FR2460296A1 - NOVEL 1-AMINOALKYL-3-PHENYL-INDOLINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS NEW 1-AMINO-ALKYL-3-PHENYL-INDOLINES NOT SUBSTITUTED IN POSITION 2 OR CARRYING IN POSITION 2 A MONOVALENT SUBSTITUTE, AND THEIR PREPARATION. THESE COMPOUNDS CAN BE USED THERAPEUTICALLY AS ACTIVE INGREDIENTS OF MEDICINAL PRODUCTS.

Description

The subject of the present invention is new

  1-aminoalkyl-3-phenylindolines, their preparation and their application

  cation in therapeutics, as active ingredients of drugs. * The invention relates more particularly to

  1-aminoalkyl-3-phenylindolines which are unsubstituted

  2 or in position 2 a monovalent substituent, and the salts that these compounds form with the acids

minerals or organic.

  More specifically, the invention comprises 1-aminoalkyl-3-phenylindolines of formula I R2

R2 (I)

RR '-R

X-N R4

  wherein R1 and R2 each independently of one another is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms, or a group hydroxy or trifluoromethyl, R 1 and R 2 each independently of one another means a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms or a hydroxy group, R2 represents a hydrogen atom or, when R2 and R2 represent an alkoxy group containing from 1 to 4 carbon atoms, also an alkoxy group containing from 1 to 4 carbon atoms, R3, R4 and R5 each signify independently of one another, a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and X represents a linear alkylene group containing from 2 to 4 carbon atoms optionally substituted by an alkyl group containing from 1 to 3 carbon atoms, the alkylene group X d to be unsubstituted when R3 represents an alkyl group, and the salts that these compounds form with

minerals or organic.

  The alkyl and / or alkoxy groups are preferably

  methyl, ethyl, methoxy or ethoxy groups, in particular methyl or methoxy. When R1, R2, R1 or R2 is a halogen atom, it is preferably

  chlorine or fluorine, in particular chlorine. X represents

  preferably a linear alkylene group

  substituted, in particular an ethylene group.

  R3, R4 and R4 preferably represent hydro-

  gene. R1 is preferably located at position 5 or 6 of the indoline skeleton. It is advantageous that R1 and

  Ri do not represent a chlorine atom located in a posi-

  When R 2, R 3, R 3, R 5 and R 5 each signify a hydrogen atom and X represents an ethylene group R2 is preferably in the meta or para position. According to the process of the invention, to prepare the new 1-aminoalkyl-3-phenylindolines,

  the corresponding 1-aminoalkyl-3-phenylindoles are reduced

  dent. Thus, to prepare the compounds of formula I, compounds of formula II are reduced (formula II see next page)

1 <R2 (II)

  Wherein R 1, R 2, R 3, R 3, R, R and X have

the meanings already given.

  The reduction can be carried out according to the methods usually used to reduce an indole

in indoline.

  For example, the reduction can be carried out with incipient hydrogen, for example with lithium, sodium or potassium in liquid ammonia, or with diborane or complexed borohydrides which

  NaBH4 / BF3 or BH3 / (CH3) 2S. Preferably, the procedure is

  the presence of an inert organic solvent, for example an ether such as tetrahydrofuran. When using liquid ammonia, the temperature is advantageously between about -70 and about -30, preferably between -40 and -30. When a borohydride derivative is used, it is advantageous to operate at a temperature of between about 0 ° C. and the boiling temperature of the reaction mixture. The complex formed is then decomposed by reacting the compound of formula II with diborane or with the borohydride complex by the addition of an acid, for example 4-5N hydrochloric acid. During the reduction with incipient hydrogen, it can happen that the halogen atoms possibly present

be eliminated.

  The compounds of the invention thus obtained can then be isolated and purified according to the methods

known.

  The compounds of the invention may exist

  in the form of enantiomers or in the form of racemates.

  When X represents a substituted alkylene group or when R 3 represents an alkyl group, the compounds of

  the invention may exist as diastereoisomers.

  Racemic and diastereoisomers can be

  separated by known methods, for example by crys-

  fractionalization of appropriate acid addition salts. The compounds of the invention may be in the form of free compounds or acid addition salts. If necessary, the compounds can be converted

  free in their salts by reaction with mineral acids.

  organic. As examples of such salts,

  include hydrochloride, fumarate, hydrogen fumarate

  spleen, cyclohexylsulfamate, naphthalene-1,5-di-

  sulfonate or hydrogen maleate. From the salts, the free compounds can be liberated by proceeding according to

known methods.

  To prepare the compounds used as

  compounds of formula II, analogous methods can be carried out, for example from formula III compounds.

X 4 R2R2 (III)

R2 H

  wherein R 1, R 1, R 2, R ", R 2 and R 3 have the significances

already given.

  To prepare the compounds of formula II in which the residue -X-NjR4 represents a residue -X'-CH -N4 represents-2 NR5 (where X 'signifies a linear alkylene group

  containing from 1 to 3 carbon atoms, optionally

  with an alkyl group containing 1 to 3 carbon atoms), a residue -X'-CONR 4 or -X'-CN is introduced on a compound of formula III (for example by reaction with Hal-X'- CON./R4 or Hal-X'-CN) and then the amide or nitrile thus obtained is reduced to the corresponding amines and the group is optionally alkylated.

unsubstituted amino.

  Compounds of formula II in which the residue -X-N / R4 represents a residue can be prepared.

0 H -R4

  -CH2-VH-CH2-N / R5 (where R is hydrogen or an alkyl group containing from 1 to 3 carbon atoms), for example by reacting a compound of formula CH2 = -CN with a compound of formula III followed by hydrogenation of the 1-cyanoethyl derivative thus obtained, for example in the presence of Raney nickel and ammonia in ethanol. The amino group can then optionally be alkylated.

  unsubstituted compounds thus obtained.

  In order to prepare the compounds of formula II in which the radical -XN R4 represents a residue of formula -CH2-XN 4, a compound of formula III is treated with a Grignard reagent for example, the product obtained is reacted with an ester of an amino acid of

  formula-HOOC-X'-NR4, then reduce to 1-

  aminoalkylindole the resulting compound of formula IV R (IV) 3!

R)

R. 2 - N <R R s

  wherein R1 to R4, R1, R1, R and X 'have the significances

  already given by reaction with, for example, an appropriate amount of borane / dimethylsulfide complex. When the preparation of the starting materials is not described, these compounds are known or can be prepared according to known or analogous methods

the methods described below.

  The following examples illustrate the present invention without in any way limiting its scope. The

  all temperatures are in degrees Celsius.

Example 1

  1-t (2-aminoethyl) -3-phenylindoline To a solution of 17 g of sodium in 500 ml

  of liquid ammonia, a solution is added dropwise

  34.7 g of 1- (2-aminoethyl) -3-phenylindole in 300 ml of tetrahydrofuran. After 30 minutes of reaction, the excess sodium is decomposed by addition, in portions,

  of solid ammonium chloride and the ammonia is evaporated.

  The hydrogen maleate of the title compound melts at 169-170

  after recrystallization from ethanol.

  To prepare 1- (2-aminoethyl) -3-phenyl-

  indole, used as starting material, the procedure is as follows: a) To a suspension of 22.7 g of sodium hydride (55% in oil) in 350 ml of dimethylformamide,

  add a 100 g solution of 3-

  phenylindole in 350 ml of dimethylformamide. When the evolution of hydrogen has ceased, 73 g of solid chloroacetamide are added and the mixture is stirred for 17 hours at room temperature. We then pour

  the mixture on ice water: 3-phenylindol-1

  acetamide precipitates. It melts at 200-202 after recreating

  metallization in methylene chloride.

  b) 54.6 g of lithium aluminum hydride in 1 liter of tetrahydrofuran are added dropwise to

  drop at -30, a solution of 14.4 ml of sulfuric acid.

  Concentrated in 200 ml of tetrahydrofuran. The temperature of the mixture is then allowed to return to 0 °, a suspension of 90.2 g of 3-phenylindol-11-acetamide in 700 ml of tetrahydrofuran is added dropwise and this mixture is stirred for a further 2 hours at room temperature. . The resulting 1- (2-aminoethyl) -3-phenylindole hydrochloride melts at

268-270.

  Example 2 1- (3-Aminopropyl) -3-phenylindoline Using the procedure described in Example 1 and using a suitable compound of formula II, the title compound is obtained. Cyclohexylsulfamate

composed of the title melts at 167-168.

  To prepare 1- (3-aminopropyl) -3-phenyl-

  indole (oxalate melts at 194-195 after recrystallization from ethanol), used as a starting material, 3-phenylindole is reacted with acrylonitrile in

  dioxane in the presence of benzyltrimethylhydroxide

  ammonium then hydrogenated with Raney nickel at 50

  and under normal pressure, 1- (2-cyanoethyl) -3-phenyl-

indole thus obtained.

Example 3

  1- (2-Aminopropyl) -3-phenylindoline (isomers A and B) Proceeding as described in Example 1 and using the appropriate compound of formula II, the title compound is obtained in the form of a mixture. isomers. From this mixture, the two isomers are obtained by fractional recrystallization from ethanol and a mixture of ethanol and ether. The hydrochlorides of these two isomers respectively melt at 249-251

and at 238-240.

  To prepare 1- (2-aminopropyl) -3-phenyl-

  indole, used as starting material, the procedure is as follows: a) To 3.6 g of magnesium turnings in 50 ml of diethyl ether, a mixture of

  ml of methyl iodide in 50 ml of diethyl ether

  and heat the mixture until all the magnesium has disappeared. Then add drop to

  drop a solution of 29 g of 3-phenyl-

  indole in 100 ml of tetrahydrofuran and, after 15 minutes, a solution of 11.7 g of ester is added

  of DL-alanine in 100 ml of tetrahydro-

  furan. After refluxing the mixture for 18 hours, it is poured onto a mixture of ammonium chloride, water and ether and separated.

  the organic phase. 1- (2-Aminopropionyl) -

  3-phenylindole with an aqueous solution of tartaric acid. After releasing the base, it is transformed into fumarate by reaction with fumaric acid in methanol. The fumarate melts at

241-243.

  b) To a solution of 14 g of 1- (2-aminopropionyl) -3-

  phenyl-indole in 100 ml of tetrahydrofuran, 15.8 ml of a borane / sulphide

  of dimethyl and the mixture is heated for 30 minutes.

  you're refluxing. After evaporation under reduced pressure, the evaporation residue is dissolved in 50 ml of glacial acetic acid and allowed to stand for 2 hours at room temperature. The solution is then poured into ice water, basified by the addition of concentrated ammonia and extracted with diethyl ether. After washing with water and drying over sodium sulfate, evaporate completely

  the organic phase and transform the 1- (2-aminopropyl)

  pyl) -3-phenylindole obtained as an oily residue, hydrogenaleate; this one melts at 186-189

  after recrystallization from ethanol.

  Proceeding as described in Examples 1 to 3, and using the appropriate starting compounds of formula II, the compounds of formula I can be prepared.

  specified in Tables I and II below.

TABLE I

  This table gathers the compounds of formula I in which R R ', R2 and R each signify an atom, which R 2 2 3 of hydrogen and the

-CH2-CH2-NH2

  remains -X-NR4R5 represents a group Example R1 R2 Melting point _ _. , _o

143-144

-183

177-180

188-190

172-176

-178

168-170

171-173

162-164

172-177

159-163

154-157

154-159

154-156

156-158

-134 -172

168-170U

  (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrogenofumarate) (hydrogen maleate) (fumarate) (hydrogen maleate) (hydrogen fumarate) (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) ) (base) -158 (hydrogen maleate) decoposition from 280 (hydrochloride) 166-167 (hydrogenaleate) 182-185 (hydrogenaleate) 193-3197 o (hydrogenaleate) 208-210 (hydrochloride) 172-175 (base) -139 (base) -F 7-F 7-Cl 7 -CH 3 HHH 4-Cl 6 -Cl HHHH Cl -OCH 3 6-F 4-F-OH 6-Cl 6 -Cl 6-F-OH -OH 6-F 6 ## STR2 ## TABLE I (contd.) ## STR2 ## ## STR2 ##

182-185

164-167

176-179

-198

168-170

-165 78 -177 -135

138-142

  * (hydrogen maleate) (hydrogen maleate) (hydrogen maleate) (hydrochloride) (hydrogen maleate) (hydrochloride) (base) (hydrogen fumarate) (hydrogen maleate) (hydrogen maleate) H H 6 CF 3 4-CF 3 -Br

6-OCH3

  H-OCH 3 -OCH 3 p-OH p-CF 3 H H H H p-OCH 3 m-OCH 3 p-F m-Cl

T A B L E A U II

  This table II groups the compounds of formula I in which R 'and R "a hydrogen atom 1 2 each signify Ex. R 1 R 2 R 2 R 3 X R 4 R 5 Melting point Salt

CH 2-CH

CI 2-CE2

CH2-CH2-CH2

CH2-CH2-CII2

  CII2-CH12-CH12-CH2 -C11H (CH3) -CH2-Cl (CH3) -CII2

ITC-II

CiH2-CIH2

CH2-CII2

ITC-ECI

C 2-12

CH2-CH2

CII 2-CH2

CH -CH

  CH3 CH3 CH3 CH3 HI H H H H H CH3 CH3 CH3 H

161-162

-151

163-164

235-237

-172

224-226

172-174

194-197

178-181

128-132

146-150

  d6comp. from 242 dCcomp. from 250

158-162

  (cyclohexylsulfamate) (cyclohexylsulfamate) (cyclohexylsulfamate)

(Na) -Hthalene-1,5-di-

  sulfonate (hydrogenofumarate) (fumarate) (hydrogenofumarate) I (hydrochloride) (hydrogen fluoride) (hydrogenalate) (cyclohexylsulfamate) (hydrochloride) (hydrochloride) | (cyclohexylsulfamate) ## STR1 ## ## STR2 ## Hi H HI H CH3 CH3 CH3 CH3 ii

  The compounds of the invention and their

  Acid production has not been described so far in the literature. In tests carried out on

  laboratory animals, they are distinguished by interest

  your pharmacodynamic properties. In particular, they possess the characteristic properties of active substances

  antidepressant, as shown by the following tests.

  The antidepressant action of the compounds of the

  vention has been demonstrated by the inhibition they exert on the syndrome caused by tetrabenazine in the rat. The method is described by Stille in Arzneimittelforschung 14, 534 (1964). Intravenously administered at a dose of 10 mg / kg, tetrabenazine causes ptosis and catalepsy in rats. The intensity of these two symptoms is evaluated according to a system of notes. When a substance has an inhibitory action on the syndrome caused by tetrabenazine, the numerical value attributed to both

  notes diminish; on the other hand, when it reinforces the

  drome, this value increases. A substance therefore exerts an antidepressant action when it significantly lowers the note of symptoms. Tetrabenazine is administered 30 minutes after administration of the test compound. In general, the compounds of the invention significantly inhibit ptosis and catalepsy caused by tetrabenazine when administered orally at doses comprised

between 1 and 50 mg / kg.

  Thanks to these properties, the compounds of the invention

  and their acid addition salts may be used.

  in therapy as antidepressants. They will be prescribed in daily doses of between approximately 1 and 300 mg of active substance, for example from 5 to 150 mg, which will be administered in one single dose or in several unit doses each containing from 0.25 to 150 mg of substance

  active, 2 to 4 times a day.

  Acute toxicity of the compounds of the invention

  was determined in mice and rats after administration

  oral treatment. For 1- (2-aminoethyl) -3-

  phenylindoline, for example, the LD50 is 213 mg / kg in the mouse and 250 mg / kg in the rat.

  The compounds of the invention may be administered

  in the form of free bases or in the form of their salts, the activity of which is of the same order as that of the bases

free, corresponding.

  The compounds of the invention as well as their pharmaceutically acceptable salts can be used as medicaments, either as such or in the form of

  pharmaceutical compositions suitable for use in

  administration by the oral, rectal or parenteral route.

  To prepare suitable pharmaceutical compositions, the active substance is worked with excipients

  minerals or organic, inert from the pharmaceutical point of view

  ecological. As excipients, it will be possible to use

example:

  for tablets and dragees: lactose, starch, talc, stearic acid etc.; for syrups: water, sucrose, invert sugar, glucose etc .; for injectable preparations: water, alcohols, glycerol, vegetable oils etc .; for suppositories: natural or hardened oils,

waxes, greases etc ...

  The pharmaceutical compositions may further contain preservatives, dissolvers, stabilizers, wetting agents, sweeteners,

  colorants, flavoring, etc., suitable.

  Pharmaceutical composition example: 1- (2-aminoethyl) -3-phenylindoline tablets 10.00 mg Magnesium stearate 1.00 mg Polyvinylpyrrolidone 4.00 mg Talc 5.00 mg Corn starch 10.00 mg Lactose 168.00 mg Dimethylsilicone 0.50 mg Polyethylene Glycol 6000 1.50 mg mg These tablets may be prepared in accordance with

known methods.

Claims (16)

  1. Non-aminoalkyl-3-phenylindolines   substituted in position 2 or in position 2   monovalent, and the salts that these compounds form with mineral or organic acids. 2. New 1-aminoalkyl-3-phenylindolines, characterized in that they correspond to formula I R R1 R2 (I) X-NR   wherein R1 and R2 each independently of one another is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms, or a group hydroxy or trifluoromethyl, R 1 and R 3 each independently of one another is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms or a hydroxy group, R represents a hydrogen atom or, when R2 and Rt 2 2   represent an alkoxy group containing from 1 to 4 carbon atoms, also an alkoxy group containing from 1 to 4 carbon atoms, R3, R4 and R5 each signify, independently of one another, a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and X represents a linear alkylene group containing   2-4 carbon atoms optionally substituted.   by an alkyl group containing from 1 to 3 carbon atoms   carbon, the alkylene group X to be unsubstituted   killed when R3 represents an alkyl group, and the salts that these compounds form with acids - minerals or organic.   3. New 1-aminoalkyl-3-phenylindolines, characterized in that they correspond to formula I R R; -X --- N R4   Wherein R1 and R2 each independently of one another is a hydrogen, fluorine or chlorine atom or a hydroxy, trifluoromethyl, methyl or methoxy group, R1 and R are each an atom of hydrogen, R is hydrogen or chlorine, R3, R4 and R5 are each independently of one another hydrogen or methyl, and X is ethylene, propylene, butylene or a-methyl-ethylene, X to be different from a-methyl-ethylene group when R3 is methyl, and the salts these compounds form with acids minerals or organic.   4. The 1-aminoalkyl-3-phenylindolines according to   any of claims 2 and 3, characterized   in that R1 and R 'are different from a chlorine atom in that R1 and R   located in position 5 of the indolinic skeleton.   5.- 1- (2-aminoethyl) -3-phenylindoline, and the salts that this compound forms with mineral acids or organic.   6. The 1-aminoalkyl-3-phenylindolines according to   any of claims 1 to 5, characterized   in that they are present as enantiomers or racemates,   7. A process for the preparation of 1-aminoalkyl   3-phenylindolines which are unsubstituted at the 2-position or which carry a monovalent substituent at the 2-position, and   salts thereof, characterized in that a 1-amino-1   corresponding alkyl-3-phenylindole and, if appropriate, the compounds thus obtained are converted into their acid addition salts by reaction with mineral acids or organic.   8. A process for the preparation of 1-aminoalkyl   3-phenylindolines of formula I R -X-N-R   wherein R1 and R2 each independently of one another is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms, or a group hydroxy or trifluoromethyl, R 'and R2 each independently of one another means a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms or a hydroxy group, R represents a hydrogen atom or, when R and R ' 2 22   represent an alkoxy group containing from 1 to 4 carbon atoms, also an alkoxy group containing from 1 to 4 carbon atoms, R3, R4 and R5 each signify, independently of one another, a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and X represents a linear alkylene group containing from 2 to 4 carbon atoms optionally substituted by an alkyl group containing from 1 to 3 carbon atoms.   carbon, the alkylene group X to be unsubstituted   killed when R3 represents an alkyl group, and their salts, characterized in that a compound of formula II is reduced R2 (I) R X - N'R4   in which R1 to R5 R, R, R, and X have the significances   already given, and, where appropriate, converting the compounds of formula I thus obtained into their acid addition salts.   by reaction with mineral or organic acids.   9.- The therapeutic application of 1-amino-   alkyl-3-phenylindolines specified in any one of   Claims 1 to 6 as Active Ingredients of drugs.   10.- A drug, characterized in that   contains, as active ingredient, a 1-aminoalkyl-3-   phenyl-indoline unsubstituted in the 2-position or in the 2-position a monovalent substituent, in the free state   or in the form of a pharmaceutically acceptable salt.   ceutical. 11. A medicament, characterized in that it contains, as active principle, a 1-aminoalkyl-3-phenylindoline corresponding to the formula I R RR2 R R. "(I) X 1 {-R4   wherein R1 and R2 each independently of one another is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms, or a group hydroxy or trifluoromethyl, R 'and R, each independently of one another, is a hydrogen, fluorine, chlorine or bromine atom, an alkyl or alkoxy group each containing from 1 to 4 carbon atoms or a hydroxy group, R represents a hydrogen atom or, when R and R ' 2 22   represent an alkoxy group containing from 1 to 4 carbon atoms, also an alkoxy group containing from 1 to 4 carbon atoms, R3, R4 and R5 each independently of one another means a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and X represents a linear alkylene group containing from 2 to 4 carbon atoms, optionally substituted by an alkyl group containing from 1 to 3 carbon atoms.   carbon, the alkylene group X to be unsubstituted   killed when R3 represents an alkyl group, in the free state or in the form of a salt acceptable from the point pharmacy.   12. A medicament, characterized in that it contains, as active principle, a 1-aminoalkyl-3-phenyl indoline corresponding to the formula I R2 R2 (I) -X 'R4   wherein R 1 and R 2 each independently of one another is hydrogen, fluorine or chlorine, hydroxy, trifluoromethyl, methyl or methoxy, R 1 and R 2 are each hydrogen, R 2 is hydrogen or chlorine, R 3, R 4 and R 5 are each independently of one another hydrogen or methyl, and X is ethylene, propylene, butylene or the like; -methyl-ethylene, X to be different from an α-methyl-ethylene group when R3 represents a methyl group, in the free state or in the form of an acceptable salt of pharmaceutical point of view.   13.- A medicament, characterized in that   contains, as an active principle, a 1-aminoalkyl-3-   phenylindoline as specified in claim 4, in the free state or in the form of a salt acceptable from the point pharmacy.   14.- A drug, characterized in that   contains, as an active ingredient, 1- (2-aminoalkyl) -   3-phenyl-indoline, in the free state or in the form of a salt   acceptable from a pharmaceutical point of view.   15.- A drug according to any of the   Claims 10 to 14, characterized in that the principle   active is in the form of racemic or enantiomeric.   16.- A pharmaceutical composition, characterized   in so far as it contains at least one of the   assets specified in any of the claims   to 15, in combination with excipients and vehicles   acceptable from the pharmaceutical point of view.