BE724813A - - Google Patents

Description

  

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  "Process for the preparation of benzodiazepine derivatives"

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The present invention relates to a process for the preparation of benzodiazepine derivatives. More particularly, the invention relates to a new process for the preparation of a benzodiazepine derivative corresponding to the formal (I)
 EMI2.1
 wherein R represents a hydrogen atom or an aloyl group of 1 to 4 carbon atoms, R1 represents an alooyl, alkoxy, or haloalkyl group of 1 to 4 carbon atoms;

   an alkyl-sulfonyl group of 1 to 4 carbon atoms, a dialkoylamino group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R represents a hydrogen or halogen atom or else an alkyl, alkoxy or lialoalkyl group of 1 to 4 carbon atoms.



   In other words, the invention relates to a process in which benzodiazepine derivatives corresponding to the formula (I) are easily obtained by reacting a 2-amino-methylindole derivative corresponding to the formula (II)
 EMI2.2
 

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 in which R, R1, R2 and R3 respectively have the meanings as those indicated above, or its ground, with an appropriate oxidizing agent.



   It is known that the bezxoidiazepine derivatives corresponding to the formula CI) exert remarkable tranquilizing, muscle relaxation, anti-convulsant and hypnotic effects.



   Some processes for the preparation of benzodiazepine derivatives have been described For example, in one of the most useful processes, a benzodiazepine derivative is obtained by reacting a 2-aminobenzophenone derivative with glycine hydrochloride or ethyl ether. glicine (German patent no.1145.626).



   A benzodiazepine derivative is also prepared by treating a chloroatetamidobezophenone with ammonia (Sternbach et al: "Journal of Organio Chemistry". 27, 3788 (1962) and German Patent No. 1,136,709).



   Contrary to these processes, surprisingly, the Applicant has found that it is possible to prepare easily and economically a benzodiazepine derivative corresponding to the formula (1) with a high yield and a high purity, by reacting a derivative of 2- aminomethylindole of formula (II) or its salt with a suitable oxidizing agent. This process of transforming a compound with a pentagonal ring into a compound with a heptagonal ring by a ring expansion reaction has not yet been described or suggested so far in the literature. Therefore, the new method of the present invention is by no means obvious from the known methods and. moreover, it is very useful and unexpected.



     These new raw materials, namely the 2-aminomethylinodle derivatives, for example by

  <Desc / Clms Page number 4>

 
 EMI4.1
 reduction of indole2-carboxamid derivatives or indole-2-carbonitriles d6r1v68.

   The new indole-2-oarbonitrile derivatives are prepared by dehydrating an indols-2-carboxmddo These indole-2-carboxanides derivatives are also new compounds that are prepared by amidation of the indole-2- acid derivatives. carboxylic acids with good yield, Ds plus
 EMI4.2
 most of the indole-2-crboxylic acid derivatives are new and are obtained, for example, by cyclization of benznediazonium compounds with eateya derivatives of al plabsnzy.w'oÂti.-ottoat5:.
All of these processes go smoothly and give the desired products in high yield, so these processes are very useful in practice.



   An object of the present invention is to provide a novel process for the preparation of benzodiazepine derivatives of formula (I). Another object is to provide a novel process for the preparation of salts of benzodiazepine derivatives by treating them. benzodiazepine derivatives of formula (I) with an inorganic salt or an organic acid.



   Another object of the present invention is to provide novel indole derivatives and novel phenyl hydrazone derivatives.



   Other objects of the present invention will emerge from the following description.



   In order to achieve these objects, the present invention pre-
 EMI4.3
 sees a process for the preparation of bsxzod3.t.z6p.rd derivatives corresponding to formula (I), this process consisting in reacting a 2-mninomethylindolo derivative corresponding to formula (II) or its salt with an oxidizing agent

  <Desc / Clms Page number 5>

   In addition, the present invention provides a process for the preparation of salts of benzodiazepine derivatives of formula (I), this process consisting in reacting a 2-amincmethylindole derivative of formula (II) or its salt with an oxidizing agent to obtain the benzodiazepine derivative of formula (I),

   then treating the obtained benzodiazepine derivative with a mineral acid or an organic acid.



   The process of the present invention is illustrated, by way of example, by the following reaction scheme, but it is understood, however, that this scheme is given merely by way of illustration and that it in no way limits the present invention.

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 EMI6.1
 

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 EMI7.1
 

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 EMI8.1
 In these formulas, R, Rl, R2 and R3 have the same meanings as those defined above, R4 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R5 represents an aloyl group of 1 to 3 carbon atoms, R5 represents an alkyl group of 1 to 4 carbon atoms, Y represents a halogen atom and Hal represents a halogen atom.



   The process of the present invention is illustrated in detail below.
 EMI8.2
 bzz- Preparation of phenylhydfazone derivative (VII) In the process of the present invention, the
 EMI8.3
 phenylhydragon derivatives (VII) by reacting a phenylhydrazine derivative (III) or its salt with a phenylpyruvic acid derivative (IV).



   Preferably, the reaction is carried out in the presence of an inert solvent such as lower alkanols, for example, methanol, ethanol and the like or an organic acid such as formic acid, acetic acid and the like. . The reaction takes place at room temperature, although a slightly elevated temperature can be employed to increase the rate of the reaction.



   According to the present invention, among the phenylhydrazone derivatives (VII), there are, for example, the following compounds
 EMI8.4
 p-methylphenylhydrazone from phenyipyruvic acid, p-methoxyphenyihydrazone from phônylpyruvic acid, p-trifluoromethyl-phenylhydrazone from phenylpyruvic acid, p-methylsultonyl-pheny1hydraone from u phenyl-lapruv3q acid, phenylhydrazone from phenylpyruvic acid, p-diethylamina-phenylhydrazons from phenylpyruviquo acid, p- (1'-piperasinyl) phenylhydra3one from phenylpyruvic acid.

   

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 EMI9.1
 la, d..2'hy.phnylhrdrs.zrao from phenylpyruvic acid, 4 .. 'rcmoH3-mtha-phzylhyàra.zono from phenylpyruvic acid, p-methylphenylbydrazone from o-ohlorophenylpyruviqu6 acid, pm , thoayphëny.hydrazons of c-ehlorophenylpyruvic acid, p-dimethylamino-phenylhydrazone of o-chlorophenyl-pyruvic acid,
 EMI9.2
 p-methyl-phenylhydrazono from o-fluorophenylpyruvic acid and p-methoxy-phenylhydrazone from o-fluorophenylpyruvic acid, p-trifluoromethyl-phenylhydrazone from o-fluorophenylpyruvic acid,
 EMI9.3
 o-fluorbpherylpyruvic acid pm6thyleulfoMl-phenylhydrazone, o-tluorophenylpyruvic acid p-dimethylamino-ph6nylhydrazone,

   Phenylpyruvi acid N.msthyl-p..m.éthy.phenylbydrazcne. as, NI-methyl-p-trifluoromethyl-phenylhydrazone of phenylpyruvic acid, p-mdthy.phnylbydrazone of methyl phenylpyruvate, p-methylphenylhydrazone of ethyl phenylpyruvate.



   In addition, in the process of the present invention, it is also possible to obtain the phenylhydrazone derivatives corresponding to the formula
 EMI9.4
 

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 EMI10.1
 i?>;:?. '' / iu? .c? "j 1i ', 0> i #;?? nn> .ÙD <; ii i:>.?. Y.:?i <ÎzJi ".. 'i' '! D'- -' 'Me? <> <± i? ", îifl> O î C> 5 = <1. - VXr ("'1 lÉ î; fl- ± 3 lLiii F; é P.i? 1.ù'?". Oc:?, O 'b' '.' 3es- "tti? .So.

   (%?) '' woo li1 to. ±>: 5.! - <J; 1 ealsoe d.J 1! Ô "ôii <> ' <'3 * = Mida (lrT), 3n effoe'isn cnl!> O? 4actioas oa peu "à faiso pëas.s' 1.? ± derived from est #; from b6ta" e6to 'aside from òzJ> iu' = 'OEX)
 EMI10.2
 
 EMI10.3
 with a benzene-amazonium sol of the formula
 EMI10.4
 
 EMI10.5
 in pr4sonce of a base, by r3 3.'byd? exyd @ of sodium, potassium hydroxide, 1.o 'methyl.te of 2joilluM sodium etbylate, acetate (sodlim and acetate of potaas1Qmû in a suitable solvent, for example water, methanol or <4.
 EMI10.6
 nol, so that the reaction proceeds easily.
 EMI10.7
 



  Due to the instability of the oel of b6nzàna-dizoni \ (V), the faction is preferably carried out below 10% According to the present invention, among the derivatives (the aII6ny1hydTazone (Vlla) t there are, for example, the composas Buiv8, n'lm: p-zh3.phct3â.hrd.ca of .mÓ'l phenylpyruvate; byJ.e la wan6thy.pérad Qz of dlthyl phenyipyruvate, p-methylphenyihydrasona of r.4vg phenyipyruvate p- methoxyphenylh, drvzor-e of phenylpyruvata from thy3.e p-trifluorome: yl-phenylhydrazne from aa 'ax2 v>;

   

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 EMI11.1
 p mthylsultor, γ1-phenylhydrazon from ethyl phenylpyruvate, pAéthy3.sulorl..pheny3hydrazone from ethyl phenylpyruvate, p-dimethylamino-phenylhydrazone from ethyl phenylpyruvate, p-diethylamino-uphenyihydrazone from ethyl phenylpyruvate ,, i p-methylphenyl hydrazone of ethyl o-fluorophenylpyruvate.

   p-methoxyphenylbydrazone from ethyl O-fluorr'rblpyruvate, p-trifluoromethyl-phenyihydrazono from ethyl o-fluoroph4nylpyruvate, p-methylsulPor1-phenylhydraZOne from 1 o-'luorophény, ethyl pyruvate, p-dimethylamino-phenylhydrazone from ethyl o-tluoropbenylpyruvate, bcomo.-3-methoxypheny.hydrazono from ethyl phenylpyruvate, 4-methylphenylhydrazono from ethyl p-methylphenylpyruvate, p-melthylphény3, ethyl o-chlorophenylpyruvato $ la gmethophény.hydraor 3. ' ethyl o-haQxopbnyâ.pyzuvate, p-dimethylamirvophenylhydrazone from ethyl o-chlorophenylpyruvato.



  II - Preparation of derivatives of indole-2-carboxylic acids (VIII)
According to the process of the present invention, the derivatives of indole-2-carboxylic acids (VIII) are prepared by heating.
 EMI11.2
 both a derivative of phenylhydrazone (VII) in a solvent or in a mixture of solvents.

   As solvents, any solvent inert to the system can be employed and among these solvents there are, for example, lower alkanols such as methanol, ethanol, isopropanol and tertiary butanol. , aromatic solvents such as benzene, toluene and xylene, organic acids such as formic acid and acetic acid or other organic solvents such as

  <Desc / Clms Page number 12>

 
 EMI12.1
 that acetone, chloroform and Cyclohexaneo De 3!, i'd, pl 'the reaction is carried out in the presence of an aid, for example mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,

   phosphoric acid and
 EMI12.2
 pOlyphosphoric acid organic acids such as formic acid and acetic acid or other acidic reagents including Lewis acids such as zinc chloride, ferric chloride, aluminum chloride and boron fluoride .

   The reaction is generally carried out at elevated temperature,
According to the present invention, among the derivatives of indole-2-carboxylic acids (VIII), there are, for example, the compounds according to st
 EMI12.3
 5-me% hyl-3-phenylindole-2-oawboxyliquo acid, 5-me% hoxy-3-phenylinaolh-2-oarboxylic acid, aoido 6 (or) -aethoxr - phenyZ.tdoie-2 .asbosl.iqu, o 5-ttifluoromethyl-j-phenylindole-2-oarboxylic acid, 5-methyleultonyl-3-phenylindole-2-carboxylic acid and 5wethylsulfon acid, yl-phenyündoe.2.carboxyliqu l ' 5-dimethyiamino-3-pheny3indalo-2-carbxylic acid 5-dié% hylamino-3-phenylindolc-2-oarboxylic acid, 5-pipéiidino-3-phônylindole-2-oearboxylic acid, - (o -ohlorophenyl.) - 5-metrlindolo..2 carboxyl.quap 3- (o-chlorophenyl) acid

  -5-methoxy-indole-2-carboxylic acid 3- (o-chlorophenyl) -5-dimethylamino-indole-2-carboxylic acid, 3 o-fluorophél) 5-mthylindoia-2.carboyl, cu0 l ' p- (o-fluorophenyl) -5-methoxy-indole - 2-carboxylic acid (o-fluorophdnyi) -5-tri, f.uorometF, v .-. ndo.a-2.ca.siao lic acid ,

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 EMI13.1
 3- (o, flurrophenyl) -5-methyp, ulfol-.indole-2aoaoxylaid 3, -d.mévhri - phenylindo.e2-ca.rboar..ue acid, 10 .meth, y acid, , -;

  -phenyl-5..triluorvmethyl.-indol-2-carboxy-
 EMI13.2
 lique,
 EMI13.3
 ethyl 5-methyl-µ-phfinylinàolo-2-narboxylate,. 5-methyl-5-ph <methyl bnylindole-2-carboxylate, 5-! Rethyl''3 "-pMnylindole''2-carboxylate from tert-butyl, 5" Nethyl-3-ph ethyl <! nylindolo-2-carboxylate, ethyl µ-phenyl-5-trtLfluoromethylinole-2-canboxylate, 5 "methylsulfo! ethyl-3'-ph6nylindole-2-carboxylate, ethyl 5-ethyl Ethyl -sulfoilyl-3-phenylindole-2-carboxylate, ethyl 5-dimethylamirio-3-phenylindole-e-carboxylate, ethyl 5-diethylanino-µ-phenylindole-2-canboxylate, - (o - '. uoxopher;,) - ethyl 5-methylindola-2-cartoxylates, ethyl µ- (o-fluorophinyl) -5-methoxy-indole-2-carboxylate, - (o-t'âuoroph:

  nyl) - trlluoromethyl-lndole-2-arbocylate
 EMI13.4
 ethyl,
 EMI13.5
 3- (o-fluorophé, iiyl) -5-methylsulfonyl-inole-2-carboxylate
 EMI13.6
 ethyl $
 EMI13.7
 the 3 <- (o-chlorophenyl) -5-methoxy-indole-2-carboxylate ethyl, 3- (o-chlorophenyl) -5-dïmethylamîno-indole-2-carboxylate
 EMI13.8
 ethyl,
 EMI13.9
 ethyl 5-bromo-6-methoxy-3-phenylindoy-2-carboxyate, ethyl 5-methyl-j- (p-tolyl) -indole-2-carboXylate.
 EMI13.10
 



  In addition, the acid derivatives can easily be prepared.
 EMI13.11
 indo.Q - oaxboxylig, usa (VIII) by reacting a derivative
 EMI13.12
 of phenylhydrazine (III) or its salt with a derivative of phenylpyruvic acid (IV). This reaction can be carried out in
 EMI13.13
 a solvent, for example an alkanol such as methanol, ethe, isopropanolt, tertiary butanol, an aro- hydrocarbon.

  <Desc / Clms Page number 14>

 
 EMI14.1
 Epic such as benena 10 toluen6 xylene and organic acid such as aid i'oi t ,. 19a1de aC ± 11 ±> qùù and the like or another inert organic solvent such as acetone, chloroform cyclohexane and analegees, preferably in the presence of an acid catalyst, for example a
 EMI14.2
 mineral acid such as hydrochloric acid broh "acid, dr ,.

   as, sulfuric acid, phosnlaca acid 3.qer poll- phosphoric acid and the like, an organic acid such as formic acid and acetic acid, a Lewis acid such as zinc chloride, ferric chloride, aluminum chloride, boron fluoride and the like, or a cation exchange resin. When a salt of the phenylhydrazine derivative (III) is used as a starting material, the reaction proceeds even in the absence of the above-mentioned acid catalyst to obtain the desired indole-2-carboxylic acid derivative (VIII).

   Among the salts of the phenylhydrazine (III) derivatives utilized in the process of the present invention, there are, for example, the salts of inorganic acids such as hydrochlorides, hydrobromides and sulphates or salts of organic acids such as organic acids. acetates and oxalates.



   The reaction usually takes place at room temperature, but the reaction can optionally be controlled by heating or cooling, although heating and cooling are not always necessary.



   According to the present invention, among the derivatives of indole-2-carboxylic acids (VIII), there are, for example, the following compounds:
 EMI14.3
 1 'methyl-phenylirdoâa-2-carboxy3iuc acid 5-metho' -; - phenylindole-2-oarboxylic acid 6 (or 8) -methoxy.-phênylindoâ, a-2..car3ocr3iqua

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 EMI15.1
 5-.btifluoromethyl-3-phenylindole-2-catboxylic acid, 5-methylsulfonyl-3-phenylindole-2-carboxylic acid, 5-ethylsulfonyi-3-phenylindolo-2-carboxylic acid, 5-ethylsulfonyi-3-phenylindolo-2-carboxylic acid, 5 -dimethyInnino-3-phenylindole-2-carboxylic, 5-diethylanino-µ-phenylindole-to-carboxylic acid,
 EMI15.2
 5-piperidino-3-phenylindole-2-carboxylic acid,
 EMI15.3
 3- (o ohlorophenyl) - 5-mthylindolo - carboxylic acid - (o-chlorophenyl) -5-methoxy-icdole-2-carboxylic acid, 3- (o'-chlorophenyl) acid

  -5-dimethylamino-indole-2-'carboxyli-
 EMI15.4
 than,
 EMI15.5
 5- (o-fluorophenyl) -5-wethylindolo-2-carboxylic acid, 3 - (o-fluorophen-1) -5-mthoxy-ir.dale-2-carboxylic acid 5- ( O-fluorophenyl) -5-trifluorom6thyl-indole-2-carboxy ..
 EMI15.6
 lique,
 EMI15.7
 3- (o fluarophényi) -5-mthy.sn3.fonyl-.ndolL-2-Qrrboxylic acid 1,5-dinethyl-µ-phenylinàole-2-carboxyliquo acid, 1-methyl-µ- acid phenyl-5-trifluoromethyl-indolo-2-catboxyli-
 EMI15.8
 than.

   
 EMI15.9
 In addition, we obtain directly derivative of cotera
 EMI15.10
 indole-2-carboxylic acids of the formula
 EMI15.11
 
 EMI15.12
 in which R1, lut R and R have the same meanings as those defined above, 6n treating a benzene-diazonium salt (V) with an ester derivative of beta-keto-acid (VI),

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 When this process is carried out, the
 EMI16.1
 beta-keto-acid ester derivative (VI) with benzene-diazonium (V) nel in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium acetate and potassium acetate in a suitable solvent such as water, methanol and ethanol,

   so that the reaction proceeds easily. Due to the instability of the benzene-diazonium (V) salt, the reaction is preferably carried out below 10 ° C., more preferably below 5 ° C. treatment of the reaction product with an acid results in the formation of the indole-2-carboxylic acid ester derivative (Villa). However) the reaction product is preferably isolated once before the next step.

   In this reaction, it is suitable to employ an acido, for example a mineral acid such as acid
 EMI16.2
 hydrochloride, hydrobromic acid, sulfuric acid, phosphoric acid, polyphosphoiic acid and the like or another Lewis acid such as zinc chloride, forric chloride, aluminum chloride, stannous chloride, boron fluoride and the like.

   In this reaction, the following solvents are most useful, for example alkanolates such as methanol, ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, organic acids such as acid. formic and acetic acid or other organic solvents such as acetone, chloroform and cyclohexane.



   According to the present invention, among the acid derivatives
 EMI16.3
 indolo ... 2-carboliquea (Villa), there are, for example, the following compositions! ethyl 5'-a3thyl-'3'-phenylindolQ-2-carboxylata or methyl 5-mthyl - phenylindclo-2-oarboxylatG,

  <Desc / Clms Page number 17>

 
 EMI17.1
 . :

   reh.-i. ph> aïr3.adr.o.-cax'oxy.wtù of tert-butyl @ t 5-iethyl-3-phìnylindole-2-canboJtyla% e ethylo, pher1.45., tx.iuoxomé hy.- : Lnco2e - ethyl o.roxyïate,
 EMI17.2
 
 EMI17.3
 ethyl 5-methylsulfo! 'tyl-3' - 'phenylindole-2-carboxylato, ethyl -étlylsul.onyi -.- pb.ény3.indola-2-carboxylata, 5-dimethylamiiio-µ-phenylindole Ethyl -2-carboxylato, ethyl 5-diethylamino-µ-phenylindole-2-carboxylate, ethyl 3- (o-fluorophtinyl) -5-m ± thylindole-2-carboxyleto, ethyl µ- ( ethyl o-fluorophéinyl) -5-methoxy-indole-to-canboxylate, 3- (o-fluoroph4inyl) -5-trifluoromethyl-indole-2-caiboxylate
 EMI17.4
 ethyl,
 EMI17.5
 - (o-'uoxaphnyi) -5-mathylsulfonyl-indoe-2-.carboxy3.ac;

   
 EMI17.6
 ethyl,
 EMI17.7
 ethyl µ- (o-chlorophé; nyl) -5-nethoxy-indole-2-canboxyla.be, 3- (o-chloiophéinyl) -5-dimethylamino-inole-2-carboxylate
 EMI17.8
 ethyl,
 EMI17.9
 ethyl 5 '-' b! 'omo'-6'-methoxy-3-phenylindole-2-carboxylate, ethyl .methyl-.- f p> tolyl) -indolo-2-carbo: ethyl cylate.
 EMI17.10
 



  In addition, according to the process of the present invention, the indole-2-carboxylic acid derivatives can be prepared.
 EMI17.11
 answering the formula
 EMI17.12
 
 EMI17.13
 in which R, Ri R and R3 have the same meanings as
 EMI17.14
 cells defined above, by converting an indole-2-carboxylic acid ester derivative of the formula

  <Desc / Clms Page number 18>

 
 EMI18.1
 wherein R1, R2, R3 and R6 have the same meanings as defined above, to its corresponding free acid.

   Thus, when treating the indole-2-carboxylic acid ester derivative (Ville) in water and / or alkanols such as methanol or ethanol, preferably in the presence of 'a hydrolyzing agent, the derivative of indole-2-carboxylic acid (VIIIb) is obtained.



  Among the hydrolyzing agents useful in this reaction are, for example, a mineral acid such as lucide hydrochloride and sulfuric acid, an alkali metal hydroxide such as sodium hydroxide and potassium hydrqxide. , an alkali metal carbonate such as sodium carbonate and potassium carbonate, an alkaline earth metal hydroxide such as barium hydroxide and calcium hydroxide and an ammonium compound such as sodium hydroxide Ammonium or the like, with alkali metal hydroxide or alkaline earth metal hydroxide being preferred. The reaction can be carried out even at room temperature, preferably at an elevated temperature.



   In addition, the indole-2-carboxylic acid ester derivative (Ville) can be converted into the indole-2-carboxylic acid derivative (VIIIb) by treatment in an organic acid such as acetic acid and propionic acid is the presence of a mineral acid.

  <Desc / Clms Page number 19>

 



   Alternatively, when R6 of the indole-2-carboxylic acid ester derivative (Ville) represents a tort-butyl group, the acid ester derivative can also be converted
 EMI19.1
 2-Carboxylic (Ville) as an ind-1- = - \ Jarboxylic acid derivative sought (VIIIb) by o "'e .- ::! :) Q .... If \; le a mineral acid or do tolueno-sulfonic acid When the indole-2-carboxylic acid ester derivative (Ville) is a benzyl group, the benzyl group can also be removed by hydrogenolyso.



    The reloaded substance can be obtained as a metallic sol or an ammonium salt.



   According to the present invention, among the derivatives of indole-2-carboxylic acids (Ville), there are, for example, the following compounds!
 EMI19.2
 5-methyl-3-phzylindo.a-2-oarboxyliquo acid! 5-methox acid, y - phenylindolt-2-carbaxyliqua, 6 (or 8) -methoxy -; - phenylindolo-2..carboxyl3 than 5-tritluoromethyl-3-phenylindole-2-carboxylic acid, 5.-methylgultonyl-3.-phenylindole-2-carboxylic acid, 5-ethylsulfonyl-3-phenylindole-2-carboxylic acid, 5-dimeth;

  ylanino-µ-phenylindolo-2 <carboxylic acid, 5-diethylamino-µ-phenylindole-2-car% oxyliquoe, 5-pip6ri.àino-3-phenylindolw-2-co, rboxyliquo, 3- (o-chloroph6nyl) acid -5-methylindole-2-o..rboxyliquo, acid - (o.-ohlorophenyl-.5-rethoxy-indol-2-ctrboxyliqur, 3- (o-chlorophenyl) -5-dimethylamino-indole- acid 2-crrboxylic acid, 3- (o-fluorophenyl) -5-methylindolo-2-carboxylic acid, 3- (o-rlu, rophenyl-5-methyloxy-indolo-2-carboacylic acid, 3- (o-fluorophenyl) -5-trifluoromdthyl-indolo-2-carboxylic,

  <Desc / Clms Page number 20>

 
 EMI20.1
 3- (o-tluorophenyl) -5-methylsulfonyl-inaolo-2-oawboxy- acid
 EMI20.2
 league,
 EMI20.3
 1,5-Dimethyl-µ-Qhenylindole-2-carboxylic acid, 1m3thy .-. Phdnyl acid;

   ptxi'1u4 omêthy? iudole - cnboxy ..-
 EMI20.4
 than,
 EMI20.5
 J'acid -mthoxy -.- methyl - péay.indola-2-carboxy3idta, 1 acid l-éthyl-5-méthylsulfonyl-3-phésylindole-2-ca.rbo: Kylique, acid 1-mdthy3 .-- methylaul'onyl - phnyl.ndo.e - cax bo.rl.que., 5-thy3.sulonyl - 1-methyl-3-ph6nylinloJ.ea2.cxsbaac ,, iâ.quo, acid 1-uathy.-3-phdnyl-5-tr.luoromthy7:

  -indcle - aarloxy
 EMI20.6
 lique,
 EMI20.7
 3- (o-'luoxophnyl-1-ndthyla5atxiluosoxietiyl.ndala -'- acid
 EMI20.8
 carboxylic,
 EMI20.9
 µ- (o- = luoroph6nyl) -1-nethyl-5-nethyl sulfonylindolLo-2- acid
 EMI20.10
 carboxylic,
 EMI20.11
 3- (o-chlorophenyl) -5-dimethylandno-l-methylindol acid <9-2 '' -
 EMI20.12
 carboxylic,
 EMI20.13
 5-dimdthylam.i.no-1-methyl - (o-txi'luoxomêthy .-. Ndolo- acid
 EMI20.14
 2-carboxylic,
 EMI20.15
 5,6-dinethyl-5-phôn> .lindolo-2-carboXylic acid, 5,6-dinthoxy -, - phenylindole-2woarboxylic acid 5-Chloro -? - methyl-5-phenylindole-2 -carboxylic, ao.do 5-methyl -? - nitro-3-ph nylindole-2-carboxylic, aoido 5-methyl-3- (p-tolyl) -indole-2-carboxylic acid 5- methyl-µ- (pm ± thoxyphenyl) -indole-2-oarboxyliquo, 5-methyl-3- (p-nitropheno, 1) -indole-2-carboXyliquo acid.



  Furthermore, according to the process of the present invention, the reporylating 1-alkyl-indole-2-carboxylic acid derivatives were prepared with the formula

  <Desc / Clms Page number 21>

 
 EMI21.1
 in which R1, R2, R3 and R4 have the same meanings as defined above and R7 represents a lower alkyl group of 1-4 carbon atoms, by reacting an indole. 2-carboxylic acid derivative corresponding to to the formula
 EMI21.2
 in which R1, R2, R3 and R4 have the same meanings as defined above, with an alkylating agent.



  The alkylation is carried out by treating the indole-2-carboxylic acid derivative (Ville) with an alkylating agent in the presence of a. alkali metal compensating agent or after the alkali metal salt has been formed by the alkali metal, then the resulting alkali metal sol is treated with the alkylating agent.



  Among the alkali agents used in the process of the present invention, there are, for example, alkali metals, alkaline earth metals, hydrides of alkali metals, hydrides of alkaline earth metals, hydroxides of alkali metals, alkaline earth metal hydroxides, alkaline metal amides and alkaline earth metal amides,
The alkylation of a derivative of indolo-2carboxylic acid (Ville) is carried out by bringing it into contact with the compounds

  <Desc / Clms Page number 22>

 
 EMI22.1
 following, pal "example, im halosenu .:

  > (1 of alkyl such as methyl chloride, ethyl iodide and ethyl bromide and butyl bromide, an alkyl sulfate such as dimethyl EUI and diethyl sulfate and an aromatic sulfonato alkyl such as paratoluene sultonate from meli, 71a and anal- '
 EMI22.2
 fords.



  According to the present invention, among the derivatives of indole-2-carboxylic acids (VIIId), there are, for example, the following compounds:
 EMI22.3
 1,5-Dimethyl-3-.phnylindole * 2-carboxylic acid, 5-methOXYpl-methyl-phenyndola-2-carboxylic acid & 6 (or 8) -methoxy-l.methyl-3- phenYlindole-2-oarboxy11qua, 1-methyl-5-trifluromethyl-3-phenylindol-2-carboxy- acid
 EMI22.4
 lique,
 EMI22.5
 1-methyl-5-methyleulfonyl - $ - phànylinàole-2-oarboxyli- acid
 EMI22.6
 than,
 EMI22.7
 1-ethyl.5-methylsultonyl - phenylindole-2-carboxylic acid and I-methyl-5-ethylsultonYl - phenylindolo-2-carboxy11quat 5.d1methylamino-1-methyl, pheny11ndole-2-carboxylic acid , 5-d acid:

  lethylamino-1..met1yl - .. phenylindole-2..carboxylic acid, I-methyl-5-piperidino-3-phenylindole-2-carboxylic acid,} - (o-onloophenyl) -lt5-dimethylindole- acid 2-carboxylic.



  1 'aoido 3- (o-chlorophenyl) -5-methoxy-1-methylindole-2-carboxy-
 EMI22.8
 lique,
 EMI22.9
 3- (owohlorophenyl) -5-dinethylamino-1-methylindole-2- acid
 EMI22.10
 oarboxylic,
 EMI22.11
 1 ';-( o-lluorophenyl) -1 ,, - dimethylindole-2.earboxylic acid, 1' acido 3 '- (o' * fluorophenyl) '* - 5'-methoxy-1-methylindole'-2-carboxy' *
 EMI22.12
 lique,
 EMI22.13
 3- (o-fluorophenyl) -1-metbyl- acid;

  -tritluoromethyl-indole-2-
 EMI22.14
 carboxylic,

  <Desc / Clms Page number 23>

 
 EMI23.1
 3 - '(o-'fluorophéayl) -1-methyl-5-methyloulfonylindole- acid
 EMI23.2
 2-carboxylic,
 EMI23.3
 Ethyl 1-ethyl - metkl 3-phenyâ.3.ndol - carboxylicuo lu 1,5-dimethyl-3-phenylindole-2 oarboxyiato, 1,5-dimethyl-µ-phenylindole-2- methyla, 3-phenyl 1-methyl, -triluoxomethylitdola-2-a.rboxlate caTboxylate
 EMI23.4
 spread out,
 EMI23.5
 1-methyl-5-methylsulfonyl-3-phenylj.ndoloe-2-carboxylate
 EMI23.6
 ethyl,
 EMI23.7
 5-6tbylsulfonyl-1 "methyl-3-phenylindole-2-carboxylate
 EMI23.8
 ethyl,
 EMI23.9
 5-dimethylamino-1-methyl-3-ph6nylindolo-2-carboxylate
 EMI23.10
 ethyl,
 EMI23.11
 5-diethylcmino-1-methyl-3-phenylindola-2-oarboxylato
 EMI23.12
 ethyl,
 EMI23.13
 µ- (o-fluorophenyl) -1,

  Ethylot 5-dimethqlindole42-oarboxylato 3- (o-'iacrophnyl) -5-aathoxy-1-methylindo7.o - aarbox, late
 EMI23.14
 ethyl,
 EMI23.15
 3- (o-fluorophenyl) -1-methyl-5-tritluoromethylindolo-2-
 EMI23.16
 ethyl carboxylate,
 EMI23.17
 3- (o-luoroph: nyl) l..mdthyl 5-methyleultonylindolo-2-aar-
 EMI23.18
 ethyl boxylate,
 EMI23.19
 3- (o-chloroph6nyl) -l-methyl-5-methoxy-indole-2-carboxyl% te
 EMI23.20
 ethyl
 EMI23.21
 3-to-.oh3.orophanyl) -5-dimethylatnino-1-nethyli, dolo-2-onr-
 EMI23.22
 ethyl boxylate,
 EMI23.23
 5-bromo-6-met.o .-. / - 1-methyl - phenylindole-2-carboxylate
 EMI23.24
 ethyl,
 EMI23.25
 ethyl 1,5-dimethyl-3- (p-tolyl) -indole-2-oarboxylate.

  <Desc / Clms Page number 24>

 



  III - Preparation of indole-2-carboxamide derivatives (x)
In the process of the present invention, indole-2-carboxamide derivatives (X) are obtained by reacting an indole-2-carboxylic acid derivative (VIIIb) or its reactive derivative,;. ¯, .- tif with ammonia.

   Among the reactive derivatives of the carboxylic acid derivatives used in the process of the present invention, there are, for example, the indole-2-carboxylic halide derivatives (IX) which are prepared by halogenation of the derivatives of. indole-2-carboxylic acids (VIIIb), or esters of derivatives of indole-2-caroxylic acids (VIIIb), for example a tert-butyl ester, a benzyl ester or a p-nitrophenyl ester, or else the anhydrides of Acids or mixed acid anhydrides of indole-2carboxylic acid derivatives (VIIIb) such as a mixed anhydride comprising the mixed anhydrides described in "Organie Reactions III, vol. 12, p. 157 (1962).



   The indole-2-carboxylic haluros derivatives (IX) which are used as starting materials in the intended amidation are prepared by reacting an indole-2-carboxylic acid derivative (VIIIb) with a halogenating agent.



   When carrying out this halogenation process, the indole-2-carboxylic acid derivative (VIIIb) is treated with a halogenating agent in the absence of a solvent or in an inert solvent such as benzene, toluene, ether, chloroform, methylene caloride and carbon tetrachloride. The following compounds are useful as a halogenating agent! for example, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride and phosgene.

   In this case, we can also provoke the same reaction by adding a sub-

  <Desc / Clms Page number 25>

   In addition, in this process, a free carboxylic acid and the metal salt can be used as the starting material.



   The reaction product is obtained by removing the solvent and the excess halogenating agents, optionally by a treatment such as extraction with an inert solvent to obtain the desired product. Isolation or purification of the indole-2-carboxylic halide derivative is not always necessary for conversion to the indole-2-oarboxamide.



   When performing the amidation of the process of the present invention, the indole-2-carboxylic acid derivative (VIIIb) or its reactive derivative is reacted with an acid halide, ester or anhydride. acid) with ammonia, in a suitable solvent.



   In the reaction, the following solvents can be used, for example alcohols such as methanol, ethanol and organic solvents such as ether, benzene, toluene, xylene, cglorobenzene and chloroform, of same as liquid ammonia.



   In the amidation reaction, ammonia can be used by introducing gaseous ammonia into the reaction mixture or by adding alcoholic ammonia (such as methanolic ammonia, ethanolic ammonia) or aqueous ammonia, in the reaction mixture.



   Because the reaction usually takes place at room temperature, there is no need to heat or cool. However, the reaction can optionally be controlled by heating or cooling.

  <Desc / Clms Page number 26>

 
 EMI26.1
 



  According to the present invention among lem derivatives 4'halgénides indol-2-carboxyliques (IX) there is for example, the oomposés sulvantas the chloride 5.-rathy.3phrliado.s - caeboay, iq, u the 5-methyl- bromide 5-phenylindole-2-carboxyliquag chloride -mdthoc, y-3-p, éralindclo --earbQxy..qu chloride 6 (or 8) -methoxy-3-phenylinàole-2-canboxylic> chloride 5-tri ± â .uoxomthyl-3-phbny3..indolv - ctxboxyl.cus, 5-methylsulfonyl-3-phenylinàole-2-carbaxyliquo chloride, 5-thylsul.fony chloride - pheny.irdole - carboryl.q, us, 5-dimethylam3.no-3-ghny.indole- .arboxy..qtaos chloride 5-diethylamino-3-phenylindole-2-carboxylîquot cyloride 5-pipàriàino-3-phenylinàole-2-c rboxylique, chloride - (o-chlorophnyl) -5- mthy.i.ndQ3.v - orrboxyi.qt 3- (o-chlorcphenyl-5-méthoacy-indvlv - cax'oa7.que chloride,

   3- (o-oh.oroghenyl-5-d3methy.aniae-.ndole-2-ço.x- chloride.
 EMI26.2
 boxylic,
 EMI26.3
 ohloride - (o-i'luorophenyl-5-mthylihdo.v-asrbvxy, lq, uo chloride 3- (o-fluorophenyl) -5-methoxy-indolo-2-garboxyliqùe, chloride 3- (o-fluorophryl) -5-tri'luoromethy.incl.oa-2-
 EMI26.4
 carboxylic.
 EMI26.5
 lo µ- (o-fluorophenyl) -5-methylsulfonylindole-2-oaiiboXyl chloride, 1,5-d.methyl-3-ahérylindo.c-2-cctrboxyi.cueg chloride 1-methyl-µ-phenyl-5 -trifluoromethylindolù-2-car-
 EMI26.6
 boxylic,
 EMI26.7
 5-methoxy-1.-methyl-3..pnyl: ndo1 - oarboxy chloride ..quea-ethyl-5-'methylaulfonyl-3-phenylindolo-2 "carboxy- * chloride
 EMI26.8
 liquo,
 EMI26.9
 1-methyl-5-methylaulfonyl-3-phenyliadote-2-carboxylic chloride, Al

  <Desc / Clms Page number 27>

 
 EMI27.1
 the chloride et:

  hy.euL "ony3.-3.-methyl-r-phenylindoâo-'Wao, rboxy.-
 EMI27.2
 lique,
 EMI27.3
 1-mebiayl-.phenylatr i.uoromethyJ.indalo-2-oa chloride
 EMI27.4
 boxyliquo,
 EMI27.5
 3- (o-fluorophenyl) -l-methyl-5-trifluoromethylindole- chloride
 EMI27.6
 2 - carboxylic,
 EMI27.7
 3- (o-fluorophenyl) -1-methyl-5-methyleulfonylindole- chloride
 EMI27.8
 2-carboxylic,
 EMI27.9
 3- (o-ohlorophenyl) -5-dimethylamino-1-methylindolo- chloride
 EMI27.10
 2-carboxylic,
 EMI27.11
 5-dimthy3.mino1-methyl-y chloride:

  .rtluocomethyl) -
 EMI27.12
 indole-2-carboxylic,
 EMI27.13
 5,6-iiinetbyl-3-phenylinàolo-2-carboxylic chloride, 5,6-iiimethoxy-3-phenylindolo-2-carboxylic chloride, 5-obloro-7-methyl-3-ph4nylindole-2-carboxylic chloride, 5-Nethyl -? - nitro-5-phenylindole-2-canboxylic chloride, 5-nethyl-3- (p-tolyl) -indolo-2-carboxyliquo chloride, 5-methyl-3- (p-methoxyphenyl) chloride -indole-2-carboxylic chloride, -methyl-3- (P-nitrophenyl) -indole-2-carboxy, ic.
 EMI27.14
 According to the present invention, among the derivatives of indole
 EMI27.15
 2-carboxamide, (X), there are, for example, the following compounds:

   5-methyl-3-phi-5nylindole-2-carboxamide, 5-mdthoxy-3-pa6nylindole-2-carboxamide, 6 (or 8) -methoxy-3-phenylindolo-2-carboxanide, 5-trifluoromethyl- 3-phenylindole-2-carboxanide, 5-methyleulfoivl-3-phenylindole-2-carboxamide, 5-etbylsulfonyl-µ-phenylindolo-2-carboxcmiàe, 5-dimethylamlno-3-phenylindole-2-carboxamidog, 5-diethylamino -µ-phenylindolo-2-carboxamidc, -piparidino - phenlindole-2-carboxaraid,

  <Desc / Clms Page number 28>

 
 EMI28.1
 le (o-ohlorophny,) - 5-mthylindc3c-tarboxam: ic le - (oarhh..orophenyl) 5-m.txgxy-indo, a - cc.rboxami.dr le, -o-clalorophtayl) -5-dl2t13 .aniao.idolm-2-oar'baxz¯d le 3-o-'luarogahény7.) - 5-mthy.inâo.e -cc.rboxamâd li c:

   3- (r-luorophxayl) w5-mthoxy-â.ndolo- carboacamido le 5- (o-i ', uorophnyl.) - 5-txii'luorom t hyl indcale-2-carbaxe.d la 5- {o-. uorophnyl) -5-ntïayl.a.orl.àoZa> co.rboc: Ldo le l, a-dimdthy .-, pheny.3.ndole - oarboct.m.dep le, -m6thyl-3-phnyl-5. .triîluoromethyl, ado3, e -orrboxam.da 5-ngthoxy -..- mth; 1-3-phéaaylïa.ola - oarboxamido $ 1-thyl-5-mthylul'onyl-3-p:

  aényâ.ixdo.o - .. carboxami.det, 1-mthwl-5-mthylaulfony7.-3-phnylindol-2-oarbox.le, -ethylsul1'onyl-1-methyl -, - phenylindola-2-ca. rboxe.mide! 1-nethy.-3-phnyl-5-tri.fluoromthyl.ndo, s- carbocmmi.do µ- (o-fluorophenyl) -1-methyl-5-trifluoromethylindole-2'-
 EMI28.2
 carboxamide,
 EMI28.3
 3- (o-fluorophenyl) -1-methyl-5-methylxultonylindolo-2oarboxanido, µ- (o-ohlorophenyl) -5-dimethylamino-1-methyline-2-car-
 EMI28.4
 boxamido,
 EMI28.5
 5-dimôthylamlno-1-! uôthyl-3- (o-'trifluorom6thyl) -indole'-2Ol1rboxClmido, 5,6-dinethµ1-5-phenylindole-2-aarboxamido, 5,6-dinethoxy-3-phenylindole- 2-oarboxamiàe, 5-chloro -? - nethyl-µ-ph6nylindole-2-carboxamide, 5-mthy7:

  -.?-nitro-5-phônylixdo.e2-crrboxe.mida 5mthy, - (p-tolyl) - indole-2.-carboxamide .5-Nethyl-3- (p-methoxyphenyl) -indolo-à -carboxamide, 5-methyl-3-P-nitrQphenyl) -indole--carboxam3.de.



  In addition, the 1-alkylindole-2carboxataidoe derivatives of the formula can be prepared.

  <Desc / Clms Page number 29>

 
 EMI29.1
 
 EMI29.2
 in which Ri i R2e 0 and R? have the same meanings as those defined above $ by alkylation of an inàù16-2-oarboxamide derivative corresponding to the formula
 EMI29.3
 
 EMI29.4
 wherein lil, R2 and: 'have the same meanings as those mentioned above.



   When this process is carried out, the derivative is transformed
 EMI29.5
 indole-2-carboxamide (Xb) is an alkali metal salt by treating it in the presence of a suitable condensing agent, then
 EMI29.6
 the metal salt obtained is reacted with an axer +, 1 '-. - -1 / - lation. The following compounds are useful as suitable condensing agents; for example, an alkali metal, an alkaline earth metal, an alkali metal hydride, an alkaline earth metal hydride, an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal amide and an amide of alkaline earth metal.
 EMI29.7
 



  1,5-Dimethyl-µ-phenylindole-2-oarboxamiào, 1-methyl-3-phenyl-5-triiluoromethylindole-2-oarboxamide, 5-methoxy-1-methyl-3-phenylindole-2-carboxamide on 1 -ethyl-5-methylsulionyl-µ-phenylindole-2-carboxamide, 1-methyl-5-nethylsulfonyl-3-phenylindole-2-carboxamido,

  <Desc / Clms Page number 30>

 
 EMI30.1
 5ethylsulfoyl. -m, ethyt ..- pônyl: ndo; ae- .r'oxamidax le.-m, thy: l.3-phenyl-5tr.: â.aaorrate, indole - oareaca.m.da le r- (o ^ fluorophenyl)) -. methy.- ;:

  3.'uoromethy.a, a.a-carboxamida, 3- (o-iluorophenyl) -1-methyl-5-methylsulfonylindole-2-
 EMI30.2
 carboxamide,
 EMI30.3
 5- (o-chlorophenyl) -5-dimethylamino-1-methylindole-2-Qak-
 EMI30.4
 boxamide,
 EMI30.5
 5-dimethô> lamino-1-methyl-3- (o-trifluDromethyl) -indole-2-
 EMI30.6
 carboxamide.
 EMI30.7
 IV - Preparation of 2-aminomethylindole derivatives (II)
 EMI30.8
 According to the process of the present invention, one prepares
 EMI30.9
 los derivatives of 2-aminomethylindoles (II) an dehydrating a derivative of indolo-2-carboxamido (X) to a derivative of indole-2oarbonitrile (XI), the hydrogenation of which gave the derivative of 2-rminomthylindoZa (II).



  According to the present invention, among the derivatives of 1-alkyl-indolo-2-earboxamides (Xa), there are, for example,
 EMI30.10
 following compounds
 EMI30.11
 1,5'-dimethyl-3-phenylindolo-2-carboxamide, 1-methyl-µ-phenyl-5-trifluoromethylindole-2-CarboXamide, 5-methoxy-1-methyl-3phenyündole-2earboxtni.t 1-ethyl -5-methylsulfonyl-3-phenylindolo-to-oarboxamido, 1-methyl-5-mthy3sulfony .-. Phésyli, ndo.e - ^ .. carboxam.da 5-ethylsulfonyl-1-methyl-3-phenylindole-2 -carboxamida 1-methyl-3-phéuyl-5tri.uoromethylindo & t-2..or, xboxa.m, da µ- (o-fluorophenyl) -1-methyl-5-trifluorowethylindole-2oarboxamida, 3- (o- fluorophenyl) -1-methyl-5-methyl8ulfonylindole-2'oarboxamido,

  <Desc / Clms Page number 31>

 
 EMI31.1
 the - (o ah.3or, hn3.-ad.mtlylaB., - ia6 hyiindoio - orbaa.aides le .d.à.mtbylamio.o-â.-tii-a (s-tr. '. uaramvtt.yi ) itdr3- carboxyamide,

  
When someone performs this process, we heat up an
 EMI31.2
 4.fi.a - '., C :. t? aCailiE3 (X), preferably in the presence of a dehydrating agent, to obtain an indole-2-carbonitrile derivative (XI). The following compounds are useful as dehydrating agents! for example, a phosphorus halide such as phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride, or an acid chloride such as
 EMI31.3
 p-to.un.o sulfoy3s chloride, methylsulfonyl chloride, acetyl chloruru, th1ony16 chloride, bonzo.yl chloride and oarboboaaoacohlrtarc in the presence or absence of an inert solvent.



   According to the present invention, among the deviated from indole-
 EMI31.4
 2-carbonitrîles (? Il), there is, for example, los composas ouivantai 5-methyl-3-phenylindole-2-carbonitnila, .ct 5-wethoxy-3a-ph <Inylinàolo-2-canbonitrile, 6 (or 8) -m6tho: y-µ-phànylindol -2-carbonitrile, 5-trifluoromêtbyl-3-phenylindole-2-carbonitriloq, 5-methyleulfonyl-3-phenylindole-2-carbonitrilej -éthyisu3tny: -r-phny3lndol - carbonitrile, 5-dimethylamino-5-phenylindole-2-canbonitrile, 5-diethylemino - 3-ph6nylindole-2-oarbonitrile, 5-pipridino-3..phenylindole-2 -carbonitrile, 3- (o-çh3orrphnyl) -5 + methy3indole-2-carbonitrilc, 3-e-ah3orophény3) -5-mthoxy-.ndolQ-2-orrbonïtri.s, µ- (o-chlorophenyl) - 5-dimethylamino-indole-2-carboni% rilo,

  <Desc / Clms Page number 32>

 
 EMI32.1
 3- (o-fluorophény.) - methyliaaso. oc: 9'artitr.a the -o-.g.'ltrophy) -metho;

  y-indca3.-2-r. it is - (o-: Pluorophenyl) -5-t., uoromethylindolo-a-carbonitri ?. 3. (o-luo, 9ophenyl) - meth; iaali'ar ... dole - o. hoaaivrio le> 1,5-din4thyl-µ-phenylindol, o-2-caiboùitxtiley le, ,,. aéthy: i.-.- g3égayâ.ndcl.o-oroa.tri. 5-méthoJçy-1-môthyl -; - phenylindole-2m-oaZ> b0nib ile> le, .thyl-.5-méthyleaalfony3 - phenp.indole = 2-oarbozaitri, le 1-mét3yl-5-méthylsulf onyl- -phenylindo.e-2-oa.rbâitr, 3e le -dthy sulfonyL-3-méthyâ-r-ghdny.insria - oaron.tri.a9 la 1.-méthy, - ghdny3.r-trifltaoroaéthy..ndo. a-2-o.rhoaxitr, 3oi le - -f. '. ao oabdnyl) -1.-mé th, yi -tr, fi ao:

  omô hy, indo.o-onr'bonit.io la 3- (o-fluorophén.-ambthyl-aethylaulfon, ndl-2rrtct.tr.lo, la - (o-ohlorophbnyl) -5-dimethylamino-l-methylinol-2 -oarbo
 EMI32.2
 nitrile,
 EMI32.3
 5-imethylamino-1-methyl-3- (o-trifluoromé'ihyl) -fInàolo-2oarbonitrilo, 5-dimethyl -. phonylindola-onrbonitzi, 5,6-dinôthoxy-3-phenylindolù-2-carbonitrile, 5-chloro -? - methyl-3-phenylindole-2-carbonitr11e lu -m6thyl -? - nitro-5'-phenylindola-2oarbonitrile, 5-methr7.-3w (p-toly.). ïnào.a-- carbp.itri3.e, 5-mbthyl-3-i, g-methoxy ghény3,) - indoJ.e-ocrhonüGx3.r 5-mdthyl - (pnitraphény3) -. ndo.o-2-carho.tr. the,
 EMI32.4
 In addition, according to the present invention, the
 EMI32.5
 derivatives of l-alooyl-indole-2-oarbonitrilas responding to the for.

   
 EMI32.6
 mule

  <Desc / Clms Page number 33>

 
 EMI33.1
 in which R1'R2, R3 and R7 respectively have the same meanings as the adhesives defined above, by N-alkyla-% ion of a derivative "of inole-2-carbonitrile corresponding to the formula
 EMI33.2
 in which R1, R2 and F3 have the same meanings as the adhesives defined above, respectively.



   When this N-alkylation is carried out, the indole-2-carbonitrile derivative (XIb) is treated with an alkylating agent, optionally in the presence of a suitable condensing agent, or after the formation of the alkali metal salts. , by treatment with an alkaline condensing agent. The following compounds are useful as alkylating agents: eg, an alkyol halide such as methyl iodide, ethyl bromide and butyl bromide, an alkyl sulphuric ester such as dimethyl sulfata, diethyl sulfate or an aromatic alkyl sulfonic ester such as methyl paratoluenesulfonate.

   The following compounds are useful as alkaline condensing agents; for example, an alkali metal, an alkaline earth metal, an alkali metal hydride, a

  <Desc / Clms Page number 34>

 
 EMI34.1
 metal hydride IllQal; tno ... ter.e \ Uf: 'i .. \; Il bydTo% q <c to 6 aê '& 3, 9.4, ea lin, a metal hydroscide alotl11 "' '! H3g!.' them an # id.e 4.9 alkali aetel and an amide of metal alQalino-'terx'euxe According to the present invention, among the derivatives of indole-2-Cerbonitriles (XIa), there are, for example, other compounds.
 EMI34.2
 vants
 EMI34.3
 15-dim6ethyl -, - phenylindole-2cabon1trilat l-methyl -, - phenyl-5-tritluoromethylindolG-2-04bon1trio. 5-methoxy-1-methyl-3-phenylindole-2-aarbonitni.le, 1-ethyl-5-mthylaulfoDyl -'-phenylindola-2-oarbonitr11 and I-methyl-5-methylsulfonyl -; - ph6nylindolo-2- oarbonitril and 5-ethyl eul.t'ony Il-mÓ thyl ...:

  ? -phenylindole-2-carbon1 t r: J.J. 6., I-methyl - phenyl-5-tritluoromethylindolo-2-oarbQn1trile, 3- (o-fluorphenyl) -1-methyl-5-tri ± luoromethylinàolo-2-car-
 EMI34.4
 bonitrile,
 EMI34.5
 3- (o-fluorophenyl) -l-methyl-5-methyleulfonylindole-2-
 EMI34.6
 oarbonitrile,
 EMI34.7
 ;-( o-cplorophenyl) -5-dimetbylamino-1-methylindole-2-oarbQ-
 EMI34.8
 nitrile,
 EMI34.9
 5-Diwethylamino-1-Rethyl-3- (o-triflUoromethyl) -indole-11-
 EMI34.10
 oarbonitrile.
 EMI34.11
 Then, we can prepare faoilomont the derivative of 2-amino '
 EMI34.12
 methylindole (II) by hydrogenation of an indole-2oarbonitrile derivative (XI).

   The hydrogenation of the derivative can be carried out
 EMI34.13
 indole-2-carbon.itrile (XI) by a usual method, for example, by electrolytic reduction, reduction by means of a
 EMI34.14
 alkali tal in alcohol, catalytic reduction with palladium, nickel or platinum, reduction with chromium acetate / alkali or reduction with hydride complexes
 EMI34.15
 metal including lithium aluminum hydride, hydruro

  <Desc / Clms Page number 35>

 do boron and their mixtures with an acid such as chloride
 EMI35.1
 aluminum, ferric chloride, boron trifluoride, cblorh3d: ic acid or the like.

   More particularly, from the point of view of simplicity and selectivity, reduction by means of lithium aluminum hydride or the mixture, for example, of lithium aluminum hydride and aluminum chloride, sodium borohydride and chloride aluminum, sodium borohydride and boron trifluoride or the like, is preferred,
According to the present invention, among the derivatives of 2 aminomethylindole (II), there are, for example, the following compounds:
 EMI35.2
 2-aminomethyl..5-methyl -; - phenylindole, 2-aminomethyl - 5-methox3r-3-phenylindole, 2-am1nomethyl.

   (or 4) -methoxy-3-phenylindole, 2-aminomethyl-5-bromo-6 (or 4) -methoxy - phnylindale, -amiaomdthyl-.3phengl-5-trituromthylindol, 2-aminomethyl "3-phenyl -6 (or 4)) - trifluoromethylindole, 2-aminomethyl..5-methylsulfonyl-3-phenylindole, 2-aminomethyl-5-ethylsulfonyl-3-phenylindole, 2-aminomethyl-, 5-dimethylamino-3-ph6nylindole , 2-aminomethyl-5-diethylamino-3-phenylindole, 2-aminomethyl ..; - phenyl-5-piperidino-indole, -am.nomthyl.3p (o-ohlarophnyl) -5-methylindole 2-aminomethyl -3- (o-ohlorophenyl) -5-methoxy-indola, 2 am, aomthyl-.

   (o-chlorophnyl) - .. dimthylaino-indo.a, 2.8: minomdthyl.3- (o-rluoraphenyl) -5-mtthy7.indole, 2-am1nomethyl -} - (o-tluorphenyl) -5-metboxy- indole, 2-aainomethyl-3- (o-fluorophenyl) -5-trifluoromethylindole, 2-aninonethyl-3- (0-fluorophenyl) -5-metllyleulfonylindole,

  <Desc / Clms Page number 36>

 
 EMI36.1
 2-aninomethyl-3- (o-fluorophenyl) -5-dimethylM4no-indola, 2-aminomethyl-l.5-dimethyl-3-phenylindolo, 2-aminomethyl-5-methoxy-1-methyl-3-phenylindoleo 2-wninomethyl1-ethyl-5-methylsultonyl-pheny11ndole, 2-nminomethyl-1-methyl -, - methylsulfonyl-3-phenylindole, 2-aminomethyl-5-ethyleulfonyl-1-methyl-;

  -phenylindole, 2-aminomethyl-1-nethyl-3-phenyl-5-trifluoromethylindolo, 2-aminomethyl-3- (o-tluorophenyl) -1-methyl-5-tritluoromethyl-
 EMI36.2
 indole,
 EMI36.3
 2-aminomethyl-3- (o-tluarophenyl) -1-methyl - methylsultonyl-
 EMI36.4
 indole;
 EMI36.5
 2-aminomethyl -, - (o-chlorophenyl) -5-dimethylamino-1-methyl-
 EMI36.6
 indole,
 EMI36.7
 -aminomethyl-5-dimethylamino-1-methyl-3- (0-tr1tluoromethyl)
 EMI36.8
 -indole,
 EMI36.9
 2-aminomethyl-5,6-dimethyl-3-phenylindole, 2-aminomethyl-5,6-dimethoxy-3-phenylindole, 2-aminomet! hyl'-5-ohloro-7 '-' m6thyl-5- phenylindolo;

   2-aminomethyl-5-methyl-7-nitro-3-phenylindole, 2-aminomethyl-5-methyl-3- (p-tolyl) -Indole $ 2-aminomethyl-5-methyl-3- (p- methoxyphenyl) -indole, 2-aminomethyl-3-methyl-5- (p-nitrophenyl) '- indole, as well as their hydrochlorides, brombdrates, sulphates and acetates
 EMI36.10
 In addition, according to the process of the present invention, it is
 EMI36.11
 can also transform a derivative of (th1o) -amide 1ndole-
 EMI36.12
 2-carboxylic acid corresponding to the formula
 EMI36.13
 

  <Desc / Clms Page number 37>

 
 EMI37.1
 in which R, Rl, n2 and respectively have the same meanings as those defined above and it represents an oxygen or sulfur atom, derived from 2-aminomethyl-indole (II).



   In formula (XIII), when W represents a sulfur atom (that is to say derivative of indole-2-oarboxylic thioamide), compound (XIII) is prepared, for example by reaction of the derivative.
 EMI37.2
 vé d .ndole-2-oar.boxai, .da (XIII) with phosphorus pentasulfide.



   The transformation of the derivative of (thio) -amido is carried out
 EMI37.3
 indole-2-carboxyl, ic (XIII) as a derivative of 2-amino-methylindole (II) by eletrolytic reduction, reduction by means of an alkali metal in alcohols, catalytic reduction in the presence of a catalyst such as a catalyst of platinum, palladium, nickel and the like, or by reduction with a metal hydride complex compound.

   Particularly preferred reducing agents are metal hydride complexes,
 EMI37.4
 for example the hydride of 11 thi UJn- "J.w: ü: '. ::!.' Q :: - According to the present invention, among the derivatives of 2-
 EMI37.5
 wninQmethylindolEI (II), there are, for example, the following compounds:

   -aminomethyl - methyl-3-rphenyl.ndole, 2-aminomethyl-5-methoxy-3-phenylinole, 2-aminomethyl-6 (or 4) -methoxy-µ-phenylinole, 2-aminomethyl-5- bromo-6 (or 4) -methoxy-µ-phenylinole, 2-aminomethyl-3-phenyl-5-trifluoromethylindole, 2-am4.nomethyl-5-phenàrl6 (or 4.) -trifluoromethylindole, 2-aminomethyl- 5-methylsulfonyl-3-phenylindole, 2-aminomethyl-5-e% hylsulfonyl-5-phenylindole, 2-aninomethyl-5-dimethylsmino-3-phenylindolo,

  <Desc / Clms Page number 38>

 
 EMI38.1
 2-aminonethyl-5-aiethylumino-5 - phéayiinàole, 2-amino! Eéthy - '"pié! yl'-5'" pip3''idino ' <'Lndcle9 le 2-amiRomethyl-3- (o-ohlorophnyl) -' 5-méthylin.do3.e9 le 2-aminosiethyl-3- (o-chlorophényl) -5''thoxy <-indels 2-amino! nôthy3.-3 - '(o-chlorophenyl) -5-d.mé-t:

  hylamiao-'indol <a, 1 e 2-aminomethyl-3- (o-fluonophenyl) -5-me% hyl, indol.o, 2-aminomethyl3 '- (o-fluorophenyl) -5-'Diethoxy "indo3.a le' 2 -aminomethyl-3- (o- ± luorophenyl) -5-tlifluoromethylinàoloh 2-aminomethyl-3- (o-fluorophenyl) -5-methylsulfonylinole, .am.nomethy..3 - 'luoroph6y1) -â-dimthylam. no.zado.a -eminomethyZ-1,5-dimëtbyl-3 phë, y..ndole 2-auinomethy.-5-methox, y.-meth! .- 3-phenyliadQla 2-aminomethyl-1-ethyl --méthrlauxfon, yl3-phen; y.ind.olel 2-aminomethyl-1-methyl-5-metbylsulfonyl-3-phenylindoloq 2-alninomethy7.-5-ethylsulfonyl-3 ... methyl3-? r-phen, Ylid.o3.ag 2-aminomethyl-1-.methyl-3-phenyl-trif..oromethyl.ndoâ.t 2-.aminomëthyl..3- (ofluorophërzyl) .l-methyl3 ..-, .- :

  r.i'haoométia7.
 EMI38.2
 indole,
 EMI38.3
 2-aninomethyl-5- (o.fluorophenyl) -1-methyl-5-methylaulfonyl-
 EMI38.4
 indole,
 EMI38.5
 2-atninom6thyl-3- (o-chloronhényî) -. d.néthy.ami.o-: metbyl
 EMI38.6
 indole,
 EMI38.7
 2-aminomethyl-5-dimethylamino-1-methyl-3-fl.triflutcmtyl) -
 EMI38.8
 indole,
 EMI38.9
 2..aminomethyl5,6 dimétbyl i-hénylindo, ay 2-aminomé hyl-5'6-diméthtxy.-phenylin <3o.e 2-aminom6thy.-5-ahloro-.?-réthyl...-phény3.indcal8a 2-aminomethyl-5-Nëthyl-'7 "! Iitro'-3''phéQylindole -amnomethyl-- 5-methyl-3 tF-'olyl) .indo.e

  <Desc / Clms Page number 39>

 
 EMI39.1
 -am.ncant3ayï, P-métby..3- (p-mthoxyphén, y7) -indole, 2-aminoéthy-5-mthy - (pn.trophny,) - indai, as well as their hydrochlorides and hydrobromides , their sulphates and their acetates,
The 2-aminomethyl compound (II),

   obtained by the above processes, can be converted into the corresponding salt by treatment with an acid, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or an organic acid such as acetic acid.
 EMI39.2
 



  In addition, one can also "'' '' '' A '' '+ - U8: r 1%",' ..1 .g Ra-S, ... -1 "derivative of the (tbio) amide of l indole-2-carboxylic acid, analo-
 EMI39.3
 gue to that employed in the case of N-alooylst10n of the description of indole-2-carboxylic acid (Ville).



    V - Preparation of benzodiazepine derivatives (I)
Following the process of the present invention, the benzodiazepine derivatives (I) are prepared by reacting a derivative
 EMI39.4
 of 2-aminowethylindole (II) with an oxidizing agent.



   When carrying out the process for the preparation of benzodiazepine derivatives according to the present invention, it is carried out.
 EMI39.5
 gir a derivative of 2-aminomethylindole (II) or its sol with a suitable oxidizing agent, for example, ozone, hydrogen peroxide, a peracid (for example performic acid,
 EMI39.6
 peracetic acid and perbenzolic acid) t chromic acid and potassium permanganate. The oxidizing agent used in the process of the present invention is however not limited to those cited above by way of example. Chronic anhydride and ozone are the preferred oxidizing agents. Generally. the reaction is easily carried out at room temperature.

   Sometimes it is found that a higher or lower temperature is more satisfactory.

  <Desc / Clms Page number 40>

 



   The reaction can be carried out in the presence of a solvent.



  The choice of solvent depends on the oxidizing agent used and it is chosen from water, acetone, carbon tetrachloride, acetic acid, sulfuric acid and other solvents. We
 EMI40.1
 employs the oxidizing agent in an etoichiometric amount or greater.



   When carrying out the oxidation using chromium trioxide in the presence of acetic acid, it is preferable to use an equal 2-3 times amount of chromic anhydride and to carry out the reaction at room temperature *
 EMI40.2
 A 2-aminomethylindole derivative or its salt% such as hydrochloride, hydrobromide, sulfate, nitrate, acetate and the like is dissolved or suspended in a solvent, followed by addition of an oxidizing agent, any shaking. The reaction is usually complete after about 24 hours,
The desired benzodiazepine derivative can be separated from the reaction mixture as a crude product, by extraction after neutralization or without neutralization and by evaporation to dryness.

   Optionally, the product can be further purified by recrystallization from a suitable solvent such as ethanol, isopropanol and the like,
According to the present invention, among the benzodiazepine derivatives (I), there are, for example, the following compounds
 EMI40.3
 ? -methyl5phenyl.l, -dihydro.-2 1,4'enxodazpinon, 7-methoxy - phenyl., -. dihydroi-i, .i9anxodiexfpin-2..onem 8-methoxy-5-phenyl-1 , 3-dihydro-2H-1,4fbenzodiazepin-2-onoe, la $ IüéthOXß, -. LJroEüo - "'phéilßL - .., 3'" fl..ilyd.rQHw.'4-b $ lodj.5lpilp, 2 -one,? -triflU r InôthYl-5-> hônYl-1,3-àihydr <-2H-1,4-benzodiazepm-2-one

  <Desc / Clms Page number 41>

 
 EMI41.1
 6 (or 6) -trifuei? omthyl-5-phenyl'.1, 3-dihydro-'SH-1,4-beazcdiezepin-2-one, la? ... methylsultor1-phen11-17, -d1hydro-2H -l, 4-benzod1azepin-
 EMI41.2
 2-one,

   
 EMI41.3
 ? -etbylsul! orl -'- phenyl-1,; - dibydro-2H-1,4-benzod1azep1n-2-
 EMI41.4
 one,
 EMI41.5
 ? -dimétbylaroino-5-phenyl-l,; - dihydro ... 2H-l, 4-benzodiazepin-
 EMI41.6
 2-one,
 EMI41.7
 la -? - diethylamino -, - phenyl-l ,, - dibydro-2H-l, 4-benzodiazÓpin-2
 EMI41.8
 one,
 EMI41.9
 7-piperidino-5-phenyl-l3-dihydro-2H-1,4-benzodiazepin-2-
 EMI41.10
 one,
 EMI41.11
 5- (o-cbloropbnyl) ...? - mthoxy-1,3-dihydro-ZH-1,4-benzod1az-
 EMI41.12
 pin-2-one,
 EMI41.13
 5- (o-chlorophé.nyl) -? - methyl-1,3-dihydro-2H-1,4-benzodiazé
 EMI41.14
 pin-2-one,
 EMI41.15
 5- (o-chlorophenyl) -7-dimethylamino-1 ,, - d1hydro-2H-l.4-banzodiazepin'-2-ona, 5- (o-tluorophenyl) -? - methyl-1,3-dihydro -2X-1,4-bonzodiaz-
 EMI41.16
 pin-2-one,
 EMI41.17
 5- (o-fluorophenyl) -7-'thoxy-1, -dihyd -'- t .4-benzodiazepin-2-ons, 1a;

  - (o-tluorophenyl) -? tr1tluoromethyl-l, -d1hydro-2H-l.4bentodiazepin-2-cne # la '- (o-tlorophenyl) "? - methylsultonyl-lt-dihydro-2H-lt4bonzodiazepin-2-one% 5- (o-tluorophenyl) -? - dimethylamino-1,3-dihydro-2H-1,4-
 EMI41.18
 benzodiazepin-2-one,
 EMI41.19
 1,? dimethyl-5.phenyl-lt5d1hydro-2H-l, 4-benzodiazep1n.2-one,

  <Desc / Clms Page number 42>

 
 EMI42.1
 1 <,, '? -iz4 <blioty-1-mµtliyl-5 - p% Bny>, - i ,, µ-tli, hyà o? ù-1,1S-l;> iiinàiaaé:

  > pn-2-'oM, l-6thyl-.?-methyl8ulfoïl"$-phenyl .l, 3-dibyd? o-'SH "9 benzodiaiepin-2-onw, 1-methyl -? - mevhylsulfunyl-5 -phepyl-1, $ - dihydro-21I-ol, 4benzodiazepin-.2-.one,? -ethylsulfonyl-1-methyl-5-phenyl-1,3-alihyàro-2X-1, lRobonzo.-
 EMI42.2
 diazepin-2-one,
 EMI42.3
 1-methyl-5-phenyl -? - trifl1.loromethyl-1 "... dihydro ... 2U ... l $ 4-
 EMI42.4
 benzodiazepin-2-one,
 EMI42.5
 5- (o - fluorophenyl) -1-nethyl -? - trifluorophenyl-1,5-àihydro- 2H-1,, 4-benzodiazepin-2-one 5- (o-fluorophenyl) -1-methyl .. .? - methylaulfonyl-l.-diJd1'0- 2H-1,4-benzodiazepin-2-ono, 5- (o-chlorophenyl) -7-dimethylamino-I-methyl-l ,, - dihydro- 2H-lt4 -benzodiazepine-2-onet? -dimethylamino-1-methyl-5- (o-trifluotonbyl). 1,5-4ihydPo- 2H-114-benzodiazepin-2-one, 7,8-dimethyl-5 "phenyl -1, 3-dihydro-2H-3.

   , 4-beazodiazepin "2 *
 EMI42.6
 one,
 EMI42.7
 la?, 8-dimethoxy-5-phenyl-1, µ-aihydro-2H-1,4-benzodiaàepin-2
 EMI42.8
 one,
 EMI42.9
 ? -chloro-9-methyl-5-phenyl-1, µ-dihydno-2X-1,4 benaodiaz6pin-
 EMI42.10
 2-one,
 EMI42.11
 ? -methyl-9-nitro-5-phenyl-1 ,, - dihydro ... 2H-l.4-benzcd1az6p1u-
 EMI42.12
 2-one,
 EMI42.13
 7-'met! hyl-5- (p-tolyl) -1, 3 -dihydro-2H "3., 4-benzodias6pin-2-ona,? -methyl-5- (p-methoxyphenyl) -1 , -dihydro-2Hlt4-b4nzod1az6-
 EMI42.14
 pin-2-one,
 EMI42.15
 ? -methyl-5- (p-nitrophenyl) -1,5-dihydro-2X-1,4-benzoàiazepin-
 EMI42.16
 2-one.

  <Desc / Clms Page number 43>

 



   It is also possible to isolate the benzodiazepine derivatives (I) obtained according to the above process in the form of an acid addition salt by treatment with an acid, for example a mineral acid such as hydrochloric, sulfuric or nitric acid, phosphoric or chronic, or an organic acid such as maleic acid; fumaric, succinic, formic or acetic.



  Example 1
Has a solution of 16.4 g of phenylpyruvic acid in
 EMI43.1
 350 ml of ethanol, 9n added 10.7 g of p-methylphenylhydrazinet and the reaction mixture was heated under reflux for 30 minutes.



   At the end of the reaction, the solvent is removed by distillation to obtain almost quantitatively the p-methyl-phenylbydrazone of phenylpyruvic acid in oily form.



    Example 2
 EMI43.2
 To a solution of 16.4 g of phenylpyruvic acid in 3.0 ml of ethanol, 12.3 g of p-methoxyphenyihydrazine is added and the reaction mixture is heated under reflux for 30 minutes. The solvent is separated off by distillation under reduced pressure to obtain a p-methoxyphenylhydrazone of oily phenylpyruvic acid.



   In an analogous manner, the following compounds are prepared
 EMI43.3
 p-tr1tluoroetbylphenylhydrazone from phenylpyruvic acid, p-methylaulfonylphenylhydrazone from phenylpyruvic acid, p "dimthylamillopbnylbydrazone from ph6nylpyruviqut acid, P-d1ethylamincuvic acid, phenylpyruvic acid piperazinyl) phenylhydrazone from ph6nylpyruvic acid, 3,4-dimethylpxbnylhydrazone from phenylpyrdvic acid, 4-bromo-µ-metb'oxyphenylhydrazone from ph6nylpyruviquov acid p-methylphenylhydra from ouvicophenylpyrdvic acid,

  <Desc / Clms Page number 44>

 
 EMI44.1
 p-methoxyphényihydrazone from o-chloaccaphëny3pyreaig, .a 'p-dimethylaminophenylhydrazone from o-chlorophenyl-pyruvic acid,
 EMI44.2
 p-meth,

  o-fluorophenylpyruvic acid phenylhydxazane, o-tluorophenylpyruvic acid p-methoxyphenylhydrazone, o-fluorophenylpyruvic acid p-trifluorophenylphenylhydrazone, o-fluorophenylpyruvic acid p-methoxyphenylhydrazone, o-fluorophenylphenylhydrazone ofluorophenylpyruvic acid, N -methyl-p-met, hy7.phenylhydrazone from phenylpyruvic acid, NI-methyl-y-trifluoromethylphenylbydrazone from phenylpyruvic acid; p-eethylphenylhydrazone from methyl phenylpyruvate, p-methylphényihydrazone from ethyl phenylpyruvate * Example 3
Dry hydrochloric acid is passed through a solution of 82 g of p-methylphenylhydrazone from ethyl phenylpyruvate in 200 ml of anhydrous ethanol.

   The mixture is stirred for one hour at 70-75 ° C. The reaction mixture is cooled with ice and the precipitate is collected by filtration, washed with water and dried to obtain the 5-.
 EMI44.3
 mdthy3 .-- ethyl ph6nyl.nda.e-2.oaboxylate with a melting point of 125-126 C Example 4
 EMI44.4
 In a solution of 25.3 g of pmethylphenylhydraxctat of phenylpyruvic acid in 20 ml of acetic acid; gaseous anhydrous hydrochloric acid is introduced and the reaction mixture is allowed to stand at room temperature for two hours.

  <Desc / Clms Page number 45>

 
 EMI45.1
 



  Pat filtration! the precipitate obtained is collected, washed with water and recrystallized from a mixture of water and acetone to obtain 18 g of 3-phenyl-5-methyl'-indole -a acid. ..carbo711que, Melting point 22? 'C *
 EMI45.2
 In an analogous manner, the following compounds are prepared
 EMI45.3
 6 (or 8-methoxy -'- pheny.3ndola-2-carboxylic acid 5-% rifluvromethyl-µ-phenylindolo-2-carboxyliqua acid, 5-methylsulfonyl-3-phenylinole-2-carboxyliquo acid, 5-ethyl-sulfonyl-µ-phenylindole-2-carboxylic acid, 5-diwethylamino-5-phenylinole-2-oarboxylic acid, 5-diethylamino-µ-phenylindole-2-carboxylic acid, 5- piperiano-5-phenylindole-2-carboxylic acid, 3 '- (o-'chlorophenyl) -5 *'! nethylindole-2-carboxylic acid '', -o - chlorophenyl, -5-methoxy-indolo -2-caxboacylic acid -o-chlorophenyl) - dimethylamino-,

  ndole-2-carbaxyli-
 EMI45.4
 than,
 EMI45.5
 3.-o-fluoxophenyl) -5.-metüylindolQ-2-carboxylic acid, -; oTflutroghnyl-5-methox.y-indole-2-carboxylic acid, µ- (o-fluorophenyl acid ) -5-trifluoromethylindole-2-carboxy-
 EMI45.6
 lique,
 EMI45.7
 µ- (o-fluorophenyl) -5-methylsulfmnpii = / ni.o-2-carboxylic acid t 1,5-àimebhyl-3-phenylindole-2-oarboxylic acid, 3 - methyl-3 -phenyl-5-trifluoromethylindole-2-carbox7li-
 EMI45.8
 than,
 EMI45.9
 ethyl 5-methyl-3-'ph $ nyliad9le-'2 "carboxylate, methyl 5-me% hyl-µ-phenylinole-e-carboxyla, 5-aethyl-'5''ph ' tert-butyl ãylindole '-' 2-carboxylate, ethyl -métbrl-3-ph'ny.indoae-carboxy.ato and µ-phenyl-5-tr: Lfluoromethylindole-2-carboxylato from ethyl.

  <Desc / Clms Page number 46>

 
 EMI46.1
 5-methy.ou2onyi-.gh;

  .r..zdcis-carfioa s of ±% lwle, 5-ethylsulfonyl-µ-phenfilindol - ± -ae> ethyl boxylato ', 5ad.nethylamiao-phéx; .. neïo3.s - os.rtox ethyl la's; 5-dithyï, amino-3-phen :, lindois - ethyl carbosiates, 5- (o-fluorophenyl) -5-methylinole-2 + ethyl cerboxylate, 3- (O-fluorophenyl ) -5-methoxy-indole-2-carboxylate, ethyl 3-o-'luorophêtaylj-5-tri'luoromethy3i.do.s - osrbocyis.ts ethyl, the '- (o-fiuorophényZ-5 -methylsu, ory, indole - ethyl cur'cxy.t, 3 o-chlorophény.) - 5-methpâcy, ndoâ, o-carbo.s.ts ethyl, 3- (o-ch3. orophlny7,), - dimethylam.n, o.indoâ, e.-2-ca ethyl baxy.ts, 5-bromo-6-methoxy-3-phernylindole-2-carboxylate de6thyl and 5-methyl-µ- Ethyl (p-tolyi) -indola-2-carboxylate.



  Example 5
For 2 hours it is heated at. 75-80 C, a solution of 26.9 g of p-methoxyphenylhydrazone of phenylpyruvic acid in 30 ml of acetic acid. When the reaction mixture is cooled, water is added thereto.

   We collect the precipitate
 EMI46.2
 by filtration and recriatal11so in a mixture of acetone and water to obtain 19.2 g of 5-phenylms-methoxyB indole-2-carboxylic acid in the form of colorless needles * Melting point 218 C Example, 6
To a solution of 18 g of phenylpyruvic acid in 30 ml of acetic acid, 10.7 g of p-methylphenylhydrazine is added and the reaction mixture is heated at 75-80 C for 3 hours. After cooling the reaction mixture, water is added thereto.

  <Desc / Clms Page number 47>

 



   The precipitate was collected by filtration and re-crystallized in a mixture of acetone and water to give 18.2 g.
 EMI47.1
 3-Phenyl.-5-methylindole-2-carboxylic acid. Melting point 227 0. Example 7
 EMI47.2
 To a solution of 18 g of phenylpyruvic acid in 30 ml of acetic acid, 3.2.3 g of p-methoxyphenylhydratins are added. The reaction mixture is heated at 75-80 ° C for 3 hours * After cooling the reaction mixture, there is added. add water.
 EMI47.3
 



  The precipitate is collected by f41 + rnttnm and 0 "vn <,: .tailiae in a mixture of acetone and water to obtain 17.9 g of 3-phenyl-5-mebhoxy-indole-2-carboXylic acid.



  Melting point 218 C
In an analogous manner, the following compounds are prepared!
 EMI47.4
 6 (or 8) .- methoxy-3-phenylindolo-2-carboxylic acid, 5-triflUotomethyl-µ-phenylindole-2-carboxyliquo, 5-methylaultonyl-3-phenylindole-2-carboxyliquo acid, 5-ethylaiilfonyl-3-phenylindole-2-carboxylic acid, 5-dimethylar.no - phenylindo.a-2-carboxylic acid, 5'-diethylaniino-3-phenylindole-2-carboxylic acid, l '5-pipsidino-3-phEzlindole-2-carbox3iquo acid, 3- (o-ohl <xophenyl) -5-methylindole-2-carboxylic acid, 3- (o-ohlorophenyl) -5-methoxy-indole-2-carboxyliquo, 5- (o-ohlorophnyi) .- 5-dimthylamino-indols acid -2-carbox ..

   lic, 3- (o-fluoroph6nyl) -5 * 'methylindole-2-carboxylic acid, 3- (o-tluorophnyl.) - 5-methoxy-indole..2..carboxylic acid 3- (o-tluorophenyl) -5-trifluotomethylindolo-2-carboXylic,

  <Desc / Clms Page number 48>

 
 EMI48.1
 3- (o-fluorophenyl) -5-methylsulfonylindole-2-carboxylic acid, 1,5-dimeth> '1-µ = phenylindole-2-cRnboxylic acid, 1-zethyl-j-phenα. 1-5-trifluonethylindole-2-catboxylic, 5-methyl-phenylindole ..-ethyl carboxylate.

   methyl 5-methyl-phenylindole-2-carboxylate, ethyl 5-methyl-µ-phenylindole-2-aarboxylate, 3-phbnyl-5-txifluoromethylizda.es2-çax boxrlate, ethyl 5- ethyl nethylsulfonyl-µ-phenylindole-2-carboxylate, ethyl 5-6thylaul.fonyl, 3 phenyïirzdole cax bax, ethyl ylato, 5 -diméthy.amino-5-phenylindola-24carboxy2at $ ethyl, 5- ethyl diethylamino-3-phenylindole-2-carboxylate * xap1l? lo q To a solution of 55 g of ethyl alpha-benzylacetoacetate. the in 250 ml of ethanol, 85 ml of a 50% aqueous solution of potassium hydroxide in aqueous solution, followed by 500 ml of ice-cold water are added, while cooling.

   To the ice-cooled mixture is added dropwise the diazonium salt solution prepared from 26.7 g of p-toluidino, 100 ml of concentrated hydrochloric acid, 150 ml of p-toluidino. water and an aqueous solution (17.9 g of sodium nitrite in 60 ml of water. The mixture is stirred at 5 ° C. for one hour and extracted with ether.



  The ether extract is dried over sodium sulfate and the solvent is removed. The oily residue is dissolved in 200 ml of ethanol and dry hydrochloric acid gas is bubbled through the solution. An exothermic reaction ensues and the mixture is maintained at 70-75 ° C. during the bubbling. The mixture is left to stand for two hours. After cooling, the precipitate is collected by filtration, washed.

  <Desc / Clms Page number 49>

 with water and dried to obtain ethyl 5-methyl-3-phenylindole-2-carboxyltae. By recrystallization from ethanol, the analytical sample is obtained, in the form of colorless needles, with a melting point of 125-126 C. Analysis for C18H17O2N;

     Calculated 0 77.39H 6.13 N 5.01% Found: C 77.53, H 6.04, N 5.01%.



    Example 9.



     A mixture of 28.3 g of p-anisidine, 95 ml of concentrated hydrochloric acid and 120 ml of water is heated in solution, then it is cooled below 0 C. A solution of 16.5 g of sodium nitrite in 50 ml of water and the mixture was stirred vigorously, then extracted with ether. The ether extract is dried over sodium sulfate and the solvent is removed. The oily residue is dissolved in 100 ml of anhydrous ethanol. Dry hydrochloric acid gas is passed through the solution for 50 minutes while maintaining the temperature at 70-75 ° C with intermittent cooling. The mixture is left to stand for 2 hours.

   After cooling on ice, the precipitate is collected by filtration, washed with ethanol, then with water and dried to obtain ethyl 5-methoxy-3-phenylinodl-2-carboxylate. . Two recrystallizations from ethanol give an analytical sample, in the form (colorless needles, with a melting point of 120-121 C Analysis for C18H17O3N: Calculated! C 73.20 H 5.80, N 4.74 % Found: C 73.07;

   H 5.61, N 4.50% IR spectrum V max 3270; 1655, 1600, 1530 cm-1

  <Desc / Clms Page number 50>

 
 EMI50.1
 In an analogous manner, the following compounds are prepared: methyl -mthyl.-3-Phel.nds e - o.boTZ.a; tert-buty16 & 3-methyl-µ-phenylindola-2-caTboitylate ethyl -phenyl-5-trifluoroMethylindclo'-2-oarboxylate;

   ethyl 5-methylsulonyl-3-phenylindole-2-oarbox3tlato, ethyl 5-ethylaulionyl-3-phenylindole-2-carboxyla ", 5-dimthylamina - phenylindole-2-oaxboxy, ethyl ato , ethyl 5-diethylamino-µ-phenylindole-2-carboxy, late, ethyl 3- (o-fluorophenyl) -5-methylindole-2-earboxylate, µ- (o-fluorophenyl) -5- ethyl methoxy-indole-2-carboxylate µ- (o-fluorophenyl) -5-toeifluoromethylindolo-2-carboxylato
 EMI50.2
 ethyl,
 EMI50.3
 µ- (o-fluorophenyl) -5-methylsulfonylindolo-2-carboxylato
 EMI50.4
 ethyl
 EMI50.5
 eth11e - (o-ohiorophény.) - 5-metiaocy3adoïo - saboxy.ato. 3- (o-chlorophenyl) -5-diwebhylamino-indole-11-carboxylata
 EMI50.6
 ethyl alcohol,
 EMI50.7
 5-.bromo-6-methoxy-3. ethyl phnylindo.c..oarboxrR.to; ethyl 5-methyl-3- (p-tolyl) -indole-2-canboxylate.



  Example 10
 EMI50.8
 Has a suspension of 1.2 g of sodium hydride in 10 ml
 EMI50.9
 of dïmethylformamidet a solution of 14 ,? g of ethyl 3phenyl-5-methoxy-indole-2-carboxylate 40 ml of diméÔhy1foxmamido.



  The mixture is stirred at 20 * 0 for one hour, then zig
 EMI50.10
 add 8 g of methyl iodide. The reaction mixture is stirred for 5 hours at room temperature.



  The resulting mixture is poured into water and extracted with ether.

  <Desc / Clms Page number 51>

 



   The organic layer is washed with water and dried over sodium sulfate.



   The following are separated off: The solvent by distillation to obtain an oily product. The oily product is crystallized from a mixture of ethanol and hexane to obtain 11.6 g of 1-methyl-.
 EMI51.1
 Ethyl 3-'phenyl-5-Bethoxy-indole-2'-carboxylate.



  Melting point 45-50 C Example 11
Has a suspension of 1.2 g of sodium hydride in 10 ml
 EMI51.2
 of dimethyltormac1da. a solution of zizi, 9 g of -pheny.-5-methyliaidoio-2-carbc is added. The mixture is stirred at room temperature for one hour, then 8 g of methyl iodide are added thereto. The reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into water and extracted with ether. The organic layer is washed with water and dried with sodium sulfate.



   The solvent is separated by distillation to obtain an oily product. The oily product is recrystallized from a mixture of ethanol and hexane to obtain the .8 g of 1,5-dimeric acid.
 EMI51.3
 ethyl thyl-3-phenylindole-2-carboxylato.

   Melting point 48-52 C. In an analogous manner, the following compounds are prepared.
 EMI51.4
 methyl 1,5-dimrth3l -phenylindo2c.2-carboxylato, ethyl 3-phenyl-5-1-methyl-trifluoromethyl - indolo-2-carboxylate, 1-methyl-5-mthylaulfonyl-3-phenylindole -2-ethyl carboxylate,

  <Desc / Clms Page number 52>

 
 EMI52.1
 5-ethylsulfonyl-1-methyl-3-phenylindole-2-carboxylaito
 EMI52.2
 ethyl,
 EMI52.3
 1 5-dinethylamino-1-methyl-µ-phenylindole-2-carboxylate
 EMI52.4
 ethyl,
 EMI52.5
 5-diethylamino-1-methyl-3-phenylindole-2-oarboxylate
 EMI52.6
 ethyl,
 EMI52.7
 µ- (o-fluorophenyl) -1,5-dimethylindole-2-oarboxyla% o
 EMI52.8
 ethyl,
 EMI52.9
 3- (o-fluoroph6nyl) -5-methoxy-1-methylindole-2-carboxylate
 EMI52.10
 ethyl,
 EMI52.11
 3- (o-fluorophenyl)

  Ethyl-1-methyl-5-'trifluoromethyliadole-S'oarboxylate, 3- (o-.uorophénya) .- 1-méthy.-5méthyiuïonyïindolaw 'ethyl carbmato, - (owthlorophénylj..lrmétihylp5- mbth4y .tdolo - oarb0cy.at
 EMI52.12
 ethyl,
 EMI52.13
 the -f a-oh.oxophbny.} - 5-dimêtiy2amiro. 1-methyl.iudol, e - our.
 EMI52.14
 ethyl boxylate,
 EMI52.15
 5-bromo-6-methoxy-1-methyl-3-pfienylindol -2-carboxylate;

  o
 EMI52.16
 ethyl $
 EMI52.17
 1,5-Dimethyl-3- (p-tolyl-.ndo.o2..ethylcarboxylate, 1,5-diaethyl-3-péryï3.ndoio-carbnxylic acid, 5-methoxy acid -1-methyl-3-phenylindol-2-oarboxylic acid, 6 (or 8) -mdthoacy.-1.-methyl-3-phenyiindola-2-oarboa..gues 1-methyl-5-trifluoromethyl acid -3-phenylindole-2-carboityli ..

   
 EMI52.18
 than,
 EMI52.19
 1-methyl-5 # methylsulfonyl-3-i,) hênylindcite-2-carboxD, li-
 EMI52.20
 quo,
 EMI52.21
 3.-Ethyl-5-methylsulfonyl-3-phenyl.ndoLra-é.-c.rbo.3.- acid
 EMI52.22
 than,

  <Desc / Clms Page number 53>

 
 EMI53.1
 aoido 1-methr.-5-ethylsulfonyl - phenylindola-2-carboxylic acid, --dimthyiam.rio-mtbl - pheny.irdolo-.carbox, 3iqua, r ditkylaaafno..i-xiethyl acid -3-phnylindolc - carboxyl.que! 1-methyl..p, pr, d.aQ-a-phryliadolo - carbaeyhiqusi 3 o-ch3'rophenyl-1, -dimthylir.dol.Q - carboxylic acid, 3- (o-chl <5Tophényi) -5-methoxy-1-methylindole-2-carboxylic acid, µ- (o-chlbtophenyl) -5-dimethylanino-1-methylindole-2oarboxyliquo, 3- (o- ± luoiophenyl) -1 acid , 5-dimethylindole-2-cArboxyliquo, 3- (o-flut'rophenyl) -5-methoxy-1-methylindole-2-carboxylic acid.

   3-io-.lucsrophenyla-1-methyl-5-trifluoromethylindole- 2-carboxylic acid} 3- (o-fluorophenyl) '- 1-methyl-5-methylsulfonylindole-2carboxylic acid, ethyl '-5-Nethyl *' 3-'phenylindole-2-oarboxylic Example, 12
 EMI53.2
 For two: hours, we heat at reflux, a! JI & "" "" '00' <> '"20 g of ethyl 5-methoxw3-phenylindola -. Caooxylate, 7.6 g of sodium hydroxide and 250 ml of ethanol.

   The mixture is cooled to 0 ° C. and the precipitate is collected by filtration, dissolved in 120 ml of water and acidified with 7 ml of concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water. water and dry it
 EMI53.3
 to obtain 16.5 g of 5-methoxy-3-phenylindole-o2-oar-boxylic acid in the form of a white solid with a melting point of 215 0 (decomposition).



   By crystallization from a mixture of acetone and water, the product with a melting point of 218 ° C. (decomposition) is obtained.

  <Desc / Clms Page number 54>

 



  Analysis for C16H13C3N: Calcula 0 71.90 H 4.90, N 5.24%
 EMI54.1
 Find ! C 71.66, il 4.a'3 $ 5.18 H Example13
For two hours, a mixture of
 EMI54.2
 20 g of -mthy, -phnyzindo3cw c, xo! Rzate of ethyl, zizi g of potassium hydroxide and 250 ml of ethanoz..9,; pra removal of the solvent, the residue is dissolved in 150 ml of water and acidify it with hydrochloric acid while cooling. The precipitate is collected by filtration, washed with water and dried to quantitatively acid.
 EMI54.3
 5-methyl-3-phenylindolo-2-carboxylic *
By recrystallization from aqueous acetone, colorless needles with a melting point of 227 C (decomposition) are obtained.



  Analysis for C16H13O2N:
 EMI54.4
 Calculated! 0.67, H 5.22, N 5.5? % Found C 76.70, H 5.06., N 5.58%
In an analogous manner, the following compounds are prepared:
 EMI54.5
 6 (or 8) -nethoxy-5-phenylindole-2-carboxyliquo acid, 5-trifluoromethyl-3-phenylindole-2-carboxylic acid, 5-methyl.sulfony3-pheny3.indoze-2..oarboxyziqu, 5-ethyleultonyl-3-phenylindole-2-carboxylic acid and -dimethylam, .na-3-phenylindole - .. carbox, yJ.ic acid 5-diethylamino-µ-phenylindole-2 acid -carboxylic acid, 5-piperidino-3-phenylindol-2-carboxylic acid # 3- (o-ohlorophenyl) -5-! oethylindole-2-.carboxylic acid 3p (b-cYiorophenylj - mthoey- iztdoze-2.oarboeyziqut 3- (o-chlorophenyl) - $ - dimétbylamino-indole-2-carboxylique acid,

  <Desc / Clms Page number 55>

 
 EMI55.1
 3. (o-tluroplenyl acid,

  -5-methylindole-2-oarbolic µ- (o-fluonophenyl) -5-methoxy-indole-2-carboxylic acid, 3, 3- (o-fluarophenyl) -5-trifluoromethyliBdole "2-oarboxylic acid, l '3 "(o-fluc'rophenyl) -' 5" methylsulfonylindole-2-carboxylic acid, 1 acidJ., Sd.methyl .-- Phenylindola - carboxylic acid! 1'-methyl-3-phenyl-5 -trifluoromethylindole-2-arbo3qyl, Example 14
Heated to reflux for one hour, a mixture of
 EMI55.2
 18 g of 5-methyl-3-phenylindole-2-cayboxylic acid ot 59.5 g of thionyl chloride. When the reaction is complete, the excess thionylo chloride is removed under reduced pressure and the residue is ground in suspension in dry tetrahydroturan.

   Ammonia gas is bubbled through the slurry for two hours while ice-cooling and stirring. Stirring is continued overnight while cooling in ice. The mixture is filtered and the filtrate is concentrated to dryness under reduced pressure to obtain a syrup which is crystallized by filtration with ether to obtain.
 EMI55.3
 obtain 13 g of 5 methyl-µ-phenylindole-2-carboxamide.



  By recrystallization from a mixture of acetone and water, an analytical sample with a melting point of 222-223 is obtained. Analysis for C16H14O2N; Calculated; C 76.56, H 5.64 N 11.19% Found: C 76.56, H 5.44 N 10.93%.
 EMI55.4
 



  IR spectrum 1) pariffine: Max 3430, 3150 (wide), 1660, 1590 ca "" 1

  <Desc / Clms Page number 56>

   Example 15
A mixture of 16 g is heated at reflux for 1.5 hours.
 EMI56.1
 of 5-methoXy-3-phenylindole-2o * oarboXyliquo acid, 20 ml of benzene and 21.4 g of thionyl chloride. The solvent and the excess of thionyl chloride are removed under reduced pressure. To the residue, 100 ml of dry ether and 350 ml of tetrahydrofuran are added, and ammonia gas is bubbled through the mixture for two hours, while cooling in ice.

   The mixture was stirred overnight at room temperature and filtered. The filtrate was concentrated to ploughshare under reduced pressure and, by addition of ethor to the residue, obtained.
 EMI56.2
 holds 11.5 g of 5-nethoxty-3-phenylinàol -2-carboxaz4da with a melting point of 180-192 C IR spectrum) paraffin, 3420, 3150 (broad), 1650, 1580 cm-1.

   In an analogous manner, the following compounds are prepared: 6 (or 8) -methoxy-3-phenylindole-2-carboxamide,
 EMI56.3
 5-trifluoromethyl-3-phenylindole-2-carboxamide, 5-methylsulfonyl-5-phenylinol-2-catboxRmiàe, 5-ethylBulfonàl-3-phenylindole-2-oarboXamide, 5-dimethylanino-µ-phenylindole-2-carboxide , 5-diethylamino-3-phenylindole-2-carboxamide, 5-Piperidino-µ-phenylindole-2-carboxmmide, 3- (o-chlorophenyl) -5-methyline-2-carboxa & ide, -ia-ohloacophen, y,) - 5-nthoxy-, zdoo-2-aarboacmmid ° 3- (o-chlorophnyl) -5-dimthylaino-indala-2-carbpxamida 5- (0.'luoraph6nyl) -5-mthylindola2-orxboxam.da µ- (O- ± luorophenyl) -5-methoxy-indole-2-car'àoxawido, 10 3- (O-fluorophen3.1) -5-trifluonomethylinole-2-Cart> oxamiàe, le;

  - (o-f luaraphnyl) -5-uthylaul'onylind3.a-2-carbtxaan.i, do. 1 5-d.methyl-3-phzyl3.ndole-2-carboxami.o

  <Desc / Clms Page number 57>

 
 EMI57.1
 1-methyl-3-phenyl-5-tril1uoromthylindola2-carboxamide r-mthoxy-1-methyl-3-phenylindola --- carboxanm..do, 1-thy3 ... mtbyisulony.-3-Tbénylindole-2- .carboxam.ide, 1-methyl-5-methylaultonyl-3-phenylindole-2-carboxamide, 5-thylsuifanyi-im.thyi-3-phenyiindolo-2-carboxamid, 1-methyl-3-phenyl-5- trifluoromethylindole-2-carboxamidet 3- (o-! luorophenyl) -1-methyl-5-tritluoromethylindole-2-
 EMI57.2
 carboxamide,
 EMI57.3
 3- (o-fluorophenyl) -1-methyl-5-methylsulfonylindole-2-car- '
 EMI57.4
 boxamide,
 EMI57.5
 3-.o-chlrophâtylj -.!> - dimétiy.amino-1-mthylindole2-carr boxamide, 5-d.méthy.arni; Za-1-mtthyl..3 .- (otrifluoacomethyl) w.ndole-2 -
 EMI57.6
 carboxamide,
 EMI57.7
 the 5,6dimt, y3.-:

  .-pherylirdo.s-.2-carbxau.dQ, 5, ± -d.mthoxy., -. phrzy.indole - carboxamid, 5-ohloro-7-mel. *, hyl-3-phenylindole-2 -carboxamide, 5-nethyl -? - nii; ro-µ-phenylindolo-2-carboxamide, 5-methrl-3- (P 'tolyl) -. ndo.c -.- a -: ü: 3. . 5-methyl-3- (p..methoxyphenyl) -indole-o2-carboxamide, 5-methyl-3- (p witrophfnyl) -indoleT2-carboacim3de :, Exem 16
 EMI57.8
 Has a suspension of 0.25 g of sodium hydride in 10 ml
 EMI57.9
 of dimethylformamide, a solution of 2.5 g of 5methyl-3-phenyliridoli-2-carboxamide in 30 ml of dimethyliorraamldop is added. The mixture is stirred at room temperature pon-
 EMI57.10
 dant one hour, then 2 g of methyl iodide are added thereto. We
 EMI57.11
 stir the mixture at 40 ° C for 4 hours.
 EMI57.12
 



  The resulting mixture is poured into water and one. The extract with chloroform.

  <Desc / Clms Page number 58>

 the organic layer is washed with water and dried with sodium sulfate. The solvent is removed by distillation. The residue is crystallized from ethanol to obtain
 EMI58.1
 1,5-dimethyl-3-phenylinole-2-caiboxamide. Point of fusions 188-191 C.



  Example 17
Has a suspension of 0.25 g of sodium hydride in 5 ml
 EMI58.2
 A solution of 2.6 g of 5-methoxy-5-p eny-indol-2-carboxamine in 30 µm of dimethyl ... 'ormazn, de, is added. The mixture is stirred at 0 a for a period of time. hour $ then adding 2 g of methyl iodide to the mixture. The reaction mixture is stirred at 30 ° C. for 6 hours.



   The resulting mixture is poured into water and extracted with chloroform. The organic layer is washed with water and dried with sodium sulfate.



   The solvent is separated by distillation,
The residue is crystallized from ethanel to obtain
 EMI58.3
 5-methoxy-1-methyl-3-phenyHndole-2-carboxamidet Melting point 152-155 C
In a similar fashion, the following compost is prepared;
 EMI58.4
 i-wëty.-5 -Phnyl-5 tn;

   : .uor. omethy l.iudols-2-.oarioxamid 5-meti.ax, -1.-methy3-phny3.indolo-2-oarboxamide9 i-tthyl - 5-nthylsulonyï-3-phgnylindole-2-carkaocan.dey 1-Mcthyl 5-nethyïau.ionyl-3-Phay3.indola.2-oarboxam.da 5-ethylsulfon3.1-1-nethyl-3-phenylindole-2-carboxan4de, 1-methyl-3-phenyl-5- trifluoromethylindolo-2-carbo9camide 3io-luoropbervi) -.- mthyl 5-trifluorometJ.indo.e-2 carboxamide, 3- (o-fluoiophenyl) -? - nethyl-5-methylaulfonylindole-2-carboxamide

  <Desc / Clms Page number 59>

 
 EMI59.1
 3- (O-Ohlorophenyl) -5-dim6thylamino-1-methylindole-2-carboxamide.



  Example 18
Refluxed for 15 minutes, a mixture of 2 g
 EMI59.2
 of -methyl-3-phnylindola-2-carboxamide and 10 g of phosphorus oxychloride.



   The ice-cooled reaction mixture was filtered off, washed with cold water and dried to give 1.6.
 EMI59.3
 g of 5-methyl-3-perylindole-2-oarbonitrile, mp 194-19? This Example19
Refluxed for 15 minutes, a mixture of
 EMI59.4
 2 g of 5-metboxy-phenylin.dolo - carouxumxua and 10 g of phosphorus oxychloride.



   The ice-cold reaction mixture was filtered, washed with ice-water and dried to obtain 1.5 g of 5-methoxy-3-phenylindole-2-carbonitrilo with a melting point of 184-. 188 C
In an analogous manner, the following compounds are prepared:
 EMI59.5
 6 (or 8) -metho.Ky-3-phenylindoloe-2-carbonitrilo, 5-trifluoromethyl-3-phenylindole-2-carbonitrile, 5-nethylsulfonyl-3-phenylindole-2-carbonitrile, 5-etbyleultonyl -3-Phenylindole-2-carbonitriloq 5-dimethylamino-3-phenylindolo-2-carbonitrila, 5-diethylanino..3-phenylindole-2-carbonitrile, 5-9iperidino-3-phenylindole-2-carbonitrile, 3 - (9-chloropheryl) -5-nethylindolo-2-carbonitrile, - (o-chlorophétyl) -5-methoxy-i.adole-2-carbonitrile, 3- (o-chloroDheryl) -5-dimétbylamino-indole- 2-carbonitril and j- (o-fluorophenyl)

  -5-methylindole-2-earbonitrile,

  <Desc / Clms Page number 60>

 
 EMI60.1
 3- (o-fluorophenyl) -5-methoxy-indole-2-carbOnitril and 3. (o-fluorophenyl) -5-trifluoromethylindole-2-carboaitrile, µ- (o-fluorophenyl) -5-methylsulfonylindola-2- oarbonitrile, 1-aâthyl -.- ph $ nyl-5-triiuoromtbyl.ndola-2-oarbon, trie? 5-mbthaxy-1methyl3.3-phenylindole-2-carbonitr.3. $ 1-ethyl-5-methylxulfonyl-3-phenylinol-2-oarbonitnile, 1-methyl-5-nethylsulfonyl-5-phenylindole-2- Qarbonitrile, 5.thylsulfonyl-1-methyl-3 phny.indole-2-aarbonit;

  cile, 3..methyl-ph6nyl-5tritiuorom6thylindole-ëanrbonitr, .aa 3- (o-fluorophenyl) -1-methyl-5-trifluoromethylindole-2-car-
 EMI60.2
 bonitrilo,
 EMI60.3
 3- (o-fluorophenyl) -1.wethyl-5-metbyl'xulfonglindole-2-oar-
 EMI60.4
 bonitrile,
 EMI60.5
 3- (o-chlorophenyl) -5-dimethylawino-1-methylindolo-2-Oarbo-
 EMI60.6
 nitrile,
 EMI60.7
 5d.néthy.iuui.no-1-methyl-3- (o-tri.uoromthy3.) -indols 2 ocrbonitrïle '10 5,6-dimethyl-3phnylindola-2-oarbon3tri., lo 5,6-dimethoxy-5 -phenylindole-2-carbonitrile, 5-ohloro -? - methyl-3-phenylindole-2-oarbonitrile, 5-methyl -? - nitro-3-phenylindolo-2-carbonitrile, 5-methyl-3- (p -tolyl) -indole-2-carbonitrile, 5-methyl-3- (p-methoxyphenyl) -indole-2-carbonitrJ .:

  Leg 5-methyl-3- (p-nitrophenyl) -indole-2-carbonitrile.
 EMI60.8
 Example 20
 EMI60.9
 Has a mixture of 0.9 g of 5-methyl-3-phenylindolo-2-carbonitrile, of? ml of acetone and 0.7 ml of an aqueous solution of potassium hydroxide to z, 0.7 ml of sulfate is added
 EMI60.10
 dimethyl and stirred at room temperature
 EMI60.11
 for two hours. Then the acetone is removed by di8t 1 .. lation under reduced pressure. We treat the residue with due l '> e ,, 1.

  <Desc / Clms Page number 61>

 filter it, wash it with water and dry it to obtain
 EMI61.1
 hold 10 xdi; néthy.-3-phëny.indols-carboniarils.

   Dot melting point 120-128 C Example 21
 EMI61.2
 To a mixture of 1.0 g of 5-methoxy-3-phenylindole-2-oar-bouitrila, 1 ml of acetono and 0.8 ml of an aqueous solution of hydroxide (70% potassium, 0.8 ml of dimethyl sulfate is added and the mixture is stirred at room temperature for two hours. Then, the acetone is distilled off under reduced pressure. The residue is treated with water, filtered, it is washed with water and dried to obtain
 EMI61.3
 hold 5-nethoxy-1-methyl-3-phenylindole-2-carbonitrile.



  Melting point 103-110 C
In an analogous manner, the following compounds are prepared:
 EMI61.4
 1-methyl-3-plienyl-5-brifluoromethylindole-2-carbonitrile, 5-methoXY-1-niethyl-3-phenylindole-2-curbonitrilo, 1-ethyl-5-nethyleulfonyl-3-phenylindole-2-earbonittilo , 1-methyl-5-methylsulfonyl-µ-phenyl-indole-2-caTbonitrile, 5-ethylBulfonyl-1-methyl-3-phenylindol -2-carbonitrile, 3.methyl -'-phenyl-5-triluoromethylinox- t w -? .. ,, -, i.-4'm, 3 '- (o-fluorophenyl) -l'-methyl-5-trifluoromethylindole-2carbonitrilo, 3- (o-fluotophenyl) -1-methyloos -methylsulfonylindole-2-carbonitrile, 113 3- (o-oh10roph, bnyl) -5-dimethylamino-1-nethylindolo-2-carbonitrile, 5-dimethylamino-1-methyl-3- (o-trifluoromethyl) "indolo-2 - 'carbonitrile.



  Example 22
Has a suspension of 8.5 g of lithium aluminum hydride

  <Desc / Clms Page number 62>

 in 400 ml of anhydrous ether is added in portions, 7! of
 EMI62.1
 5-methyl, -3-phenylindals-carboxam. And the mixture is heated under reflux for 4 hours. After cooling, the excess hydride is decomposed by adding ethyl acetate and wet ether, followed by water. The resulting mixture is filtered and the filtrate is acidified with 50 ml of 12% hydrochloric acid. The precipitate is collected by filtration and separated.
 EMI62.2
 che to obtain 2-aminomethyl'-5 - "'methyl-3-phenylindole hydrochloride. By recrystallization from ethanol, colorless needles with a melting point of 240 C (decomposition) are obtained.



  Example 23
For 4 hours and while stirring, a mixture of 11.1 g of lithium aluminum hydride, 400 ml of anhydrous tetrahydrofuran and 9.7 g of 5-methoxy-3-phenylindole is heated to reflux. -2-carboxamide. After leaving to stand overnight at room temperature, 130 ml of water are added dropwise to the reaction mixture * The mixture obtained is filtered and the dry filtrate is concentrated under reduced pressure * The residue is dissolved in 40 ml of ethanol and treated with ethanolic hydrochloric acid. After allowing to stand for gentle hours at room temperature,

   the mixture is concentrated and ether is added. After cooling, the precipitate is collected by filtration to obtain
 EMI62.3
 2-aminomethyl-5-methoxy-3-phenylindole hydrochloride with a melting point above 300 C,
In an analogous manner, the following compounds are prepared: 2-aminomethyl-6 (or 4) -methoxy-3-phenylindole,
 EMI62.4
 2-aminomethyl-5-bromo-6 (or 4) -méthoJç / -3-phenylindole, 2-aminomethyl-3-phen-yl-5-trifluoromethylindole, 2-aminomethyl-3-phenyl-6 (or 4 ) -triâluoromethylindo.a,

  <Desc / Clms Page number 63>

 
 EMI63.1
 2-aminomethyl-soomethylsulfonyl-3-phenylindolv, 2-aminomethyl-5-ethyleulfonyl-3-phenylindole, 2-aminomethyl-5-dimethylanino-3-phenylindole, 2-sminonethyl-5-diethylanino-3-phenylindolo,

   2-aminomethyl-3-phenyl-5-Piperidino-indole, .am.nomethyi-3 - (- oàlorophnylj-5-methylinaola '2-aminomethyl-3- (o-chlorophbnyl) -5-methoxy-indle, 2-aminomethyl-3- (o-ohlorophenyl) -5-dimé% hylamino-indole, 2-aminomethyl-3- (o-fluorophenyl) -5-methylindole, -aminomthyl 3- (otluorophdnyl) -5-methcxy -inola, 1a, -rxm3.nomethyl-3-io-luorophészyl) -5-rl;

  nrnmthy7 ".ndnl, 8, c-aminomcthyl-3o-fluorophenyl) -.- nethylsultonylindolat -aminomthyl-3- (o-fluorophEnyl) -5-ümethylamino-, ndole, 2éuni.nométbyl l, 5-diméthyi-3 .-Phenylindolo, 2-aminomethyi-5-methoxy-1rabthyl-5-phnylindolo, 2-aminomethyl..l-ethyl-5-methylsulfonyl-3-phenylindolo, 2-emiuomethyl-1-mdthyl-5-mthy. cultonyl-3-phbnylitdolo? aminon6thyl. 5-thyleuxtonyl-1-methyl-3-phnyl3ndolo, -amiaQmethylx-mthyl-5-phnyl-5-tritluoromëthyl.ndol, o, 2-aminombthyl-3- (o-fluorophenyl ) -1-methyl-5-trifluoromethyl-
 EMI63.2
 indole,
 EMI63.3
 2-amino-3- (o-i'luoroph6nyl) -1-methyl-5-nethylsulfonylindolo, 2.;

  minomthyl..3- (o-ahiorophenyl) -5-dimethylamino.-1-r & thyl-
 EMI63.4
 indole.
 EMI63.5
 -2-Aminomethyl-5-dimethylamino-1-methyl - (o-tritluoromethyl1 '
 EMI63.6
 indole,
 EMI63.7
 -umi.momethyl., 6-dimethyl - phrylindola, 2-aminonethyl-5,6-dinethoxy-3-phenylindol, 2-aminomethyl-5-ehloro-7-methyl-3-phenylindoloq

  <Desc / Clms Page number 64>

 
 EMI64.1
 2-wninomethyl-5-methyl -? - nitro-3-phenylindolo, 2-aminomethyl-5-methyl-3- (p-tolyl) -indole, -aminomethyl-5-mdthyl -. (p-methephenyl) -indole lo 2-aminomethyl-5-methyl-3- (p-nitrophenyl) -indole, as well as loura hydrochlorides, their hydrobromides, their sulphates and their acetates.



  Example 24
To a suspension of 2 g of lithium aluminum hydride in 300 ml of dry ether is added dropwise, 3.5 g of
 EMI64.2
 5-methoxy-1-methyl-µ-phenylindolJ-2-carbonitrile, while stirring. After addition, the mixture is heated under reflux for 4 hours.



   The reaction mixture is cooled with ice and water is added dropwise to the mixture. The ether layer was separated, dried over sodium sulfate, and the solvent was distilled off to give 3.2 g of 2-
 EMI64.3
 aminomethyl-'5-methoxy-3tphenylindole. Has a solution of 8 <"Aminomethyl-5-Bethoxy-1-naethyl-3-phenylindole in ether, 10% hydrochloric acid is added and the mixture is stirred.



   The precipitate is collected by filtration to obtain
 EMI64.4
 2-aainomethyl-5-methoxy-i-ethyl-3-phenylindole hydrochloride. By rocrystallization from ethanol, crystals with a melting point above 300 ° C. are obtained.



  Example25
To a suspension of 2 g of lithium aluminum hydride in 300 ml of ether is added dropwise 3.6 g of 1.5-
 EMI64.5
 d, m3-ethyl-3-phenylindol-carbonitriln 'while stirring. After the addition, the reaction mixture is heated under reflux for 4 hours. The reaction mixture is cooled with ice.

  <Desc / Clms Page number 65>

 
 EMI65.1
 and water is added to the mixture. We separate the ether layer,
 EMI65.2
 it is dried over sodium sulfate. To the ether solution is added α, 3 hydrochloride to los and the mixture is stirred vigorously.
 EMI65.3
 sowing the mixture The precipitate is collected by filtration to obtain
 EMI65.4
 ne 2-aminoméÉhy1-1,5-dinethyl.µ-phenylindole hydrochloride.



  260-270 "C (decomposition).
 EMI65.5
 



  In an analogous manner, the following compounds are prepared!
 EMI65.6
 2-aminomethyl "6 (or 4) -methoxy-3-phenylindole, 2-aninomôthyl..5-bromo-6 (or 4) -methoxy-3-phenylindole, -am.nomethyl3-phnyl-5-trifluoromthylindolo '2-amitomethylâ-phenyl-f (or 4) -trifluoromethylindole, -aminomethyl5-methylsulfony, .. 3-phenylindole, G-chuLLnoiQthyl'S-l3thy.i.sti.l.oiii% 1 wx. #'. j. .1, -aminomthy.-f-dimth;

  plamino-3-phenylindole, -aainomethyl-5-dithylamino.-3-phen, Ylindole, 2-aninomethyl-, 3-phenyl-5-piporidino-indole, c-aminomethyl-3- (o-chlorophenyl) -5 -methylindo3. ' 10 2-aminomethyl ,, '3- (o-chlorophenyl) -5-methoxy-indole, 2-aminomethyl-3- (o-chlorophenyl) -5-dimethylamino-indole, 2 - am3.nomethyl - ( o-fluorophnyl) -5-methylindole, 2-.aminomethyl - (oTfluorophzyl) -5-methaxy-indole 2-aminomethyl-3- (o-fluorophenyl) -5-trifluoromethylindole, 2-aminomethyl-3- ( o-fluorophenyl) -5-methyleulfonylindolet 2-aminomethyl-5- (o-fluorophényi) -5-dimethylamino-indole, 2-aminomethyl-5-methoxy-1-nethyl-3-phenylindole, 2-aminomethyl-1 -ethyl-5-methyleulfonyl-3-phenylindolq, 2-aminomethyl-1-nethyl-5-nethylsulfonyl-5-phenylindole, 2-aminomethyl-5-ethylaulionyl-1-methyl-3-phenylindole,

   2-aminomethyl-1-methyl - .. phenyl-5-tritluoromethylindole,

  <Desc / Clms Page number 66>

 
 EMI66.1
 2-aminomethyl-3- (o-tluorophenyl) -1-methyl-5-% rifiUotomethylindole, 2-am.n, omethyl - .. (o + .luorophny, l) -.- methyl, - mthyular.indole , 2-oednomethyl-3- (o-chlorophenyl) -5-dinethylanino-1-nethylindole, 2-aminom6thyl-5-dimethylamino-'l-methyl-3 - '(o-trifluorom'Hhyl) -indole, ..aminomtnyi-5, s-.d.mthy ..- 3-.hnrlindo.e, 2-aminonethyl-5,6-dine% hoxy-3-phenylindole, -aminomethy. S-chloro -? - methyl-3-Pn3'indola 2-am.nomthyl-5 mthyl -? - n.itro-3 pheny,: ndoie, 2-aminomethyl-5-methyl-3- (p- tolyl) -indole, 2-aminomethyl-5-methyl-3- (p-methoxyphenyl) -indole, 2-aminonethyl-5-methvl-3- (p-nitrophenyl) -indole.



  Example 26
Stirred at room temperature, a mixture of 1.9 g
 EMI66.2
 of 2-aminomthyl-5.-methyl-3-phenylind.ag hydrochloride with 40 ml of glaoial acetic acid and 25 ml of 30% hydrogen peroxide. When the reaction is complete, the reaction mixture is made basic with ammoniacal water and extracted with ether. The ether extract was extracted with 10% aqueous hydrochloric acid solution, made basic with ammoniacal water, extracted with ether, dried over sodium sulfate, then the solvent is removed under reduced pressure, the residue is recrystallized from
 EMI66.3
 acetone to obtain? methylSaphriyl-1,3-dihydrc 2H ..



  1,4 ... 'benzodiazin-c-ona mp 2C? 9-21Q C,

  <Desc / Clms Page number 67>

 Example 27
A solution of 3 g of chromic anhydride in 3 ml of water is added dropwise, while cooling, to a mixture
 EMI67.1
 stirred with 3 g of 2-ominomethyl-3-phenyl-5-methylindole hydrochloride and 30 ml of glacial acetic acid. The mixture is stirred at room temperature overnight. The reaction mixture is diluted with water, round basic with ammoniacal water and extracted with ethor. The ether extract is dried over sodium sulfate and the solvent is removed under reduced pressure.

   The residue is rocristalliso
 EMI67.2
 in acetone to obtain 1q ^ - ^ ro --phenyl7.1, - dihydro-2H-1'4..benzodiapin-rone with a melting point of 210-211 0.



  Example 28
Has a mixture of 3 g of 2-aminoethyl-5- hydrochloride
 EMI67.3
 Methdxy-1-methyl-µ-phenylindole and 30 ml of acetic acid, a solution of 3 g of chromic anhydride in 3 ml of water at 10 ° C. is added dropwise. The mixture is stirred at temperature. ambient overnight. The reaction mixture is poured into a large quantity of water, made alkaline with aqueous ammonia, and extracted with ether.



     We dry it. Ether layer on sodium sulfate and the solvent is removed by distillation.



   The residue was crystallized from isopropanol to obtain
 EMI67.4
 keep ..methcacy-1-methyl-phenyl-1, j-dihydro-ü-i, tybouzodiazepin-2-one with a melting point of 112-120 C
In an analogous manner, the following compounds are prepared:
 EMI67.5
 8-methoxy-5-j: henyl-1,3-dihydro-2H-1,4-bonzodiazepin-2-onot 8.mtthox, - '= troraa-5-phny.-1;

  -dihydxoAH-i, + - bvnzodirzpin-2-ono, la 6 (or 8j-tr.fluoronethyl-5-peryl-1, -dihydro-2H-l, + - bsnxo- diseépin-2-non,

  <Desc / Clms Page number 68>

 
 EMI68.1
 ? -mthyîaui'onys-5phnyi-à, - dihydro-H-3.'oa.zod.aaiw- 2-ono,? -dimbhy.rzm.no- phny ..-, 5-di.hydro- I -., S.bsnzodia6pin
 EMI68.2
 2-one,
 EMI68.3
 ? .- di.hylamino-5-pnyi-1,3-d.ihydro2i -., - banzod.azpâ.r-one,? -pipenidino-5-phenyl-1, µ-dihydi, o-2H- 1,4-Benzoàiazepin-2ons, La 5 (o-ohioroph6ny.) -? - mthoxy-1,3-d.hydcor-, e.benod.az-
 EMI68.4
 pin-2-one,
 EMI68.5
 5- (o-ahiorophényi) -? .- methyl -., 3-.ihydro-H .., 4.

   banzociazb pin-2-one, 5- (o-chlotophenyl) -? - dinethylamino-1,3-dihydro-2H-1, + - benzodiazpin-2-pna la 5- (o-iluorophenyl) -? - methyl- 1, µ-dihydro-2H-1,4-benzodiazé
 EMI68.6
 pin-2-ono,
 EMI68.7
 5- (O-.l.ua.rophnyl.) -? - methocy.-3., 5-dihydo-2H-i, F .. 'bsnzodiaz
 EMI68.8
 pin-2-one,
 EMI68.9
 5- (o-âluorophnyl) -7-mthyisu.fony3 .- ,, 5-d.hydro-2H -., + .. benzodiazepin-2-one 5- (o-'luoroph # ny7.) - 7 -dimGhylamino-i9r-dhydrQ.Il, +. bonzodiaz6pin-2-one, la? -dimthyz-5-.phry.-1, -dirydro-2z -., + - bnod.aZp.nA ona, la? -methoxy-1-'nthyi.r5-phnyl- 1, -dib.ro.-2H .., 4..benodiax
 EMI68.10
 pin-2-one,
 EMI68.11
 1-ethyl -? - nethylsulfonyl-5-phenyl-1,3-aihydro-2H-1, 'k-benzo-
 EMI68.12
 diazepin-2-ono,
 EMI68.13
 la, -oiyl -? - mthy.eul'onyZ-5-pï.rl-, 3-a.ihaa-2i -, -.

   bonzodiazepin-2-onot

  <Desc / Clms Page number 69>

 
 EMI69.1
 .3thy.ulapn, wI-methyl.-5-phenyl-3-dihydro-2H -., t - benzodiazepin-2-one, 3 ..- meihyl - phEinyi ..- trif3uoromethyl-1, 3-dü, ydro-Hl, + - benzo.
 EMI69.2
 diezepin-2-un,
 EMI69.3
 5 - (o-fluorophEinyl) -l-methyl-7-trifluorophenyl1,5-dihyd:

  ro- 2H-I, 4-benzodiazéopin-2-one, 3- (p..fluoroph nyl) - --méthy3.-7-n6 4hy18ulf onyl-1,3-dihydro- 2X-1,4-bcnzodiazepin- 2-one, la -o-ohlorophenyl) - d.wéthy3traina-1-mëthy3.-7,3-dihydro-2Il, 1> -benzodinzopin-2-ono, la .diméthy7..amno-1-méthyi .-5- (o-trifluo.ronethyl) -1,3-d.hydroH-1,4-tanzodiazepin - pna, la, 8-.dimethyl-.5-phenyl-1'3-dihydro-2H-1 , 4-bonzodiazepin-2-.

   
 EMI69.4
 we,
 EMI69.5
 la?, 8-dimethoxy-5-phenyl-1, µ-dihydro-2H-1,4-benzodiazepin-2-
 EMI69.6
 ono,
 EMI69.7
 la -ohloro - methyl-5-pkeny-1,3-dir., yaro 2H -., 4-bonzodiazepin-
 EMI69.8
 2-ona,
 EMI69.9
 '? .- methrl-9-nitr .-- phly1-1,3-dihydro-.2H - a., .. benza.zept-
 EMI69.10
 2-one,
 EMI69.11
 7-metbyl-5- (p-Goolyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one,? -môthyl-5- (p-iùethoxyphenyl) -1, µ-dihydro- 2H-1,4-benzodiazepîn-2-onal la -.mthyl-5- (p-nitrophenyl) -1,3.dihydro-H -., 4-bunzodiazepin-
 EMI69.12
 2-one.

 

Claims (1)

CLAIMS 1. Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI70.1 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy group, a haloalkyl group of 1 to 4 carbon atoms, an alkyl-sulfonyl group of 1 to 4 atoms of carbon, a dialkylamine group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alooyl group, an alkoxy group or a haloalokyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen or halogen atom or an alkyl group, alkoxy or haloalkyl of 1 to 4 carbon atoms, characterized in that it consists in reacting a 2-aminomethylindele derivative corresponding to the formula EMI70.2 <Desc / Clms Page number 71> wherein R, R1, R2 and R respectively have the same meanings as those defined above, or its salt, with an oxidizing agent. 2. Process for the preparation of bonzodiazepine derivatives corresponding to the formula EMI71.1 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms, an alkyl-sulfonyl group of 1 to 4 carbon atoms. carbon, a dialkylamino group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen or halogen atom or an alkyl group, alkoxy or halogenoalkyl having 1 to 4 carbon atoms, characterized in that it consists in hydrogenating an indole-2-carbonitrile derivative corresponding to the formula EMI71.2 <Desc / Clms Page number 72> wherein R 'R1, R2 and R3 have respectively! the same meanings as those mentioned above, after its possible 1alkylation, to obtain a 2-aminomethylindole derivative corresponding to the formula EMI72.1 in which R, R1, R2 ot R3 have rospoctively the same meanings as those defined above, then reacting the 2-aminomethylindole derivative obtained of formula (II), or its salt, with an oxidizing agent. 3. Process for the preparation of benzodiazepino derivatives corresponding to the formula EMI72.2 wherein R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R 1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms; an alkylsulfonyl group of 1 to 4 carbon atoms, a <Desc / Clms Page number 73> dialocylanine group of 1 to 4 carbon atoms or a piperidine group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a d atom 'hydrogen or halogen or an alkyl, alkoxy or halo-alkyl group of 1 to 4 carbon atoms, characterized in that it consists in heating an indole-2-carboxanido derivative corresponding to the formula EMI73.1 in which R, R1, R2 and R3 respectively have the same meanings as those defined above, after its optional 1-alooyl ation, to obtain a @@@@ -2-carbonitrila corresponding to the formula EMI73.2 <Desc / Clms Page number 74> in which R, R1, R2 and R3 ext respectively the Bounds meanings that collas defined above, hydrogenate the derivative of indole-2-carbonitrile obtanu, sprÇs its optional a-alkylation, to obtain a derivative of 2-aminomethylinodole corresponding to the formula EMI74.1 (II) in which R, R1.R2 and R3 respectively have the same meanings as collas defined above, then reacting the 2-aminomethylindole derivative obtained of formula (II), or its sol, with an oxidizing agent 4, Process for the preparation of bonzodiazepine derivatives corresponding to the formula EMI74.2 wherein R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alooxy, haloalkyl group of 1 to 4 carbon atoms, an alkylsulfonyl group of 1 to 4 carbon atoms, a group <Desc / Clms Page number 75> dialkylamino with 1 to 4 carbon atoms or a pipridino group, R2 represents a halogen or hydrogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents an atom hydrogen or halogen or an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms, characterized in that it consists in reducing an indole- 2-carboylic acid (thio) anide derivative corresponding to the formula EMI75.1 in which R, R1, R2 and R3 respectively have the same meanings as those defined above and W represents oxygen or called sulfur, after its possible 1-alkylation, to obtain a 2-aminomethylindele derivative corresponding to the formula EMI75.2 <Desc / Clms Page number 76> in which R, R1, R2 and R3 respectively have the same meanings as those defined above, then te.ire react lo derivative of 2-aminomethylindole obtained of formula (II), or its salt, with an oxidizing agent, to obtain the benzodiazepino derivative of formula (1) 5. Process for the preparation of a benzodiazepine derivative corresponding to the formula EMI76.1 where R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms, an alkylsulfonyl group of 1 to 4 carbon atoms a group dialkylamino of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents an atom of hydrogen or halogen or an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms, characterized in that it consists in reacting an indole-2-carboxylic acid derivative corresponding to the formula EMI76.2 <Desc / Clms Page number 77> in which R, R1, R2 and R3 respectively have the same meanings as those defined below 'or its derivative reactive with ammonia, after its optional 1-alkylation, to obtain an indole-2-carboxyamide derivative answering the formula EMI77.1 in which Et R1 R2 ot R3 respectively have the same meanings as those defined above, heat the indolo derivative obtained of formula (X), after its possible 1-alkylation, to obtain an indolo-2-carbonitrile derivative answering the formula EMI77.2 where R, R1, R2 and R3 have the same si-, respectively. gnifications than those defined above, reduce the indole-2-carbontrile derivative obtained of formula (XI), after its optional 1-alkylation, to a 2-aminometylindole derivative corresponding to the formula <Desc / Clms Page number 78> EMI78.1 in which R, R1, R2 ot R3 respectively have the same meanings as those defined above, then reacting the 2-aminomethylindols derivative obtained of formula (11), or its salt, with an oxidizing agent, to obtain the derivative bonzodiazepino of formula (I), 6. Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI78.2 in which R represents a hydrogen atom or an alooyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alooxy, haloalkyl group of 1 to 4 carbon atoms, an alkylsulfonyl group of 1 to 4 carbon atoms, a dialkoylamino group of 1 to 4 carbon atoms one or epiperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents an atom of hydrogen or halogen or an alkyl, alkoxy or halogen group. <Desc / Clms Page number 79> noalkyl of 1 to 4 carbon atoms, characterized in that it consists in reacting an indole-2-oarboxyliquu acid derivative corresponding to the formula 4 EMI79.1 in which R, R1, R2 and R3 respectively have the same meanings as the glues defined above, with a halogenating agent, after its possible 1-alkylation, to obtain EMI79.2 nir a derivative of hclogenuro indo3.e-2-ccrboxyliquG corresponding to the formula EMI79.3 EMI79.4 in which R, nl, R and R3 have respect the same meanings as those defined above and Hal represents a halogen atom, in order to react the derivative of indolo-2-oarboxyliquo halide obtained with ammonia, after its 1-possible alkylation, to obtain an indole-2-oarboxamide derivative corresponding to the formula <Desc / Clms Page number 80> EMI80.1 in which R, R1, R2 and R3 respectively have the same meanings as those defined above, heating the indole-2-carboxamido derivative obtained of formula (X), after its evontuolle 1-alooylation, to obtain a derivative of 'indole-2-carbonitrile corresponding to the formula EMI80.2 in which R, R1, R2 ot R respectively have the meanings as those defined above, hydrogenate the indolo-2-carboitrile derivative obtained of formula (XI), after its optional 1-alkylation, to obtain a 2-aminomethylindolo derivative corresponding to the formula EMI80.3 <Desc / Clms Page number 81> in which R, R1, R2 and R3 respectively have the same meanings as saddles defined above, then reacting the 2-aminomethylindole derivative obtained of formula (11), or its salt, with an oxidizing agent, to obtain a derivative of bonzodiazepine formula CI). 7- Process for the preparation of bezodiazepine derivatives corresponding to the formula EMI81.1 in which R: represents a hydrogen shell or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms, an alkylsulfonyl group of 1 to 4 carbon atoms, a dialkoylamino group of 1 to 4 carbon atoms or a piperidno group R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R represents a hydro atom. gene or halogen or an alkyl group, alkoxy or haloalkyl of 1 to 4 carbon atoms, characterized in that it consists in converting an ester derivative of indola-2-carboxylic acid corresponding to the formula EMI81.2 <Desc / Clms Page number 82> in which R, R1, R2 and R3 have the same meanings as defined above and R6 represents an alkyl group of 1 to 4 carbon atoms, after optional 1 - alkylation, to an indole-2- acid derivative carboxylic acid corresponding to the formula EMI82.1 in which R, R1, R2 and R3 respectively have the same meanings as those defined above, reacting the indole-2-carboxylic acid derivative obtained of formula (VIIIb) or its reactive derivative, after its optional 1-alkylation, with ammonia and then, optionally, reacting the obtained compounds with phosphorus pentasulfide to obtain an indole-2-carboxylic acid do (thio) amide derivative corresponding to the formula EMI82.2 <Desc / Clms Page number 83> in which R, R1, R2, and R3 respectively have the same meanings as those defined above, W represents an oxygen or sulfur atom, reduce the indole-2-carboxyliquo acid derivative obtained of formula (XIII), after its possible 1alkylation, to obtain a 2-aminomethylindole derivative corresponding to the formula EMI83.1 where R, R1, R2 ot R3 respectively have the same meanings as glues defined above, then react the derivative of 2-aminomethylindole obtained of formula (II) or its sol, with an oxidizing agent, to obtain the benzodiazepine derivative of formula (1) . 8. Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI83.2 <Desc / Clms Page number 84> in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalocle group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a dialkoylamino group of 1 to 4 carbon atoms or a piperidino group R2 represents a hydrogen or halogen atom an alkyl, alkoxy or haloalkl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen atom or halogen or an alkyl group, alkoxy or halogenoalkyl of 1 to 4 carbon atoms, characterized in that it consists in converting an ester derivative of indole-2carboxylic acid corresponding to the formula EMI84.1 in which R, R1, R2 and R3 have the same meanings as the glues defined above and R6 represents an alkyl group of 1 to 4 atoms of oarbono, after its optional 1-alkylation, indole-2-carboxylic acid is derived answering the formula EMI84.2 <Desc / Clms Page number 85> in which R, R1, R2 and R3 have the same meanings as those defined above, reacting the aoido indole-2-carboxylic derivative obtained of formula (VIIIb) with a halogenating agent, after its 1-alkylation possible, to obtain an indole-2-carboxyliquo halide derivative corresponding to the formula EMI85.1 in which R, R1, R2 and R3 respectively have the same meanings as those defined above and Hal represents a halogen atom, faixe react the indola-2-carboxylic halide obtained with ammonia, after its 1- optional alkylation, to obtain an indole-2-carboxamide derivative corresponding to the formula EMI85.2 in which R, R1, R2 and R3 have the same meanings as those defined above, respectively, reduce the indolo- <Desc / Clms Page number 86> 2-carboxamide obtained of formula (X), after its optional, 1-alkylation, to obtain a derivative of 2-aminomethylindole corresponding to the formula EMI86.1 in which R, R1, R2 and R3 respectively have the same meanings as those defined above, then react the obtained 2-aminomethylindole derivative of formula (II) or its salt, with an oxidizing agent, to obtain the derivative of benzodiazepine of formula (I) 9. Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI86.2 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R 1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms. an alooylsulfonyl group of 1 to 4 carbon atoms, a group <Desc / Clms Page number 87> dialkylamine of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen or halogen atom or an alkyl, alkoxy or haloalkyl do 1 to 4 carbon atoms, characterized in that it consists in reacting a phenylpyruvic acid derivative corresponding to the formula EMI87.1 in which R4 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms and R3 has the same meaning as defined above, with a phenylhydrazine derivative corresponding to the formula EMI87.2 in which R, R1 and R2 respectively have the same meanings as the glues defined above, to obtain an indolo-2-carboxyliquo acid derivative corresponding to the formula <Desc / Clms Page number 88> EMI88.1 in which R, R1, R2, R3 and R4, respectively have the same meanings as those defined above, optionally converting the indole-2-carboxylic acid derivative obtained (VIII), after its optional 1-alocylation, to obtain an indole-2-carboxylic acid derivative corresponding to the formula EMI88.2 in which R, R1, R2 and R respectively have the same meanings as those defined above, reacting the indele-2-carboxylic acid derivative obtained of formula VIIIb or its reactive derivative, with ammonia and then, even - tuullumont reacting the reaction product with phosphorus pentasulfide, after its possible 1-alooylation, to obtain a do (thio) derivative indole-2-carboxylic acid amide of the formula EMI88.3 <Desc / Clms Page number 89> in which R, ni $ R3 and R3 respectively have the same meanings as those defined above and W represents an oxygen or sulfur atom, reduce the indole-2-carboxylic acid derivative obtained from formula (XIII), after its optional 1-alkylation, to obtain a 2-aminomethylindole derivative corresponding to the formula EMI89.1 in which R, R1, R2 and R respectively have the same meanings as those defined above, then fairo react the derivative ,, of 2-aminomethylindole of formula (II) or its salt, with an oxidizing agent, to obtain the derivative of benzodiazepine of formula (I). 10. Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI89.2 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy haloalkyl group of 1 to 4 carbon atoms, <Desc / Clms Page number 90> an alkylsulfonyl group of 1 to 4 carbon atoms; a dialkylamino group of 1 to 4 carbon atoms or a pigedidino group, R2 represents a hydrogen or halogen atom! an alkyl, alooxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen or halogen atom or an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms, characterized in that it consists in reacting a phenylpyruvic acid derivative corresponding to the formula EMI90.1 in which R4 represents a hydrogen tern or an alkyl group of 1 to 4 carbon atoms and R3 has the same meaning as defined above, with a phenylhydrazino derivative corresponding to the formula (III) EMI90.2 in which R, R1 and R2 respectively have the same meanings as those defined above, to obtain an indole-2-oarboxylic acid derivative corresponding to the formula <Desc / Clms Page number 91> EMI91.1 in which R, R1, R2, R3 at R4 ot respectively the marls meanings as those defined above, convert optionally the derivative of indole-2-carboxylic acid obtained (VIII), after its possible 1-alkylation, a derivative of indole-2 acid -carboxylic corresponding to the formula EMI91.2 in which R, R1R2 and R 'respectively have the same meanings as those defined above, reacting the indole-2-carboxylic acid derivative obtained of formula (VIII) or its reactive derivatives, with ammonia, after its' 1alcoylation ventulle, to obtain an indole-2carboxamie derivative corresponding to the formula EMI91.3 <Desc / Clms Page number 92> in which R, R1, R2 and R3 respectively have the same meanings as defined above, reduce the indole-2-carboxylic acid derivative obtained of formula (X), after its optional 1-alkylation, to obtain a derivative of indole-2-carbonitrile corresponding to the formula EMI92.1 in which R, R1, R2 and R3 respectively have the same meanings as the adhesives defied above, hydrogenating the indole-2-carbonitrile obtained (XI), after its optional 1-alkylation, to obtain the 2-aminomethylindole derivative repon - due to the formula EMI92.2 in which R, R1, R2 and R3 respectively have the same meanings as Cellas defined above, then reacting the 2-aminomethy derivative; indole obtained of formula (II) or its salt, with an oxidizing agent, to obtain the benzodiazepine derivative of formula (1), <Desc / Clms Page number 93> 11. Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI93.1 wherein R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a graupe dialkoylamine of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen or halogen atom or an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms , characterized in that it consists in reacting a derivative of β-keto-aoid ester corresponding to the formula EMI93.2 <Desc / Clms Page number 94> EMI94.1 in which R5 represents a RICOYIO group of 1 to 4 carbon atoms and R6 represents an alkyl group of 1 to 4 carbon atoms, while R3 has the same meaning as that EMI94.2 defined above, with a bctn! 5ene "diazonium salt of the formula EMI94.3 in which R1 ot R2 have the same meanings as those defined above and Y represents a halogen atom, to obtain a derivative of indolo-2-carboxylic acid having the formula EMI94.4 EMI94.5 in which Ri Ruz, R and R Qnt reapect1vement the same meanings as those defined above, transforming the derivative of indolo-2-oarboxylic acid ester of formula (Villa), after its possible l-alkylation) to a derivative indole- 2-carboxyliquo acid corresponding to the formula EMI94.6 <Desc / Clms Page number 95> in which R, R1, R2 and R3 respectively have the same meanings as those defined above, reacting the indole-2-carboxylic acid derivative of formula (VIIIb) or its reactive derivative, with ammonia, after its optional 1-alxoylation and then, optionally, reacting the compound obtained with phosphorus pentausofide to to obtain an indola-2-oarboxylic acid (tbio) amide derivative corresponding to the formula EMI95.1 in which R, R1, R2 and R3 respectively have the same meanings as those defined above, 'it represents an oxygen or seufre atom, reduce the derivative of indole-2-carboxylic acid (thio) amide obtained (XIII), after its possible 1-alkylation, to a derivative of 2-aminomethylindolo corresponding to the formula EMI95.2 <Desc / Clms Page number 96> where R, R1, R2 and R3 respectively have the same meanings as those defined above, then reacting the 2-aminomethylindole derivative obtained of formula (11), or its salt, with an oxidizing agent to obtain a bonzodiazepine derivative of formula (1 ). 12. Process for the preparation of a benzodiazepine derivative corresponding to the formula EMI96.1 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R 1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms, an alkylsulfonyl group of 1 to 4 carbon atoms, a dialooylamino group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alocyl, alkoxy or haloalkyl group of 1 to 4, carbon atoms or a nitre group ut R3 ropresont an atom hydrogen or halogen or an alkyl, alkoxy or halogen'-alkyl group of 1 to 4 carbon atoms, characterized in that it consists in reacting a derivative of a beta-keto-acid ester of the formula EMI96.2 <Desc / Clms Page number 97> in which R5 represents an alkyl group of 1 to 4 carbon atoms and R6 represents an alkyl group of 1 to 4 carbon atoms, while R3 has the same singification as defined above, with a bonzene-diazonium sol corresponding to at. the formula EMI97.1 in which R1 and R2 have the same meanings as those defined above ot Y represents a halogen atom, to obtain an aster derivative of indole-2-carboxylic acid corresponding to the formula EMI97.2 in which R1, R2, R3 and R6 have the same meanings as those defined above, respectively, converting the indole-2-carboxylic acid derivative obtained from formula (Villa), after its optional 1-alkylation, to a derivative of 'indolo-2-carboxylic acid corresponding to the formula <Desc / Clms Page number 98> EMI98.1 EMI98.2 in lnquolle R, Ri R2 and n3 respectively have the same meanings as those defined above, to react the indole-2-carboxylic acid derivative obtained of formula (VIIIb) EMI98.3 or its reactive derivative, with ammonia, after its evontuollo 1-alooylation, to obtain an indole-2-onrboxami- derivative of the formula EMI98.4 where R, R1, R2 and R3 have the same meanings as those defined above, respectively, dehydrate the EMI98.5 indolo-2-oarbo'xamido derivative obtained (X), after its 1-alòylation eon, tullap to obtain an indole-2 + carbonitrile derivative corresponding to the formula EMI98.6 <Desc / Clms Page number 99> in which R, R1, R2 and R3 respectively have the same meanings as those defined above, hydrogenating the obtained indole-2-carbonitrile derivative (XI), after its optional 1-alkylation, to obtain a derivative of 2- aminomethylindole corresponding to the formula EMI99.1 in which R, R1, R2 and R3 respectively have the same meanings as defined above, then react the obtained 2-aminomethylindole derivative of formula (II) or its salt, with an oxidizing agent, to obtain the benzodiazepine derivative of formula (1). 13 'Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI99.2 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents a group <Desc / Clms Page number 100> alooyl, alkoxy, haloalkoyl of 1 to 4 carbon atoms, EMI100.1 an alkylfonyl group of 1 to 4 carbon atoms, a dialooylamino group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms. 4 carbon atoms or a nitro group and R2 represents a hydrogen or halogen atom or an alkyl, alooxy or haloalkyl group of 1 to 4 carbon atoms, characterized in that it consists in reacting a phenylpyruvic acid derivative corresponding to the formula EMI100.2 in which R3 has the same meaning as defined above and R4 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, with a phenyl-hydrazine derivative corresponding to the formula EMI100.3 EMI100.4 in which R, R 1 and R 2 have rospectivomqnt the least meanings than those defined above, to obtain a derivative of phenylhydrazone corresponding to the formula <Desc / Clms Page number 101> EMI101.1 in which R, R1, R2, R 'and R4 respectively have the same meanings as those defined above, treating the obtained phenylhydroazone derivative (VII), after its optional N-alkylation, to obtain an indole-2-carboxylic acid derivative corresponding to the formula EMI101.2 in which R, R1, R2, R3 and R4 respectively have the same meanings as those defined above, possibly converting the obtained indole-2-carboxylic acid derivative (VIII), after its optional 1-alkylation, to to obtain an indole-2-carboxylic acid derivative corresponding to the formula EMI101.3 <Desc / Clms Page number 102> in which R, R1R2 and R3 respectively have the same meanings as those defined above, reacting the indole-2-oarboxylic acid derivative obtained of formula (VIIIb) or its reactive derivative, with ammonia and then, optionally reacting the reaction product with phosphorus pentasulphide, after its optional 1-alkylation, to EMI102.1 obtain a derivative of (thio) anide of ae.da indole-2-carboxy- 'liquu corresponding to the formula EMI102.2 EMI102.3 in which R, Rl, R2 and R3 have respectiver4ont the mtaes meanings as those defined above, W represents an oxygen or sulfur atom, reduce the derivative of indole-2-carboxylic acid obtained from formula (XIII) after its optional 1-alkylation, to obtain a 2-aminomethylindole derivative corresponding to the formula 4 EMI102.4 <Desc / Clms Page number 103> where R, R1, R2 and R3 respectively have the same meanings as those defined above, then reacting the obtained 2-aminomethylindole derivative of formula (II), or its salt, with an oxidizing agent to obtain the benzodiazepine derivative (the formula (I). 14. Process for the preparation of benzodiazepine derivatives corresponding to the formula EMI103.1 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms, an alkylsulfonyl group of 1 to 4 carbon atoms, a dialkylamine group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a d atom hydrogen or halogen or an alkyl, alkoxy or haloalkyl group of 1 to 4. oarbonu atoms, characterized in that it consists in reacting a derivative of phänylpyruvic acid responding to the foxuule EMI103.2 <Desc / Clms Page number 104> in which R3 has the same meaning as defined above and R4 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, with a phenylhydrazine derivative of the formula EMI104.1 EMI104.2 in which R 'RI and R2 respectively have 188 mOes 81gnifi oations as those defined above, to obtain a phenylhydroazone derivative corresponding to the formula EMI104.3 EMI104.4 in which R, Rit R2t R and R have respeotivemont log m3mee meanings as glues defined above, treat the obtained phenylhydrazone derivative (VII) after its N¯alkyllatoin event EMI104.5 tuelle, to obtain a derivative of indole-2-oarboxylic acid corresponding to the formula EMI104.6 <Desc / Clms Page number 105> in which R, R1, R2, R3 and R4 respectively have the same aignifications as those defined above, optionally converting the indele-2-carboxylic acid derivative obtained (VIII) after its optional 1-alkylation, into a derivative of 'indolo-20carboxylic aoi- corresponding to the formula EMI105.1 where R, R1, R2 and R3 respectively have the same meanings as those defined above, fairo react the derivative of indole-2-carboxylic acid obtained of formula (VIII) or its reactive derivatives, after its optional 1-alkylation, to obtain a derivative d 'indole-2-carboxamide of the formula EMI105.2 in which R, R1, R and R3 respectively have the same meanings as those defined above, reduce the indole-2-carboxylic acid derivative obtained of formula (X), after <Desc / Clms Page number 106> EMI106.1 its possible 1-aiooylation, to obtain a derivative of lnrlolû-2-carbonitriiw responding to fo? au3. '& EMI106.2 in which R1, R1, R2 and R3 respectively have the meanings as those defined above, hydrogenating the indole-2-carbonitrile obtained (XI) after its eventual 1-alkylation EMI106.3 tual, to obtain the derivative of 2-aminomethylindole corresponding to the formula EMI106.4 in which R, R, 1 R2 and R3 respectively have the same meanings as those defined above, puia to react the derivative of 2-aminomethylindole obtained of formula (II) or its salt, with an oxidizing agent, to obtain the derivative of benzodiazepine of formula (I). 15. Process for the preparation of benzodiazepine derivatives corresponding to the formula <Desc / Clms Page number 107> EMI107.1 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalkl group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a dialkoylamino group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group ot R represents a hydrogen or halogen atom or an alkyl group, alkoxy or halo-alooyl of 1 to 4 carbon atoms, characterized in that it consists in reacting a benzene-diazonium salt corresponding to the formula EMI107.2 in which R1 and R2 respectively have the same meanings as those defined above and Y represents a halogen atom, with a beta-keto-acid enter derivative corresponding to the formula EMI107.3 <Desc / Clms Page number 108> in which R has the same meaning as defined above, R5 represents an alkyl group of 1 to 4 carbon atoms and R6 represents an alkyl group of 1 to 4 carbon atoms, to obtain a phenylhydrazone derivative corresponding to the formula EMI108.1 EMI108.2 in which R 1, R 2 # R ot HG have roepaativemont the same signfications as those defined above, treat the obtained phenylhydrazono derivative (VIla) after its possible N-alkylation, to obtain an indole-2-carboxy acid derivative. lique responding to the formula EMI108.3 where R1, R2, R3 and R6 have respectively? the accesses EMI108.4 meanings that callen defined above, tpanafermer derivative of estor of indole-2-carboxyliquo acid obtained of formula (Villa) after its possible 1-alkylation, in a derivative of acid EMI108.5 Indole-2-carboxylîquo corresponding to the formula <Desc / Clms Page number 109> EMI109.1 where R, R1, R2 and R3 respectively have the same meanings as those defined above, reacting the derivative of indole-2-carboxylic acid obtained of formula (VIIIb) or a derivative reactive with ammonia, after its possible 1-alkylation and then optionally reacting the compound obtained with phosphorus pantasulfide to obtain an indole-2-carboxylic acid (thio) amide derivative corresponding to the formula EMI109.2 in which, R R1, R2 and R respectively have the same meanings as those defined above, W represents an oxygen or sulfur atom, reduce the derivative of indole-2-carboxyliuqe acid (thio) obtained ( XIII) after its possible 1-alkylation, there is a 2-aminomethylindole derivative corresponding to the formula <Desc / Clms Page number 110> EMI110.1 (II) in which R, R1, R2 and R3 respectively have the same meanings as those defined above, then reactivate the 2-aminometylindole derivative obtained of formula (II) or its salt, with a oxidizing agent, to obtain the benzodiazepine derivative of formula (I) 16. Process for the preparation of benzodiazepine derivatives of the formula EMI110.2 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, halogenocalocyl group of 1 to 4 carbon atoms, an alocylsulfonyl group of 1 to 4 carbon atoms, a dialkoylamineo group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalkyl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen or halogen atom or an alkyl, alkoxy or <Desc / Clms Page number 111> haloalkyl of 1 to 4 carbon atoms, characterized in that it consists in reacting a bonzene-diazonium salt corresponding to the formula EMI111.1 in the glue R1 and R2 have respectively the same assignments as glues will define above and include a halogen atom, with a beta-keto-acid ester derivative having the formula EMI111.2 in which R3 has the same meaning as cello defined above, R5 represents an alkyl group of 1 to 4 carbon atoms and R6 represents an alkyl group of 1 to 4 carbon atoms, to obtain a phenylhydrazono derivative corresponding to the formula EMI111.3 <Desc / Clms Page number 112> EMI112.1 in which Rit R2, R3 and R are respectivoment leu m8me. meanings as those defined above $ treating the obtained phenylhydrazone derivative (VIIa) after its N-alkylation EMI112.2 possibly, to obtain an in, do.a-2..oarboxylic acid derivative corresponding to the formula EMI112.3 in which R1, R2, R3 and R6 respectively have the same meanings as those defined above, transforming the derivative of indole-2-oarboxylic acid obtained of formula (VIIIa) after its optional 1-alkylation, there is an acid derivative indole- 2-oarboxyliquo corresponding to the formula EMI112.4 in which R, R1, R2 and R3 respectively have the same meanings as those defined above, reacting the EMI112.5 dêrJ, v6 of indolo-2-carboxyliquo acid obtained of formula (VIIIb) or its reactive derivative, with ammonia, after its optional 1-alkylation, to obtain an indole-2-carboxamide derivative corresponding to the formula <Desc / Clms Page number 113> EMI113.1 in which R; Fil, R2 and R3 respectively have the same meanings as those defined above, dehydrate the indole-2-carboxamide derivative obtained (X) after its possible 1-aloylation, to obtain an indole-2- derivative carbonitrile corresponding to the formula EMI113.2 in which R. R1, R2 and R respectively have the same meanings as those defined above, hydrogenating the indelo-2-carboniutrile derivative obtained (XI), after its possible 1-alkylation, to obtain a 2-aminomethylindole derivative corresponding to to the formula EMI113.3 <Desc / Clms Page number 114> in which R, R1, R2 and R3 respectively have the same meanings as those defined above, then reacting the 2-aminomethylindole derivative obtained of formula (II) or its salt, with an oxidizing agent, to obtain the derivative of lentodiazepine of formula (1). 17 'Process for the preparation of benzodiazepino derivatives corresponding to the formula EMI114.1 in which R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R1 represents an alkyl, alkoxy, haloalkyl group of 1 to 4 carbon atoms, an alocylsulfonyl group of 1 to 4 carbon atoms, a diclcoylamino group of 1 to 4 carbon atoms or a piperidino group, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or haloalocl group of 1 to 4 carbon atoms or a nitro group and R3 represents a hydrogen or halogen atom or an alkyl group, alkoxy or haloalkyl of 1 to 4 carbon atoms, characterized in that it consists in reacting a 2-aminomethylidole derivative corresponding to the formula <Desc / Clms Page number 115> EMI115.1 in which R, R1, 82 and R3 have respectively the same meanings as those defined above, or its selk, with an oxidizing agent, to obtain the benzodiazepine derivative of formula (I) and to react lo benzodiazepine derivative of formula (1) with a seide to get its salt