DE2735537A1 - INDOLACETOXYACETYLAMINO ACID DERIVATIVES, METHOD FOR THEIR MANUFACTURING AND USE AS A MEDICINAL PRODUCT - Google Patents

Description

Ib / (Pha) Ks / bc

Aug 5, 1977

Indole acetoxyacetyl amino acid derivatives, method to their manufacture and their use as medicinal products

The present invention relates to new indole acetoxyacetylamino acid derivatives, processes for their preparation and their Use as medicaments, especially as anti-inflammatory drugs and anti-inflammatory drugs.

The invention relates to new indolylacetoxyacetylaminoacetic acid derivatives of the general formula

0 0 0 0

"-TCH ₀ -CO-CH ₉ -CX-CH-C- F-NH-CH-CH-H ^ K-CH-CI -R _ü

Il '· - * ir. · "" N

? J 3 ^ l ^ 2 ** '3

(D

909808/0015

in soft ^

m and η stand for the digits O or 1, ie / O 5 5 3 /

X stands for a -NH- or -OCH ^ group,

R ₁ , R ₂ and R, can be identical or different and represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic methyl group with 1 or 2 rings and each with 5, 6 or 7 Ring members in which 1 or 2 members can be replaced by heteroatoms, and in the event that m and η stand for the number 0,

R _{1 represents} an amino group, an alkoxycarbonyl group or an aralkoxycarbonyl group,

R, for a hydroxyl group or for an optionally substituted alkoxy group, an optionally substituted one Aralkoxy group, an amino group or an optionally substituted alkylamino group, an optionally substituted aralkylamino group, an optionally substituted arylamino group stands,

and their physiologically compatible salts, if appropriate formed with acids and bases.

It has been found that the compounds of the general formula (I) _{according to the invention, in which X, m, η and R 1} to Rj have the meaning given above, are obtained if

a) ß- (4-chlorobenzoyl) -S-methoxy ^ -methyl-a-indolyl / acetoxyacetic acid (hereinafter referred to as ACE-OH) with chloroformic acid esters of the general formula

IP4 - 2 -

909808 / OOeS

in which

R _{5 represents} an alkyl group,

to mixed anhydrides of the general formula

H ₃ C-

0 0

it n it

(III),

C = O

Cl

in which

Rr has the meaning given above,

converts and these with compounds of the general formula

0 0

H ₀ N-CH-C- Γ-NH-CH-Cl - Γ-NH-CH-CI -R _ü (IV),

¹ m 'η R ₁ R ₂ R ₃

in which m, n, R- to R _{4 have} the meaning given above, reacts or

b) the compound ACE-OH with an appropriately substituted phenol to form an activated ester of the general formula

TP 4 - 3 -

909808/0085

in which

Y for 2 to 5 halogen atoms, 1 to 2 nitro groups

or for several other electron-attracting ones

Groups stands,

condensed and with compounds of the general formula (IV), in which m, n, R ₁ to R _{4 have} the meaning given above, or reacts

c) in the event that amino acid derivatives containing hydroxyl groups are to be linked in ester-like fashion, the compound ACE-OH with compounds of the general formula

0 HO-CH ₉ -CH-CR ₁ .

² KH ^(VI)

"6 in which

R _{4 has} the meaning given above and R _{6 represents} an amino protective group customary in peptide chemistry, for example an alkoxycarbonyl or an aralkoxycarbonyl group, and then _{cleaves off the radical R 4} in a known manner

and optionally the compounds of the general formula (I) converted with acids and bases into the physiologically compatible salts.

909808/0085

ORIGINAL INSPECTED

J735537

In the general formula (I), an optionally substituted alkyl group for R ₁ to R ₃ preferably denotes a straight-chain or branched-chain alkyl group with up to 5 carbon atoms. Examples include the methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups, in particular the methyl, ethyl and isobutyl groups. It is preferably substituted by halogen atoms, in particular by chlorine, bromine, fluorine, hydroxyl, mercapto, alkoxy or alkylthio groups, amino groups, acylamino groups, carboxyl groups and nitro groups, the mentioned alkyl, alkoxy and acyl groups up to 4 Contain carbon atoms, in particular hydroxyl, amino, mercapto, methoxy and methy! Mercapto groups.

An optionally substituted aralkyl group for R ₁ to R ₃ preferably denotes the benzyl group, phenylethyl group or phenylisopropyl group, in particular the benzyl group; it can be substituted by 1 to 2 hydroxyl groups, lower alkoxy groups with 1 to 4 carbon atoms, nitro groups, halogen atoms, preferably by a hydroxyl group.

An optionally substituted heterocyclic _{methyl group for R 1} to R ₃ preferably denotes a thenyl, pyrrole methyl, pyrrolidinyl methyl, piperdine methyl, indole methyl, imidazole methyl, quinoline methyl group, in particular the indolyl methyl group and imidazole methyl group; it can be substituted, preferably by halogen atoms, lower alkyl or alkoxy groups with 1 to 4 carbon atoms or nitro groups.

An optionally substituted amino group for R ₁ preferably denotes an acylamino group, in particular

"909808 / OOIS

nlGiMÄL iisispEcfib

/ IO

2735637

a lower alkoxycarbonyl group with up to 5 carbon atoms or a benzyloxycarbonyl group.

An optionally substituted aryl group for R ₁ to R ₃ preferably denotes a phenyl or naphthyl group, which is optionally substituted one to three times by halogen atoms, hydroxyl groups, alkoxy groups with up to 4 carbon atoms, nitro groups, trifluoromethyl groups and / or lower alkyl groups with up to 4 carbon atoms is.

An optionally substituted alkoxy group for R ₄ preferably represents an alkoxy group with 1 to 4 carbon atoms, in particular a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyloxy group, which in turn can be substituted one to three times by halogen atoms, hydroxyl groups and / or alkoxy groups with up to 4 carbon atoms.

An optionally substituted aralkoxy group for R ₄ is in particular the benzyl, phenylethyl, phenylpropyl, phenylisopropyloxy group, preferably the benzyloxy group; it can be substituted by 1 to 2 halogen atoms or alkoxy groups having 1 to 2 carbon atoms.

An optionally substituted arylamino group for R ₄ preferably denotes the phenylamino group, which can be substituted by halogen atoms, alkyl or alkoxy groups having 1 to 4 carbon atoms or by a trifluoromethyl group .

TP 4 - 6 -

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An optionally substituted aralkylamino group for R ₄ stands in particular for a benzyl, phenylethyl, phenylpropyl or phenylisopropylamino group, which can also be substituted as described above for the arylamino group.

In the event that the compounds of the general formula (I) contain a free acid group (R ₄ = OH), physiologically compatible addition salts can be formed with organic and inorganic bases.

Examples of such salts are sodium salts, potassium, magnesium, ammonium, methylammonium, dimethylammonium salts or the 2-hydroxyethylammonium salt.

In the event that the compounds according to the invention of general formula (I) have a free amino group can also be physiologically compatible with acids Addition salts are formed.

Examples of such salts are halides, preferably chlorides, sulfates, citrates, tartrates, maleate and sulfonates.

Surprisingly, the compounds of the general formula (I) according to the invention show a more advantageous activity than the indomethacin serine derivatives of DOS 2,413,125 known from the prior art. The compounds according to the invention thus represent an enrichment in pharmacy.

909808/0085

If ACE-OH and chloroformic acid ester are used as starting compounds, the reaction sequence of variant a) can be represented by the following equation:

0 0 CH.-C-0-CH ..-C-OH

(ACE-OH)

(ID (IV)

\ J V /

NH ₂ -CK-C- ^ MH-CH-C J-

(III)

Cl

(D

^Π 3

The chloroformic acid esters of the general formula (II) which can be used as starting compounds are known and are known as ACE-OH used as the starting compound is also known (DOS 2 234 651).

TP 4

909806/0085

The mixed anhydrides of the general formula (III) formed as an intermediate are new, but cannot be identified because they - like the majority - are different of the mixed anhydrides known from the literature - decompose during work-up (cf. Houben-Weyl, Methods of Organic Chemie, 4th edition, Volume 15/2, page 172 3rd paragraph).

The compounds of the general formula (IV) which can be used as starting compounds are largely known from the literature or can be prepared by known methods (cf., inter alia, Houben-Weyl, Methods of Organic Chemistry, U. Edition, Vol. 15/1 and 2).

The reaction is expediently carried out in the presence of diluents. Suitable diluents are inert organic solvents, in particular those which are polar aprotic. Tetrahydrofuan, dioxane, dimethylformamide and hexamethylphosphoric acid triamide may be mentioned by way of example.

The reaction is expediently carried out in the presence of acid binders, As acid binders, all conventional agents can be used which prevent the hydrogen chloride being released from being bound. These preferably include alkali metal hydroxides and carbonates or organic bases such as pyridine and triethylarine.

909808/0085

The reaction temperatures are expediently below 0 ° C, since otherwise Racemisierur.gen occur; you can can be varied within a certain range. In general works r.ar. at temperatures between 0 ° and -25 ° C, preferably between -10 ° and -20 ° C.

The initialization is usually carried out at normal pressure.

When carrying out the process according to the invention, use is preferably made of 1 mol of ACE-OH, 1 mol of chloranic acid ester, 1 oil of the amino acid derivative and 1 col of the acidic acid.

The reaction time is between 6 and 2 hours, preferably up to 20 hours.

Working up is preferably carried out by evaporation in the Vacuum, taking up in one of the usual organic solvents, neutral washing, optionally Heinissn ar. Silica gel and recrystallization.

Used for the reaction instead of a mixed one Anhydride of ACE-OH an activated ester of the general formula (V), the reaction of variant b) can be represented by the following reaction scheme:

TP 4. ₁₀ .

$ 909803/008

ο ο

CH ₂ -CO-CH ₂ -C-OH

(ACE-OH)

4 HO

(V)

(IV)

R,

(I)

The compounds of the general formula (V) used as reactants are not yet known, but they can in a manner known per se by reacting 1 mole of ACE-OH and 1 mole of the correspondingly substituted phenol in one polar aprotic organic solvent, such as tetrahydrofuran, in the presence of 1 mole of a carbodiimide, such as e.g. dicyclohexycarbodiimide or carbonyldiimidazole Obtained in about 1 1/2 hour reaction time at room temperature will.

TP 4

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909808/0085

·> Γ-y ά r ~ s— "t> *

2 7 j b D j;

The method according to the invention (V)> (I) is expedient

in the presence of thinners. As a dilution number only 5sr.mediate The organic solvents known from the literature for this reaction, preferably dimethylformamide, dioxane, pyridine or mixtures thereof with water, are suitable.

As far as addition salts of (IV) are used for reactions, the process is expediently carried out in the presence of acid by. Examples include alkali metal hydroxides, carbonates or strong organic anines, preferably triethylar.in.

The peak temperatures can be varied within a certain range. Usually you work at 15-25 ° C, there at lower temperatures the reaction times are disproportionately extended, but at higher temperatures the Racer.atbildung is promoted. A certain Paceratbildur.g cannot be ruled out even with the reaction at low temperatures. The process is usually carried out at normal pressure.

When carrying out the method according to the invention preferably 1 XoI des per mole of the activated ester (V) Ar.inosäurederivates (IV) used. The work-up is expediently carried out by diluting the batch with water, Cleaning up in a suitable organic solvent, Neutralization, evaporation and recrystallization from suitable solvents.

In the event that the amino acid derivatives of the general formula (VI) are to be linked ester-like with ACE-OH, the reaction of variant c) can be represented by the following reaction scheme:

TP 4 - 12 -

909808/0085

H "-C-O-CH, -C-OH

(ACE-OH)

It

HO-CH ₂ -CH-CP ,,

NH

^R 6

VI

dd

H ₂ -CO-CH ₂ -CO-CH ₂ -CH-CR ₁ , H,

NH t

rrCH, -C-0-CH, -C-0-CH, -CH-CR _ü Jl-CH, NH,

The Serir.derivate der used as starting compounds general formula (VI) are known. The peak is preferably achieved in the presence of diluents. Polar aprotic organic solvents can be used as diluents. Examples include tetrahydrofuran, dioxane, dimethylformamide, hexamethylphosphoric acid trihydrate. The reaction according to the invention is preferably carried out in the presence of a dehydrating agent. Examples include dicyclohexylcarbodiimide or carbonyldiir.idazole in the presence of catalytic amounts of a basic catalyst, preferably sodium hydride.

TP 4

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909808/0085

The reaction temperatures can vary within a relatively wide range will; Usually one works between 10 and 40 C, preferably between 15 and 25 C.

It is expedient to first react 1 mol of the ACE-OH with 1 mol of carbonyldiimide and add 1 mol of the amino acid derivative only after the evolution of CO has ended. Working up is carried out in the customary manner, preferably by evaporation in vacuo, taking up in a suitable solvent and cleaning on silica gel. The amino protective group R ₆ is split off according to the methods known from the literature customary in peptide chemistry.

The following are examples of new active ingredients:

N-ACE serine, ethyl ester, N-ACE serine, N-ACE yethionine, N-ACE-Tyrosine, N-ACE-Tryptophan, N-ACE-DL-Threonine, N-ACE-phenylalanine, N-ACE-serine-N'-methylanide, N-ACE histidine methyl ester, N-ACE serine benzyl ester, O-ACE serine ethyl ester, O-ACE serine ethyl ester, N-ACE phenylalanyl tyrosine methyl ester, N-ACE-GIy cylalanylphenylalaninr.ethy reads N ^ -ACE-N ^ -benzyloxycarbonyldiaminobutyrylphenylalanylphenyl =

alanine methyl ester.

- 14 TP 4

909808/0085

As ACE, here and in the further course, the rest is

O O

Understood.

The new active ingredients can be converted into the usual formulations in a known manner, such as tablets, capsules, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, solutions, ointments, gels, creams, jellies, using inert, non-toxic, pharmaceutically suitable carriers or solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture , ie in amounts which are sufficient to achieve the stated dosage range.

The formulations are prepared, for example, by extending the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of use With water as diluent, organic solvents can optionally be used as auxiliary solvents.

TP 4 - 15 -

909808/0085

Examples of auxiliaries are: water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesan oil), alcohols (e.g. ethyl alcohol, glycerine), glycols (e.g. Propyl glycol, polyethylene glycol); solid carriers such as e.g. natural rock throat (e.g. kaolin, clay earth, talkun, Chalk), synthetic stone throats (e.g. highly dispersed silicic acid, silicates), sugar (e.g. raw, ilch and corn sugar); Emulsifiers such as nonionic and anionic emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol Xther, alkylsulphonates and arylsulphonates), dispersants (e.g. lignin, sulphite waste liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. "agr. esium stearate, talc, stearic acid and sodium lauryl sulfate").

The application takes place in the usual way, preferably orally or parenterally, locally, intraruscularly or intravenously.

In the case of oral use, tablets, of course, in addition to the carrier substances mentioned, can also contain additives such as Sodium citrate, calcium carbonate and dicalcium phosphate together n with various additives like starch, preferably Contain potato starch, gelatin and the like. Lubricants such as magnesium stearate, atrium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs intended for oral Applications are intended, the active ingredients can except rr.it the various flavor enhancers or colorings are added.

. ₁₆ _

909808/0085

In the case of parenteral use, solutions of the Active ingredients are used with the use of suitable liquid carrier materials.

In the case of topical application, solutions, emulsions, ointments, gels, creams, aerosols or jellies are preferred, advises suitable aforementioned auxiliaries.

In general, it has been found to be advantageous for oral administration to use amounts of about 1 to 100 mg, in particular 10 to 40 mg per dose for 2 to 3 times daily Use administration to achieve effective results, with rectal administration the dosage is about 10 to 2OO, especially 30 to 80 mg per dose.

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909808 / 008S

Example 1 N-ACE serine methyl ester

ACE-NH-CH-CO-CHj CH ₂ -OH

5 g (0.012 mol) of ACE-OH are dissolved in 50 ral of absolute tetrahydrofuran, treated with 1.8 ml (0.0131 mol) Trilthylar.in, cooled to -10 ⁰ C and during half an hour nit dropwise 1.7 ml (0.0131 mol) n-butyl chlorine acid ester were added. The mixed anhydride ACE-O-COO-r.-C ^ Hg thus formed cannot be isolated because it decomposes at room temperature. It is - as well as further processed in the further examples · in solution by 2.05 g (0.0131 !! oil) L-Serinnethylester dissolved in 20 ml of dimethylformamide and a further 1.8 ml Triäthylanin at -10 ⁰ C in the above solution drips in. After stirring at -10 ⁰ C and another 12 hours of standing at -l8 ° C, the mixture is evaporated bei.3 Torr and 30 ⁰ C, the residue dissolved in chloroform, 2 nHCl and then washed neutral with water, Na ₂ SOj, dried, filtered and evaporated. After cleaning on silica gel with a mixture of chloroform / methanol, evaporation, taking up the residue in 50 nl ethanol and adding water until crystallization begins, 5.05 g of ACE serine methyl ester (= 82.1 % of theory) of Pp 88 ^° C. obtained. l ° - -2.6 (c * 0.5; dimethylformamide).

- 18 -

909808/0085

For C ₂₅ H ₂₅ ClN ₂ O ₈

Calculated: C 58.09 X, H * », 87 X, Cl 6.86 X, N 5, ^ 2 X; found: C 58.05 X, H U _t Sk X, Cl 6.75 X, N 5, * »3 X.

The following can be produced in the same way: Example 2

N-ACE serine

ACE-NH-CH-COOH
CK ₂ -OH

nit L-serine; Mp. 133 ^° C., yield 70.8% of theory.

For C ₀₁₁ H ₀ , CIN-O « klf = +6.8 (c * 0.5; Dir.ethylform-

^{2112328 D} anid)

Calculated: C 57.32 %, H O, 61%, Cl 7.05 S, N 5.57 Sj found: C 57.22 X, HU, 59 S, Cl 7.22 ?, N 5.51 X.

example
K-ACE methionine

ACE-NH-CH-COOH

CH ₂ -CH ₂ -S-CH ₃

Mp. 165 ° C, yield 70.1% of theory, [ocj ²⁰ r -0.8 (c * 0.5; for C ₂₆ H ₂₇ ClN ₃ O ₇ S dimethylformamide

Calculated: C 57.09 X, HU, 97 X, Cl 6, M8 X, N 5.12 X, S 5.86 Xj found: C 57.26 X, H 5.01 X, Cl 6.7 * X , N 5.2U X, S 5.97 X.

Example 4

N-ACE tyrosine

ACE-NH-CH-COOH
CH.

Pp. IiI ⁰ C, yield 3 ¹ », 7% of theory.

* * ⁷ » ^{3 (c} " ° »5i DinethyIfornanid) - 19 -

909808/0085

calculated: C 62.23 %, HU, 70 *, Cl 6.12 *, Ν «1.81 *; found: C 62.33 *, HH, 70 *, Cl 6.00 *, N »», 78 t.

Example 5

X-ACE tryptophan

ACE-NK-CH-COOH

CH

sinters at 12O-15O ^q C, yield 65.3 % of theory.

For ΰ ,, Η-, οΰΙΝ, Ο, U] n ° = ♦ 9, ¹ ^ (c = 0.5; Dir.ethylform-32 28 3 7 ^LJ D _anid)

calculated: C 63, BU t, H » , 69 %, Cl 5.89 ϊ, Ν 6.95; found: C 63.76 %, HU, 72X, Cl 5.82 Ϊ, N 6.9 " % .

Example 6 N-ACE-DL-threonine

ACE-NH-CH-COOH CH-OH
CH ₃

. Mp 119 ⁰ C, yield * »7% of Theorie.f * Cj§ ° = -0.8 (c = 0.5; for C ₂₅ H ₂₅ ClN ₂ O ₈ dimethylformamide)

calculated: C 58.09 %, HU, 87 %, Cl 6.86 %, N 5, ^ 2 Ϊ; found: C 57.96 %, HH, 8M * »Cl 6.77 ϊ, Ν 5.56 %.

Example 7
N-ACE-phenylalanine

ACE-NH-CH-COOH CH-,

Mp. 17 ° C., yield 57.8 % of theory. Md ° * * ^k ' ^{9 (c =} ° » ^{5i dim} ethylformamide)

- 20 -

^{TP 4} 909808/0085

calculated: C 6 »», 00%, H 4.83 %, Cl 6.30 ί, N 4.98 I; Found: C 64.14 *, H 4.83 *, Cl 6.28 *, N 5.06 *.

Example 8 K'ACE-Alenin

ACE-NH-CH-COOH CHj

Mp. IHO ⁰ C, yield 48 % of theory. [-C ^ ⁰ = -4.6 (c = 0.5; Fa- CM 'ei N 0 Dinethylforr.ar.id)

Calculated: C 59.20 *, H 4.76 %, Cl 7.28 S, N 5.76 %; found: C 59.32 *, H 1.83 *, Cl 7.15 % » N 5.73 t.

example 9 N-ACE phenylglyein

ACE-NH-CH-COOH

Mp. 179-182 ° C. _t yield 57.6 % of theory. fc / fe ⁰ - * 6l, 8

For C ₂₉ H ₂₅ ClN ₂ O ₇ (cs 0.5; dimethylformamide

Calculated: C 63.45 %, H 4.59 t, Cl 6.46 *, N 5.10 S; found: C 63.6l *, H 4.57 *, Cl 6.44 I , N 5.03 X.

Example 10

N-ACE-DL-O-methylserine

ACE-NH-CH-COOH

CH ₂ -O-CH ₃

Mp. 96 ° C., yield 39 % of theory. [* ϋη ° * ° (c * 0.5; Di-

For C ₂₅ H ₂₅ ClN ₂ O ₈ methyl foreanide)

Calculated: C 58.09 *, H 4.87 *, Cl 6.86 S, N 5.42;

found: C 57.89 *, H 4.91 f, Cl 6.74 *, N 5.46.

TP 4 - 21 -

909808/0085

K-ACE-DL-Serir.r.ethylar.id

ACE-NH-CH-CONH-CH CH -OH

² - -20.

Mp. IHl ⁰ C, yield »» 2.3 % of theory. Mi - * 3.2 (c «0.5;

rM ^ "",., _Λ dimethylformamide)

For C ₂₅ H ₂₆ ClH ₃ O ₇

Calculated: C 58.20 *, H 5.08 J, Cl 6.87 <"N 8.1"*; found: C 58.19 S, H 5.16 *, Cl 6.85 %, N 8.13 f.

Example 12 ACE-2, h, 5-trichlorophenyl ester

ACE-O

2 g (0.0051 mol) ACE-OH and 1 g (0.0051 mol) 2, t, 5-trichlorophenol are dissolved in 25 ml tetrahydrofuran with 1 g (0.0Ct8: * ol) dicyclohexylcarbodiir.id added and stirred for 1 1/2 hours at room temperature. Then the precipitated dicyclohexyl resin is suctioned off, the solution is removed and triturated with 20 nl of ethanol. When the crystallization is complete, the mixture is filtered off with suction and the crystal pulp is washed with ethanol and petroleum ether. Mp. 132-13 ^ ⁰ C, yield 2.3 g ^s 80, U % of theory.

It is an intermediate for the preparation of the following compounds.

Example 13 K-ACE histidine r. Ethyl ester

ACE-NH-CH-COOCH, CH ₂

TP 4 - 22 -

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4.86 s (0.02 mol) of L-Histidinnethylesterdihydrochlorid u: id 8.3 nl (0.06 koi) Triäthylanin are dissolved in 100 rl dimethylformamide and at -10 ⁰ C with 5.67 g (0.02 mol) the compound described in the example is added, after stirring and standing at room temperature, the mixture is diluted with water and extracted several times with ethylene chloride. The ethylene chloride solution is shaken out with r.HCl and washed neutral with water. The organic phase is then _{dried over Na 2} SO ₁₄ , filtered and purified. The Hückstar.d is purified on silica gel in chloroform / Xethar.ol (9: 1). Mp. 119 ° C., yield 3.7 g = 3 * 2 of theory.

For C ₂₈ H ₂₇ Cl ^ O ₇ Wd ° ⁼ * ³ ' ^{5 (c = 3} '^5; 3ir.ethylforir.ar.id)

Calculated: C 59.31 %, H U-, 80%, Cl 6.25%, N 9.89%; found: C 59.37 ί, H 5.01 %, Cl 6, 18 ί, Ü 9.82 %.

example N-ACE serine benzyl ester

ACE-NH-CH-COOCH CH ₂ -OH

analogous to Example 13 using L-serine benzyl ester. Mp. 158-159 ° C, \ j ° t \ l ° = 10.9 ° (cs 0.5; ·. Dinethylfornamide) Yield 67 % of theory. For C ₃₁ H ₂₉ ClN ₂ O ₈

Calculated: C 62.78 %, HH, 93 %> Cl 5.98 *, N H.72 S; found: C 62.93 %, H 5.01 %, Cl 6.15 S, N 4.72 t.

example 15th

O-ACE-M-Boc-Serine R. ethyl ! ester

ACE-O-CH5-CH-COOCH, ^c « j

NH CH ₃

COO-C-CH,

CH ₃

4 »15 g (0.01 mol) of ACE-OH are dissolved in 15 ml of tetrahydrofuran dissolved, 1.78 g (0.011 mol)!,! »- carbodiinidazole were added and stirred until the evolution of COg has ceased.

TP 4 - 23 -

0O98O8 / OO8S

BATH ORIGINAL

A solution of 2.25 g (0.01 mol) of N-Boc-serine methyl ester in 10 ml of tetrahydrofuran in the presence of catalytic amounts of sodium hydride is added to this solution and stirred at 35 ° C for 7 hours. Then the Solution evaporated at 3 Torr, the residue is taken up in ethyl acetate and purified on silica gel. The compound is an oil. Yield 5.1 g (= 82% of theory).

Example 16 O-ACZ Serir.r. ethyl ester trifluoroacetate

ACE-O-CK ₂ -Ch-COOCH ₃ . ρ CC ₀₀₁₅

KH ₂ ⁵

The compound is formed in a known manner by adding trifluoroacetic acid to the compound from Example 15. Mp. 69 ° -70 ° C., yield 65% of theory.

° ₌ «.0.3 (c = 0.5; Dir.ethylforr.ar.id)

For C ₂₅ H ₂₅ ClN ₂ O ₈ · C ₂ HF ₃ O ₂

Calculated: C 51, * 0 X ₁ H ft, 15 *, Cl 5.62 *, P 9.03?, NU ₁ IU * ', found: C 51.52 %, HU, 22%. Cl 5.52 t, F 8.8 Ϊ, N ft, 5U

Example 17 O-ACE-N-Boc-Serine-Thvlester

ACE-O-CH ₂ -CH-COOC ₂ H ₅ NH CH ₃ COO-C-CH, CH ₃

analogous to example 15 from 10.15 g ACE-OH and 5.7 g Eoc-serine:

diethyl ester.

Mp. 99-10O ⁰ C, yield 6.2 g. (Raw product)

example l8

0 ACS serine ethy ! ester trifluoroacetate

ACE-O-CH ₂ -CH-COOC ₂ H ₅ • P ₃ CCOOH NH ₂

TP 4 - 24 -

«09808/0085

Analogously to example 16 from the compound described in example 17.

M.p. 56-8 ° C, ["^ Jd ^{0 =} ~ ² * ^{k (c} ' ° ^t5; Dinethylforr.anid); Yield · 77 % of theory.
For C ₂₆ H ₂

calculated: 52.11 I, H 1.33 f, Cl 5.50 *, F 8.81 *, M 1.31 X found: 52.21 *, H 1.36 ί, Cl 6.30 Ϊ, F 8.63 %, N 1.37 ί

example 19th

N-ACZ -? :: er.ylalar.yltyrosinr.e thy! Ester

0 0

ACE-MH-CH-C-NH-CH-C-OCh ₁ CH-

A suspension of 0.005 mole in 15 ml of absolute Phenylalanyltyrosinr.ethylestertrifluoracetat Dimethylforr.ar.id with stirring at 0 ⁰ C 0,005 nit first XOI Triäthylar.in and r.ach 10 minutes nit 0.005 mol ACE-2,1,5-trichlorophenyl ester are added . After two hours of stirring, finally at room temperature, the reaction mixture is mixed with 150 ml of water, extracted three times with ethyl acetate and the organic phase is extracted three times with nHCl solution. The solution is then washed neutral with water _{, dried over Na 2} SO ₁ and evaporated. After recrystallization from acetone / petroleum ether, 81 % of theory of N-ACE-phenylalanyltyrosine methyl ester of melting point 131-132 ° C. is obtained.

* Cj3 ° ^s -5.2 ° (c - 0.5; dimethylformamide). For C ₁ J ₃ H ₃₈ ClN ₃ O ₉

Calculated: C 61.90 J, H 5.17 *, Cl, H, 79 *, N 5.68 S; found: C 61.87 t, H 5.36 %, Cl 5.20 ί, Ν 5.63 %.

TP 4 - 25 -

909808/0085

Example 20

ACE-G Iy oyl al ar.y! Phenylalanine thy le st er

0 OO

ACE-HH-CH ₁₅ -CO-NH-CH-C-NH-Ch-C-OCH

CH ₃ CH ₂

analogous to example 19 with glycylalanylphenylalarine. ethyl ester hydrochiorid ,; Mp 1.5-1.7 ° C (from isopropanol); | ° = -7.2 ° (c = 0.5; Dir.ethylfornar.id);

Austeut- »83 ί of theory. For C y'i Cl * J O

calculated: C 61.32 S, H 5.29 *, Cl 5.03 *, N 7.95 % i found: C 60.82 % _t H 5.38 %, Cl 5.19 Ϊ, N 8.32 %.

Example 21

a) N ^ -Forryl-'jy-benzyloxycarbonyldiaminobutyry! phenyl = alarir.hydrazid

53 g (C, 12 mol) of N-formyl-N ^ ^ = -benzyloxycarbonyldiaT.inobutyryl be phenylalaninnethylester Urd ^ dissolved at ⁰ ° C. in 1 * 00 rl methanol nit 10 g (about 0.16 mol) of hydrazine hydrate 80 Xigem After standing at room temperature for 2 hours, the precipitate is filtered off with suction, the mother liquor is concentrated to 50 ml and crystallized again. Mp. 205-2O7 ° C (from aqueous dimethylformamide); Yield 50 g * 91 ί of theory;

I " -11.5 ° (c * 2; dimethylfornamide). For C ₂₂ H ₂₇ N ₅ O ₅

Calculated: C 62.57 %, H 6.17 J, N 9.52 J; found: C 62.16 *, H 6.15 %, N 9.65 %.

TP 4 - 26 -

909808/0085

BATH ORIGINAL

b) N ^ -FDrryl-ü ^ -benzyloxycarbonyldiar.lnobutyrYlPhenylal.anylg

pher.ylalanir.rethy! ester

88.3 g: o, 2 !! oil) of the compound described under a) above are dissolved in 1000 Erwärr.en nl dime thy If orr.ar.id r.it and 20 nl of glacial acetic acid and i »00 ml nKCl verr .ish. laughing cooling to -10 ⁰ C! are first slowly IU, U g (0.208 KOI) Katriur.iitrit in 60 nl of water and then a superiors. A cooled solution of 35.8 g (0.02 mol) of L-phenylalanir.r.ethyl ester * hydrochloride, dissolved in 200 ml of dimethylformamide, was added. The Pea ^ tionslösur.g is neutral to be about 5 ¹ »g Triäthylar.in and stored 2k hours. In the fridge!. 'Oh slurring r.it double amount of water, the precipitated precipitate filtered off, nit η hydrochloric acid and water, dried and recrystallized from "ethanol. Mp. 179-181 ° C., Mp ° = -22.5 ° (c = 2; dimethylformamide); yield 108 g - 92 % of theory.
For C ₃₂ K ₃₆ M ₁₁ O ₇

Calculated: C 65.29 *, H 6.16 t, N 9.52 %; found: C 65.26 %, H 6.33 %, N 9.6l t.

c)? J ^ -3enzyloxycarbonyldianinobutyrylphenylalanylphenyls alanine methyl ester hydrochloride

52 g of 0.0885 WoI) of the compound described above under b) are suspended in 150 ml of methanol and 35 ml of ethanolic HCl and stirred for 20 hours at room temperature. The nowir.ehr clear solution is evaporated and the residue is recrystallized from methanol / ether.
Mp 220-222 ° C., yield 29 g (5U of theory). P ° s +1.65 (c * 2; dimethylformamide)

For C ₃₁ H ₃₇ ClN ₁₁ O ₆ · 1/2 H ₂ O

Calculated: C 61.26 S, H 6.32 S, Cl 5.85 S. N 9.32 % found: C 61.26 *, H 6.60 S, Cl 5.53 S ₉ N 9.27 *.

TP A - 27 -

909808/0085

273553?

d) N ^ ACg-iiy-genzyloxycarbonyldlaninobutyrylPhenylalanyli pher.ylalanirrethyles ter

0 CH ₂ CH ₂

AOE-NH-CH-C-NH-CK-C-NH-CH-C-O-CH,

^CH 2 ° ° CH ₀ -NH-CO-CH - ^ 0

analogously to Example 19 from the compound described above under c) and ACE-2, ¹ », 5-trichlorophenyl ester.

Mp 22-227 ° C. (from dioxane / Xther 2: 1); Yield 69 % of theory,

° - -20.6 (cs 0.5; dimethylfornamide) For C ₅ -H ₅

Calculated: C 65.16 %, H 5, * 7 *, Cl 3.70 J, K 7.31 J; found: C 6K, 72 t, H 5.63 *, Cl 3.96 *, N 7.17 f.

- 28 -

909808/0085

Claims (5)

Claims 1) Indolylacetoxyacetylaminoacetic acid derivatives of the general formula 0 0 0 0 0 H ₂ -CO-CH ₂ -CX-CH-C- [-ilH-CH-C ^ j - [jKK-CH-C ··] - ^r 'R ⁿ R ₂ (D in which m and η stand for the digits 0 or 1, X stands for an -NH- or -OCHj group, R ₁ , R ₂ and R can be identical or different and are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted one Aryl group, an optionally substituted aralkyl group, an optionally substituted Heterocyclusmethylgruppe with 1 or 2 rings and each with 5, 6 or 7 ring members, in which 1 or 2 members can be replaced by heteroatoms, and in the event that m and η for the Digit O,
R _{1 stands} for an amino group, an alkoxycarbonyl group TP 4 - 29 - 909808/0085 if or an aralkoxycarbonyl group ^stent »27 35 5 37 R _{4 represents} a hydroxyl group or an optionally substituted alkoxy group, an optionally substituted aralkoxy group, an amino group or an optionally substituted alkylamino group, an optionally substituted aralkylamino group, an optionally substituted arylamino group, and their physiologically compatible salts, if appropriate formed with acids and bases. 2) Process for the preparation of Indolylacetoxyacetylaminoessiqäure derivatives according to claim 1, characterized in that one a) [\ - (4-Chlorobenzoyl) -S-methoxy-Z-methyl-S-indolyl-acetoxyacetic acid (hereinafter referred to as ACE-OH) with chloranic acid esters of the general formula 0 Cl-COR ₅ (II), in which Rr stands for an alkyl group, to mixed anhydrides of the general formula 0 0 0 H ₂ -CO-CH ₂ -COCOR ₅ 3 (HD » TP 4 - 30 - 90Ö30Ö / 008 5 R- has the meaning given above, converts and these with compounds of the general formula 0 _ 0 0 H ₅ N-CH-C-I-KH-CH-CI-f-NH-CH-C-1 -R ₁ . (IV), ² ' ^L '"" in ¹ - _R ^J n ^H R ₁ R ₂ Rj in which m, n, R ₁ to R _{4 have} the meaning given above, to react or b) the compound ACE-OH with an appropriately substituted phenol to form an activated ester of the general Form1 0 0. . ^ Y -C-O-CH.-C-o / v O (V), in which Y for 2 to 5 halogen atoms, 1 to 2 nitro groups or for several other electron-attracting ones Groups stands, condensed and with compounds of the general formula (IV), in which m, n, R ₁ to R _{4 have} the meaning given above, or reacts TP h - 31 - c) in the event that amino acid derivatives containing hydroxyl groups To be linked ester-like, the compound ACE-OH with compounds of the general formula HO-CH ₂ -CK-SR ₁ ,
KH »6
in which R ₄ has the meaning given above and R ^ group is a conventional amino protection in peptide chemistry, for example, an alkoxycarbonyl or an aralkoxycarbonyl group, are reacted and then the remainder R ₄ is split off in a known manner and optionally the compounds of the general formula (I) thus obtained with acids and bases in the physiological compatible salts. 3) Medicinal products containing at least one indolylacetoxyacetylaminoacetic acid derivative according to claim 1. 4) Process for the production of pharmaceuticals, characterized in that that one indolylacetoxyacetylaminoacetic acid derivatives according to claim 1 mixed with inert, non-toxic, pharmaceutically suitable carriers. 5) Use of indolylacetoxyacetylaminoacetic acid derivatives for the treatment of inflammation and rheumatic diseases. TP 4 - 32 - 909808/0085