DE1620441A1 - 1-Acryl-3-indolylcarboxylic acid compounds, processes for their production and their use for the production of pharmaceutical preparations - Google Patents

Description

DR. ELISABETH JUNG. DR. VOLKER VOSSIUS, DIPU-ING. GERHARD COLDEWEY

Patent attorneys' _ _{Ä Λ} . _. . _t "

8 MUNICH 23 · CtEMENSSTRASSE 30. TELEPHONE 345067 - TELEGRAM ADDRESS: IN VENT / MONCHEN. TELEXS-29686

23. Ükl.1969

Double

tu Sos G 507 (Vo / fcS)
PGS-9937

SUMITOMO CHEMICAL COMBANiy
Osaka, Japan

¹¹ I- = acyl "3 ~ Uidolylcarbonaäureverbindungen, process for their production and their use for the production of medicinal products"

Priority 12 ο January 1966, - Japan, no «. 1999/66 April 28 1966, . Japan, No. ₀ 27300/66 28 ο April '- 1966, Japan, No. 273C1 / 66 2.May 1966, Japan, No. ₀ 28125/66 4 ο May 1966, Japan, No. ₀ 28400/66 June 21st 1966, Japan, No. ₀ - 40591/66 8th of July 1966, . Japan »No. ₀ 44725/66 8th of July 1966, ■ Japan »No. ₀ 44724/66 August 19th 1966 ,, Japang Sr * 54674/66 August 19th 1966, Japan »No. 54675/66

The invention relates to n © ue l - = »acyl«> = indole?

1 * "Λ,? - * V

'<ίίυΐ1

CH

in which R is an unsubstituted or hslogensubstituted alkyl- '

2 3

or alkenyl radical with up to 10 carbon atoms, · R and R. Hydrogen £ ~ atoine or lower alkyl radicals with up to 3 carbon atoms, R is a hydrogen atom, a carboxyl group or an alkoxycarboxyl group

with up to 4 carbon atoms “R an alkoxy group with up to 4 carbon atoms men, a benzyloxy, setrahydropyranyloxy, hydroxyl or ami- · nograppe, R a lower AUcy! group with up to 4 carbon atoms, a Alkoxy group with up to 3 carbon atoms, an alkyl mercapto group with mean up to 3 carbon atoms, a halogen or hydrogen atom, m and ρ has the value 0 or 1 and η the value 0, 1, 2 or 3

The invention also relates to a method for producing the

Compounds of the general formula Σ «The method according to the invention can be illustrated by the following reaction scheme «

KX

• Μ

II

CO

III

. · I

N ¹ -acylphenylhydric compound '

aliphatic acid compound

HGl

In the formulas, the radicals R to Κ as well as ja, η and ρ have the meaning given above

■ ' ^: λ ' ^ y-- · ^{:: /} : ■■■ ■■■ -; :. · Y'yy - ■ ι

The inventive method proceeds even in the absence of a solvent smooth _f but will in some cases, the encryption * expression * B * used by iösungsniitteln vorgesogenο Z, is preferably organic solvent acids, such as acetic acid, formic acid, propionic acid in the condensation of free aliphatic Garbonsäuren , Hilchsäure or butyric acid, non-polar organic solvent, such as; -. 'Cyclofcexan, * ii-hexane, benzene and to-Iuöl, or polar solvent "as Bioxan and dimethylformamide ₄ At the ICondensation alipnatischer carboxylates ~ USAGE one det yosmtgsweise besides the genaniiten solvents also i 'Alcohol The reaction takes place at a temperature in the range from about 50 to © tm 20'0 ° 0σ Bex preferred; - temperature range is miBdhsn 65.ssaa 90 ⁰ G ₀ Bia Kosdensationsmitt.eX-iat always sees ustosaetlißiiB- aoeh fÖtet . ^; di @ Yerweaöimg: esorgaaiöiJher Saur © a _& -Me S © .l ^ ssur © e 'sulfuric acid u && Vhüs ^ hoT @ äu ^ ® _ß la me ± aea i

eti'fsta £ äi8s © a said, oil © invention is niefet äms @ M £ foe ·

00081371876 '

... ■ ". ■ .- ■■■, * .. - ■ - .BAD

. ■ * 4- - .. ■

The preparation of l-Acylindölverbindungon iot eg "tu the book by Elderfield" Heterocyclic Compounds ", Vol 3 (1952), Chapter 1, p. 1 - 247 and in the book by WoC. Sumpter and P. Mo Hiller ^ Heterocyclic Compounds with Indole and Carbazole Syetems "(1954) _f page 1 - 69, described»

! -substituted acyl groups of 1-acylindoxo compounds so easily split off hydrolytically by acid or alkali that it was regarded as impossible by "l ~ a" ylindole compounds directly from the corresponding K -acylated phenylhydrazine compounds Suvorov obtained after Fischer's indole synthesis and kit workers, Doklady Acad. Nauk S.S "S.R. 156, page 840 (1961), Cheo. Abstr., 55, 17621 (1961), J. Gen. Chem., U.S.S.H. 28 1058 (1958) reported on this problem as follows:

CH ₉ -CH-

'XX

GH-CH,

In their view, Fischer's indole synthesis does not proceed without acylation of a hydrasin compound IV ₁ or formation

a new carbon

Kohlönstoff ^ ii aO'98t-3/18 7-ß

a free p-slectro

SAD

pair available β must be «

The erfindungsgeraässe process is novel, d, h _o not previously described and eggs gröaste! Part of Ausgangsverbinctungeni, d "h, the asymmetric Hydrazinderivateuiid, their salts, are also new * l ~ Acylindolylcarbonsäuren have been hergestelltj by a process one at the first. Indolyl carboxylic acid ester produced * then this ester is acylated and if necessary the ester acid-free acid has been saponified * This process has to be carried out * every day and gives low yields »

According to the process according to the invention, carboxylic acid compounds can be obtained in very high yields and to a substantial extent easier way to be produced * The inventive Procedure is not only particularly beneficial when working in the laboratory scale but also for technical production <,

Specific examples of easy to prepare according to the invention L-Aeyl ^^ indolylcarboxylic acid. Compounds are M- »Heptanoyl - = - 2-

5 ~ *

iesg ®tQht $ will elö Isaaol ^^ srfeiadtasii; ü®T fossel I ein®

»8o aaslat go ia cäilg © HQia @ E

ο © Mi '"''

OK,

+ CH ₃ COCH ₂ Oh ₂ COOH

K-NH ₀ -HCl CO

JKK

.CH ₂ COOH

CH ₂ COOH

CHsCH-CHsCH-CH,

i co

CH = CH-CH = CH-CH ₅

The two isomers, however, must be separated from each other » if they are chromatographed on a suitable adsorbent and then eluted with a suitable developer

Special connections are mentioned below! which can be obtained easily and in high yield by the method according to the invention
l-Acetyl-2-methyl ^ 6-metlioxy-5 ⁱ -'indolyless3, gäure, und

and

^ methoxy ^ S-ittdolyleasigsauref,.

, "^ SB ^ ta ^ y-S-SiidoXyleeai ^ eSuyet ■. ;

3 "ir ^ olyle3sis" urge us

· «■ .- ■■ .-" ■

© AD

162044t

and 4-ffi ^

yindolylessig ^ Bttreme and

l-n-hexanoyl-2-jES 5

1-n-HexanoyI-2

btttyleßter and,

In-hexalioyl-2 ⁱ 'methyl "-4-ffietiiGxy-3-indoxyl acetic acid

! ■ ~ n «Hexaiiöy2 ^ 2. ~ methyl ~ 6 ~ m ^
and l * n ^ hexanoyl <-2 "methyl-4« nisthoxy = -3 = 'inäolylessigsäurebenzyl- »

- ■ - ■ - "■■: .- ■■ - ■. ■■■■■ - ■■ - ■■■ ■■ -; ■.: -. '

l * n-Hexanoyl-2-ffletliyl = -5 »6 = -dimethoxy-3" iadolyl-acetic acid and

methyl-4 _f 5-dimethoxy «3« xxid olyl acetic acid,: '"" -.

-methoxy ^ -indoXyieseigeäUTO. and l- (2 * ₍ 4 '^ ez8Utieno3rX) ~ 2-iae.tt ^ l ^ 4 ^^ eth.äxy-3-iM'

indal ^

■■ - "■■■""■" ■■ ■■ '-: -: ■' · ■ and

■ - ^ö "" 1620UT

! Λ go -Bu tasi oyl- 2, A- " dine thy 1 - 5 ~ inu olyl acetic acid, 3.-n-octanoyl ~ 2-eissethyl« 6-iJie'üho :: y'-3 " indoly] leosissic acid and l ~ iv »Oc tan oy 1-2-methyl ~ 4« - »e. tu oxy --- 3 ~ ind ο IyI ess ig acid ©,

and

V / enn the alipliätisohs carboxylic acid compound III, in the ß- one

5
Carboxyl group and R is a hydroxyl group and ρ has the value 1 _{9 is} reacted with the hydride compound or its salt of the formula II, in some cases the acyl-3-indolylcarboxylic acid compound of the formula I obtained is decarboxylated, so that R is a hydrogen atom will «This reaction is adjusted

♦ -

purifies.

- SH

The working temperature is in this Pail between 60 and 200 C "preferably zv / een 80 and 140 ⁰ C ₀ organic acids such as acetic acid are as a solvent," propionic acid and lactic acid ν nonpolar solvents such as benzene and toluene, or polar organic solvent such as acetonitrile and butane oil _{} is} used. Inorganic acids, such as hydrochloric acid and sulfuric acid, or Lewis acids, such as zinc chloride or boron fluoride, are used as condensing agents. . '- ~. _

009813 / 1S76.

i) aa -described "inventive method" requires 'No cumbersome process measures and the yield is in comparison 'to that of the known method particularly high .. The The above-described method is therefore particularly advantageous not only when working in the laboratory sassabi but also on a technical scale, Jiaoh standing becomes an example of this procedure given i

CB ₂ GOGU

become 1 «(4 ⁴

Tferbinöiaageiif the nacfe

bath

W .el Si

1-Acety 1-2.5 "-dimethyl" 5 ^ iniolyl-acetic acid, of "/ l- (4 * -Chlorbutyroyl ^ Z-methyl-S ^ inethoxy ~ 3" * inaolyl / -propion ~ acid,

1 ~ (4 '-Chlorbutyroyl) ~ 2 ~ methyl "5 ~ chloro ~ 3 - indolyle3si _£> acid l- (4 ^r" Chlorl3U..tyroyl) -' _f 5 ^<* -niethoxy-3-indolyleßBigeäure ■■ 1- (4 '-chlorobutyroyl) = -2'-methyl = -4-me1; hoxy-3-indolyleacetic acid and 1- (4'"-chlorobutyroyl) -2-methyl-6-metho% y <-3-inaolyllacetic acid ₉ 1 ^ (4 "-chlorobutyroyl) - = 2 _i 4 = -di-diethyl-3-iridol.ylacetic acid and 1- (4 ⁵ " -chlorobutyroyl) -2, & -dimethyl-3-inciolylacetic acid _p

1-Hexanoyl-2-methyl; hyl-5-Hiethoxy-3-indolylacetic acid and 1-Ogt anoy 1-2-methyl-1 = 5- »methyl-3-indolylacetic acid ₀

The .l = acyl-3 ° indolylcarboxylic acid compounds of the formula I can by converting N »acylphenylhydraBone compounds of the formula

(VI)

in which fi and E have the preceding meaning and B is a keto » or aldehydreat, with the aliphatic carboxylic acid; rMn- ~ Preparation of the formula III can be produced.

Organic acids such as formic acid, Propionic acid »lactic acid or butyric acid, non-polar organic

like cyclohexane »n-hexane $ benaol with toluene, or

e®iesiii © fe © ISsMsgsslttel ^ like g £% $ &. o2v _s YesfWöRitet «. These-

l91iiS / 1 ^ O "'BADORfGfNAL ■"

In the sera range from 65 to 05 ⁰ G 1st .. preferred «As a condensation agent, an Orsejische acids» such as hydrochloric acid and sulfuric acid, Lewis acids _P ZyBV HetallhalOf-eniüe, such as zinc chloride and copper chloridey heavy metal powder, boron fluoride or polyphosphoric acids are used *

The verfahrensseaäss used SP Acylphenylhydrazonderivat can be prepared in the following example ₀

iauJfllg-

VIII

Cl CO

A phenylhydrazine of the formula VIII is reacted in a suitable solvent s z, Bo an alcohol, with a ketone or aldehyde of the formula 0 »B to give the corresponding phenylhydrazone VII. This is then acylated with a carboxylic acid chloride of Pormöl-.R ¹ CGCl in pyridine as the solvent. The desired compound of the formula VI is obtained

Per residue S should preferably not take part in the ring closure reaction * Suitable groups B are ζ »B _e CH ^ CHe, CgHcCH», CgHc-CHai odes CCl-CHa, The N ^ C ^ bond of hydrazone VII is rather unstable in acid in an N _β solvent in the presence of an acid following reaction is performed: ^[

-α-

co

IWIH, 00

HCX

N * N = O CO

I.
GO

^ (GH) _p .OOR ⁵

0 09813/1878

Special cases for connections, which aacii this procedure can be made are

i s o-Bütyr oyl ^ Z-nie tliyl-S-methoxy-S ^ iado lyle ssigsäureme thyl «

5 ^th e

ta1 ^

4: '-l ^

■ BAD ORIQfNAL

ι ö / s

The N '"~ acylphenylhydrazine compounds VI and the JS-« acylphenylhydrazine compounds II and their salts, which are used as output compounds are used in the method according to the invention also new connections »

The hydrazane compounds of the formula

R ⁶ - ^ 0 ^ (VI)

CO.

in which R ",, R and ß have the above meaning;» and the hy- *

and their Salae of the formula

so

3 β ■: ■■ -

in the R " ^J 'wa.d K" which vorsteheia.de B © deütusg have, are on

^ following © W @ iae produced _o The HydraZoaYerbindimgen of the formula

■ · B-

. "ί« C -E ¹ ■■■ '■' ■ V ..

3.
.lsi - ':; jw M "ii © ^ © gütefcesiod! © äeutung' has and X a

009813- / 1870 "'■■■ ^ _Aö

- · 15

VI or the new phenylhydraain compounds of the formula II kon ~ deneierto ■■ *.: ■:

The above-described reaction proceeds via the stages ßljj + ZJX / - * ßXJ -Ϊ OXj ₀ To prepare the compounds of formula VI or II, the hydrazine compounds of JOriuel VII

- 2

all output verbiiiduntie used when the nitrogen atom Ii was acylated without blocking with suitable ketones or aldehydes to be, can not selectively the desired - hyärazine " Connections received o In this case, the process continues according to the following equation

WdCOBT

■ * ■ * CO

E ¹

in which R _p R and T have the above meaning »

Ketones or aldehydes, which are condensation of the Bticketoff atoms

2 '^;"■■■■'

ίί T © rw © M © t werden & @ i32iexL _r are not restricted to certain CJ groups. In practice, however, such carbony compounds are used as a matter of precaution »which do not enter into any lifting reactions and which are cheap» Examples of suitable compounds are acetaldehyde » Chloral and benzaldehyde o

ÖO9ai3 / 187S

For specific examples of hydrazone _e the, the processes described above can be produced, are acetaldehyde «= · *! "" (2 ™ chloropropionyl) "H ^ (p ~ methoxyphenyl) - ~ hydrazone _r acetaldehyde * ^" ~ (4 -chlorobutyro3rl) «- N - (. P-methoxyphenyl) <~ hydrazone * acetaldehyde ·« !! "-» (2-methy 1-3-CbIOrPrOPionyl) -K ~ (p <-methoxyphenyl) ~ hydrasone, acetaldehyde-H - (3-chloropropionyl) ~ W ^A - (p-tolyl) -hydra ~ zonρ Acetaldehyde-H - »■ (3-pentenoyl) -N - (p-metho: typhenyl) ~ hydrazone, acetaldehyde" N - (chloroacetyl) -H - (m-methoxyphenyl) -hydrazoni acetaldehyde-K - (chloroacetyl) -H - (m ~ tolyl) -hydrazonj acetaldehyde-N "(chloroacetyl) - 3S - {p-meth -.zypheny 1)" hydrazo} .i _r benzaldehyde-K '"(chloroacetyl) -iT-phenylhydrazone * acetaldehyde- ^ - (2 ₁ 4 = * hexadienoyl) - »N ^J '- {p-methoxyphenyl) = hydrazone, beiizaldehyde-N ^ -acetyl-N -phenyl-»

11 hydrazone and acetaldehyde-K -> acetyl = «N'-pheny! Hydrazone

When the hydrazone compounds of formula VII are reacted with compounds of the formula IX, the NC bond is weakened by the radical B in some cases and the hydrazone compounds of the formula VI are generally obtained, e.g. in the case of the hydrazones of acetaldehyde or methyl levulinate ₉ or the reaction was carried out under relatively severe conditions, and the hydrazone compound is slightly opened after the acylation and immediately gives the hydrazine compounds of formula II instead of hydrazone compounds of formula VI. For example, K => {2j, 4-hexadienoyl) ~ li - (p-methoxyphenyl) hydrazine and N - (chloroacetyl) ~ phenyl hydrazine are obtained directly from the corresponding hydrazone compounds «

The ayl halides are particularly suitable as acylating agents.

However, the implementation goes just as well Z ₀ B ₀ m ^ t. Acid anhyäri * -

the" - . . - ■■ - λ

■ 009813/1878

new hydrazinverbiMungeji of the formula Ii and their salts are generally in high yield by decomposition of the Hydrazone compounds of the formula? I obtained in the presence of acid »- ■". "Ν" "." ... ..

The PhenylhydrazonverWindungen dev formula TI riding a look from a variety ■■ Ketonen.oderAldehydenab - such as diethyl ketone, Phenyläthylketona Athylbutylketon, Hetho ^ yaceäön, benzaldehyde, acetaldehyde, ChIoral, levulinic acid methyl ester and / ^ methoxy like butyralclehyd ₀ In the aforementioned ffall it is desirable} a connection m'verwenden- that .xtaoh completion of reaction are readily cleaved kasm and no attsösuteveraindernde Hebenrea ^ tion received, and which is readily available _o In this regard Aoetaldehyd is as carbonyl compound! particularly suitable

The preferred solvents for the named hydrazones are the alcohols "If ^: Any more VaIs -sin Iqui-valent Al";

becomes ₉ one can _; also-'2100h ■ - a gsMötoliciies simgs! sttt®l _? as ltlier _S : BähsoI or 'toluene' ^ use ».- |

_edoöli: ia den- mbXb% ®u Mll®a nielat be =>. "f @ CTj @ iidiii2g nioh't'.mehr-äie -.- yield © aie = ·

ä% fao @] 3h &% ®'iMg &<> In this. Case k.öaR <sa gtes-feiger ©

The reaction is completed in a short time, even at a low temperature, and the yield is surprisingly high. "Furthermore, the desired hydrazine compounds are obtained in the form of salts which can easily be obtained in crystalline form either by concentrating the solvent or by cooling the solution." these salts are treated with bases _t the free hydrazine compounds are obtained in quantitative yield *

Specific examples of hydrazine compounds «those according to the above described processes can be produced, are N - (3 ~ chlorop3? Opicmyl) ~ ii ~ (p ~ -metlioxydighenyl) - hydrazine, Λ - (- 4- * Chlorobutyroyl) -N = Cp ~ methoxyphenyl) -hyurazine "M - (2-Metj: iyl-3 ~

1 1

chlprpropionyi) -! ~ (p-methoxyphenyl) hydrazine. II ~ {3-chloro-

i ι i

propiOHyI) = K - (p-tolyl) »hydrazine _f N <- (3 ~ JPentenoyl) -K - (p-meth-

oxy phenyl ) "hjdra, s ± n ₉ M -C chloroacetyl) -N - (m ^ methoxy phenyl) -hyd £ azirsj, I ¹ - (GlilOÄe © tjl) = 'B ¹ - (m <-tülyl)' - hydrazine, M ^3- -C Chlorace ty IJ-N ¹ - (p «t & ethoxyph @ ny2 °)» liydrasisi _t . Ji ■ - (OhI or ac e ty 1} «» * ί -piieny! hydrazine, N ¹ ^ C Chi oracetjl) -Si ¹ - {p-chlorphexty 1> -hy drazin ₉ ■ H ³ "- (2,4-UexadieAO-" yl) -M- C p-methoxyphenyl} = - hy drazin , H- (2 , 4 ~ hexadi en oyl) '- H - {pmetteyltMöphQisflj-hydraziii, H -acetyl-B-phenr / hydraain and M -acetyl-M ^ piieiiylhyctraiin and H -acetyl-H - {m-chlorophenyl) - mid the Hydroeliloride _f Sulphates and Pnoephates cliefler

The l-Aeyl ^ -inöolifleartoojisäureverblnduHgen of the formula I _f in which ρ has the value 0, feösmett also according to the following procedure. will be presented. Phenylhydrazone compounds of the formula

009813/1878

in which R * R _e R _f R, m and a have the above meaning _s are condensed in a suitable solvent ait acyl compounds of the above general formula IX; »

Examples of suitable solvents in ... this process are non-polar solvents, organic acids and esters. Examples of inert solvents are benzene, toluene, ethylene, cyclohexane, hexane and tetrahydrofuran. Examples of organic acids are acetic acid, chloroacetic acid, propionic acid, butyric acid , caproic and Heptancarbonsäureo Beißpiele of esters are Chloressigeäureäthy ester. "-! Buttersäuremethylesteri methyl acrylate, Vaieriänsäureiaethylester and sorbic ^ r-uremethy ester ₀

Acyl chloride is the most common acyl compound of the formula IX In addition, the acyl bromide or the Acid anhydride can be used «

The reaction temperature is between 50 and 15O ⁰ C _f advantages ^ example between 80 and 120 ⁰ Co Generally, the Unisetzung int ended After reaction is complete within several hours xv'ird the solution evaporated or Eesigeäure, water, or Pe = troläther added, the desired product precipitates ₀ If the solution is evaporated, the residue is extracted with ether, benzene or chloroform and the purified product can be obtained from the extract »

0098Ί3 / 187Θ

Specific examples of compounds made after the above described processes, can be produced, are

l-chloroacetyl-2 ~ methyl-5 = ^ 3-methoxy-indolyles8igsäureinethyle8terj ₍ "chloroacetyl-Z-methyl-S-inethoxy-i-indolylacetic acid tert ^ ,, -! _p butyleßter

GH ₂ COOC (

l-Chloraeetyl - ^ - nietiiyl-S-inethoxy - ^ '- indolylessigsäurebenzyleater! ! "CüloraGetyl ^ -methyl-S-methoxy-J-indolylessigsäuretrahydropyranyleeter _t

l-chloroacetyl-S-methyl-S-metiiylthiO'-i-'indjlyleesigsäuremethyl-

eeter

l-Cliloracetyl "2-methyl - '5 - chloro-3-indolyleseigsäuremethyleter _f i-chloroacetyl" 2 ₉ 5-dimethyl-3-indolylessi ^ ätemethylebt,

metayleeter _e SAD ORiGJNAL

f3 / 1S7 6

methylestar,
l-chloroacetyl-S-methoxy-J-indtJlylacigsäureaethylßter,

1-Buty royl-2-methy l «5 ^CT ethoxy-3-iiidQlylgic acidiiiyl ether,

and l- (2 ^f _P 4 *

methy! ester _o

All mentioned l-acyl-J-indolylcairbonaaurevtirtiindungen are new and have antiphlogistiscJie ₈ analytical and ahtipyretische effect α üinige these esters ,. S ₄ B ₀ tert-butyl esters, benzyl esters and tetrahyuropyraxyl esters are saponified under suitable conditions to give the corresponding 1-acyl = 3-indolyl car) onic acids * The free acids have a higher pharmacological activity than the esters

The 1 ~ acyl = "3-indolylcarboxylic acid compounds of the formula I _s in the

ρ has V.ert G and R is a hydroxyl group _s can also be prepared on (the following V / eise _β compounds of the formula

XI

• β η · ζ C. "■■""-.-

in the R \ R- ,. R ^ -, ".R ₅ m and η have the above meanings and ft ^{1 is} an alkoxy- ^ amino or benzyl group, ssu the new 1 ~ acyl-3 ~ indolylcarboxylic acid compounds of the formula

BATH ORIGINAL

f
(GH) _n - {

, (XlI)

■> η ~ r C

decomposed, in which R, R,. R, R, d and η have the preceding meaning o

An example is a benzyl ester of a 3-indolyl carbonic acid compound in the presence of a metal catalyst, v / ie palladium, hydrogenated. In this way the free 3-indullyl carboxylic acid is obtained connection «For example, the ümsetsun ^ exits as follows:

CH ₂ QOOH

CH,

CH

CH,

CH ₃

If a tertiary butyl ester of said carboxylic acid with an aryl sulfonic acid,. For example, "p-2oluolsulfcmsäuxe, is treated" takes place saponification, · There are a few PaIIe ₇ at aexiezi, the desired product is already through. Heating and melting the

- ..; 009813/1876 '

tertiary eutyleetera. get"! will". .This is Reaction of the case «." * "

at

CH

GIi

CH

CH

CH *

CH ₂ COOH

When a 3-indolyl carboxylic acid aniide in an inert solvent treated in the equivalent of a suitable amount of nitrous acid

is also obtained in some cases the free 3-indolyl « carbonic acid -

Specific examples of Yerbindungen _s can Verden prepared by the processes described above are; 1- (2 * 1 4 ^l -hexadienoyl) -2-aiethyl-5-ittethoacy-3-indolyle8Sig3äure, 1- (2 ^r , 4 ^f -hexadienoyl) -2-ethyl ^ 4-iae thoxy-3-inäolyleesigsäur e ι 1-C2 ¹ , 4 '-HeXadienoyi) ^ 2 "! - i & ethyl-6-ethoxy-3-inaplylacetic acid _t f - /% - ( 2. *, 4 * -hexadienoyl) -2-methyl-5-methoxy-3 -indplyl / -

butyric acid,

l- (2 *, 4 * ^ hexadienoyl) ^ 2-methyl- * 5 - methylthio-3-indolyleBSetic acid, ö (-Zi- (2 S4 ^f Hae ^ dienoyl) ^ 2 - metayl- _? §-methoxy- -3-i "doly / - propionic acid""- ■ .-" ■, ^; - ;. ^'v;:!. ".";■; .- ..-- ,.;.... _: ". ■ '".

* '. ■ ".- ■■" ■ - ■■ -. ■' .-. '■' ■ · '- ■. ■■ ■■■ "■■ -. ■ .- ■ - ■■■ - - ¹ ; - ^.; · - BAD -OfMGiNAt

ÖO'0'.B-.t'3. / L.ä7.e

1 ~ (3 S3 ⁵ -diethylacryloyl) ~ 2 ~ methyl - i5 '~ methoxy - ;; - indolylbetic acid,

1- (5 ^f -Chlor-3 ^f "- pentenoyl) ^ 2, 1-chloroacetyl ^

W l- (5 • -Chlor-? ^F - pentenoyl) -2-methyl-5-ynethylthio «3-indolyl acetic acid

Cf-Zl "(5 '-chloro ^ 3." - pen-tenoyl) -2 propionic acid p

J .- (5 '? -Chloro =' -peiitenoy 1) * - 2 ~ 6 ~ taetriyl _{"iaethoxy-J-i'indol} ylessig.aäure 1 ~ ^(5-chloro-β = 3 '-penteiioyl) ~ 2 , 4-dime-3-indo tiiyl Jylessigsäure, 1- (5 '-chloro = 3 ⁸ -pentenoyl) »2 _s 6-dime thyl-3-indo3, yleesigsäure, I-Cn-Heptanoyi) -2" -Eiethyl ~ 5 ~ ittethoxy-3 ^ indolyls £ 'ßigsäure _r l- (2 ^J = 1 -Äthylhexanoy) -2-methyl-5 ~ never thoxy-3-INDC lylessigsäure,

l-ChloraGetyl-S-methyl-e-methoxy-S-indolylessjgeäure, l ~ (n-Caproyl) -2-me-ti.yl ° "5-methoxy ~ 3-indolyleB8lgBäure, l- (3 ^| ~ chloropropionyl) - »2-methyl '» 5 ~ methoxy ~ 3-ynaolyl acetic acid ₉ l- (2'-chloropropionyl) -2-methyl-5 ~ metJioxy-3-inc. Olylethyl acid, l-crotonoyl ~ 2-methyl-5-methoxy- 3 "-indolyleselgEäure _r 1- (n-hexanoyl) *» 2-methy 1-5-methoxy-3-indolyleetige acid and 1 => (methacryloyl) -2-methyl-5 '= Hiethoxy ~ 3-'indolyles8igaäuree

009813/187 6 *

.-. ■. ■ ■■■■■ * .25 - / ■ . . "■. .- ■

Another method for producing the l-acyl-3-indoiyicar * 'bonsäurever windings of the formula I is the following process

IrAcyI-2-ijidQlylessigBäureve-ruindiungeii-.Using formula I> in which m and ρ have the value 0 », can be obtained by washing off water or by hydrolysis of l-aeyl-3
Acid compounds of the formula

2 ■■■■■ """
^Ä '(XIlI)

1 2 5 6 of the R " _s S _? .L rad.R 'the preceding -B @«

This lieafetion is generally carried out by M

ia in.- one in

The reaction takes place in the temperature range of 70 S of esa. gsöoefc. the Uiaset-süng nielit runs smoothly ₉ becomes oil © "

either mater Hüokfimss boiled _t fe-obei.äaa water ait © inea -Bosmittelp as -Beasoi. ₉ .- Solaol · or X ^ IoI ₂

from external connection - becomes through ErMtgea

cleaved". ". ¥ © sa the remainder B © j SJt« 0 ^ jird äie fe ^ Madßmg in the .present i 4i © -

ORlCBlNAL

~ ²⁵ ~ "■ - 162D441

Napolaron organic solvent in the presence of Ziiiis.Uiid & q ~ if necessary a trace of iodine produced «For example, this reaction runs as follows:

CH ₃ O

W- /

.0

H + BrOHgCOpt-Bu

OH
0H ₂ COOt-Bu

- £ st @ rs receives

= ■ - ■ "- · ai?

SAD

1 - Aery 1.OJfI * 2-ethyl ~ .5 ~ methoxy- 3 ^Ä indoXyl acetic acid _β ln-decajaoyl-2-methyl-5-niethoxy-3-indolyl acetic acid

(3 ^{ - Chlorprapioiioyl) «2 -metiiyl - ^ - methoxy-3 ^ indoj.yleaetic acid _f

l «ButyröyX - 5 - niethox3 '- 3 == ind: olyl acetic acid, _Ν l'-Butyr oy l ^ -methyl-S-chloro-3 = -indolylacetic acid ^! 8 acid »

The X ^ Aayl-3 = -indoXylcarljansäüreverbindungen of the formula I ₉ in which m is 1 and ρ is 0 and R- is a hydroxyl group. _r can also be obtained by a method in which * X "acyl" -2 _f 3- "dihydro-3'-en indolylcar'aonsäureverBindun _ei of the formula." · - ''. ". '- ■ _ -;' _.:. ■■ ₌ ■ -.

.CHCOOH

(XIV)

in which R ^ t R _e R and R have the above meaning * dehydrated.

In this Dehydrierungsrealction unpoXare solvent such as benzene, xylene or toluene »can sowiedie verEchiedensten other organic. Solvent used will n ₉ as acetone» acetic acid, chloroform, ethanol and methanol "" ίUr dehydrogenation

009813/1876: ..- · .- -

■■ - ■ "■" ■ ·. "■: ■ - ■" ■■ - ■ "■",: .-: BAD

be Oxydati r <i> emit "feel as Chi or anil - SeXenrtioxyd or halogen ,, used" Specific examples of compounds that each can be produced easily by the method described above, are
l-chloroacetyl-t-aiethy l "5

1 "ChXoracetyX ~ 2" niethy 1 - 5- chXo-r-3 ~ indοIyIe a aigßiiur e X «chloroacet; yl-2 methyl- S

3-acryloyl-2-iuethy 1 -5-nistnc: cy-3'-incioly! Acetic acid- _t

I "= (2 ^s y4 '' HexadienoyX / -Z ^ methyl- 5-. '. ^R ietho2: y- 3 ~ indoljXesslgsäure _?

1- (2 _'r 4'-HexadienoyX) _{-2-methyl-3-r} inaolyXesaigsäure

X- (2 'j. 4' «HexaaienoyX} - 2- * r; iethyX" 4-rae tho3cy - * i - ■ indolj lese ig acid,

!: - '(2 ⁵ , 4 ⁵ - "HeXaCLienoyX) .2-t: iethy7» ™ 6- «me" th.oxy -3 X- (2 ^{ j 4 ^f -hexadienoyl) * - 5: = - raethcixy -3 Xn = -Decanoy X -2-me -thy 1 · - 5 -sie thoxy-3'-in d ο Xy X es sigaäure "X" n --- Octanoyl '= - 2 = methyX-'5-'methoxy'-3 - '' ind "üXyXeGsigsät-.re and

V-acyl-2 _: 2 ^ dihydro-3 ~ incLolyl """caramic acid compound" used in the process according to the RS method is converted in high yield by conversion, a corresponding 2 _? J-Dihydro - ^ - indoXyXcarbonBaureverbindungen with an AcyichXorid in the presence of a?. · Base erhaXt-eru

The inventively available new X Acid compounds are valuable drugs ia with high anti-phxogistic, analgesic and antipyretic activity, In addition, they work against arteriosclerosis and they lower the Blood cholesterol level.

009813/1876

For example, l- (2S4'Heaadienoyl) -> 2 "Moet] iyl - = - * 5i iiietlioxy-3-Indolylessigßäure a new connection _f having due pharma kologiecher UntersuciiuHiSsii a besonderg nlearige loxiaität t, however, an excellent pharma & o ogische activity! has a very high therapeutic quotient »This can be seen from the table below»

Tabel

"^ - ^^^ effects
Connection ~ ^^^ - »^^^^ Henunung of the carrageenin
Edema on the hind leg of the
Rat »iäDcQi. mg / Jcgs p ° o <, LDkq ßatte »po"
mg / kg ¹ ^ ₅ O / ^ 5O j X ~ p ~ chlorobenzoyl ~ 2 ~ methyl · ·.
5 ~ methoxy- <3-idolyl acetic ~
acid
(Indometacift) 7.5 about 600 Butaaolidine = 3/5 ^ DAoxy-
1 ρ 2-dipheny 1-4-Xi-butyl -
pyrazoltdiR 520 > 1,000 about 1.9 1 «- (2 ^S , 4'-hexadienoyl) -
2-methyl ~ 5-methoxy »·
5-inullyleeac acid 75 > 13.3
j

O Q

cn

, ■ - si.- \:.; -. , ■■■:,: ■ '- ■■.

Of the well-known uninhibited fcsw _q am; iphiogiisstiBche-n drugs that do not contain steroids ej.nd ^: _r does indomethaciri have the greatest activity? however, a very high toxicity ,, On oral administration of 10 mg / this compound kg in rats were observed in these oceulte bleeding = AuiiSßrdem tend all known anti-inflammatory drugs danu, bleeding of digestive organs su promote _a JSs are numerous deaths or by Magendurchbrueh " Sarmdurcnbruoh has been reported- Butazrlidi52. _? The most widely used anti-inflammatory drug, _D , with its high level of acute care, has only one low act, ie the pure, small therapeutic quotient «· λ

In contrast fcat 1 ~ {2 ^'% -4 ^s --HexadienOyl) "2 - niethyl" 5-methoxy-3- · indolxleseigsäure a distinctly low in oral To ^ izitäto Seibat Verabfcigung of 1 000 mg / kg or mice .an Hatten do they show strange toxic symptoms _? and actual bleeding cannot be ascertained. The activity of this acid is higher than that of butazolxdine, and the therapeutic quotient is therefore considerably greater than that of any other compound, with a similar effect ^ i) this compound is therefore of particular value - full AraneiiaittelV

In addition, l- {3% 3 ^ diethylacryloyl) -2-niethyl ^ 5-ffiethoxy ~ 3-indolyl acetic acid, i ~ (5'-chloro-3 ^f -pentenoyl) -2 · = methyl-5-methoxy-3 ~ ind .olyl acetic acid _! .
indolylesBetic acid _r l-tert.

indolylessigskure ■; Γ = £ ί ~ $ 2 ³ _s Λ '-hexadienoyl} - 2-methyl-5-biethoxy 3-indolylj-butyric acid and 1- (4 ^ = methylpent6mqyl / «2-methyl"5-' methoxy-3 ^ indoly3. acetic acid essentially pharinakology before effects, "

Most of these connections have a higher ** anal ge ti see and antipyretic effects a.lß amlnopyrin and aspirin ;, Furthermore these compounds show preventive effects in experimental arteriosclerosis and a considerable reduction in the Cholesterol Blood Levels Sc -

The invention is illustrated in more detail by the examples

Example 1
2 _? 8 g N ¹

and 9? 3 g of levulinic acid to be 1 hour and 45 minutes under Rüh ren to ^"0 75 Q heated for ₃ dora After cooling, v / ith the liquid reaction mixture into cold" water _r poured precipitated. Crystals are filtered off and dried. 2.2 g of crude l- = chloroacetyl = 2-methyl "5'-ne1; hci: y-3'-indoly3 acetic acid are obtained * Haoh circulation from ethanol melts the pure compound 155 to 156 ⁰ C-.

According to the method of Eelspiel 1, the ilydroehXorid of the ent P öprecuendßn H7 / drazine compound with an aliphatic carboxylic acid compound 90 minutes to 2.5 hours after stirring to 75 80 C heated0 The following in Examples 2 and 3 named compounds,

Example 2

! «Acetyl-2-iaethyl ~ 5 ~ methoxy" 3-indolylacetic acid, m.p. 163 - 164? 5 ⁰ C after recrystallization from acetone *

Example 3

l- (2 '' 54- ^l -HexBdlenoyX} -2-methyl ^ 5 jnethoxy-3-> irdolyleeaigeäare _f 157 - ■ 160 ⁰ C after recrystallization from / oet> ο _ΛΓ ,

009813/1876

Example 4 · '.-'- ■

1 1

4 "8 g H"Ace'byX ^ ir "{p ~ iaethoxy.phenyl)" - feydyazin '"3ayd; i ^> octi.iprid wad 2.5 g levuXic acid are introduced into 20 ml acetic acid ₉ and the mixture becomes Z hours imterBühren to 76 ⁰ C ₀ heated Thereafter, the KeaktionsgeinieGh with about 60 ml of water ^ and the precipitated crystals are dried and are ahfiltriert 4 ₈ 2 g of crude l ~ = acetyl -2> methyl-5-methoxy-3 ^ indolyleBslg "acid obtained from acetone unüsristallieiert werUeiia mp <165 - °

When carrying out the dissolution in formic acid. · ,. Propionic acid _? Lactic acid _s butyric acid _δ cyclohexane _s η-hexane or lJioxane the product is also obtained in higher yield »-

Example 5

The procedure of Example 4 is carried out with methanol as the solvent repeated It is l-acetyl ^ ZsS ^ diniethyl-J ^ iHdolylessigsäu.remethylester obtained as a light yellow oil *

Example 6

2, | N ~ g Chl0racetyl "-N - (pi" raetho2yphenyl) hydrazine and 1 * 6 g Lavulinaäure be registered in 50 ml of glacial acetic acid Des mixture is treated with about 2 ml of concentrated hydrochloric acid and stirring for 2 hours at 75 ⁰ C erv / ärmto After When the reaction has ended, the precipitated crystals are filtered off and dried. 2.3 g of crude 1-chloroacetyl-2-methyl-5-metfii "oxy-3" -indalyl-acetic acid are obtained, which according to Umkri isation at 155 ~ 157 ° Cf ecbmilzto

^: - "-" - * ■ '' ν ^'-;: *' BADORIGiNAL

■ 5 -j ■

20 g ^ "" - Crotonoyl-Ϊ: '* ··· (p-methc ^ yphenyX; <~ hydrasin · -hydroohloz'ici which is entered in 40 g of levuXic acid, and -das jeai.sc/i

2j, 5 stood under! '. Clock up', '8 G heated, after unseting is finished the liquid Ksalrtionsgemiseh in 200 a ?. Old water is singegossenj, the crystals obtained are v / ercen abfiVbx'iert _s extracted with ether and then the ether of the ti 11 Ie rt. What remains is crude crystalline X ~ Cro fconoyl = 2 - Eiethyl- 5 izet.ao:iy -. _3-f irtdolylessigsäure consisting of a 65 ί 15 Gerdsoh yoi "Itner alcohol and recrystallized, yield 7 ₃ 5 g (44 i> represents theory) i'eine compound of smpo 130 -. 131 G,

According to Example 7, the compounds mentioned in Example 8 ^ is 10 are obtained, /

Example 8

, 0-

after urakriatallization from acetone.

Example 9 1-Crotonoyl-2-'nietliyl-5 "-niethoxy-3-indolylacetic acid ethyl ester;

Oil. '.' ■ ..

Example 10

• 5 oil.

Example 11

20 g of K "caproyl-H = - (p-" methoxyphenyl) -hydrazine-hydrochloride are added to 40 g of levulinic acid, and the mixture is heated to 75 ° C. for 2 hours while stirring. "Then 100 ml of the liquid reaction mixture is added cold water poured, and the _h

BATH ORIGINAL

0098T3 / 1876

- ■ · "■■■■.. 16204Λ1

crystals obtained are filtered off and dried ■■ * Bs are. "1.5" O g of crude 1-Caprcyl-2 "niethyl * 5? -Methoxy-3- = lE.clolyleseigsäure obtained * which after Umkristalllsation from a Mi schundvon acetone and water 8.7 g (37 # theory) pure compound of Smp * 140 ~ 141 ⁰ C resulting '

Example 12

17 g N "> _ (2% 4 '~ hexadiengyl)"' K ^A --- (p "nietnoxyphenyl) -hydra2ih - = hydrochloride and 10 g el · acetylvalerian acid are ir. 35 ml i-sine added, and the mixture is stirred for 2 hours "

heated to 70 to 80 ^{0 G.} The liquid reaction mixture is then poured into 150 ml of cold water and the resulting crystalline ϊ & 1! Ιη & is filtered off and dried _o 10 g of raw / "- /!" (2 *? 4- * - Hexadienoyl> 2-methyl.-S-met ^ butteric acid obtained, which after recrystallization from a mixture of acetone and water for 4 _{s give} 6g pure product with a melting point of 127 ■ = - 129 ° C «

Haoh. Following the procedure of Example 12, those in the Examples 1? up to 15 named connections here »

Example 15

(2 *> 4 * -hexadienoyl > -2-sie thyl -5 = -me thoxy-3-incl 0

acid, m.p. 166-167 ° C. after crystallization from aqueous Acetone.

Example 14

1 '(4' -Methylpentenoyl) -2 ~ iae ~ thyl 5-me thoxy _T -3-indoj.ylessigsäure, mp 135 _o C to-Umkristallieation from aqueous iiceton _c

'. ■'. '■■:;. ■ '. ■ - \ / λ,' - ■ .. BW

Ö098T3 / 1876

162044t

Example 15

1 - '(4 ^{ -ChiorbutyroyI) ^ - IHefchyi-S- ^ iaethoxy ^ J-iridclyl ^ ssi ^ acid "149 - 15C ⁰ C after recrystallization aue acetone"

Example 16

10 g. N - (n ~ Decanoyl} ~ H "(p-taethoxy phenyl) -hydiazi; .i ~ hydrochloride and 9 g of levulinic acid benzyl ester are heated in 30 ml of dioxane with stirring. The crystals obtained are aDflivriert, the A filtrate is A reduced truck evaporated and the concentrate washed with cold water ₅ Here an oil from ο 3) the oil is rubbed with a mixture of acetor and water _r whereby the l-decanoyl-2-methyl-5 - = - nietho: -y -5 - i? Idolyle8eig "-benzyl ester from Sinp _e 85 - 85 ^J C auskristaÜ-.liBiert-.

Following the procedure of Example 16, the compounds mentioned in Examples 17 and 18 are prepared,

Example 17
! • = -Decanoyl ~ 5 ~ niethoxy ~ 3-indolyle88igEäurebenzy; Lester; oil _f .

Example 18
l-decanoyl-S-chloro - ^ - indolylessigsäurebenzyleiiterj oil »

Example 19

10 g of H - (n-octanoylJ-ni-tolylhydrazine hydrochloride and 10 g of laevulinic acid are raised to 75 "- * 77 ° C for 4 hours: .tz.tr After the reaction mixture has cooled, it is diluted with 30 ml of acetone, and the insoluble materials are filtered off Piltrat is poured into 30 ml water and the liquid over Kacht stand in the refrigerator transmitted the precipitated Ki * istalle be;. filtered off and dried "are 6 _y 8 g of a Geöiieoheß of

, 009813/4876

37 "- ■■ - ■■. ■. ■

1-Cn-Octanuyl} - 2 _T 4 -dime tiiyl -I-indolylessigöäure and "noyi) -2j6 ™ difflethyl ~ 3« indolylöS3igsäur8 get ₀

Beisjgdel _{> =} 2b _r

4 x 7 g of l- (2 ^{{ j4 l} ~ rexadienoyl} ^ 2-methyl-5-ynethoxy-3-indoIyleasigsäure-terto-butylesiier ^ verden with 45 ial benzo ". Versetat" After the addition of p-idoluenesulfonic acid the mixture is under The reflux is heated to the boil. The reaction mixture is then washed with 30 ml of 10% aqueous sodium bicarbonate solution and then washed several times with water and then dried. The Benacl is then distilled off under reduced pressure and the residue is recrystallized from acetone. 2 ^s _? 4 ^S -Hexadie3ttoyl) -2-iaethyl-5 = 'niethoxy-'3-indoly / acetic acid from Sap ο 161 = 162 Co The elementary analysis gave the following value

about _o ! 65 _? 64? 5 ₂ 84 x; 4 _f 25i gefiS 65 _? 53; 5 ₃ 62; 4 _? 41 *

Following the procedure described above, the Examples 21 to 23 mentioned compounds prepared *

Example, 21

1-decanoyl = 2 <= - methyl "5-iiiethoxy"5-'indolyl acetic acid / mp _P 126 ⁰ C "

GH K

i 70 _s 80; 8? 32? 3y75;

Example 22

1- (4 * -Chlorbutyroyl) -2-methyl-5-methoxy-J-indolylacetic acid ₉

Smp, 149-150 ⁰ Go

. ■ '* - ■ "· ■■"': - />' ^: = ^; ".. BAD OFUQINAL

C H ϊϊ Cl

ber ,; 59.35; 5.60; 4.33; 1Ο, 95ί gefo: 59 _ε ΟΟ? 5 »6Ο; 4 _S 22; 10-23 *

Example 23

λ - (4 * -Methyl pentanoyl) -2 «-methy 1 ~ 5 = -isa fchoxy-3 = inci ο 3..y! acetic acid _s

CH I

berV: 68.12; 7 * 30; 4 _f l &; found: 68p15; 7.45; 4 _; 46 ₅

Example 24

1 ■ ■. χ 1

hydrochloric and 2.4 g acetony! malonic acid are added for 4 hours in 10 al acetic acid heated to 85 ° G with stirring, then cooled down

the reaction mixture is poured into cold water

The precipitated crystals are filtered off and dried. 3 _P 0 g of crude 1- (2 ^S f4 '~ hexadienoyi} -2 ~ me1 & ^ «= 5 ~ methoxy« 3 "indolylacetic acid are obtained, the wet overcrystallization from aqueous acetone in yellow IJadeln ^ osi Schmelzpiinkt 162 - 163 ⁰ C crystallize.

Following the procedure described above, apply the Examples 25 and 26 obtained compounds,

Example 25

1- (n-Hexanoyl) »2- methyl-.5-niethoxy-3 '= - indolyl acetic acid3, m.p. 140 141 ° Co

Example 26
l-chloroacetyl-2- = iaethyl ~ 5 ~ 3-aetLoxy indolyleasigsäure, mp 156 _o -

^{157 Co.} 009813 / 18TS "bad oriqinal

Example 27

7c5 g of acetaldehyde «K ^ ~ -" chlra «etyl-If ^ (p-'isethoxj'pheiiyD ^ hyctrazrtn we mature with 53-ß xavulinic acid and while cooling with ice 1-14? G of dry hydrogen chloride gas are introduced The temperature of the reaction mixture gradually rises and finally the mixture is heated to 80 ° 0 for 5 hours. The semicircle is left to stand overnight and then poured into a large kenge wafer ? .Along sau with some AJctivkohle Sntfarfeung umlsristallisiert you received l-chloroacetyl-2-Eie1;. hyl-5 '' iaetli02cy "3 * indolylacetic acid echmiiat at 156 - 157 ° C * - _v

Kach that. The ¥ described above will be experienced in the di5 Examples 28 and 29 compounds mentioned

Example 28

! »Acetyl ^ -aethyl-S ^ methoxy - ^ - inüolyleBsigsäurej. Smpo Ib2 164 ° C.

Example 29

! - (n-Hexanoyl) -2-iae1: hyl-5 "-aiethoxy '* 3"' indclyle3sigsaure \ _ mp _a

- HO ⁰ G, V

Example 30

A mixture of 3 _S 8 g of 1-acetyl'-2-methyl'-3-hydroxy = 5 ~ m3thoxy-2s _f 3 = · aihyάro'-3- · indαlyles8ig8 acid «tert, -butyl ester, 500 ml of toluene and 3 g of p ^{-Toluenesulfonic acid is heated to ICO 0} C for 5 hours with stirring, the reaction mixture is washed three times with water and the OfoluollÖsuzig dried over sodium sulfate anechlease, the Toluölö8ttng is evaporated while standing in the

t 1

■ ~. 40 -.

Refrigerator separates out crude crystalline 1-acetyl-2 * raethyl-> 5 "methoxy-3-indolylesEigaäurc abj Gmp .. after crystallization from aqueous acetone λ«? - 16Ö ⁽ C,

over ₀ ; 64, -36: 5 _? 79; 5.36; gefos 63 _; ^ '6; £ .26;

In the same way, those in Examples α 31 and 32 mentioned yerblztcluiiße ·.! manufactured.

Example 51

ß- / i- (2 ⁵ j4 '"Iiexadlenoyl) = 2-methyJ, -5 ■ methox.y-"5-'indolyiy-propionic acid, m.p. 166-16T ⁰ C-

Example 32

(2 ' ₅ 4'"hexadienoyl)» 2 ^

acid "Sspo 127»} .29 ° 0,

Example 3? "·

2s5 gp ~ Methoxyphenylhydrai? On des Lavuiir-sau-remetixyleMteys- are added in 5C ml iäisesej «a ^ etr ^ gejio The mixture is t.7opfiinwe.i.eif with Op 9 g acetylohlori egg and. from 'in Ii ο ο u end 3 .'Stunrlen heated to 8O ⁰ C Then, the mixture is in 50 αϊ! cold water; he stirs in.- It separates from oil _v . dae with <\ txu; r ~ fjxtrnhiert v / ird .. One obtains! «Acetyl-2-ffiefchyl- 5- niethoxy-3 indo3ylsigt? auremethyl'-ester _c The IR ^ absorptiona;.: pelctrum of the product int m: .t that of an authentic terbindun ^; iaeii ^ isch, which was obtained by acetyl if ^ r and from 2 '- ^^ ethyl · "5-Πletlloxy -5-indoiylessigeäureinethylester"

^BATH ORIGINAL

O09 8T3 / 1876

Example 54 '

The procedure of Example 74 is 1.2 g KsaigSäureanhydrid place of acetyl chloride repeated ₀ is obtained also the

Example 35

3 _P 7 g! -Acetyl-2-methyl-5 - = - inethoxy ~ 2 _? 3-dihyiiro-3 * indolyl, sBig acid are added to 100 ml of benzene and then 7 "5 g of chloranil" are added. The reaction mixture is heated to boiling for 3 hours under% _reflux? then the solvent is distilled off under reduced pressure? the residue is taken up in acetone and filtered off from insoluble substances. The acetone solution is evaporated to a high temperature. The crude crystalline l-Acetyl-2 · »niethyl-S ^ ^^^ iQethoxy indolylacetic acid is from aqueous acetone umkristallisierto The light yellow crystals melt at 163 ~ 164 C ⁰ ₉

Example 36

According to Example 35, the l-chloroacetyl-2-iuetiiyl'-5-niethoxy = "3 x = * indolylacetic acid of mp 156 _o ~ 15? ° G hergöstellta

BATH ORIGINAL

009813/1

Claims (1)

P a t e η t a η β ρ r ti c he 1. l * Acyl-3 ™ indolyloarboxylic acid compound at the general formula co 3
in the B "an unsubstituted or halogen-substituted alkyl 2 ■? or alkenyl radicals with up to 10 G atoms R and R hydrogen atoms or lower alkyl radicals with up to 3 G atoms _; R is a hydrogen atom, a carboxyl group, or alkoxy carbonyl & ina = group with up to 4 C atoms au-n _s H an alkoxy group having up to 4 C = Atotnen _s benzyloxy _g Tetraöydropyranylox; .'- _f hydroxyl "or amino group “R is a lower alkyl group rai ^; bit; to 4 carbon atoms, an alkoxy group with up to 5 carbon atoms _? an alkyl mereapto group with up to 3 carbon atoms _a denotes a halogen oc.er hydrogen atom, ia and ρ have the value 0 or 1 and a η the value C ₈ 1, 2 or 3 _o 2c l-chloroacetyl-2-methyl-5 = 'methoxy-3-indolylacetic acid, 3 o · l «acetyl-2-methyl-5-niethoxy ~ 3-indolylacetic acid 4o l- (2 ³ , 4' -hexaäienoyl) - 2 Acid, 5 ο l-Aeetyl- = 2,5-dime ttiy 1-3-indolylessigsäureme ^ hyleeter _o 6β l = -Crotonoyl-2-methyl- »5-Biethoxy-3-indolylesBigsäure _o ünienagen ia «* · / sι» os. ^^ r.t sau3 αβκΑηαβηιαιβΐΗ.% Αι $ ι1ΒβΙ & c i-crotonoyl S-ester =, ■ II «, γ * · / ΐ." (Ζ ■ "- ■ - = butter acid, 12- ß ^ A-CZ proprixic acid 13 ■ l- (4 ' acid «■■ ..-" ■ ■ .- · "■■" ■ -. ■ ..- ..; ■ .-.. ". ■ -.- 15 c X-Iieoattoyl "2-niethLyl ·" ^ - methoxy ^ J ^ indoiyl ^ ssigsäurelaenzyl - M ester «, 18o 1- (n-octanoyl) -2 _f 4 "-diiaethyl-3-indolyl acetic acid 19ο 1- (n ^ Gctanoyl) -2ye-dimethyl-J-indolylacetic acid ■ --- ■ '"0Q981 3/1 44- - ■ - ' 22c method aur the preparation of the compounds according to claim 1, characterized by having an N « acylated phenylhydrazine or its salt of the general formula in which R and R have the meaning given in claim 1, · With a carboxylic acid compound of the general formula S-CO-CMg- (OH) _n - (OHg) _n - (OH) -COR ⁵ in the R _ΰ R- ₉ R _s R ₉ m _? η and ρ have the meaning given in claim 1 _s condensed 23 ο Use of the compounds according to Claims 1 to 21 for the production of Ar ^ ne! Preparations 009813/1876