DE2315148A1 - NEW QUINOLINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE - Google Patents

Description

r ^ ATENTANV / OLD

DR.-ING. FROM KRHSLFR OR.-ING. SCHÖNWALD

DR.-ING. TH. MEYER DR. FUES D IPL-CHEM. ALEK VON KREISLER DIPL-CHEM. CAROLA KELLER DR.-ING. KLÖPSCH DIPL-ING. SELTING

COLOGNE 1, DEICHMANNHAUS 2315148

Cologne, March 24th, 1973 Kl / Ax

OMNIUM CH IMTQUE ,

16, Rue des Trois Arbres, 1180 Brussels (Belgium) .

New quinoline derivatives, processes for their preparation and their uses

The invention relates to new quinoline derivatives of the general my formula

CO - CH ₂ -CH ₂ - / NR

CH = CH ₂

Here, R stands for a linear or branched alkyl radical which contains 2 to 6 carbon atoms and ^{can contain a radical of the formula -NR 1} R ", in which R ¹ and R" separately represent alkyl radicals with 1 to 4 carbon atoms or together with the nitrogen atom to which they are bonded form a five- to seven-membered heterocycle which can contain an oxygen atom or a nitrogen atom as the second hetero atom, the latter nitrogen atom itself being able to contain a phenylalkenyl radical or pheoylalkenylcarbonyl radical, the alkenyl radical of which is 1 to 6 ° C Contains atoms and its phenyl component is meth-

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may contain oxy radicals, or for a phenylalkenylcarbonyl radical, which contains 1 to 6 carbon atoms in the alkenyl part and May contain methoxy radicals on the phenyl nucleus, or for one Benzoyl radical, which is a halogen atom or a methoxyoarbonyl radical may contain on the ring. The invention also includes non-toxic acid addition salts of these quinoline derivatives.

The abovementioned heterocycles are advantageously morpholino, pyrrolidino, piperidino or piperazino groups.

The compounds according to the invention can be prepared are made by reacting compounds of the formula

(II)

with a halogenated derivative of the formula RX, in which X is a halogen atom and E has the abovementioned meaning, in an organic solvent in the presence of an acid reactor, ζ .3. an alkali metal carbonate insoluble in the reaction medium, a tertiary amine or an alkali metal hydroxide. The reaction is advantageously carried out by refluxing, preferably under an inert atmosphere.

Examples of suitable organic solvents are aromatic hydrocarbons such as benzene, toluene and xylene, and solvents such as diethylene chloride and ethanol.

As an alkali carbonate; potassium carbonate is preferred.

Triethylamine is preferably used as the tertiary amine. The two last-mentioned compounds have the purpose of binding the hydrohalic acid HX released during the reaction. This enables the shift of the equilibrium in the desired direction \) ivl consequently an increase dor yield.

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7 3 1 5 H 8

The process is further illustrated by the following examples.

example 1

1- (6 -Methoyy- '^ - quinolyl) -3- (3- vinyl- ^z ^ - N-butylpiperidyl)

A solution of 15 S 1- (6-methoxy-4-quinolyl) -3- (3-vinyl-4-piperidyl) -propanon-l in I50 ml of xylene is mixed with Jo g of n-butyl bromide and 22.1 g of triethylamine with stirring heated on the reflux condenser. After boiling for two hours the reaction is complete with the exclusion of light in an inert atmosphere. The triethylamine hydrobromide is filtered off and washed with 20 ml of xylene. The organic phase is extracted with a 1N hydrochloric acid solution. the The acidic aqueous phase is then made alkaline with 1N sodium hydroxide and extracted with benzene. The benzene phase is decanted, washed with water and dried over anhydrous sodium sulfate. the Benzene solution is subjected to column chromatography on 20 parts of aluminum oxide. The elution will be sequential carried out with benzene, a mixture of benzene and methylene chloride (50:50) and pure methylene chloride. That obtained oil (15 »2 g) is with oxalic acid, fumaric acid or ascorbic acid converted into the salt. The obtained salts have the following indicators:

1. Acid oxalate, melting point 158 ^° C

Elemental analysis: C_ H N

Calculated: 66.56 7.28 5.95

Found: 66.24 7.29 5.83

2. Acid fumarate, melting point

Elemental analysis: CH N

Calculated for C ₂₈ H ₅₆ N ₂ O ₆ : 67.72 7.31 5.64

Found: 67.67 7.42 5.72

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3. Ascorbate, melting point 62 ⁰ G

Elemental analysis, at G H 24 5 N Calculated: 64.73 7, 18th 5 , 03 Found: 64.69 7, , 12 game 2

2-propyl) -4-piperidyl7 ~ propanone-1

A solution of 3 »24 g of 1- (6-methox; 7-4-quinolyl) -3- (3-vinyl-4-piperidyl) propanone-1 in 50 ml of xylene is mixed with 1.5 E of 2-chloro i-dimethylaminoprcpan and 1.1 g of triethylamine heated on the reflux condenser with stirring. After three hours of boiling with the exclusion of light and under an inert atmosphere, the reaction has ended. The triethylamine hydrochloride is filtered off and the organic phase is extracted with an IN hydrochloric acid solution. The acidic aqueous phase is then made alkaline with 1N-lithium hydroxide and extracted with benzene. The benzene phase is decanted, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is taken up in isopropanol and acidified with gaseous hydrochloric acid. The precipitate is filtered off and recrystallized from a methanol-isopropanol gel. This gives 2.9 g of d & s hydrochloride with a melting point of 217 218 ⁰ G as a product »

Elemental analysis: GHN

Calculated for C ₂₅ EU ₇ N ₇ O ₂ Cl ₂ : 62.25 7.73 8.71 Found: 62.14 7.68 8.52

Example 3
1- (6-methoxy ~ 4-quinolyl) -3 ~ (3-vinyl-4-H-cinnamoyl-

piperidyl) propanone-1

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' _s "2315U8

A solution of 3.24 g of 1- (6-ethoxy-4-quinolyl) -3- (3-vinyl-4-piperidyl) -oropanone-.l in 25 inl methylene chloride is prepared. The solution is at room temperature with 10 ml of 2N NaOH were stirred. A solution of 1.7 g of cinnamoyl chloride in 25 ml of methylene chloride is then added. The reaction has ended after half an hour of stirring. The methylene chloride is decanted and washed with water and dried over magnesium sulfate. The solvent is evaporated to dryness to give 4.45 S (98%) of a pale yellow, amorphous, solid varnish.

Monochlorohydrate; The methylene chloride is concentrated to about 10 ml and mixed with 20 ml of dry ether. While stirring with a magnetic stirrer, 0.365 g of hydrochloric acid (5 ml of a 2N ether solution) are added to the solution while it is cooled to ^{0 ° C.} The product is precipitated immediately. The mixture is then stirred for a further 30 minutes. The precipitate is sucked off and rinsed with ether. 4.8 g (98%) of a yellow powder with a melting point of 105 to 110 ° C. are obtained.

Elemental analysis: C H N Cl

Calculated: 70.93 6.36 5.70 7.22

Found: 70.70 6.47 5.68 7.30

Infrared spectrum: bands at 1690 cm (Ar-CO-CH ₀ -) and

-1
1610 cm (conjugated amide)

Example 4

1- (6-Methoxy-4-quinoly l-3- _/ / 3-vinyi-ii- (3,4,5-trimethoxycinnamoyl) -4-piperidyl7_propanone-1 «

Production takes place in the manner described in Example 3 Manner using 3.24 g of 1- (6-methoxy-4-quinolyl) -3 ~ / 3-vinyl-4-piperidyl7 ~ propanone-1 and 2.6 g of 3,4,5-trimethoxycinnamoyl chloride. The! Response time is

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2 31514 3

1 hour. 5,1 · S residue (92} j) is obtained, which is crystallized in isopropanol. Melting point I ¹ I ^ C to

JtJl em en t ar an aly s e: C. H N Calculated: 70.57 6.65 5 14 Found: 70.32 6.73 5.06

Infrared spectrum: bands at 1690 a (Ar-GO-GH ^ -) and

1
1610 cm (conjugated amidj.

The hydrochloride is prepared in the same way as described in Example 3.

Example 5
l) - ;; - / 3-vin ^

4-piperidyl7-propanone-i

Production takes place in the manner described in Example 3 Manner using 11 g of 1- (6 - methoxy-4-quinolyl) -3- (3-vinyl-4-piparidyl) -propanoa-I and 6 g of p-chlorobenzoyl chloride. The response time is one Hour. A residue is obtained which, by recrystallization from 200 ml of ether, gives 11.9 S white crystals. The concentrated ether gives a second crop of 1.1 g. Yield 83%. Melting point 107.5-108 ° C.

Elemental Analysis: C H H Gl Calculated: 70.04 5.83 6, OS 7.67

Found: 69.98 5.90 6.11 7.67

—1 infrared spectrum: bands at 1690 cm ™ (Ar-OO-GH ₀ -) and

-1
160 cm "(conjugated amide,

The hydrochloride is prepared in the same way as described in Example 3.

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Example 6

1- (6-Methoxy-4- quinolyl) -3- / 3-vinyl-N (acetylsalicyloyl) -4-piperidyl-7-propanone-1

5 δ 1- (6-methoxy-4- ChInOIyI) -J- (J-ViIIyI- ^ piperidyl) -propanon-1 are dissolved in 50 ml of dry benzene. 1.6 g of triethylamine and then 3.2 g of acetylsalicyloyl chloride are added to the solution. The mixture is stirred for 2 hours with a magnetic stirrer at room temperature. The triethylamine hydrochloride formed is filtered off and the benzene is evaporated. 7.1 g (95 %) of a yellow foam which crystallizes in a cyclohexane-benzene mixture are obtained. Melting point 70 C.

Elemental analysis: 71 C. 6th H N Calculated: 71 , 59 6th , 16 5.75 Found: , 63 , 20 6.63

—1 1

Infrared spectrum: bands at 1770 cm (ester), 1690 cm "(Ar-GO-CH ₂ -) and 160 cm" * (conjugated amide).

The hydrochloride is obtained by adding the base to the Minimum amount of methylene chloride is dissolved and then added to ether.

In the manner described in Example 3, the yellow monochlorohydrate with a melting point of 111 ^° G is obtained by adding ethyl ether.

Example 7
1- (6-iuethoxy-4-quinolyl) -3- / 3-vinyl-N {2- (1-cinnamoyl- ^ i-piperazinyl) -eth:, l \ - ^ - piperidylj ⁷ -propanone-1

3.24 g of 1- (6-lethoxy-4-quinolyl) -3- (3-vinyl-4-piperidyl) -1-propanone were added to 50 ml of ethanol solved. Ί, 2 g of potassium carbonate and 2 g of sodium iodide are added to the solution. The mixture is stirred magnetically and refluxed

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B -

2 3 1 5 1 A 8

heated. Then 3.5 S 1-ginn a: aoy 1-4- ß-chloroäthylpiperaK.inhydrochlo.rid are added within 50 minutes. After 4 hours, the mixture is concentrated to the maximum. The residue is diluted with water and the aqueous phase is extracted with methylene chloride. The methylene chloride is decanted, dried over magnesium sulfate and evaporated to dryness. The remaining oil (55 g = 95 %) is taken up in 25 ml of ethanol. A solution of 2.5 g of oxalic acid in 25 ml of ethanol is then added. The pure moxalate crystallizes out immediately. 5.5 S white crystals are obtained.

The difumarate is obtained under similar conditions, It melts at 204 bis,
Hardly soluble in alcohols.

It melts at 204 to 205 ° C and is in water as well

G 12th H 9 N 94.00 9 , 90 74, · 7.52 , 96

Elemental analysis of the base;
Calculated:
Found:

Infrared spectrum: bands at 1690 cm "^ Ar-OO-GH -, -) and

—1 * ~

1610 cm "(conjugated amide),

Beis'ciei. 3
1- (6-methoxy-4-quinolyl) -3 - ^? - vinyl-IT- {2- (1-cinnamyl-

4-piperazinyl) -2-ethyl) 4-pipar-idyly-propanone-1

The preparation is carried out using the method described in Figure 7 using 3} 24 g of 1- (6-L-ietlioxy-4-quino.lyl) -5- (5-vinyl-4-piperiayi; - ; ": r'Cpanoii-1 and 3.7 Si-cinnamyl-4-ß-chloroätbylpiperasindihydrochlorid. This gives 5.4 g of a crude oil (98% ) , which is taken up in 100 ml of methanol» To the solution a mixture of 3, Sg oxalic acid is added to ICO 211 Methanoi the Trioxalat is precipitated and from V ater containing 1% oxalic acid, recrystallized / the released by Hatriimhydroxyd Q: -:.. slr.t yields 1.87 g of wascer -

3 0 9 8 4 2/1215

free purified base (34%).

Tetrahydrochloride: The purified base is taken up in ethanol. A saturated hydrochloric acid solution in ethanol is added ^{at 0} ° C. while stirring with the magnetic stirrer.

Trioxalate: melting point 219 ° C (decomp.) Tetrahydrochloride: melting point 227.5 to 228.5 ° C

Elemental analysis of base: C, H, N Calculated: 76.05 8.02 1.01

Found: 75.98 8.00 1.07

-1 Infrared spectrum of the hydrochloride: band at 1700 cm (Ar-CO-CH ₂ -).

Example 9

1- (6-Methoxy-4-quinolyl) -3-Z3-vinyl-N- {2- (3 ·, 4 ·, 5'-triraethoxy-1-cinnamoyl-4-piperazinyl) ethyl} 4-piperidyl7-propanone-1

4.5 g of 1- (6-methoxy-4-quinol3 ^r l) -3- (3-vinyl-4-piperidyl) -propanon-1-hemioxalate are dissolved in 50 ml of ethanol containing 0.4 g of NaOH . 1.4 g of KpCCU and 5 g of NaI are added to the solution. The mixture is brought to the boil, whereupon a suspension of 4.5 β 3 ', 4', 5'-trimethoxy-1-cinnarnoyl-4-ß-chloroethylpiperazine in 50 ml of ethanol containing 0.45 g of NaOH in J. > 0 minutes is added dropwise. The mixture is then refluxed for a further 5 hours. The mixture is worked up in the manner described in Example 7. 6.5 S of crude Ba3o (99%) are obtained, which is converted with 3.8 g of oxalic acid in ethanol into 8.8 g of de3 trioxalate, which is recrystallized from water containing 1% of oxalic acid.

The hydrochloride is based on that described in Example 6

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S ■> ID h

Way made. Ks has a melting point of 130 ^ i 140 ⁰ C and becomes amorphous in the process.

Elemental analysis of the base: CH IT Calculated: 69.4-9 7.55 8.52

Found: 69.40 7.41 8.58

—1 Infrared spectrum: bands at 1690 era "(Ar-CO-CiI ₀ -) and

-1
1590 cm (conjugated amide).

Example 10

1- (6-Methoxy-4-quinolyl) ~ 3- / 3-vinyl-ii (2-methylpholinoethyl) -4-piperidyl7-propanor ₁ ~ l

15.48 g of 1- (6-methoxy-4-quinolyl) · ■ j5- (3-vinyl-4-piperidyl) preparation are dissolved in 140 ml of ethanol. 13.40 g of potassium carbonate and 8 g of sodium iodide are added to the solution. The mixture is stirred with the megometer stirrer and heated on the reflux condenser. A solution of 8.182 g of 2-i.iorpholino-1-chloroethane in 15Ο ml of ethanol is added dropwise within one hour. The mixture is then refluxed for a further 2.5 hours. The product is concentrated to the maximum and diluted with water. The aqueous phase is extracted with benzene. The decanted organic phase is dried over magnesium sulfate. The together gege Berten first ViEX "yields (11.4 g = 76%) be converted to the 4'beschriebene in example with hydrochloric acid in the H.ydrochloricl having a melting point of ⁰ to 140 G 1J0 has UNAE this is amorphous.

Elemental analysis of the basses: G K K Calculate t: 71.56 8.52 9.83

Found: 71.44 8.50 9.90

Infrared spectrum: band at 1690 cu ~ ^ (Ar-CO-OHp).

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2 3 1 5 H 8

The Quinolj.nderivate according to the invention have valuable pharmacological properties. You have an influence on the arterial flow rate by an antispasmodic Effects of the papaverine type and can act as vasodilators in affections of the peripheral vessels, in embolism and thrombosis and mainly to guarantee good cerebral circulation. Attempts have a predominant effect on give the flow rate of the vertebral artery.

The doses of active ingredient in vivo are in the range from 1 to 2 mg / kg for an increase in the arterial flow rate of 15 to 20 %. The DL _cn (intravenous) is between 25 and 40 mg / kg. This corresponds to a very favorable therapeutic index.

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Claims (7)

Claims in which R stands for a linear or branched A] ky] radical which contains 2 to 6 carbon atoms and can contain a radical of the form] -NR ¹ R ", where R 'and R" are separately for alkyl radicals with 3 to 4 C atoms or, together with the nitrogen atom to which they are attached, form a five- to seven-g] lower heterocycle which can contain an oxygen atom or a nitrogen atom as the second hetero atom, the latter nitrogen atom itself being a phenyl alkenyl radical or phenyl alkenyl ] carbony] radical, whose alkenyl radical contains 1 to 6 carbon atoms and whose phenyl component can contain methoxy radicals, or for a phenyl alkeny] carbonyl radical which contains 1 to 6 carbon atoms in the alkenyl part and methoxy radicals on the phenyl nucleus may contain, or a benzoyl radical, which may contain a halogen atom or a methoxycarbony] radical on the ring, and non-toxic acid addition salts of these quinoline derivatives. 2) Process for the production of quinoline derivatives according to claim 1, characterized in that compounds of the general formula 0 - CH ₂ - CH ₂ ~ A NH CH = CH 309842/1215 2315H8 in an organic solvent] with a ha] ogenated Derivative of the form] RX, in which X is a halogen atom and R has the abovementioned meaning, in the presence of an acid acceptor implements. 3) Method according to claim 2, characterized in that that the reaction is carried out by heating on the reflux cooler will. 4). Method according to claims 2 and 3 »characterized in that that the reaction is carried out under an inert atmosphere. 5) Process according to Claims 2 to 4, characterized in that a3s acid acceptor is an alkali metal carbonate, in particular Potassium carbonate is used. · 6) Process according to Claims 2 to 4, characterized in that a3s acid acceptor is a tertiary amine, in particular Triethylamine is used. 7) Medicines] Preparations with, in particular, antispasmotic and vasodilatory action, characterized by a content of a compound according to claim ] as an active ingredient. 309842/1215