DE2705863A1 - NEW ANTI-HYPERTONIC PREPARATIONS - Google Patents

Description

Patent attorneys Dr.-Ing. Waiter Abitz Dr. Dieter F. M ο rf Dlpl.-Fiiys. M. ü.itschneder 8 monks 86, Pienz

February 11, 1977 15 858Y

MERCK & CO., INC. Rahway, New Jersey 07065, V.St.A.

New anti-hypertensive preparations

The invention relates to new pharmaceutical preparations. The preparations contain an aryl-substituted alanine and a substituted phenylhydrazino propionic acid. The preparations are suitable for the treatment of hypertension or high blood pressure.

The present invention relates to new pharmaceutical preparations, that have anti-hypertensive activity. The preparations contain (a) an aryl-substituted one Alanine and (b) a substituted phenylhydrazinopropionic acid decarboxylase inhibitor.

Hydroxyphenylalanines and their derivatives are described in U.S. Patents 2,868,818, 3,230,143 and 3,344,023. Benzimidazolylalanines are in J.Med.Chem. T7: 1223-1225 (1974) J. Med. Chem. 13.1 741-742 (1970) and Abstract No. 964 of Fifth International Congress On Pharmacology, 23.-28. July 1972, described.

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The hydrazino-substituted phenylpropionic acid class of decarboxylase inhibitors is also described in the literature (see U.S. Patents 3,462,536, 3,781,415, and 3,830,827). the Combination of certain compounds including the hydroxyphenylalanines with decarboxylase inhibitors of these Class is also described in the literature (see CA-PS 737 907 and ÜS-PSs 3 839 585 and 3 462 536).

It has now been found that new arylalanines and their esters together have an increased antihypertensive activity with the aforementioned decarboxylase inhibitors.

The invention thus relates to new pharmaceutical preparations which (a) an aryl-substituted alanine or its salt and (b) a hydrazino-substituted phenylpropionic acid decarboxylase inhibitor contain. The invention also relates to a method for treating high pressure in living beings.

The invention relates in particular to a pharmaceutical preparation, which contains

(A) an arylalanine compound of the formula

^R 1

Ra-CHo-C-COO-R «NH ₂

I.
and / or their pharmaceutically acceptable salts, wherein

R ₁ and R _{2 can represent} a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and

(1) a substituted benzene ring of the formula

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Y ₁ iind Y _{2 are} identical or different and represent hydrogen, cyanoamino, carboxyl, cyano, thiocarbamoyl, amino methyl, guanidines, hydroxy, methanesulfonamido, nitro, amino, methanesulfonyloxy, carboxymethoxy, formyl, methoxy and a substituted or unsubstituted 5- or 6-membered heterocyclic ring which contains carbon and one or more nitrogen, sulfur or oxygen atoms, specific examples of such heterocyclic rings being pyrrol-1-yl, 2-carboxypyrrol-1-yl, imidazol-2-ylamino, indole -1 -yl, carbazol-9-yl, 4, S-dihydro- ^ hydroxy- ^ trifluoromethylthiazol-3-yl, 4-trifluoromethylthiazol-2-yl, imidazol-2-yl and 4,5-dihydroimidazol-2-yl are such that (a) Y ₁ and Y _{2 are} not both hydroxy; (b) Y ₁ and Y _{2 are} not both hydrogen; and (c) when one of the substituents Y ₁ and Y _{2 is} hydrogen, the other is not hydroxy,

(2) a substituted or unsubstituted benzohetero cyclic ring of the formula

wherein the benzoheterocyclic ring is selected from the group indolin-5-yl, 1 - (H-Benzoylcarbamtml doyl) -indolin-5-yl, i-carbamimidoyl-indolin-5-yl, 1H-2-0acindol-5-yl, Indol-5-yl, 2-mercaptobenzimidazol-5 (6) -yl, 2-aminobenzimidazol-5 (6) -yl, 2-methanesulfonamido-benzi ml dazol-5 (6) -yl, IH-benzoxazol-2-one -6-yl, 2-aniinobenzothlazol-6-yl-2-amino-4-> mercaptobenzothiazol-6-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-2,2-dioxo- 2,1,3-benzothiadiazol-5-yl, t, 3-Deiqrdro-1 _t 5-d4methyl-2,2-dioxo-2,1,3-benzothiadiazol-5-yl, 4-methyl-2 (IH) -oxoquinolin-6-yl, quinoxalin-6-yl, 2-hydroxyquinoxalin-6-yl, 2-hydroxyquinoxalin-7-yl, 2,3-dihydroxych1 nnxal i n-6-yl and 2 _f 3-dihydro-3 ( 4H) -oxo-1,4-benzoxazin-7-yl, and

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(3) a substituted or unsubstituted heterocyclic ring of the formula

(hetj

means wherein the heterocyclic ring is selected from the group 5-hydroxy-4H-pyran-4-on-2-yl, 2-hydroxypyrid-4-yl, 2-aminopyrid-4-yl, 2-carboxypyrid-4-yl or tetrazolo [i.5-a] -pyrid-7-yl, and / or their pharmaceutically acceptable salts and

(B) a decarboxylase inhibitor of the formula

II
wherein

R., Rc, R ^ and R ~ independently of one another are hydrogen atom or a CL-C ^ -alkyl group, and / or its pharmaceutically acceptable salts.

The compounds (A) and (B) all have an asymmetric carbon atom. You are therefore optically active. The connections include all enantiomers, individually as the L- and D- or S-, R-isomers, and also mixtures, including the racemic mixtures. The isomer mixtures are suitable, and the L-isomer which is essentially free of the D-isomer is the most preferred form of these compounds.

The pharmaceutically acceptable salts include the salts of the compounds (A) and (B) with organic acids and inorganic acids Acids as well as carboxylate salts such as those of Na, K,

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Ca, NH ^ etc. Suitable organic acids are generally Carboxylic acids with up to 24 carbon atoms. Examples of such acids are acetic acid, tartaric acid, citric acid, pamoic acid, Isethionic acid, fumaric acid, maleic acid, oxalic acid, propionic acid, etc. Suitable inorganic acids are e.g. the hydrohalic acids, e.g. HCl, HBr, HJ, sulfuric acid and the phosphoric acids, e.g. Η, ΡΟ ^.

In some cases the compounds exist as hydrates. These hydrates are also used in the present invention includes.

Specific examples of compounds of Formula I are the following:

4-cyanoamino-α-methylphenylalanine

3-carboxy-a-methylphenylalanine

3-cyano-α-methylphenylalanine methyl ester a-.Methyl-4-thiocarbamoylphenylalanine methyl ester 4- (aminomethyl) -a-methylphenylalanine 4-guanidino-a-methylphenylalanine

3-Hydroxy-4-methanesulfonamido-a-methy-phenylalanine 3-Hydroxy-4-nitro-a-methylphenylalanine 4-Amino-3-methanesulfonyloxy-α-methylphenylalanine 3-carboxymethoxy-4-nitro-a-methylphenylalanine, 4-amino-a-methyl-3-nitrophenylalanine 3,4-diamino-α-methylphenylalanine

α-methyl-4- (pyrrol-1-yl) phenylalanine 4- (2-Aminoimidazol-1-yl) -a-methylphenylalanine 4- (Imidazol-2-yl-amino) -a-methy! Phenylalanine 4- (4,5-Dihydro-4-hydroxy-4-trifluoromethyl-thiazol-2-yl) -amethylphenylalanine methyl ester

α-Methyl-4- (4-trifluoromethylthiazol-2-yl) -phenylalanine α-Methyl-3- (4-trifluoromethylthiazol-2-yl) -phenylalanine

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4- (imidazol-2-yl) -α-methy! Phenylalanine ^ - (^ »5-dihydroimidazol-2-yl) -α-methy! Phenylalanine 3- (imidazol-2-yl) -α-methylphenylalanine 3- (A, 5-dihydroimidazol-2-yl) -α-methylphenylalanine 4- (imidazol-2-yl) -phenylalanine 4- (4,5-dihydroiniidazol-2-yl) -phenylalanine 3- (Imidazol-2-yl) -phenylalanine 3- (2,3-Dihydro-1H-indol-4-yl) -α-methylalanine α-Methyl-3- (iH-2-oxindol-5-yl) -alanine 3- [i- (N-Benzoylcarbamimidoyl) -2,3-dihydro-1H-indol-5-yl] -amethylalanine

3- (1-Carbamimidoyl-2 ^ -dihydro-IH-indol-S-yl) -α-methylalanine 3- (1H-indol-5-yl) -a-methylalanine 3- (Benzimidazol-2-thion-5-yl) -a-methylalanine 3- (2-aminobenzimidazol-5-yl) -2-methylalanine 2-methyl-3- (benzoxazol-2-on-6-yl) -alanine 3- (2-aminobenzothiazol-6-yl) -2-methylalanine 3- (2-Amino-4-mercaptobenzothiazol-6-yl) -2-methylalanine 3- (2-aminobenzothiazol-6-yl) -alanine 2-methyl-3- (2,1,3-benzothiadiazol-5-yl) alanine 3- (i, 3-Dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide

3- (i, 3-Dihydrobenzo-2 _f 1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide-methyl ester

3- (i, 3-Dihydrobenzo-2,1,3-thiadiazol-5-yl) -alanine-2,2-dioxide 3- (i, 3-Dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide

α-Methyl-3- [4-methyl-2 (1H) -oxoquinolin-6-yl] -alanine 3_ [4-Methyl-2 (1H) -oxoquinolin-6-yl] -alanine 2-methyl-3- (quinoxalin-6-yl) -alanine 2-methyl-3- (2-hydroxyquinoxalin-6-yl) -alanine 2-methyl-3- (2-hydroxyquinoxalin-7-yl) -alanine 3- (2 ^ -dihydroxyquinoxalin-δ-yl) -2-methylalanine 3- (quinoxalin-6-yl) alanine

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3- (2,3-Dihydroxyquinoxalin-6-yl) -alanine 3- (1,4-Benzoxazin-3-on-6-yl) -2-methylalanine 3- (ΐ ^ -Benzoxazin ^ -one ^ -yl) -alanine 3- (5-Hydroxy-4H-pyran-4-on-2-yl) -2-methylalanine 3- (2-Hydroxy-4-pyridyl) -2-methylalanine 3- (2-Carboxy-4-pyridyl) -2-methylalanine 3-formyl-a-methyltyrosine

3-cyano-oc-methyl tyrosine

3-carboxy-a-methyltyrosine

α-methyl-4- (pyrrol-1-yl) phenylalanine

4- [2- (carboxy) pyrrol-1-yl)] phenylalanine

3-Hydroxy-α-methyl-4- (pyrrol-1-yl) -phenylalanine 3-methoxy-cc-methyl-4- (pyrrol-1-yl) -phenylalanine α-methyl-3- (pyrrol-1-yl) -tyrosine 4-methoxy-α-methyl-3- (pyrrol-1-yl) -phenylalanine 4- (Indol-1-yl) -a-methylphenylalanine 4- (carbazol-9-yl) -a-methylphenylalanine α-methyl-3- (4-trifluoromethylthiazol-2-yl) tyrosine 3- (Imidazol-2-yl) -α-methyltyrosine 2-methyl-3- (2-methanesulfonylamido-benzimidazol-5-yl) -alanine 2-methyl-3- (2-amino-4-pyridyl) -alanine, 2-methyl-3- (tetrazo] ifi.5-a3pyrid-7-yl) -alanine.

A preferred class of compounds of the formula I are those selected from the group:

D, L-4-cyanoamino-α-methylphenylalanine O, L-4-guanidino-a-methylphenylalanine D, L-3-Hydroxy-4-methanesulfonamido-α-methylphenylalanine O, L-4-amino-3-methanesulfonyloxy-α-methylphenylalanine D, L-4- (2-aminoimidazol-1-yl) -a-methylphenylalanine and D, L-4- (imidazol-2-yl-amino) -a-methylphenylalanine

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D, L-4- (imidazol-2-yl) -α-methylphenylalanine D, L-4- (4,5-dihydroimidazol-2-yl) -a-methy! Phenylalanine D, L-2-methy1-3- (benzoxazol-2-on-6-yl) -alanine D, L-3- ^ -amino ^ -mercaptobenzothiazol-ö-yl) -2-methylalanine D, L-3- (i, 3-dihydΓobenzo-2 _f 1 , 3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide

D, L-3- (1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-3,3-dioxide-methyl ester

D, L-3- (1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -alanine-5,5-dioxide D, L-3- (i, 3-dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide

D, L-2-methyl-3- (quinoxalin-6-yl) alanine dihydrochloride D, L-3- (quinoxalin-6-yl) alanine

D, L-3- (2,3-dihydroxyquinoxalin-6-yl) alanine hydrochloride D, L-3- (5-Hydroxy-4H-pyran-4-on-2-yl) -2-methylalanine D, L-3- (2-Hydroxy-4-pyridyl) -2-methylalanine their salts and their hydrates.

The compounds of Formula II are generally described in US Pat 3,462,536. Examples of suitable compounds of the formula II are:

methyl α-hydrazino-β-3,4-dihydroxyphenylpropionate α-hydrazino-α-methyl-ß-3f4-dihydΓoxyphenylpropionsäuΓe-butyl-

α-hydrazino-β-3,4-dihydroxypheny! propionic acid α-hydrazino-β-3,4-dibutoxypheny! propionic acid α-hydrazino-β-3,4-dimethoxypheny! propionic acid α-hydrazino-α-butyl-β-3,4-dihydroxypheny! propionic acid α-hydrazino-α-ethyl-β-3,4-dihydroxyphenylpropionic acid α-hydrazino-α-propyl-β-3,4-dimethoxypheny! propionic acid and others

Compounds of the formula II in which R ^ is a hydrogen atom or is a methyl group are preferred, and compounds in which R ^ is a methyl group are most preferred.

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Particularly preferred compounds of the formula II are the L-isomers preferred compounds which are essentially free of the D-isomer. A particularly preferred compound of formula II is L-a-hydrazino-a-methyl-β ^ j ^ -dihydroxyphenylpropionic acid.

The preparations according to the invention furthermore comprise combinations in which the weight ratio can vary, as the ratio depends to some extent on the activity of the compounds will depend. A weight ratio of arylalanine (A): Decarboxylase inhibitor (B) from about 20: 1 to about 1: 9000 is suitable. A preferred weight ratio is about 10: 1 to about 1: 100. A more preferred weight ratio is about 5: 1 to about 1:20, and a weight ratio of about 5: 1 to about 1: 2 is most preferred.

The preparation is administered to hypertonic living beings in an amount sufficient to achieve the desired reduction in the Blood pressure. The dose, on a daily basis, can range from about 0.005 to about 1000 mg / kg and more preferably from about 0.05 to about 300 mg / kg animal body weight. A particularly preferred dose range is from about 0.05 to about 100 mg / kg, with the most preferred range being about 0.1 to about 75 mg / kg. This dose can be used as the only one Unit or, more commonly, the dose can be divided into a number of smaller units that are used during administered one day.

The preparation can be administered orally or parenterally. The preparations can be in suitable dosage forms, in a manner known per se, generally together with suitable carriers, diluents, starches, dyes etc. are prepared. For oral administration, the preparations can e.g. in the form of tablets, capsules, liquid

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in mixtures, among others. For parenteral administration the preparations can be produced as a solution with a suitable liquid diluent. It will methods known per se are used for the preparation of the preparation.

The following examples explain compounds of the formula I by way of example. All temperatures are given in ^° C.

example 1 D, L-4-cyanoamino-a-methylphenylalanine hydrate

To a solution of 3.2 g (12 mmol) of D, L-4-amino-α-methylphenylalanine dihydrochloride [Saari et al, J. Med. Chem., JK), 1008 (1967)] and 5.05 g (63 mmol) of sodium acetate in 25 ml of water are added 1.6 g (15 mmol) of cyanogen bromide. After 30 minutes, a fine, white solid begins to separate out. 0.5 g (5 mmol) of further cyanogen bromide are added. The mixture is left to stand at room temperature for 16 hours. D s _a product, which has crystallized, is filtered off, washed with water and dried; Yield 2.02 g (77%), mp 370 °.

Example 2

DL-3-carboxy-q-methylphenylalanine hydrochloride m.p. 280-285 ° (dec.).

Example 3

D. L-a-Methvl-A-thiocarbamovlphenvlalanine-Methvlester

A. Methvl-DL-3- (4-cyanophenyl) ^ - isocvano ^ -methylpropionate

43 »5 g (385 mmol) of methyl 2-isocyanopropionate are slow added to a suspension of sodium methylate (20% excess) in 225 ml of dry dimethylformamide at -10 to -15 °.

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The resulting solution slowly becomes a solution of 49, Og (0.25 mol) 4-cyanobenzyl bromide [Case, J. Am. Chem. Soc., 47, 1143 (1925)] in 200 ml of dry dimethylformamide at -10 given up to -15 °. After the addition is complete, the reaction mixture can reach room temperature. The mixture will added with stirring to a mixture of ice and water, and the solid is filtered off. The solid is in 200 ml V / ater suspended, stirred for 1 h, filtered, rinsed with water and dried in the air; 45.5 g (80 #) of methyl D, L-3- (4-cyanophenyl) -2-isocyano-2-methylpropionate are obtained, M.p. 90 to 91 °.

B. D, L-4-cyano-Nformvl-tt-methylphenylalanine methyl ester

50 g (0.22 mol) of methyl D, L-3- (4-cyanophenyl) -2-isocyano-2-methylpropionate, prepared as described in step A, are dissolved in 500 ml of ethyl acetate. To the resulting solution give 4 ml of conc. Hydrochloric acid, and the mixture is stirred for 10 to 15 minutes at room temperature. The ethyl acetate solution is rinsed with water until neutral, dried, filtered and evaporated to dryness. The oily residue is triturated with ether and allowed to crystallize. The solid is filtered, rinsed with cold ether and air dried; 32.7 g (60 #) D, L-4-cyano-N-formyl-a-methylphenylalanine methyl ester are obtained, Mp. 152 to 153 °.

C. D, L-N-Formyl-α-methyl ^ -tMocarbamoylphenylalanine methyl ester

5.0 g (20.3 mmoles) of D, L-4-cyano-N-formyl-α-aethylphenylalanine methyl ester are dissolved in 150 ml of pyridine. 2.1 g of triethylamine are added to the resulting solution and hydrogen sulfide is passed in 2 h through the solution. The mixture is stirred at room temperature for 18 hours and evaporated to dryness. Of the The residue is dissolved in chloroform. The chloroform solution

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is rinsed with water, dried, filtered and taken under Evaporated to dryness formation of a gum. A layer of ether is applied to the rubber. The mixture can be kept for 48 hours at room temperature crystallize. The solid is filtered off, rinsed with ether and air-dried; you get 5.36 g (94%) D, L-N-formyl-a-methyl-4-thiocarbamoylphenylalanine methyl ester, Mp 135-137 °.

D. DL-α-methyl 1-thiocarbamoylphenylalanine methyl ester

To a solution of 4.4 g (15 »7 mmol) of D, L-N-formyl-cc-methyl-4-thiocarbaraoylphenylalanine methyl ester 5 l of conc. in 120 ml of methanol are added. Hydrochloric acid. The mixture will Left for 3 days at room temperature. The solution is evaporated to dryness. The residue is dissolved in 100 ml of water solved. It is then washed with 2 × 50 ml of ethyl acetate. Sodium bicarbonate is added to the aqueous phase until it is alkaline Reaction. It is then extracted with 2 × 100 ml of ethyl acetate. The ethyl acetate extracts are dried, evaporated and the residue is triturated with 15 ml of ether. The resulting solid is filtered off; 3.6 g are obtained (76%) D, L-a-methyl-4-thiocarbamoylphenylalanine methyl ester, Mp. 126 to 128 °.

Example 4

D, L-4- (aminomethyl) -tt-methylphenylalanine-dihydrochloride-hvdrat m.p. 178 to 186 ° (dec.)

Example 5

D, L-4-guanidino-q-methylphenylalanine dihydrochloride

A. D _t LN-Acetyl-α-methyl-4-aminophenylalanine methyl ester

40 g (143 mmoles) of D ^ -N-acetyl-cc-methyl ^ -nitrophenylalanine methyl ester [Zenker et al, J. Med. Chem., R £, 1223 (1974)] in

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Methanol hydrogenated at 3.1 kg / cm ² over 5% palladium on charcoal. The solution is filtered and concentrated; 15.8 g of DjL-N-acetyl-a-methyl- ^ aminophenylalanine methyl ester, melting point 145 ° to 148 °, are obtained. The mother liquors are evaporated; a further 17.8 g of N-acetyl-α-methyl-4-aminophenylalanine methyl ester are obtained. 94% overall yield.

B. D, L- N -acetyl-4- (3-benzoylguanidino) -a-methylphenylalanine methyl ester

3.0 g (12 mmoles) of DiL-N-acetyl-α-methyl-1-aminophenylalanine methyl ester are dissolved in 50 ml of methanol. Dry hydrogen chloride is bubbled into the solution. The solvent is removed in vacuo. The evaporation is repeated several times with methanol. The residue is dissolved in 25 ml of methanol and then refluxed with 1.76 g (12 mmol) of benzoylcyanamide for 24 hours. Another 352 mg (2 mmol) of benzoylcyanamide will be added admitted. The solution is refluxed for a further 24 hours. The solution is evaporated in vacuo and the solids are triturated with ethyl acetate. 4.75 g are obtained Solids. The solids are further triturated with 50 ml of hot ethyl acetate; 4.12 g (79.2%) of D, L-N-acetyl-4- (3-benzoylguanidino) are obtained ) -a-methylphenylalanine methyl ester, m.p. 234 to 245 ° (decomp.).

C. D, L-4-guanidino-tt-methylphenylalanine dihydrochloride

3.45 g (8 mmoles) of D, L-N-acetyl-4- (3-benzoylguanidino) -a-methylphenylalanine methyl ester are in 160 ml of 7N hydrochloric acid Heated under reflux for 6 h. The solution is extracted with 3 x 20 ml of diethyl ether to remove the benzoic acid and the aqueous part is evaporated. The residue is treated with 1: 1 ethanol: benzene; a dry product is obtained. Finally, it is triturated with hot ethanol; 1.53 g (61.9%) of D, L-4-guanidino-a-methylphenylalanine dihydrochloride are obtained, M.p. 299-3 ° (dec.).

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Example 6

D, L-5-hydroxy-4-ynethanesulfonamido-oc-methy! Phenylalanine

A. D, LN-Formyl ^ -hydroxy ^ -iiitro-α-methylphenylalanine-methyl ester

In a 3 l three-necked flask equipped with a mechanical stirrer, drying tube and thermometer, 14O.5 g (0.75 moles) 3-hydroxy-4-nitro-benzyl chloride, prepared as described by S.B. Hanna et al, J. Chem. Soc. 221 (1961), described, dissolved in 750 ml of dimethylformamide. The solution is cooled in an ice bath. 40.5 g (0.75 mol) of powdered sodium methylate are added over 5 minutes. The flask is then cooled and held at -55 °. In a separate The flask is added to a suspension of 81 g (1.5 mol) of sodium methylate in 1.0 l of dimethylformamide, which is kept at -55 °, 171 g (1.5 mol) of methyl 2-isocyanopropionate. One lets the temperature does not rise above -50 °. This solution is then placed in a flask containing the anion of 3-hydroxy-4-nitrobenzyl chloride contains, whereby the temperature is always kept at -50 °. In the course of 30 minutes, the temperature can rise to -35 °. Thereafter, the TLC analysis (thin-layer chromatographic Analysis) a complete disappearance of the 3-hydroxy-4-nitrobenzyl chloride. 1000 ml of water will be then added and the mixture is extracted three times with ether to remove excess methyl 2-isocyanopropionate. The aqueous phase is acidified by adding 180 ml of acetic acid in 180 ml of water and three times with ether extracted. The organic phase is washed with water, dried over magnesium sulfate and concentrated in vacuo. The remaining oil is dissolved in 1.5 l of ethyl acetate. It is kept at 0 ° and concentrated by adding 15 ml. Hydrochloric acid and stirring for 10 minutes. The solution is washed with water and dried over magnesium sulfate and concentrated in vacuo; 155 g (7350

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Solid after trituration in petroleum ether, melting point 113 ° to 115 °.

B. D, L-3-Hydroxy-4-methanesulfonamido-g-methylphenylalanine 14.1 g (50 mmol) of D ^ N-Forayl ^ -hydroxy ^ -nitro-oc-methylphenylalanine methyl ester, dissolved in 50 ml of methanol , are hydrogenated over 5% palladium on charcoal on a Parr hydrogenator. After the hydrogen absorption has ended, the catalyst is filtered off and the solvent is evaporated in vacuo. A red, thick oil remains, which is dissolved in 200 ml of acetone and 20 ml of water. 22.2 g (195 mmol) methanesulfonyl chloride and 27 g (195 mmol) potassium carbonate are added and the reaction mixture is stirred for 1 hour. The insoluble substances are filtered off and washed with acetone. The filtrate is concentrated; a dark, oily residue is obtained which is taken up in ethyl acetate, washed with dilute hydrochloric acid and with water. The organic layer is dried over magnesium sulfate and concentrated. 6 g of the residue are absorbed on a silica gel column and eluted with ethyl acetate; 5.5 g of a residue consisting of D, LN-formyl-4-bis (methanesulfonyl) -amino-3-methanesulfonyloxy-α-methylphenylalanine methyl ester are obtained. This is taken up in 50 ml of 5% sodium hydroxide and heated on a steam bath for 2 h. The pH of the solution is adjusted to neutral and the solution is passed through a column filled with Dowex 50W-X8 0.149-0.074 mm (100-200 mesh) H ⁺ . Elution with 5 # ammonium hydroxide gives 1.64 g (11.496) D, L-3-hydroxy-4-methanesulfonamido-a-methylphenylalanine, m.p. 298 ° (dec.).

Example 7

D, L-4-amino-3-methanesulfonyloxy-a-methylphenylalanine dihydrochloride

M.p. 162 ° (dec.).

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Example 8

D, L-3 ~ carboxymethoxy-4-nitro-g-methyphenylalanine hydrochloride, m.p. 250 ° (dec.).

Example 9

D, L ~ 4-amino-g-methyl-3-nitrophenylalanine dihydrochloride

Mp. 239 Ms 241 ° (decomp.)

Example 10

D, L-3 «4-diamino-a-methylphenylalanine dihydrochloride

M.p. 135 to 140 ° (dec.).

Example 11

D, L-oc-methyl-4- (pyrrol-1-yl) -phenylalanine

A. D, LN-formyl-g-methylphenylalanine methyl ester

35 g (153 mmoles) of D, L-α-methylphenylalanine methyl ester hydrochloride are according to the method of Stein et al, J.Am.Chem. Soc, 77, 700 (1955), with the exception that one uses a mixture of formic and acetic anhydride instead of acetic anhydride; 27 g (80%) of D, L-N-formyl-a-methylphenylalanine methyl ester are obtained, Mp. 64 °.

B. D, LN-formyl-q-methyl-4-nitrophenylalanine methyl ester

10 g (45.3 mmol) of the product from stage A are slowly added to 25 ml of stirred ENT, (red, smoking) at -15 °. To stirring for a further hour at -15 °, the mixture slowly becomes a vigorously stirred, ice-cold, saturated one NaHCO, solution given. The resulting precipitate is filtered off, washed with water and then with 25 ml of ether; 4.24 g, melting point 108 ° of product are obtained. The mother liquors result in a further 7.0 g (oil) crude product; Overall yield: 94%.

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C. D, LN-Formyl-tt-methyl-4-aminophenylalanine methyl ester

184 g (690 mmoles) of D ^ N-formyl-α-methyl ^ -nitrophenylalanine methyl ester in methanol are at 3 »1 kg / cm over 5 # igem Palladium-on-animal charcoal hydrogenated. The solution is filtered iind evaporated; a rubber is obtained. The rubber is in 2n Dissolved hydrochloric acid and extracted with ethyl acetate.

The acidic aqueous solution is made alkaline with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution it is evaporated and the residue is crystallized from methanol; 79.5 g (48.530 D, L-N-formyl- <xmethyl-4-aminophenylalanine methyl ester, Mp 105-108 °.

D. D, LN-Formyl-α-methyl-4- (pyrrole-1 -yl) -phenylalanine-methyl ester

A solution of 13 »5 g (57 mmol) of D, L-N-formyl-a-methyl-4-aminophenylalanine methyl ester (prepared as in step C) and 8.44 g (64 mmol) of 2,5-dimethoxytetrahydrofuran in 60 ml of acetic acid is heated for 30 min on a steam bath under nitrogen. The mixture is cooled, 150 ml of water are added and the aqueous mixture is extracted with 6 × 150 ml of chloroform. The combined chloroform extracts are with Washed water / water, dried over magnesium sulfate, filtered, and the filtrate is evaporated to dryness in vacuo; man receives 19.4 g of crude product. The crude residue is made from a Silica gel column eluted with chloroform. After removal of the chloroform, the residue is washed with low-boiling petroleum ether rubbed in; 8.32 g (5Ο9 δ) D, L-N-formyl-a-methyl-4- (pyrrole-1) are obtained -yl) -phenylalanine methyl ester, melting point 118 to 119 °.

E. DL-α-Methvl-4- (pyrrol-1-yl) -phenylalanine

7.9 g (27.6 mmol) of D, L- N -formyl-a-methyl-4- (pyrrole-1 -yl) -phenylalanine methyl ester are under nitrogen on one overnight

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15 858Ϊ IS ^2705863 steam bath heated in 75 ml of methanol and 16 ml of 7N sodium hydroxide solution. Another 4 ml of 7N sodium hydroxide solution are added and the solution is heated on the steam bath for a further 4 hours. The mixture is evaporated in vacuo, the solid residue is dissolved in 100 ml of water and 6.78 g (113 mmol) of acetic acid are added. The mixture is cooled and the solids are collected. The solids are refluxed with water for 1 hour, filtered, washed with ethanol and then with diethyl ether and dried for several hours in a vacuum oven at 60 °; 6.45 g (79.5%) of D, La-methyl-4- (pyrrol-1-yl) -phenylalanine, melting point 290 to 293 ° (decomp.) are obtained

Example 12

D, L-4- (2-aminoimidazol-i-yl) -a-methylphenylalanine hydrochloride and D, L-4- (imidazol-2-yl-amino) -a-methylphenylalanine hydrochloride

A. D, LN-Acetyl-4-cvanamido-q-methvlphenvlalanine-methyle ^ ter

16 g (64 mmoles) of D, L-N-acetyl-4-amino-cc-methylphenylalanine methyl ester (prepared as in step A of Example 5) are suspended in 225 ml of water. Then 4.8 ml of concentrated hydrogen chloride are added acid in 25 ml of water, followed by 12.7 g (155 mmol) of sodium acetate and finally 13.6 g (128 mmol) Cyanogen bromide. The mixture is left to stand at room temperature for 0.5 h. Many solids precipitate during this time. The solids are collected and air dried; 16.8 g (95.2 #) of D ^ -N-acetyl ^ -cyanaiaido-a-methylphenylalanine methyl ester are obtained, Mp 171.5-173.5 °.

B. D _T LN-Acetyl-α-methyl-4-thioureidophenylalanine methyl ester

16.8 g (61 mmoles) of D, L-N-acetyl-4-cyanamido-α-methylphenylalanine methyl ester are dissolved in a solution of 350 ml of dry pyridine and 6.8 g (67.1 mmol) of triethylamine. Drier Hydrogen sulfide is passed through for 2 hours with stirring. The solvent is removed in vacuo. The residue is with

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Chloroform triturated, filtered and dried; 18.4 g (97.5%) of DL-N-acetyl-α-methyl- ^ thioureidophenylalanine methyl ester, melting point 202-204 °, are obtained.

C. D, LN-Acetyl-α-methyl - ^ - (2-methyl-1 -isothioureido) -phenyl alanine methyl ester

18.3 g (59 mmoles) of DjL-N-acetyl-cc-methyl-1-thioureidophenylalanine methyl ester are suspended in 350 ml of acetonitrile and treated with 7.4 g (64.9 mmol) of methyl fluorosulfonate. That Mixture is stirred for 1 hour to cause dissolution. The solution is concentrated in vacuo and the residue is between Ethyl acetate and dilute sodium bicarbonate distributed. The ethyl acetate extracts are dried over magnesium sulfate, evaporated to dryness, and the residue is crystallized from ethyl acetate: diethyl ether; you get 15.4 g (80.7 #)

D, L-N-Acetyl-a-methyl ^ -) 2-methyl-1-iso thioureido) -phenylalanine methyl ester, M.p. 156-158.0 ° (dec.).

D. D, L-4- (2-Arainoimidazol-1 -yl) -oc-methylphenylalanine hydrochloride and Ο, Ι ^ -4- (Ιπώα3Ζθ1-2 ^ 1-αΒΐ1ηο) -α-ΐηβ · 0 ^ 1ρ1ιβ ^ 1 - alanine hydrochloride

15 g (47.6 mmoles) of D, L-N-acetyl-a-methyl-4- (2-methyl-1-isothioureido) -phenylalanine methyl ester v / earth is heated for 14 h at 83 ° with 63.3 g (476 mmol) of 2-aminoacetaldehyde diethyl acetal. Excess acetal is removed by distillation in vacuo; 20 g (approx. theory) of D, L-N-acetyl-4- [2- (2,2-diethoxyethyl) -guanidinoiJ) henylalanine methyl ester are obtained in the form of an oil. This product is used in the next reaction without further purification.

About 20 g of D, L-N-acetyl-4- [2- (2,2-diethoxyethyl) guanidino] phenylalanine methyl ester are dissolved in 200 ml of 6N hydrochloric acid at room temperature. The solution is immediately afterwards in a vacuum at a bath temperature maintained at 45 °

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Evaporated dry. The residue is dissolved in water with ammonium hydroxide to adjust the pH to 10 treated and then extracted with chloroform. The combined chloroform extracts are dried over magnesium sulfate. The filtrate is evaporated and the residue is crystallized from acetonitrile; 2.75 g of D, L-N-acetyl-4- (2-aminoimidazol-1-yl) -a-methylphenylalanine methyl ester are obtained (which contains a small amount of its isomer), m.p. 179 to 183 °. 2.75 g of this Esters are concentrated in 55 ml. Hydrochloric acid refluxed for 5 hours; 2.33 g of D, L-4- (2-aminoimidazo 1-1 -yl) -a-methylphenylalanine hydrochloride [which about 1096 D, L-4- (imidazol-2-yl-amino) -cc-methylphenylalanine hydrochloride contains].

The after removal of the crystalline D, L-N-acetyl-4- (2-aminoimidazol-1-yl) -a-methylphenylalanine methyl ester residues obtained are concentrated in 125 ml for 6 h. Hydrochloric acid heated to reflux. The solvent is then removed in vacuo and the product is triturated with ethanol. the Ethanol extracts give 424 mg of C, L-4- (imidazol-2-yl-amino) -cc-methylphenylalanine hydrochloride after treatment with benzene, Mp.> 360 ° (dark color over a wide area). The residues yield 6.2 g of one on further cleaning Mixture of the hydrochlorides of D, L-4- (2-aminoimidazole-1IyI) -a-methy! Phenylalanine and D, L-4- (imidazol-2-yl-amino) -a-methylphenylalanine.

The ammoniacal mother liquors from the first acid hydrolysis are evaporated, the resulting residue is in 125 ml conc. Dissolved hydrochloric acid and refluxed for 6 h. The solution is evaporated, the crude product is dissolved in ammonia, evaporated, the residue is dissolved in water dissolved and with a cation exchange resin Dowex 50W-X4 0.297 to 0.149 mm (50 to 100 mesh) filled column. The liquid is evaporated to dryness, the solids

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v / earth dissolved in dilute hydrochloric acid, with animal charcoal treated, filtered and partially evaporated; 1.19 g of pure D, L-4- (2-aminoimidazol-1-yl) -a-methylphenylalanine hydrochloride are obtained, Mp. 320 ° (dec.). The mother liquors of these solids yield 2.25 g of a 1: 1 mixture of the hydrochlorides of D, L-4- (2-aminoimidazol-1-yl) -a-methylphenylalanine and D, L-4- (imidazol-2-yl-amino) -a-methylphenylalanine.

Example 13

D, L-4- (4,5-dihydro-4-hydroxy-4-trifluoromethylthiazol-2-yl) - <x methylphenylalanine methyl ester

M.p. 118 to 120 °.

Example 14

D, La-methyl-4- (4-trifluoromethylthiazol-2-yl) -phenylalanine hydrochloride

Mp. 220 to 230 °.

Example 15

D, L-cc-methyl-3- (4-trifluoromethylthiazol-2-yl) -phenylalanine hydrochloride

M.p. 230 ° (decomp.).

Example 16

D, L-4- (imidazol-2-yl) -a-methylphenylalanine dihydrochloride hemihydrate

A. D, LN-Formyl-cc-methyl ^ - (methylthiocarboximidato) -phenyl alanine methyl ester

4.0 g (14.3 mmol) of ^, L-N-Formyl-a-methyl - ^ - thiocarbamoylphenylalanine methyl ester from stage C of Example 3 are dissolved in 120 ml of acetone. 1.6 g (14.25 mmoles) of methyl fluorosulfonate become

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added and the mixture is stirred at room temperature for 18 h. The solution is evaporated to dryness and the The residue was partitioned between water and ethyl acetate. The aqueous layer is extracted twice with 50 ml of ethyl acetate. Sodium bicarbonate is added to the aqueous extract until it has an alkaline reaction, and the mixture is extracted with ethyl acetate. the Ethyl acetate extracts are combined, dried, filtered and evaporated to dryness; 3 g (71%) of D, L-N-formal-oc-methyl-4- (methyl thiocarboximidato) phenylalanine methyl ester, m.p. 119 to 120 °.

B. D, L-4- (imidazol-2-yl) -a-methylphenylalanine dihydrochloride hemihydrate

A mixture of 6.5 g (22 mmol) D, LN-formyl-cc-methyl-4- (methylthiocarboximidato) -phenylalanine methyl ester, 2.0 g (22 mmol) oxalic acid and 3.0 g (22.5 mmol) Aminoacetaldehyädiäthylacetat in 150 ml of methanol is stirred for 18 h at 25 °. The reaction mixture is evaporated to dryness and the residue is dissolved in 100 ml of water. The aqueous solution is extracted with 50 ml of ethyl acetate, which is discarded. Solid sodium bicarbonate is added until the reaction is alkaline and then extracted with 2 × 100 ml of ether, which is discarded. The aqueous solution is then evaporated to dryness. A gummy residue remains, which is stirred with 500 ml of chloroform for 24 hours. The chloroform solution is filtered to separate off inorganic salts, dried and evaporated; an oil is obtained which is dissolved in 80 ml of concentrated hydrochloric acid. The solution is treated at 50 ° for 30 minutes and then refluxed for 4 hours. Cooling and filtering the precipitated solid gives 2.1 g of D, L-4- (imidazol-2-yl) -a-methylphenylalanine dihydrochloride hemihydrate, melting point 225 ° to 230 °. Concentration of the filtrate gives a further 0.88 g of product, which increases the yield to h2% .

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Example 17

D, L-4- (4,5-dihydroimidazol-2-yl) -α-methylphenylalanine hydrochloride tetrahydrate

M.p. 145 to 148 ° (dec.).

Example 18

D, L-3- (Imidazol-2-yl) -a-methylphenylalanine dihydrochloride hvdrat

A. D, LN-Formyl-a-methyl-3- (methyl thiocarboximida to) -phenyl alanine methyl ester

4 g (14.25 millimoles) of DjL-N-formyl-α-methyl ^ -tniocarbamoylphenylalanine methyl ester from stage B of Example 15 are dissolved in 120 ml of acetone. 1.6 g (14.25 mmoles) of methyl fluorosulfonate are admitted. The mixture is stirred at room temperature for 18 hours. The solution is evaporated to dryness. The residue is divided between water and ethyl acetate. The aqueous layer is extracted twice with 50 ml of ethyl acetate. Sodium bicarbonate is added to the aqueous extract until it has a basic reaction, and the mixture is extracted with ethyl acetate. the Ethyl acetate extracts are combined, dried, filtered and evaporated to dryness; 4.1 g (97.5? 0 D, L-N-formyl-a-methyl-3- (thiomethylcarboximidato ) -phenylalanine methyl ester, m.p. 115 to 117 °.

B. D, L-3- (Imidazol-2-yl) -cc-methylphenylalanine dihydrochloride hydrate

9.0 g (30.6 mmol) of D, L-N-formyl-a-raethyl-3- (methylthiocarboximidato) -phenylalanine methyl ester are used as starting material and operates as in Step B of Example 16 described, after recrystallization from 50 ml of water, 2.0 g of (19Ji) D, L-3- (imidazol-2-yl) -a-methylphenylalanine dihydrochloride hydrate are obtained, M.p. 295 to 298 °

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Example 19

D, L-3- (4,5-dihydroimidazol-2-yl) -α-methylphenylalanine dihydrochloride hydrate

Use 5.0 g (17 mffol) of D, L-N-formyl-a-methyl-3- (methyl-thiocarboximidato) -phenylalanine methyl ester (prepared v / ie in Step A of Example 18) as a starting material and works v / ie described in Example 17, 4.23 g (74%) of D, L-3- (4,5-dihydroimidazol-2-yl) -cc-methylphenylalanine dihydrochloride hydrate are obtained, Mp. 308 to 315 ° (decomp.)

Example 20

D, L-4- (imidazol-2-yl) phenylalanine dihydrochloride hydrate

M.p. 120 to 140 ° (decomp.).

Example 21

D, L-4- (4 ₁ 5-dihydroimidazol-2-yl) phenylalanine dihydrochloride

Mp. 240 to 245 ° (dec.).

Example 22

D. L-3- (Imidazole-2-vl) -phenvlalanine-dihydrochloride-hydrate

Mp. 250 to 255 °.

Example 23 D.L-3- (2.3-Dihydro-1H-indol-5-yl) -tt-methylalanine m.p. 264-268 ° (dec.).

Example 24

D. L-oc-Methvl-3- (1H-2-oxindole-5-vl) -alanine

A. D, L-3- (1 -Benzoyl-2,3-dihydro-1H-indol-5-yl) ^ - methylpropionic acid methyl ester

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9.4 g (83 mmol) of methyl 2-isocyanopropionate are added with cooling added to a cold solution of 4.5 g (83 mmol) of sodium methylate in 50 ml of dimethylformamide. The solution is in Course of 10 minutes to a solution of 14.9 g (55 mmol) of 1-benzoyl-S-chloromethyl ^, 3-dihydro-1H-indole

in 50 ml of dimethylformamide, which at 0 to

12 ° is given. The mixture is stirred for 0.5 h, then poured into 1000 ml of ice-water. The solids will isolated and dried; 16.1 g (84%) of crude product are obtained. The crude product is crystallized from ethyl acetate; you get D, L-3- (1-Benzoyl-2,3-dihydro-1H-indol-5-yl) -2-isocyano-2-methylpropionic acid methyl ester, M.p. 148 to 150 °.

B. D, L-3- (1-Benzoyl-2,3-dihydro-1H-indol-5-yl) -N-formyl-a methylalanine methyl ester

348 mg (1 mmol) of D, L-3- (1-Benzoyl-2,3-dihydro-1H-indol-5-yl) -2-isocyano-2-methyl-propionic acid methyl ester are 0.5 h under Np in a solution of 11 ml of ethyl acetate, the 3 drops conc. Contains hydrochloric acid, stirred. The mixture is extracted with water. The ethyl acetate layer is poured over magnesium sulfate dried, filtered and evaporated; 365 mg of crude product are obtained. The residue is made from a mixture Chloroform and ethyl acetate crystallized; 291 mg (79.4%) of D, L-3- (1-benzoyl-2,3-dihydro-1H-indol-5-yl) -N-formyloc-methylalanine methyl ester are obtained, Mp. 163 to 166 °.

C. D, L-3- (1 -Benzoyl-1 H -indol-5-yl) -N -formyl-α-methylalanine methyl ester

8.1 g (22 mmoles) of D, L-3- (1-Benzoyl-1H-indol-5-yl) -N-formyl- <xmethylalanine methyl ester are dissolved in 400 ml of chloroform. The solution is cooled to 40 °. Then 7.5 g (33 mmol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is added and the solution is refluxed for 3 h under N £. The solution is cooled, diluted with 200 ml of chloroform and the chloro-

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Form solution is mixed with 3 x 10 ml of 5% sodium carbonate solution extracted. The combined Cliloroform extracts are with Washed water / water, dried over magnesium sulfate, filtered and evaporated. A solid residue is obtained. The solid is crystallized from ethyl acetate-diethyl ether; 6.24 g (77.8% D, L-3- (1-benzoyl-1H-indol-5-yl) -N-formylcc-methylalanine methyl ester are obtained, Mp 111-115 °.

D. D, L-3- (1 -BenzoylO-bromo-IH-indol-S-yl) -N-formyl-cc-methyl alanine methyl ester

6.56 g (18 mmol) of D, L-3- (1-Benzoyl-1H-indol-5-yl) -N-formyl-amethylalanine methyl ester are dissolved in 55 ml of chloroform. Then 2.96 g (18.5 mmol) of bromine in 50 ml of chloroform im Added in the course of 10 minutes. There is a slight increase in temperature. The solution is 15 min at room temperature left to stand, extracted with water, the combined chloroform extracts are dried over magnesium sulfate and evaporated; 9 g of solids are obtained. The solids are triturated with about 100 ml of diethyl ether; you get 7.37 g (92.4%) D, L-3- (i-Benzoyl-3-bromo-1H-indol-5-yl) -N-formyla-methylalanine methyl ester, Mp. 183 to 185 °.

E. DL-oc-methyl-3- (1H-2-oxindol-5-yl) -alanine

6.21 g (14 mmoles) of D, L-3- (i-Benzoyl-3-bromo-1H-indol-5-yl) -N-formyl-cc-methylalanine methyl ester are concentrated in a mixture of 200 ml of methanol, 40 ml. Hydrochloric acid and 80 ml Suspended water and heated at 80 ° for 3 h. The methanol is removed in vacuo. 120 ml conc. Hydrochloric acid added and the solution is heated for a further 8.5 h. The solution is evaporated in vacuo. The residue is in water dissolved and evaporated several times. Ammonium hydroxide is added and the solution is evaporated. The residue will triturated with ethanol; 4.7 g of solids are obtained. The solids are crystallized from ethanol-water; you get

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1.1 g (28.5 #) D, L-α-methyl-3- (iH-2-oxindol-5-yl) -alanine, m.p.

300 ° (decomp.).

Example 25

D, L-3- (1H-indole-5-vl) -α-methylalanine

M.p. 283 to 285 ° (dec.).

Example 26

D »L-3 - (Benzimidazol-2-thion-5-yl) -2-methylalanine-hvdrat

A. D, LN-Formyl-a-methyl-4-foi ^ lamino-3-nitrophenylalanine methyl ester

91.4 g (387 mmoles) of DjL-N-formyl-α-methyl-1-aminophenylalanine methyl ester (from step C of Example 11) are added to 500 ml of benzene. Ant acetic anhydride (5OS6 excess) is added and the mixture is refluxed for 30 minutes. The resulting solution is mixed with 1N aqueous sodium carbonate solution, until the washing solution reacts basic, washed. The benzene solution is then dried over MgSO ^ and evaporated; 80.3 g of D, L-N-formyl-a-methyl-4-formylaminophenylalanine methyl ester are obtained than oil. Nitration, as described in Step B of Example 11, of this oil gives 63.5 g D, L-N-Formyl-a-methyl-4-formylamino-3-nitrophenylalanine methyl ester, Mp. 177 to 179 °.

B. D, LN-Formyl-a-methyl-4-amino-3-nitrophenylalanine-methyl ester

15 g (48.5 mmol) of D, L-N-formyl-a-methyl-4-formylamino-3-nitrophenylalanine methyl ester will

treated accordingly. "This gives 13» 6 g (100 #) D, L-N-Forayl-a-methyl ^ -amino ^ -nitiO-phenylalanine methyl ester, Mp. 133-136 °.

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C. D _t L-314-Diamino-N-formyl-α-methylphenylalanine methyl ester

A mixture of 3.0 g (10.7 mmol) of D, L-N-formyl-a-methyl-4-amino-3-nitrophenylalanine methyl ester and 100 ml of methanol v / ird over 0.20 g of 10% palladium on charcoal at a Hydrogen pressure of 18.2 kg hydrogenated for 30 minutes. The reaction mixture is filtered and the filtered solution becomes Evaporated dry. 50 ml of benzene are added and it is evaporated again. The residue is with 25 ml of ether rubbed in. The resulting solid is filtered; 2.5 g (94%) of D, L-3,4-diamino-N-formyl-a-methylphenylalanine methyl ester are obtained, M.p. 118 to 120 °.

D. D, L-3- (Benzimidazol-2-thion-5-yl) -2-methylalanine hvdrat

To a solution of 6 g (24 mmol) of D, L-3,4-diamino-N-formyl-ocmethylphenylalanine methyl ester 5.4 g (72 mmol) of carbon disulfide and 4.0 g (72 mmol) of potassium hydroxide pellets are added to 100 ml of methanol, dissolved in 15 ml of water. The reaction mixture is refluxed for 2 hours and then to remove evaporated the methanol. 50 ml of water are then added to the residue, followed by 5 ml of acetic acid. The precipitation is filtered off and washed with water. The crude D, L-3- (benzimidazol-2-thion-5-yl) -N-formyl-a-methylalanine methyl ester is heated on a steam bath with 200 ml of 6N HCl for 3 h. The solution is evaporated and the residue is taken up in 50 ml of water. The solution with ammonium hydroxide added to a basic reaction, evaporated to dryness and then boiled in water. The product is filtered off and dried at 100 °. Yield 2.2 g (3390, m.p. 280 ° (dec.).

Example 27

DL-3- (2-aminobenzimidazol-5-yl) -2-methylalanine dihydrochloride A. D, LN-acetyl-3,4-diamino-cc-methylphenylalanine methyl ester A suspension of 10.0 g (34 mmol) D , LN-Ac etyl-4-amino-cc-

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methyl 3-nitrophenylalanine methyl ester

and 1.0 g 10bigem palladium-on-

Animal charcoal in 300 ml of methanol is under hydrogen at a Pressure of 18.2 kg until the hydrogenation has ended (30 min). The reaction mixture is filtered, evaporated to dryness; the residue is mixed with 50 ml of ethyl acetate slurried and evaporated again. The emerging Solid is slurried well with 100 ml of ether and filtered off; 7.87 g (87 #) of D, L-N-acetyl-3,4-diamino-α-methylphenylalanine methyl ester are obtained, Mp. 136 to 139 °.

B. D, L-3- (2-aminobenzimidazol-5-yl) -2-methylalanine-dihydro chloride

To a mixture of 1.0 g (3.8 mmol) of D, L-N-acetyl-3,4-diamino-α-methylphenylalanine methyl ester and 30 ml of water are added 1.0 g (9.5 mmol) of cyanogen bromide in two equal parts at intervals of 30 minutes. The reaction mixture is 1 h stirred at 25 ° and then extracted with 2 × 50 ml of ethyl acetate, which is discarded. The aqueous phase becomes dry evaporated. The residue is concentrated in 20 ml. Hydrochloric acid dissolved. The resulting solution is refluxed for 1 hour heated, cooled and the resulting precipitate is filtered off, washed well with ethanol and ether; man receives 0.64 g (55%) D, L-3- (2-aminobenzimidazdl-5-yl) -2-methylalanine dihydrochloride, M.p. 300 to 305 ° (dec.).

Example 28 D, L-2-Methvl-3- (benzoxazol-2-one-6-vl) -alanine-hvdrochloride

M.p. 285 ° (dec.).

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Example 29

D _f L-5- (2-aminobenzothiazole-6-vl) -Z-methylalanine dihydrochloride

A. D, LN-Acetyl-3- (2-aminobenzothiazol-6-yl) -2-methylalanine methyl ester

To a mixture of 5 »0 g (20 mmol) of D, L-N-acetyl-4-amino-amethylphenylalanine methyl ester (prepared as in step A of Example 5) and 3 »56 g (44 mmol) of sodium thiocyanate in 50 ml of acetic acid, cooled to 10 °, are added to a solution of 3.52 g (22 mmol) of bromine in 10 ml of acetic acid in the course of 15 minutes added. The reaction mixture is then stirred at 25 ° for 2 h. The inorganic salts which precipitate are filtered off. That The filtrate is evaporated to dryness. The residue is divided between 150 ml v / ater and 150 ml ethyl acetate.

Solid sodium hydroxide is added to the aqueous solution until it has a basic reaction (pH > 10) and extracted with 100 ml of ethyl acetate. Crystals begin to form during the extraction deposit from the organic layer; after filtration they give 2.58 g (8.4 mmol, 42 #) D, L-N-acetyl-3- (2-aminobenzothiazol-6-yl) -2-methylalanine methyl ester, Mp 228-229 °.

B. D, L-3- (2-Amino-benzothiazol-6-yl) -2-methylalanine-dihydro chloride

A mixture of 2.58 g (8.4 mmol) D, L-N-acetyl-3- (2-aminobenzo thiazol-6-yl) -2-methylalanine methyl ester and 60 ml of conc. Hydrochloric acid is refluxed for 1.5 hours and im Refrigerator cooled down. The precipitated solids are filtered off; 1.91 g (5.9 mmol, 70 #) D, L-3- (2-aminobenzothiazol-6-yl) -2-methylalanine dihydrochloride are obtained, M.p. 315-320 ° (dec.).

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D, L-3- (2-aminobenzothiazol-6-yl) -alanine-dihydrochloride m.p. 295-300 ° (dec.).

Example 31 D. L-2-methyl-3- (2.1.3-benzothiadiazol-5-yl) alanine hydrochloride

M.p. 272-274 ° (dec.).

Example 32

D, L-3- (1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine- 2,2-dioxide hydrate

Mp 234-236 °.

Example 33

D, L-3- (i, 3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine- 2,2-dioxide-methyl ester hydrochloride

A. D, L-3- (i, 3-Dihydrobenzo-2,1,3-thiadiazol-5-yl) -N-formyl-2- methylalanine-2,2-dioxide-methyl ester

To 30 ml of diglyme, which is heated under reflux, are added 560 mg (5 _f 8 mmol) of sulfamide in 15 ml of diglyme. 1.4 g (5.6 mmol) of D ^^^ - diainino-N-formyl-a-raethylphenylalanine methyl ester (prepared as in step C of Example 26) are then added. The mixture is refluxed for a further 30 minutes. The solvent is evaporated and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and then with 5% sodium bicarbonate solution. The bicarbonate solution is then acidified with hydrochloric acid, extracted with ethyl acetate, and the organic extracts are dried and evaporated. Trituration of the residue with chloroform gives the crystalline product, 0.70 g (40%), melting point 175 ° to 178 °.

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B. D, L-3- (1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methyl- alanine ^^ - dioxide methyl ester hydrochloride

To a solution of 2.0 g (6.4 mmol) D, L-3- (i, 3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -N-formyl-2-methylalanine-2, 2-dioxide methyl ester in 100 ml of methanol are 5 drops of conc. Hydrochloric acid and the solution is allowed to stand at 25 °. The addition of acid is repeated every 2 days over the course of 2 weeks. Then the solvent is evaporated and the residue is refluxed in 50 ml of toluene for 20 h to remove residual methanol. Filter off and dry 1.76 g (85 #) D, L-3- (1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide methyl ester hydrochloride, M.p. broadly 145 to 165 ° (decomp.).

Example 34

D, L-3- (i, 3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -alanine-5,5- dioxide hydrate

M.p. 195 to 225 ° (dec.).

Example 35

D, L-3- (1,3-Dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide hydrate

A. D, L-3- (i, 3-Dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5-yl) - N-formyl-2-methylalanine-2 ₁ 2-dioxide-methyl ester

To a solution of 1.9 g (6.1 mmol) D, L-3- (1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -N-formyl-2-methylalanine-2, 2-dioxide methyl ester (prepared as in step A of Example 33) in 50 ml of methanol is added in parts to a solution of 4 g (95 mmol) Diazomethane in 200 ml of ether. The solvents are evaporated. The residue is dissolved in 150 ml of ethyl acetate. the organic solution is washed with 5% sodium bicarbonate solution and water, dried and evaporated, recrystallization of the residue from ethanol gives 1.2 g (58%) D, L-3-

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(1,3-Dihydro-1,3-dimethylbenzo-2,1,3-thladiazol-5-yl) -N-formyl-2-methylalanine-2,2-dloxide-methyl ester, M.p. 167 Ms 168 °.

B. D, L-3- (1,3-dihydro-1,3-dimethylt> enzo-2,1,3-thiadiazole-5- vl) -2-methalanine-2 «2-dioxide hydrate

A device of 1.0 g (2.9 mmol) D, L-3- (i, 3-dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5-yl) -N-formyl-2- methylalanine-2,2-dioxide-methyl ester, 0.50 g of sodium hydroxide and 6 ml of water are heated on the steam bath for 45 minutes. The reaction mixture is cooled and acidified with 3N hydrochloric acid. Then you give conc. Add ammonium hydroxide to a basic reaction and evaporate to dryness. Consecutively three parts of 25 ml of water are added to the residue and evaporated therefrom, then 25 ml of water added and the insoluble solid is filtered off; 0.85 g (92%) of D, L-3- (1,3-dihydro-i, 3-dimethylbenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2- are obtained dioxide hydrate, Mp. 250 to 252 ° (dec.).

Example 36 D, L-tt-methyl-3-f4-methyl-2 (1H) -oxoquinoln-6-yl 1-alanine

Mp. 259 to 263 ° (dec.).

Example 37

D »L-3 r4-Methvl-2 (1 H) -oxoquinolin-6-yl 1-alanine hydrate

Mp. 247 to 249 ° (gas formation).

Example 38

D. L-2-methyl-3- (quinoxalin-6-yl) alanine dihydrochloride

A. DL-N-Formyl-2-methyl-3- (quinoxalin-6-yl) -alanine, methyl ester

A mixture of 10.0 g (35 »6 mmol) of D, L-4-amino-N-formyl-ctmethyl-3-nitrophenylalanine methyl ester (made as in

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Stage B of Example 26) and 300 ml of methanol is over 1.0 g 10% palladium on charcoal at hydrogen pressure hydrogenated by 18.1 kg for 1 h. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in 70 ml of hot water. A solution of 7.0 ml of 40% strength aqueous glyoxal (50 mmol) and 8 »0 g (77 mmol) of sodium bisulfite in 50 ml of water. The resulting solution is heated on a steam bath for 25 minutes, cooled and mixed with sodium carbonate for a basic reaction. Filtration and drying of the resulting precipitate result 7.9 g (81%) D, L-N-formyl-2-methyl-3- (quinoxalin-6-yl) -alanine methyl ester, M.p. 167-168 °.

B. DL-2-methyl-3- (quinoxaline-6-vl) alanine dihydrochloride

A mixture of 7.3 g (26.8 mmol) of D, L-N-formyl-2-methyl-3- (quinoxalin-6-yl) -alanine methyl ester and 70 ml conc. Hydrochloric acid is refluxed for 1 hour. The solution is then evaporated to dryness, 50 ml of water are added and it is again evaporated to dryness. The residue is dissolved in 100 ml of water and decolorized by treatment with 1 g of animal charcoal at 60 ° for 1 h. The mixture will filtered. The filtrate is evaporated to dryness and the residue is slurried with 50 ml of ethanol. Filtration of the resulting solid gives 5.57 g (6895) D, L-2-methyl-3- (quinoxalin-6-yl) -alanine dihydrochloride, M.p. 235 to 250 ° (dec.).

Example 39

Mixture of D, L-2-methyl-3- (2-hydroxyquinoxalin-6-yl) -alanine and D, L-2-methyl-3- (2-hydroxyquinoxalin-7-yl) -alanine, m.p. 220 to 225 ° (dec.). The nuclear magnetic resonance spectrum shows indicate that the two isomers are present in approximately equal amounts.

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Example 40

D, L-3- (2,3-dihydroxyquinoxalin-6-yl) -2-methylalanine hemi hydrochloride

M.p. 280 to 285 ° (dec.).

Example 41

D, L-3- (quinoxalin-6-yl) alanine dihydrochloride

A. D, L-4-acetamido-H-acetylphenylalanine methyl ester

A solution of 89.5 g (0.38 mol) of D, L-N-Acetyl-4-aminophenylalanine methyl ester [Chem.Abst., £ 4, 22673b 0960)] in 680 ml Benzene and 100 ml of acetic anhydride is 15 min on the steam bath heated and then left to stand at 25 ° for 16 h. The crystallized solid is filtered off and washed with 200 ml of ether and air dried; 98.5 g of (93S0 D, L-4-acetamido-N-acetylphenylalanine methyl ester, melting point 173 are obtained up to 175 °.

B. D, L-4-acetamido-N-acetyl-3-nitrophenylalanine methyl ester

To 250 ml 90 # nitric acid cooled to -15 ° is added 98.5 g (0.35 mol) of DjL4 -acetamido-N-acetylphenylalanine methyl ester added over the course of 20 minutes with stirring. The reaction mixture is stirred for 1.5 h at -15 to -10 ° and then in 2 l Poured ice cold saturated sodium bicarbonate solution. If necessary more solid sodium bicarbonate is added to make the solution weakly basic. After storage of the mixture in the refrigerator overnight, the crystals formed are filtered off, washed with water and dried; 98.2 g (8696) of D, L-4-acetamido-N-acetyl-3-nitrophenylalanine methyl ester are obtained, Mp. 123 to 125 °.

C. DL-N-Acetyl ^ -amino ^ -nitrophenylalanine methyl ester

A mixture of 86 g (0.266 mol) of D, L-4-acetamido-N-acetyl-3-nitro-phenylalanine methyl ester and 33 »7 g (0.318 mol) sodium

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carbonate in 2 l of methanol is refluxed for 2 h. The mixture is filtered hot to remove the precipitated salts. The filtrate is evaporated, leaving an oil. 300 ml of water are added to this oil. After rubbing a crystalline solid is obtained which is filtered off and dried; 36.3 g (49%) of D, L-N-acetyl-4-amino-3-nitrophenylalanine methyl ester are obtained, Mp. 133-134 °.

D. D, L-3- (quinoxalin-6-yl) alanine dihydrochloride

One works as described for stages A and B of Example 38, but uses 10 g (35 »6 mmol) as starting material D, L-N-acetyl-4-amino-3-nitrophenylalanine methyl ester. 4.52 g (4455) D, L-3- (quinoxalin-6-yl) alanine dihydrochloride are obtained, Mp 185-200 ° (dec.).

Example 42 D.L-3- (2,3-Dihydroxyquinoxalin-6-yl) alanine hydrochloride

M.p. 270 to 280 ° (dec.).

Example 43

D, L-3- (1,4-benzoxazin-3-on-7-yl) -2-methylalanine-hemihydro chloride

M.p. 308 ° (dec.).

Example 44

D.L-3- (1-4-Benzoxazin-3-on-7-yl) -alanin-hemihvrochloride

M.p. 285 ° (dec.).

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Example 45

D, L-3- (5-Hydroxy-4H-pyran-4-on-2-yl) -2-methylalanine

To a solution of 1.60 g (0.07 mol) of sodium in 210 ml of ethanol is added 17.73 g (0.07 mol) of iodo-kojic acid [T.Yabuta, J. Chem. Soc, 575 (1924)] and 3 g (0.024 mol) of ethyl 2-isocyanopropionate. A solution of 1.60 g is added to the above solution, which is stirred under a nitrogen atmosphere (0.07 mol) of sodium and 8.9 g (0.07 mol) of ethyl 2-isocyanopropionate in 175 ml of ethanol were added over a period of 45 minutes. That The reaction mixture is stirred for a further 3 h at room temperature and evaporated to dryness. The residue is in V / water dissolved and extracted with ethyl acetate. The aqueous phase is acidified with hydrochloric acid and again extracted with ethyl acetate. The ethyl acetate is evaporated and the brick-red residue is dissolved in 200 ml of 3N hydrogen chloride acid heated under reflux for 15 h, cooled and extracted with ethyl acetate. He is then treated with animal charcoal and evaporated to dryness. The residue is redissolved in water, and ammonium hydroxide is added until it has a basic reaction and evaporated to dryness. After adding 25 ml v / ater, the product is obtained as a light yellow solid, which is filtered off and dried. Yield 2.26 g (15/0, m.p. 239-241 °.

Example 1 46

D. L-5- (2-Hydroxy-4-pyridyl) -2-methylalanine

A solution of 20 g of crude 4-bromomethyl-2-fluoropyridine [P.T. Sullivan et al, J. Med. Chem. 1 ^, 211 (1971)] containing about 13 g (73 mmol) of pure material in 100 ml of dimethylformamide is cooled in an ice bath. For this solution one gives a cold solution of 11.3 g (100 mmol) methyl 2-isocyanopropionate and 11.2 g (10OmMoI) potassium tert-butoxide in 75 ml dimethylformamide. The temperature can rise to 25 ° and the reaction

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tion mixture is stirred at 25 ° for 1 h. It is then poured into 1 l of ice water. The aqueous mixture is with 3 x 200 m of ether extracted, which is washed back with 2 × 100 ml of water. The ether extracts are dried and evaporated; 24 g of a thick oil are obtained. To this oil is added 100 ml of conc. While cooling and stirring. Hydrochloric acid. The mixture is then refluxed for 1 hour and evaporated to dryness. 100 ml of water are added and then is again evaporated to dryness. The residue is finally dissolved in 200 ml of water and mixed with 2 × 100 ml of ethyl acetate extracted. 4.1 g of 4-dibromomethyl-2-hydroxypyridine, melting point 159 to 160 °, are obtained from the organic extract formed by the hydrolysis of 4-dibromomethyl-2-fluoropyridine, which is present as an impurity in the starting material will.

The aqueous fraction is heated for 30 min to 80 ° with 1 g of animal charcoal, filtered, evaporated, and the residue is in 50 ml of water added. Conc. Ammonium hydroxide is added until the reaction is basic, and then it is evaporated. Of the The residue is treated with 10 ml of water, cooled and filtered; 2.2 g (11.2 mmol, 15.5%) of D, L-3- (2-hydroxy-4-pyridyl) -2-methylalanine are obtained, M.p. 315-316 ° (dec).

Example 47 D, L-3-cyano-q-methyltyrosine methyl ester hydrochloride

A. 3- (Diacetoxymethyl) -4-acetoxybenzyl chloride

675 g (3.96 moles) 3-formyl-4-hydroxybenzyl chloride in 3.5 liters Acetic anhydride is refluxed for 24 hours. The reaction mixture is evaporated to dryness, with a slight Amount of ether triturated and filtered; 987 g (79%) of 3- (diacetoxymethyl) -4-acetoxybenzyl chloride, melting point 93 to 95 °, are obtained.

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B. 3- (Diacetoxymethyl) -4-acetoxybenzyl iodide

987 g (3.14 moles) 3- (diacetoxymethyl) ^ - acetoxybenzyl chloride and 494 g (3.29 mol) of sodium iodide in 3.5 1 of acetone are refluxed for 6 hours. The reaction mixture is filtered, the filtrate is evaporated to dryness, triturated in ether and filtered; 1162 g of (91 #) 3- (diacetoxymethyl) -4-acetoxybenzyl iodide are obtained, M.p. 117 to 120 °.

C. D, L -S-Forayl-oc-methyltyrosine methyl ester hydrochloride hydrate

The anion of methyl 2-isocyanopropionate is produced by one at -50 ° 167 ml (1.5 mol) of methyl 2-isocyanopropionate to a solution of 165 g (1 »5 mol) of potassium tert-butoxide in 700 ml of dimethylformamide. To a solution of 500 g (1.23 mol) of 3- (diacetoxymethyl) -4-acetoxybenzyl iodide in 1.5 DMF, cooled to -10 °, is added to the freshly prepared anion solution in the course of 20 minutes. Towards the end of this reaction the temperature is around 5 °. The mixture is stirred for 2 hours at room temperature. It is then poured into cold water, extracted with ethyl acetate, washed with water, dried and evaporated to dryness; 130 g are obtained (84%) methyl D, L-2-methyl-2-isocyano-3- (3-diacetoxymethyl-4-acetoxyphenyl) -2-propionate. This intermediate product is dissolved in 2.2 l of ethyl acetate. 10 ml conc. Hydrochloric acid in 30 ml of water are slowly added. External cooling is required to maintain the temperature at around 20-25 °. The mixture is then neutralized with sodium bicarbonate, washed with water, dried and evaporated to dryness; 410 g (9196) of D, L-N-formyl-a-methyl-3-diacetoxymethyl-4-acetoxyphenylalanine methyl ester are obtained. This derivative is dissolved in 21% methanol and 150 ml of conc. Hydrochloric acid will be present. The resulting mixture is stirred for 3 days at room temperature. The solution is evaporated to dryness,

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rubbed in ether and filtered. The solid will then treated with a small amount of hot isopropanol. It is then cooled and filtered, washed with ether and air dried; 151 g [42% from the 3- (diacetoxymethyl) -4-acetoxybenzyl iodide) are obtained D, L-3-formyl-a-methyltyrosine methyl ester hydrochloride ^ onohydrate, M.p. 145 to 150 ° (decomp.). ^

D. D, L-3-cyano-Nformyl-oc-methyltyrosine methyl ester

119 g (0.41 moles) of DiL ^ -formyl-α-methyl-tyrosine methyl ester hydrochloride hydrate ground with 54 g (0.78 mol) of hydroxylamine hydrochloride and 95 g (1.4 mol) of sodium formate in 1.2 liters of formic acid Heated to reflux for 3 h; 72 g (67%) of D, L-3-cyano-N-formyl-α-methyltyrosine methyl ester are obtained.

E. D, L-3-cyar-oa-methyltyrosine methyl ester hydrochloride

A Geraisch from 40 ml conc. HCl and 3.68 g (15 mmol) of D, L-3-cyano-N-formyl-a-methyltyrosine methyl ester are refluxed for 1 h. After cooling to room temperature the crystals are filtered off and washed with diethyl ether; about 2.06 g (54%) of D, L-3-cyano-a-methyltyrosine methyl ester hydrochloride are obtained, M.p. 267 ° (dec.).

Example 1 48

L-α-methyl-4- (pyrrol-1-yl) -phenylalanine

A. Lq-methylphenylalanine methyl ester hydrochloride methanol

47 ml of thionyl chloride are added to 210 ml of methanol in the course of 30 minutes. 98 g (0.50 mol) of L-oc-methylphenylalanine hydrate [F. V /. Bollinger, J. Med. Chem. 14 , 373 (1971)] with cooling. The reaction mixture is then stirred and ^{heated at 50 °} C. for 16 h. The mixture is then evaporated to dryness. The residue is with

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500 ml of ether slurried. The resulting solid is filtered off; 12Ag (about 10090) of L-a-methylphenylalanine methyl ester hydrochloride methoxide are obtained, M.p. 103-104 °.

B. LN-formyl-α-methylphenylalanine methyl ester

To a suspension of 124 g (0.50 mol) of L-oc-methylphenylalanine methyl ester hydrochloride methoxide 41 g (0.60 mol) of sodium formate are added to 65 ml of formic acid with stirring and cooling in an ice bath. After 15 minutes, 82 ml of formic acetic anhydride are added added to the stirred and cooled mixture at 25 ° over 18 hours. Then another 82 ml Formic acetic anhydride is added and the reaction mixture is left to stand for a further 3 hours. After that time is the implementation completed. The insoluble salts are filtered off and washed with 100 ml each of ether and chloroform. the Wash liquids are combined with the filtrate and the entire mass is evaporated. A thick oil is obtained which is stirred for 1.5 h with 500 ml of cold water. This mixture is then extracted with 3 x 500 ml of chloroform. the combined chloroform extracts with 200 ml of 1N hydrochloric acid, 200 ml of water, Seigern sodium bicarbonate, until the aqueous washing water reacts basic, and finally washed with 2 × 100 ml of water. After drying the chloroform solution, Evaporation and trituration of the residue with petroleum ether gives a crystalline solid which is filtered off; 98.4 g (8996) of L-N-formyl-cc-methylphenylalanine methyl ester are obtained, Mp 55 to 58 °.

C. LN-formyl-q-methyl-4-nitrophenylalanine methyl ester

To 250 ml of 90 # nitric acid kept at -15 to -10 ° 97.8 g (0.44 mol) of L-N-formyl-a-methylphenylalanine methyl ester are added in portions over the course of 0.5 h. That The reaction mixture is kept at this temperature for a further hour. It is then slowly poured into 2000 ml of an ice cream

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Given a water slurry containing 200 g of sodium bicarbonate. If necessary, more sodium bicarbonate is added to adjust the pH up to 7. The rubbery one Product that separates out is a granular solid when the mixture is mechanically stirred for 1 hour. The solid after filtering, it is washed with 500 ml of water and dried; 99.4 g (84 #) of L-N-formyl-α-methyl-4-nitrophenylalanine methyl ester are obtained, Mp. 90 to 95 °.

D. L-4-Amino-N-formyl-α-methylphenylalanine methyl ester

Using the procedure of Part C of Example 11 and uses 98.9 grams (0.35 moles) of L-N-formyl-a-methyl-4-nitrophenylalanine as starting material, but if the final recrystallization is omitted, 69.3 g (83.590 L-4-amino-N-formyl-oc-methylphenylalanine methyl ester, Mp. 70 to 76 °.

E. LN-Formyl-q-methyl-4- (pyrrol-1-yl) -phenylalanine

A mixture of 10 g (42 mmol) of L-4-amino-N-formyl-a-methylphenylalanine methyl ester, 5.6 g (42 mmol) 2,5-dimethoxytetrahydrofuran, 50 g of Amberlite® IRC 50 (H) resin and 250 ml of toluene is stirred and refluxed for 4 h. After filtration to remove resin and after evaporation of the filtrate 8.9 g of a semi-solid residue remain, which after slurrying with 25 ml of ether and recovery of the insoluble Product by filtration 6.15 g (51 #) L-N-formyl-oc-methy 1-4- (pyrrol-1-yl) -phenylalanine methyl ester, Mp. 106 to 109 ° »results.

F. L-oc-Methyl-4- (pyrrol-1 -yl) -phenylalanine

A mixture of 12 g (42 mmol) of L-N-formyl-a-methyl-4- (pyrrol-1-yl) -phenylalanine methyl ester, 48 ml of 40% strength aqueous sodium hydroxide and 180 ml of methanol are refluxed for 5 hours.

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It is then evaporated to dryness. The residue is in 300 ml of water dissolved. Sufficient 12N hydrochloric acid is added to raise the pH to about 5, with the product crystallizes. It is filtered off, each with 50 ml Washed water, ethanol and ether and finally dried in vacuo at 50 ° for 18 h; 8.3 g (81Ji) L-α-methyl-4- (pyrrol-1-yl) -phenylalanine are obtained, M.p. 294 to 295 ° (dec.).

Example 49 D-q-methyl-4- (pyrrol-1-yl) phenylalanine

Following the procedures of Parts A, B, C, D, E and F of Example 48 for the synthesis of the L-isomer and used 18.7 g (95 mmol) of D-α-methylphenylalanine hydrate [F.W.Bollinger, J.Med.Chem. , 14, 373 (1971)] as the starting material one 3.7 g (total yield 15.8 #) D-α-methyl-4- (pyrrol-1-yl) -phenylalanine, M.p. 297 to 299 °.

Example 50

La-methyl-4- (pyrrol-1-yl) -phenylalanine methylester hydrochloride

Mp 200 to 202 °.

Example 51

D. L-4- Γ2- (carboxy) -pyrrol-1 -yl 1-2-methylphenylalanine dihydrate

M.p. 304-306 ° (dec.).

Example 52

D, L-α-methyl-3- (pyrrol-1-yl) -phenylalanine hydrochloride

Mp 205-207 ° (dec.).

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Example 53

D, L-4- (pyrrol-1-yl) phenylalanine
Mp. 288 ° (dec.)

Example 54

D, L-cc-methyl-4- (pyrrol-1-yl) -phenylalanine methyl ester

Mp 207 ° (dec.).

Example 55

D _t L-3-Hydroxy-g-methyl-4- (pyrrol-1-yl) -phenylalanine hydrate

A. D, LN-Formyl ^ -hydroxy-oc-methyl ^ - (pyrrol-1 -yl) -phenyl alanine methyl ester

Using 2 g of 1 above palladium-on-animal charcoal as Catalyst ground 25 g (88 mmol) of D, L-N-formyl-3-hydroxy-ocmethyl-4-nitrophenylalanine methyl ester of Part A of Example 6 dissolved in 300 ml of methanol, reduced using a Parr hydrogenator. The catalyst is filtered off and the filtrate is evaporated; 21.1 g (95/0 of an oil are obtained, the quality of which is sufficient for the next stage.

9 g are added all at once to a solution of 16.3 g (65 mmol) of D, L-4-amino-N-formyl-3-hydroxy-α-methylphenylalanine methyl ester, prepared as described above, in 100 ml of acetic acid (68 mmol) 2,5-dimethoxytetrahydrofuran. The solution is refluxed for 30 minutes and then poured into ice and water. The aqueous mixture is extracted with ethyl acetate. The organic layer is washed with dilute sodium bicarbonate and water, _{dried over Na 2} SO 4, filtered and evaporated. The residue is purified on silica gel; 6.12 g (30%) of D, LN-formyl-3-hydroxy-α-methyl-4- (pyrrol-1-yl) -phenylalanine methyl ester, melting point 132 ° to 135 ° are obtained.

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B. D, L-5-Hydroxy-a ~ ynethyl-4-Cpyrrol-1-yl) -phenylalanine hydrate

20 ml of 40% NaOH and 50 ml of methanol are placed in a glass bomb and 5 g (16 mmol) of D, L-N-formyl-3-hydroxy-a-methyl-4- (pyrrol-1-yl) -phenylalanine methyl ester. The sealed bomb is heated at 120 ° for 1 hour. The cooled solution is evaporated and the residue is redissolved in 50 ml of water. The solution is neutralized with acetic acid and the product becomes filtered, washed with water and dried in a vacuum oven at 50 ° for 18 h; 4.0 g (8796) D, L-3-hydroxy-a-methyl-4- (pyrrol-1-yl) phenylalanine hydrate are obtained, M.p. 315 ° (dec.).

Example 56

D, L-3-methoxy-a-methyl-4- (pyrrol-1-yl) -phenylalanine-oxalic acid salt

With magnetic stirring, a mixture of 3.5 g (26 mmol) of methyl iodide, 2 g (14 mmol) of potassium carbonate, 120 ml of acetone and 4.0 g (13 mmoles) of D, L-N-formyl-3-hydroxy-α-methyl-4- (pyrrol-1-yl) -phenylalanine methyl ester of Part A of Example 55 heated to reflux for 5 hours. The mixture is filtered and that The filtrate is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried over NaSO ^ and filtered and evaporated; one receives 4.3 g (93? 0 of an oil, which for the next stage is sufficiently pure.

A solution of 12 ml of 40 # NaOH, 40 ml of methanol and 4.3 g (13 mmol) D, L-N-Formyl-3-methoxy-a-methyl-4- (pyrrol-1-yl) -phenylalanine methyl ester, prepared as described above, is refluxed for 3 hours with magnetic stirring. the Solution is evaporated and the residue is redissolved in 40 ml of water. The solution is made with hydrochloric acid neutralized. The product is filtered, washed with water and dried in a vacuum oven at 50 ° for 18 h; you get 3.27 g (92%), m.p. 230 ° (dec.).

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The oxalic acid salt is prepared by adding a mixture of 1.0 g (11 mmol) of oxalic acid, 50 ml of methanol and 3.0 g (11 mmol) D, L-3-methoxy-a-methyl-4- (pyrrol-1-yl) -phenylalanine, prepared as described above, stirred magnetically for 1 h. The insoluble impurities are filtered off and the filtrate occurred is treated with animal charcoal. The solution is evaporated and the residue is used to remove excess oxalic acid washed with diethyl ether; 3.15 g (78%) are obtained D, L-3-methoxy-a-methyl-4- (pyrrol-1-yl) -phenylalanine oxalate, M.p. 188 ° (decomp.).

Example 57 D, L-q-methyl-3- (pyrrol-1-yl) tyrosine oxalate monohydrate

A. D, La-methyl-3-nitrotyrosine methyl ester hydrochloride

A solution of 42.0 g (180 mmol) D, La-methyl-3-nitrotyrosine [prepared as described by Saari et al, J. Med. Chem., IC), ¹ ° 08 (1967)] in 200 ml with methanol saturated with dry hydrogen chloride is refluxed for 10 h. It is then evaporated to dryness and the residue is suspended in 200 ml of ether. The solid is filtered off; 50 g (97/0 D, La-methyl-3-nitrotyrosine methyl ester hydrochloride, melting point 202 ° to 203 ° (decomp.) are obtained.

B. D, LN-formyl-a-methyl-3-nitrotyrosine methyl ester

To a solution of 50 g of D, L-a-methyl-3-nitrotyrosine methyl ester hydrochloride 100 ml of formic acid anhydride are added to 200 ml of formic acid and the mixture is stirred at 25 ° for 2 h. The precipitate is filtered off. The resulting solid (9 »5 g) is identified as D, L-N-formyl-a-methyl-3-nitrotyrosine. The filtrate is evaporated to dryness and the residue is slurried with 100 ml of water and filtered; 37 g of crude product are obtained. This is suspended in 200 ml of water and the mixture is ex-

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traced. After drying and evaporation, the ethyl acetate extracts give 30.8 g (78%) of D, L-N-formyl-cc-methyl-3-nitrotyrosine methyl ester, Mp. 129 to 132 °.

C. D, L-3-Amino-Nfo rmyl-q-methyl tyrosine methyl ester

To a solution of 20 g (71 mmol) of D, L-N-formyl-α-methyl-3-nitrotyrosine methyl ester 2.0 g of 1Obiges palladium-on-charcoal are added to 300 ml of methanol. The resulting mixture is reduced for 30 min at a water pot pressure of 18.1 kg. The reaction mixture is filtered and the filtrate is evaporated to dryness. The crystalline residue is with 25 ml of methanol is slurried and the solid is filtered off; 15.5 g (86 #) D, L-3-amino-N-formyl-a-methyltyrosine methyl ester are obtained, Mp 197-199 °.

D. D, LN-Formyl-q-methyl ^ - (pyrrole-1 -yl) -tyrosine methyl ester

A solution of 15 g (60 mmol) of D, L-3-amino-N-formyl-a-methyltyrosine methyl ester and 6.2 ml (66 mmol) of 2,5-dimethoxytetrahydrofuran in 80 ml of acetic acid is refluxed for 30 min. The reaction mixture is then poured into 400 ml of ice and water and then extracted with 3 x 200 ml of ethyl acetate. The combined ethyl acetate extracts are washed with 1N sodium bicarbonate, until the aqueous layer is basic, washed, dried and concentrated. The residue by passage through cleaned a silica gel column. Elution with ethyl acetate gives 7.3 g (4OJ6) crystalline D, L-N-formyl-q-methyl-3- (pyrrol-1-yl) tyrosine methyl ester, Mp. 151 to 152 °.

E. DL-q-Methyl-3- (pyrrol-1 -yl) -tyrosine-oxalate-monohydrate

A mixture of 2.0 g (6.6 mmol) of D, L-N-formyl-a-methyl-3- (pyrrol-1-yl) -tyrosine methyl ester, 8 ml of 40 # strength sodium hydroxide and 30 ml of methanol are refluxed for 4 h. The solvent is evaporated and the residue is in

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50 ml v / ater dissolved. Conc. Hydrochloric acid becomes up to for acidic reaction and then ammonium hydroxide is added until the reaction is weakly basic (pH 9). The solution will be then evaporated to dryness and the residue is stirred for 30 min with 50 ml of water. The insoluble material is filtered off; 1.51 g of crude product are obtained. The crude product is added to 25 ml of methanol and then 540 mg of oxalic acid are added added. The insoluble impurities are filtered off and the filtrate is evaporated to dryness. the end 50 ml of water are evaporated from the residue and the residue is dried in vacuo at 50 ° for 5 h; 1.66 g are obtained (68%) D, L-a-methyl-3- (pyrrol-1-yl) -tyrosine-oxalate-monohydrate, Mp. 105 to 115 °.

Example 58

D, L ^ -Methoxy-a-methyl -? - (pyrrol-1 -yl) -phenylalanine oxalate monohydrate

M.p. 100 to 110 °.

Example 59

D, L-4- (indol-1-yl) -a-methylphenylalanine hydrate

Mp. 270 to 273 °.

Example 60

D.L- (Carbazol-9-vl) -q-methy! Phenylalanine

Mp. 271-274 °.

Example 61

D, L-3- (imidazol-2-yl) -α-methyltyrosine dihydrochloride

A. D, LN-formyl-q-methyl-3-thiocarbamoyl tyrosine methyl ester

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15 858Υ

A solution of 1.5 g (5.7 mmol) DjL - ^ - cyano-N-formyl-octnethyltyrosine methyl ester, prepared as described in Part D of Example 47, in 15 ml of pyridine and 2 ml of triethylamine is saturated with hydrogen sulfide and heated in a glass bomb at 70 ° for 18 h. The reaction mixture is evaporated to dryness, dissolved in ethyl acetate, washed with water / water, dried and evaporated to dryness. The residue is dissolved in 10 ml of chloroform. 1.36 g ($ 85) of D, L-N-Fo rayl-a-methyl-3-thiocarbamoyltyrosine methyl ester crystallize therefrom off, pp. 177 to 179 ° (decomp.).

B. D, LN-Formyl-a-methyl-3- (methyl thiocarboximida to) -tyrosine methyl ester

4.75 g (50 mmol) of D ^ N-formyl-a-methyl ^ -thiocarbamoyltyrosine methyl ester, from Part A of Example 61, are suspended in 150 ml of acetone and 4.35 ml of methyl fluorosulfonate are added. A solution is obtained after 5 minutes and an increase in temperature to 35 ^{a is} observed. After stirring for 2 hours at room temperature, the solution is evaporated to dryness, the residue is dissolved in water and the solution is extracted with ethyl acetate. Sodium bicarbonate is added to the aqueous layer until it is basic, then it is extracted with ethyl acetate. The extract is then dried and evaporated to dryness; an oil is obtained which crystallizes when rubbed with ether. After filtering off, 13.64 g of (8S #) D, LN-Formyl-a-methyl-3- (methyl thiocarboximidate) -tyrosine methyl ester, melting point 140 ° to 143 ° (decomp.).

C. D, L-3- (imidazol-2-yl) -a-methyltyrosine dihydrochloride

8 g (25.8 mmoles) of D, L-N-Formyl-a-methyl ^ - (methylthiocarboximida to) tyrosine methyl ester, 3.4 g (25.6 mmol) aminoacetaldehyde diethyl acetal and 2.32 g (25.8 mmol) of oxalic acid in 200 ml of methanol are refluxed for 2 hours. The resulting

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15 858Y

the mixture is evaporated to dryness, 200 ml of water become added to the solution of the residue and the solution is extracted with ethyl acetate. Add to the aqueous layer solid sodium bicarbonate until basic and washes with 100 ml of ether and 20 ml of ethyl acetate and evaporate to dryness. The residue from the aqueous solution becomes violent with 200 ml of chloroform stirred. After separation and drying, it is evaporated to dryness; 10 g of an oil are obtained.

8.4 g of the oil are concentrated in 100 ml. Dissolved hydrochloric acid. The mixture is refluxed for 1 hour. Evaporation to dryness gives 4.7 g (7090) D, L-3- (imidazol-2-yl) -ct-methyltyrosine dihydrochloride, M.p. 160-175 ° (dec.).

Example 62

D, L-2-methyl-3- (2-methanesulfonylamidobenzimidazol-5-yl) alanine dihydrochloride hemihydrate

M.p. 250-251 ° (dec.).

Example 65

D. L-methyl-3- (2-amino-4-pyridyl) alanine dihydrochloride

Mp. 258 to 260 °.

Example 64

D.L-2-methyl-3-Γ tetrazolΓ1.5-a1pyrid-7-vl) -alanine hydrochloride

Mp. 240 to 245 °.

Example 65

D.L-3-cyano-tt-methylphenylalanine methyl ester hydrochloride

Mp. 160 to 165 °.

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Example 66

D. L-3-Hydroxy-4-nitro-α-methylphenylalanine hydrochloride

M.p. 230 to 243 ° (dec.).

Example 67

D, L-3- (2-Carboxy-4-pyridyl) -2-methylalanine ammonium salt dihydrate

Mp, 195 ° (dec.).

Example 68

D, L-2-methyl-3- (3-formyl-4-hydroxyphenyl) -alanine-methyl ester hydrochloride-monohydrate mp. 145 to 150 ° (dec.).

Example 69

D _t L-3-carboxy-a ~ methyltyrosine hydrochloride salt dihydrate

Mp. 258 ° (dec.)

Example 70

D, L-cc-methyl-3- (4-trifluoromethylthiazol-2-yl) -tyrosine hydrochloride

M.p. 285 ° (dec.).

The preparations according to the invention can be used to achieve a hypertonic effect, i.e. a decrease in blood pressure, administered to hypertonic living beings. It is known that the decarboxylase inhibitors are a remarkable one have blood-lowering activity. The new compounds of formula I include compounds that have a certain antihypertensive Have activity, as do compounds that do not

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Have antihypertensive activity. The new compounds of the formula I ₁ which have an antihypertensive activity on their own show an increased activity when the compounds are used together with the decarboxylase inhibitors. The new compounds of the formula I _1, which on their own have no antihypertensive activity, show an antihypertensive effect together with the decarboxylase inhibitor.

The antihypertensive activity or enhancement of activity is demonstrated in vivo in spontaneously hypertensive (SH) rats. The method used is as follows.

The test animals are male SH rats weighing about 290 to about 3 ^ 0 g and are conscious. The arterial blood pressure is determined by a direct method in which a cannula is inserted into the tail artery. The initial blood pressure is measured. The decarboxylase inhibitor will then administered intraperitoneally (i.p.) and about 5 minutes later a compound of formula I is administered (i.p.). The blood pressure is then recorded continuously at half hour intervals for 24 hours.

The effect on blood pressure is also demonstrated by exemplary decarboxylase inhibitors and exemplary compounds of formula I determined by this method alone.

The test results are called antihypertensive activity that is, the degree of decrease in mean arterial blood pressure. The antihypertensive values obtained for exemplary preparations are listed in the following table.

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709 83 3/09 89

15 858Y ίο 2705863 Anti-hypertensive activity dose
(mg Ag) Evaluation in the case of the blood
pressure reduction Table I. Connection (1) 25th essentially inactive Carbidopa 80 something active attempt Example 27 40
25th Il Il 1 Example 27
+ Carbidopa 80 essentially inactive 2 example 1 0.3
25th something active 3 example 1
+ Carbidopa 80 essentially inactive 4th Example 6 0.3
25th something active 5 Example 6
+ Carbidopa 80 essentially inactive 6th Example 7 0.3
25th something active 7th Example 7
+ Carbidopa 80 essentially inactive 8th Example 12 (2) 0.3
25th moderately active 9 Example 12 (2)
+ Carbidopa 80 essentially inactive 10 Example 17 0.3
25th moderately active 11 Example 17
+ Carbidopa 80 essentially inactive 12th Example 56 0.3
25th moderately active 13th Example 56
+ Carbidopa 80 something active 14th Example 21 0.3
25th moderately active 15th Example 21
+ ■ carbidopa 80 essentially inactive 16 Example 29 80
25th something active 17th Example 29
+ Carbidopa 80 something active 18th Example 30 0.3
25th Il It 19th Example 30
+ Carbidoüa 20th 21

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709833 / 098Ö

15 858Y I (continued) dose
(mg / kg) Evaluation in the case of the blood
pressure reduction inactive Tabel link 80 essentially attempt Example 33 10
25th moderately active inactive 22nd Example 33
+ Carbidopa 80 essentially 23 Example 35 10
25th moderately active inactive 24 Example 35
+ Carbidopa 80 essentially 25th Example 38 0.08
25th active inactive 26th Example 38
+ Carbidopa 80 essentially 27 Example 41 0.3
25th something active inactive 28 Example 41
+ Carbidopa 80 essentially 29 Example 42 0.3
25th something active inactive 30th Example 42
+ Carbidopa 80 essentially 31 Example 45 10
25th moderately active inactive 32 Example 45
+ Carbidopa 80 essentially 33 Example 46 0.3
25th something active inactive 34 Example 46
+ Carbidopa 80 essentially 35 Example 3 ro ro
UiO something active inactive 36 Example 3
+ Carbidopa 80 essentially 37 Example 8 ro ro
Ul O something active inactive 38 Example 8
+ Carbidopa 80 essentially 39 Example 36 20th
25th something active inactive 40 Example 36
+ Carbidopa 80 essentially pronounced activity; ii
essentially inactive 41 Example 70 20; 0.3
25th 42 Example 70
+ Carbidopa 43

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709833/09 * 3

15 858Y I (continued) dose
(ms / kff) Evaluation in the case of the blood
pressure reduction Tabel link 80 (Rise in blood pressure) attempt Example 5 40
25th moderately active 44 Example 5
+ Carbidopa 80 active 45 Example 9 0.3
25th active 46 Example 9
+ Carbidopa 80 essentially inactive 47 Example 57 0.3
25th pronounced activity 48 Example 57
+ Carbidopa 80 something active 49 Example 49 0.3
25th Il Il 50 Example 49
+ Carbidopa 1.25 active 51 Example 11 0.3
25th active 52 Example 11
+ Carbidopa 20th
80 essentially inactive
active 53 Example 55 0.3
25th pronounced activity 54 Example 55
+ Carbidopa 20th essentially inactive 55 Example 48 20th
25th something active 56 Example 48
+ Carbidopa 80 essentially inactive 57 Example 61 0.3
25th pronounced activity 58 Example 61
+ Carbidopa 20th
80 essentially inactive
moderately active 59 Example 18 0.3
25th moderately active 60 Example 18
+ Carbidopa 80 essentially inactive 61 Example 16 0.08
25th active 62 Example 16
+ Carbidopa 80 essentially inactive 63 Example 19 0.3
25th pronounced activity 64 65 Example 19
+ Carbidopa

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15 858Y

Notes on table:

(1) Carbidopa are dissolved in 1N HCl, while the arylalanines are dissolved in either H ₂ O or 1N HCl, if desired.

(2) D, L-4- (imidazol-2-yl-amino) -cc-methylphenylalanine. HCl.

The values in Table I explain that the antihypertensive activity of the new arylalanine compounds is achieved by an oleic decarboxylase inhibitor be reinforced. The results of experiments 2 and 3 and 46 and 47 show how the

non-hypertensive decarboxylase inhibitor the antihypertensive activity of the arylalanines improves, which alone has a certain antihypertensive activity own. The other test results show that a mixture of a non-hypertensive decarboxylase inhibitor exhibits antihypertensive activity with a non-hypertensive arylalanine.

In evaluating the antihypertensive activity, the test compounds were administered intraperitoneally individually. The results illustrate the effect that can be seen when the compounds are administered either orally or parenterally (A) and (B) either alone or simultaneously or as a mixture. The invention also relates to methods for the treatment of high pressure in hypertensive animals by administering an antihypertensive amount of the amount according to the invention Preparations.

The term "living beings" also includes people.

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709833/0989

Claims (1)

Merck & Co., Inc. 15 858Y Claims 1. Pharmaceutical preparation, characterized in that that it contains (A) a compound of the formula R ₃ -CH ₂ -C-COOR ₂
NH ₂ and / or their pharmaceutically acceptable salts, wherein R ₁ and R _{2 can represent} a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and (1) a substituted benzene ring of the formula ^{1 line}
wherein Y ₁ and Y _{2 are} independently selected from hydrogen, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminomethyl, guanidino, hydroxy, methanesulfonamido, nitro, amino, methanesulfonyloxy, carboxymethoxy, formyl or methoxy or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing one or more nitrogen, sulfur or oxygen atoms, so that (a) Y ₁ and Y _{2 are} not both hydroxy, (b) Y ₁ and Y _{2 are} not both hydrogen and (c) when one of the substituents Y ₁ and Y _{2 is} hydrogen, the other is not hydroxy; (2) a substituted or unsubstituted benzoheterocyclic ring of the formula 709833/0989 ORIGINAL INSPECTED 15 858Y Z wherein the benzoheterocyclic ring is selected from Group indolin-5-yl, 1- (N-benzoylcarbamimidoyl) -indolin-5-yl, 1-carbamimidoyl-indolin-S-yl, 1H-2-oxindol-5-yl, indol-5-yl, 2-mercaptobenzimidazol-5 (6) -yl, 2-aminobenzimidazol-5 (6) -yl, 2-methanesulfonamido-benzinidazol-5 (6) -yl, IH-benzoxazol-2-on-6-yl, 2-aminobenzothiazol-6-yl, 2-amino-4-mercapto-benzothiazol-6-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-2,2-dioxo-2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-1,3-dimethyl-2,2-dioxo-2,1,3-benzothiadiazol-5-yl, 4-methyl-2 (iH) -oxoquinolin-6-yl, Quinoxalin-6-yl, 2-hydroxyquinoxalin-6-yl, 2-hydroxyquinoxalin-7-yl, 2,3-dihydroxyquinoxalin-6-yl and 2,3-dihydro-3 (4H) -oxo-1 ^ -benzoxalin-T-yl j and (3) a substituted or unsubstituted heterocyclic ring of the formula wherein the heterocyclic ring is selected from the group 5-hydroxy-4H-pyran-4-on-2-yl, 2-hydroxypyrid-4-yl, 2-aminopyrid-4-yl, 2-carboxypyrid-4-yl and tetrazol [i.5-a] pyrid-6-yl, means and / or their pharmaceutically acceptable salts, (B) a decarboxylase inhibitor of the formula U f 4 -C-COOR ₅ ^! H NH 709833/0989 15 858Y J R ^, Rc, Rg and R ~ independently of one another are hydrogen mean atom or a C ^ -C ^ -alkyl group, and / or its pharmaceutically acceptable salts. 2. Preparation according to claim 1, characterized in that both the compound (A) and the decarboxylase inhibitor Are L-isomers that are substantially free of the D-isomer. 3 preparation according to claim 1, characterized in that that the decarboxylase inhibitor is essentially the D-isomer is free L-isomer. 4. Preparation according to claim 3, characterized in that it is a compound of the formula as a decarboxylase inhibitor C ₃ H ₂ -C-COOH HO-L. ) ¥ and / or contains their pharmaceutically acceptable salts. 5. Preparation according to claim 4, characterized in that the decarboxylase inhibitor is essentially of the D-isomer is free L-isomer. 6. Preparation according to claim 1, characterized in that the compound (A) is selected from the group: 709B33 / 0989 15 858Y 4 D, L-4-cyanoamino-a-methy! Phenylalanine, D, L-guanidino-cc-methy! Phenylalanine, £ / 05863 D, L-3-hydroxy-4-methanesulfonamido- <x-methy! Phenylalanine, D, L-4-Amino-3-methanesulfonyloxy-oc-methy! Phenylalanine, D, L-4- (2-Aminoimidazol-i -yl) -a-methylphenylalanine / DjIr ^ - (Imidazol-2-yl-araino) -cc-methylphenylalanine mixture, D, L-4- (imidazol-2-yl) -a-methylphenylalanine, D, L-4- (4,5-dihydroimidazol-2-yl) -a-methylphenylalanine, D, L-2-methyl-3- (benzoxazol-2-one-6-yl) -alanine, D, L-3- (2-amino-4-mercaptobenzothiazol-6-yl) -2-methylalanine, D, L-3- (i, 3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide, D, L-3- (1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide methyl ester, D, L-3- (i, 3-dihydrobenzo-2,1,3-thiadiazol-5-yl) -alanine-5,5-dioxide, D, L-3- (1,3-dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5-yl) -2-methylalanine-2,2-dioxide, D, L-2-methyl-3- (quinoxalin-6-yl) -alanine, D, L-3- (quinoxalin-6-yl) -alanine, D, L-3- (2,3-dihydroxyquinoxalin-6-yl) alanine, D, L-3- (5-Hydroxy-4H-pyran-4-on-2-yl) -2-methylalanine and D, L-3- (2-Hydroxy-4-pyridyl) -2-methylalanine, their pharmaceutically acceptable salts and their hydrates. 7. Preparation according to claim 6, characterized in that it is a compound of the formula as a decarboxylase inhibitor and / or contains their salts. 709833/0989 8. Preparation according to claim 7, characterized in that the decarboxylase inhibitor is essentially of the D-isomer is free L-isomer. 9. Preparation according to claim 6, characterized in that it is a compound of the formula as compound (A) _f " CH ₂ -C-COOH and / or contains their salts. 10. Preparation according to claim 6, characterized in that it is a compound of the formula as compound (A) f, CH ..- C-COOH ² I. NH ₂ and / or contains their salts. 11. Preparation according to claim 4, characterized in that FU is a substituted benzene ring (1) and / or their salts. 12. Preparation according to claim 4, characterized in that FU is a substituted or unsubstituted benzoheterocyclic Ring (2) means and / or their salts. 709833/0989 13. Preparation according to claim 4, characterized in that FU is a substituted or unsubstituted heterocyclic Ring (5) means and / or their salts. 14. Preparation according to claim 11 »characterized in that that the compound (A) has the formula in which Y ₁ denotes a heterocyclic substituent from the group consisting of pyrrole, imidazole and dihydroimidazole, so that Y _{1 is} in a position other than the 2-position in the benzene ring, and Y ₂ denotes —H, —OH or —OCH *. 15- Preparation according to claim 14, characterized in that Y _{1 is} pyrrole and Y _{2 is} -H or -OH. 16. Preparation according to claim 15, characterized in that it is used as compound (A) L- QC-methyl-4- (pyrrol-1 -yl) -phenylalanine, D-a-Hethyl-4- (pyrrol-1 -yl) -phenylalanine, D, L-3-hydroxy-2-methyl-4- (pyrrol-1 -yl) -phenylalanine or D, L-cc-methyl-3- (pyrrol-1 -yl) -tyrosine contains. 1?. Preparation according to claim 14, characterized in that Y _{1 is} imidazole or dihydroimidazole and Y _{2 is} -H or -OH. -6f- 709833/09 18. Preparation according to claim 17, characterized in that the compound (A) D, L-3- (imidazol-1-yl) -α-methyltyrosine or D, L-3- (4,5-dihydroimidazol-2-yl) -cc-methylphenylalanine is. 709833/0989