BE713513A - - Google Patents

Description

  

   <Desc / Clms Page number 1>
 



    BRUSSELS.



   The applicant wishes to point out that the following corrections should be made to the text of this patent:
Page 3, in the first equation:
 EMI1.1
 after "DCCD" insert "dicyclohexyle earbodi.mido" ae 18, penultimate line - read t "..... 2-; ethyl-5-methyl ...." instead of: "..... 2 - methyl-7-methyl .... "Page 12, lines 13 - 14:
 EMI1.2
 remove ; 1; Help! - L-2'-thnoyl-2-methy .--: athocy-â. ; 3ndoly- bu4yric "

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 Ministry of Economic Affairs
 EMI2.1
 Scrviaede la Proiri - 4u-é Indllstriel.



  PaSe 2àt l.itnes 2 - 2 1 .supprimer: "lef ± 1-nicotinoyl-2-nethyl-5-môthoxçy-fi-indolyiÙl-potassium butyrate".



  Page 24, lines 23 - 24; delete: "the piperadinium salt of acid # - (1-
 EMI2.2
 cinnaznoyl-2-methyl-5-methoxy-3-izzde yl) propionic ".



    Page 25, lines 1 - 2
 EMI2.3
 delete: "sodium - (1-ciznamoyl-2-methyl - méthōcy -.- indolyl) propionate" Page 26, lines 1 - 2:
 EMI2.4
 delete: "1- (2 - Naphthylaoryloyl) -2-methyl-5methoxy-3-indolyl-acetic acid" Page 26, line 3! delete: "-5-methyl" Page 35, lines 7 - 10 delete example 18 entirely Page 40, line 24:
 EMI2.5
 read "example 3t?" instead of "example 1".

 <Desc / Clms Page number 3>

 



  Ministry of Economic Affairs
The undersigned is aware that no document attached to the file of a patent for invention can be of a nature to make, either to the description or to the drawings, substantive changes and declares that the content of this note does not make such changes and has no other purpose than to point out one or more material errors.



   He acknowledges that the content of this note cannot have the effect of making patent application N 56995 valid in whole or in part if it was not in whole or in part by virtue of the legislation currently in force. force.



   He authorizes the Administration to attach this note to the patent file and to issue a photocopy of it.



   Enclosed you will find, in revenue stamps, the amount of the required tax.



   Please accept, Sir, the assurance of our highest consideration.

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 "Indole derivatives and their salts" Priority of nine patent applications filed in Japan on: - April 11, 1967, under N 23337/67,
May 6, 1967, under N 28825/67, - May 8, 1967, under N 29311/67, - May 23, 1967, under N 33038/67,
May 27, 1967, under N 3385/67,
 EMI4.1
 - May 29, 196? Ï under the N 34427/6? E - November 8, 1967, under the 1; 0 72079/67,?. 2 December 1967, under the N? G923 / 6 ?, December 14, 1967 under the Ne 80 ; 2/67 @ & R jt4; 1: into concer-ncî um no & .iea% to pCédé de K'êpa.s'e.ion .fe dN'i '"' és d": acidea 1-aoj + 1 µ -intlolyl-ùlphatiques,: 1.fiàfl (; .. \\ '9?.> #; = s salts or, 1.e; z oespess and a pro at> 54,: É 4e, ji <li # a * # Ti.vi, from <Mg halfiex-3.

 <Desc / Clms Page number 5>

 



   The derivatives of 1-acyl-3-indolyl-aliphatic acids, as well as their salts or their molecular compounds according to the present invention exert remarkable anti-inflammatory and anti-pyretic activities.



   Among the processes for the preparation of 1-acyl-3-indolyl-aliphatic acid derivatives, the following processes are known: For example, the synthesis of an indole ring is first carried out, then its acylation by reacting metal indole salts formed from NaH, NaNH2 and KNH2, a.veo a halogenated acyl derivative, in most cases, according to the following equation:
 EMI5.1
 This process is very complicated and its yield is usually very low.



   In addition, when this method is adopted, when synthesizing an indolo compound substituted with an acid:; ... free aliphaticf its carboxylic acid group should be covered by es- Check. However) if one carries out a transformation into a usual estes of methyl or ethyl, during the hydrolysis of the ballast after the acylation, the amide bond is at the same time broken as indicated by the following equation @
 EMI5.2
 

 <Desc / Clms Page number 6>

 Therefore, a special ester has to be formed, for example the tert-butyl ester. This esterification is very difficult.

   As will be indicated, for example, below, it is converted into an anhydride of indolyl-aliphatic acid and the resulting anhydride is added to tert-butyl alcohol to effect the synthesis of the oster. butyl indolylaliphatic acid. In addition, hydrolysis after acylation is a reaction requiring very strict conditions and, moreover, the yield of each process is very low.
 EMI6.1
 

 <Desc / Clms Page number 7>

 
 EMI7.1
 
 EMI7.2
 



  On the other hand, these 1-acyl-3-indolyj-aliphatic acid derivatives are weak acids with a pKa value of about 4 and their solubilities in water are low (for example, that of acid 1- (p-chlorobenzoyl-2-methyl-5-methoxy) -3-indolyl-acetic is 20 - 30 / ug / ml) and, therefore, it is very difficult to prepare their injection.



  In addition, when these derivatives are administered in tablet form, their pharmaceutical effect manifests itself in an irregular manner due to the different rates of absorption, which gives rise to side effects such as
 EMI7.3
 gastrointestinal disturbances or the like. Therefore, these derivatives are generally used in capsule form.



   With respect to the process for preparing a sodium salt and a potassium salt of certain 1-acyl-3-indolyl-aliphatic acids, U.S. Patent No. 3,294,811 describes a process of dissolving alpha- acid
 EMI7.4
 trifluoromethyl-alpha- "1- (5-chloroth: azal-2-c & rbonyl) -methyl-5-methoxy-3-indcly! 7-acetic in 0% methanol; add sodium methoxide dissolved in methanol to it ) condense the mixture obtained at 10 - 20 C under reduced pressure. and add ether to it to recover the corresponding salt.
 EMI7.5
 before.

   Another United States Patent No. z.2-1.416 describes a process for the preparation of a sodium salt comprising reacting,

 <Desc / Clms Page number 8>

 in a stream of nitrogen, alpha- (1-benzyl-2-methyl-5-amino-3-indolyl) -propionic acid with sodium methoxide, oondens the reaction product and add ether to it to recover the corresponding sodium salt.



   However, when carrying out these methods, the compounds are prone to undergo staining etc., due to hydrolysis of the 1-acylo group, as well as oxidative deterioration. This is why it is essential to control the temperature and to carry out the reaction in a stream of nitrogen, which considerably complicates the operations. Neither of these methods has been found to be industrially satisfactory.



   An object of the present invention is to provide a novel process for the preparation of 1-acyl-3-indolyl-aliphatic acid derivatives. Another object of the present invention is to provide new salts or new molecular compounds.
 EMI8.1
 culars of 1-acyl-5-indolyl-aliphatic acid derivatives.



  A further object of the present invention is to provide a process for the preparation of salts of 1-acyl-3indolyl-aliphatic acid derivatives. Other objects of the present invention will emerge from the following description.



   In order to achieve these objects, the present invention provides a new process for the preparation of acid derivatives.
 EMI8.2
 1-acyl-3-inâolyl-ali.phatiques corresponding to the formula:
 EMI8.3
 

 <Desc / Clms Page number 9>

 where n is 0 or 1; R1 represents a hydrogen atom or a halogen atom, a lower alkyl group having up to 3 carbon atoms, a lower alkoxy group having up to 3 carbon atoms or a lower alkyl-thio group having up to 3 carbon atoms;

   R2 represents a naphthyl or phenyl group unsubstituted or substituted by a halogen, a lower alkyl group, a lower alkoxy group or a lower alkyl-thio group, or alternatively a 5 or 6 membered heterocyclic ring unsubstituted or substituted by a halogen, containing an oxygen, sulfur or nitrogen atom; each of the radicals R3 and R4 representing a hydrogen atom or a lower alkyl group having up to 3 carbon atoms;

   R5 represents a hydrogen atom or a lower alkyl group; and [A] represents a saturated or unsaturated aliphatic carbon chain, unsubstituted or substituted by a halogen and having up to 4 carbon atoms, or their salts or molecular compounds thereof with a metal of group I, II or III of Table Periodic of Mendeleev, or else an organic amine, this process consisting in heating, to 40 -? 00 C, a derivative of phenyl-hydrazone Nl-acylated corresponding to the formula
 EMI9.1
 in which n, R1, R2, R3, R ', R and [A] have the same meanings as those indicated above, in the presence

 <Desc / Clms Page number 10>

 or in the absence of an appropriate calayseur,

   to obtain the 1-acyl-3-indolyl-aliphatic acid derivative of formula CI) and optionally, when R5 of the 1-acyl-3-indolyl-aliphatic acid derivative obtained of formula (I) is an alkyl group, hydrolyzing the 1-acyl-3-indolyl-aliphatic acid derivative obtained of formula (I), in which R5 represents an alkyl group, to obtain the 1-acyl-3-indolyl-aliphatic acid derivative of formula (I) ), in which R5 represents a hydrogen atom, and then optionally react the 1-acyl-3-indolyl-aliphatic acid derivative obtained of formula (I) in which R5 represents a hydrogen atom, with a metal of group I, II or III of the Periodic Table of Mondeleev,

     a salt or a hydroxide of this metal or else an organic amine, in a solvent, to obtain the sol or the molecular compound of the 1-acyl-3-indolyl-aliphatic acid derivative of formula (I) in which R5 represents a hydrogen-atom.



   In addition, the present invention provides a new process for the preparation of derivatives of 1-acyl-3-indolyl-aliphatic acids corresponding to the formula:
 EMI10.1
 

 <Desc / Clms Page number 11>

 where n is 0 or 1; R1 represents a hydrogen atom or a halogen atom, a lower alkyl group having up to 3 carbon atoms, a lower alkoxy group having up to 3 carbon atoms or a lower alkyl -thio group having up to 3 carbon atoms;

   R2 represents a naphthyl or phenyl group which is unsubstituted or substituted by a halogen, a lower alkyl group, a lower alkoxy group or a lower alkyl-thio group, or alternatively a 5 or 6 membered heterocyclic ring, unsubstituted or substituted by a halogen and containing an oxygen, sulfur or nitrogen atom; each of the radicals R3 and R4 representing a hydrogen atom or a lower alkyl group having up to 3 carbon atoms;

   R5 represents a hydrogen atom or a lower alkyl group; and [A] represents a saturated or unsaturated aliphatic carbon chain, unsubstituted or substituted by a halogen and containing up to 4 carbon aromas, or even salts or molecular compounds of these derivatives, with a metal of group I, II or III of the Periodic Table of Mendeleev or an organic amine, this process comprising reacting a phenyl-hydrazone derivative of the formula:
 EMI11.1
 in which R1, R3, R4 and R5 have the same meanings as those defined above, with a compound of formula:

   

 <Desc / Clms Page number 12>

 in which R2, [A] and n have the same meanings as those indicated above, X represents a halogen atom or an ester radical, to form the phenyl-bydrazone derivative
 EMI12.1
 in which R1, R2, R3, R4, R5, [A] and n have the same meanings as indicated above, heat, to 40 - 200 0, the product obtained in the presence or absence of a suitable catalyst, to obtain a 1-acyl-3- indolyl-aliphatic acid derivative of formula:
 EMI12.2
 wherein R1, R2, R3, R4, R5, [A] and 11 have the same meanings as those indicated above;

   and optionally, when R5 of the 1-acyl-3-indolyl-aliphati- acid derivative

 <Desc / Clms Page number 13>

 that obtained from formula (I) is an alkyl group, hydrolyze the 1-acyl-3-indolyl-aliphatic acid derivative obtained from formula (I), in which R5 represents an alkyl group, to
 EMI13.1
 give the 1 "acyl-3-indolyl-aliphatic acid derivative of formula (I), in which R5 represents a hydrogen atom, then optionally react the 1-acyl-3indolyl-aliphatic acid derivative obtained of formula (I), in which R5 represents a hydrogen atom, with a metal from group I, II or III of the Periodic Table of Mendeleev, a salt or a hydroxide of this metal, or alternatively with an organic amine in a solvent ,

   to obtain the soil or the molecular compound of
 EMI13.2
 1-acyl-3-indolyl-aliphatic acid derivative of formula (I) in which R5 represents a hydrogen atom.



   In addition, the present invention provides new salts or new molecular compounds of derivatives of acids 1-
 EMI13.3
 acyl-3-indolyl-aliphatiçues corresponding to the formula:
 EMI13.4
 in which [A], R1, R2, R3 and R have the meanings as those indicated above, with a metal of group I, II or III of the Periodic Table of Mendeleev or an organic amine.



   In addition, the present invention provides a process for the preparation of salts or molecular compounds of acid derivative.
 EMI13.5
 1-acYl-3-indolyl-aliphatics responding to the formula

 <Desc / Clms Page number 14>

 
 EMI14.1
 wherein n, R1, R2, R3, R4 and [A] have the same meanings as defined in formula (I) above, this process comprising dissolving about 1 mole of the 1-acyl-3 acid derivative -indolyl-aliphatic corresponding to formula (V) in an organic solvent, for example acetone or methanol, then reacting, in the presence of a small amount of water, the mixture obtained with approximately 0.5 mole of carbonato or about 1 mole of sodium or potassium bicarbonate, 'or else about 1 mole of an organic amine, for example ethanolamine, triethanolamine,

   diethylaminoethanol,, ethylene diamine, histidine, arginino, lysine, ornithino, citrulline, gluoosamine, aminopyrine, chlorpheniramine, ergotamine, urotropine, thiamine or pyridoxamine.



   The compound of formula (II) can be obtained by reacting the compound of formula (III) with the compound of formula (IV). This acylation reaction can be carried out by adding a compound of formula (IV) to the compound of formula (III) in a basic solvent such as pyridino, triethylamine or an inert solvent such as benzene, toluene, xylene, ether, tetrahydrofuran or dioxane, etc., in the presence of a basic agent, for example a tertiary amine such

 <Desc / Clms Page number 15>

 as pyridine or triethylamine, at room temperature or blind cooling.

   Then the reaction can be completed by allowing to stand or by optionally heating. When the reaction is completed, the desired product can be isolated by separating the solvent by distillation or by adding a solvent which does not dissolve or slightly dissolves the rock compound. The desired product thus obtained has sufficient purity to be used as an intermediate for the following steps, but it can be further purified by recrystallization or column chromatography.



   As the acylating agent of formula (IV), an acid chloride is most commercially preferred.



   Among the compounds prepared by the present invention, there are, for example, the following compounds:
 EMI15.1
 N 1-p-chlorobonzoyl-N '- (p-m6thoxyphenyl) -hydrazone of methyl levulinate N 1-nicotinoyl-N I- (p.-methoxyphenyl) -hydrazone of methyl levulinate N1-isonicotinoyl-N1- ethyl (p-methoxyphenyl) -hydrazone 16vau- linate N1-nicotinoyl-N '- (p-methoxyphenyl) -hydrazone ethyl levulinate 1
 EMI15.2
 N "-isonicotinoyl-N" - (p-methoxyphenyl) -hydrazone de'lévu.

   ethyl linate Nl-nicotinOY1-Nl¯ (p-mthoXYPhenyl) -hydrazone of levulinic acid N1-nicotinoy7.-N1- (p-methoxyphenylj-, ydraZOne of t-butyl levulinate N-nicotinoyl-III - <p-netSoxyphény1> -hydrazone of benzyl levulinate

 <Desc / Clms Page number 16>

 
 EMI16.1
 Nl.n1cotinoyl-Nl¯ (p-methylthiophenyl) -hydrazone from levu-
 EMI16.2
 methyl linate
 EMI16.3
 levuli- Nl.n1ootino1l-Nl¯ (p-ethylthioPhenyl) -hydrazone
 EMI16.4
 methyl nate
 EMI16.5
 N 1-nicotinoyl-Nl-P-tolylhydrazone from methyl levulinate Ni-nicotinoyl-N '- (p-ethylphenyl) -bvdrazone from levulinato
 EMI16.6
 methyl
 EMI16.7
 Methyl levulinate Nl-nicotinoy.-phenylhydrazonv levulinate N 1-nicotinoyl-N '- (p-chlorophenyl) -hydrazone
 EMI16.8
 methyl
 EMI16.9
 N 1-nicotinoyl-N1- (p-bromophenyl)

  -levulinate hydrazone
 EMI16.10
 do methyl
 EMI16.11
 levulinate N1-phenylacetyl-N1- (p-methoxyphenyl) -hydrazone
 EMI16.12
 do methyl
 EMI16.13
 la.N 1-cinnamoyl-N '- (p-methoxyphenyl) -hydrazone of -m6thyl-
 EMI16.14
 methyl levulinate
 EMI16.15
 N 1-cinnamoyl-N '- (p-mothoxyphonyl) -hydrazone of the acid
 EMI16.16
 levulinic
 EMI16.17
 levulinate N 1-cinnamiDyl-N '- (p-mothoxyphortyl) -hydrazone
 EMI16.18
 methyl
 EMI16.19
 levulinate N1-cinnamoyl-h '' - (p-methoxyphenyl) -hydrazone
 EMI16.20
 ethyl
 EMI16.21
 levulinate N 1-cinnamoyl-N 1- (p-chlorophenyl) -hydrazone
 EMI16.22
 methyl
 EMI16.23
 Nl- (P-methoxycinnamoyl) -N '- (p-methoxyphenyl) -hydrazone
 EMI16.24
 methyl levulinate
 EMI16.25
 N 1-cinnamoyl-N '- (p-methoxyphenyi)

  -levulinate hydrazone
 EMI16.26
 t-butyl
 EMI16.27
 levulinate N1-cina.amoyl-Nl- (p-methoxyphenyl) -hdrazona
 EMI16.28
 benzyl

 <Desc / Clms Page number 17>

 
 EMI17.1
 Nl¯ (-mthylcinnamOY1) -Nl¯ (p-methoxyphenyl) -hydrazone
 EMI17.2
 methyl levulinate
 EMI17.3
 Nl- (p-nitrocï = amoyl) -Iql- (p-methoxyphenyl) -hydrazone from
 EMI17.4
 methyl levulinate
 EMI17.5
 Methyl levulinate N1-cinnamoyl-ph6nylldrazono N1-cinnrmoylN1- (p-ehoxyphenyl) -hydrazonv do levulinate
 EMI17.6
 methyl
 EMI17.7
 Ni-cinnamoyl-N '- (p-methylthiophenyl) -hydrazone from levuli-
 EMI17.8
 methyl nate
 EMI17.9
 N1- (p-brozocinnamoyl) -N - (p-methophenyl) -hydrazone from
 EMI17.10
 methyl levulinate
 EMI17.11
 N1- (p-chlorophnylacetyl) -N1- (p-mthoxyphânyl)

  -hydrazono
 EMI17.12
 methyl levulinate
 EMI17.13
 Nl- (41-phenyl-31-butenoyl) -N '- (p-methoxyphenyl) -hydrazone
 EMI17.14
 methyl levulinate
 EMI17.15
 N1-, - (0-naphthyl) -aarylovl "% - N1- (p-methoxyphenyl) -hydra-
 EMI17.16
 methyl levulinate zone
 EMI17.17
 N- ± - (ù-pyriâyl) -acrykoy17-N- (p-methoxyphenyl) -% àra-
 EMI17.18
 methyl levulinato zone
 EMI17.19
 Nl¯-P-C21-QUin01Yl-aOrylOy! 7-Nl¯ (p-methoXYPhenyl) -hydra-
 EMI17.20
 methyl levulinate zone
 EMI17.21
 Nl¯lp- (2'-fUryl) -aCrylOYl7-Nl¯ (p-methoXYPhenyl) -hydrazone
 EMI17.22
 methyl levulinate
 EMI17.23
 Nl¯ - (2'-thienyl) -acryloy! 7-Nl¯ (p-methoxyphenyl) -hydra-
 EMI17.24
 methyl levulinate zone
 EMI17.25
 Nl- (31-phenylerotonoyl) -N '- (p-methoxyphenyl)

  -hydrazone
 EMI17.26
 methyl levulinate
 EMI17.27
 Ni- (2'-phenylbutyroyl) -N 1- (p-methoxyphenyl) -hydrazone from
 EMI17.28
 methyl levulinate
 EMI17.29
 Nl- (p-methoxyphenylacetyl) -Nl- (p-methoxyphenyl) -hydrazone
 EMI17.30
 methyl levulinate

 <Desc / Clms Page number 18>

 
 EMI18.1
 Methyl levulinate N - (3 ', 4'-dimethoxyphenylacetyl) -N- (p-methoxyphenyl) hydrazone N1- (tolylacetyl) -N1- (p-methoxyphenyl) -hydrazone from methyl levulinate N1 - (o-naphthylacetyl) -N1- (p-nethoxyphenyl) -hydrazono of methyl levulinate Nl¯ (2'-furylacetyl) -Nl¯ (p-methoxyphenyl) -hydrazone of methyl levulinate N1- (2 '. .thienylacetylj-Nl- (p-methoxphenyl) -hydrazone from methyl levulinate la Nl-ci = amoyl-Nl-o-tolyl-hydrazone from methyl levulinate
These compounds are not very stable,

   so it is better not to let them sit laying for a long time.



   Then, the reaction products of formula (II) are treated in the presence or absence of a suitable catalyst for
 EMI18.2
 to obtain the 1-acyl-3-indolyl-aliphatic acid derivatives of formula (I). Preferably, the reaction can take place in the presence of a suitable acid catalyst such as hydrochloric acid, sulfuric acid, phosphoric acid, zinc chloride, cupric chloride, boron fluoride or acid. polyphosphoric acid, an ion exchange resin or a heavy metal powder, but it is not always necessary to employ the catalyst. The reaction temperature is in the range of 40 to 200 ° C., preferably 60 to 120 ° C. As the reaction solvent, a usual organic solvent, for example, ethanol or acetic acid, can be employed.

   When the reaction is complete, the isolation of the desired product can be completed by removing the solvent by distillation or by precipitating the desired product as a crystalline solid by adding water or petroleum ether.

 <Desc / Clms Page number 19>

 



   If the 1-acyl-3-indolyl-aliphatic acid derivative of formula (I) is an ester, it can be hydrolyzed under slightly alkaline or slightly acidic conditions to give the corresponding free acid, although it is difficult to isolate the pure free acid with a good yield, owing to the instability of the 1-acyl group. If R5 in formula (I) is a tert-butyl group, the group is removed by treatment with an arylsulfonic acid, such as p-toluene-sultonic acid, to produce a free acid.



   If only a tert-butyl ester is melted by heating, it is degraded to form a free 3-indolyl-aliphatic acid derivative. As mentioned above, the new process of the present invention gives the intended product in good yield, and is an excellent industrial process for the preparation of 1-acyl-3-indolyl-aliphatic acid from formula (I)
According to the process of the present invention, it is easily possible to obtain derivatives of 1-acyl-3-indolyl-aliphatic acids comprising, for example, the following substituents:

     R1: methoxy, ethoxy, propoxy, methyl, ethyl, propyl, chloro, bromo, methylthio, ethylthio, hydrogen R: phenyl, p-chlorophenyl, p-methylphenyl, p-methoxyphenyl, p-methylthiophenyl, p-bromophenyl, m -chlorophenyl, p-ethylphenyl, p-ethoxy-phenyl, 4-pyridyl, 5-chloro-2-thienyl, 3-pyridyl,
2-furyl, 2-thienyl
R3 and R4: hydrogen, methyl, ethyl R5::

   methyl, ethyl, t-butyl, hydrogen, potassium, magnesium, calcium, aluminum or
 EMI19.1
 

 <Desc / Clms Page number 20>

 
 EMI20.1
 Among the composa thus obtained, there is, for example,
 EMI20.2
 the following compounds!
 EMI20.3
 methyl 1-phenylacetyl-2-methyl-5-methoxy-3-indolylacetate 1-cinnamoyl-2-methyl-5-methoxyindole - indolylacetate
 EMI20.4
 methyl -:

   
 EMI20.5
 methyl 1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetato 1-cinnanoyl-2-nethyl-5-atethoxy-3-indolylacetate ethyl 1-cinnamoyl-2-methyl-5-nethoxy- T- 3-indolyl-aoetate
 EMI20.6
 butyl
 EMI20.7
 1- (p-nethoxyoinnanoyl) -2-methyl-5-nethoxy-3-indolylacetate
 EMI20.8
 methyl
 EMI20.9
 1- (p-nethoxyoinnamoyl) -2-methyl-5-nebhoxy-3-indolylacetate
 EMI20.10
 ethyl
 EMI20.11
 1- (p-methoxycinnanoyl) -2-methyl-5-nethoxy-3-inolylacetate
 EMI20.12
 by t-bùtyle
 EMI20.13
 aethyl 1-oinnamoyl-2-nétbyl-5..chioro-3-indolylacetate 1- (-nethylcinnanoyl) -2-methyl-5-methoxy-3-indolylacetate
 EMI20.14
 methyl
 EMI20.15
 1- (p-nitrocinnamoyl)

  -2-methyl-5-nethoxy-3-indolylacebate
 EMI20.16
 methyl
 EMI20.17
 methyl 1-cinnamoyl-2-nôthyl-3-indolylacetate; methyl i-cinnamoyl-2-methyl-5-ethozy-3-indolylaoetate; methyl 1-cinnamoyl-2-methyl-5-thoxy-3-: ndo291acetate d 'ethyl,
 EMI20.18
 
 EMI20.19
 1-cinnanoyl-2-methyl-5-methylthio-3-indolylacetate from 1
 EMI20.20
 methyl
 EMI20.21
 1- (p -benzylcinnamoyl) -2-methyl-5-methow-3-indolylacetate
 EMI20.22
 methyl
 EMI20.23
 1- (p-bromoeinnamoyl) -2-methyl-5-methoxy-5-indolylacetate
 EMI20.24
 methyl
 EMI20.25
 1- (p-chlorocinnamoyl) -2-methyl-5-methoxy-3-indolylacetate
 EMI20.26
 methyl

 <Desc / Clms Page number 21>

 
 EMI21.1
 1- (4'-phenyl-µ'-bu% enoyl) -2-metbyl-5-nethoxy-3-indolylao-
 EMI21.2
 methyl tate
 EMI21.3
 1-C - (<? (-naphthyl)

  -acryloy-2-mbthyl-5-mbthoxy-3-lndolyl-
 EMI21.4
 methyl acetate
 EMI21.5
 1- (fi - (o-p9ridyl) -acryloy-2-methyl-5-mthoy-3-.ndoiy. '
 EMI21.6
 methyl acetate
 EMI21.7
 1 - (2-quinolyl) -acryloy> -2-methy.-5-metho - indol ;.
 EMI21.8
 methyl acetate
 EMI21.9
 1 - (2'-furyl) -tlOryloy! 7-2-meth;

  yl -'- methoXY-3-ind01Yl-
 EMI21.10
 methyl acetate
 EMI21.11
 1 - .. (2'-thienyl) -aoryloy-2-mbthyl-5-metho-3-indoly, -
 EMI21.12
 methyl acetate
 EMI21.13
 1- (3'-phenylcrotonoyl) -2-nethyl-5-nÔthoxy-3-indolylacetate
 EMI21.14
 methyl
 EMI21.15
 1- (2'-phenylbutyroyl) -2-mbthyl-5-mbthoy-3-indohylacetate
 EMI21.16
 methyl
 EMI21.17
 1- (p-nethoxyphenylacetyl) -2-nétbyl-5-nethoxy-3-indolyl-
 EMI21.18
 methyl acetate
 EMI21.19
 methyl 1- (3 ', 4'-dinethoxyphenylacetyl) -2-nethyl-5-nethoxy-3indolylacetate 1- (p-tolylacetyl) -2-nethyl-5-n6thoXy-3-indolylacetate
 EMI21.20
 methyl
 EMI21.21
 10 1 - (- naphthylaoetyl) -2-methyl-5-methoxy -'- 1ndolylacetate
 EMI21.22
 methyl
 EMI21.23
 1- (2'-furylacetyl)

  -2-Nethyl-5-net% oxy-3-indolylacetate
 EMI21.24
 methyl
 EMI21.25
 1- (2'-thienylacetyl) -2-methyl-5-methoxy-3-indolylacetate
 EMI21.26
 methyl
 EMI21.27
 methyl 1-cinnamoyl-2-methyl-7-methyl-3-indolylacetate ethyl 1-benzoyl-2-methyl-5-methoxy-3-indolylacetate

 <Desc / Clms Page number 22>

 
 EMI22.1
 l-p-chloro'benzoyl-2-methyl-5-Biethoxy-3-indolylacetate
 EMI22.2
 methyl
 EMI22.3
 l-benzoyl-2,

  Methyl 5-dimethyl-3-indolylacetate 1-p-nethylbonzoyl-2-methyl-5-nôthoxy-3-inéolylacétiquo acid 1-p-methoxybenzoyl-2-nethyl-5-methoxy-3-indolylacéti-
 EMI22.4
 than
 EMI22.5
 0 (-LT-p-chlorobonzoyl-2-methyl-5-methoxy-3-indolyl7- acid
 EMI22.6
 propionic
 EMI22.7
 1 1-p-chlorobonzoyl-2-methyl-5-methoxy-3-indolylac4tiquo acid 1-benzoyl-2-methyl-5-chloro-3-indolylacetic acid 1-nicotinoyl-2-nétliyl-5- nemioxy-3-indolyl-acetic acid i-isonieotinayl-2-methy7.-5-m.éthor.y-3-, ndolylacét.quc 1 'acid - 2'-thenoyl-2-methy, -5-mthoxy -5-indo3.y buty-
 EMI22.8
 tick
 EMI22.9
 1-2'-futoyl-2,5-dimébhyl-3-indoly Acid 1 - aaphthoyi-2-mdthyl..5-mthoxy. 5 ... ndolylactts of
 EMI22.10
 methyl
 EMI22.11
 1-p-ohlarotonoy3-R ,, S-diathyl acid.

   5-indo.ylact, qus acid.-P-bxomobonzoy .- .. mthyl-5-methuxy-3-indo3ylaati, us 1-benzoyl-2-Nethyl-5-nethoxy-µ-indolylacetato benzyl the o -tl-p-mthyZth3.obcnzoyl - methyl.-5-mthox-5- acid
 EMI22.12
 indolyl) -propionic
 EMI22.13
 1-p-chlorobenzoyl-2-methyl-5-fluoro-3-indolylacetate from
 EMI22.14
 t-butyl In addition, it is optionally converted into a salt or a
 EMI22.15
 molecular compound, 1-rcyl-3-indoxy2- acid derivatives. aliphatic in which the radical R5 of the formula (1)
 EMI22.16
 represents a hydrogen atom.



  In other words, we react an acid derivative
 EMI22.17
 1-acyl-3-indolyl-acgtique in which the radical R5 of the
 EMI22.18
 formula (I) is a hydrogen atom, with a metal from the group

 <Desc / Clms Page number 23>

 I, II or III of the Mendeleev Periodic Table, a salt or a hydroxide of this deraier or an organic amine in a suitable solvent, to form a salt or a molecular compound of the free indolyl-aliphatic acid derivative of formula (I) .



   In the process of preparing the salt, as the solvent, a customary organic solvent such as methanol, ethanol or acetone can be employed. It is preferable to carry out the reaction at a pH of about 7.0. In fact, it has been observed that the acyl group of the 1-acyl-indole derivative could be very easily hydrolyzed at pH less than 1 or greater than 9.



   Alternatively, the formation of salts according to the present invention is carried out by dissolving about 1 mole of these indolyl-aliphatic acid derivatives in an organic solvent, preferably in acetone or methanol and reacting, in presence of a small amount of water, with about 0.5 mol of carbonate or about 1 mol of bicarbonate of an alkali metal such as sodium or potassium, or alternatively about 1 mol of an organic amine such as as ethanolamine, diethylaminoethanol, triethanolamine, diethanolamine, ethylene diamine, histidine, arginine, lysine, ornithino, oitrulline, glucosamine, amine-pyrina, chlorpheniramine, ergotamine,

   urotropine, thiamine or pyridoxamine. The amount of water is 1 - 20% by volume of the organic solvent.



   After formation of salts, the desired salts are separated from the reaction mixture by a conventional method such as solvent distillation.



   This process of direct treatment with a carbonate, a bicarbonate or an organic amine in an organic solvent not only gives higher yields compared to the known process, but it also does not require any advice.

 <Desc / Clms Page number 24>

 strict temperature conditions, nor a complicated reaction apparatus in a stream of nitrogen, thus providing the most favorable process for industrial manufacture.



   In addition, alkaline earth metal salts and aluminum salts of the acid derivative can also be obtained.
 EMI24.1
 1-acyl-3-inaolyl-aliphatic by reacting soluble salts of alkaline earth metals and a soluble aluminum salt with an aqueous solution of soluble salts of the acid derivatives
 EMI24.2
 1-acyl-3-indolyl-aliphatics obtained in accordance with the process of the present invention.



   Among the metals of Group I of the periodic table, the salts or hydroxides thereof, there are, for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide. sodium and potassium hydroxide. When the reaction is carried out in an organic solvent, sodium or metallic potassium can be employed, but it is preferable to employ them in the form of sodium alkoxide or potassium alcoholate.



   Among the metals of Group 11 of the Periodic Table, the salts and hydroxides of the latter, there are, for example, magnesium hydroxide, calcium hydroxide, magnesium methoxide, calcium methoxide, magnesium chloride and calcium chloride. It is, however, advantageous to use magnesium chlorura or calcium chloride in the presence of a basic substance such as sodium hydroxide, sodium carbonate or sodium bicarbonate.



   Among the salts and hydroxides of the metals of Group III of the periodic table, there are, for example, aluminum hydroxide, aluminum sulphate and aluminum chloride. he

 <Desc / Clms Page number 25>

 however, it is preferable to use aluminum sulphate; or aluminum chloride in the presence of a basic substance such as an alkali hydroxyd, an alkali carbonate or an alkali bicarbonate.



   Among organic amines, there are, for example, lower alkyl amines such as n-butylamine or ethylenediamine, lower alkanolamine such as
 EMI25.1
 ethanolair.ino, a diulocylaninoalkanol such as dimthylemino-dthanol, norpholine, choline, glucos # mine, mtr.yl-cyc2ohexy7.amine, triethylamine; aniline, 2 * 3-xylidine or piperidine.



   For the salts or molecular compounds thus obtained, there are, for example, the following:
 EMI25.2
 lo 1-isonicotinoyl - rethyl-5-mthoxy-3-indolylxctat sodium 1-isonicot3, noyl-2-thyl - $ - xethoxy-3-indo.y3aotate potassium 1-niootinoà> 1..3-inàolylacétatu do sodium sodium 1-nicotinoyi-2-màbhyi-5-néthoXy-3-indolylacetate sodium 1-nicotinoyi-2-nethyl-5-methoxy, -µ-inàolylaoetate potassium l-nicotinoyl-2-meth1-5- alkium methoxy -'- indolylaoetate aluminum 1-nicotinoyl-2-methyl-5-nethoxy-3-indolylaoetate n-butyl ammonium salt of 1-nico% inoyl-2-n ± thyl- 5 acid -ne% hoxy-µ-indolylaoetic the ethanol-ammonium salt of 1-nicotinoyl2-methyl-5 Qethoxy-3-indolylao4tiquo the N, N-dimethylethanol-amranium salt of 1-n acid,

  iaatinoy 2-methyl-5-methoxy-3-indolylacetic

 <Desc / Clms Page number 26>

 
 EMI26.1
 2. * ad d 'Toli'm d <3 cl lHfnlotillt.yl-.2 "! 46tllJ: $ 5AD.ç; thoxy-3-àsào> .à. 1.;.> # ± rigs. ± la s; >?. 4 E, ehmi 1: #. # == m - = 1 # ', ad o I-niectisoyI-S.yl - .. sts-' ft '' - '-': "31? 1: ' E 'zli; .i = .i; .vF, - = # .: i E.> i. "% Cis.e liotir.c.yl-Ëhylr.é: t]: -t.: X ..- . = 7 = .1 "'. *' Ls. & Â * 3. 'ue'.? = to ¯ z¯) =, t ': l - ::.: {,:' :: "ci ::! lMJ! 1..CDL: i to;>" é w r fl. ' - .r.!? '' "- 'TC3'-it. h? 1 = Fn ± + hzr Nz:" *) =: ir.ù #> ljil +. to é.biq% at'], = Q ,Not a word ,; q,; ,,; = =. G <'x ..

   X%, 1 b 4 *%, & -1, - -.fi ± z é to - *> -ze j. ", = - - m--. Ii..dlps'. '.' '' <. - ', is the Si ti =' -rith.ySs.muB of lucid l-nieotiE ..- 2-nêtyl- 5-sthy -. idc.lyl3.aé-cique?: * sel is at, 3 = # '1.àW n5,% m = ie l-niootinGyl-2Ei'S-shyl <-5-aethoxy --iclyl.s.eétiqua 19 ael ±: i-> é # 1: 1.5.> I * : a # to a acid 1 -n 'c O Zà.nCJ1 - * - ìthj? 1 = 5
 EMI26.2
 3 '. << s7 iy'ß.; ,, v3 ..? ¯ -i .s', '¯sr.' le - r: z. :: ..,. cè.-E- â-1 '' i5-'hlcpq,] -p; 5, T '', .. 't' "3 To 7, àln: àiixà e3 "'' '. 1: i.iT': â â g 3m -.;,. ' '"3; î .i.or,'" -;,: t; ' ¯-isw do. ;;, .-, <'1 ""' "rà.'m 'r.iv'" '!' FIF-J ..; ^ ai.wt: 2 5 syyT i- de sal- ium 3 '. ', alY ... T: iethyl, Z .. - â.olG'Oic' ': i.te d 30: .. Ns p -iotino -2-eth3l-5-.thoyw-.izL:;. -;

   ,. t.
 EMI26.3
 potassium
 EMI26.4
 1 αi.yi; .. i 'Ds'ß.R.-methyl-5- s, -inà lyJé' aJ.; Te potassium 1-ct-nanoyl-2-nnethyl-5-z6thoxy-3-inol > .lacate # of a.9. .l-cinnaIloyl-2-methyl-5-methoxy-3-indolylacÔtll't; of potas-
 EMI26.5
 sium
 EMI26.6
 Bagne- 1-cinnamoyl-2-netbyl-5-nethoxy-3-indolylaaétaie. if 1.1m calcium 1-cinnemoyl-2-netbyl-5-nethoxy-3-indolylaa

 <Desc / Clms Page number 27>

 
 EMI27.1
 the self of: rj.W) 'b \ 1tyl :: -:' d :; ';: -:.: -, 1 .. P ...: - ¯..z ... ::? j, "- ..v ': C>: - = - :: - = - 0 -:' ¯ - 3-indolylac et <ti ::; ...:; 1 .1'0t .: tfJJ1 "'; -: l: l': {:.!,; J.:;" ;: '!'; ::.. <;: ',,:; -' -: ':' '' '' '' '¯ 2 = .. i -1' = i3 's "y.:. E'.aâ'. ', J the salt of :: nd.i :: l <, <jh71 :)} ". :: l ,,:. ¯-; '': '' 'J' '>;, .¯¯ .. ¯¯ ¯., ¯¯¯-¯¯ 2-Nëthyl - êthoiK-i: 6 '' ':: .. 0 # -, lo sel ds Sl1.1.'o8at1iTn1 .:'. '; Fix. L = a, .E =' -.



  . Se:; i '': i. ...: j 1 is. the salt of x, # b: ß.l, wïßsas'j, r.:, ',' ..., ... ¯. . ¯. ¯ ¯¯¯. ". ¯. I",. <'1. = .. --- 1 -: ¯? ¯C '.. =. Thf.' ",, j,": â -,?. '' 1'-ndo i>: c. i '^.' . 4. ..i the salt t1r.; r,: 1orpholir.d1. "J'1 .do .. t. <2 ...;. ¯¯ ¯¯.¯ ¯ .. # ¯: .-: F z neth oxy-3- ii: òïyrlae µ tigù <. the choliniun salt of 1;; J ,. <1. => ai i; -: - i. <j-? - .- == - i. - # jl - =? -. -: -.'--- 3-indolylacêtiquo triÓtÎ \ Vlr.!; 1? Lonl'.L.:.>? - ': - ::: "...: -' :. . '", -" - L :: -. '-: - "' - # 1: = - =; 9 = mô thoxy-3-inào iylxe é xiq = # é> the salt of aniliniuu ie 1; '::"' J..i.1E: == ;; i ::::: ..;>.; ..: - ;: f1 ..,.,; -:.:;:, j:> ':>,': '- =. - 3-indolylacetic salt do 2, µ -> qyl idinj.e>: u de: 1.

   D, i:, ±, ', 1 "" i2 <;' ;. rc7l ":::, = ¯; -: ù: # = - = - 1 == ,, 1. = '<mëthcxy-3- iRdolylaoëtique piperidiniun salt of 1 ': .1 ..;'; "':. llr'.-rs-j3'j., methoxy-3-indolylacetic 'pLpéraàin salt <.oeiml de lj.ci: ? "" (1 = 1: tli1a - =: ',; 16; ±' '' '- T,.:>: J3l7 =
 EMI27.2
 '5-nethoxy-3-iRdolyl) propionic -c.:n.oyl.--athy=3- rcâv; . e da fiô ± xssàz: 1 l-cinrnoyl-2-mhyj-¯;:. os -.,. drll: ztat of gvd1 l-cinnamoyl-2-thyl-3.indolyl state. 3 of potassium 1- in,: oy1-2-aGhyi - thn.- ,, nv.y3 âawe de so & i 'le (- (1-c3.nnaroy.-2-zhyl-5-thoxy -'-. ndïylraaion of sodiun

 <Desc / Clms Page number 28>

 
 EMI28.1
 le Ù = (1-c #mn; = oji-2 - = Ôtl-yl -5- l thJxy- 1 in-ioi, ji), rcp i n = fl. "> << = sodius.



  ¯ 'e - (l -': nï.i -... y-thyl5-othcxy-3-dolyl) butyrst3 of
 EMI28.2
 .sodium.
 EMI28.3
 



  ; -3? - ', # imài: h = 1> = ± x: - <- = yl) -2 - Jrnyi-µ-> sthox-1-3-inào17iùcé "J = <ti le 0": îm 3 J lm. (. Ù -nô thyl-e5,1: nn.nfaà # 1) -? - :: é.th3.1-5-nl tho> .1 -3-ind #> iyi <¯ # é = t ;; 1 of sodiUn li L- lty "* .nÉ imhô'l. p-cÎ # lorcc innw.:i- l Î -2-né rhyl-5- i 'tb a> T = -% inòlj; iacét 'te de Eodium l -? Byl-innoyl) -thyl-3-Bêtho-3 - dclas, ë-ë.:.', de potaasi'ur Le 1- (ib -b = * # z rl- t = 1mesroyl) -2 - +. ± tÎ = yl-5-netî-Jxy-3-iY. J '= "# #. ± "" = = ..



  + 'e pot, ss1uôl la J- (5i; # -àil = l' ± = 1lOC àF ±, Rn ± yl) -? - 1 etiàWl-5-l2ét 'Wherey-3-1' ft '"' => , 3 potassium '= kétah.3 ::? Ot ;; \! \ I 1. --ein.:c,?.....S-ist.:2yl-5-.séT;hylthic-3 -iRdolylasetate .lB stagsiuB .la 1- (p-at;] - <# Tn.iiurnzojqî) -2- # ethyl-5-e-reth * zy-3-in.ào # iTl5ir- = 1; 5c,, ; pc, 1: .iaiur l- (p-roc3RRnojl) -2-.n & Ëyl-3.nthoxy-3-iiidolyl & .stâ-s. de> t-zasi- .um l3 L- (p-> Ethcx # == ì # = 1; à'-uoyî) -2 = -aiEtônyl-5-n'thoxy-5-ÀnàJlyl = - + Ôtaf2 from pctssiB: 1e 1- (p- = L.5tF.Jai-ii1- ## joyl) -2-zéEhyl-5-n-thoxy-3-1 == dolylmeà.ba> fie µù5À9iÎà13 "1 2e 1- (pT -chyl-chiosinnsnoyl) -2-thyl'-5-set: hcxy-3 Sodium indelylacetate 1- (3 '-Dl; enylerotonoyl) -2-nethyl-5-methoxy-3-indolylacetate-n of soal

 <Desc / Clms Page number 29>

 
 EMI29.1
 lucid r b w Ln'ctiL.rsCl sdz.f 1 ta- '; hi .x ° .xs.ß.: ... / .ar¯ .., ir, =, 1:.:

   fl i 1 "? ±> acetic l zw (-.,: - 'Yzc r.,: ¯ #; .. =, ...:, 4. ¯>. --- -" .. "' <" : 'r, ncêtato de as-lcium 1 z' wvsi'.t7tf .. 'S9.ww "ß; a = -¯ - .. s ..' '. ¯ .t - .c ....". '., - A * \ a7 "#. .-. Sodium 1- (2-tMenyl3tyl.) - 2-.t.yl' '-:.:;" É' / J '>', ..- . .µ., - = 9'fi of sodiur.:. le 1: ph6nyl: t: St: ll2nÓ-t: iy: t3: 1 ':' 2f.} d ': = 1 1 "1. 1 ¯ 7 '1: -:] # - ..: - ..

   I l:.: Di.an lo 1¯ ('-' ¯ "" '1 O "" "J!' Il'él'V'1", "'.' D-: vl1,2-f ', c '\' ;: '. <";:;'" ", 'I." T' 1- vIn: -; ¯¯ ¯¯¯¯¯¯¯¯ ¯¯¯¯ -, i tate do scdiua le "'rY'T''C''j.eAv s, Y.SF'L'a.ta.i!, v.' xri3G H7m ..." '. ¯' ': ßA¯'¯s.' : a 1. '-' - ';.,'.; ', .., acetabulum of ca-lslum le 1- (p - t ol, z; 1 = .c4tyl) -2 - <6zbyl = 3 --ir F.Jn ::,;., = j - ,, ji -. ī ¯ ¯ i, =: ".; ¯. ī -"; /: 5. ,, calciui ie 1¯ (- ;: '1;'; $ i aT yfYLinnlli f it..s aJV '.yq.r. D -'? J4¯it 'F¯' = 3.7 "" ¯.¯ ...; <-. G; = -; indolylacetut3 do:., the. of calcium Leg t3: a 'sf, aC' J3d'Sn l :: c2 .--:., :) ,, r ', J "-: Jf t .: "<1 -: ': .-- .. i. By the i..fc ..4i of t': pr, sO" it.1 s .rA¯ W: l. ¯: 3 1 # ri-n ai =. "y.:¯=é, .- a .. - .., n.> ... of n" 'U "' 1 ';: i1J- = compounds ..

   These, ", .... r:";.;.,;:, .A: .¯ = y .1 = ¯. 3 = - == ¯ t¯ ¯ '] activity v.nti-in! La!: LD, [J; "; ::,:. I!'! 2 f # #. A ',: -;:. tJ> .m J; =:., - = ..-,.;:.? i -. = ¯J == ..; iI C31.L.Y'.û: s 0 'es'!:; thus "', 536: (; 03.': '. è: l2 -:.,:' '' ',, - ¯¯ ¯ ¯ ¯ .. = r ¯ ..... ¯ ¯.v¯? :, .natory in "-1 <Jc: es':", i; ''. -, i'ée.i \ '! [- ":::.:" t:' 7-: .. ¯. ..: 'b., ¯¯.¯ ¯.,: ¯¯? ¯!: having a very low .3 #>; iLài = é.



  The sodium salts are 3.3:;! Ta ± 5iTh d'jg, bzz '-'73 ù "3gi, J zD izdtzyi ¯w3.:. S obtained by 5 .-, = n ¯:.;'. ': . ::: '= - + i; :::' :; Í3: J;: -; iinvention, have a solubility iaxs 1. ' , !!. \ i. ": ii !:": "" ;;, 'JiJ1.: L'3: 2.: i;' 'G =

 <Desc / Clms Page number 30>

 Prepare a solid injection with an injectable medicine such as mannitol, glucose, sodium chloride, glycine, sodium glutamate, aminopyrine, caffeine and sodium salicylate. When administered orally in capsule form, the rate of absorption is very high and the maximum concentration in the blood can be reached in about 30 minutes.

   Do more, they; can be compressed directly into tablets and, in addition, an excipient such as magnesium aluminasilicate having antacid activity can be employed together.



   The soluble salts of the indolyl-aliphatic acid derivatives according to the present invention are very soluble in fats, the partition coefficient between chloroform and water being 25 at pH 7, so that they are very useful as ointments and suppositories.



   The molecular compounds of indolylaliphatic acid derivatives of the present invention with arginine hardly undergo color change under the action of ultraviolet rays compared to other derivatives of indolylaliphatic acids, which means Lour offers a wide field of application in the pharmaceutical field.



   By applying the salts of indolylaliphatic acid derivatives such as aluminum or calcium salts, which are less soluble than sodium or potassium salt, side effects such as gastrointestinal disturbances can be reduced. intestinal. Molecular compounds of indolyl-aliphatic acid derivatives with a compound exerting anti-pyretic and analgesic activities, and a substance combining uric acid, for example aminopyrine or urotropine, increase pharmacological activities with less

 <Desc / Clms Page number 31>

 
 EMI31.1
 side effects. clust why they are pharmacologically very useful.



   In the accompanying drawings, Figures 1, 2, 3, 4, 5 and 6 show individually infrared ray absorption spectra (Nujol) for the salts of sodium, potassium, magnesium, calcium, strontium and d. aluminum acid
 EMI31.2
 N- (p-ahlorobanxoyâ) - aethyl-5 methaxy5-indoly.-doétiquo obtained would relate to the present invention, while Figures 7, 8 and 9 show those of arginine, aminopyrine and
 EMI31.3
 of urotripine / molecular compound for N- (p-etlorobenzoyl) -2-methyl-5-nethoxy-3-indolyl-acotic acid obtained in accordance with the present invention.

   Fig. 10 shows the infrared ray absorption spoctre (Nujol) of anino-
 EMI31.4
 py1ini / molecular compound of N- (nicotinoyi> -2-methyl-5-methoxy-3-indolyl-acetic acid obtained in accordance with the present invention. Figure 11 shows absorption spectrum of infrared rays (Nujol) in the present invention. : ninopyr.n6 / molecular compound of N-cirmanoyl-2-iabthyl-5-ratthoxy-3-.ndol, yl-aliphati, ue obtained conf adorned with the present invention.

   Figures 12-14 and 16 show the infrared ray absorption spectrum (Nujol) of sodium, calcium and aluminum salts
 EMI31.5
 N-nicotinoyl-2-methyl..5-xethoxy.-3-indolyl-acét.gua and Figures 13, 15 and 17 show the infrared ray absorption spectra (Nujol) of sodium salts, of cal-
 EMI31.6
 ciun and alumin1UQ of N-cinnmioyl-2-methyl-5-methoxy-3-indolyl-aetic acid obtained according to the present invention.



   The following examples are given in order to illustrate the invention, but they do not limit it in any way.



  Example 1
For 15 minutes, at a temperature of 0 to 5 C, everything

 <Desc / Clms Page number 32>

 with stirring with a stream of nitrogen, 7.1 g of benzoyl chloride was added dropwise to a solution of 13.2 g of ethyl levulinate p-methoxy-phenyl-hydrazone and 4.0 g of pyridine in 200 ml of ether. Then stirring was continued for a further two hours with cooling, then the mixture was heated and refluxed for one hour.

   After cooling, a precipitate was removed by filtration and the filtrate was concentrated to a residue which was subjected to chromatography on silica gel and elution with ethyl acetate. Ethyl acetate was evaporated under reduced pressure, to obtain ethyl levulinate N1-benzoyl-p-methoxy-phenyl-hydrazone as a yellow oily substance.



  Absorption spectrum of infrared rays 0 paraffin (ce ') .. max
1730, 1650 Elemental analysis: N calculated 7.60%; found 7.38%.



  Example2
To a mixture of 11.2 g of methyl levulinate p-methoxy-phenyl-hydrazone, 60 ml of tetrahydrofuran and 5 ml of pyridine was added dropwise a solution of 7 g of nicotinoyl chloride. said 10 ml of tetrahydrofuran at 15 ° C. Stirring was continued for a further 3 hours at 25 ° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to give 15.7 g of. N1-nicotinoyl-p-methoxy-phenyl-hydrazone from methyl levulinate as an oily substance.



  Absorption spectrum of infrared rays # paraffin (cm-1). max
1725, 1645, 1600

 <Desc / Clms Page number 33>

 Following the process described above, the compounds were obtained.
 EMI33.1
 posed: Nl-nicotino11-p-ethoxy-phen: 1-dralone from methyl levulinate and Nl-ieonicotinoyl-p-methoX1-phenyl-hydrazone from methyl levulinate. Example 3
 EMI33.2
 To a mixture of 11.2 g of methyl levulinate 9-nethoxy-phenyl-hydrazone, 4.3 g of pyridine and 60 ml of tetrahydrofuran was added a solution of 9 8 of cinnamoyl chloride in 10 ol. of tetrahydrofuran to 3.4! C. Stirring was continued for an additional 12 hours at 10 C.

   After filtering the reaction mixture, the mixture was concentrated.
 EMI33.3
 filtrate under reduced pressure, to obtain N'-c.nn, amt1-p-methoxy-phenyl-hydrazone of nethyl levulinato in the form of an oily substance.
 EMI33.4
 Absorption spectrum back rays, infrared 9 paraffin c-1 max
1735, 1655, 1620 According to the process described above, we prepared
 EMI33.5
 the following compounds:

   Ni-cinnamoyl-p-ethoxy-phenyl-b7drazone from methyl levulinato and Ni-oinnamoyl-p-methoxy-phenyl-hydrazono from ethyl levulinate. Example 4
 EMI33.6
 To a solution of 14.6 g of t-butyl levulinate p-nethoxy-phenyl-hydraione and 4.0 g of pyridine in 200 ml of dioxane was added dropwise 8.8 g of p-chloride. -
 EMI33.7
 Ci, prObD'IàzO; l9 with cooling in a stream of nitrogen.



  After stirring at room temperature for 2 hours, 5 g was added thereto. of concentrated hydrochloric acid and the mixture was heated at 75-80 ° C for 2 hours,;. after cooling, the solvent was distilled off, to give a residue to which 50 ml of cold water was added and, by filtration, the precipitate formed was collected, then washed with

 <Desc / Clms Page number 34>

 
 EMI34.1
 the water. By recrystp-llization from 1-eth $ .tlol, white crystals of lp-chlorobenzoyl-2-nethyl-5-Eethoxy'- -indoly3-actate of t-butyl with a melting point of t-butyl were obtained. 103 - 104 C.

   While stirring under a nitrogen atmosphere for about 2 hours, a mixture of 1.8 g of the ester and 0.2 g of the powdered ceramic plate was heated to 200-215 ° C.
 EMI34.2
 After cooling the product was dissolved in benzene and extracted with an aqueous solution of sodium bicarbonate. The aqueous layer was weakly acidified with hydrochloric acid. The crude product was recrystallized from aqueous acetone. Melting point: 152 - 155 * 0.



  Example
 EMI34.3
 To a solution of 12.5 g of methyl levulinate p-tlethoxy-phenyl-hydrazone in 200 ml of dioxane was added
 EMI34.4
 drop by drop 8.8 g of chloride do -ch.flrcbeury3o below 5 * 0. The mixture was heated to 80-85 C for 2 hours. After cooling, the dioxane was distilled off under reduced pressure to give an oily residue which was left to stand overnight in a tower refrigerator and solidified. By filtration, the substance was collected
 EMI34.5
 raw solid and washed with water. By restalization in aqueous methanol, methyl 1-p-nblorbenooyl-2-methylooos-methoXy-3-indolyl-acetate with a melting point of 89-90C was obtained.



  Example 6
In accordance with the process described in Example 4, we prepared
 EMI34.6
 d 1-Bencyl-2, -dtsy .--. ndoly3 - methyl acetata.



  Melting point: 165 - 167 0.



  Example 7 In accordance with the process described in Example 5, we prepared

 <Desc / Clms Page number 35>

 
 EMI35.1
 d 1-p-Nethyl-benzoyl-2-methyl-5-aeth-xy-3-indolyl-acetic acid.



  Melting point: 155 - 156 c.



  Example 8
In accordance with the process described in Example 4, we prepared
 EMI35.2
 d 1-p-nethoxy-benzoyl-2-uethyl-5-nethoxy-3-ind.ol, 1 .. acetic acid.



  Melting point: 160 - 161 C.



  Example 9
In accordance with the process described in Example 4, we pre-
 EMI35.3
 prepared with alpha- (1-p-Chlonobonzoyl-2-methyl-5-nethoxy-3-Indol7l) -ProPionic acid- Melting point; 8? - 88 0.



  Example 0 In accordance with the method described in Oxenpy 4, 1-p-chlorobarizoyl-2-methyl, 71-5-n6thoxy-3-indolylacetic acid was prepared. Melting point: 160 - 161go.



  10 g of lp-chlorobenzoyl-2-methyl-5-met: aoxy -? - indo.y1-a,: Gts.p: e aid was suspended in a solution of 2.2 g of sodium bicarbonate. in 70 ml of water and the suspension was stirred at room temperature for 1.5 hours.
 EMI35.4
 Then the mixture was heated to 50-60 ° C. until substantially all of the crystals had dissolved. The mixture was treated with activated carbon and filtered while still chud. The filtrate was allowed to stand with cooling to give light yellow crystals of 1-p-chloro-.
 EMI35.5
 sodium bonzoyl-2-methyl-5-methoxy-3-indolyl-acetate.

   These crystals were dissolved in chloroforue with heating and a small amount of water was added to the mixture which was left to stand in a refrigerator, to obtain needles.
 EMI35.6
 the blanks of sodium 1-p-chlorobinzoyl-2-methyl-5-nethoxy-3-indolyl-acetate having a melting point of 235 C (decomposi-

 <Desc / Clms Page number 36>

 
 EMI36.1
 1-pohlorobensoyl-2-uothyl-5-nethoxy-3-indolyl-acetate from al1-% dual by treating 1-p-ohlorobenzoyl-2-nethyl- Sodium 5-nethoxy-3-indo, γ-acetates with aluninius chloride or aluminum sulfate in water. Example 11
 EMI36.2
 To a solution of 10 g of.-P-ch.obnzar3 acid,

  -2methyl-5-nethoxy-3-indolyl-acetic in 50 μl of acetone, a solution of 2.4 g of sodium bicarbonate in
 EMI36.3
 5 ml of water and the mixture was heated with stirring until the formation of carbon dioxide gas ceased. The reaction mixture was concentrated to a residue which was
 EMI36.4
 recrystallized from a mixture of ethanol and ether, to obtain 3.t, 1 g of light yellow sodium 1-p-chlonobenzoyl-2-nethyl-5-nethoxy-3indolyl-acetate.



    Example 12
In accordance with the process described in Example 11, by way of
 EMI36.5
 When taking 10 g of light yellow lp-ohlorobenzoyl-2-methyl-5-nethosy-3indoly1-acetic acid with 2.6 g of potassium bicarbonate in acetone, 10.8 g of 3 - p-cha were obtained. .orobenzoyl-2-nethyl-5-môthoXy-3-indolyl-acetate de potassium having a melting point of 128 - 131 C. Example 13
 EMI36.6
 To a solution of 1-p-ahlonobenzoyl-2-nethyl-5methoxy-3-indolyl-acetic acid in 50 nl of acetone were added 4.9 g of arginine and 5 ml of water.

   After this addition, acetone was distilled off to an oily residue. The residue was dried to obtain 15 g (quantitative yield) of 1-p-chloro-.
 EMI36.7
 bezogl-2-r, thyl..5-rathoxy -? - iadc.y, -. yellow arginine ctate.

 <Desc / Clms Page number 37>

 Example 14
 EMI37.1
 In accordance with the process described in Example 4, I-bQnzoyl-2-methyl-5-oh! Oro -'-Indolyl-acetic acid was prepared. Melting point: 170 - 171 C.



  Example 15
In accordance with the process described in Example 4, we pre-
 EMI37.2
 trimmed with 1-Benzoyl-2-! -nethyl-3-indolyl-acetic acid <t 9, Tin% melting: 167 - 168 C. Example 16
 EMI37.3
 In accordance with the process described in Example 4, 1-niaot.noyl-2-thwl.5thoxy = -. Rdal3.- acetic acid was prepared. Melting point. - 194 - 195 C.



   By adding 1.6 g of sodium bicarbonate to a suspension
 EMI37.4
 mixture of 6.5 g of 1-nicotinoyl-2-nethyl-5-methoxy3'-indolyl-acetic acid in 50'nl of water, the pH of the
 EMI37.5
 mixture at 7 <0 - 7.3. Stirring was continued for a period of 5 hours. Then the māl: 3.r.a-ol is slowly heated until almost all of the crystals are dissolved. Insoluble crystals were removed by filtration and the filtrate was concentrated under reduced pressure, to obtain a residue. The residue was dissolved in chloroform by heating and then a small amount of water was added.

   After cooling, the yellow solid formed was filtered off and washed with ether, to
 EMI37.6
 obtain sodium 1-niootinoyl-2-methyl-5-mlthoxy-5-inaolyl-acetate.



  Example 17
 EMI37.7
 To a solution of 6.5 g of 1-nicotinoyl-2-nethyl-5-ethoxy-3-ïrdalyl-aotique acid in 170 tal of anhydrous trahy3csasrv was added 1.8 g of d, thy3.-ano- tha.aol. After heating the mixture for about 1/2 hour, it was evaporated.

 <Desc / Clms Page number 38>

 
 EMI38.1
 pord the solvent to obtain 6 -, - 5 g of% TiBùB5X n.1.'U: iBB of the diet salt% lanWQ-é% hBnol àu 1-oicotinoyl-2-métbylJq5Bêho --- ia & o33 .- 'ssétate esrsmt - = poinij; 40a fusion of 1: I! TB -nooc (dens ml n61.fmge of #m: ba and 4'4, ethar 13âtrol *) Absorption spectrum of * have I.BfMax # eBs fin9 <cn): 32C0 1670, .990. 1.e 18 Cont'or # nen't au proctdê described at 'l.tù'1I!: PTW 4,: on 11: PZîparé de 1'laelde V- (i'thBByi-3.-5-nêt-- imd -but3rique.

   Po1.nt; de 1wd.on: 118 - l3D "D * Exell1) 1e 1 Confundoen% au proe6m àécw3 t A l" E3Eaa3. -9 xn separated from: Acid l '- # 35-iitl-dQ13Q'-M Point; from: tu.sion: 160 - 16YC.



  Exonp1e 20 Conf'o:!. '2: .1é n1i to the jprosedé describes to: I "exem .PU ma has gmêparé l-lïMcotioQ.-N - Acetic BêSmas. Point of: f' -. LSicn 1fi3 - J.'55 ....



  Bxeople 21 aonfoenénanb had asedé aêcadtA 4.3 a Ddparé of the 1-p-naphth of nétble. Point de Stsioms! 24 = '- lXt5% heuple 22 conf adorned with the process deca% A l.t1e 4, in a MW6paré of 1; 1-p-eehlooeoboezayl + 2 Udt% If-àd <# 1acetic acid. Bob * from fmaicms 2a1 - 2o9 "cexample 23 Co! NfozEiÉtMm6 au J.! # 'OCM' Mcr1.t. to], fie # en: p1e 4. un a priparé of 1 fi acid l - KPom! Be: Mqyl -3-t & yl-5-iMxs aeétiqme. Melting point: 162 - 164cC.,

 <Desc / Clms Page number 39>

   Example 24
 EMI39.1
 In accordance with the process described z, Itexenple 4, es a rl'o> paré 1-benzojl-2-méthyi-5-néthoxy-3-indolyl-niàtat e benzyl. Melting point: 85 - 87 C.



    Example- 25
In accordance with the procedure described in Example 4, we have pre-
 EMI39.2
 adorned with alpha- (1-p-Nethyl-thiobenzoyl-2-netbyl-5-nethoxy-3-indolyl) -propionic acid. Melting point: 172-17% m.



  Example 26
In accordance with the process described in Example 4, we pre-
 EMI39.3
 trimmed with 1-p-chlorobenzoyl - aétlzyl-5-.uoro - in.do3y.-butyl actate. Melting point: 67 - 69 C. Example 27
 EMI39.4
 Has a solution of 7.4 g of 1 enzoyi zthocy-ph. ethyl levulinato hydrazone in 50 ml of ethanol, 2 g of concentrated hydrochloric acid was added, then the mixture was heated and refluxed for 1.5 hours * After
 EMI39.5
 After cooling, the mixture was concentrated to a residue, to which 100 ml of ether was added, followed by. removed the insoluble substance by filtration. The ether was evaporated to approximately dryness, the crystals formed were filtered off and washed.
 EMI39.6
 with a small amount of ether.

   By recrystallization from a mixture of water and ethanol, white needles of ethyl 1-benzoyl-2-methyl-5-metho2y-3-indolyl-acetate were obtained. Melting point: 64 - 65 C.



     In accordance with the process described above, the following compounds were prepared:
 EMI39.7
 1-benzoyl-µ, 4-dinethyl-µ-inaolylacetic acid Melting point: 165 * - 167 0. 1-p-chlorobenzoyl-2-nethyl-5-nethoxy-3-indolylacetic acid Melting point: 1590 - 160 C.

 <Desc / Clms Page number 40>

 
 EMI40.1
 1 "aeiào 1-1-21-5-me''J: I-
 EMI40.2
 than
 EMI40.3
 Point of fusion: 160- - 161.-C ...



  : 1. '1 acidlÎli -p-tBI & eBZ! -BSi-5-1 &
 EMI40.4
 than
 EMI40.5
 Melting point. - 155 * - J.56 <DC ,. the acid -benzoyJ.-2- # 1; b71-3-: iDdoqJAc! iàque Melting point-. 167. - 3.68'C. at ide Melting point. - 170 - 171, l t acid - (1-. é, y -.- t -d, l) rr oae Po1.n't melting-. 131 - 88 th .. ie -nmy. -5-.ho - nro3ia t de 'be'nzyl-e Melting point: 851) - 37 "S <le -o ...- -aaàh -, -. D. Acetate .de Point; de:! usioa: 89. - 9D C. benzoyl 1-p-loro.onzty -5aet -3-ndo, ct of 1i-le Point of iuBion: i03 - 1 ±> WQ le - cl 3-? o3-? 2pi. cnse de tt-bu.1;, 7: l'f! Subatmme 1mi.leuse. acid 1-âal3,5-i, t, 31 .-. tiq.



  P: oi.n1; de .'ir 207 - 2-S.



  3. *. 3 - benzozl-'l-5-atoxy-r-.nt3.3acetic 3n xï 'aa., - Exërl'J) 1e .2B For 2 hours, with 2'ti # l, in SL ubmamî, at B5- 9Oo0 a mixture of .17.0 g of N "'- nRTM-ai & y &' a. #

 <Desc / Clms Page number 41>

 
 EMI41.1
 nethyl ldvulinnut hydrazone, 2 g of hydrochloric acid and 41 g of acetic acid. The reaction mixture was cooled under reduced pressure to an oily substance which was dissolved in benzene then washed and dried. Then the solution was subjected to a sur
 EMI41.2
 silica gel, then to a reaction with cN.cro'oT.c to obtain a yellow needles of 1-ciimsscyl-2-.sëtkyl'-5-methoxy-3-indolyl-acetate of a point of tasîon of 87 - 87.5 * 0 (in Dethanol) ...



  Infrared ray absorption spectrum l) aX.r1] le (if :: J; J.-1)., Max
1740, 1665, 1625 Example 29
In accordance with the process described in Example 28, we have
 EMI41.3
 prepared from 1-cinnaQoyl-.2-Bethyl-5-nethyl-is.aolyl-acetic acid. Melting point: 164-165 ° C. 1-cinnoyl acid 1.0 g of 1-cinnoyl acid -2ethyl clans 120 ml of water, was added
 EMI41.4
 a solution of 116 g of aodiun bicarbonate in 0 Ni of water while maintaining the pH at 7.0 - 7.5. The treatment was continued at the same temperature for 1/2 hour after application ± = -ental.

   By filtration, an insoluble substance was removed and the filtrate was treated with active carbon and then concentrated to give a crude product. Recrystallization from water gave yellow crystals of 1-
 EMI41.5
 cinnamoyl-2-methyl-5-methox, v-3-indolyl-ac64, -atü sodium with a melting point of 26700 (deconposition).



  Absorption spectrum of infrared rays by affine, ..., - 1 15 O, 1E201590il560 Example 30 A suspension of 14.7 g of 1-cinnasoyl-2-n6tj3yl- acid.

 <Desc / Clms Page number 42>

 
 EMI42.1
 5-methoxy-3-indolyl-acetic in 70 ml of absolute methanol, a solution of 0.42 g of potassium tertiary butoxide in 95 ml of t-butyl alcohol was added dropwise while maintaining the pH at 7- 8. After the addition, stirring was continued at room temperature for about 1/2 hour. Further processing by the above process resulted in the formation of 13.5 g of crystals.
 EMI42.2
 Potassium 1-cinnanoyl-2-Bethyl-5-nethoxy-3-indolyl-aoetate yolks with a melting point of 260 C (decomposition). Infrared ray absorption spectrum: paraxfinom-1) = max
1670, 1610, 1570.



    Example 31
In accordance with the process described in Example 30, we pre-
 EMI42.3
 pared '7.8 g of yellow crystals of 1-cinnaixoyl-2-nethyl-5nethoxy'-3-indolyl-aoétato do N, N-dithyltra.no.éthano from 7.0 g of l-ci: maraoyl acid -2-methyl 5-zdthoxy-j indolyl-aedtiquo and 1.8 g of N, N-dinethylanino-ethanol. Point of fusions 103 - 104 C.
 EMI42.4
 Infrared ray absorption spectrum; t paraffin Qm-1) max
3525, 3330, 1670, 1615.



  Example 32
In accordance with the process described in Example 27, we have
 EMI42.5
 prepared from ethyl 1-cinnamoyl-2-methyl-5-methoxy-3-indol3rl-acetate. Melting point: 162 - 163 C.



    Example 33
In accordance with the process described in Oxenple 27, we have pre-
 EMI42.6
 trimmed with ethyl 1-diphenyl-acetyl-2-nethyl-5-nethoxy-3-indolyl-acetate. Melting point: 121 - 122 0.



  Example 34
In accordance with the process described in Example 27, we have
 EMI42.7
 , prepared from ethyl 1-cinnanoyl-2,5-dimethyl-3-indolyl-acetate

 <Desc / Clms Page number 43>

 Fusion point! 198 - 200 C.
 EMI43.1
 . ExeI: 1 "le 3? To a solution of 10 g of 1-p-chlorobanzoyl-2nethyl-5-nethoxy-µ-indiyi-acetic acid in 50 μl of acetone was added a solution of 2.4 g of sodium bicarbonate in 5 µl of water and the mixture was heated with stirring until formation of carbon dioxide gas broke.

   At the end of the reaction, the reaction mixture was concentrated to a residue which was recrystallized from a mixture of ethanol and ether, to afford 10.1 g of crystalline.
 EMI43.2
 slightly yellow levels of sodium 1-p-ohlorobenzoyl-2-methyl-5- 'nthoxy-3-indolyl-actate.



  Following the procedure analogous to that of Example 35, yellow crystals of sodium, cinnaraoy, -2-methyl, - 5-nethoxy-3-indolyl-aoetate with a melting point of 247 - 252 were obtained. C (deoonposition) and pale yellow crystals of sodium N- (isoniootin'jyl) "2" methyl-5-methoxy-aoetate with a melting point of 72 - 75 C.



  Example 36
In 50 ml of acetone, 10 g (0.028 mole) were dissolved
 EMI43.3
 1- (p-chlrobenzoyl) -2-nethyl-5-nethoxy-3-indolyl-acetic acid and 2.8 g (0.028%) of potassium bicarbonate were added, as well as 5 ml of water . The mixture was treated by a process analogous to that of Example 1, to obtain
 EMI43.4
 10.8 g of pale yellow crystals of 1- (p-chlotobenzoyl) -2-methyl.



  Potassium 5-neuhoxy-5-indolylac4tate with a melting point of 128 - 131 C. Yields 97 Example 37
In 100 ml of water, 10 g of l- (p-ohloro-
 EMI43.5
 benzoyl) -? - sodium n4thyl-5-nethoxy-5-indolyl-ac4tate.

 <Desc / Clms Page number 44>

 An aqueous solution of magnesium chloride was added thereto until no further crystal deposition was observed. By filtration, the deposited crystals were collected, washed with water and ethanol, and then dried, to obtain white crystals of N- (p-chlorobonzoyl) -2-.
 EMI44.1
 Methyl-3-mdthoxy-3-indolyl-magnesium acetate.



   According to a process analogous to that described above, the calcium salt (pale yellow crystals) and the strontium salt (yellow crystals) of 1- (p-) acid were obtained.
 EMI44.2
 chlorobenzoyl) -2-aethyl'-5-nethoxy-3-indolyl-acetic, 1- (niootinoyl) -2-nethyl-5-n4thoxy-3-indolyl-acetate, calcium yellow crystals; melting point: 185-190 C; (d6conposition) -7, as well as IT- (oinnamoZrl) -2-methyl-5-methoxy-3-indolyl-calcium acetate (yellow crystals). Example 38
 EMI44.3
 In 20 µl of water, 10 g of sodium 1- (p-chloroben zoyl) -2-methyl-5-nbthoy.3-iadolyl-acetate was dissolved. To this was added an aqueous solution of sodium chloride. aluminum until no more crystal deposition is observed.

   By filtration, the obtained crystals were collected, washed with water, and then dried to obtain 1- (p-chloroben-
 EMI44.4
 yellow aluminum zoyl) -2-ethyl-5-nethoxy-3..indolyl-acetate.



  According to a process analogous to that described above, there were obtained 1- (niootinoyl) -2-methyl-5-nethoxy-3indolyl-acetate of aluminum (yellow crystals) and 1- (cinnanoyl) -2-methyl- Aluminum 5-nethoxy-3-indolyl-acetate (yellow crystals).



  Example 39
The mixture was heated with 10 g (0.028 sole) of acid
 EMI44.5
 1- (pchl arobv nzoyl) -'- nthy ..- 5-methoxy-3-indo.ys-ao etic, 6.5 g (0.028 mole) of aminopyrine and 75 ml of acetone

 <Desc / Clms Page number 45>

 until the reaction is complete.

   We concentrated the
 EMI45.1
 celango e8actior.r.el under reduced pressure and the residue was dried to obtain yellow crystals of a molecular compound of 1- (p-chlorobenzoyl) -2-nethyl-5-ne% hoxy-3indolyl- acid. acetic acid with aminopyridineo In the manner described above, Liol6oulairon compounds of 1- (niaatanoyl) 2-methyl-5-nethoxy-5-indolyl-acetic acid (yellow crystals) were obtained and 1- (cinnanoyl) -2-methyl-5-aethoxy-3-indolyl-acostic acid (yellow crystals).



    Example 40
The mixture was heated with 10 g (0.028%) of the acid
 EMI45.2
 1- (p-chlorobonzoyl) -2- = 6yl-5-mdthoxy-3-Indolyl-acetiquoq 3.9 g (0.028%) urotropin and 75 ml ushanol until the reaction is complete. The reaction mixture was concentrated under reduced pressure to a residue which was dried, to give yellow crystals of a compound.
 EMI45.3
 1- (p-Chlorobonzoyl) -2-methyl-5 acid molecular molecule. nethoxy-3-indolyl-aootiquo and urotropin.



  Example 41 Requirement 1
 EMI45.4
 Sodium N- (p-Chlorobanzoyl) -2-athyl-5-rethoxy- 3-in.dolyl-aotato 10.0 g Magnesium alwzinate-silicate 104.4 g Calcium carboxy-mebyloel1ulose 6.3 g
 EMI45.5
 
<tb>
<tb> Talc <SEP> 3.8 <SEP> g
<tb> Magnesium <SEP> stearate <SEP> <SEP> 0.6 <SEP> g
<tb> 125.1 <SEP> g <SEP>
<tb>
 
A mixture of 71.6 g of magnesium aluminate silicate and 10.0 g of the sodium salt was passed through a sieve, then 32.8 g of sodium aluminate silicate was added.

 <Desc / Clms Page number 46>

 3.8 g of talc and 0.6 g of magnesium stearate, then we have.
 EMI46.1
 pressed directonont the mixture into conpriné.



  Prohibition 2
50 mg of the sodium salt and 50 mg of the potassium salt were mixed homogeneously with 450 ng of an excipient such as mannitol, glucose, sodium chloride, glycine, sodiun glutaminate or sodium salicylate and the mixture was sterilized by an appropriate method, to prepare for a solid injection.



   The results of a stability test are shown below (at 50 ° C in an ampoule).
 EMI46.2
  - ---- "" "------" -----
 EMI46.3
 
<tb>
<tb> 'Residual <SEP> percentages <SEP> of <SEP> salts <SEP> of
<tb> sodium <SEP> and <SEP> from <SEP> potassiun <SEP> do <SEP> acid
<tb>
 
 EMI46.4
 i N- (p-chlorobenzoyl) -2-tlethyl-5-! nethoxy-3-indolyl-aoétiquo ¯¯¯¯¯ ¯ ¯¯¯¯¯¯ ¯¯¯¯¯¯ r¯f1¯w wllw 15 É '30 1' 60 daysj i lww.y¯ww¯www / lwwllaww) j 15 30 60 days; Sodium salt 1 1 1 + 1 CC9%) 97% j 93% J 93% Mannitol Mannitol! "" "wwwwww¯w¯¯r¯wawwwww¯w rww¯wwt w¯¯..¯ .. 81 d0 potBj.LLL1 1 d 98% i) '98% 100 100%! 98% 98%
 EMI46.5
 
<tb>
<tb> Mannitol
<tb>


 

Claims (1)

CLAIMS 1. Process for the preparation of 1-acyl-3-indolyl-aliphatic acid derivatives corresponding to the formula: EMI47.1 where n is 0 or 1; R1 represents a hydrogen or halogen atom, a lower alkyl group having up to 3 carbon atoms, a lower alooxy group having up to 3 carbon atoms or a lower alkylthio group having up to 3 carbon atoms. carbon; R2 represents a naphthyl or phenyl group which is unsubstituted or substituted by a halogen, a lower alkyl, lower alkoxy or lower alkyl-thio radical, or a 5 or more heterocyclic ring. 6 members unsubstituted or substituted by a halogen containing an oxygen, sulfur or nitrogen atom; each of the radicals R3 and R4 representing a hydrogen atom or a lower alkyl group having up to 3 carbon atoms; R5 represents a hydrogen atom or a lower alkyl group; and [A] represents a saturated or unsaturated aliphatic carbon chain, unsubstituted or substituted by a halogen and containing up to 4 carbon atoms, or else salts or molecular compounds of these derivatives, with a metal of group I, II or III of the periodic table Mendeleev, or an organic anine, this process consia- <Desc / Clms Page number 48> both to heat, to 40 .. 200 C, a derivative of phenyl-hydrazone N1-acylated corresponding to the formula: EMI48.1 in which n, R1, R2, R3, R4, R5 and [A] have the n8ne meanings as defined above, in the presence or absence of a suitable catalyst, to obtain the 1-acyl acid derivative. 3-indolyl-aliphatic of formula (1), and optionally, when R5 in the 1-acyl-3-indolyl-aliphatic acid derivative obtained from formula (I) is an alkyl group, degrading the acid derivative 1- acyl-3-indolyl-aliphatic obtained of formula (I), in which R5 represents an alkyl group, to obtain the 1-acyl-3- indolyl-aliphatiquo acid derivative of formula (I), in which R5 represents a hydrogen atom, and then optionally react the 1-acyl-3-indolyl-aliphatic acid derivative obtained from formula (I), in which R5 represents a hydrogen atom, with a metal from group I, II or III of the Mendeleev periodic table, a salt or a hydroxide of this netal, or alternatively with an organic anine, in a solvent, to obtain the salt or molecular compound of the 1-aoyl-3-indolyl-aliphatic acid derivative of formula (I), in which R5 represents a hydrogen atom. <Desc / Clms Page number 49> 2. Process for preparing 1-acyl-3- indolyl-aliphatic acid derivatives corresponding to the formulas EMI49.1 where n is 0 or 1; R1 represents a hydrogen or halogen atom, a lower alkyl group having up to 3 carbon atoms, a lower alkoxy group having up to 3 carbon atoms or a lower alkyl-thio group having up to 3 carbon atoms of carbon; R2 represents a naphthyl or phenyl group which is unsubstituted or substituted with a halogen, a lower alkyl, lower alkoxy or lower alkyl-thio or alternatively a 5 or 6 nenbrea heterocyclic ring, unsubstituted or substituted by a halogen and containing a oxygen, sulfur or nitrogen atone; each of the radicals R3 and R4 representing a hydrogen atom or a lower alkyl group having up to 3 carbon atoms; R5 represents a hydrogen atom or a lower alkyl group; and [A] represents a saturated or unsaturated aliphatic carbon chain, unsubstituted or substituted by a halogen and containing up to 4 carbon atoms, or even salts or molecular compounds of these derivatives with a netal of group I, II or III of the Mendeleev Periodic Table, or an organic amine :, co-process consisting in reacting a phenyl-hydrazone derivative of formula <Desc / Clms Page number 50> EMI50.1 EMI50.2 in which tl, R3, R4 and R5 have the mono, 3 algniflons as those defined above, with a conposed of to1 "!! m1e I1- .. CAJn .. CO .. X (IV) in which R2, [A] and n have the new meanings as those defined above, X represents a halogen atom or an ester radical, to force the N1-acylated phenyl-hydrazone derivative of formula: EMI50.3 EMI50.4 in which Ri, R2, R3, le, 1P 1 CAJ and n have the meanings other than those defined above, heat the product obtained to 40 - 200 C, in the presence or absence of a suitable catalyst, to obtain a 1-acyl-3-indolyl-aliphatic acid derivative of the formula: <Desc / Clms Page number 51> EMI51.1 in which R1, R2, R, R4, R5, [A] and n have the same meanings as those defined above and optionally ;, when R5 of the 1-acyl-3-indolyl-alipha- acid derivative tick obtained of formula (I) is an alkyl group, hydrolyze the 1-acyl-3-indolyl-aliphatic acid derivative obtained from for- = le (I), in which R5 represents an alkyl group, to give the derivative d '1-acyl-3-indolyl-aliphatic acid of formula (I), dU.'lA in which R5 represents a hydrogen atom and optionally reacting the 1-acyl acid derivative 3-indolyl-aliphatic obtained from fornulo (I), in which R5 represents an atouo of hydrogen, with a metal of the group I, II or III of the periodic table of Mondeleev, a salt or a hydroxide of this netal, or alternatively with an organic amine, in a solvent, to obtain the salt or the molecular compound of. 1-acyl-3-indolyl-aliphatic acid derivative of formula (I), in which R5 represents a hydrogen atom. 3. Salts or molecular compounds of acid derivatives 1-acyl-3-indolyl-aliphatics corresponding to the formula: EMI51.2 <Desc / Clms Page number 52> EMI52.1 in which ± 1.J, 2F., R2, 1P and If on% the names d¯1r '! wish that those defined for the revemucatlon 1 "awwc Ttn mît %% EMI52.2 EMI52.3 of group I, II or ni from the JEEEMLas prioâlNB table or with a #: 11 # orgoD1quo. 4. Process of preparing ¯18 <# I1I1 Il culars of 1-1-inI-MsËN repoIidan1 acid derivatives: at the formula: EMI52.4 EMI52.5 where n is 0 or 1; There is a lack of hydrogen or halogen, an alkyl group: bII: r6Jd.'ItIUDJr ayamt up to 3 a% cn * a of carbon, an alcohol group:! Jm! '6DiIIIIm!' qramt up to 3 carbon atoms or an eleoxl: 1 m.t "d thio having up to 3 carbon atoms; B2 re raz naphthyl or unsubstituted phenyl group or 8 \ II1beti: tt # bzz a halogen, a radical 0.1001'1e inféoeieua, aJ1.cmr; r:! 1Jm.t '& J!. # M # or alcoyl iDt6X'1eur- thio, or one. = Wau bftï = cOEol2q z 5 or 6 Del1brea unsubstituted or eubet1tu.6 paar wa Bt # BE & Ms and containing an atone dlox7 ne, de BoUf> o% 1 d! L.1 ;; no radicals and B, 4 repr6een1> aa. ' uat aboBMe 4I! .1t or interior alkyl group t jiTtMm * & 3 atomm of carbon! and t: 1J represents a carbmm6o a3 ± zkaaqm 'ebtue, saturated or unsaturated, not eu.bst1Wêe sm -.1I # tt!: We by halogen and containing up to 4 atoms of NaSMams) this p cM6 EMI52.6 <Desc / Clms Page number 53> consisting in dissolving about 1% of the acid derivative 1- EMI53.1 ôcyl-5-indolyl-aliphatiquo responding to the torcula (V) in an organic solvent, for example acetone or methanol, and reacting the mixture obtained in the presence of a small quantity of water, with approximately 0 , 5 drops of carbonate or about 1 drops of sodium or potassium bicarbonate, or about EMI53.2 1 drown of an organic U1ine, by axaaplv l'thano3oW, ne, a riethanola3.na, di6thyl = ino-ethahol, ethylenediamine, histidine, arginine, lysine, ornihin, eitrulline, glucosaino, aninopyrine, ahloxpheniranine, 1.'ergotanine, l urotropine, thiamine or pyridoxamine. 5. Process for the preparation of alkaline metal salts EMI53.3 earth or alumina of 1-aoyl-3-indolyl-aliphatic acid derivative according to Claim 4, characterized in that the soluble salt of the 1-aoyl-3indolyl-aliphatic acid derivative obtained according to Claim 4 is reacted with EMI53.4 a salt of a metal, alkaline earth or an aluminum salt. 6. Process for preparing a solid injection of 1-acYl-3-indolYl-aliphatic acid derivatives, characterized in that one adds, to the soluble salts obtained according to step 4, an appropriate amount of an injectable drug. such as nannitol, glucose, sodium chloride, glycine, sodium glutamate, aninopyrino, oaffeine and sodium salicylate.