HU207859B - Process for producing new amino-quinoline derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

New anti-arrythmic amino-quinoline derivs. and their acid adducts (general formulae (1/a) and (1/b)) are active cpds. in pharmaceutical prepns. In (1/a) and (1/b); A is 1-4C alkylene gp.; B: single or double bond; R is e.g. Hydrogen or (1-4C)-alkyl. R2 is Hydrogen, (1-4C)-alkyl, (1-4C) alkoxy, halogen, or a trihalogen-methyl.

Description

Scope of the description: 8 pages (including 1 page figure)

HU 207 859 Β

The present invention relates to novel antiarrhythmically active 4- and 2-aminoquinolines of formulas I / a and I / b.

In the general formulas, the variable substituents have the following meanings:

A is a C 1-4 alkylene group,

B is a single or double bond,

R 1 is hydrogen, (C 1 -C 4) alkyl, or trifluoromethyl,

R ₂ is hydrogen, (C 1-4) alkyl, (C 1-4) alkoxy, halogen, or trihalomethyl.

Certain aminoalkyl derivatives of certain aminoalkylaminocarbonylpyrroline and pyrrolidine compounds are known to have antiarrhythmic activity (J. Med. Chem. 1986, 29, 1138-1152). However, there are no known derivatives and their effects which contain the amino group at the end of the chain in an aromatic amine moiety.

The present invention is directed to the 4- and 4- compounds of formulas I / a and I / b, respectively. 2-Aminoquinoline derivatives have excellent antiarrhythmic activity. Their potency is significantly higher than its commercially available formulations (Quinidine, Lidocaine), but also its derivatives known from the literature for aminoalkylaminocarbonylpyrroline and pyrrolidine.

The 4- or 4- compounds of the formulas I / a and I / b, respectively. The 2-aminoquinolines of the present invention are prepared by reacting 4-chloroquinolines of formula ΙΙa or 2-chloroquinolines of formula IIb with aminoalkylcarboxamide derivatives of formula III.

The reaction may be carried out in the presence or absence of solvents, preferably polar aprotic (dimethylformamide, dimethylacetamide) or polar protic (phenol) solvents, in the melt phase.

The reaction temperature is generally maintained at 100-200 Celsius, preferably at 120-160 Celsius. In the reactions, the aminoalkylcarboxamide derivative (III) is used in an amount of 1 to 3 molar equivalents relative to the chloroquinoline (ΙΙ / a or ΙΙ / b), without the presence of an acid-binding base.

Preferably, the reaction mixture is worked up by diluting it with water, optionally basifying with the addition of an organic (triethylamine) or inorganic (NaOH) base. The crystalline product is filtered off, the oily residue is extracted with chloroform and the solvent is evaporated.

The bases of the formulas I / a and I / b can be converted into the hydrochloride salt by the addition of dry hydrochloric acid gas or by the addition of hydrochloric acid ethanol in aprotic solvents (acetone, diethyl ether) and other acid addition salts.

The preparation of the aminoquinolines of formulas I / a and I / b is described in Examples 1-6. with examples. The compounds were prepared as described in Schemes I and II. Table.

The intermediates of formulas ΙΙ / a, Π / b and III are known in the art. The preparation of 4-chloroquinolines of formula ΙΙ / a and 2-chloroquinolines of formula Π / b can be found in the following monograph and references therein: The Chemistry of Heterocyclic Compounds Vol. 32 Quinolines. 387-398. Ed. by Gumós Jones; aminoalkylcarboxamides of formula III were prepared as described in Golding, Ioannon, OBrien, Synthesis 1975, 462.

The compounds of formulas I / a and I / b of the present invention are effective in eliminating cardiac arrhythmias of various origins, including, most often, post-infarction fibrillation leading to sudden death.

These compounds, in the form of pharmaceutical compositions, are useful in the prevention and / or treatment of heart attacks, cardiac arrhythmias.

Recently, a number of drugs and potential compounds with local anesthetic activity have been identified that may be useful in the treatment of cardiac disorders of various origins (Tocainid, Encainid, Lorcainid, Transcainid, Recainam). However, these substances, in addition to their beneficial therapeutic effects, have many undesirable effects, e.g. central nervous system, cardiovascular side effects.

Thus, the development of a novel antiarrhythmic drug that is effective, well absorbed and tolerated against selective, life-threatening ventricular arrhythmias remains an important goal in drug research.

Compounds of formulas I / a and I / b exhibit antiarrhythmic activity in several experimental arrhythmias in excess of the standard formulations used for comparison (Quinidine, Lidocaine, Mexiletin).

Their effective antiarrhythmic doses were generally 5- to 25-fold lower than those of Mexiletine, Lidocaine or Kinidine for parenteral administration, and were approx. It was 4 to 20 times lower than Mexiletine or Kinidin with enteral administration. The cardiac electrophysiological effects of the new compounds can be summarized as follows:

At concentrations of 1-5 mg / L, they increase the electrical stimulus threshold, decrease the conduction velocity of the isolated myocardium and spontaneous frequency of the right atrium, and extend the refractory period of the isolated left atrium, as seen in experiments on rabbit heart preparations. These effects were also much more intense than those of Mexiletine used for comparison.

The acute haemodynamic effects of the novel compounds are mainly characterized by moderated depression of myocardial contractility and arterial blood pressure, but these effects were not more pronounced than those of the control drugs mentioned above.

A particular advantage of the compounds of formulas I / a and I / b is that they do not affect the central nervous system at multiple or very few antiarrhythmic doses.

They do not cause convulsions, tremor and no impairment of muscle strength or motor coordination in rats after administration of the compounds of the invention.

HU 207 859 Β

Under in vitro conditions, these compounds do not inhibit neurotransmitter-induced convulsions at concentrations of up to 10 mol / l when tested in various isolated drug formulations.

The antiarrhythmic properties of the compounds of formulas I / a and I / b were tested according to the test methods described in Examples 7 and 8, respectively. and shown in Table V. The compounds of formulas I / a and I / b may be administered alone, however, in general, it is preferable to administer the compound in admixture with a pharmaceutical carrier. The carriers may be those conventionally used.

The active ingredient is e.g. for oral administration it may be in the form of tablets containing fillers or capsules containing the active ingredient alone or in admixture with excipients. Other oral compositions include elixirs or suspensions, which also contain various flavoring or coloring agents.

The active compounds may be injected parenterally, e.g. intravenously, intramuscularly or subcutaneously. For parenteral administration, the active compounds may be used, in particular, in the form of sterile aqueous solutions which contain other solutes, e.g. containing sufficient salt or glucose to render the solution isotonic.

For the prevention or treatment of cardiac disorders, such as arrhythmias of various origins, in a person of average weight (70 kg), when administered enterally, the daily dose of the active ingredient of the present invention may generally range from 5 to 500 mg.

Split into 2-4 pieces.

In the case of intravenous treatment, the single intended dose may be in the range of 0.5 to 100 mg.

Example 1

2,8-Dimethyl-4 - ((2,2,5,5-tetramethyl-3-pyrrolidin-3-yl) carbonyl-2-aminoethylamino) quinoline (Chemical 1)

1.92 g (0.01 M) of 2,8-dimethyl-4-chloroquinoline and 4.22 g (0.02 M) of N- (2-aminoethyl) -2,2,5,5- Tetramethyl-3-40 pyrrolidinecarboxamide was stirred in 10 ml of dimethylformamide at 100 ° C for 10 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), basified with 2N NaOH, filtered and recrystallized from ethanol-water.

Product: 2.60 g (71.2%);

169-171 degrees Celsius

Example 2

-methyl 4 - ((2,2,5,5-tetramethyl-3-pyrrolidin-3-yl) carbonylamino-2-ethylamino) (Compound 2)

1.78 g (0.01 M) of 2-methyl-4-chloroquinoline and 4.22 g (0.02 M) of N- (2-aminoethyl) -2,2,5,5-tetramethyl- 3-Pyrrolidinecarboxamide was stirred in 10 mL of dimethylacetamide at 140 ° C for 2 hours. The reaction mixture was poured into 50 ml of water. After basification with 2 N NaOH, the precipitated product is filtered off and recrystallized from ethanol-water. Product: 1.42 g (40.3%);

Mp: 140-142 degrees Celsius

Example 3

2-Methyl-8-chloro-4 - ((2,2,5,5-tetramethyl-3-pyrrolidin-3-yl) carbonyl-2-aminoethylamino) quinoline (Compound 3)

2.12 g (0.01 M) of 2-methyl-4,8-dichloroquinoline and 3.17 g (0.015 M) of N- (2-aminoethyl) -2,2,5,5-tetramethyl- 3-Pyrrolinecarboxamide was stirred in 4 g of phenol at 140 ° C for 1 hour. After completion of the reaction, it was poured into 50 ml of 1 N NaOH solution, the precipitate was filtered off, washed with water and recrystallized from ethanol-water.

Product: 2.75 g (71.1%);

Mp: 192-194 degrees Celsius

Example 4

2,8-Dimethyl-4 - ((2,2,5,5-tetramethylpyrrolidin-3-yl) carbonyl-3-aminopropylamino) quinoline dihydrochloride (Compound 11)

1.92 g (0.1 M) of 2,8-dimethyl-4-chloroquinoline and 3.41 g (0.015 M) of N- (3-aminopropyl) -2,2,5,5-tetramethyl- Pyrrolidine-3-carboxamide was stirred in 4 g of phenol at 140 ° C for 1 hour. After completion of the reaction, the reaction mixture was poured into 50 ml of 1 N NaOH solution, the oily substance was partitioned between chloroform and the chloroform solution was dried and concentrated in vacuo.

The residue was dissolved in 10 mL of diethyl ether and 3 mL of 8N hydrochloric acid ethanol was added. The cooled dihydrochloride salt was filtered and washed with diethyl ether. Product: 3.0 g (66.2%);

119-120 degrees Celsius (b).

By the method of Examples 3 or 4, the following compounds of formula I / a were prepared (Table I, Table 45):

Table I

Preparation of 4-aminoquinoline derivatives of formula Ia

Vegyíllet- song ^R 1 r ₂ THE B Method reactions (H) Yield: (%) Op. Celsius 1 Me 8-Me -ch ₂ -ch ₂ - = 3 2 76.3 169-171 2 Me H -ch ₂ -ch ₂ - = 3 1 59.7 140-142 3 Me 8-C1 -ch ₂ -ch ₂ - = 3 1 71.1 192-194 4 Me 7-C1 -ch ₂ -ch ₂ - = 3 1 70.4 187-189 5 H 7-C1 -ch ₂ -ch ₂ - - 3 1 69.9 204-206

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Compound- song R. % THE B Method reactions (H) Yield: (%) Op. Celsius 6 Me 8-Me -CH ₂ -CH ₂ -CH ₂ - = 3 1 78.2 171-173 7 H 7-C1 -ch ₂ -ch ₂ -ch ₂ - = 3 1 66.5 179-180 8 Me 8-Me -ch ₂ -ch ₂ - - 4 2 66.1 222-224 ^(b) 9 H 7-Cl -ch ₂ -ch ₂ - - 3 1 65.3 183-185 10 H 7-C1 -ch ₂ -ch ₂ -ch ₂ - - 4 1 72.4 151-153 ^(b * 11 Me 8-Me -ch ₂ -ch ₂ -ch ₂ - - 4 I 66.2 119-120 ^(b) 12 H H -ch ₂ -ch ₂ - 4 2 84.4 205-207 ^tb) 13 H 8-Me -ch ₂ -ch ₂ - = 3 2 69.3 181-183 14 -cf ₃ 8-CF3 -CH ₂ -CH ₂ - = 3 3 61.2 155-157 15 Me 8-Et -CH ₂ -CH ₂ - = 3 1 82.4 187-189 16 Me 8-i-Pr -ch ₂ -ch ₂ - = 3 4 73.5 181-183 17 Me 8-OMe -ch ₂ -ch ₂ - = 3 1 71.2 233-235 18 Me 8-CF ₃ -ch ₂ -ch ₂ - = 3 4 73.3 195-196

(a) The compounds of Example 3 are bases, the compounds of Example 4 are dicylo-hydrochloride salts.

(b) melts during decomposition

Example 5

3-Methyl-2 - ((2,2,5,5-tetramethyl, -3-pyrrolin-3-yl) carbonyl-2-aminoethylamino) quinoline (Compound 19)

1.78 g (0.01 M) of 2-chloro-3-methylquinoline and 6.33 g (0.03 M) of N- (2-aminoethyl) -2,2,5,5-tetramethyl- The melt of 3-pyrrolidine carboxamide was stirred at 140 ° C for 3 hours. After completion of the reaction, the melt was poured into water (50 mL), the precipitate was filtered and crystallized from ethanol / water.

Product: 2.49 g (70.7%);

135-137 degrees Celsius

Example 6 35

4-Methyl-2 - ((2,2,5,5-tetramethyl-3-pyrrolidin-3-yl) carbonyl-3-aminopropylamino) -quinoline dihydrochloride (Compound 23)

1.78 g (0.01 M) of 2-chloro-4-methylquinoline and 6.75 g (0.03 M) of N- (3-aminopropyl) -2,2,5,5-tetramethyl- The melt of 3-pyrrolidine carboxamide was stirred at 140 ° C for 3 hours. After completion of the reaction, the melt was poured into water (50 mL) and the oily product was triturated with chloroform, dried over the chloroform solution and concentrated in vacuo. The residue was dissolved in 10 ml of diethyl ether and 3 ml of 8N hydrochloric acid ethanol was added. The dihydrochloride precipitate which formed upon cooling was filtered off and washed with diethyl ether.

Product: 2.77 g (63.0%);

Mp: 305-307 degrees Celsius (b)

By the method of Examples 5 or 6, the following is used

Compounds of formula I / b were prepared (Table II):

ll. spreadsheet

Preparation of 2-aminoquinoline derivatives of formula I / b ⁶¹ *

We have a staff R r ₂ THE B Method Reaction time (h) Yield (%) Op. Celsius 19 3-Me H -CH ₂ -CH ₂ - = 5 3 70.7 135-137 20 3-Me 7-Me -ch ₂ -ch ₂ - = 5 4 80.1 129-131 21 4-Me H -ch ₂ -ch ₂ - = 6 3 58.6 272-274 ^(b * 22 3-Me H -ch ₂ -ch ₂ -ch ₂ - = 5 4 77.0 92-94 23 4-Me H -ch ₂ -ch ₂ -ch ₂ - = 6 3 63.0 305-307 < ^b) 24 3-Me H -ch ₂ -ch ₂ - - 6 5 66.2 183-185 ^(b *

(a) Compounds prepared according to Example 5. bases, the compounds of Example 6 are the dihydrochloride salts.

(b) melts during decomposition.

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Example 7

Determination of the in vivo antiarrhythmic activity and acute toxicity of the compounds of the formulas Ha and I / b.

The "in vivo" antiarrhythmic efficacy of the compounds I / a and 3 / b of the present invention was determined in aconitine-infused ventricular arrhythmias [Zetler and Strubelt, Arzneim. Forch. (Drug Slit.)

30, 1497 (1980)].

Wistar rats (200-200 g) were anesthetized with urethane and a polyethylene cannula was attached to the jugular vein. About animals Standard ECG II. lead ECG recording was performed. The test compound and saline used as controls were administered intravenously (i.v.) five minutes before the aconitine infusion.

The aconitine solution was continuous at 5 g / kg x min;

0.1 ml / 100 g / min infused v. jugularis, which continued until the appearance of the ECG isoelectric line. The time needed to elicit ventricular extrasystole and ventricular tachycardia was determined during the experiment.

For some compounds, the results are exemplified in Table III. in Table.

After administration of an antiarrhythmic compound, the onset time of induced arrhythmias was significantly delayed compared to control animals. ED ₁₂₅ and ED ₁₅₀ values were calculated based on the retardation time of ventricular extrasystole (Table IV).

Example 8

Determination of the effect of Ha and IIb compounds on basic cardiac electrophysiological parameters.

The effects of the compounds I / a and Eb on the basic cardiac electrophysiological parameters were investigated in isolated cardiac preparations of rabbits weighing 1.5 kg.

During this procedure, young rabbits (regardless of gender) were sacrificed by necrosis, their hearts were isolated, and the left atrium and the spontaneously functioning right atrium were prepared in oxygenated medium. The formulations were placed in a drug bath containing modified Locke solution at 32 degrees Celsius. Oxygenation and continuous agitation of the medium was effected by bubbling a mixture of 95% O ₂ and 5% CO ₂ .

The isolated left atrium at 1.2 Hz was 1 m sec. pulsed width driven by a square pulse generator via platinum electrodes; while the right atrium contracted spontaneously.

In the electrically stimulated left atrium, the electric stimulation threshold, the effective refractory section, was determined. Myocardial contraction and frequency were measured in the spontaneously operating right atrium. The results for some compounds are given in Table V by way of example.

Acute toxicity studies were performed on CFLP mice by intravenous administration. The _LD50 values after a one-week observation period was calculated Litekfield-Wilcoxon method (see Table IV.).

III. spreadsheet

Influence of the required ECG lesions on aconitine infusion in rats

Vegyil- headcount Dose mg / kg n Ventricular extrasystole (min) ± S. E. M. Kamrai tachicardia (min) + S. E. M. a contrast roll - 20 3.90 + 0.09 5.73 + 0.14 1 0.1 4 5.36 + 0.14 6.80 + 0.47 0.2 4 7.10 ± 0.40 9.30 + 0.38 0.4 4 9.35 & 0.37 15.15 + 0.49 3 0.2 4 5.00 & 0.27 5.97 + 0.47 0.5 4 6.70 + 0.36 7.80 ± 0.45 2.0 4 8.30 + 0.70 12.20 ± 0.60 6 0,125 4 5.15 ± 0.29 6.15 ± 0.20 0.50 4 6.40 + 0.59 8.05 ± 0.54 1.0 4 9.65 ± 0.85 U 90 ± 0.59 8 0.2 4 5.02 + 0.25 5.96 ± 0.37 0.5 4 5.88 ± 0.57 8.95 ± 1.69 0.8 4 7.37 ± 0.68 8.76 ± 0.67 19 1.25 4 4.95 & 0.08 6.12 ± 0.08 2.5 4 5.77 & 0.16 7.45 ± 0.17 5.0 4 7.12 + 0.45 8.95 ± 0.56 23 1.0 4 5.77 + 0.14 7.23 ± 0.19 2.5 4 7.38 ± 0.30 9.42 ± 0.47 5.0 4 8.38 ± 0.13 12.55 ± 0.60 Kini- dyne 0.5 4 5.33 ± 0.32 6.93 ± 1.53 10.0 7 6.61 ± 0.40 9.14 ± 1.98 12.0 4 6.90 & 0.72 8.16 ± 0.47

n = number of experimental animals 50 S. E. M. = mean error

ARC. spreadsheet

Effective Doses of Compounds of Formula I and Quinidine in Aconitin Infusion-Induced Arrhythmia and Acute Toxicity (LD ₅₀ 95% Confidence Limit) in Mice

compound Number EDt25 ^(a) (mg / kg) iv ED 150 ⁰ ° (mg / kg) iv LD _{5 (} ) (mg / kg) iv TI LD _5O / ED _15U 1 0.12 (0.10-0.15) 0.18 (0.14-0.22) 13 (10.5 to 16.3) 72 2 0.96 (0.64-1.46) 1.88 (1.24 to 2.84) 16 (13.3 to 19.9) 8.5

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compound Number ED | 25 ^(µl) (mg / kg) iv ED, 5) ^; (mg / kg) iv LD _S o (mg / kg) iv Ti LD _5O / ED _15O 3 0.16 (0,09-0.31) 0.33 (0.17-0.62) 30 (24.2-37.2) 90 4 0.30 (0.20-0.47 0.62 (0.40-0.95) 40 (34.5-47.3) 64 5 0.79 (0.44-1.40) 2.59 (1.46-4.61) 44 (39.6-49.7) 17 6 0.17 (0.10-0.37) 0.30 (0.16-0.53) 18 (14.1-24.2) 60 7 0.94 (.71-1.24) 1.77 (11.34-2.34) 48 (42.9-52.9) 27 8 0.35 (0.19-0.65) 0.72 (0.38-1.34) 3.0 <1.9-4.81) 4.1 9 0.41 (0.31-0.54) 0.55 (0.42-0.73) 31 (25.1-39.3) 56 10 0.18 (0.11 to 0.28) 0.31 (0.19-0.50) 36 (30.9-41.7) 116 11 1.04 (0.88-1.24) 1.30 (1.16-1.65) - - 12 1.04 (0.93 to 1.16) 1.20 (1.15 to 1.43) - - 13 0.59 (0.49-0.71) 0.80 (0.66-0.95) - - 14 0.77 (0.62-0.90) 1.13 (0.91-1.32) - - 15 0.21 (0.18-0.25) 0.35 (0.11-0.42) - - 16 0.87 (0.64-1.08) 2.36 (1.68-2.85) - - 19 1.92 (1.42-2.59) 3.87 (2.87-5.22) 37 (32.3-42.0) 9.5 20 1.46 (1.44-1.88) 3.18 (2.35-4.09) 29 (22.4-37.3) 9.1 21 2.28 (1.92-2.72) 6.93 (5.81-8.25) 37 (31.5-45.4) 5.3 22 2.01 (1.69-2.39) 3.07 (2.58-3.66) 37 (32.3-42.0) 12 23 0.97 (0.77-1.21) 1.96 (1.55-2.47) 38 (34.5-45.4) 19 24 2.11 (1.78-2.50) 3.92 (3.31-4.65) 56 (49.8-63.6) 14 quinidine 7.98 (5.70-11.18) 15.8 (11.31-22.2) 95 (78-118) 6.0

(a) In animals pretreated with physiological saline, infusion of aconitine (5 g / kg / min) produces ventricular extraseptol after 6.1 minutes. The ED ^ ED and ED EDo values correspond to infusion times of 7.6 and 9.2 minutes, respectively.

TI: therapeutic index

Table V.

The effect of the compounds of the formula I on the basic cardiac electrolyzological parameters in rabbit heart preparations is 60 minutes after the addition of the compound.

compound Number Dose in mg / l n Change in EIK (%) ± S. E. M. Change in ERP (%) ± S. E, M. Change in KE (%) + S. E. M " 1 5 5 + 1 U, 80 ± 13.28 + 96.0 ± 18.71 -6.21 ± 3.82 2.5 4 + 50.9 ± 5.33 + 33.5 + 8.60 -45.2 ± 5.95 3 5 4 + 49.5 + 19.00 + 34.7 ± 6.23 46.7 ± 3.14 6 5 4 + 23.4 ± 5.49 21.1 ± 4.42 -39.4 ± 4.53 8 5 4 + 38.6 ± 6.66 -13.0 ± 1:17 -21.5 ± 1.58 19 5 4 + 31.3 ± 8.95 + 9.7 ± 2.42 -9.5 + 4.88 23 5 4 + 19.6 + 0.40 + 20.0 ± 0.90 -30.7 ± 2.60 lidocaine 5 6 + 37.5 ± 4.06 + 48.4 + 4.78 -27.0 ± 2.33 mexiletine 5 10 + 49.6 ± 3.84 + 79.8 ± 6.28 -22.9 ± 1.46

EIK »electrical stimulus threshold ERP - effective refractory period KE = contraction force n - number of attempts S.E.M.-average error

Claims (3)

A process for the preparation of a compound of formula I / a and I / b wherein A is C 1-4 alkylene, B is a single or double bond, R 1 is hydrogen, (C 1 -C 4) -alkyl or trifluoromethyl; R ₂ is hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo or trihalomethyl new aminoquinoline derivatives and acid addition salts thereof, characterized in that a ΙΙ / or Reaction of an aminoalkylcarboxamide derivative of the Formula II / b wherein R 1 and R ₂ is the above compound, wherein A and B are as defined above, and optionally form an acid salt of the resulting aminoquinoline derivative. A process according to claim 1, characterized in that: The reaction is carried out in a melt phase or in the presence of a solvent at a temperature of 100 to 200, preferably 120 to 160 degrees Celsius. A process for the preparation of a new pharmaceutical composition, characterized in that at least one of the claims 1 to 3 is used I / A and Eb according to Formula 10 - wherein A, B, R 1 and R ₂ is as defined above - the aminoquinoline derivative or a pharmaceutically acceptable acid addition salt thereof is prepared by the addition of additives to a medicament for human use.