CS272789B2 - Method of sulfonamidoindane production - Google Patents

Abstract

The method of production of this compound of general formula I, where R1 is hydrogen, C1-4-alkyl, C1-4-alkoxyl or halogen, the symbols R<2>, which are the same, represent C1-4-alkyls, X is oxygen or the direct link and n is a number with 1 or 2, where, if X is oxygen, n is 2, and their pharmaceutically applicable salts, significant by the fact that the compound of general formula II is allowed to react with C1-4-alkane sulphonyl chloride or bromide or with the anhydride of C1-4-alkane sulphonic acid and the resulting product can be transformed into a salt. The produced compounds are anti-arrhythmic agents that can be used for prevention and treatment of a wide range of ventricular and supraventricular arrhythmia, including atrial and ventricular fibrillation.<IMAGE>

Description

The invention relates to certain sulfonamidoindanes which are effective as antiarrhythmic agents and to intermediates necessary for their preparation.

The antiarrhythmic agents of the invention extend the duration of action potential in cardiac muscle and conductive tissue, thereby increasing refractory to premature stimuli. Thus, they are class III antiarrhythmic agents according to the Vaugham Williams classification (Anti-arrhythmic Action, E.M. Vaughan Williams, Academic Press, 1980). These agents act in atria, ventricles and conductive tissue both in vitro and in vivo and are therefore useful for the prevention and treatment of a wide variety of ventricular and supraventicular arrhythmias, including atrial and ventricular fibrillation. Since the disclosed compounds do not alter the rate at which the impulses are driven, they tend to have less tendency than current drugs (belonging mostly to Class I) to induce or worsen arrhythmias, and also produce less neurological side effects. Some of these compounds also exhibit some positive inotropic activity and are therefore particularly suitable for patients with impaired heart pumping function.

Accordingly, the compounds of formula (A) are described

wherein the individual Rs, which may be the same or different, each represent -NO ₂ , -NH ₂ or -NHSO ₂ alk, where alk is a C 1 -C 4 alkyl group,

X represents an oxygen atom or a direct bond,

R ¹ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen; and R ¹ is 1 or 2, provided that when X is O, R 6 is 2, and their salts.

Those compounds of formula (A) in which both R is -NHSO ₂ alk are antiarrhythmic. Compounds of formula (A) in which both R cells are -NO ₂ or -NH ₂ are intermediates for the synthesis of the above active ingredients.

It is an object of the present invention to provide a process for the preparation of antiarrhythmic compounds of formula I

(AND)

CS 2727 $ f S2 in which

R ¹ represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a halogen atom; each R, which may be the same or different, each represents a C 1 -C 4 alkyl group,

X is an oxygen atom or a direct bond and n is 1 or 2 with the proviso that when X is an oxygen atom, n is 2, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula II

wherein R @ 1, X and R @ 2 are as defined above, reacted with an alkanesulfonyl chloride or a bromide containing from 1 to 4 carbon atoms in the alkyl moiety or with an alkanesulfonic anhydride of 1 to 4 carbon atoms, whereupon the resulting product is optionally converted to a pharmaceutically acceptable salt thereof.

Of course, at least two equivalents of the acylating agent must be used for the acylation of the invention and the residues R in the final product are of course the same.

The reaction is generally carried out at room temperature and optionally in the presence of an acid acceptor, such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of an acid acceptor is particularly useful when an alkanesulfonyl chloride or bromide is used as an acylating agent. Particularly expediently, the reaction is carried out using an alkane sulfonyl chloride in pyridine, which acts simultaneously as both an acid acceptor and a solvent. The resulting product of formula (I) can then be isolated and purified in a conventional manner.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts forming nontoxic acid addition salts containing pharmaceutically acceptable anions such as hydrochlorides, hydrobromides, hydroiodides, sulfates or hydrogen sulfates, phosphates or hydrogen phosphates, acetates, maleates, fumarates, lactates, tartates, citrates, gluconates, benzoates, methanesulfonates, besylates and p-toluenesulfonates. These salts also include alkali metal salts, especially sodium and potassium salts. The salts described are prepared by conventional methods.

A preferred alkyl group is a methyl group. A preferred alkoxy group is methoxy. The C 3 and C 4 alkyl and alkoxy groups may be straight or branched. Halogens are fluorine, chlorine, bromine or iodine.

R @ ⁷ is preferably hydrogen.

A preferred antiarrhythmic agent of formula (I) has the structure represented by the following formula (IA)

The compounds of formula (A) are optically active and the invention includes both the R, S and R / S forms.

To determine the effects of the compounds of the invention on atrial refractory, true guinea pig hemi-sodium is placed in a bath containing physiological saline and one end thereof is connected to a force transducer. Tissue was stimulated at 1 Hz using surface electrodes. The effective refractory period (ERP) is measured by introducing a premature stimulus (S ^) after every eight baseline stimulus (S ^). The interval between S ^ and S ^ increases gradually until the stimulus S ^ reproducibly elicits a propagated response, is defined as ERP, then the concentration of test compound required to increase ERP by 25% (ED25) is measured, and ERP is measured using guinea pig paper muscle in physiological saline, stimulated at one end with bipolar electrodes and at the other end. The conductivity time is determined from an oscilloscope with a memory by measuring the interval between the artificial stimulus and the peak of the electrogram (i.e., the time it takes for the pulse to travel through the entire length of the muscle).

Atrial and ventricular ERP are also measured on an anesthetized or awake dog using extraordinary stimuli. The atrium or right ventricle is maintained at a constant frequency.

In the above assay for representative compounds of the invention, the following values of ED ₂ 5 'active ingredient (Example no.) ED j ₂ (molar concentration)

1 1,2 X 10 ~ ⁶ 2 6.7 X 10- ⁸ 3 1,2 X 10 ~ ⁷

The compounds of formula I may be administered as such, but are generally administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. The disclosed compounds can be administered to both patients suffering from arrhythmia as well as prophylactically to potential patients who are expected to develop arrhythmias. For example, the compounds may be administered orally in the form of tablets containing starch or lactose as carriers, or in the form of capsules containing either alone or in admixture with carriers or excipients, or in the form of elixirs or suspensions containing coloring or flavoring agents. The compounds of the invention may also be administered by parenteral injection, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, these substances are best used in the form of a sterile aqueous solution which may contain other soluble substances, for example, salts or glucose to render the solution isotonic.

For human medical applications for curative or prophylactic treatment of cardiac diseases, such as ventricular and supraventicular arrhythmias, including atrial and ventricular fibrillation, oral doses of compounds of Formula I range from 2 to 150 mg per day for an average adult patient (70 kg ). This total dose can be administered in up to four divided doses per day. For intravenous administration, the dosage ranges from 1.0 to 20 mg per unit dose. In severe cardiac arrhythmias, the active ingredients are preferably administered intravenously to patients in order to achieve a rapid transition to normal rhythm. Thus, individual tablets or capsules for typical adult patients may contain 2 to 50 mg of the active ingredient in a suitable pharmaceutically acceptable diluent or carrier. As is known in the art, various variations may occur depending on the weight and condition of the patient being treated.

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention further provides a method of preventing or treating cardiac arrhythmias in human medicine, comprising administering to a patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above.

The invention also relates to the use of the compounds of the formula I or their pharmaceutically acceptable salts as medicaments, in particular as antiarrhythmic agents.

The invention further provides the use of the compounds of formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention or treatment of cardiac arrhythmias.

The starting materials of formula (A) in which both R are amino can be prepared by reduction of the corresponding compounds in which both R are nitro. This reduction is carried out in a conventional manner, for example by treating with hydrogen in the presence of palladium on carbon in a suitable organic solvent, for example ethyl acetate or a mixture of ethyl acetate and methanol, at a temperature around room temperature.

The starting materials of formula (A) in which both R are nitro may be prepared according to the following reaction scheme:

(A) (both R = -4í0 ₂ )

CS 272789 82

Q represents a leaving group such as chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy, preferably bromo. This reaction is usually carried out in an organic solvent, for example acetonitrile or a mixture. acetonitrile and ethanol under reflux and in the presence of a base such as potassium carbonate or sodium bicarbonate.

The starting indane derivative can be prepared by the procedure detailed in Preparations 1-3. The starting substituted nitrohenzenes are generally known compounds or can be prepared according to methods known in the art, such as those described below in the Preparations.

When R is 1 or 2 and X is a direct bond, such starting materials of formula (A) in which both R is nitro can be prepared according to the following schemes, which are described in detail in the preparations below.

(n) [n = 2]

ch ₂ nh (ch ₂ )

-NO, (i) H (ii) NaBH ₄ (iii) HCl

(b) fn = V

The invention is not to be construed as limiting the invention. The following exemplary embodiments denote the signal shapes which, however, are intended to illustrate the scope of the invention in no NMR spectra in these examples and in the following preparations by the following common abbreviations:

s = singlet, q = quartet, d = doublet, m = multiplet, t = triplet, w = broad signal.

Example 1

5-methanesulfonamido-2- [N- (2- / 4-methanesulfonan) idophenoxy / ethyl) -N-methylamino] indane

pyridine

IN

Η

A solution of 0.25 g of 5-amino-2- [N- (2- [4-aminophenoxy] ethyl [-N-methylaninino] indane in pyridine) was added with 0.15 ml of methanesulfonyl chloride and stirred at room temperature for 17 hours. The solvent was evaporated in vacuo and the gummy residue was purified by silica gel column chromatography using methylene chloride with increasing methanol content (from 0% to 1%) as eluent to give product-containing fractions and evaporated in vacuo to give 0.06 g of the title compound in the form of a foam.

@ 1 H-NMR (CDCl3): 7.25 (d, 2H), 7.2 (dd, 1H), 7.1 (s, 1H), 7.0 (d, 1H), 6.95 (d) (2H), 4.1 (t, 2H), 3.55 (t, 1H), 3.1 (m, 2H), 3.05 (s, 3H), 3.0 (s, 3H), 2 9 (m, 4H); 2.45 (s, 3H).

Example 2

5-methanesulfonamido-2- | N- (4-methanesulfonamidophenethyl) -N-methylamino | indane

Pyridine

To a solution of 0.28 g of 5-amino-2- [N- (4-aminophenethyl) -N-methylamino) indane in 30 ml of pyridine was added 0.155 ml of methanesulfonyl chloride and the reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the gummy residue was dissolved in methylene chloride, the solution was washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography using methylene chloride with increasing amounts of methanol (from 0 to 6 X) as eluent. The product containing fractions were combined and evaporated to dryness in vacuo to give the title compound as a foam (0.27 g).

Analysis: for ^C 20 ^H 27 ^N 3 ° 4 ^S 2 Calculated: 54.9% C, 6.2% H, 9.6% N;

Found: C 54.5%, H 6.2%, N 9.35%.

¹ H-NMR (CDCl 3) _: 7.2 (q, 4H), 7.15 (d, 1H), 7.1 (s, 1H), 7.0 (d, 1H), 3.45 (t, 1H), 3.05 (m, 2H), 3.0 (d, 6H), 2.95 (m, 2H), 2.90 (m, 2H), 2.85 (m, 2H) 2.4 (s, 3H).

Example 3

5-methanesulfonamido-2- | N- (4-methanesulfonamidobenzyl) -N-methylamino) indane

CH ₃ SO ₂ N

AND

H

To 1.1 g of 5-amino-2- [N- (4-aminobenzyl) -N-methylamino] indane in pyridine was added 0.53 ml of methanesulfonyl chloride and the reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was taken up in methylene chloride, the solution was washed with aqueous sodium bicarbonate solution and, after drying over magnesium sulfate, evaporated in vacuo. The resinous residue was purified by silica gel chromatography, eluting with methylene chloride with increasing amounts of methanol (from 0% to 2%). Product containing fractions were combined and evaporated to dryness in vacuo to give the title compound as a colorless foam. The foam was dissolved in chloroform and the solution was evaporated to dryness in vacuo. Yield 0.2 g of the title compound as a colorless foam.

Analysis:

Found Calcd for C ₁₉ H ₂₅ N ₃ 0 ₄ .2 / ₃ CHC1 ₃ ^x) 53.9% C, 5.9% H, 9.6% N; % C, 54.0%;% H; 6.0%;

X) the fact that the product is a solvate was determined and quantitated by 1 H-NMR spectrum 1 H-NMR (deuterated trifluoroacetic acid, values): 7.72 (s, 1H), 7.63 (t, 1H),

7.45 (dd, 2H), 7.4 (dt, 2H), 7.3 (d, 1H), 4.8 (d, 1H), 4.5 (,, 1H), 4.35 Cd,

1H), 3.6 (m, 4H), 3.2 (d, 6H), 2.9 (dd, 3H).

The following preparations illustrate the preparation of the starting materials used in the preceding examples.

2-formylaminoindane

ml of acetic anhydride is mixed with 20 ml of formic acid, the mixture is heated to 50 ° C with stirring for 15 minutes, and 25 g of 2-aminoindan-byarochioride (see J. Med. Chem., 1980, 23, p. 745) and 20 g of sodium acetate and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and extracted three times with methylene chloride. The combined organic layers were washed with water and an aqueous sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuo. Yield 17.6 g, m.p. 72-74 ° C.

Analysis calculated for: ^C 10 ^H 11 ^NO : C 74.5%, H 6.9%, N 8.7;

Found: C, 74.25; H, 7.0; N, 8.6.

1 H-NMR (CDCl 3): 8.0 (s, 1H), 7.1 (s, 4H), 4.7 cm -1, 1H), 3.4 (dd,

H, 2.8 (dd, 2H).

Preparation 2

2-formylamino-5-nitroindane

CS 272789 82

Κ 30 g of fuming nitric acid (density 1,5 g / ml) are added in portions, maintaining the temperature between 0 ° C and -5 ° C, with 2 g of 2-formylaminoindane. The reaction mixture was stirred at 0 ° C for 1 h, then poured into ice water and extracted with methylene chloride. The organic layer was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by silica gel column chromatography, eluting first with methylene chloride containing decreasing amounts of hexane (from 20% to 0%) and then with methylene chloride containing increasing amounts of methanol (from 0% to 2%). Product containing fractions were combined and evaporated. Yield: 7.7 g (m.p. 91-92 ° C).

Analysis: ^{C H} jq iq 2 ^N ° 3: calculated: 58.25% C, 4.9% H, 13.6% N Found: 58.1% C, 4.8% H, 13.5% N .

Preparation

2-methylamino-5-nitroindan hydrochloride

To a stirred mixture of 4.6 g of 2-formylamino-5-nitroindane and 4.22 g of sodium borohydride in 65 ml of tetrahydrofuran was added dropwise 6.4 ml of acetic acid while cooling to 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 15 minutes, then heated under reflux for 2 hours, then evaporated to dryness in vacuo. The residue was diluted with 2M hydrochloric acid, basified with aqueous sodium carbonate solution to pH ~ 12 and extracted with methylene chloride. The organic layer was dried over magnesium sulphate, evaporated in vacuo and stirred with ethereal hydrogen chloride. The precipitate was filtered off and dried, yielding the title compound (m.p. 221-223 ° C).

Analysis calculated for ^C 18 ^H 12 ^N 2 ^O 2 ^HCl

52.5% C, 5.7% Fi, 12.25 X N; 52.75 »C, 5.6 X H, 12.15% N.

Preparation 4

2- [N-methyl-N- (2- (4-nitrophenoxy / ethyl) amino) -5-nitroindane

no ₂ -

0.46 g of 2-methylamino-5-nitroindanohydride, 0.49 g of 2-bromoethoxy-4-nitrobenzene (see CA, (1960), 54, 11046a) and 2 g of potassium carbonate are mixed in a mixture of 50 ml of acetonitrile and 20 ml. ml of ethanol was heated to reflux for 20 hours. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with methylene chloride. The organic layer was dried over magnesium sulphate and evaporated to an oily residue which was purified by silica gel column chromatography using methylene chloride containing increasing amounts of methanol (from 0% to 1X) as eluent. Product containing fractions were combined and evaporated to give the title compound as an oil (0.28 g).

@ 1 H-NMR (CDCl3): 8.0 (d, 2H), 7.9 (m, 2H), 7.2 (d, 1H), 6.8 (d, 2H);

2H), 4.1 (t, 2H), 3.4 (m, 1H), 2.9 (bd, 4H), 2.8 (t, 2H), 2.3 (s, 3H).

Example 5

5-amino-2- [N- (2- (4-aminophenoxy) ethyl) -N-methylamino] indane

NO.

62

H ₂ / Pd / C

A solution of 0.3 g of 2- [N-methyl-N- (2- / 4-nitrophenoxy / ethyl) amino] -5-nitroindane in 30 ml of ethyl acetate is stirred for 2 hours in the presence of 0.03 g of 5% palladium on carbon. at room temperature under a hydrogen atmosphere at a pressure of 20 psi. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 0.25 g of the title resin which was used directly without further purification.

Preparation 6

2- | N-methyl-N- (4-nitrophenethyl) amino | -5-nitroindane

0.45 g of 2-methylamino-5-nitroindan hydrochloride, 0.46 g of 4-nitrophenethyl bromide and 2 g of potassium carbonate were refluxed in 30 ml of acetonitrile for 3 days. The reaction mixture was filtered, the filtrate evaporated in vacuo and the residue purified by silica gel column chromatography using methylene chloride containing increasing amounts of methanol (from 0% to 1%) as eluent. Product containing fractions were combined and evaporated in vacuo to give a gummy residue which, after crystallization from ethanol, yielded 0.16 g of the title compound, m.p. 138-141 ° C.

Analysis: for ^C 19 ^H I8 ^N ° 3 4 Calculated: 63.3% C, 5.6% H, 12.3% N;

Found: C 62.8, H 5.5, N 12.1%.

1 H-NMR (CDCl 3): 8.2 (d, 2H), 8.1 (d, 1H), 8.05 (s, 1H), 7.4 (d, 2H), 7.3 (d, 1H), 3.5 (t, 1H), 3.15 (q, 2H), 2.9 (m, 4H), 2.8 (t, 2H), 2.4 (s, 3H).

(i) (ii) (iii)

H ©

NaBH ^

HCl

k-ch ₂ ch ₂ - (/ - / - no ₂ .hci

2.8 g of 2-indanone and 3.83 g of N-methyl-4-nitrophenethylamine (see J. 0. C _in (1956), 21,

45) and 0.1 g of toluene-4-sulfonic acid in 100 ml of toluene are refluxed for 1 hour with a Dean-Stark well. During this time, all the reaction water (about 0.4 mL) was collected in the azeotropic cap. The solvent was evaporated in vacuo, the residue was dissolved in 100 ml of ethanol, to which 0.8 g of sodium borohydride was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was then heated to reflux for 10 minutes, cooled and evaporated to dryness in vacuo. The residue was added to 150 ml of 2M hydrochloric acid with stirring. After 0.5 h, the precipitated semi-solid precipitate was filtered off, the filtrate was washed with ether and dried. Yield 1.2 g, m.p. 201-203 ° C.

Analysis: for C ^ ř ^^ %O Oz · HCl: calculated: 64.85% C, 6.45% H, 8.3% N;

Found: C 64.95, H 6.4%, N 8.4%.

@ 1 H-NMR (CDCl3): 8.3 (d, 2H), 7.6 (d, 2H), 7.2 (q, 4H), 4.2 (quintet, 1H), 3.4 (m, 8H), 2.8 (d, 3H).

Preparation 8

2- [N-methyl-N- (4-nitrophenethyl) amino] -5-nitroindane (alternative to preparation 6)

n-ch ₂ ch ₂ - <

.HCl

CH,

Κ 20 ml of fuming nitric acid (density 1,5 g / ml), cooled to -5 ° C, is added in portions over 10 minutes 1,2 g of 2- | N-methyl-N- (4-nitrophenethyl) -amino Indan hydrochloride. Stirring is continued for 2 minutes and then the reaction mixture is poured into ice-water. The aqueous mixture was extracted with methylene chloride, the organic extract was washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was recrystallized from ethanol to give 0.78 g of the title compound, m.p. 138-140 ° C.

Preparation 9

H ₂ / Pd / C

N-CH ₂ -CH ₂ _ // \\ - NH ₂

A solution of 0.5 g of 2- [N-methyl-N- (4-nitrophenethyl) amino] -5-nitroindane in a mixture of 40 ml of ethyl acetate and 10 ml of methanol is stirred for 4 hours in the presence of 0.05 g of 5% palladium on carbon. at room temperature under a hydrogen atmosphere at 20 psi. The catalyst was filtered off and the filtrate was evaporated in vacuo to a gummy residue which was triturated with ether. The ether was collected by decantation and evaporated in vacuo to give the title compound (0.33 g). A small sample of the product melts after recrystallization from diisopropyl ether at 112-114 ° C.

Analysis: for ^C 23 ^H JG ^N 3 Calculated: 76.8% C, 8.2% H, 14.9% N;

Found: C, 76.6; H, 8.3; N, 14.6.

¹ H-NMR (CDCl 3): 7.05 (d, 2H), 7.0 (d, 1H), 6.7 (d, 2H), 6.55 (s, 1H), 6, Δ (d, 1H), 3.6 (bs, 4H), 3.4 (quintet, 1H), 3.0 (m, 2H), 2.8 (m, 2H),

2.7 (d, 4H); 2.4 (s, 3H).

Preparation 10

2- (N-benzyl-N-methylamino) indane hydrochloride

(ii) NaBH 4; (iii) SCI

A solution of 5.28 g of 2-indanone, 4.84 g of N-benzylmethylamine and 0.15 g of 4-toluenesulfonic acid in 120 ml of toluene was refluxed for 1.5 hours with a Dean-Stark well. During this time, all the reaction water (0.8 mL) was collected in the azetropic cap. The solvent is evaporated in vacuo, the residue is dissolved in 150 ml of ethanol containing 1.6 g of sodium borohydride and the mixture is stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was carefully diluted with 200 ml of 2M hydrochloric acid and extracted twice with 100 ml of methylene chloride each time. The combined organic extracts are evaporated in vacuo, the residue is triturated with isopropanol, the precipitate formed is filtered off and dried. Yield: 2.5 g (m.p. 204 DEG-206 DEG C.).

For C,4 yHH jNNHCl: C, 74.6; H, 7.4; H, 5.1;

Found: C 74.1%, H 7.4%, 5.0 X N.

@ 1 H-NMR (CDCl3) .delta. 7.7 (dd, 2H), 7.5 (m, 3H), 7.15 (q, 4H), 4.4 (q,

1H), 4.15 (q, 1H), 4.05 (quintet, 1H), 3.8 (q, 1H), 3.6 (q, 1H), 3.5 (q, 1H),

3.25 (q, 1 H), 2.6 (d, 3H).

Preparation 11

2- (N-benzyl-N-methylamino) intiane hydrochloride (alternative to preparation 10)

CS 272789 82 (i) to ₂ co ₃ (ii) HCl

HCl

0.65 g of 2-methylaminoindan (see J. Med. Chem., 1980, 23, p. 745), 0.6 g of benzyl bromide and 1.0 g of potassium carbonate are heated under reflux in acetonitrile for 8 hours. The reaction mixture was filtered and evaporated to dryness in vacuo. The oily residue is dissolved in ethyl acetate, the solution is diluted with ethereal hydrochloric acid, the precipitate formed is filtered off and recrystallized from isopropanol. Yield: 0.5 g (m.p. 204 DEG-206 DEG C.).

2.6 g of 2- (N-benzyl-N-methylamino) indane hydrochloride are added. The reaction mixture was stirred for a further 2 minutes and then poured into ice water. The water was decanted off, the resin residue was taken up in methylene chloride, the organic solution was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. 2.4 g of the title compound are obtained.

A 0.1 g sample of this material was dissolved in ether and ethereal hydrogen chloride was added to the solution. The precipitate formed is filtered off and dried to give the hydrochloride of the title compound, melting at 210-212 ° C.

Analysis for CC yHH^N^O ^ · HCl · 1/2 Calcd: C, 54.8; H, 5.1; N, 11.3;

Found: C 55.2%, H 5.0%, N. 11.2%.

1 H-NMR (deuterated trifluoroacetic acid, cf +): 8.8 (s, 1H), 8.7 (t, 1H),

8.35 (d, 2H), 8.1 (d, 1H), 7.9 (m, 1H), 7.6 (dd, 1H), -5.0 (d, 1H), 4.7 (m) (1H),

4.6 (d, 1H), 3.8 (m, 4H), 3.0 (s, 3H).

Example 13

5-amino-2- (N-4-aminobenzyl) -N-methylamino] indane

2.3 g of 2- [N-methyl-N- (4-nitrobenzyl) amino (-5-nitroindan) in 60 ml of ethyl acetate containing 0.25 g of 5% palladium on carbon are stirred at room temperature under hydrogen atmosphere under pressure for 1 hour. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo, and the residue is purified by silica gel column chromatography using methylene chloride containing an increasing amount of methanol (from 0 Ϊ to 1 Ϊ) as the eluent. The title compound was obtained as an oil which was used without further purification.

Claims (5)

A process for the preparation of sulfonamidoindanes of the general formula I (I) CS 272789 82 wherein. R @ ¹ represents a hydrogen atom, a C1 -C4 alkyl group, a C1 -C4 alkoxy group or a halogen atom; R @ 1 which is the same is C1 -C4 alkyl, X represents an oxygen atom or a direct bond and n has a value of 1 or 2, provided that when X represents an oxygen atom, it has a value of 2 and their pharmaceutically acceptable salts, characterized in that the compound of formula II in which. R @ 1 and R @ 2 are as defined above, • reacted with an alkanesulfonyl chloride or a bromine having from 1 to 4 carbon atoms in the alkyl moiety or with an alkanesulfonic anhydride of 1 to 4 carbon atoms, whereupon the resulting product is optionally converted to its pharmaceutically acceptable salt. 2. A process according to claim 1 wherein the reaction is carried out in the presence of an acid acceptor. 3. The process according to claim 2, wherein the acid acceptor is pyridine, triethylamine, potassium carbonate or sodium bicarbonate. 4. A process according to claim 3 wherein the reaction is carried out by treatment with methanesulfonyl chloride in pyridine. 5. The process of item 1, for the preparation of 5-methanesulfonamido-2- [N- (4-methanesulfonamidophenethyl) -N-methylamino] indane, characterized in that 5-amino-2-1N- (4-aminophenethyl) - N-methylamino] indane is reacted with methanesulfonyl chloride in the presence of an acid acceptor.