JPS6134404B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is a new drug based on quinoline derivatives,
Especially the serotoninergic system (serotoninergic system)
Relates to drugs effective in the treatment of pathological conditions due to dysfunction of systems. Such drugs can be used in particular as psychotic drugs (more particularly antidepressants) and as sleep regularizing drugs. They also have interesting activities on the cardiovascular system and can be used in this respect, in particular as antiarrhythmics and vasoconstrictor modifiers, in particular in the treatment of migraine headaches. This medicine has as an active ingredient a compound represented by the following general formula or a salt thereof with a pharmaceutically acceptable acid. In the formula, R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms, and X represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms. Awarashi, provided that when R is other than a hydrogen atom, the carbon atom and group of the piperidine ring carrying the R group Both carbon atoms of the piperidine ring have the R configuration. Compounds of general formula () can be prepared by reduction of the products of (). In the formula, X and R have the same meaning as in the formula (). This reduction can be carried out using methods known per se that are capable of converting CO groups into CH ₂ groups, such as RBWagner
and HDZook (Synthetic Organic Chemistry, p. 5, J.
Wiley & Sons, 1953). Hydrazine hydrate may be used as the reducing agent in a solvent (eg alcohol) in the presence of an alkali metal hydroxide (eg sodium hydroxide). A variant of the process for preparing products of the general formula () in which R is an alkyl group consists in catalytic reduction of the corresponding products of the formula () in which R is an alkenyl group. This reduction may be carried out, for example, on a catalyst (such as palladium, nickel, rhodium, ruthenium or platinum) in a solvent (such as an alcohol (such as methanol or ethanol) or an acid (such as acetic acid)) at ambient temperature and under hydrogen pressure equal to atmospheric pressure. It can be carried out in the presence of Once the reaction has stopped, the reaction mixture obtained in the above procedure is immediately treated using conventional physical methods (evaporation, extraction with solvents, distillation, crystallization, chromatography, etc.) or conventional chemical methods (salt formation and base formation). By processing the expression ()
The product is isolated in pure form in the form of the free base or a salt of this free base with an acid. A compound of formula () in free base form can be converted into an addition salt with a mineral or organic acid in a suitable solvent. Several products of formula () are known. For example, the product of formula () where R and
According to the reaction scheme below, the ethyl ester of quinoline 4-carboxylic acid of the formula () and the formula ()
was prepared by condensation of β-(N-benzoyl-4-piperidyl)propionic acid with ethyl ester and hydrolysis of the resulting β-ketoester of formula (). (a) (b) This method was later developed in principle when R is CH=CH ₂ or C ₂ H ₅ and X is H, OH, OCH ₃ , CF ₃ ,
used in the preparation of products of formula () that are alkyl or halogen (U.S. Pat. No. 3,753,992;
3857846, 3869461), and can be extended to the synthesis of all derivatives of formula (). Instead of this, in the reaction (a) above, the ester of formula () is replaced by the general formula () where X has the same meaning as formula ().
and replace the ester of formula () with the general formula () where R has the same meaning as formula ().
It may be replaced with an ester. The condensation reaction (a) and the hydrolysis reaction (b) are carried out using methods known per se [Acetoacetate condensation, CR Hauser et al., Organic Reactions, Vol.
Vol. 266 (Wiley & Sons, 1942) and Cleavage of β-Ketoesters, R.B. Wagner and H.
D. Zook, Synthetic Organic Chemistry, 327 pages (Wiley &
Sons, 1953). R is CH=CH ₂ or C ₂ H ₅ and X is H at the 6th position
or _OCH3 , in particular, the starting product of formula () can be advantageously prepared by rearranging the main cinchona alkaloid with the corresponding hydroxyl group or its stereoisomer in an acid medium [SW
Pelletier, Chemistry of Alkaloids, p. 313 (Reinhold, 1969)]. For example _, quinisine [a compound of _formula () where R is CH=CH ₂ and A compound of formula ()] is obtained from cinchonine or cinchonidine. Some of the compounds of formula () are known. These known compounds include R is H, C ₂ H ₅ ,
CH=CH ₂ , X or H, and R
or C ₂ H ₅ or CH=CH ₂ and X is in the 6th position
Corresponding to that which is OCH ₃ [V. Prelog et al.
Berichte der deutschen chemischen
Gesellschaft 72B, pp. 1325-1333, (1939);
SPPopli and MLDhar, J.Sci.Ind.Res.Sect
C19, pp. 298-302 (1960)]. However, in any of such known compounds, R is CH
= CH ₂ and X is OCH ₃ at position 6, although it shows antiamoebic activity against experimental amebiasis in rats (see Popli and Dhar above), to date it has not been described as a drug. It has not been. The following examples are illustrative of the invention and do not limit it. Example 1 4(R)-[3-(6-methoxyquinolyl-4)
Propyl-1]3(R)-vinylpiperidine 18 g of sodium hydroxide in pellet form are added to a suspension of 48 g of quinicine in 200 ml of diethylene glycol and 23 g of an 85% aqueous hydrazine hydrate solution. Heat gradually until the temperature reaches 110
Once the temperature is reached, the medium becomes homogeneous. Next, heat at 130℃ for 1 hour, and then until the nitrogen evolution stops.
Heat at 150°C for 2 hours. The reaction medium is placed in 1 part of ice-cold water. The oil will release salt, so extract it with 500 ml of ether. Decant the organic, wash, dry over magnesium sulphate and evaporate. The oil obtained is treated with hydrochloric acid in isopropanol medium (150 ml). Thus, it melts at 175-180℃,
20.5 g of 4(R)-[3-(6-methoxyquinolyl-4)propyl-1]3(R)-vinylpiperidine dichlorohydrate are obtained. Analysis of C ₂₀ H ₂₆ N ₂ O・2HCl Calculated value C=62.8 H=7.31 N=7.31 Measured value C=62.5 H=7.21 N=7.45 Example 2 4(R)-[3-(quinolyl-4)propyl-
1] 3(R) Vinylpiperidine By carrying out the procedure of Example 1 starting from cinchonacin, 4(R) melting at 189-191°C
-[3-quinolyl-4)propyl-1]3(R)-
Vinylpiperidine is obtained in the form of its dichlorohydrate. C ₁₉ H ₂₄ N Analysis of ₂・2HCl Calculated value C=64.55 H=7.37 N=7.94 Measured value C=64 H=7.34 N=7.63 Example 3 4(R)-[3-(6-methoxyquinolyl-4 )
Propyl-1]3(R)ethylpiperidine 5.5 g of 4(R)-[3-
(6-methoxyquinolyl-4)propyl-1]3
A well-stirred suspension containing (R)-vinylpiperidine chlorohydrate is kept at ambient temperature under a hydrogen pressure corresponding to a 50 mm hydraulic excess compared to atmospheric pressure until no more gas is absorbed. The palladium is then separated and the alcoholic solution is concentrated. 5.5 g of crude product is obtained which is recrystallized from 20 ml of a 1/1 mixture of ethanol and isopropyl ether to give 4.4 g of 4(R)-[3-(6-methoxy) which melts at 200°C. Quinolyl-4)propyl-1]3(R)ethylpiperidine is obtained in the form of its dichlorohydrate. Analysis of C ₂₀ H ₂₈ N ₂ O・2HCl Calculated value C=62.3 H=7.8 N=7.28 Measured value C=62.05 H=8.04 N=7.10 Example 4 4-[3-(quinolyl-4)propyl-1]piperidine 24 g of 1-(4-quinolyl)-3-(4-piperidyl)-1-propanone (method of Rabe, Ber.
55, p. 532, 1922), 85 ml of diethylene glycol and 13.5 g of an 85% aqueous solution of hydrazine hydrate is heated to 130° C. for 1 hour. 31 g of potassium hydroxide in the form of pellets are added in portions to obtain a homogeneous solution, which is then heated at 140 DEG C. for 4 hours until no evolution of gas occurs. The reaction medium is placed in 500 ml of ice-cold water and extracted three times with 100 ml of chloroform. The organic phase is decanted, washed, dried over potassium carbonate and evaporated. 23 g of crude product are obtained which is treated with hydrochloric acid in isopropanol medium to form the dichlorohydrate. The latter substance dissolves at 170° C. after recrystallization from a 1/1 mixture of ethanol and ether. C ₁₇ H ₂₂ N Analysis of ₂・2HCl Calculated value C=62.8 H=7.35 N=8.57 Measured value C=61.8 H=7.45 N=8.46 Example 5 4(R)-[3-(quinolyl-4)propyl-
1] 3(R)-Ethylpiperidine 40g of 4(R)-[3-(quinolyl-4)propyl-1]3(R)-vinylpiperidine, 300ml of ethanol, 30ml of 37% hydrochloric acid and 15g of 10% A well-stirred suspension containing palladium-carbon is
Contact with hydrogen at 20°C and atmospheric pressure. Hydrogen absorption is very rapid, reaching 2400 ml within 1 hour and remaining constant at this value thereafter. The solution is separated from the palladium-carbon by filtration and then evaporated to dryness. The residue is taken up in 20 ml of water and made alkaline with 35 ml of a 10N solution of sodium hydroxide. Extract this medium with 200 ml of chloroform. The organic phase is dried over potassium carbonate, filtered and evaporated. The residue is treated with fumaric acid in ethanol medium. 20 g of 4(R)- thus melting at 143°C
[3-(quinolyl-4)propyl-1]3(R)-
Ethylpiperidine fumarate is obtained. Analysis of 2C ₁₉ H ₂₆ N ₂・3C ₄ H ₄ O ₄ Calculated value C=65.7 H7.02 N=6.13 Measured value C=65.28 H=7.14 N=6.47 Example 6 4-[3(6-Butylquinolyl-4) Propyl-1]piperidine 1-(6-butylquinolyl-4)-3-(piperidyl-4)-1-propanone (P. Rabe, Ber. No. 55
Vol. 1] Obtain piperidine. MNR spectrum: -CH ₂ -N 2 to 3 ppm -CH ₂ -CH ₂ 0.5 to 1.6 ppm Pharmacological properties (1) Effect of product on serotonin absorption Currently known antidepressants are It is known to have properties that inhibit absorption. Therefore, the antidepressant action of the product according to the invention (in
in Vitro), the method of Kannegiesser et al. (Biochem.Pharmacol., Vol. 22, p. 73, 1973
This was demonstrated by experiments conducted in 2007 to inhibit the absorption of brain monoamines (particularly serotonin) by rat brain synaptosomes. This experiment is performed using whole brains from young female Charles River rats (19-21 days old). The whole rat brain was cut out, weighed, and then subjected to the method of Whittaker [Handbook of Neurochemistry, Vol. 2, p. 327 (Plenum Publishers) 1969.
homogeneously suspended in 0.32M sucrose solution (20 ml) according to the following year). The supernatant (S ₁ ) obtained from centrifugation of a 900 g sample was diluted with 100 mM NaCl, 4 mM
40mM sodium phosphate buffer (PH7.0) containing KCl and 11mM D-glucose
Dilute to 100ml with A certain amount of this suspension (5
ml) in the presence or absence of the test compound at ¹⁴ C.
- Incubate with 5HT. After incubation, the sample was immediately cooled in ice, an aliquot was separated for radioactivity measurement, and the rest was
100000g for 10 minutes at 4° with 50Ti rotor
centrifuge (Beckman, model L2 75B)
using an ultracentrifuge). The resulting pellet (P ₂ ) is rinsed twice with cold phosphate buffer (1 ml) and extracted with 0.4N perchloric acid (300μ). After removing precipitated proteins by centrifugation, radioactivity in the extract is measured. From this measurement value, calculate the dose (μM/) of the test compound at which serotonin absorption is reduced by 50%. The results expressed as the 50% inhibition dose I ₅₀ are shown in the table below.

[Table] It can be seen that the products according to the invention are potent serotonin absorption inhibitors. (2) Synergistic effect of 5-HTP The effectiveness of the compounds of the present invention in inhibiting serotonin absorption is also demonstrated by the synergistic effect on 5-hydroxytryptophan (5-HTP). The products of the invention have the interesting property of very highly synergizing (ie reinforcing) the effects of 5-HTP, a precursor of serotonin. This property was confirmed in vivo by CD ₁ (Charles
This was revealed by the technique described below in (male) River) mice. When 5-HTP is administered parenterally to mice in large doses, characteristic behaviors occur (tremor, torso twisting, hindlimb displacement, head shaking, and general increased propriomotility). is known.
To see synergy with 5-HTP, we use one such property of the precursor of serotonin (tremor). The method used was described by C. Gouret [J. Pharmacol.
(Paris), Vol. 5, p. 453, 1975]. Groups of 8 male mice are used. The operating order of the experiment is as follows for the groups treated with both 5-HTP and the product according to the invention. At point t=0, 150mg/Kg of 5-HTP at 9%
Inject intraperitoneally (IP) as a NaCl aqueous solution. At t = 30 minutes, the test product was added to 9% NaCl.
Inject subcutaneously (SC) as an aqueous solution. At t=75 minutes, each animal's tremors are measured using the scale described below. 0 = no shivering 1 = shivering of average intensity 2 = strong shivering This operating sequence is similar for the "Control 5-HTP" and "Control Product" groups, except that in the first case instead of the product solution 9%
SC injection of NaCl aqueous solution, 5 in the second case
-I.9% NaCl aqueous solution instead of HTP solution.
P. Inject. The "control product" group received the same dose of the test product as the group receiving both 5-HTP and product, in order to see possible product-specific effects. The scores for each group are totaled to determine the average value of tremor. ED ₅₀ for each test product according to this standard
(50% of the maximum possible effect, i.e. a mg/Kg dose with an average value of tremor equal to 1). The results obtained are shown in the table below.

Table: At a dose of 25 mg/Kg, the products of Examples 1 and 2 do not have any intrinsic effect (ie no effect in the absence of 5-HTP). The compounds of the invention are therefore strong 5-HTP synergists. Such activity is consistent with the remarkable serotonin absorption inhibitory effect observed in rat synaptosomes. (3) Antiarrhythmic activity The antiarrhythmic activity of the compounds of the present invention is demonstrated by an aconitine experiment in rats. This method is based on the time required for the onset of ventricular arrhythmia due to aconitine slowly perfused into rats. Antiarrhythmic products delay the onset of arrhythmia, and this delay in onset is proportional to the activity of the product. Groups of 5 male rats are used. Each rat is anesthetized (10% urethane: 1 g/Kg ip) to allow catheterization of the penile vein to be performed. Record an electrocardiogram. At time t=0, the product is injected in the form of an aqueous solution at a rate of 2.5 ml solution/Kg in 30 seconds. At t=90 seconds, 1 minute after the end of the infusion, aconitine is perfused at a rate of 20 μg/min until supraventricular extrasystole appears. Record the aconitine perfusion time. The results are expressed as _ED50 , which is the difference in perfusion time for aconitine compared to the perfusion time in control animals.
The product dose (mg/Kg) increases by up to 50%. The results obtained are shown in the following table, in which the activity (ED ₅₀ ), toxicity (LD ₅₀ ) and therapeutic index (LD ₅₀ /ED ₅₀ ) are given.

Table: The products of the invention are therefore potent antiarrhythmic agents. In particular, the products of Examples 1, 3 and 5 are not only more effective than the reference products (quinidine and disopyramide), but also have a higher therapeutic index than quinidine and disopyramide. (4) Synergy of sleep by serotonin The role of brain serotonin in sleep is a well-known fact (M.Jouvet et al., CRAcad.Sc.Paris,
Volume 264, page 360, 1967). Even if serotonin is administered to adult animals, the hypnotic effects of this neurotransmitter cannot be observed because serotonin does not cross the blood-brain barrier. Chickens, on the other hand, do not have such a barrier, so it is possible to inject serotonin intravenously into chickens and observe the central effects of serotonin. Using a flock of 12 chickens, we gave them serotonin.
Administer intravenously at a dose of 0.1 mg/Kg. It is recorded that 25% of chickens fall asleep under such conditions. When the products of the invention are administered intravenously at various doses simultaneously with serotonin (dose 0.1 mg/Kg), it is recorded that much more than 25% of the chickens fall asleep. For example, when the product of Example 1 is administered at a dose of 3 mg/Kg, it is recorded that 60% of the chickens fall asleep. The products of the invention therefore synergize the hypnotic effects of serotonin. (5) Vascular effects The vascular effects of serotonin were studied by JJ Loux (Arch.
Int.Pharmacodyn.Therap.Volume 183, Page 98,
(1970) experiment revealed that BB
Vargafitig (Eur. J. Pharmacol. Vol. 25, 216
(Page, 1974), this method consists of injecting increasing cumulative doses of serotonin into the carotid artery of an anesthetized dog. 0.20
An increase in the total volume of the sinuses by μg/Kg or more is seen, demonstrating vasoconstriction of the nasal mucosa. This increase is measured with a manometer in a nasal sinus isolated airtight from the outside. The products of the invention do not exhibit any intrinsic vasoconstrictor effect in this experiment, but strongly synergize the effects of serotonin. For example, when the product of Example 1 is administered intravenously at a dose of 1 μg/Kg, 0.05μ
g/Kg of serotonin (pressure drop measured by manometer is twice as large). This activity of the products of the invention can be used for the treatment of migraine (F. Sicuteri et al., Psychopharma-
cologia, vol. 29, p. 347, 1973). Toxicity The acute toxicity and symptoms of the compounds according to the invention were determined in CD ₁ (Charles River) male rats after intravenous and oral administration. LD ₅₀ was determined after 3 days of observation by JJ Reed and H. Muench (Amer.
J. Hyg., Vol. 27, p. 493, 1938). Symptoms observed at toxic and side-toxic doses are similar for each product and the two methods of administration. They consist primarily of catatonia of the tail, tremors, decreased breathing and hilar convulsions. The obtained LD ₅₀ is shown in the table below.

[Table] Therefore, this compound is a substance that is relatively non-toxic to mice. Therapeutic use The drug according to the invention can be used in the treatment of humans in the form of tablets, capsules, gelatin-coated pills, suppositories, ingestible or injectable solutions, etc. for pathological conditions due to dysfunction in the serotonergic system, in particular It can be used as a therapeutic agent for various mental disorders that cause depression, a drug that regularizes sleep, an antiarrhythmic drug, and a vasoconstriction regulating agent. The dosage depends on the desired effect and the method of administration used. For example, for oral administration, the amount of active substance per day is between 5 and 250 mg, and the unit dose is between 1 and 50 mg.

Claims (1)

[Claims] 1. As an active ingredient, the general formula (wherein R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms, and X is hydrogen or an alkoxy group having 1 to 4 carbon atoms. Yes, but if R is other than a hydrogen atom, the carbon atom and group of the piperidine ring holding the R group A therapeutic agent for serotoninergic system dysfunction, characterized in that it contains a compound represented by the formula (Both carbon atoms of the piperidine ring have an R configuration) or a salt thereof with a pharmaceutically acceptable acid. 2 As an active ingredient General formula (wherein R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms, and X is hydrogen or an alkoxy group having 1 to 4 carbon atoms. Yes, but if R is other than a hydrogen atom, the carbon atom and group of the piperidine ring holding the R group (Both carbon atoms of the piperidine ring have an R configuration) or a salt thereof with a pharmaceutically acceptable acid.