FR2470128A2 - Tetra:hydro pyridinyl chloro indole(s) - useful in the treatment of psychic and behavioural disorders, nausea and vomiting - Google Patents

Abstract

Tetrahydropyridinyl indoles of formula (I) and their salts are new. X is pentyl, 2-phenyl ethyl, butyl, or 2-propenyl. Parent patent covers the compounds of formula (I) in general terms, but does not specifically describe them. Used for the treatment of psychic and behavioral disorders, and also nausea and vomiting.

Description

 In its French patent application filed on June 12, 1979 under number 79-14979, in the form of a division and transformed into an independent patent application on November 5, 1979, the applicant described and claimed new derivatives of tetrahydropyridin-4-yl- indole and their salts, the preparation process, the application as medicaments of said products, and the compositions containing them.

dans laquelle R représente un atome d'hydrogène ou d'halogène, ou un radical alcoxy renferment de 1 à 3 atomes de carbone, R1 et R2 représentent un atome d'hydrogene ou un radical alcoyle renfermant de 1 à 3 atomes à 3 atomes de carbene, X r présente un radical alcoyle reniermant de 1 à 6 atomes de carbone, cycloalcoyle renfermant de 4 à 7 atomes de carbone alcynyle ou alcényle, renfermant de 2 à 5 atomes de carbone ou aralcoyle renfermant de 7 à 17 atomes de carbone, etant entendu que si X représente un radical méthyle, un au moin des substituants R, R1 et R2 a plus d'un atome de carbone, que si X représente un radical alcoyle renfermant de 1 à 6 atomes de carbone, R ne peut représenter un atome d'hydro- ou un radical alcoxy renfermant de 1 à 3 atomes de carbone, et que Si X représente -* -adical benzyle, l'un au moins des substituants R, R1 et R2 ne représente pas un atome d'hydrogène.The main patent, that is to say, the French patent application number 79-14979, described more particularly of calves derived from tetrahydropyridin-4-yl-indole, as well as their addition salts with mineral acids or organic, characterized in that they correspond to the general formula (I)

in which R represents a hydrogen or halogen atom, or an alkoxy radical containing from 1 to 3 carbon atoms, R1 and R2 represent a hydrogen atom or an alkyl radical containing from 1 to 3 atoms to 3 atoms of carbene, X r has an alkyl radical containing 1 to 6 carbon atoms, cycloalkyl containing 4 to 7 carbon atoms, alkynyl or alkenyl, containing 2 to 5 carbon atoms or aralkyl containing 7 to 17 carbon atoms, and understood that if X represents a methyl radical, at least one of the substituents R, R1 and R2 has more than one carbon atom, than if X represents an alkyl radical containing from 1 to 6 carbon atoms, R cannot represent an atom of hydro- or an alkoxy radical containing from 1 to 3 carbon atoms, and if Si X represents - * -adical benzyl, at least one of the substituents R, R1 and R2 does not represent a hydrogen atom.

dans laquelle R , R1 et R2 ont la signification déjà énoncée, avec un halogénure de formule générale
Hal - X (III ) dans laquelle Hal représente un atome de chlore, de brome ou d'iode et X 2 la signification déjà énoncée, pour obtenir un produit de formule (I ) 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 tetrahydropyridin-4-yl-indole derivatives repo: dant to formula (I) above, as well as their salts, said process being characterized in that one reacts a product of formula (II)

in which R, R1 and R2 have the meaning already stated, with a halide of general formula
Hal - X (III) in which Hal represents a chlorine, bromine or iodine atom and X 2 the meaning already stated, to obtain a product of formula (I) which is isolated and, if necessary, treated with an acid to form the salt.

The main patent also claimed the application as medicaments of derivatives corresponding to general formula (I) above, and their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing, as active principle at least one of the derivatives above or one of its addition salts with pharmaceutically acceptable acids.

This request for a certificate of addition, in the production of which Messrs Lucien NED3LEC participated,
Jacques GUILLAS 2 and Claude DUMONT aims to illustrate with new examples, the invention described in the main patent.

It relates more particularly to the derivatives corresponding to formula (I) of the main patent, the names of which follow
5-chloro 3- (1-pentyl 1,2,3,6-tetrahydropyridin-4 yl) lb indole,
5-chloro 3- / 1- (2-phenylethyl) 1,2,3,6-tetrahydropyridin4-yl / 1H-indole,
5-chloro 3- (1-butyl 1,2,3,6-tetrahydropyridin-4-yl) 1Hindole,
5-chloro 3- / 1- (2-propenyl) 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.

5-chloro 3- (1-methyl 1,2,3,6-tetrahydropyridin-4-yl) 1Hindole, and their addition salts 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, sropionic, benzoic, maleic, fumaric, succinic, tartaric, citric acids. - that, oxalic, glyoxylic, aspartic, alkanesulfonic, such as methane or ethanesulfonic acids, arylsula foniques, such as benzene or paratoluene sulfonic or arylcarboxylic acids
Among the preferred derivatives of the invention, the products prepared in examples are chosen more particularly.

5-chloro 3- (1-pentyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride,
5-chloro 3- / 1- (2-phenylethyl) 1,2,3,6tetrahydropyridin-4-yl / I H-indole hydrochloride,
5-chloro 3- hydrochloride (1-butyl 1,2,3,6-tetrahydropy ridin-4-yl) I 1indole,
5-chloro 3- / 1 (2-propenyl) 1,2,3,6-tetrahydropyridin-4-yl / 1H-indole hydrochloride,
5-chloro 3- (1-methyl 1,2,3,6-tetrahydropy ridin-4-yl) I H -indole hydrochloride.

dans laquelle Rss représente un atome des chlore en position 5 de l'indole, et R1 et R2 représentent un atome d'hydrogène avec un halogénure de formule générale
Hal - X" (III") dans laquelle Hal représente un atome de chlore, de brome ou d'iode et X" représente un radical pentyl, phénétyl, butyl, propen-2-yl ou méthyle, pour obtenir un dérivé de formule générale (I ) tel que défini ci-dessus que l'on isole et, le cas-échéant, traite par un acide pour en former le sel.The present application also relates to a process for the preparation of the derivatives of formula (I ') as defined above, as well as their addition salts with mineral or organic acids, characterized in that the reacting a product of formula (II ")

in which Rss represents a chlorine atom in position 5 of the indole, and R1 and R2 represent a hydrogen atom with a halide of general formula
Hal - X "(III") in which Hal represents a chlorine, bromine or iodine atom and X "represents a pentyl, phenetyl, butyl, propen-2-yl or methyl radical, to obtain a derivative of general formula (I) as defined above which is isolated and, if necessary, treated with an acid to form the salt.

 The products which are the subject of the present application, like the products of the main patent, have very interesting pharmacological properties; they are endowed, in particular, with antidepressant, neuroleptic and antiemetic properties.

 These properties justify the use of the new derivatives of tetrahydropyridin-4-yl-indole and their salts as medicaments. The present application thus also relates to the application, as medicaments, of the new derivatives of tetrahydropyridin-4-yl-indole, as defined above, as well as their addition salts with pharmaceutically acceptable acids. .

Among the drugs which are the subject of the invention, there are particularly the drugs characterized in that they consist of the new derivatives of tetra hydropyridin-4-yl-indole, the names of which follow
5-chloro 3- hydrochloride (I-butyl 1,2,3,6-tédtrahydropy-ridin-4-yl) 1H-indole, -
5-chloro 3- / 1- (2-propenyl) 1,2,3,6-tetrahydropyridin-4-yl) I H -indole chlorphdrate,
5-chloro 3- (1-methyl 1,2,3,6-tetrahydro pyridin-4-yl) 1H-indole hydrochloride.

The drugs which are the subject of the present invention,
find, for example, their use in the treatment of
mental disorders, behavioral disorders, disturbances
characteristic, as well as in the treatment of vomit
nausea and nausea of all originals.

The usual dose, which varies depending on the product used,
the subject treated and the affection in question, can be, for example-
ple, from 5 mg to 200 mg per day, orally in humans, of the product of Example 3.

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

 As a 4th medicament, the derivatives which are the subject of this application and their addition salts with pharmaceutically acceptable acids can be incorporated in ons pharmacentically intended for the ditestive or parenteral route.

These pharmaceutical compositions can be, for example. solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, capsules, granules, suppositories, injectable preparations: they are prepared according to the usual methods The active ingredient (s) may be incorporated therein into containers usually used in these pharmaceutical compositions, such as tale, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aceous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

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

EXAMPLE 1 5-chloro 3 - / (1-pentyl) 1,2,3,6 tetrahydropyridin-4-yl / 1H-indole hydrochloride

Stage A: 5-chloro 3- / 1-pentyl 1,2,3,6-tetrahydropyridin-4 yl / 1H-indole.

The mixture is stirred for 4 hours at ambient temperature, under an inert atmosphere 12. 5-chloro 3- (1,2,3,6-tetrahydropyridin4-yl) 1H-indole dissolved in 120 cm3 of dimethylformamide, with II g of sodium carbonate and 9.6 cm3 of iodopentane, diluted with 360 cm3 d distilled water, leaves to precipitate, come out, rinse with water and then with ethanol, dry under vacuum in the presence of a desiccant, purify by recrystallization from ethanol and obtain 7.55 g of the desired product, melting at 200 -202 C.

Stage B: 5-chloro 3 - / (1-pentyl) 1,2,3,6tetrahydropyridin-4-yl / 1H-indole hydrochloride

The 7.5 g of the product obtained in Stage A are suspended in 75 cm3 of ethanol, ice, hydrochloric ethanol in saturated solution is added until acidic pH, stirred for 1 hour 30 minutes at OOC, drained, rinsed with ethanol, dried under vacuum, collects 11.8 g of crude product which is recrystallized from ethanol, and obtains 7.38 g of yellow crystals of the sought product, melting at 2350 C.

Analysis: C18 H24 Cl2 N2 = 339.302
Calculated: C% 63.71 H% 7.13 Cl% 20.9 N% 8.26
Found: 63.5 7.1 20.6 8.4
The starting 5-chloro 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole can be prepared according to a process described in Belgian patent No 858 101.

Example 2: 5-chloro 3 / 1- (2-phenylethyl) 1,2,3,6-tetrahydroDyridin-4-yl / IR-indole hydrochloride

Stage A: 5-chloro 3- / 1- (2-phenylethyl) 1,2,3,6-tetrahydropyridin-4-yl / 1H-indole.

Stirred for 5 hours at 47 ° C., under an inert atmosphere, 8.147 g of 5-chloro 3- (1,2,3,6-tetrahydropyridin-4-yl) 1Hindole dissolved in 105 cm3 of dimethylformamide, with 7.42 g of sodium carbonate and 5.95 cm3 of ss-phenylethyl bromide, leaves to cool, diluted with water to 300 cm3, leaves to crystallize, stir for one hour, spin dry, rinse with water, with water - 50% thanol, dried under vacuum in the presence of a deshvdratant, purified by chromatography on a silica column (eluent chloroform-ethanol -TEA 6/3/1) then by recrystallization from ethanol and obtained 8.3 g of sought product melting at 191 C.

Stage B: Chlo hydrates 5-chloro 3 / 1- (2-phenylethyl) 1,2,3,6-tetrahydropyridin-4-yl / 1H-indole.

7.89 g of the product obtained in Stage A are suspended in 75 cm3 of ethanol, ice, ethanol chlorhydrate in saturated solution is added to acidic pH, a-to tare butters.

leave to stand for 2 hours at 0 ° C., wring, rinse with ethanol. dried under vacuum, collects 8.67 g of crude product which is re-crystallized in ethanol, and obtains 5.6 g of pale yellow oristals of the sought product, melting at 240 C (Maquenne)
Analysis: C21 H22 Cl2 N2 = 373.328
Calculated: C% 67.56 H% 5.93 Cl% 18.99 N% 7.5
Found: 67.3 5.9 19.3 7.3
Example 3: 5-Chloro 3 - / (1-butyl) 1,2,3,6tetrahydropyridin-4-yl / 1H-indole hydrochloride

Stage A: 5-chloro 3- / 1-butyl 1,2,3,6-tetrahydropyridin-4 yl / 1H-indole.

Agitation is carried out for 2 hours 30 to 50 ° C., under an inert atmosphere, 9.5 g of 5-chloro 3- (1,2,3,6-tetrakydropyridin-4-yl) 1 Hindole dissolved in 180 cm 3 of dimethylformamide, with -8 , 7g of sodium carbonate and 5.85 cm3 of n-butyl bromide, leaves to cool, diluted with 360 cm3 of water, leaves crystal to set, filter, rinse with water, take up in ethyl acetate, washed with dilute ammonia, with water and salt water, dried in the presence of a desiccant, evaporated to dryness, purified by recrystallization from ethanol and obtained 6.27 g of the desired product, melting at 198 -199 C.

Stage B: 5-chioro 3 tetrahydropyridin-4-yl / 1H-indole hydrochloride.

8 g of the product as obtained at the stage are suspended
A in 80 cm3 of ethanol, ice, add hydrochloric ethanol in saturated solution to an acidic pH, stir for 3 hours under an inert atmosphere at 00C, filter, rinse with ethanol, dry under vacuum, recover 8.35 g of crude product which is recrystallized from ethanol, and 7.23 g of pale yellow crystals of the sought product are obtained, melting at 233-2350C.

Analysis: C17 H22 Cl2 N2 = 325.294
Calculated: C% 62.77 H% 6.81 Cl% 21.80 N% 8.61
Found: 62.7 6.9 21.6 8.4
Example 4: 5-chloro 3- / 1- (2-propenyl) 1,2,3,6-tetrahydropyridin-4-yl / 1H-indole hydrochloride

Stage A: 5-chloro 3- / 1- (2-propenyl) 1,2,3,6-tetrahydropyrin-4-yl / 1H indole.

Stirred for 1 hour 30 minutes at room temperature, under an inert atmosphere 11.6 g of 5-chloro 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole dissolved in 170 cm3 of dimethylformamide, with 13 , 5 g of sodium carbonate and 5.7 cm3 of allyl bromide, add in 15 min 340 cm3 of water, leave to precipitate with stirring for 1 hour 30 minutes, spin dry, rinse with water, then with ethanol, dry under empty in the presence of a desiccant, and obtains 6.13 g of the sought product melting at 130 - 131 C.

Stage B: 5-chloro 3 / 1- (2-propenyl) 1,2,3,6 tetrahydropyridin-4-yl / 1H-indole hydrochloride

The 6.13 g of the product obtained in stage A is suspended in 65 cm3 of ethanol, ice, hydrochloric ethanol in saturated solution is added to the acidic pH, stirred for 1 hour under an inert atmosphere with OOC, drained, rinsed with ethanol, dried under vacuum at 700C, collects 6.73 g of crude product which is recrystallized from ethanol, and obtains 5.07 g of yellow crystals of the sought product, melting at 203 C.

Analysis: C16 H18 Cl2 N2 = 309.24
Calculated: C% 62.14 H% 5.86 Cl% 22.92 N% 9.05
Found: 61.9 5.9 22.7 8.9
Example 5: 5-Chloro 3 - / (1-methyl) 1,2,3,6tetrahydropyridin-4-yl / I H-indole hydrochloride

By operating according to a process identical to that described in Example 1, starting from methyl iodide, instead of iodopenta, crystals of the sought product melting at 2650C are not obtained.

Analysis: C14 H16 Cl2 N2 = 283.208
Calculated: C% 59.37 H% 5.69 Cl% 25.04 N% 9.89
Found 58.5 5.6 24.7 9.6
Example 6
Tablets corresponding to the formula were prepared - 5-chloro 3- (1-butyl) 1,2,3,6tetrahydropyridin-4-yl) 1H-indole hydrochloride ............. ..... 25 mg - Excipient qs for a tablet finished at ...... 100 mg (Details of the excipient: lactose, starch, talc, magnesium stearate).

Example 7
Tablets corresponding to the formula were prepared - 5-chloro 3- / 1-methyl hydrochloride 1,2,3,6tetrahydropyridin-4-yl) 1H-indole ........... 25 mg - Excipient qs for a tablet finished at .......... 100 mg (Details of the excipient: lactose, starch, talc, magnesium stearate).

PHARMACOLOGICAL STUDY.

1) - Antagonism with regard to apomorphine stereotypies.

The tests are used on batches of 5 rats according to a protocol inspired by JANSSEN et al. (Arzneim. Forsch. 1965, 15 104-117; 1967, 17, 841-854). Each animal is placed individually in a plexiglass box (20 X 10 X 10 cm;
NICOLFT) whose bottom is covered with a thin layer of wood frieze.

A dose of 1.5 mg / kg of apomorphine hydrochloride is injected intravenously, 1/2 hour after the intraperitoneal administration of the comnose studied.

The animals are observed napping one minute, 15 minutes after the injection of the anomornhine. The stereotypical movements of an oral snhere are evaluated according to BOISSIER and
SIMON (Therapy, 197O, 25, 933-949): no characteristic reaction (0), some sniffing, licking and nemrnts chewing (1), intense sniffing and continuous licking (2), continuous chewing (3).

The intensity of the stereotypies is expressed in the form of a score between 0 and 15 corresponding to the sum of the values obtained on the 5 rats in a batch, 15 minutes after the injection of the apomorphine.

The dose of the compounds which reduces the sum of the scores by approximately 50% is 15 mg / kg for the compound of Example 3 and 6 mg / kg for the compounds of Examples 4 and 5.

2) - Antagonism of catalepsy induced by prochlorpemazine.

The tests are carried out on ots of 5 male rats weighing approximately 100 g.

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

Cataleptsia is assessed every hour for 7 hours following the homolate paw growth test (BOISSIER, SIMON, Therapie, 1963, 18, 1257-1277) with the following rating
The animal refuses the growth of the front legs with the homolateral hind legs (0), it accepts the desired growth only by one side (0.5), it accepts the growth on both sides (1).

The compound of Example 3 strongly opposes catalepsi induced by prochlorpemazine at a dose of 20 mg / kg.

3) - Antiemetic activity.

The antagonism towards vomiting caused by anomorphine is studied in dogs (CHEN and ENSOR J. Pharmac.

 Therap. 1959, 93, 245-250).

The number of vomiting caused by a subcutaneous injection of 0.1 m / kg of apomorphine hydrochloride is determined on each animal 8 days before the test.

The studied compound, placed in an aqueous solution, is administered subcutaneously at variable doses half an hour before apomorphine hydrochloride.

The compound of Example 2 reduces the vomiting caused by apomorphine at a dose of 2 mg / kg by approximately 50%.

4) - Study of the diluted toxicity.

The agitated 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 the administration of the compound.

The lethal dose 50 (LD50) of the compounds of Examples 3 and 4 is equal to 400 m / kg: that of the compounds of Examples 1 and 2 is respectively equal to? 0 and 500 mg / kg and that of the compound of Example 5 is greater than 200 mg / kg.

Claims (7)

1) - The products conforming to formula (I) of claim 1 of the main patent yes are represented by the general formula (I '), in which X' represents a pentyl, 2-phenylethyl, butyl or propene radical -2-yl, as well as their addition salts with mineral or organic acids

2) - 5-chloro 3- (1-pentyl 1,2,3,6-tetra-hydropyridin-4-yl) 1H-indole hydrochloride 3) - 5-chloro 3- / I- (2 -phenylethyl) 1,2,3,6-tetrahydropyridin-4-yl / 1 H-indole 4) - S chloro hydrochloride 3- (1-butyl 1,2,3,6-tetrahydropyridin-4-yl) 1 H-indole. 5) - 5-chloro 3- / 1- (2-propenyl) 1,2,3,6tetrahydropyridin-4-yl) 1 H-indole hydrochloride. 6) - Process for the preparation of tetrahydropyridin-4-yl-indole derivatives as defined in claim 1, as well as their salts, characterized in that a product of formula (II ") is reacted

with a halide of general formula  Hal - X'l (III ") in which-Hal represents a chlorine, bromine or iodine atom and X'l represents a pentyl, phenethyl, butyl, or propen-2-yl radical, to obtain a derivative of general formula (I ') as defined in claim 1, which is isolated and, where appropriate, treated with an acid to form the salt. 7) - Medicines, characterized in that they consist of the new derivatives of tetrahydropyridin-4-yl-indole as defined in claim 1, as well as their addition salts with pharmaceutically acceptable acids. 8) - Drugs, characterized in that they consist of new derivatives of tetrahydropyr.idin-4-yl-indole as defined in claim 4 or 5. 9) - Pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicaments as defined in claim 7 or 8.