FI87350C - Process for the preparation of antiarrhythmic agents and intermediates for these agents - Google Patents

Description

1 87550

This invention relates to certain sulfonamides, which are antiarrhythmic agents, and to intermediates for these agents.

The antiarrhythmic agents of the invention prolong the duration of action potential in myocardium and vascular tissue and thus increase the unacceptable response to premature stimuli. They are thus class III antiarrhythmic agents according to the classification of Vaughan Williams (Anti-Arrhythmic Action, E.M. Vaughan Williams, Academic Press, 1980). They are effective in the atria, ventricles and duct tissue both in vitro and in vivo and are thus useful in the prevention and treatment of a wide variety of ventricular and supraventricular arrhythmias, e.g. for the prevention and treatment of atrial and ventricular fibrillation. Because they do not alter the rate at which the impulses result, they tend to accelerate or exacerbate arrhythmias less than current drugs (mostly class I drugs) and have a lower tendency to produce neurological side effects. Some of the compounds also have; some inotropic activity and these compounds are particularly good for patients with impaired cardiac pumping function.

The invention thus relates to compounds of the formula 30, "0" r "<a) 35 r1 and their salts.

2,87550 wherein each R is the same and is NC> 2, NH 2 or -NHSO 2 (C 1-6 alkyl); X is O or a direct bond; R * is H and n is 1 or 2, provided that when X is O, then n is 2.

Compounds of formula (A) wherein R is -NHSO 2 - (C 1-4 alkyl) are antiarrhythmic agents. Compounds of formula (A) wherein each R is -NO 2 or each R is -N 1 · 2 are intermediates used in the synthesis.

The invention thus relates to antiarrhythmic compounds of the formula

CH

R2SO? NH 1

R

And pharmaceutically acceptable salts thereof, wherein in formula 1 R is H; each R is the same and is C 1-6 alkyl; X is O or a direct bond and n is 1 or 2, provided that when X is O, then n is 2. The preferred alkyl group is methyl. The C 1-4 and C 1-4 alkyl groups may be straight or branched chain.

The preferred antiarrhythmic compound of formula (I) has the formula (γλ) ·

‘CH SO J

3 2 3 87 850

The compounds of formula (Λ) are optically active and the invention thus comprises the R, S and R / S forms.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with non-toxic acid addition salt-forming acids having pharmaceutically acceptable anions: examples include hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate, phosphate. acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, besylate and p-toluenesulfonate. Alkali metal salts are also possible, especially sodium and potassium salts. The salts are prepared by conventional methods.

To determine the effect of the compounds on atrial non-reception, the guinea pig's right hemiatrium is placed in a bath containing physiological saline and the other end is connected to a force transducer. Tissue är-20 is ignited by means of a field electrode at a frequency of 1 Hz. The effective refractory period (ERP) is measured by causing premature irritation (S2) after every eighth basic irritation (S2). The switching interval of S.jS2 is gradually increased until a reproducible increased response is obtained for S2. This is defined as the ERP. The concentration of compound required to add 25% ERP (ED25) is determined. ERP is also measured in the guinea pig’s right nodule muscles, which are incubated in physiological saline. The muscles 30 are stimulated at one end using bipolar electrodes, and the stimulus-induced electrogram is recorded on the opposite side with a unipolar surface electrode. ERP is determined as above using additional stimuli. The conduction time is obtained with a digital recording oscilloscope by measuring the interval between the induced stimulus and the electrograviran peak (i.e., the time required for the pulse to travel from end to end of the muscle).

Atrial and ventricular ERPs are also measured in anesthetized or awake dogs using an additional 5-stimulus technique while the atrial or right ventricle is synchronized to a constant rate.

The compounds of formula (I) may be administered as a medicament as such, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. They can be given both to patients with arrhythmias and prophylactically to people who are very likely to develop an arrhythmia. They can be administered, for example, orally in the form of tablets containing excipients such as starch or lactose, or in capsules containing them as such or with excipients, or as elixirs or suspensions containing flavoring colorants. They can be administered by parenteral injection, for example, intravenously / intramuscularly or subcutaneously. For parenteral administration, they are preferably used in the form of sterile aqueous solutions which may contain other solutes, for example, amounts of salts or glucose which render the solution isotonic.

When the compounds of the invention are administered to an average human subject (70 kg) to improve heart condition or prevent a disease state such as ventricular or supraventricular arrhythmia, including atrial and ventricular fibrillation, orally, a dose of the compounds of formula (I) 150 mg / day taken in divided doses (2-4) per day. When administered intravenously, the dosage could be 1.0-20 mg per dose as needed to provide a rapid change to a normal t 5 87550 rhythm. Thus, for a typical adult patient, the individual tablets or capsules may contain from 2 to 50 mg of active compound in a suitable pharmaceutically acceptable medium or carrier. These values can be varied depending on the weight and condition of the subject being treated, as is well known to the attending physicians.

The invention thus relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

The invention also provides a method of preventing or reducing arrhythmias in a human heart by administering to the human an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above.

The invention further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicament, in particular for use as an antiarrhythmic agent.

The invention further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or reduction of cardiac arrhythmias.

Compounds of formula (I) may be prepared by acylation of a compound of formula (A) wherein each R is -NH 2 / using N-alkanesulphonyl chloride or bromide or N-alkanesulphonic anhydride for acylation. It is obvious that at least two equivalents of acylating agent are required and that in the final product the groups R are the same.

The reaction is typically carried out at room temperature, optionally in the presence of an acid scavenger such as pyridylamine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of an acid scavenger is particularly preferred when alkanesulfonyl chloride or bromide is used. In fact, the reaction is particularly preferably carried out using alkanesulfonyl chloride in pyridine, which acts as both an acid scavenger and a solvent. The product of formula (I) can then be isolated and purified in a conventional manner.

Starting materials of formula (A) in which each R is NH 2 may be prepared by reduction of the corresponding compounds in which each R is -NC> 2 in a conventional manner, e.g. using hydrogen and a Pd / C catalyst in a suitable organic solvent, e.g. in ethyl acetate or a mixture of ethyl acetate and methanol, at about room temperature.

Starting materials of the formula (Λ) in which each R is -NC 2 can be prepared as follows: 20 μl of NHCH + Q- (CH_) -X -Ur-NO_ 1jMJ-y 3 n: R 1 • \ -. 25 base n /! . Compound (A) wherein each of R = NC 2 Q is a leaving group such as Cl, Br, I, methanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy. Q is preferably Br. The reaction is typically carried out in an organic solvent, e.g. acetonitrile or acetonitrile / ethanol at reflux temperature and in the presence of a base such as potassium carbonate or sodium bicarbonate.

7 87350

The indane starting material can be prepared by the method detailed in Preparations 1-3. The substituted nitrobenzenes used as starting materials are generally known compounds or can be prepared analogously to known methods, for example as described in the following preparations.

When n is 1 or 2 and X is a direct bond, the following reaction pathways detailed in the following preparations can also be used to prepare starting materials of formula (A) wherein each R is -NC 2.

(a) [n = 2] 15 + CH 3 NM (CH 2) NO 2 (i) H R 1 20 (ii) NaBH 4 (iii) HCl: ·: CH 3: R 1

smoky HNO

- - *. 3 r

CH

: ·; 2 R1 8 87550 and (b) fn = 17 O + CH ^ NHCH 7 or | Γ ^ \ - ΝΗΟΗ + BrCH _- ^ \ 3 2 \ = | = / ~ Ol ^ 2Λ == / \ R1 „! \ \ (i) H® \ / (i) KCO_

\ / 1 J

(ii) NaBH4 \ / (ii) HCl 10 \ / (iii) HCl \ / rrvi- j ~ \ N ~ CH2 \ _ | _ / · Hcl

R

smoky HNO3 ... 20 \ / o2n ^: 25 R1

The following examples, in which all temperatures are in degrees Celsius, illustrate the preparation of compounds of formula (I).

Example 1 5-Methanesulfonamido-2- (N-2- [4-methanesulfonamidophenoxy} ethyl) -N-methylamino] indan-9,87550

5 CH

aa 1 | V-n-ch2ch2o / NH2 \ = / \ CH3SO2Cl, 1 n \ ιυ \ pyridine

CH

ΛΛ 1 'j I \ - N-CH2CH2O NS02CH3

15 CH SO

J H

Methanesulfonyl chloride (0.15 ml) was added to a pyridine solution of 5-amino-2- [N- (2- (4-aminophenoxy) ethyl) -N-methylamino] -indane (0.25 g), and the mixture was stirred at room temperature for 17 hours. The solvent was then evaporated in vacuo and the residual gum was purified on a silica gel column using methylene chloride containing methanol (0-1%) as eluent. The product-containing fractions were combined and evaporated in vacuo to give 0.06 g of the title compound as a foam.

H-N.c.r. (CDCl 3): δ = 7.25 (d, 2H); 7.2 (d. 1H); 7.1 (s. 1H); 7.0 (d, 1 H); 6.95 (d. 2H); 4.1 (t. 2H); 3.55 (t, 1 H); 3.1 (m. 2H); 30 3.05 fs, 311); 3.0 (s. 3H); 2.9 (m. 4H); 2.45 (s, 311).

10 87550

Example 2 5-Methanesulfonamido-2- / N- (4-methanesulfonamidophenethyl) -N-methylamino / indan 5 ch3 \ CH3SO2Cl-J0 pyridine

CH

and ^ VA 1 / ΓΛ “I) —N-CH2-CH2 - // Λ — NS02CH3 ch so \ = /

15 J H

Methanesulfonyl chloride (0.155 ml) was added to a solution of 5-amino-2- [N- (4-aminodenethyl) -N-methylamino] indane 2q (0.28 g) in pyridine (30 ml) and the reaction mixture was stirred at room temperature for 17 hours. The solvent was removed by evaporation in vacuo, and the resulting gum was dissolved in methylene chloride, the solution was washed with aqueous NaHCO 3 and aqueous NaCl, dried (MgSO 4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel using methylene chloride containing methanol (0-2%) as eluent, and the product-containing fractions were combined and evaporated to dryness in vacuo to give 0.27 g of the title compound as a foam.

Analysis,%

Found: C, 54.5; H, 6.2; N, 9.35; . · ·. Calculated for C20H27N3O4S2: 0.54.9; H, 6 # 2; N, 9 # 6.

t 11 87550 1 H-N.m. r. (CDCl 3): δ, = 7T 2 (q, 4H); 7.15 (d, 1 H); 7.1 (s, 1H); 7.0 (d, 1 H); 3.45 (t, 1 H); 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__ 1 ° ch 3 - XCH 3 SO 2 Cl pyridine 15 \ CH .. ___ * I „// A_Sso, c» 3 (11 VN ') CH2 AW ''

CH Sonn

J "H

Methanesulfonyl chloride (0.53 ml) was added to a pyridine solution of 5-amino-2- [N- (4-aminobenzyl) -N-methylamino] indane (1.1 g) and the reaction mixture was stirred at room temperature for 17 hours. The solvent was then removed in vacuo and the residue was dissolved in methylene chloride, the solution was washed with aqueous NaHCO 3, dried (MgSO 4) and evaporated in vacuo. The resulting gum was purified by chromatography on a silica gel column eluting with eluent. ; methylene chloride containing methanol (0-2%).

The product-containing fractions 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 evaporated to dryness in vacuo to give 0.2 g of the title compound as a colorless foam.

12 87350

Analysis,%:

Found C, 54.0; H, 6.0; N, 9.5;

Calcd for C 19 H 25 N 3 O 4 • CH 2 Cl 2: C, 53.9; H, 5.9; N, 9.6.

* The solvate form of the product was detected and quantified by H-N.m.r. 10 H-N.m.r. (TFA): δ = 7.72 (s, 1H); 7.63 (t, 1 H); 7.45 (fd, 2 H); 7.4 (t. 2H); 7.3 (s. 1H); 4.8 (d. 1H); 4.5 (m. 1H); 4.35 (d, 1 H); 3.6 (m. 4H); 3.2 (d. 6H): 2.9 (dd, 3H).

15

The following preparations, in which all temperatures are in degrees Celsius, illustrate the preparation of the starting materials used in the examples.

Preparation 1 2 2-Formylaminoindan, NaOAc / NH2. HCl - CH2 O = CH2-acetic anhydride; -. · Formic acid * 25

Acetic anhydride (40 ml) and formic acid (20 ml) were stirred and heated at 50 ° C for 15 minutes. To the mixture was added 2-aminoindan-hydro-. chloride (25 g) (see J. Med. Chem. 1980, 23, page 30 754) and sodium acetate (20 g) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and extracted 3 times with methylene chloride. The combined organic layers were washed with water and aqueous NaHCO 3, dried (MgSO 4) and evaporated in vacuo to give 17.6 g of the title compound, m.p. 72-74 °.

Analysis,%: 87550

Found: C, 74.25; H, 7.0; N, 8f6;

Calculated for C 10 H 11 NO: C, 74.5; H, 6.9; N, 8.7.

• H-N.m.r. (CDCl 3: δ = 8TO (s, 1H); 7.1 (s, 4H); 4.7 (m, 1H); 3.4 (dd, 2H); 2.8 (dd, 2H).

10

Preparation 2 2-Formylamino-5-nitroindan 15

I smoke hno .. H

\\ T \ -N-CH = 0 ____ 3 ί V \ <> j 20 2-Formylaminoindan (15 g) was added portionwise to fuming nitric acid (30 ml, density = 1.5 g / ml) keeping the temperature between 0 ° and -. Between 5 °. Stirring was continued at 0 ° for 1 hour, then the reaction mixture was poured into ice water and extracted with methylene chloride.

The organic layer was washed with aqueous NaHCO 3, dried (MgSO 4) and evaporated in vacuo to an oil which was purified by column chromatography on silica gel using methylene chloride containing 30 hexanes (0-2%) as eluent. Fractions containing product vhdis-. . and evaporated to give 7.7 g of the title compound, m.p. 91-92 °.

Analysis,%: .- •• 35 Found: C, 58; 1; H, 4.8; N, 13.5;

Calculated C, 58.25; H.4,9; N, 13.6.

: for the formula cioH10 2 3 'r

14 8 7 6 5 O

Preparation 3 2-Methylamino-5-nitroindan hydrochloride

CH

(ii) HCl

Acetic acid (6.4 ml) was added dropwise with stirring to a cooled mixture of 2-formylamino-5-nitroindan (4.6 g) 10 and sodium borohydride (4.22 g) in tetrahydrofuran (65 ml). Stirring was continued at 0-5 ° for 15 minutes, then the reaction mixture was heated to reflux for 2 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was diluted with 2M hydrochloric acid, then basified (pH about 12) with aqueous Na 2 O 4 and extracted with methylene chloride. The organic layer was dried (MgSO 4), evaporated in vacuo and the residue stirred in ethereal HCl to give 1.5 g of the title compound, m.p. 221-223 °.

Analysis,%;

Found: C, 52.75; H, 5; 6; N, 12.15;

Calculated r _c; ; For C 10 H 12 N 2 O 2 * HCl: c, 52f · * ’H, 5.7,,,

Preparation 4 2- [N-Methyl-N- (2- (4-nitrophenoxy) ethyl) amino] -5-nitroindan 8 7 3 50 C-CH 2 Cl 2

ιί ^ -Λ I

[1N-NH.HCl + BrCH2CH2O-> 2N

NT

10 CH3 15 2-methylamino-5-nitroindan hydrochloride (0.46 g), 2-bromoethoxy-4-nitrobenzene (0.49 g) / see CA, (1960), 54, 11046a and potassium carbonate (2 g) heated to reflux in a mixture of acetonitrile 20 (50 ml) and ethanol (20 ml) for 20 hours. The solvent was then evaporated in vacuo and the residue was diluted with water and extracted with methylene chloride. The organic layer was dried (MgSO 4) and evaporated and the residual oil was purified by chromatography on a silica gel column using methylene chloride containing methanol (0-1%) as eluent. The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.28 g.

- 30 'H-N.rc.r. (CDCl 3): δ = 8 ° (d * 2H) (7 * m * 2H); 7i2 (d ‘1H)’ 6.8. . (d, 2 H); 4.1 (t. 2H); 3.4 (m, 1 H); 2.9 (br d, 4 H); 2.8 (t. 2H); 2.3 (s. 3H).

16 87 350

Preparation 5 5-Amino-2- [N- (2- [α-aminophenoxy] ethyl) -N-methylamino] indan______________ 5 ch3 N, N-ca2CH2O - (^ y ~ K02 o2n

\ H / Pd / C

A solution of 2- [N-methyl-N- (2- (4-nitrotenoxyethyl) amino] -5-nitroindan (0.3 g) in ethyl acetate (30 ml) was added. containing 5% Pd / C catalyst (0.03 g) was stirred under a hydrogen atmosphere (206.8 kPa) for 2 hours at room temperature. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to give 0.25 g of the title compound as a gum which was used directly without further purification.

t

17 8 7 6 'ο O

Preparation 6 2- [N-methyl-N- (4-nitrophenethyl) amino] -5-nitroindan

5 \ CH

V \ I 3 / "V

2-methylamino-5-nitroindan hydrochloride (0.45 g), 1 H -NH + BrCH 2 CH 2 J - NO 2 O 2 N .HCl 4-Nitrophenethyl bromide (0.46 g) and potassium carbonate (2 g) were heated at reflux in acetonitrile (30 ml) for 4 days. The reaction mixture was then filtered, the filtrate evaporated in vacuo and the residue purified by column chromatography on silica gel using methylene chloride containing methylene chloride as eluent. . : tanol (0-1%). The product-containing fractions were combined and evaporated in vacuo to give a residual gum which was crystallized from ethanol to give 0.16 g of the title compound, m.p. 138-141 °.

Analysis,%: Y: Found: C, 62.8; H, 5.5; N, 12.1;

Calculated for 3 ^ ^ ^ 19 19 ^ ^ 41 c * 63.3; 11,5,6; N, 12.3.

• H-N.m.r. (CDCl 3): δ = 8.2 (d, 2H); 8.1 (d, 111); 8.05 (s, 1 H); 7.4 (d. 2H); 7.3 (d. 1H); 3.5 (t, 1 H); 3.15 (q, 2 H); 2.9 (m. 4H); 2.8 35 (t, 211); 2.4 (s. 3H).

1. 87350

Preparation 7

2- [N-methyl-N- (4-nitrophenethyl) amino] indane hydrochloride 5 CH

\ (i) H®

\ (ii) NaBH

10 (iii) HCl cn3 (iP N - N-CH CH - / NO. HCl 15 w 2-indanone (2.8 g), N-methyl-4-nitrophanethylamine (3.83 g) / see JOC , (1956), 21, 457 and toluene-4-sulfonic acid (0.1 g) were heated to reflux in toluene (100 ml) in a Dean-Stark apparatus for one hour, during which time the total amount of water produced (about 0.4 ml) was azeotroped, the solvent was 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 at room temperature for 6 hours.

The mixture was then heated to reflux for 10 minutes, cooled and evaporated to dryness in vacuo. The residue was added with stirring to 2M hydrochloric acid and after 0.5 hours the mixture was filtered through a semi-solid precipitate, the filtrate was washed with ether and dried to give 1.2 g of the title compound, m.p. 201-203 °.

Analysis,%

Found: C.64.95; H, 6.4; N, 8.4; CI8 «20N2 ° 2-HCI! C'M'85i * · 6 · 45 * »· 8'3 · 19 87350 (DMSO d6>: -5 = 8.3 (d, 2H); 7.6 (d, 2H); 7.2 (q , 4H), S2 (quintet, 1H), 3.4 (m, 8H), 2.8 (d, 3H).

Preparation 8 (alternative to Preparation 6) 5 2- [N-methyl-N- (4-nitrophenethyl) amino] -5-nitrohanane__________ CH3 10 ”'c“ 2ch2 O n ° 2. HCl \ smoke hno3 15 \ i Γ3 r.— ^ if N-CH_CH - (/ ^ -NO.

2- [N-Methyl-N- (4-nitrophenethyl) amino] indan hydrochloride (1.2 g) was added portionwise over 10 minutes to fuming nitric acid cooled to -5 ° (20 ml, density 1.5). . Stirring was continued for another 2 minutes, then the reaction mixture was poured into ice water. The aqueous mixture was extracted with methylene chloride and the organic extract was washed with aqueous NaHCO 3, dried (MgSO 4) and evaporated to dryness in vacuo. The residue was crystallized from ethanol to give 0.78 g of the title compound, m.p. 138-140 °.

20 87550

Preparation 9 N- (amino-2-, N- (aminophenyl), -N-methylamino-indan c-I

Jj | \ -1N-ch2ch2 / ~ NO2 O-N \ \ H2 / Pd / c \

CH

A solution of 2- [N-methyl-N- (4-nitrophenethyl) amino] -5-nitroindan (0.5 g) in ethyl acetate (40 ml) and methanol (10 ml) was added. ) in a mixture of 5% Pd / C catalyst (0.05 g) was stirred under a hydrogen atmosphere (206.8 kPa) at room temperature for 4 hours, then the catalyst was filtered off and the filtrate was evaporated in vacuo and the resulting gum was triturated. The ether was decanted and evaporated in vacuo to give 0.33 g of the title compound A small sample was crystallized from di-isopropyl ether, mp 112-114 °.

Analysis, _%:

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

Calculated H N. C, 76T8; H, 8.2; N, 14.9.

30 for the formula L18M23 3 '1 H-N.m.r. (CDCl 3): δ = 0.05 (d * 2H) δ 7 ° (d * 1H); 6.7 (d> 2H) δ 6.55 (s, 1H); 6.5 (d. 1H); 3.6 (br s, 4 H); 3.4 (quintet, 1H) δ 3.0 ·; · 35 (m, 2H); 2.8 (m. 2H); 2.7 (d. 4H); 2.4 (s. 3H).

21 87 550

Preparation 10 2- (N-Benzyl-N-methylamino) indan hydrochloride 5 i * 3 | V = 0 + HN-CH 2 Ph

(i) H (ii) NaBH

10 (f) HCl CH 2 Cl 2 3 N 2 - N-CH 2 Ph.HCl 15 A solution of 2-indanone (5.28 g) in N-benzylmethylamine (4.84 g) and 4-toluenesulfonic acid (0.15 g) in toluene (120 mL) was heated at reflux in a Dean-Stark apparatus for 1.5 hours during which time all of the water produced (ca. 0.8 mL) had been azeotroped. The solvent was then 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 at room temperature for 17 hours. The solvent was then evaporated in vacuo and the residue was carefully diluted with 2M hydrochloric acid (200 ml). The acidic solution was extracted twice with methylene chloride (2 x 100 ml) and the combined organic extracts evaporated in vacuo, the residue triturated. in isopropanol, the precipitate formed was filtered off and dried, yielding 2.5 g of the title compound, mp 204-206 °.

Analysis,%:. Found: C, 74; H, 7f4; N, 5.0; 35 Calculated for C 18 H 18 NCl: 0.74.6; H. 7.4; N, 5.1.

22 87550 Ή-M.ro.r. (CDCl 3): 8 s 7/7 <dd »2H); 7r5 <m · 3H); 7.15 (q, * H); 4.4 (q, 1 H); 4.15 (q, 1 H); 4.05 (quintet, 1H); 3.8 (q, 1 H); 3.6 (q, 1 H); 3.5 (q, 1 H); 3.25 (q, 1 H); 2.6 (d. 3H).

Preparation 11 (alternative to Preparation 10) 2- (N-benzyl-N-methylamino) indan hydrochloride CH 3 10 + Br-CH 2 - ^ (1) K 2 CO 3 (i) HCl N-civic 2 2-methylaminoindan (0.65 g) (see J. Med.

Chem. 1980, 23, page 745), benzyl bromide (0.6 g) and potassium carbonate (1.0 g) were heated at reflux in acetonitrile for 8 hours. The reaction mixture was filtered and evaporated to dryness in vacuo. The resulting oil was dissolved in ethyl acetate, the solution was diluted with ethereal HCl and the precipitate was filtered and recrystallized from isopropanol to give 0.5 g of the title compound, m.p. 204-206 °.

23 87550

Preparation 12 2- [N-Methyl-N- (4-nitrobenzyl) amino] -5-nitroindan-5

CH

. HCl \ smoking hno

10 \ J

CH

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 °.

Stirring was continued for a further 2 minutes, then the reaction mixture was poured into ice water. The water was decanted, the resulting gum was dissolved in methylene chloride, the solution was washed with water and saturated aqueous NaHCO 3, dried (MgSO 4) and evaporated in vacuo to give: 2.4 g of the title compound. A 0.1 g sample thereof was dissolved in ether and the solution was treated with ethereal HCl. The precipitate formed was filtered off and dried to give the hydrochloride salt of the title compound, m.p. 210-212 °.

. ·. : 30 Analysis,%:: Found: C.55.2; H, 5F0; K.11,2;

Calculated for C 17 H 17 N 3 O.HCl.H 2 O: C, 54.8; H, 5.1; N, llr3.

24 87350 ^ JS ^ L, (TFA): S = 8.8 (s, 1 ,,); 8 | 7 ft, 1 ,,); 8.35 (d. 2H); 8.1 (d. 1H); 7.9 (m, 1 H); 7.6 (d. 1H); 5fO (d, 1 H); 4.7 (m, 1 H); 4.6 (d. 1H); 3.8 (m. 4H); 3.0 (s. 3H).

5

Preparation 13 5-Amino-2- [N- (4-aminobenzyl) -N-methylamino] -indane _______ 10

Me 15 H2 / Pd / c

Me 2 2 2- [N-methyl-N- (4-nitrobenzyl) amino] -5-nitroindan (2.3 g) was stirred in ethyl acetate (60 ml) containing 5% Pd / C catalyst ( 0.25 g), in a hydrogen atmosphere (206.8 kPa) for 1 hour at room temperature.

The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was purified by chromatography on a column of silica gel using methylene chloride containing methanol (0-1%) as eluent. The product-containing fractions were combined and evaporated to give. . 30 g of 1.1 g of the title compound are obtained in the form of an oil which is used directly without further purification.

Claims (6)

25 87350 A process for the preparation of a therapeutically useful compound of formula 5 ... R 1 wherein R 1 is hydrogen, each R 2 is the same and is C 1-4 alkyl, X is O or a direct bond and n is 1 or 2, provided that when X is 0, then n is 2, or a pharmaceutically acceptable compound thereof. -15 for the preparation of a mass-acceptable salt, characterized in that a compound of the formula 20 »- 'CH2» n- * - "^ - ΝΗ2 2 R1 in which R1, X and n have the same meaning as above is reacted with C1.4- with an alkanesulfonyl chloride or bromide or a C 1-4 alkanesulfonic anhydride, and then optionally converting the compound of formula I to a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that the reaction is carried out in the presence of an acid-binding agent. Process according to Claim 2, characterized in that the binding agent is pyridine, triethylamine, potassium carbonate or sodium bicarbonate. 26 87350 Process according to Claim 3, characterized in that the reaction is carried out using methanesulfonyl chloride in pyridine. Process according to Claim 1, characterized in that 5-methanesulfonamido-2- [N- (4-methanesulfonamidophenethyl) -N-methylamino] indane is prepared by reacting 5-amino-2- [N- (4- aminophenethyl) -N-methylamino] indane to react with methanesulfonyl chloride in the presence of an acid scavenger. A compound of the formula f ^ V \ 1 "3 Ra I II> - N -ICH 2'n-x - (y R 15 R wherein R 1 is hydrogen, X is O or a direct bond, n is 1 or 2 and each Ra is the same and is -NH2 or -NO2.20 27 8 7 ö 5 O