DE1470107A1 - [Benzyl-indolyl- (3)] -aminoacetic acid compounds and process for their preparation - Google Patents

Description

DR. DIETER MORF Telephone 483225 and 486415

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MERCK & CO., ZNCORPORATSD Rahway, New Jersey, V.3t.A.

^ 3en2yl-indolyl - (^} 7- ^a n «inoesalgic acid compounds and process for their preparation

The invention relates to ^ Benzyl-indolyl - (^ X? -Aminoacetic acid compounds the general formula

-CH-COOH
-lower-alkyl

-nledrig-Alkylthio (R - lower alkoxy or dimethylamine ») and a process

. 1 . 909822/1308

I * / U I U /

for the preparation of these compounds, which is characterized in that an oxime compound of the general a formula

NOH R- ^ ^ S. .-C-CQOH

-lower-alkyl

"Lower-alkylthiο

in which R has the meaning given above »reduced.

When an α-amino-2-indolyl acetic acid in the N-I position is substituted by a lower-alkylthio-benzyl group »such as p-methylthiobenzyl, instead of a lower-alkyl group» the resulting N-I-subet.-benzyl » compounds »as found, anti-inflammatory effectiveness. These N-I-substituted-benzyl-a-amino-2-indoiyiessigeäuren show, in addition to their property of having anti-inflammatory activity, also antipyretic Effectiveness and also have value in treatment of arthritic and dermatological diseases and disorders and similar conditions that relate to treatment respond with anti-inflammatory agents.

909822/1308

For these purposes, the compounds obtainable according to the invention are normally administered orally in the form of tablets or capsules, the optimal dosage of natUrliph depending on the particular compound used and the type and severity of the infection to be treated. The optimum range of the compounds according to the invention to be used in this way depends on the compound used and the particular nature of the disease state to be treated, but dosages of the preferred compounds are in the range from 1.0 to 2000 mg per day in the control of arthritic diseases states depending on the i activity of the particular compound and the Reaktionssensibilit t of the patient, is useful.

An advantage of the present invention is that the substitution of the N-I position with a substituted one Benzyl group in a cc-amino-2-indoly / acetic acid of the previously inactive compound confers anti-inflammatory effectiveness.

One of the starting materials for carrying out the invention can be obtained by reacting a substituted indole formula

R-.

1 ii ii

-lower-alkyl

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in which R has the meaning given above «where the groups must be compatible with the aralkylation and / or reduction stage of this procedure, be prepared with oxalylochloride. The acid chloride thus formed can with a low-allyl alcohol, water, ammonia »substituted AmIn or an alkali base with formation of the ester «der free acid, the amld «of a substituted amide or treated with an acid salt of the indoleglyoxalic acid compound will. This indoleglyoxalic acid compound is then used in the N-I position aralkylated to form the starting material according to the invention, namely the N-I-substituted benzyl-substituted ^ -indolylglyoxalic acid compound (Scheme I). Also can the starting material can also be produced «by the Indole is first aralkylated "after which treatment with Oxalylohlorid and finally the reaction with a lower alkyl alcohol "water." Ammonia "a substituted one AmIn or an alkali base follow.

The treatment of this starting material with hydroxylamine yields the corresponding oxide in the case of the on the base-less reduction the α-amino-N-1-subst.-benzylsubst. -2-indole acetic acid compound results. (This procedure is shown in Scheme II as Steps 1 and 2.) Others Compounds can be made according to the invention by treating the above

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named product (nSralioh of 1-substituted-benzyl-substituted-2-indole acetic acid) with an alkyl halide to form the a-amino-substituted compounds. (This procedure is shown as step 2 in Scheme II.) Another process for the preparation of the «t-amino and α-mono- and di-substituted-amino-N-1-substituted-benzyl-subst. -3-indolylessigsäureverbindungen geraäss the invention comprises the treatment of a N-1-substituted-benzyl-substituted-indole with an i amine base (such as ammonia, mono- or disubstituirtem Aiain) and a GlyoxalsSureverbindung (such as glyoxylic acid or an ester, Amide, substituted amide or alkali salt thereof). (This procedure is shown in Scheme II as Step 4.) This last procedure is used when mono- and disubstituted amines are desired, or when the other procedures for making the substituents in the α-amino group are unsuitable. In addition, the procedure given last is also used if the substituents on the indole compound are those that are influenced by the reduction stage of the first-mentioned procedure, such as nitro, cyano, alkenyl groups and the like. Groups and groups that prevent the reduction or can prevent it completely.

909822/1308

WUTU /

The production of the anhydrides according to the invention comprises the implementation of an α-di-substituted-amino-1-subst. · benzyl-subs t "-; 5-indolylacetic acid with cyclohexylcarbodiimide to form the α-di-substituted-amino-1-substituted-benzyl-substituted ^ -indolylacetic anhydride. (This procedure is step 5 in the scheme ZI shown.)

* 'The for the production of the starting materials for the Invention used 1-unsubstituted substituted indoles can easily be sorted according to the Prepare the procedure indicated in columns 2 and 2 of US Pat. No. 2,825,73 *.

The inventive synthesis of different Compounds «where R denotes dimethylamine, is generally based on the 5-nitro compound. ) This is converted into the dimethylamino substituent. Such conversions can be before or after the aralkylation of the! position Depending on the

909822/1308

measure to which the desired 5-substituent the Can interfere with aralkylation. If such a disturbance is possible, the .1-aralkylation should be carried out on the 5-nitroindole are »and the nitro group can later be converted into the desired 5-substituent. Such transfers can be accomplished in a number of ways. The reduction of the 5-nitro groups, gives a 5-amino group. The reaction of the amino group with methyl halides leads to mono- and Dimethy! Amino groups. Oils can alkylate auoh be carried out simultaneously with a reduction, for example with formaldehyde and Raney-Nlokel and hydrogen.

The preferred compounds obtainable according to the invention are those which have methyl in the 2-position and the 5-position of the indole ring system ⁽

contain.

909822/1308

Oils lower-alkylthicbeney group is preferably p-methyl thiοbenzyl. The preferred compound let 1-p-methyl-

* I

thiobenzyl-S-methyl-S-methoxy-J-indolyl-α-aminoacetic acid. -,:, ■

8th -

909822/130

Scheme I Preparation of starting materials

Oxalyl chloride

Alcohol H ₂ O

NH,

Alkali-base substituted amines

Aralkylation

also: -C-C-R

Aralkylation

N '
ι

Oxalyl chloride

H ₅ -

substituted amines alkali base

-C-C-Cl

H-C-P

<* 6> 1

Sohema II Production of compounds according to the invention

II

III

IV

- 10 -

+49 98 22/1308

Scheme II (continued)

VI

- 11 -

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U70107

Scheme II (continued)

I ⁵

-CH-COOH

(5)

0 0 R,

Il III ⁵

c-o-c-c-

VII

VIII

- 12 -

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Meanings s

can be "a: Hydroxy, nledrlg-alkoxy, monooyol 6-membered oarbocyolieohes Ar-low-alkoxy" halogenated and low-alkoxylated monooyolisohee 6-membered oarboeyo-isohe Ar-lower-alkoxy, halogen "amino, low · mono-alcoholo-alcoholo-alcoholohee Aroylamino »low-alkylamino, lower-Oialkylamino, low-alkanoylamidino» Mer- ' λ

oapto »nitdrlg-Alkylthlo, monoeyollsohes 6-glledriges oarboeyolisöhes arylthio, monooyolisohee 6-glledriges oarbooyollsohes Ar-lower-alkylthlo * halo-nledrigalkyl »nledrig-alkanoyl, halogenated lower-alkanoyl, monoyclic 6-membered oarboxylisohes aryl-lower-alkanoyl, halogenated lower-alkoxy, halogenated lower-alkylthio, sulfamyl, benzylthioraido-alkyl, carboxyl-low-alkanoyl »Carb-low-alkoxy» Carboxyamld »low-alkylaoetals of aldehyde, lower-alkyl thioaoetals of aldehyde;

/ 909822/1308

b can be: a positive integer less than 4; R ₂ can be: hydrogen and lower-alkylj

Rjj can be: hydrogen, lower-alkyl, lower-alkoxy, Fluorine and trifluoromethyl;

R _P can be: hydrogen, hydroxy, lower-alkyl, lower-alkoxy, amino, lower-alkylamino, di- (lower-alkyl) -amino, lower-alkanoylamino, lower-alkanoyl, bis- (hydroxy-lower-alkyl) -amino , 1-pyrrolidino, 4-methyl-i-piperazinyl, 4-morpholinyl, trifluoromethyl, halogen, di- (lower-alkyl) -sulfamyl, benzylthio, lower-alkylbenzylthio, lower-alkoxybenzylthio, halobenzylthio, benzyloxy, lower-alkylbenzyloxy, lower alkoxybenzyloxy, halobenzyloxy, I-azacyclopropyl, cyclopropyl (lower alkoxy) methyloxy and cyclobutyl (lower alkoxy) methyloxy and dimethylsulfamyl;

R can be: OH, NHg, Hethylaraino, Xthylamino, Propylamino, Butylamino, dimethylamino, diethylamino, ethylethylamino, Methylbutylamino, dibutylamino, gluoosamino, olycosylamino, Qlucosylamino, Allylamino, Phenyttthylanino, N-Ethylphenäthylamino, p-chloroanilino, i-ethyl-2-aminomethylpiperidino, Tetrahydrofurfurylaraino, 1,2,5,6-tetrahydropyridino, Morpholino, N-methylpiperazino, piperazino, N-phenylpiperazino. Piperidino, benzylamino, anilino, p-thoxyanilino, Cyolohexylaraino, Pyrrolidino, M-HydroxyUthylpiperazino, N, N-Dimethylcarboxamidomethylamino, Ν, Ν-Dläthylaminoäthylamino,

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Benzyloxy, lower alkoxy and OZ (where Z is a cation) ι and P can be: hydrogen and lower-alkyl,

Rg, R ₁ ^, Rr and Rg for the starting material for stage 4 have the meanings given above with the exception that all groups influenced by aralkylation and primary and secondary amino groups are not included. Because of this limitation, the groups included in the final product can be: -. i

Rg can be: hydroxy, lower-alkoxy, monooyclic 6-membered oarbooyclisohes aryloxy, monooyollsches 6-membered oarbocyolisob.es Ar-nledrlg-alkoxy, halogenated and low-alkoxylated monocyclic 6-membered carbooyclic-halogeno-alkoxy, nitrous-alkoxy , lower-dialkylamino, lower-alkanoylaraido, mercapto, lower-alkylthlo, monocyclic 6-membered oarbooyclic arylthio, monocyclic 6-membered carbocyolic ar-lower-alkylthio, halo-lower-alkyl, lower-alkanoyl, halogenated lower-alkanoyl, monooyclic 6 -linked carboxyl! -. sches aryl-lower-alkanoyl, halogenated lower-alkoxy i halogenated nledrlg-alkylthio, SuIf & myi. Benzylthiomethyl ,. Cyano, di-lower-alkylsulfonamido, carb-lower-alkoxy, lower-alkyl acetals of aldehyde, lower-alkylthioaetals of aldehyde j

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-. "·. Ί AVUIUV

b can be: a positive integer less than 4;

Rp can be: hydrogen, lower-alkenyl and lower-alkyl;

R ₅ can be: amino »low-monoalkylamino, low-dialkylamino, benzylamino, low-alkylbenzylamino, cyclohexylamine, N-pyrrolidino, N-piperidino, N-tetrahydropyridino, N-morpholino, N-piperazino, acetyl-N-piperazino, ß -Di-hiedrig-alkylamino, ethylamino, and N-Dläthanolaminoj

R ^ can be: hydrogen, lower-alkyl, lower-alkoxy, Fluorine and Trifluorme.thyl;

Re can be: hydrogen, lower-alkyl, lower-alkoxy, Nitro, di- (lower-alkyl) -amino, lower-alkanoyl, 1-pyrrolidino, 4-methyl-1-piperaziryl, 4-corpholinyl, cyano, trifluoromethyl, halogen, di- (lower-alkyl) -sulfamyl. Benzyl thio, lower-alkylbenzylthio, lower-alkoxybenzylthio, halobenzylthio, benzyloxy, lower-alkylbenzyloxy, lower-alkoxybenzyloxy, halobenzyloxy, low-alkenyl, lower-alkenyloxy, I-azacyolopropyl, Cnolopropyl - »(lower-alkyl-alkoxy) -methanol -alkoxyJ-methyloxy and dimethylsulfam-yl;

R can be: OH, NH ₂ , ethylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, ethylethylamino, methylbutylamino, dibutylamino, glucosamino, olycosylamino.

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Glucosylamino, Allylamino, PhenUthylamino, N-Ethylphenäthylamino, p-chloroanilino, 1-ethyl-2-aminomethy! piperidino, tetrahydrofurfurylamino, 1,2,5,6-tetrahydropyridino, morpholino, N-methylpiperazino, piperazine N-phenylpiperazino, Piperidino, Benzylamino, Anllino, p-Äthoxyanilino, Cyclohexylamine, Pyrrolidino, N-Hydroxyäthylpiperazino, N, N-Dimethylcarboxamldonvsthylamlno, Ν, Ν-diethylarainoäthylamino, Benzyloxy, lower alkoxy, OZ (where Z is a cation) j 'and

P. can be: hydrogen, lower-alkyl and lower-alkenyl.

Rg, R ,, R ₂ ^, Re and R ^ for the starting material of step 5 have the meanings given above with the exception that no group contains a primary or secondary amino group, a hydroxyl group or a carboxyl group. Because of this limitation, the groups involved can be:

R ^ can be: lower alkoxy, monooyolic 6-glledriges carbocyolic aryloxy, monocyolic 6-membered carbocyclisohes Ar-lower alkoxy, halogenated and lower alkoxylated monocyclic 6-membered carbocyclic amino-lower alkoxy, Nitro, halogen, lower dialkylamino, lower alkylthlo, monooyclic 6-membered carbocyolic arylthio, monocyclic 6-membered carbooyclic Ar-lower alkylthio, halo-lower alkyl, lower-alkanoyl, halogenated low-alkanoyl, monoyclic 6-membered carboxyl! -

. ■■■■ ·. Ί 47 U I UV

aryl-low-alkonoyl, halogenated low-alkoxy * . halogenated lower alkylthio, sulfamyl, benzylthiomethyl, Cyano, di-lower-alkylsulfonamido, carb-lower-alkoxy ,. Carboxamido, CHO, lower-alkyl acetals of aldehyde, lower-alkyl thioacetals of aldehyde j

b can be: a positive integer less than 4;

. Jl ₂ can be: hydrogen, lower-alkenyl and nledrlg-alkyl;

R can be: low-dialkylainino, cyclohexylamino, N-pyrrolidino, N-Piperldinö, N-Tetrahydropyridino, N-Morpholino, Acetyl-N-piperazino, ß-Dl-lower-alkylamino-ethylaraino;

R ^ can be: hydrogen, lower-alkyl, lower-alkoxy, Fluorine and trifluoromethyl;

Re can be: hydrogen, lower-alkyl, lower-alkoxy, Nitro, Dl- (lower-alkyl) -amino, lower-alkanoyl, 1-pyrro-A lidino, ty-methyl-1-piperazinyl, 4-morpholinyl, cyano, trifluoromethyl, Halogen, di- (lower-alkyl) -sulfamyl, benzylthio, lower alkylbenzylthio, lower alkoxybenzylthio, halobenzylthio, benzyloxy, lower alkylbenzyloxy, low * Alkoxybenzyloxy, halobenzyloxy, low-alkenyl, low-alkenyloxy, l-azacyclopropyl, cyolopropyl (lower alkoxy) methyloxy and cyclobutyl (lower alkoxy) yinethyloxy and dimethyl sulfamyl; and

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P can be: hydrogen and lower alkyl.

Reactions and conditions ι

Stage 1: reaction with NHgOH or salts thereof (preferably 2 moles of NHgOH. HCl) in a solvent for this purpose (e.g. HgO-ethanol, glycerine or propylene glycol, preferably tert-butanol for esters and otherwise propylene glycol) at any given temperature (reaction time varies with temperature, steam bath is preferred). .

Stage 2: Reduction over a catalyst (e.g. palladium, Platinum or Raney Niokel, preferably 5 # palladium carbon) under moderate hydrogen pressure [preferably 2.8 to 210 at (4θ - ^ 000 psi) 3 in a lower alkyl alcohol (e.g. methanol, Ethanol or propanol, preferably ethanol with a sufficient amount Amount of HCl to keep the reaction medium acidic} at any desired temperature (room temperature is preferred), until the reaction has practically ended.

Step 3: reaction with a lower alkyl halide, e.g. Methyl chloride, bromide, iodide, ethyl chloride, bromide, iodide, preferably methyl iodide, preferably at 1.1 moles for one Monoalkylamino and 2.5 moles for a dialkylamino, in an inert solvent (e.g. 1,2-dimethoxyethane, tetrahydrofuran, Dimethylformamide, ether, low-alkyl alcohols. benzene

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or toluene, preferably 1,2-DImethoxyUthane) at any one desired Temperature (heating tent fluctuates with temperature, steam bath for 3 hours is preferred).

Step 4: reaction with an amine base (preferably 1.1 mol) (e.g. ammonia, primary amine or secondary amine, preferably secondary amines such as morpholine, piperadine, pyrrolidine and the like) and a glyoxalic acid compound (preferably 1.1 mol), e.g. glyoxalic acid, ester, the amide, substituted amides or an acid salt thereof (glyoxalic acid is preferably) in water or a mixture of water and a miscible organic solvent such as dimethylformamide, 1,2-diraethoxyutane, tetrahydrofuran, or without Solvent (the use of water and 1,2-dimethoxyethane is preferred) at a temperature between 30 and 80 ° C (The reaction time varies with the temperature, room temperature is preferred).

t Stage 5: reaction with a disubstituted carbodiimide, tpreferably e.g. dicyclohexylcarbodiimide (* 0.5 mol dicyclohexylcarbodiimide) in a solvent, e.g. tetrahydrofuran (THF), 1,2-dimethoxyethane, Pyridine, dimethylformamide (DMP) or ethyl acetate, preferably THF, at any temperature desired (reaction time will vary with temperature, room temperature for 2 hours is preferred).

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In step 1 (shown in Scheme II), hydroxylamine · HCl and other acid salts normally used as hydroxylamine itself is not stable. However, if hydroxylamine is generated in the reaction and used directly, it can do without Be used considering its stability.

In stage 2 (scheme II), the reduction can be carried out without using an acidic medium. Will the reduction However, carried out under acidic conditions, the yield is considerably increased. Organic as well as inorganic sow Ren that are soluble in the solvent can be used, the only limitation being that no acid is used that can be reduced.

In stage 4 (as shown in Scheme II) a medium is used with neutral to alkaline reaction to form the amino or mono- or disubstituted aminoacetic acid compound. The inventive reaction is at temperatures between 60 and 80 ° C in a medium with a pH of 7 to 11, preferably 8 to 10, performed. It can be a Excess of amine, for example two to three times the amount of the squimolar amount, can be used. The excess Amine can be used to keep the reaction mixture alkaline until the condensation has ended. However, it can also an equimolar amount of sodium hydroxide or potassium hydroxide in this procedure instead of the excess

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Amines can be used. Water is used as a solvent applies to which, if desired, to improve the Solubility in water of the reaction components organic solvents can be added that are miscible with water, such as methanol, ethanol, dimethylformamide, 1,2-Dimefchoxyi £ than, Tetrahydrofuran, Isopropanol, Dioxane and the like. If the amine used is sufficient Has water solubility, it can also be used as a co-solvent. The reaction can also be in absent-mindedness be carried out by solvents. In this case, external heating is sometimes unnecessary the reaction is initially exothermic and can simply be allowed to proceed at room temperature.

In cases where the indole or benzyl substituents Contain reducible groups such as Nicro, Cyano, Alkenyl and the like., This procedure is used.

In those cases where it is desired that a Hydroxyl substituent on the indole ring or on the benzyl radical of the final product is present, the starting materials may have a benzyloxy substituent in the position in which the Hydroxyl group as long as it is desired, contain. In this case the benzyloxy group becomes the appropriate hydroxy group reduced in the reduction stage (stage 2, scheme II).

In addition, the starting materials should, if primary amino substituents to be present on the indole ring or the Benzylreet, a nitro substituent in the position in which

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the amino group is ultimately desired. In this In the case of the nitro group becomes the corresponding amino group reduced in the reduction stage (stage 2, scheme II). It is desirable to have a secondary amino group on the indole the nitro substituent can be used) Arallcyclization of the indole, reduction of the nitro group to the amine and alkylation of the amine result in the secondary amino group. In stage 5, the anhydride is formed in those compounds carried out which do not contain a primary or secondary amino group, hydroxyl group or carboxyl group, the be influenced by the reaction.

The following examples illustrate the invention without illustrating it restrict"

Example 1

tert. -Butyl-2-methyl-5-methoxy-3-indolyl glyoxalate

To a solution of 0.005 mol of oxalyl chloride in 15 ml of anhydrous ether, a solution of 0.005 mol of 2-methyl-5-methoxyindole in 15 ml of ether is added with stirring over a period of about 1 hour. The mixture is then stirred under nitrogen for several hours. The mixture is concentrated to about half the volume, k ml of tert-butanol are added, and the mixture is stirred for several hours. After removing the ether and the excess butanols

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the residue on a column of 100 g silica gel using from Kther-Petrolät-her (Voi./Vol. 10 to 100 j £) as Chromatographed eluent. This gives tert-butyl-2-methyl-5-methoxy-5-indolyl glyoxalate.

If you proceed according to the above procedure using methanol, ethanol, benzyl alcohol, methylamine, ethylarain, Propylamine, butylamine, dimethy lamin, diethylamine, methylethylamine, Methylbutylamine, dibutylamine, glucosamine, olysosylamine, Glucosylarain, Allylamine, Phenethylamine, N-Ethylphenäthy larain, ρ-chloro aniline, i-ethyl-2-aniinomethylpiperidine, Tetrahydrofurfurylamine, 1,2,5,7-tetrahydropyridine, morpholine, N-methylpiperazine, piperazine, N-phenylpiperazine, piperidine, Benzylamine, aniline, p-ethoxyaniline, cyolohexylamine, pyrrolidine, N-Hydroxyäthylpiperazin, Ν, Ν-DimethylcarboxaraidomethylamiTi or Ν, Ν-diethylarainoäthylarain instead of the tert. -Butanols of the above example, in a corresponding manner, methyl ^ -methyl-S-methoxy-jJ-indolylglyoxylate, ethyl 2-methyl-S-methoxy-J-indolylglyoxylate, Benzyl-ä-methyl-S-mefchoxy-J- ^ * indolyl glyoxylate, 2-methyl-5-methoxy-3-indolylglyoκa3.methyl-

t *

amide, 2-methyl-5-methoxy-3-indolylglyoxalethylaraid, 2-methyl-S-methoxy-J-indolylglyoxalpropylamide, 2-methyl-5-methoxy-2-indolylglyoxalbutylamide, 2-methyl-5-methoxy - ^ - indolylglyoxaldimethylamide, 2-methyl-5-methoxy-5-indolylglyoxaldiHthylanJid _# 2-methyl-5-methoxy-3-indolylglyoxalπlsthyläthylarid, 2-methyl-S-methoxy-J-indolylglyoxalmethylbutylaniid, 2-methyl-5-methoxy-2-indolutylglyoxaldib Methyl-5-methoxy-3-indolyl-

. 24 J09822 / 1308

. glyoxal-glucosarnine-amide, 2-methyl-5-ßuioxy-5-indolylglyoxal-glycosylara: ln-amide ₉ 2-methyl-5-methoxy-; 5-indolylglyoXalglucoxylamine-amide,. 2 ~ methyl-5-methoxy-5-indolyiglyoxalallylamide, 2-methyl-5-πle'choxy-3-indolylglyoxalphenäthylamid, 2-methyl-5-methoxy-5-indolylglyoxal-N-ethylphenäthylamid, a-methyl-S-raethoxy- ^ -indolylglyoxal-p-chloroaniline-amld, 2-Kethyl-5-methoxy-3-indolylglyoxal-1-ethyl-2-aπlinomethyl-piperidln-amide, 2-methyl-5-Iπethoxy-5-indolylglyoxaltΓahydΓofurfuryl-amid, 2- Methyl-5-π3ethoxy-3-indolylglyoxal-1,2,5 * 6-tetrahydropyridine-arald, 2-methyl-5-methoxy-3-indolylglyoxalmorpholide, 2-methyl-5- ^ methoxy-3-indolylglyoxal-N-πιethyl -plperazin-aniid, 2-methyl-5-methoxy-3-indolylglyoxal-N-phenyl-.

. piperazine amide, S-methyl-S-methoxy-J-indolylglyoxalpiperidinamld, 2-methyl-5-methoxy-5-indolylglyoxalbenzylamide, 2-methyl 5-methoxy-35-indolylglyoxalaniline amide, 2-methyl-5-niethoxy-3-indolylglyoxal-p-ethoxyaniline amide, S-methyl-S-ethoxy - ^ - ind olylglyoxalcyclohexylamide, 2-methyl-5-a! ethony-3 ~ indolylglyoxal-pyrrolidine-amld, 2-methyl-5-mefchoxy-j5-indolylglyoxal-N-hydroxyethylpip3razine amide, 2- ^ ϊethyl-5-πlethoxy-5-indolylglyoxal-N, N-dimethylcarboxamldomethylamide or 2-methyl-5-methoxy-3-indolylglyoxal-N, N-diethy! aminoethylamide.

If one uses ^ -Methyl-5-methylindole, 2-Hethyl- ^ί ^ -methylindole, 2-methyl-5-methylindole, 2-methyl-4-methyl-5-methylindole, 2-mefchyl-5-propylindole, 2-penfcyl -5-niethylindole, 2-methyl- ^, 5-dimethoxyindole, 2-methyl-4-propoxy-5-niethoxyindole, 2-methyl-5-pentoxyindole, 2-methyl-4-fluoro-5-methoxyindole, 2-methyl -4-

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trifluoroethyl-5-raethoxyindole, S-methyl-S-nltroindole, 2-methyl-5-aoetylindole, 2-methyl-5-butyrylindole, 2-methyl-5-bis (benzyloxyethyl) aminoindole, 2-methyl-5- bis (benzyloxybutyl) aminoindole, 2-methyl-5-bis (benzyoxypentyl) aminoindole, 2-methyl-5- (1-pyrrolidino) indole, 2-methyl-5- (4-methyl-1-piperazinyl ) indole, 2-methyl-5- (4-morpholinyl) indole, 2-methyl-5-trifluoroethylindole, 2-methyl-5-chloroindole, 2-methyl-5-broraindole, 2-methyl-5-fluorideidol, 2-methyl-5-dimethylsulfamylindole, 2-methyl-5-dipropylsulfamylindole, 2-methyl-5-benzylthioindole, 2- ^ ίethyl-5-P-Π3ethylbenzylthioindole, 2-methyl-5-P-pentyl-benzylthioindole, 2 -Methyl-5-pmethoxybenzylthio-indole, 2-Kethyl-5-P-p2Opoxybenzylthioindole, 2- ^ ethyl-5-P-pentoxybenzylti ■ lio-indole, 2-methyl-5-P-chlorobenzylthio-indole, 2 - ^ * βthyl-5-p-bromobenzylthio-indole, 2-methyl-5-p-fluorobenzylthio-indole # 2-MOtIIyI-S-CyClOPrOPyI-methoxy-indole, 2-methyl-5-ethoxyindole, 2-methyl-5-cyolobutylm3thoxymethyloxy- indole # 2-hathyl-5-N, N-dimethylcarbamylindole, 2-ethy l-5 - <^ iIπβthylaIΠino-indole ₁ 2-methyl-5-dipropylaraino-indole, 2-methyl-5-dipentylainino-indole, 2-methyl-5-benzyloxy-indole and 2-methyl-5-diethylamlno-indole instead of 2-methyl-5-n3ethoxyindole, tert-butyl-4-methyl-5-methyl-5-indolylglyoxalate, tert ^ butyl ^ -methyl-Jl-methyl-ji-indolylglyoxalate, tert * - butyl-2-ni8thyl-5-raethyl-3-indolyl6lyoxalat, tert-butyl-2-methyl-4-methyl-5-niethyl-> iadolylglyoxalat _# tert-butyl-2-methyl-5-propyl-5-indolylglyoxalat _# tert-butyl-2-pentyl-

5-methyl-: 5-indolylglyoxalate, tert-butyl-2-methyl-4-methoxy-

'- 26 - 909822/1308

5-methoxy-3-indolyl glyoxalate, tert. -Butyl-2-methyl-4-propoxy-5-methoxy-2-indolyl glyoxalate, tert-butyl-2-methyl-5-pentoxy-3-indolyl glyoxalate, tert-butyl-2-methyl-4-fluoro-5 -methoxy-3-indolylglyoxalate, tert-butyl-2-methyl-4-trI-fluoromethyl-5-methoxy-3-indolylglyoxalate, tert-butyl-2-raethyl-5-nitro-3-indolylglyoxalate, tert.- Butyl-2-methyl-5-aaetyl-J-indolylglyoxalate, tert-butyl-2-methyl-5-butyryl-3-indolylglyoxalate, tert-butyl-2-methyl-5-bis- (benzyloxyethyl) -amino- 3-indolylglyoxalate, tert-butyl ^ -methyl-S-bis- (benzyloxybutyl) -amino-3-indolylglyoxalate, tert-butyl-2-raethyl-5-bis- (benzyloxypentyl) -amino-3-indolylglyoxalate, tert .-Butyl ^ -methyl-S- (1-pyrrolidino) -3-indolylglyoxalate, tert. -Butyl ^ -methyl-S- (^ -methyl-T-piperazinyl) -3-indolylglyoxalate, tert-butyl-2-raethyl-5 - {^ - ™ orpholinyl) -5-indolylglyoxalate, tert-butyl- 2-methyl-5-trifluoromethyl-3-indolyl glyoxalate, tert-butyl-S-methyl-S-chloro-J-indolyl glyoxalate, tert-butyl-2-methyl-5-bromo-3-indolyl glyoxalate, tert-butyl -2-methyl-5-fluoro-3-indolylglyoxalate, tert-butyl-2-methyl- · S-dimethylsulfamyl-J-indolylglyoxalate, tert-butyl-2-methyl-5-dipropylsulfamyl-3-iiidylglyoxalate, tert . -Butyl-2-methyl-S-benzylthio-J-indolyl glyoxalate , tert. -Butyl ^ -methyl-SP-methylbenzylthio-3-indolylglyoxalate, tert-butyl-2-methyl-Sp-pentylbenzylthio-J-indolylglyoxalate, tert-butyl-2-methyl-Sp-methoxybenzylthio- ^ - indolylglyoxalate, 'tert .-Butyl-2-methyl-SP-propoxybenzylthio-J-indolylglyoxalate , tert-butyl-2-methyl-SP-pentoxybenzylthio-J-indolylglyoxalate, tert.-

- 27 -

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H70107

Butyl ^ -methyl-Sp-chlorobenzylthio-J-indolylglyoxalate, tert. Butyl ^ -methyl-Sp-bromobenzylthio-jJ-indolylglyoxalate, tert, butyl-2-methyl-5-P-fluorobenzylthio-3-indolylglyoxalate, tert. Butyl ^ -methyl-S-Uthoxy-J-indolylglyoxalate, tert-butyl-2- methyl-S-cyclobutylmethoxymethyloxy- ^ - indolylglyoxalate, tert-butyl-2-methyl-5-N, N-dlraethylcarbaraylO-indolylglyoxalate, tert. -Butyl-2-methyl-S-diraethylamino-OJ-indolylglyoxalate, tert-butyl ^ -methyl-S-dipropylamino-jJ-indolyl-A glyoxalate, tert. -Butyl-2-nlethyΓ-5-dipentylaπlino-3-indolyl-

glyoxalate, tert-butyl-2-methyl-5-ben2yloxy-5-indolylglyoxalate or tert-butyl-S-njethyl-S-diethylamino-J-indolyl glyoxalate.

Example 2

tert. -Butyl »(1 ♦ • p-chlorobenzyl-g-methyl-S-methoxy-jS-indolyl) - glyoxalate

a) A solution of 0.021 mol of tert-butyl- (2-methyl-5-meth oxy-2-indoIyI) glyoxalate in 20 ml of dimethylformamide dropwise to a cold suspension of 1.0 g (0.022 mol) of sodium hydride (52 # dispersion in mineral oil) and 25 ml of dimethylformamide were added. The mixture is stirred at room temperature for 20 minutes, cooled and 0.0222 Mol p-chlorobenzylochloride treated. The reaction mixture is stirred at room temperature for about 16 hours and in

. - 28 -

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1A70107

Poured 26o ml of ice water. The aqueous mixture is used three times extracted with 250 ml of ether each time. The animal extract is with, 100 ml potassium bicarbonate solution and three times with 100 ml each Water washed. The ether layer is dried and concentrated under reduced pressure. This gives tert-butyl- (1 -p-chlorobenzyl - ^ - methyl-S-methOKy-jJ-indolyl) -glyoxalate.

b) If 1-p-methylthiobenzyl chloride, 1-p-propylthiobenzyl chloride, 1-p-pentylthiobenzyl chloride, 1-p-fluorobenzyl chloride, 1-p-bromobenzyl chloride, 1-p-chlorobenzyl chloride, 1-p-trifluoromethylbenzyl chloride, 1-p- Methoxybenzyl chloride, 1-p-propoxybenzyl chloride, 1-p-pentbxybenzyl chloride, 1-p-methylbenzyl chloride, 1-p-propylbenzyl chloride, 1-p-pentylbenzyl chloride, 1-p-acetylbenzyl chloride, 1-p-propionylbenzyl chloride, 1-p-pentanoylbenzyl chloride, 1-p-tert-butylbenzyl chloride, 1-p-difluoromethylbenzyl chloride, 1-o-methyl-p-chlorobenzyl chloride, i-miP-dichlorobenzyl chloride, 1-o, p-dichloro-benzyl chloride, io-fluorine-p-methylthiobenzyl chloride , 1-p-propylthiobenzyl chloride, 1-p-pentylthiobenzyl chloride, IO-methyl-p-methylthiobenzyl chloride, i-cmiP-trimethoxybenzyl chloride _, 1-p-acetoxybenzyl chloride, 1-p-propionoxybenzyl chloride, 1-p-pentfyloxybenzyl chloride. 1-p-pentfyloxybenzyl chloride , 1-p-dimethylaminobenzyl chloride, 1-p-dipropylaminobenzyl chloride, 1-p-dipentylaminobenzyl chloride, 1-p-methylchlorobenzyl chloride , 1-p ^ i-Propylchlorbenzylchlorid, 1-p-1-Pentylchlorbenzylohloriä, 1-m-Chlorbenzylohlorid 1-o-BrombenzylchlorId,

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909822/1308

ip-chloroacetylbenzyl chloride, 1-p-phenylacetylbenzyl chloride, 1-p-sulfamylbenzyl chloride, 1-p-dimethylsulfonamidobenzylchlo-. rid, ip-Dipropylsulfonamidobenzylchlorid, 1-p-Methyloarboxybenzylchlorid, 1-p-Propyloarboxybenzylchlorid, 1-p-PentylcarboxybenzylQhlorid , 1 -ο, ΐη, ρ-Trimethylbenzylchlorid and io ^ m ^ p -trip-zylo-p-chlorobenzylchloride in corresponding way tert. -Butyl-1-p-möthylthiobenzyl-S-methyl-S-inethoxy - ^ - ^ indolyl glyoxalate, tert-butyl-1-p-propylthiobenzyl-2-methyl-

5-msthosy-3-indolylglyoxalate, tert-butyl-1-p-pentylthiobenzyl-2-methyl-5-ynethoxy-3-indolylglyoxalate, tert. -Btityl-1-p-fluorobenzyl-2-methyl-5-raethoxy-3-indolylglyoxalate, tert. -Butyl-1-p-brynbenzyl-2-methyl-S-methoxy.-J-indolylglyoxalate, tert. -Sutyl-1-p-chlorobenzyl ^ -methyl-S-niethoxy-3-indolylglyoxalate, tert-butyl-1-p-trifluoromethylbenzyl-2-methyl-5-methoxy-3-indolylglyoxalate tert-butyl-1-pnjethoxybenzyl -2-methyl-5-methoxy-3-indolyl glyoxalate _# tert-butyl-1-p-propoxyfcenzyl-2-methyl-5-methoxy-] S-indolyl glyoxalate, tert. -Butyl-1-p-pentoxybenzyl ^ -methyl-S-methoxy-jj-indolyl-. glyoxalate, tert. -ButyL-1-p-methylbenzyl-2-methyl-5-πlethoxy-3-indolylglyoxalate, tert-butyl-1-p-propylbenzyl-2-methyl-5-methoxy-3-indolylglyoxalate, tert-butyl-1 -p-pentylbenzyl- '2-methyl-5-methoxy-3-indolylglyoxalate, tert-butyl-1-p-. aoetylbenzyl ^ -methyl-S-niethoxy-jS-indolyiglypxalate, tert-butyl-1-p-proplonylbenzyl ^ -inethyl-S-methoxy-jS-indolylglyoxalate, ter1; - butyl-1-p-pentanoylbenzyl-2-raethyl -5-Ineth-

909822/1308

oxy-3-indolylglyoxalate, tert-butyl-1-ρ- (tert-butyl) -benzyl-2-methyl-5-methoxy-3-indolylglyoxalate, tert-butyl-1-p-difluoromethylbenzyl-2-mefchyl- fj-methoxyO-indolyl glyoxalate , tert. -Butyl-1 - (o-methyl-p-chlorobenzyl) ^ -methyl-S-methoxy-3-indolylglyoxalate, tert-butyl-1 - (m, p-dichlorobenzyl) -2-methyl-5-methoxy-3 indolyl glyoxalate, tert-butyl 1- {ο, p-dichlorobenzyl) -2-methyl-5-methoxy-3-indolyl glyoxalate, tert-butyl-1- (o-fluoro-p-methylthiobenzyl) -2-methyl-5 -methoxy-3-indolylglyoxalate _# tert-butyl-1- (p-propylthiobenzyl) -2-niethyl-5-raethoxy-5-indolylglyoxalate, tert-butyl-1- (p-pentyl- mk thiobenzyl) -2- methyl 5-methoxy-2-indolylglyoxalate _i tert-butyl-1 - (o-methyl-p-methylthlobenzyi) -2-inethyl-5-methoxy-3-indolylglyoxalate, tert. -Butyl-1 - (o, id, p-trimethoxybenzyl) -2-methyl-5-njethoxy-3-indolyl glyoxalate, tert. -Butyl-1 - (pacetoxybenzyl) ^ -methyl-S-methoxy-J-indolylglyoxalate , tert. -Butyl-i - (p-propionoxybenzyl) -2-ynethyl-5-πlethoxy-3-indolylglyoxalate, tert-butyl-1 - (p-pentanoxybenzyl) -2-BIe ^ yI-S- -methoxy-3-indolylglyoxalate , tert-butyl 1- (p-phenyloxybenzyl) -2-methyl-5-ynethoxy-3-indolyl glyoxalate, tert. -Butyl-1 - (p-dimethyiaminobenzyl) -2-methyl-S-methoxy-J-indolylglyoxalate, tert. -Butyl-1 - (p-dipropylaminobenzyl) -2-π ^ ethyl-5-methoxy-3-indolylglyoxalate, tert-butyl-1- {p-dipentylamino- 'benzyl) ^ - methyl-S-methoxy-J- indolyl glyoxalate, tert-butyl 1- (p-1-methylchlorobenzyl) -2-methyl-5-methoxy-3-indolyl glyoxalate, tert-butyl 1- (p-1-pentylchlorobenzyl) -2-methyl-5- methoxy-3-indolylglyoxalate, tert-butyl-1- (m-chlorobenzyl) -2-

- 31 -

... 909822/1308

methyl-S-niethoxy- ^ - iridoiylglyoxalate, tert-butyl-1- (obrombenzyl) -2-methyl-5-methoxy-3-indolylglyoxalate, tert-eutyl-1- (p-chloroacetylbenzyl) ^ -methyl-S methoxy-J-indolyl glyoxalate, 1; ert. -Butyl-1- (p-phenylaoetylbenzyl) -2-methyl-5-methoxy-2-indolylglyoxalate, tert-butyl-1- (p-sulfamylbenzyl) ^ - methyl-S-methoxy - ^ - indolylglyoxalate, tert.- Butyl 1- (p-dimethylsulfonamidobenzyl) -S-methyl-S-methoxy - ^ - indolylglyoxalate , tert-butyl-1- (p-dipropylsulfonaroidobenzyl) -2-methyl-5-methoxy-3-indolylglyoxalate, tert. -Butyl-1 - '(p-methylcarboxybenzyl) -2-methyl-5-methoxy-5-indolylglyoxalate, tert-butyl-1- (p-propylcarboxybenzyl) ^ - methyl-S-methoxy-J-indolylglyoxalate, tert. -Butyl-1- (p-pentyloarboxybenzyl) -2-methyl-5-methoxy-5-indolylglyoxalate, tert-butyl-1 - :( trraethylbenzyl) -2-methyl-5-methoxy-3-indolylslyoxalate tert. -Butyl-1 - (ο, ιη, ρ-tripropylbenzyl) -2-methyl-5-methoxy-3-indolylglyoxalate.

c) If one uses instead of the.2-methyl-5-methoxy-3-indolyl- * glyoxalate of Example (2a) above an equivalent amount the tert-butyl-substituted 5-indolylglyoxalate specified in Example 1, the corresponding tert-butyl-I-p-chlorobenzyl-substituted 5-indolylglyoxalates are obtained in this way.

d) If the procedure of Example 2a is followed using the 2-methyl-S-methoxy-J-indolylglyoxal-substituted amide obtained in Example 1 instead of

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909822/1308

ysy so receives

one die.- corresponding t-P-chlorobenzyl-a-methyl-S-methoxy ^ -indolylglyoxal-subst.-amide.

Example 3

tert. "Butyl ^ i -p-chlorobenzyl - ^ - methyl-S-methoxy - ^ - 'indolyl q-aminoacetate

A mixture of 0.01 mol of tert-butyl-1-p-chlorobenzyl-2-methyl-5-ynethoxy-j5-indolyl glyoxalate, 0.02 mol of hydroxylamine hydrochloride, 20 ml of tert-butanol and 5 ml of pyridine is added heated on a steam bath under nitrogen for 3 hours. The mixture is concentrated in vacuo to about 10 ml and poured into about 250 ml of an ice-water mixture with stirring. To Melting the ice - the organic material is collected, washed well with water until the odor of pyridine disappeared is, dried and dissolved in 25 ml of ethanol and 0.02 mol of 28 # hydrochloric acid. The mixture is then under a Hydrogen pressure of 210 at (JOOO psi) at room temperature in the presence "of 1 g of 5 # palladium carbon. The The mixture is filtered and 50 ml of 2.5N hydrochloric acid are added.

given. The solution is twice with 50 ml of chloroform each time washed, cooled, weakly with concentrated NH ^ OH made alkaline and extracted three times with 50 ml of chloroform each time. The chloroform extracts are combined, washed twice with 100 ml of water each time, over anhydrous potassium carbonate

+49 98 22/1308

dried, filtered, and concentrated in vacuo to a syrup, which can be grown on a column of silica gel using Ether / rthylacetate is chromatographed as the eluting agent. So tert. -Butyl-1-p-chlorobenzyl ~ 2-methyl-5'-niethoxy-3-indolyl-cc-aminoacetate.

If you use the methyl or Kthylglyoxalat with the appropriate Alcohol solvents in the above procedure, the methyl or ethyl-i-p-chlorobenzyl-2-A is obtained methyl-S-methoxy - ^ - indolyl-a-amine acetate.

Example 4 ■

The procedure of Example 3 is followed using the tert-butyl-1-aralkyl-substituted-3-indolylglyoxalate obtained according to Example 2 instead of tert-butyl-1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolylglyoxalate and thus receives the corresponding tert-butyl-1-aralkyl-substituted-3-indolyl-a-aminoacetate.

Following the procedure of Example 3 using of T-p-chlorobenzyl ^ -methyl-S-methoxy ^ -indolylglyoxal-subst.-amides from Example 2 instead of tert-butyl-i-p-chlorosnzyl ^ -methyl-S-methoxyO-indolylglyoxaläts ,. the corresponding ones are obtained in a corresponding manner i-p-Chlorobenzyl-S-methyl-S-niethpxy ^ rindolyl-a-arainoäthylsubst.-amide.

.Sü. 909822/1308

14 / UIUV

as

Example 5

a) tert. -Butyl-ct- (1-p-chlorobenzyl ^ -methyl-S-methoxy -;? - indolyl) -a-methylaminoacetate

A mixture of 0.01 mol of tert-butyl (1 «rp-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) -a-arainoacetate, 0.011 moles of methyl iodide and 0.015 moles of sodium bicarbonate in 50 ml of anhydrous 1,2-Dimethoxyethane are on a steam bath under nitrogen Heated for 5 hours. The solution is filtered, the solvent removed in vacuo and the residue on a column of 150 g of neutral aluminum oxide using ether-petroleum ether (Vol.AoI. 20 to 100 #) as the eluent chromatographed. This gives tert-butyl-α- (1-p-chlorobenzyl-2-methyl-5-niethoxy-3-indolyl) -a-methylaminoacetate,

If the corresponding methyl or ethyl ester is used in the above procedure, one obtains in a corresponding manner Methyl or ethyl a- (1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) -a-methylamino acetate.

Example 6

The procedure of Example 5 is repeated using equivalent amounts of those obtained in Example 4 terfr.-Butryl-i-aralkyl-Bubst.-3-indolyl-oaminoacetate instead of tert-butyl-1-p-ohlorbenjrl-2-

- 35 -

.909822 / 1308

· Ι ^ / υ IU /

a-atninoacetafce and thus receives the

corresponding tert-butyl-1-aralkyl-substituted-3-indolyl-amethylaminoacetate

If you use the procedure of Example 5, the 1-p-chlorobenzyl ^ -methyl-S-methoxyO-indolyl-a-aminoethyl-substituted-amide from Example 4 instead of the tert-butyl-1-p-chlorobenzyl-2- methyl-5-methoxy-3-indolyl-a-aaiinoacetats _<r is obtained in a corresponding manner the corresponding 1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolyl-a-methylaraino-ethyl-subst. -amide.

Example 7

tert. -Butyl-α- (1 -p-chlorobenzyl-2-

g-dlniethylajpinoaoetat

A) A mixture of 0.01 mole of tert-butyl-α- (1-p-chlorobenzyl _v 2-methyl-5-methoxy-3-indolyl) -o-aminoacetate, 0.022 mol methyl iodide and 0.03 m_ mol sodium bicarbonate in 50 ml of anhydrous "~ 1,2-dimethoxyethane is heated for 5 hours on a steam bath under nitrogen. After filtering, the Lösungemittel is removed in vacuo and the residue chromatographed on a column of 20Q g _v alumina using Xther-petroleum ether (v ./VoI, $ 20 to $ 100) as the eluent, giving tert-butyl-α- (1-p-chlorobenzyl-a-methyl-S-methoxy-3-indolyl) -a-dimethylamino acetate.

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909822/1308

■ · 3?

B) If you use the appropriate method in the above procedure Methyl and ethyl esters, one obtains methyl resp. Ethyl-α- (1-p-chlorobenzyl-S-methyl-S-x-methoxy-3-indolyi) -ad / methylaminoacetate.

Example 8

The procedure of Example 7 is followed, using equivalent amounts of the tert-butyl-1-aralkyl-substituted-3-indoly1-a-aralkyl-substituted 3-indoly1-a-arkoacetate W obtained in accordance with Example 4 instead of the tert-butyl-ip-chlorobenzyl-E methyl-S-methoxy-3-indolyl-a-aminoacetate and thus receives the corresponding tert-butyl-α- (1-aralkyl-substituted-3-indolyl) -a-dimethylaminoacetate.

Follow the procedure of Example 7 using the 1-p-chlorobenzyl-2-methyl-5-njethoxy-5-indolyl-a-amino-ethyl-subst. -amides instead of tert-butyl-i-p-chlorobenzyl-a-methyl-S-niethoxy-J-Jj indolyl-a-aminoacetats, the corresponding ones are obtained α- (1-p-chlorobenzyl-2-methyl-5-niethoxy-j5-indolyl) -α-dimethylamino-ethyl-substituted amide.

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909822 / 13Ü8

Example 9

tert. -Butyl-α- (1-p-chlorobenzyl ^ -methyl-S-amlno ^ -indolyl) - tt amino acetate

The procedure of Example 3 is followed using of tert-butyl-i-p-chlorobenzyl ^ -methyl-S-nitro ^ - indolyl glyoxalate instead of tert-butyl-1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolyl glyoxalate. and thus obtains the 5-nitro-α-oxime ester. The raw oxime is then put into a solution of about 30 ml of ethanol and 0.04 mole of 38 # hydrochloric acid and the mixture is placed under 2.8 at (40 psi) hydrogen pressure Reduced at room temperature in the presence of about 5 #iger Palladiurakohle. Then the mixture is filtered, and 50 ml of 2,5N hydrochloric acid are added. The aqueous phase is washed twice with 50 ml of chloroform each time, cooled, made weakly alkaline with concentrated ammonium hydroxide and extracted three times with 50 ml of chloroform each time. The chloroform extracts are combined, washed twice with 100 ml of water each time, over anhydrous potassium carbonate dried and filtered, the solvent is removed in vacuo removed, and the residue is on a column of 200 g Aluminum oxide using ethyl acetate ether (Vol./Vol. 0 to 100 Ji) as a solution ratio te! System chromatographed. One obtains eo tert-butyl-a- {1-p-chlorobenzyl-2-me thyl-5-aniino-3-indolyl} -a-aminoace tat.

ι 4 / υ ι υ / ·

If tert-butyl-1-p-chlorobenzyl-2-methyl-5-nitro-methyl-2-indolylglyoxalate , tert-butyl-1-p-chlorobenzyl-2-methyl-5- (1-nitrobutyl) -3- indolyl glyoxalate and tert-butyl 1-1 -p chlorobenzyl-2-methyl-5-0-nitropentyl) -2-indolylglyoxalate instead of tert-butyl-1-p-chlorobenzyl ^ -inethyl-S-nitro-3-indolylglyoxalate Sjso in a corresponding manner, tert-butyl- (1-p-chlorobenzyl-3-methyl-S-aminoraethyl-} - indolyl) -a-aminoacetate, tert-butyl- (1-p-chlorobenzyl-2-methyl-5) is obtained -aminopropyl-j5-indolyl) -a-anilnoacetat or tert-butyl- (1-p-chlorobenzyl-2-methyl-5-aminopentyl-3-indolyl) -a-aminoacetate.

Example 10

tert-butyl-α- (1-p-chlorobenzyl-2-methyl-5-dimethylamino-

3-indolyl) -a-dimethylamino acetate

An amount of 0.01 mol of tert-butyl-α- (1-p-chlorobenzyl-2-methyl-5-aniino-3-indolyl) -a-arainoaoetat, 0.044 mol of methyl iodide and 0.06 mol of sodium bicarbonate in 75 ml of anhydrous 1,2-Dimethoxyäthaii is heated on a steam bath under nitrogen for 6 hours. The solution is filtered and the solvent is removed in vacuo. The residue is ohromatographed on a column with 250 ζ aluminum oxide using Kthylacetat-Xthor (Vol.AoI. 0 to 100 %) as the elution system. This gives tert-butyl-α- (1-p-oleobenzyl-2-methyl-5-hydroethylajnino-3-indolyl) -α-dimethylarninoaoe tat.

; ,,,: - '., - 9 09822/130 8

I 4 I UIU I

Example 11

tert-butyl ^ a-fi-p-chlorobenzyl ^ -inethyl-S-aethylaiiiino-? ·· indolyl) -a-methylaniinoacetate

A mixture of 0.01 Hol tert-butyl-α- (1-p-chlorobenzyl-2-methyl-5-amino-3-indolyl) -a-amino acetate, 0.022 mol of methyl iodide and Ο, Οβ mol of sodium bicarbonate in 75 ml of anhydrous • 1,2-Diraethoxyethane is on a steam bath under nitrogen

Heated for 6 hours. The solution is filtered and the solution φ medium removed in vacuo. The residue is on a column with 250 g of aluminum oxy oil using ethyl acetate-ether (Vol./Vol. 0 to 100 Jd) as the elution system chormatographed. This gives tert-butyl (1-p-chlorobenzyl-2-methyl-5-methylamino-3-indolyl) -a-methylaminoacetate.

If propyl iodide and pentyl iodide are used instead of the methyl iodide in the above example, tert-butyl-α- (1-p-chlorobenzyl ^ -methyl-S-propyl- s araino-5-indolylJ- a-propylaminoacetate or 5-butyl-a- (1-p - "* chlorobenzyl-2-methyl-5-pentylamino-3-indolyl) -a-pentylaminoacetate.

" Example 12 ·.

1-p-chlorobenzyl * 2-methyl-5-methoxyindole

To a solution of 0.21 mol of 2-methyl-5-methoxyindole in 2 ml

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9Q9822 / 1308

A cold suspension of 0 * 22 mol of sodium hydride (52 # dispersion in mineral oil) and 23 ml of dimethylformamide is added dropwise to dimethylformamide. The mixture is stirred at room temperature for 20 minutes, cooled and with. Treated 0.22 moles of p-chlorobenzyl chloride. The reaction mixture is stirred for about 16 hours at room temperature and then poured into 260 ml of ice water. The aqueous mixture is extracted three times with 250 ml of ether each time. The ether extract is washed with 100 ml of potassium bicarbonate solution and three times with 100 ml of water each time. The ether layer is dried overall W, concentrated at reduced pressure and 800 g acid-washed alumina using petroleum ether-Kther (Vol.AoI. 0 to 20 Ji) as eluent. This gives lp-chlorobenzyl ^ -methyl-S-methoxyindole.

If the substituted benzylochlorides of Example 2 are used instead of the 1-p-chlorobenzyl chloride, one obtains in a corresponding manner the corresponding 1-subst «-benzyl-2-methyl-5-methoxyindoles.

Uses the substituted Xndole of example to t in place of 2-methyl-5- ⁱ nethoxyindols _# ^yields the corresponding substituted in corresponding catfish 1-p-Chlorbenzylindole,

909822/1308

Example 13

_ι t _ι e rt. '^^ B ^ ltyl-1 ^^ p-chlorobenzyl ^ »2-π ^ βfchyl · -'5-πl3thoxy ■ · 3-indol · yl ^ · glycxalate.

To a solution of 0.005 mol of oxalyl chloride in 15 ml of anhydrous ether, a solution of 0.005 mol of 1-p-chlorobenzyl-2-methyl-5-nietho: cyindQl in 15 ml of ether is added with stirring over the course of about 50 minutes. The mixture is then stirred under nitrogen for several hours. The mixture is then concentrated to about half the volume, 4 ml of tert-butanol are added, and the mixture is stirred for several hours. After removal of the ether and the excess butanol, the residue is chromatographed on a column of 100 g of silica gel using ether-petroleum ether (v / v 10 to 100% ) as the eluent. This gives tert-butyl-ip-chlorobenzyl-S-methyl-S-methoxy-5-indolyl glyoxalate.

Using methanol, ethanol and benzyl alcohol P is obtained in place of the tert-butanol in the above example.

methyl i-p-chlorobenzyl-2-methyl-5-methoxy-5-indolylglyoxalate, Ethyl 1-p -chlorobenzyl-2-methyl-5-methoxy-5-indolyl glyoxalate and benzyl 1-p-chlorobenzyl-2-methyl-5-niethoxy-2-indolyl glyoxalate, respectively.

The above procedure is followed using

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the substituted amines from Example 1 instead of the tert-butyl compound of the above example and thus receives the corresponding 1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolylglyoxal subst. -amide. .

Example 14 2-methyl-5-rcethoxy-3-indolylglyoxalic acid

To a solution of 0.005 mol of Oxalylchlorld in 15 ml of anhydrous Ether, a solution of 0.005 mol of 2-methyl-5-methoxyindole in 15 ml of ether is added within about about 50 minutes too. The mixture is then under for several hours Nitrogen stirred. Then the mixture is concentrated to about half the volume. 1.5 rol of water are added, and the mixture is stirred for several hours. After removing the ether and the excess water, the The residue was chronographed on a column with 100 g of silica gel using Kther-Petroluther as the eluent. E-Kethyl-S-mathoxy-J-indoly / glyoxylic acid is obtained.

Correspondingly, ammonia water and a solution of sodium hydroxide are used instead of water in the above example 2-methyl-5-methoxy-; 5-indolylglyoxalamide or 2-methyl-5-methoxy-2-indolylglyoxyl.-acid Sodium.

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■? · - ■■■■ '. I 4 / U I U /

Example 15

α-Ν, Ν-Dimethylamino- (1-p-chlorobenzyl - ^ - methyl-S-methoxyindole) -3-acetic acid ethyl ester

0.11 mol of diethylamine are added dropwise at 0 to 4 ° C to a solution of 0.11 mol of ethyl glyoxylate j50 Parts by volume of dimethylformamide were added. After the addition is complete, the entire mixture becomes the same for 1 hour Temperature stirred. 0.10 moles of 1-p-chlorobenzyl - ^ - methyl-S-raethoxyindole are then added in small portions at .0 to 4 ° C. After that reaction mixture has reached tin temperature It is stirred for 2 hours at this temperature and then heated for between 5 and 7 hours at 50 ° C. The dimethylformamide is made in vacuo under a nitrogen atmosphere distilled off and the RUokotand dissolved in ether. The ethereal solution is then extracted with 2N hydrochloric acid or 2N tartaric acid cooled with ice-water, and the extracts are extracted each immediately under good cooling with 2N sodium hydroxide made alkaline. The deposited material is extracted with Xther. The ethereal solution is washed with water and dried over sodium sulfate. After distilling off the Solvent, the residue from ether-petroleum ether and Ether-cyclohexane crystallizes. This gives α-Ν, Ν-dimethylamino- (1-p-chlorobenzyl ^ -Hsethyl-S-methoxylndol) ~ 2-acetic acid ethyl ester.

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If you use benzylamine, diethanolamine, p-benzylbenzylamine, n-butylamine, cyolohexylamih and 1,2,5> 6-tetrahydropyridine instead of dimethyl amine, a corresponding Way a-N-Benzylamino-a-O-p-chlorobenzyl-S-raethyl-S-niethoxyindole) -3-acetic acid ethyl ester, a-N, N «diethanolamino-a- (1-pchlorbenzyl-2-ynethyl-5-nietho3cyindc> l) -3-ethyl acetate, cc-N-p-Methylbenzylamlno-a- (1 -p-chlorobenzyl - ^ - methyl-S-Bie thoxyindol} -5-acetic acid ureäthylesfcer, a-n-Butylaraino-a- (1-pchlorbenzyl-2-niethyl-5-nietho.Kylndol) -5-ethyl acetate,

a-Cyclohexylämlno-a- (1-p-chlobericyl-2-methyl-5-methoxy- ^

indolJ - ^ - EssIgsaureätllylesfcer, ct-N-1,2 _# 5 »6-TetrahydropyridI-no-a- {1 -p-chlόΓbenzyl-2-Iπethyl-5-tπethoxylndöl} -3-ethyl acetate» or a-Benzylatnlno- (1-p-oleofbenzyl-2-methyl-5-methoxyindole) - ^ - ethyl acetate.

Following the above procedure, using is obtained deriving from the amines given in Example 1 Olyoxalaiaideri instead of Glyöxälsäüreäthylesters in des above example in a corresponding manner the corresponding a-N; N-DImethyianiinö- {1 -p »chiorbenzyi-2-niethyl-5-methoxylhdol) -3-subst.- acetaniide.

Example-4-6 '

One proceeds according to the method of working from example 15 under Use of SitüiValehter Quantities älr säMMiüiereön 1-Äratäy

4 '/ 4

H70107

indoles from Example 12 instead of 1-p-chlorobenzyl-2-ynethyl 5-methoxyindole and thus obtains the corresponding a-N, N-dimethylamino- (1-aralkyl-substituted-indole) -J-acetic acid ethyl ester.

If the above procedure is followed using ip-chlorobenzyl-2- (eth-1-ene) -5- (eth-1-ene) -indole, 1-p-chlorobenzyl-2- (prop-1-en) -5- (prop-1-en) indole, 1-p-chlorobenzyl-2- (pent-1-en) -5- (pent-1-en) indole, 1-p-chlorobenzyl- ^ 2-raethyl-5- (1-ethenoxy) indole, 1-p-chlorobenzyl ^ -methyl-S- (1 -propenoxy) indole, 1 -p-chlorobenzyl ^ -methyl-S-O-pentenoxy) indole and 1-p-ChloΓbenzyl-2-methyl-5-azacyclopropylindole instead of the i-p-chlorobenzyl ^ -methyl-S-iaethoxyindole, in a corresponding manner, α-Ν, Ν-Dimethylamlno-a- [1 -p-chlorobenzyl-2- (äth-1 -en) -5- (äth-1 -en) -indole] -3-ethyl acetate, a-N, N-dimethylamino-a- [1-p -chlorobenzyl-2- (prop-1 -en) -5- (prop-1-en) -indolJ-3-acetic acid ethyl ester, a-NiN-Dimethylamino-a-ti-p-chlorobenzyl-S-Cpent-i-en) -5- (pent-1-en) -indolJ-jS-acetic acid ethyl ester, ä-N, N-Dimethylamlno-a- [ 1-p-chlorobenzyl-2-methyl-5- (1 -ethenoxy) indole] -jj-acetic acid ethyl ester, a-N, N-dimethylamino-a- [i -p-chlorobenzyl-2-methyl-5- (1 -propenoxy) -indole J-jJ-ethyl acetate, a-NiK-diraethylamino-a-fi-p-chlorobenzyl-S-ynethyl-S- (1-peritehoxy) indole] -5-ethyl acetate or a-N, N-Dimethylainifto-ά- (1 -p-chlorobenzyl-Ö-methyl-S-azaeyolöpropyi-

If the above procedure is followed using i-p-chlorobenzyl ^ -methyl-S-benzyloxylndol, 1-p-chlorobenzyl-2-methyl-5-p-niethylbenzyloxyindole, 1-p-chlorobenzyl-2-methyl-5-p-propylbenzyloxyindole, 1-p-chlorobenzyl-2-methyl-5-p-pentylbenzyloxyindole * 1 -p-Benzyloxybenzyl ^ -methyl-S-nieth oxyindole, i-o-eenzyloxybenzyl ^ -methyl-S-methoxyindole, 1-p-nitrobenzyl-2-methyl-5-methoxyindole, 1 -p-chlorobenzyloxybenzyl-2-methyl-5-nsethoxyindole, 1 -p-methylbenzyloxybenzyl-2-methyl-5-methoxyindole, 1-p-Propylbenzyloxybenzyl-2-methyl-5-methoxyindole and i-p-pentylbenzyloxybenzyl ^ -methyl-S-methoxyindole instead of i-p-chlorobenzyl - ^ - methyl-S-ynethoxyindole, this gives the corresponding α-N, N-dimethylamino- (1-eu'allcyl-substituted-indole) r5-ethyl acetate.

Example 17

cc-M orpholino- (1 ^ p-chlorobenzyl-2-methyl-5-π ^ ethoxyindol5 -3-

esslgsSure

0.11 mol of morpholine is added to a solution of 0.11 mol of glyoxylic acid at 0 to ^ ⁰ C in 50 parts by volume of dimethylformamide. When the addition is complete, the whole mixture is stirred for 1 hour at room temperature. 0.10 mol of ip-chlorobenzyl ^ -methyl-S-niethoxyindole are added to this mixture in small portions at a temperature of 0 to 4 ° C. After the reaction mixture has reached room temperature, it is heated for 2 hours at room temperature.

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Stirred temperature and finally heated at up to 80 ° C for 3 to 7 hours. The dimethylformamide is distilled off in vacuo under a nitrogen atmosphere and the residue is dissolved in ether. The ethereal solution is extracted at ⁰ ° C. with 2N hydrochloric acid or with 2N tartaric acid, and the extracts, while remaining cold, are made alkaline with 2N sodium hydroxide. The deposited oily base is extracted with ether, washed with water and dried over sodium sulfate. After the solvent has been distilled off, the residue is crystallized from ether-petroleum ether and ether-cyclohexane. This gives α-morpholine- (1-p- · chlorobenzyl-a-methyl-S-methoxyindole) - ^ - acetic acid.

One uses piperazine, N-acetylpiperazine, piperidine and Pyrrolidine instead of the morpholine in the above example, a-piperazino- (1-pchlorobenzyl-2-methyl-5-methoxyindole) -j5-acetic acid is obtained in a corresponding manner, a- (4'-. "Aoetylpiperazino) - (T-p-chlorobenzyl-2-methyl-5-methoxyindole) -2-acetic acid, a-piperidino-ii-p-chlorobenzyl-S-raethyl-S-, methoxyindole) -3-acetic acid or α-pyrrolidino- (1-p-chlorobenzyl-2-methyl-5-methoxyindole) -3-acetic acid.

The above procedure is followed using ethyl acetate instead of oxyoxy and thus receives the corresponding ethyl ester.

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Example t8 i-p-Chlorobenzyl-'a-niethyl-S-methoxy-g-indolylacetic anhydride

0.049 mol of dicyclohexylcarbodiimide are dissolved in a solution of 0.10 mol of ip-chlorobenzyl-S-methyl-S-njethoxy-I-indolyl acetic acid in 200 ml of THF, and the solution is left to stand at room temperature for 2 hours. The precipitated urea is filtered off _; and the filtrate is evaporated in vacuo to a residue which is rinsed with Skellysolve B.

Using any of the other free indolyic acids described herein in the above procedure gives in a corresponding manner the corresponding anhydride.

Bet game 19

t art. -Butyl- '1 -p-methoxybenzyl-2-methyl-5- ⁱ hydroxy-3-indole) -

q-aminoacetate

A mixture of 0.05 hol tert-butyl- (T-p-methoxybenzyl-2-methyl-S-benzyloxy-I-indolyloxime-acetate in 200 ml of ethanol is treated with 10% Palladic charcoal under hydrogen pressure from 2> 16 at (45 psij at room temperature reduced » up to 0.05 mol of hydrogen is absorbed filtered, evaporated in vacuo and on a column of 800 g

. "■. U70107 ■ '

Silica gel using ether-petroleum ether (50 to 100 % v / v) as the eluent. The solvent is evaporated and the product is recovered.

If one uses tert-butyl [1-p-methoxybenzyl ^ -methyl-S-bis- (1 -benzyloxyäthylamino) indolyloxime] acetate , tert. -Butyl * [1-p-methoxybenzyl ^ -methyl-S-bis- (1-benzyloxybutylamino) -indolyloximj-acetate and tert-butyl- [1-p-methoxybenzyl-2-methyl-5-bis- (1 -benzyloxypentylamino) -indolyloxim] -aoetät instead of the tert. -Butyl- (1-p-methoxy-Si-methyl-S-benzyloxyindolyloxime) -acetate «is obtained in the corresponding catfish tert. -Butylr [i -p-methoxybenzyl-S-methyl-S-bis-Ct -hydroxyethylamino) - ^ - indole) -a-aminoacetafc, teft. -Butyl- [1-p-ynethoxybenzyl ~ 2-methyl-5-bis- (1-hydroxybutylamino) -3-indole Ja-aminoaoetat or tert-butyl- [ip-methoxybenzyl ^ -methyl-S-bls- ( 1 «hydroxypentylamino) -3-indole] -a ~ amino acetate.

Beis p iel 20:

tert. -Butyl- (1-p-chlorobenzyl-g-meth'yl-S-hydroxy-J-indole) -

a-amino acetate .

A qemisoh of 1 part tert-butyl "1" -p "^ lilorbenz3rl-2 * inefcnyl" S-benzyloxy-J-indolyloxiiBacetat and to parts of pyridine hydrochloride is heated at 160 ° C. under nitrogen for about 1 hour. The reaction mixture is cooled and poured into water. The solution is then extracted twice with too ml of ether.

3er8

The ether extract is chromatographed on a column of silica gel using ether-petroleum ether (vol. AoI. 50 to 100 %) as all eluents. The solvent is evaporated and the product recovered.

If you use other N-1-substituted indoles with a benzyloxy radical in the 5-position, one obtains in a corresponding manner the corresponding 5-hydroxy compounds.

If one uses tert-butyl- [ip-chlorbenzyl ^ -mathyl-S-bis- W (i-benzyloxyäthylaniinoj-j-indolyloximj-acetate, tert-butyli, 1-p-chlorobenzyl-2-methyl-5-bie- (1-benzyloxybutylamino) -5-indolyloxime] acetate and tert-butyl-ji-p-chlorobenzyl-2-methyl-5-biB- (1-bensyloxypentylamino) -3-indolyloxime] acetate instead of tert-butyl - (1-p-chloΓbenzyl-2-methyl-5-benzyloxy-3-indόlyloxime) acetate, then in a corresponding manner tert-butyl- [1-p-chlorobenzyl-S-methyl-S-bis- ( 1-hydroxyethylamino) -5-indolyl] -a-aminoacetate, tert-butyl- [1-p-chlorobenzyl-2-methyl-S-bis-O-hydroxybutylaminoJ-J-indolylJ-a-aminoacetate or A tert. -Butyl- [1-p -chlorobenzyl-2-methyl-5-bis- (1-hydroxypentylamino) -> - indolyl3-α-aminoacetate.

» Example 21 tert-butyl (2-nrethyl-5-methyl-5-indolyl) -glyoxalate

To a solution of 0.005 mol of oxalylochloride in 15 ml of water

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1470103 5 «

Free ether becomes a solution of 0.005 mol of 2-methyl-5-methylindole with stirring in 15 ml of ether within about 30 minutes admitted. The mixture is then stirred under nitrogen for several hours. Then the mixture is reduced to about half the amount Concentrated in volume, 4 ml of tert-butanol are added, and the mixture is stirred for several hours. After removing the ether and the excess butanol, the residue becomes a column of 100 g silica gel using ether-petroleum ether (V / v 10 to 100 #) as eluent chro- ™ matographed. Tert-butyl - ^ - methyl-S-methyl-J-indolyl) glyoxalate is obtained.

If you use 2-methyl-5-methoxyindole instead of 2-methyl-5-methylindole, in a corresponding manner, tert-butyl (2-methyl-5-methoxy-3-indolyl) glyoxalate is thus obtained.

Example 22

tert-butyl- (1-p-chlorobenzyl-g-methyl-S-methyl - ^ - indolyl) - glyoxalate

A solution of 0.021 mol of tert-butyl- (2-methyl-5-methyl-3- " indolyl) glyoxalate in 20 ml of dimethylformamide is added dropwise to a cold suspension of 1.0 g (0.022 mol) of sodium hydride (52 # dispersion in mineral oil) and 25 ml of dimethylformamide. admitted. The mixture is left at room temperature for 20 minutes.

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stirred, cooled and treated with 0.0222 mol of p-chlorobenzyl chloride. Reactlonsgeraisoh is about at room temperature Stirred for 16 hours and poured into 260 ml of ice water. The aqueous mixture is extracted three times with 250 ml of ether each time. Of the Ether extract is mixed with 100 ml of potassium bicarbonate solution and three - Washed times with 100 ml of water each time. The ether layer is dried and concentrated under reduced pressure. Tert-butyl (1-p-chlorobenzyl ^ -methyl-S-methyl-jJ-indolyl) glyoxalate is obtained.

If one uses teiM> .- butyl- (2-methyl-5-ynethoxy-3-indolyl) ~ glyoxalafc and p-methylthlobenzyl chloride instead of the tert-butyl (2-me'i; hyl-5-n-methyl-3-indolyl) -glyoxalate or p-chlorobenzyichloride, tert-butyl- (1 -p-methylthiobenzyl ^ -msthyl-S-methoxy-J-indolyl) glyoxalate.

Example 23

tert-Butyl-1-p-chlorobenzyl ^ -methyl-S-niethylO-indolyl-tt amino acetate

A mixture of 0.01. Mol of tert-butyl (1-p-chlorobenzy1-2-methyl-5-methyl-3-indolyl) glyoxalate, 0.02 mole of hydroxylamine hydrochloride, 20 ml of tert-butanol and 5 ml of pyridine is placed on a steam bath heated under nitrogen for 3 hours. The mixture is concentrated in vacuo to about 10 ml and in about 250 ml of an ice-water mixture poured with stirring. After the ice melts

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SH

the organic material is collected and washed well with water until the odor of pyridine has disappeared, dried and dissolved in 25 ml of ethanol and 0.02 mol of hydrochloric acid. The mixture is then at a hydrogen pressure of 210 at (3000 psi) reduced at room temperature in the presence of 1 g of 5% palladium carbon. The mixture is filtered, and 50 ml of 2.5N hydrochloric acid are added. The solution is washed twice with 50 ml of chloroform each time, cooled and concentrated with Aramonium hydroxide made weakly alkaline and extracted three times with 50 ml of chloroform each time. The chloroform extracts are combined, washed twice with 100 ml of water each time, dried over anhydrous potassium carbonate, filtered and concentrated in vacuo to a syrup, which was deposited on a silica gel column using ether / ethyl acetate as the eluant is chroraatographiert. Tert-butyl- (1-p- · chlorobenzyl ^ -methyl-S-methylO-indolyl) -α-aminoacetate.

If tert-butyl (Ip-methylthiobenzyl-S-methyl-S- ψ methoxy-3 = indolyl) glyoxalate is used instead of tert-butyl (1-pchlorobenzyl-2-methyl-5-methyl-3-indolyl) ) glyoxalate, tert-butyl (1-p-methylthiobenzyl-. 2-methyl-S-methoxy - ^ - indolyl) -oc-aminoacetate is obtained in a corresponding manner.

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147UlUV

example 2k

The procedure of Example 15 is followed using of glyoxylic acid instead of ethyl glyoxylate and thus receives a-NiN-Dlmethylaraino-Ci-p-chlorobenzyl-S-methyl-5-methoxyindole) -3-acetic acid.

Example 25

q-Morphollno- (1-p -trlfluoromethylbenzyl-g-methyl-S-methoxy indole) -5-acetic acid ethy ester

0.11 mol Morpholln are added dropwise at 0 to 4 ⁰ C to a solution of 0.11 mol Qlyoxylsäureäthylester in 50 parts by volume of dimethylformamide. After the addition is complete, the entire mixture is 1 hour at the. stirred at the same temperature. 0.10 mol of ip-Triraethylfluorbenzyl ^ -methyl-S-raethoxyindole are added in small portions at 0 to 4 ° C. After the reaction mixture has reached room temperature, it is stirred for 2 hours at this temperature and finally heated at 50 ° C. for 5 to 7 hours. The dimethylformamide is • distilled off in vacuo under a nitrogen atmosphere and the residue is dissolved in ether. The ether solution is then extracted with 2N hydrochloric acid or 2N tartaric acid cooled with ice water, and the extracts are in each case immediately made alkaline with 2N sodium hydroxide while being well cooled. The deposited

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TAVU107

$ 6

The material is extracted with ether. The ethereal solution becomes washed with water and dried over sodium sulfate. After distilling off the solvent, the residue from ether, Petroleum ether and ether cyolohexane crystallized. You get so oc-morpholino- (1-p-trifluoromethylbenzyl-S-methyl-5-niethoxy-. indole) -3-acetic acid ethy ester.

Example 26

a-Pyrrolidino- {1-p-chlorobenzyl-2-methyl-5-methoxyindole) -

3-acetic acid

0.11 mol of pyrrolidine is added to a solution of 0.11 mol of glyoxylic acid at 0 to 4 ^° C. in 30 parts by volume of dimethylformamide. When the addition is complete, the entire mixture is stirred for 1 hour at room temperature. 0.10 mol of 1-p-chlorobenzyl ^ -raethyl-S-methoxyindole are added in small portions at a temperature between 0 and 4 ° C. to this mixture. After the reaction mixture has reached room temperature, it is stirred for 2 hours at room temperature and finally heated at 30 to 80 ° C. for 3 to 7 hours. The dimethylformamide is distilled off in vacuo under a nitrogen atmosphere and the residue is dissolved in Xther. The ether solution is extracted at 0 ⁰ C with 2N hydrochloric acid or 2N-tartaric acid, and the extracts are * while they remain cold, with 2N sodium triumhydroxyd made alkaline. The deposited oily base

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is extracted with ether, washed with water and over sodium sulfate dried. After the solvent has been distilled off, the residue is made up of ether-petroleum ether and ether-cyano-

hexane crystallizes. This gives ar-pyrrolidino- (1-p-chlorobenzyl-2-methyl-5-methoxyindole) -3-acetic acid.

Example 27 *

α-Cyclohexylamino- (1-p-methylthlobenzyl-2-methyl-5-i'luoro- indole) ^ acetic acid

0.11 mol of cyclohexylaniine in 250 parts by volume of dimethylformamide are added ^{at 0 to 4 °} C. to a solution of 0.11 mol of glyoxylic acid. When the addition is complete, the entire mixture is stirred for 1 hour at room temperature. 0.10 mol of 1-methylthiobenzyl-2-methyl-5-fluoroindole are added to this mixture in small portions at 0 to 4 ° C. After the reaction mixture has reached room temperature, it is stirred at room temperature for 2 hours and then heated at 30 to 80 ° C. for 3 to 7 hours. The dimethylformamide is distilled off in vacuo under a nitrogen atmosphere and the residue is dissolved in ether. The ether solution is extracted at 0 ⁰ C with 2N hydrochloric acid or with 2 N tartaric acid, and the extracts are "wöhrend they remain cold, made alkaline with 2N sodium hydroxide. The separated oily base is extracted with ether, washed with water and After the solvent has been distilled off, the residue from Kther-

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·. I <4 / U I U /

Petroleum ether and ether-cyclohexane crystallized. You get so a-Cyolohexylamino-O-p-methylthiobenzyl-a-methyl-S-fluoroindole) -3-acetic acid.

Example 28 i-p-Chlorobenzyl ^ -methyl-S-nitroindole

A solution of 0.21 mol of 2-methyl-5-nitroindole in 20 ml of dimethylformamide is added dropwise to a cold suspension of 1.0 g (0.022 mol) of sodium hydride (52 # dispersion in Mineral oil) and 25 ml of dimethylformamide were added. The mixture is stirred at room temperature for 20 minutes, cooled and treated with 0.022 mol of p-chlorobenzyl chloride .. The reaction mixture is stirred at room temperature for about 16 hours and Poured into 250 ml of ice water. The aqueous mixture is extracted three times with 250 ml of ether each time. The Xtherextrakt is with 100 ml of potassium bicarbonate solution and three times with 100 ml of water each time washed. The ether layer is dried and at reduced Pressure restricted. 1-p-chlorobenzyl-S-methyl-S-nitroindole is obtained.

Example 29 ^l .

* tert. -Butyl- (1-p-chlorobenzyl ^ -methyl-S-'nitro ^ -indolyl) -glyoxalate

To a solution of 0.005 mol of oxalyl chloride in 15 ml of water

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free ether, a solution of 0.005 mol of 1-p-chlorobenzyl-2-methyl-5-nitroindole in 15 ml of ether is stirred within added about 30 minutes. The Oemlsoh is then stirred for several hours under nitrogen. The mixture is then Concentrated to about half the volume, 4 ml of tert-butanol are added and the residue is passed on to a column of 100 g of silica gel using ether-petroleum ether. Chromatographed (v / v 10 to 100 #) as the elution agent. Tert-butyl (1-p-chlorobenzyl ^ -methyl-S-nitro-J-indolyl) glyoxalate is obtained.

Example 30 '

tert-butyl- (1-p-chlorobenzyl ^ -methyl-S-aminoQ-indolyl) - glyoxalate

To a solution of 0.01 mol of butyl (1-p-chlorobenzyl-2-methyl-5-nitro-2-indolyl) glyoxalate in 30 ml of ethanol, 0.04 mol 38 # hydrochloric acid added, and the mixture is under 2.8 at (40 psi) at room temperature in the presence of 5% PaJIadium carbon. The mixture is then filtered, and 50 ml 2.5N hydrochloric acid are added. The aqueous phase is used twice washed with 50 ml of chloroform, cooled and concentrated with. Trlertem ammonium hydroxide made alkaline and extracted three times with 50 ml of chloroform each time. The 'chloroform extracts are combined, washed twice with 100 ml of water each time, over

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dried anhydrous potassium carbonate and filtered, the solvent is removed in vacuo, and the residue is on a column with. 200 g of aluminum oxide were chromatographed with ethyl acetate-Xther (volume / volume 10 to 100 %) as the solvent system. Butyl (ip-chlorobenzyl-2-methyly $ -aminp- _t 3-indolyl) glyoxalate is obtained.

Example 31

tert-butyl- (1-p-chlorobenzyl-g-methyl-S-methylamino - ^ - indolyl) - glyoxalate

A mixture of 0.01 mol of tert-butyl (1-p-chlorobenzyi-2-methyl-5-araino-3-indolyl) glyoxalate in 0.011 mol of methyl iodide and 0.015 mol of sodium bicarbonate and 50 ml of anhydrous 1,2-dimethoxyethane are heated on a steam bath under nitrogen for 3 hours. The solution is filtered, the solvent is removed in vacuo, and the residue is chromatographed on a column of 150 g of neutral aluminum oxide using petroleum ether (v / v 20 to 100 %) as the eluent. One receives tert. -Butyl- (1-p-chlorobenzyl ^ -methyl-S-methylamino-3-indolyl) ^ glyoxalate. .

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Bel a ρ 1 e 1 32

^ T-p-Methylthi ob enzyl- 2 ~ methyl-5 ~ methoxyindolyl acetic acid

One solves. 22 g of the Oxima of
5-methoxyindolyl- (3j7- ^{acetic acid in} 300 ^{ml of} absolute methanol. To this, 440 g of double sodium amalgam are added in part over the course of one hour. The mixture is kept acidic by adding lactic acid and the mixture is stirred for 4 hours. Then decanted and filtered man'das mixture. the filtrate is concentrated in vacuo to a heavy oil and this was diluted with distilled water to approximately 500 ml .. It superimposes the mixture for 16 hours at O ⁰ Cj, then filtered and crystallized from methyl acetate to the resulting solid substance UMJ Po 163-165 ⁰ C (decomposition) '.

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Claims (2)

k & DEL 1918 8864 / M 6? 232 New claims 1. ^^ Benzyl-indolyl- (5j7 ° ^emi noes8ig8äureverbindungen of the general formula -CH-COOH -lower-alkyl low-edrig-alkylthio (R »lower alkoxy or dimethylamine). 2. Process for the preparation of the compounds according to claim 1, characterized in that «an oxime compound of general formula -C-COOH
-lower-alkyl lower alkylthio In which R has the meaning given in claim 1, reduced » Medicinal whirlcatoff, characterized by the fact that it is a compound according to Claim 1.