NO792590L - ALFA-aminophenylacetic acid. - Google Patents

Abstract

1. Alpha-Aminophenylacetic acid derivatives of the general formula see diagramm : EP0011092,P18,F1 in which R**1 represents hydroxy or alkoxy with 1 to 4 carbon atoms, R**2 represents hydrogen, alkyl with 1 to 4 carbon atoms, trifluoromethyl or halogen, R**3 and R**4 are identical or different and in each case represent hydrogen, allyl or alkyl with up to 4 carbon atoms, the alkyl radicals being optionally substituted by amino, cyano or alkoxy with 1 to 2 carbon atoms or R**3 and R**4 together with the nitrogen atom form a 5-membered to 7-membered aliphatic ring, which can optionally be saturated or unsaturated and which can contain one oxygen atom, one sulphur atom, one SO grouping, one SO2 grouping or one N-R''' grouping, wherein R''' represents hydrogen, alkyl with 1 to 2 carbon atoms or methoxyethyl,or together with the nitrogen atom form a triacolyl radical. R**5 represents hydrogen or alkyl with 1 to 4 carbon atoms and R**6 represents hydrogen or alkyl with 1 to 2 carbon atoms, and pharmacologically acceptable salts thereof, for use in the treatment of inflammatory diseases.

Description

The present invention relates to &-aminophenylacetic acid derivatives, a method for their production and their use as medicine, especially as antiphlogistics.

It is previously known that phenylacetic acid derivatives have pharmacological effects. In US Patents 3,692,819, 3,767,800, 3,766,260, 3,868,391, 3,936,467, 3-997,669; in British patent 1,299,172 and in Dutch patent NE 68, 10359, phenylacetic acid derivatives are described which, among other things, have anti-inflammatory and antipyretic properties. Corresponding amino acid derivatives are not known to date.

The present invention relates to new cfc-aminophenylacetic acid derivatives with the general formula I

in which

R stands for hydroxy, alkoxy, amino acid ester (peptidyl)

or the rest

in which R' and R" are the same or different and stand for hydrogen or alkyl,

R 2 stands for hydrogen, alkyl, trifluoromethyl, halogen, alkoxy,

hydroxyl, cyano or alkyl mercapto,

3 4

R and R are the same or different and stand for hydrogen,

alkyl or alkenyl, whereby the alkyl residues are optionally substituted with hydroxyl, mercapto, amino, cyano, alkoxy, alkyl mercapto, carboxyl or sulfo (-SO^H)

or

3 4

R and R together with the nitrogen atom form a 5- to 7-membered ring which can contain as an additional heteroatom oxygen, sulphur, 2 nitrogen atoms (as triazole), 3 nitrogen atoms (as tetrazole), a

wherein R"' means one or two oxygen atoms or alkyl

and R"" means alkyl, alkenyl or alkoxyalkyl,

R stands for hydrogen, alkyl or acyl

and

R<6> stands for hydrogen, alkyl, NC-CH2-, H^COOC-CR^-, H^CO-CR^-or H^CS-Ct^-.

With regard to the seriality center C, the compounds according to the invention can exist in both possible R(D) and S(L) configurations and as racemic mixtures (DL).

It is known that substances from the indole series have strong antiphlogistic and antipyretic properties. However, these known antiphlogistics have the disadvantage that they either show unwanted side effects or have only a small therapeutic activity and therefore have to be administered in large quantities. The compounds according to the invention show, in addition to a strong therapeutic activity, only very minor side effects and therefore constitute an enrichment of the pharmacy.

The method according to the invention for the production of new ot,-aminophenylacetic acid derivatives of formula I is carried out by reacting substituted benzaldehyde derivatives of formula II

in which

R , R and R have the meaning given above,

with sodium cyanide and ammonium carbonate to hydantoin derivatives of the general formula III

and then hydrolyze these to corresponding amino acids with the general formula I and then esterify or amidate the carboxyl group and in a manner known per se and/or acylate the amino group. The conversion of the hydantoin compounds of the general formula III to the α-aminophenylacetic acid compounds of formula I is carried out in a manner known per se by acidic or alkaline hydrolysis.

The compounds according to the invention exist in stereoisomeric forms. The antipodes as well as the racemate forms and the diastereomer mixture are the subject of the present invention. The racemates can be separated in the same way as the diastereomers in the known manner into stereoisomerically uniform constituents (compare E.L. Eliel, Stereochemistry of Carbon Compounds, Mc Graw Hill, 1962).

Depending on the nature of the starting materials used, the synthesis of the compounds according to the invention can, for example, be represented by the following formula core:

The aldehydes of the general formula II used as starting materials are known or can be prepared according to known methods, reacting e.g. correspondingly substituted aniline derivatives according to Vilsmeier with phosphorus oxychloride and dimethylformamide to aldehydes (cf. G.A. Olah et al, Priedel-Crafts and Related Reactions, vol. III, part 2, 1153-1256). Furthermore, the compounds of formula II can be obtained by varying the corresponding aminobenzaldehydes in a manner known per se to the amine function.

All inert organic solvents, water and mixtures thereof come into consideration as diluents in the method according to the invention. These preferably include alcohols such as methanol, ethanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether or dimethylformamide, dimethyl sulfoxide and acetonitrile.

The reaction temperatures can be varied over a larger range. In general, you work between 10 and 120°C, preferably in the range between 25 and 100°C.

When carrying out the method according to the invention, sodium cyanide and ammonium carbonate are preferably reacted in excess with the aldehyde of formula II. It is particularly advantageous to use these reactants in

about. 2- to 5-fold profit.

Of particular interest are the compounds according to the invention with the general formula I in which R<1> stands for hydroxy, alkoxy with 1-4 carbon atoms, amino acid residues or the residue

whereby R' and R" are the same or different and stand for hydrogen or alkyl with 1-4 carbon atoms,

R stands for hydrogen, alkyl with 1-4 carbon atoms, trifluoromethyl, halogen, especially fluorine, chlorine or bromine, alkoxy with 1-4 carbon atoms, hydroxyl, cyano or alkyl mercapto with 1-4 carbon atoms,

R 3 and R 4 are the same or different and stand for hydrogen, alkyl or alkenyl with up to 4 carbon atoms, whereby the alkyl residues are optionally substituted with hydroxy, mercapto, amino, cyano, alkoxy or alkylmercapto with 1-4 carbon atoms

or

3 4

R and R together with nitrogen atoms form a 5- to 7-membered ring, which may be saturated or unsaturated and may contain an oxygen atom, a sulfur atom, an SO group, an SOg group, one or two CO groups, an N-R "'-grouping, whereby R"' stands for hydrogen, alkyl or

nyl with up to 4 carbon atoms, or 1, 2 or 3 nitrogen atoms,

R stands for hydrogen, alkyl with 1-4 carbon atoms or acyl,

whereby in the acyl group CO-R"" the substituent R"" stands for alkyl with 1-4 carbon atoms, aralkyl, especially benzyl, or for the remainder

and

R stands for hydrogen or alkyl with 1-4 carbon atoms, whereby the alkyl group is optionally substituted with cyano, alkoxy, alkylmercapto with 1-2 carbon atoms or with carbo- alkoxy with 1-2 carbon atoms in the alkoxy group,

as well as their pharmaceutically acceptable salts.

In addition to the embodiment examples specified below, the following compounds according to the invention must be specified, for example:

DL-α-amino-(X-[4-(3,5-diketo-1,4-thiazanyl)phenyl]acetic acid DL-α-amino-ot-[4-(4-methyl-piperazine-3 ,5-dion-l-yl)phenyl]-acetic acid DL-oc-amino-ot-L2-chloro-4-(piperazin-2-on-l-yl)phenylacetic acid DL-oL-amino-oc- L4-(1,4-thiazinyl)phenyl]acetic acid DL-øO-amino-cC-(4-thiomorpholino-2-methyl-phenyl)acetic acid • DL-α-amino-cv (4-thiomorpholino-2-methoxyphenyl )acetic acid DL-α-amino-(4-thiomorph olino-2-chlorophenyl)acetic acid

4-thiomorpholino-&-methylphenylglycine DL-α^amino-oo-(,4-(1 ,2 ,3,4-tetrazol-1-yl)phenyl]acetic acid DL-tx-amino-α-t 4-(4- methoxy-2H-1,2,3-triazolyl-2)phenyl]-acetic acid

DL-α-amino-α-{_4-bis(fl-sulfoethyl)aminophenyl]acetic acid

The new active substances can be used in and of themselves

known manner is transferred to preparations such as tablets, capsules, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutical suitable carriers or solvents. Hereby, the therapeutic active compound must be present in a concentration of approx. 0.1 to 95

% by weight, in particular from 0.5 to 90% by weight, of the total mixture, i.e. in amounts sufficient to achieve the indicated dosage spiHerom.

The preparations are, for example, prepared by diluting the active substance with solvents and/or carriers, possibly using emulsifiers and/or dispersants, whereby e.g. in the case of using water as diluent, organic solvents can optionally be used as auxiliary solvents.

For example, the following must be stated as excipients:

Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut/sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol , polyethylene glycol), solid carriers such as e.g. natural stone flour (e.g. kaolin, clay, talc, chalk), synthetic stone flour (e.g. highly dispersed silicic acid, silicates), sugar (e.g. raw, milk and grape sugar), emulsifiers, such as non-ionic anionic emulsifiers (e.g. polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, alkyl sulphonates and aryl sulphonates), dispersants (e.g. lignin, sulphite leachate, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate) , talc, stearic acid and sodium lauryl sulfate).

Administration is usually carried out orally or parenterally, especially perlingually, intravenously or intramuscularly. In the case of oral use, the tablets naturally contain, in addition to the aforementioned carriers, additional substances such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatins and the like.

Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for the production of

the tablets. In the event that aqueous suspensions and/or elixirs are intended for oral use, active substances can be added in addition to the auxiliaries mentioned above with various taste-improving substances or dyes. In case of parenteral application, the solutions of the active substances can be added to liquid carrier materials.

In general, it has been shown to be advantageous for intravenous administration to give approx. 0.001 to 10 mg/kg, preferably approx. 0.05 to 5 mg/kg body weight per day to achieve the desired result and for oral administration the dosage is approx. 0.01 to 20 mg/kg, preferably 0.1 to 5 mg/kg body weight

weight per day.

In spite of this, it may be necessary to deviate from the specified amounts, depending on the body weight of the experimental animal or the nature of the administration, but also because of the species of animal and their individual relationship to the drug or the nature of the preparations and the time respectively the interval at which the administration takes place. Thus, in some cases it may be sufficient to use less than the minimum amount stated above, while in some other cases the upper limit stated above must be exceeded. In the case of administration of larger amounts, it may be recommended to distribute these in several single doses over the day. For administration in human medicine, the same dosage leeway is assumed. In the same way, the above-mentioned designs also apply.

Example 1

a) DL-α-amino-OC-[4-(tetrahydro-1,4-thiazinyl)phenyl]acetic acid or DL-α-amino-OL-(4-thiomorpholino-phenyl)acetic acid. 105 g (0.378 mol) of 5~[4-(tetrahydro-1,4-thiazinyl)-phenyl]-2,4-imidazolidinedione is heated in 720 ml of 10% caustic soda at 100°C for 20 hours with stirring. The mixture is cooled to 0°C, acidified with concentrated hydrochloric acid to pH 1 and then stirred for a further 10 minutes. Then the resolution becomes adjusted to a pH of 5.0 with 4N NaOH under ice cooling. The light yellow precipitated material is filtered off and washed thoroughly with water. After drying at 50°C, 90 g of crude product is obtained, which is taken up twice in boiling ethanol, then filtered off and washed with ether.

Yield: 84.5 g (83%).

<C>12<H>16N2°2S*H2° (270.3)

Calculated C 53.32 H 6.71 N 10.37 S 11.88

Found C 54.4 H 6.2 N 10.7 S 12.1

<1>H-NMR (DCOOD, 60 MHz) : 6 = 3.10-3.25 (m, 3"CH2, 5-CH"2, thiazine), 3.90-4.06 (m, 2- CH" 2 , 6-CR" 2 , thiazine), 5.42 (s, OC-CH), 7.74 ppm (s, 4H, phenyl).

b) 5-[4-(tetrahydro-1,4-thiazinyl)phenyl]-2,4-imidazolidinedione 102 g (0.47 mol) 4-(thiomorpholino)benzaldehyde,

o dissolved in 1200 ml ethanol, is added dropwise to a suspension of 34.8 g (0.71 mol) sodium cyanide and 184 g (1.91 mol) ammonium carbonate in 1200 ml water in a 4 1 three-necked flask at 60°C and stirred for 30 hours at 60°C. From the one at the beginning

clear light green solution is precipitated overnight a bright material. After distillation of the ethanol in a vacuum, the residual solution is acidified with concentrated hydrochloric acid at pH 2. The suspended material thereby dissolves. The clear solution is stirred for 15 minutes and adjusted to pH 7 at 5°C with 4N NaOH. The precipitated material is filtered off and washed with water. The dry filtered off product is then taken up three times with ether, filtered off and dried at 60°C.

Raw yield: 185 g.

The crude product is taken up in 700 ml of hot ethanol, filtered off while hot and washed with ethanol.

Yield: 105 g (8l %).

<C>13<H>15N3°2S ^77.3)

Calculated C 56.31 H 5^5 N 15.15 S 11.56

Found C 56.4 H 5.8 N 15.5 S 11.4

<1>H-NMR ([Dg] DMSO, 60 MHz): cT = 2.63-2.72 (d, 3-CR"2, 5-CH"2, thiazine), 3.49-3.60 (d, 2-CH~2, 6-CH"2, thiazine), 5.03 (s, 5-H), 6.83-7.27 ppm (AA'BB' system, 4H).

Example 2

a) DL-α-amino-oL-[4-(1-oxo-thiomorpholin-4-yl)phenyl acetic acid

A solution of 2.7 g (0.01 mol) of DL-dz-amino-Ck-(4-thiomorpholinophenyl)acetic acid in 30 ml of IN hydrochloric acid is added to 11.3 ml (0.01 mol) of a 3% hydrogen peroxide solution and stored for 90 minutes at room temperature. After filtering out smaller amounts of undissolved parts, the solution is loaded onto an ion exchange column (Amberlite IR-120, H+-foamn). After neutral washing of the column with water, the product is eluted with 2N ammonia solution. The eluate becomes strong evaporated, added ethanol, filtered off, precipitated, washed with ether and dried. Yield 1.4 g. After concentration of the mother liquor and renewed precipitation with ethanol, a further 0.45 g of sulfoxide can be recovered.

Yield: 1.85 g (70%).

Melting point: 204°C

C12<H>l6<N>2°3S (268'3)

Calculated C 53.71 H 6.01 N 10.44 S 11.95

Found C 52.96 H 6.17 N 10.42 S 11.75

Example 3

a) DL-<%-amino-06-(4-thiomorpholinophenyl ).acetic acid-S. S-dioxide

162 g (0.524 mol) of 5-(4-thiomorpholinophenyl)-2,4-imidazolidinedione-S.S-dioxide is stirred in 1300 ml of 10% caustic soda for 40 hours at 100°C. After cooling to 0°C, the solution is acidified with concentrated hydrochloric acid to pH 2, then reset to pH 4.6 and, after a longer period of time, a precipitate is separated. The filtrate is evaporated to an approximate volume of 1 liter and 1500 ml of ethanol is added. The precipitated product is filtered off and washed with ethanol.

Yield: 167 g (112%, contains 24% sodium chloride).

C12Nl6N2°4S <284>3)

Calculated C 3§.5 H 4.3 N 7.5 S 8.57

Found C 37.6 H 4.3 N 7.3 S 7.9 Cl 14.6

<1>H-NMR'([Dg] DMSO, 100 MHz) : cf = 3.03-3.15 (m, 3-CR"2, 5-CR"2, thiomorpholine dioxide) , 3.65- 3.80 (m, 2-CH"2, 6-CH2, thiomorpholine dioxide), 6.87-6.99 (BB' system, 3-H, 5-H), 7.16-7.32 ppm (AA' system, 2ZH, 6-H).

b) 5-(4-thiomorpholinophenyl)-2,4-imidazolidinedione-S,S-dioxide

Analogously to Example 1, the corresponding hydantoin is prepared from 87.7 g (0.367 mol) of 4-thiomorpholino-benzaldehyde-S.S-dioxide, 26.8 g (0.546 mol) of sodium cyanide and 143 g (1.49 mol) of ammonium carbonate in 1100 ml of water and 1100 ml

ethanol.

Yield: 87 g (77%)

C13H15N3°4S (309.3)

Calculated C 50.48 N 4.89 N 13.58 S 10.37

Found C 49.4 H 5.0 N 13.9 S 10.0

<1>H-NMR ([D^DMSO, 60 MHz) : δ = 2.95"3.30 (m, 3"CH2, 5"CH2, thiomorpholine dioxide) , 3.62-3.95 (m , 2-CH2, 6-CH"2, thiomorph or in-dioxide), 7.05 (d, J = 8.4 Hz, 3-H, 5-H), 7.3 ppm (d, J =

8.4 Hz, 2-H, 6-H).

Example 4

a) DL-oC-amino-(X-[2-chloro-4-(1-piperazinyl)phenyl]acetic acid

Through a suspension of 20 g of finely divided palladium in 350 ml of methanol, in which the sodium salt of 19.5 g (0.0362 mol) of DL-06-benzyloxycarbonylamino-α-2-chloro-4-[4-(benzyl- oxycarbonyl)-1-piperazinyl]phenyl|acetic acid is dissolved, hydrogen is allowed to flow for 3 hours. The catalyst is then separated, washed with methanol and the filtrate evaporated in vacuo to dryness.

Yield: 9.6 g (86%). ■

<C>12H15C1N3Na02'H2° (309.7)

Calculated C 46.54 H 5.54 N 13.56 Cl 11.45

Found C 46.9 H 5.6 N 11.7 Cl 11.5

<1>H-NMR (NaOD, 60 MHz): £ = 2.67-3.18 (broad s, 8H, piperazinyl), 4.32 (s, ot-CH), 7.03 (d, J = 8.4 Hz, 3-H, 5-H), 7.37 ppm (d, J = 8.4 Hz, 6-H).

b ) DL-<X-benzyloxycarbaylJ:amino-ct-{2-chloro-4-[4-(benzyl-oxycarbonyl)-1-piperzinyl]phenyl-acetic acid

^5.0 g (0.167 mol) of DL-<X-amino-<X-[2-chloro-4-(1-piperazinyl)phenyl]acetic acid is dissolved in 200 ml of water and adjusted to a pH value of 8, 8-9.0 with 2N NaOH. The clear solution is cooled to 0 to 5°C and in the course of 50 minutes 6l ml (0.401 mol) of chloroformic acid benzyl ester is added dropwise with the simultaneous addition of 1N NaOH. After a short time a greasy suspension is formed which, after further addition of 200 to 300 ml of 2N NaOH, is converted into a clear dark red colored solution. Now the rest of the chloroformic acid benzyl ester is added dropwise at 5°C and left to stir overnight. The reaction solution is then extracted once with 600 ml of ether, the aqueous phase containing an oily layer is separated, acidified with concentrated hydrochloric acid by ice-cooling to pH 2 and extracted with ethyl acetate. After washing with water, drying with sodium sulfate and evaporation of the organic phase, 66.9 g (74%) of benzyloxycarbonyl-protected amino acid is obtained.

C28H2gClN3O6(538.0)

Calculated C 62.51 H 5.25 N 7.8l Cl 6.59

Found C 63.6 H 5.4 N 7.1 Cl 6.1

<1>H-NMR (CDCl 2 , 60 MHz): 2.85 - 3.22 (broad s, 2-CH 2 , 6-CH 2 , piperazinyl), 3.40-3.71 (broad s, 3-CH 2 , 5~CH2, piperazinyl), 4.6 (s, oi-CH), 5.04 (s, benzyl-CH2), 5.13 (s, benzyl-CH2), 6.76-7.50 ppm ( wide m, 13H, phenyl).

c) DL-o-amino-(X-[2-chloro-4-(1-piperazinyl)phenylacetic acid

67.1 g (0.229 mol) of 5-[2-chloro-4-(1-piperazinyl)-phenyl]-2,4-imidazolidinedione is heated in 750 ml of 48% hydrogen bromide solution for 48 hours under reflux. The solution is then evaporated in vacuo to dryness, the residue dissolved in 150 ml of water and adjusted with 2N NaOH to a pH value of 4.5. The aqueous phase is added approx. 4 1 ethanol, thereby

the amino acid is partially formed in the form of a paste.

Yield: 38.1 g (62%)

A further 95.7 g of substance is isolated from the filtrate.

<1>H-NMR (NaOD, 60 MHz): δ = 2.94 (broad s, 8H, piperazinyl), 4.66 (s, OC-CH), 6.97 (d, J = 8.4 Hz , 3-H, 5-H), 7.33 ppm (d, J = 8.4 Hz, 6-H).

d) 5-[2-chloro-4-(1-piperazinyl)phenyl]-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

from 99.6 g (0.384 mol) 2-chloro-4-(1-piperazinyl)benzaldehyde • hydrochloride, 28.2 g (0.576 mol) sodium cyanide and 312 g (3.26 mol) ammonium carbonate in 600 ml water and 500 ml methanol. Yield: 1st fraction 33.7 g (30%)

2nd fraction 34.4 g (31%)

C13H14C1N402(293.7)

Calculated C 53.16 H 4.8l N 19.08 Cl 12.07

Found C 52.5 H 5.4 N 16.6 Cl 14.4

<1>H-NMR ([Dg]DMSO, 60 MHz): cT = 2.84-3.50 (broad m, 8H, piperazinyl), 5.21 (s, 5-H), 6.93-7 .41 ppm (m, 3H, phenyl).

The 2-chloro-4-(1-piperazinyl)benzaldehyde is prepared according to a method by D. Rosi et al., J. Med. Chem. 10, 877-880 (1967).

Example 5

a) DL-o-amino-QÉ-(4-pyrrolidino-phenyl)acetic acid

From 63.5 g (0.259 mol) of 5-(4-pyrrolidino-phenyl)-2,4-imidazolidinedione, the new phenylglycine derivative is prepared analogously to example 1.

Yield: 22.3 g (37%)

<C>12<H>l6N2°2(220>3)

Calculated C 65.43 H 7.32 N 12.71

Found C 64.8 H 7.2 N 12.8

^■H-NMR (NaOD/D 2 O): δ = 1.75-2.08 (m, 3"CH 2 , 4-CH 2 , pyrrolidine), 3.0-3.34 (m, 2-CH" 2 , 5-CH2, pyrrolidine), 4.32 (s, O^CH), 6.74 (d, J = 8.3 Hz, 3-H, 5-H), 7.36 ppm (d, J = 8 ,3 Hz, 2-H, 6-H).

b) 5-(4-pyrrolidino-phenyl)-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

of 130.4 g (0.745 mol) p-pyrrolidinobenzaldehyde, 55 g (1.12 mol) sodium cyanide and 287 g (2.99 mol) ammonium carbonate.

Yield: 127.4 g (74%)

C13H15N3°2 <245.3)

Calculated C 63.65 H 6.16 N 17.13

Found C 62.8 H 6.2 N 16.7

<1>H-NMR ([Dg]DMSO, 60 MHz): & = 1.79-2.09 (m, 3"CH2, 4-CH2, pyrrolidino), 3.07-3.36 (m, 2 -CH2, 5"CH2, pyrrolidino), 4.99 (s, 5-H), 6.53 (d, J = 8.3 Hz, 3-H, 5-H), 7.10 ppm (d, J in 8.3 Hz, 2-H, 6-H).

N-phenylpyrrolidine and p-pyrrolidinobenzaldehyde are prepared according to regulations from Brevet d'Invention No. 616,609 (18.4.1962) to the Wellcome Foundation Lmt.

Example 6

a) DL-OC-amino-α-(4-piperidino-phenyl)acetic acid From 76.5 g (0.295 mol) of 5-(4-piperidino-phenyl)-2,4-imidazolidinedione, analogously to example 1, the new p-piperidinophenylglycine.

Yield: 51 g (64%)

<C>13<H>l8N2°2'2H2° (270>3)

Calculated C 57.77 H 8.20 N 10.37

Found C 56.8 H 6.8 N 10.3

<1>H-NMR (DCOOD, 60 MHz): δ = 1.65-2.34 (m, 3"CH2, 4-CH2, 5~CH2, piperidino), 3.61-3.92 (m, 2-CH 2 , 6-CH 2 , piperidino), 5.49 (s, rtrCH), 7.86 ppm (s, 4H, phenyl).

b) 5-(4-piperidino-phenyl)-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

of 80 g (0.423 mol) of p-piperidine benzaldehyde, 31 g (0.633 mol) of sodium cyanide and 164 g (1.71 mol) of ammonium carbonate.

Yield: 78 g (72%)

Cl4H17N3°2 (259>3)

Calculated C 64.85 H 6.6l N 16.20

Found C 64.5 H 6.6 N 16.2

H-NMR ([Dg] DMSO, 60 MHz): δ = 1.60 (broad s, 3"CH2, 4-CH2, 5-CH2, piperidino), 3.02-3.31 (m, 2-CH2 , 6-CH2, piperidino), 5.05 (s, 5-H), 6.86 (d, J = 8.3 Hz, 3-H, 5-H), 7.34 ppm (d, J = 8.3 Hz, 2-H, 6-H).

The preparation of the N-phenylpiperidine is described by H.D. Nitzschke and H. Budka, Chem. Pray. 88_, 264-268 (1955).

Example 7

a) DL-&-amino-oi-(4-hexamethyleneimino-phenyl)acetic acid

From 55 g (0.202 mol) of 5_(4-hexamethyleneimino-phenyl)-2,4-imidazolidinedione, the new phenylglycine derivative is recovered analogously to example 1.

Yield: 31.5 g (59%)

Cl4H20N2°2'H2° (266>3)

Calculated C 63.15 H 8.33 N 10.52

Found C 62.3 H 7.5 N 10.1

<1>H-NMR (NaOD, 60 MHz): <T = 1.45 (broad s, 8H, hexamethyleneimino), 3.06-3.43 (m, 2-CH2, 7-CH2, hexamethyleneimino), 4 .23 (s, <X-CH), 6.62 (d, J = 8.3 Hz, 3-H, 5-H), 7.26 ppm (d, J = 8.3 Hz, 2-H , 6-H).

b) 5_(4-hexamethyleneimino-phenyl)-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

of 55.5 g (0.273 mol) of p-hexamethyleneimino-benzaldehyde, 20.1 g (0.41 mol) of sodium cyanide and 105.5 g (1.1 mol) of ammonium carbonate.

Yield: 65 g (87%)

C15H19N3°2 (273.3)

Calculated C 65.92 H 7.01 N 15.37

Found C 64.5 H 7.0 N 15.1

<1>H-NMR ([Dg] DMF, 100 MHz): 6 = 1.4-1.96 (m, 8K, hexamethyleneimino), 3.43-3.61 (t-2-CH2, 7-CH2 , hexamethyleneimino), 5.10

(s, 5-H), 6.75 (d, J = 8.5 Hz, 3-H, 5-H), 7.22 ppm (d, J =

8.5 Hz, 2-H, 6-H).

Example 8

a) DL-oC-amino-øG-(4-morpholinophenyl)acetic acid

From 50 g (0.192 mol) 5-(4-morpholinophenyl)2,4-imidazolidinedione, p-morpholine-phenylglycine is recovered analogously to Example 1.

Yield: 29.6 g (60%)

<C>12<H>16<N>2°3 ' H2° (<2>54'3)

Calculated C 56.68 H 7.13 N 11.02

Found C 57.5 H 6.8 N 11.0

<1>H-NMR (D2O/NaOD, 60 MHz): 2.9"3.2 (m, 3"CH2, 5~CH2, morpholino), 3.66-3.96 (m, 2-CH2, /6-CH2, morpholino), 4.30 (s, A-CH), 6.98 (d, J = 8.3 Hz, 3-H, 5-H), 7.34 ppm (d, J = 8.3 Hz, 2-H, 6-H).

b) 5-(4-morpholino-phenyl)-2,4-imidazolidinedione

The hydantion is prepared analogously to example 1

of 61.9 g (0.324 mol) p-morpholino-benzaldehyde, 23.8 g (0.485 mol) sodium cyanide and 126 g (1.31 mol) ammonium carbonate.

Yield: 51.4 g (61%)

C13H15N3°3 (26l>3)

Calculated C 59.76 H 5.79 N 16.08

Found C 60.4 H 5.8 N 16.3

<1>H-NMR ([Dg] DMSO, 60 MHz): <f = 3.0-3.29 (m, 3"CH2, 5"CH2, morpholino), 3.66-4.93 (m, 2-CH2, 6-CH2, morpholino), 7.0 (d, J=8.3 Hz, 3-H, 5-H), 7.29 ppm (d, J = 8.3 Hz, 2-H , 6-H).

Example 9

a) DL-&-amino-<X-£4-(4-methylpiperazin-1-yl)phenyl]acetic acid or 1-phenylglycinyl-4-methylpiperazine

From 220 g (0.803 mol) of 5-[4-(4-methylpiperazin-1-yl)phenyl]-2,4-imidazolidinedione, p-(4-methylpiperazin-1-yl)phenylglycine is recovered analogously to example 3.

Preparation: The alkaline solution is acidified to pH 2 at 0°C, then reset to pH 5 and extensively evaporated (600 ml). After adding approx. 2.5 1 ethanol, the precipitated material is filtered off. Yield: 143.5 g (contains ~75% sodium chloride).

The filtrate is added once more with 4 1 ethanol and stored for 3 days in a refrigerator. The precipitated product is filtered off and dried.

Yield: 96 g (contains 30% NaCl)

C13<H>19<N>3°2(249>3)

Calculated C 43.7 H 5.35 N 11.75 Cl 18.3

Found C 42.1 H 6.4 N 11.6 Cl 18.3

<1>H-NMR (NaOD, 60 MHz): = 2.28 (s, CHj), 2.46-2.69 (m, 3-CH2, 5-CH2, piperazinyl), 2.99-3, 23 (m, 2-CH2, 6-CH2, piperazinyl), 4.31 (s, ct-CH), 6.97 (d, J = 8.4 Hz, 3-H, 5-H), 7, 32 ppm (d, J = 8.4 Hz, 2-H, 6-H).

b) 5-[4-(4-methylpiperazin-1-yl)phenyl]-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

of 148 g (0.725 mol) of p-(methyl-piperazin-1-yl)benzaldehyde, 53.4 g (1.09 mol) of sodium cyanide and 282 g (2.93 mol) of ammonium carbonate.

Processing: Ethanol is distilled off from the suspension in vacuum and the residue is acidified with concentrated hydrochloric acid to pH 1.5. The clear solution is then adjusted to pH 7.5-8.0 with 4N NaOH and the precipitated product is filtered off, washed with water and dried.

Yield: 146 g (73%)

Cl4Hl8N4°2(274.3)

Calculated C 61.30 H 6.6l N 20.42

Found C61.4 H 6.6 N 20.5

<1>H-NMR ([Dg]DMSO, 60 MHz): cf = 2.23 (s, CH^), 2.34-2.61 (m, 3-CH2, 5-CH2, piperazinyl), 3 .08-3.30 (m, 2-CH2, 6-CH2, piperazinyl), 5.05 (s, 5-H), 6.97 (d, J = 8.4 Hz, 3-H, 5- H), 7.22 (d, J = 8.4 Hz, 2-H, 6-H).

c ) DL-<X-benzyloxycarbonylamino-Æ-[4-(4-methyl-piperazin-1-yl)-phenyl]acetic acid

In connection with a regulation by Y. Wolman,

D. Ladkany and M. Frankel, J. Chem. Soc. 1967, 689-690, 14.6 g (0.0273 mol) of DL-α-amino-oC-[4-(4-methylpiperazin-1-yl)-phenyl]acetic acid containing 53.5% sodium chloride, suspen -dert in 60 ml water, added 2.3 g (0.0273 mol) ammonium hydrogen carbonate and 9.0 g (0.033 mol) p-nitrophenyl benzyl carbonate in 60 ml dioxane. The reaction mixture is heated for 4 hours under reflux. 200 ml of water and 200 ml of acetic acid are then added to the clarified solution, shaken and the acetic acid phase is separated. A precipitate is obtained from the aqueous solution by acidification with 2N HC1 at 0°C, which is filtered off and dried.

Yield: 6.1 g (59%).

C21H25N3°4<H>2° (401>5)

Calculated C 62.82 H 6.78 N 10.46

Found C61.3 H 6.7 N 10.2

<X>H-NMR (TDg] DMSO, 60 MHz): δ = 2.31 (s, CH^), 2.42-2.71 (m, 3-CH2, 5-CH2, piperazinyl), 2, 96-3.27 (m, 2-CH2, 6-CH2, piperazinyl), 55.01 (s, oC-CH), 5.17-5.36 (broad s, benzyl-CH2,

-NH-), 6.71-7.31 (AB system, 4H, phenyl-H), 7.31 ppm (s, £Hijy phenyl-H). Example 10

a) DL-o-amino-ol-(4-diallylaminophenyl)acetic acid

From 95 g (0.35 mol) of 5-(4-diallylaminophenyl)-2,4-imidazolidinedione, p-diallylamino-phenylglycine is recovered analogously to example 1. The raw material is finally taken up in 700 ml of boiling ethanol. After cooling to 0°C, the amino acid is filtered off and washed with cold ethanol.

Yield: 57.3 g (67%)

Cl4Hl8N2°2<2i|6>3)

Calculated C 68.28 H 7.37 N 11.37

Found C 66.5 H 8.3 N 10.5

<1>H-NMR ([Dg] DMSO, 60 MHz): cf 3.86-4.06 (d, 4H, 2-CH2~), 4.22 (s, cX-CH), 4.99- 5.38 (m, 4H, 2CH2=), 5.60-6.22 (broad m, 2H, 2-CH=), 6.63 (d, J = 8.4 Hz, 3-H, 5- H), 7.21 (d, J = 8.4 Hz, 2-H, 6-H).

b ) 5-[4-(diallylamino)phenyl]-2,4-imdazolidinedione

The hydantoin is prepared analogously to example 1

of 108 g (0.536 mol) of p-diallylaminobenzaldehyde, 39.7 g (0.81 mol) of sodium cyanide and 209 g (2.18 mol) of ammonium carbonate.

Processing: After distilling off the ethanol in a vacuum, the residual solution is acidified with cold concentrated hydrochloric acid to pH 1.5 and stirred for 15 minutes. The solution is then adjusted to pH 7 with 4N NaOH at 5-10°C.

The precipitated product is filtered off, washed with water and suctioned to dryness. The material is then absorbed three times

with ether, filtered off and dried in vacuo.

Yield: 95.6 g (66%).

<C>15H17N3°2(271.3)

Calculated C 66.40 H 6.32 N 15.49

Found C 65.4 H 6.4 N 16.0

<1>H-NMR ([Dg] DMSO, 60 MHz): cf = 3.92-4.00 (d, 4H, 2-CH"2-), 4.97-5.35 (m, 4H, 2CH2=), 5.70 (s, 5-H), 5.62-6.21 (broad m, 2H, 2-CH=), 6.72 (d, J = 8.4 Hz, 3-H , 5-H), 7.12 ppm (d,

J = 8.4 Hz, 2-H, 6-H).

p-diallylamino-benzaldehyde is prepared from p-diallylaniline via the Vilsmeier reaction. The synthesis of diallylaniline is described in Ch.L. McCormick and G.B. Butler, J. Org. Chem. 41, 2803-2808 (1976).

Example 11

a) DL-&-amino-O6-[4-bis((^-methoxyethyl)aminophenyl]acetic acid

From 70 g (0.0228 mol) of 5-[4-bis(/9-methoxy-ethyl)-aminophenylj-2,4-imidazolidinedione, the new phenylglycine derivative is recovered analogously to example 3.

Processing: Cool to 0°C, acidify with concentrated hydrochloric acid to pH 1 and stir for 15 minutes. The pH value of the solution is then brought to pH 4.6, whereby the precipitated product (5.2 g) is filtered off and discarded. The filtrate is evaporated in vacuo and the residue is stirred with 2 1 methanol for 2 to 3 hours at room temperature. Undissolved material (sodium chloride) is then filtered off and the methanolic filtrate is evaporated in vacuo to dryness. Yield: 60.2 g (94%, contains 14.8% sodium chloride).

C14H22N2°4(282.3)

Calculated C 50.8 H 6.7 N 8.47

Found C 49.6 H 6.4 N 9.0 Cl,9.0

1

<1>H-NMR (NaOD, 60 MHz): S = 3.29 (s, 6H, 20^0), 3.48 (s, 8H, 4CH2), 4.26 (s, cX-CH), 6.72 (d, J = 8.4 Hz, 3-H, 5-H), 7.25 ppm (d, J = 8.4 Hz, 2-H, 6-H).

b ) 5-[4-bis (|3-methoxyethyl)aminophenyl]-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

of 108 g (0.455 mol) of N,N-bis(Æ-methoxyethyl)aminobenzaldehyde, 33.7 g (0.688 mol) of sodium cyanide and 177 g (1.84 mol) of ammonium carbonate.

Preparation: After stirring for 20 hours at 60°C, ethanol is distilled off in a vacuum. The residual solution is acidified with semi-concentrated hydrochloric acid to pH 1.5 by ice-cooling and after 10 minutes of stirring adjusted with 4N NaOH to pH 7.2. The aqueous suspension is extracted thoroughly with chloroform, the chloroform phase is washed and dried. After evaporation of the organic phase, a tough, viscous mass is obtained.

Yield: 72 g (51%)

C15H2#3°4

Calculated C 58.6l H 6.88 N 13.67

Found C 58.8 H 6.9 N 13.5

<1>H-NMR <CDC13, 60 MHz): S = 3.34 (s, 6H, 20^0), 3.55 (s, 8H, 4CH2), 4.93 (s, 5-H), 6.57-7.29 ppm (AA'BB' system, 4H, phenyl).

The N,N-bis ((3-methoxyethyl)aminobenzaldehyde is prepared from the bis ((3-methoxyethyl)aniline via the Vilsmeier reaction. The bis-(/5-methoxyethyl)aniline is obtained according to W.R. Boon, J. Chem. Soc. 1147, 307-318.

Example 12

a) DL-α-amino-<5t-[4-(4-(3-methoxyethyl-piperazin-1-yl)-2-methyl-phenyl]acetic acid

q From 42 g (0.127 mol) of 5-[4-(4-(3-methoxyethyl-piperazin-1-yl)-2-methylphenyl]-2,4-imidazolidinedione, the phenylglycine derivative is recovered analogously to example 11.

Yield: 40 g (103%, contains 30.6% sodium chloride).

Cl6H25N3°3 (307.4)

Calculated C 43.3 H 5.69 N 9.5

Found C 43.0 H 6.4 N 11.0

<1>H-NMR ([Dg] DMSO/D2O, 60 MHz): cf = 2.4 (s, 2-CHj) , 3.04-3.4 (m, 8H, piperazinyl, 2H, a-CH2 "), 3.32 (s, CH^O-), 3.59-3.79 (m, 2H, O-CH2-), 4.6 (s, O6-CH), 6.66-7, 4 ppm (m, 3H, phenyl).

b) 5-[4-(4-(2>-Methoxyethyl-piperazin-1-yl)-2-methylphenyl]-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

and 11 of 58.7 g (0.224 mol) 4-[4-(£-methoxyethyl)piperazin-1-yl]-2-methylbenzaldehyde, 16.6 g (0.339 mol) sodium cyanide and 88 g (0.916 mol) ammonium carbonate.

Yield: 42 g (57%)

C17H24N4°3(332.4)

Calculated C 61.43 H 7.78 N 16.86

Found C 60.8 H 7.2 N 16.4

<1>H-NMR (CD^OD, 60 MHz): = 2.35 (s, 2-CH^), 2.63 (d, 3"CH2, 5-CH2, piperazinyl, 2H, U-CE2~ ), 3.03~3.25 (m, 2-CH2, 6-CH2, piperazinyl), 3.31 (s, CH3O-), 3.45-3.63 (t, 2H, (3-CH2- ),

5.25 (s, O6-CH), 6.58-7.15 ppm (m, 3H, phenyl). The 4-[4-(/3-methoxyethyl)-piperazin-1-yl-2-methyl-benzaldehyde is prepared from the N-(2-methylphenyl)-N'-(2-methoxyethyl)-piperazine via the Vilsmeier reaction.

The synthesis of N-(2-methylphenyl)-N'-(2-methoxyethyl)-piperazine is described in US patent 2,891,063.

Example 13

a) DL-#-amino-Ct-f4-(1,2,3-triazol-1-yl)phenyl]acetic acid

Analogous to example 1, the new phenylglycine derivative is recovered from 39.5 g (0.172 mol) of 5-[4-(1,2,3-triazol-1-yl)-phenylj-2,4-imidazolidinedione.

Yield: 24.5 g (65%, contains 11.8% sodium chloride).

<C>10<H>10N4°2'2H2° (25^3)

Calculated C 41.7 H 4.82 N 19.4

Found C 41.4 H 3.9 N 19.4 Cl 7.2

<1>H-NMR (NaOD/CD^OD, 60 MHz): cf = 4.57 (s, OC-CH), 7.75 (s, 5H, phenyl-H, triazolyl-H), 8.0 ppm (s, 1H, triazolyl-H).

b) 5-[4-(1,2,3-triazol-1-yl)phenyl]-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

of 57 g (0.33 mol) p-(1,2,3-triazol-l-yl)benzaldehyde, 28.5 g (0.583 mol) sodium cyanide and 144 g (1.5 mol) ammonium carbonate in 300 ml methanol and 300 ml of water.

Yield: 65.7 g (75%)

C11H9N5°2'2H2° (265.3)

Calculated C 49.80 H 4.94 N 26.40

Found C 50.7 H 4.3 N 25.2

■"■H-NMR ([Dg] DMSO, 60 MHz): S = 5.4 (s, OL-CK), 7.57"8.9 ppm (broad m, 4H, phenyl-H, 2H, triazolyl -H).

Example 14

a) DL-06-amino-O.-[3-(1,2,3-triazol-1-yl)phenyl]acetic acid

Analogous to example 11 m-(1,2,3- triazol-1-yl)phenylglycine.

Yield: 32.5 g (60%)

C10<H>10N4°2<2l8>2)

Calculated C 55.05 H 4.62 N 25.68

Found C 54.5 H 4.3 N 24.8

b) 5-[3-(1,2,3-triazol-1-yl)phenyl]-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 1

of 6l g (0.352 mol) m-(1,2,3-triazol-l-yl)-benzaldehyde, 26.2 g (0.535 mol) sodium cyanide and 137.8 g (1.435 mol) ammonium carbonate in 1000 ml water and 1000 ml of ethanol.

Processing: After 24 hours at 60°C, 2N hydrochloric acid is added to the reaction solution by ice-cooling to pH 2, then the pH value is reset with 4N NaOH to 4 and only then is the largest part of the ethanol distilled off in a vacuum. Upon cooling to 0°C, solid material precipitates which is filtered off and washed with water.

Yield: 33.9 g (40%)

The filtrate is further evaporated in a vacuum, whereby a fatty product is precipitated which after a short time turns into solid form.

Yield: 26.3 g (31%)

<C>11H9<N>5°2 (<24>3>2)

Calculated C 54.33 H 3.73 N 28.80

Found C 54.3 H 3.7 N 28.4

<1>H-NMR ([Dg] DMSO, 60 MHz): 6 = 5.36 (s, OC-CH) , 7.46-8.00 (broad m, 4H, phenyl, 1H, triazolyl), 8 .77 ppm (s, 1-triazolyl-H).

Example 15

a) DL-<X-[ ( 3-methylsulfonyl-imidazolidin-2-on-l-yl )carbonyl-amino] - OL- [4 - [ ( 3_methylsulfonyl-imidazolidin-2-on-l-yl) -

carbonylaminoj]•phenylacetic acid

10 g (0.06 mol) of DL-CC-amino-Æ-(p-aminophenyl)-acetic acid is dissolved in 100 ml of water and 100 ml of THF by addition of 2N NaOH at pH 7.5 to 7.8 . 1-Chloro-carbonyl-3-methylsulfonyl-imidazolidinone-(2) is added in portions with ice-cooling and, by simultaneous addition of 2N NaOH, the pH value is maintained at 7.5. The mixture is then stirred for a further 2 hours without cooling.

Preparation: THF is distilled off, the residual solution is added to 150 ml of water and extracted once with vinegar. The aqueous phase is separated, 2N NaCl is added to pH 2 and extracted with ethyl acetate. After washing with water, drying with sodium sulfate and evaporation of the organic phase, 10.9 g of crude product is obtained, which is recrystallized from THF/petroleum ether.

Yield: 9.0 g (27%)

<C>18<H>22<N>6°10<S>2(<546>><5>)

Calculated C 39.56 H 4.05 N 15.37 S 11.75

Found ,C 39.4 H 4.2 N 14.4 S 11.2

<1>H-NMR ([Dg] DMSO, 60 MHz): 6 - 3.39 (s, 6H, 2CH3), 3.73" 4.96 (m, 8H, imidazolidinone), 5.08 (d, OC-CH), 7.36 (d, J = 8.3 Hz, 3-H, 5-H), 7.58 ppm (d, J = 8.3 Hz, 2-H, 6-H).

The synthesis of 1-chlorocarbonyl-3-methylsulfonyl-imidazolidinone-(2) is described in DOS 2,152,968.

b ) DL-O--amino-OC-(4-aminophenyl)acetic acid

From 70 g (0.366 mol) of 5-(4-aminophenyl)-2,4-imidazolidinedione, p-aminophenylglycine is recovered analogously to example 1.

Processing: After 29 hours of stirring at 100°C with 10% caustic soda, the solution is cooled to 0°C and acidified with concentrated hydrochloric acid to pH 2.5. The aqueous solution is then adjusted to pH 5.0 and evaporated in vacuum to a smaller volume, after which the amino acid is precipitated after ice-cooling. The precipitate is filtered off, washed with a little water and dried.

Yield: 57.3 g (94%).

C8H10N2°3<l66>2)

Calculated C 57.82 H 6.06 N 16.86

Found C57.4H6.2Nl6.6

1H-NMR ([.Dg] DMSO/NaOD, 60 MHz): (f = 4.1 (s, d-CH), 6.63 (d, J = 8.3 Hz, 3-H, 5-H ), 7.15 ppm (d, J = 8.3 Hz, 2-H, 6-H).

c) 5-(4-aminophenyl)-2,4-imidazolidinedione

The hydantoin is prepared analogously to example 9

of 90 g (0.495 mol number of dry matter) of water-moistened p-amino-benzaldehyde, 37.0 g (0.75 mol) of sodium cyanide and 193.9 g (2Q02 mol) of ammonium carbonate in 1000 ml of water and 1000 ml of ethanol. Yield: 69.4 g (73.3%)

C9H9N302(191.2)

Calculated C 56.54 H 4.74 N 21.99

Found C 56.8 H 4.7 N 21.8

<1>H-NMR ([Dg] DMSO, 60 MHz): S = 4.95 (s, 5"H), 6.65 (d, J = 8.3 Hz, 3-H, 5-H) , 7.03 (d, J = 8.3 Hz, 2-H, 6-H).

Example 16

a) D-oC-amino-ot-[4-(imidazolidin-2-on-1-yl)phenyl]acetic acid

18 g (0.0537 mol) of D-OL-tert.butyloxycarbonyl-amino-α-[4-(imidazolidin-2-on-1-yl)phenyl]acetic acid are stirred in 120 ml of trifluoroacetic acid and 40 ml of anisole 30 minutes at room temperature. The trifluoroacetic acid is then distilled off in a vacuum and the oily precipitate is added to 300 ml of ether. The precipitated crystallisate is filtered off, washed with ether and dried in a desiccator over KOH.

Yield: 23.2 g (93%)

<C>11<H>13<N>3°3'CP3C00H (349.3)

Calculated C 44.70 H 4.33 N 12.03

Found C 45.3 H 4.3 N 11.3

<1>H-NMR (D 2 O, 60 MHz): cf = 3.36-3.94 (m, 4h, imidazolidinone), 7726-7.85 (m. ^H, phenyl).

b ) D-α-tert.butyloxycarbonylamino-(X-[4-(imidazolidin-2-on-1-yl)phenyl]acetic acid 49 g (0.127 mol) D-α-tert.butyloxycarbonylamino-Ct" (4-[ 3-(( b -Chloroethyl)-ureido]phenylacetic acid is introduced portionwise over 60 minutes into an ethanolic solution of potassium hydroxide (28.4 g) (0.508 mol) KOH in 260 ml of 70 µg ethanol, and then heated for 60 minutes under reflux. The batch is then poured over with 2 L of ice water and acidified with 2N HCl to pH 2.8. The precipitated fatty material is extracted with ethyl acetate, the ethyl acetate extract is washed once with water, dried over sodium sulfate, and the organic solvent is distilled off in vacuo.

Yield: 31.7 g (73%)

C16H21N3°5(335.4)

Calculated C 57.30 H 6.31 N 12.53

Found C 57.1 H 4.9 N 11.3

<1>H-NMR (CD30D, 60 MHz): δ = 1.44 (s, 9H, tert.butyl), 3§26-3.64 (m, 4-CH2, imidazolidinone), 3.64-4 .06 (m, 5-CH2, imidazolidinone), 5.16 (s, o(,-CH), 7.11-7.59 ppm (broad m, 4H, phenyl). D-0c-tert.butyloxycarbonylamino- Beer-j 4-£ 3-(O-chloro-ethyl)ureidoJphenyl]acetic acid is prepared by condensation of chloroethyl isocyanate to D-CX-tert-butyloxycarbonylamino-<t-(p-aminophenyl)acetic acid.

Example 17 (racemate separation)

A solution of 25.2 g of DL-o-amino-o- (4-thiomoro-folinophenyl)acetic acid (Example 1) in 210 ml of formic acid is added while cooling with 70 ml of acetic anhydride and hydrolyzed after approx. 1 hour by adding 80 g of ice. After extraction of the solvent, the resin-like precipitate is taken up in water, treated with active carbon and, after filtration, gradually evaporated. The precipitate formed during evaporation is removed by filtration until no further precipitate is formed. The filtrate is evaporated to dryness and recrystallized from methanol/ether. 15.7 g (56% of the theoretical amount) of the formyl derivative of the starting compound is obtained. Melting point l48°C.

The formyl compound thus obtained is reacted in a manner known per se in ethanol. Due to different solubility, both diastereomers of the salt pairs are fractionally crystallized. 8.95 g (41.6% of theoretical amount) of a dextrorotatory salt in methanol and 8.25 g (38.3% of theoretical amount) of a levorotatory salt in methanol are obtained.

a) The dextrorotatory salt (6.9 g) is added to 300 ml of water with 60 ml of concentrated ammonia. They hereby freed

dehydroabiethylamine is extracted with methylene chloride, an aqueous solution is evaporated to dryness and the remaining ammonium salt is added to 35 ml of 2N hydrochloric acid and heated for 15 minutes at 50°C. After cooling to 5°C, 140 ml of semi-concentrated ammonia is added and then evaporated in vacuo, whereby the L-oC-amino-tX.-(4-thiomorph olino-phenyl)acetic acid is precipitated, which is washed with water and ether. 1.7 g of the optical compound according to example 1 with a melting point of 229°C was obtained.

Rotation value: fix]^° = + 101.5° (c = 1, nHCl).

b) 8.2 g of the levorotatory dehydroabiethylamine salt are added to 450 ml of water with 90 ml of concentrated ammonia.

The separated dehydroabiethylamine is extracted with methylene chloride and the aqueous phase is evaporated to dryness. 4.35 g of the ammonium salt was obtained, which was dissolved in a mixture of 25 ml of water and 10 ml of ethanol and 2.0 g of D-+-phenethylamine was added. After evaporation of the solvent and recrystallization from isopropanol, 4.0 g of the D-+-phenethylamine salt was obtained with a melting point of 177-178°C (Turn value:

[oC]o° 135.6° (c = 1, methanol)).

This salt is then dissolved in 160 ml of water and 63 ml of concentrated ammonia is added. The phenethylamine is then extracted with methylene chloride, the aqueous phase is evaporated to dryness and the residue is taken up in 56 ml of 2N hydrochloric acid and heated for 7 minutes at 50°C. After cooling to 5°C, 200 ml of semi-concentrated ammonia is added. After extraction of the ammonia in a vacuum, the levorotatory amino acid crystallized. 1.5 g of D-o-amino-ol(4-thiomor-folino-phenyl)acetic acid with a melting point of 227°C were obtained. Turn value:

[oC] p° = -100.0° (c = 1, n HC1)

Claims (1)

1. £X-aminophenylacetic acid derivatives with the general formula I in which R stands for hydroxy, alkoxy, amino acid ester (peptidyl) or the rest whereby R' and R" are the same or different and stand for hydrogen or alkyl, R p stands for hydrogen, alkyl, trifluoromethyl, halogen, alkoxy, hydroxyl, cyano or alkyl mercapto, R 3 and R 4 are the same or different and stand for hydrogen, alkyl or alkenyl, whereby the alkyl residues are optionally substituted with hydroxyl, mercapto, amino, cyano, alkoxy, alkyl mercapto, carboxyl or sulfo (-SO^ H) or 3 4 R and R together with the nitrogen atom form a 5- to 7-membered group ring which may contain as additional heteroatom oxygen, sulfur, 2 nitrogen atoms (such as triazole), 3 nitrogen atoms (such as tetrazole), a whereby R"' means one or two oxygen atoms or alkyl and R"" means alkyl, alkenyl or alkoxyalkyl, R^ stands for hydrogen, alkyl or acyl, and R <6> stands for hydrogen, alkyl, NC-CH2", H^COOC-CH^-, H^CO-CH^- or H^ CS-CR^ -.s 2. oC-aminophenylacetic acid derivatives of the general formula I according to claim 1, in which R"1" stands for hydroxy, alkoxy with 1-4 carbon atoms, amino- acid residues or the residue whereby R' and R" are equally different and stand for hydrogen or alkyl with 1-4 carbon atoms, R stands for hydrogen, alkyl with 1-4 carbon atoms, trifluoride methyl, halogen, especially fluorine, chlorine or bromine, alkoxy with 1-4 carbon atoms, hydroxyl, cyano or alkylmercapto with 1-4 carbon atoms, 3 4 R and R are the same or different and stand for hydrogen, alkyl or alkenyl with up to 4 carbon atoms, whereby the alkyl residues are optionally substituted with hydroxy, mercapto, amino, cyano, alkoxy or alkylmercapto with 1-4 carbon atoms or 3 4 R and R together with the nitrogen atom form a 5_ to 7-membered ring which may be saturated or unsaturated and may contain an oxygen atom, a sulfur atom, an SO group, an SC^ group, one or two CO group rings, an N-R"' group, where R"' stands for hydrogen, alkyl or alkenyl with up to 4 carbon atoms or 1, 2 or 3 nitrogen atoms, R 5 stands for hydrogen, alkyl with 1-4 carbon atoms or acyl, whereby in the acyl group CO-R"" the substituent R"" stands for alkyl with 1-4 carbon atoms, aralkyl, especially benzyl, or for the remainder and R^ stands for hydrogen or alkyl with 1-4 carbon atoms, whereby the alkyl group is optionally substituted with cyano, alkoxy, alkyl mercapto with 1-2 carbon atoms or with carbo- alkoxy with 1-2 carbon atoms in the alkoxy group, as well as their pharmaceutically acceptable salts. 3-(X-aminophenylacetic acid derivatives of the general formula I according to claim 1, in which R <1> stands for hydroxy or alkoxy with 1-4 carbon atoms, R 2 stands for hydrogen, alkyl with 1-4 carbon atoms, trifluoride methyl or halogen, R 3 and R 4 are the same or different and stand for hydrogen, alkyl or alkenyl with up to 4 carbon atoms, whereby the alkyl residues are optionally substituted with hydroxy, amino, cyano or alkoxy with 1-2 carbon atoms or R 3 and R 4 together with the nitrogen atom form a 5- to 7-membered aliphatic ring which may be saturated or unsaturated and may contain an oxygen atom, a sulfur atom, an SO group, an SO2 group, an N-R"' group, where R"' stands for hydrogen or alkyl of 1-2 carbon atoms, whereby this aliphatic ring may optionally further contain a nitrogen atom, R 5 stands for hydrogen, alkyl with 1-4 carbon atoms or for one acyl group CO-R"", whereby R"" stands for alkyl with 1-4 carbon atoms, benzyl or for the remainder and R stands for hydrogen or alkyl with 1-2 carbon atoms, as well as their pharmaceutically acceptable salts.4. Process for the preparation of o&-aminophenylacetic acid derivatives according to claim 1, characterized in that substituted benzaldehyde derivatives with the general formula II are reacted 2 3 4 in which R , R and R have the above meaning, with sodium cyanide and ammonium carbonate to hydantoin derivatives with the general formula III and subsequently hydrolyzes these to corresponding amino acids of the general formula I and in connection therewith esterifies or amidates the carboxyl group and in a manner known per se and/or acylates the amino group, whereby the reaction of compounds of the general formula III to compounds of the formula I is carried out in and per se known manner by acid or alkaline hydrolysis. 5- Method according to claim 4, characterized in that the reaction is carried out at temperatures between 10 and 120°C. 6. Method according to claim 4, characterized in that sodium cyanide and ammonium carbonate are used in a 2- to 5-fold excess. 7. Method according to claim 4, characterized in that the reaction is carried out in the presence of inert organic solvents. 8. Medicines containing at least one fo-amino-phenylacetic acid derivative with the general formula I according to claim 1. 9- Process for the production of pharmaceuticals, characterized in that one transfers d-aminophenylacetic acid derivatives with the general formula I according to claim 1, possibly by using common excipients and carriers in a suitable administration form. 10. Use of O-aminophenylacetic acid derivatives with the general formula I according to claim 1 in the treatment of inflammation. 11. Procedure for the treatment of inflammatory diseases, characterized by administering £G-aminophenylacetic acid derivatives according to claim 1 to humans or animals in cases of need.