DE1445103A1 - Indolyl lower aliphatic acids and process for their preparation - Google Patents

Description

Indolyl lower aliphatic acids and processes xu their manufacture

For many years the treatment of arthritis has been used and related conditions with steroids * such as cortisone, prednisone and the like., performed. These remedies are effective, However, to varying degrees have the disadvantage that they cause certain undesirable side effects. The remedies, which were known to be non-sterile, were not used fully satisfactory since they also tend to cause undesirable side effects in many grooves. As a result

there was «1a need for new effective anti-inflammatory agents Means free from such drawbacks.

Hau · documents «Mt i 11 ***. a no. ι

8 ^ 08105/1075

The invention compounds are now all of the common formula =

CHCOOH

in which mean:

R ₁ and R, hydrogen, lower alkyl or lower galkenyl H ₂ hydrogen or lower alkyl

E ^ lower alkyl, hydroxy, halogen, nitro, amino, mono »and binary alkylaraino, mer © apto, lower alkyl mereapto, cyano,

Halogen alkyl or carboxy;
R ₅ lower alkyl

a is an integer from 1 to 4; and
b a whole number, from 0 to 3 »

as well as their salts and esters and a process for the preparation of this compound, which is characterized by the fact that one is a compound of the general formula

- 2

80980 5/1075

CHCOOY

in which the symbols R ₂ * IW * R ^ and a have the meanings given above »and Y denotes hydrogen or a hydrocarbon radical * in an alkaline medium with a compound of the general formula

HCR ₁

in which the symbols R ₁ * R ₅ and b have the meanings given above * and X denotes an anion of a strong anionic acid or an organic sulfonic acid, and converts any nitro groups present in an ester thus obtained into amino groups »optionally with simultaneous alkylation of the same * reduced and optionally saponified a obtained sster.

"O-

λ η η η η er I A η η

■ The effinäuogsgemisgeii terbindungen can be as substituted indole &, nge & @ h®i% . You can use another- "but amen aiu la es -position by an indolyl-O) -H © st substituted lower galiphatic acids (or the salt © oaer Essfetss ⁵ ) with a benzyl radical in the 1-3t © ll H5G of IAAE © lk ^ i @ @ fe @;? s ^ © iehnet werdea Di © type of SubsMtuenfcen In ä®n Sis @ lIiMgen 2, 4 _S 5 _P 6 and 7 ISS * ^ä füt the Brfiiädiasag Bi © ät teitissh , sdlaag © them under dl® © b @ ß ang © g @ fegn © ai -D © flnitions for d £ @ symbols E «« ad Hj _{1 fell}

inventu23gsg @ saMsg © a ^ Is ^ position dM ^ sli a 1 » ii5) -E © st substituted sliplaatlschen are advisable ©. low aliphatic® acids, such as

the K- _< ^ "" BensjliBöolyI-C3j7 '° ^{l) eriva} ' ^{6 @ d @ r} acetic acid, • propionic acid, .butyric acid, Yaleriansur ©, S-halopropionic acid, acrylslis? e _a pentene- (4) -. acid and the like

One of the hydrogen atoms in the methylene group of the N «l« benzyl radical can optionally clureh a low Alkyl radical or lower alkenyl radical * such as a * Methyl, ethyl., Propyl, allyl or vinyl radical, be replaced.

809805/1075

The radical R ₂ can be, for example, a methyl, ethyl, propyl, butyl, isopropyl, amyl or hexyl radical or a cycloaliphatic radical, such as, for example, the cyolohexyl radical. In the preferred compounds, the alkyl radical has fewer than 12 carbon atoms.

An important feature of the invention is that at least one group other than a hydrogen atom or a hydrocarbonoxy group is bonded to the six-membered ring of the indole nucleus. Thus, R 1 in the formula can be a lower alkyl radical, such as methyl, ethyl, isopropyl, benzyl, halogenobenzyl or alkoxybenzyl, or a halogen atom, al, 3o chlorine, bromine, iodine or fluorine. Furthermore, R ₁ ^ can be a lower alkyl mercapto radical, such as ain meth / l mercapto, ethyl mercapto, propyl mercapto or benzyl mercapto radical. The six-membered ring can optionally be haloalkylated, for example with iinem trifluoromethyl, trifluoroethyl, perfluoroethyl, β-chloroethyl or a similar substituent.

809805/1075

.As dl® geigt above structural formula contains; Over the six-membered ring of the compounds obtained according to the invention, at least one functional substituent of the type described above (%) and can contain up to % a four such substituents. If the aromatic ring polysubstltulerfe -Isfe * can use the "Substituenteis equal to one another © eggs from each ¥ @ @ rsohi wob®i the i in _e the only © Besohränkung the neiler by wersGhimaener imposing ^ ypes func · = Group available steheaäsn methods related 1st .

The scope of the invention includes the manufacture of in "position" inen l-BenzylincfolylrCiO-Eest having lower aliphatic acids * those in the benzyl radical substituted with a lower alkyl radical or alkenyl radical are, for example with methyl, ethyl, propyl, tert-butyl, allyl, methallyl or vinyl.

Typical examples of new ones according to the invention in the α-position substituted by a l-benzylindolyl (j5) radical lower aliphatic acids with substituted benzyl radicals are the following:

809805/1075

a - ^ - Benzyl-2,5-dimethylindolyl- OJff-proplom & are, a- / To- Methylbenzyl-2-methyl-5-trifluoromethylindolyl- (2l7-propionic acid, a- ^ Tp-methylbenzyl-S-methyl-S-propylindolyl- (3j7-propionic acid, a-2r-benz dichloroindolyl- (5X7-eseige acid, a-ZT -5-chloroindolyl- (5) J7-PJ ^: " ⁱ > P ⁱ -one acid and a- ^ To-methyl- · benzyl-2-methyl-6-trifluoromethylindolyl- (3j7-propionic acid.

It is mentioned that the lower aliphatic acids of the invention substituted in the α-position by a 1-benzylindolyl-C5) radical vary in their physiological activity and certain of them represent preferred ranges of the invention. Preferred compounds include those "For which R ₂ in the formula is a lower alkyl" radical "such as methyl or ethylreate, and R ^ is hydrogen or a methyl radical. Likewise, those products are preferred which have a lower alkyl substituent in the benzyl radical (R ₅ ) and a lower alkyl radical in the 5-position of the Xndolkerae

809805/1075

U4'5103

igfeQS ' wiä Saig® ά®ρ &3> φά

it SSisi? ©

wii? ö el £ @

©! © © In © ijiel o ^ / m a aliphatic

₅ places

how

wi ©

M © © Ffiaßmigsgsülsis Water-

slä # lmtiseliea Sl

To the Eraieiung

809805/107 5 "

can count on salts, such as 4io Natriur> - _f Kalius- cder A ^ ncriur: Salse. Ander »Sal * ·, a" 2 "Glucaaivaln- _{t f} llcrpholin- Egg & thylanin- OTDR Cholinealsa and may also need ar according to si ca bekanirtta wsieen easily usrden made ^. ,.

The lower aliphatic Sli'araai described here in a setting by a 1-Seniyl · inäolyl- (3) -He3t substituted lower aliphatic Sli'araai can be prepared by various methods, the method of choice in each particular.! YbXI in a wide range:! & £ «vcn the category of the remainder Rg ^{un (} ^ ^ 4 i &. The F ^ product depends. According to one process, an aliphatic substitution by an indoyl (3) -beat first becomes aliphatic "Sure or one of the same with the desired substituent! * In the. 2,4,5,6 and 7-positions of the indole nucleus liörgCiRt *" l ^ t connection with the formation of the corresponding cmdaa in Aubotituitrten by a l-3enzylinäolyl ~ (3) ~ residue aliphatic acid bcw «of the corresponding seter i If an ester is jetted, it can nitt ·! » «Intr Bftaa * xrie for example an alkali hydroxide or • be saponified su the free acid.

The aralkylation is carried out when the indolyl-substituted aliphatic acid or the ester thereof is the benzyl ester of a strong inorganic acid or an organic sulfonic acid in the presence of a strong condensation agent, such as, for example, hydrohydride, hydride, alkali metalide, an alkyllithium or an alkyllithium.

BATH

809805/1075

kylat is. © let

lS sUiii is

ICentnkt g@teaefe.t wircL Ss M14 © t '©! © Μ oaeyet

ßa®

ait des

ig2i © t® & lea

will. Typi

di © applied

Example © fü t υγ @ Μ®-ιι k

olmol © d @? XyIoI ₀ mad

2 © tralijdr

^ fdte

© Sa «

o s @ is

?> I @ agea i, @@ .Igt

the free acid he;

la dea Heal £ ti © asgeoigexi. educated

Di © Seapera'öi-S's, feel ^ sXcÄer si® will, is never & t Iss-itimoho ^ s is

i ia about 1 hour® PraktiseJa aktioneseitea scliadea not "and kU will be used» ^Λ longer

8098CT5 / 1Ü75

-AA-

UA5103

The Aralkyllerungsreaktion can be represented formula moderately in the following manner ι

CHCOOY

-CHCOOY

In these formulas, R ₁ , R ₂ * R * »R ^ * Ry a and b have the meanings given above and Y is hydrogen or a hydrocarbon and X is a halogen. If Y represents hydrogen, a metal salt is formed under the reaction conditions.

If it is unsuitable to use this synthesis for the preparation of compounds "in which R ^ means a basic term" which would complicate the aralkylation stage, then this is the case it su prefer to have such a substituent or the Aral « introduce kylation. So it is with the synthesis of an in α-position by an i-benzyl-5-aminoindolyl- (3) radical substituted lower aliphatic acid is advantageous, first the corresponding in ct-3 position by a 1 »benzyl-5- * ntroindolyl- (5) -rest eubstmulerte low allphatlsohe 8Kure

- 11 -

809805/1075

daam this substance

to reduce.

to the

used Ina ά ± ® formula

in the above reaction, aliphatic acids

_# from Y. the ones given above

synthesized in different ways

if α Be $ © Mt <gte Bg hydrogen © the alnen methyl residue »s © it is too fe © i $ wssyg @ &, such bonds disr'eh Ursissetsiang eiaes g @ Eigii © t substituted phenylhydrazine (II ) .mife eisies "¥ © £ Fb invention of Foraiel III to form hite © s as Zwlsöli © iipx" odukfe occurring phenylhydrazone umzueetaen _a uater the H @ aktlonsbedlngungen to the indole compound

IF

ti

III

Rj

CHCOOY

12 -

809805/1075

In this scheme, R1, R1, and Y are as given above Meanings and Rg means hydrogen or a methyl radical « The reaction is usually carried out in a lower alkanol, such as methanol, ethanol « Isopropanol or butanols the one acid * such as Hydrochloric acid »hydrobromic acid, sulfuric acid or acetic acid contains. The acid acts as a catalyst in the condensation and ring closure reactions that lead to the indole compound IV lead. If the compound III is an ester, the nature of the ester is not critical, but it is preferable a lower alkyl star, e.g. the methyl, ethyl, Use propyl, isopropyl or isobutyl esters. To avoid the possibility of transesterification is preferably the same alcohol used as the solvent medium that the Forms alcohol residue of the ester. If Rg is hydrogen, it is expediently, the aldehyde in the form of an acetal, e.g. methyl-YiY-diinethoxybutyi-at, to use. Normally, for practical reasons, an acid addition compound of the ß-methoxyphenylhydrs.zin reaction component, for example the hydrochloride, preferred to the free base, but such are Salts and the base in the reaction itself are equivalent.

■ The formation of those substituted in the α-position by an indolyl (5) radical aliphatic acids or their esters is carried out at elevated temperatures; good results will be achieved through at least Achieved about 15 minutes of refluxing the reaction mixture. Longer response times do not hurt and

. - 13 -

. '/ 809805/1075

can be applied if desired «The desired compound is obtained from the reaction mixture and processed by methods such as solvent extraction, chromatography, water or water. Distillation, purified. Since the esters of the formula IV are low-melting solids, they are purposefully purified by distillation under reduced pressure. They are saponified by treatment with an alkali hydroxide «

As one of the starting materials in these syntheses verwsnd th substituted Pheraylhydrazine be prepared by known methods "Sine sweckmässige method consists in BiazöfcieruKg the appropriately substituted aniline to form the Dlazoverbinctung * Treatment of the latter with Stamioshlorid to form a tin complex and cerium this complex with Kfatriunihydroxyd to the phenylhydrazine.

- 14 0-9805 / 1075

-AS-

The compounds according to the invention have anti-inflammatory activity and inhibit or prevent them Formation of granuloma tissue. Some of the new compounds show high levels of this effectiveness and are in the treatment of arthritic and dermatological Diseases and similar conditions responsive to treatment with anti-inflammatory agents valuable. In addition, some of the compounds have potent antipyretic activity.

The compounds according to the invention are also valuable as sunscreens and as intermediates for syntheses of substituted tryptamines and tryptamine derivatives, which have a beneficial effect; counteract serotonin. Furthermore, they are also ice intermediates for the synthesis of derivatives and analogues of reserpine useful.

example 1

A. A solution of 27 g (0.156 mol) of 2,4-Diinethylphenylhydrazinhydrochlorld ve η 24.7 g (0.136 NoI) is heated Ethyl-α-methyl levulinate in 173 ml of ethanolic 3 N hydrochloric acid and 87 tal of ethanol for 11/2 hours under reflux.

- 15 -

809805/1075

14451Ό3 ^:

The reaction mixture is concentrated under reduced pressure to remove the Hattpfcm © sig @ of the ethanol. -The remaining oil was distributed between: water and ether »whereby the aqueous phase is extracted with a total of" three 150 ml portions of ether "- the ether extracts" are washed with sodium bicarbonate solution and with water. <> Oils are seen with ether ! dried and reduced to a small volume with reduced © ruek. Of the product - ethyl "e ^^^ -. T-trimethyl-indolyl (3J7-propi0natvom F« «129 crystallized to Λ $ 6 ⁰ ₁₁ G Man" restricted <ea & Flltrat-dryness and disengages from the ether * the residue in Gyelohexan to give 'a second fraction of the crystalline products from F "" is 12 ^ rock 136 ⁰ C.

-Dureh ümkristallisatiön from cyclohexane -re obtained purified

from F.; · 136 to

B. A solution of 6.8 g (0 ^ 0262 mol) of methylindolyl- (5j7 »prepioiiate in 25% cimethylformamide is added dropwise with stirring to a cooled suspension of 1.26 g (0.0276 mol ) to a 52.7% sodium hydride dispersion in mineral oil and 35 ml of pimethylformamide. The oil is stirred at -Zinuoer ^ emper & tur '' for half an hour, cooled to Q? G and · with 3 _S 2 g (0.0278 mol) Benzyl chloride treated, Stirring is continued for 16 hours, after which the reaction mixture is extracted into 270 ml of ice water and the aqueous mixture is extracted

- 16 809 805/107

three times with 250 ml of ether each time and wash the ether extracts with potassium bicarbonate solution and with water. After drying, the combined extracts are concentrated to dryness and the oily residue is crystallized from petroleum ether. Thus obtained total of 5 * 5 g of ethyl-a- ^ r-benzyl-2,5-trimethylindolyl- * 7 (5X7 propionate from F «95 to 99 ⁰ C.

C. "of heating a solution of 5 * 0 S (8 * 57 mmol) Kthyl-a- _(^ r-benzyl-2,5,7-.trimethylindolyl- (5l7-Pi'oP ⁱ o ^ ^{at 10} ml 54% aqueous sodium hydroxide solution and 50 ml of ethanol under reflux for 2 hours. The solution is concentrated to a small volume under reduced pressure, diluted with 150 ml of water and washed twice with 100 ml of ether each time p _H value of from 1 acidified. The product precipitates and crystallized. recrystallization from a mixture of chloroform and petroleum ether (boiling range 60 to 80 ⁰ C) is obtained a- / T-benzyl-2,5 "7 · trimethylindolyl- ( 5y [7-prQplonsäure from F "178 to 186 ⁰ C.

Example 2

A. You put 20 g of p-methylphenylhydrazine hydrochloride and

17 -

BAD ORSGINAL

809805/1075 *

20 s ityl - ^ - nethyl levulinate to 250 al ätha & olleoher'-.

2 2i-hydrochloric acid §su and heated, the S @ alse2i until the reaction ■> i [ sets in ". Kaoh stop the initial glißh @ a sxotfrersea Esaktioxi _? Fixd the & eE & 3Qh for about half an hour under Rüok £ 3.u8.er * »* 'I-Mtst and then in a vacuum to about 1 / S volume is 400 ml V / water and extracts oil .I «Ö8ua, g. sit JLthero Me Ätherextrakt® are old liats'iuasbicarb'oiiatlösung and washed with water and then over @ a? Katriwasulf & t Sie Itlierlöaung will-ira. Yakuiam on- a little. concentrated and over'with acid ©

chT-omatographed £ "0 ^ 45 kgfia © in '@ r column with

Tone 57 _f l§ am (2 2 / A ^m ) J ^ a ^ ®> ® bit

(Vol./Vol «9? X ^ is lsi) tlutffft © K in a Kursvegdeettll & tlonsappapatusr • ~ /" 2 _iJ 5-dinethylindoljl «. {3) ^ 7-p2 ⁱ © pl © imt 2a & temperature of 150-170 ° C / O _t l on and crystal air

Pstrolether «Hi @ .Subataäa a © hsilst \ i® ± ββ * bis

E »By treating 0.01 mole

iüdolyl-C3) _- 7 ~ propionate old 0.01 hol. ITatriiuÄyarld in 30 id Dinsthylfornaiaid, © nschlieSenas Uisssetsim ^ de® erhaltsnii ^ ^ atriuaderivats with 0.012 mol p-ethylbshz ^ lcfelorla öäali deif.r in example 2 the method followed receives- sian Xthyl-i- '- - "; / "lp-sethylbc-nsyl-2,5-dim © thylindolyl- (Si ^ J-propionate _β You treatment of this latter called Batera rit äthanoiliis ciier , _m potassium hydroxide solution and isolation 'ν r.«%.

«~ ■ ■

results in ui-./f"l-p final.Xeti

'■ example ft'

- ^ V-Sensyl ^, s-diEetliylindoljfo- C 3) _7 «propionic acid

20 g Half an hour after the reflux is obtained and the vacuum is generally reduced to about 1/3 of a tube in a tube. 400 ml of water are added and the aqueous solution is drowned with ether. The ether extract ο vrtrdan ratriunbicarbonatlÖBung and with W & oaw Ä «w * Bofe» n and aann About KatriUESulfat getrocloiet »Kan reduces the ethoil solution in the Vatuua to a small volume and chroBatograpaiart sit in acid-washed Aluainiua5 ^ d £" a column Qit a Innendurchmese "r δ of? _f 15 ota (2 1/4 ⁿ i> as / ird in a Kurswegdeatillationeapparatur deatilliert v with Xther-petroleum ether (Vol.Aol · 9 * 1 FCIE ITI) elu ^ ert" material · Sas Ethyl- .4 "/ ~ 2 ^" dimothylJidolyl- (5) _- / - 'prdpioaatt' ^ ^: 'Bath temperature 150 "to 170 ° ö / 0, l aia, crystallized fceltt rub with tetrolether;?» 88 to 88, 5 ⁰ O. ^Λ - 3. Add to a suspension of 0.25 g of a 52 hydriädispsion in äüiieralöl in 50 al tsOckenem forssanid

-. I.

8098057TÜ7T

a - / "" 2, 5-dinethyiUidoiyl (J ^ -propionate zu, Saoh *
• For 20-ointitigo-n cooling at room temperature, a solution of 0.8 g of Senzylchlörld in 5 al.
drop by drop and stir the reaction odor for 18 hours "at ZicsierteEiperatu.r · For the destruction of any excess *?
Katriuohydrid gives nan a few drops of Xthanol and rerdtont the reaction liquid with 200 xsl water «Kan extracts the
Product cit Xther "washes the ether solution grtbidlioli old -V & eee trooknet over anhydrous Ha'feriuxasulfat una in" The solid RUökatand obtained is washed with a small amount of cold Pötrolether and crystallized from ethanol UB ,. wpljei nan Xthyl-ci- ^ lb eaayl * 2,5- <ii »ethylindolyl- (3) JT'-ppopionate
receives. Uncrystallized from JUher-Petrol & taeff, does the product have a tendon lap? from 81 to 82 ° G. '' ■ -

Ο »A solution of 1.1 g of X is obtained
2 jS-diDethyl ISdOIyI- (J) _-1 J-PrOPi onat in IQQ al ethanol and
10 nl 34 Seiger Katriualiydroxydlösung under nitrogen 17 stun "the under reflux. The solution is then diluted with 100 ml water _r ia vacuum aur removal of the ethanoia concentrated "ad sit ether extracted * Me aqueous I" 8oung is bit diluted
Acidified hydrochloric acid. The δ * - ^ * l «-3enzyl« 2,5-dinethylindolyl- <3) _eB «propionic acid precipitates out of the solution. By recrystallizing from benzene, nan obtains practically pure material from? * 191 to

bath

- 20 -

805/4 «^

U45103

3eisT> iel fe *

A, methyl- / ~ l-benzyi-2,5-dins thylindolyl- (3

acetate

A mixture of 25 g of KV-benzyl-p-tülylliydrasine hydrochloride and 15 g of methyl levulinate in 150 ml of ethereal hydrochloric acid is heated at reflux for 1 hour. The solution is diluted with $ 00 a barrel and aiii ether is extracted. Wan dries the ether extract over hair-free iatriuc sulfate , filtered and evaporated to a dark brown syrup 1/2 ") using a Gsoisehs of ether-petroleum ether (3? 7) ala sluice agent chronatoga'ßp'aiert. The crystalline product obtained on concentration of those fractions ^ which show iceine Ix-H absorption in infrared, is crystalline a product obtained from Xther -Potroläther uckristallisiert, ^ obei ^ an Hethyl- ^ f * l-benzyl-2,5-diiaethylindolyl- (3) J7 «» aoetat at P - 65 ° C.

I »

Analysis ^ O ^ l ^^

calculated! 0 · 78.14 »H» 6.89 $ i . found: C «73.61, H * 6.93; δ _β

B. 1-Benzyl-2,5-dinethylindolyl- (3) -essi $ acid

3.0 g Xtliyl- ^ TL-l> 3rL2yl-2 _f 5-diiethyliE.dolyi- {3) _- 7-acetate is heated under reflux for 90 minutes in 10 al 34% Katriunliydroa ^ dlöfiuag * anc 50 al ethanol * The solution it will then

80 9 805/107

Concentrated almost to Trookne in vacuo and the residue dissolved in 50 ml of water * The aqueous solution is washed twice with 50 ml of zither each time and the aqueous solution is slowly acidified with 2.5 η hydrochloric acid. The 1-benzyl-2,5-dimethylindolyl-0) acetic acid precipitates out of the solution. After recrystallization from Benzcl-Skellysolve B, the product has a melting point of 179-180 ⁰ C.

»22 -

09 805 / TO75

-Vi-

lb e: icy 1-2-ne thyl-5 ~ nitroindolyl-

"will

prepared according to the processes described in the literature for the preparation of 5-kitroindolyl- (3) -acetic acid3;
heated 10 g of p-liitrophenylhydrasone

t; ·

and 28 pounds of fresh, chopped zinc chloride in 20 al a ^ aoiutez ^! |

vaiter nitrogen. »

Ätlj ^ nol / 12 hours under reflux. The Heaktionagocian trlrd I

-s 200 rJ. 2.5 N-Salcsäura diluted and three times cit ^ e 200 al j

A .. ". I2r extracted" The ethereal Iib3img esctr & hi-ert can < ire (

ait He 100 nl 5 ^ iger sodium bicarbonate solution acidifies the Trier «|

certain aqueous solutions with 2.5 η-hydrochloric acid an! rad ex- \

tracted again dreiaal, IAIT The 150 al Xther · The ethereal - - '[ng is Katriunsulfat getroclcnet _t in Yakuua ini a

Syrup concentrated and nit 200 si ethanolic 1 n- |

8 hours. at reflux temperature "treated. The äthanoüsch ©
Reading, vard is Vacuvn restricted to about 50 Bl, nit 25 <I d
Nasser diluted and extracted three times about 3 ^e 150 sheets of ether
The ether solution is v-washed with 50 ial saturated itetriuabi -
carbonate solution and dried over sodium sulfate. By sir.
Draining the ethereal solution gives a syrup that through
Chromatography on 100 g of acid-washed aluminum egg
Purified using vcr * ether as the eluent
vobei nan Äthyl-cL - / "" 2-aiethyl-5-nitroindolyl- (5) _illl 7-'Propior.: ·
receives »

804805/1 & 7S

The setter obtained in accordance with Section A above, dissolved in dimethylformamide, is carefully reacted with a cold suspension of triumhydride in mineral oil and dimethylformamide. After this re & ktloa, the reaction Ögemicoh is treated with p-methylbenzyl chloride. Ethyl-a -. / Rp-methylbenzyl-S-methyl'-S-siitroindole (3Ji7-P ^ro P ^ionate * da ». It is heated under reflux with an ethanolic sodium hydroxide solution. Duron work-up of the reaction product gives a- / fp- Mefchylbeazyl-2-iaethyl 5-nitroindolyl- (3j7-propionsi £ ur.

«C. 0.05 mol of o- ^ rp-methoxybenatyl-S-methyl-5-nitroinolyl- (5X7-propionic acid in 200 ml of ethanol in an amount of 25 mg of the above palladium or charcoal catalyst is hydrogenated at 2.8 at room temperature. After 0.15 mol of hydrogen has been absorbed, the hydrogenation is terminated and the solution is filtered to remove the catalyst. The filtrate is evaporated to dryness in vacuo, α - ^ - P-kethoxybenzyl-2-methylene-5 -amincindolylic acid.

ο η ο ο η c / ι η η c

Example 6

(5) propionate

A. One hydrogenates 0.025 mol of ethyl - «- / T-p-methylbenzyl - ^ - methyl 5-nitroindolyl- (3j7-propionate in 100 ml ethanol In the presence of 120 mg IQ ^ igem palladium or carbon catalyst at 2.8 at at room temperature, after 0.0075 mol of hydrogen have been absorbed, one breaks the The hydrogenation is removed and the solution is filtered to remove the catalyst. The piltrate becomes dry in vacuo concentrated, whereby one ethyl ~ a ~ ^ = p-methylbenzyl-2-methyl-

receives.

B. y2p3

is obtained from the corresponding

25-

5-amino compound by adding the latter substance a 2 molar excess of dimethyl sulfate in 10% sodium hydroxide solution Treated for about 5 hours at 0 and 5 ° C. The reaction mixture is then extracted with ether and washed the ether extract with water, dried over potassium carbonate, filtered and concentrated to dryness, where you want the desired Get product practically pure

0.02 mol of the last-mentioned ester is dissolved in 200 oil of 5 η hydrochloric acid and the mixture is refluxed under nitrogen for 18 hours. The solution is then cooled, treated with activated charcoal, filtered and reduced to a volume of about 20 ml evaporated, 200 ml of ethanol are added to the concentrate and the solution is evaporated again and this time to dryness. dimethylafflinoindolyl »(3) _7- ^> propionic acid hydrochloride c

- 26 -

80 9.8 0 5/107 5

Claims (1)

? 3. * ΐ * ^ P 14 45 105. 7
Merok 4 Co., Inc. 7258 / Μ 46 New claims 1. Compounds of the general formula H-C-R, β J in which mean: R ₁ and R, hydrogen, lower alkyl or lower alkenyl; R ₂ hydrogen or ll-lower alkyl j R ^ lower alkyl, hydroxy * halogen, nitro, amino, mono- and o-lower alkylamino. Mercapto, lower alkyl mercapto, cyano, Haloalkyl or carboxy; Rc lower alkyl; a is an integer from 1 to 4; and b is an integer from 0 to 2, and their salts and esters. 809805/1075 - 27 - 2. Ethyl-ao / r-bfenzyl-2,5,7-trimethylindolyl-027-propionate » . Ethyl-α °, / r-benzyl ° 2.5 "= diraethylindolyl - (5j7 ⁼ P ^r 0P ^io nat 5. a -> / T-Benzyl-> 2,5-dimethylindolyl "'(5j.7-propionic acid 6. Methyl- _< / r ° benzyl-2,5-diraethylindolyl 8. A process for the preparation of the compounds according to claim 1, characterized in that one connects the general formula ■■ ?? ■■■ CHCOOY in which the symbols Rg, R ,, R ^ and a claim the have given meanings and Y is hydrogen or a Hydrocarbon residue means «in an alkaline medium 8 0980 5/10 75 a compound of the general formula in which the symbols R ₁ , R ₁ - and b have the meanings given in claim 1 and X is an anion of a strong anionic acid or an organic sulfonic acid, and converts any nitro groups present in an ester thus obtained to amino groups, optionally with simultaneous alkylation the same, reduced and optionally saponified a obtained ester. 9. Arsneimifcfcelwii'Ecstcff, bmtühand from a connection after ., 29 ~
809805/1075