CH672792A5 - - Google Patents

Description

DESCRIPTION The present invention relates to new peptides, their preparation and use and pharmaceutical preparations containing them, according to claims 1 to 11.

The invention relates to a peptide in which at least one methylene group in the chain is disubstituted, one or

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both substituents represent fluorine and / or chlorine, in free form or in salt form. The new peptides are hereinafter referred to as the “compounds according to the invention”.

The compounds according to the invention are enzyme inhibitors. Depending on the type of peptide or peptide analogue, they can be used to inhibit various enzymes, e.g. of esterases, in particular lipases such as phospholipase A2, or of proteases such as: aspartyl proteases, in particular chymosin, renin, cathespsin D and pepsin; Zinc proteases, especially the "angiotensin converting" enzyme; Aminopeptidases, especially leucine aminopeptidase; Thiol proteases, especially papain; Serine proteases, especially elastase; Carboxypeptides, in particular carboxypeptidase A and B; Juvenil homonase rase and acetylcholinesterase.

It can therefore be seen that the compounds according to the invention have an overall structure which is dependent on the particular enzyme which it is desired to inhibit. In general, their structure is similar to that of inhibitors and / or substrates known for the particular enzyme. The fluorinated and / or chlorinated methylene group is usually most advantageous if it is located on or near the part of the inhibiting peptide or peptide analog that corresponds to or reacts with the active center of the enzyme to be inhibited.

For example, as renin inhibitors, the compounds according to the invention have an overall structure which is expediently related to the structure of the specific partial structure which effects the binding to the active center of the renin in the renin substrate angiotensinogen.

The methylene group in the chain defined above is preferably substituted by fluorine.

The invention relates in particular to a peptide defined above in which the fluorinated and / or chlorinated methylene group is part of a 4 (S) -amino-3 (S) -hydroxy-6-methylheptanoyl (statin) or a 4 (S) -amino-3 -oxo-6-methylheptanoyl (staton) -amino acid ester.

A preferred group of compounds according to the invention consists of the compounds of the formula I

A-HN

wherein

A represents hydrogen or a substituent,

B represents hydroxy or a further substituent with the proviso that at least one of A and B represents a peptide residue,

Ri means fluorine or chlorine,

R2 represents fluorine, chlorine or another substituent, either R3, hydroxy. Alkoxy or acyloxy and R4 are hydrogen or R3 and R4 together are oxo and

R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or an aryl, aralkyl, heteroaiyl or heteroarylalkyl group which is optionally substituted in the alyl or heteroaiyl group,

R! preferably means fluorine. R2 preferably represents fluorine.

R3 preferably means hydroxy or together with R4, oxo, it means in particular together with R4 oxo. R preferably represents alkyl. A preferably represents a substituent. B preferably represents a further substituent.

A peptide residue consists of one or more amino acids. If there is more than one amino acid residue in a peptide residue,

are the amino acid residues by a peptide carbamoyl group, i.e. connected by -CONH-.

A peptide residue preferably consists of natural amino acid residues in their natural configuration. If amino acid residues are present in the unnatural configuration, it is preferably only one or two, in particular only one residue.

A peptide residue preferably consists of 1 to 7 amino acid residues.

The

-HN

C0-

Part of compounds of the formula I has the same configuration as the natural statin on the carbon atom to which R is bonded if this carbon atom is asymmetrically substituted. If it is asymmetrically substituted, the carbon atom to which R3 and R4 are bonded preferably has the R configuration.

Another preferred group of compounds according to the invention consists of the compounds of the formula Ia,

wherein

R and R [to R4 have the above meaning,

X represents hydrogen or a peptide amino end-blocking group,

Y represents hydroxy or a peptide carboxy end-blocking group,

one of Aa and Ba represents a peptide residue, the other represents a bond or a peptide residue,

X preferably represents a peptide amino end blocking group.

Y preferably represents a peptide carboxy endblocking group.

A peptide amino endblocking group is e.g. an alkoxycarbonyl group with a total of 2 to 20 carbon atoms, alkynoyl with a total of 2 to 10 carbon atoms, cyclo-alkylcarbonyl with a total of 4 to 8 carbon atoms, aroyl or alkylsufonyl with a total of 1 to 10 carbon atoms, in particular alkoxycarbonyl with a total of 4 to 6 carbon atoms, in particular tert-butoxycarbonyl (BOC), or alkanoyl with a total of 2 to 6 carbon atoms, especially isovaleroyl (Iva). Cycloalkylcarbonyl preferably contains a total of 4, 6 or 7 carbon atoms. Aroyl preferably means benzoyl. Alkyl sulfonyl preferably contains 3 to 6 carbon atoms, it is preferably branched.

A peptide carboxy endblocking group is e.g.

Alkoxy with 1 to 5 carbon atoms, amino, alkylamino with 1 to 5 carbon atoms, dialkylamino with independently 1 to 5 carbon atoms in the alkyl parts (1-benzylpiperidin-4-yl) amino or (pyridin-2-yl) methylamino, in particular Alkoxy having 1 to 5 carbon atoms, amino, alkylamino having 1 to 5 carbon atoms (l-benzylpiperidin-4-yl) amino or (pyridine-2-yl) methylamino, in particular alkoxy having 1 to 3 carbon atoms, in particular methoxy or ethoxy , represents.

Alkoxy preferably contains 1 to 5 carbon atoms, it means in particular methoxy. Acyloxy preferably contains 2 to 6 carbon atoms, it means in particular acetoxy.

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Alkyl preferably contains 1 to 5 carbon atoms, it is in particular branched, it preferably means isobulyl. Cyclo-alkyl preferably contains 3 to 7 carbon atoms, it means in particular cyclopentyl or cyclohexyl. Cycloalkylalkyl preferably contains 3 to 7 carbon atoms in the cycloalkyl part, in particular 5 or 6 carbon atoms, and preferably contains 1 to 5 carbon atoms, in particular 1 carbon atom in the alkylene part. Aryl preferably means phenyl. Aralkyl preferably means phenylalkyl having 7 to 12 carbon atoms, especially benzyl. Heteroaiyl is preferably pyridinyl, in particular 4-pyridinyl, thienyl, in particular 2-thienyl, or fuiyl, in particular 2-furyl; especially pyridinyl. Heteroaiyl-alkyl preferably contains 1 to 6 carbon atoms, in particular 1 carbon atom, in the alkylene part. The heteroaiy part of heteroaiylkyl preferably has the meanings designated above as preferred for heteroaiyl. The possible substituents of an aryl or aralkyl group are preferably one or two alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 5 carbon atoms, halogen with an atomic number from 9 to 35, hydroxy and / or amino, preferably one or two methyl, methoxy, Chlorine, bromine, hydroxy or amino, in particular a hydroxy, amino, chlorine or bromine, if appropriate expediently in protected form.

Aa and Ba have e.g. Meanings for which it is described in the literature that they give known enzyme inhibitors high affinity and selectivity, e.g. for renin inhibitors:

for Aa:

a bond -His - Phe - Leu - Phe-Phe - ß- (l-naphthyl) -Ala - Val-Val - Phe-His - Pro-Phe-His - His-Pro-Phe -His - His-Phe-Pro-His-Leu - Pro-His-Pro-Phe-His-

for Ba:

a bond

-Ile-

-Leu-

-Val-

-Val-

-Val-Phe-

-Val-Tyr-

-Leu-Phe-

-Ile-Phe-

-Ile-His-

-Ala-Phe-

-Phe-Phe-

-Leu-Tyr-

-Leu-Val-Phe-

-Val-Ile-His-

-Ile-His-Lys-

-Val-Ile-His-Lys-

and for pepsin inhibitors: for Aa:

for Ba:

a bond -Val - Val-Val-

a binding -Ala-

wise BOC. Alkanoyl preferably has a total of 2 to 6 carbon atoms, it is preferably branched, it means in particular Iva. Cycloalkylcarbonyl preferably has a total of 4, 6 or 7 carbon atoms. Aroyl preferably means benzoyl. 5 Alkylsulfonyl preferably contains 3 to 6 carbon atoms, it is preferably branched.

Dictionary:

BOC tert-butoxycarbonyl io His L-histidine

Iva Isovaleroyl

Ile L-isoleucine

Leu L-leucine

Lys L-lysine

15 Phe L-phenylalanine

Per L-proline

Statin * 4-amino-3-hydroxy-6-methylheptanoic acid

Staton * 4-amino-3-oxo-6-methylheptanoic acid

Tyr L-tyrosine

20 Val L-Valin * the absolute configuration is specifically stated in the text.

Another preferred group of compounds according to the invention consists of the compounds of the formula Iaa

Xa - Aaa - HN

30th

CO - B

aa

3 4

Y Iaa wherein R 1 to R 4 have the meaning given above; 35 Xa is hydrogen, alkoxycarbonyl or alkanoyl with a total of 2 to 10 carbon atoms, cycloalkylcarbonyl with a total of 4 to 8 carbon atoms, aroyl or alkylsulfonyl with a total of 1 to 10 carbon atoms;

V for hydroxy, alkoxy with 1 to 5 carbon atoms, 40 amino, alkylamino with 1 to 5 carbon atoms, dialkylamino with independently 1 to 5 carbon atoms in the alkyl parts, (l-benzylpiperidin-4-yl) amino or (pyridin-2-yl ) methylamino;

Ra hydrogen; Alkyl of 1 to 5 carbon atoms; Çycloal-45 kyl with 3 to 7 carbon atoms; Cycloalkylalkyl with 3 to 7 carbon atoms in the cycloalkyl part and with 1 to 5 carbon atoms in the alkylene part; Phenyl or phenylalkyl with 7 to 12 carbon atoms, optionally mono- or disubstituted in the phenyl ring with alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 50 5 carbon atoms, halogen with an atomic number from 9 to 35, hydroxy or amino; Pyridinyl, thienyl or fuiyl or pyridinylalkyl having 6 to 11 carbon atoms, ihienylalkyl having 5 to 10 carbon atoms or furylalkyl having 5 to 10 carbon atoms; and 55 one of Aaa and Baa represents a peptide residue with 1 to 15 amino acid residues,

the other stands for a bond or a peptide residue with 1 to 1f amino acid residues.

In a sub-group, Y3 does not mean (pyridin-2-yl) methyl-60 amino.

Another group of compounds according to the invention consists of the compounds of the formula Iaaa

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Alkoxycarbonyl preferably has a total of 4 to 6 carbon atoms, it is preferably branched, it preferably means

C0-B *** - Y "Iaaa

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wherein R, to R) have the meaning given above,

Xaa represents hydrogen, alkoxycarbonyl with a total of 2 to 6 carbon atoms or alkanoyl with a total of 2 to 6 carbon atoms,

Va denotes hydroxy, alkoxy having 1 to 5 carbon atoms, amino, alkylamino having 1 to 5 carbon atoms, (1-benzylpiperidin-4-yl) amino or (pyridin-2-yl) methylamino,

Raa represents alkyl having 1 to 5 carbon atoms,

one of Aaaa and Baaa means a peptide residue with 1 to 7 natural amino acid residues in its natural configuration,

the other stands for a bond or a peptide residue with 1 to 7 natural amino acid residues in its natural configuration.

In one subgroup, Va does not mean (pyridin-2-yl) methylamino.

Another group of compounds according to the invention consists of the compounds of the formula Iaaaa

R, # Ri R2

Xaa-Aaaaa-NH. - - CO-Baa, a-Y, a

R3 R4

Iaaaa in which Ri to Rj, Xaa, Yja and Raa have the meaning given above,

Aaaaa stands for a bond, -Val-, -His-Pro-Phe-His-, -Phe-Phe or -Phe-His and

Baaaa means a bond, -Ala-, -Leu-, -Val-, -Ile-, -Ile-Phe-, -Val-Phe-, Ile-His- or -Leu-Phe-,

with the proviso that at least one of Aaaaa and Baaaa does not represent a bond.

In the subgroup, Aaaaa stands for a bond, -Phe-Phe-or -Phe-His-. In another subgroup, Baaaa means -Val-Phe-, -Ile-His- or -Leu-Phe-.

A compound according to the invention can be in free form, e.g. Amphoteric form, or in salt form, e.g. Acid addition salt form or anionic salt form occur. A compound in free form can be converted to a salt form in a known manner and vice versa. Examples of salt forms are e.g. the trifluoroacetate, the hydrochloride, the sodium, potassium and ammonium salt. The compounds according to the invention are obtained by a process which is characterized in that it comprises the step of coupling two corresponding peptide residues, or their precursors, where appropriate converting a compound thus obtained into a precursor form.

The method can be carried out analogously to known methods. A precursor of a peptide residue is e.g. a rest in protected form, e.g. containing a peptide amino end and / or a peptide carboxy end group which one wishes to split off or replace in the compound to be obtained according to the invention, or containing another functional group, such as hydroxy, which one wishes to convert into a further functional group, such as oxo. A peptide residue can e.g. a single amino acid representing the length of the peptide to be produced.

The coupling is carried out using general methods known for peptide synthesis. It will e.g. performed in an inert solvent such as dimethylformamide. It is preferably carried out at a temperature between about 0 ° and 25 ° C. The presence of a base such as N-methylmorpholine is preferred. Any conversion is also carried out analogously to known methods. The oxidation of a hydroxy to an oxo group is e.g. performed in an inert solvent such as methylene chloride. The oxidizing agent e.g. represents the chromium trioxide dipyridinium complex. The reaction temperature is e.g.

from about 0 ° to about 50 ° C, preferably room temperature. In particular, a compound of the formula Ia is obtained by a process which is characterized by coupling a corresponding compound of the formula IIa,

R Ri ^ R2

X'-A * '- HN- ^ "C00H

wherein

R, Ri and R2 have the above meaning,

X 'represents a peptide amino end protecting group and

Aa 'represents a bond or a peptide residue,

and a corresponding compound of the formula purple,

H-Ba'-Y purple in which

Y represents a peptide carboxy end protecting group and Ba 'represents a peptide residue, or by coupling a corresponding compound of the formula IIb,

X'-Aa "-Z IIb wherein

X 'has the meaning given in this claim,

Aa "stands for a peptide residue and

Z means a leaving group,

and a corresponding compound of the formula Illb,

C0-B * "- Y '

.IIb

R, Ri, R2 and Y have the above meaning,

Ba "stands for a bond or a peptide residue and

A ~ an anion means

where appropriate in a compound obtained in this way the hydroxyl group is converted into the corresponding oxo group and / or a protective group which may be present is replaced by a further group.

A peptide amino end or peptide carboxy end protecting group means e.g. a group selected from the peptidaminoend- or peptidcarboxyendblockenden groups defined above, in this respect expedient.

X 'preferably denotes alkoxycarbonyl with a total of 2 to 6 carbon atoms, in particular BOC. Y preferably represents alkoxy with 1 to 5 carbon atoms, especially methoxy. Z preferably means -N3 • A® preferably stands for the anion of a strong mineral acid such as trifluoroacetate.

A compound according to the invention can be isolated and purified from the reaction mixture analogously to known methods. Racemic and / or diastereoisomeric mixtures can be split up analogously to known methods.

A compound used as a starting product can also be obtained analogously to known methods.

It can be seen that if the fluorinated and / or chlorinated methylene group is part of a statin-based amino acid unit, then the basic starting product for obtaining a compound according to the invention is a corresponding statin substituted in 2-position by fluorine and / or chlorine.

A compound of formula II can e.g. obtained by reacting a corresponding compound of formula III

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6

R

X '- Aa' - HN- ^ CM I "

in which X ', Aa' and R are as defined above, with a corresponding compound of the formula IV,

Br X ^ jCOOAlk IV

wherein R; and R2 have the above meaning and

Alk represents alkyl having 1 to 4 carbon atoms, in particular ethyl,

and hydrolysis of the alkoxy group from the ester thus obtained.

Insofar as the production of a specific starting material is not specifically described, it can be carried out in a known manner or analogously to the manner described here.

In the following examples, all temperatures are in degrees Celsius and uncorrected.

Example 1: N-BOC- (4S, 3R) -2,2-difluorstatin-Val-PheOCH3 (coupling)

727 mg of N-BOC- (4S, 3R) -2,2-difluorstatin, 800 mg of H-Val-PheOMe hydrochloride and 630 mg of N-hydroxybenzotriazole are dissolved in 5 ml of dimethylformamide and 0.4 ml of N-methylmorphopholine added. A solution of 480 mg of dicyclohexylcarbodiimide in dimethylformamide is then added at 0 °. After 24 hours at room temperature, the reaction mixture is taken up in ethyl acetate, washed with water, dried over potassium carbonate and evaporated. The residue is chromatographed on silica gel using ether / hexane as the eluent. The title compound is obtained (mp. 105-108 °).

The starting product is obtained as follows: a) 1.45 g of zinc dust are suspended in 30 ml of tetrahydrofuran and heated to the reflux temperature. 4.4 g of ethyl bromide fluoroacetate are added all at once. As soon as a violent reaction occurs, 2 g of N-BOC-L-leucinal dissolved in 5 ml of tetrahydrofuran are added dropwise. After 30 minutes the reaction mixture is cooled, taken up in ethyl acetate and washed with 2N tartaric acid solution. The organic phase is over

Magnesium sulfate dried, evaporated and chromatographed on silica gel using ether / hexane 2: 8 as eluent. The N-BOC- (4S, 3R) -2,2-difluoro-statinethyl ester is obtained ([a] n ° = - 12.2 °, c = 0.29 in ethanol). 5 b) 1 g of N-BOC- (4S, 3R) -2,2-difluorostatin ethyl ester is dissolved in 10 ml of methanol / water and 0.25 g of conc. aqueous sodium hydroxide solution implemented. After 2 hours the solution is acidified with 2N tartaric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. The N-BOC- (4S, 3R) -2,2-difluorstatin (crude) is obtained.

Example 2: N-BOC- (4S) -2,2-difluorstaton-Val-PheOCH3 (conversion of a compound into precursor form by oxidation)

30 mg of the title compound from Example 1 are added to a solution of 90 mg of chromium trioxydipyridinium complex in 20 ml of methylene chloride. After 30 minutes at room temperature, the reaction mixture is filtered through silica gel and the filtrate is evaporated 2o. The residue is chromatographed on silica gel using ether / hexane as the eluent. The title compound is obtained.

Example 3: (4S, 3R) -2,2-difluorstatin-Val-PheOCH3-trifluoroacetate 25 (conversion of a compound into precursor form by deprotection)

1 g of the title compound of Example 1 is dissolved in 5 m methylene chloride and reacted at 0 ° with 5 ml of trifluoroacetic acid. After 30 minutes the mixture is evaporated in vacuo. 30 residues of the trifluoroacetic acid are removed azeotropically by repeated evaporation of benzene. The title compound (crude) is obtained.

Example 4: N-BOC-Phe-His- (4S, 3R) -2,2-difluorstatin-Val-35 PheOCH3 (coupling)

500 mg of the title compound from Example and 420 mg of N-BOC-Phe-His-N3 are dissolved in 3 ml of dimethylformamide, reacted with 0.1 ml of N-methylmoipholin and left to stand at 0-5 ° for 24 hours. The mixture is then taken up in ethyl acetate 40, washed with water, dried over potassium carbonate and evaporated. The residue is recrystallized from methanol / methylene chloride / ether. The title compound is obtained (mp. 133-136 °); [a® = -41.1 ° (c = 1.0 in methanol).

7,672,792

The following compounds according to the invention are obtained analogously to Examples 1 to 4:

Example No.

connection

N-8QC-Phe-His- (4S) -2,2-difluorstaton -Val-Phe-OCH3 'Iva-Val- (4S) -2,2-difluorstaton -Ala-NH (3-methylbutyl)

Iva-Val- (4S, 3R) -2,2-difluorstatin -Ala-NH (3-methylbutyl)

N-B0C-Phe-Phe- (4S, 3R) -2,2-difluorstatin -Leu-Phe-nh2 N-B0C-Phe-Phe- (4S) -2,2-di f1uorstaton -Leu-Phe-NHg N -B0C-Phe-Phe- (4S, 3R) -2,2-difluorstatin -Leu-NH- ^ ^ -benzyl

N-BOC-Phe-Phe- (4S) -2,2-difluorstaton-Leu-NH -o -benzyl

N-BOC-Phe-Phe- (4S, 3R) -2,2-di f1uor stati n -Val-Phe-OCH ^ N-BOC-Phe-Phe- (4S) -2,2-di fluor staton -Val -Phe-0CH3 N-B0C-Pne-Phe- (4S, 3R) -2,2-difluorstatin -Ile-His-0CH3 N-B0C-Phe-Phe- (4S) -2,2-difluoro staton. -Ile-His-OCH ^

Iva-His-Pro-Phe-His- (4S, 3R) -2,2-difluorstatin -Ile-Phe-OCH ^ Iva-His-Pro-Phe-His- (4S) -2,2-difluoro staton -Ile -Phe-OCHj

(4S, 3R) -2,2-difluorstatin -Ala-NH (3-methylbutyl) trifluoroacetate N-B0C- (45.3R) .- 2,2-difluorstatln -Ala-NH (3-methylbutyl)

N-B0C- (4S) -2,2-difluorsta.ton -Ala-NH (3-methylbutyl)

Thin layer chromatography:

R

0.3

(CHC13 / .1CH3COOC2H5) thin layer chromatography:

rf = o.7 (chci3 / ch3cooc2h5)

[a] n ° = -40.5 ° (c = 0.8 in methanol)

Rf = 0.15 (ethyl acetate / hexane 3: 7)

^ Analogous to example 2, starting from the compound of example 4 Analogous to example 2, starting from the compound of example 7

3) Analogously to Example 4, starting from the compound of Example 18, by reaction with Iva-Val-OH (mp. 196-198 °); the latter compound is obtained by reacting isovaleric acid with L-valine ethyl ester hydrochloride in dimethylformamide in the presence of 4-methylmorpholine and isobutyl chloroformate.

^ Analogous to example 3, starting from the compound of example 19 Analogous to example 2, starting from the compound of example 19

^ Analogously to Example 1, starting from the compound of Example la), by reacting L-alanylisoamylamide acetate (mp. 102-104 °) in chloroform. The latter compound is obtained by reacting N- (benzyloxycarbonyl) -L-alanylisoamylamide (mp. 107-108 °) in acetic acid and methanol with hydrogen over 10X-Pd-C.

^ Mass spectrum (fast atomic bombardment)

Mass / charge m / z (relative intensity): 864 (15), 863 (30), 763 (100)

672 792

The compounds according to the invention have pharmacological activity. They can be used as a medicine.

They have typical effects, in particular for enzyme inhibitors. The inhibitory effect with regard to a specific enzyme naturally depends on the peptide structure as a whole. The above compounds, which are particularly suitable as inhibitors of renin activity, bring about a 50% inhibition of the renin activity of the submaxillary gland of the mouse on the synthetic octapeptide substrate at a concentration of 10-5M to 10μm, according to the method of K. Murakami et al. (Analyt. Biochem. 110 [1981] 232-239 [with the change that the concentration of synthetic substrate is reduced from 20 (iM to 7 μM]) and according to the method of P. Corvol et al. (Biochem. Biophys. Acta 523 [1978] 485-493).

In the antibody trapping method by K Poulsen and J. Jorgensen (J. Clin. Endocrin. Metab. 39 [1974] 816-825), they inhibit human plasma arena activity at a concentration of 10_5M to 10 "" M.

The compounds according to the invention are therefore suitable for use in the prophylaxis and treatment of conditions which are characterized by an enzymatic disfunction and for which an inhibition of the enzymatic activity is indicated.

As renin inhibitors they are e.g. suitable for use in the prophylaxis and treatment of hypertension and congestive heart failure.

As elastase inhibitors, they are for use in the prophylaxis and treatment of general inflammation, emphysema, arthritis and the degeneration of the elastic tissues resulting from e.g. Infection occurs, suitable. The compounds of Examples 6 and 7 inhibit pepsin with k; values of 6x 10 ~ Mb and 5x 10_IOM, respectively.

Among the compounds according to the invention in which the fluorinated and / or chlorinated methylene group is part of a statin or statonamino acid residue, those compounds based on staton are preferred. Also preferred are those compounds in which the methylene group is fluorinated, in particular difluorinated.

The title compounds of Examples 4 and 5, in particular of Example 5, are preferred for the prophylaxis and treatment of hypertension and “congestive heart failure”.

A suitable daily dose is from about 1 mg to about 500 mg, suitably administered, e.g. orally, in partial doses from about 0.25 mg to about 250 mg, or in sustained release form.

The compounds according to the invention can be administered in free form or in pharmacologically acceptable salt form. Such salt forms have an effect of the same order of magnitude as the free forms and can be produced in a known manner. The present invention also relates to pharmaceutical preparations containing a compound according to the invention in free form or in pharmaceutically acceptable salt form, optionally together with pharmaceutically acceptable auxiliaries and / or carriers. Such pharmaceutical preparations can be formulated for use in enteral, preferably oral, administration, e.g. as tablets, or for use in parenteral administration, 25 e.g. as injectable solutions or suspensions.

The compounds of Examples 1 to 5 and 8 to 17 are particularly suitable as renin inhibitors. The compounds of Examples 6, 7 and 18 to 20 are particularly suitable as pepsin inhibitors.

Claims (11)

672 792 1. A peptide in which at least one methylene group in the chain is disubstituted, one or both substituents representing fluorine and / or chlorine, in free form or in salt form. 2. A peptide according to claim 1, in which the fluorinated and / or chlorinated methylene group is part of a 4 (S) -amino-3 (S) -hydroxy-6-methylheptanoyl- or a 4 (S) -amino-3-oxo 6-methylheptanyl amino acid residue. 2nd PATENT CLAIMS 3. A peptide according to claim 1 of the formula I, HN CO-B wherein A represents hydrogen or a substituent B stands for a substituent, in particular hydroxy, with the proviso that at least one of A and B represents a peptide residue. Ri means fluorine or chlorine R2 represents a substituent, in particular fluorine or chlorine, and either R3 is hydroxy, alkoxy or acyloxy and R4hydrogen or R3 and R4 together are oxo and R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or an aryl, aralkyl, heteroaiyl or heteroarylalkyl group which is optionally substituted in the aryl or heteroaiyl group, in free form or in salt form. 4. A peptide according to claim 3 of the formula Ia, A * - HN wherein R 1 to R 4 have the meaning given in claim 3, X represents hydrogen or a peptide amino end-blocking group, Y represents hydroxy or a peptide carboxy endblocking group, one of Aa and Bb represents a peptide residue, the other represents a bond or a peptide residue, in free form or in salt form. 5. A peptide according to claim 1 as a renal inhibitory agent. 6. A peptide according to claim 1 as an agent for combating elevated blood pressure and chronic heart failure. 7. A method for producing a peptide of formula Ia according to claim 1, wherein R3 hydroxy and R4 means hydrogen and X is a peptide amino end protecting group and Y represents a peptide carboxy end protecting group and Aa for a bond or a peptide residue and Ba represents a peptide residue, characterized by the coupling of a compound of formula IIa HN COOH IIa in which R, R! and R2 have the meaning given in claim 3, X 'represents a peptide amino end protective group and Aa' represents a bond or a peptide residue, and a compound of the formula purple, H-Ba'-Y 'purple in which Y represents a peptide carboxy end protecting group and Ba 'represents a peptide residue, wherein the compounds of formula Ia thus obtained are obtained in free form or in salt form. 8. A method for producing a peptide of formula Ia according to claim 4, wherein R3, R4, X and Y have the meaning given in claim 7 and Aa for a peptide residue and Ba stands for a bond or a peptide residue, characterized by coupling or a compound of the formula IIb, X'-Aa "-Z IIb wherein X 'has the meaning given in claim 7, Aa "stands for a peptide residue and Z means a leaving group, and a corresponding compound of the formula Illb, OH wherein R, R [and R2 have the meaning given in claim 3, Y has the meaning given in claim 7, Ba "stands for a bond or a peptide residue and A ~ means an anion, wherein the compounds of formula Ia thus obtained are obtained in free form or in salt form. 9. A process for the preparation of a peptide of the formula Ia according to claim 4, characterized in that in compounds of the formula Ia obtained according to the process of claims 7 or 8, the hydroxy is converted into the corresponding oxo group and the compound thus obtained in free form or wins in salt form. 10. A process for the preparation of a peptide of the formula Ia according to claim 4, characterized in that a protective group is split off in compounds of the formula Ia obtained according to the process of claims 7 or 8. 11. Pharmaceutical preparation containing a peptide according to claim 1 in free form or in pharmaceutically acceptable salt form.