FR2460946A2 - 3-Tetra:hydro:pyridyl-indole derivs. - useful as antidepressants, antiemetics and antiparkinsonian agents - Google Patents

Abstract

New indole derivs. of formula (I) and their acid-addn. salts are claimed: (where X is H, F, Cl, Br, 1-3C alkoxy or NO2; R is H or 1-3C alkyl). (I) have antidepressant, antiemetic and antiparkinsonian activity. Prod. comprises reacting a cpd. of formula (II) with 4-piperidone hydrochloride (III) in an alkaline medium (pref. 2N KOH in MeOH).

Description

In its French patent application filed on August 26, 1976 under number 76-25798, the applicant described and claimed new derivatives of piperidyl-indole and their salts, the process for the preparation and the application as medicaments of said products.

dans laquelle X représente un atome de fluor, de chlore ou de brome lorsque Y et Z représentent un atome d'hydrogène ou forment ensemble une double liaison, ou X représente un atome d'hydrogène ou un radical alcoxy renfermant de 1 à 3 atomes de carbone lorsque Y et Z forment ensemble une double liaison.The main patent described more particularly new derivatives of piperidyl-indole, as well as their addition salts with mineral or organic acids, characterized in that they correspond to the general formula I

in which X represents a fluorine, chlorine or bromine atom when Y and Z represent a hydrogen atom or together form a double bond, or X represents a hydrogen atom or an alkoxy radical containing from 1 to 3 atoms carbon when Y and Z together form a double bond.

In formula I and in what follows, the substituent X may be in position 5 or in position 6 of the indole, the alkoxy radical containing from 1 to 3 carbon atoms denotes for example a methoxy, ethoxy or propoxy radical.

 The addition salts with mineral or organic acids can be, for example, the salts formed with hydrobromic, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric acids. , oxalic, glyoxylic, aspartic, alkanesulfonic, such as methane sulfonic acid and arylsulfonic, such as benzene sulfonic acid.

dans laquelle X représente un atome de fluor, de chlore-ou de brome, avec de la pyridine et du chlorure d'acétyle, pour obtenir un produit de formule

dans laquelle X a la signification déjà indiquée, réduit ledit produit de formule III pour obtenir un produit de formule

dans laquelle X a la signification déjà indiquée, puis saponifie ce dernier pour obtenir un produit de formule

dans laquelle X représente un atome de fluor, de chlore ou de brome et Y et Z représentent un atome d'hydrogène, que l'on isole et, le cas échéant, traite par un acide pour en former le sel.The main patent also claimed a process for the preparation of the piperidyl-indole derivatives corresponding to formula I above, as well as their salts, said process being characterized in that a product of formula is reacted

in which X represents a fluorine, chlorine or bromine atom, with pyridine and acetyl chloride, to obtain a product of formula

in which X has the meaning already indicated, reduces said product of formula III to obtain a product of formula

in which X has the meaning already indicated, then saponifies the latter to obtain a product of formula

in which X represents a fluorine, chlorine or bromine atom and Y and Z represent a hydrogen atom, which is isolated and, if necessary, treated with an acid to form its salt.

dans laquelle X représente un atome d'hydrogène, un radical alcoxy renfermant de 1 à 3 atomes de carbone ou un atome de fluor, de chlore ou de brome avec du chlorhydrate de 4pipéridone dans l'acide acétique en présence ou non d'un acide fort, pour obtenir le sel correspondant d'un produit de formule

dans laquelle X représente un atome d'hydrogène, un radical alcoxy renfermant de 1 à 3 atomes de carbone ou un atome de fluor, de chlore ou de brome, Y et Z forment ensemble une double liaison, que l'on isole sous forme de sel ou de base correspondante et, si désiré, salifie cette dernière.The main patent also claimed a process for the preparation of the derivatives defined by the general formula I in which X represents a hydrogen atom, an alkoxy radical containing from 1 to 3 carbon atoms or a fluorine, chlorine or bromine atom and Y and Z together form a double bond, as well as their salts, said process being characterized in that a product of formula is reacted

in which X represents a hydrogen atom, an alkoxy radical containing from 1 to 3 carbon atoms or a fluorine, chlorine or bromine atom with 4piperidone hydrochloride in acetic acid in the presence or absence of an acid strong, to obtain the corresponding salt of a product of formula

in which X represents a hydrogen atom, an alkoxy radical containing 1 to 3 carbon atoms or a fluorine, chlorine or bromine atom, Y and Z together form a double bond, which is isolated in the form of salt or corresponding base and, if desired, salifies the latter.

The main patent also claimed the application as medicaments of the derivatives corresponding to general formula I above, and of their pharmaceutically acceptable salts, as well as the pharmaceutical compositions containing, as active principle, one or more of the derivatives of general formula I and / or their pharmaceutically acceptable salts.

This request for a certificate of addition, in which Messrs DUMONT Claude participated,
GUILLAUME Jacques and NEDELEC Lucien, aims to illustrate with a new example, the invention described in the main patent.

It relates in particular to the piperidyl-indole derivative corresponding to formula I of the main patent, the name of which follows - 6-methoxy 3- (1,2,3,6 tetrahydropyridin-4-yl) 1H-indole and its salts addition with mineral or organic acids.

The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric acids. , oxalic, glyoxylic, aspartic, alkanesulfonic, such as methane or ethanesulfonic, arylsulfonic, such as benzene or paratoluenesulfonic and arylcarboxylic acids.

 The product named above and its salts can be prepared according to the process described in the main patent and mentioned above.

Among the preferred products of the invention, there is more particularly retained the hydrochloride of 6-methoxy 3- (1,2,3,6 tetrahydropyridin-4-yl) 1H-indole.

dans laquelle lorsque R' représente un radical alcoyle renfermant de 1 à 3 atomes de carbone, X' représente un atome de fluor, de chlore ou de brome, un atome d'hydrogène, un radical alcoxy renfermant de 1 à 3 atomes de carbone, un radical nitro, en lorsque R' représente un atome d'hydrogène X' représente un radical nitro, étant entendu que lorsque R' représente un radical méthyle, Xl ne peut représenter en position 5 de l'indole un atome d'hydrogène ou de chlore, ou un radical méthoxy.The present application also relates to the products related to formula I of the main patent, of general formula I '

in which when R 'represents an alkyl radical containing from 1 to 3 carbon atoms, X' represents a fluorine, chlorine or bromine atom, a hydrogen atom, an alkoxy radical containing from 1 to 3 carbon atoms, a nitro radical, when R 'represents a hydrogen atom X' represents a nitro radical, it being understood that when R 'represents a methyl radical, Xl cannot represent in the 5-position of the indole a hydrogen atom or chlorine, or a methoxy radical.

 In formula I 'and in what follows, the substituent X' can be in position 5 or in position 6 of the indole; the alkoxy radical containing 1 to 3 carbon atoms denotes, for example, a methoxy, ethoxy or propoxy radical and the alkyl radical containing 1 to 3 carbon atoms denotes, for example, a methyl, ethyl, propyl or isopropyl radical.

dans laquelle X' représente un radical alcoxy renfermant de 1 à 3 atomes de carbone ou nitro, un atome d'hydrogène, de fluor, de chlore ou de brome, et Rt représente un atome d'hydrogène ou un radical alcoyle renfermant de 1 à 3 atomes de carbone avec le chlorhydrate de 4-pipéridone en milieu alcalin, pour obtenir les produits de formule I et I' cherchés, que l'on isole sous forme de base et si désiré, salifie cette dernière.The present application for a certificate of addition also relates to a process for the preparation of the products of general formula I and of the products of general formula I 'as defined above as well as their salts, said process being characterized in that the 'a product of general formula II is reacted'

in which X 'represents an alkoxy radical containing from 1 to 3 carbon or nitro atoms, a hydrogen, fluorine, chlorine or bromine atom, and Rt represents a hydrogen atom or an alkyl radical containing from 1 to 3 carbon atoms with 4-piperidone hydrochloride in an alkaline medium, to obtain the desired products of formula I and I ', which are isolated in the form of the base and if desired, salifies the latter.

Under preferred conditions for carrying out the invention, the process described above is characterized in that a) the alkaline medium consists of 2 N methanolic potassium hydroxide, but sodium hydroxide or an alkaline alcoholate can also be used.

b) the reaction is carried out at reflux of the reaction mixture.

dans laquelle X' et R' ont.la signification déjà énoncée, avec du chlorhydrate de 4-pipéridone dans l'acide acétique en présence ou non d'un acide fort, pour obtenir le sel correspondant d'un produit de formule

dans laquelle X' et R' ont la signification déjà énoncée que l'on isole sous forme de sel ou de base correspondante et si désiré, salifie cette dernière.The present application for a certificate of addition also relates to a process for the preparation of products of general formula I 'as defined above, said process being characterized in that a product of formula is reacted

in which X 'and R' have the meaning already stated, with 4-piperidone hydrochloride in acetic acid in the presence or not of a strong acid, to obtain the corresponding salt of a product of formula

in which X 'and R' have the meaning already stated that is isolated in the form of the corresponding salt or base and if desired, salifies the latter.

 As indicated in the main application, the addition salts of the abovementioned derivatives can be prepared by reacting, in substantially stoichiometric proportions, a mineral or organic acid with said derivatives.

 The products which are the subject of the present application, that is to say the 6-methoxy 3- (1,2,3,6 tetrahydropyridin-4-yl) ÎH-indole as well as the products defined by the general formula I ' and their salts have very interesting pharmacological properties; they are endowed, in particular, with certain anti-depressive, anti-Parkerinsian and antiemetic properties.

 These properties are illustrated later in the experimental part.

These properties justify the use of the new piperidyl-indole derivatives, the subject of this application for the 1st certificate of addition and their salts as medicaments.

 The present application thus also relates to the application, as medicaments, of these new derivatives, as well as their addition salts with pharmaceutically acceptable acids.

These drugs find, for example, their use in the treatment of mental disorders, behavioral disorders, character disorders, in the treatment of akinetic and dyskinetic states as well as in the treatment of vomiting and nausea of all origins.

 The usual dose, which varies according to the product used, the subject treated and the condition in question, can be, for example, from 5 mg to 500 mg per day, orally in humans.

 Finally, a subject of the invention is pharmaceutical compositions which contain at least one aforementioned derivative or one of its addition salts with pharmaceutically acceptable acids, as active principle.

As medicaments, the derivatives which are the subject of the present application and their addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.

 These pharmaceutical compositions can be, for example, solid or liquid and can be in the pharmaceutical forms commonly used in human medicine, such as, for example, tablets, simple or coated, capsules, capsules, granules, suppositories, preparations injectables; they are prepared according to the usual methods.

The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 Examples of implementation of the invention will now be given, without implied limitation.

Example 1: Neutral fumarate of 6-methoxv 3- (1.2.5s6 tetrahvdro-pyridin-4-yl) 1 H-indole.

 20 g of 1H-indole 6methoxy with 41.75 g of hydrate of 4-piperidone hydrochloride in 205 cm 3 of methanolic potassium hydroxide are heated to reflux under an inert atmosphere for 8 h 30 min, diluted slowly with water to 1, 2 liter, crystallizes, agitates 30 minutes, rinses with water, dries vacuum under 500C in the presence of desiccant and obtains 23.05 g of the base of the sought product.

Fumarate preparation
10 g of the base obtained are dissolved in 300 cm 3 of methanol at 500 ° C., filter, add 2.5 g of fumaric acid, crystallize, stir for 3 hours away from light, filter under reduced pressure, rinse with methanol , dried under vacuum at 50 cl, collects 9.3 g of crude product which is redissolved in 300 cm3 of distilled water, filtered hot and then cooled to initiate crystallization. After 2 hours of standing at room temperature, filter, rinsing with batten, drying under vacuum at 500C in the presence of a desiccant and obtains 6.3 g of the expected product melting at 257-2600C,
Analysis: C32H36N406 = 572.667
calculated C% = 67.11 H% = 6.33 N% = 9.78
found 67.2 6.4 9.9
Example 2: 5-chloro 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H
indole.

 15.1 g of 1H-indole chlorine is brought to reflux under an inert atmosphere with 30.7 g of 4piperidone hydrochloride hydrate and 150 cm 3 of 2 N methanolic potassium hydroxide for 7 h 30 min, left overnight at room temperature, poured into 1.5 liters of water, extracted with ethyl acetate, washed with water and salt water, dried over magnesium sulfate and evaporated to dryness.

The 20.5 g of crude product obtained are redissolved at reflux in 1 l of benzene, filtered hot, allowed to crystallize, after 3 hours wrung, rinsed with benzene and 10.2 g of the desired product melting at 1770C are obtained, then 2, 49 g melting at 1751770C by concentration of the mother liquors and crystallization, ie in total 12.69 g of the sought product.

Analysis after purification by salification then return to base
F = 177-179 C
C13H13ClN2 = 232.72
Calculated: C% = 67.09 H% = 5.63 Cl% = 15.23 N% = 12.03
Found: 67.4 5.8 15.1 11.7
Example 3: 5-methoxy 3- (1,2,3,6 tetrahydropyridin-4-yl) 1H
indole.

14.7 g of 5-methoxy-indole are refluxed under an inert atmosphere with 30.7 g of 4-piperidone hydrochloride monohydrate in 150 cm 3 of 2 N methanolic potassium hydroxide for 8 h 30 min. After cooling, 300 cm 3 of water are added , crystallizes, cools to 10 C, filters, empates 3 times with water, 2 times with methanol, 2 times with ether, dries under reduced pressure at 200C and obtains 18.25 g of the sought product in the form of a light yellow powder melting at 1830C.

Example 4: 5-nitro 3- (1,2,3,6 tetrahydropyridin-4-yl) 1H-indole hydrochloride.

 Is brought to reflux under a nitrogen atmosphere for 3 hours, 7.7 g of 5-nitro 1H-indole with 225 cm3 methanol saturated with hydrochloric acid, 22.5 g of hydrated 4-piperidone hydrochloride, then stirred for 1 hour at temperature room temperature and 1 hour at OOC, filter, rinse with ice-cold methanol, with ethyl acetate, with ether and obtain 14 g of the crude product sought.

 The 14 g of the product obtained are recrystallized from 600 cm3 of mixture of equal parts of methanol and water, left to stand overnight in a refrigerator, filter, rinsed twice with methanol, dried under vacuum in the presence of a desiccant and obtained 9 , 8 g of the pure product sought melting at 2750C.

Analysis: C13H14ClN3 2 = 279.733
Calculated: C 0A 55.82 H% 5.04 Cl% 12.68 N% 15.02
Found: 56.0 5.1 12.8 14.7
Example 5: 6-Methoxy 2-methyl 3- hydrochloride (1,2,3,6 tetra hvdrooyridin-4-yl) 1 H-indole
Stirred at 100 ° C. under an inert atmosphere 2 g of 6-methoxy 2-methyl 1H-indole with 4 g of 4-piperidone hydrochloride monohydrate in 40 cm 3 of acetic acid, after 1 h 30 cools, poured onto a mixture of 150 g of ice and 80 cm3 of pure ammonia 220 Bé, extracted with ethyl acetate, washed with water, dried over magnesium sulphate, distilled to dryness under reduced pressure, takes up the residue in acetate d ethyl, empate hot, allowed to cool, wrung, washed with ethyl acetate, dried under reduced pressure and obtained 2.5 g of crude product.

Preparation of the hydrochloride
The product obtained is dissolved in 50 cm3 of hot isopropanol, cooled, dropwise added a solution of gaseous hydrochloric acid in isopropanol to acid pH, initiates crystallization, after spin drying overnight, washing with isopropanol, dried under vacuum and obtains 2.25 g of the expected product, melting at 2700C.

Analysis
C15H19ClN20
Calculated: C 0A = 64.62 H% = 6.87 Cl% = 12.72 N% = 10.05
Found: 64.5 7.0 13.0 9.9
Example 6
Tablets corresponding to the formula - 5-Nitro 3- hydrochloride (1,2,3,6 tetrahydropyridin-4-yl) 1H- were prepared.
indole................................................. ... 25 mg - Excipient qs for a tablet finished at ................. 200 mg
(detail of excipient: talc, starch, magnesium stearate).

Example 7
We have prepared an injectable solution corresponding to the formula - Neutral fumarate of 6-methoxy 3- (1,2,3,6 tetrahydropyridin
4-yl) 1H-indole ........................................... .. 25 mg - Sterile aqueous excipient qs ........................... 2 ml
Pharmacological study.

1) Potentiation test for amphetamine stereotypies
The tests are carried out on batches of 5 male rats weighing 150 to 180 g. Each animal is placed individually in a wire cage (29 x 25 x 17 cm) containing some pieces of broken wood.

 A one hour delay is observed between the administration of the studied compound and the injection of 5 mg / kg of dexamphetamine sulfate.

 The behavior of the animals is then noted every 1/2 hour for 5 hours with the rating recommended by HALLIWELL et al. (Brit. J. Pharmacol. 1964, 2D, 330-350).

 The animal is asleep (0), it is awake but immobile (1), it turns in the cage (2), it sniffs the cover (3), it licks the walls (4), it touches the shavings or the bars of the cage with the teeth (5), it bites the chips or the bars of the cage (6).

 The intensity of the stereotypes is expressed in the form of a score between 0 and 30 corresponding to the sum of the values obtained on the 5 rats of a batch at each time. The sum of the scores recorded in 5 hours is calculated.

 The compounds are administered intraperitoneally.

 The dose of compound which increases the sum of the scores by approximately 100% over 5 hours is 20 mg / kg for the compound of Example 4.

2) Test of ant ~ gonism vis-à-vis cataleSsie with prochlorperazine:
The tests are carried out on batches of 5 male rats weighing approximately 100 g.

The test compound is administered intraperitoneally simultaneously with a dose of 15 mg / kg of prochlorperazine intraperitoneally.

Catalepsy is assessed every hour for 7 hours following the homolateral leg crossing test (BOISSIER, SIMON, Therapie, 1963, 18, 1257-1277) with the following rating
The animal refuses the crossing of the forelegs with the homolateral hind legs (O), it accepts the desired crossing only with one side (0.5), it accepts the crossing on both sides (1).

The compound of Example 4 is opposed to catalepsy induced by prochiorperazine at a dose equal to 1 mg / kg.

3) Study of acute toxicity5
The acute toxicity is determined on batches of ten mice weighing approximately 20 g to which are administered intraperitoneally increasing doses of the compound studied.

 Mortality is noted 48 hours after administration of the compound.

The approximate lethal doses 50 (LD50) of the compounds of Examples 1 and 5 are equal to 100 mg / kg. The approximate LD50 of the compound of Example 4 is equal to 165 mg / kg.

Claims (7)

1) - - your products related to formula I of the main patent, general formula I '

in which when R1 represents an alkyl radical containing from 1 to 3 carbon atoms, X 'represents a fluorine, chlorine or bromine atom, a hydrogen atom, an alkoxy radical containing from 1 to 3 carbon atoms, a nitro radical and when R 'represents a hydrogen atom, X' represents a nitro radical, it being understood that when R 'represents a methyl radical, X' cannot represent in positon 5 of the indole a hydrogen atom or chlorine, or a methoxy radical. 2) - Process for the preparation of products corresponding to formula I 'of claim (1), in which the substituents X 'and R' have the meaning already indicated, as well as their salts, characterized in that a product of general formula II is reacted

 in which X 'represents an alkoxy radical containing from to 3 carbon atoms or nwtro, a hydrogen, flaor, chlorine or bromine atom, and R' represents a hydrogen atom containing a racial alkyl containing 1 with 3 atoms arbone with the hydrochloride of 4-piperidone in an alkaline medium, to obtain the product of formula I 'sought that one isolates in the form of base and, if desired, salifies the latter. 3) - Method according to claim 2, characterized in that the alkaline medium consists of methanolic potash 2 N. 4) - Method according to claim 2 or 3, characterized in that the reaction is carried out at reflux of the reaction mixture. 5) - Process for the preparation of the derivatives defined by the general formula I 'of claim 1, in which X' and R 'have the meaning already indicated, as well as their salts, characterized in that the reaction reacts a formula product

 in which X 'and R' have the meaning already stated, with 4-piperidone hydrochloride in acetic acid in the presence or absence of a strong acid, to obtain the corresponding salt of a product of formula

 in which X 'and R' have the meaning already stated) which is isolated in the form of a salt or corresponding base and, if  desired, salify the latter. 6) - Medicines, characterized in that they are made up  by the new derivatives as defined in claim 1, as well as their addition salts with pharma acids ceutically acceptable. 7) - Pharmaceutical compositions, characterized in that they containing, as active principle, at least one of the medicaments as defined in claim 6.