IL27944A - In dole derivatives - Google Patents

Description

Patents Form No. 3 PATENTS AND DESIGNS ORDINANCE.

SPECIFICATION.

"INDOLE DERIVATIVES" \ I / WE , . flUMiTQ Q..CHEMICAL ..CQMPAl^.^. TD^.,....a....c.o.rp.or.atlon organised under* the lawe of Japan^ 1^» Kitahama-S-Ghome, H. gasM- ,...^s.a^ ....Ja.an.> do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described aud ascertained in and by the following s atement : - Background of the Invention (1) Field of the Invention The present invention relates to novel N-substituted indole derivatives having high anti-inflamma ory, anti-pyretic and analgesic activities and to processes for producing the same. More par icularly, the present invention relates to novel l-acyl-3-indolyl aliphatic acid derivatives and processes for producing the same. (2) Prior Art Of the developed non-steroidal anti-inflammatory .compounds, l-(p-chlorobenzoyl) -2-methyl-5-methoxy-3-indolyl- acetic acid is greatest in activity. But it is high in toxicity. The present inventors also observed that even when 10 mg./kg. of said compound was orally administrated, a rat showed an occult bleeding. In addition thereto, all the conventional anti-inflammatory compounds tend to promote -the bleeding of digestive organs and not few examples have been reported that perfolations of the stomach and intestines brought one to death. Further, 1, 2-diphenyl- , 5-dioxo-4-n butylpyrazolidine (phenylbutazone), which is most widely used as antiphlogistic at present, has low activity in comparison to its high acute toxicity and hence is considerably small in therapeutic ratio.

The synthesis of indole derivatives having acyl groups at the N-positions is described in, for example, Elderfield: "Heterocyclic Compounds", Vol. 3 (1952), Chapter 1, pages 1-247, and W.C. Sumpter and F.M. Miller: "Heterocyclic Compounds with Indole and Carbazole Systems" (1954), pages 1-69. 1-Substituted acyl groups of 1-acyl- indole derivatives are so easily hydrolyzed by acid or alkali that it has been considered impossible to obtain 1-acyl- indole derivatives directly from corresponding N"^-acylated phenylhydrazine derivatives by Fischer's indolization.

Suvbrov et al. [Suvorov et al. : Doklady Acad. Nauk S.S.S.R. 156. 840 (1961), Chem. Abstr. , 5_5_, 17621 (1961), J. Gen. Chem. , U.S.S.R., 28, 1058 (1958)] have recently reported this problem as follows: They have explained that an important requirement for indole formation is the deacylation of the N^-acyl group of hydrazine derivative, which ¾» free; from- a p-electron pair on the N"*"- nitrogen atom.

Summary of the Invention The present inventors found that novel l-acyl-3-indolyl aliphatic acid derivatives having high anti-inflammatory, antipyretic and analgesic activities were prepared by novel or known ■per- oc processes.

One object of the present invention is to provide novel l-acyl-3-indolyl aliphatic acid derivatives having high ant.i- inflammatory, anti-pyretic and analgesic activities and processes for producing such derivatives. Another object of the present invention is to- provide processes for economically manufacturing these compounds in a high yield. A further object of the present invention is to provide a novel pharmaceutical composition contain' ing these compounds as the effective ingredient. Still further objects will be apparent from the following description.

In order to accomplish these objects, the present invention provides novel l-acyl-3-indolyl aliphatic acid derivatives of the formula: wherein p^†'n- η h]riilirni? i"' (i-lana., an unsubstituted or a lower alkyl-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen-substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or au. a furyl or thien lj unoubo itutod or a methyl »—ethyl—or halogen oubo itutod 5—e^? 6-meroberec heterocyclic ring group containing an ox gen;—oulfur or nitiO bui nl'ui'ir, R 2 and R- each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; R^" is a hydrogen atom, a carboxy group or an alkoxycarbonyl group having up to 4 carbon atoms; R is an alkoxy group having up to 4 carbon atoms, a benzyloxy. group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R is an alkyl group having up to 4 carbon atoms, V an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an un-substituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl-substituted having/ saturated hydrocarbon ch in/up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight one or aT¾¾ano¾e one; m and £ each are 0 or 1; and n is 0 or an integer of from 1 to 3.

Further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives represented by the formula (I), which comprises reacting an "^-acylated phenylhydrazine derivative of the formula: wherein R"", R^ and A have the same meanings as defined above, with an aliphatic acid derivative of the formula: - COR5 (III) wherein R , RJ , R , R , m, n and £ have the same meanings as identified above.

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives represented by the formula (I), which comprises decomposing an N1-acylated phenylhydrazone derivative of the formula: wherein R , R and A have the same meanings as identified above, and B is a ketone or aldehyde residue, with a decomposing agent to yield an N^-acylated phenylhydrazine derivative of the formula: A wherein R 1, R6 and A have the same meanings as identified above, and reacting the resultant N"^-acylated phenylhydrazine derivative with an aliphatic acid derivative represented by the formula (III) to yield the l-acyl-3-indolyl aliphatic acid derivative (I).

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives represented by the formula (I), which comprises reacting a phenylhydrazone derivative of the formula: β wherein R and B have the same meanings as identified above, with a ^compound, having the formul : Y I CO I (vi) A wherein R1 and A have the same meanings as identified above and Y represents a halogen or an ester residue, to yield an N^-acylated phenylhydrazone derivative represented by the formula (IV), decomposing the resultant N1-acylated phenylhydrazone derivative with a decomposing agent to give an N1-acylated phenylhydrazine derivative represented by the formula (II), and reacting the resultant N1-acylated phenylhydrazine derivative with an aliphatic acid derivative represented by the formula (III) to yield the l-acyl-3-indolyl aliphatic acid derivative (I).

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (I); which comprises reacting a phenylhydrazone derivative of the formula (V) with a compound having the formula (VI) to yield an N^-acylated phenylhydrazine derivative of the formula (II), and reacting, the resultant N1-acylated phenylhydrazine derivative of the formula; (II) with an aliphatic acid compound of the for-mula (ΙΠ) to (I) .

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (I), which comprises reacting an N^-acylated phenylhydrazone derivative of the formula (IV) with an aliphatic acid derivative of the formula (III) to yield the l-acyl-3-indolyl aliphatic acid derivative of the formula (I).

Still further, the present invention provides a process ' for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (I), which' comprises reacting a phenylhydrazone derivative of the formula (V) with a compound having the formula (VI) to yield an N^-acylated phenylhydrazone derivative of the phenylhydrazone the formula (III) o yie e -acyl-3-indoly aliphat c acid derivative (I).

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (VII) : R1 wherein.R , R , R , R , A and m have the same meanings as identified above, which comprises reacting an N^-acylated phenyl- hydrazine derivative of the formula (II) with a compound of the formula: wherein R 2,· R and m have the same meanings as identified above, to yield the l-acyl-3-indolyl aliphatic acid derivative (VII).

Still further-, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (VII), which comprises reacting an N -acylated phenylhydrazone derivative of the formula (IV) with a compound of the formula (VIII) to yield the l-acyl-3-indolyl aliphatic acid derivative of the formula (VII).

Still further, the present invention provides a process for producing novel l-acyl-3-indolylacetic acid derivatives of the formula': wherein R , R and A have the same meanings as identified above, which comprises reacting an N"^-acylated phenylhydrazine derivative of the formula (II) with acetosuccinic acid or 2-ketoadipic acid to yield the l-acyl-3-indolylacetic acid derivative of the formula (IX) .

Still further, the present invention provides a process fo producing novel l-acyl-3-indolylacetic acid derivatives of the formula (IX), which comprises reacting an ■ N^-acylated phenylhydrazone. derivative of the formula (IV) with acetosuccinic acid or 2-ketoadipi*iic acid to yield the l-acyl-3-indolyla.cetic acid (IX).

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (I), which comprises reacting a phenylhydrazine derivative of the formula: wherein has the same meaning as identified above, with a compound having the formula (VI) to yield an ^-acylated phenylhydrazine derivative of the formula (II), and reacting the resultant N^"-acylated phenylhydrazine derivative (II) with an aliphatic acid compound of the formula (III) to yield the l-acyl-3-indolyl aliphatic acid derivative (I).

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (I), which comprises reacting a phenylhydrazine deriva ive of the formula (XI) : £ -H - NH2 R6 C = NH I (XI) A wherein R1, R6 and A have the same meaning as identified in the formula (I), Still further, the present invention provides a process for preparing novel l-acyl-3-indolyl aliphatic acid derivatives represented by the formula: R1 wherein R , R , R^, R , A, m and n have the same meanings as identified in the formula (I), which comprises converting a derivative represented by the formula? I A 1 2 3 6 wherein R , R , R , R , A, m and n have the same meanings as 7 identified above; and R' represents tertiary butyloxy, tetra-hydropyranyloxy , benzyloxy or amino, into the said l-ac l-3-indolyl aliphatic acid derivative (XII).

^ Still- further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (XII), which comprises reacting an N^-acylated phenylhydrazine derivative of the formula (II) with a compound of the formula: R2 _ CO - CH - - (CHJ^ - CO - R7 (XIV) 2 m 2 Ώ 2 3 wherein R , R , m and n have the same meanings as identified above and R represents a tertiary butyloxy group, a benzyloxy group, a tetrahydropyranyloxy group or an amino group, to yield a 1-aoyl-3-indolyl aliphatic acid derivative of the formula (XIII), and decomposing the resultant l-acyl-3--indolyl aliphatic acid derivative of the formula (XIlJ.) to yield/i¼^l-acyl-3-indolyl aliphatic acid derivative (XII).

Still further, the present invention provides a process for preparing novel 1-acyl—3-indolyl. aliphatic acid derivatives represented by the formula: C = 0 I A wherein R , R , R , R and A have the same meanings as identified above, which comprises oxidizing an indole-3-aliphatic aldehyde derivative represented by the formula: A wherein R"1", R*1, RJ , RO and A have the same meanings as identified above .

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (XV) , which comprises reacting an N"^-acylated phenylhydrazine derivative of the formula (II) with a compound of the formula: R2C0CH2 - CH - CH(0R8)2 (XVII) wherein R and R^ have the same meanings as identified above and 8 R is a lower alkyl group, to yield a 3-indolyl aliphatic aldehyde acetal derivative of the formula: R- (XVIII) wherein R , R , R , R , R and A have the same meanings as identified above, decomposing the resultant 3-indolyl aliphatic aldehyde acetal derivative to yield a 3-indolyl aliphatic aldehyde * derivative of the formula (XVI), and oxidizing the resultant 3-indolyl aliphatic aldehyde derivative to yield the l-acyl-3-indolyl aliphatic acid derivative (XV) .

Still further, the present invention provides a process for preparing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula'- R- CO I A wherein R , R , R , R and A have the same meanings as identified above, whioh comprises oxidizing an indole-3-ethanol of the formula: R- wherein R , R , R , R and A have the same meanings as identified an above, to yield/¼ke l-acyl-3-indolyl aliphatic acid derivative of the formula (XV) .

Still further, the present invention provides a process for producing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (XV) which comprises reacting an N^-acylated phenylhydrazine derivative of the formula (II) with a compound of the formula : R- CO - CH2 - CH - CH2 - OH (XX) wherein R and RJ have the same meanings as identified above, to yield a l-acyl-3-indolyl aliphatic alcohol derivative of the, formula (XIX) and oxidizing the resultant l-acyl-3-indolyl aliphatic alcohol derivative (XIX) to yield the l-acyl-3-indolyl aliphatic acid derivative (XV).

Still further, the present invention provides a process for preparing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula ( V) which- comprises dehydrogenating a 2, -dihydro-3-indolyl aliphatic acid derivative of the formula:' A wherein R 1, R2, R**5 , R6 and A have the same meanings as identified above .

Still, further, the present invention provides a process for preparing novel l-acyl-3-indolylacetic acid derivatives of the formula: R- wherein R , R , R , R and A have the same meanings as identified above, which comprises dehydrating or dehydrating and hydrolyzing thereafter a 2-hydro-3-hydroxy-3-indolylacetic acid derivatives of the formula: (XXIII) A wherein R , R , R3, R and A have the. same meanings as identified above.

Still further, the present invention provides a process for preparing novel l-acyl-3-indolyl aliphatic acid derivatives of the formula (XV) which comprises subjecting '( N-ac l-anilino) -aliphatic acid derivatives of the formula: wherein R , R , R , R and A have the same meanings as identified above, to ring formation reaction.

Still further, the present invention provides a process for preparing novel l-acyl- -indolylacetic acid derivatives of the formula (IX), which comprises heating a 3-( 21 -acylaminophenyl)-levulinic acid derivative of the formula: A wherein R 1, R6 and A have the same meanings as identified above, in the presence of an inorganic acid in a suitable solvent.

According to the present invention, a l-acyl-3-indolyl aliphatic acid derivative represented by the formula (I) is prepared by the reactions shown by the following equations: (V) (VI) (IV) (ID I A RJ (III) CO I A (I) Rl In the above formulas, R , R , R^, R , R° , R , A, B, Y, m, n and £ have the same meanings as identified above.

In the processes of the present invention, ^-acylated phenylhydrazine derivatives (II) and l^-acylated phenylhydrazone derivatives (IV) may be synthesized as intermediates by other processes than those disclosed herein. These intermediates, the compounds (II) and (IV), are novel compounds.

Next, the process of the present invention is explained in due order as follows.

Firstly, the reaction of a phenylhydrazone derivate (V) and a compound (VI) will be described.

The reaction of a phenylhydrazone derivative (V) with a compound (VI) is carried out in the presence of a hydrogen halide acceptor. As the hydrogen halide acceptor, a tertiary amine, for example, pyridine or dimethylaniline can be used. These hydrogen halide acceptors themselves can be used as solvents. Inert solvents such as ether, benzene, toluene, and tetrahydrofuran are also able to be used as reaction solvents in the presence of equimolar or larger amounts of these hydrogen halide acceptors. The compound (VI), may be chloride, bromide, iodide or fluoride and chloride is most preferable from a commercial point of view. The reaction proceeds at room temperature in many cases, and even below 0°C. in some kind of solvent used. The exothermic reaction finishes in a few minutes or several hours. After the reaction finishes, the produced hydrogen halide salt of the hydrogen halide acceptor is filtered off and the filtrate is concentrated under a reduced pressure, or the reaction mixture is poured into water when a water-soluble solvent like pyridine is used as the solvent, theiii -j^ And/ihe aimed N -acylated phenylhydrazone compound is easily obtained as crystals or an oily substance. These products can be purified with an appropriate solvent, for example, the solvent mixture of alcohol and water.

In case a compound having a comparatively weak -N=C<^ bonding is used as a derivative (V) or under severe conditions of reaction, an I^-acylated phenylhydrazine derivative (II) is directly obtained in place of an N^-acylated phenylhydrazone derivative (IV).

According to the method of the present invention, the following compounds can be obtained in a high yield. As the N^"-acylated phenylhydrazone compounds (IV), there are illustrated: Acetaldehyde N^-cinnamoyl-N^-ip-methoxyphenylJhydrazone Acetaldehyde N1-cinnamoyl-N1-(p-methylphenyl)hydrazone Acetaldehyde N^-cinnamoyl-N^-(p-chlorophenyl) hydrazone Acetaldehyde N^-cinnamoyl-N^-(p-methylthiophenyl)hydrazone Acetaldehyde N -cinnamoyl-N -( p-ethoxyphenyl)hydrazone Acetaldehyde N1-(5 ' -phenyl-2' ,4' -pentadienoyl)-N1-(p-methoxyphenyl)- hydrazone Acetaldehyde N1-( ' -phenyl-2 ' , 4 ' -pentadienoy1 )-N1-( p-ethoxyphenyl) - hydrazone Acetaldehyde N1-cinnamoyl-N1-(m-methoxyphenyl)hydrazone Acetaidehyde N^-cinnamoyl-N^-( m-toly1 )hydrazone Acetaldehyde ^-(4' -phenyl-3' -butenoyl)-N^"-(p-methoxyphenyl)hydrazone 1 1 Benzaldehyde N -cinnamoyl-N -(p-methoxyphenyl)hydrazone Chloral N^"-cinnamoyl-N'1"-(p-methoxyphenyl)hydrazone Acetophenone N^-cinnamoyl-N^-(p-methoxyphenyl)hydrazone Acetaldehyde N1- (^-21 -furylacryloyl ) -N1- ( p-methoxyphenyl )hydrazone Acetaldehyde N1-(^-21 -furylacryloyl)-N1-(p-methylphenyl)hydrazone Acetaldehyde ^-(^-2 ' -furylacryloyli-N^-ip-chlorophenylJhydrazone Acetaldehyde N1- -2 ' -furylacryloyl ) -N1-( p-methylthiophenyl) hydra- zone Acetaldehyde Ν1-(?-2' -furylacryloyli-l^- C p-ethoxyphenyl) hydrazone Acetaldehyde N1-(o<v-naphthylacryloyl)-K'1-( p-methoxyphenyl)hydrazone Acetaldehyde N1-(^-naphthylacryloyl)-N1-(p-ethoxyphenyl)hydrazone Acetaldehyde N1-(^-2 ' -thienylacryloyl -N -(m-methoxyphenyl)hydrazone Acetaldehyde N1-(^-2' -thienylacryloyl -N1-(m-tol 1)hydrazone Acetaldehyde N1-(^-2' -pyridylacryloyl -^-(p-methoxyphenyl)hydrazone Benzaldehyde Ν1-((β-2' -thienylacryloyl - ^-(p-methoxyphenyl)hydrazone Chloral N1-^^' -thienylacryloyl) -N1- p-methoxyphenyl )hydrazone Acetophenone N1-(^-2' -thienylacryloyl -N -(p-methoxyphenyl )hydrazone Acetaldehyde N1-(m-nitrocinnamoyl)-N1-( p-methoxyphenyl )hydrazone Acetaldehyde N-^-im-nitrocinnamoylJ-^- p-methylphenylihydrazone Acetaldehyde N1-(m-nitrocinnamoyl)-N1-(p-chlorophenyl)hydrazone Acetaldehyde N^ C m-nitrocinnamoylJ-N'^-ip-methylthiophenylJhydrazone Acetaldehyde N1-(m-nitrocinnamoyl)-N1-(p-ethoxyphenyl)hydrazone Acetaldehyde N^-(p-methoxycinnamoyl)-N^"-( p-methoxyphenyl)hydrazone Benzaldehyde N1-cinnamoyl-N1-(p-methoxyphenyl)hydrazone Chloral. N1-( p-methoxycinnamoy1) -N1-( p-methoxyphenyl)hydrazone Acetophenone N""-( p-methoxycinnamoyl )-N""-(p-methoxyphenyl)hydrazone Acetaldehyde N1^ 5 ' -p-chlorophenyl-2 ' , 4 ' -pentadienoyl)^1-!p- methoxyphenyl)hydrazone Acetaldehyde N^- G -phenyl-p-chlorocinnamoyli-N^- C p-methoxyphenyl)- hydrazone Acetaidehyde N1- ( -ρ-tolylacryloyl )-N1-( p-methoxyphenyl )hydrazone Acetaldehyde N^-^-methyl-p-chlorocinnamoylJ-N^- p-methoxyphenyl)- hydrazone Acetaldehyde N^"-( p-chlorocinnamoyl )-N^-( p-methoxyphenyl )hydrazone Acetaidehyde N^-( p-methylthiocinnamoyl )-N^"-(p-methoxyphenyl )hydra- zone Acetaldehyde N 1-( p-chlorocinnamoyl) -N1~(p-methoxyphenyl)hydrazone Acetaldehyde N^-(phenylacetyl)-N^-( p-methoxyphenyl)hydrazone Acetaldehyde N p-tolylacetyl)-N -( p-methoxyphenyl)hydrazone Acetaldehyde F phen lacetyl) -N1-( p-methylphenyl)hydrazone Acetaldehyde N' 5-phenyl-n-pentanoyl)-N1-( p-methoxyphenyl )hydrazone Acetaldehyde N' phenylacetyl)-N1-(m-chlorophenyl)hydrazone Acetaldehyde N' phenylacetyl) -N1-( p-chlorophenyl)hydrazone Acetaldehyde phenylacetyl)-N1^ p-methylthiophenyl)hydrazone Acetaldehyde F p-chlorobenzylacetyl)-F^"-(p-methoxyphenyl)hydrazone Acetaldehyde N" p-methylphenylacety1 )-N1-(m-methoxyphenyl)hydrazone Acetaldehyde F p-methoxyphenylacetyl) -F^"- ( p-methoxyphenyl) - hydrazone Acetaldehyde N - (f-phenyl-n-butyroyli-N^-Cp-methoxyphenyl)hydrazone Aeetaldehyde LT b-yl-) - ^(p-methoxyphenyl)hy razone . Acetaldehyde N - 21 -thienylacetyl)-N -( p-methoxyphenyl)hydrazone Acetaldehyde N - 2 ' -furylacetylJ-^-Cp-methoxyphenyl)hydrazone Acetaldehyde N1- diphenylacetyl) - ^-( p-methoxypheny1 )hydrazone Acetaldehyde N1- phenylacetyl)-N1-(m-methoxyphenyl )hydrazone Acetaldehyde N1- phenylacetyl) -F^- (m-methylpheny1)hydrazone Acetaldehyde Benzaldehyde Chloral -( phenylacetyl)-N""-( p-methoxyphenyl)hydrazone Methylethylketone N1-(phenylacetyl) -N1-(p-methoxyphenyl)hydrazone Acetophenone N^-(phenylacetyl)-N"^"-( p-methoxyphenyl)hydrazone The following N -acylated hydrazine derivatives can he very easily obtained directly from hydrazone derivative of ethyl levulinate, ethyl acetoacetate, methyl 4-methoxy-3-oxo-n-butyrate etc., under some conditions of the reaction: N'^-cinnamoyl-N"'"-( p-methoxyphenyl)hydrazine N^-cinnamoyl-N^-Cp-tolyl )hydrazine ^-cimamoyl-N'^- m-methoxyphenylJhydrazine Ν1-(m-nitrocinnamoy1 )-N1-(p-methoxyphenyl) hydrazine N1-( phenylacety1) -N1-( p-methoxyphenyl )hydrazine N1-( p-tolylacetyl )-N1- (p-methoxyphenyl )hydrazine N1^ 2' -furylacetyl) -N1-( p-methoxyphenyl)hydrazine .

Those novel N^"-acylated phenylhydrazone derivatives and N"*"-acylated phenylhydrazine derivatives which are obtained by the method of the present invention have psychic, stimulating, antitumor, bactericidal, and fungicidal effects and they are very important compounds as intermediates for producing remarkably effective anti-inflammatory drugs, analgesics and anti^-pyretics.

Next, the process for producing an N^"-acylated phenylhydrazine derivative (II) by decomposing an N^-acylated phenylhydrazone derivative (IV) will be described.

An N^-acylated phenylhydrazone derivative (IV) is dissolved or suspended in an adequate solvent, for example, alcohol, ether, benzene or toluene. When alcohol is used, absolute alcohol achieves the good yield. Then, more than equivalent of dry hydrogen chloride gas is absorbed into the resultant solution or the suspension. Then the HC1 salt of the N^-acylated phenyl-hydrazine derivative (II) precipitates as crystals in good yield. Sulfuric acid or others can be used in place of gaseous hydrogen chloride. When ether, benzene or toluene is used as the solvent, a small quantity of alcohol should be added to it. The reaction temperature is preferably 0°-25°C. though may be below 0°C, As the N^"-acylated phenylhydrazone derivative (IV), various compounds can be illustrated. For example, the hydrazones of acetaldehyde, chloral, benzaldehyde, acetal, ethyl acetoacetate and methoxy acetone can be easily decomposed in general cases to give the aimed N^-acylated phenylhydrazine derivative (II). Among them, the hydrazone of acetaldehyde has especially distinctive commercial advantages.

According to the present invention, the following N^-. acylated phenylhydrazine derivatives (II), for example, can be obtained: J^-cinnamoyl-N1-( p-methoxyphenyl )hydrazine N1-cinnamo l-N1-(p-meth lphenyl) hydrazine N1-cinnamoyl-N1-(p-chlorophenyl)hydrazine N^-cinnamoyl-N"1"- (p-methylthiophenyl)hydrazine N^-cinnamoyl-N^-(p-ethoxyphenyl)hydrazine N 1-(5 ' -phenyl-2' , 4 ' -pentadienoyl)-N1-(p-methoxyphenyl)hydrazine N^-( 5 ' -phenyl-2 ' , 4 ' -pentadienoyli-N^-ip-ethoxyphenylihydrazine 1 1 N -cinnamoyl-N -(p-methoxyphenyl)hydrazine 1 1 1" N -cinnamoyl-N -jfaethylphenyl)hydrazine N"^-( ' -phenyl-3' -butenoylJ- ^-i p-methoxyphenyl)hydrazine N*1"-( m-nitrocinnamoy1) -N"1"-(m-methoxyphenyl)hydrazine N^-(m-nitrocinnamoy1 )-N1-( p-methylphenyl)hydrazine N"'"-(m-nitrocinnamoy1 )-N"*"-(p-chlorophenyl)hydrazine N"''-i m-nitrocinnamoylJ- ^-i p-methyIthiophenyl)hydrazine m-nitrocinnamoyl) -N"1"-(p-ethoxyphenyl )hydrazine N""-(methyIthiocinnamoy1 )- ^"-( p-methoxyphenyl)hydrazine N^"-(p-methoxycinnamoy1) ( p-methoxyphenyl)hydrazine N^"-( p-chlorocinnamoyl)-N~*"-( p-methox phenyl)hydrazine N1-^ ' -(p-chlorophenyl)-2 ' , 4 ' -pentadienoylj -N1^p-methoxyphenyl)- hydrazine N'1"-(<-phenyl-p-chlorocinnamoyl)-N1-( p-methoxyphenyl)hydrazine N"^-(^-p-tolylacryloyl)-N^-( p-methoxyphenyl)hydrazine N^"-((^-methyl-p-chlorocinnamoyl ) ( p-methoxyphenyl)hydrazine N~^"-(p-chlorocinnamoyl) -N"1"-( m-methoxyphenyl)hydrazine N^-phenylacetyl-N^"-(p-methoxyphenyl)hydrazine N- phenylacetyl-N^-(p-methylthiophenyl)hydrazine (p-methylphenylacetyl)-N"*"- (p-methoxyphenyl)hydrazine N -phenylacetyl-N -phenylhyd azine ' -pyrld.yla!u l.y l) -N1-( p-we hu plmnj 1) dra ine 1 "L ■g' -pyinidylacetyl)-N1-(p'"me,¾!ho¾yphGnyl)hydi'aoino 2' -thienylacetyl)-N -(p-methoxyphenyl)hydrazine N - 2' -f rylacetyl)-N1-(p-methoxyphenyl)hydrazine ' -chloro-21 -thienylacetyli-N^-ip-methoxyphenylJhydrazsiine diphenylacetyl)-N1-( p-methoxyphenyl )hydrazine N 2-pheny1-n-butyroyl)-N -( p-methoxyphen l)hydrazine (p-methoxyphenyl )hydrazine N" [3-naphthylacetyl)-N -(p-methoxyphenyl)hydrazine m, p-dimethoxyphenylacetyl)-N -( p-methoxyphenyl)hydrazine 4 ' -p-me hoxyphenyl-n-butyroyl) -N1-(p-methoxyphenyl)hydrazine 5 ' -phenyl-n-pentanoyl)-Nx-( p-methoxyphenyl)hydrazine N - 5 ' -phenyl-n-pentanoyl)-N -(p~ethoxyphenyl)hydrazine N -•phenylacetyl-N^"-(m-methoxyphenyl)hydrazine N1-phenylacetyl-N -(m-methylphenyl)hydrazine N - ' -phenyl-n-butyroyl)-N -(p-methoxyphenyl)hydrazine β-2 ' -thienylacryloyl) -N -( p-methoxyphenyl)hyd I:razine |S-2 ' -thienylacryloyl) -N -( p-methylphenyl )hydrraazziinnee - | -2 ' -thienylacryloyl) -N - (p-chlorophenyl)hydI:razine [3-2 ' -thienylacryloyl) -N -(p-methylthiophenyl)hyd I:razine N - '^-2' -thienylacryloyl) -N -(p-ethoxyphenyl)hydrazi.nnee 3-2 ' -thienylacr loyl) -N -( m-methoxypheny1)hydrazs:ine · N1- ^-2 ' -furylacryloyl) -N1-( p-ethoxyphenyl )hydrazine * '|ff-g' -pyr dylacryloyl ) (m roc hoxyphonyl)hyd]rasine- N1- (β-2 ' -pyridylacryloyl )-N1-(m-methylphenyl)hydrazine N1- -2 ' -furylacryloyl J-N1- ( p-methoxyphenyl )hydrazine N1- ^-('^' -naphthyl)-acryloylj -N1^ p-methoxyphenyl)hydrazine Their salts, for example, hydrochlorides, sulphates and phosphates, can be easily obtained. All of them are novel compounds that have not been reported in any literature.

These compounds have psychic, stimulating, anti-tumor, bactericidal and fungicidal activities and are very important as intermediates for producing strong anti-inflammatory drugs, analgesics and anti-pyretics.

In some cases the novel N^-acylated phenylhydrazine derivatives (II) are directly obtained by reacting a phenyl-hydrazine derivative (X), wherein has the same meaning as identified in the formula (I), or salts thereof, with a compound (VI) R1 _ A - CO - Y (VI) wherein and A have the same meanings as identified in the formula (I) and Y is a halogen atom in this case, 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 dehydrogenhalide agent such as a tertiary amine. As the tertiary amine, triethyl amine, pyridine or dimethylaniline is suitable and the amount thereof is required preferably at least equal mole of the said phenylhydrazine derivative (X).

This reaction proceeds so rapidly that the compound (VI) is added slowly to a phenylhydrazine derivative (X) in a suitable phenyl-hydrazine^, solvent while cooling. The N -acylated rderivative (II) thus obtained is contaminated with a by-product such as N -acylated\ 2 2 1 compound or N ,N -diacylated compound, however the objective N - > phenyl-hydrazine J acylated (derivative (II) is separated and purified by removing the by-products by a suitable method such as column chlorpmatography . However, the purification of the N"^"-acylated compound is not necessary, because only the E^-acylated derivative' is concerned with the following reaction in the present invention.

According to the process of the present invention the compounds having the following substituents, which are represented by R1, R6 and A in the said formula (II), (VI) and (X) are . obtained.

R^": phenyl, p-chlorophenyl, p-methylphenyl, p-methoxy-phenyl, p-bromophenyl, p-ethylphenyl, p-ethoxyphenyl, g-pyridyl,-Ί .. yrAd,y;L, 2-furyl, 3-f ryl, 2-thienyl, 3-thienyl, 5-chloro-2-thienyl, Jff-methyl-3-pypora yJ.., o-naphthyl4, hydrogen n nm;, A: -CH2-, -CH2-CH=CH-, -CH=CH-, -CH=CH-CH=CH-, -CH2-CH2-CH2-CH2-, - , -CH2-CH=CH-CH2- and -CH2-CH=CH2 R : chlorine, bromine, fluorine, hydrogen, methyl, ethyl, isopropyl, methoxy, ethoxy, propioxy, methylthio, ethylthio and isopropylthio .

Lastly the process for producing a l-acyl-3-indolyl aliphatic acid derivative (I) by the reaction of an N^-acylated phenylhydrazine derivative (II) with an aliphatic acid derivative (III) will be described.

This reaction is carried out on heating in the presence of an adequate condensing agent or not in an organic solvent or not. The yield is very high.

The present reaction proceeds smoothly without a solvent but it is preferable to use a suitable solvent in many cases. As the solvent, organic acids, for example acetic acid, formic acid, propionic acid, lactic acid, butyric acid, non-polar organic solvents, for example cyclohexane, n-hexane, benzene, toluene, and other organic solvents, such as dioxane and dimethyl formamide are used in the ring formation reaction. When an alcohol is used as a solvent in this reaction, a corresponding ester ox indole aliphatic acid is produced. For example, A 5-substituted indole derivative can be prepared in derivative, /nwevw^r^Rsr meta-substituted phenylhydrazine derivative 3-Θ·- *ΘΘ&> two isomers, 4- and 6-substituted indole derivatives can be obtained.

These isomers can be generally separated by column chromatograph .

At a temperatures within a range of 50° to 200°C., the reaction generally proceeds but a temperature within a range of 65° to 95°C is preferable. The reaction proceeds rapidly and is generally finished in a short period of reaction time, mostly in one or two hours. The condensing agent is not needed in some cases but desirable results are generally achieved by using a condensing agent. The condensing agent includes inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, metal halides such as zinc chloride and copper chloride, heavy metal powder such as copper powder, Grignard's reagents, boron fluorides, polyphosphoric acid or ion-exchange resins. Hydrochloric acid or the like is required in an equimolar or larger amount while copper powder or the like may be in a small amount.

In after treatment, the reaction mixture is allowed to stand at room temperature or in a refrigerator (about 5°C.), and then a large amount of crystals of the product is mostly obtained.

When crystals do not produce, the reaction mixture is concentrated under reduced pressure, or water, acetic acid-water or petroleum ether is adequately added to the mixture. And then, the beautiful crystals can be obtained. Ether, acetone, acetone-water, alcohol, alcohol-water, benzene and acetic acid are generally preferred as a solvent for recrystallizing the present compound. Polymorphic crystals are often given in these compounds, and their crystal system varies with kind of a recrystallizing solvent and crystallizing velocity. The produced crystals are collected by filtration and they are generally washed with an aqueous solution of acetic acid, alcohol-water, water or petroleum ether before they are dried. Objective products are generally crystalline, but oily products are sometimes given in ester compounds.

Reaction solvents, reaction conditions, condensing agents and recrystallization solvents which have mentioned above are only presented as illustrative of the present invention but not in its limitation, needless to speak of.

The following compounds are easily obtained in good yield, theoretically or in nearly theoretically, according to the process of the present invention: l-einnamoyl-2-methyl-5-methoxy-3-indolylacetic acid l-Cinnamoyl-5-methoxy-3-indolylacetic acid l-Cinnamoyl-2, 5-dimethyl-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-chloro-3-indolylacetic acid l-Cinnamoyl-2-methyl-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-methylthio-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-ethoxy-3-indolylacetic acid Dimethyl l-cinnamoyl-2-methyl-5-methoxy-3-indolylmalonate l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetamide t-Butyl l-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate Ethyl l-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate Methyl l-cinnaraoyl-2-methyl-5-methoxy-3-indolylacet te Benzyl l-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate Tetrahydropiranyl l-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate ¾-(l-Cinnamoyl-2-methyl-5-methoxy-3-indolyl)butyric acid o(v-(l-Cinnamoyl-2-methyl-5-methyl-3-indolyl)propionic acid ^-(l-Cinnamoyl-2-methyl-5-methoxy-3-indolyl)propionic acid c acid and l-cinnamoyl-2,6-dimethyl-3-indolylacetic acid A mixture of l-cinnamoyl-4-methyl-3-indolylacetic acid and 1- cinnamoyl-6-methyl-3-indolylacetic acid l-(4' -Phenyl-3' -butenoyl)-2-methyl-5-methoxy-3-indolylacetic acid d- l-(4' -Phenyl-31 -butenoyl)-2-methyl-5-methoxy-3-indolyl| propionic acid l-( 2' -d -Naphthylacryloyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(p' -Nitrocinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid _P enylcinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(3 ' -•Phenylcrotonoyl)-2-methyl-5-methoxy-3-indolylacetic acid ' -Benzylcinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(p' -Bromocinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(p ' -Chlorocinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(p' -Methoxycinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid l-ic , |31 -Dibromocinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid l-( 3 ' -Phenyl-3 ' -benzylidenebutyroyl) -2-methyl-5-methoxy-3- indolylacetic acid l-(Cinnamylidenepropionyl)-2-methyl-5-methoxy-3-indolylacetic acid 1-(β ' -Styrylacryloyl)-2-methyl-5-methoxy-3-indolylacetic acid f- jl-(( ' -Styrylacryloyl)-2-methyl-5-methoxy-3-indolyl butyric acid l-(p' -Styrylacryloyl)-2-methyl-5-ethoxy-3-indolylacetic acid Dimethyl l-(phenylacetyl)-2-methyl-5-methoxy-3-indolylmal0nate l-(Phenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid "j)f- )l-(Phenylacetyl)-2-methyl-5-methoxy-3-indolyl butyric acid (^-l-(Phenylacetyl)-2-methyl-5-methoxy-3-indolylpropionic acid l-(Phenylacetyl)-2, -dimethyl-3-indolylacetic acid l-(Phenylacetyl)-5-methoxy-3-i-indolylacetic acid l-(Phenylacetyl)-2-methyl-5-chloro-3-indolylacetic acid Methyl l-(phenylacetyl)-2-methyl-5-methoxy-3-indolylacetate l-(Phenylacetyl)-2-methyl-5-methoxy-3-indolylacetamide Benzyl l-(phenylacetyl)-2-methyl-5-methoxy-3-indolylacetate Tertiary butyl l-(phenylacetyl)-2-methyl-5-methoxy-3-indolylacetate l-(Phenylacetyl)-2-methyl-3-indolylacetic acid l-(Furylacetyl)-2-methyl-5-methoxy-3-indolylacetate l-( 2' -Phenylpropionyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(4 ' -Methoxyphenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid l-( ' , 4 ' -Dimethoxyphenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid Besides these compounds indole derivatives having the following groups as 1-substituent of indole ring represented by -CO-A-R^ can be prepared by the process of the present invention in good yield.

-CO-A-R"": p-Cyanocinnamoyl, m-Cyanocinnamoyl, o-Iodohydrocinnamoyl, o-Iodophenyl-2' -nitrocinnamoyl, 4' -Chloro-3' -nitrocinnamoyl, ,β ' -Dichlorocinnamoyl, p' -Methylcinnamoyl, 1*,4'-Diphenyl-1' -butylene-1' -carbonyl, 3' , 4 ' -Diphenyl-11 -butylene-1 ' -carbonyl, 1' , 1' -Diphenyl-1' -butylene-2' -carbonyl, 1' ,4'-Diphenyl-1' ~butylene-2 ' -carbonyl, 1' , 4 ' -Diphenyl-1* -butylene-3 ' -carbonyl, 1' , 1' -Diphenyl-1' -butylene-41 -carbonyl, 1' , 3 * -Diphenyl-1' -butylene-4'-carbonyl, 1' , 4' -Diphenyl-2* -butylene-1* -carbonyl, 2'-j?'-naphthylacryloyl, o ' -Nitrocinnamoyl, 3 ' -(p1 -Methoxyphenyl)-crotonoyl, ■¾.'■-( 4 " ■Quirtolyl) «ac-yloyl.> ' -Benzylcinnamoyl, o'-Bromocinnamoyl, m' -Bromocinnamoyl, o* -Chlorocinnamoyl, p'-Chloro-cinnamoyl, -Chloro-2' -nitrocinnamoyl, rj^ -Chloro-31 -nitrocinnamoyl, c -Chloro-4' -nitrocinnamoyl, β 1 -Chloro-3' -nitrocinnamoyl, o-Iodophenylacetyl ( ~VcH2C0- p-Isopropylhydrocinnamoyl (CH-j) 2CH- CH2CH2C0- o-Metho yhydrocinnamoy1 m-Methoxyhydrocinnamoyl CH2CH2CO OCH, CEL -Methylhydrocinnarao 1 2-Methyl-2-phenylbutyroyl CH, CH_ I 3 ! 3 2-Methyl-3-phenylb tyroyl CH - CH- 2-Methyl-4-phenylb tyroyl -CH2-CH2-CH-CO- 2-Methyl-4-/3-naphthylb tyroyl. 0- 2-Phenylisobutyroyl 3-Phenylisovaleroyl C0- OH, -Phenylvaleroyl CH2CH2CH2CH2CO- C^-Bromophenylacetyl -CHCO- o-Bromophenylacetyl o-Chlorohydrocinnamoyl m-Chlorohydrocinnamoyl I p-Chlorohydrocinnamoyl I Cl-f -CH2CH2CO- CI o-Chlorophenylacetyl I ί VCH2C0- -Chlorophenylacetyl -Chlorophenylacetyl -Tolylbutyroyl -Dibromohydrocinnamoyl (Br- VCHBrCH2C0 2,3-Dichlorohydrocinnamoyl ( ά,ά -Dichlorophenylacetyl 2, 6-Dichlorophenylacetyl d,o-Dichloro-]f-phenylbutyroyl O- |3-2, 3-Dichlorophenylb tyroyl 2, -Dimethylphenylacetyl 2,4-Diphenylbutyroyl [ 3 , 3-Diphenylbu.tyroyl 3 , -Diphenylb-utyroyl 2, 3-Diphenylb-utyroyl 4 , 4-Diphenylbutyroyl CHCH„CH CO- 3 , 3-Diphenylpropionyl 2-Meth 1-2-( -naphthyl)propionyl 2-Ethyl-2-(o;-naphthyl)b tyroyl CE, Methyl-(4-phenyl)phenyl < < Many other l-acyl-3-indolyl aliphatic acid derivatives can be thus synthesized.

In this method of the present invention, when the aliphatic acid derivative (VIII) of which R^" is carboxy group, n is 0 and p is 1 in the formula (III) reacts with an N^-acylated phenylhydrazine derivative (II), an l-acyl-3-indolyl aliphatic acid derivative (VII) can be obtained as follows.

A (VIII) R1 (II) wherein R 1, R , R , R 6 , A and m have the same meanings as mentioned above.

The following compounds, for example, are easily obtained in a good yield by this method . l-Phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-ethoxy- -indolylacetic acid l-Cinnamoyl-2-methyl-3-indolylacetic acid Further in some cases an l-acyl-3-indolylacetic acid derivative of the formula, CO I A R1 (IX) wherein R^", and A have the same meanings as identified in the formula (I), is prepared from an· N^-acyl phenylhydrazine derivative acetosuccinlc A (II) or salt thereof and/«¾-δ¾5ββϊϊ%ΐβ acid or 2-ketoadipic acid.

An example of this method is shown as follows: The following compounds, for example, are prepared in a good yield, by this method. l~Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid l-(p-Methoxycinnamoyl)-2-methyl-5-methoxy- -indolylacetic acid l-Phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-ethoxy-3-indolylacetic acid l-Cinnamoyl-2-methyl-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid 1«(^»,2' iPyridy-Laory-Loyl)-2"mothyl 5 mothoxy ^-indolylaootio aoid* Further, in the process of the. present invention, a 1-acyl-3-indolyl aliphatic acid derivative (I) can be obtained directly from an N -acylated (IV) in some cases, in which a 1 -acyl-3-indolyl aliphatic acid derivative (I) is produced by reacting an N -acylated phen l-hydrazone derivative (IV) with an aliphatic acid derivative (III) on heating in the presence Of a suitable condensing agent or not in an organic solvent or not* According to this method, as a solvent, organic acids such as formic acid, propionic add, lactic acid and butyric acid^ non^polar organic solvents stich as oyolohexane, n-hexane, benzene and toluene or an alcohol may be available* The reaction generally proceeds at 50° to 200°0·, preferably at 65° to 95QC.

Inorganic acids such as hydrochloric acid and sulfuric acid, metal halides such as zinc chloride copper chloride* boron fluoride and polyphosphoric can be used as a condensing agent in the reaction* The following i -acyl^3-indolyl aliphatic acid derivatives, for example, can be prepared by the method* t-Phenylacetyl-2^ethyl-5"^ethoxy-»3-indolylacetlc acid A I-, Rx (VII) Following compounds, for example, are obtained by this method. l-Phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid Still further, according to the present invention a 1-acyl-3-indolyl aliphatic acid derivative represented by the formula (I) is prepared from the phenylhydrazine derivative of the formula (XI) or a salt thereof and an aliphatic acid derivative of the formula (III) in the presence or absence of a suitable solvent, and in the presence or absence of a condensing agerit.

In the reaction, suitable solvents are organic acids, such as acetic acid, formic acid, propionic acid and lactic acid, non-polar solvents such as cyclohexane, n-hexane, benzene, toluene and xylene, ether compounds such as dioxane and diisopropyl ether or other conventional organic solvents. Suitable condensing agents are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrogenchloride , metal halides such as zinc chloride, copper chloride, a metal powder, such as copper powder, a Grignard ' s reagent, a boron fluoride, polyphosphoric acid or an ion-exchanger resin. However, it is not always necessary to use a solvent or a condensing agent. This indole ring formation proceeds under heating the reaction mixture at 50° to 200°C., and is completed within several hours. Preferably, the reaction is continued at 65° to -95°C. for 1 to 4 hours.

After completion of the reaction, the reaction mixture is allowed to cool, a large amount of crystals are generally when produced as precipitate. Even in the case wkiefe crystals are not produced, if the solvent is removed by distillation or water or petroleum ether is added to the reaction mixture, a large amount of crystals can be obtained. The crude crystals are collected by filtration, washed with water and thereafter recrystallized from a suitable solvent to give a pure objective product.

This process of the present invention, for example, is shown by a chemical equation as follows: For example.,, l-racyl-3-indolyl aliphatic acid derivatives which are prepared by this method are as follows, but it is. not acid / necessary to say that l-acyl-3-indolyl aliphaticderivatives are not restricted only to them. l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid Benzyl l-phenylacetyl-2-methyl-5-methoxy-3-indolylacetate l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetamide l-Cinnamoyl-5-methoxy-3-indolylacetic acid (-(l-Cinnamoyl-5-methoxy-2-methyl-3-indolyl) -propionic acid l-(p-Methylcinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid *l" (|S"2-Pyridylaoryloyl) "i2-mothyl-5- mothoxy-'3 indolylaootio aoid l-((3-Styrylacryloyl)-2-methyl-3-indolylacetic acid l-Cinnamoyl-2, 5-dimethyl-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-chloro-3-indolylacetic acid l-Cinnamoyl-2-methyl-4-methoxy-3-indolylacetic acid 1-Cinnamoy1-2-methy1-6-methoxy-3-indolylacetic acid l-Cinnamoyl-2-methyl-5-methylthio-3-indolylacetic acid l-Cinnamoyl-2-methyl-3-indolylacetic acid l-Cinnamoyl-2-ethyl-5-methoxy-3-indolylacetic acid Still further, according to the present invention a l-acyl-3-indolyl aliphatic acid derivative (XII) is obtained by converting an ester or amide derivative (XIII) of a corresponding 3-indolyl aliphatic acid.

For example, a benzyl ester of a 3-indolyl aliphatic acid is converted to a free 3-indolyl aliphatic acid derivative (XII) by hydrogenating with decomposition in the presence of a metal catalyst such as palladium.

This method is shown, for example, as following reaction formula: If the alcohol moiety of the ester compound (X) is tertiary butyl alcohol, the ester is treated with an arylsulfonic acid such as p-toluenesulfonic acid to yield an objective product.

If a tertiary butyl ester is only fused by heating, it is decomposed to yield an objective free 3-indolyl aliphatic acid derivative (XII). derivative! In a few cases a free 3-indolyl aliphatic acid may be obtained by treating an amide of the corresponding 3- derivative f indolyl aliphatic acid †ooffipo¾»w with a suitable amount, of nitrous acid in an inert solvent.

The following compounds, for example, are prepared by this method. l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid l-Phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid l-(p-Tolylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(p-Isobutylphenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid l-Phenylacetyl-2-methyl-5-chloro-3-indolylacetic acid l-Phenylacetyl-2, 5-dimethyl-3-indolylacetic acid l-Phenylacetyl-2-methyl-5-methylthio-3-indolylacetic acid ^-(l-Phenylacetyl-2-methyl-5-methoxy-3-indolyl) propionic acid o(-(l-Phenylacetyl-2-methyl-5-methoxy-3-indolyl)propionic acid l-(m-Chlorophenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid l-Phenylacetyl-5-methoxy-3-indolylacetic acid l-Phenylacetyl-2-methyl-4-methoxy-3-indolylacetic acid l-Phenylacetyl-2-methyl-6-methoxy-3-indolylacetic acid l-(^-Naphthylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid 1- ||3- ( 2' -F-uryl)-acryloylj-2-methyl-5-methoxy-3-indoiylacetic acid l-(2' -Thienylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid &-. 2' r-i (d>,. P ]ridyl)-aor lo l]- 2- methyl 5 mothoxy-3-indolylaoctio aoid l-(2' -Phenylbutyroyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(2'-Phenylbutyroyl)-2,5-dimethyl-3-indolylacetic acid l-(3' -Phenylpropionoyl)-2-methyl-5-methoxy-3-i dolylacetic acid l-(3' -Phenylpropionoyl)-2-methyl-5-chloro-3-indolylacetic acid ¾«Piyaloyl-»2-mQthyl-5-mothoxy" 3 indolylaoctio aoid- Still further, according to the present invention^ a 1-acyl-3-indolyl aliphatic acid derivative represented by the formula (XV) can be prepared by oxidizing an indolyl-3-acetaldehyde derivative · represented by the formula (XVI).

In this process of the present invention, potassium permanganate, hydrogen peroxide, organic peroxide, silveroxide, selenium dioxide and copper hydroxide can be used as an oxidizing agent, and especially potassium permanganate or copper hydroxide is most preferable in many cases.

The following groups, for example, are given as the 1 2 ^ substituents shown by -A-R , R and R^ of the l-acyl-3-indolyl aliphatic acid derivatives of the said formula (XV) which are easily prepared by this method, -A-R1: benzyl, styryl, cinnamyl,* 2-phenylvinyl, 2-( 2 ' -thienyl)- Vinyl, 2"( ? ' ~pyr>i d l ) -v nyl ; P- ( ? 1 -fnrany1 ) -vi n 1 } p-methoxybenzyl, p-methylbenzyl, 2, 2-diphenylvinyl, 2-( cinnamyl) -vinyl, t-fnB.Qthyl--he¾ahydro-3-pyyicylmothyl, 2-( ή '.»pyir-LdyiL)-vi» 3a and 2-( 5 ' -chloro-2 ' -thienyl) -vinyl.

-R and R^: hydrogen, methyl and ethyl.

-R^ ' . methoxy, ethoxy, iso-propyloxy, methyl, ethyl, n-propyl, propyl, tertiary-butyl, methylthio, ethylthio and. hydrogen An indole-3-acetaldehyde derivative . (XVI) , which is a starting . substance of this method, can be prepared according to the following reaction process: (XVIII) R I ) R1 wherein R , R , R , R and A have the same meanings as~.identif.iecL above; and R means a lower alkyl.

For example, N -(phenylacetyl)-Ii -(p-methoxyphenyl)-hydrazine hydrochloride is reacted with levulinic aldehyde diethylacetal to yield l-( phenylacetyl)-2-methyl-5-methoxy-3-indolyl-acetaldehyde diethylacetal, and the resulting diethyl-acetal derivative is treated with water in the presence of a small amount of an acid to yield l-(phenylacetyl)-2-methyl-5-methqxy-3-indolyl-acetaldehyde as shown by the following reaction formula: N-NH -HC1 + CH_C0CH CH CH(0C H--) 2 2 2 2 5 2 Still further, according to the present invention, a 1-acyl-3-indolylacetic acid derivative of the formula (XV) is prepared by oxidizing the corresponding indoles-methanol derivative of the formula (XIX).

That is, an indole-3-ethanol derivative (XIX) is oxidized chromic j by potassium permanganate or/ &∞αΆθ~ acid to give a l-acyl-3- ■ indolylacetic acid derivative (XV) in a good yield.

Substituent represented by and A of a l-acyl-3-indolyl acetic acid derivative (XV) which can be prepared by this method, aire as follows: -A-R1: benzyl, styryl, cinnamyl, 2-(2' -thlenyl) -vinyl,. - (3' - - pyr-idy 1) -vinyX, 2-(2' -furanyl)-vinyl, p-methoxybenzyl, p-methylbenzyl, 2, 2-diphenylvinyl, 2-(cinnamyl)-vinyl, .

^Tnmet lhgaa ydro^-p r d -Lmothyl, 2-( ' -pyridyl)-vinyl and 2-(5'-chloro-2'-thienyl)-vinyl, - -R 2' and -R^': 'hydrogen,, methyl and ethyl. · -R 6 : methoxy, ethoxy, iso-propyloxy, methyl, ethyl, n-propyl, iso-propyl, tertiary-butyl, methylthio, ethylthio and hydrogen.

The indole-3-ethanol derivative (XIX), a starting compound of this method, is prepared by following reaction process: wherein R , R , R , R and A have the same meanings as identified above .

For example, 2-(l' -Cinnamo l-2 ' -methyl~5 ' -methoxy-3' -indolyl)-ethanol is obtained in high yield according to the following reaction process: 1 + CH,C0CH CH CH 0H Still further, according to the present invention, a 1 acyl-3-indolylacetic acid derivative (XV) is prepared by dehydro genation of the corresponding 2, -dihydro-3-indolylacetic acid derivative (XXI).

In this dehydrogenation, non-polar solvent, such as benzene, xylene and toluene and other various organic solvents, such as acetone, acetic acid, chloroform, ethanol and methanol can be used.

As agents for the dehydrogenation, chloranil, selenium dioxide, halogen and the like oxidizing agents can be used.

According to the above method, the following compounds can be easily obtained: l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid l-(p-Chlorocinnamoyl)-2-methyl-5-methoxy- -indolylacetic acid l-(Cinnamylacryloyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(p-Methoxyphenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid l-(p-Tolylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid A starting substance, l-acyl-2, 3-dinydro-3-indolyl aliphatic acid derivative (XXI) is obtained in a high yield by reacting a 2, -dihydro-3-indolyl aliphatic acid derivative with a corresponding acyl chloride in the presence of a hydrogen chloride acceptor.

Still further, according to the present invention a l-acyl-3-indolylacetic acid derivative of the formula (XXII) is prepared by dehydration of a 2-hydro-3-hydroxy-3-indolylacetic acid derivative of the formula (XXIII) and then, if necessary, by hydrolysis of the resultant ester compound.

The reaction proceeds at a temperature within the range of 70° to 200°C. However, if a reaction does not proceed smoothly, the compound (XXIII) is azeotropically refluxed with an azeotropic solvent, for example benzene, toluene or xylene, or is heated in the presence of a suitable dehydrating agent, for example a proper amount of anhydrous sodium' sulfate , whereby a dehydration reaction takes place.

When a l-acyl-3-indolylacetic acid derivative (XXII), in which is an alkyl group, for example t-butyl group, is treated in the presence of arylsulfonic-acid, it is converted without affecting the acid-amide bonding to the desired free acid.

The 2-hydro-3-hydroxy-3-indolylacetic acid derivative (XXIII), the starting compound of the above process, is prepared by heating the mixture of alkyl halogenoacetate and a corresponding indole derivative with stirring in a non-polar organic solvent in the presence of zinc powder and, if necessary, a small piece of iodine. One example of the above reaction is as follows: L The following compounds, for example, are prepared ..by this method. l-Phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid . l-Phenylacetyl-2-methyl-5-chloro-3-indolylacetic acid . (β-Cinnamylacryloyl) ? l- p-ei»fta»eyia9Jsyl&3ii -2-^ acid . l-(p-Chlorocinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid. 1-(p-Tolylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid . l-(p-Methoxycinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid . l-(Phenylacetyl)-2-methyl-5 ^¾S$¾t-3-indolylacetic acid . l-(Naphthylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid.

Still further, according to the present . invention, a crude l-acyl-3-indolylacetic acid derivative (XV) is obtained by <3Γ heating an^(N-acyl-anilino)-aliphatic acid derivative (XXIV) in the presence of a suitable catalyst or a dehydrating agent. The crude product thus obtained can be purified by recrystallization from a proper organic solvent or, if the recrystallization fails, a column-chromatography can be used. 3-Indolylacetie acid derivatives having the following η 'τ. C. groups as R , R , R , R and A in the formula (XV) are easily obtained by this method.

-A-R1: benzyl, styryl, cinnamyl, 2-( 2' -thienyl) -vinyl, 3 (foi ■> pyridyJi) »v.inyl.» 2-( 2 ' --furanyl)-vinyl, 2-( cinnamyl )-vinyl, ..-J*mothy-L-hoxahydro- -pyridyl~mothyl,—5- ( ' -pyridyl )-vinyl, 2, 2-diphenylvinyl and 2-( 3 ' -chloro-2' -thienyl) -vinyl.

-R2 and hydrogen, methyl and ethyl.

-R : Methoxy, ethoxy, iso-propylox , methyl, ethyl, n-propyl, iso-propyl, tertiary butyl, methylthio, ethylthio and hydrogen. .

The-fe-(N-acyl-anilino) -aliphatic acid derivative (XXIV), which is a starting substance of this method, is generally prepared by following processes: wherein R1, R2, R5, R5, R6 and A have the same meanings as identified above. For example, the reaction of p-anisidine with cinnamoyl chloride gives N-cinnamoylanisidine, which is subjected to give an oily substance of 4- pHmethoxyphenyl)-N-(phenyl-acetyl ) amino-3--oxovaleric acid.

Still further, according to the present invention, a 1-acyl-3-indolylacetic acid compound (IX) is prepared from a 3-(2*-acylaminophenyl) - levulinic acid derivative represented by the formula (XXV) in the presence of inorganic acid in a suitable solvent .

A range of reaction temperatures is from 40° to 120°C., and the most desirable result is obtained at temperature within the range of 60° to 90°C.

After a completion of reaction, a reaction mixture is neutralized, concentrated, and extracted with a suitable organic solvent, and then a separated organic layer is dried and concentrated to a crude crystalline substance. Recrystallization from ether, acetone or acetone-water gives a pure product.

Among novel 3-indolyl aliphatic acid derivatives of the present invention, there are not only a few useful compounds, which indicate excellent anti-inflammatory action but also possess extremely low toxicity.

In contrast to the above facts, the many compounds of this invention are markedly low in toxicity, and even when over 1,000 mg/kg of these compounds are orally administrated to each of rat and mouse, they scarcely show toxic symptoms and occult bleeding is negative in feces thereof.. Nevertheless, the activities of these compounds are much higher than those of 1,2-diphenyl-3, 5-dioxo-4-n-butylpyrazolidine (phenylbutazone) and oxyphenbutazone. Therefore, the therapeutic ratios of the compounds of the present invention are far greater than any other drugs. Therefore, these compounds are markedly""valuable in practical use.

The therapeutic ratios of these compounds of the present prior art compounds, Cp-chlorobenzoy1 )-2-methy1-5-methoxy-3-indolylacetic acid (Indomethacin) and 1, 2-diphenyl-3, 5-dioxo-4-n-butylpyrazolidine (Phenylbutazone) are given in the following table.

The present inventors prepared many other l-acyl-3-indolyl aliphatic acid derivatives than the compounds shown in the aforesaid table and evaluated the pharmaceutical effects thereof by animal tests.

The present inventors have found that many derivatives (I) of l-acyl-3-irtdolyl aliphatic acid, which are prepared by the present invention, are superior to l-( p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid (indomethacin) and 1, 2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine (phenylbutazone) in the therapeutic ratios thereof and has a great practical value.

It has found that these compounds also have comparatively potent analgesic activities shown by Haffner's method, and. antipyretic activities in a pyrogen test.

Description of the Preferred -Embodiments The following Examples are given ,to illustrate the present invention more particularly but it 'is not intended to limit the present invention only to them.

Example 1 13.8 g. of Phenylacetyl chloride was dropped to 13.1 g. of acetaldehyde ^-( p-methoxy henyl)hydrazone in 50 ml. of pyridine under cooling with ice. Thereafter stirring of the reaction mixture; was continued for' additional overnight under cooling with ice, and then it was poured into 250 ml. of cold water. As a result, a large amount of crystals were produced. The resultant crystals were collected by filtration, washed with water, and dried to yield 20 g. of acetaldehyde N1-(phenylacetylJ-N'^-ip-methoxyphenylJhydrazone, m.p. 98° -101°C .

In a way similar to that in Example 1, the following hydrazones were obtained.

Example 2 - Acetaldehyde N -(β-phenylpropiony1)-N -(ρ-methoxyphenyl)· hydrazone, m.p. 134° - 135°C.

Example 3 Acetaldehyde N1-( p ' -chlorophenylacetyl)-N1-( p-methoxy- phenyl)hydrazone, m.p. 93° - 96°C.

Example 4 Acetaldehyde N1-|y-(p' -methoxyphenyl) -n-butyroylj -^-(p- metho phen l) hydrazone , m.p. 96° - 98°C.

' Example 5 Acetaldehyde N^"-(cA-chlorophen lacetyl)-N^-(p-methoxy- phenyl)hydrazone, m.p. 107° - 110°C.

Example 6 Acetaldehyde N"*"-.(d-naphthylacetyl)-N^-(p-me hoxyphenyl )- hydrazone, m.p. 100° - 103°C.

Example 7 Acetaldehyde N^-(m, p-dimethoxyphenylacetyl)-N^-( p- methoxyphenyl)hydrazone, m.p. 88° - 90°C.

Example 8 Acetaldehyde N^-cinnamoyl-N^tp-methoxyphenyl)hydrazone, m.p. 166° - 170°C.

Example 9 Acetaldehyde N -(o(-methylcinnamoyl)-N -( p-methoxyphenyl) -hydrazone, m.p. 114° - 115UC.

Example 10 Acetaldehyde N -(p-chlorocinnamoyl)-N -( p-methoxyphenyl)-hydrazone, m.p. 168° - 174°C.

Example 11 . Acetaldehyde N -(p-methoxycinnamoyl)-N -(p-methoxyphenyl) hydrazone, m.p. 172° - 179°C Example 12 Acetaldehyde N1-(p-tolylacryloyl )-N1-( p-methoxyphenyl) -hydrazone, m.p. 169° - 172°C.

Example 13 Acetaidehyde N1- (m-nitrocinnamoy1)-N1-(p-methoxyphenyl) -hydrazone, m.p. 170° - 180°Ck Example 14 Acetaldehyde ^-(^-2' -furylacryloyl)-N1-( p-methoxyphenyl) hydrazone, m.p. 143° - 146°C.

Example 15 g. of acetaldehyde N -J.cihnamoyl-N -( p-methoxyphenyl )-hydrazone was suspended in 100 ml. of ethanol and the suspension mixture was shaken under cooling with ice* 0 g. of gaseous hydrogen chloride was absorbed in the reaction mixture for one hour under cooling with ice. The produced crystals were filtered, washed with 100 ml. of ether and dried to give 18.5 g. of N -cinnamoyl-N^-(p-methoxyphenyl)hydrazine hydrochloride; m.p. l"g£^C. (decomposed).

In a way similar to' that in Example 15, the followin compounds were obtained.

Example 16 N^-(m-nitrocinnamoyl)-N^-(p-methoxyphenyl)hydrazine hydrochloride, m.p. 165° - 170°C . (decomp.).

Example 17 N^cinnamoyl-^-Cp-tolylJhydrazine hydrochloride, m.p. 173° - 175°C (decomp. ).

Example 18 N -(o-phenylcinnamoyl)-N -( p-methoxyphenyl)hydrazine hydrochloride m .p. 145° - 160°C. (decomp.).

Example 19 N1- olylacryloy1) -N -( p-methoxyphenyl)hydrazine hydrochloride 187°C. (decomp.).

Example 20 N1-i-methylcinnamoyl)-N -(p-methoxyphenyl)hydrazine hydrochlorid m.p. 174°C. (decomp.).

Example 21 N1- p-chlorocinnamoy1) -N -(p-methoxyphenyl)hydrazine hydrochloride m.p. 179° - 182°C (decomp.) Example 22 N"*"-( p-methoxycinnamoyl )-N^"- ( p-methoxyphenyl)hyd hydrochloride, m.p. 178°C. (decomp.).

Example 25 N - (d-methy1-m-nitrocinnamoyl) -N - (p-methoxyphenyl) -hydrazine hydrochloride, m.p. 168° - 171°C (decomp.). : Example 24 N1-(phen lacetyl ) -N1-( p-methoxyphenyl)hydrazine hydrochloride, m.p. 165° - 166°C. (decomp.).

Example 25 N1- (B-phenylpropionyl ) -N1- (p-methoxyphenyl )hyd hydrochloride, m.p. 179°C (decomp.).

Example 26 N1- ( p ' -chlorophenylacetyl )-N1- ( p-methoxyphenyl )hydrazine hydrochloride, m.p. 202° - 203°C (decomp.).

Example 27 N1-j -("ρ-' -methoxypheny1) -n-butyroylj -N1-( p-methoxyphenyl) ■ hydrazine hydrochloride, m.p. 166°C. (decomp.)..

Example 28 ^-(oi-chlorophenylacetyli-N^^-ip-methoxyphenylihydrazine hydrochloride, m.p. 130°C . (decomp.).

Example 29 N1- ( diphenylacetyl ) -N1- ( p-methoxyphenyl )hydrazine hydro- chloride, m.p. 144 - 146°C. (decomp.).

Example 30 N^-(p 1 -nitrophenylacetyl)-N^-( p-methoxyphenyl )hydrazine hydrochloride, m.p. 204° - 205°C (decomp.).

Example 1 N1-((A-naphthylacety1 )-N1-( p-methoxyphenyl)hydrazine hydrochloride, m.p. 173°C (decomp.).

Example 32 , 1 1 N -phen lacetyl-Ή -(p-methylphenyl)hydrazine hydrochloride, m.p. 151° - 152°C. (decomp.).

Example 33 N"^-( phenylacetyl)-N"^-phenylhydrazine hydrochloride, m.p. 145° - 149°C (decomp.).

Example 34 N^-( phenylacetyl)-N^-(p-chlorophenyl)hydrazine hydrochloride, m.p. 167°C. (decomp.).

Example 35 N 1-(m, p-dimethoxyphenylacet l)-N1-(p-methoxyphenyl )-hydrazine hydrochloride, m.p. 165°C. (decomp.).

Example 36 58 g. of ace.taldehyde N1-(|9-2 ' -furylacryioy-O-N1-^-methoxyphenyl)hydrazone was suspended in^ 400 ml. of ethanol, and the suspension mixture was shaken under cooling with ice. g. of gaseous hydrogen chloride was absorbed in the reaction mixture over one hour.

The produced crystals were filtered, washed with 100 ml. of ether and dried to give 35.0 g. of N1-(^i-2' -furylacryloylJ-N1-(p-methoxyphenyl)hydrazine hydrochloride; m.p. 166°C. (decomp.).

In a way similar to this, N1-(^-2' -thienylacryloyl)-N1-(p-methoxyphenyl)hydrazine hydrochloride was obtained.

Example ^7 7.7 g. of phenylacetyl chloride was dr.opwise added to the solution mixture of 6.1 g. of p-tolylhydrazine and 5 g. of triethylamine in 150 ml. of toluene under cooling with ice.

Thereafter the temperature of the reaction mixture was raised slowly up to 70° - 75°C. and the heating of the mixture was continued at 70° - 75°C. for an additional 20 minutes. After the reaction mixture was allowed to cool, the crystals produced were removed by filtration, and the filtrate, was concentrated to oily residue, which was recrystallized from a solution mixture of ethanol and water to give N^-phenylacetyl-p-tolylhydrazine , m.p, 86° - 87°C It was treated with ethanolic hydrogen chloride to ggiivvee NN"^--pphheennyyllaaccee"tyl-p-tolylhydrazine hydrochloride; m.p.. 151 152°C. (decomp.).

Example 38 6.0 g. of cinnamoyl chloride was dropwise added to a mixture of 8.7 g. of p-methoxyphenylhydrazine hydrochloride, .1 g. of triethylamine and 200 ml. of toluene under cooling at -5° to 0°C. ' . .

The reaction mixture was stirred at 20° - 25°C. for one hour. The separated precipitates were filtered off and dry gaseous hydrogen chloride was introduced into the filtrate. As a result a , i^-cinnamoylj large amount of crystals of N -( 2 ' , ^^&xii&i-mv i)-N -(p-methoxy-phenyl)hydrazine hydrochloride were produced. These crystals were to that in- Example 38.

Example Q N -(phenylacetyl)-N -(p-methoxyphenyl)hydrazine hydrochloride, m.p. 166° - 167°C (decomp.).

Ex mple -40 a2in©—hydrochloride j 0 Example 4 N -(ρ' -methoxycinnamoyl)-N -(p-methoxyphenyl)hydrazine hydrochloride, m.p. 178 C. (decomp.).

C1 Example N1-(p-chlorophenylacetyl) -N^-ip-methoxyphenyl)hydrazine hydrochloride, m.p. 202°C. (decomp.). . 2 Example ¾ N1- -2 ' -furylacryloyl) -N1-( p-methoxyphenyl)hydrazine hydrochloride, m.p. 166°C. (decomp.).

Example 44 3 N^-((^-chlorophenylacetyl)-N^-(p-methoxyphenyl)hydrazine hydrochloride, m.p. 123°C. (decomp.).

Example 45- UU N1-(diphenylacetyl)-N1-(p-methoxyphenyl)hydrazine hydrochloride, m.p. 140° - 145°C. (decomp.).

Example 6- 5 N^-(o(-phenyl-n-butyroy 1 )-N^-( p-methoxyphen l)hydrazine hydrochloride, m.p. 159°C. (decomp.).

Example ·? i+6 N^- ( -phenylpropionyl) -N^- ( p-methoxyphenyl )hydrazine hydrochloride, m.p. 179°C. (decomp.).

"Example 48- l N^-cinnamoyl-N^-(m-methoxyphenyl)hydrazine hydrochloride, m.p. 168° - 169°C (decomp.).

Example 8> A mixture of 10 g. of N1-(phenylacetimidoyl)-N1-(p- methoxyphenyl)hydrazine hydrochloride, 5 g. of levulinic acid and 30 ml. of acetic acid was heated at 80° - 85°C for 3 hours under vigorous stirring.

After the reaction mixture was allowed to cool 50 ml. of water was added thereto to give crystals. They were collected by filtration, washed with 50 ml. of water and recrystallized from a mixture of acetone and water to give l-phenylacetyl-2-methyl-5- methoxy-3-indolylacetic acid, m.p. 138° - 139°C .

The following compounds were prepared according to a method similar to that of Example 49.

Exam-pie Θ U9 l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 164° - 165°C Example ■¾· 50 J'-(l-Cinnamoyl-2-methyl-5-methoxy-3-indolyl)b-atyric acid, m.p. 125° - 126°C.

Example -5-3- 51 fi-(l-Cinnamoyl-2-methyl-5-methoxy-3-indolyl)propionic acid, m.p.. 189° - 190°C.

Example 52 1-(^-2-Furylacryloyl) -2-methyl-5-methoxy-3-indolylacetic acid, m.p. 163° - 164°C Example -54» 53 l-(p-Hethoxycinnamoyl)-2-methyl-5--methoxy-3-indolylacetic acid, m.p. 193° - 195°C Example -- 5U 1-( p-Chlorophenylacetyl )-2-methyl-5-methoxy--3-indolyl--acetic acid, m.p. 180° - 182°C.

Example ·%- 55 Ethyl l-cinnamoyl-2-methyl-5"methoxy-3-indolylacetate , m.p. 162° - 163°C Example ¾■?- 56 l-(c,-Phenylb tyroyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 123° - 125°C Example 5Θ- 57 acetyl j l-(3' ,4' -Dimethoxypheny-l/-2-methyl-5--methoxy-3-indolyl-acetic acid, m.p-. 169° - 170°C.

Example 5» 8 l-(o(-C lorophenylacetyl)-2-methyl-5-methoxy- -indolyl-acetic acid, m.p.. 165° - 166°C.

Example -frfr 59 g. of N1-(phenylacetyl)-N1-(p-methoxyphenyl) ydrazine hydrochloride was added to 30 g. of levulinic acid. The mixture was heated at 76°C. for 3 hours, and then allowed to stand at room temperature overnight. The precipitates were collected by filtration, washed with water and dried to give crude crystals of l-(phenylacetyl)~2-methyl-5-methoxy-3-indolylacetic acid, which was recrystallized from acetone-water to give 9· 7 g. of a purified product, m.p. 141.5° - 143°C Microanalysis : Calculated 71.20 5.63 4,15 Found 71.54 5.84 3.96 According to this method, l-(phenylacetyl)-2~meth l-5-methoxy—3-indolylacetic acid was prepared in a similar yield from a mixture of 10 g. of levulinic acid and 25 ml. of acetic acid instead of 30 g, of levulinic acid.

Example 6¾ 60 A mixture of 10 g. of N1-(diphen lacetyl)-N1-(p-methoxy-phenyl)hydrazine hydrochloride and 20 g. of levulinic acid was heated at 75° - 83°C. for 2.5 hours with stirring. After the completion of reaction, the reaction mixture was poured into water, and then precipitate was produced. It was collected by filtration, washed with water and recrystallized from acetone-water to give light gray crystals of l-diphenylacetyl-2-methyl-5-methoxy-3~ indolylacetic acid; m.p. 150° -· 151°C.

Microanalysis C (#) H (#) N { ) Calculated 75.53 5.61 3.39 Found 74.92 5.56 3.69 Example &g-"6l In a way similar to that of Example 61, l-((?(-chloro-phenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 165° -166°C-„ , was prepared from N^-(d-chlorophenylacetyl)-N^"-(p-methoxyphenyl)hydrazine hydrochloride and levulinic acid.

Microanalysis Calculated 64.18 4.88 3-77 9.54 Found 63-70 4.89 . 3.86 9<77 Example 62 In a way similar to that in Example 61, !-(<?( -phenyl-butyroyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 123·5° -125°C. was prepared from ^-(c^-phenylbutyroylJ-N^-Cp-methoxyphenyl) hydrazine hydrochloride and levulinic acid.

Microanalysis C (96) H W N (96) Calculated 72.33 6.30 3.84 Found 72.51 6.38 3-94 Example -6 63 In a way similar to that in Example 61, l-(o-naphthyl" acetyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. .165.5° ~ 166.5°C was prepared from ^-((^-naphthylacetyli-N^-ip-methoxy-phenyl)hydrazine hydrochloride and levulinic acid„ Microanalysis C (*) H (96) N (96) Calculated 74.39 5,42 3.62 Found 74.43 5-54 3-70 Example 62+ A mixture of 10 g. of ^-(diphenylacetylJ-^-ip-methoxy-phenyl)hydrazine hydrochloride and 20 g. of ethyl levulinate was heated in 20 ml. of ethanol at 80° - 83°C. for 6.5 hours with stirring. After completion of the reaction, the mixture was allowed to cool and poured into water to give a dark blue homogeous solution, which was extracted with ether, and then the ether layer was dried on anhydrous sodium sulfate and concentrated to give light yellow crystals. The recrystallization from ether-alcohol gave pure pale yellow crystals of ethyl 1-diphenylacetyl-2-methyl-5-methoxy-3-indolylacetate, m.p. 121° -· 122°C. ■ Microanalysis C (96) H (96) N (96) Calculated 76.19 6,12 3-17 Found 75-59 6.21 3-13 Example ' 65 In a way similar to that in Example 61, l-(p-chloro-phenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 178°C, was prepared from 10 g. of ^-(p-chlorophenylacetyli-N^p-methoxy-phenyl)hydrazine hydrochloride and 30 ml. of levulinic acid.

Microanalysis C ( ) H ( ) N (*) Calculated 64.60 4.89 3.77 Found 64.45 4.96 3.86 Example 66 g. of N1-(p-nitrophenylacetyl)-N1-(p-methoxyphenyl)-hydrazine hydrochloride and 10 g. of levulinic acid were added to 30 ml. of acetic acid. The mixture was heated at 90° - 95°C. for 2 hours under stirring. Thereafter the mixture was poured into 150 ml. of water, and the resultant precipitates were collected by filtration, washed with water and recrystallized from dioxane to give . l-(p-nitrophenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 207°0.

Microanalysis Calculated 62.82 4.75 7.33 Pound 63.11 4.77 7.26 Example 67 In a way similar to that in Example 61, l-(^-p-methoxy-phenyl-n-butyroyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 163°C., was prepared from N^-C^-p-methoxyphenyl-n-butyroylJ-N^-ip-methoxyphenyl)hydrazine sulfate and levulinic acid.

Example -6368 In a way similar to that in Example 61, l-(m,p- dimethoxyphenylacetyl) -2-methyl-5-methoxy-3-indolylacetic acid , m.p. 169° - 170°C, was prepared from -^-(n^p-dimethoxyphenyl- acetyl)-N1-(p-methoxyphenyl)hydrazine hydrochloride and levulinic acid.

Microanalysis C (*) H { ) N (*) Calculated 66.49 5.83 3.55 Found 66.46 5-93 3-41 Example Ψ569 In a way similar to that in Example 61, Ι- -phenyl- n-propionyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 163° - 164°C., was prepared frpm N1-(|9-phenyl-n-propionyl)-N1-( p-methoxy- phenyl)hydrazine hydrochloride and levulinic acid.

Microanalysis Calculated 71.78 6.02 3.98 Found 71.85 6.07 4.08 Example ¾ 70 g. of N^-cinnamoyl-N^-ip-methoxyphenylihydrazine hydrochloride was added into 50 g. of levulinic acid, and the mixture was heated at 75°C. for 2 hours under stirring. Thereafter the reaction mixture was poured into 200 ml. of water under vigorous stirring, the resultant crystals were collected hy filtration, dried to give 34 g. of crude crystals of 1-cinnamoyl- 2-methyl-5-methoxy-3-indolylacetic acid, m.p. 158° - 160°C., which ■ was recrystallized from acetone twice. The melting point was raised to 164° - 165 Example W 71 In a way similar to that in Example 71, l-(| -p-tolyl-acryloyl)-2-methyl-5-methoxy- -indolylacetic acid, m.p. 195°C., was prepared by reacting N^-^-p-tolyl-acryloyli-N^-^p-methoxyphenyl)hydrazine hydrochloride with levulinic acid.

Example Ψ*τ 72 ■ In a way similar to that in Example 71, l-(p-chloro-cinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 220° -221°C, was prepared by reacting N^-(p-chlorocinnajnoyl)-N^"-(p-methoxyphenyl)hydrazine hydrochloride with levulinic acid.

Microanalysis Calculated 65-71 4.69 3-65 9.26 Pound 65.46 4.64 3.56 8.93 Example 73 According to a method similar to that in Example 71, l-(oti-methylcinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid , m.p. 153.5° - 154.5°C, was prepared by reacting N1-(o-methyl-cinnamoyl)-N^-(p-methoxyphenyl)hydrazine hydrochloride with levulinic acid.

Example g» 7k g. of N1-cinnamoyl-N1-(p-methoxyphenyl)hydrazine hydrochloride and 12 g. of acid were added to 30 ml. of acetic acid, and the mixture was stirred at 75°C. for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool, poure.d into 150 ml. of water, and the resultant precipitates were collected by filtration, washed with water and dried to give 18 g. of crude crystals of ^-(1-cinnamoyl-2-methyl-5-methoxy-3-indolyl)propionic acid, m.p. 182° - 186°C. The crude product was recrystallized from acetone-water to give ·.¾. 9.3 g. of the pure product, whereby the melting point was raised to 189° - 190°C.

Microanalysis Calculated 72.71 5.83 3-58 Found 72.59 5.96 3,43 Example ¾ 75 In a way similar to that in Example 75, 1-cinnamoyl- 2-methyl-5-methoxy-3-indolyl) utyric- acid , m.p. 125° - 126°C, was: prepared by reacting N^-cinnamoyl-N^-(p-methoxyphenyl)hydrazine hydrochloride with ~-acetyl-n-valeric acid.

Microanalysis Calculated 73.19 6.14 3.71 Found 73.23 6.14 3-61 Example 76 In a way similar to that in Example 75, yellow needle crystals of l-(m-nitrocinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 203° - 204°C . , was prepared by reacting N1-(m-nitro-cinnamoyl) -N"*"-(p-methoxyphenyl)hydrazine hydrochloride with levulinic acid.

Microanalysis Calculated 63.94 4.60 7.10 Found 63.98 4.66 7.01 Example 77 g. of N1-(j8-2'-f r lacryloyl)-li1-(p-methoxyphenyl)-. hydrazine hydrochloride was added to 15 g. of levulinic acid, and the mixture was stirred at 75° - 80°C. for 2 hours. Thereafter, the mixture was allowed to cool and poured into cooled water. The resultant brown precipitates were collected by filtration, washed with water thoroughly. The washing liquor and the precipitates were combined and ether was added thereto, and then the mixture was shaken, and the ether layer was separated. Similar procedures were repeated several times, and each ether layer was combined, dried on anhydrous sodium sulfate and concentrated to oily residue, which was recrystallized from methanol twice to give 3 g. of yellow crystals of Ι-ψ-21 -fur lacryloyl)-2-methy1-5-methoxy-3-indolylacetic acid, m.p. 163.5° - 165°C.

Microanalysis C W H (*) N W Calculated 67.26 5.01 4.13 Found 67.26 5.13 3.94 Example ¾ 78 g. of N1-Cinnamoyl-N1-(p^methoxyphenyl)hydrazine hydrochloride and 20 g. of ol-methyl levulinic acid were added to 10 ml. of acetic acid and the mixture was stirred at 80°C. for 2 hours. The reaction mixture was allowed to stand to cool, and poured into water to give an oily substance, which was washed with water thoroughly, and extracted with each 100 ml. of ether three times. Each ether layer was combined and dried on anhydrous sodium sulfate, and ether was removed by distillation to give a residue, which was dissolved in ethyl acetate and column-chlomatographed on neutralized active alumina to give crystals of d-(l-cinnamoyl-2-methyl-5-methoxy-3-indolyl)propionic acid. The recrystallization from acetone-water gave light yellow crystals of pure product, m.p. 154.5° - 155.5°C.

Microanalysis Calculated 72.73 5.79 3.86 Found 72.97 5.70 3-92 Example 8Q 79 In a way similar to that in Example 75, l-(p-methoxy-cinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 193° -195°C., was prepared from N^-(p-methoxycinnamoyl)-N^-(p-methoxy-phenyl)hydrazine hydrochloride and levulinic acid.

Microanalysis C (#) H (#) N (#) Calculated 70.68 5.72 3.90 Found 69.97 5.68 3.79 Example §¾· 80 In a way similar to that in Example 71, ethyl 1-cinnamoyl-2,5-dimethyl-3-indolylacetate, m.p. 198° - 200°C., was prepared from N^-cinnamoyl-N^-ip-tolylihydrazine hydrochloride and ethyl levulinate.

Example g 81 l-a-phen l-cinnamoyl I In a way similar to that in Example 71 « «*¾a«ey4-2- methyl-5-methoxy-3-indolylacetic acid, m.p. 174° - 175°C., was N prepared from -e-iim*arao i-N - p-methoxyphenyl )hydrazine hydrochloride and levulinic acid.

Example - 82 to) According' to a method similar/that in Example 71, 1- phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 137° - 139°C., was prepared from N"^-(phenylacetyl)-N1-(p-methoxyphenyl)- hydrazine hydrochloride and levulinic acid.

Example -§4 83 In a way similar to that in Example 71, l-(p-chloro- cinnamoyl) -2-methyl-5-methoxy-3-indolylacetic acid, m.p. 220° - 221°C, was prepared from N"1'-(p-chlorocinnamoyl)-N"'"-(p-methoxy- phenyl)hydrazine hydrochloride and levulinic acid.' Example -85 81+ A mixture of 4.0 g. of N1-(o(-chlorophenylacetyl)-N1- (p-methoxyphenyl)hydrazine hydrochloride and 2.4 g. of acetonyl- molonic 0 /-®ei©¾e acid was heated in 10 ml. of acetic acid at 85 C. for 4 hours with stirring. Thereafter, the reaction mixture was allowed to cool, and was poured into 25 ml. of cold water, and then crystals were produced. They were collected by filtration, and dried to give crude product of l-(c{-chlorophenylacetyl)-2- methyl-5-methoxyr-3-indolylacetic acid. The recrystallization from acetone-water gave fine white needle crystals, m.p. 165° - 166°C.

In a way similar to that in Example 85, the "following compounds were prepared.

Example B6 85 l-0innamoyl-2-methyl-5-methoxy-3-indolylacetic acid , m.p. 164°— 165°C Example W 86 l-Phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 141.5° - 143°C Example 87 l-(c^-Naphthylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 165.5° - 166. °C.

Example &9- 88 A mixture of 3.6 g. of N1-(phenylacetyl)-N1-(p-methoxy-phenyl)hydrazine hydrochloride, and 2.4 g. of acetosuccinic acid was heated in 10 ml. of acetic acid at 85°C. for 4 hours with stirring. Thereafter, the mixture was allowed to cool, and was poured into 25 ml. of cold water. The produced crystals were collected by filtration and was dried to give a crude product of 1-(phenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid. The recrystallization from acetone-water gave white needle crystals, m.p. 142° - 143°C By this method, the same product was obtained by using 2-keto-adipic acid instead of acetosuccinic acid.

Example 9Θ 89 In a way similar to that in Example 89» l-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 164° - 165°C., was prepared from N^-cinnamoyl-N^-(p-methoxyphenyl)hydrazine hydrochloride and acetosuccinic acid.

Example QsS. 90 4.8 g. of tertiary butyl l-(phenylacetyl)-2-meth l-5- methoxy-3-indolylacetate was added to 40 ml. of benzene, then a small amount of p-toluenesulfonic acid was added thereto. The reaction mixture was refluxed to complete the reaction.. After was purified and crystallized by using acetone and recrystallized from acetone-water to give l-(phenylacetyl)-2-methyl-5-methoxy- 3-indolylacetic acid, m.p. 138° - 139°C In a way similar to that in Example 91, the following compounds were prepared.

Example ·¾¾· 91 l-(o( -Naphthylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 165° ~ 167°C Example <¾¾. 9 1-[(^-(p-Tolyl)acryloyl|-2-methyl-5-methoxy-3-indolyl- acetic acid, m.p. 195° - 196°C Example -3 93 l-(p-Chlorocinnamoyl)-2-methyi-5-methoxy-3-indolylacetic acid, m.p. 220° - 221°C.

Example 33, 9k _(l_Cinnamoyl-2-methyl-5-methoxy-3-indolyl)butyric acid m.p. 125° - 126°C.

Example «9695 1-(j}-2 * -Fur lacryloyl) -2-meth 1-5-methoxy-3-indolylacetic acid, m.p. 163° - 165°C Example 96 ,^-(l-Cinnamoyl-2-methyl-5-methoxy-3-indolyl)propionic acid, m.p. 154° - 156°C.

Example 97 l-(p-Methoxycinnamoyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 193°.- 195°C m.p. ; 6ii?C.

Example -tea.99 7.6 g. of acetaldehyde N1-phenylacetyl-N1-(p-methoxy-phenyl)hydrazone was added to 30 g. of levulinic acid containing 1 g. of hydrogen chloride, and the mixture was heated at 80°C . for 3 hours. Thereafter, the mixture was allowed to cool, and poured into 200 ml. of water. And then the solid produced was collected by filtration, and was column-chloromatographed on silica gel by using ethyl acetate as developer and then was recrystallized from acetone-water to give white needle crystals of l-phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid,., m.p1. 139° - 142°C.

Example ISa 100 1.7 g. of acetomalonic N -(p-methoxyphenyl)hydrazone were added to 20 ml. of acetic acid ■ containing 0.37 g. of dried hydrogen chloride, and the mixture was stirred at 95°C. for 4 hours. Thereafter, the mixture was allowed to cool, and poured into cold water and then benzene was added thereto. The mixture was shaken thoroughly and a benzene layer was separated, and it was dried on anhydrous sodium sulfate and concentrated by distillation. The resultant solid was dissolved in acetic acid, and the solution was column-chroma o- graphed on silica gel and then recrystallized from acetone-water to give l-phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 140° - 142°C.

Example ίθ£ 101 .0 g. of N1-(phenylacetyl)-N1-(p^methoxyphenyl)hydrazine hydrochloride was added to 20 ml. of diethyl acetal, and the mixture was heated at 80°C. for 6 hours. Thereafter the mixture was cooled, concentrated under reduced pressure and allowed to stand overnight. The resultant solid was collected by filtration and washed with water, and then recrystallized from ethanol to give l-(phenylacetyl)-2-methyl-5-methoxy-indole-3- acetaldehyde diethylacetal.

Example H$ > 102 A suspension of 12 g. of silver oxide in 50 ml. of benzene was slowly added to 14 g. of l-(phenylacetyl)-2-methyl-5- methoxy-3-indolylacetaldehyde under stirring; After completion of the reaction, the reaction mixture was filtered within 10 minutes and the filtrate was concentrated under reduced pressure to dryness^ Recrystallization from ethanol gave l-(phenylacetyl)-2-methyli-5- methoxy-3-indolylacetic acid, m.p. 138° - 139°C.

In a way similar to that in Example 103, the following compound was prepared.

Example ¾4103 l»Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid . m.p. 164° - 165°C«, was prepared from l-cinnamoyl-2-methyl-5" methoxy-3-indolylacetaldehyde .

Example 3385 ^0k ■ 5.0 g. of N1-(phenylacetyl)-N"!"~(p-methoxyphenyl)hy razine -oxo- { hydrochloride was added to 20 ml, of/n-pentanol, and the mixture was heated at 80°C . with stirring. After completion of the reaction, the filtrate was concentrated to give a solid substance.

Recrystallization from a mixture of ethanol and water gave 2-(l'- acetylt phenylV-2' -methyl-51 -methoxyindole-3 ' ) ethanol.

Example 105 . 6 g. of 2-(l ' -phenylacetyl-2' -methyl- 1 -methoxy-indole- 3 ') ethanol was added to acetone, and then 5 g. of potassium permanganate was' slowly added to' the mixture at 50°C. The mixture was heated at the same temperature for an additional one hour and then was allowed to stand at room temperature. The precipitates produced were filtered off and washed with acetone. The filtrates were collected and concentrated under reduced pressure to- dryness. Recrystallization of the solid residue from ethanol gave l-phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 137° - 139°C.

Example 106 In a way similar to that in Example 106, 1-cinnamoyl- 2-methyl-5-methoxy-3-indolylacetic acid was prepared, m.p. 164° -165°C Example 1 0$ 4.3 g. of l-phenylacetyl-2-methyl-5-methoxy-2, -dihydro-3-indolylacetic acid was added to 100 ml. of benzene and then 7c 5 g. of chloranil was added thereto. The mixture was heated under reflux for 3 hours. Thereafter the mixture was concentrated under reduced pressure to a solidal residue, which was diluted with acetone. After removing unsoluble substance by filtration, the acetone solution was concentrated to dryness under reduced pressure to give crude crystals of l-phenylacetyl-2-methyl-5-methoxy-3-indolylacetic acid. Recrystallization from acetone-water to give a light yellow pure product, m.p. 142° - 143°C.

In a way similar to that in Example 108, the following compounds were prepared.

Example 1 08 l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 163° - 164°C.

Example 1 09 -(l-Cinnamoyl-2-methyl-5-methoxy-3-indolyl)butyric acid, m.p. 125° - 126°C.

Example ½½ 110 42 g. of ter iary-butyl l-cinnamoyl-2-hydro-2-methyl-3- metho a^ hydroxy-57<Se5iS^I-:3-indolylacetate was added to 500 ml. of toluene, and then 3 g. of p~toluenesulfonic acid was added thereto. The mixture was heated at 100°C. for 3 hours with stirring. After completion of the reaction, the reaction mixture was washed with water three times and was dried on anhydrous sodium sulfate.

Thereafter the solution mixture was concentrated and allowed to stand in a refrigerator to give crude crystals of l-cinnamoyl~2~ methyl-5-methoxy-3-indolylacetic acid. Recrystallization from acetone-water gave the pure product, m.p. 164°'- 165°C.

Microanalysis C { ) H ( ) N (*) Calculated 72.19 5.48 4-01 Found 72.46 5.71 4.03 In a way similar to that in Example 111, the following compounds we-re prepared. m.p. l t>tf - 1$7°C .

Microanalysis Calculated 74.48 5.58 3.71 Found * 4- 4-44- Exanrple 2 l-(o{-Phenylhutyroyl)-2-meth l-5-methoxy- --indolylacetic acid, m.p. 123.5° - 125°C Microanalysis C (#) H (#) N (*) Calculated . 72.33 6,30 3.84 Found 72.51 6.38 3-94 Example .¾¾¾- 113 l-(p-Chlorophenylacetyl)-2-methyl-5-methoxy-3-indolyl-acetic acid, m.p. 178°C.

Microanalysis Calculated 64.60 4.89 3.77 Found 64.45 4.96 3.86 ) Example it±9* "\ Μ 1-(^-Phenyl-n-propionyl)-2-methyl-5-methoxy-3-indolyl-acetic acid, m.p. 163° - 164°C.

Microanalysis Calculated 71.78 6.02 3.98 Found 71.85 6.07 4.08 Example Sb±& 115 l-(m,p-Dimeth.oxyphenylacetyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 169° - 170°C.

Microanalysis . Calculated 66.49 5.83 3.55 Found 67.00 5.94 3.61 Example 116 A mixture of 2 g. of N-( p-methoxyphenyl)-N-(phenylacetyl)-4-amino-3.^oxo-valeric acid and 1.3 g. of anhydrous zinc chloride was heated at 120° - 140°C„ for 40 minutes. After cooling, the mixture was extracted with 25 ml. of benzene, and the benzene layer was washed with water and dried on anhydrous sodium sulfate.

Thereafter the mixture was concentrated under reduced pressure to dryness, and. column-chlorOmatographed on silica gel by using ethyl acetate as developer to give l-phenylacetyl-2-methyl-5-n 0hoxy-3-indolylacetic acid, m.p. 138° - 139°C.

In a way similar to that in Example 117, the following-compounds were prepared.

Example ¾¾& 117 l-Cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid , m.p. 164° - 165°C Example 3±¾- 118 l-(^-2-Furylacryloyl)-2-methyl-5-methoxy-3-indolylacetic acid, m.p. 163° - 165°C.

Example 119 3.0 g. of 3-( ' -phenylacetylamino-5 '--methoxyphenyl)-levulinic acid was added to 60 ml. of dioxane and then 1 ml. of 10 hydrochloric acid was added thereto, and was heated at 80°C, with stirring. After completion of the reaction, a precipitate was filtered off and the filtrate was concentrated under reduced pressure to a solid substance. Recrystallization twice from acetone-water gave l-phenylacetyl-2-methyl-5-methoxy-3-iri'dolylaceti acid, m.p. 138° - 140°C.

Example 120 1 -|^-(2-thienyl) acryloyl]-2-methyl-5-methoxy-3- indolylacetic acid, m.p. 137°-138°C

Claims (14)

HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is : wyjy¾iYy¾y»y¾Tf¾yyvyyinc

1. A compound of the formula: wherein R is a hyrivogcm atom) an unsubstituted or a lower alkyl-lower alkoxy-, lower alkylthio-, nitre-, cyano- or halogen- oarbojcylle substituted aromatic ring group, each of said alkyl, alkoxy and a fur l alkylthio substituents containing up to 4 carbon atoms, or -aaa or thienyl; wiBubotituted or a methyl-, othyl—or halogen oubotitutod 5- or -e-membered heterocyclic Ting group oontaining an oxygon» oulf-ur or ni rogon ct omj R 2 and R each are hydrogen atoms or alkyl groups having up to carbon atoms; R^ is a hydrogen atom, a carboxy group or an alkoxycarbonyl group having up to 4 carbon atoms; R^ is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R is an alkyl group- having up to 4 carbon atoms an alkoxy group having up to - 4 carbon atoms, an alkylthio group having up- to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an un-substituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl having substituted saturated hydrocarbon chair up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight one or a branched blanohod. one; m and £ each are 0 or 1; and n is 0 or an integer of from 1 to 3.

2. A process for producing a 3-indolyl aliphatic acid derivative of the formula: wherein Ra is a hyArogon. ctQift^ an unsubstituted or a lower alkyl-,. - lower alkoxy-, lower alkylthio?-, nitro-, cyano- or halogen- substituted aromatic ring group, each of said alkyl, alkoxy and nitrogen atom; R 2 and each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; R^ is a hydrogen atom, a carboxy 5 group or an alkoxycarbonyl group having up to 4 carbon atoms; R is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a; hydroxy group; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl-substituted saturated hydrocarbon chain up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight one or a branched one; m and JD each are 0 or 1; and n is 0 or an integer of from 1 to 3» which comprises reacting an N^-acylated phenylhydrazine derivative of the formula: wherein R 1, R6 and A have the same meanings as identified above with an aliphatic acid derivative of the formula: - (CH2)n - VCH/p - COR5 (III) wherein R^, R^, R^", R^, m, n and JD have the same meanings as identified above to yield the 3-indolyl aliphatic acid derivative (I).

3. A process for producing a 3-indolyl aliphatic acid derivative of the formula: l-, substituted aromatic rihg group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or sua. a furyl or thienyl; 5 «unoubotituted or a methyls,—ethyl- or halogen-subst-i-tu ed 5- or -fr- nombor-od 'hotoroo olio ring group oontaining an oitygonj oulfutr σι«Νΐΐ?ιΐΐφο¾&¾ι atools ^ and R^ each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; ^" is a hydrogen atom, a carboxy group or an alkoxycarbonyl group having up to 4 carbon 10 atoms; R is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or g a hydroxy group; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group 15 having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon Λ20 chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl- havinf substituted saturated hydrocarbon chain up xo 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight one or a branched one; m and JD each are 0 or 1; and n is 0 or an integer of from 1 to 3> which comprises decomposing an ^-ac lated phenyl-hydrazone derivative of the formula: wherein R , R and A have the same meanings as identified above, and B is a ketone to yield an ^-acy a: I A wherein R 1, R6 and A have the same meanings as identified above, and reacting the resultant N^-acylated phenylhydrazine derivative with an aliphatic acid derivative of the formula: wherein R^, R^, R^, R5", m, n and JD have the same meanings as identified above to yield the 3-indolyl aliphatic acid derivative (I).

4. A process for producing a 3-indolyl aliphatic acid derivative of the formula: 1 wherein R is a hydrogon atom; an unsubstituted or a lower alkyl- lower alkoxy-, lower alkylthio-, nitro-, cyano-.. or halogen- car¾o^lioj substituted aromatic^ rin group, each of said alkyl,. alkoxy and alkylthio substituents containing up to.4. carbon atoms, or sm— a fur l or thienyl 5 unoubotitutod ' or a methyl- » Othyl—or halogen oubatltutod 5 or ov> nit-cogon aton>y and R- each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; ^ is a hydrogen atom, a carboxy group or an alkoxycarbonyl group .having up to 4 carbon 0 atoms; R is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R^ is an alkyl group having up to 4 carbon atoms an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group 5 having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; - A is an un- substituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon 0 chain having up to 5 carbon atoms, a halogen-substituted un-j saturated hydrocarbon chain having up to 5.carbon atoms, a phenyl / having I substituted saturated hydrocarbon chain/up to 5 carbon atoms or a ' phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight one or a branched one; m and JD each are 0 or 1; and n is 0 or an integer of from 1 to 3> which comprises reacting a phenylhydrazone derivative' of the formula: wherein R has the same meaning as identified above and B is a ketone or aldehyde residue, with a compound having the formula: Y I CO I (VI) A wherein R^ and A have the same meanings as identified above; and Y is a halogen atom or an ester residue, to yield an N^-acylated phenylhydrazone ' derivative of the formula: wherein R 1 , R6 , A and B have the same meanings as identified above, decomposing the resultant N^-acylated phenylhydrazone derivative with a decomposing agent to yield an N^-acylated phenylhydrazine derivative of the formula: whe and A have the same meanings as identified above, and reacting the resultant l^-acylated phenylhydrazine compound with an aliphatic acid derivative of the formula: wherein R^, R^, R4, ^, m, n and £ have the same meanings as identified above to yield the 3-indolyl aliphatic . acid derivative (I).

5. A process for producing a 3-indolyl aliphatic acid derivative of the formula: CO I A wherein R^" is a hydrogen atom, an unsubstituted, or a lower alkyl-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen- substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or ear- a furyl or thienyl; ¾mouboti od or a methyl-, ethyl- or halogon oubotitutod 5. or ■6 mcmbcr-od hotorooyolio ring group oon a-Lr-ing aza oxygen, oilfvir » · nitrogen a om R 2 and R^y each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; R4 is a hydrogen atom, a carboxy group or an alkoxycarbonyl group having up to 4 carbon atoms; R is an alkoxy group having up to 4 carbon atoms., a benzyloxy group, a tetrahydropyranyloxy group., an amino group or a hydroxy group; R^ is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alk lthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an un-substituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl-substituted having ^ saturated hydrocarbon chain up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon .branched \ atoms, the hydrocarbon chain being a straight one or a (¾ ίΜΐΜ>¾οΑ· one; m and JD each are 0 or 1; and n is 0 or an integer of from 1 to 3> which comprises reacting a phenylhydrazone derivative of the formula: wherein R has the same meaning as identified above and B is a ketone or aldehyde residue, with a compound having the formula: Y I CO I (vi) wherein R1 and A have the same meanings as identified above and Y is a halogen atom or an ester residue,. to yield an N^-acylated phenylhydrazine derivative of the formula: R1 wherein B?~ , R^ and A have the same meanings as identified above, and reacting the resultant N^-acylated phenylhydrazine derivative with an aliphatic acid compound of the formula: R^C0CH - iVC'H3)/ - (CH ) - iVC'H4V - COR5 ■ ' 2 m 2 n x p 5 (III) wherein R 2 , R3 , R4 , . R5 , m, n and JD have identified above to yield the 3-indolyl

) 6. A process for producing a.3-indolyl aliphatic acid derivative of the formula*. CO R1 wherein Ra is a .hydrogen atom, an unsubstituted or a lower alkyl-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen- substituted aromatic ring group, each of. said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms., or » a furyl or thienyl; -uiisuba it ted or a methyl ,—ethyl—or halogen-auba ituted 5- ov 6"-membercd hctorooyclio ring group oontaining an oxygen, sulfur» 2 3 -"I 11 ri ÷iii"Tcmin 1 nt'ftrrr; R and R^ each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; R^ is a hydrogen atom, a carbdxy group or an alkoxycarbonyl group having up to 4 carbon atoms; R5 is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted un-saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to having; 5 carbon atoms, a phenyl-substituted saturated hydrocarbon chain/ up to 5 carbon atoms or a phenyl-substituted unsaturated hydro-carbon chain having up to 5 carbon atoms, the hydrocarbon chain f being a straight one or a branched one; m and £ each are 0 or 1; and n is 0 or an integer of from 1 to 3* which comprises reacting an N^-acylated phenylhydrazone derivative of the formula: wherein and A have the same meanings as identified above and B is a ketone or aldehyde residue, with an aliphatic acid derivative of the formula: R2C0CH2 - - COR5 (III) wherein R^, R^, R^, R5, m, n and £ have the same meanings as identified above to yield the 3-indolyl aliphatic acid derivative (I).

7. A process for producing a 3-indolyl aliphatic acid derivative of the formula: I A . wherein R is a hydrogon atom, an unsubstituted or a lower alkyl-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen-substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or -est- a furyl or thienyl; ■tanoubotituted or a methyls,—ethyl- or halogon- oubotitutod 5 — 6-mombored heterocyclic ring group containing an oxygon, sulfur"— nr n i tragf?n ii , ai cin R and R^ each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; R^ is a hydrogen atom, a carboxy group or an alkoxycarbonyl group having up to 4 carbon atoms; R is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a* hydrogen atom; A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl- having r substituted saturated hydrocarbon chair/ up to 5 carbon atoms o a phenyl-substituted unsaturated hydrocarbon chain having up t 5 carbon atoms, the hydrocarbon chain being a straight one or a Γ. branched one; m and £ each are 0 or 1; and n is 0 or an integer of from 1 to 3, which comprises reacting a phenylhydrazone derivative of the- formula: wherein R has the same meaning as identified above and B is a ketone or aldehyde residue, with a compound having the formula: Y I CO I (vi) A wherein R^" and A have the same meanings as identified above and Y is a halogen or an ester residue,, to yield an N^-acylated phenyl-hydrazone derivative of the formula: A wherein R , R , A and B have the same meanings as identified above, and reacting the resultant N^-acylated phenylhydrazone derivative with an aliphatic acid compound of the formula: - COR55 (III) wherein R^, R^, R^, R5, m, n and jo have the same meanings as identified above to yield the 3-indolyl aliphatic acid derivative (I).

8. A process for producing a 3-indolyl aliphatic acid derivative of the formula: CO I A wherein R^" is a hydrogen atom, an unsubstituted or a lower alk l-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen-substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or «*· a ur l or thienyl; ¾m.Dubo ituted or a met yls,—ethyln or aLogaft-embotit^t eci 5- oa* 6 mcmborod hotorooyolii'o ring group oontaining a oit go n oulfur^ o Hi lO yn afcsm? R 2 and each are hydrogen atoms or alkyl groups having up to 3 carbon atoms; R^ is a hydrogen atom, a carboxy group or an alkoxycarbonyl group having up to 4 carbon atoms; R5 is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms,, an alkenyloxy group having up to 4' carbon atoms, a halogen atom or a hydrogen atom; A is an 'on-substituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl- havingj substituted saturated hydrocarbon chain/up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight one or a branched Isl iiehuxi one; m and £ each are 0 or 1; and n is 0 or an integer of from 1 to 3» which comprises reacting a phenylhydrazine derivative of the formula: wherein R 6 have the same meaning as identified above, with a compound having the formula: Y I CO I (VI) A R1 wherein R^" and A have the same meanings as identified above and Y represents a halogen atom or an ester residue, to yield an N"^-acylated phenylhydrazine derivative of the formula: 1 6 wherein R , R , A have the same meanings as identified above, and reacting the resultant N1-acylated phenylhydrazine derivative with an aliphatic acid compound of the formula: wherein R^, ^, R^, R^, m, n and £ have the same meanings as identified above, to yield the 3-indolyl aliphatic acid derivative (I).

9. A process for producing a 3-indolyl aliphatic acid derivative of the formula: -, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen- 10 substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or -eat a furyl or thienyl; •■•umoubotitutod or a mothyl-, othyl- or halogon oubotitutod 5 ov ^ momborod hotorooyolio ring group containing aii onygcsn^ oulfixr each are hydrogen atoms or alkyl c 15 groups having up to 3 carbon atoms; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; ' 1 A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen- substituted unsaturated hydrocarbon chain having up to 5 carbon having_j atoms,' a phenyl-substituted saturated hydrocarbon chain up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a branchedj straight one or a pal fl/nrbaad. one ; and m is 0 or 1, which comprises reacting an N^-acylated phenylhydrazine derivative of the formula: R1 wherein and A have the same meanings as identified above, with a compound of the formula: wherein R , R^ and m have the same meanings as identified above, to yield the 3-indolyl aliphatic acid derivative (VII) . .

10. A process for producing a 3-indolyl aliphatic acid derivative of the formula: CO I A wherein R^" is a hydrogen atom, an unsubstituted or a lower alkyl-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen- substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or aa* a furyl or thienyl; ¾moubotitutod o - a mothyl-',—othyl- or halogon oubotitutcd 5 or &'-mcmborod hotorooyolio ring group oontoining an θΑ^^υιΐ; ou-kftwc it ntoptj R 2 Όΐ» ]d8g;? and R >each are hydrogen atoms or alkyl c groups having up to 3 carbon atoms; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to.4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen- substituted .unsaturated, hydrocarbon chain having up to 5 carbon havingj atoms, a phenyl-substituted saturated hydrocarbon chainup to 5 carbon atoms or a -phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight ¾ranch§j¾_y one or a n hidrone and m is 0 or 1, which comprises reacting -acylated phenylhydrazone derivative of the formula: wherein R , R and A have the same meanings as identified above, and B is a ketone or aldehyde residue, with a compound of the formula: R3\ ~ I /COOH R - CO - CH„ - \CH/ - CH (VIII) ά ■ m \COOH 2 3 wherein R , R^ and m have the same meanings as identified above to yield the 3-indolyl aliphatic acid derivative (I).

11. A process for producing a 3-indolyl acetic acid derivative of the formula: (IX) wherein R is a hydr-ogon a-tom an unsubstituted or a lower alkyl-lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen-substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, or-β**- a furyl or thienyl; ■¾an.oubo itutod or a methyl-; . othyl- or halogon ou o itul d p UJ.LV. fr-membered heterocyclic ring group containing an ox gi.-» aulfm 6 •o^rwrtawgom.■ criom ; R is an alkyl group having up to 4 carbon at an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; and A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having tip to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl-substituted saturated having i hydrocarbon chain/up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the branched; hydrocarbon chain being a straight one or a TuluiiuhudfSne, '.which, comprises reacting an N^-acylated phenylhydrazine derivative of the formula: wherein R , R and A have the same meanings as identified above with acetosuccinic acid or 2-ketoadipic acid to yield the 3- indolyl- aliphatic acid derivative (IX),

12. A process for producing a 3-indolyl acetic acid derivative of the formula: (IX) wherein R is " ^A^Q ~+ ^ unsubstituted or a lower alkyl-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen-substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing p to 4 carbon atoms, or «n=- a fur l or thienyl; ■taitoubotitutod or a mothyl»,—ethyl.-, or halo oa-ouboti wfroiA 5·· or 6· momborod hoterocyo-l-ic ffiing. roup gontminin an ojrygcn, oilfur or nitrogen stem? R^ is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an un-substituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated .hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl- having^ substituted saturated hydrocarbon chain/up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, the hydrocarbon chain being a straight one or a branched ifcLaiftg-ed—one , which comprises reacting an N -acylated phenyl-hydrazone derivative of the formula: wherein R^, Ru and A have the same meanings as identified above, and B is a ketone or aldehyde residue, with acetosuccinic acid or 2-ketoadipic acid to yield the 3-indolyl aliphatic acid (IX).

13- A process for producing a 3-indolyl aliphatic acid derivative of the formula: CO I A ii wherein R"*" is ¾jhyrlT"niffliin a orrn} an unsubstituted or a lower alkyl-, lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen- substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon' atoms, or «a» a fur l or thienyl; ¾B¾aubotitutod- or a mothyl-; othyl—or halogen oubotitutod 51 or- ■6imombQrod heterocyclic .ring group oontaining an ojrygonf oulfui*' j r .liLrngm trmj R and R^ each , are hydrogen atoms or alkyl groups having up to carbon atoms; R^" is a hydrogen atom, a carboxy group or an alkoxycarbonyl group having up to 4 carbon atoms; R is an alkoxy group having, up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R is an alkyl group .having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up to 4 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted saturated hydrocarbon , chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl- havi g^ substituted saturated hydrocarbon chain/up to 5 carbon atoms or a phenyl-substituted unsaturated hydrocarbon chain having up to 5 1 carbon atoms, the hydrocarbon chain being a straight one or a r b anched one; m and n. each are 0 or 1; and n is 0 or an integer of from 1 to 3, which comprises reacting a phenylhydrazine derivative of the formula: 5 wherein and A have the same meanings as identified above, with a compound of the formula: RDC0CH2 - - CO - R (III) wherein ^, R^, R^, , m, n and JD have the same meanings as identified above to yield the 3-indolyl aliphatic acid derivative (I). 10

14. A pharmaceutical composition containing, as the essential ingredient, a 3-indolyl aliphatic acid derivative of the formula: CO I A R1 wherein Ra is a iayiljioggif. c i sm, an unsubstituted or a lower alk l- J lower alkoxy-, lower alkylthio-, nitro-, cyano- or halogen- substituted aromatic ring group, each of said alkyl, alkoxy and alkylthio substituents containing up to 4 carbon atoms, a furyl or thienyl; 1 wnoubotitu ed or. a methyl-, —othy - or halogon ouboti utod 5 —οτ-θ* .aomborod hotoroo olio ring group containing cm oxygon, oulfui1 or- each are hydrogen atoms or alkyl groups having up. to 3 carbon atoms; R^ is a hydrogen atom, a carboxy group 5 or an alkoxycarbonyl group having up to carbon atoms; R- is an alkoxy group having up to 4 carbon atoms, a benzyloxy group, a tetrahydropyranyloxy group, an amino group or a hydroxy group; R is an alkyl group having up to 4 carbon atoms, an alkoxy group having up to 4 carbon atoms, an alkylthio group having up. to 4 , 10 carbon atoms, a nitro group, an alkenyl group having up to 4 carbon atoms, an alkenyloxy group having up to 4 carbon atoms, a halogen atom or a hydrogen atom; A is an unsubstituted saturated hydrocarbon chain having up to 5 carbon atoms, an ' unsubstituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a halogen- 15 substituted saturated hydrocarbon chain having up to 5 carbon atoms, a halogen-substituted unsaturated hydrocarbon chain having up to 5 carbon atoms, a phenyl-substituted saturated hydrocarbon chain having up to 5 carbon atoms on a phenyl-substituted unsaturated hydrocarbon- chain having up to 6 carbon atoms, the hydrocarbon "branched 20 chain being a straight one or a bl finiahoffr one; m and JD each are 0 or 1; and n is 0 or' an. integer of .from 1 to . Dated fc lQ Ninth aay of May 1 67 MDX-FORD Agent for Applicants*