CH625800A5 - Process for the preparation of derivatives of quinoline - Google Patents

Description

The present invention relates to a process for the preparation of quinoline derivatives. useful especially for the treatment of pathological conditions caused by a disturbance in the functioning of serotonergic systems. In particular, these compounds can find applications as psychotropic drugs. more particularly as antidepressants and as sleep regulators. They present, on the other hand, interesting activities on the cardiovascular sphere and can be used as such more particularly as a medicament.

wherein R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, X represents a hydrogen atom, an alkyl, alkoxy or alkylthio group, each of these groups possibly containing 2 to 1 to 4 carbon atoms, or alternatively a halogen atom (chlorine, fluorine, bromine or iodine), a trifluoromethyl, nitro, hydroxy or amino group, the latter being substituted or not by one or two alkyl groups, via an acyl or alkylsulfonyl group, each of these groups possibly comprising from 1 to 4 carbon atoms.

The process according to the invention for the preparation of quinoline derivatives of formula (I) is characterized in the preceding claim 1.

For this reduction, can we use as a reducing agent? " hydrazine hydrate in the presence of an alkali metal hydroxide such as sodium hydroxide, in a solvent such as an alcohol.

A variant for the preparation of the products of general formula (I) in which R represents an alkyl group consists in catalytically hydrogenating the corresponding products of formula (I) in which R represents an alkenyl group. This hydrogenation can, for example, be carried out at room temperature, under a hydrogen pressure equal to atmospheric pressure, in an inert solvent such as an alcohol (for example methanol or ethanol) or an acid. (for example acetic acid), in the presence of a catalyst such as palladium, nickel, rhodium, ruthenium or platinum.

Once the reaction is complete, the reaction mixture obtained in the above processes is treated according to conventional, physical methods (evaporation, solvent extraction, distillation, crystallization, chromatography, etc.) or chemical (salt formation and regeneration of the base, etc.) in order to isolate the product of formula (I) in the pure state, either in the form of the free base, or in the form of a salt of this with an acid.

The compounds of formula (I) in the form of the free base can be converted into addition salts with a mineral or organic acid by the action of such an acid in an appropriate solvent.

A number of products of formula (II) are already known. Thus, the product of formula (II), in which R and X are hydrogen atoms, was prepared by P. Rabe ["Ber.", 55, 532 "(1922)] by condensation of the ethyl ester quinolinecarboxylic acid-4 of formula (III) with the ethyl ester of 'i- (N-benzoylpiperidyl-4) propionic acid of formula (IV) and hydrolysis of the' i-ketoester of formula (V) obtained , according to the following reaction scheme:

fit)

<Next pay formulas)

This method was subsequently applied, in principle, to the preparation of products of formula (II) in which -5 R = CH = CH; or C, H <. with X = H. OH. OCH "CF" alkyl or halogen (cf. US Pat. Nos. 3753992, 3857846, 3869461) and it can be extended to the synthesis of all the derivatives of formula (II). It suffices for this to replace in reaction a) set out above the ester

at)

COOC H CH_-CH -COOC H 2 5 i 2 2 2 5

+

Co-c base, h_

O D

co-çh-ch2

ooc2h5

625800

n-co-c6h5

~ \

NOT-

y

+ C2H5OH

(III)

(IV)

(v)

b) (V) + 2 H20

Acid>

co-ch2-ch2

N-H

+ co „+ c„ hcoh + c, h cooh 2 2 5 6 5

of formula (III) with an ester of general formula (VI), in which X has the same meanings as in formula (I), and the ester of formula (IV) with an ester of general formula (VII), in which R has the same meanings as in formula (I):

OOC2H5

ch2-ch2 "cooc2h5

(VI)

(VII)

The implementation of type a) condensation reactions and type b) hydrolysis reactions calls for methods known per se [(cf. respectively: "The acetoacetic acid ester condensation", CR Hauser et al., "Organic Reactions", vol. 1, p. 266 (Wiley & Sons, 1942) and "Cleavage of ß-keto-esters", RB Wagner and HD Zook, "Synthetic Organic Chemistry", p. 327 (Wiley & Sons, 1953)].

In the particular case where R = CH = CH2 or C2H5 with X = H or OCH3 in position 6, the starting materials of formula (II) can be advantageously prepared by rearrangement in acid medium of the major quinine alkaloids and the corresponding hydrobases or their stereoisomers [(cf. SW Pelletier, “Chemistry of the Alkaloids”, p. 313 (Reinhold, 1969)]. Thus laquinicin (compound of formula (II) in which R = CH = CH, and X = OCH3 in position 6) is obtained from quinine or quinidine and cinchonicin (compound of formula (II) in which R = CH = CH, and X = H) is obtained from cinchonine or cinchonidine.

A number of compounds of formula (I) are already known. These known compounds correspond to the cases R = H, C2H5, CH = CH, with X = H and R = C2H5 or CH = CH, with X = OCH3 in position 6 [cf. V. Prelog et al., "Berichte der deutschen chemischen Gesellschaft", 72B, 1325-1333 (1939); S.P. Popli and M.L. Dhar, “J. Sci. Ind. Res. Sect. ”, C 19,298-302 (1960)]. But none of these compounds has been proposed to date as a drug, although

° -C6H5

45 that the compound corresponding to R = CH = CH, with X = OCH3 in position 6, was found to have an amoebicidal activity in experimental amoebiasis in rats (cf. Popli and Dhar already cited).

The following examples illustrate the invention without limiting it. Example 1:

50 [(6-Methoxy-4-quinolyl) -3propyl-1] -4 (R) vinyl-3 (R) piperidine

To a suspension of 48 g of quinicine in 200 ml of diethylene glycol and 23 g of an 85% aqueous solution of hydrazine hydrate, 18 g of sodium hydroxide in pellets are added. It is heated slowly and, when 110 C is reached, the medium is homogeneous. Then heated for 1 h at 130 C, then for 2 h at 150 C, until cessation of nitrogen evolution. The reaction medium is thrown into 1 1 of ice water. An oil released, which is extracted with 500 ml of ether. The organic phase is decanted, washed, dried over magnesum sulfate, then evaporated. An oil is obtained which is treated, in isopropanol medium (150 ml), with hydrochloric acid. This gives 20.5 g of [(6-methoxy-quinolyl-4) -3 propyl-1] -4 (R) vinyl-3 (R) piperidine dihydrochloride, which melts at 175-180 C.

Analysis for C20H2 (, N20.2 HCl Calculated: C62.8 H 7.31 N7.31 Found: C 62.5 H 7.21 N 7.45

625800

4

Example 2:

[l Quinolyl-41-3propyl-I] -4 (R) vinyl-3 (R) piperidine

By operating as in Example 1, but starting from cinchonicin, the [(quinolyl-4) -3 propyl-1] -4 (R) vinyl-3 (R) piperidine is obtained in the form of its dihydrochloride which background at 189-191 C.

Analysis for C, „H, 4N ,, 2 HCl Calculated: C 64.55 H 7.37 N 7.94 Found: C 64 H 7.34 N 7.63

Example 3:

[f 6-methoxy-4-quinolyl-3-propyl-1] -4 (R) ethyl-3 (R)

piperidine

A well stirred suspension containing 5.5 g of [(methoxy-6-quinolyl-4) -3 propyl-1] -4 (R) vinyl-3 (R) piperidine dihydrochloride dissolved in 100 ml of absolute ethanol and 1.5 g of palladium-on-carbon at 10% palladium is maintained at room temperature under a hydrogen pressure corresponding to an overpressure of 50 mm of water relative to atmospheric pressure until absorption of the gas has ceased .

The palladium is then separated by filtration, then the alcoholic solution is concentrated. 5.5 g of a crude product are obtained which, after recrystallization from 20 ml of a 1/1 mixture of ethanol and isopropyl ether, provides 4.4 g of [(6-methoxy-4-quinolyl) - 3 propyl-1] -4 (R) ethyl-3 (S) piperidine in the form of dihydrochloride melting at 200 C.

Analysis for C20H28N2O, 2 HCl Calculated: C 62.3 H 7.8 N 7.28 Found: C 62.05 H 8.04 N7.10

Example 4:

/ / Quinolyl-4) -3 propyl-1 J-4 piperidine

A solution of 24 g of (quinolyl-4) -1 (piperidyl-4) -3 propanone-1 (prepared according to the method of P. Rabe, "Ber.", 55, 532, 1922), 85 ml of diethylene glycol and 13.5 g of an 85% aqueous solution of hydrazine hydrate for 1 h at 130 C. To the homogeneous solution obtained, 31 g of potassium hydroxide in pellets are added in portions, then heated for 4 h at 140 C until cessation of gas evolution. The reaction medium is thrown into 500 ml of ice water, then extracted with 3 times 100 ml of chloroform. The organic phase is decanted, washed, dried over potassium carbonate, then evaporated. 23 g of crude product are obtained which are treated with hydrochloric acid in an isopropanol medium so as to form the dihydrochloride. The latter, after recrystallization from a 1/1 ethanol / ether mixture, melts at 170 C.

Analysis for C17H22N2, 2HC1 Calculated: C 62.8 H 7.35 N 8.57 Found: C61.8 H 7.45 N 8.46

Example 5:

1tQuinolyl-4) -3propyl-1] -4 (R) ethyl-3 (R) piperidine

A suspension of 40 g of [(quinolyI-4) -3 propyl-1] -4 (R) vinyl-3 (R) piperidine. 300 ml of ethanol, 30 ml of 37% hydrochloric acid and 15 g of palladium-on-carbon at 10% palladium, vigorously stirred, are brought into contact with a hydrogen atmosphere at 20 ° C. and at atmospheric pressure. The absorption of hydrogen is very rapid and stabilizes, after 1 hour, at 2400 ml of hydrogen. The solution is separated from the carbon by filtration, then concentrated to dryness. The residue is taken up in 20 ml of water, basified with 35 ml of a 10N solution of sodium hydroxide.

Extraction is carried out with 200 ml of chloroform. The organic phase is dried over potassium carbonate, filtered, then concentrated. The residue is treated with fumaric acid in ethanolic solution.

20 g of [(quinolyl-4) -3 propyl-1] -4 (R) ethyl-3 (S) piperidine fumarate are obtained, melting at 143 C.

Analysis for 2 C19H2eiN2, 3 C4H404 Calculated: C65.7 H 7.02 N6.13 Found: C 65.28 H 7.14 N 6.47

Example 6:

[(Butyl-6 quinolyl-4J-3 propyl-1] -4piperidine By operating as for Example 1, but starting from (butyl-6 quinolyI-4) -l (piperidyl-4) -3 propanone-1, prepared according to the method of P. Rabe [“Ber.”, 55, 532 (1922)], we obtain [(butyl-6 quinolyl-4) -3 propyl-1] -4 piperidine, the fumarate of which melts at 140 ° C.

NMR spectrum: - CH2 - N: 2 to 3 ppm

- CH2 — CH2: 0.5 to 1.6 ppm

Pharmacological properties:

1. Action of the products on the reuptake of serotonin:

It is known that the currently known antidepressant products have the property of inhibiting the reuptake of cerebral monoamines.

The antidepressant activity of the products according to the invention has therefore been demonstrated, in vitro, using the test for inhibition of the reuptake of cerebral monoamines (serotonin in particular) by rat brain synaptosomes, according to the method of Kannengiesser et al. ("Biochem. Pharmacol.", 22, Ti, 1973).

The results, expressed by a 50% inhibitory dose (I50) which represents the dose of product in micromoles per liter decreasing by 50% the reuptake of serotonin, are collated in the following table:

Product

I50 (fj.mol / 1)

Example 1 Example 2 Example 3

0.004 0.035 0.008

It can be seen that the products according to the invention are powerful inhibitors of serotonin reuptake.

2. Effect and potentiator of 5-HTP:

The effectiveness of the compounds of the present invention in blocking the reuptake of serotonin has also been demonstrated using the 5-hydroxytryptophan (5-HTP) potentiation test.

The products of the invention have the interesting property of potentiating (that is to say of strengthening) very strongly the effects of 5-HTP, agent precursor of serotonin.

This property has been demonstrated in vivo in male CD mice (Charles River) using the technique described below.

It is known that the administration of 5-HTP by the parenteral route in mice leads, at high doses, to a characteristic behavior: tremors, torsions of the trunk, movements of the hind legs, shaking of the head and increased general motility. To highlight a potentiating power with respect to 5-HTP, we therefore took advantage of one of the characteristic properties of the precursor of serotonin: tremors.

The protocol used is inspired by that of C. Gouret ("J. Pharmacol." (Paris), 5, 453, 1975).

Groups of eight male mice are used. For the groups to which both 5-HTP and the products according to the invention are administered, the chronology of the test is as follows:

At time t = 0, 150 mg / kg of 5-HTP is injected intraperitoneally (PI) in the form of a 9% o NaCl aqueous solution.

At time t = 30 min, the product to be tested is injected subcutaneously (SC) in the form of an aqueous solution containing 9% o NaCl.

At time t = 75 min, the tremor is measured for each animal, using the following quotation:

0 = no tremor

1 = medium intensity tremors

2 = intense tremors

5

10

15

20

25

30

35

40

45

50

55

60

65

5

625800

For the 5-HTP control and product control groups, the chronology is the same, except that, in the first case, an SC 9% o NaCl aqueous solution is injected instead of the product solution and, in the second case, a 9% aqueous solution of NaCl is injected by IP route instead of the 5-HTP solution.

The product control groups receive the same doses of product studied as the groups to which both 5-HTP and the product are administered, in order to search for a possible specific effect of the product.

For each group, the number of points is totaled and the average tremor index is determined. From there, we define, for each product tested, an ED50 which is the dose of product in mg / kg for which we obtain 50% of the maximum possible effect, i.e. an average tremor index equal to 1.

The results obtained are collated in the following table:

5-HTP dose

Product tested

DES0 (mg / kg) SC

150 150

Example 1 Example 2

14 12

At a dose of 25 mg / kg, the products of Examples 1 and 2 show no specific effect (that is to say no effect in the absence of 5-HTP).

The compounds of the invention are therefore potent potentiators of 5-HTP. These activities are consistent with the remarkable inhibitory effects of serotonin reuptake observed on rat synaptosomes.

3. Antiarrhythmic activity

The antiarrhythmic activity of the compounds of the present invention has been demonstrated using the aconitine test in rats.

The principle of the technique is based on the induction time of ventricular arrhythmias caused by aconitine in slow infusion in rats. An antiarrhythmic substance delays the onset of arrhythmias, and this delay is proportional to the activity of the molecule.

Groups of five male rats are used. Individual anesthesia is performed (10% urethane: 1 g / kg intraperitoneally) to allow catheterization of the penile vein. The electrocardiogram is recorded.

At time t = 0, the substance studied is injected in the form of an aqueous solution, at the rate of 2.5 ml solution / kg in 30 s. At time t = 90 s, ie 1 min after the end of the injection, the aconitine is perfused at a rate of 20 [ig / l / min, until the appearance of supraventricular extrasystoles. The aconitine infusion time is noted.

The results are expressed in ED50, dose in mg / kg which, compared to the control animals, increases the infusion time of aconitine by 50%.

The results obtained are collated in the following table, where the activity (DES0), the toxicity (DLS0) and the therapeutic coefficient are expressed -

Products

LD50 (IV)

DE50 (IV)

DLS0 DE50

Example 1

30

2

15

Example 2

30

12

2.5

Example 3

21

0.7

30

Example 4

42

15

2.8

Example 5

22

2.3

9.6

Quinidine

70

7.5

9.3

Diisopyramide

26

4

6.5

The products of the invention are therefore powerful antiarrhythmics. In particular, the products of Examples 1, 3 and 5 are not only more active than the reference products (quinidine and diisopyramide), but also have a higher therapeutic coefficient than quinidine and diisopyramide.

4. Potentiation of serotonin-induced sleep

The role of cerebral serotonin in sleep is a well established fact (M. Jouvet et al., "C.R. Acad. Se. Paris", 1967, 264, 360).

Administration of serotonin to adult animals does not make it possible to observe the hypnogenic effects of this mediator, since serotonin does not cross the blood-brain barrier. On the other hand, since the chick does not have such a barrier, it is possible to inject it serotonin IV and to measure its central effects.

Groups of 12 chicks are used and IV serotonin is administered at a dose of 0.1 mg / kg. It is observed, under these conditions, that 25% of the chicks are asleep.

If, by the IV route, serotonin is administered at the dose of 0.1 mg / kg and one of the products of the invention at variable doses, it is found that a proportion much greater than 25% of the chicks is asleep.

By way of example, using the product of Example 1 at a dose of 3 mg / kg, it is found that 60% of the chicks are asleep.

The products of the invention therefore potentiate the hypnogenic effects of serotonin.

5. Vascular action

The potentiation of the vascular effects of serotonin has been demonstrated according to the protocol of JJ Loux ("Arch. Int. Pharma-codyn. Therap.", 1970,183,98) modified by BB Vargaftig ("Eur. J. Pharmacol." , 1974, 25, 216), which consists in injecting into the carotid artery of an anesthetized dog increasing and cumulative doses of serotonin. From 0.20 mg / kg. an increase in the overall volume of the sinus is observed, reflecting vasoconstriction of the nasal mucosa. This increase in volume is measured by connecting the nasal sinus, hermetically isolated from the outside, with a pressure sensor.

The products of the invention do not exhibit any specific vasoconstrictor effect in this technique, but strongly potentiate the effect of serotonin. By way of example, the product of Example 1, at a dose of 1 mg / kg by IV route, potentiates the vascular effect of 0.05 (ig / kg of serotonin: the reduction in pressure recorded by the sensor is multiplied by 2.

This activity of the products of the invention can be used for the treatment of migraine (F. Sicuteri et al., "Psychopharmacolo-gia", 1973, 29, 347).

Toxicological properties

The acute toxicities and symptomatologies of the compounds according to the invention were determined in the male CD mouse (Charles River) by the IV and oral routes. The LD50s were calculated, after 3 days of observation, by the cumulative method of J.J. Reed and H. Muench ("Amer. J. Hyg.", 27,493, 1938).

The symptoms observed at toxic and subtoxic doses are similar for the three products and for the two routes of administration used. They mainly consist of tail catatonia, tremors, respiratory depression and clonic convulsions.

The DL, 0 obtained are collated in the following table:

Products

Acute toxicity in mice

DLS0 (mg / kg)

IV

per os

Example 1

30

600

Example 2

30

525

Example 3

21

600

Example 4

42

600

Example 5

22

600

5

10

15

20

25

30

35

40

45

5 "

55

60

65

625800

6

The compounds therefore behave as relatively non-toxic substances in mice.

Therapeutic use

The medicaments according to the invention can be used in human therapy in the form of tablets, capsules, capsules, suppositories, ingestible or injectable solutions, etc., for the treatment of pathological conditions caused by a disturbance in the functioning of the serotonergic systems, in particular disorders psychic with a depressive component, as sleep regulating drugs, as antiarrhythmic drugs and as regulators of vasoconstriction of blood vessels.

5 The dosage depends on the effects sought and the route of administration used. For example, orally, it can be between 5 and 250 mg of active substance per day, with unit doses ranging from 1 to 50 mg.

R

Claims (6)

625,800 CLAIMS 1. Process for the preparation of quinoline derivatives of formula (I) CH0-CH -CH 2 2 2 antiarrhythmic elements and as regulators of vasoconstriction of blood vessels, in particular for the treatment of migraine conditions. The compounds obtained by the process correspond to formula (I): wherein R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, X represents a hydrogen atom, an alkyl, alkoxy or alkylthio group, each of these groups possibly comprising from 1 to 4 carbon atoms, or alternatively a halogen atom, a trifluoromethyl group. nitro, hydroxy or amino, the latter being substituted or not by one or two alkyl groups, by an acyl or alkylsulfonyl group, each of these groups being able to contain from 1 to 4 carbon atoms, characterized in that the group is reduced carbonyl of the compounds of formula: ch2-ch2-ch2 n-h co-ch2-ch2 N-H (ii) in which X and R have the same meanings as in formula (I). 2. Method according to claim I, characterized in that X is chlorine, fluorine, bromine or iodine. 3. Method according to claim 1, characterized in that the reduction of the compounds of formula (II) is carried out by means of hydrazine hydrate in the presence of an alkali metal hydroxide such as sodium hydroxide, at within a solvent such as an alcohol 4. Quinoline derivatives of formula (I), prepared by the process according to claim 1. 5. Use of the quinoline derivatives of formula (I) according to claim 4, for which R represents an alkenyl group, to obtain by catalytic hydrogenation - the corresponding compounds of formula (I) for which R represents an alkyl group. 6. Use according to claim 5, characterized in that the catalytic hydrogenation of the compounds with R = alkenyl is carried out at ambient temperature, under a hydrogen pressure equal to atmospheric pressure, in an inert solvent such as an alcohol such as methanol or ethanol or an acid such as acetic acid, in the presence of a catalyst such as palladium, nickel, rhodium, ruthenium or platinum.