DE1493824A1 - Process for the preparation of aminocarboxylic acid amides - Google Patents

Description

Dr. Expl.

RAN 4039/18

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basal (Switzerland)

Process for the preparation of aminocarboxamides

The invention relates to a process for the preparation of new α-amino-carboxamides, which is characterized is that you have DL- or D-amphetamine with one in the a-amino group and any other reactive groups protected, optically active α-amino-carboxylic acid acylated, optionally splitting off the protective groups from the amides obtained and, if desired, the carboxamides obtained thereby and having a free α-amino group in the α-amino group acylated.

The optically active α-aminocarboxylic acids used according to the invention for the acylation of the amphetamine are primarily those derived from proteins such as Bo optically active alanine, valine, leucine, isoleucine, proline, serine, threonine, lysine, arginine, histidine, phenylalanine, tyrosine, Tryptophan, cysteine, methionine, or optically active glutamic acid and aspartic acid. Both a-amino-carboxylic acids can be used Hl / Og / Rü

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the L- and the D-configuration as starting materials be used. The L-series acids are preferred, however, since the process products derived from these acids are generally more therapeutically valuable.

The amphetamine can be used as a racemate [DL-amphetamine] of acylation be subjected. However, optically pure D (+) - amphetamine is preferably used; H. the (+) - rotating, configurative form of 1-phenyl-2-aminopropane derived from D-phenylalanine [by replacing its carboxyl group with a methyl group].

The inventive acylation of the amphetamine with an α-amino-carboxylic acid requires the protection of the α-amino group the acid component. There are those from the

Peptide chemistry known protecting groups into consideration, for example the Carbobenzoxy-, Tojfcyl-, Pormyl-, Benzyl-, Mbenzyf, Phthalyl, trifluoroacetyl or nitro group. In protected The α-amino group is also present when it is an acyl radical of an aliphatic or aromatic carboxylic acid carries, e.g. B. an acetyl, priTpionyl, butyryl, palniitoyl, Benzoyl or salicoyl radical. Are process products with acylated a-amino group desired, so you can accordingly

ro start from α-amino-carboxylic acids, which have the desired N-acyl radical **** already included. As a rule, however, you will also be in

_OT such cases of α-amino-carboxylic acids with actual ο

Protecting groups, such as the carbobenzoxy group, go out, diwse Splitting off protective groups after condensation has taken place and then

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the desired acyl radical, e.g. B. a palmitoyl residue, in introduce the α-amino group.

In the case of cysteine, the α-amino group can also be protected by using the cysteine in a manner known per se [cf. J. Amer. Chem. Soc. 8O _x II58 (1958)] into a thiazolidine carboxylic acid derivative, e.g. B. in 2,2-dimethylthiazolidine-4-carboxylic acid of the formula

CHr CH COOH

1 ² I.

H (T CH

is converted , the secondary amino group of which can additionally be protected , e.g. B. by N-formylation.

In the case of α-amino-carboxylic acids with other reactive groups, such as another amino group [e.g. Arginine, lysine], a thio group [e.g. B. cysteine] or another carboxyl group [as in the a-amino-dicarboxylic acids, e.g. As aspartic acid or glutamic acid] are also protected these further reactive J ₀ tive groups. Another amino group can with

NJ the protective groups already mentioned above are blocked. ^ The thio group of cysteine can z. B. with the benzyl group

cn or simultaneously with the a-amino group by conversion σ

of the cysteine in the mentioned thiazolidine derivative

will. A protection of the -carboxyl group of a-amino-dicarbon-BAD OWQiNAL

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acids are obtained, for example, by amidation with ammonia or by esterification of the U) -carboxyl function.

Methods are preferred for the acylation according to the invention of the amphetamine with optically active α-amino-carboxylic acids applied, which allow a sterically uniform reaction course as possible, in which racemization if possible is avoided. Such methods are, for example, the following:

a) Implementation of the amphetamine with the α-amino-carbonic acid in Presence of a condensing agent such as a carbodiimide e.g. Dicyclohexylcarbodiimide, of carbonyldiimidazole, or of 2-ethyl-5-meta-sulfonato-phenyl-isoxazolium. Such condensing agents enable the use of α-amino-carboxylic acids with a free [not activated] carboxyl function.

b) Reaction of the amphetamine with a reactive derivative of a-amino-carboxylic acid, e.g. with the azide, the chloride, an energy-rich ester ,, [such as phenyl-, p-nitrophenyl-, Thiophenyl or cyanomethyl ester], a mixed anhydride with an inorganic or organic acid [e.g. an ester of Chloroformic acid, such as ethyl chloroformate]. Such activated derivatives of the carboxyl component can be mixed with the amphetamine component at room temperature or lower temperature

realize. _OA _

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c) A method which allows activation of both the carboxy1 and the amino group is that according to Anderson [J ₀ Am »Chem. Soc. J ± (1952), 5304 and 5309], in which by means of tetraethylpyrophosphite [C ₂ H ₅ O) Ap-OP ^ (OC ₂ H ₅ ) ₂ ] the carboxyl group is converted into a -COOP (OC ₂ H ₅ ) ₂ group and the Amino group is converted into an -NHP (OC ₂ H ₅ ) _{2 group.}

d) Reaction of the amphetamine with an intramolecular anhydride of α-aminocarboxylic acid of the so-called »LeuchVsehen type Anhydrides which can be obtained from the α-amino-carboxylic acids and phosgene and in which the α-amino and the carboxy function Part of a ring of the formula

-CH CO

NH CO

form. These anhydrides react with amines with evolution of CO ₂ . Also the thio analogs with rings of the formula

CH CO

-egg

NH can be used.

e) Reaction of the amphetamine with the (N-acyliertea), -Amlao-carbone »« ™ converted into an oxazolone derivative in the manner shown below. 9Q9821 / 1160 ""

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R-CH COOH R-CH-COOH R-CH-COCl

In addition to the amides obtained according to the invention, the protective groups can, if desired, be split off by methods known per se. For example, the benzyl and carbobenzoxy groups can be split off by hydrogenolysis with Pd-carbon or by sodium in liquid ammonia * The carbobenzoxy group can also be removed with HBr / glacial acetic acid. The ToajF-J. * Residue can also be eliminated with sodium in liquid ammonia. The cleavage of the pormyl radical takes place under mild action of acid, the cleavage of the trifluoroacetyl radical takes place under mild action of alkali. The phthalyl group can be split off selectively using hydrazine. Groups introduced to protect other than the α-amino function can likewise be removed in a manner known per se. Thus the γ-esterified carboxyl group can be, for example, an inventive Glutaminsäareamids obtained after cleavage of the N-protecting group by the action of alkali _y as ammonia, saponified to the free carboxyl group * Since the free

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γ-carboxyl group under the conditions mentioned with the α-amino group reacts with lactam formation, leads to the aforementioned saponification reaction to pyrrolidinone compounds. An example of such a pyrrolidinone compound is that obtainable according to the process L-Pyrrolidin-2-one-5-carboxylic acid a- [D (+) - 1-phenyl-propyl- (2)] - amide the formula

CH ₀ - CH CONH-

I ² I CH ₀ NH

Process products from which the N-protective group initially present in the amino acid component has been removed, can, if desired, by methods known per se in acylate the oc-amino group. Possible acyl radicals are, for example, the acyl groups already mentioned above as possible N-protective groups of aliphatic or aromatic carboxylic acids, for example from Alkanecarboxylic acids with up to 20 carbon atoms, such as acetyl, propionyl, butyryl, palmitoyl etc., or from benzoic acid, salicylic acid etc.

Process products with free amino groups can if desired, for example for medicinal preparations, in acid addition salts be transferred. The usual inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, p-toluenesulfonic acid, sulfosalicylic acid, β-naphthalic acid, citric acid, benzoic acid, sorbic acid, etc. can be used. 909821/1160

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The amphetamine derivatives obtainable according to the invention differ in their effect in a desirable way from that of the amphetamine itself. As is well known, amphetamine has, among other things, an appetite-suppressing and central-stimulating effect depending on the type of α-amino carboxylic acid used to acylate the amphetamine and, if appropriate, the protective groups it is necessary to improve the therapeutic range »In some cases, there is also a differentiation between appetite-suppressing and central-stimulating Effect one. For example, the 3-formyl-2,2-dimethyl-Ir ~ thiazolidine-4-carboxylic acid [D (+) - 1-phenyl-propyl- (2)] amide has an effect formula

CH ₀ CH CONH CH - CH ₀

N CHO CH

H-C CH, 3 3

appetite-suppressing, -but only slightly central stimulating "

The products of the process can be used as remedies, for example in the form pharmaceutical preparations find use which they or their

cd salts mixed with one for enteral or parenteral

<° application suitable pharmaceutical, organic or inorganic

They do not contain inert carrier material such as water, gelatine, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum, polyfiJkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets, suppositories

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sitoriums, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If applicable, they are sterilized and / or contain auxiliary substances such as preservatives, Stabilizing agents, wetting agents or emulsifying agents, salts to change the osmotic pressure or buffers «You can too contain other therapeutically valuable substances »

example 1

a) 20 g of N-carbobenzoxy-D-leucine methyl ester are dissolved in 150 ml of ethanol and mixed with 10 ml of hydrazine hydrate. The mixture is left to stand at room temperature for 3 days. The mixture is then concentrated and the N-carbobenzoxy-D-leucine hydrazide is precipitated with ether. ■ Melting point 120-121 ⁰ C [on. Snoie ester / petroleum ether].

b) 5.6 g of the hydrazide obtained are in 45 ml of 1 η Dissolved hydrochloric acid and 10 ml of glacial acetic acid. 1.4 g of sodium nitrite in 10 ml of water are added dropwise to the solution at -5.degree. C., the azide begins to fail. After half an hour the mixture is with

to ethyl acetate extracted and the extract with water, sodium bicarbonate

«Ο natural solution and washed again with water with the addition of ice and

^ finally dried with sodium sulphate. After standing for 2 hours - »at 0 C the solution is mixed with a solution of 3» 2 g of D (+) -amphetaiain ^? added in Esaigester and the mixture in the refrigerator for 24 hours

ditched. The ethyl acetate solution is then mixed with sodium bi-BAD ORIGINAL

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carbonate solution, hydrochloric acid and water, then dried and evaporated. The N-carbobenzoxy-D-leucine- [D (+) - 1-phenyl-propyl- (2)] - amide thus obtained melts at 143-145 ° C [from ethanol / water], (a) ^ ³ = + 34 ° [c = 1.35 in methanol],

c) 25 g of the carbobenzoxy amide obtained are dissolved in 200 ml of glacial acetic acid and hydrogenated with the addition of approx. 2 g of palladium carbon. After filtration, the solution is evaporated under reduced pressure, the residue is extracted with hydrochloric acid, the extract is washed with ether, the acidic aqueous phase is made alkaline with ammonia, extracted with ethyl acetate and the ethyl acetate solution is evaporated after drying. The D-leucine- [D (+) - 1-phenyl-propyl- (2)] - amide thus obtained melts after sublimation at 35-36 ^{° C., (a) p 5} = + 0.4 ° + 1 ° [c = 1 , 2 in methanol] «

Example 2

^a) 4.8 g [20 mMo3] N-carbobenzoxy-1-serine and 2 "8 mL [20 mmol] of triethylamine are dissolved in 60 ml of tetrahydrofuran, and ⁰ C with 1.9 ml of [20 mM] ethyl chloroformate at -1O . After 30 minutes, ^{2.7 g [20 mmol] D (+) - amphetamine are added at 0} ° C. and the mixture is left to stand for 2 hours at room temperature Washed in hydrochloric acid, potassium bicarbonate solution, water and saturated sodium chloride solution, then dried and evaporated under reduced pressure. The firm one

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The residue is recrystallized from chloroform / carbon tetrachloride. This gives 3.5 g of (49 #) N-carbobenzoxy-L-serine- [D (+) - 1-phenyl-propyl- (2)] - amide with a melting point of 125-132 C. After a further recrystallization, the melting point is around 129-131 ° C "(a) ^ ⁷ = -8.6 ° [c = 1.06 in methanol].

b) 18.6 g [52 mmol] of the carbobenzoxy amide obtained are hydrogenolyzed in 200 ml of glacial acetic acid with 3 g of 10 ^ iger palladium carbon until no more CO _{2 can} be detected in the escaping gas. After filtering off, 100 ml of 2 η methanolic hydrochloric acid are added, whereupon the mixture is evaporated under reduced pressure. Are thus obtained 9.2 g (62%) of the hydrochloride of L-serine [D (+) - l-phenyl-propyl- (2)] - amide of melting point 154-157 ⁰ C [from methanol / ether 1: 8 ]. (<x) _D = + 3.82 ° [c = 1.0 in methanol],

Example 3

30.7 g of N-carbobenzoxy-L-glutamic acid-Y-methyl ester are dissolved in 150 ml of dry acetonitrile by gentle heating. The solution is cooled to -10 ° C. 17 g of carbonyldiimidazole are added with stirring, and solution slowly occurs. After about 1 hour, 14 g of D (+) - amphetamine in 50 ml of acetonitrile are added, a slight rise in temperature to +5 ° C. being observed. After some time, the N-carbobenzoxy-L-glutamic acid-a- [D (+) - 1-phenyl-propyl- (2)] - amide-Y-methyl ester precipitates. Melting point 171-172 ⁰ C [methanol], (α) _β = + 15.0 ° [c = 2 in dimethylformamide],

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Example 4

21 g of N-carbobenzoxy-L-glutamic acid a- [D (+) - 1-phenyl-propyl- (2) J-amid-y-methyl ester obtained according to Example 3 are subjected to hydrogenolysis as described above The solution is evaporated, the residue is absorbed in water, made alkaline with ammonia and the solution is extracted with ether propyl- (2)] - amide of melting point 220-222 ⁰ C.,.

Example 5

3.9 g of N-carbobenzoxy-L-leucine-p-nitrophenyl ester are dissolved in 50 ml of ethyl acetate. 1.4 g of D (+) - amphetamine are added to the solution with cooling and the mixture is left to stand for 2 hours. Then this is washed with hydrochloric acid, a lot of sodium bicarbonate solution and water, then dried and evaporated. Is obtained as the N-carbobenzoxy-L-leucine- [D (+) - l-phenyl-propyl- (2)] - amide of melting point 119-121 ⁰ C [methanol], (α) = ²² -12, 7 ° [c = 1 in methanol].

Example 6

a) A solution of 30 g of N-carbobenzoxy-L-phenylalanine in 300 ml of acetonitrile and 60 ml of dimethylformamide is cooled to -10 ⁰ C. 16.2 g of carbonyl-

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diimidazole. After one hour, 1 × 5.5 g of DL-amphetamine in 50 ml of acetonitrile are added. The mixture is stirred for one hour at room temperature, then evaporated, the residue taken up in ethyl acetate, the extract washed with sodium bicarbonate solution, hydrochloric acid and water, then dried and evaporated. This gives N-carbobenzoxy-L-phenylalanine-FDL-l-phenylpropyl (2)] - amide of melting point 127-128 ⁰ C. (Ct) Jp = + 4.2 ° (c = in methanol].

b) 25 g of the carbobenzoxy amide obtained are as above described subjected to hydrogenolysis with palladium carbon and converted into the hydrochloride. The hydrochloride of L-phenylalanine- [DL-l-phenyl-propyl- (2)] - amide becomes more horJ. £, -like as a product Maintain consistency. Ninhydrin reaction positive.

Example 7

16 g of 3-Pormyl-2,2-dimethyl-L-thiazolidine-4-carboxylic acid (prepared from L-cysteine) is slurried in 120 ml of absolute tetrahydrofuran under stirring at -10 ⁰ C. 14.4 g of carbonyldiimidazole (95%) are then added. The mixture is stirred for 20 minutes at -1O ⁰ C. 11.45 g of D (+) - amphetamine in 30 ml of tetrahydrofuran are added to the clear solution. The mixture is stirred for a further hours at -3 ⁰ C, allowed to then overnight in the cold 8teken and then evaporated under reduced pressure. The residue is taken up 4 times with the solution in ethyl acetate

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-U-

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0.1 η tartaric acid / ice and then extracted with lO ^ potassium bicarbonate until a sample with ^3N hydrochloric acid gives no turbidity. The ethyl acetate solution is then dried and evaporated and the residue is recrystallized from ether. This gives 3-formyl-2,2-dimethyl-L-thiazolidine-4-carboxylic acid [D (+) - 1-phenylpropyl- (2)] ] -amide, melting point 107-108 ⁰ C. {α.) ψ = -133 ° Lo = 0.898 $ 95 in acetic acid].

Example 8

19.6 g of L-leucine- [D (+) - l-phenyl-propyl- (2)] - amide are dissolved in 250 ml of tetrahydrofuran, mixed with 14 ml of triethylamine and cooled to -30.degree. 21.7 g of palmitic acid chloride are added dropwise to the solution with rapid stirring. Before the end of the dropping, the contents of the flask become viscous, whereupon the cooling is removed and some dimethylformamide is added. After adding the remaining palmitic acid chloride, the temperature is allowed to rise to +10 G with vigorous stirring and the solvent is then removed under reduced pressure. The residue is taken up in ethyl acetate / 2 η hydrochloric acid with warming, the ethyl acetate solution is quickly washed 3 times with 1 η hydrochloric acid and 2 times with water, then dried and evaporated under reduced pressure. This gives 25.2 g (50 #) N-palmitoyl-L-leucine [D (+) - 1-phenyl-propyl- (2)] amide with a melting point of 82-83 ° C. [from ethyl acetate]. (a) _D = 16.9 ° [c = 1.16 in 95 # acetic acid].

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Example 9

32.6 g of N-carbobenzoxy-L-leucine- [D (+) - 1-phenyl-propyl- (2)] - amide (prepared according to Example 5) are added to 200 ml of 90% acetic acid hydrogenolyzed with 3 g of 5% palladium carbon, after Absorption of 1 equivalent of hydrogen, the catalyst is filtered off, the filtrate was taken up in water, washed twice with ether and made alkaline with concentrated ammonia / ice. The mixture is then extracted twice with ether, the ethereal solution with water and concentrated sodium chloride solution washed, dried and evaporated under reduced pressure. The residue is, together with 11.9 g of salicylic acid in 700 ml Dissolved ethyl acetate, mixed with 17.9 g of dicyclohexylcarbodiimide and left to stand at 2-4 ° C. for 16 hours. After removing Urea is the filtrate four times with 1N hydrochloric acid and four times with 10 ^ iger potassium bicarbonate solution, once each with water and saturated Washed sodium chloride solution, then dried and evaporated under reduced pressure. The dark residue will dissolved in ethanol and water is added to the solution until crystallization begins. After recrystallizing twice Ethanol / water gives 4.4 g of N-salicoyl-L-leucine- [D (+) - 1-phenyl-propyl- (2)] - amide with a melting point of 177 ° C. (a) ^ = -22.2 ° [c = 0.98 in 95 # acetic acid].

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Example 10

a) 46.7 g of N-carbobenzoxy-S-benzyl-L-cysteine and 18.3 g of & (+) - amphetamine, dissolved in 300 ml of ethyl acetate, are mixed with 27.8 g of dicyclohexylcarbodiimide and overnight at 2-4 ° C left to stand. Then the mixture is briefly boiled and sucked hot. After cooling and standing for four hours in the cold, 50.9 g ($ 81) of N-cybobenzoxy-S-benzyl-L-cysteine [D (+) - 1-phenylpropyl (2)] amide crystallize from the filtrate of melting point 125-127 ⁰ C (ct) ^ ⁵ = -15.4 ° [c = 0.97 in 95% acetic acid].

b) 23 g of the carbobenzoxy amide obtained in 100 ml 33 $ HBr / glacial acetic acid are left to stand for 1 fc hours at room temperature. The mixture is then evaporated under reduced pressure and

the residue is shaken four times with 150 ml of ether each time and decanted. The residue is then taken up in water, washed twice with ether, made alkaline with concentrated ΝΗ - ,, / ice and extracted with ethyl acetate. After washing, drying and evaporation of the ethyl acetate solution, the residue is dissolved in 50 ml of pyridine, and 13 g of acetic anhydride are added while cooling with ice. The mixture is left to stand at room temperature for 16 hours and then evaporated to dryness under reduced pressure. This gives 14.3 g ($ 77.6) of N-acetyl-S-benzyl-L-cysteine [D (+) - 1-phenyl-propyl- (2)] amide with a melting point of 164-165 ° C [from ethyl acetate], (a) ^ ⁴ = -10.7 ° [c = 1.03 in 95% acetic acid],

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a) 44.4 g of Κ, Ν'-dicarbobenzoxy-L-eyiJtia are converted into the acid chloride in a manner known per se. This is added immediately and with vigorous stirring to a solution of 21.7 g of D (+) - amphetamine and 25 ml of triethylamine in 30 ml of tetrahydrofuran ^{at -5C 0 C nbr ^ Hih.lten.} Additional triethylamine is added until the mixture remains alkaline. The pulp is left to stand for 16 hours at room temperature, then heated on the steam bath and filtered hot. The filtrate is evaporated under reduced pressure and the residue is recrystallized from hot ethanol. This gives 20 g of N, N'-dicarbobenzoxy-L-cystJn-bis [D (+) - 1-phenyl-propyl- (2)] - amide with a melting point of iyy-201 ° Co (oc) ' = -8 , 4 ° [c = 1.30 in 95% acetic acid] ο

b) 19.2 g of the dicarbobenzoxy amide obtained are dissolved in 100 ml of glacial acetic acid and 100 ml of 33% HBr / Eisessie l> v. Ra.urr temperature gp. ■ shakes, whereby solution enters "After l- £ · hours, the solution is evaporated under reduced pressure and the residue is shaken several times with ether and decanted. The residue is then dissolved in water, washed twice with ether, made alkaline with concentrated NH / ice and immediately extracted with ethyl acetate. After washing, drying and evaporating the ethyl acetate solution, the residue is taken up in 250 ml of 2 η methanolic hydrochloric acid and the solution is again evaporated under reduced pressure. 7.9 g of L-cystine bis [D (+) - l ~ phenyl-propyl-

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- (2)] - amide of melting point 243-246 ⁰ C [from methanol / ether]. (οί) ^ ⁴ -23.3 ° [c = 1.01 in water].

According to one or the other, described in the examples above The working method is as shown in the table below recorded amides.

Tabel

Melting point

(α)

23 D

D-pyrrolidin-2-one-5-carboxylic acid
a- [D (+) - 1-phenyl-propy1- (2)] - amide 126-127 ° C " + 17.6 °
[c = 1 in
Methanol] + 36 °
[c = 1 in
Methanol] LG-lut amic acid ea- [D (+) -1-phenyl-
pr opy 1- (2)] - amide-γ-methyle st
hydrochloride OeI,
ninhydrin
positive N-carbobenzoxy-D-glutamic acid
a- [D (+) - 1-phenyl-propy1- (2)] -
amide-γ-methyl ester 122-124 ⁰ C. ₊ 24 °
[c = 1 in
Methanol J L-As paragin-a- [D (+) - 1-phenyl-
pr opy 1- (2)] amide 211-212 ⁰ C. + 18.9 °
[c = 1 in
Methanol] D-phenylalanine- [D (+) - 1-pheny1-
propyl (2)] amide dihydrochloride obtained as a lyophilisate L-phenylalanine- [D (+) - 1-phenyl-
pr opy 1- (2)] amide 95-96 ⁰ C.

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Melting point

N-formyl-L-phenylalanine- [D (+) - 1-
phenyl-propyl- (2)] - amide 146-148 ⁰ C. - L-leucine- [D (+) - 1-phenyl-propy1-
(2)] - amide 79-8O ⁰ C. - N-formyl-L-tyrosine- [D (+) -1-phenyl-
pr opy l- (2)] amide 192-195 ⁰ C. + 27.1 °
[c = 2 in
Methanol] L-tyrosine- [D (+) - 1-phenyl-propy1-
(2)] - amide 163-165 ⁰ C. + 29.7 °
[c = 2.4 in
Methanol] N ^a , N'-di-carbobenzoxy-D-lysine-
[D (+) - 1-phenyl-propy1- (2)] -
amide . 142-143 ⁰ C. + 15.1 °
[c. = 2 in
Dimethyl
formamide] D-lysine- [D (+) - 1-phenyl-propy1-
(2)] - amide-dioxalate 204 ⁰ C - 14.2 °
[c = 2 in
Water] ü ^ -Tosyl-L-lysine- [D (+) - 1-phenyl-
propyl- (2)] amide 224-225 ⁰ C + 31.8 °
[c = 1 in 959S-.
iger acetic acid N-carbobenzoxy-S-benzyl-L-
cysteine- [D (+) - l-phenyl-propyl-
(2)] - amide 136-138 ⁰ C. -9.6 °
[c = 1.3 in
Methanol] S-Benzyl-L-cysteine- [D (+) - l-
phenyl propyl (2)] amide oxalate 198-200 ⁰ C. - 2,2-dimethyl-L-thiazolldin-4-
carbonic acid [D (H -) - l-phenyl-
propyl- (2)] - amide-hydrochloride 69-75 ⁰ C + 9.8 °
[c = 1 in 95% -
acetic acid]

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Example 12

Using 3-pormyl-2,2-dimethyl-L-thiazolidine-4-carboxylic acid [D (+) - l-phenyl-propyl- (2)] - amide as the active ingredient, tablets or push-fit capsules with the following fcusammew composition can be produced :

Tablet:

G-elatine plug-in capsule:

Effectiveness 20 mg Lactose 50 mg Cornstarch 120 mg Talk 10 mg Total 200 mg Active ingredient 20 mg Calcium carbonate 20 mg Lactose 250 mg Talk 10 mg Total 300 mg

Using N-carbobenzoxy-L-glutamic acid-a- [D (+) - 1-phenyl-propyl- (2)] - amide-Y-methyl ester Tablets of the following composition can be produced as an active ingredient:

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Tablet: active substance 50 mg

Milk sugar 50 mg

Corn starch 140 mg

Talc 10 mg

Total 250 mg

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Claims (4)

.22- Pat ent claims 1 .. Process for the production of α-amino-carboxamides, characterized. that one DL- or D-Amphetamln with acylated an optically active α-amino-carboxylic acid protected in the α-amino group and any other reactive groups, optionally splitting off the protective groups from the amides obtained and, if desired, the one obtained thereby, a free one acylated carboxamides containing a-amino group in the a-amino group. 2 "Method according to claim 1, characterized in that a component of proteins forming α-aminocarboxylic acid for Acylation of amphetamine used. 3 «Method according to claims 1 and 2 _? characterized in that D (+) -amphetamine with N-Carbobenr, oxy -L --rl <t.ia ''>'·· ■ γ-methylester of N ~ carbobenzoxy-L-glutamic acid ~ ~ or - [D (+) - 1-phenyl ■ propyl- (2) I -amido-y-methyl ester acylated; " 4. The method according to claim 1 and 2, characterized in that D (+) - amphetamine with L-cysteine in the form of 3-formyl-2,2-dimethyl-L-thiazolidine-4-carboxylic acid to 3-formyl - 2 ,? - dimethyl-L-thiazolidine ^ -carboxylic acid-CDi + Jl-phenyl-propyl-i ^) amide acylated " 909821/1160