DE2721760A1 - PEPTIDE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Patent attorneys

/.-ing. Reiner F. Meyer

Munich 80

Luci / e-Grahn-S!, -. 22. IeI. (089) 472947

1 May 3 «77

RAN 4105/24

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Peptide derivatives and processes for their preparation

The present invention relates to new peptide derivatives, particularly those of phosphonic and phosphinic acids Process for their production and pharmaceutical preparations containing these compounds.

The peptide derivatives of the present invention are compounds the general formula

R ³ _r R ² _, R ¹ C

I Γ I I I Il

H - N - CH - CO - J - NH - CH - CO + NH - CH - Ρ - (a) L (b) J (C) I

R ⁴ (D

η OH

wherein η is 1, 2 or 3;

12 3
R, R and R are the radicals usually

represent α-amino acids occurring in proteins, with the restriction that R never Ka ^ g ^ j ^ j ^^ d a

272Ί760

Represents methyl group when η = 1;

4th
R denotes hydroxy or methyl and where the configurations on the carbon atom (a) are D, on the carbon atom (b) L and on the carbon atom (c) R.

2 1
(if R and R φ hydrogen),

and their physiologically acceptable salts.

The expression "residue of an α-amino acid normally occurring in proteins" as used in the description is intended to mean R radical of an α-amino acid of the general formula

H ~ N - CH- COOH

² I.

as it normally occurs in proteins. For example, if the amino acid is glycine, then adjusts to R. Hydrogen atom and when the amino acid is alanine, R represents a methyl group. For valine, R is an isopropyl group, for leucine an isobutyl group, for glutamic acid the 2-carboxyethyl group and for phenylalanine the benzyl group. However, R can also additionally be bonded to the α-amino atom and be part of a nitrogen-containing ring, such as, for example in proline and in pyroglutamic acid.

In the event that R ψ hydrogen, the configuration on carbon atom (c) is R, that is the configuration obtained by replacing the carboxyl group of a natural L-amino acid with a phosphorus radical.

If η in formula I is 2 or 3, the Substi-2
tuent R represent the same or different a-amino acid residues.

Preferred compounds of the formula I are those

4th
in which R represents a hydroxyl group. Also preferred are compounds of the formula I in which R is a methyl group

2 represents, as well as compounds in which R represents a methyl group and R represents a methyl, isopropyl or isobutyl group.

709848/0976

Examples of compounds of formula I are the following:

(IR) -1- (D-alanyl-L-alanylamino) -ethylphosphonic acid,

(IR) -1- (D-Alanyl-L-alanyl-L-alanylamino) -ethylphosphonic acid,

(IR) -I- (D-valyl-L-alanyl-L-alanylamino) -ethylphosphonic acid,

(IR) -1- (D-Leucyl-L-alanyl-L-alanylamino) -ethylphosphonic acid and

(IR) -l- (D-alanyl-L-alanyl-L-alanyl-L-alanylamino) -ethylphosphonic acid.

According to the invention, the peptide derivatives of the formula I and their physiologically tolerable salts can be prepared thereby be that one

a) in a manner known per se, the protective group (s) of a compound the formula

30 .20 _M _

^{1 !} «- _R ~ _(II)

R ^JU _ R "-, * 0

ei. · ... i "Ü" 40 R ³

I Γ ι ι »

⁵ -NH-CH-CO 4-NH-CH-CO-NH-CH-Ρ - (a) L (b) J _n (C) L ₁

where η as above and the configurations at the carbon atoms (a), (b) and (c) analogous to are defined above;

R is hydrogen or an amino protecting group;

R ¹⁰ , R ²⁰ and R ^{30 represent} the radicals of α-amino acids normally occurring in proteins with the restriction analogous to the above and with any amino groups and other functional groups that may occur in protected form;

40
R is methyl, hydroxy or a lower alkoxy protective group and R is hydroxy or a lower

709848/0976

mean alkoxy protecting group,
splits off or
b) from a (R, S) diastereomer mixture of the formula I that

R diastereomers isolated in a manner known per se and optionally a compound of the formula I obtained in transferred to a physiologically compatible salt.

One or more amino group (s) present in the radicals R, R and R of a compound of the formula II can (can) are in protected form, the amino protective groups known from peptide chemistry being suitable. Particularly suitable Amino protective groups are aralkoxycarbonyl groups, in particular the benzyloxycarbonyl and tert-butoxycarbonyl groups. The formyl, trityl or trifluoroacetyl radical can also be used as amino protective groups. A carboxy or hydroxyl group present in the radicals R, R and R of a compound of the formula II can through one of the usual carboxyl or hydroxyl protecting groups. A carboxyl group can, for example, through Conversion into an alkyl ester or aralkyl ester function, for example a tert-butyl ester or a benzyl ester, be protected. A hydroxyl group can, for example, by means of an aralkoxycarbonyl radical, ζ.B. of the benzyloxycarbonyl radical, an alkanoyl radical, e.g. acetyl or propionyl radical, an aroyl radical, e.g. benzoyl radical, a Alkyl radical, e.g. of the tert-butyl radical, or an aralkyl radical, e.g. of the benzyl residue. The protection of other functional groups, the parts of the substituents R, R and R can be carried out in a manner known per se. In the case of the radical R of the general formula II mentioned protective group can be any, in connection with the radicals R, R ° and R already above act called amino protective group.

The cleavage of the protective groups of a compound of the formula II can be carried out in a manner known per se,

709848/0976

i.e. by processes that are necessary for the splitting off of the protective groups Time actually applied or described in the literature. Accordingly, for example, an aralkoxycarbonyl radical / Z.B. the benzyloxycarbonyl or the tert-butoxycarbonyl group, are split off hydrolytically, for example by Treat with a mixture of hydrogen bromide and glacial acetic acid. An aralkoxycarbonyl radical, e.g. the benzyloxycarbonyl radical, can also be split off by hydrogenation, e.g. in the presence of palladium on charcoal or palladium oxide. Of The tert-butoxycarbonyl group can expand by means of hydrogen chloride are split off in dioxane. One as the rest

40 41

R and / or R present lower alkoxy group can be straight or branched chain and preferably 1-6 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy etc.) and converted into a hydroxyl group by treatment with a mixture of hydrogen bromide in glacial acetic acid or by means of trimethylchlorosilane and subsequent aqueous hydrolysis being transformed. It is understood that, depending on requirements, the cleavage of the protective groups in a single Reaction stage or can be carried out in several stages.

The resolution of an R, S-diastereomeric compound of the general formula I into its diastereomers and the Obtaining the R-diastereomer can be carried out by methods known per se, for example by fractionated Crystallization or by high pressure liquid chromatography.

The compounds of the formula I are amphoteric and form salts with physiologically acceptable strong acids (for example methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid) and physiologically acceptable bases (for example sodium hydroxide).

The starting compounds of the general formula II can, for example, by condensation of a compound of the general formula

709848/0976

^r2 ° ί ^r10 °

H-j-NH-CH-CO-NH-CH-P -R ° (III)

L (b) J (C) I ₄₁

wherein m is 0, 1, 2 or 3 and

_π 1Ο "2O _π 4Ο, _π 41. ,. R, R, R and R as well as the

Configurations at the carbon atoms (b) and (c) are as defined above,

with an appropriately protected α-amino acid, an appropriately protected di-, tri- or tetrapeptide or a reactive derivative of such a compound in a manner known per se.

Thus, a compound of the formula III with m = 0, with a suitably protected dipeptide or a reactive derivative thereof to form a compound of the formula II with η = 1 or with a suitably protected one Tripeptide or a reactive derivative thereof to one Compound of the formula II with η = 2 or with a suitable one Way protected tetrapeptide or a reactive derivative thereof to a compound of formula II be condensed with η = 3.

On the other hand, a compound of the formula III with ITi = I, with a suitably protected α-amino acid or a reactive derivative of an α-amino acid to form a Compound of the formula II with η = 1 or with a suitably protected dipeptide or a reactive one Derivative thereof to a compound of the formula II with η = 2 or with a suitably protected tripeptide or a reactive derivative thereof to be condensed to a compound of the formula II with η = 3.

However, a compound of the formula III with m = 2 can also

709848/0976

with an appropriately protected α-amino acid or a reactive derivative thereof to form a Compound of formula II with η = 2 or with a suitably protected dipeptide or a reactive one Derivative thereof to be condensed to a compound of the formula II with η = 3.

Finally, a compound of the formula III with m = 3 can be combined with a suitably protected α-amino acid or a reactive derivative of such an acid can be condensed to a compound of the formula II with η = 3.

On the other hand, the compounds of the formula II can be prepared by those described above Carries out condensations using an R, S compound of the formula III and the R compound from the obtained R, S product isolated in a manner known per se, for example by crystallization, chromatography or fractionated Crystallization using a suitable base such as α-methylbenzylamine.

The aforementioned condensations can be carried out by methods well known in peptide chemistry are, for example by the method of mixed anhydrides, activated esters, azide or acid chloride method .

According to one of these methods, a suitable compound of the formula III with a suitably protected α-amino acid or with a suitably protected di-, tri- or tetrapeptide - condensed as desired where the terminal carboxyl group is part of a mixed anhydride with an organic or inorganic one Acid is. Such an amino acid or such a di-, tri- or tetrapeptide is expediently with free carboxyl group with a tertiary base, such as a tri (lower alkyl) amine, e.g. triethylamine, or with N-ethyl

709848/0976

-Jf -

away

morpholine in an inert organic solvent (e.g. tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, toluene, Petroleum ether or a mixture of these solvents) treated and the salt obtained with a chloroformic acid ester, e.g. the ethyl or isobutyl ester, reacted at low temperature. The resulting mixed anhydride is then conveniently condensed in situ with the compound of formula III.

According to another method, a suitable compound of the formula III with one in an expedient manner protected α-amino acid or with an appropriately protected di-, tri- or tetrapeptide - as desired are condensed, the terminal carboxyl group being in the form of an acid azide group. This condensation is preferably in an inert organic solvent such as dimethylformamide or ethyl acetate, at low temperature carried out.

According to a further method, a suitable compound of the formula III is protected with one in a suitable manner α-amino acid or with a suitably protected di-, tri- or tetrapeptide - condensed as desired, the terminal carboxyl group being in the form of an active ester group, e.g. a p-nitrophenyl, 2,4,5-trichlorophenyl or N-hydroxysuccinimide ester group. This condensation is either in an inert organic

40 solvents, such as dimethylformamide, or, if R and / or

41
R represent lower alkoxy groups, carried out in an aqueous alkanol, for example aqueous ethanol.

According to a further method, a suitable compound of the formula III with a suitably protected α-amino acid or with a suitably protected di-, tri- or tetrapeptide - condensed as desired where the terminal carboxyl group is in the form of an acid chloride. This condensation will

709848/097 6

-yf -

272Ί760

preferably carried out in the presence of a base and at low temperature.

The peptides of the present invention potentiate the activity of D-cycloserine. You also own antibacterial activity against organisms such as Escherichia coli, Klebsiella aerogenes, Streptococcus faecalis and Haemophilus influenzae.

The compounds according to the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. can be used. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets, suppositories, capsules; in semi-solid form, for example as ointments; or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain other auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, agents for improving the taste, salts for changing the osmotic pressure or buffer substances. The pharmaceutical preparations can be produced in a manner familiar to any person skilled in the art.

But the novel peptide derivatives can also be used in combination with D-cycloserine, both as a mixture and as single components and are optionally administered by separate routes. The amount of the peptide derivative to be administered , as well as the ratio of the peptide derivative to the D-cycloserine, can be varied within wide limits and depends on factors such as the type of specific compound, the route of administration and the pathogen to be controlled. The ratio of peptide derivative to D-cycloserine can

709848/0976

ytf-

for example 100: 1 to 1: 100 (v // w).

Example 1

4.3 g of the benzylamine salt of (IR) -1 - [(N-benzyloxycarbonyl-D-alanyl-L-alanyl-L-alanyl) -amino] -ethylphosphonic acid were added with stirring and rinsing with 4 ml of glacial acetic acid to 12 ml of a 45% solution of hydrogen bromide in glacial acetic acid. The mixture was stirred for 6 hours at room temperature. Then 100 ml of ether were added and the supernatant liquid was decanted and the residue treated with 100 ml of ether. The obtained gum was taken up in 30 ml of methanol. the Solution was then treated with 3 ml of propylene oxide in 5 ml of methanol. It formed a white precipitate, which over Left to stand overnight at room temperature, filtered off and washed successively with methanol and ethanol and dried became. Crystallization from water / ethanol yielded 1.96 g (IR) -1- (D-alanyl-L-alanyl-L-alanylamino) ethylphosphonic acid, F. 318 ° -32O ° C (dec.): [A] ^ ° = -107 ° (c = 0.5% in 1 N sodium hydroxide).

The starting material was produced as follows:

To a solution of 2.7 g of (IR) -1- (L-alanyl-L-alanylamino) ethylphosphonic acid in 50 ml of water, 2.0 g of triethylamine and 50 ml of ethanol were added with stirring at 5 ° C. The clear solution obtained was ^{cooled to 0} ° C. and mixed with 3.8 g of solid N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-alanine and 25 ml of ethanol. The mixture was stirred at 0 ° C. for 2 hours and at room temperature for 16 hours. The clear solution was evaporated and the residue was partitioned between 150 ml of water and 100 ml of chloroform. The aqueous solution was washed again with 100 ml of chloroform and the organic phase with 50 ml of water. The combined aqueous extracts were evaporated, the residue was taken up with a mixture of 40 ml of water and 40 ml of methanol and replaced by a

709848/0976

Sent column of a freshly regenerated cation exchange resin. It was eluted with a mixture of water and methanol (1: 1, v / v). The eluate was evaporated and the residue was taken up in 250 ml of water. The aqueous solution was extracted twice with 100 ml of ether, the ether extract was washed with 50 ml of water and the combined aqueous extracts were then concentrated to about 100 ml. The same amount of methanol was added and the resulting solution was titrated to pH 4.5 with 1 M aqueous benzylamine. The solution was concentrated to dryness and the residue was recrystallized from 100 ml of hot water to which 400 ml of ethanol and 500 ml of ether were added. 4.38 g of the benzylamine salt of (IR) -1 - [(N-benzyloxycarbonyl-D-alanyl-L-alanyl-L-alanyl) -amino] -ethylphosphonic acid were obtained; Mp 240-243 ° C (dec.); [a] ^ ⁰ = -38.1 ° (c = 0.53% in acetic acid).

Example 2

In a manner analogous to Example 1, the benzylamine salt of (IR) -1 - [(N-benzyloxycarbonyl-D-valyl-L-alanyl-L-alanyl) -amino] ethylphosphonic acid (IR) -1- (D-valyl -L-alanyl-L-alanylamino) ethylphosphonic acid, m.p. 301 -304 C (dec.), [Α] ²⁰ = -105 ° (c = 0.45% in 1 N sodium hydroxide).

The starting material was prepared as follows:

3.8 g of N-benzyloxycarbonyl-D-valine in 2OO ml of petroleum ether (boiling point 60 ° -80 ° C.) were admixed with 1.5 g of triethylamine while stirring and cooling to -5 ° C. After adding 2.1 g of isobutyl chloroformate, the mixture was cooled to -5 ° C. for a further 30 minutes. Then a solution of 2.7 g of (IR) -1- (L-alanyl-L-alanylamino) ethylphosphonic acid in a mixture of 2.0 g of triethylamine and 15 ml of water, and a further 5 ml, was added dropwise at -5 ° C Water added. The mixture was stirred for a further 2 hours at -5 ° to ⁰ ° C. and overnight at room temperature. After addition of 150 ml of water, the aqueous became

709848/0976

272176Q

Phase separated, evaporated, the residue taken up with a mixture of 40 ml of water and 40 ml of methanol and over a Column with a freshly regenerated cation exchanger based on a sulfonated polystyrene resin. the Column was eluted with a 1: 1 mixture of water and methanol, the eluate was evaporated and 5 times with 50 ml each time Water taken up and concentrated again. The residue was finally treated with 100 ml of ether, filtered off and dissolved in dissolved in a mixture of 400 ml of methanol and 400 ml of water. The solution was adjusted to pH 4.5 with 4 M aqueous benzylamine titrated and concentrated to dryness. The residue obtained was made from a mixture of 100 ml of methanol and 100 ml of ether recrystallized and gave 3.24 g of the benzylamine salt of (IR) -1 - [(N-benzyloxycarbonyl-D-valyl-L-alanyl-L-alanyl) amino] ethylphosphonic acid, Mp 238-244 ° C (dec.).

Example 3

In a manner analogous to Example 1, the benzylamine salt became of (IR) -1 - [(N-Benzyloxycarbonyl-D-alanyl-L-alanyl-L-alanyl-L-alanyl) -amino] -ethylphosphonic acid (IR) -I- (D-alanyl-L-alanyl-L-alanyl-L-alanylamino) -ethylphosphonic acid, M.p. 323 ° -325 ° C (dec.), [Α] £ ° = -121 ° (c = 0.48% in 1N Sodium hydroxide).

The starting material was produced as follows:

In a manner analogous to Example 1, the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine was converted and (IR) -1- (L-alanyl-L-alanylamino) ethylphosphonic acid

(IR) -1 - [(N-Benzyloxycarbonyl-L-alanyl-L-alanyl-L-alanyl) -amino] -ethylphosphonic acid, m.p. 255 ° -257 ° C (decomp.), [A) ^ ° = - 62.0 ° (c = 0.4% in glacial acetic acid).

This connection was then also used in example

1 in an analogous manner in (IR) -1- [(N-benzyloxycarbonyl-L-alanyl-L-

no] ethyl phosph

709848/0976

alanyl-L-alanyl) amino] ethylphosphonic acid, m.p. 312-313 ° C

(Decomp.), [Α] ρ ° = -101 ° (c = 0.53% in 1 N sodium hydroxide), convicted.

Finally, in a manner analogous to Example 1, but acidifying to pH 2 and the ion exchange with subsequent ether extraction was replaced by a simple ether extraction, the benzylamine salt of (IR) -1 - [(N-Benzyloxycarbonyl-D-alanyl-L-alanyl-L-alanyl-L-alanyl) -amino] -ethylphosphonic acid, M.p. 272 ° -277 ° C (dec.) »[Α] = -47.0 ° (c = 0.5% in acetic acid), from the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-alanine and (IR) -1- (L-alanyl-L-alanyl-L-alanylamino) -ethylphosphonic acid obtain.

Example 4

10.85 g of (IR) -1 - [(N-benzyloxycarbonyl-D-leucyl-L-alanyl-L-alanyl) -amino] -ethylphosphonic acid dimethyl ester were in 30 ml of a 35% solution of hydrogen bromide in glacial acetic acid solved. The mixture was stirred for 4 hours at room temperature and 130 ml of ether were added with continued stirring. The ether was then decanted off and this procedure was repeated twice using 80 ml of ether each time. The residue was dissolved in 70 ml of methanol and the resulting solution was mixed with 10 ml of propylene oxide and overnight stored in the refrigerator. The resulting precipitate was filtered off, washed with ethanol and ether and taken under dried under reduced pressure to constant weight of 7.99 g; M.p. 293-295 ° C (dec.). Recrystallization from 500 ml of cold water and from 700 ml of ethanol yielded 6.6 7 g of (IR) -1- (D-leucyl-L-alanyl-L-alanylamino) ethylphosphonic acid, Mp 300-320 ° C (dec.); [α] * ° = -129.3 ° (c = 1% in water).

The starting material was produced as follows:

12.9 g of (IR) -1 - [(N-benzyloxycarbonyl-L-alanyl-L-alanyl) -amino] -ethylphosphonic acid dimethyl ester were in 150 ml

709848/0976

μ-

Methanol containing 0.032 moles of hydrogen fluoride solved. The solution was at room temperature and under normal pressure in the presence of 1 g of a 10% Pd / C catalyst hydrogenated, the catalyst was filtered off, the filtrate was concentrated under reduced pressure and the oily hydrochloride Evaporated twice with ethyl acetate.

The product obtained and 10.9 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-leucine were in the presence stirred by 100 ml of dry dimethylformamide. At a temperature below 15, 4.2 ml became dry Triethylamine was added dropwise with stirring. The mixture was then stirred overnight at room temperature, which Triethylamine hydrochloride filtered off and the filtrate under an oil pump vacuum at a bath temperature below 40 constricted. The remaining oil was treated with 50 ml of water and the resulting mixture was treated 4 times with 50 ml each time Chloroform extracted. The combined organic phases were washed with 20% strength potassium carbonate solution and washed over Dried sodium sulfate. After concentration to dryness and evaporation twice with ethyl acetate, 15.5 g were obtained (IR) -1 - [(N-Benzyloxycarbonyl-D-leucyl-L-alanyl-L-alanyl) -amino] · Obtained ethylphosphonic acid dimethyl ester, the melting point of which after recrystallization from acetonitrile was 173 ° -176 ° C; [a] p ° = -36.6 ° (c = 1% in methanol).

Example 5

In a manner analogous to Example 4, 9.92 g

(IR) -1 - [(N-Benzyloxycarbonyl-D-alanyl-L-alanyl) -amino] -ethylphosphonic acid dimethyl ester treated with 45 ml of a 35% solution of hydrogen bromide in acetic acid. Similar work-up yielded 6.16 g of a crude product with a melting point of 282 ° -285 ° C. and, after recrystallization from water / ethanol, 5.47 g of pure (IR) -1- (D-alanyl-L-alanylamino) ethylphosphonic acid, F. 292 ° -:
(c = 1% in water).

Phonic acid, m.p. 292-293 ° C (dec.), [α] ²⁰ = -101.2 °

709848/0976

The starting material, (IR) -1 - [(N-Benzyloxycarbonyl-D-alanyl-L-alanyl) -amino] -ethylphosphonic acid dimethyl ester, ^{mp 115 O} -117 ° C, [a] p ° = -28.4 ° (c = 0.5% in methanol), yield: 11.1 g, was in a manner analogous to Example 4 by reacting 7.82 g of (IR) -1- (L-alanylamino) ethylphosphonic acid dimethyl ester hydrochloride obtained with 9.6 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-D-alanine.

The following example illustrates a typical pharmaceutical preparation containing one according to the invention Link:

Example 6

1000 ml of an injection solution of the following composition were prepared:

per 100 ml

(IR) -I- (D-alanyl-L-alanylamino) -ethylphosphonic acid 100, o g

Chlorocresol 1.0 g

Glacial acetic acid 1.2 g

Sodium hydroxide solution (0.1 N) q.s. ad pH 4.5

Water for injection solutions up to 1000 ml

Manufacturing :

The (IR) -1- (D-alanyl-L-alanylamino) -äthylphosphonsäure was suspended in 500 ml of water for injections. To this solution was added a solution of the chlorocresol in 200 ml of water for injections. Then the acetic acid was added with stirring, as well as the 0.1 N sodium hydroxide solution up to a pH of 4.5. Finally it was made up to 1000 ml with water, filtered through a sterile membrane filter (0.22 μ) and filled into ampoules. The ampoules were closed and sterilized in an autoclave at 121 ° C. for 20 minutes.

709848/0976

■ / ·

Claims (1)

Claims 12 3
R, R and R are the radicals usually represent α-amino acids occurring in proteins, with the restriction that R is never hydrogen and represents a methyl group when η = 1; R denotes hydroxy or methyl and where the configurations on the carbon atom (a) are D, on the carbon atom (b) L and on the carbon atom (c) R (if R and R f are hydrogen), and of physiologically acceptable salts of these compounds, characterized in that one a) in a manner known per se, the protective group (s) of a compound the formula 30th .20 (a) R -NH-CH-CO-i-NH-CH-CO-NH-CH-P-R (b) Il (C) (II) .41 where η as above and the configurations at the C atoms (a), (b) and (c) are defined analogously to above; R is hydrogen or an amino protecting group; R, R and R are the radicals usually represent α-amino acids occurring in proteins with the restriction analogous to the above and where 709848/0976 ORiGlNAL INSPECTED any amino groups that may occur
be in slotted form, as well as others
functional groups, if necessary, are also present in slotted form; 40
R methyl, hydroxy or a lower alkoxy 41
protecting group and R hydroxy or a lower mean alkoxy protecting group,
splits off or
b) from a (R, S) diastereomer mixture of the formula I that R-diastereomers isolated and in a manner known per se
optionally a compound of the formula I obtained in
transferred to a physiologically compatible salt. 2. The method according to claim 1, characterized in that that a peptide derivative of the formula I is prepared in which R represents a hydroxyl group. 3. The method according to claim 1 or claim 2, characterized in that a peptide derivative of the formula I is prepared, in which R represents a methyl group. 4. The method according to any one of claims 1-3, characterized characterized in that a peptide derivative of the formula I is produced 2
represents, in which R is a methyl group and represent propyl or isobuty! group. 2 3 represents, in which R is a methyl group and R is a methyl, iso- 5. The method according to claim 1, characterized in that one (IR) -1- (D-alanyl-L-alanylamino) ethylphosphonic acid
manufactures. 6. The method according to claim 1, characterized in that (IR) -1- (D-alanyl-L-alanyl-L-alanylamino) ethylphosphonic acid manufactures. 7. The method according to claim 1, characterized in that (IR) -1- (D-valyl-L-alanyl-L-alanylamino) ethylphosphonic acid manufactures. 709848/0976 - J / 5 - 8. The method according to claim 1, characterized in that that one (IR) -1- (D-leucyl-L-alanyl-L-alanylamino) ethylphosphonic acid manufactures. 9. The method according to claim 1, characterized in that (IR) -1- (D-alanyl-L-alanyl-L-alanyl-L-alanylamino) ethylphosphonic acid manufactures. 10. The method according to claim 1, characterized in that the starting compound of formula II is obtained by condensation a compound of the general formula _ R ²⁰ - R ¹⁰ O Γ · Ί ι ^{! |} ok Η-ρΝΗ — CH-CO-t-NK —CH-Ρ — R L (b) (C) I ₄₁ m R ⁴ⁱ in) wherein m is 0, 1, 2 or 3 and R ¹⁰ , R ²⁰ , R ⁴⁰ and R ⁴¹ and the configurations at the carbon atoms (b) and (c) are as defined in claim 1, with an appropriately protected α-amino acid, an appropriately protected di-, tri- or tetrapeptide or a reactive derivative of such a compound in a manner known per se. 709848/0976 11. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula I from claim 1 or a physiologically acceptable salt of such a compound, as an active ingredient, with for therapeutic use Administration of suitable, non-toxic, inert, solid or liquid carriers which are customary in such preparations mixed and the mixture obtained brings into a suitable pharmaceutical form. 12. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula I from claim 1 or a physiologically acceptable salt of such a compound and D-cycloserine as active ingredients with non-toxic, inert, solid or otherwise customary in such preparations suitable for therapeutic administration mixed liquid carriers and brings the mixture obtained into a suitable galenic form. 709848/0976 13. Pharmaceutical preparations, characterized by a content of a peptide derivative of the formula I from claim 1 and a non-toxic, inert, solid or liquid carrier suitable for therapeutic administration. 14. Pharmaceutical preparations, characterized by a content of a peptide derivative of the formula I from claim 1 and D-cycloserine as well as a non-toxic, inert, solid or suitable for therapeutic administration liquid carrier. 709848/0976 15. Peptide derivatives of the general formula f χ f 1 ι "» 4 ZH-CO-NH-CH-CO + NH-CH-P-R H "N — CH-CO- (a) (D (b) J (C) η OH wherein η is 1, 2 or 3; 12 3
R, R and R are the radicals usually represent α-amino acids occurring in proteins, with the restriction that R is never hydrogen and one Represents methyl group when η = 1; 4th
R is hydroxy or methyl and where the configurations on the carbon atom (a) D, on the carbon atom (b) L and on the carbon atom (c) are R (provided that R ² and R ¹ ^ are hydrogen), and physiologically acceptable salts of these compounds. 16. A peptide derivative according to claim 15, characterized in that that R represents a hydroxyl group. 17. Peptide derivatives according to claim 15 or claim 16., 4th
characterized in that R represents a hydroxyl group. 18. Peptide derivatives according to any one of claims 15-17, 2 3 characterized in that R represents a methyl group and R represents a methyl, isopropyl or isobutyl group. 19. (IR) -1- (D-Alanyl-L-alanylamino) -ethylphosphonic acid. 2Q. (IR) -1- (D-Alanyl-L-alanyl-L-alanylamino) -ethylphosphonic acid. . (IR) -I- (D-valyl-L-alanyl-L-alanylamino) -ethylphosphonic acid. 709848/0976 22. (IR) -1- (D-Leucyl-L-alanyl-L-alanylamino) -ethylphosphonic acid . 23. (IR) -I- (D-alanyl-L-alanyl-L-alanyl-L-alanylamino) -ethylphosphonic acid. 709848/0976