the solution was heated to reflux with stirring and then refluxed for 1 hour. The reaction was terminated before the green gum commonly seen in this reaction could separate out. The dark greenish yellow solution was allowed to cool and then poured onto ice and water (100 ml). The mixture was extracted with ether (4 x 100 ml) and the extract was washed with 8% sodium bicarbonate solution (3 x 20 ml) and dried (Na2S04). Removal of the solvent provided an oil (2.2 g). This was absorbed from ethyl acetate (5 ml) and cyclohexane (5 ml) on Merck silica gel 60 (50 g). Elution with ethyl acetate / cyclohexane (1: 9, 200 ml) and (1: 4, 200 ml) provided the starting material (0.57 g). Further elution with ethyl acetate / cyclohexane (2: 3, 300 ml) gave the ketone (1.26 g) as a light yellow gum, which crystallized on stirring with cyclohexane. This was collected in the form of prisms and recrystallized from ether / petroleum ether (60 to 80 ° C), whereby a sample with an mp of 65.5 to 67 ° C was obtained.

(b) Methyl 5-bromoacetyl-2-dimethylaminobenzoate:

A solution of methyl 5-acetyl-2-dimethylaminobenzate (0.5 g) in chloroform (25 ml) was treated with 48% hydrogen bromide in acetic acid (1.3 ml). To the stirred room temperature solution was added bromine (0.366 g) in chloroform (5.9 ml) over 30 minutes. The solution was diluted with ether and decanted. The remaining gum was treated with water (25 ml) and extracted with ether (3 x 50 ml). The slightly yellow extract was dried (Na2S04.). Removal of the solvent gave the compound mentioned as a yellow oil which crystallized on trituration with ether and cyclohexane. The product was collected as a light yellow solid (0.44 g), mp 94-97 ° C. Recrystallization from ethyl acetate / petroleum ether (bp 60 to 80 ° C) gave a sample with an mp of 96.5 to 98.5 ° C.

(c) 2-Dimethylamino-5 - [[bis- (phenylmethyl) amino] -

acetyl] methyl] benzoate:

A solution of methyl 5-bromoacetyl-2-dimethylaminobenzoate (1.5 g), dibenzylamine (1.1 g) and propylene oxide (3.0 g) in butanone (100 ml) was refluxed for 3 hours. The light yellow solution was concentrated by rotary evaporation to an oil which was taken up in ethanol (100 ml) and treated with sodium borohydride (0.34 g). The solution was kept at room temperature for 18 hours and then acidified with 2N hydrochloric acid (10 ml) to remove excess borohydride. Then

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it was made alkaline with sodium bicarbonate and diluted with water (200 ml). The cloudy solution was extracted with ether (5 x 100 ml) and the ethereal extract was washed with water (4 x 25 ml) and dried (Na2SC> 4.). Removal of the solvent provided the named compound as a light yellow thick viscous oil (2.28 g). This material was used in the next step without further purification.

(d) 2-Dimethylamino-5 - [[bis- (phenylmethyl) aminoacetyl] benzamide:

A solution of methyl 2-dimethylamino-5 - [[bis- (phenylmethyl) amino] acetyl] benzoate (1.08 g) and ammonia (7.5 g) in methanol (100 ml) was added in 65 h heated to 100 ° C in a Roth autoclave. The temperature was then raised to 110 ° C and heating continued for 21 hours. Removal of the solvent provided a gum which was absorbed from ethyl acetate (10 ml) and cyclohexane (10 ml) on Merck silica gel 60 (20 g). Elution with cyclohexane (50 ml), cyclohexane / ethyl acetate (9: 1, 100 ml; 4: 1,100 ml) provided the starting ester (0.58 g). Further elution with cyclohexane / ethyl acetate (1: 1, 50 ml) and ethyl acetate (150 ml) provided the named compound as a glass (0.51 g).

A portion of this material (0.22 g) was taken up in ethanol. The solution was filtered and treated with ethereal hydrogen chloride. The dihydrochloride separated as a cream-like solid which was collected and dried in vacuo to give a material (10.23 g) which darkens at 180 ° C and melts at 235 to 240 ° C.

(e) 2-Dimethylamino-5- [l-hydroxy-2- [N- (l-methyl-3-phenylpropyl) amino] ethyl] benzamide dihydrochloride:

10% palladium oxide on charcoal (0.28 g) was prehydrogenated in ethanol (40 ml). A solution of 2-dimethylamino-5 - [[bis- (phenylmethyl) amino] acetyl] benzamide (1.05 g) and benzylacetone (0.43 g) in ethanol (40 ml) was added and the The mixture was hydrogenated at room temperature and pressure. The hydrogen uptake ceased after 24 hours.

The solution was filtered through diatomaceous earth to remove the catalyst and concentrated to an oil. This oil formed a light gray solid when mixed with ether and cyclohexane. This was collected and dried in vacuo (0.65 g), mp 104-115 ° C. The remaining solid was extracted with hot toluene (50 ml). The extract was filtered and concentrated. The residue was taken up in ethyl acetate (100 ml). This was washed with water (3 x 10 ml) and dried (Na2S04). Removal of the solvent provided a gum. This was absorbed from ethyl acetate (10 ml) and methanol (2 ml) on Merck silica gel 60 (15 g). Elution with ethyl acetate (100 ml) provided a fraction which was discarded. Further elution with ethyl acetate (50 ml) and ethyl acetate / methanol (20: 1, 100 ml; 9: 1, 200 ml) provided the phenethanolamine as a colorless gum (0.5 g). This was taken up in ethanol and treated with ethereal hydrogen chloride. The dihydrochloride separated out as a cream-colored solid, mp 176 to 178 ° C. (dec.).

Example 10

2-Chloro-5- [l-hydroxy-2- [N- (l-methyl-3-phenylpropyl) amino] ethyl] benzamide hydrochloride. (a) 5-acetyl-2-chlorobenzamide:

A solution of 4-chloro-3-cyanoacetophenone (7.6 g) in absolute alcohol (150 ml) was added with sodium hydroxide

(2n, 5 ml) and hydroperoxide (28%, 50 ml) treated. The mixture was heated to 50 ° C with vigorous stirring. After 1 h, a thin layer chromatographic examination showed that the reaction had ended. The solution was neutralized with 2N hydrochloric acid and the ethanol was removed under reduced pressure. The resulting mixture was diluted with water (100 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with water (100 ml), dried and evaporated to dryness to give a yellow solid which was recrystallized twice from ethanol to give said compound (5.3 g) mp 183-184 ° C, was obtained.

(b) 5- (2-bromoacetyl) -2-chlorobenzamide:

A solution of 5-acetyl-2-chlorobenzamide (1.0 g) in glacial acetic acid (30 ml) at 50 ° C. was slowly and dropwise mixed with a solution of bromine (0.26 ml) in glacial acetic acid (10 ml). The resulting straw-colored solution was kept at 50 ° C. for a further 30 minutes after the addition had ended. The acetic acid was removed under reduced pressure and the resulting solid was recrystallized twice from ethyl acetate to give the title compound (0.57 g), mp 158-160 ° C.

(c) 2-Chloro-5- [l-hydroxy-2- [N- (l-methyl-3-phenylpropyl) -N- (phenylmethyl)] - amino] ethyl] benzamide:

A solution of 5- (2-bromoacetyl) -2-chlorobenzamide

(2.0 g) in acetone (50 ml) was treated with N-benzyl-2-amino-4-phenylbutane (3.5 g) from room temperature overnight. The resulting red solution was evaporated to dryness and stirred with dry ether. The precipitated N-benzyl-2-amino-4-phenylbutane hydrobromide was filtered off, washed with ether and the ethereal solution was evaporated to dryness. The resulting yellow oil was dissolved in ethanol (150 ml) and treated with sodium borohydride (1.2 g) for 2 hours at room temperature. Excess borohydride was removed under reduced pressure. The residue was made alkaline with 2N sodium hydroxide solution and extracted with ethyl acetate (2 x 100 ml). The organic layer was washed with water, dried and evaporated to dryness to give a yellow foam which was dissolved in dry ether (100 ml) and treated with ethereal hydrogen chloride. In this way, the compound mentioned was obtained as a fine white solid. This material was used directly in the next stage.

(d) 2-Chloro-5- [1 -hydroxy-2- [N- (1 -methyl-3-phenylpropyl) amino] ethyl] benzamide hydrochloride:

A solution of l- (3-carboxamido-4-chlorophenyl) -2- [N- (phenylmethyl) -N- (l-methyl-3-phenylpropylamino)] - ethanol-hydrochloride (0.3 g) in absolute Ethanol (30 ml) was hydrogenated over palladium on kieselguhr (10%, 30 mg) for 2.5 h until the hydrogen uptake had ended (20 ml, theoretically 15 ml). The catalyst was filtered off, washed with ethanol and evaporated to dryness to give the title compound as a white foam (0.24 g).

Found:

theoretical values for Ci9H23C1N202 - HCl C 59.5 H 6.3 N 7.0%

C 59.5 H 6.3 N 7.3%

Example 11

2-Chloro-5- [2 - [[3- (4-fluorophenyl) -l-methylpropyl] amino] -1-hydroxyethylj-benzenesulfonamide hydrochloride hydrate:

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(a) 2-chloro-5- [2 - [[3- (4-fluorophenyl) -1-methylpropyl] phenylmethyl] amino] -1-hydroxyethyl] -

benzenesulfonamide hydrochloride.

A solution of 5-bromoacetyl-2-chlorobenzenesulfonamide (2.0 g) in acetone (60 ml) was treated with N- [3- (4-fluorophenyl) -l-methylpropyl] -N- (phenylmethyl) amine (from 2 , 6 g, 0.012 mol of the hydrochloride) at about 20 ° C for 16 h. The acetone was then removed under reduced pressure and the remaining oil was stirred with dry ether. The solid hydrobromide was filtered off and the ether solution was evaporated to dryness. The residue was dissolved in ethanol (40 ml) and treated with sodium borohydride (1.0 g, 4.0 equivalents). The mixture was stirred at room temperature for 2 hours before acidifying with 2N hydrochloric acid and the ethanol was removed under reduced pressure. The pH was adjusted to 10 by adding 5N sodium hydroxide solution and the mixture was extracted with ethyl acetate (3 x 100 ml). The organic layer was washed with water (2 x 30 ml), dried (MgS04) and evaporated to dryness. The resulting oil was chromatographed on preparative silica plates. The main component was separated and treated with ethereal hydrogen chloride, whereby the compound mentioned was obtained as a white solid, 0.7 g, mp 110 to 120 ° C.

(b) 2-Chloro-5- [2 - [[3- (4-fluorophenyl) -l-methyl-propyl] -amino] -1-hydroxyethylj-benzenesulfonamide hydrochloride hydrate:

A solution of 2-chloro-5- [2 - [[3- (4-fluorophenyl) -l-methylpropyl] phenylmethyl) amino] -1-hydroxyethylj-benzene-sulfonamide hydrochloride (0.2 g) in absolute ethanol (30 ml), hydrogenation was carried out over 10% palladium oxide on charcoal (20 mg) until the hydrogen uptake had practically ended and 15 ml of hydrogen had been absorbed. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give said compound, 0.135 g, as a white brittle solid.

Found:

theoretical values for C18H22C1FN203S • HCl ■ H20

C 47.5 H 5.3 N 5.9%

C 47.4 H 5.5 N 6.1%

Example 12

2-Dimethylamino-5- [2 - [[3- (3-fluorophenyl) -1-methyl-propyl] -amino] -1-hydroxyethyl] -benzenesulfonamide dihydrochloride:

A solution of 5- [2- [bis- (phenylmethyl) amino] 1-hydroxyethyl] -2- [dimethylamino] benzenesulfonamide (2.2 g) in absolute ethanol (300 ml) was added to palladium on charcoal (0 , 5 g) and platinum on charcoal (0.5 g) with 4- (3-fluorophenyl) butan-2-one (3.3 g) at 3.52 kg / cm2 for 18 h. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give a colorless oil which was filtered through a column of silica gel. The column was eluted with ethyl acetate / ammonia (10 drops per 250 ml EtOAc) to give the product as a white foam. This was dissolved in ethyl acetate and treated with ethereal hydrogen chloride, whereby the compound mentioned was obtained as an amorphous white solid. Yield 1.25 g, mp 115 to 125 ° C.

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Example 13

2- (butylmethylamino) -5- [l -hydroxy-2 - [(l -methyl-

3-phenylpropyl) amino] ethyl] benzenesulfonamide dihydrochloride:

A solution of 5 - [[bis (phenylmethyl) amino] acetyl] -2-fluorobenzenesulfona.mid hydrochloride (3 g) and methyl butylamine (2.2 g) in ethanol (150 ml) was on 18 h Reflux heated. The ethanol was removed and the residue was dissolved in ethyl acetate (150 ml), washed with sodium bicarbonate solution (8%, 200 ml) and water (200 ml) and dried (MgS04). The solution was evaporated to a small volume and petroleum ether (bp 60-80 ° C, 250 ml) was added. A red-brown rubber (1.8 g) separated. This was dissolved in ethanol (150 ml), added to a solution of 4-phenylbutan-2-one (4.9 g) in ethanol (150 ml) and over palladium oxide on charcoal (10%, 0.7 g) and platinum oxide hydrogenated on charcoal (5%, 0.7 g) at 2.81 kg / cm2 for 24 h in the presence of acetic acid (2 ml). The catalyst and solvent were removed to give a mobile yellow oil (5 g) which was chromatographed on a silica column (Merck Art, 7734, 75 g). After eluting with ethyl acetate (500 ml) the product was isolated by eluting with ethyl acetate / methanol (9: 1) containing a trace of 0.88-ammonia. The product was obtained as a colorless foam (0.35 g). This material was dissolved in ethyl acetate (10 ml) and treated with ethereal hydrogen chloride (5 ml) to give the title compound, 0.4 g, mp 105 to 110 CC.

Example 14

2-Fluoro-5- [l -hydroxy-2 - [[3- (3-fluorophenyl) -1-methylpropyl] amino] ethyl] -benzenesulfonamide hydrochloride hemihydrate:

A solution of 5 - [[bis- (phenylmethyl) amino] acetyl] -2-fluorobenzenesulfonamide (2.4 g) and 4- (3-fluorophenyl) -bu-tan-2-one (2.9 g) in absolute ethanol (100 ml) was hydrogenated in the presence of pre-reduced 5% Pt / C (0.5 g) and 10% Pd / C (0.5 g) until after 69 h the reaction was considered to be complete by thin layer chromatography. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give a light yellow oil which was chromatographed on silica (silica gel 60.210 to 63 (im) (100 g). The column was washed with ethyl acetate (11) which was a Sj ) Contained ur ammonia, and then eluted by 10% methanol / ethyl acetate (600 ml). The latter eluant was concentrated under reduced pressure to give an oil (1.2 g) which was stirred with ethyl acetate / petroleum ether (bp 60-80 ° C). In this way, a light viscous rubber was obtained. This material was dissolved in ethyl acetate and treated with ethereal hydrogen chloride to give said compound as a brittle solid, 0.77 g, mp 65-85 ° C.

Found:

theoretical values for Ci8H22F2N203S • HCl • 1 / 2H20: C 50.5 H 5.7 N 6.5%

C 50.3 H 5.4 N 6.5%

Example 15

5- [1-Hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] -2- (1-pyrrolidinyl) -benzenesulfonamide dihydrochloride-

sesquihydrate: (a) 5- [2- [bis- (phenylmethyl) amino] -l-hydroxy-

ethyl] -2- (l-pyrrolidinyl) benzenesulfonamide dihydrochloride:

A mixture of 5 - [[bis (phenylmethyl) amino] acetyl] -2-fluorobenzenesulfonamide hydrochloride (0.5 g), pyrrolidine

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(0.2033 ml) and absolute ethanol (30 ml) was refluxed for 5 h. Another aliquot of pyrrolidine (0.101 ml) was added and the solution was refluxed for a further 2 hours.

The solution was allowed to cool and sodium borohydride (0.168 g) was added in one portion. After 2 h the mixture was evaporated to dryness, acidified with hydrochloric acid and made alkaline with sodium bicarbonate before being extracted with ethyl acetate (4 x 40 ml). The combined extracts were washed with water (25 ml), dried (MgS04) and evaporated to dryness to give an off-white foam (0.5 g). This material was chromatographed on silica gel 60 (210 to 63 µm) and eluted with 1: 1 cyclohexane / ethyl acetate (250 ml). Evaporation of the solvent gave the product as a light cream-colored foam (0.45 g), mp 45 to 55 ° C.

(b) 5- [l-Hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] -2- (1-pyrrolidinyl) benzenesulfone amide dihydrochloride sesquihydrate:

A solution of 5- [2- [bis- (phenylmethyl) amino] -l-hydroxyethyl] -2- (l-pyrrolidinyl) -benzenesulfonamide (3.5 g), 4-phenylbutan-2-one (4th , 43 g) and glacial acetic acid (1 ml) in absolute ethanol (400 ml) was at 18 to 20 ° C and 3.52 kg / cm2 in the presence of 10% palladium oxide on carbon (0.5 g) and 5% platinum oxide Carbon (0.5 g) hydrogenated. The formation of the main product was monitored by thin layer chromatography. The reaction was considered complete after 118 h.

The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an oil which was stirred with ethyl acetate and petroleum ether (bp 60-80 ° C). A light brown solid (2.7 g) was obtained in this way. This material was chromatographed on a silica column (silica gel 60, 210 to 63 μm) (50 g) and eluted as follows:

1. Ethyl acetate (450 ini).

2.10% methanol / ethyl acetate + NH4OH * (450 ml). 3.10% methanol / ethyl acetate + NH4OH * (300 ml). * (10 drops of 0.880 ammonium hydroxide per 250 ml of 10% methanol / ethyl acetate).

Evaporation of fraction 3 gave an off-white foam (0.75 g), mp 50-65 ° C. This material was dissolved in ethyl acetate and treated with ethereal hydrogen chloride, whereby the compound mentioned was obtained as the dihydrochloride salt, 0.45 g, mp 140 to 150 ° C.

Example 16

2- (ethylmethylamino) -5- [I-hydroxy-2 - [(l-methyl-

3-phenylpropyl) amino] ethyl] benzenesulfonamide dihydrochloride:

(a) 5- [2- [bis (phenylmethyl) amino] -1-hydroxyethyl] -

2- (ethylmethylamino) -benzenesulfonamide dihydrochloride: A mixture of 5 - [[bis- (phenylmethyl) -amino] -acetyl] -2-fluorobenzenesulfonamide hydrochloride (1.0 g) and ethylmethylamine (0.53 g) in absolute Ethanol (100 ml) was heated to 100 ° C overnight in an autoclave. The brown solution was allowed to cool and was stirred with sodium borohydride (0.336 g) for 1 hour.

The mixture was evaporated to dryness, acidified (hydrochloric acid), made alkaline (sodium bicarbonate) and extracted with ethyl acetate (4 x 50 ml). Evaporation of the dried, which was chromatographed on silica gel 60 (210 to 63 (im, 30 g). It was with 20% ethyl

acetate / cyclohexane (500 ml) eluted. Evaporation of the solvent provided an off-white foam (0.5 g) which was dissolved in ethyl acetate and treated with ethereal hydrogen chloride of ethanol / ethyl acetate, whereby the compound mentioned as a gray-white solid, 0.26 g, mp 188 to 190 ° C (from ethanol / ethyl acetate).

(b) 2- (ethylmethylamino) -5- [l-hydroxy-2 - [(l-methyl-

3-phenylpropyl) amino] ethyl] benzenesulfonamide

dihydrochloride:

A mixture of 5- [2- [bis (phenylmethyl) amino] 1-hydroxyethyl) -2- (ethylmethylamino) benzenesulfonamide (1.68 g), 4-phenylbutan-2-one (2 g) and glacial acetic acid (2 ml) in absolute ethanol (400 ml) was hydrogenated in the presence of 10% palladium oxide / carbon (0.2 g) for 48 h at 3.52 kg / cm 2 and 18 to 20 ° C.

The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give a light brown oil (3.5 g). This material was partitioned between 8% aqueous sodium bicarbonate solution (25 ml) and ethyl acetate (25 ml). The ethyl acetate layer was separated, washed with water (10 ml), dried and evaporated in vacuo to give a light brown oil (2.7 g). The crude product (1.3 g) was chromatographed on silica (silica gel 60.210 to 63 μm) (26 g) and eluted as follows:

1. Ethyl acetate (75 ml).

2.10% methanol / ethyl acetate + NH4OH (125 ml).

3.10%> methanol / ethyl acetate -1- NH4OH * (150 ml).

* 10 Tropifen 0.880 ammonium hydroxide per 250 ml 10% methanol / ethyl acetate.

Evaporation of fraction 3 gave an off-white foam (1.1 g). This material was dissolved in ethyl acetate and treated with ethereal hydrogen chloride, whereby the compound mentioned was obtained as a yellow solid, 1.10 g, mp 130 to 150 ° C.

Analysis found:

theoretical values for C2iH31N303S • 2HC1 • 1 / 3EtOAc •

2 / 3h2o

C 51.7 H 7.1 N 7.8%

C 51.6 H 7.2 N 8.1%

Example 17

5- [l-Hydroxy-2 - [(l-methyl-3-phenylpropyl) amino] ethyl] -2- (4-methylpiperazin-l-yl) benzenesulfonamide trihydrochloride: (a) 5- [2- [Bis- (phenylmethyl) amino] -l-hydroxyethyl] -2- (4-methylpiperazin-l-yl) -benzenesulfonamide:

A solution of 5 - [[bis (phenylmethyl) amino] acetyl] -2-fluorobenzenesulfonamide hydrochloride (4.48 g) in absolute ethanol (200 ml) containing N-methylpiperazine (4.485 g) was used for 21 hours heated at reflux.

The solution was allowed to cool and stirred with sodium borohydride (1.52 g) at 18 to 20 ° C for 2 h.

The resulting mixture was evaporated to dryness and acidified with hydrochloric acid. The solution was made alkaline with aqueous sodium bicarbonate solution and extracted with ethyl acetate (4 x 50 ml). The organic phase was washed with water (25 ml), dried and concentrated under reduced pressure to give a gum (4.45 g). The reprecipitation from ethyl acetate with petroleum ether (bp 60 to 80 ° C.) gave a light cream-colored solid, 3.9 g, mp 120 to 130 ° C.

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642 057

(b) 5- [l -hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] -2- (4-methylpiperazin-l-yl) benzene sulfonamide trihydrochloride:

A solution of 5- [2- (bis (phenylmethyl) amino] 1-hydroxyethyl] -2- (4-methylpiperazin-1-yl) -benzenesulfonamide (3.5 g), 4-phenylbutan-2-one (4.22 g) and acetic acid (1 ml) in absolute ethanol (400 ml) was hydrogenated at 3.52 kg / cm2 and 18 to 20 ° C in the presence of 10% palladium oxide / carbon and 5% platinum oxide / carbon.

After 70 hours, the catalysts were replaced and the hydrogenation was continued in the presence of an additional amount of 4-phenylbutan-2-one (4.22 g) and acetic acid (1 ml) for 18 hours.

The catalysts were filtered off and the filtrate was evaporated to dryness to give a brown oil. This material was stirred with ethyl acetate / petroleum ether (bp 60 to 80 ° C). The crude product (2.2 g) was chromatographed on silica gel 60 (210 to 63 (xm) (50 g) and eluted as follows:

1. Ethyl acetate.

2.10% methanol / ethyl acetate 4- NH40H *. 3.15% methanol / ethyl acetate + NH4OH *.

* (10 drops of 0.880-NH4OH per 250 ml of eluent).

Evaporation of fraction 3 gave a colorless oil (0.73 g) which was dissolved in ethyl acetate and treated with ethereal hydrogen chloride. In this way, the compound mentioned was obtained as the trihydrochloride salt, 0.58 g, mp 180 ° to 190 ° C.

Pharmaceutical Examples Examples of pharmaceutical compositions, (a) tablets:

1) Instructions for the production of 10,000 tablets with an active ingredient content of 20 mg:

200 g of active ingredient, 795 g of microcrystalline cellulose BPC and 5 g of magnesium stearate BP are mixed. The powder is compressed on a suitable tablet press to give tablets with a diameter of 6.5 mm and a weight of approximately 100 mg.

2) Instructions for the production of 10,000 tablets with an active substance content of 100 mg:

1000 g of active ingredient, 250 g of lactose BP, 172.5 g of dried corn starch BP are mixed. 70 g of pre-gelatinized maize 5 starch BP are dispersed in 11 cold water and the powder mixture is moistened with it to produce a moist, coherent mass. The moist mass is passed through a sieve with a mesh size of 1.2 mm (14 mesh BSS sieve) and the resulting granules are dried at 60 ° C. The dried granulate is passed through a sieve with a mesh size of about 0.9 mm (22 BSS sieve) and mixed with 7.5 g of magnesium stearate. The lubricated granules are compressed on a suitable tablet press to give tablets with a diameter of 15 mm and a weight of 150 mg. The tablets can be coated with a suitable film-forming material, e.g. Methyl cellulose or hydroxypropylmethyl cellulose, coated according to standard techniques. The tablets can also be coated with sugar.

(b) capsules:

Regulation for the production of 10,000 capsules, each with an active substance content of 50 mg.

500 g of active ingredient are mixed with 700 g of microcrystalline cellulose BPC and the mixture is introduced into hard gelatin capsules No. 3 so that each capsule contains approximately 120 mg of mixture.

(c) Injectable preparation:

Instructions for the preparation of an injectable preparation with an active substance content of 10 mg per ml:

10 g of active ingredient and 7.5 g of sodium chloride BP are dissolved in 950 ml of water for injection. If the solution. is complete, make up to 11 with more water for injection. The solution is divided into ampoules of suitable size (1, 5 or 10 ml) and the ampoules are closed and sterilized by heating in an autoclave. The active ingredient in the preparations can be any compound according to the invention. -

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Claims (13)

642 057 2nd PATENT CLAIMS 1. Benzene sulfonamide and benzene carboxamide derivatives of the general formula: ch-chg-nh-ch (ch3) ch2 x OH (Ï) wherein R! represents a halogen atom or the group NR2R3; R2 and R3, which may be the same or different, represent hydrogen or straight-chain or branched (QC ^ -alkyl), or where R2 and R3 together with the nitrogen atom can form a 5- or membered heterocyclic ring which is a further heteroatom the group can contain O, N or S, or where R2 is hydrogen and R3 is the group R4CO or R4S02, in which 15 R4 is hydrogen or (C1.4) alkyl; R5 represents hydrogen or one or more halogen atoms or hydroxy or (C1 ^}) alkoxy groups; X represents CH2.0 or the group NR6, in which R6 is hydrogen or (C 1-4 alkyl), and Y stands for S02NH2 or CONH2, and the acid addition salts with organic or inorganic acids thereof. 2. Derivatives according to claim 1, of the general formula: wherein R1; R5 and X have the meanings given in claim 1, and the acid addition salts with organic HgNOC see or inorganic acids thereof. 3. Derivatives according to claim 1, of the general formula: ■ nh-ch (cii3) chs <9 * wherein Rj, R5 and X have the meanings given in claim 1, and the acid addition salts with organic or inorganic acids thereof. 4. Derivatives according to one of claims 1 to 3, characterized in that R! represents chlorine, fluorine, amino (C ^ -Al-kylamino, (Cw) -dialkylamino, piperidino, pyrrolidino or 4-methylpiperazino. 5. Derivatives according to one of claims 1 to 4, characterized in that R5 is hydrogen or halogen. 6. Derivatives according to claim 5, characterized in that Rs represents a para-fluorine group. 7. Derivatives according to one of claims 1 to 6, characterized in that X is CH2-. 8. Derivatives according to claim 1, characterized in that 2-fluoro-5- [l-hydroxy-2 - [[3- (4-fluorophenyl) -1-methyl-propyl] -amino] -ethyl] -benzenesulfonamide. 9. Derivatives according to claim 1, characterized in that 2-fluoro-5- [l-hydroxy-2 [l-methyl-3-phenylpropyl) -amino-no] ethyl [-benzenesulfonamide. 10. Derivatives according to claim 1, characterized in that 2-dimethylamino-5- [l-hydroxy-2- [N- (1-methyl-3-phe-nyl-propyl) -amino] ethyl] -benzamide. 11. A process for the preparation of benzenesulfonamide and benzenecarboxamide derivatives according to claim 1, characterized in that a compound of the general formula: or the corresponding alcohol thereof, where Y and Rx have the meanings given in claim 1 and R7 is benzyl and R8 is hydrogen or benzyl, 40 with a ketone of the general formula: ooch I CH. wherein R5 and X have the meanings given in claim 1, reductively alkylated. 12. Medicament, characterized in that they contain as active ingredient one or more compounds according to one of claims 1 to 3 together with a physiologically acceptable carrier or diluent. 55 - & ■ CO-CH2-NR? R8