FI92395B - Process for preparing therapeutically utilizable heterocyclic sulphonamides - Google Patents

Description

92395

A process for the preparation of therapeutically useful heterocyclic sulfonamides

The invention relates to the preparation of certain heterocyclic sulfon-5 amides which are antiarrhythmic agents and intermediates of these agents.

The compounds of the invention prolong the duration of action potential in myocardium and ductal tissue and thus increase the unresponsiveness to premature irritations. 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 affect the atria, ventricles, and ductal 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 are generated, 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 thus these compounds are particularly good for patients with cardiac pumping.

. ’Pause is deficient.

The invention relates to a process for the preparation of therapeutically active compounds and their pharmaceutically acceptable salts of the formula 30 "(C 2-4 alkyl) SO 2 NH-N 2 - (CH 2) 2 -N-CH 2 -. 92395 2 wherein R1 is lower alkyl and "Het" is a group of the formula X 6 -NHSO 2 (C 2-4 alkyl) N-J 1 -N-NHSO 2 (C 1-4 alkyl) or 10 -N-NHSO 2 (C 1-4 alkyl) 15 wherein X is O or S, and R 2 is H or CH 3.

The substituent Rb is preferably in the 6- or 7-position when "Het" contains a quinolyl group and otherwise in the 5- or 6-position (i.e., when the benzene ring is fused to a 5-membered heterocycle).

The most preferred individual compounds are those of formulas (IA) and (IB): NHSO-CH-

jfX l * 3 li — iT ^ T

: ‘25 CH3SO2NH- ^ y— (CH2) tIA> * · * * • ·: Y: j7- \ T3

Da ch3so2nh - (/ V- <ch2) 2-ν ^ 2- ^ ν ^^ 30 X == 'UB).

Compounds of formula (I) pharmaceutically. acceptable salts include acid addition salts which are ·· · ·; ·; formed with non-toxic acid addition salt-forming acids, the anions of which are pharmaceutically acceptable; examples of these are hydrochloride, hydro- ·· *: ***: bromide, hydroiodide, sulphate or bisulphate, phosphate- · »· • ♦ • · ♦ · · * # · • · ♦ · • · · • II ♦ ♦ 92395 3 t or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, besylate and p-toluenesulfonate. The salts are preferably prepared by conventional methods.

The process according to the invention is characterized in that (A) a compound of the formula 1 °> - R1 is acylated

Ra — y (CH2) 2-N-CH2-Het (B)

Wherein R 1 is -NH 2 or -NHSO 2 (C 1-4 alkyl), R 1 is lower alkyl-15 and "Het" is a group of the formula -XX 5 -R b 'or wherein X is 0 or S, and R 2 represents same as above and. Rb is -NH2 or -NHSO2 (C1-4alkyl), provided that Ra and Rb are not both -NHSO2 (C1-4alkyl), with C1-4alkanesulfonyl chloride or bromide, or: \ S5 with C1-4 alkanesulfonic anhydride, or • · (B) a compound of the formula • · • · · • · · · <ci ^ - »» yyU) so2nh - ^^ _ (ch2> 2-rc is reacted with a compound with the formula ··· »··· :: d R-CH ^ -Het:: 135« «· in which formulas one of the groups Re and Rd is -NHR1 and the other is» · • »• · · • · 92395 4 is a leaving group and R 1 and "Het" have the same meaning as above, and the compound of formula (1) obtained after carrying out method (A) or (B) is optionally modified 5. as an acceptable salt.

The reaction is typically performed at room temperature and optionally in the presence of an acid scavenger such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of an acid scavenger is especially necessary when alkane sulfonyl chloride or bromide is used. In fact, it is particularly suitable to carry out the reaction with an alkanesulfonyl chloride in pyridine. The reaction product of formula (I) can then be isolated and purified by conventional methods.

The starting materials for the acylone reaction are obtained by conventional methods, e.g. as follows: (a) 20 no2- ^ ^ - (CH2) 2-NHR + Q-CH2-Het K2CO3 'at reflux, ....: organic solvent • »• · • • · 1

·· · r ~ \ R

\ fcs ·. N ° 2 — P y— (CH2) 2-N-CH2-Het V .: Catalytic hydrogenation (e.g.

: V * ^ H2 / Raney-Ni / 344 kPa) 30 // - \ f1 NH2 - (/ y— (CH2) 2-N-CH2-Het 1 · ···· * * • · • · :: 35 The meanings of the symbols R1 and "Het" appear from formula (I) and Q is a leaving group such as chlorine, bromine, iodine or methanesulfonyloxy.

92925 (b) NO2— ^ ^ - (CH2) 2 “Q + R1NH-CH2-Het 5 Κ2002, reflux, organic solvent v rv R1 NO2- ^ y— (CH2) 2-N-CH2-Het 10 \ = / catalytic hydrogenation (e.g. yfH2 / Raney-Ni / 344 kPa) / "'" "' λ f1 15 NH2 \ y ~ (CH2) 2-N- CH2-Het R1, Het and Q have the same meaning as in (a) above.

(c) The syntheses of reaction schemes (a) and (b) can also be performed using starting materials in which the Rb substituent of the Het ring is nitro and not a C 1-4 alkanesulfonamido to give a dinitro intermediate which can be reduced catalytically by hydrogenation to the diamino starting material, i.

* 1 as a starting material of formula (A) wherein both R and R3 are amino.

T1> 5 (d) V1: (C1-4alkyl) SO2NH- ^ - ^ - (CH2) 2NHR1 + Q-CH2-Het II (Rb in the Het group = NO2) • · • · 3Q Reflux, organ

solvent \ P

--k R1 *; · // \\ ih (C1-4 "alkyl, SO2NH \ y- (CH2) 2-N-CH2-Het (RD = NO2> • # · '1 • ·. .135 catalytic hydrogenation (e.g.

** j1 v H2 / Raney-Ni / 344 kPa) ***** / V ^: 1 ·, 1 (C1-4-alkyl) SO2NH - (/ y- (CH2) 2-N-CH2-Het ( R 1 = NH 2) 1 · ΐ «· 92395 6 R 1 is lower alkyl," Het "is a nitro-substituted heterocycle as defined in the first step in connection with formula (A) and Q is a leaving group as defined in (a) above.

The starting materials used in process (a) to (d) are either known compounds or can be prepared by conventional methods, e.g., the methods described in the following Preparation Examples.

(2) Another process for the preparation of compounds of formula (I) can be described as follows: (C 1-4 alkyl) SO 2 NH <y (CH 2) 2 NHR 1 + Q-CH 2 -Het®> Comp. (I) or 15 (C 1-4 alkyl) SO 2 NH-V y - (CH 2) 2 -Q + R 1 NH-CH 2 -Het -> Comp. (I) R 1 is lower alkyl, "Het" is as defined in formula (I) and Q is a leaving group such as chlorine, bromine, iodine, C 1-4 alkanesulfonyloxy (preferably methanesulfonyloxy), benzenesulfonyloxy or toluene. eenisulfonyylioksi. The reaction is typically carried out in an organic solvent at reflux temperature at most. The reaction is most preferably carried out under heating at reflux. An acid scavenger may be used, and it is particularly preferred to use it when Q is Cl, Br or I. Typical acid scavengers: Y are pyridine, triethylamine, potassium carbonate and sodium bicarbonate. The starting materials are again known compounds or can be prepared by conventional methods.

To determine the effect of compounds on atrial #. to unacceptable, the guinea pig's right hemiatrium 'III was placed in a saline containing physiological saline. The PYY and the other end were connected to the power converter. Tissue: j * 35 was stimulated with a field electrode at a frequency of 1 Hz.

: *** Effective refractory period (ERP) was measured by inducing premature irritation (S2) every eighth basal stimulus (S!): 925: / 5 7 period = ERP. ). The SxS2 switching interval is gradually increased until a reproducible increased response to S2 is obtained. This 5 is defined as 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 are stimulated at one end using bipolar electrodes and the stimulus-induced electrogram is recorded on the opposite side with a unipolar surface electrode. The 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 är-15 heart rate and the electrogram 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 the extra är-20 heart rate technique while the atrial or right ventricle is synchronized to a constant rate.

The compounds of formula (I) may be administered as such, but will generally be administered in admixture with a pharmaceutical carrier selected from 1.25, taking into account the intended route of administration and standard pharmaceutical practice. They can be administered both to patients suffering from arrhythmias and prophylactically to individuals who are very likely to develop arrhythmias. They can be administered, for example, orally in the form of tablets containing 30 excipients such as starch or lactose, or in capsules containing them. as such or with excipients or as elixirs ·· ••• j or suspensions containing flavoring and coloring agents.

• «'· 1 ^ They can be given as parenteral injections, for example: 135: intravenously, intramuscularly or subcutaneously» ·· »« · ·· «• · • · • ♦ • ·» 1 • · • · 8 9' / night 9 5 sesti. 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 adult (70 kg) to improve cardiac condition or prevent a disease state such as ventricular or supraventricular arrhythmia, including treatment or prophylaxis of atrial and ventricular fibrillation, an oral dose of compounds of formula (I) mg / day taken in divided doses (2-4) per day. When administered intravenously, the dosage could be 1.0 to 20 mg per dose, if necessary. Severe cardiac arrhythmia is preferably treated intravenously to provide a rapid transition to a normal 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 may vary depending on the weight and condition of the subject being treated, as is well known to the attending physicians.

· »·; 1, The pharmacological properties of the compounds of the invention were determined by the above method.

Thus, the following anti-arrhythmic effects were determined.

• · • · t · • «. ·. · Example ERP ED25 (m) 1 3 x 10'6 30 2 2.3 x 10'6 3 1.4 x 1016 4 2.5 x 1016 ··« 5 5 .0 x 10'6 ··· V 7 2.0 X 10 "6 • · '♦ 1 35 ·» · ♦ e »• f ♦ ·» • ♦ »· ♦ · • 92395 9

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

Example 1 N-Methyl-N- (3-methyl-5-methanesulfonamidobenzofur-2-ylmethyl) methanesulfonamidophenethylamine N, N-pyrrolidinamine

J 2k \ / V ^ NSOCH

V CH. \ __ 2 3 20

Methanesulfonyl chloride (0.21 g, 1.85 mmol) li-. N-methyl-N- (3-methyl-5-aminobenzo [fur-2-ylmethyl) -4-methanesulfonamidophenethylamine] (see Preparation 10B - 0.78 g, 1.68 mmol) was added dropwise. to a solution in pyridine (125 ml) and the solution was stirred at room temperature for 60 hours. The solvent was evaporated and the residue was triturated with toluene. The toluene was decanted, the residue was stirred in aqueous sodium bicarbonate, the precipitate was filtered off and recrystallized from methanol to give 0.38 g of the title compound, m.p. 142 - 143.5e.

Analysis for C 21 H 27 N 3 O 5 S 2,%:

Calculated: C 54.2 H 5.85 N 9.0 * ::: Found: C 54.4 H 5.8 N 9.1 • · · »ti» • · • · ♦ • · 1 »· · • · · • · • · I1 • · • »• 1 · • · · * · · ♦ · · · 10 92395

Example 2 N-Methyl-N- (5-methanesulfonamidobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine XJ \ ch3so2ci, h H2N 'Cpyridine CB ____ ° 2CH3

i .3 jTT T

CT3SO2 g Methanesulfonyl chloride (0.76 g, 6.6 mmol) was added dropwise N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (see Preparation 3 to 0.9 g, 3 .0 mmol) in pyridine (25 mL) and the mixture was stirred at room temperature for 18 hours. The solvent 20 was then evaporated and the residue was diluted with aqueous NaHCO 3 and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO 4) and evaporated - and the residue was purified by chromatography on silica gel; gel using ethyl acetate as eluent. The product-containing fractions were combined, evaporated and the residual solid crystallized from ethyl acetate / methanol to give 0.35 g of the title compound II, m.p. 177-179 ° C.

* 1 Analysis for C20H25N3 ° 5S2 '30 Calculated: C 53.2 H 5.6 N 9.3 Found: C 53.2 H 5.7 N 9.0 • · · ··· «• · · * ♦ · • · • · • · · · · · »· • ·» • • ♦ • · • · • ♦ • ♦ • ♦ • ♦ • • H 92395

Example 3 N-Methyl-N- (5-methanesulfonamidobenzoxazol-2-ylmethyl) -4-methanesulfonamidophenethylamine ηΓτ "η2ν ^> ^ Nct3so2ci, N. pyridine ___ NHSO-CH.

CH N-2 3

10) 3 II H I

CH3SO2 [b] Methanesulfonyl chloride (0.38 g, 3.3 mmol) and N-methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine (see Preparation 1C - 0.45 g, 1 , 5 mmol) was reacted in pyridine (20 ml) under similar conditions to Example 2 to give the title compound, yield from ethanol 0.25 g, m.p. 174-176 °.

Analysis for the formula t'i9H24N4O5S2f Calculated: C 50.4 H 5.35 N 12.4 ·: 1: Found: C 50.4 H 5.1 N 12.4 ** · 2: Example 4 j · .2. 25 N-Methyl-N- (6-methanesulfonamidobenzofur-2-yl- ♦ ·. ·.: Methyl) -4-methanesulfonamidophenethylamine • · ♦ φ · • · CH w *. :: | 3 - ::> fin 1 30 sCH3so2ci, pyridine * pr s' ^ Vsx ^ ox ^ si: 2gso2cH3 V 35 ca3so2f ^^

• · H

··· 1 ··· • · • · ·· · • · • 2 • · ♦ • · · · • e 2 · • · «• ·· 12 92395

Methanesulfonyl chloride (0.21 g, 1.8 mmol) and N-methyl-N- (6-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (see Preparation 2 - 0.24 g, 0.82 mmol) was reacted in pyridine (3 ml) under similar conditions to Example 2 to give the oily title compound, yield 0.18 g.

Analysis for ^ 20H25N3 ° 5S2 /

Calculated: C 53.2 H 5.6 N 9.3 Found: C 53.0 H 5.7 N 9.1 10 Example 5 N-methyl-N- (6-methanesulfonamidoquinol-2-ylmethyl) -4 -methanesulfonamidophenethylamine - CH3SO2Cl h

\ pyridine CH

^ 13 H il 20. ---

B

J1.1; Methanesulfonyl chloride (0.15 g, 1.3 mmol) and • · N-methyl-N- (6-aminoquinol-2-ylmethyl) -4-aminophenethyl] -1; Lamine (see Preparation 4 - 0.17 g, 0.37 mmol) was reacted in pyridine (20 mL) under similar conditions to Example 2 to give the title compound. 1 · te, yield 0.70 g of ethyl acetate, m.p. 163-165 °.

Analysis for C 21 H 26 N 4 O 4 · 1!

Calculated: C 54.5 H 5.7 N 12.1

Found: C 54.3 H 5.45 N 12.1 • · · ··· 1 ♦ ·· • ♦ • · • · • · »• · · ** · ··· • $ Φ 9« «· ♦ · • ·

• · I

• · · • · · • · · • · • • 92395 13 ^ ss £ JsSi_6 ^ ^ yyr i'N' / i-methanesulfonamido "2-benzoylthienyl] -4-methanesulfonamidophenethylamine v-CT ^ ' ^ lo \ ct3so2ci

pyridine CH, NHSO CH

\ ~ NXJCCX

N-methyl-N - [(5-amino-2-benzo [al] thienylmethyl) -4-n-phenethylamino) (0.26 g - see Preparation 13) with hand-methanesulfonyl chloride (0.23 g) in pyridine by the method of Example 2 to give the title compound (0.167 g), m.p. 175-177 °.

Analysis for the formula c20H25N3 ° 4S3 '%:

Calculated: c 52.37 H 5.39 N 8.99

Found: C 50.99 H 5.39 N 8.93. Example 7 N-Ethyl-N- (6-methanesulfonamidoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine hydrochloride Hydrogen chloride 30 [mu] l (1 ) CSjSOjCi «3 ** ^ \ ai) bci / ec2o .. ^^ Aso ca

a 12 5 fT ny 'J

** .. 35 CH-SO-M '^ SS ^ .HCl.HjO

. J 3 2 »

ϊ ϊ H

·· * ··· • * ··· • ♦ • ♦ * / ·.

• * V ·: 14 92395

Methanesulfonyl chloride (0.1 g, 1.28 mmol) was reacted with N-ethyl-N- (6-aminoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine (see Preparation 11B - 0.51 g, 1.23 mmol). ) in pyridine in the same manner as in Example 2 to give the title compound as a gummy free base. The fibrous product was dissolved in ethyl acetate, diluted with ethereal HCl and evaporated to dryness. The residue was triturated with ether to give the foamy title compound 10, yield 0.06 g, m.p. 96 °.

Analysis for C22H28N4 ^ 4 ^ 2 * HC ^ 'H2i)'

Calculated: C 49.75 H 5.9 N 10.5 Found: C 50.2 H5.5 N 10.0

Example 8 N- (6-Methanesulfonamido-2-quinolylmethyl) -N-methyl-4-methanesulfonamidophenethylamine

Iso2ch3 + WhQ ^ (CH2) 2NHCH3 Ψ * * cg 3 | .V 25 (CH2) 24-CH24n • · • * »• ·> • * •« • «· • 4- ^ 2- (methylamino) ethyl7methanesulfonanilide • · * · * · (0.228 g, 1 mmol - see Preparation 14B) and 2-chloromethyl-6-methanesulfonamidoquinoline (0.135 g, 0.5 mmol - see Preparation 12D) were heated at reflux in ethanol (5 mL) for four hours. hours. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride, washed with water, dried (MgSO 4), filtered and the residue was evaporated in vacuo. The obtained rubber was purified by K-chromatography on a silica gel column using 92595 methylene chloride containing methanol (0-1%) as eluent. ♦ ·· • · ♦ · • »• ·« · t * m · · φ t 92595 The product-containing fractions were combined and evaporated in vacuo to give a foam which crystallized from ethanol to give 0.45 g of the title compound, m.p. 165 -5 166 *; the compound was found sepktroskoopplsestl identical to the product of Example 5.

• 9 · • »• · e» l e * • • · •> • ».

• · • · • «* • · •» »• · '• ·» · ···· ··· • · • · 9 9 9 9 9 999 • 99 999 9 9 • 9 9 9 • 9 9 9 9 9 hrs • ·· • ·

Claims (3)

A process for the preparation of a pharmaceutically active compound having the formula 5 (C 1-4 alkyl) (CH 2) 2-H-CH 2 -Het (I) or for the preparation of a pharmaceutically acceptable site thereof, in which formula R 1 is lower alkyl and "Het" represents a group of the formula N- [j-NH-NHSO 2 (C 2-4 alkyl) or 1-NHSO 2 C 1-6 alkyl) where X is 0 or S, and R 1 is H or CH 3, characterized in that: · A · acylates a compound of the formula ♦ · · • · / - v R · ^ y · .....- (CHg) 2 ~ N-CH2 ~ Hot · Wherein R 1 is -NH 2 or -NHSO 2 (C 1-4 alkyl), R 1 is lower alkyl and "Het" is a group of formula t · • s »· • · ·· • · · ♦ ♦ ·« • · 20 92395 'Xa ^ χχ> · “· -QO1b where X represents O or S, R3 represents the same as above and Rb is -NHj or - NHSO 2 (C x 4 alkyl), provided that R 1 and R b do not both represent -NHSO 2 (C x 4 alkyl) groups, with a C1-4 alkanesulfonyl chloride or bromide or a C1-4 alkanesulfonic anhydride, or (B) reacting a compound of the formula ···· • 1 ϊ \\ in which formulas one of the groups Rc and Rd is -NHR1 • · 1: ·, · and the other is a leaving group and R1 and "Hot" denote * · 1> 25 same as above, • · · »• · 1 l. and after the method (A) or (B) has • · · *; optionally, the compound of formula (I) is converted into a pharmaceutically acceptable salt. 2. A process according to claim 1, for the preparation of a compound of the formula ··· ·· »___ NHSOCH-: Ύ / -y 1 3 1-2 3 V CH3S02NH 2-N-CH2-l | ^ (IA) # e ·· • · ♦ · • · «♦ · · • ·. Characterized in that N-methyl-N- (5-amino-benzofur-2-ylmethyl) -4-aminophenethylamine is reacted with methanesulfonyl chloride 1 in the presence of an acid binding agent. ···· ·· e • · · • · ·· 9 9 9 9 9 9 # · • * · »· • · • 9> · • · 9 9 9 9 9 9 9 9 9 99 9 999 • 99 9 9 9 9 9 9 9> 99 ♦ 99 9 9 9 9 f 99 9, 9 9