DE1227462B - Process for the preparation of quinoline derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

German class: 12 ρ -1/10

Number:
File number:
Registration date:
Display day:

1227462
I25807IVd / 12p
May 11, 1964
October 27, 1966

The invention relates to a process for the preparation of new quinoline derivatives with / S-adrenergic blocking effectiveness, therefore, in the treatment of heart diseases, such as cardiac arrhythmia or angina pectoris or tan, or are useful in preventing them.

According to the invention, a process for the preparation of quinoline derivatives of the general formula

OCH ₂ CHOHCh ₂ NHR ¹

CH ₃

wherein Z is the group

- CH - CH ₂

or denotes the group - CHOH · CH ₂ X, in which X is a halogen atom, is ^{reacted with an amine of the formula R 1} NH ₂ , in which R ^{1 has} the meaning given above, or a compound of the general formula

OCH ₂ CHOHCh ₂ NR ¹ R ²

CH ₃

wherein R ^{1 has} the meaning given above and R ^{2 is} a hydrogenolytically cleavable radical be-process for the preparation
of quinoline derivatives

CH ₃

wherein R ¹ denotes an alkyl or hydroxyalkyl radical with 3 or 4 carbon atoms, and proposed acid addition salts thereof, which is characterized in that a compound of the general formula in a manner known per se

Applicant:

Imperial Chemical Industries Ltd., London

Representative:

Dr.-Ing. H. Fincke, Dipl.-Ing. H. Bohr

and Dipl.-Ing. S. Staeger, patent attorneys,

Munich 5, Müllerstr. 31

Named as inventor:
Bernard Joseph Mcloughlin,
Macclesfield, Cheshire (UK)

Claimed priority:
Great Britain of May 10, 1963 (18,620),
dated April 8, 1964

draws, is reacted with hydrogen in the presence of a hydrogenation catalyst, whereupon, if the acid addition salts are desired, the product obtained is reacted with an acid.
An example of a suitable substituent for R ¹ is the isopropyl, s-butyl, t-butyl or 2-hydroxy-1,1-dimethylethyl radical.

Examples of suitable radicals for R ² are benzyl and benzyloxycarbonyl radicals.
Suitable acid addition salts of the quinoline derivatives obtainable according to the invention are salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates or sulfates, or salts derived from organic acids, for example oxalates, lactates, tartrates, acetates, salicylates or citrates.

Quinoline derivatives obtainable according to the invention are, for. B. l- (l, 2-dihydro-l-methyl-2-oxo-4-quinolyloxy) - - isopropylamino - 2 - propanol, 1 - (1,2 - dihydro - methyl - 2 - oxo - 4 - quinolyloxy) - 3 - tert. - butylamino-2-propanol and 1- (1,2-dihydro-1-methyl-2-oxo-4-quinolyloxy) -3- (2-hydroxy-l, 1-dimethylethylamino) -2-propanol.

609 708/397

The reactions mentioned can be conveniently carried out by the application of heat and / or pressure accelerated or completed, and they can optionally in the presence a diluent or solvent.

The invention is illustrated by the following examples, which are not to be construed as limiting where the parts are parts by weight.

IO

B e i s ρ i e 1 1

A. A mixture of 2.68 parts of 1- (1,2-dihydro-1-methyl-2-oxo-4-quinolyloxy) -3-chloro-2-propanol and 20 parts of isopropylamine was placed in a tightly closed vessel 10 Heated to 100 ^° C. for hours. The reaction mixture was then cooled and filtered and the filtrate was evaporated to dryness under reduced pressure. To the residue was added 20 parts of acetone, and the mixture was heated and stirred for about 1 minute and then cooled and filtered. The solid residue obtained in this way was l- (l, 2-dihydro-l-methyl-2-oxo-4-quinolyloxy) -3-isopropylamino-2-propanol hydrochloride, which, after recrystallization from a mixture of ethyl acetate and ethanol, had a melting point of 227 to 229 ° C (with decomposition).

B. The 1- (1,2-dihydro-l-methyl-2-oxo-4-quinolyloxy) -3-chloro-2-pro- panol can be obtained as follows:

A mixture of 0.88 parts of 1,2-dihydro-1-methyl-2-oxo-4-hydroxyquinoline, 6 parts of epichlorohydrin and 0.01 part of piperidine was heated to 90 to 100 ° C. for 12 hours. The reaction mixture was then cooled and the excess epichlorohydrin was removed by distillation under reduced pressure. The residue was dissolved in 50 parts of chloroform, and the resulting solution was shaken with 10 parts of concentrated hydrochloric acid. The mixture was then filtered and the solid residue was washed with 50 parts of cold acetone. The solid residue was then shaken with 50 parts of 2N aqueous sodium hydroxide solution, and the mixture was extracted three times with 30 parts of chloroform. The combined chloroform extracts were washed with 50 parts of water, dried over anhydrous magnesium sulfate, and the chloroform was then removed by distillation. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60 to 8O ⁰ C), and so was l- (l, 2-dihydro-l-methyl-2-oxo-4-quinolyloxy) -3-chloro-2 -propanol with a melting point of 167 to 169 ° C.

Example 2

A mixture of 1.9 parts of 1- (1,2-dihydro-1-methyl-2-oxo-4-quinolyloxy) -3-chloro-2-pro- panol and 20 parts of tert-butylamine in a tightly closed vessel at 100 ° C. for 10 hours heated. The reaction mixture was then cooled and the excess tertiary butylamine became removed by distillation. The residue was suspended in 50 parts of acetone and it became a saturated ethereal solution of hydrogen chloride added until there was an excess of hydrogen chloride Template. The mixture thus obtained was filtered.

and the solid residue was recrystallized from a mixture of ethyl acetate, ethanol and ether. Thus became 1- (1,2-dihydro-1-methyl-2-oxo-4-quinolyloxy ^ -tert.-butylamine ^ -propanol sesquihydrochloride monohydrate obtained with a melting point of 156 to 158 ° C (with decomposition).

B e i s ρ i e 1 3

A mixture of 1.9 parts of 1- (1,2-dihydro-1-methyl-2-oxo-4-quinolyloxy) -3-chloro-2-propanol and 1.3 parts of 2-amino-2-methyl ^{-l-propanol heated to 100 °} C. for 10 hours in a tightly closed vessel. The reaction mixture was cooled and then rinsed into a flask with 50 to 100 parts of ethanol. The ethanol was removed by distillation and the residue was dissolved in 50 parts of 2η hydrochloric acid. The acidic solution was extracted twice with 20 parts of ether and the extracts were discarded. The aqueous solution was made alkaline with 2N sodium hydroxide solution, and the mixture was extracted three times with 50 parts of chloroform. The extracts were combined, washed twice with 50 parts of water each time, dried over anhydrous magnesium sulfate, and the chloroform was removed by distillation. The residue, which

1 - (1,2 - dihydro -1 - methyl - 2 - oxo - 4 - quinolyloxy) 3 - (2 - hydroxy -1,1 - dimethylethylamino) - 2 - propanol was dissolved in 50 parts of acetone, and the solution was stirred while a saturated ethereal solution of hydrogen chloride was added dropwise until an excess of hydrogen chloride was present. The mixture was filtered and the solid residue was recrystallized from a mixture of acetone, methanol and ether. Thus, l- (1,2-dihydro-l-methyl-2-oxo-4-quinolyloxy) -3- (2-hydroxy-1,1-dimethylethylamino) -2-propanol sesquihydrochloride monohydrate with a melting point of 143 to 144 ³ C (with decomposition ) obtain.

B e i s ρ i e 1 4

A. There were 0.6 parts of l- (l, 2-dihydro-l-methyl-

2 - 0x0 - 4 - quinolyloxy) - 3 - [(N - isopropyl - N - benzyl) amino] -2-propanol oxalate dissolved in 50 parts of water, and the solution was concentrated by adding Ammonium hydroxide solution made alkaline. The mixture was made four times with 20 parts each Chloroform extracted, and the combined chloroform extracts were washed with 20 parts of water, dried over anhydrous magnesium sulfate and the chloroform was removed by distillation removed. The residue was dissolved in 20 parts of ethanol, and there were 0.5 parts of 5% Palladium on charcoal added as a catalyst. The mixture was in a hydrogen atmosphere at a pressure of 1 atm and shaken at room temperature until no further hydrogen absorption took place. The mixture was filtered and the solvent was removed by evaporation removed under reduced pressure. The residue was dissolved in 20 parts of a saturated ethereal Triturated solution of hydrogen chloride. The mixture was filtered and the solid residue was recrystallized from a mixture of ethyl acetate, ethanol and ether. Thus 1- (1,2-dihydro-1 - methyl - 2 - oxo - 4 - quinolyloxy) - 3 - isopropylamino-2-propanol hydrochloride obtained with a melting point of 228 to 229 C (with decomposition).

B. The 1- (1,2-dihydro -1 - methyl - 2 - oxo - 4 - quinolyloxy) - 3 - [(N - isopropyl-N-benzyl) amino] -2-propanol oxalate required as starting material can be made as follows:

There was a suspension of 3.5 parts of 1,2-dihydro-1-methyl-2-oxo-4-hydroquinoline in 25 parts of an ethanolic solution of sodium ethylate or sodium ethoxide (prepared by dissolving 0.46 part of sodium in 25 parts ethanol) l in a sealed vessel with 4.1 parts, heated 2-epoxy-3- (N-isopropyl-N-benzyl) -aminopropane 10 hours at 100 ⁰ C. The mixture was cooled and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 50 parts of 2N hydrochloric acid, and the acidic solution was extracted twice with 20 parts of ether, the extracts being discarded. The aqueous mixture was made alkaline by adding 5N sodium hydroxide solution, and the basic solution was extracted three times with 100 parts of chloroform each time. The combined extracts were washed with 50 parts of water, dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 20 parts of acetone and treated dropwise with stirring with a saturated ethereal solution of oxalic acid until the precipitation was complete. The oily precipitate was triturated in acetone and filtered. The solid was recrystallized from a mixture of ethyl acetate, ethanol and ether to give 1 - (1,2-dihydro-1-methyl-2-oxo-4-quinolyloxy) ^ - [(N-isopropyl-N-benzyl ) -amino] -2-propanol oxalate with a melting point of 188 to 189 ° C (with decomposition).

Comparison results

The effectiveness of the quinoline derivatives obtainable according to the invention as / tf-adrenergic inhibitors and known compounds which also function in this manner were measured as follows :

Cats were anesthetized with intravenous chloralose (80 mg / kg) and their heart rates were set. Standard amounts of 1 - (3,4 - dihydroxyphenyl) - 2 - isopropylamino - ethanol were added at intervals of about 10 minutes (= Substance A) administered intravenously, the amount of which depends on the "respective sensitivity of the Cat and was generally between 0.25 and 0.5 μg / kg. These injections worked an increase in heart rate (tachycardia), and the mean of three administrations was called Control tachycardia determined. The compound to be investigated was used in amounts of 1 to 100 μg / kg / min. administered by continuous intravenous infusion over 30 minutes. Substance A was in the same dose as used during the control period at approximately 10 minute intervals administered during administration of the test compound. The connections, the one / J-adrenergic inhibitory effect prevented the occurrence of tachycardia, which would otherwise occur due to substance A. The effectiveness of such compounds is usually expressed as the percentage inhibition of control tachycardia expressed.

The ß-adrenergic inhibitory effect of a characteristic Selection of quinoline derivatives obtainable according to the invention was measured by the method given above and resulted in following results:

total
dose 'Percentage link mg / kg Inhibition of
Control tachycardia l- (l, 2-dihydro-l-methyl-2-oxo- 4- quinolyloxy) - 3 - isopropyl- 1.2 amino-2-propanol 80 3-tert-butylamino-l- (l, 2-di- hydro-l-methyl-2-oxo- 0.6 4-quinolyloxy) -2-propanol 59 1 - (1,2-dihydro-1-methyl-2-oxo- 4-quinolyloxy) -3- (2-hydroxy- 1,1 -dimethylethylamino) - 0.6 2-propanol 2.5 92 Substance Bl comparative J
Substance CJ substances 1 1.5 80 90

The / i-adrenergic inhibitory effect of [2-hydroxy-2- (2-naphthyl) ethyl] isopropylamine (= Substance B), which according to Belgian patent specification 603 416 is said to have such an effect tested in the manner indicated above and gave the following result: total dose (mg / kg) 2.5; percent prevention of control tachycardia 80.

The jtf adrenergic inhibitory activity was also observed of N - [/? - (3,4-dichlorophenyl) - / i-hydroxyethyl] isopropylamine (syn, DCI) (= substance C) determines that according to Furchgott, Pharmacological Reviews, 11 (1959), p. 429, in this sense supposed to be effective and it produced the following results: total dose (mg / kg) 1.5; percentage Inhibition of control tachycardia 90.

However, it is known from the cited literature that this compound / 3-adrenergic stimulatory Properties besides those of a / 3-adrenergic Inhibition possesses, and when this compound is tested in the manner indicated above it gets a 49% increase in heart rate at a total dose of 1.5 mg / kg emerged. In this context it should be noted that when a connection increases the size of the Heart rate, their apparent inhibition of control tachycardia is greater than the real effect. Accordingly, this compound appears to be 3-adrenergic because of its potent / 3-adrenergic properties stimulant properties to be a far more potent / i-adrenergic inhibitor than it actually is the case is.

The above results indicate that the products obtainable according to the invention have a larger one Have ß-adrenergic inhibitory effect than the previously known / J-adrenergic inhibitors is the case, at doses that do not have undesirable stimulation of the heart rate have as a consequence. The products obtainable according to the invention are therefore known β-adrenergic Superior to inhibitors.

Claims (1)

Claim: Process for the preparation of quinoline derivatives of the general formula OCH2CHOHCH2NHR ¹ CH ₃ in which R ¹ denotes an alkyl or hydroxyalkyl radical with 3 or 4 carbon atoms, as well as their acid addition salts, characterized in that in a manner known per se a compound of the general formula OCH ₂ Z wherein Z is the group - CH - CH ₂ or denotes the group - CHOH · CH ₂ X, in which X is a halogen atom, is ^{reacted with an amine of the formula R 1} NH ₂ , in which R ^{1 has} the meaning given above, or a compound of the general formula OCh ₂ CHOHCH ₂ NR ¹ R ² CH ₃ wherein R ^{1 has} the meaning given above and R ² denotes a hydrogenolytically cleavable radical, is reacted with hydrogen in the presence of a hydrogenation catalyst, whereupon, if the acid addition salts are desired, the product obtained is reacted with an acid. 609 708/397 10.66 O Bundesdruckerei Berlin