PL158278B1 - Method of obtaining novel derivatives of indanosulfonamides - Google Patents

Abstract

1. The method of producing new derivatives of indano sulphonamides with the formula presented in 2 and their pharmacologically accepted salts, where 2 R<1> stands for the hydrogen atom, C1-C4 alkyl group or C1-C4alkoxy group, or the halogen atom, each of R <2> substituents, which is identical, stands for C1-C4 alkyl group, X stands for the oxygen atom or the bonding and n is number 1 or 2, provided that if X stands for the oxygen atom then n is number 2, characterized in that the compound with the formula presented in 14 in which R<1>, X and n have the meaning specified above, is subject to the reaction with C1-C4 alkane sulfonyl chloride or C1-C4 alkane sulfonyl bromide or with C1-C4 alkane sulfone anhydride and the obtained product with the formula presented in 2 is possibly transformed into a pharmacologically accepted salt.<IMAGE>

Description

The present invention relates to a process for the preparation of new indanesulfonamide derivatives which are anti-arrhythmia agents.

The anti-arrhythmia compounds of the present invention prolong the duration of the potential action in the myocardium and in the vascular tissue, and therefore increase resistance to premature stimuli. These compounds therefore belong to the class III anti-arrhythmic agents according to the Vaughan Williams classification (Anti-Arrhythmic Action, E. M. Vaughan Williams, Academic Press, 1980). They are effective in atria, ventricles, and vascular tissue both in vitro and in vivo, and are therefore useful in the prevention and treatment of a wide variety of ventricular and extraventricular arrhythmias, including atrial fibrillation and ventricular fibrillation. The compounds obtained do not alter the impulse conduction velocity and therefore have a lesser tendency than the currently used drugs, mainly class I, to induce or exacerbate arrhythmia, as well as having less neurological side effects. Some of the compounds in question also have some positive inotropic activity and, as a result of this feature, are particularly advantageous for patients with impaired blood pumping function.

The compounds of formula I, as well as their salts, are prepared by the process of the invention, in which formula I each R which is the same is the group -NHSOz (C1-C4alkyl), i.e. compounds of formula II, X is oxygen or a bond, R 1 is hydrogen, C 1 -Caikyl or C 1 -C 4 alkoxy or halogen, and n is 1 or 2 with the proviso that if X is oxygen, n is 2.

Compounds of formula I in which each of R is -NHSOa (C 1 -C 4 alkyl) are anti-arrhythmia and those compounds of formula I in which each of R is -NO2 or -NH2 are intermediates for synthesis.

The process of the invention provides compounds of formula II and their pharmacologically acceptable anti-arrhythmic salts, wherein R1 is hydrogen, C1-C6 alkyl or C1-C4 alkoxy, or halogen, each of R2 which is is the same, is C1-C4alkyl, X is oxygen or a bond, and n is 1 or 2, provided that when X is oxygen, n is 2.

158 278 ³

A preferred alkyl group is methyl and a preferred alkoxy group is methoxy. The 3 or 4 carbon, alkyl and alkoxy groups can be straight or branched chain. The halogen can be a fluorine, chlorine, bromine or iodine atom. R ¹ is preferably a hydrogen atom.

The preferred anti-arrhythmia is represented by Formula 2a, which is within the range of Formula 2.

The compounds of formula I are optically active and the process according to the invention allows them to be obtained in the R, S or R / S forms.

Pharmacologically acceptable salts of compounds of Formula 2 include acid addition salts formed with acids that form non-toxic acid addition salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, meleinate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, p-toluenesulfonate benzenesulfonate. The term also includes the alkali metal salts, especially the sodium and potassium salts. The salts mentioned above are prepared by known methods.

The compounds of formula 2 are prepared by acylating a compound of formula 1 wherein each of R is -NH2, ie a compound of formula 14, with a C1-C4 alkanesulfonyl chloride or bromide or a C1-C4 alkanesulfonic anhydride. Of course, at least two equivalents of the acylating agent will be needed for the reaction, and of course the R groups in the final product will be the same. The reaction is usually carried out at room temperature and optionally in the presence of an acid acceptor such as pyridine, triethylamine, sodium or potassium carbonate or bicarbonate. The presence of an acid acceptor is particularly useful when an alkanesulfonyl chloride or bromide is used in the reaction. In practice, it is particularly advantageous to carry out the reaction with an alkanesulfonyl chloride in pyridine, which acts as both an acid acceptor and a solvent. The product of Formula 2 is then isolated and purified by conventional methods.

The starting compounds of formula I, in which each of R is -NH2, are obtained by reduction of the corresponding compounds in which R is -NO2 by known methods, e.g. by using hydrogen in the presence of palladium on carbon, in a suitable organic solvent, e.g. ethyl acetate or a mixture of ethyl acetate and methanol at about room temperature.

The starting compounds of Formula 1 in which each of R is -NO2 is obtained according to Scheme 1 in the figure by reacting a compound of Formula 3 with a compound of Formula 4 in which Q is a leaving group such as chlorine, bromine or iodine, methanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy, preferably bromine, and X, R1 and n are as defined above in the presence of a base. The reaction is usually carried out in an organic solvent, e.g. acetonitrile or acetonitrile / ethanol, under reflux and in the presence of a base such as potassium carbonate or sodium bicarbonate.

The starting indane compound of formula 3 is obtained by the methods illustrated in detail in Examples IV, V and VI. The substituted nitrobenzenes of formula IV are generally known compounds or can be prepared analogously to literature methods such as those described in the examples.

If n is the number 1 or 2 and X is a bond, it is possible to proceed as illustrated in scheme 2 if n = 2 and in scheme 3, respectively, if η = 1. Both procedures are detailed in the examples leading to to obtain the starting compounds of formula I in which each R is -NO2.

To evaluate the effects of the compounds produced on vestibular immunity, the right half-atriums of guinea pigs are placed in a bath containing saline and one end is connected to the power transducer. Tissues are stimulated at 1 Hz using field electrodes. The Effective Duration of Immunity (ERP) is measured by applying the premature stimulus S2 after each 8th Si baseline stimulus. The conjugate interval S1S2 is progressively increased until S2 repeatedly reveals a reaction transfer. It is known as ERP. The concentration of compound necessary to increase the ERP by 25% (ED25) is thus determined.

158 278

ERP is also measured on the guinea pig's right papillary muscles incubated in a physiological saline solution. The muscles are stimulated at one end by the bipolar electrodes and the electrograph obtained at the opposite end is recorded by the unipolar electrode surface. ERP is determined as above using the additional stimulus technique. Conduction time is obtained from a digital oscilloscope by measuring the time interval between the stimulus artifact and the peak of the electrograph, that is, the time required for the pulse to travel through the length of the muscle.

Atrial and ventricular ERP are also measured in anaesthetized or not asleep dogs by using the supplemental stimulus technique when measuring atrial or right ventricular stimulus at a constant rate.

The compounds of Formula 2 may be administered alone, but are typically used in admixture with a pharmaceutical carrier depending on the intended route of administration and standard pharmaceutical practice. They can be used both for patients suffering from arrhythmia and prophylactically in people suspected of developing arrhythmia. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring additives. They can also be administered by the parenteral route, for example, intravenously, intramuscularly, or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other solutes, for example an amount of salt or glucose which makes the solution isotonic with blood.

For human administration for therapeutic or prophylactic purposes, such as ventricular or extraventricular arrhythmias, including atrial and ventricular fibrillation, oral doses of compounds of Formula 2 in the range of 2 to 150 mg per day, taken in maximum 4 servings a day for an average adult patient (70 kg). For intravenous administration, the expected single dose will be in the range 1.0 to 20 mg. Severe cases of cardiac arrhythmia are preferably treated by intravenous administration of the drug to rapidly restore normal heart rhythm. Thus, for the average adult patient, single tablets or capsules may contain 2-50 mg of the active compound in a suitable pharmaceutically acceptable carrier or vehicle. Deviations from these ranges may occur depending on the weight and condition of the patient being treated, and will be known to those of skill in the art.

Thus, the pharmaceutical composition comprises a compound of Formula 2, optionally a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier, and the ingestion of these compositions counteracts or reduces arrhythmia in humans.

The following examples illustrate the process of the invention for the preparation of compounds of formula 2, with examples I, II and III relating to the preparation of compounds of formula 2 and examples IV-XVI relating to the preparation of the starting compounds used in cases I-III.

Example 1.5-Methanesulfonamido-2- {N- [2 - (< 4-methanesulfonamidophenoxy) ethyl] -N-methylaminojindane (scheme 4).

For the solution 5-amino-2 - ^^ - ^ [: ^^ (4 ^^ and ^ ii ^ <^ l ^^ i ^ i ^ lks ^^^ 1 ^ t ^ l ^ o] - ^^ '^ Methylsulfonyl chloride (0.15 ml) was added in pyridine and the mixture was stirred for 17 hours at room temperature, then the solvent was removed by evaporation in vacuo. to give a gum which was purified by column chromatography on silica gel eluting with methylene chloride containing methanol (0% to 1%) The fractions containing the product were combined and evaporated in vacuo to give the title compound as a foam, 0.06 g.

'Η-nmr (CDCb): δ = 7.25 (d, 2H), 7.2 (d, 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 II. 5-Methanesulfonamido-2- [N- (4-methanesulfonamidophenethyl) -Netylaminojindane (scheme 5).

Methanesulfonyl chloride (0.155 ml) was added to a solution of 5-amino-2- [N - (4-aminophenethyl) -N-methylamino] indane (0.28 g) in pyridine (30 ml), and the mixture was stirred for 17 hours at room temperature. . The solvent was then removed by evaporation in vacuo and the resulting gum was dissolved in methylene chloride, the solution was washed with an aqueous sodium bicarbonate solution and brine, dried (MgSO 4) and evaporated in vacuo. The residue was purified by chromatography

A silica gel column eluted with methylene chloride containing methanol (0% to 2%) was combined and the product fractions were evaporated in vacuo to dryness to give the title compound as a foam, 0.27 g.

Analysis (%): for C20H27N3O4S2:

Found: C 54.5 H 6.2 N 9.35

Calculated: C 54.9 H (5.2 N, 9.6 ¹ H-nmr (CDCl3): δ = 7.2 (q, 4H), 7.15 (d, 1H), 7.1 (s, H ), 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 III. 5-Methanesulfonamido-2- [N- (4-methanesulfonamidobenzyl) -N-methylaminojindane (scheme 6).

Methanesulfonyl chloride (0.53 ml) was added to 5-amino-2- [N- (4-aminobenzyl) -N-methylamino] -indan (1.1 g) in pyridine, and the mixture was stirred for 17 hours at room temperature. The solvent was then removed by evaporation in vacuo and the residue was dissolved in methylene chloride. The solution was washed with an aqueous sodium bicarbonate solution, dried (MgSO 4) and evaporated in vacuo. The resulting gum was purified by silica gel column chromatography eluting with methylene chloride containing methanol (0% to 2%). The fractions containing the product were combined and evaporated to dryness in vacuo to give the title compound as a colorless foam. This foam was dissolved in chloroform and the solution was evaporated to dryness in vacuo to give the title compound as a colorless foam, 0.2 g.

Analysis (%): for Ci _e H ₂ 5N3O ₄ -2 / ^ 3CHCl3 ^X :

Found: C 54.0 H 6.0 N 9.5

Calculated: C 53.9 H 5.9 N 9.6 x The fact that the product was a solvate was detected and estimated by H-nmr analysis.

¹ H-NMR (TFAd): 6 = 7.72 (s, 1H), 7.63 (t, 1H), 7.45 (d, 2H), 7.4 (t, 2H), 7.3 ( s, 1H), 4.8 (d, 1H), 4.5 (m, 1H), 4.35 (d, 1H), 3.6 (m, 4H), 3.2 (d, 6H), 2.9 (d, 3H).

P r x l a d IV. 2-Formylindane (scheme 7).

Acetic anhydride (40 ml) and formic acid (20 ml) were stirred and heated at 50 ° C for 15 minutes. To this mixture was added 2-aminoindane hydrochloride (25 g) (see J. Med. Chem. 1980, 23, p. 745) and sodium acetate (20 g), and the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into ice / water and extracted three times with methylene chloride. The combined organic phases were washed with water and an aqueous sodium carbonate solution, dried (MgSO 4) and evaporated in vacuo to give the title compound, 17.6 g, mp 72-74 ° C.

Analysis (%): for C10H11NO:

Found: C 74.25 H 7.0 N 8.6

Calculated: C 74.5 H 6.9 N 8.7 '-nmr (CDClb): <= 8.0 (s, 1H), 7.1 (s, 4H), 4.7 (m, 1H) 3.4 (dd, 2H), 2.8 (dd, 2H).

ExampleV. 2-Formylamino-5-nitroindane (scheme 8).

2-Formylaminoindane (15 g) was added portionwise to fuming nitric acid (30 ml, density = 1.5 g / ml), keeping the temperature between 0 ° C and -5 ° C during the addition. Stirring at 0 ° C was continued for 1 hour before pouring the reaction mixture into ice / water and extracting with methylene chloride. The organic layer was washed with aqueous sodium bicarbonate, dried (MgSO 4) and evaporated in vacuo to afford an oil which was purified by silica gel column chromatography eluting with methylene chloride containing hexane (20% to 0%) followed by methylene chloride containing methanol (0 % to 2%). The product fractions were combined and evaporated to give the title compound, 7.7 g, mp 91-92 ° C.

Analysis (%): for C10H10N2O3:

Found: C 58.1 H 4.8 N 13.5

Calculated: C 58.25 H 4.9 N 13.6

Example VI. 2-Methylamino-5-nitroindane hydrochloride (scheme 9).

To a mixture of 2-formylamino-5-nitroindane (4.6 g) and sodium borohydride (4.22 g) in tetrahydrofuran (65 ml) cooled to 0-5 ° C, acetic acid (6.4 g) was added dropwise with stirring. ml). Stirring was continued for 15 minutes at 0-5 ° C before heating the mixture for 2 hours under reflux. Reaction mixture

The 158,278 was then evaporated to dryness in vacuo, and the residue was diluted with 2M hydrochloric acid, then basified (to about pH 12) with aqueous sodium carbonate and extracted with methylene chloride. The organic layer was dried (MgSO4), evaporated in vacuo and the residue was stirred with ethereal hydrogen chloride to give a solid which was filtered and dried to give the title compound, 1.5 g, mp 221-223 ° C.

Analysis (%): for C10H12N2O2 HCl:

Found: C 52.75 H 5.6 N 121.15

Calculated: C 52.5 Η 5.7 N 12.25

Example VII. 2- {N-Methyl-N- [2- (4-nitrophenoxy) ethyl] amino} -5-nitroindane (scheme 10).

2-Methylamino-5-nitroindane hydrochloride (0.46 g), 2-bromoethoxy-4-nitrobenzene (0.49 g) [C. A. (1960), 54, 11046a] and potassium carbonate (2g) were heated to reflux for 20 hours in acetonitrile (50 ml) / ethanol (20 ml). The solvent was then removed by evaporation in vacuo and the residue was diluted with water and extracted with methylene chloride. The organic layer was dried (MgSO4) and evaporated to give an oil which was purified by silica gel column chromatography eluting with methylene chloride containing methanol (0% to 10%). The product fractions were combined and evaporated to give compound as an oil, 0.28 g.

H-nmr (CDCl): <= 8.0 (d, 2H), 7.9 (m, 2H), 7.2 (d, 1H), 6.8 (d, 2H), 4.1 (t , 2H), 3.4 (m, 1H), 2.9 (hrd, 4H), 2.8 (t, 2H), 2.3 (s, 3H).

Example VIII. 5-Amino-2- {N- [2-04-minophenoxy)) yl]] N-methylamino} incbn (scheme

11).

A solution of 2- {N-methyl-N - 2-44-ittophenoxy)) yl] mino]] 5-niiroindane (0.3 g) in ethyl acetate (30 ml) containing 5% palladium on carbon (0 0.03 g) was stirred in a hydrogen atmosphere (206.8 kPa) for 2 hours at room temperature. The catalyst was then removed by filtration and the filtrate was evaporated in vacuo to give the title compound as a 0.25g gum which was used directly without further purification.

Example IX. 2- [N-methyl-N- (2-niirophenethyl) amino] -5-nitroindane (scheme 12).

2-Methylamino-5-nitroindane hydrochloride (0.45 g), 4-nitrophenethyl bromide (0.46 g) and potassium carbonate (2 g) were heated in acetonitrile (30 ml) for 3 days under reflux. The reaction mixture was then filtered off, the filtrate was evaporated in vacuo, and the residue was purified by silica gel column chromatography eluting with methylene chloride containing methanol (0% to 1%). The fractions containing the product were combined and evaporated in vacuo to give a gum which was crystallized from ethanol to give the title compound, 0.16 g, mp 138-141 ° C.

Analysis (%): for C18H19N3O4:

Found: C 62.8 H 5.5 N 12.1

Calculated: C 63.3 H 5.6 N 12.3.

H-nmr (CDCb): δ = 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).

Example X. 2- [N-Methyl-N- (4-nitrophenethyl) amino] indane hydrochloride (scheme 13).

Indanone-2 (2.8 g) N-methyl-4-nitrophenethylamine (3.83 g) [J. OC (1956), 21, 45] and 4-toluenesulfonic acid (0.1 g) in toluene (100 ml) were refluxed in a Dean and Stark aperture for 1 hour, during which time all the water produced ( about 0.4 ml) is withdrawn by azeotorphic distillation. The solvent was then evaporated in vacuo, and the residue was dissolved in ethanol (100 ml), to which sodium borohydride (0.8 g) was added, and the mixture was stirred for 6 hours at room temperature. The mixture was then heated to reflux for 10 minutes, cooled and evaporated to dryness in vacuo. The residue was added to a 2M solution of hydrochloric acid (150 ml) with stirring and after 1/2 hour a semi-solid was collected by filtration and the filtrate was washed with ether and dried to give the title compound, 1.2 g, mp 201-203 ° C.

Analysis (%): for C18H20N2O2 HCl:

Found: C 64.95 H 6.4 N 8.4

Calculated: C 64.85 H 6.45 N 8

158 278 7 ¹ H-nmr (DMSO d _e ): δ = 8.3 (d, 2H), 7.6 (d, 2H), 7.2 (q, 4H), 4.2 (quintet, 1H) , 3.4 (m, 8H), 2.8 (d, 3H).

Example XI. (alternative to Example IX). N- [N-Methyl-N- (4-nitrophenethyl) amino] -5-nitroindano (scheme 14).

2- [N-Methyl-N- (4-nitrophenethyl) amino] indan hydrochloride (1.2 g) was added portionwise over 10 minutes to fuming nitric acid (20 ml, density = 1.5 g / ml). cooled to -5 ° C. Stirring was continued for a further 2 minutes before pouring the reaction mixture onto ice / water. The water mixture was extracted with methylene chloride and the organic extract was washed with aqueous sodium hydrogen carbonate solution, dried (MgSO 4) and evaporated to dryness in vacuo. The residue was recrystallized from ethanol to give the title compound, 0.78 g, mp 138-140 ° C.

Example XII. 5-Amino-2- [4-aminophenethyl) -N-methylamino] indane (scheme 15).

A solution of 2- [N-methyl-N- (4-nitrophenethyl) amino] -5-nitroindane (0.5 g) in ethyl acetate / methanol (40 ml / 10 ml) containing 5% palladium on carbon (0.05 g) was stirred under a hydrogen atmosphere (206.8 kPa) for 4 hours at room temperature. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to give a gum which was triturated with ether. The ether was decanted and evaporated in vacuo to dryness to give the title compound, 0.33 g. A small sample was taken and recrystallized from isopropyl ether, mp 112-114 ° C.

Analysis (%): for CieHzsNs:

Found: C 76.6 H 8.3 N 14.6

Calculated: C 76.8 H 8.2 N 14.9 ¹ H-nmr (CDCl 3): <= 7.05 (d, 2H), 8.0 (d, 1H), 6.7 (d, 2H) . 6.55 (s. 1H). 6.5 (d, 1H), 3.6 (broad s, 4H), 3.4 (quintet, 1H), 3.0 (m, 2H), 2.8 (m, 2H), 2.7 ( d, 4H), 2.4 (s, 3H).

Example XIII. 2- (N-bεnzyl-N-methyltoamino) indane hydrochloride (Scheme 16).

A solution of indanone-2 (5.28 g), N-benzylmethylamine (4.84 g) and 4-toluenesulfonic acid (0.15 g) in toluene (120 ml) was heated 1 1/2 hours under reflux. in a Dean and Stark apparatus, during which time all the water formed (about 0.8 ml) was collected by azeotropic distillation. Then the solvent was evaporated in vacuo and the residue was dissolved in ethanol (150 ml) to which sodium borohydride (1.6 g) was added, and the mixture was stirred for 17 hours at room temperature. The solvent was then evaporated in vacuo and the residue carefully diluted with a 2M hydrochloric acid solution (200 ml). The acidic solution was extracted twice with methylene chloride (2 × 100 ml) and the combined organic extracts evaporated in vacuo. The residue was triturated with isopropanol and the resulting precipitate was filtered off and dried to give the title compound, 2.5 g, mp 204-206 ° C.

Analysis (%): for Ci ₇ H ₁₉ N HCl:

Found: C 74.1 H 7.4 N 5.0

Calculated: C 74.6 H 7.4 N 5.1 ¹ H-nmr (CDCl 3): 6 = 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, 1H), 2.6 (d, 3H).

Example XIV. (alternative to Example XIII). 2- (N-benzyl-N-methylamino) indane hydrochloride (scheme 17).

2-Methylaminoindane (0.65 g) (J. Med. Chem. 1980, 23, p. 745), benzyl bromide (0.6 g), and potassium carbonate (1.0 g) were heated to reflux for 8 hours. in acetonitrile. The reaction mixture was then filtered and evaporated in vacuo. The resulting oil was dissolved in ethyl acetate, diluted with ethereal hydrogen chloride, the precipitate was separated by filtration and recrystallized from isopropanol to give the title compound, 0.5 g, m.p. 204-206 ° C.

Example XV. 2- [N-Methyl-N - {(- nitrobenzyl) amino] -5-n-iroindane (scheme 18).

2- (N-benzyl-N-methylamino) indane hydrochloride (2.6 g) was added portionwise over 10 minutes to fuming nitric acid (25 ml) cooled to -5 ° C. Stirring was continued for a further 2 minutes before pouring the reaction mixture into ice water. The water was decanted to a gum which was dissolved in methylene chloride, washed with water and saturated aqueous sodium bicarbonate solution, dried (MgSO 4) and evaporated in vacuo.

To give the title compound, 2.4 g. A sample (0.1 g) was dissolved in ether and treated with ethereal hydrogen chloride. The resulting precipitate was separated by filtration and dried to give the hydrochloride salt of the title compound, mp 210-212 ° C.

Analysis (%): for C17H17N3O4HC1-1 / 2 H ₂ O Found: C 55.2 H 5.0 N 11.2

Calculated C 54.8 H 5.1 N U.3

H-nmr (TFAd), <= 8.8 (s, 1H), 8.7 (t, 1H), 8.35 (d, 2H), 8.1 (d, 1H). 7.9 (m, 1H), 7.6 (d, 1H), 5.0 (d, 1H), 4.7 (m, 1H), 4.6 (d, 1H), 3.8 (m , 4H). 3.0 (s, 3H).

Example XVI. 5-Amino-2- [N- (4-aminobenzyl} -N-methylamino] indane (scheme 19).

2- [N-Methyl-N - ((4-nitrobenzyl) amino] -5-nitroindane (2.3 g) in ethyl acetate (60 ml) containing 5% palladium on carbon was stirred under a hydrogen atmosphere (206.8 kPa) for 1 hour at room temperature The catalyst was then removed by filtration and the filtrate was evaporated in vacuo to dryness The residue was purified by column chromatography on silica gel, eluting with methylene chloride containing methanol (0% to 1%). The fractions containing the product were combined and evaporated, giving the title compound (1.1 g) as an oil which was used directly without further purification.

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Claims (5)

Patent claims A method for the preparation of new indanesulfonamide derivatives of formula 2 and their pharmacologically acceptable salts, wherein R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, or a halogen atom, each of R ² which is the same , is a Ci-C4alkyl group, X is an oxygen atom or a bond,. and n is 1 or 2, provided that if X is oxygen then n is 2, characterized in that the compound of formula 14, wherein R ¹ , X and n are as defined above, is reacted with a chloride or C 1 -C 4 alkanesulfonyl bromide or with C 1 -C 4 alkanesulfonic anhydride and optionally the resulting product of formula 2 is converted into a pharmacologically acceptable salt. 2. The method according to p. The process of claim 1, wherein the reaction is carried out in the presence of an acid acceptor. 3. The method according to p. 2, based on the fact that pyridine, triethylamine, potassium carbonate or sodium bicarbonate are used as the acid acceptor. 4. The method according to p. 3, the reaction was to employ methanesulfonyl chloride in pyridine. 5. The method according to p. The method of claim 1, characterized by BeEsay in that 5-amino-2- [N- (4-aminophenethyl) -N-methylaminojindane is reacted with methanesulfonyl chloride in the presence of an acid acceptor.