JPS61186397A - Peptide derivative for controlling rennin and acid protease - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel peptides that inhibit renin and acid grotease. The invention also relates to methods of production and therapeutic applications thereof.

In 1970, Umedewo isolated pentapeptide from a culture of Streptomyces. This pentapeptide is called pepstatin, and its structure was subsequently established and corresponds to the following two.

Isovaleryl-L-valyl-L-parylose-statyl-L
- In the alanylous statin formula, "statin" is a rare amino acid (3s, 4S) -
Pepstatin inhibits acid proteases and has been shown to be particularly active against pepsin, cathepsin D, and renin. In particular, renin, an enzyme produced from the kidneys, is involved in the conversion of angiotensinogun to angiotensin.
Involved in the angiotensin pathway.

As a powerful vasoconstrictor, angiotensin plays a role in controlling arterial blood pressure. The possibility of using ibustatin to combat arterial hypertension in humans has been considered. However, ibustatin acts on all acid proteases,
Its low solubility in aqueous media and low affinity for renin have made its therapeutic use difficult. Ibstatin derivatives have been described in the scientific literature. For example, attempts have been made to solubilize pepstatin by lengthening the peptide chain (JaCardiovas
c, Pharmacol al 980, 2.

687-698).

In contrast, this invention relates to model peptides based on ibustatin. In certain cases, the introduction of unnatural amino acids makes it possible to increase the solubility and proteolysis of these compounds. Quite surprisingly, according to the present invention, with hydrophilic groups at various positions (putide is
It was found to have a high level of activity that is significantly superior to that of pepstatin as an inhibitor of renin in humans.

This invention relates to peptides with high levels of activity as inhibitors of renin and other acid proteases.

The following abbreviations are used in this specification and claims.

Amino acids and protecting or activating groups This abbreviation corresponds to that given by the IUPAC-IUB Nomenclature Committee, Biochemistry Division.

Ala: Alanine Aan: Asparagine Amp: Asnoglagic acid Gin: Glutamine G17 Nigericin Hls: Histidine 11m: Isoleucine L@u: Leucine M@t: Methionine Nle: Norleucine Nva: Norvaline ph・: Phenylalanine Ser: Serine Sta: Statin ARPPA : 4-amino-3-hydroxy-5-phenylintanoic acid ACHPA : 4-amino-5-cyclohexyl-3
-Hydroxypentanoic acid Met (O□): Methionine dioxide (PhCHz
) Asp: O-pendyl asno parent rutinate Abu
: 2-7 minoracic acid (Pyr-2)Ala, : (pyridin-2-yl)
Alanine (p7r-3)Ala: (pyridin-3-yl)alanine (Pyr-4)Ala: (pyridin-4-yl)ara=y(tauMe)Hla: (tele-methyl)histidine (tauEt)Hls: ( ter-ethyl) histidine (piMe) Hls: (
Pros-methyl)histidine H3 (2-methylthiazol-4-yl) Gly: (1
-methylimidazol-2-yl) Ala:Hph
: Homophenylalanine Phg : Phenylglycine cpg Nidiclopentylglycine (CH30H20)Ser : Ethyl ether of serine ((CHs)gco)Ser : tert-butyl ether of serine (PhCH,O)8・r: Benzyl ether of serine ((Pyr -2) CH20) Ser: Serine (
Pyridin-2-yl) methyl ether (Pentyl)Ala: 2-aminooctanoic acid (
Ph)Gin: N-phenylglutamine (Ph)A
an: N-7x Unless otherwise specified, these amino acids have the L configuration.

Special K, fx, Sta, AHPPA and H ACHPA have 3S and 4S configurations.

AC Niacetyl Hoe: t-butoxycarbyl(Boc)2
0: bis(tart, -butoxycartenyl, di)anhydride - HONSu: N-hydroxysufushiimide ogt
: Ethyl ester OMe : Methyl ethyl ONP' : P-nitrophenyl ester 0N
Su: N-hyproxysuccinimide ester 0T
cp: 2,4.5-)lichlorophenyl ester iVa: isovalerylz: penzoyloxycardenyl The following abbreviations are also used.

AeOEt: ethyl acetate AcOH: acetic acid B Op: benzyloxytrisdimethylaminophosphonium hexafluorophosphate TLC: thin layer chromatography DCCI dicyclohexylcal diimide DC
HA dicyclohexylamine DCU = dicyclohexylurea DIPEA: Diisopropylene ethylamine DMF
Nidimethylformamide DMSO Nidimethyl sulfoxide Ether: Ethyl ether aont: 1-Hydroxybenzotriazole
'KHso4-, so4: tL potassium bisulfate 16.6.9 and potassium sulfate 33.3 Ii
Aqueous solution containing M・OH=methanol NEM: N-ethylmorpholine NMM:
N-methylmorpholine RT: room temperature TFA nitrifluoroacetic acid 1': min h: time The compound according to the invention has the following general formula: O, where -R, represents an acyl group selected from the following groups: Represent: Alkyl car is a nyl group, alkoxycarbonyl group, aryl car is a nyl group, arylalkyl car? Nyl group, OK-
alkoxycardenyl group, a heterocyclic carbonyl group, a heterocyclic alkylcargenyl group, in which the alkyl group may optionally be a hydroxyl group, a heterocyclic carbo-nylalkylcargenyl group, a Nyl group,
and a cycloalkylcargonyl group which may be substituted, or an alkyl group is polysubstituted or unsubstituted by a free amino group or an amino group having a protecting group, or by a phenyl group. A phenylsulfonyl group which represents a (lower alkyl)sulfonyl group or whose phenyl nucleus is polysubstituted or unsubstituted by a lower alkyl group.

-R2 represents a lower alkyl group polysubstituted or unsubstituted by a phenyl group, a naphthyl group, a cyclohexyl group or a pyridyl group, or R2 represents a phenyl group, a naphthyl group, a cyclohexyl group or a pyridyl group.

-13 is a 5- or 6-membered monomer substituted or unsubstituted with hydrogen, a lower alkenyl group, a phenyl group, a naphthyl group, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkyl group, or a trifluoromethyl group. Represents a ring heterocyclic group,
Alternatively, a di(lower alkyl)amino group may be esterified with a lower alkyl or pencil group. xyl group,
A carbamoyl group or a free carbamoyl group substituted with 1 or 2 lower alkyl or phenyl, a lower alkoxy or benzyloxy group, a pyridylmethoxy group, a (lower alkyl)sulfinyl or a (lower alkyl)sulfonyl group, a carbon A cycloalkyl group having 3-6 atoms,
or represents a lower alkyl group substituted with a 5- or 6-membered monocyclic heterocyclic group substituted with a lower alkyl group or a trifluoromethyl group or not. However, it is not an (imidazol-4-yl)methyl group.

-R4 represents a hydroxyl group, a lower alkoxy group, a benzyloxy group, a free amino group, or an amine group substituted with one or two lower alkyl groups.〇-2 represents isopropyl, phenyl, or cyclohexyl, and each of the following The residue of the amino acid statin with the radical NH-CH-CHOH-CH2-Co-CH2, i.e. (38°48)
-4-amino-3-hydroxy-6-methylhebutanoic acid residue, (38,48)-4-amino-3-hydroxy-5-7enylintanoic acid (AHPPA) residue, (
38,48)-4-amino-5-cyclohexyl-3-
Forms the residue of hydroxypentanoic acid (ACHPA).

-xy is Ala-8ta, Ala-L@u,
Leu-Phs.

Vat-Sta, Abu-Sta, Its
-Sor and Phg-8ta.

The invention also encompasses pharmaceutically acceptable mineral acid, organic acid, alkali metal, or alkaline earth metal salts of the peptides of formula (1).

The term "alkyl" refers to a saturated or unsaturated aliphatic hydrocarbon group containing 1 to 10 carbon atoms. Preferred "alkyl" groups in this invention are lower alkyl groups as defined below.

"Lower alkyl" and "lower alkenyl" used here
, and the expression "lower alkylidene" refer to a saturated or unsaturated aliphatic hydrocarbon radical having up to 6 carbon atoms.

The expression "lower alkoxy" refers to a hydroxyl group substituted with a lower alkyl group as defined above.

The expression "5-membered or 6-membered monocyclic heterocyclic compound" includes pyrrolidine, imidazole, thiazole, thiophene, furan, virol, triazole, oxazole, isoxazole,
Contains pyridine and thiadiazole.

The expression "protecting group" is understood to mean the protecting groups commonly used in peptide chemistry, such as Boa, Z or iVa.

The expression "acyl group" used to define R1 includes aliphatic, cycloaliphatic, aromatic, or heterocyclic carboxylic acid residues. Preferred acyl groups are residues of esterified carganic acids, especially Bee and 2 groups, residues of alkanoic acids having 2 to 6 carbon atoms, especially the iVa group, cyclohexyl car? residues of phosphoric acids, residues of phenylaliphatic acids, especially phenylacetyl,
3-phenylpropionyl, and residues of arylcarboxylic acids, such as dibenzylacetyl groups, naphthoic acids, biphenylcarboxylic acids, and benzoic acids with or without substitution of the phenyl nucleus, especially benzoyl groups, car-xyl The radicals are 5- or 6-membered monocyclic heterocycles, especially biphenyl groups, xyl groups, bicolinoyl, nicotinoyl and isonicotinoyl groups, K-bonded carboxylic acid residues, and alkanes such as acetic acid, propionic acid, lactic acid, valeric acid. acid or alkenoic acid residues, and omega-hydroxy or omega-oxo derivatives thereof in which the omega position is substituted with a 5- or 6-membered monocyclic heterocycle as exemplified above.

This invention particularly provides R,, R,, R4, X, Y, and 2. is defined above and R1 represents a group of formula (I)
This invention relates to peptide derivatives of.

(CH3)5COC- (CH,), CH-CH2-C- and n++al@213@4or5 OCH,0 where E--Hor-CH5 and @xi, 2.3(1y4 C4H1, -C- NH2CH2CH2 -8o□- BoeNHCH2CH2-802- ZNHCH2CI(2-8o2- A-8O□-1 where A is lower alkyl group c6a5-(
cu, ), -5o2* where a=0.1or2 Particularly preferred are R2, Rs, R4, X, Y.

and 2. is defined above and R1 represents an acyl group selected from the following groups:

-isovaleryl, -4-(pyridin-2-yl)-4-oxobutyryl, -4-(pyridin-2-yl)-4-hydroxybutyryl, -3-(hy+J syn-3-yl)flopionyl, - 4
-(pyridin-3-yl)butyryl, -nicotinoyl and monobenzenesulfonyl.

Particularly preferred are R,, R2, R4, X, and Y.

and Z, 75s, and R3 is ff1-CH(R
3) A compound of formula (1) in which the -CO- residue represents a (tauMe)-H3s residue.

The substances according to the invention can be produced by methods commonly used in peptide chemistry. In particular, 1 formula % formula % [wherein R'4 is lower alkoxy, benzyloxy, a free amino group or an amino group substituted with 1 or 2 lower alkyl, Y is an amino acid, Sta, L@11
, Phe and B@r residues], various amino acids are coupled stepwise with appropriate protection, and the products obtained in each step are further processed. Prior to coupling, decoupling and purification operations are carried out in the presence of a dicyclohexyl diimide using an activated ester of the amino acid to be coupled or an N-protected amino acid, respectively, by known methods. The starting material is advantageously the lower alkyl ester of the C-terminal amino acid to which the next amino acid in the sequence is condensed. After the amino group of the dipeptide is liberated, the peptide chain is lengthened by coupling with the next suitably protected amino acid.

Each coupling step is followed by a selective operation to liberate the amines participating in the reaction to create the new -eftide bond. Various coupling operations are carried out in the presence of dicyclohexyl diimide using activated esters of coupling amino acids or N-protected amino acids. Depending on the nature of the protecting group used, steps involving selective deprotection of the amine may be carried out by hydrogenolysis or acidolysis in a strong medium such as trifluoroacetic acid. If the amino acid introduced into the sequence has a reactive group in its side chain, this group should be capped with a suitable protecting group and then removed.

Protection of the first amino acid with R1 is carried out in known manner before the group R1 constant-C plate 2-co- is coupled with the next amino acid.

The group -[-CHR, -Co- is an unusual amino acid produced by known methods. This is then pulled with the next amino acid in the usual manner.

The acid form (R4-OH) of the peptide (1) is obtained from the compatible ester by saponification in dilute alkaline medium. It is also possible to produce its salts. Amide type (R4=NH
2 or R4=N(Anc)2) can be obtained directly using a commercially available amino amide as a raw material.

Generally speaking, it is also possible to manufacture the entire desired array;
It is also possible to produce 27 fragments of this sequence and finally couple them to form the desired peptide.

Pharmaceutically acceptable mineral acid, organic acid, alkali metal or alkaline earth metal salts of the peptides according to the invention can be prepared by conventional methods.

The compounds of this invention have a very strong inhibitory effect on human plasma membrane activity, which is generally much greater than that of the natural substance, pepstatin. Due to this property,
Used to treat arterial hypertension.

These substances also have an excellent inhibitory effect on acid groteases, especially pepsin. It is therefore envisaged to use the substances according to the invention in therapeutic fields where inhibition of such enzymes is justified. Other particularly relevant areas besides arterial hypertension are gastric and duodenal ulcers and inflammatory diseases.

This invention also provides a peptide of formula (1) or a mineral thereof,
It also relates to antihypertensive pharmaceutical formulations in which pharmaceutically acceptable salts of organic acids, alkali metals or alkaline earth metals are present as active ingredients.

The peptides of this invention can be used intravenously, intramuscularly,
Alternatively, it can be administered by subcutaneous injection. This includes solvents such as physiological serum (isotonic saline), or buffers such as phosphate buffers.

Used in Fa. Additionally, they can be suspended in pharmaceutically acceptable aqueous or non-aqueous diluents.

Each dosage unit can contain 1-1000 In9 of active ingredient.

The amount of active ingredient used will vary depending on the desired therapeutic effect, the severity of the disease being treated and the chosen method of administration. It should be determined for each patient, but generally 0.100I of active ingredient
It is between i and 2g.

The following examples are provided to illustrate the invention, but are not intended to be limiting.

In all cases the voice of the solution in organic solvent was measured or checked using wet-indicator paper.

The indicated melting points (mope) were determined by the capillary method.

Each magnetic resonance spectrum was performed at 250 MHz in DMSO solution using hexamethyldisiloxane as an internal standard.

The following abbreviations were used:

S: Single term +i: doublet m: Multiple rings or unanalyzed signal q: quartet Furthermore, the following abbreviations were used.

φHar represents aromatic H.

・Him indicates H of imidazole.

・Hpyr indicates H of pyridine.

Chemical shifts (delta) were measured in ppm.

Example 1 Boa-Ala-ONSu of 2.86I, 1.81
1 L@u-OMe, HCt and 1.15 g NE
M is then dissolved in 1c5Qil of CH2CA2 at RT. Check that the voice is 6-7. If not, adjust by adding NEM. RT organic solution for 4 hours
Stir at L, then at 5% KHSO3-K, 80
4 solution, water and 5% NaHCOa solution. Drying over Na, SO2 and evaporation of the solvent leaves an oil.

Yield 2.9311 (92%) Cover the previous material of 360/9 with 51 TFA, after 20 minutes the TFA is evaporated and the residue is taken up with an equal mixture of pentane and ether. A white solid appeared on stirring, filtered off, rinsed with ether and dried.

Yield: 320 Da (85 Chi) 3, B61! -8ta-Ala-Leu-OM*
The TFA salt obtained before 330~ is dissolved in dioxane 3017 containing 230In9 of NEM. 275rn9 B
oa-8ta-OH, 2061! DCCI of Q and 13
Add HOBt from 5 to 6-7 with NEM if necessary and stir the mixture for 24 hours at RT. The DC"U was filtered off, the solvent was evaporated, the residue was dissolved in an equal mixture of AeOEt and hexane, and the solution was purified with Mer in the same solvent mixture.
Chromatograph on a column of 60 silica.

Elution was carried out with 250 d1 of the same solvent mixture, then 250 d1 of a mixture in a 75/25 volume ratio, then 1001 d1 of Ac0Kt.
It will be expanded in 14. The product-containing portion is evaporated and the residue taken up in ether and dried.

Obtained before 47311v (Putide was incubated with gmoTFA at 0°C.
Treat for 15 minutes. The mixture was heated under reduced pressure at t=25
Concentrate at °C, take the concentrate in ether and evaporate the mixture. A solid was obtained, taken up with CH,ct, and the salt was neutralized with a slight excess of NMM under cooling to obtain 405rn9 Boa-(Ph
Ch2) Asp, 191 IQ HOBt and 25
Add 8■ DCCI. - is adjusted to 7 by adding chlorine and the mixture is stirred for 18 hours.

Then K) Wash with ISO4 solution (approximately IM), dry and concentrate. Chromatograph on a silica column with Ac0Et as eluent. The expected product is obtained from 169 and crystallizes on evaporation. mp=147-149℃.

The product obtained before 169rn9 was incubated with 8d TFA at 0°C.
Process for 5 minutes. The mixture is concentrated under reduced pressure at 25° C., the concentrate is taken up with ether and the mixture is evaporated. oil is obtained,
Remove with CH2CA2 and neutralize the salt with slightly excess NMM while cooling. 100 Da Boa-Phe-ONp, 38m
A mixture of 1 HOBt and 26 m 9 ONMM was heated at C for 2 hours.
Stir in H2CA2 and then add the above salt. 24 hours
After stirring, the organic phase is washed with KH804 solution and NaHCO3 solution, dried and concentrated. Chromatograph on silica (
After eluent: Ac0Et) the expected product is obtained and crystallizes on evaporation of the solvent.

Yield: 103 da (sob) mp■154-155℃.

NMR Spectrum Example 2 This substance is
978-984.

6.5 g of the previously prepared compound is stirred for 3 days in 60° water with 8.11 Boc 20.32.5 Il dioxane and made alkaline with triethylamine. The mixture is concentrated at 300 °C, the concentrate is taken up with ether, the mixture is washed with water and then with a solution of KHSO3, water and NaC05, dried and concentrated.

8.5 g of yellow oil are obtained.

3. (R9S)-(2-Methylthiazol-4syn) The compound obtained before 4.51 is reacted with 0.72 μl of sodium hydroxide dissolved in 1517 μl of water in 39 sl of dioxane. The reaction is followed by TLC. After 2 h, add another 0.6.9 ml of sodium hydroxide in 2 h. After 3 h, no additive is present. Reduce the volume to 5 with 15 g of NHC and mix the mixture. The mixture is acidified with KHSO3 and extracted with Ac0Et. The extract is washed with water, dried and concentrated. A yellow powder of 2.7I is recovered.

4. Boa-8ta -Ala-L@a -0M
mThis peptide is prepared as described in Example 1.

Lou 4-i A/) Gly -Sta -Aim-
The previous product of L@u-OMe473rI9 was incubated at 0 °C for 5
d in TFA. After 20 minutes, the mixture is concentrated and the concentrate is taken up in three portions with anhydrous ether.The mixture is then concentrated to a minimum volume. The resulting product was added to 201 Ll of CH2C.
A, dissolved in - to about 7 by addition of DIPEA.

The compound obtained in step 3 of 26011I9 and 441 da Bop are then added. After stirring for 4 days at pH 7, the mixture is treated with an aqueous solution of sodium chloride, then with a solution of bicarbonate and water, dried and concentrated. The concentrate is then chromatographed on silica 6 Ac0Et and then Ac0
By elution with an Et/Menu mixture, 9/1 volume basis, an amorphous solid fraction of 607 cm is recovered by precipitation in pentane.

6. 44-TF of the compound obtained before SR43059 2511119 at 0 °C
Put it in A and process it in the usual way. The resulting TFA salt was placed in 15 m cH2ct2 and the reaction medium was diluted with DIPE.
Addition of A to pH 7 and 149WI9 Bee-Ph
Add e-ONp and HOBt of 61.2~. After 24 hours, the mixture is washed and chromatographed on silica in the same manner as in the previous step. Elute with an AaOEt/MeOH mixture, 9/1 volume basis. A white powder of 2301n9 is collected.

NMR spectrum example 3 Boa -Phe-(Pyr-3) Ala-8ta-
L@u-Phe-OMe (SR43064 and SR4
11J'
Add 36y of 3-chloro-methylpyridine hydrochloride while heating to reflux and keep the mixture under reflux for 5 h.
The OH is evaporated, the residue is taken up with water, the mixture is extracted, the extract is dried, concentrated and chromatographed on silica. CH
Elution with 2CL, /Ac0Et mixture, 60/40 volume basis gives 23 g of the expected compound.

2, (R,S)-(Pyr-3)Alm, 2HC
Diester before j15.9 in 200 ml of 5 N HCt
Heat at reflux for 5 h in d. Concentrate the mixture to dryness.

Add EtOH and evaporate the mixture. This process is repeated until the dihydrochloride is recrystallized.

15 lo 1 g of dihydrochloride is dissolved in an equal volume of water and dioxane mixture. 350 ~ of sodium hydroxide and 11 (Boc), O are added and the mixture is stirred at RT overnight. Evaporate the dioxane and add water to reduce the medium to 8JF.
Neutralize with Amberlite CG 1201 (acid type),
Stir for 1 h at RT and transfer to a column containing 8I of the same resin.

The eluate was developed with distilled water until -5, then 4%
Develop with a distilled aqueous solution of ammonia. Concentrate the eluate. 0.69 g of expected compound is recovered.

465% Sta-OMe, TFA and 500~Bo
The mixture of a-(Pyr-3)Ala is stirred at RT for 3 days in the presence of 780In9 Bop in 10 da acetonitrile, the medium being kept at s about 7 by addition of DIPEA. Evaporate the mixture to dryness, add water and reduce the mixture to Ac0
Extract with Et and wash the extract with a solution of Na2C03, water and aqueous IJum solution, dry over MgSO4 and evaporate to dryness. The residue was purified with CH2C22 on a silica dal.
/Ac0Et mixture, 1/9 volume basis, chromatographed with K elution. The next one elutes in succession.

Less polar A isomer = 15 o more polar B isomer: 1801n9 5, Leu-Phe-OMe This dipeptide is prepared by the coupling method described in the previous example.

OM• This compound is isolated in step 2 and is prepared first from the 9A isomer. The 2001v A isomer is hydrolyzed in an equal mixture of water and dioxane for 1 h at RT. The mixture is partially evaporated under reduced pressure at RT, a trace amount of HCl is added to a value of -4, then the mixture is evaporated to dryness and the residue is dried under reduced pressure.

200 rlQo
Leu-Ph e -0CHs-T FA and 230
1n9 Bop is added and the reaction medium is kept at approximately pH 7 for 18 h with the addition of DIPEA.

The mixture was then evaporated to dryness and an aqueous bicarbonate solution was added to the Ac
Extract at 0E, t. The organic phase is washed with water and aqueous sodium chloride solution and dried over MgSO4.

Chromatographed on silica gel using CH, Cj2/Ac0It, 1/4 volume basis as eluent. A product of 300η is obtained.

197 The previous compound is contacted with 5d TFA for 20 min at 0°C, the solvent is then evaporated and the resulting salt is dried under reduced pressure. The residue was suspended in CH2Cl2 and DIPE
Neutralize with A. 110In9 Boa-Phe-O
Add a solution of Np and 45rn9 of HOBt in CH2CL2. Stir the mixture for 18 h at RT, voice DIP.
Keep it at about 7 by adding EA. The mixture is evaporated to dryness, an aqueous solution of carbonate is added and the mixture is extracted with AeOET. After washing several times with water, dry over MgSO4. Chromatograph the residue on silica gel (eluent a AeOEt)
5R43066 of o 150 r119 is obtained.

8, 8R43064 Starting from the 9B isomer isolated in step 4, 5R43064
The methods of steps 4 and 5 are carried out to produce.

NMR spectrum of SR43066 NMR spectrum of SR43064 Example 4 Following the method of the previous example, Boa-Ph·-(Pyr-4
) Alm is first prepared and this product is Sta-OM.

Coupling with TFA. The two isomers are subsequently isolated chromatographically.

The less monopolar A isomer-B isomer 2, 8R43065 compound is obtained from the A isomer according to the method of the previous example.

3, 8R43144 This compound is obtained from the B isomer according to the previous example.

NMR spectrum of SR43065 NMR spectrum example 5 of SR43144 Boa -Phe -(Pyr -2) Ala-8t
a-L@u -Phe -OMel, (R,S)-
Pyridin-2-ylalanine dihydrochloride of Boc-Phe-(Pyr-2)AlmII and 1.65.9
of Boa -Ph・-0Np at 48h% RT at 3Qm/
of DMF/dioxane mixture, ■volume basis, medium 2.5
d. Stir in the presence of triethylamine. A small amount of insoluble material is concentrated, the solution is evaporated to dryness and the residue is chromatographed on silica gel. CHCLs /M@OH/
The dipeptide is eluted in water-soluble form with a NHaOH mixture (84/1515, by volume). Yield: 58%.

2. Boa-Phe-(Pyr-2)Ala-8
ta-OM@880 da Bop and DIPEA 0M2
8081 previous product in CL2 [added at 0°C. 15
After a contact time of 600~Sta-OM@,T
FA was then added and the volume was increased by the addition of DIPEA at about 6-7
Make it. The mixture was stirred for 4 days at RT, then evaporated to dryness and an aqueous solution of carbonate was added. l! Extract #A with AeOEt. After washing with water and sodium chloride, the oil is isolated. 850rR9 was chromatographed on silica gel,
The following are subsequently isolated by elution with AcOEt.

Tripeptide with low unipolarity, A, homogeneous in TLC, Contains 30 highly unipolar tripeptides, B and A.

3, 8R43150 This compound is obtained from the A isomer according to the method of Example 3.

4, 8R43151 This compound is obtained from the B isomer and after formation 5R4315
Contains 30-40% of 0.

NMR spectrum example 6 of 5R43150 (SR42845) 1, H-8ta-OMe of Z-Ala-3ta-OM@1.44.9. TPA, 595
NEM of rng, 2.06, Z-Ala- of F
Dissolve 0Tep and 1,291 HOBt in 35a/DMF K at room temperature. If you need a voice, please use NEM on 6-7 and i! l! ! l! 1. Stir the mixture at RT. DMFlt 40 under mercury pressure of 0.01 vx
Evaporate in a water bath c'. Remove residual oil by 50 d CI A
c0Et 7 mixture to 5% K)tSO,-2
S04 solution, NaC2/H20, 5% NaHCOs
solution and NaC2/H20, MgSO4
Dry on top and evaporate the solvent. When the residue is taken up with ether, a solid appears. After 1 hour in the refrigerator, thicken and dry the solid.

Yield: 1.46JF (86%); mp: 117-1
1.031 ammonium formate is then added at RT and the mixture is stirred until a solution is formed, 400 η of 10% PA7C is added and the mixture is stirred for 5 min at RT. After 5 minutes, a check by TLCK indicates that the material has disappeared. There are 8 voices in one paper. The entire mixture is concentrated over Celite and the methanol solution is concentrated over a column of Anno-Nite 1R45 resin (OH) and the methanol is evaporated. The residue is taken up with ether, the mixture is evaporated to dryness, the residue is dissolved in CH2Cl2, the insoluble material is concentrated, and the concentrate is evaporated to dryness to give a white powder.

Yield: 810rIT9 (75%); mp: 123-
134°C 3, Boc-8ta-Ala-8ta-OMa9
60rI#9 H-Ala-8ta-OMe, 11 Bae-Sta-OH, 4201R9 HONSu
and 750 Da DCCI sequentially at RT of 50-CH, C
2, dissolves in. A white precipitate appears immediately. The mixture was stirred at RT for 7 h, and the DCU that formed was concentrated and CH2
Wash with Cl. The organic solution was sequentially converted into KH8O4-2S
04 (H2020% 5% NaHCOx (H20
20% solution). Dry over MgSO4, concentrate and evaporate the solvent. The product should be added to a minimum of 7 o/l.
/A/M@OH mixture (97,5/2.5, Mo
1/Vol) and precipitated on the top of a silica dal, elution is carried out using the same mixture and the eluate is fractionated.

One batch of pure product and two batches of recycled product are collected under the same conditions, giving a total yield of 67 batches. mp:9
5-98℃.

Treat with 3.5 d of TFA at 0°C. RT the mixture
Stir for 20 minutes. After concentrating under reduced pressure, the oily residue is extracted by successively adding anhydrous ether and concentrating. A white solid is obtained.

! In addition to R9), set the voice to 7 with NMM. 56.3 da Boa -M@t(02) -OH,45,9rR9
of HOBt and 45.4 cm of DCCI are introduced at -5°C. - After the check, the mixture is stirred at RT for 6 days.

Add 1 drop of AeOH to the reaction mixture, stir for 30 min,
Set the DCU to the dark side. The concentrate is taken up with an AeOH/butan-1-ol mixture, 75/25 by volume. The organic phase was sequentially treated with a saturated solution of NaCt, a solution of KHSO3, water, and NaH.
One solution of COs is finally washed with water. After drying and concentration,
A white solid residue of 120IR9 was recovered and analyzed on silica.
eOIt then Ac0Et /MeO with capacity standard 9/1
60 ■ of type B white solid precipitate were obtained.

6. 3R42845 60 da of the product obtained in the previous example was dissolved in 2 d of TFA at 0°C.
and stir the mixture for 20 minutes at RT.

After concentration under reduced pressure, the oily residue is extracted with successive additions of anhydrous ether. Add 1Qal of CH,C70 to the thus obtained white solid TFA salt and adjust - to 7 with NMM 633.4
7Q Hoe -Phe -ONp and 14m20HO
Bt was then introduced and after -che, the mixture was heated at RT for 7
Stir for 2 hours. The solution was diluted by the addition of cH, ct2 and the organic phase was sequentially diluted with NaC2 saturated solution, KH8O41 solution,
Wash with NaHCO31'fb solution and then with water.

After dry concentration, the solid residue of 58IR9 was collected and purified with AeO
The silica is mixed with an Et/MeOH mixture, 9/1 volume basis. An amorphous white solid precipitates in 37 Da of hebutane.

NMR sulfur example 7 (R,S) -Bee -Phe -Hph-8ta
-Alt-8ta-OMe (SR42727) 1, Bee -Ala-8ta-0Et4, IJF
H-Sta-OMe, TFA in 250-cH
2ct2.1.7 cll of NEM, 3.86 N of Boa-Ala-ONSu and 2! I HOBt was added sequentially, then NEM was added to adjust the - to 7, and the mixture was diluted twice with 500 cd of NaHCO3 saturated solution.
Wash twice with 2SO4 solution in KHSO3- and 500 cd Na(4) saturated solution, dry over MgSO4,
Evaporate to dryness under reduced pressure.

Yield: 3.8611 (74.7%) Homophenylalanine hydrochloride J Med, C
b@m, 1968, 11, 1258-1262.

5 (1/part water, 2.8# above hydrochloride is mixed with trimethylamine and the solution is neutralized to pH 7-8.

25 in which 3.121i t@rt-butoxyl dissolved nyl anhydride, (B oc ) 2Q s in advance.
The dioxane is then slowly added at about 30-40°C and the mixture is stirred at RT overnight. The resulting solution is diluted with water and washed twice with ether.

Add Ac0Et and gradually bring the - of the aqueous phase to about 2-3 by adding 6N H2BO3. After three extractions with Aeolt, the organic phase is dried over Na5O4 and concentrated.

The amorphous solid of IJ' is collected and precipitated into hexane.

4341R9 Boe-8ta-OMe 5d TFA
at 0°C and the mixture was stirred at 0°C for 20 minutes.

After concentration at RT and reduced pressure, the oily residue is extracted by successive additions of ether and concentration. Add 15Ml of cH2ct2 to the white solid residue thus obtained, - to 7 with NMM, 309.5In9 DCCI, 229.5m9 HO
Boa-Hph obtained before Bt and 419rn9
*HC1 is then added. 7) Stir the mixture at RT for 72 h.

Insoluble substances are poured into hot water, and methylene chloride leakage is sequentially treated with Na.
CL saturated solution, 1% solution of KHSO3, water, NaHCO
Wash with a 1% solution of 3 and water. After drying and concentration, 900~
An oil tablet residue of 100% is obtained, which is chromatographed on finely divided silica using AeOEt. 230 rv of an amorphous solid precipitated in hexane are obtained.

Boc-Ala-St obtained in step 1 of 182■
Add a-OMe to 4d TFA at 0 °C; mix at 0 °C
Stir for 30 minutes and then concentrate excess TFA. The oily residue is successively extracted by addition and concentration of anhydrous ether. A white residue remains, add 1017 of CH2Cl2,
-7KL in NMM, then HOBt of 76.5 Da,
Add 103.2 μ of DCCI and 220 μ of the product obtained in step 4. Turn on the air (7) and stir the mixture at RT for 72 h.

The insoluble material was filtered off and the concentrated material was sequentially dissolved in NaCl saturated solution,
Wash with a 1% solution of KHSO3, water, a 1% solution of NaHCO3 and water. After dry concentration, 364 ml of oily residue is obtained, which is chromatographed on AcOEt K finely divided silica. 190 μm of an amorphous white solid is obtained. This is a mixture of isomers.

The product obtained in the previous step of 170Iv was added to 3d TFA.
C. and after stirring for 30 minutes at 0.degree. C., the excess TFA is concentrated and the oily residue is extracted by successive additions and condensations of anhydrous ether. Add 1Qd of CH2Cl2 to the resulting white residue and adjust - to 7 with NMM to give 96.6 mg of Boa -
Add Phe-ONp and HOBt of 38.31R9. Adjust the volume to 7 and stir the mixture at RT for 120 h.

This solution was diluted with CH2Cl2 and the organic phase was sequentially diluted with NaC2.
solution, 1% solution of KHSO3, water, 1% of NaHCOs
Wash with solution and water. After dry concentration, 300 q of residue are collected and chromatographed on fine silica in AaOEt/M@OH, 9/1 volume basis.

Amorphous white solid in the form of a mixture of isomers with respect to Hph 17
You will get 0 da.

NMR Spectrum Example 8 (SR43061) This material was prepared from the following histidine protected by 2 Bee groups, 1 an amine group and the other histidine telenitrogen.

1. Bi5(Boa)Hls-Sta-OMe
3.71 Bog-8ta-OMe is reacted with 15m TFA for 20 minutes between 0<0>C and +5<0>C. Concentrate the mixture, remove the concentrate three times with anhydrous ether, and concentrate the mixture to a minimum volume. Add the obtained TFA salt to 1,501,111 ca2ct and K and cool to 7 using DIPEA. Bls- in the form of DCHA salt of 6.6JF
Add Bee-Hlg, set - to 7 with DIPEiA, and turn to 6
．． 311 Bop is added and the mixture is stirred at RT and pH 7 for 3 days. Wash with aqueous sodium chloride solution, aqueous bicarbonate solution and then water, dry and concentrate. Chromatograph on silica with AeOEt as eluent and collect a white powder of 7.81i.

The product IIi obtained in the previous step, anhydrous DMF of 10- and methyl iodide of 5d are heated under mild reflux. 48h
After standing, concentrate using a vacuum pump. The concentrate is taken up with anhydrous ether to give a yellow gum which hardens in AaOEt and solidifies in anhydrous water. Dry with a leakage gun. Add the solidified portion and concentrated mother liquor to 20jlj(Z)TFA, treat three times with anhydrous ether and concentrate to minimum volume. The resulting TFA salt was dissolved in 251E/CH2 (4,
Set it to 7 with M. 724.519 Bee-Phe-
ONp and 299 da HOBt are added and the mixture is stirred at R'r for 4 days.

Wash with aqueous sodium chloride solution, aqueous bicarbonate solution and then water, dry and concentrate. Chromatograph on silica and A
Elute with c0Et/MeOH, 8/2 vol., and collect the bipolar portion which solidifies in anhydrous ether. 6
A product of 39tIg is obtained.

Starting from 300fflf, 13g of MeOH, 21L/
of water and 167 In9 of hydrated barium hydroxide are added, followed by saponification with 84.9 In of water barium hydroxide after 1 h. TLC shows the ester has disappeared.

Add small pieces of solid carbon dioxide until the - drops to 7, strain the mixture over Celite, rinse the material on the filter with methanol and concentrate the leakage. The residue was taken up with a minimum amount of warm MeOH, the mixture was filtered and the filtrate was concentrated to 2481n9.
A white powder is obtained.

The compound obtained in the previous step was converted into Bee-Ala by the above method.
-Sta -Couples with OM@.

NMR spectrum example 9 Boa-Phs-(tauMs)Hls-8ta-A
la-8ta-OMa (8R43062) 1゜(tauMe) Hls -OHt-J, RsN*
'th e, Chem*Soe,, 1978, 97
, 293-295.

4.5j' of dihydrochloride of the above product
M of OH and the solution was heated to 10-15 °C with Hct gas.
Saturate at 72°C and stir at 72°C. Concentrate to dryness and take up the residue twice with ether and then with acetone.

It crystallizes and 4I crystals are separated.

508 g of the above product are placed in 251 L/CH, CL and sifted by addition of DIPEA. 772 da B
Add oa-Phe-ONp and 306II HOBt.

After stirring for 2 days at RT, the mixture is washed with ice-cold water and concentrated to dryness. Chromatography on silica and AeOE
The expected product 849IR9 is recovered by elution with a t/MeOH mixture, 9/1 volume basis.

4. Boa-Phe-(tauMe)H1m768
The above product of Part I is dissolved in 33 d of MeOH and 5 d of water and 561 ml of barium hydroxide is added. After 1 h, 280 IR9 barium hydroxide is added and the mixture is stirred for a further 1 h. Small pieces of solid carbon dioxide are added until the temperature drops to -7, the mixture is filtered over Celite, and the filtrate is concentrated. The concentrate is taken up with MeOH, a small amount of cine-soluble material is filtered off, and the filtrate is concentrated. Take up the concentrate in ether and filter the mixture to obtain the white product 634rn905, H-Sta-Ala-8ta-OMe, T
FA this is 1301! #9 Boa-Sta-Al
Prepared as described in Example 1 from a-Sta-OMa.

6. Bee-Phe-(tauMe)Hls-
8ta-Ala-8ta-OM・゛Put the previously obtained TFA salt into lQd cH, ct and DI
Add PEA to make the voice 7. 124In9 Bop and 104Da of the product obtained in step 4 are added, followed by 3- anhydrous DMF and the mixture is stirred at pH 7 for 72 h. Wash with aqueous sodium chloride solution, dilute bicarbonate solution and water, dry and concentrate.

The concentrate is chromatographed on silica by elution with an AcOEt/MeOH mixture, 9/1 volume basis, K. A portion of 80 cm of white product is isolated.

NMR Spectrum Example 10 Me N-Boe-(2-alpha-cyclohexyl)glycine is prepared from L-alpha-phenyl 7-lysine by catalytic hydrogenation over Adams catalyst (pto□). 5R
The method described above continues to produce 43091.

Example 11 Bionate 489 diethylacetamide malonate was dissolved in EtOH3
00j! /Add 11 J'lC of sodium chloride solution and heat under reflux, 36. F a-chloro-methylpyridine hydrochloride is added and the mixture is kept under reflux for 5 h. Et
Evaporate the OH, take up the residue with water, extract the mixture,
The extract is dried, concentrated and chromatographed on silica.

By elution with a CH2Ct2/AcoE mixture, 60/40 volume basis, K) the expected compound 23!1 is obtained.

1! The diester before 1 mL of 200-5N H under reflux
Heat in C1 for 5 h. The mixture was concentrated to dryness and diluted with EtOH.
and evaporate the mixture. This process is repeated until the dihydrochloride is recrystallized. 15!10 Dissolve the dihydrochloride before 11i in an equal mixture of water and dioxane. 350 I49 of sodium hydroxide and 20 of III (Bee) are added and the mixture is stirred with BT overnight. The dioxane is evaporated, water is added, the medium is neutralized with 8II Amberly) CG1201 (acid form), stirred for 1 h at RT and transferred to a column containing the same resin. Elution is carried out with distilled water until the number reaches 5, and then with a 4% solution of Annex in distilled water. Concentrate the eluate.

The expected product of 0.691i is recovered.

A mixture of 465 mg Sta-OM@, TFA and 5001 v Boc-(Pyr-3) Alt was stirred in the presence of 7801119 Boa in 10 d acetone for 3 days at RT, and the medium was reduced by the addition of DIPEA. Maintain pH 7.

The mixture was then evaporated to dryness, water was added and the mixture was evaporated to AeO
Extract with Et and wash the extract with Na2CO3, water, aqueous solution of sodium chloride, dry over MgSO4 and evaporate to dryness. The residue was mixed with CH2C22/Ac0Et mixture, 1/9
When chromatographed on silica gel on a volumetric basis, the following are eluted in sequence:

The less polar A isomer: 150rn9 - the more polar B isomer = 1801n9 The expected compound is obtained in pure isomeric form from the B isomer by conventional coupling methods.

tTMR Suiktor The following compounds were prepared using the same coupling method.

These substances are characterized by their NMR spectra.

NMR spectrum of SR42928 NMR spectrum of SR42939 NMR spectrum of SR42980 NMR spectrum of SR43075 NMR spectrum of SR43266 NMR spectrum of FiR43281 NMR spectrum of SR゛43297 NMR spectrum of SR43365 NMR spectrum of SR I3391 SR4336 NMR spectrum of SR43428 (2 Isomer Near/
3) NMR spectrum of SR43554 NMR spectrum of SR43556 NMR spectrum of SR43761 The substance of this invention was investigated for its therapeutic properties, especially its inhibitory effect on enzymes. "in
Evaluation was made using "Vitro".

The results are superior to those obtained with the natural substance, ibustatin.

■One method for evaluation is the presence of a substance under study at a concentration that increases inhibition of PRA.A renin-rich human plasma pool (1 incubate at 37°C for 60 minutes) in a phosphate buffer of 7.4 mm (per milliliter and time) angiotensin released, anglotensin 1
GUYENE (
J a C1in, Endoerinol *M@
tab*.

Based on the method of 1976.43, 13011.

Human plasma contains the substrate angiotensin R and the enzyme renin released during the reaction.
radioimmunoassay using Ravanol or Lanoplasma Renin Kit (A CA333553).
). A converting enzyme inhibitor, phenyl dimethylsulfonyl fluoride (PMSFI), is added to the culture medium. The total culture volume is 555 microliters and is divided as follows.

-420 microliters of human Cilasmar 11-50
Substances to be considered in various concentrations of microliters - 119 - 80 microliters of phosphate) each 5 microliters of PMSF Methanolic solution of acetic acid [19/1, by volume] and methanolic solution of sodium hydroxide Adjust [μ, volume standard]. A mixture of equal volumes of these two solutions, o, ooIM
- Prepare a stock solution of <7°. Subsequent dilution of the peptide takes place in the phosphate nozzle.

0, OOOIM The amount of solvent present in the solution of lower concentrations of eftide does not interfere with the results.
The results obtained for the various substances of the invention are given in the following Table CI
). It shows an IC5o value for inhibition of human plasma renin activity at pH 7.4. This IC.

Show value. 5-10 doses are required to define this IC5o value. Pepstatin, used as reference substance, is always tested in parallel in each experiment. The results are expressed as logarithm values [-lIC5°].

Table I The toxicity of the substances according to the invention is satisfactory for their therapeutic use.

Claims (1)

[Claims] (1) Peptide derivatives: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, -R_1 represents an acyl group selected from the following groups: alkylcarbonyl group, alkoxy carbonyl group, arylcarbonyl group, arylalkylcarbonyl group, arylalkoxycarbonyl group, heterocyclic carbonyl group, heterocyclic alkylcarbonyl group, in which the alkyl group may optionally be a hydroxyl group, heterocyclic carbonylalkylcarbonyl group, heterocyclic group Represents an alkyl group optionally substituted with an alkenylcarbonyl group or a cycloalkylcarbonyl group, or an alkyl group substituted with a free amino group or an amino group with a protecting group, or a phenyl group, or unsubstituted (lower alkyl)
It represents a sulfonyl group, or a phenylsulfonyl group in which the phenyl nucleus is substituted or unsubstituted with a lower alkyl group. -R_2 represents a lower alkyl group substituted or unsubstituted with a phenyl group, a naphthyl group, a cyclohexyl group, or a pyridyl group, or R_2 is a phenyl group,
Represents a naphthyl group, a cyclohexyl group, or a pyridyl group. -R_3 is a 5- or 6-membered monomer substituted or unsubstituted with hydrogen, a lower alkenyl group, a phenyl group, a naphthyl group, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkyl group, or a trifluoromethyl group. A carbamoyl group or a free carbamoyl group which represents a cyclic heterocyclic group or is substituted with one or two lower alkyl or phenyl groups by a carboxyl group esterified with a di(lower alkyl)amino group or a lower alkyl or benzyl group. , a lower alkoxy or benzyloxy group, a pyridylmethoxy group, (
5- or 6-membered monocyclic heterocycles with lower alkyl)sulfinyl or (lower alkyl)sulfonyl groups, substituted or unsubstituted with cycloalkyl groups having 3 to 6 carbon atoms, or with lower alkyl or trifluoromethyl groups; Represents a lower alkyl group substituted with a ring group. However, R_3 is not an (imidazol-4-yl)methyl group. -R_4 represents a hydroxyl group, a lower alkoxy group, a pendyloxy group, a free amino group, or an amino group substituted with one or two lower alkyl groups. -Z_1 represents isopropyl, phenyl, or cyclohexyl, each of the following groups: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ together with the residues of the amino acid statin, i.e. (3S, 4S)
-4-amino-3-hydroxy-6-methylheptanoic acid residue, (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) residue, (3
S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA). -X-Y is A1a-Sta, Ala-Leu, Leu
-Phe, Va1-Sta, Abu-Sta, I1e-
It is a dipeptide selected from the group consisting of Ser and Phg-Sta. ] and pharmaceutically acceptable salts of mineral acids, organic acids, alkali metals, and alkaline earth metals of the peptide. (2) The peptide derivative according to claim 1, wherein R_1 represents any of the following groups, or a pharmaceutically acceptable salt of a mineral acid, an organic acid, an alkali metal, or an alkaline earth metal of the peptide. ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where a = 0, 1
or2 ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where n = 0, 1
, 2, 3, 4, 5 or 6 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, where D = ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ And n = 1 , 2, 3, 4 or 5 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, where E = -Hor-CH_3 and a = 1, 2, 3 or 4 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, where n = 0 , 1, 2, 3, 4, 5 or6 ▲, etc. There are formulas, chemical formulas, tables, etc. ▼ ▲ ▼ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ formula, chemical formula, tables, etc. ▼ NH_2ch_2ch_2-2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2ch_2 SO_2- ASO_2-, where A is a lower alkyl group C6H5-(CH_2)a-SO_2-, where a=0
, 1or2, (3) The peptide derivative according to claim 1, wherein R1 is selected from the following groups. -isovaleryl, -4-(pyridin-2-yl)-4-oxobutyryl, -4-(pyridin-2-yl)-4-hydroxybutyryl, -3-(pyridin-3-yl)propionyl, -4- (
pyridin-3-yl)butyryl, -ecotinoyl and -benzenesulfonyl. (4) The residue -NH-CH(R_3)-CO- is (tau
Peptide derivative according to claim 1, which represents a Me)-Hia residue. (5) Formula: H-Y-R' [In the formula, R_4' is lower alkoxy, benzyloxy,
A free amino group or an amino group substituted with 1 or 2 lower alkyl, Y is an amino acid, Sta, Leu, P
[selected from he and Ser residues], various amino acids or fragments of the amino acid sequences are coupled stepwise with appropriate protection, and the The products are decoupled by known methods before being subjected to further coupling, each coupling operation being carried out using an activated ester of the coupling amino acid or an N-protected amino acid in the presence of dicyclohexylcarpodiimide. , where appropriate, saponifying the resulting compound to form a peptide of formula (I) with R_4=OH, and/or, where appropriate, saponifying the resulting peptide with its mineral, organic or alkali acid. A method for producing a peptide derivative according to claim 1, which comprises converting the peptide derivative into - of a pharmaceutically acceptable salt of a metal or an alkaline earth metal. (6) A pharmaceutical composition containing the substance according to claim 1 as an active ingredient. (7) Claim 6 containing 1-1000 mg of the substance claimed in Claim 1 per dosage unit, mixed with a pharmaceutical excipient, which can be used in particular for the treatment of intra-arterial pressure. Pharmaceutical composition.