BE698378A - - Google Patents

Description

  

    <Desc / Clms Page number 1>
 



  Ministry of Economic Affairs Industrial Property Department
The applicant wishes to point out that the following corrections should be made to the text of this patent:
Page 63, line 26:
 EMI1.1
 read: "from N1-cinnamoyl-N 1- (Pau instead of:" from N1 - (2 ', 4'-cinnamoyl) -N' - (p- Page 63, line 27 read: ..... F = 179 C (with decomposition) instead of: ..... F '= 183 - 185 C.

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 EMI2.1
 



  ; nà.ntet < <h '::: 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 Modifications 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 No. 698,378 valid in whole or in part - if the latter was not:. 'Was not in whole or in part under the legislation currently in force. vigor,
 EMI2.2
 It authorizes the Minister to attach this note to the patent file and to issue a photocopy thereof.



   Herewith you will find, in revenue stamps, the amount of the required tax *
Please accept, Sir, the assurance of our highest consideration.

  <Desc / Clms Page number 3>

 
 EMI3.1
 



  "Indole derivatives" Priority, the 22 patent applications filed in Japan under the
 EMI3.2
 .Q. ::; The 03 and on the dates indicated below:
 EMI3.3
 
 <tb>
 <tb> N <SEP> 30306/66 <SEP> - <SEP> 12 <SEP> May <SEP> 1966 <SEP> N <SEP> 82650/66 <SEP> - <SEP> 16 <SEP> December <SEP> 1966
 <tb>
 
 EMI3.4
 ,; 0 4JG / j6 - June 27, 1966> 1 83748/66 - December 20, 1966 1 'i / 6 - June 50, 1966 N 1351/67 - January 6, 1967' ro v-: 1. - j0 June 1966 N 1j52 / 67 - 5 January 1967 ', V LJ. + i.5 / (j; ::' - 8 July 1966 1Ç 1499/67 - 7 January 1907.; V + 1? 14, / L6 - d uil ev 1966 HO j223 / û? - January 16 J.967 é1 à-Jô> 1/66 - August 1, 1966? j224 / 67 - January 16, 1967 1; 3473 / uj - August 19, 1966 N j530 / 67 - January 17, 1967,.

     . > .t. / J5 - August 19, 1966 N "3531/67 - January 17, 1967 .i. ,, 2 - ..> / Rj - December 15, 1966 31 3532/67 - January 17, 1967 1 'BJÉJ'F' ) / 66 - December 16, 1966? 3962/67 - January 20, 196 '?.'
The present invention relates to new N-substituted indole derivatives endowed with high anti-inflammatory, antipyretic and analgesic activity, and to processes for the preparation of these derivatives. The invention is more
 EMI3.5
 particularly relating to new derivatives of (1-aoyl-3-indolyl) aloanolques acids and to methods of preparation. tion of these derivatives.



   Among the non-steroidal anti-inflammatory compounds
 EMI3.6
 Known, (1 - parachlorobenzoy.-2-mCthy-5 - metho: i: y -., '# ir-J.olyl) acetic acid is the most active, but it is very toxic. The inventors have observed that the administration of

  <Desc / Clms Page number 4>

 
 EMI4.1
 . ',' <; ç ,, of this eoaposed to a rat: was enough to produce an ià; .-:;.:., zie r.1; ernè. In addition, touc leu coy.p033 anti-1; ila> -
 EMI4.2
 ma; oirea CIn;> siçui> s tending to favor the hemorrhage of the acute organs, e # of many C: 1: J mortals do p (: r.t'o: = - atiOf4 .jtonac.ale and-intostinalo have been reported.

   In addition, '1, 2-di? H: r.'yl-'Tb; yl-3, 5-p, yX'D .: olir.ddione (pi6nylbutazone), which is a: aci- in ± 1 mmatory most used at the present time, has a low activity compared to its high toxicity, hence a low "therapeutic ratio".



  The synthesis of derive indole containing
 EMI4.3
 of acyl groups to nitrogen is decreed for example in
 EMI4.4
 -iôJ ±: <1 <'iE1-j, "lieterocyclÍc Compound $, 1: ¯voL 3, oh. 1 pp. 1-247 ( <y; 2) 1, and in 5U, >> J.ÈR et wôlLjà-li, "lieùfrooyclic Compounds with --idole and Carbazole 8ys * 4ems '!, jp.fl-69 (fl9 $ P), Les'; "j - ..,. ii '-; acyl groups of 1-acyl-indàioÉ jôqj, 1.so easily hyùroly-.,.,. 4th its phj acids and alca; \ t .., seemed impossible to obtain. dir.Qct9! a & r '& ir derivatives of the corresponding-phenylhydrazides by 1 1 ind, te, o-r., of F4.scher. SOJV0HOV and others (Doklady Akad.,: Nau) ;; , jjµ, 840 (1961), Chen.



  Abstr. 22, 17621 (1961), J. G; Ù.B.S.R. ,. 1058 (1958)) have recently stated as follows:
 EMI4.5
 

  <Desc / Clms Page number 5>

 
They explain that an important condition for indole formation is the deacylation of the hydrazide, which releases a pair of p electrons on the 1 'nitrogen atom.



   The inventors have discovered that it is possible to prepare new derivatives of (1-acyl-3-indolyl) alkanoic acids endowed with a great anti-inflammatory, antipyretic and analgesic activity, by new or already known methods.



   One of the objects of the present invention is to provide new derivatives of (1-acyl-3-indolyl) alkanoic acids endowed with high anti-inflammatory, antipyretic and analgesic activity, and methods of preparation. of these derivatives. Another object of the invention is to provide economical manufacturing methods. of these compounds with high yields. Another object of the invention is to provide novel pharmaceutical compositions in which these compounds form the active ingredient. Other objects of the il.- vention will emerge from what follows.



   In order to achieve these objects, the present invention provides novel derivatives of (1-acyl-3-indolyl) alkanoic acids of general formula:
 EMI5.1
 where R1 represents an aromatic radical which is unsubstituted or substituted by lower alkyl groups,

  <Desc / Clms Page number 6>

 lower alkoxyl, lower thioalkoxyl, nitro or cyano or with halogen atoms, each of the alkyl, alkoxyl or thioalkoxyl groups containing up to 4 carbon atoms, or a 5 or 6 membered heterocyclic radical unsubstituted or substituted by groups methyl or ethyl or with halogen atoms and containing an oxygen, sulfur or nitrogen atom; R2 and R3 each represent a hydrogen atom.
 EMI6.1
 ne or aronte alkyl, containing up to 3 carbon atoms;

   R represents a hydrogen, a carboxyl group or a carbalkoxyl group contained. up to 4 carbon atoms; R5 represents an alkoxylb. Group, containing up to all carbon atoms, a benzoxyl group, a [5.1 ... '.........> "" ahydropyra.nnoxyl, an amine group or a hydroxyl group; , .6 represents an alkyl group containing up to 4 carbon atoms, a thioalkoxyl group containing up to 4 carbon atoms, a nitro group, an alkenyl group containing up to 4 carbon atoms, an alkenoxyl group containing up to 4 carbon atoms, a halogen shear or a hydrogen atom;

   A represents an unsubstituted saturated hydrocarbon chain containing up to carbon terminals, an unsubstituted unsaturated hydrocarbon chain containing up to 5 carbon atoms, a halogenated saturated hydrocarbon chain containing up to 5 carbon atoms, a halogenated unsaturated hydrocarbon chain containing up to 5 carbon atoms, a saturated hydrocarbon chain substituted with a phenyl group and 'containing up to 5 atoms' of carbon, or an unsaturated hydrocarbon chain substituted with a phenyl group and containing up to 5 carbon atoms, this hydrocarbon chain possibly being straight or branched;

   m = 0 or 1; p - or 1; and n = 0, 1, 2 or 3.

  <Desc / Clms Page number 7>

 



   Further, the present invention provides a process for making novel derivatives of (1-acyl-3indoly) alkanoic acids represented by formula I, which comprises reacting a phenylhydrazide of formula;
 EMI7.1
 where R1, R6 and A have the meanings above, on an aliphatic acid derivative of the formula:
 EMI7.2
 where R2, R3, R4, R5, m, n and p have the meanings above.



   The present invention also provides a process for the preparation of the novel (1-acyl-3indoly) alkanoic acid derivatives represented by formula I, which comprises decomposing a 2'-alkylidene-1'-phenylhydrazide of the formula :
 EMI7.3
 where R1, R6 and A have the meanings above and where B is

  <Desc / Clms Page number 8>

 an alkylidene group, using a decomposition agent, so as to obtain a 1'-phenylhydrazide of formula:
 EMI8.1
 where R1, R6 and A have the meanings above, and reacting the obtained 2'-alkylidene-1'-phenylhydrazide with an aliphatic acid derivative represented by the. formula II, so as to obtain the 1-acyl-3-indolyl-alkanecarboxylic acid derivative I.



   The present invention also provides a process for the preparation of the novel 1-acyl-3-indolyl-alkanecarboxylic acid derivatives represented by the formula I, which comprises reacting a phenylhydrazone of the formula:
 EMI8.2
   where R6 and B have the meanings above, on a compound of formula:
 EMI8.3
 where R1 and A have the meanings above, and where Y represents a halogen atom or an alkoxyl group, so as to obtain a 2'-alkylidene-1'-phenylhydrazide represented by formula IV;

   to decompose this alkylidene-phenylhydrazide IV

  <Desc / Clms Page number 9>

 
 EMI9.1
 so as to obtain a 1'-pnenylhydrazide represented by formula II, and to react this phenylhydrazide with an aliphatic acid derivative represented by formula III, so as to obtain the acid derivative (1- acyl-3-indolyl) alkanoic I.



   The present invention also provides a process for preparing the novel derivatives of (1-acyl-3-indolyl) alkanoic acids represented by formula I, which comprises reacting a phenylhydrazone of formula V with a compound.
 EMI9.2
 made of formula VI, so as to obtain a '1'-phenylhyârazide of formula II, and to react this fl'-phenylhydrazide with an aliphatic acid derivative of formula III, so as to obtain an acid derivative (fl -acyl-3-indolyl) alkanoic of formula I.



   The present invention also provides a process for preparing the novel (1-acyl-3-indolyl) alkanoic acid derivatives of formula I, which comprises reacting: '
 EMI9.3
 a 2'-alkylidene-'l'-phenylhydrazide of formula IV on an aliphatic acid derivative of formula III, so as to obtain the (1-acyl-3-indolyl) alkanoic acid derivative of formula I.



   The present invention also provides: a process for preparing the novel (1-acyl-3-indolyl) alkanoic acid derivatives represented by formula I, which consists
 EMI9.4
 reacting a phenylhydrazone of formula V with a compound of formula VI so as to obtain a 2'-alkylidéno-1'-phôiiylhydrazide of formula IV 'and i reacting this alkylid5ncphenylnyùrazide IY with an aliphatic acid derivative of formula III of so as to obtain the derivative of (1-acyl-3-indolyl) alkroic acid of formula I.

   The present invention also provides a method

  <Desc / Clms Page number 10>

 for the preparation of new (1-acyl-3-indolyl) alkanoic acids of formula VII
 EMI10.1
 where R1, R2, R3, A and m have the meanings above, which consists in reacting a 1'-phenylhydrazide of formula II with a compound of formula
 EMI10.2
 where R2, R3 and m have the meanings above, so as to obtain (1-acyl-3-indolyl) alkanoic acid VII.



   The present invention also provides a process for preparing the novel (1-acyl-3-indolyl) alkanoic acids of formula VII, which comprises reacting a 2'-alkylidene-1'-phen, virazide of formula IV with a compound; . Formula VIII so as to obtain the (1-acyl-3indolyl) alkanolic acid of formula VII.



   The present invention orally provides a process for the preparation of novel (1-acyl-3-indolyl) acetic acids of the formula:
 EMI10.3
 where R1, R6 and A have the meanings above, which consists

  <Desc / Clms Page number 11>

      reacting a 1'-phenylhydrazide of formula II with acetyl-succinic acid or with 3-oxoadipic acid, so as to obtain (1-acyl-3-indolyl) acetic acid of formula IX.



   The present invention also provides a process for preparing the novel (1-acyl-3-indolyl) acetic acids of formula IX which comprises reacting a 2'-alkylidene-1'-phenylhydrazide of formula IV on acetyl succinic acid or on 3-oxoadipic acid, so as to obtain (1-acyl-3-indolyl) acetic acid IX.



   The present invention also provides a process for preparing the novel (1-acyl-3-indolyl) alkanoic acid derivatives of formula I, which comprises reacting a phenylhydrazine of formula:
 EMI11.1
 where R6 has the meaning above, on a compound of formula VI, so as to obtain a 1'-phenylhydrazide of formula II, and to react 1'-phenylhydrazide II with an aliphatic acid derivative of formula III, so as to obtain the derivative of (1-acyl-3-indolyl) alkanoic acid I.



   The present invention also provides a process for preparing the novel derivatives of (1-acyl-3-indolyl) alkanoic acids of formula I, which comprises reacting a 1'-phenyl-imidohydrazide of formula XI:
 EMI11.2
 

  <Desc / Clms Page number 12>

 where R, R6 andA have the meanings above, on an aliphatic acid derivative III.



   The present invention also provides a process for the preparation of the novel (1-acyl-3-indolyl) alkanoic acids represented by the formula;
 EMI12.1
 where R1, R2, R3, R6, A, m and n have the meanings above, which involves transforming a compound represented by the for-
 EMI12.2
 mule; (1 {3 \ muï.e: '6 e "(cil) i3 m - (CU2) n- COR7 (XIII) bzz do A n1 where. R1, R2, R3, R6, A, m and n have the meanings above, and where R7 represents a t-butoxyl, tetrahydropyrannoxyl, benzoxyl or amine group, in (1-acyl-3-indolyl) alkanoic acid of formula XII.



   The present invention also provides a process for the preparation of the novel (1-acyl-3-indolyl) alkanoic acids of formula XII which comprises reacting an 1-phenyl hydrazide of formula II with a compound of formula:
 EMI12.3
 

  <Desc / Clms Page number 13>

 or R2, R3, m and n have the meanings above, and where R7 represents a t-butoxyl, benzoxyl, tetrahydropyranno-xyl or amine group, so as to obtain an acid derivative
 EMI13.1
 (fl-acyl-3-indolyl) alkanotque ae formula XIII, and decomposing this 0 iormulo ìll derivative due to maniote to obtain an acid, '1-acyl-3-indo'Lylal-canolaue-c, o formula XII.

   The present invention also provides a method
 EMI13.2
 preparation dice for the new (α-acyl-3-inaolyl) alkanoic acids shown; by the formula:
 EMI13.3
 
 EMI13.4
 where R, n2, 3, R and A have the meanings above, zizi consists in oxidizing a (".-acyl - indolyl) alkanal of the formula:
 EMI13.5
 
 EMI13.6
 where 'il R,: 35, Ru e:' a have 1. meanings above.



  The present invention orally provides a process for the preparation of novel (1-acyl-3-indolyl) alkanoic acids -fora2e X1, which comprises reacting an 11-phenylhydrazide of formula; 11 on a coapoxô -I formulated:

  <Desc / Clms Page number 14>

 
 EMI14.1
 where R2 and R3 have the meanings above, and where R8 is a lower alkyl group, so as to obtain an acetal
 EMI14.2
 of (3-indolyl) alkanal of formula!
 EMI14.3
 
 EMI14.4
 where R1, R2, i13, R6, li and A have the meanings above, A decompose this acetal XVIII so as to obtain a (j-indolyl) -alkanal of formula XVI, and to oxidize this aldehyde
 EMI14.5
 1 ± '/ 1 so as to obtain the acid (' t-acyl-3-indolyl) alkanoi-- quesXV.



   The present invention also provides a pro-
 EMI14.6
 preparation of new acids (1-aoyl-3-indolyl) alkanoiquos from tormu;
R3
 EMI14.7
 
 EMI14.8
 where R1, U2, H ;, n6 and A nt the above meanings, which consists in oxidizing an indolylalkanol of formula

  <Desc / Clms Page number 15>

 
 EMI15.1
 where R1, R2, R3, R6 and A have the meanings above, so as to obtain a (1-acyl-3-indolyl) alkanoic acid of formula XV.



   The present invention also provides a process for preparing the novel (1-acyl-3-indolyl) alkanoic acids of formula XV, which comprises reacting a 1'-phenylhydrazide of formula II with a compound of formula:
 EMI15.2
 where R2 and R3 have the meanings above, so as to obtain a (1-acyl-3-indolyl) alkanol of formula XIX, and to oxidize this alkanol XIX so as to obtain the acid (1-acyl-3-indolyl ) alkanoic XV.



   The present invention also provides a process for the preparation of (1-acyl-3-indolyl) alkanoic acids of formula XV, which comprises dehydrogenating a (2,3-dihydro-3-indolyl) -alkanoic acid of formula:
 EMI15.3
 

  <Desc / Clms Page number 16>

 
 EMI16.1
 0 ', R11 U2, U5. i6 and A have the above meanings.



  The present invention also provides a process for the preparation of new derivatives of (1-aoyl-3indolyl) acetic acids of the formula:
 EMI16.2
 
 EMI16.3
 where 1, H2, n5, R6 and A have the meanings above, which
 EMI16.4
 consists of dehydrating or possibly hydrolyzing after
 EMI16.5
 dr =;:. y.rc '.. rûiOn a derivative of (-hydroxy-2,3-dihydro-3indolyl) -acetic acid of formula:
 EMI16.6
 
 EMI16.7
 where LI ,, il, i5, R 'and A have the above meanings.
 EMI16.8
 



  The present invention also provides a process for the preparation of the novel acids (1-acyl-3-indolyl) al-
 EMI16.9
 Caaoic acids of formula XV, which consists in subjecting the - (ï-acyl-pheny7.amino) -, -. oxoalkanoic acids of formula:

  <Desc / Clms Page number 17>

 
 EMI17.1
 where R1, R2, R3, R6 and A have the meanings above, to a cyclization reaction.
 EMI17.2
 The present invention further provides a method of preparing the novel (1-acyl-3-indolyl) acetic acids of formula IX, which comprises heating an acid
 EMI17.3
 3- (2-acylaminophenyl) levulic of the formula:
 EMI17.4
 where R1, R6 and A have the meanings above, in the presence of a mineral acid in the care of a suitable solvent.



   In accordance with the present invention,
 EMI17.5
 (-acyl-3-indolYl) alkanoic acid derivatives) represented by formula I, by the reactions indicated by the following equations:

  <Desc / Clms Page number 18>

 
 EMI18.1
   Rice6 In the above formulas, R1, R2, R3, R4, R5, R6, A, B, Y m, n and p have the meanings indicated above.

  <Desc / Clms Page number 19>

 



   In the methods of the invention, 1'-phenylhydrazides II and 2'-alkylidene -1'-phenylhydrazides IV can be synthesized by methods other than those indicated herein. These intermediates II and IV are new compounds.



   In the following, the methods of the invention will be described in order.



   We will first describe the reaction of a phenylhydrazone V with a compound VI.



   A phenylhydrazone V is reacted with a compound VI in the presence of a hydrohalic acid scavenger.



  A tertiary amine such as pyridine or dimethylaniline can be used as the hydrohalic acid scavenger.



  These hydrohalic acid fixers can themselves serve as solvents. It is also possible to use inert solvents such as ether, benzene, toluene or tetrahydrofuran, in the presence of at least equimolecular quantities of these hydrohalic acid scavengers. Compound VI can be chloride, bromide, iodide or fluoride; chloride is industrially preferable. The reaction takes place at room temperature in many cases, and even below 0 C in some solvents. The exothermic reaction is complete in a few minutes to a few hours.

   When the reaction is complete, the halohydrate formed is removed by filtration and the filtrate is concentrated under reduced pressure, or the reaction mixture is poured into water when a water-soluble solvent such as pyridine is employed, and the desired 2'-alkylidene-1'-phenylhydrazide is readily obtained in the form of crystals or oil.



  These products can be recrystallized in a solvent

  <Desc / Clms Page number 20>

      appropriate, such as a mixture of alcohol and water.



   If a compound with a weak N = C bond is used as compound V, or if the reaction conditions
 EMI20.1
 are energetic, a 1'phenylhydrazide II is obtained directly instead of '-alkylidene 1-pyenylhydrazide IV.



   In accordance with the process of the invention, the following compounds can be obtained in high yields:
 EMI20.2
 ? ' -L; .l: .i, -1 -paraiMthoxyphenyl-cinnamhydrazide 21-ethylidùne-11-paratolyl-cinnamhydrazide 2 '-ethylien-fl'-parachlorophànyl-einnamhydrazide 2' -6thylidene-1 '' -parathiomethoxyphenandrazide 2 ' -ethylidune-1 '-paraethoxyphenyl-cinnamhydrazide' -é th; # lidene -. 'I' -paramwthox, yphenyl-5-phenyl-2, -pentadienohydrazide '.' - t nr: i.ci;

  ne-1 '-paraethoxyphenyl-5-phenyl-2, + -pentadienohydrazide -?' - i> thylidênQ-'1 '- metamethoxyphenyl-cinnamhydrazide 2' -ethylidene-fl '-metatolyl-cinnatlhydrazide' -ethylidene-1'- paramethoxyphenyl-4-phenyl-3-butenohydrazide 2'-benzylidene-1'-paramethoxyphenyl-cinnamhydrazide
 EMI20.3
 ? ' - trichlorinated thy.idene-1 '-parame thoxyphenyl-cinnamhydrazide 1- (a-methylbenzylidene) -1'-paramethoxyphenyl-cinnamhydrazide 2'-ethylidene-1'-paramethoxyphenyl-3- (2-furyl) acrylhydrazide 2' -ethylidene-1'-paratolyl-3- (2-furyl) acrylhydrazide
 EMI20.4
 2'-ethylidene-1'-parachlorophenyl-3- (2-furyl) aorylhydrazide

  <Desc / Clms Page number 21>

 
 EMI21.1
 2 '-ethylidene-1' -parathio! Mthoxyph6nyl-3 - (2-furyl)
 EMI21.2
 acrylhydrazide
 EMI21.3
 2'-ethylidene-1'-paraethoxyphenyl-j- (2-furyl) acryl-;

   
 EMI21.4
 hydrazide
 EMI21.5
 1 2'-ethylidene-11-paramethoxyphenyl-3- (1-naphthyl) a.crylhy-
 EMI21.6
 drazide
 EMI21.7
 2'-ethyliucne-1'-paraethoxyphenyl-3- (1-naphthyl) acryl-
 EMI21.8
 hydrazide
 EMI21.9
 2 '-ethylidèr.e-1' - .. f tā ,: f: x;, pr.rnYl-3- (2-thicnyl) acryl-
 EMI21.10
 hydrazide
 EMI21.11
 2'-ethylidene-1'-metatolyl-j- (2-thiÓnyl) acrylhydrazide 2'-ethylidene-1'-paramc, hoxJpWny1-3- (2-pyridyl)
 EMI21.12
 acrylhydrazide
 EMI21.13
 d '-benzyliene-fl'-pai <amethoxypiiùnyl-µ- (2-thienyl) aeryl-
 EMI21.14
 hydrazide
 EMI21.15
 2 '-trichlorethylidne-1' -paramétnoxypiiényl-3- (2-t.iàn; '3.) -
 EMI21.16
 acrylhydrazide
 EMI21.17
 2 '- (α-methylbenzylidene) -' I '-prramthoxyphenyl, -; - (- tiu = 'nv.) -
 EMI21.18
 acrylhydrazide
 EMI21.19
 ..: 1-ethylidene-; a '-p: ai.ail:

   û: o: cyphtnyl-mttanitxocinr "n3.y .ira-
 EMI21.20
 zide
 EMI21.21
 2'-úthylidone-1'-paratolyl-mÓtQnitrocinnamhydrazi1e 2 '-ethylidene-1' -parachlorophenyl-môtanitrocinna'silydraside Z '-thrlidene-1' -pa: at :: i o., F: tox, yp? L: nyl .-mC tan, ï trocinnamhyàra:; 14e 2'-tthylidc: na- î '-: axa toxyphcinyl-m. tanitrocinnamhyrir.a-
 EMI21.22
 zide
 EMI21.23
 2 '' -éth.Ààdene-1 '-;,: ar.im, étt> oxyphenyî-paramethoxyu1xlnamhy-
 EMI21.24
 drazide

  <Desc / Clms Page number 22>

 
 EMI22.1
 2 '-benzylidèn.e-1' '-paran> .hthoxyphenyl-cinnamhyàraziàe 2' -triehlorethylene-fl'-paramethoxyphenyl-paramethoxlrein-
 EMI22.2
 namhydrazide
 EMI22.3
 2 '- (o:

  -methylbenzylidèIle) -'1 '-paramÓthoxyphényl-paraméthoxycinnamhy4raziàe 2'-Óthylidène-'1'-parmethoxyphenyl-5-parachlorophenyl-2,4-
 EMI22.4
 pentadienohydrazide
 EMI22.5
 2 '-ethylidene-l' -paramethoxyphenyl-a-phenyl-parachT.orf ''.
 EMI22.6
 namhydrazide
 EMI22.7
 2 '-eth> .liàene-fl'-paramethoxyphônyl-j-paratolylaerylhydra-
 EMI22.8
 zide
 EMI22.9
 2 '-; thylidene-' '-parartlcthoxyphenyl-a-methyl-parachlorocinziamhydraz. Of 2' .. c.thylidene-'l'-paramethoxyphenyl-parachlorocinnamhydrazi-
 EMI22.10
 of
 EMI22.11
 2 '-ethylidone-fl'-paramethoxyphenyl-parathiomethoxyeinnamhydrazine 2' -ethylien-fl'-paramethoxyphônyl-parachloroeinnamhyàra-
 EMI22.12
 zide
 EMI22.13
 , 21 - "; thyHdme-1 '-po.ra: ..", .s.:;, Rlhenyl-phenyïac4thydrazide 2'-cthylid'jne-1' -parafe ù. '. Enyl-paratolylacethydrazide "¯é thylid: ne-1'-1 arabolyl-r ::.;

  lßac: thydraz.de,! - '' iLhylidenu-1 '-par: ... mÔthoxyphûn.y l-: rPlényl1ralérhydrazido 21-étnylid n-1'-Ótachlorophnyl-phÓnylactlirazide 2'-uthyH.dcne-1' -i) iIaC'tii4'Oi): IHri; fi-ÎInyltG: hyü: '; nLli.e 2'-thylidene-'1'-prirathio,:. Ctho: cyjhénvl-pYlé.ay.acéthycirazi, from 2' -''- tiiylid & ne- '! '-paranuthoxyphnyl - parachlorophenylpropionhytiraziue a ".-r: thylid: ne-1' -r ;: trrn ,:

   : .oxyphé zyl-parato lylrcé thydrazide '' -ethylidene-'1 '-param.thoxyphenyl-para.rrethoxyphe: nylaceous-
 EMI22.14
 thydrazide

  <Desc / Clms Page number 23>

 
 EMI23.1
 2 '-ethylidene-fl' -puramétbio; yphenyl-4-phenylbubyrhydrazide 2'-ethylidene-1 '-param6thoxyphenyl- (3-pyridyl) acethydra-
 EMI23.2
 zide '
 EMI23.3
 2 '-ethylidene-fl' -paramethoxyphônyl - (& - pyridyl) acethydrazi-
 EMI23.4
 of
 EMI23.5
 of 2 '-ôthylidene-fl <-paramethoxyphenyl- (4-pyridyl) acethydrazide 21-ethylidene-11-param6thoxyphenyl- (2-thienyl) acethydra-
 EMI23.6
 zide
 EMI23.7
 2 '-ethylidene-fl'-parametho;

  yphenyl- (2-iuryl) acethydnazide 2 '-ethylidene-1' -parame tioxJphenyl.-d.phenylaceous thydrazide 2'-ithylidene-1'-metamethoxyphrnyl .-- phnylacethydrazide 2'-ethylidene-1'-metatolhydrazide -phenylidene-1'-metatolyl-phenylacetraz ethylidene-1'-parachloroprenyl-3-phenylpr.opionYdxazide 2 '-benzyliàone-fl' -paramethoxyphenyl-phenylaeethyàrazLde 2'-trichlorethylidèae-1 '.- paramethoxyphdnyl-phenylaCéthy.

    
 EMI23.8
 drazide
 EMI23.9
 2 '- (fl-methylpropylaene) -fi' -paramethoxyphenyl-phenylae-
 EMI23.10
 thydrazide
 EMI23.11
 '- (a-methylbenzylidane, l-1'-paramethoxyphdnyl-phenylacethy ..
 EMI23.12
 drazide The following hydrazides are very easy to
 EMI23.13
 obtain directly from hydrazones derived from ethyl levu- 3.ate, ethyl acetylacetate, 4-m, * -, thoxy-3-
 EMI23.14
 Methyl oxobutyrate etc., under certain reaction conditions:

   
 EMI23.15
 1 '-. Paramethoxyphenyl-cinnamhydrazide 1'-paratolyl-cinnamhydrazido
 EMI23.16
 1'-metamethoxyphenyl-cinnamhydrazide
 EMI23.17
 1 '- paramethoxyphenyl-metanitrocinnmhydrazide
 EMI23.18
 1'-Paramethoxyphenyl-phenylacethydrazide

  <Desc / Clms Page number 24>

 
 EMI24.1
 11-paramethoxyphenyl-paratolylac6thydrazide 1 '-paramethoxyphenyl - (- furyl) acethydrazide These new alkyàiàene-phôn, Yl.iY4razides and phenylhydrazides, obtained by the process of the present invention, have psychological, stimulating, anti-tumor effects bactericides and fungicides, and are important intermediate compounds for the preparation of anti-inflammatory drugs,
 EMI24.2
 analgesics,

   and remarkably effective auti-pyretics. The preparation process will then be described.
 EMI24.3
 of a phúnylhydrazide II by decomposition of an alkylidene-phenylhydrazide IV.



   An alkylidene-phenylhydrazide IV is dissolved or suspended in a suitable solvent, for example alcohol, ether, benzene or toluene. When alcohol is used, it is absolute alcohol that gives good returns. A quantity of dry hydrochloric acid gas greater than one equivalent is then absorbed by the solution or suspension.



  Phenylhydrazide II chlornyirate precipitates in crystalline form in good yield. Hydrochloric acid can be replaced by sulfuric acid or another acid. When using ether, benzene or toluene as a solvent; add a small amount of alcohol. The reaction temperature is preferably between 0 C and 25 C, but can be less than 0 C
Various alkylidene-phenylhydrazides can be used. Thus, the derivatives of acetaldehyde, chloral, benzaldehyde, acetal, ethyl acetylacetate and methoxyacetone generally decompose easily giving the corresponding phenylhydrazides II.



  Among the derivatives, those of acetaldehyde are particularly

  <Desc / Clms Page number 25>

 
 EMI25.1
 economically advantageous from an industrial point of view.
 EMI25.2
 According to the present invention, one can
 EMI25.3
 obtain for example the following phenylhydrazides: 1'-paramethoxyphenyl-cinnamhydrazido
 EMI25.4
 11-paratolyl-cinntimhydrazide 1 '-parachlorophenyl-cinna''nhydrazide 1'-parathiomethoxyLhé: vi-cinnamhydrazide 1' -parl1Ó thoxyphÓr .: I-cinmtF.Inydraz ide 1 '-paramethoxyphenyl-j-pII': n .-pentadienohydrazide 1'-paraethoxyphenyl-5-; aenyl-, 4-pentadienohydrazide 1-paramethoxyphenyl-cin - ,, i;, iiydraz ide 1'-paramethoxyphenyl - * - phsnyl-3-buténohydrazià.e 1'-metamethoxyphenyl -;

  nutanitrocinnamhydrazidQ 11-paratolyi-metanitrocinnamhyd.-azide '1' -parachloropizenyl-metanitrocinnamhydraz. of 1'-parathiomethoxyphúnyl-útanitrocinnahydra7, ide-paraethoxyphenyl-metanitrocinamhydrazide 1 '-parathiomethoxyphúnyl-útanitrocinnahydra7, 1'-paraethoxyphenyl-metanitrocinamhydrazide 1' -nethoxyphenyl-metanitrocin-amoxyphoxy-arnyphoxy-nethoxyphenyl-thoxy-amoxyphoxy-arnoxy-arnoxy-innoxy-arnoxy-innoxy-arnoxy-innoxy-arnoxy-arnoxy-arnoxy-arnoxy-arnoxy-arnoxy-thoxyphenyl- paras! 6thoxyoinnamhydrazidc 1'-paramethox = fpht'nyl-pûrachlorocinnamhydrazide '' '-parametho :: phc: n; ri-5-parachlorophenyl-2,4-pentadi-
 EMI25.5
 nohydrazide
 EMI25.6
 1'-Paramethoxyphen; 1-a-phcnyl-paruchlorocinnamhydrazide 11-paramethox, vpheny'j.-J-paratolylacrylhydrazide 1 '-parame thox ;;

   i.r.ur yl-a-: methyl-parachlorocizrnmhydrazide 1 '-prr amt. thoxypht ::: yl-p :: r.ylacéthydrazide 1 '-parachloroph:;: yl-pr.:ylrcéthydraT ide 1 parachloroph,, .yl-, -c. f-> 1 '-parathionicthoxyph6nyl-phcnylacuthydrazide 1'-paraethoxyphc: nyl-p: <: n; flacc:;. hydrazide 1 '-parac! ûthoxypMnyl-paratolylaCt''thydrazide' l '1 -ph-nyl-ph6nyltie t tliy-À raziçio J

  <Desc / Clms Page number 26>

 
 EMI26.1
 1'-Paramethoxyphenyl- (3'-pyrldyl) acethydrazide 1'-paramethoxyphenyl- (4-pyridyl) aaethydraide 1'-paramethoxyphenyl "- (2-pyridyl) acethydrazide 1'-paramethoxyphenyl- (2-thiÓnyl) acethydrazide 'phenyl paramethoxyphenyl" - (2-fuxyl) acethydrazide 1'-paramethoxyphy1- (5-chlorc-2-hiényl) acethydrazide
 EMI26.2
 1'-Paramethoxyphenyl-diphenylacethydrazide
 EMI26.3
 11-paramethoxyphenyl-2-phenylbutyrliydrazide 11-paramethoxyphenyl- (I-naphthyl)

  acetliydrazide 11-paramethoxyphenyl- (2-naphthyl) acethydrazide 1'-paramethoxyphenyl-3,4-dimethoxyphenylacethydrazide fl '-paranôthoxyphenyl-4-paramethoxyphenylbutyrhydrazide 1'-paramethoxyphenyl-5-phenylvalerra
 EMI26.4
 1'-paraethoxyphenyl-5-phenylvalerhydrazide
 EMI26.5
 1'-metamethoxyphenyl-phenylacethydrazide 1 '-metatolyl-'phenylacéthydrazi.de fl' -paramethoxyphenyl-4-phenylbutyrhydrazide 11-paramethoxyp ,, Ônyl-3- (2-thienyl) acrylúhydrazide 1'-paratolidenyl-; -thiúhydrazide 1'-paratolidenyl-; -parachlorophéi., -3- (2-thienyl) acrylhydrazide 1'-prruthiom: thoxyphür.y - (2-thienyl) acrylhydrazide 1 '-para <thoxyphnyl-3- (2-thiGnyl) acrylhydrazide 11 '-môtamé5Îioxypi enyl-j- (é-thiônyl) aci'ylhjvàrazide fl' -paraethoxyphenyl-j- (2-furyl) acryInydraziiie 't'-meGamethoxyphenyl ) rxcrylhyûra.zide 1'-metatolyl-;

  - (- pyridyl) acrylhydrazide 3'-purameGhox, yphenyl - ('napnty.) acrylhydrazide
 EMI26.6
 Their salts, such as hydrochlorides, sulfates, and phosphates, are easy to obtain. These are all new compounds, which have not been described in any publication.

  <Desc / Clms Page number 27>

 



   These compounds have psychologic, stimulating, anti-tumor, bactericidal and fungicidal activities, and are very important intermediates for the manufacture of strong anti-inflammatory, analgesic and antipyretic drugs.



   In some cases, the new phenylhydrazides II can be obtained directly by reacting a phenylhydrazide X
 EMI27.1
 where R6 has the same meaning as in formula I, or a gall of this phenylhydrazine, on a compound VI:
R1 - A - CO - Y (VI) where R and A have the same meanings as in formula I and where Y represents a halogen atom, in the presence of a basic reagent.



   This reaction is carried out in a conventional solvent such as benzene, toluene, xylene, ether, dioxane or tetrahydrofuran, in the presence of a dehalohydrator such as a tertiary amine. Pyridine or dimethylaniline can be used as the tertiary amine; the amount of tertiary amine is preferably at least equivalent to the amount of phenylhydrazine X.



   This reaction is so rapid that compound VI must be added slowly, with cooling, to the phenylhydrazine X dissolved in the appropriate solvent. The obtained phenylhydrazide II is contaminated with a by-product such as 2'-phenylhydrazide or N-phenyl-N, N'-dihydrazide, but it can be isolated and purified by separating the by-products by

  <Desc / Clms Page number 28>

 a suitable method, such as column chromatography. However, it is not necessary to purify 1'-phenylhydrazide, since it is the only one to react in the next reaction of the present invention.



   According to the process of the invention, compounds are obtained having the following substituents, represented by R1, R6 and A in the formulas II, VI and X:
R1 phenyl, parachlorophenyl, paratolyl, paramethoxyphenyl, parabromophenyl, paraethylphenyl, paraethoxyphenyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 5-chloro-2-thionyl, N -methyl-3-piperidyl, 1-naphthyl, hydrogen atom.



   A = -CH2-, -CH2-CH = CH-, -CH = CH-, -CH = CH-CH = CH-,
 EMI28.1
   -CH2-CH = CH2, R6 = - chlorine, bromine, fluorine, hydrogen, methyl, ethyl, isopropyl, methoxyl, ethoxyl, propoxyl, thiomethoxyl, thioethoxyl, thio-isopropoxyl.



   Finally, the process for obtaining a 1-acyl-3-indolyl-alkanecarboxylic acid derivative I will be described by reaction of a phenylhydrazide II with an aliphatic acid derivative III.



   The reaction is carried out by heating, in the presence or absence of a condensing agent, with or without an organic solvent. The yields are very high.



   The reaction takes place easily without a solvent, but the use of a solvent is often preferable. Organic acids such as acetic acid, formic acid, propionic acid, etc. can be used as solvents.

  <Desc / Clms Page number 29>

 lactic acid, butyric acid; nonpolar solvents such as cyclohexane, hexane, benzene, toluene,; or other organic solvents such as dioxane or dimethylfornamide, in the cyclization reaction. When an alcohol is used as a solvent in this reaction, one obtains; the corresponding ester of indolyl alkanoic acid, for example:
 EMI29.1
 3flg CH3 'Q' "-CO- CtT" - rtl'r J '2 -'Joon. c0 N-NH.

   C1H. ########### CHO CH ,, - COOCH, ave Cii OiI CIï CIi -COOCïi, CH with "5 \ ## CI! Il ç j ri) CI !..,% CI! É11
A substituted indole derivative can be prepared by cyclizing a para-substituted phnylhydrazide, if the phenylhydrazide is meta-substituted, two indole derivatives are obtained which are 4- and 6-substituted isomers.
 EMI29.2
 



  CH30 CH? COOH, 1 N - idH CH.COCH, CH .-, COOH, 2 3 aCil2 COOH CH? COOH co cxjcoox CH #########. Cil 3 0 1-11 GHCOOII here CH Cl "wi li cii -" N- "CH- 61 C0 Cil c il 1 (0

  <Desc / Clms Page number 30>

 
 EMI30.1
 Cil ç) N - CH3COCH2 CH2COOH "µ /" 2 CH3COCH2CH2COOH CO OH il CH 2COOL OCH, CH2COOH 2 2 HC.l 0- CH 0 "CH3. CH :; HC1 CH 3H il x CH CH 6
These isomers can generally be separated by column chromatography.



   The reaction can be carried out at temperatures between 50 C and 200 C, but it is preferred to operate between 65 C and 95 C. The reaction takes place quickly, and is generally completed in one to two hours. The employment of a
 EMI30.2
 condensation is not necessary in some cases, but gives 1.In, jL'alomont de bon- ": 1 tatn. Among the! l! 5 levels of condensation that can be used are mineral acids such as hydrochloric acid, sulfuric acid and acid
 EMI30.3
 phonphoric, metal halides such as zinc chloride and copper chloride, powders of heavy metals such as copper powder, Grignard reagents, boron fluoride, polyphosphoric acids and ion exchange resins .

   At least an equimolecular amount of hydrochloric acid or the like is needed, while a small amount of copper powder or the like is sufficient.

  <Desc / Clms Page number 31>

 



   The reaction mixture is then left at room temperature or in the refrigerator (about 5 ° C.), and a large quantity of crystals of the reaction product is generally obtained.



   If no crystals form, the reaction mixture is concentrated under reduced pressure, or water, dilute acetic acid or petroleum ether is added:: then beautiful crystals are obtained. Ether, acetone pure or diluted with water, alcohol pure or diluted with water, benzene and acetic acid are generally preferred as solvents for recrystallization of these compounds. Polymorphic crystals are often obtained, the crystal system of which varies depending on the solvent and the rate of crystallization. The crystals formed are collected by filtration, and they are generally washed with dilute acetic acid, dilute alcohol, water or petroleum ether before drying them.

   The products sought are generally crystallized, but the esters are sometimes oily.



   The reaction solvents, the reaction conditions, the condensing agents and the recrystallization solvents mentioned above are given only by way of illustration and not by way of limitation,
The following compounds are easy to obtain with good yields (theoretical or close to theoretical yields) by the process of the present invention:

     
 EMI31.1
 (Fl-ciImamoy1-2-methyl-5-methoxy-3-indolyl) acetic acid (1-cinnamoyl-5-methoxy-3-indolyl) acetic acid
 EMI31.2
 (1-Cinnamoyl-2,5-dimethyl-3-indolyl) acetic acid (1-Cinnamoyl-2-methyl-5-chloro-3-indolyl) acetic acid (1-Cinnamoyl-2-methyl-3-indolyl) acetic

  <Desc / Clms Page number 32>

 
 EMI32.1
 (1-Cirmamoyl-2-methyl-5-thiomethoxy-3-indolyl) ac- acid
 EMI32.2
 tick
 EMI32.3
 (1-Cinnamoyl-α-methyl-5-ethoxy-3-indolyl) acetic (-ci.nnamoyl -methyl-5-m: thoxy -; - indolyl) malonate lk '('> c innanayl) acid 2-: é t: yl.-5 - methocy-3-indolyl.) Acetamide 16'l-cinnamoyl-2-nethyl-5-methoxy-j-indolyl) acetate
 EMI32.4
 t-butyl
 EMI32.5
 (r-c:

  inne.mayl - methyl-5-methoxy-3-.ndolyl) ethyl acetate (1-cinnamoyl-2-methyl-5-methoxy-3-indolel) methyl acetate
 EMI32.6
 the
 EMI32.7
 Benzyl {'tc.nnamoy .-- methyl-5-methoxy-3-.ndolyl) acetate (' 1-cinnamoyl-2-methyl-5-methoxy-3-indolyl) trahydropyranyl acetate 4- (1- cinn.amoyl-2-methyl-5-methoxy-3-indolyl) butyri-
 EMI32.8
 than
 EMI32.9
 2- (fl-¯cinnaaioyl-2-methyl-5-methoxy-3-inaolyl) propio- acid
 EMI32.10
 fuck
 EMI32.11
 3 - {'1-Cinnamoyl-2-methyl-5-methyl -3-indolyl) propionic acid lez. d '1) A') l: - (1-Ginrn''1o: rl-2 -! '1, t;

   .yl-J - !! ht y - ..> - 1.n 0, -: 'pr0p, .Otuque Mixture of (1-cinhamoyl-2-methyl-4-methoxy-3-indolyl) acetic acid and d (1-Oinnamoyl-2-Diethyl-6-methoxy-3-idolyl) acid acotic Acid mixture (1-cinnamoyl-2,4-dimethyl-j-indolyl)
 EMI32.12
 acetic and (1-cinnamoyl-2,6-dimethyl-3-indolyl) acetic acid
 EMI32.13
 Acid / -I- (4-Phenyl-3-butenoyl) -2-methYl-5-methoxy-3-
 EMI32.14
 indolyl¯7-acetic
 EMI32.15
 Acid 2 - / - '1- (4-phenyl, -3-butenoyl) -2-methyl-5-methoxy-3-
 EMI32.16
 indolyl 7propionic

  <Desc / Clms Page number 33>

 
 EMI33.1
 1--2- (1-naphthyl) acryloyl¯7-2-methyl-5-methoxy-3- 1 acid
 EMI33.2
 indolyl -acetic
 EMI33.3
 16'i-Paranitrocinnamoyl-2-methyl-5-methoxy-3-indolyl acid) -
 EMI33.4
 acetic
 EMI33.5
 Acid -1-C3-PhenY1CinnamOY1)

  -2-methYl-5-methOXY-3-ind01YJ} -!
 EMI33.6
 acetic
 EMI33.7
 Acid / -I- (3-phenylcrotonoyl) -2-meth, -fl-5-methoXY-3-indo-
 EMI33.8
 lyl - 7-acetic
 EMI33.9
 Aci,> e j 1 - / - 2- (2-piridyl) -acryloyl-7-2-methyl-5-methoxy-3-
 EMI33.10
 indolyl acetic
 EMI33.11
 Acid.! 1 - / '.- (2-quinolyi) uc;

  rylayl -% - 2-methyi-5-methoxy--
 EMI33.12
 indolyl acetic
 EMI33.13
 Acid / -1- (3-Benzylcinnamoyl) -2-methyl-5-methoxy-3-indolyll.
 EMI33.14
 acetic '.
 EMI33.15
 Acid (1 -parabron! Ocinnamoyl-2-methyl-5-methoxy "3-indolyl) -
 EMI33.16
 acetic
 EMI33.17
 Acid (1-parachlorocinnllmoyl-2-m thyl-7-methoxy-indo.
 EMI33.18
 lyl) -acetic
 EMI33.19
 itci'le (1-paramethoxycinnrmoyl-2-methyl-5-methoxy- ..- Inda-
 EMI33.20
 lyl) -acetic
 EMI33.21
 Fl- (2, j-ibroinocinnamoyl) -e-methyl-5-methoxy-3indoly1 7-acOtic acid -1- (3-PlienYl-3-bonzylidèno) butyroyl-2-methyl-5methoxy-3-indolyl-7acetic acid Acid (1-cinnamylidtnep:

  opionyl-2-methyl-5-methoxy-3-
 EMI33.22
 indolyl) -acetic
 EMI33.23
 Acid / fl- (j-styryl) acryloyl-2-methyl-5-methyloxy-3-indo-
 EMI33.24
 lyl¯7-acetic
 EMI33.25
 Acid - / - 1- (3-styryl) ucryloyl-2-nthyl-5-mcStnoxy-3.indolyl - butyri.ue

  <Desc / Clms Page number 34>

 
 EMI34.1
 J-'t- (3-styryl) rzaryl.oyl-2-methyl-5-ethoxy-3-indolyl acid -? -
 EMI34.2
 acetic
 EMI34.3
 (Î-phenylacetyl-2-methyl-5-methoxy-3-indolyl) malonate
 EMI34.4
 methyl (1-Phenylaoetyl-2-methyl-5-methoxy-3-indolyl) acetic acid
 EMI34.5
 1 ^ ('1 ^ phenylacetyl-2-methyl-5-methoxy-3-indolyl) acid
 EMI34.6
 butyric
 EMI34.7
 2- (I-phenylacetyl-2-methyl-5-methoxy-3-indolyl) acid
 EMI34.8
 propionic
 EMI34.9
 (Fl-phenylacetyl-2µ5-dimethyl-µ-indolyl) acetic acid (fl-phenylacetyl-5-methoxy-3-indolyl) acid

  acetic Acid ('i-phezyiaoetyl-2-methyl-5-ch2oro-3-indolyl)
 EMI34.10
 acetic
 EMI34.11
 (i-phenylacdtyl-2-n thyl-5-m <thoxy-3-indolyl) acetate
 EMI34.12
 methyl
 EMI34.13
 Banzyl (1-phenylacetyl -, .'-- methyl-5-methoxy-3-indolyl) acetamide (fl-phenylacetyl-2-methyl-5-methoxy-µ-indolyl) (1-phenylacetyl-2-rr. ;, -5-methoxy-µ-indolyl) tetrahydropyranyl acetate ('l-phc':

  nylucéty7 .- '^ m5thy1-5-methoxy - indolyl) acetate
 EMI34.14
 t-butyl
 EMI34.15
 (1-pMeny lac etyl-2-mothyl-3'-indolyl) aca tic Acid (fl-furylacetyl-2-inethyl-5-methoxy-3-indolyl) -aaéti-
 EMI34.16
 than
 EMI34.17
 Aaiùe. ± fl- (é-phôiiyl) -propionyl-2-methyl-b-métiioxy-µindolyl¯7-uc tiquo -1- (L} -methoxyphenyl) acÓtyl-2-methyl-5-mÓthpxy- 3indolyl 7-acôtique

  <Desc / Clms Page number 35>

 
 EMI35.1
 Acid, -1- (3,4-Dimethoxyphenyl) acetyl-2-methyl-5-methoxy-3-indolyl-7acetic
In addition to these compounds, it is possible to prepare in good yields, by the process of the invention, the indole derivatives which contain the following substituents -CO-A-R1 in position 1:

   
 EMI35.2
 -CO-AR m paraoyanoeinnamoyl, metacyanocinnamoyl, orthoiodohydrocinnamoyl, ortho-iodo-metanitrocinnamoyl, parachlorometanitrocinnamoyl, 2,3-dichlorocinnamoyl, paramethylcinnamoyl, 2,5-diphenyl-2-4,5-pentenoyl, 2-diphenyl-2-4,5-pentenoyl, 2-pentenoyl , 2-diphenyl-2-pentenoyl, 2-phendthyl-cinnamoyl, 2-benzyl-4-phenyl-3-butenoyl, 5,5-diphenyl-4-pentonoyl, 3,5-diphenyl-4-pentenoylo, 2,5 -diphenyl-2-pentenoyl, 2- (2-naphthyl) acryloyl, orthonitrocinnamoyl, 3-paramethoxyphenyl-crotonoyl, 2- (4-quinolyl) acryloyl, 2-benzylcinnamoylo, orthobromocinnamoyl, metabromocinnamoyl, orthochlorocinna-
 EMI35.3
 moyle, parachlorocinnamoyl, 2-ehloro-orthonitrocinnamoyl,

   2-chloro-metanitrocinnamoyl, 2-chloro-paranitrocinnamoyl, 3-chloro-metanitrocinnamoyl,
 EMI35.4
 ortho-iodo-phenylacetyl (CH2CO-), ¯ 3-paracumenyl-propionyl ((CH) 2CH -o-CH2CH2CO-), 3-ortho-anisyl-propionyl (0 CH2CH2Co-) 3-meta-anisyl-propionyl 0- CI ! 2CH2CO-) 'OCH3' OCH \ # / 3-paraanisyl-propionyl (CH -o-CH2CH2CO-) 3-methyl-3-phenylvaleryl CH3, -methyl-3-phenYlvleryl -CH2CO-) C2H5

  <Desc / Clms Page number 36>

 
 EMI36.1
 c-methyl-2-iiiryl) actyJ.pi 1 CH cHgCO- 2-paratolyl-propionyl 2-Pi'TatÔlYl-PTOPi nYl CHSÉ'IC 2-benxylpropionyl liI, CiiC0-) \ / 1TT CH3 3-orthotolyl-propionyl (Qciicxc0 - cii3 3-metWolyl-prpionyl -cli2cH2coCH3 3-paratalyl-prdpionyie çix 3 '22) 3-pa.-atolyl-propiony-Le (CH 3> --- i cil 2-lléthyi-2-phenylbut> .ryie (CH 3 2 Cil 2 Co CH3 2-neth 1-µ-phenylbutyryl \ 1 V211 5 CH3 CH,

   2-mth.y .---. Phenylbutyrßl / "\ - ¯ fî CoH3 '' cil 2 CH 2-bH-00CH CH CHICO- 2-methyl-4- (1-naphthyl) butyryl L ii. J 6n & - methyl-4- (fl-naphthyl) butyryl 2 bzz CHCHpCHCO-.



  CIiCHzHCO- 1-naphthylacetyl (i 1.4 H3 A

  <Desc / Clms Page number 37>

 
 EMI37.1
 4 - ('t-naphthyl) butyryl CH2Co- 4- (fl-naphthyi) butyryl CH2CO-) 4- (1-naphthyl) butyryl CH2CH2CH2CO-) 3- (1-naphthyl) butyryl Cil 2CH2Co-) Cil 2 CH 2 COPhenyl -chloracetyl) 2-phenyl-isobutyryl (C '\ ",' =. / <; 1 3-phenyl-isovaleryl 3-phenyl-isovaleryl o-L;

   co-) 5-phenylvaleryl CH3 CH2C0- CH3 (2-pyridyl) acetyl (o-CII2CH2CH2CH2CO-) (4-pyridyl) acetyl ± jh Efi0- -Ii "" CH) 00- (2-quinolyl) acetyl (:;) - CH2C0- (2-quinolyl) acetyl -N; -j- Cil2Gō <Y'WA CH2CO-

  <Desc / Clms Page number 38>

 
 EMI38.1
 µ- (2-quinolyl) propionyl (3- (2-quinolyl) propionyl OH2-0H2-00- 3-bromo-3-phenylpropiony] e - CHBrCH2CO-) Br 3-orthobromophdnyl-propionyl (- CH2CH2CO-) Phdnyl-bromacdtyle (0-? HCO-) Br Ozthobromophenylacdtyle (Qr CH2CO-) r Cl 3-orthochlprophdnyl-prop: onyl CH2CH2CO 3-metachlorophenyl-propionyl (ClCH2CH2Co- 3-p;

  rtchlorophdnyl-propionyl C1. / \ Cii2CH2C0ci orthoehlorophenylacetyl (Ó-cH2CO-) methach1orophény1acÓty1e (C10-- Cli2Co-)

  <Desc / Clms Page number 39>

 
 EMI39.1
 Parachlorophenylacetyl (Cl CII2CO-) 3-paratolyl-butyryl (H3C-o-CHCH2CO-) N == / 5 3-bromo-3-parabromophenyl-propionyl Br / \ CHBrCÜ2C0- 3- (2'3-diChlorOPhenYl) prOPCHiOnYl CH COphenyl-dichloroacetyl \ CC1C0Cl 2,6-dichlorophenyoetyl (QCH2CO-) Cl 2,2-diOhlOrO-4-PhenYlbut; yrYl (H2CH2CC12CO-) CH3 3- (2, 3-dichlorophenyl) butyryl HCH2CO-) Cl Cl (2, 5-xYiYi) aeety CH3 -Q-CH2CO-) CH3

  <Desc / Clms Page number 40>

 
 EMI40.1
 4-diphenylbutyryl;

   0-Cil2 CH2licō \ === / --J 3 3,3-diphnylbutyrylef / f '--ccli 2 Cō 3t4-diphenylbutyryl cil2ClicH2Co 2% 3-diphenylbutyryl 0- CII2cnCH2CO), 3-dphenylbuyryl (1 Q-yn ¯co-) CH "/" 1 4,4-diphenylbutyryl orHCH2CH2CO- 3,3-diphenylpropionylo / HCH2C0CH 3 2-m <'thyl-2- (1-aaphthyl) proplonyl OH -0-00- 2-methyl-2- (1-nephthyl) prOPionyl frS /

  <Desc / Clms Page number 41>

 
 EMI41.1
 C2H5 \ 2-ethyl-2- (1-naphthyl) -butyryl / C2H5-b-co- g "', Î I H3 2- (4-biphenylyl) propi.onyl - ± 11C0- \ = /
Many other derivatives of (1-acyl-3-indolyl) alkanoic acids can thus be obtained by synthesis.



   In the process of the invention in which the aliphatic acid derivative VIII, where R4 = COOH, n = o and p -. 1 in formula III, reacts with a 1'-phenylhydrazide II, a known (1-acyl-3-indolyl) alkanoic acid can be obtained
 EMI41.2
 follows sui i6 R2 cocii .i3 Il) -CIi .cocu -1c: l -NH2 2 m 1 - l cooii CO 1 A 1 (VIII) Cm) (II) f 3. li6 .LI (il 2 3) m - C "2000" ¯¯ 1? ± j g Cii - CiIC00ii CO, '' (VII) R1, R2, R3, R6, A and m having the meanings above.



  This is how the following compounds are obtained with good yields:

  <Desc / Clms Page number 42>

 
 EMI42.1
 (1-Phenylacetyl-2-methyl-5-methoxy-3-indolyl) acetic acid (1-cinnamoyi-2-methyl-5-ethoxy-3-indolyl) acetic acid (-cinnamoyl-2-methyl-3-indolyl) )acetic
In some cases, a (1-acyl-3-indolyl) -acetic acid of the formula is prepared:
 EMI42.2
 where R1, R6 and A have the same meanings as in the form
 EMI42.3
 mule I, from a '-phnylhydrazide II or a salt of this hydrazide and acetyl-succinic acid or 3-oxo-adipic acid.



   Here is an example of this process:
 EMI42.4
 
The following compounds are thus obtained with good yields:
 EMI42.5
 Acid (1-clnnamoyl-2-ml: thyl-5-mf) thoxy-; -indolyl) ac6tlque Acid (1-paramethoxycinnamoyl) -. 2-methyl-5-mttloxy-3-indolyl) acstiquo Acid (1-püényla. ctyl-.¯'-m thyl - $ - mhthor.y - indolyl) acc'et.ique

  <Desc / Clms Page number 43>

      
 EMI43.1
 (Fl-Cinnamoyl-2-methyl-5-thoxy-µ-indolyl) acotic acid ï (1-Cinnamoyl-2-methyl-3-indolyl) aceic acid
 EMI43.2
 1 .- / - 3- (2-pyridyl) acryloyl-7-2-methyl-5-methoxy-3-indolylt acetic acid
Further, in the process of the invention, an acid derivative (1-acyl-3-indolyl) can be obtained

  alkanolque I direc-
 EMI43.3
 mentally from a 2'-alltylidene-fl'-phenylhydraziàe IV in certain cases, by reacting this compound IV with an aliphatic acid derivative III by heating in the presence or absence of a condensing agent, with or without organic solvent.



   An organic acid such as formic acid, propionic acid, -l'acid lacti-; that or butyric acid, or a nonpolar solvent such as cyclohexane, hexane, benzene or toluene.



   A mineral acid such as hydrochloric acid or sulfuric acid, a metal halide such as zinc chloride or copper chloride, boron fluoride or a polyphosphoric acid can be used as the condensing agent,
The following compounds are thus obtained;
 EMI43.4
 (1-Phenylacetyl-2-methyl-5-methoxy - indolyl) acetic acid (1-Cinnamoyl-2-methyl-5-methoxy-3-indolyl) acetic (1-phenylacetYl-2-methyl-5-methoxy- acid ; indolYl) methyl acetate (fl-phenylaeetyl-2-methyl-5-methoxy-µ-indolyl) t-butyl aeetate
In this case, when R4 is a carboxy group in formula III, that group is removed to provide indolyl-aleanoic acid VII or 1-acyl-3-indolylaliphatic acid VII.

  <Desc / Clms Page number 44>

 
 EMI44.1
 This is how we obtain the following compounds:

   
 EMI44.2
 (Fl-phenylaaetyl-2-methyl-5-methoxy-µ-indolyl) aetic acid
(1-Cinnamoyl-2-methyl-5-methoxy-3-indolyl) acetic acid
It is also possible to prepare, in accordance with the invention,
 EMI44.3
 a derivative of (-acyl-3-indolyl) alkanoSque I from phenyl-iminohydrazide XI or from one of its salts and from an aliphatic acid derivative of formula III, in the presence or absence of an agent condensation, '' with or without solvent.



   An organic acid such as acetic acid, formic acid, propionic acid or lactic acid, a non-polar solvent such as cyclohexane, hexane, benzene, toluene or xylene, an ether such as dioxane or isopropyl ether, or other common organic solvents. A mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, a metal halide such as zinc chloride or

  <Desc / Clms Page number 45>

 copper chloride, a metal powder such as copper powder, Grignard reagent, boron fluoride, polyphosphoric acid or an ion exchange resin.



  But it is not always necessary to use a solvent or a condensing agent. This indole nucleus formation is done by heating the reaction mixture between 50 C and 200 C, and is completed within a few hours. Preferably ntro 65 C and 95 C is heated for 1 to 4 hours.



   Once the reaction is complete, the reaction mixture is allowed to cool; there is generally abundant crystallization. If no crystals form, the solvent is distilled off or water or petroleum ether is added. The crude crystals are collected by filtration, washed with water and recrystallized from a suitable solvent, in order to obtain the desired pure product.



   This implementation of the invention can be represented by the following equation
 EMI45.1
 

  <Desc / Clms Page number 46>

 
 EMI46.1
 'J' "'. 1 t' <yes. that the following compounds can be obtained; .. L k (1-c iiina # ioyl-2-ne. Tb + y1-5-me ihoxy-5-indolyl) acetic (1-ph-ny3.ao "tyl.-2-mthyl.-j-mthoxy -3-indolyl) acetate;.: Rice;, (1 - c inniàoeoyl-2-ià thyl -5-nà thoxy- µ -inl o lyl) aoeta "iide Acil (1-cinn '! Loyl-5 -thoxy-3-indolyl) acetic Acetic acid 2- (1-cinnoyl-5-methoxy-2-methyl-3-indolyl) propionic Ac ic '(1.-parfum UIt8thylcinnamoyl-.2-m & thyl- 5-! Xl1 Lhoxy -3-indolyl) acetiue Acid'3 (1-to7- (2-pyridyl) acryloyl¯,% - 2-mthyl-5-tethox, y-3 iadolylj acetic el <; il> o L 1 -. (3-.aL; rylcrylvyl) -2-.méthy.-3-inâolyl 7 acetic Acid 1-ci.nn ..- noyl-2,5-linthyl-3-indolyl) acetic 'Acidu (i-cinn:

  moyl-2-nàtfyî-5-chloro-j-indolyl) acetic Acid (1-Cinnamoyl-2-Nethyl-4-m6thoxy-3-indolyi) acetic A; ii> 3 (l-.i.nnaamoy.-2 -: ": tizyl-6-mthoxy-3-in3olyl) acetic Acid 1-c.nna =: oyl -'- m = ti.; l-5-thiom.thoxyW-inciolyl) acetic Acid (1 -cinnaraoyl-2-mthyl-3-ind'olyl) acetic Aci <to <; ;, i.-c.i.nrm :: zcyl.-2-: '.' l, rl-5-metl1oxy -.?- i: J.dolyl) acetic 0 '. l ';;'., i again, '- ":' f.1.É:. :: 'f.hlt to the invention, get a.:;. i": (L-cyl-3-ir ..olyl L,, oo ;:! .1e XII en t '; Ù3form'J.nt un' .L3: - "':':) 1J: ';;, d' .1'1" \ .III -1'1 c-3t acids.



  -J '",. O'.:;. W lNl .u'0n transforms a 1, .. ^; ylL.ue acid (-J.ol.yl) alcsjioic into free acid XIi - .. x hj "ilrogé"; .. 1j, vn in "4; '.-: ice of a" u.jtf: i ::' 1.ir.te catalyst such as pU'iilN.



  '.r¯ S, .J: 1 i) .v'.to r3pres "nt"' "..t'i f :: e:; y. # 'la C1.:t'tQ 1"> ", 1.) ..2:

  <Desc / Clms Page number 47>

 
 EMI47.1
 
If the alcohol from which ester X is derived is tertiary butyl alcohol, the ester is treated with an arylsul- acid.

  <Desc / Clms Page number 48>

 
 EMI48.1
 tonic such as toluene-parasulfonic acid to obtain
 EMI48.2
 the product sought.



  If a t-butyl ester is melted by heating
 EMI48.3
 fage, it breaks down to give indolyl-alkanoic acid
 EMI48.4
 sought XII.



  In some cases, the free acid can be obtained by treating the corresponding amide with the desired amount of nitrous acid, in an inert solvent.



  This is how we obtain the following compounds:
 EMI48.5
 (1-Cinnamoyl-2-methyl-5-methyl-3-indolyl) acetic acid (1-Phônylacetyl-L) -m (t; hyl-5-methyloxy-3-indolyl) acetiq-ae (1¯paratolylac6tyl) acid --môthyl-5-methoxy-3-indolyl) acetiqua (1-paracumenylac6tyl-2-methyl-5-methoxy-3-indolyl) -acetic acid-
 EMI48.6
 tick
 EMI48.7
 (1-pii, inylacatyl-2-methyl-5..chloro-3-indolyl) acetic acid
 EMI48.8
 (1-Phenylacetyl-2,5-dimethyl-3-indolyl) acetic acid
 EMI48.9
 (1-Penenylacetyl-2-methyl-5-thiomethoxy-3-indolyl) -acid- acid
 EMI48.10
 tick
 EMI48.11
 3- (1-Phenylacetyl-2-methyl-5-methoxy-3-indolyl) propio- acid
 EMI48.12
 fuck
 EMI48.13
 Acid? - ('- phenylacetyl-2-methyl-5-methoxy-3-indolyl) propioni-
 EMI48.14
 than
 EMI48.15
 Acid (1-metachlonophônylaeetyl-e-methyl-5-nethoxy-3-inaolyl)

  -
 EMI48.16
 acetic
 EMI48.17
 (1-Phenylacetyl-5-methoxy-3-indolyl) acetic acid (1-Phenylacetyl-2-methyl-4-methoxy-3-indolyl) acetic acid
 EMI48.18
 (1-Phenylacetyl-2-methyl-6-methoxy-3-indolyl) acetic acid
 EMI48.19
 Acid / -1- (1-naphthyl) acetyl-2-methyl-5-methoxy-3-indolyl-7-
 EMI48.20
 acetic
 EMI48.21
 1 - / - (2-furyl) acryloyl) -% - 2-methyl-5-methoxy-3-indolyl acid
 EMI48.22
 -acetic

  <Desc / Clms Page number 49>

 
 EMI49.1
 / -1- (2-thienyl) acetyl-2-methyl-5-methoxy-3-indolyl-7- acetic acid 1--2- (2-pyridyl) acryloyl¯7-2-methyl-5-methoxY- acid 3-indolyl acetic Acid -1- (2-phenylbutyryl) -2-methyl-5-methoxy-5-indolyl¯7acetic acid / -1- (2-phenylbutyryl) -2,5-dimethyl-3- indolyl-7acetic Acid / -I- (3-phenylpropionyl) -2-methyl-5-methoxy-3-indolyl) 7 acetic Acid / -1- (3-phenylpropionyl)

  -2-methyl-5-ehloro-3-indolyl¯7- 1 acetic
 EMI49.2
 Acid (1-pivaloyl-2-methyl-5-methoxy-3-inalyl) acet% pe It is also possible to prepare, according to the invention
 EMI49.3
 tion, a (1-acyl-3-indolyl) alkanoic acid XV by oxidizing a (3-indolyl) -alkanal XVI.



   Potassium permanganate, hydrogen peroxide, organic peroxides, silver oxide, selenic anhydride or cupric hydroxide can be used as oxidant; potassium permanganate or cupric hydroxide is preferable in many cases.
 EMI49.4
 



  Among the acids (1-acyl-3-indolyl) a.eanoque :. XV which can be prepared in this way are those in which the groups -A-R1, R2 and R3 are as follows: -A-R1: benzyl, styryl, cinnamyl, 2-phenylvinyl, 2- (2-thienyl) vinyl, 2- (3-pyridyl) vinyl, 2- (2-furyl) vinyl,
 EMI49.5
 paramethoxybenzyl, paramethylbonzyl, 2,2-diphenylvinyl, 2-cinnamylvinyl, (N-methyl-3-piperidyl) methyl, 2- (4-pyridyl) vinyl, and e- (5-chloro-2-thienyl) viliyl.



   R2 and R3: hydrogen, methyl, ethyl.



   R6: methoxyl, ethoxyl, isopropoxyl, methyl., Ethyl, propyl, isopropyl, t-butyl, thiomethoxyl, thioethoxyl, hydrogen.

  <Desc / Clms Page number 50>

 



   The (3-indolyl) acetaldehydes XVI of the invention can be prepared by the following reaction
 EMI50.1
   -where R1, R2, R3, R6 and '. have the meanings above, and
 EMI50.2
 where R8 represents a group; lower aikyle.



  This is how the hydrochloride of 1'-paramethoxyphenyl-phenylacôthydrazide can be reacted with the diethyl-acetal of the levulic aldehyde, hence the diethylacetal of (1-phenyl-acetyl-2-methyl-5 -methoxy-3-indolyl) ac, '! taldDhyde, and treat this diethyl-acetal with water in the presence of a small amount of acid to obtain the free aldehyde, according to the equation:

  <Desc / Clms Page number 51>

 
 EMI51.1
 
According to the invention, the (1-acyl-3-indolyl) acetic acids XV can also be prepared by oxidizing the corresponding (3indolyl) ethanols XIX. In other words, a (3-indolyl) ethanol XIX is oxidized with potassium permanganate or chromic acid to obtain a (1-acyl-3-indolyl) acetic acid XV with a good yield.



   The substituents R1, R2, R3, R6 and A of (1-acyl-3-indolyl) acetic acids XV which can be prepared by this process are as follows:

  <Desc / Clms Page number 52>

 
 EMI52.1
 --21: benzyl, styryl, cinnamyls, - {2rthietly7.jviny.e,
 EMI52.2
 
 EMI52.3
 "(3-pyridyl) vinyla, 2- (2-uranyl) vinyl, paramé5hoxy'oenzyl, par :; <3th% lbenzyl,, 2-diphbnylvinyle ,. ,. 2-cinllamyl vinyl, {-: Wtx: yl-j-piperidyl) methylo, 2- (4-pyridyl) vinyl, 2- (5chloro-2 = th.iàr, yl) -vinyl.



  . <..: e Rj i aydnolaine, methyl, '. el ;; hyl.



  0: sethoxyl, e-thoxyl, isopropoxyl, methyl, ethyl, propyl, isopropyl, t-butyl, thioffi0thoxyl, thioethoxyl, hyv.:; Za ....



  The (3-indolyl) ethanols XIX, int \ 1rr. Products of the process of the invention are prepared by the reaction
 EMI52.4
 next :
 EMI52.5
 
 EMI52.6
 where R 3, 1 i3 1? and A, have the above meanings.



  Thus, ('1-cinnamoyl-2.-methyl-5-methoxy-j-indolyl) ethanol is obtained in a high yield by the
 EMI52.7
 reaction:
 EMI52.8
 

  <Desc / Clms Page number 53>

 
 EMI53.1
      According to the invention, it is possible to prepare
 EMI53.2
 also the (1-acyl-.:,-indolyl)acetic acids XV are d6ahydrogenating the corresponding (2,3-dihydro-3-indolyl) acetic acids XXI.



   In this dehydrogenation, a nonpolar solvent such as benzene, toluene or xylene, or other organic solvents such as acetone, acetic acid, chloroform, ethanol or methanol can be employed.
 EMI53.3
 



  As a dehydrogenating agent, op can employ chloranil, sodium anhydride, halogens or other oxidants.



  According to this process, fuc is obtained. Are the following compounds Acid (i-Cinramoyl-2-mettiyl-5-methoxy-j-indolyl) iAceiic Acid (-parachlorocinnamoyl-2-methyl-5-m0thoxy-3-indolyl) -ae6tic Acid ± 1 - (j -cinnamylacryloyl) -2-methyl-5-methoxy-5indolyl) ¯7-acôtique (l-parac! ethoxyph6nylacôtyl '-' 2-methyl-5-methoxy-3-indolyl) -acetic acid (fl-paratolylacôtyl-2- methyl -) - methoxy-5-indolyl) acetic Acids are obtained '1.-acy3.-2,3.-diiydro -; .. intiolyl) alkanoic XXI with high yieldeiaônta by making

  <Desc / Clms Page number 54>

 reacting a (2,3-dihydro-3-indolyl) alkanoic acid with an acid chloride in the presence of a. hydrochloric acid fixative.



   According to the invention, it is also possible to prepare the derivatives of (1-acyl-3-indolyl) acetic acids XXII by dehydrating a derivative of (3-hydroxy-2,3-dihydro-3-indolyl) acetic acid XXIII and optionally hydrolyzing the ester group.



   The reaction takes place between 70 C and 200 C. However, if the reaction does not take place easily, the compound XXIII can be heated to reflux with a solvent such as benzene, toluene or xylene, or it can be heated in the presence of a suitable desiccant such as anhydrous sodium sulfate: under these conditions the dehydration reaction has taken place.



   When treating a derivative of (1-acyl-3-indolyl) acetic acid XXII, in which R5 is an alkyl group, for example a t-butyl group, in the presence of an arenesulfonic acid, it turns into the free acid without the amide group being hy @@@ lysed,
We prepare 'deprived of acids (3-hydroxy-2,3dihydro-3-indolyl) acetic XXIII by heating with stirring a solution of alkyl haloacetate and indolo derivative in a nonpolar organic solvent * is presented. zinc powder, and if necessary in * the presence of a small:

     fragment of iodine. Here is an example of this reaction:

  <Desc / Clms Page number 55>

 
 EMI55.1
        This is how the following compounds are prepared
 EMI55.2
 (Fl-phenylacetyl-2-methyl-5-methoxy-5-indolyl) acetic acid
(1-Phenylacetyl-2-methyl-5-chloro-3-indolyl) acetic acid
 EMI55.3
 -1- (3-Cinnamylacryloyl) -2-methyl-5-methoxy-3-indQlyl) ¯7-acetic acid ('I-parachlorocinnamoyl-2-methyl-5-methoxy-3-indolyl) acetic acid (' I -paratolylacetyl-2-methyl-5-methoxy-3-indolyl) acetic ('i-paramethoxycinnamoyl-2-methyl-5-metthoxy-3-indolyl) acetic acid (1-phenylaceous-tyl-2-methyl-5- ethoxy-3-indolyl) acetic -1- (1-naphthylacetyl) -2-methyl-5-methoxy-3-indolyl¯7-acetic acid
According to the invention,

   crude (1-acyl-3-indolyl) acetic acids can also be prepared by
 EMI55.4
 heating Y- (N-acylanilino) -3-oxoalkanoic acid XXIV in the presence of a suitable catalyst or dehydrator. The crude product thus obtained can be purified by recrystallization from an appropriate organic solvent, or failing this by column chromatography.

  <Desc / Clms Page number 56>

 Acids are easily obtained by this process.
 EMI56.1
 (3-indolyl) -ae6tiques for which Ruz, R21 a3, a6 and A have the following meanings in formula XV: -A-Il 1: benzyl, styryl, cinnam, yée, 2- (2-thienyl) vinylo,? - (3-PYridyl) vin.yla, 2- (2-furannyl) vinyl, 2-cinnamylvinyl, (ir; tly1-3-pipcridyl) mttxyle ,. - (+ - pyridyl) vinyl, 2,2-diphenyl-vinyl, 2. (3-.chloro-2-thienyl) vinyl.

   R2 and R3: hydrogen, methyl, ethyl.
 EMI56.2
 R: methoxyl, 6thoxyl, isopropoxyl, methyl, ethyl, propyl, isopropyl, t-butyl, thiomethoxyl, thioethoxyl, hydrogen.
 EMI56.3
 D- (N-acylanilino) -3-oxoalkanoic acid XXIV is generally prepared, an intermediate product of the process of the invention;

  , ion, by the following reaction!
 EMI56.4
 
 EMI56.5
 where R 21 it, R, R6 and `` A have the meanings above, .this is how the reaction of paranesidin with cinnamoyl chloride gives cinnamo-para-anisidide, which is reacted with t-butyl 4-bronio-3-oxovalerate to obtain 4- (N-paramethoxyphenyl-phenylacetamido) -3-oxovale-

  <Desc / Clms Page number 57>

 t-butyl spleen, which is hydrolyzed to obtain 4- (N-
 EMI57.1
 paramÓthoxyphenyl-phenylacetamido) -3-oxovaleric. oily substance.



   In accordance with the invention, it is also possible to prepare (1-acyl-3-indolyl) acetic acids IX from a 4- (N-phenyl-acylamino) levulic acid XXIV, in the presence of an acid, mineral, in a suitable solvent.



   The reaction temperature can vary from 40 C to 120 C; best results are obtained between 60 C and 90 C.



   After the reaction is complete, the reaction mixture is neutralized, concentrated and extracted with a suitable organic solvent, the organic layer is dried, and evaporated to obtain the crude crystalline compound. Recrystallization from ether, acetone or a mixture of water and. of acetone gives the pure product.
 EMI57.2
 



  Among the novel (3-indolyl) alkanoic acid derivatives of the invention are useful compounds, which possess not only excellent anti-inflammatory action, but also extremely low toxicity. even when more than 1000 mg / kg of these compounds are administered orally to rats or mice, they show almost no symptoms of intoxication, and no blood is found in their feces.

   Nevertheless, the activity of these compounds is much greater than that of
 EMI57.3
 1,2-dipheryl-E-buty: c-, 5-pyra2olidïnedione (phenylbutazone) or oxyphenylbutazone. The "therapeutic ratios" of the compounds of the invention are therefore much higher than those of any other drug. These compounds therefore present. very great practical interest.



   The "therapeutic ratios" of several compounds of

  <Desc / Clms Page number 58>

 invention, (1-parachlorobenzoyl-2-methyl-5-
 EMI58.1
 mthaxy - indolyl) actiqu, e- (2ndomethacin) and 1,2diphenyl-3,5-dioxo-4-butylpyrazolone (Pherylbutazone) are shown in the table, which follows

  <Desc / Clms Page number 59>

   Board
 EMI59.1
 
 <tb> Dose <SEP> inhibitory <SEP> to <SEP> Dose <SEP> deadly <SEP> Report <SEP> therapeutic
 <tb> 50% <SEP> of <SEP> edema <SEP> of <SEP> to <SEP> 50 <SEP>% <SEP> for <SEP> on <SEP> (report <SEP> between <SEP> the <SEP> dose
 <tb>
 
 EMI59.2
 rat carrahenin, lethal at 50 <,;

  > and the
 EMI59.3
 
 <tb> the <SEP> paw <SEP> posterior Oral <SEP> <SEP> (mg / kg) <SEP> dose <SEP> inhibitory <SEP> to <SEP> 50%
 <tb> from <SEP> rat, <SEP> by <SEP> channel <SEP> ora- <SEP> of <SEP> edema <SEP> of <SEP> the
 <tb> the <SEP> (mg / kg) <SEP> carrageenan)
 <tb>
 
 EMI59.4
 Acid (1-Parachlorobenzoyl- --'-------- "" "- ¯-¯ 2-ethyl-5-methoxY-3-indolyl) - 7 5 2 0
 EMI59.5
 
 <tb> acetic <SEP> 7.5 <SEP> 15 <SEP> 2.0
 <tb> (Indomethacin)
 <tb>
 
 EMI59.6
 1,2-dipl: 1.enyl-3,;> - dioxo-4- - - r
 EMI59.7
 
 <tb> butylpyrazolidine <SEP> 320 <SEP> ca <SEP> 600 <SEP> ca <SEP> 1.9
 <tb> (Phenylbutazone) <SEP> ca <SEP> 1.9
 <tb>
 
 EMI59.8
 Acid / - 'I- (2-furyl-acryloyl) -2-met-Tiyl-¯5-methoxy-3-indoly7,25> 11000 4010 -2-metF.iYl-5-methOXy-3-ind01Y: J) ;

  1> 1.000.> 40.0 -acetic Acid / - 't- (3-phenyl-propionyl) ¯2-methyl-5-methyl-3-250 1,500'.,> 6i 0.
 EMI59.9
 
 <tb> indolyl¯7-acetic
 <tb> 1-cinnamoyl-2-methyl-5-
 <tb>
 
 EMI59.10
 methyl-3-indolyl) -aceta- 65,500> 2j, fl
 EMI59.11
 
 <tb> ted'ethyl
 <tb>
 

  <Desc / Clms Page number 60>

 
 EMI60.1
 ¯ ¯ = ¯ ¯¯ = ¯ - :: ;; :::; "= Z ::::: ==: &laa.r40-iIi; ..



  Dose iniô.4'lc Do :::: e lethal Therapeutic ratio 50; 0 of 1 t ocdeffie from to 50 for the (ratio between the dose la carra, tenzne rat, by the lethal route at 50; & and the - ' "'- oral hind paw (/ kg) 50% inhibitory dose
 EMI60.2
 rat, through edema of the
 EMI60.3
 ¯¯¯¯¯¯¯¯¯ oral (/ rj carrashcnine) ¯¯¯¯¯ ¯.¯-s = a - =: cc¯¯c = rc = .¯¯¯ ... ¯¯¯¯¯. .¯x¯¯ .... ¯.xarā¯ === n == x = 1 = # x ===> ===== m => x Acid (1-phenylacetyl-2methyl-5-methoxy -3-indolyl) 210> 1,500 71 acetic uu Acid (l-cinnamoyl-2-methyl- ÉÀ ± ÎbilµµÎl / Î1] ÉIÉaIÎiÉÎ 12> a, soo.> Q25 than 1500 Acid ./-1-(2-thienyl -acryloyl fl8> a, 2àO 6?, O -2-metEyl-5-! Dethoxy-3-indo- '18> 1 pOO> 67.0 lyl¯7-ac.etic ---', <-iju "67.0 Acid 2- (1-Cinnanoyl-2-methyl-5-metboxy-3-indolyl) 20:

  > 1500>? 5, O propionic --- ', uu 75.0 Acid /' '1- (2-methyl-cinnamoyl -2-metEyl-5-methoxy-3-indolyl7 ca 40> 1500' 3, 5 -acetic, - "'u -5

  <Desc / Clms Page number 61>

 The inventors have prepared a large number of other
 EMI61.1
 Very derived from (1-aoyl-3-indolyl) alkanoic acids, and have measured their pharmaceutical effects in animal tests.



   The inventors have found that a large number of (1-acyl-3-indolyl) alkanoic acid derivatives, prepared in accordance with the present invention, are greater than
 EMI61.2
 (1-parachloroh3nzoyl-2-methyl-5-methoxy-3-indolyl) acetic acid (indomethacin) and 1, --diphenl-4-buty-; , - pyrazolidinedione (phenylbutazone) by their therapeutic ratios, and are of great practical interest.



   These compounds were also found to have fairly high analgesic activities by the Haffnor method, and fairly high antipyretic activities by the pyrogen test.



   The examples which follow are given by way of illustration and without limitation.



    Example 1
13.8 g of phenylacetyl chicory are poured dropwise into a solution of 13.1 g of acetaldehyde paramethoxyphenylhydrazone in 50 cm3 of pyridine, with cooling in ice. The reaction mixture was then stirred overnight while cooling in ice, and poured into 250 cm3 of ice water. A large quantity of crystals is obtained. These crystals are collected by filtration, washed with water and dried, from which
 EMI61.3
 z0 g of 2'-ethylidcne-1'-paramethoxyphenyl-phenylacethydrazide, F - 98 -101bC.

   The following hydrazides are also obtained:

  <Desc / Clms Page number 62>

 Example 2
 EMI62.1
 2-ethylidane-1'-paramethoxyphenyl. 3-.phenylpropionhydrazide, F. 134-135 "C.



  Example 2 '-ethylidene-'l'-paramethoxyphenyl-parachlorophenylacethydrazide, F 93 -96 C. Example 4
 EMI62.2
 21-ethylidene-11-paramethoxyphériyl-4-param6thoxyphenylbutyrhydrazide, M = 96 -98 C. Example 5
 EMI62.3
 â'-ethylidene-11-paramethoxyphenyl-phenylchloracethydrazide, F 10'7 -'l'I 0 0.



  Example 6 2 '-e thj / lidene-fl' -panamethoxypAenyl- (fl -naphthyl) acethydrazide, F fl00 -fl0j C., Example? 21-ethylidene-11-pàramethoxyphenyl-2,4-dim6thoxyphenylacethydrazide, Mp = 88 -90 C. Example 8.
 EMI62.4
 4 '-: tylidéno-'l'-paramethoxyrinyl-ainriamhydrazide F - fl66 - 170 C.



  Example
 EMI62.5
 2 '-é trhy.idéno.-1' -pararné thophenyl-a-methylinnamhydrazide, '..' the i4 -'t1 C, F, xc.mple 10 '-éGhyliddne-1' -. Paramethoxyphenyl-parachloxocinnamhydrazid4,
F = 168 -174 C. Example 11
 EMI62.6
 2 '-r hy., Dene .-' .paramethoxyphenyl-paruméhoxβCinnamhyùraxido ¯ '1'f2 -1G) C.!

  <Desc / Clms Page number 63>

      Example 12
 EMI63.1
 2'-ethylidene-fl'-ãramé Ethoxyphenyl-paratolylacrylhydraziàe, F = 169 -172 C.



  Example 13
 EMI63.2
 2 '-ethylidene-fl'-paramethoxyphenyl-xetanitrocinnamhydrazide, F ". 170 -180 0 .. Example 14 2' -ethylidene-fl'-paiamethoxyphéiyl-3- (2-funyl) acrylhydrazide, F 143 -146 C.



  Example 15
 EMI63.3
 20 µg of 2'-ethylidene-1'-para-i methoxyphenyl-cinnaiùhydnazidv is suspended in 100 µm3 of ethanol, and the suspension is stirred while cooling in ice. We do
 EMI63.4
 absorb 30 g of hydrochloric gas by the reaction mixture over one hour, while cooling in ice.

   The crystals formed are filtered off, washed with 100 cm3 of ether and dried, from which
 EMI63.5
 18.5 g of 1'-paramethoxyphenyl-cinnanihydrazide hydrochloride, Mp = 184 C (with decomposition), The following compounds are likewise obtained: Example 16
 EMI63.6
 1'-Paramethoxyphenyl-metanitrocinnamhydrazide hydrochloride, F =. 165 -170 C (with decomposition). Example 17
 EMI63.7
 1'-Paratolyl-cinnamhydrazide hydrochloride, F - 173 -175 C (with decomposition) Example 18
 EMI63.8
 1'-Paramethoxyphenyl-a-henylcinnamhydrazide hydrochloride, Mp = 145 -160 C (with decomposition) Example 19
 EMI63.9
 Fl'-Paramethoxyphenyl-3-paratolylacnylhydrazide hydrochloride M = 187 C (with decomposition).

   

  <Desc / Clms Page number 64>

   Example 20
 EMI64.1
 Para: net, oacyphenl-a-methyloinnamhydrazide hydrochloride,; Mp = 174 C (with decomposition). Example 21
 EMI64.2
 1 '-paranethoxyphenyl.-parachlorocinnamhydrazide hydrochloride F = 179 -182 C (with decomposition) Example 22
 EMI64.3
 1'-Paramethoxyphenylparamethoxycinnamhydrazide hydrochloride, Mp = 178 C (with decomposition) Example 23
 EMI64.4
 11-Paramethox-ypheriyl-a-methyl-metanitrocinnamhydrazide hydrochloride, Fi fl6E -fl? F1 Q (with decomposition) Sxonpie 24 -pareth4xyphéry.-pheny.aaétb hydrochloride;

  ydxazide Fi 'i ..' 1 C (with decomposition) pxempl 22 1'-paran! ethoxyphenyl '- 3-phenylpropionhydrazide hydrochloride M = 179 C (with decomposition) Example 26
 EMI64.5
 Hydrochloride of. 1'-paI'amethoxyphenyl, -parachlorophenylacéthydra ... zide.F - 202 -203 C (with decomposition) Example 27
 EMI64.6
 1'-Paramethoxyphenyl-4-paramethoxyphenyl-butyrhydrazide hydrochloride, Mp = 166 C (with decomposition) Example 28
 EMI64.7
 1'-Paramethoxyphenyl-phenylch.oroacethydrazide hydrochloride, M = = 130 C (with decomposition) Example 29
 EMI64.8
 1 '-. Paramethoxyphenyl-diphenylacethydrazide hydrochloride F = 144 -146 C (with decomposition)

   

  <Desc / Clms Page number 65>

 Example 30
 EMI65.1
 1'-Paramethoxypnenyl-paranitrophenylacethydrazide hydrochloride, Mp = 204 -205 C (with decomposition) Example 31.



  1'-Paramethoxyphenyl- (1-naphthyl) acethydrazide hydrochloride, Mp = 173 C (with decomposition) Example 32
 EMI65.2
 1'-Paratolyl-phenylacethydrazide hydrochloride, - 151 -! 152 C (with decomposition)! Example 33
 EMI65.3
 1'-Phenyl-phenylacethydrazide hydrochloride, F. 145 -149 C (with decomposition) Example 34
 EMI65.4
 1'-Parachlorophsnyl-phenylacethydrazide hydrochloride, Mp = 167 C (with decomposition) Example 35
 EMI65.5
 1'-Paramethoxyphenyl-3,4-dimethoxyphenyl-acethydrazide hydrochloride, F = = 1G5 C (with decomposition) Example 36
 EMI65.6
 58 g of 2'-ethylidene-1'-paramethoxy-phenyl-3- (2-furyl) acrylhydrazide are suspended in 400 cm 3 of ethanol, and this suspension is stirred while cooling in ice.

   absorbs 30 g of hydrochloric gas by the reaction mixture in one hour. The crystals formed are filtered off, washed with ether and dried, resulting in 35.0 g of paramethoxyphenyl-3- (2-furyl) acrylhydrazide hydrochloride, Mp = 166 C (with decomposition).



   The hydrochloride of 1'-parametho xyphenyl-3- (2-thienyl) acrylhydrazide is likewise obtained.

  <Desc / Clms Page number 66>

 



  . Example 37
7.7 g of phenylacetyl chloride are poured dropwise into a solution of 6.1 g of paratolylhydrazine and 5 g of triethylamine in 150 cm 3 of ice-cold toluene. The temperature of the reaction mixture is then slowly brought to 70 -75 C, and the heating is continued at
70 -75 C for 20 minutes. The reaction mixture is allowed to cool, the crystals formed are collected by filtration and the filtrate is concentrated until an oil forms, which is recrystallized from a mixture of ethanol and water, from which
 EMI66.1
 1'-paratolyl-phenylacethydrazide, F-86 -87 0. Treated with an ethanolic solution of hydrochloric acid to give 1'-paratolyl-phenylacethydrazide hydrochloride, F 151 -152 C (with decomposition).



    Example 38
6.0 g of cinnamoyl chloride is added dropwise to a solution of 8.7 g of para-hydrochloride.
 EMI66.2
 methoxyph6nylhydrazine- and 10.1 g of triethylamine in 200 cm3 of toluene, cooled to between -5 C and 0 C, the reaction mixture is stirred at 20 -25 C for one hour. The crystals formed are filtered off and dry hydrochloric gas is bubbled through the filtrate.



   Abundant crystals of hydrochloride are obtained
 EMI66.3
 of ï- (2 ', +' - cinnamoyl) -I- (p-mtYuyphenyl) hYdrazine, which. collected by filtration and washed with 20 cm3 of ether and
 EMI66.4
 dries, hence the hydrochloride. of N1- (2 ', 4'-cinnamoyl) -N- (p- methoxyphenyl) hydrazine, F a flà3 -fl8µ C.



   The following compounds are prepared in the same way:.



    Example 39
 EMI66.5
 11-Paramethoxyphenyl-pheny'lacethydrazide hydrochloride, Mp = 166 -167 C (with decomposition)

  <Desc / Clms Page number 67>

 Example 40 1'-Paramethoxyphenyl-cinnamhydrazide hydrochloride, Mp = 179 C (with decomposition) Example 41
 EMI67.1
 1'-Paramethoxyph.enyl-paramethoxycinnamhydrazide hydrochloride, Mp = 178 C - (with decomposition) Example 42
 EMI67.2
 1'-Paramethoxyphenyl-parach Zorophenylacethy-drazide hydrochloride, Mp = 202 C (with decomposition) Example 43 1'-Paramethoxyphenyl-3- (2-furyl) acrylhydrazide hydrochloride, Mp = 166 C (with decomposition) Example 44
 EMI67.3
 1'-Paramethoxyphenyl-phenylchloracethydrazido hydrochloride, Mp = 123 C (with decomposition)

   Example 45 1'-Paramethoxyphenyl-diphenylacethydrazide hydrochloride.



    F == 140 -145 C (with decomposition) Example 46
 EMI67.4
 1'-ParamethoxyphenyZ-2-phenylbutyrhydrazide hydrochloride F = 159 C (with decomposition) Example 47
 EMI67.5
 R-Paramethoxyphenyl-3-phenylpropionhydrazide hydrochloride, M = 179 0 (with decomposition) Example 48
 EMI67.6
 1'-Metamethoxyphenyl-cin.namhydrazide hydrochloride, Mp = 168 -169 C (with decomposition) Example 49
Was heated at 80 -85 0 for three hours, with vigorous stirring, a mixture of 10 g of hydrochloride of

  <Desc / Clms Page number 68>

 
 EMI68.1
 11-param6thoxy-phayl-phenylacetimioh ,, vdrazide, 5% of levulic acid and 30 cm3 of acetic acid. The mixture is allowed to cool and 50 cm3 of water are added.

   The twisted crystals are collected by filtration, washed with 50 cm3 of water and recrystallized from a mixture of acetone and water, -d'oÙ acid
 EMI68.2
 (1..phenylac: tyl - 2-mthy.-5-mcthoxy-5-indolyl) acetal, M = 138 -139 C.



   The following compounds are obtained in the same way: -. Example 50
 EMI68.3
 Acid (1-CinnamoyZ-2.-mQhy, -5-methoxy-3-indoly? Acct3.que, 1 μm fl64 -fl65 C.,, Example 51 Acid - (1-c3.nnamoyl -. Mthyl-5 -mthox3-3..indolyl) buty, rique, M = 125 -126 C. Example 52
 EMI68.4
 3- (1-Cinnamoyl-2-methyl-5-methoxY-3-indolyl) propionic acid
F = 189 -190 C. Example 53
 EMI68.5
 1- '' 3- (2-furyl) aoryloyl7-2-methyl-5-methoxy-3-indolyl - acetic acid M = 163 -164 C. Example 54
 EMI68.6
 (Fl-paramethoxycinnamoyl-2-methyl-5-methoxy-3-indolyl) acetic acid, Mp = 193 -195 C.



  Example 55
 EMI68.7
 Acetic acid ('1-parrchloropb.nylaoétyl - 2-mthyl-5-methoxy-3-indolyl j acetic F = 180 -182 C. Example 56'
 EMI68.8
 (fl-cinnamoyl-e-ethyl-5-methoxy-e-indolyl) ethyl acetate F = 162 -163 C.

  <Desc / Clms Page number 69>

 Example 57
 EMI69.1
 /-1-(2.phenyl)butyryl-2-methyl-5-methoxy-3-inucï :,: .- ?. acetic F = 123 -125 C. Example 58
 EMI69.2
 / -1- (3,4-Dimethoxyphenyl) -2-methyl-5-methoxy-3-indolyl-- acetic acid F = 169 -170 C. Example 59
 EMI69.3
 (Fl-phenylchloroac4tyl-2-methyl-5-methoxy-µ-indolyl) - acetic acid M = 165 -166 C.



  Example 60
20 g of 1'-Paramethoxyphenyl-phenylacethydrazide hydrochloride is added to 30 g of levulic acid. The mixture was heated at 76 ° C for three hours, then left at room temperature overnight. The crystals formed are collected by filtration, washed with water and dried. The crude product is recrystallized in a mixture
 EMI69.4
 acetone and water, from which 9.7 g of pure (1-phenylaoetyl-2-- methyl-5-methoxy-3-inalyl) -acetic acid, Mp = 141 5-143 C.



  Microanalysis: Calculated: C, 71.20%; H, 5.68%; N, 4.15% Found: C, 71.54%; H, 5.84%; N, 3.96%
Similarly, with a similar yield, acidic acid is prepared.
 EMI69.5
 of (1-phenylacetyl-2-methyl-µ-methoxy-µ-indolyl) acetic from a mixture of 10 g of levulic acid and 25 cm3 of acetic acid instead of 30 g of levulic acid.



  Example G1
A mixture of 10 g of 1'-paramethoxy hydrochloride is heated at 75 -83 C for 150 minutes with stirring.
 EMI69.6
 phenyl-diphenylacethydrazide and 20 g of 16vulic acid. Once the reaction is complete, the mixture is poured into water,

  <Desc / Clms Page number 70>

   The crystals formed are collected by filtration, washed with water and recrystallized from a mixture of acetone and water,
 EMI70.1
 from where gray crystals ciai, r 'of acid (fl, diphenyiacétyi-2-méthyi 5-muthoxy-3-indolyl) ao.etic, F = 150 "-15100.- Microanalysis:. Calculated: C, 75, 53 9 bed 5.61 gb; Ni 3.39% Found: C, 74.92%; H, '5.56%;

   N, 3.69% Example 62
The acid (1-phenylchlo-
 EMI70.2
 racetyl -'-'- m, thyl-5-methoxy-3-indolyl5acetic, F = 165 -166 C,. from r-paramethoxyphenyl-phenylchloracethydrazide hydrochloride and levulic acid, Microanalysis:
 EMI70.3
 Calculated 0.64.18%; I, 4 t 88 i; N, 3, ?? 51; cl, 9.54 po Found: s C, 53.70%; H, 4.89%; ; Ni 3.86%; Cl, 9.77% Example 63
The acid [1- (2-phe-
 EMI70.4
 nl) butyryl-2-methyl-5-inethoxy-3-indolyl-7ac6tique, F = 123 5-125 C, From hydrochloride of 1'-paramethoxyphenyl-2pli6nylbutyrllydrazide and d <levuliquo acid.

   Micronanlse:
 EMI70.5
 Calculated C, 72.33 1-1, 6.30%; Nui 3.84% Found :: C, 72.51%; H, 6.38%; N, 3.94 Example 64
The acid [1- (1-naph-
 EMI70.6
 tyl) acetyl - m4thyl-5-mcthox3-3-indolyl-? acetic, Bzz x fl6µ µ- 16605 C, from 'î'-paramathoxyph6nyl- (1naphthyl) ao6bhydrazide hydrochloride and levulic acid, Microanalysis: Calculated: C, 7'k, 39 S; H ', 5, LP2yb j -, Ni 3.62 zoo Found:: C,? LÙ, LP3 bd; -'lit 5.54%; N, 31? 0 io

  <Desc / Clms Page number 71>

 Example 65
Heated to 80 - 83 0 for 6.30 hours, with stirring,
 EMI71.1
 a solution of 10 g of hydrochloride of '1'-paramethoxyphenyl-diphenylacethydrazide and 20 g of levulic acid in 20 cm3 of ethanol.

   Once the reaction is complete, the mixture is allowed to cool and poured into water, resulting in a homogeneous-dark blue solution, which is extracted with ether. The ethereal layer is dried over anhydrous sodium sulfate and evaporated to give light yellow crystals. Recrystallization from a mixture of ether and alcohol gives pale yellow crystals
 EMI71.2
 ethyl (fl-diphenyiacetyl-2-methy? -5-niethoxy-3-indolyl) -acetate, Mp = 121 -122 C.



    Microanalysis: Calculated: C, 76.19%; H, 6.12%; N, 3.17% Found: 0.75.59%; H, 6.21%; N, 3.13% Example 66
The acid (1-para-
 EMI71.3
 chlorophenyl-acetyl-2-meth> .1-5-methoxy-3-indolyl) acetate, Mp = 178 C, from 10 g of 1'-paramethoxy-phenyl-parachlorophenylacethydrazide hydrochloride and 30 g of levulic acid.



    Microanalysis: Calculated: C, 64.80%; H, 4.89%; N, 3.77% Found. C, 64.45%; H, 4.96%; N, 3.86% Example 67
5 g of 1'-paramethoxy-phenyl-paranitrophenylacethydrazide hydrochloride and 10 g of levulic acid are dissolved in 30 cm3 of acetic acid. The mixture is heated at 90-95 ° C. for two hours with stirring. The mixture is then poured into 150 cm3 of water, the crystals formed are collected. by filtration, washed with water and recrystallized from

  <Desc / Clms Page number 72>

 
 EMI72.1
 dioxane, hence - (1-pàranitrophenylacetyl-2-methyl-5methoxY-3-indoly) -aetic acid, Mp = 207 C.



  .,; icro: n..va; Calculated: 1st, 62.82%; H, 4.75% N, 7.35% Found: s C, 63.11% H, 4.,? 7% d 1f. 7.26% Example 68
As in Example 61, the acid [1- (4-
 EMI72.2
 by a: uèthoxyphény, hu tyry3.-mé'hyl-mé'hoxy-3-.3.ndolyl-7acé ".q a, '= 16; oC, from the sulfate of 1'paramethoxyphenyl- <r - ;; D.r; :: ú; hoxyphenyl ... butyrhyd.1'a.z.ida and levulic acid, Example 69
The acid [1- (3,4-
 EMI72.3
 dithoxyphenyl) -acÓtyl-2-methyl-5-m4thoY-3-indolyl¯7acétiqàc, P '6 -1'7 (3 G, from hydrochloride of 1' .. paraméhoXTi) hônyl-3, L-dimÓthoxyphenyl-acethydrazj , and levulic acid.



  Microanalysis:
 EMI72.4
 Calculated: i 4, 66.4.9% '; 11, 5.8j) 1; N, 3.55 Found: C, vt 6.46%; H, 5.93% -! N, 3441 Example 70
We. in the same way prepares the acid [1- (3-phe-
 EMI72.5
 zylpropionyl) - ethyl-5-methoxy-3-indolyl-acetiquo,? , 1G3 -1G C, from fl'-paramethoxyphenyl-3-phenylpropionhydrazide hydrochloride and levulic acid.



    Microanalysis: Calculated: C, 66.49%; H, 5.83%; N, 3.55% Found: C, 66.46%; H, 5.93%; N, 3, 41% Example 70
The acid [1- (3-phenyl-
 EMI72.6
 propionyl) -2-methyl5-methoxy - indolyl acetig, ue, F g flô3 -

  <Desc / Clms Page number 73>

      
 EMI73.1
 '164 C, from 1'-Paramethoxyphenyl-3-phenylpropionhydrazide hydrochloride and levulic acid.

   Microanalysis:
 EMI73.2
 Calculated: C, 7-1.8%; H, 6.02%; king ', 3.98% Found: C, 71.85%; H,, 6.0? in; N, 4.08% Example 7 1
30 g of 1'-Paramethoxy-phenyl-cinnamhydrazide hydrochloride is added to 50 g of (levulic acid, and the mixture is heated.
 EMI73.3
 start it at 75 C for gentle hours with stirring. The reaction mixture is then poured into 200 cm3 of water with vigorous stirring, the crystals formed are collected by filtration;
 EMI73.4
 ez we scohe them, hence. 34 g of crude (fl-einnamoyl-2-methyl-5-rrlethoxy-3-indolyl) acetic acid, F 58 ... '160 C, Two recris! Tallizations in acetone raise the melting point to 164 -165 C.



  Example 72
The acid [1- (2-para-
 EMI73.5
 to ly1 j acryloyl-2 - m thy.-5.-mihaxy-3-indolyl-% acbiquc,? at fl95 C, reacting the hydrochloride of 11-pv.ra [. 6 ... 1.1ox, y-phenyl-3-paratolylacrylhydrazido on levulic acid. Example 73
The acid (1-parachlo-
 EMI73.6
 rocinr.u, ^ oy1-t-mlthyl.5-mthoxy - 3.ndolyl) acGt.qup, t20 - 22'i G, by reacting 1'-paramóthoxy-phcnyl-parachlorocinnamhydrazide hydrochloride with levulic acid .

   Microanalysis:
 EMI73.7
 Calculated: C, i, '1%; ! i, 4.69%; g 1.3a, 65a; Ci, 9.26% Found: C, 6.46 ± H 4.6lt%; g X, 3.56% Cl, 8.93% Example 74 i
The acid [1- (2-methyl-

  <Desc / Clms Page number 74>

 
 EMI74.1
 cinnamoyl) -2-methyl-5-methoxy-j-indolyl¯7a'cetic, Mp = 153 5 - 15. 5, by reacting. du'fl'-paTamethoxyphenyl-2-aethylcinna! nhydra2 hydrochloride <ide on levulic acid.



  Example'75
20 g of 1'-paramethoxy- hydrochloride is dissolved.
 EMI74.2
 phenyl-oinnamhydrazide had 12 g of 5-oxohexanorque acid in 30 cm3 of acetic acid, and the mixture was stirred at 75 C for two hours. Once the reaction is complete, the reaction mixture is allowed to cool, poured into 150 cm3 of water, the crystals formed are collected by filtration, washed with water and dried, from which 18 g of crystals of '3- (1-
 EMI74.3
 cinnamoyl-2-rnethyl-5-methoxy-3-indolyl) propionic crude, Fi 18 -1r ", The crude product is rer-rista! 14ze'e in a mixture of acetone and water, from where 9, 3 g of pure product, Mp = 189 -190 C.



  Microanalysis: Calculated: C, 72.71; H, 5.83%; N, 3.58%
 EMI74.4
 Found: in, c "11.56 H, 5.96%; N, 3.43% L3 ± f: t: E? We prepare 4- (1" cinna- : no; l -.- twhy7 .-- mhoxy-¯indoly.) bu; rri, uo '= 12 -1G Q, by reacting 1'-paramethoxyphenylcin hydrochloride nam: yirtx3, on 6- acid oxoheptanoic, ...; icroa: r.Yse: calcd: C, 73.19% H., 14%; Ni 51% Found: e, 723%; i t, 6.14%; N, 5, éfl $ S Example 77 Crystals are obtained in the same way;
 EMI74.5
 in needle of acid. ('i m. & tanitroe.nnamayl: -2-cthy1 - mehoxy-µ-indoiy1) acetic, P m 203 04 0; by making the

  <Desc / Clms Page number 75>

 
 EMI75.1
 1'-Paramethoxyphenyl-metanitrocinnamhydrazide hydrochloride on levulic acid.



  Microanalysis: Calculated: C, 63.94%; H, 4.60%; N, 7.10%
 EMI75.2
 Found: 1 C, 63.98%; H, 4.66%; NOT,'. %, 0I% Example 78
1'-Paramethoxy- hydrochloride is added 5 g.
 EMI75.3
 phenyl-3- (2-furyl) acrylhydrazid.é to 15 g of levulic acid, and the mixture is heated with stirring at 75-80 C for two hours. The mixture is allowed to cool and poured into ice water. The brown crystals formed were collected by filtration, and washed thoroughly with water. Mix the crystals and the washing water and add ether, stir and separate the ether layer. We repeat this operation several times. The ethereal layers are combined, dried anhydrous sodium sulphate and evaporated.

   The oily residue is recrystallized twice from methanol, from which 3 g of crystalline.
 EMI75.4
 yellow levels of t1-i-3- (2-fUrYl) aCrY10Y1¯7-2-methYl-5-methoxy-3-indolyl) acetic acid, F =. 163 5-165 C.



  Microanalysis: Calculated: C, 67.26%; H, 5.01%; N, 4.13% Found: C, 67.26%; H, 5.13%; N, 3.94% Example 79
10 g of 1'-paramethoxyphenyl-cinnamhydrazide hydrochloride and 20 g of 2-methyl-levulic acid are dissolved in 10 cm3 of acetic acid, and the mixture is stirred at 80 ° C. for two hours. The reaction mixture was allowed to cool, then poured into water, resulting in an oily substance, which was washed thoroughly with water and extracted three times with 100 cc of ether / ether. The layers are combined and dried over sodium sulfate.

  <Desc / Clms Page number 76>

 sodium anhydrous.

   The ether is distilled off, the residue is dissolved in ethyl acetate, and chromatographed on a column of neutralized activated alumina, from where
 EMI76.1
 2- (1-cinnatnoyl-2-methyl-5-methoxy-3-indolyl) propionic acid crystals, Recrystallization from a mixture of acetone and water gives light yellow crystals of the pure product, M = 154 5 -155 5C.



  Microanalysis:; Calculated: C, 72.73%; H, 5.79%; N, 3.86%
 EMI76.2
 Found: C, 72.97% 1H, 5, 70%;. N, 3, 92% Example 80
As in Example 75, the acid (1-para-
 EMI76.3
 mthoxycinnamoyl - mthyl-5-methoxy-indolyl) actic, F 1 d .. '5 C, starting from 1'-paramethoxyphenylparam5thoxyaimamhydra.zide hydrochloride and levulic acid.



  Microanalysis: Calculated. C, 70.68%; H, 5.72%; N, 3.90% Found; C, 69.97%; H, 5.68%; N, 3.79% Example 81
As in Example 71, (1-cinnamoyl-
 EMI76.4
 Ethyl 5-d.mlthyl-3-iudolyl) acctate, F 13.200 C, from 1'-paratolyl-cinnamhydrazide hydrochloride and ethyl levulate.



  Example 82
As in Example 71 ', the acid (1- [alpha] -
 EMI76.5
 phenyl-cinnamoyl-2-methyl-5-methoxyj-indolyl) acetic, Fi 174 -17 C, from N1-a..phnylcinnamoyl-N1¯ (p-methoxyphenyl) hydrazine hydrochloride and levulic acid .

  <Desc / Clms Page number 77>

      



  Example 8.3
As in Example 71, the acid is prepared
 EMI77.1
 (1-phenylacetyl-2-methyl-5-m6thoxY-3-indolyl) acetic F = 1µ? -fl39 C, from 1'-paramethoxy-phenyl-phenylacethydrazide hydrochloride and levulic acid.



  Example 84
The acid (1-
 EMI77.2
 parachlorocinnamoyl-2-; ethyl-5-methoxy-3-indolyl) acetiq, ue, Mp = 220-221 C, from hydrochloride of. 1'-Paramethoxy-phenyl-parachlorocinnamilydrazide and levulic acid.



  Example 85
We heated to 85 while stirring for four hours,
 EMI77.3
 a solution of 4. C g of 1'-pllrllmethoxyphonyl-phenylchloracéthydrazide hydrochloride and 2.4 g of acetonylmalonic acid in 10 cm3 of acetic acid. The reaction mixture is allowed to cool and is poured into 25 cm3 of cold water. The crystals formed are collected by filtration, and
 EMI77.4
 dries them, from where the crude aoetic acid (1-phcnylchloracetyl-2-methyl-5 "methoxy-3-indolyl), Recrystallization in ... a mixture of acetone and water gives puckers white needles, M = 165 -166 C.



   The following compounds are obtained in the same way.



  Example 86
 EMI77.5
 (1-Cinnamoyl-2-methyl-5-methoxy-3-indolyl) acetic acid, Mp = 164 -165 C. Example 87
 EMI77.6
 (1-Phenylaoetyl-2-methyl-5-methoxy-3-indolyl) acetic acid F. 141 5-143 C. Example 88
 EMI77.7
 J-I - ('¯raphtflacetyi-2-zethyl - 5-mthoxy - indo.yl-- acetic acid, Mp = 165 5 - 166 5C.

  <Desc / Clms Page number 78>

 



    Example 89
Heat at 85 for four hours, with stirring,
 EMI78.1
 a solution of 3.6 g of 1'-paramethoxyphenylphenyl-ae6thydrazide hydrochloride and 2 ,! g of acetyl-succinic acid in 10 cm3 of acetic acid. The mixture is allowed to cool and is poured into 25 cm3 of ice water. The crystals formed are collected by filtration and dried, hence the acid.
 EMI78.2
 (fl-phenylacetyl-2-m & thyl-5-methoxy-µ-in401yl) aaetic crude.



  Recrystallization from a mixture of acetone and water to give white needles, F = 142 - 143 C.



   The same product is obtained by replacing acetyl succinic acid with 3-oxoadipic acid in the above procedure.



  Example 90
The acid is prepared as in Example 89
 EMI78.3
 (1-cinnamoyl-2-methyl-5-methoxy-3-indolyl) acetic, M = 164-. .1165 C, from 11-paramethoxyphenyl-cinnamhydrazide hydrochloride and acetyl-succinic acid. Example 91
 EMI78.4
 4.8 days are dissolved. Butyl (1-phenylacet;, {1-2-methyl-5-methoxy-3'-indolyl) acetate in 40 cm3 of benzene, then a small amount of toluene-parasulfonic acid is added. The mixture is heated to reflux to complete the reaction, then it is allowed to return to room temperature.



  Washed twice with 60 cm3 of water, and dried. The solvent is distilled off, the residue is crystallized from acetone and recrystallized from a mixture of acetone.
 EMI78.5
 tone and water, from where the acid (fl -phenylacetyl-2-methyl-5methoxy-3-indolyl) acetic, -e-138'-1390cri, The following compounds are prepared in the same way:

  <Desc / Clms Page number 79>

 Example 92
 EMI79.1
 /-1-(naphthylacetyl)-2-methyl.5-methoxy-3-inâolyl-- acetic acid, F165 -167 C. Example 93
 EMI79.2
 / -I- (3-Paratolylacryloyl) -2-methyl-5-methoxY-3-indolyl-7-acetic acid, F. 195 -196 C.



  Example 94 (1-Parachlorocinnamoyl-2-methyl-5-methoxy-3-indolyl) - acetic acid, F 220 -221 C.



  Example 95
 EMI79.3
 4- (fl-cinnamoyl-2.nmethyl-5-methoxy-.µ-indolyl) butyric acid, Mp = 125 -126 C. Example 96
 EMI79.4
 1- / 3- (2-furyl) acryloy-2-m.ethyl7.-5-methoxy-3-indolyl- - acetic acid, Mp = 163 -164 C. Example 97
 EMI79.5
 2- (fl-cinnamoyl-2-methyl-5-methoxy-3-indolyl) propionic acid, Mp = 154 -156 C. Example 98
 EMI79.6
 (1-Paramethoxycinnamoyl-2-niethyl-5-niethoxy-3-indolyl) - acetic acid, F 193 -195 C.



  Example 99 1-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid, M = 1640.



  Example 100
7.6 g of 2'-ethylidene-1'-paramethoxyphenyl-phenylacethydrazide are added to 30 g of levulic acid containing 1 g of hydrochloric acid, and the mixture is heated at 80 0 for three hours. Allowed to cool and poured into 200 cm3 of water. The crystals formed are filtered and purified

  <Desc / Clms Page number 80>

 pure chromatography on silica gel, using ethyl acetate as eluent, then recrystallized from a mixture of acetone and water,. '. from which white needles of acid
 EMI80.1
 Acotic (fl-phanyl-acetyl-2-methyl-smethoxy-3-inÀolyi), Mp = 139 -142 C.

   Example 101
 EMI80.2
 1, acetonyl-malonic acid and 2.6 g of 2'-ethyl, idene-.l'rparamethoxyphenyl-hénylactthydrazide are dissolved in 20 cm3 of acetic acid containing 37 g of dry hydrochloric acid, and the mixture is stirred at 95 ° C. for four hours. The mixture is allowed to cool, poured into water and added benzine. The mixture is stirred thoroughly and the benzene layer is separated, dried over anhydrous sodium sulfate and concentrated by distillation.

   The residue is dissolved in acetic acid, chromatographed on a silica gel column and recrystallized from a mixture of acetone and water, from which the acid (1-phenylacetyl-2-methyl-5 -methoxy-
 EMI80.3
 3-indolyl) -acetic, F = '! 40 -142 C, Example 102
5.0 g of 1'-paramethoxy- hydrochloride is added.
 EMI80.4
 phenyl-phenylacethydrazide, 20 cm3 of 4-oxopentanal diethylacetal. The mixture is cooled, concentrated under reduced pressure and left overnight. The crystals formed are filtered off, washed with water and recrystallized from ethanol, hence the diethyl acetal of (1-phenylacetyl-2-methyl-3-indolyl) acetaldehyde.



  Example 103
Slowly added, with stirring, a suspension of 12 g of silver oxide in 50 cm 3 of benzene to 14 g of (1-phenylacetyl-2-methyl-3-methoxy-3-indolyl) acetaldehyde.

  <Desc / Clms Page number 81>

 



  Once the reaction is complete, it is filtered over a 10-minute boub and the filtrate is evaporated to dryness under reduced pressure. Recrystallization from ethanol gives the acid (1-phenylacetyl-
 EMI81.1
 2-methyl-5-methoxy-3-i.ndolyl) acetic, F. 138 -139 C.



  Example 104, Example The acid (1-cinnamoyl-
 EMI81.2
 2-methyl-5-methoxy-3-indolyl) acetic, Mp = 164 -165 C, from (1-.cinnamoyl-2-.rethy.-5-nethoxy-j-indolyl) acetaldehy de.



  Example 105
1'-Paramethoxy-phenyl-phenylacethydraide hydrochloride 5.0 g was added to 20 g of 4-oxo-n-pentanol, and the mixture was heated to 80 ° C. with stirring. Once the reaction is complete, the filtrate is evaporated to dryness. Recrystallization from a mixture of ethanol and water gives 2- (1-phenylacetyl-2-methyl-5-methoxy-3-indolyl) ethanol.



  Example 106
G of 2- (1-phenylacetyl-2-methyl-5-methoxy-3-indolyl) ethanol is dissolved in acetone G, then heated to 0 C and slowly added 5 g of potassium permanganate. The mixture is maintained at 50 C for one hour, then allowed to cool. The crystals formed are filtered off and washed with acetone. The filtrates are combined and evaporated to dryness in vacuo.

   Recrystallization of the residue from ethanol gives
 EMI81.3
 (fl-pbenylacetyl-2-methyl-5-methoxy-3-indolyl) acetiqiae acid, M = 137 -139 C. Example 1-0?
 EMI81.4
 The acid (1-cinnamoyl-2-methyl-5-wethor.y-3-indoly3.) IcGiclua, F - 1 ± 15 C. is prepared in the same manner.

  <Desc / Clms Page number 82>

 Example 108
 EMI82.1
 3 g of acid (β-phenylacetyl-2-methyl-5-methoxy-2,3-dihydro-3-indblyl-acetic acid is dissolved in 100 cm3 of benzene, and 7.5 g of chloranil is added. The mixture is heated at reflux for three hours, evaporated to dryness under vacuum and taken up in acetone, After filtration, evaporated to dryness under vacuum, from which crystals of acid (1-phenylacetyl-2-
 EMI82.2
 crude methyl-5-methoxy-µ-indolyl) aoetic.

   Recrystallization from a mixture of acetone and water gives the pure light yellow product, Mp = 142 -143 C.



   The following compounds are prepared in the same way; Example 109
 EMI82.3
 ('! -Cinnamoy.-¯methyl-5-methoy -. Ndolyl) acetic acid, Mp = 163 -164 C.



    Example 110
 EMI82.4
 4 .. ('1-Cinnamoyl - meth, yl-5-metho; cy-3-indolyl) butyric acid, Mp = 125 -126 C. Example 111
 EMI82.5
 Is dissolved - g of t-butyl (1-oinnamoyl-2-hydro-2-methyl-3-hy'Jroxy-5-ntethoxy-3-indoly'i) aoetate in 500 cm3 of toluene, and add 3 g of toluene parasulionic acid. The mixture is heated at 100 ° C. for three hours with stirring. When the reaction is complete, the mixture is washed three times with water and dried over anhydrous sodium sulfate. We then concentrate the mixture and we abandon it
 EMI82.6
 in the refrigerator, hence crystals of crude ('1-cinnamoyi -'. 'methyl-5-methoxy-3-indolyl) -aoetic acid.

   Recrystallization from a mixture of acetone and water gives the pure product, Mp = 164-165C.

  <Desc / Clms Page number 83>

 



    Microanalysis Calcula: C, 72.19%; H 5.48%; N, 4.01%
Found: C, 72.46%; H 5.71%; N, 4.03%
The following compounds are prepared in the same way:
Example 112
 EMI83.1
 (Α-Naphthylaeetyl-2-methyl-5-methoxy-µ-indolyl) aoetic acid, M = = 165-167 C. Microanalysis: Calculated: C, 74.50%; H, 5.47%; N, 3.62% Found: C, 74.48%; H, 5.58%; N, 3.71% Example 113
 EMI83.2
 -1- (2-Phenylbutyryl) -2-methyl-5-methoxy-3-indolyl¯7-acetic acid, Mp = 123 5-125 0.



  Microanalysis Calculated: C, 72.33%; H, 6.30%; N, 3.84% Found. C, 72.51%; H, 6.38%; N, 3.94% Example 114 - ¯
 EMI83.3
 (Fl-parachlorophenylacetyl-2-methyl-5-methoky-µ-indolyl) -acetic acid, M = 178 C. Microanalysis;
 EMI83.4
 Calculated: C, 64.60%; H, 4.89%; ' N, 3.7'J. Found: C, 64.45%; H, 4.96%; N, 3.86% Example 115
 EMI83.5
 ± fl- (µ-phenylpropionyl) -2-methyl-5-methoxy-3-indolyl¯7-acetic acid, Mp = 163 -164 C.



    Microanalysis: Calculated: 0.71.78%; H, 6.02%; N, 3.98% Found: C, 71.85%; H, 6.07%; N, 4.08%

  <Desc / Clms Page number 84>

 
 EMI84.1
 ,? ..! ¯'i3 "'r at'C> Acid f- - (3, a-dim thox ,,' p: zny, actyl) -2-mdthyl-5-mthoxy-3indolyl¯7nctic,? Tü9 -17G C.



  L ... i calcUl '? i C, dr, 49; n, 5.83 5 '; N, 3.55 P3 found: 0, Cr (4I1 / Îv AL, 5.94 5; N, 3.61% Example 117
Heated to 120-140 C for 40 minutes a half
 EMI84.2
 lut. ;; <.; .l- (:: -: pa.ramÓ lihoxyph6nyl: phenylacetamido) - 3-oxovul6ric acid and 1.3 g of anhydrous zinc chloride. After cooling, it is extracted with 25 cm3 of benzene, the benzene layer is washed with water and dried over sodium sulfate.
 EMI84.3
 d ±> ni anhydrous. Evaporated to dryness in vacuo and chromatographed on a silica gel column using ethyl acetate as the eluent, hence the acid (1-phenylacetyl-2-methylj..mct: oxy-3-iutio2yl) e.ctiç, ue, y 138 -'I39 C
The following compounds are prepared in the same way: Ex +, 118
 EMI84.4
 (1-c, nnamayl- -methyl-5-methoxy-3-indoyl) actic acid, if) ;; 0 ¯J 65 c.

   Example 119
 EMI84.5
 scz.de -f-3 - ('-. fuxyl) acxyl.oyl -2-methyl-methoxy-3.-indalyl -act: ic, fi i ± 3 - r C. Example 120
 EMI84.6
 3.0 is dissolved; of 3-C acid Phény.actamido-parnr4thaxyplSny.). dvullqua in 60 cm5 of dioxane, 1 cm3 of 10% hydrochloric acid is added, and the mixture is heated to 80 ° C. with stirring. Once the reaction is complete, it is filtered and the filtrate is evaporated to dryness. Two recrystallizations from a mixture of water and acetone give the acid (1-phenylacetyl-
 EMI84.7
 '-mc: Ghyl..5-m3thoxy-3-indolyl) acetic, F =' 138 -140 C.

 

Claims (1)

SUMMARY 1.- Compounds of general formula: i EMI85.1 where R1 represents an aromatic radical which is unsubstituted or substituted by an alkyl, alkoxylo or thioalkoxyl group containing up to 4 carbon atoms or by a nitro group EMI85.2 or cyano or a halogen atom, or a 5- or 6-membered heterocyclic radical containing an oxygen, sulfur or nitrogen atom, unsubstituted or substituted by a methyl or ethyl group or by an atom of halogen; R2 and R3 each represent a hydrogen atom or an alkyl group containing up to 3 carbon atoms; It 4 represents a hydrogen atom, a carboxyl group or a carbalkoxyl group containing up to 4 carbon atoms; R5 represents EMI85.3 te an alkoxyl group coner.i.4iAt Up to lk carbon atomos, ur. benzoxyl group, a tetrahydropyrannoxylo group, an amine group or a hydroxyl group; R6 represents a wildebeest EMI85.4 eg alkyl2 containing j "-x5qu'E:" carbon atoms, a nitro group, an alc.lr group, y2; containing up to 4%, 1% Q:. 'iE; α of carbon, un': C? i.18 3., ',. C: i: O.; t: .c: DO1'.erlt. rlv z, Liâ'ty ', tt't-i f aicmex due to carbon, a FatfSnè C.': ... i.:C;,;:xs or a -lo ± of hydrogen; A rep4aentc an unsubstituted hydrocarbonuo caturéc chain <Desc / Clms Page number 86> EMI86.1 ca; 5e:; anà up to 5 carbon atoms, a hydrocarbon chain nos. crossed out unsubstituted containing up to 1 to. 5 carbon atoms, one halogenated saturated hydrocarbon chain containing up to 5 carbon atoms, one non-carbonated hydrocarbon chain EMI86.2 ature no.:'oL;0n::o containing up to 5 carbon atoms, an S hydrocarbon chain (uro phenylôo containing up to 5 carbon atoms, or an unsaturated phenylated hydrocarbon chain containing up to :. 5 carbon atoms, the hydrocarbon chain possibly being linear or branched; m = 0 or 1; p 0 or 1; and n = 0, 1, 2 or 2.- Process for the preparation of acid derivatives EMI86.3 (3-indolyl) alkanoids of the general formula: EMI86.4 EMI86.5 \ J *,,., 35, ,, 4- -'1 ,. rr., have the,., .. t 0 ....., it ", R, i, have the same meanings: ... or.o as in 10 pana ,,: :: 0 1, consisting of reacting a 1 '-1> iaénylr> j / <irazido of formula: EMI86.6 EMI86.7 . ' ii ',:. r 4.7 ¯: s. , ons' Les ", A, ..., 1" icnt 0 "'' '' above, on a c:.:. t'e: of acid ali 9 = iLque toe formula: EMI86.8 <Desc / Clms Page number 87> where R2, R3, R4, R5, m, n and p have the meanings above, EMI87.1 so as to obtain the (3-indolyl) alkanoic acid derivative of formula I. 3. - Process for preparing acid derivatives EMI87.2 (3-indolyl) -alkatiolques of general formula: EMI87.3 where R1, R2, R3, R4, R5, R6, A, m, n and p have the same meanings as in paragraph 1, consisting in decomposing EMI87.4 a 2'-alkylidene-1'-phenylhydrazide of the formula: EMI87.5 where R1, R6 and A have the meanings above and where B is an alkylidene group, using a decomposing agent, so as to obtain a 1'-phenylhydrazide of the formula: EMI87.6 -where R1, R6 and A have the meanings above, and reacting this 1'-phenylhydrazide with an aliphati- acid derivative <Desc / Clms Page number 88> what formula EMI88.1 EMI88.2 where .2, It3, R4 R5, m, n and p have the above meanings, so as to obtain the (3-indolyl) alkanol acid derivative of formula I. 4.- Process for preparing acid derivatives EMI88.3 (3-indolyl) -a.lcanoques of the formula: EMI88.4 where R1, R2, R3, R4, R5, R6, m, n and p have the same meanings as in paragraph 1, consisting in reacting a phenylhydrazone of formula s EMI88.5 where R6 has the meaning above and where B is an alkylidene group, on a compound of the formula: EMI88.6 where R1 and A have the meanings above and where Y is a halogen atom or an alkoxyl group, so as to obtain <Desc / Clms Page number 89> EMI89.1 a 2'-alkylidene-1'-phenylhydrazide of the formula! . EMI89.2 where R1, R6 and A have the meanings above, to be broken down EMI89.3 This 2'-alkylldene-1'-phônylhydrazide II, helps a dt "*>" tion agent so as to obtain a 1'-phenylhydrazide of the formula EMI89.4 where R1, R6 and A have the meanings above, ot to react this 1'-phenylhydrazide with an aliphatic acid derivative of the formula EMI89.5 EMI89.6 where R2, R3t R41 R5, m, n and p have the meanings above so as to obtain the (3-indolyl) alkanoic acid derivative of formula I. 5.- Preparation process for acid derivatives EMI89.7 (5-indolyl) -alkanolques of the formula: <Desc / Clms Page number 90> EMI90.1 where R1t R2, R3, R4, R5, R6, A, m; n and p have the same meanings as in paragraph 1, consisting in reacting a phenylhydrazone of formula EMI90.2 where R6 has the meaning above and where B is an alkylidene group, on a compound of the formula: EMI90.3 where R1 and A have the meanings above and where Y is a halogen atom, so as to obtain a 1'-phenylhydrazide of formula! EMI90.4 where R1, R6 and A have the meanings above, and reacting this 1'-phenylhydrazide with an aliphatic acid derivative of the formula: <Desc / Clms Page number 91> EMI91.1 EMI91.2 where R2,? ruz, R, and have the Bignifications above, so as to obtain the acid derivative (3-indolyl) alkanol of formula I. 6. - Process for preparing acid derivatives EMI91.3 (3-indolyl) -alkanoics of formula EMI91.4 EMI91.5 where R 1 1 R 2 3 1 R 4 5 6 Ah means R-, have the same meaning as in paragraph 1, consisting in reacting EMI91.6 a 2'-alkylidèïie-1'-phenylhydrazide of the formula: EMI91.7 where R1, R6 and A have the meanings above and where B is an alkylidene group, on an aliphatic acid derivative of the formula EMI91.8 <Desc / Clms Page number 92> where R2, R3, R4, R5, m, n and p have the above meanings, so as to obtain a (3-indolyl) alkanol acid derivative of formula I. 7.- Process for preparing acid derivatives EMI92.1 (3-indolyl) -alkylolques of formula s EMI92.2 EMI92.3 where 2, R, R3, Ruz, R5, R, A, m, n and p have the same meanings as in paragraph 1, consisting in reacting a phenylhydrazone of formula EMI92.4 where R6 has the meaning above and where B is an alkylidene group, on a compound of the formula: EMI92.5 where R1 and A have the meanings above and where Y is a halogen atom or an alkoxyl group, so as to obtain EMI92.6 a 2'-alkylidene-1'-phnylhydrazide of the formula: EMI92.7 <Desc / Clms Page number 93> where R1, R6, A and B have the meanings oi above, and to EMI93.1 reacting this 2'-alkylidene -'- phenylhydrazide with an aliphatic acid derivative of formula: EMI93.2 where: R2, R3, R4, R5, m, n and p have the meanings above, EMI93.3 so as to obtain a derivative of (3-indolyl) alkanoic acid of formula I. 8. - Process for preparing derivatives of (3-indolyl) -alkanoic acids of formula: EMI93.4 EMI93.5 where R1, R21 R3, R, R5, R61 A, m, n and p have the marls "-i. '. instructions as in paragraph 1, consisting in reacting a phenylhydrazine of formula EMI93.6 where R6 has the meaning above, on a compound 'the formula; EMI93.7 where R1 and A have the meanings above and where Y represents <Desc / Clms Page number 94> te a halogen atom or an alkoxyl group, so as to obtain a 1'-phenylhydrazide of formula EMI94.1 where R1, R6 and A have the meanings above, and reacting this 1'-phenylhydrazide with an aliphatic acid derivative of the formula EMI94.2 where R2, R3, R4, R5, m, n and p have the meanings above, so as to obtain a (3-indolyl) alkanol acid derivative of formula 1. 9.- Process for preparing acid derivatives EMI94.3 (3-indolyl) -alkanoic formula EMI94.4 where R1, R, R3, R6, A and m, have the same meanings as in paragraph 1, consisting in reacting a 1'-phenylhydrazide of formula <Desc / Clms Page number 95> EMI95.1 where R1, R6 and A have the meanings above, on a compound of formula EMI95.2 where R2, R3 and m have the meanings above, so as to obtain a derivative of (3-indolyl) alkanoic acid of formula VII. 10.- Process for preparing acid derivatives EMI95.3 '(3-indolyl) alkanoids of the formula EMI95.4 where R1, R2, R3, R6, A and m have the same meanings as in paragraph 1, consisting in reacting a 2'-alkyl- EMI95.5 lidene-phenylhydrazide of the formula EMI95.6 <Desc / Clms Page number 96> where R1, R6 and A have the meanings above, and where B represents an alkylidene group, on a compound of the formula: EMI96.1 where R2, R3 and mounts the meanings above, so as to obtain a derivative of (3-indolyl) alkanoic acid of formula I. 11.- Process for the preparation of (3-indolyl) acetic acids of formula: EMI96.2 where R1, R6 and A have the same meanings as in paragraph 1, consisting in reacting an 11-phenylhydrazide of the formula: EMI96.3 where R1, R6 and A have the meanings above, on acetyl-succinic acid or 3-oxoadipic acid, so as to obtain a (3-indolyl) acetic acid of formula IX. <Desc / Clms Page number 97> 12.- Process for the preparation of (3-indolyl) - acetic acids of formula: EMI97.1 where R1, R6 and A have the same meanings as in paragraph 1, consisting in reacting a 2'-alkylidene-1'phenylhydrazide of formula EMI97.2 where R1, 6 and A have the meanings above and where B is an alkylidene group, on acetyl-succinic acid or '.'aai- of 3-oxoadipic, so as to obtain a (3-indolyl) acetic acid of formula IX. 13.- Process for preparing acid derivatives EMI97.3 (3-indolyl) -alkanolquos of the formula: EMI97.4 EMI97.5 where R11 R, R3t R, R5t R, A, m, n and p have the same meanings <Desc / Clms Page number 98> fications than in paragraph 1, consisting in reacting a 1'-phenyl-imidohydrazide of formula EMI98.1 where R1, R6 and A have the meanings Above, on a Formula Compound: EMI98.2 where R2, R3, R5, R5, m, n and p have the meanings above, so as to obtain a derivative of (3-indolyl) alkanoic acid of formula 1 14.- Pharmaceutical compositions containing as essential ingredient a 3 ,, riveted with (3-indolyl) alkanoic acid of the formula: EMI98.3 where R1, R, R3, R4, R, R6, A, m, n and p have the same meanings as in paragraph 1.