HU207048B - Process for producing 3-aminomethyl quinolines - Google Patents

Abstract

Novel prepn. of anti-arhythmic 3-amino-methyl-quinolines or their salts of general formulae (I), where: R1= chlorine atom, hydroxy-, aryloxy-, 1-4C alkoxy-, alkenyl-oxy-, alkynyl-oxy-gps.; 3-6C heterocyclic gps. contg. at least one nitrogen atom 1-4C alkyl-amino-, aryl-thio-, alkyl-thio- alkenyl-thio-, alkinyl-thio-gps.. - R2 and R3= hydrogen atom, phenyl-, 1-4C alkyl- alkenyl-, alkynyl-, amino-(1-4C)-alkyl, (1-4C)-alkyl-amino-, (1-4C)-di- alkyl-amino-alky piperidine-1-yl-(1-4C)-alkyl, pyrrolidine-1-yl-(1-4C) -alkyl, morpholine-4-yl-(1-4C)-alkyl- or aryl-oxy-(1-4C)-alkyl, or R2 and R3 together = 2-5C alkylene gp., in this case interrupted by a heteroatom or substd. heteroatom. R4 and R5 = hydrogen atom, halogen atom, 1-4C alkyl or 1-4C alkoxy gp..

Description

The present invention relates to a process of formula (I) wherein

R 1 is halogen, hydroxy or C 1-4 alkoxy, 2-piperazinyl or 2-thienyl optionally substituted with halogen,

R ₄ and R ₅ are hydrogen or halogen, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy,

R ₂ is hydrogen

R ₃ is hydrogen, alkenyl, dimethylphenoxy (C 1-4) alkyl, amino or (C 1-4) dialkylamino (C 1-4) alkyl, too (1-piperidinyl) ) - (C 1 -C 4) alkyl, or

R ₂ and R ₃ together with the nitrogen atom to which they are attached may form a piperidine, morpholine or piperazine ring; and the latter may be optionally substituted on the 4-nitrogen atom with a C1-C4 alkyl, hydroxy (C1-C4) alkyl or phenyl group to produce new compounds having antiarrhythmic activity and their salts.

They are known from the literature [Pharmazie 1976,31 (12), 845] in Π. 3-arylaminomethyl-quinolines of formula I, however, do not have a substituent at the 2-position, nor have their antiarrhythmic activity been studied.

In one embodiment of the process of the present invention, compounds of formula I wherein R ₂ is hydrogen, R _b R ₃ , R ₄ and R ₅ are as defined above, in quinoline 3-azomethines of formula III or in polar solvents thereof in a mixture of 10 to 50 degrees Celsius. The reaction is preferably carried out in chloroform-methanol at room temperature with sodium borohydride.

Compounds of formula III wherein R _b R ₃ , R ₄ and R ₅ are as defined above are 3-formylquinolines of formula IV and amines of formula H ₂ NR _{3 in} polar solvents 30-120 ° C reaction temperature. The reaction is preferably carried out in ethanol at reflux temperature. The 3-formylquinolines of formula (IV) were prepared by methods known in the art. (I. Chem. Soc. Perkin Trans. 1,1981 1520 and J. Chem. Soc. Perkin Trans. I, 1981, 2509).

In another embodiment of the present invention, compounds of formula I wherein R 1 is halogen or hydroxy, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above are 2-chloro-3-chloromethyl of formula V quinolines and amines of the formula HNR ₂ R ₃ , wherein R ₂ and R ₃ are prepared by reaction of 10 or 120 degrees Celsius with or without an acid acceptor in the above polar solvent or mixture thereof. The reaction is preferably carried out in a mixture of chloroform-ethanol at 2060 degrees Celsius.

The 2-chloro-3-chloromethylquinolines of formula (V) were prepared according to methods known in the art. (J. Chem. Soc. Perkin Trans. 1,1981,1537)

The compounds of formula (I) were prepared in the form of salts for ease of handling in frameworks.

The following examples illustrate the process without limiting the invention to these.

Example 1

2-diethylamino-N- (2,7-dichloro-8-methyl-quinolin-3-yl) methylene-ethylamine

4.8 g (0.02 mol), 2,7-dichloro-3-formyl-8-methylquinoline and 2.8 g (0.024 mol) of 2-diethylaminoethylamine are refluxed in 30 ml of ethanol for 1 hour and the solution is evaporated. . The residual solid was crystallized from hexane-chloroform (2: 1). The precipitated product was filtered and air-dried.

Product: 5.0 g

Yield: 74.0%

Mp: 73-74 degrees Celsius

Following the procedure of Example 1, the following compounds were prepared.

Example 2

2 - (] - piperidinyl) -N- (2-chloro-7-methyl-kmoUn-3-yl) methylene-ethylamine

Yield: 59.4%

Mp: 81-83 degrees Celsius

Example 3

2- (l-piperídmo) -N- (2,7-dimethoxy-quinolin-3-yl) methylene-ethylamine

Yield: 69.3%

95-97 degrees Celsius

Example 4

2-Diethylamino-N- (2-ethoxy-7-chloro-quinolin-3-U) methylene-ethylamine Yield: 72.7%

64-66 degrees Celsius

Example 5

2-diethylamino-N- (2-piperazin, ynyl-7-chloro-8-methylquinoline-3 dl) methylene-ethylamine

Yield: 76.2%

Mp 78-79 ° C

Example 6

2-Diethylamino-N- [2- (4-bromothiophenyl) -7-chloro-8-methyl-quinolin-3-yl] -methylene-ethylamine Yield: 85.8%

M.p.

Example 7

2-diethylamino-N- (2-hydroxy-7-methylquinoline-3-yl) methylene-ethylamide

3-Formyl-2-hydroxy-7-methylquinoline (1.9 g, 0.01 mol) and 2-diethylaminoethylamine (5.6 g, 0.048 M) were refluxed in ethanol (30 mL) for 1 hour and the solution was cooled. The precipitated product is filtered off and washed with hexane. Product: 1.8 g

Yield: 62.5%

Mp .: 158-160 degrees Celsius.

Following the procedure of Example 7, the following compounds were prepared.

HU 207 048 B

Example 8

1-Methyl-2- (2,6-dimethyl) -phenoxy-N- (2,7-dichloro-8-methyl-quinolin-3-yl) -methyl-ethylamine

Yield: 88.5%

142-143 degrees Celsius

Example 9

N- (2-chloro-7-methylquinolin-3-yl) methylene allylamine Yield: 73.6%

Mp: 77-79 degrees Celsius

Example 10

2-Diethylamino-N- (2,7-dichloroquinolin-3-yl) methylene ethylamine

Yield: 44.8%

Mp: 63-65 degrees Celsius

Example 11

3- (2-Diethylamino-ethyl) -aminomethyl-2,7-dichloro-8-methyl-quinoline hydrochloride g (0.0089 M) 3- (2-diethylamino-ethyl) -azomethyl-2,7- Dichloro-8-methylquinoline was dissolved in a mixture of chloroform (50 ml) and methanol (10 ml), and sodium borohydride (0.68 g, 0.018 M) was added in small portions while cooling with water and stirred for 8 hours. After extraction with water (50 ml), the chloroform layer was dried over sodium sulfate and evaporated. The residue was dissolved in 20 ml of hot ethanol and an equivalent amount of hydrochloric acid ethanol was added. The precipitate was filtered off and washed with ethanol.

Product: 2.2 g

Yield: 65.8%

Mp 202-204 degrees Celsius

Example 14

3- (Allyl) aminomethyl-2-chloro-7-methylquinoline hydrochloride

Yield: 36.7%

M.p. 189-192 degrees Celsius Example 75

3- [2- (1-Piperidino) ethyl] aminomethyl-2-chloro-7-methyl-quinoline hydrochloride

Yield: 80.0%

Mp 210-213 degrees Celsius

Example 16

3- (2-dtetilamino-ethyl) aminomethyl-2,7-dichloro-quinoline hydrochloride

Yield: 71.5%

Mp: 186-190 degrees Celsius

Example 17

3- [2- (l-piperidino) ethyl] aminomethyl-2,7-dimethoxyquinoline hydrochloride

Yield: 73.0%

Mp 244-248 degrees Celsius

Example 18

3- (2-diethylaminoethyl) aminomethyl-2-ethoxy-7-chloroquinoline hydrochloride

Yield: 32.2%

M.p. 171-173 degrees Celsius Example 79

3- (2-diethylaminoethyl) aminomethyl-7-chloro-8-methyl-2-piperazin-LDL-quinoline hydrochloride

Yield: 40.8%

Mp: 201-202 degrees Celsius

Example 72

3- (2-Diethylamino-ethyl) -aminomethyl-2-hydroxy-7-methyl-quinoline hydrochloride was dissolved in 1.0 g (0.0035 mol) of 3- (2-methanol) in a mixture of 1 ml of chloroform and 10 ml of methanol. diethylaminoethyl) azomethyl-2-hydroxy-7-methylquinoline was added in small portions under cooling with sodium borohydride (0.3 g, 0.007 M) and stirred for 8 hours. It is then extracted with 50 ml of water, the chloroform phase is dried over sodium sulphate and evaporated. The residue is dissolved in 20 ml of hot ethanol and equivalents of hydrochloric ethanol are added. The precipitate was filtered off and washed with acetone.

Product: 0.8 g 50

Yield: 70.7%

Mp .: 220-223 degrees Celsius

Following the procedure of Examples 11 and 12, the following compounds were prepared.

Example 75

3- [1-Methyl-2- (2,6-dimethyl) -phenoxy-ethyl] -aminomethyl-2,7-dichloro-8-methyl-quinoline hydrochloride Yield: 73.0%

178-181 degrees Celsius 60

Example 20

3- (2-Diethylaminoethyl) aminomethyl-7-chloro-8-methyl-2- (4-bromothiophenyl) quinoline hydrochloride Yield: 34.6%

115-118 degrees Celsius

Example 27

3- (2-Diethylaminoethyl) aminomethyl-2-chloroquinoline hydrochloride

Yield: 65.6%

Mp: 100-102 degrees Celsius

Example 22

2-chloro-3- [4- (2-hydroxyethyl) piperazin-l-yl] -metilkinolin dihydrochloride

2-Chloro-3-chloromethyl-quinoline (4.24 g, 0.014 M), 1-hydroxyethylpiperazine (2.9 g, 0.0224 M) were stirred at 60 ° C for 6 hours in 10 ml of chloroform and 10 ml of ethanol. Add 20 ml of 2N hydrochloric acid ethanol, cool in a refrigerator, filter the precipitated dihydrochloride salt, and wash with ethanol. The crude product was crystallized from a mixture of dimethylsulfoxydethanol.

Yield: 6.51 g (86%)

Mp 260-262 degrees Celsius

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Following the procedure of Example 22, the following compounds were prepared.

Example 23

2-chloro-3- (4-phenyl-piperazin-l-yl) methyl-quinolone dihydrochloride

Yield: 74%

Mp: 238-240 degrees Celsius

Example 24

2-chloro-3- (4-methylpiperazin -] - yl) methyl-quinoline dihydrochloride

Yield: 73%

Mp: 240-242 degrees Celsius

Example 25

2-chloro-3- (piperidin-l-yl) methyl-quinoline hydrochloride

2-Chloro-3-chloromethyl-quinoline (4.24 g, 0.02 M) and piperidine (3.6 g, 0.042 M) were stirred at room temperature for 3 hours in 10 ml of chloroform and 10 ml of ethanol. To the reaction mixture was added 20 ml of 2N hydrochloric acid ethanol, and the precipitated hydrochloride salt was filtered and washed with ethanol.

Yield: 3.96 g (67%)

Mp 265-266 degrees Celsius

Following the procedure of Example 25, the following compound was prepared.

Example 26

2-chloro-3- (morpholin-4-yl) methyl-quinoline hydrochloride

Yield: 59%

Mp: 236-238 degrees Celsius

Example 27

2-chloro-3- (2-aminoethyl) amino-methylquinoline hydrochloride

2-Chloro-3-chloromethyl-quinoline (4.24 g, 0.02 M) and ethylenediamine (2.4 g, 0.04 M) were stirred in ethanol (20 mL) at room temperature for 20 hours. The reaction mixture was poured into 50 mL of water and filtered. The filtrate was made basic with sodium hydroxide solution, the product was extracted with chloroform (3 x 50 ml), and the combined chloroform phases were dried and evaporated. The residue was taken up in ether, neutralized with 2N hydrochloric acid and the hydrochloride crystallized.

Yield: 3.78 g (69.5%).

Mp: 209-210 degrees Celsius

Following the procedure of Example 27, the following compounds were prepared.

Example 28

2-chloro-3- (2-aminopropyl) amino-methylquinoline hydrochloride

Yield: 67%

160-163 degrees Celsius

Example 29

2-Chloro-3- (piperazin-1-yl) methyl-quinoline hydrochloride Yield: 47%

Mp 247-249 degrees Celsius

Example 30

2-hydroxy-3- (4-methylpiperazin-l-yl) methyl-quinoline

3.48 g (0.01 M) of 2-chloro-3- (4-methylpiperazin-1-yl) methylquinoline dihydrochloride in 10 ml cc. hydrochloric acid, 10 ml of water and 10 ml of ethanol are stirred at reflux for 2 hours. The reaction mixture was evaporated and the solid residue was triturated with ethanol and filtered.

Yield: 2.32 g (70.5%).

Mp: 248-250 degrees Celsius (b)

Following the procedure of Example 30, the following compounds were prepared.

Example 31

2-hydroxy-3- (piperazin-l-yl) methyl-quinolin dihydrochloride

Yield: 92%

Mp: 206-208 degrees Celsius (b)

Example 32

2-hydroxy-3- (4-phenyl-piperazin-j-yl) methyl-kinolindihidroklond

Yield: 79%

Mp 222-225 degrees Celsius

Example 33

2-hydroxy-3- [4- (2-hydroxyethyl) piperazin -] - yl] methyl-quinoline dihydrochloride

Yield: 97%

270-273 degrees Celsius (b)

Example 34

2-hydroxy-3- (piperidin-l-yl) methyl-quinoline hydrochloride

Yield: 71%

225-227 degrees Celsius

In our studies, it has been found that the compounds of formula I according to the invention are also practically significant regulators of cardiac arrhythmias. have antiarrhythmic properties.

In various pharmacological models, the new compounds exhibit comparable, sometimes more beneficial effects, than clinically proven drugs, such as Kinidin, Lidocaine.

Against this background, compounds of Formula I may be considered as potential drugs for the treatment of cardiac arrhythmias of various origins, including severe cases such as ventricular fibrillation or sudden cardiac death.

Biological example

1.5-2.0 kg rabbits were used for the tests. The animals were sacrificed by nape stroke, their hearts were isolated, and the left atrium was prepared in oxygenated medium. The composition was placed in an experimental bath surrounded by a heating jacket containing modified Locke solution. The composition of the solution was as follows:

Na ⁺ , 140; K ⁺ , 5.63; Ca ²⁺ , 2.17; glucose, 11; HCO ₃ -, 25; Cl, 125;

Total: 309 mM at pH 7.4.

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The solution was constantly circulated and at the same time oxygenated by bubbling a 95% oxygen gas bubble. The temperature of the organ bath was maintained at 32 degrees Celsius. The left atrium was artificially driven with 1 msec quadrature pulse stimuli at 100 rpm.

During the studies, contractility, electrical stimulus threshold and effective refractory period measured using a triple stimulus threshold were determined.

(Papp Gy. And Vaughan Williams, E.M. Brit. J. Pharmacol. 7,380-390)

The new compounds were added directly to the circulating medium. Our results are shown in Figures I, II, III. are summarized in tables.

Table 1:

Effect of compounds of formula (I) on electrical stimulation threshold of isolated left atria of rabbit heart

example of song con- centralization tion mg / liter n change in electrical stimulation threshold (%) at various times after compound addition 15 minutes 30 minutes 45 minutes 60 minutes 21 10 3 +22.7 +6.3 +40.7 +7.7 +47.9 +3.9 +50.4 +1.76 24 10 6 +6.4 +4.1 +17.1 +4.2 +21.5 +5.1 +27.1 +3.5 22 10 4 +10.9 +4.2 +30.0 +5.3 +30.3 +9.1 +37.1 +2.2 29 10 4 +12.7 +2.3 +15.1 +1.8 +23.8 +2.4 +33.1 +2.9 11 10 3 +31.3 +7.1 +37.3 +6.9 +47.7 +7.0 +63.6 +9.7 14 10 3 +14.5 +1.3 +23.3 +4.5 +35.3 +9.7 +35.5 +9.7 16 10 3 0 0 0 0

Mean + S.E. n - number of preparations

II. spreadsheet:

Effect of Compounds of Formula (I) on Effective Refractory Period of Isolated Rabbit Heart

example number concentration mg / liter n change in effective refractory period at different times after the addition of the compounds 30 minutes 60 minutes 21 10 3 +10.4 +6.9 +15.9 +9.1 24 10 6 +31.7 +3.9 +41.9 +3.3 22 10 4 +15.7 +0.4 +18.2 +2.6 29 10 4 +28.8 +4.13 +53.4 +10.1 11 10 3 +30.5 +5.7 +46.1 +17.1 14 10 3 +10.8 +3.1 +12.9 +1.5 16 10 3 +35.9 +5.3 +45.2 +7.3

Mean + S.E. n - number of preparations

III. spreadsheet:

Effect of compounds of formula (I) on contractility of isolated left atria of rabbit heart

example of song con- centralization tion mg / liter n change in contractility at various times after the addition of the compounds 15 minutes 30 minutes 45 minutes 60 minutes 21 10 3 -9.5 +2.7 -6.6 +3.3 -3.8 +2.0 0 24 10 6 -15.5 +3.2 -12.1 +3.1 -11.2 +3.1 -12.7 +3.3 22 10 4 -17.4 +3.8 -13.1 +5.4 -16.5 +4.8 -19.2 +4.1 29 10 4 -29.3 +5.8 -30.1 +5.2 -26.8 +5.4 -31.4 +4.1 11 10 3 -25.0 +3.5 -34.0 +1.0 -41.5 +2.9 -44.8 +3.1 14 10 3 -23.1 +1.2 -23.1 +1.2 -22.1 +1.9 -24.3 +2.4 16 10 3 -9.5 +5.2 -9.5 +5.2 -8.8 +1.3 -7.9 +2.4

Mean + S.E. n - number of preparations

Claims (5)

PATENT CLAIMS A process for the preparation of the 3-aminomethylquinolines of formula (I) R 1 is halogen, hydroxy or C 1-4 alkoxy, 2-piperazinyl or 2-thienyl optionally substituted with halogen, R ₄ and R ₅ are hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, R _{2 for} hydrogen R ₃ is hydrogen, alkenyl, dimethylphenoxy (C 1-4) alkyl, amino or (C 1-4) dialkylamino (C 1-4) alkyl, m- ( 1-piperidinyl) (C 1 -C 4) alkyl, or R ₂ and R ₃ together with the nitrogen atom to which they are attached may also form a piperidine, morpholine or piperazine ring, which at the 4-position of the nitrogen may be optionally C 1-4 alkyl, hydroxy (C 1-4) alkyl or phenyl. group, and their salts, characterized in that: a) for the preparation of compounds of formula I wherein R ₂ is hydrogen, R _b R ₃ , R ₄ , R ₅ are as defined above, a compound of formula III wherein R 1, R ₃ , R ₄ , R ₅ is as defined above - quinoline-3-azomethine is reduced b) for the preparation of compounds of formula I wherein R 1 is halogen, hydroxy, R ₂ , R ₃ , R ₄ , R ₅ is as defined above, a compound of formula V wherein R 1 is halogen, hydroxy, R ₄ , R ₅ is as described above - 3-chloromethylquinoline is reacted with an amine of formula HNR ₂ R ₃ and the resulting compounds are optionally converted to their salts. Process a) according to claim 1, characterized in that the reaction is carried out in polar solvents or in a mixture thereof, preferably in a mixture of chloroform and methanol; It is carried out at a temperature of 10-50 degrees Celsius. Process (a) according to Claim 1, characterized in that the reduction is carried out under a hydrogen atmosphere in the presence of a catalyst (palladium carbon, Raney nickel) or with reducing agents (sodium borohydride, lithium aluminum hydride, metal sodium), preferably sodium borohydride. Process b) according to Claim 1, characterized in that the reaction is carried out in polar solvents or mixtures thereof, preferably in a mixture of chloroform-ethanol; 10 to 120 degrees Celsius; preferably at a temperature of 2060 degrees Celsius; with or without an acid acceptor; the amine reagent is used in an amount of 1 to 2 molar equivalents. Process according to claim 1, characterized in that the compounds are prepared in the form of their base or of their salts with organic or inorganic acids (oxalate, citrate, hydrochloride, phosphate), preferably in the form of their hydrochloride salts.