CH673655A5 - - Google Patents

Description

DESCRIPTION 40 The invention relates to new peptides and peptide derivatives, their preparation and pharmaceutical compositions containing them according to claims 1 to 6. The compounds described in claim 1 are referred to below as the compounds according to the invention. 45 A protective group of the peptidic amino group is, for example, an alkoxycarbonyl group with a total of 2-10 carbon atoms, an alkanoyl group with a total of 2-25 carbon atoms, a cycloalkylcarbonyl group with a total of 4-8 carbon atoms, an aroyl group or an alkylsulfonyl group with a total of 1-10 carbon atoms, in particular, however an alkoxycarbonyl group with a total of 4-6 carbon atoms, in particular a tert-butoxycarbonyl (BOC) group or an alkanoyl group with a total of 2-6 carbon atoms, in particular a isovaleroyl group (Iva). A cycloalkylcarbonyl group together preferably has 4,6 or 7 carbon atoms. Aroyl preferably means benzoyl. Alkylsulfonyl preferably has 3-6 carbon atoms and is preferably branched.

60 A protective group of the peptic carboxyl group is, for example, an alkoxy group with 1-5 carbon atoms, an amino group or alkylamino group with 1-5 carbon atoms or a dialkylamino group with independently 1-5 carbon atoms in each of the alkyl 65 residues, (l-benzylpiperidine-4- yl) amino or (pyridin-2-yl) -methylamino, in particular alkoxy with 1-5 carbon atoms, amino, alkylamino with 1-5 carbon atoms, (l-benzylpiperidin-4-yl) amino or (pyridin-2- yl) methyl

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mino, especially alkoxy with 1-3 carbon atoms, especially methoxy or ethoxy.

A peptide residue consists of 1 or more amino acid residues. If more than one amino acid residue is present in the peptide residue, the amino acid residues are separated by a peptidic car-bamoyl, i.e. -CONH-, group connected.

A compound according to the invention may optionally also be in isosteric form, i.e. for example with one or more peptide carbamoyl residues in isosteric form or with one or more amino acid residues in the unnatural configuration if there is a natural counterpart.

A peptidic carbamoyl in isosteric form is, for example, -CH2NH- (reduced), -COCH2- (keto), -CH (OH) CH2- (hydroxy), -CH (NH2) CH2- (amino), -CH2CH2- or -CH2CH2CH2 - (hydrocarbon). A compound according to the invention preferably has no peptic carbamoyl in isosteric form. However, if it has a peptide carbamoyl in isosteric form, it preferably has one or two, preferably one peptide carbamoyl in isosteric form.

A peptide residue preferably consists of a residue of a natural amino acid in its natural configuration. If amino acid residues are present in the unnatural configuration, it is preferably only one or two amino acid residues in the unnatural configuration. Amino acid residues used here include amino acid residues such as proline and hydroxyproline.

A peptide residue preferably has 1-7 amino acid residues.

The part

-HN

0-

1, R2R5

of formula I is the homostatin amino acid residue or a derivative of the homostatin amino acid residue. It is preferred that it have the same configuration as the natural statin on the carbon atom to which R is attached if it is asymmetrically substituted. The carbon atom to which R 1 and R 2 are attached preferably has the R configuration if it is asymmetrically substituted.

Alkyl preferably has 1-5 carbon atoms and is in particular branched and very particularly means isobutyl. Cycloalkyl preferably has 3-7 carbon atoms and is especially cyclopentyl or cyclohexyl. Cycloalkylalkyl preferably has 3-7 carbon atoms, in particular 5 or 6 carbon atoms in the cycloalkyl part and

1-5 carbon atoms, especially one carbon atom in the alkylene part. Aryl is preferably phenyl. Aralkyl is preferably phenylalkyl with 7-12 carbon atoms, especially benzyl. Heteroaryl is preferably pyridinyl, in particular 4-pyridinyl, thienyl, in particular

2-thienyl or furyl, especially 2-furyl, but preferably for pyridinyl. Heteroarylalkyl preferably has 1-6 carbon atoms, especially 1 carbon atom in the alkylene part thereof. The heteroaryl part of the heteroarylalkyl radical preferably has the meanings given above, as are preferred for heteroaryl. The optional substituents of an aryl or aralkyl part are preferably one or two alkyl groups with 1-5 carbon atoms, alkoxy with 1-5 carbon atoms, halogen with an atomic number of 9 to 35, hydroxy and / or amino, but preferably one or two Methyl, methoxy

Chlorine, bromine, hydroxyl or amino groups, in particular a hydroxyl, amino, chlorine or bromine group, if appropriate in a protected form, if appropriate.

Alkoxy preferably has 1-5 carbon atoms and is especially methoxy. Acyloxy preferably has 2-6 carbon atoms, in particular it stands for acetoxy.

X is preferably a protecting group of the peptide amino group.

Y is preferably a protecting group of the peptide carboxyl group.

A and B are each preferably peptide residues.

A and B together have at least 2 and preferably no more than 10 amino acid residues. They preferably have meanings which are similar to the corresponding meanings in known renin inhibitors. For example for A: a bond

-His-m -Phe - Leu - Nle - Phe-Phe - Val-Val-25 -Phe-leu - Phe-Nle - Phe-His - Pro-Phe-His-and for B: a bond so -Ile - Leu - Val - Val-Phe - Val-Tyr-35 -Leu-Phe - Ile-Phe - Ile-His - Ala-Phe - Phe-Phe-40 - Leu-Tyr - Leu-Val-Phe - Val-Ile-His - Ile-His-Lys - Val-Ile-His-Lys-.

45

R is preferably alkyl or cycloalkyl. Ri is preferably hydroxy or together with R2 oxo. It is especially along with R2 Oxo. R3 preferably represents fluorine. R4 is preferably hydrogen or fluorine, in particular 50 fluorine. R5 is preferably fluorine. Rö preferably has a different meaning than hydrogen, it is in particular fluorine or alkyl, preferably it stands for alkyl. Preferably 3 or 4 of the substituents R3 to R.6 have the meaning fluorine or chlorine and the fourth has another meaning than hydrogen, fluorine or chlorine. In particular, R3, R4 and Rs are fluorine and Rô are alkyl.

A preferred group of compounds according to the invention are the compounds of the formula Iaa,

«0

65

X-Aaa-HN

C0 "BaaY

Iaa la 2a 5a R6a

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4th

where X and Y are as defined above, one of Aaa and Baa is a peptide residue with 1 to 7 amino acids and the other is a bond or a peptide residue with 1 to 7 amino acids,

Ra for hydrogen, alkyl with 1 to 10 carbon atoms, cycloalkyl with 3 to 10 carbon atoms, cycloalkylalkyl with 4 to 10 carbon atoms in the cycloalkyl part and 1 to 5 carbon atoms in the alkylene part, phenyl or phenylalkyl with 7 to 12 carbon atoms, which are optionally in the phenyl ring by alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 5 carbon atoms, halogen with an atomic number of 9 to 35, hydroxy or amino, pyridinyl, thienyl or furyl or pyridinylalkyl with 6 to 11 carbon atoms, thienylalkyl with 5 to 10 carbon atoms or furylalkyl with 5 to 10 Are carbon atoms and either Ria hydroxy, alkoxy having 1 to 5 carbon atoms or alkanoyloxy having 1 to 5 carbon atoms and R2a are hydrogen or Ria and Rza together are oxo,

Rja, Rta and R5a independently of one another represent fluorine or chlorine and R6a represents hydrogen, fluorine, chlorine, alkyl having 1 to 5 carbon atoms, cycloalkyl having 3 to 7 carbon atoms in the cycloalkyl part and 1 to 5 carbon atoms in the alkylene part, phenyl or phenylalkyl having 7 -12 carbon atoms which are optionally mono- or disubstituted in the phenyl ring by alkyl having 1-5 carbon atoms,

Alkoxy with 1-5 carbon atoms, halogen with an atomic number of 9-35, hydroxy or amino, pyridinyl,

Thienyl or furyl or pyridinylalkyl with 6-11 carbon atoms, thienylalkyl with 5-10 carbon atoms or furylalkyl with 5-10 carbon atoms or an isosteric form thereof.

A particularly preferred group of compounds according to the invention are the compounds of the formula Iaaa,

X-A. -HN

ad '

C0-B -Y

aa

Iaaa what

X, Y, Aaa and Baa have the meaning given above, Raa stands for alkyl with 1-10 carbon atoms or cycloalkyl with 4-12 carbon atoms,

Röaa means fluorine, chlorine or alkyl with 1-5 carbon atoms, and either Riaa stands for hydroxy and R2aa for hydrogen or Riaa and R2aa together stand for Oxo and R3aa, Riaa and Rsaa each mean fluorine or an isosteric form thereof.

An even more preferred group of compounds according to the invention are the compounds of the formula laaaa,

aa

-A -HN aaa

0-8 -Y, aaa a k1aa

2aa

6aa laaaa where

Raa, Riaa Rjaa and r6aa have the meaning given above,

Xa represents hydrogen, alkoxycarbonyl with a total of 2-25 carbon atoms or alkanoyl with a total of 2-25 carbon atoms,

Ya stands for hydroxy, alkoxy with 1-5 carbon atoms, s amino, alkylamino with 1-5 carbon atoms, for example isobutylamino or 2-methylbutylamino, (1-benzylpiperidin-4-yl) amino or (pyridin-2-yl) - methylamino,

one of Aaaa and Baaa is a peptide residue with 1-7 natural amino acids in their natural configuration and the other is a bond or peptide residue with 1-7 natural amino acids in their natural configuration.

Aaaa is preferably a bond, -Phe-Phe-, -Phe-His-, -Phe-Nle-, -Phe-leu-, -Val-, -Hid-Pro-Phe-His-, especially a bond, -Phe -Phe- or -Phe-His-.

is Baaa is preferably a bond -Val-Phe-, -Ile-His-, -Leu-Phe-, -Ala-, -Leu-, -Ile-Phe- or -Ile-, especially -Ile-, -Leu- or -Val-Phe.

Explanation of abbreviations:

20 BOC = tert-butoxycarbonyl His = L-histidine Iva = Isovaleroyl Ile = L-isoleucine Leu = L-leucine 25 Lys = L-lysine Phe = L-phenylalanine Pro = L-proline Tyr = L-tyrosine Val = L- Valine 30 Bly = (2S) -2-amino- (4E) -hexenoic acid statin * = 4-amino-3-hydroxy-6-methylheptanoic acid staton * = 4-amino-3-oxo-6-methylheptanoic acid homostatin * = 5- Amino-4-hydroxy-7-methyloctanoic acid homostaton * = 5-amino-4-oxo-7-methyloctanoic acid 35 ch-homostatin * = 5-amino-6-cyclohexyl-4-hydroxy-hexanoic acid ch-homostaton * = 5 -Amino-6-cyclohexyl-4-oxo-hexanoic acid * The absolute configuration is specifically stated in the text.

40

The compounds according to the invention can be in free form, for example in amphoteric form or in salt form, for example in acid addition or in anionic salt form. A compound in free form can be converted into a salt form and vice versa. Examples of salt forms are, for example, the trifluoroacetates, hydrochlorides, sodium, potassium or ammonium salts.

A compound according to the invention can thus be obtained with the aid of a method which consists in coupling two corresponding peptide residues or their precursors and, if desired, converting the compounds obtained in the precursor form into the compounds according to the invention.

55 The process is carried out using methods known per se. A precursor of a peptide residue is, for example, a compound in protected form, which has, for example, a peptidic amino and / or carboxyl end group which is cleaved off or replaced in the desired compound according to the invention if desired or some other functional groups such as hydroxy if desired transferred to other functional groups such as Oxo l. For example, a peptide residue can be a single amino acid residue depending on the length 65 of the desired peptide. The above also applies to the isosteric forms.

The coupling step is carried out using methods known in peptide chemistry, for example

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as it is carried out in an inert solvent such as dimethylformamide, preferably at a temperature of about 0 to 25 ° C. Alkaline conditions, which arise using N-methylmorphine, for example, are expedient here.

The desired transformation is carried out in a manner known per se. Oxidation of a hydroxy group to a keto group is carried out in an inert solvent such as methylene chloride. The oxidizing agent can be, for example, a chromium trioxide dipyridine complex. The reaction temperature can be from about 0 to 50 ° C, but the reaction is preferably carried out at room temperature.

The compounds according to the invention obtained according to the above can be isolated from the reaction mixtures in a manner known per se and purified using known methods. Racemic and / or diastereoisomeric mixtures can be fractionated using known methods.

If the preparation of starting compounds is not particularly described, this can be carried out in a manner known per se using known methods.

In the following examples, all temperatures are given in degrees Celsius and are not corrected. The purity of the compounds obtained is determined using high pressure liquid chromatography with retention times obtained using a Lichtrosorb RP8 column (diameter 4 mm, length 250 mm) and a buffered solvent gradient (acetonitrile / water, pH 5) (10 to 90% in 40 minutes) at a flow rate of 1.5 ml per minute.

example 1

N-BOC- (4R, 5S) -2-isobutyl-2,3,3-trifluoromostatin-ValOCH3 (coupling of peptide units)

150 mg of a mixture of diastereoisomers of N-BOC- (4R, 5S) -2-isobutyl-2,3,3-trifluorohomostatin-OC2H5 are mixed with 80 mg of valine methyl ester and heated to 80 ° for 24 hours. The mixture is then allowed to cool, poured into an aqueous potassium bisulfate solution, then extracted with ether, the ethereal solution is separated off, dried and evaporated. The residue is chromatographed on silica gel using methylene chloride / ether 50: 1 as the eluent.

Two diastereoisomeric compounds are obtained:

Isomer A: [a] D20 = -32 ° (c = 0.88 in methylene chloride) retention time 38 minutes.

Isomer B: [a] D20 = -290 (c = 0.85 in methylene chloride) retention time 37.5 minutes.

The starting products can be manufactured as follows:

a) 0.85 g of sodium are dissolved in 15 ml of ethanol and 5 ml of diethyl fluoromalonate and 4.5 ml of isobutyl iodide are gradually added to the solution obtained. The mixture is shaken at 60 ° for 15 hours and then extracted with ether. The 2-fluoro-2-isobutyl-malonic acid diethyl ester (boiling point 6 mm = 155 °) is obtained.

b) 5.5 g of the diethyl ester obtained according to section a) are dissolved in 100 ml of dioxane and the solution obtained is added to a solution of 0.95 g of sodium hydroxide in 60 ml of water. After 15 hours the solution is evaporated under reduced pressure, the residue is dissolved in water and the aqueous solution is extracted with ether. The aqueous phase is acidified with phosphoric acid and extracted again with ether. The organic phase is evaporated at room temperature. The 2-fluoro-2-isobutylmalonic acid monoethyl ester (crude) is obtained.

c) 4.05 g of the monoethyl ester obtained in accordance with section b) and 3 g of N-BOC- (4S, 3R) -2,2-difluorostatin are dissolved in 25 ml of methanol and the solution is neutralized with 4 ml of triethylamine. The mixture is electrolyzed at 15 5 to 20 0 for 6 hours using a current of 1A. The reaction mixture is subsequently diluted with ether, washed with aqueous potassium bisulfate and aqueous sodium bicarbonate solution and then evaporated to dryness. The residue is chromatographed on silica gel using hexane / ether 1: 2 as the eluent. N-BOC- (4R, 5S) -2-isobutyl-2,3,3-trifluorohomo-statin-OCîHs is obtained as a mixture of stereoisomers with an Rf value of approx. 0.35 (silica gel, ether / hexane 1: 1) .

The N-Boc- (4S, 3R) -2,2-difluorstatin, which is used in step c), can be prepared as described below:

a ') 1.45 g of zinc powder are suspended in 30 ml of tetrahydrofuran and the suspension is heated to the boiling point. Then 4.4 g of ethyl bromodifluoroacetate are added in 20 additions and as soon as a strong 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 allowed to cool, then taken up in ethyl acetate and washed with 2N aqueous tartaric acid. 25 The organic phase is separated off, dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel using ether / hexane 2: 8 as the eluent. This gives N-BOC- (4S, 3R) -2,2-difluorostatinethyl ester ([a] D20 = -12.2 °, c = 0.29 in 30% ethanol).

b ') 1 g of N-BOC- (4S, 3R) -2,2-difluorostatinethyl ester is dissolved in methanol / water and reacted with 0.25 g of concentrated aqueous sodium hydroxide solution. After 2 hours the mixture is acidified by adding 2N aqueous tartaric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. This gives the N-BOC- (4S, 3R) -2,2-difluorostatin (crude).

40 Example 2

N-BOC-Phe-Phe- (5S) -2-isobutyl-2,3,3-trifluorohomostaton-ValOCH3 (conversion by oxidation)

10 mg of the isomer A of the title compound of Example 6 are added in a solution of 200 mg of chromium trioxydipyridine-45 complex in 2 ml of methylene chloride. After standing for 24 hours at room temperature, the reaction mixture is filtered off over silica gel and the filtrate is evaporated to dryness. The residue is chro-matographed over silica gel using ether / methylene chloride as eluent. This gives isomer A of the compound mentioned in the title (retention time 23.1 minutes).

The isomer B of the compound mentioned in the title is obtained in an analogous manner starting from the isomer B of the compound described in the title of Example 6.

Example 3

(4R, 5S) -2-isobutyl-2,3,3-trifluorohomostatin-ValOCH3 (deprotection of the precursor)

60 30 mg of isomer A of the compound mentioned in the title of Example 1 are dissolved in 1 ml of methylene chloride, the solution is cooled to 0 to 50 and 1 ml of tri-fluoroacetic acid is added. After standing at 0 to 5 ° for 2 hours, the solvent is evaporated, the residue is dissolved in ethyl 65-acetate and the solution is extracted with an aqueous sodium bicarbonate solution. The organic phase is dried and the solvent is evaporated off. This gives isomer A of the compound mentioned in the title.

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The isomer B of the compound mentioned in the title is obtained in an analogous manner from the isomer B of the title compound of Example 1.

is obtained as a colorless solid. [a] D20 = -42.0 ° (c = 1 in methylene chloride).

Example 4

N-BOC-Phe-Phe- (4R, 5S) -2-isobutyl-2,3,3-trifluorohomo-statin-ValOŒb (coupling of peptide units)

56 mg of N-BOC-Phe-Phe-OH are dissolved in 1 ml of tetrahydrofuran and 56 mg of the title compound of Example 3 (isomer A), 37 mg of hydroxybenzotriazole and 29 mg of N, N'-dicyclohexylcarbondiimide are added at 0 °. The reaction mixture is then concentrated under reduced pressure.

After standing for 24 hours, the reaction product is chromatographed on silica gel using a solvent gradient of ether in methylene chloride (0.1-20%) as the eluent. This gives isomer A of the compound mentioned in the title. [a> D20 = -26.2 0 (c =

0.805 in methylene chloride); Retention time 34.0 minutes.

Diastereoisomer B is obtained using the same procedure starting from isomer B of the title compound of Example 3. [a] D20 = -32.8 ° (c = 0.53 in methylene chloride); Retention time 34 minutes.

Example 8

5 N- (bis (1-naphthylmethyl) acetyl) -Nle- (4R) -2,2,3,3-tetra-fluoro-ch-homostaton-butylamide

28 mg of the compound of Example 7 are treated with 170 ml of Collin's reagent as described in Example 2. The compound 10 obtained after purification and named in the title has an [a] D20 = -31.6 0 (c = 0.2 in methylene chloride).

Example 9

N-BOC-Phe-Nle- (4R, 5S) -2,2,3,3-tetrafluoro-ch-homostatin-butylamide

143 mg BOC-Phe-NleOH, 135 mg tetrafluoro-ch-homo-satin-butylamide, 104 mg hydroxybenzotriazole and 81 mg N, N'-dicyclohexylcarbodiimide are reacted with one another as described in Example 7. After appropriate purification, the compound mentioned in the title has an [a] D20 = (c = 0.18 in methylene chloride).

Example 5

N-BOC-Phe-Phe- (4R, 5S) -2-isobutyl-2,3,3-trifluorohomostatin-Val-OH

68 mg of the isomer A of the title compound of Example 4 are dissolved in 3 ml of dioxane and 0.5 ml of water and the solution is treated with 14 ml of aqueous sodium hydroxide solution at room temperature for one hour. The mixture is then acidified with 2N aqueous tartaric acid and extracted with ethyl acetate. The isomer A of the compound mentioned in the title is obtained.

[a] D20 = -29.1 ° (c = 0.82 in methylene chloride); Retention time is 23.1 minutes.

Diastereoisomer B is obtained in an analogous manner, starting from isomer B of the title compound of Example 4. [a] D20 = -26.2 ° (c = 1.05 in methylene chloride).

Example 6

N-BOC-Phe-Phe- (4R, 5S) -2-isobutyl-2,3,3-trifluorohomo-statin-Val-Phe-OCH3

48 mg of isomer A of the title compound of Example 5, 15 mg of L-phenylalanine methyl ester, 16 mg of hydroxybenzotriazole and 13 mg of N, N'-dicyclohexylcarbodiimide are dissolved together in 1 ml of tetrahydrofuran at 0 ° and the solution is then concentrated under reduced pressure. After standing at room temperature for 15 hours, the crude product is purified by chromatography on silica gel using a gradient of ether in methylene chloride (0.1-20%). This gives isomer A of the compound mentioned in the title. [a] D20 = -45.2 ° (c = 0.79 in methylene chloride); Retention time 36.1 minutes.

The isomer B is obtained in an analogous manner starting from the isomer B of the title compound of Example 5.

Example 7

N- (bis- (l-naphthylmethyl) acetyl) -Nle- (4R, 5S) -2,2,3,3-tetra-fluoro-ch-homostatin-butylamide

76 mg of N- (bis- (l-naphthylmethyl) acetyl) -Nle-OH are mixed with 60 mg of 2,2,3,3-tetrafluoro-ch-homostatin-butylamide and 46 mg of hydroxybenzotriazole, which are dissolved in 1.5 ml of tetrahydrofuran are mixed. At 0 °, 36 mg of N, N'-dicyclohexylcarbodiimide are added to the mixture and the mixture is stirred for a further 15 hours. The crude product obtained is purified on silica gel using a solvent gradient of ether in methylene chloride (0.1-10%) as the eluent. The connection mentioned in the title

Example 10

N-BOC-Phe-Nle- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-butylamide

25 23 mg of the compound described in the title of Example 9 are oxidized using 230 mg of Collin's reagent as described in Example 2. After purification, the compound mentioned in the title has an [a] D20 = -51.3 ° (c = 0.26 in methylene chloride).

30th

Example 11

N-BOC-Phe-Nle- (4R, 5S) -3,3-difluoro-ch-homostatin-butyl-amide

97 mg BOC-Phe-Nle-OH, 83 mg difluoro-ch-homostatin-35 butylamide, 70 mg hydroxybenzotriazole and 55 mg N, N'-dicyclohexylcarbodiimide are reacted with one another as described in Example 7. After cleaning, the compound mentioned in the title has an [a] D20 = -19.4 ° (c = 0.3 in methylene chloride).

40

Example 12

N-BOC-Phe-Nle- (4R) -3,3-difluoro-ch-homostaton-butylamide

25 mg of the title compound of Example 11 are oxidized using 150 mg Collin's reagent and the procedure of Example 2. After purification, the compound mentioned in the title has an [a] D20 = -42.3 ° (c = 0.17 in methylene chloride). The compound obtained in the title is in equilibrium with the corresponding enol form, i.e. N-BOC-Phe-Nle- (4R) -3,3-difluoro-ch-homostatin-50 butylamide.

Example 13

N-BOC-Phe-Bly- (4R, 5S) -2,2,3,3-tetrafluoro-ch-homostatin-Leu-a-picolin

55 163 mg BOC-Phe-Bly-OH, 218 mg H-tetrafluoro-ch-homo-statin-Leu-a-picolin, 116 mg hydroxybenzotriazole and 92 mg N, N'-dicyclohexylcarbodiimide are in 2 ml methylene chloride for 15 hours at room temperature implemented. The crude product is chromatographed on methanol gel using methanol / methylene chloride (0.1 -5%) 60. [a] D20 = -50.5 ° (c = 0.3 in methylene chloride).

Example 14

«S N-BOC-Phe-Bly- (5S) -2,2-3-3-tetrafluoro-ch-homostaton-Leu-a-picolin

20 mg of the title compound of Example 13 are dissolved in 7 ml of methylene chloride and treated with 150 mg of Collin's reagent, such as

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described in Example 2, oxidized. [a] D20 = -19.4 ° (c = 0.17 • The following compounds are made analogously in methylene chloride). Obtained way to Examples 1 to 14.

Table 1

No. Connection example

15 N-BOC-Phe-His- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-homostatin-Val-Phe-OCH3

16 N-BOC-Phe-His- (5S) -2-isobutyl-2,3,3-trifluoro-homostaton-Val-Phe-OCH3

17 N-BOC-Phe-Hos- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-homostatin-Ile-His-OCH3

18 N-BOC-Phe-His- (5S) -2-isobutyl-2,3,3-trifluoro-homostaton-Ile-His-OCH3

19 N-BOC-Phe-His- (4R, 5S) -2-isobutyl-2,3,3-trifluoro -ch-homostatin-Val-Phe-OCH3

20 N-BOC-Phe-His- (5S) -2-isobutyl-2,3,3-trifluoro -ch-homostaton-Val-Phe-OCH3

21 N-BOC-Phe-His- (4R, 5S) -2-isobutyl-2,3,3-trifluoro -ch-homostatin-Ile-His-OCH3

22 N-BOC-Phe-His- (5S) -2-isobutyl-2,3,3-trifluoro -ch-homostaton-Ile-His-OCH3

23 N-BOC-Phe-His- (4R, 5S) -2,2,3,3-tetrafluoro-ch-homostatin-Ile-His-OCH3

24 N-BOC-Phe-His- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-Ile-His-OCH3

25 N-BOC-Phe-His- (4R, 5S) -2,2,3,3-tetrafluoro-ch-homostatin-Val-Phe-OCH3

26 N-BOC-Phe-His- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-Val-Phe-OCH3

27 N-BOC-Phe-His- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-2-methylbutylamine

28 N-BOC-Phe- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-2-methylbutylamine

The compounds according to the invention have favorable pharmacodynamic effects.

In particular, they show typical effects of renin inhibitors. This is shown in standard tests. Thus, they show a 50% inhibition of the submaxillary glands renin activity on the synthetic octapeptide substrate at a concentration of IO "5 M to 10" 11M in the test method by K. Murakami et al. from analyte. Biochem. 110 (1981), pages 232-239 (with the modification that the concentration of the synthetic substrate is reduced from 20 jo.M to 7 H.M) in the method of P. Corvol et al. from Biochem. Bio-phys. Acta 523 (1978), pages 485-493 and pure human renin activity according to Corvol et al., BBA (in press).

According to the antibody capture method by K. Poulsen and J. J0rgensen, Journal Clinic Endocrinology Metab. 39 (1974), pages 816-825, the compounds inhibit human plasma renin activity at a concentration of IO-5 M to 10-1! M.

The compounds according to the invention are therefore useful for the inhibition and treatment of hypertension and chronic heart failure.

For the above application, the dosage used depends on the compounds used, the mode of administration and the treatment desired. In general, satisfactory results are obtained if the compounds are administered in a daily dose of approximately 0.02 mg / kg to approximately 50 mg / kg of animal body weight. For larger mammals, the daily dose is approx. 1

25 mg to approximately 500 mg, which are expediently administered in partial doses two to four times a day from 0.25 mg to approximately 250 mg. Administration in sustained release form is also possible.

The compounds can be administered in a manner similar to compounds known for this type of administration, for example for the treatment of elevated blood pressure such as captopril. The appropriate daily dose for a particular compound depends on a number of factors, such as its relative potency. It is therefore indicated that the compounds are administered in doses similar to those known for this purpose.

The compounds according to the invention can be administered in free form or in the form of pharmaceutically acceptable acid addition salts. Such salts have the same efficiency as the free forms and can be prepared in a manner known per se. The present invention therefore also relates to a pharmaceutical composition which contains a compound 45 according to the invention in free form or in pharmaceutically active form together with a pharmaceutical carrier or diluent. Such compositions can be prepared in a manner known per se and can be used for enteral, preferably oral, administration, for example as tablets or parenterally, for example as a solution for injection or suspensions.

B

Claims (6)

673 655 2nd PATENT CLAIMS 1. Compound of Formula I wherein R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or aryl, aralkyl, heteroaryl or heteroarylalkyl, it being possible for the last four radicals in the aryl or heteroaryl part to be substituted and either Ri to represent hydroxy, alkoxy or acyloxy and R2 to denote hydrogen, or Ri and R2 together represent oxo and R3 to Rö independently of one another represent hydrogen, fluorine, chlorine, alkyl, cycloalkyl, cycloalkylalkyl or aryl, aralkyl, heteroaryl or heteroarylalkyl, where the last four radicals in the aryl or heteroaryl part can be substituted, with the proviso that at least one of R3 to Ra means fluorine or chlorine, X represents hydrogen or a protective group of the peptide amino radical, Y represents hydroxy or a protective group of the peptidic carboxyl group, one of A and B represents a peptide residue and the other of A and B represents a bond or a peptide residue, or an isostereform thereof, in free form or in the form of a pharmaceutically acceptable salt. 2. N-BOC- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-homostatin-ValOCH3 N-BOC-Phe-Phe- (5S) -2-isobutyl-2,3,3-trifluorohomostaton-ValOCH3 (4R, 5S) -2-isobutyl-2,3,3-trifluorohomostatin-ValOCH3 N-BOC-Phe-Phe- (4R, 5S) -2-isobutyl-2,3,3-trifluorohomo- statin-ValOCH3 N-BOC-Phe-Phe- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-homo-statin-ValO-H N-BOC-Phe-Phe- (4R, 5S) -2-isobutyl-2,3,3-trifluorohomo-statin-Val-Phe-OCH3 N- (bis- (l-naphthylmethyl) acetyl) -Nle- (4R, 5S) -2,2,3,3-tetra-fluoro-ch-homostatin-butylamide N- (bis- (l-naphthylmethyl) acetyl) -Nle- (4R) -2,2,3,3-tetra-fluoro-ch-homostaton-butylamide N-BOC-Phe-Nle- (4R, 5S) -2,2,3,3-tetrafluoro-ch-homostatin-butylamide N-BOC-Phe-Nle- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-butylamide N-BOC-Phe-Nle- (4R, 5S) -3,3-difluoro-ch-homostatin-butylamide N-BOC-Phe-Nle- (4R) -3,3-difluoro-ch-homostatin-butylamide N-BOC-Phe-His- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-homo- statin-Val-Phe-OCEb N-BOC-Phe-His- (5S) -2-isobutyl-2,3,3, -trifluoro-homostaton-Val-Phe-OCHs N-BOC-Phe-His- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-homo-statin-Ile-His-OCHî N-BOC-Phe-His- (5S) -2-isobutyl-2,3,3-trifluoro-homostaton-Ile-His-OCHs N-BOC-Phe-His- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-homo-statin-Val-Phe-OCH3 N-BOC-Phe-His- (5S) -2-isobutyl-2,3,3-trifluoro-ch-homo-staton-Val-Phe-OCH3 N-BOC-Phe-His- (4R, 5S) -2-isobutyl-2,3,3-trifluoro-ch-homo-statin-Ile-His-OCH3 N-BOC-Phe-His- (5S> 2-isobutyl-2,3,3-trifluoro-ch-homo-staton-Ile-His-OCH3 s N-BOC-Phe-His- (4R, 5S) -2 , 2,3,3-tetrafluoro-ch-homostatin-Ile-His-OCHs N-BOC-Phe-His- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-Ile-HÌS-OCH3 N-BOC-Phe-His- (4R, 5S) -2,2,3,3-tetrafluoro-ch-homostatin-xo Val-Phe-OCb N-BOC-Phe-His- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-VaI-Phe-OCb N-BOC-Phe-His- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-2-methylbutylamine 15 N-BOC-Phe- (5S) -2,2,3,3-tetrafluoro- ch-homostaton-2-met-hylbutylamine N-BOC-Phe-Bly- (4R, 5S) -2,2,3,3-tetrafluoro-ch-homostatin-Leu-d-picolin or N-BOC-Phe-Bly- (5S) -2,2,3,3-tetrafluoro-ch-homostaton-Leu-20 d-picolin in free form or in the form of a pharmaceutically acceptable salt as a compound according to claim 1. 3. Compounds according to claims 1 and 2 wherein Rs and Rö are not simultaneously fluorine if R3 and R4 25 each have a different meaning than fluorine. 4. A process for the preparation of the compounds according to claim 1, characterized in that two corresponding peptide residues are coupled together. 5. Pharmaceutical composition containing compounds according to claims 1 and 2 together with a pharmaceutical carrier or diluent. 6. A compound according to claim 1 for combating increased blood pressure and chronic heart failure. 35