JPS6348252A - Renin-inhibiting di- and tripeptides and manufacture - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION European Patent No. A-152,255, No. A-155
, No. 809, No. A-164237, No. A-1B-172.34tS, No. A-172,547 and No. A-179.352, each of which describes Disclosed are their uses.

It has now been discovered that new peptyl-r derivatives are extremely active inhibitors of the enzyme renin in vitro and in vivo.

The present invention relates to compounds of the formula (wherein, R1 is al) absent or represents hydrogen, C2) hydroxyl, (01-C7)-alkoxy, (01-C7)
)-alkanoyloxy, carboxyl, (c, ~C7
)-alkoxycarbonyl, (C1-cB)-alkanoyloxy, chlorine, bromine, amino, (01-C7)-alkylamino, di(C1-c7)-alkylamino,
(C1-C3)-alkoxycarbonylamino or ha(
optionally substituted with 1, 2 or 3 same or different groups selected from the group consisting of -aralkyloxycarbonylamino (01-Ct1)
20)-represents alkyl or (Cg~c6)-
Cycloalkyl, (Cs-C5)-cycloalkyl-(
C1-Cl0)-alkyl, or optionally fluorine, chlorine, AX, hydroxyl, (
Substituted with one or two identical or different groups selected from the group consisting of 01-Cy)-alkoxy, (C1-C7)-alkyl, (01-C7)-alkoxycarbonyl, amino or trifluoromethyl was done (06
~C14)-aryl-(C1-c6)-alkyl, or C3) formula ■ Ra-W-(I ) (wherein, W is -CO-1-0-CO-, -802
- or -Nn-co-, and x''h hydrogen,
optionally has one or two unsaturated bonds, and optionally has proxyl, (C1-C7)-alkoxy, (01-C7)-alkanoyloxy, carboxyl S (at-C7)- Alkoxycarbonyl, chlorine, bromine, amino, (C1-c7)-alkylamino, di(
Up to three selected from the group consisting of C1-C7)-alkylamino, (01-C3)-alkoxycarbonylamino, (C7-C15)-aralkoxycarbonylamino and 9-fluorenylmethoxycarbonylamino polysubstituted with the same or different groups (01-C1o)
-alkyl or (C3-c6)-cycloalkyl, (C3-C3)-cycloalkyl-(c1-
Cd)-alkyl, optionally fluorine, chlorine, bromine, iodine, hydroxyl, (01-C7)-alkoxy, (C1
~C7)-alkyl, (C1-C7)-alkoxycarbonyl, amino, optionally one or two selected from the group consisting of anilino and trifluoromethyl polysubstituted with up to two halogenos. ((4-C14)-aryl substituted by the same or different radicals or optionally in the aryl moiety υfluorine, chlorine, bromine, iodine, hydroxyl, (C1-C7)-alkoxy, (C1-C7) )-alkyl, (01-07)-alkoxycarbonyl, amino, (01-C7)-alkylamino, di(C1-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7
)-alkyl, (C1-c7)-alkylamino-(C
1-c7)-alkyl, di(C1-c7)-alkylamino-(01-C7)-alkyl, (C1-c7)-
polysubstituted with one or two identical or different groups selected from the group consisting of alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (C1-C7)-alkoxysulfonyl, sulfo- and guanidinomethyl (Cs-C14 )-aryl-(01-C6)-alkyl, or at least one carbon atom, 1
~4 nitrogen atoms and/or 1 sulfur atom contain an oxygen atom as a ring atom, and optionally the above a
2) Mono-, di- or tri-substituted 5-membered or 6-membered as defined for (06-C14)-aryl
represents a group of a monocyclic or 9- or 10-membered bicyclic aromatic heterocyclic compound, and R4 represents a group of the formula ■ -X-(CH2)n/ -R7(IV) [wherein the formula During,
X is absent or represents oxygen or sulfur; n
' may be 0.1.2.3 or 4, and R
7 represents hydrogen, hydroxyl, amine or partially or fully hydrogenated heteroaryl (heteroaryl represents a group of an aromatic heterocyclic compound as defined in a3 above); or -CH-(CH2)p-Y-(CH2)q-Rlo(V
l) (In the formula, R9 is hydrogen, (01-C7)-alkyl, Mataha hydroxyl, (01-c5)-alkoxy, (01-C5)-alkylthio, carboxyl, (
01-C3)-alkoxycarbonyl, fluorine, chlorine, bromine, iodine, (01-C5)-alkylamino, di(c
.

-Cs) -fulkylamino, (01-c5)-alkoxycarbonylamino or (C7-Ct5)-aralkoxycarbonylamino monosubstituted (C1-
c7)-alkyl, R10 represents hydroxyl or amino, Y represents absent H or -CH-, p and q each independently represent 0.1.2.6 or 4 H" represents a group of or differently, 0.
1.2.3 or 4, and R5 and R6 are the same or different, phenyl, 2- or 3-chenyl, 2
-13- or 4-pyridyl, 1-12- or 4-imidazolyl, 1- or 2-naphthyl, 2- or 3-
[b) chenyl, hydroxylmataha represents hydrogen], or b2) phenylalanine, histidine, tyrosine, tryptonine, methionine, leucine, isoleucine, asnogragin, asno'? U'f acid, β-2-f enylalanine, β-3
-f enylalanine, β-2-71J lualanine, β-
3-7 Lylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxyP12-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohe26- Xylglycine, 1m-methylhistidine, 0-methyltyrosine, 0-penzyldyrosine, 0-tert-butyltyrosine, phenylglycine, 1-naphthylalanine, 2-
naphthylalanine, 4-nitrophenylalanine, β-
2-pen/[b) F-enylalanine, β-3-benzo[b) chenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, norleucine, cysteine, 8-methylcysteine, 1. 2.5.4-Tetrahyr-lysoquinoline-3-carboxylic acid, homophenylalanine, DOPA
.

o-di)f-Y-A, 2-7minor 4-<2-chenyl)butyric acid, 2-amino-4-(3-chenyl)butyric acid, g-
(2-chenyl)serine, / /I/ HaIJn, (Z
)-7'hyPlophenylalanine and (g) --j
The N-terminus of an amino acid selected from the group consisting of hypophenylalanine is bonded to R1, and the C-
Represents a group whose terminal is bonded to B, Btib2
), or R4 represents a group of an amino acid as defined in formula represents a group of the defined aromatic heterocyclic compound] or represents a group of the above formula (■);
A and B are the same or different, and - of the groups A and B:
lj: an amino acid selected from the group consisting of β-2-chenylalanine, β-3-chenylalanine, β-2-benz[b]chenylalanine and β-3-penz[b]chenylalanine and the other is as defined under b 2') above) and their physiologically acceptable salts.

The carbon atoms substituted by R2, hydroxyl and R5 have the RlS or R15-configuration, respectively.

Alkyl may be straight chain or branched.

The same applies to groups derived therefrom, such as alkoxy, alkylthio, alkylamino, dialkylamino, alkanoyl and aralkyl.

Cycloalkyl includes an alkyl-substituted group such as 4
-Methylcyclohexyl or 2,3-dimethylcyclohexyl is understood to be included.

Examples of (06-C14)-aryl are phenyl, naphthyl, biphenylyl or fluorenyl, preferably phenyl. The same applies to the groups derived therefrom, such as aryloxy, aroyl, aralkyl and aralkyloxy. Aralkyls are (C1-C6
unsubstituted or substituted (au~C14)-aryl bonded to )-alkyl, for example benzyl, α- and β-naphthylmethyl, halopencyl and plucoxybenzyl, Aralkyl is not limited to the above groups.

5- or 6-membered monocyclic or 9- or 10-membered bicyclic ring containing at least 1 carbon atom, 1 to 4 nitrogen atoms and/or 1 sulfur or oxygen atom For example, the group of an aromatic heterocyclic compound has a force) +
7tsky, Labowski, Chemistry of Heterocyclic Compounds J (K
by atri-tzky, Lagowskir Che
mistry of Heterocyclic Com
pounds J) Berlin, Heidelberg, 196
It is understood that the radicals of aromatic heterocycles as defined in 1998, pages 3 to 5 are included.

The groups of aromatic heterocyclic compounds are fluorine, chlorine, bromine, hyproxyl, (C1-C7)-alkoxy, (C1-C7)-
substituted by one, two or three, preferably one or two, identical or different groups selected from the group consisting of alkyl, (C1-C7)-alkoxycarbonyl, amine or trifluoromethyl; You can leave it there. Examples of monocyclic aromatic heterocyclic compounds are thiophene, furan, virol, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2.4-) lyazole, thiazole, tetrazole, inthiazole,
These are oxazole and isoxazole. Examples of bicyclic aromatic heterocycles are benzothiophene, benzofuran, indole, isoinrol, imidazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline and cinnoline.

The same applies to groups derived from heteroaryl, such as fully or partially hydrogenated heteroaryl, heteroaryloxy, heteroaryl and heteroarylaryl.

The amino acids A and B of formula I are linked together by an amyl bond and are natural or synthetic σ-amino acids of the L, D or ILL configuration, preferably of the L configuration. The same applies to amino acids or their derivatives as group R4.

Salts of the compounds of formula (1) are understood to be particularly pharmaceutically useful or non-toxic salts.

These types of salts are suitable, for example, for compounds of the formula 1 containing acid groups such as carboxyl and alkali metals or alkaline earth metals such as sodium, potassium, magnesium and calcium, and physiologically acceptable organic amines such as triethylamine. and tri(2-hydroxyethyl)amine.

Compounds of formula I containing basic groups, such as amino or guanidino groups, are suitable for use in salts with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, and organic carboxylic or sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, etc. Forms salts with the acids fumaric acid, tartaric acid or p-)luenesulfonic acid.

Preferred compounds of formula I are those where the radicals are defined as follows.

R1 is preferably absent or represents hydrogen or (01-C1o)-alkyl, cyclopentyl, cyclohexyl, cyclopentyl-(C1-C1o)-alkyl, cyclohexyl-(01-C10)-alkyl,
optionally substituted phenyl-(01-C3)-alkyl, H2N-(C1-Cl0)-alkyl, [0-
(01-C1o)-alkyl, (01-C4)-flukoxy-(01-C1o)-alkyl, (C1-C4)
-Alkoxycarbonyl-(C1-C1o)-alkyl, carboxy-((4-C1o)-alkyl e.g. 2
-hyroxypro♂onyl or 2-hyproxy3-
Methylzotyryl, (01-C9)-alkanoyloxy-(01-C1o)-alkyl, (01-C11)-alkanoyl such as n-decanoyl, formyl, acetyl, 2paroyl, isovaleryl or isoquinoline, optionally protected amino -(C2-C11)-Alkanoyl such as 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert-zotoxycarbonylaminoptyryl, 5-N-tert-hydroxycarbonylaminopentanoyl or 6-N-tert-butoxycarbonylaminohexanoyl, di(C1-c7)
-alkylamino-(02-C11)-alkanoyl such as dimethylaminoacetyl, (04-C9)-cycloalkylcarbonyl such as cycloalkylcarbonyl, cycloditylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl, (06-Cl0)
-Aryl-(02-C11)-alkanoyl such as phenylacetyl, phenylpropanoyl or phenylcitanoyl, 2-C2,6-dichloroanilino)phenylacetyl, 2-(N-benzyl-2,6-dichloroanilino) Phenylacetyl, optionally/Smouthyy,
(Ct-C7)-furkyl, (01-C7)-flucoximata is benzoyl substituted by (01-C7)-alkoxycarbonyl, such as 4-chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxybenzoyl , 2-pyrrolylcarbonyl, 3-pyridylcarbonyl, benzenesulfonyl, (01-C1o) -alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, di-substituted by /10rn *(
C1-C1o) -Alkoxycarbonyl such as 2.
2.2-) dichloroethoxycarboel or 1.1
-dimethyl-2,2,2-trichloroethoxycarbonyl, (04-C14)-aryl-(C1-C6)-alkoxycarbonyl, such as benzyloxycarbonyl or 9-fluorenylmethylcarbonyl.

R2 is preferably isobutyl, benzyl or cyclohexylmethyl.

R5 is preferably hydrogen, isozorobyl or isobutyl.

R4 is preferably as defined above, but %H
10 represents amino or optionally substituted heteroaryl as defined above but having 1 or 2 nitrogen atoms.

R5 and R6 are the same or different, preferably haphenyl, 2-4enyl% 2-hyridyl, 1-su7tyl, 2-benzo[b'')chenyl, 3-pen/(b]
f represents enyl, hyproquine or hydrogen, and n
', p and q preferably represent 0 or 1.
□ Preferred amino acids suitable for groups A and B are phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, aspartic acid-thienylalanine, β-5-f enylalanine, lysine, ornithine, 2,4-diaminobutyric acid, arginine,
4-chlorophenylalanine, methionine sulfone, methionine sulfoxy) + 112-pyridylalanine, 3
-Pyridylalanine, cyclohexylalanine, cyclohexylclycine, 1m-methylhistidine, 0-methyltyrosine, 0-benzyltyrosine, 0-tert-butyltyrosine, phenylglycine, 1-naphthylalanine, 2
- Naphthylalanine, 4-nitrophenylalanine, norleucine, fucillin, alanine, 1.2.3.4
-Nato2hydroisoquinoline-5-tJ Rubongan, homophenylalanine, 2-amino-4-(2-chenyl)
butyric acid, (Z)-dehydrophenylalanine, nornoline, β-2-7lylalanine, or (m)-dehydrophenylalanine. Furthermore, A is preferably the above b
Represents the group 2) as described in 1).

The present invention also relates to a process for the preparation of compounds of formula (1), which involves coupling a fragment having a terminal carboxyl group or a reactive derivative thereof with a suitable fragment having a free amino group and, if appropriate, other It consists of removing the protective group or groups temporarily introduced to protect the functional groups and, if appropriate, converting the compound obtained into its physiologically tolerable salt.

Fragments of the compound of formula (1) having a terminal carboxyl group have the following formulas (1) a to (2) d.

R1-OH (■a) R1-A-OH (■b) R1-A-B-OH (■0) Seven fragments of the compound of formula I having a terminal amino group are represented by the following formulas ■a to ■d. have

NH2-R8(■d) Suitable methods for producing the amide bond include, for example, Ho
uben - Mr. Wey1 rMethoden der
OrganischenChemie (Methods of Organic Chemistry) Volume 15/2, rPe by Mr. Bodanszky et al.
Ptide 5 synthesis J 2nd edition (Wiley Ann R. Sons, New York, 1976)
Or Gross, Meienhofer rT
he Peptides.

Analysis, 5 synthesis, biolog
yJ (Academic Press, New York, 197
(published in 1999). The following methods are active ester methods using N-hydroxysuccinimide as the ester component, coupling with carbodiimides such as dicyclohexylcarbodiimide P, or propanephosphonic anhydride, and mixed acid anhydride using piperoyl chloride. The physical method is preferably used.

The optically active amine of the formula OH used as a starting compound, in which R2, R3 and R4 are as defined above, is prepared starting from an optically active amino acid; In this case, the asymmetric center is preserved. For this purpose, an N-protected aldehyde of an amino acid is prepared by known methods, coupled to a suitable heteroarylalkyl synthon by al-P-ru-like addition, and after removal of the N-protecting group, the formula of amino alcohol is obtained. A mixture of diastereomeric compounds in the OH-bearing center is obtained and separated by methods known per se, such as fractional crystallization or chromatography. The purity of diastereomers can be determined by high performance liquid chromatography (HPLC), and the purity of mirror isomers can be determined by conversion to Mosher derivatives by known methods [H, S, Mo5her et al. “J.

Org, Chem, J Vol. 34, p. 2543 (19
1969)].

The N-protected aldehyde of the amino acid was prepared using the method of Mr. Picastro et al.
sisJ, p. 676 (1985)].

N-protected aldehydes of amino acids (preferably N-
Aldol-like additions to tertiary butoxycarbonyl and penzyloxycarbonyl protecting groups are performed in base-inert solvents such as ether, tetrahydrofuran, toluene, dimethylformamide, dimethylsulfoxide or dimethoxyethane. It will be held in

Bases that can be used to deprotonate the heteroarylalkyl moiety include alkali metal alcoholates such as potassium tertiaryzotylate and sodium methylate, alkali metal hydrides such as sodium or potassium hydride, organometallic bases such as n - butyllithium, secondary dithyllithium, methyllithium or phenyllithium, sodium amine)% and alkali metal salts of organic nitrogen bases such as lithium diisopropylaminium P.

The substituted 4-amino-3-hydroxybutyric acid contained in the compound of the general formula (1) according to the present invention (wherein R4 is defined as a group of the formula (2)) is known in the literature, as described by Ashi, D. H., et al. Method CD, H, R1eh et al. r J
, Org, Chem, J Vol. 43, p. 3624 (197
8 years)].

The diamine of formula V (wherein Y is not present) is prepared starting from an optically active α-amino acid;
In that case their asymmetric centers are preserved. The reaction of converting a protected amino acid to a nitrile via amyl is known in the literature, and the subsequent reaction to give the amine can be carried out using a catalyst, for example using Raney nickel in a suitable hydrogen stream.

H The diamines of the formula ■ (wherein Y is -C'H-) can be prepared by the aldol-like addition of, for example, nitromethane, from the N-protected aldehyde of the amino acid, followed by the addition of, for example, a transition metal catalyst, such as Raney nickel. obtained by catalytic hydrogenation in the presence of

Formula V by converting into a Mosher derivative by known methods
It is also possible to check the enantiomeric purity of diamines with . The above and the following operations necessary for preparing the compounds of formula I, such as the introduction and removal of protecting groups, are known in the literature, for example from Tieda Pruegreen, Protecting Groups in Organic Synthesis J (T, W, , “Protective Groups in Or” by Mr. Greene.
ga, nic 5 synthesis J). The salts of compounds 2) having a salt-forming group can be prepared by methods known per se, for example by reacting a compound of formula I having a basic group with a stoichiometric amount of a suitable acid. Ru.

The mixture of stereoisomers, especially the diastereomers obtained when using racemic 72-noic acid A or B, is
The separation can be carried out in a manner known per se, for example by fractional crystallization or chromatography.

The compounds of formula I according to the invention have enzyme inhibitory action.

In particular, they inhibit the action of the natural enzyme renin. Renin is a proteolytic enzyme belonging to the group of asnoglutyl proteases and is secreted into the blood circulation from the paraglobular cells of the kidney in response to various stimuli (volume loss, sodium deprivation, β-receptor stimulation). It removes angiotensin 1, a decapeptide from angiotensinone, which is then excreted by the liver.

Angiotensin 1 is angiotensin converting enzyme (AC)
! E) is converted to cyangiotensin 2. Since angiotensin 2 directly increases blood pressure by constricting blood vessels, it plays an essential role in the regulation of blood pressure. Furthermore, it stimulates the secretion of aldosterone from the adrenal glands and in this way inhibits sodium excretion, thereby increasing the volume of extracellular fluid and thereby increasing blood pressure. Enzyme activity inhibitors of renin reduce the production of angiotensin 1 and, as a result, the production of angiotensin 2. Reducing the concentration of this active peptide hormone is directly responsible for the blood pressure lowering effect of renin inhibitors.

The activity of renin inhibitors can be determined by in vitro tests. These are accompanied by a decrease in anzeotensin 1 production, which is measured in various systems (human plasma, renin from pigs). For this, for example, human plasma, which contains both renin and angiotensinon r, is incubated at 37° C. with the compound to be tested. A radioimmunoassay is then used to measure the concentration of aniotensin 1 produced during the incubation. The compounds of the general formula I described in the present invention have approximately 10-5 to 1
It exhibits an inhibitory effect at a concentration of o-10 mad/l.

Renin inhibitors cause a decrease in blood pressure in salt-deprived animals. Because human renin is different from renin in other species, primates (Arnus macaques, Bengal delus) are used for in vivo testing of renin inhibitors. Primate renin and human renin are substantially the same in their sequence order. Endogenous renin release is stimulated by intravenous injection of furosemide. Test compounds are then administered by continuous infusion and their effects on blood pressure and heart rate are measured.

Compounds of the invention tested approximately 0.01 to 5.41 in this test.
．． It is active at dosages in the range of v. The compounds of general formula (2) described in this invention can be used as antihypertensive agents and for treating heart failure.

The invention therefore also relates to the use of compounds of formula I as pharmaceuticals and to pharmaceutical products containing these compounds. Preferably, it is administered to primates, especially humans.

The pharmaceutical product contains an effective amount of the active compound of formula (1) together with inorganic or organic pharmaceutically useful excipients. Administration can be intranasal, intravenous, subcutaneous, or orally. The amount of active compound administered depends on the species of warm-blooded animal, body weight, age and method of administration.

The pharmaceutical products of the invention can be prepared by dissolving, mixing,
Manufactured by granulation or tablet coating operations.

For forms for oral administration, the active compound is mixed with the additives customary for this purpose, such as excipients, stabilizers or inert diluents, and formulated in the usual manner into the appropriate dosage form. For example, tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or solutions. Examples of inert excipients that can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially corn starch. This formulation can be used both as dry and wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil and fish liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts may be dissolved or suspended together with the substances normally used for this purpose, such as solubilizers, emulsifiers or other auxiliaries. to form a suspension or emulsion. Examples of suitable solvents are water, saline solutions or alcohols and evaporated ethanol, zolonozone diol or glycerol, and sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned above.

List of abbreviations used Ac Acetyl ACHPA [38,481-4-amino-3-hyP
Roxy 5-cyclohexylpentanoic acid BOC! 5th-butoxycarbonyl TLC thin layer chromatography DCC dicyclohexylcarbodiimide PDNP 2
．． 4-Dinitrophenyl I Dimethylformamide DM80 Dimethylsulfoxy P Otori Ethyl acetate Etoc Ethoxycarbonyl FA3 Fast atom bombardment H Hexane HOBt 1-Hydroxypenztriazole Iv
a Isovaleryl M Molecular peak MeOH methanol M8 Mass spectrum MTB Methyl tertiary f-thyl ether R,T,
Room temperature m, p Melting point Sta [38,481-4-amino-3-hyproxy-6-methylhebutanoic acid Thi])-]2-chenylalanine'rHF
Other abbreviations used for 2ndyloxycarbonyl amino acids are those commonly used in peptiP chemistry, such as yourrapzeipiochem (rEu
rop, J, Biochem, J) Volume 138, No. 9~
The three-letter code P listed on page 37 (1984)
corresponds to Unless otherwise specified, amino acids are always L-
Has an arrangement.

For example, the rlRJ designation in rIle-NH2J represents an amiP bond in which the carbonyl group is replaced by a methylene group.

EXAMPLES In order to better understand the present invention, examples will be described below, but the present invention is not limited thereto.

Reference Example 1 Boa-Phe-Hls-ACHPA-Leu --N
Boc-Phe-Hi dissolved in H2 methanol 10-
Hydrogenation is carried out under atmospheric pressure using 501 kg of radium-activated carbon (10%) using s -ACHPA-Leu -NH780Q as a catalyst. After being kept at room temperature for 6 hours, the catalyst is removed by passing through diatomaceous earth. The filtrate is concentrated and lyophilized to give a colorless powder.

Rf=(EA/methanol 1:1)=Q, 15
;M8(FAB):698(M+1) a) Boc-Phe-Hls-ACHPA-Leu
-Boc-Phe-Hl in NHzDMF 51114
s(DNP)-AC! HPA-Leu-NH22501
1P is stirred with 7.1 m/-L of thio, 5d at room temperature for 6 hours. The mixture is concentrated under vacuum and the residue is incubated three times with diisopropyl ether. Chromatography on silica gel (mobile phase ethyl acetate/methanol 15:1) and concentration of the 7-lactone containing the product give a colorless powder.

Rf (EV methanol 5: 1) = 0.5; M8
(F'AB): 832 (M+1) b) Boa-Phe-Hls(DNP)-ACHPA
-Leu -NHz Boa in methylene chloride 10d
-Phe-H1s(DNP)-OH192W, Viridi:
/ ? i 0 Ill and N-ethylpiperidine 50
Add 44 μl of Piparoylchlori P to μ/μl at -5°C.

The mixture was stirred for 30 minutes at +5 to +10 °C and
Cool to ℃, and methylene chloride! H in '5yLl
-ACHPA-Leu-NH216Ep9 is added dropwise.

The mixture is stirred for 16 hours without cooling, concentrated under vacuum and the residue is dissolved in 100 d of ethyl acetate. The solution is extracted three times with aqueous potassium carbonate solution and once with water, dried over sodium sulfate and concentrated under vacuum. Chromatography on silica dal (mobile phase ethyl acetate/methanol io:i) gives the title compound as a pale yellow powder.

Rf (EV meta/-r 10:1)=0.5;M
S (FAB): 998 (M+1) c) H-ACHPA-Leu -NHzBOC-AC
Dissolve 200 mg of HPA-Leu-NHz in 5 dK of dioxane. While cooling slightly (+10'C), 12% hydrochloric acid in dioxane is added.

After being kept at room temperature for 3 hours, the mixture was concentrated under vacuum, the residue was dissolved in water, the solution was adjusted to -9 to 10 using saturated aqueous carbonate solution, and acetic acid was added. Extract three times with ethyl. Dry with sodium sulfate,
and concentrated under vacuum to give the above title compound,
It can be used in the coupling step of the knife without further purification.

d) Boc-Phe-Hls(DNP)-OH The above title compound was prepared by the active ester method.
-N-8ue and H-Hta(pNp)-oH. (r J, Amer, C!hem, 8o
c, J Vol. 86, p. 1839 (1954)] e) Boc-ACHPA-OH250 in Boa-ACHPA-Leu-NHz TetrahyP Lofuran 10-
If CrJ, Med, chem, J Volume 28, No. 177
9 (1985)] and HOBt 160"f are added dropwise at 0° C. DCC 180 Wv dissolved in tetrahydrofuran 5-. After holding for 1 hour without cooling, tetrahydrofuran 1
Add H-Leu 279 # in 0 d at 0°C. After 16 hours at room temperature, the mixture is filtered, the filtrate is concentrated and the residue is dissolved in ethyl acetate. This solution was treated twice with saturated aqueous sodium carbonate solution.
Then extract once with water. After drying with IJ sulfuric acid, the solution is concentrated. Chromatography on silica silica (mobile phase ethyl acetate/n-hexane 2:1) gives the title compound as a colorless powder.

Rf (EA/n-hexane) = 0.7; MS (FAB
): 548(M+1) f) H-Leu NHz In the same manner as in Reference Example 1 c), Boc-Leu −
Starting from NHz 350 If, the above title compound is obtained as an oil, which is used for the next coupling without further purification.

g) Boc-Leu -NHz Boc-Leu dissolved in dimethylformamyl
-AmiP600 and zo-succinimide 695
Stir IF for 16 hours at room temperature. The mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, and the solution is dissolved twice with saturated aqueous sodium chloride solution, twice with saturated aqueous potassium hydrogen sulfate solution, and twice with saturated aqueous sodium chloride solution. Extract once. Concentration under vacuum affords the above title compound as a colorless oil, which is used further without further purification.

Rf (KA) = 0.8; MS (FAB): 551
(M+1)h,) BoC-Leu-Amyr Boa-Leu -=Tolyl 2.8 f Cr J, A
mer, Chem.

Soc, J Vol. 88, p. 2033 (1966)] was added to dilute ammoniacal methanol
Raney nickel pretreated in 4 (pretreatment/treatment = (1) thoroughly washed with water, (2) heated with decalin, and separated by decantation, (3) suspended in methanol, and decanted) (separate well) and hydrogenate for 2 hours at room temperature. After filtration and concentration in vacuo, the aqueous 2N<- is adjusted to 2 using citric acid and the mixture is extracted three times with methylene chloride. The aqueous phase is adjusted to pH 8-9 with aqueous 2N sodium hydroxide solution and then extracted six more times with methylene chloride P. The combined organic extracts are washed once with water, dried over sodium sulfate, and concentrated. This pale yellow oil can be used in the next reaction without further purification.

Rf (methanol/1% ammonia) = 0.6MS:
217(M+1) Example 1 Etoc-Thi-Hls-ACHPA-11e -N
H2Etoc-Thi-Hls-ACHPA-11e
280 ml of -NHz are dissolved in 31 L of a solution of 33% strength hydrobromic acid in glacial acetic acid and the solution is stirred for 3 hours at room temperature.

50 d of saturated aqueous carbonic acid) are added, the mixture is extracted twice with 50 d each of ethyl acetate, and the organic phase is dried over sodium sulfate. Silica dal chromatography (methanol) gives the above title compound as a colorless oil.

Rf (methanol) = 0.08, MS (FAB): 6
76(M+1)a) gtoc-Thi-Hls-A
CHPA-11e” NHzEtoc-Thi-Hl
s-(DNP)-ACHPA-11e fi NHz
Reaction of 475 da with thiophenol analogously to reference example 1 a) gives the above title compound.

R1-(Elv Buddha 0)(8:1)=0.20;M
S(FAB) :810(M+1)b) Etoc-
Thi-Hls(DNP)-ACHPA-fle-N
HzBoC-Hls(DNP)-ACHPA(le-
NHz 380 W is dissolved in dioxane 2- and an iso-compound of dioxane and concentrated hydrochloric acid 9- is added. The mixture was stirred at room temperature for 3 hours, the dioxane was removed in vacuo, the residue was dissolved in ethyl acetate 50 m/saturated aqueous sodium bicarbonate, and the aqueous phase was dissolved in ethyl acetate 50 m/saturated aqueous sodium bicarbonate.
-Extract twice. The organic phase is dried over sodium sulfate and concentrated under vacuum. The residue was diluted with 5I of tetrahydrofuran! / and dissolve the sono solution in l'i,t,oc
'-Thi-OH104W, 1) CC97■Ohage HO
Stir with Bt86■ at room temperature for 15 hours. The dicyclohexyl urea is removed by evaporation, the filtrate is concentrated under vacuum, and the residue is dissolved in 50+ tons of acetic acid. The solution is extracted twice with 50° of saturated aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate and concentrated under vacuum. The above title compound is obtained as a yellow oil, which is reacted without further purification.

Rf(EA/MeOH5: 1) −[1,61c)
Boa-Hls-(DNP)-AC! HPA-11e
-NHz "Boc- in methylene chloride 100-
Hls(DNP)-om t3at, pyricin 0.
26 Wtl o! Hee N-! tilhyheridine o, j6-
Add 0.37 WLl of pivaloyl chloride at 5°C. The mixture was stirred for 30 minutes at +5° to +10°C and −10°C.
℃ and H-A in methylene chloride 50d.
C! Add HPA-11e-NHz132f dropwise. The mixture is stirred for 16 hours without cooling, concentrated under vacuum and the residue is dissolved in 30011 tl of ethyl acetate. This solution was extracted once with 100% of potassium carbonate solution and once with 100% of water, dried over sodium sulfate,
and concentrate under vacuum. Chromatography on silica gel (mobile phase methyl tert-butyl ether) gives the title compound as a pale yellow powder.

Rf (MTB) m0.1; MS (FAB): 8
51 (M+1)d) H-AC'HPA-11s
-NH2Boc-ACHPA-11e -NHz 1.
5 Of is dissolved in dioxane 25-. 12% hydrochloric acid 55% in dioxane is added at 0°C. After 4 hours at room temperature, the mixture was concentrated in vacuo, the residue was dissolved in water, adjusted to 9-10 using saturated aqueous carbonate solution, and the solution was dissolved in acetic acid. ethyl 1
Extract 3 times with 00 pieces. Drying over sodium sulfate and concentration under vacuum affords the title compound above, which can be used in the next coupling step without further purification.

e) Boc-AC'HPA-O in 10CIIj of tetrahydrofuran with 1,8t of DCC dissolved in 50-NHZ tetrahydrofuran
H2,5f CrJ, Med, chem, J Vol. 28, p. 1779 (1985)] and 1-hydroxybenzotriazole 1.
61 dropwise at 0°C. After holding for 1 hour without cooling, H-11e − in tetrahydrofuran 100 −
2.8 t of NHz are added at 0° C. After 16 hours at room temperature, the mixture is stirred, the p solution is concentrated and the residue is dissolved in 100 d of ethyl acetate. This solution is diluted with 5 t of sodium carbonate solution. 〇- twice, and 50 water
- Extract once.

It is dried with sulfuric acid), concentrated under vacuum,
The residue is then subjected to chromatography on silica gel (mobile phase ethyl acetate/n-hexane 1:1). The above title compound is obtained as a colorless powder.

Rf (Etv'n-hexane 1:1) m0.2
; Ms(FAB): 54B(M+1) f) H-11e -NHz Boc-IIs -NH2 in the same manner as in Example 1 d)
Starting from 3,5t, the above title compound is obtained as a foam, which is used for the next coupling without further purification.

g) Boc-11e -NHz Boc-Il dissolved in dimethylformamide ¥100d
e -NH26,Of and 2-0-Sakushinimi P6
．． 9t is stirred at room temperature for 16 hours. After concentration in vacuo, the residue is dissolved in 100 d of ethyl acetate and the solution is diluted with 100 ml of saturated aqueous potassium bisulfate solution.
Extract times. Drying over sodium sulfate and concentration under vacuum affords the above title compound as a colorless oil, which is used without further purification.

Rf (EA) = α8; MS (FAB): 351
(M+1)h) Boc-11e -NH2 Boc-L-2-amino-3-methylvaleronitrile 2
B, Of [rJ, Amer, Chem, 5o
88, p. 2033 (1966)] in 1 part dilute ammonia in methanol,
Using pretreated nickel (treatment: (1) thoroughly washed with water, (2) heated with decalin and separated by decantation, (3) suspended in methanol and separated by decantation) and hydrogenate for 2 hours at room temperature. After heating and concentrating under vacuum, the residue is dissolved in 500 ml of ethyl acetate and the solution is extracted three times with 200 d of 5% aqueous hydrogen sulfate solution. The aqueous phase is adjusted to 90% with 2N hydroxide solution and extracted three times with 200 m66 of ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. This pale yellow oil can be reacted further without further purification.

Rf (MeOVl 96a/monia) = α6; M8:2
17(M+1) The compounds of Examples 2 to 4 are prepared in the same manner as in Example 1.

Example 2 Iva-Thi-Hls-ACHPA-11e-NH
4Br(E~'MeOH1:1)=0.1; M
s(FAB): 688 (M+1) Example 3 Etoc-Thi-Hls-ACHPA-Leu -N
H4Br(MeOH)=0.08; Ms(FAB)
: 676(M+1) Example 4 Iva-Thi-Hls-ACHPA-Leu-NH
4Br (Bv horse OH1: 1) = 0.1; Ms (F
AB): 688 (M+1) Example 5 Iva-Phe-Hls-1(8)-cyclohexylmethyl-2(8),4-dihyroxybutylamide P Iva-Phe-Hls(DNP
)-Cyclohexylmethyl-2(8),4-dihyroxybutylamide 310 is reacted with thiophenol to give the above title compound.

Rf (acetonitrile/water 10:1) = 0.20
:Ms(FAB) :570(M+1) a) Iva-Phe-Hls(DNP) -1(8)
-Cyclohexylmethyl-2(8),4-dihydroxyditylamide
Phe-Hls(DNP)-0H657 da and 1(S
)-Cyclohexylmethyl-2(8), 360 μl of 4-dihyP-roxybutylamine is coupled with piparoyl chloride.

Rf(EAAleOH102 1 )=o, 45;
Ms(FAB): 736(M+1) 1))1(8)-cyclohexylmethyl-2(8),4
-Dihydroxyzotylamine Reference Example 1 Similarly to c), N-Boc-1(S)-cyclohexylmethyl-2(S), 4-dihydroxyditylamine was prepared from 620 Da using hydrochloric acid/dioxane. Remove protecting group.

Rf(Moon) = o, 13 c) N-Boc-1(8)-cyclohexylmethyl-
2(8),4-di,hydroxy! BoC-ACHPA-O in thylaminetetrahyP lofuran 50d
Et1. Of [rJ, Med, chem, J 2nd
8, p. 1779 (1985)] was added in small portions at 0° C. under argon, a total amount of 0.17 F lithium aluminum hydride, and the mixture was stirred at room temperature for 2 hours. 0.9 of potassium hydrogen sulfate in 20 g of water was added dropwise, the tetrahydrofuran was removed under vacuum, and the residue was dissolved in methylene chloride)2O
Extract 3 times with WLl each.

After drying over sodium sulfate and concentration under vacuum, chromatography of the residue on silica dal (mobile phase MTB/cyclohexane 1:1) gives the above title compound as colorless crystals.

m, ]) -777 to 79 °C f (MIIIB/cyclohexane 1:1) = Q,
11; Ms(FAB): 302(M+1) (1) Iva-Phe-Hls(DNP)-OH The above title compound was prepared using the active ester method (rJ, Amer.

Chem, 8oc, J Vol. 86, p. 1839 (196
4)] yo F) Iva-Phe-ON8uc
and H-His(DNP)-OH.

Example 6 fva-Phe-Hls -1(8)-Cyclohexylmethyl-2(R,8)-hyproxy3-(2-pyridyl)propylamide Reference Example 1 Iva-Phe- H1
sΦNP)-1(s)-cyclohexylmethyl-2(R
,8)-HyProxy 3-(2-pyridyl)propylamide P380■ is reacted with thiophenol to give the above-mentioned title compound.

Rf (to E/methanol 5:1) = 0.15;
Me (FAB): 617 (M+1) a) Engineering va-Phe-His (DNP)-1 (8)-
cyclohexylmethyl-2(R,8)-hydroxy-3
-(2-Pyridyl)propylaminerIva-Phe-Hls(DNP)-OH61 group and 1(S)-cyclohexylmethyl-2(R,8)-hydroxy-3-(2-pyridyl)propylamine 300■
Biparoylchlori P was prepared in the same manner as in Example 1 b).
The above title compound is obtained by reaction according to the method.

Rf(E~θtanolio: 1) = [], 3
;Me(FAB)・;783(M+1) b) 1(S)-Cyclohexylmethyl-2(R,8
)-Hyproxy3-(2-pyridyl)propylamine Reference Example 1c) Analogously to BOC-[1(8)
Reaction of 400 μl of -cyclohexylmethyl-2(R,8)-hyproxy3-(2-pyridyl)]propylamine with dioxane/hydrochloric acid gives the above title compound.

c) Boc[1(8)-cyclohexylmethyl-2(
R,8) -Hydroxy-3-(2-pyridyl)]furobylaminetetrahyrofuran 20- to 2-methylpyridine 2d dissolved in n-butyllithium (151 in hexane) 13
Add d at -30°C. The mixture was stirred for 1 hour without cooling, then B in 25 tIll of tetrahydrofuran.
oc-cyclohexylalaninal 2.55f at 10℃
Add dropwise.

Then immediately add 10 d of water. The mixture was extracted three times with ethyl acetate, the extract was dried over sodium sulfate,
and concentrate under vacuum. Chromatography on silica dal (mobile phase EA/n-hexane 1:1) gives the diastereomers of the title compound separately as yellowish oils. (This applies to all similar embodiments).

Rf (EAy' n -hexane) = 0.15 (polar diastereomer) MS:! 149(M+1) Example 7 Iva-Phe-Hls-1(8)-cyclohexylmethyl-2(R,8)-hyProxy3-(1-methylimidazol-2-yl)propylamine P Reference Example 1a) Similarly, Iva-Phe-Hl
s(DNP)-1(S)-cyclohexylmethyl-2
(8)-Heats 3- roxy 3-(1-methylimidazol-2-yl)
Reaction of i-rolamide 328 W9 with thiophenol provides the title compound above.

Rr (acetone/water 10:1)=0.05;M
S(FAB): 620(M+1) a) Iva-Phe-Hls(DNP) -1(s)
Iva-Phe-
Hl 5(DNP)-OH717 and 1(S)-cyclohexylmethyl-2(S)-hydroxy6-(1
-methylimidazol-2-yl)propylamine 62
5■ is coupled with piparoyl chloride.

Rf (acetonitrile/water 8:1) = α11; MS
(FAB) Near 86 (M+1) b) 1(S)-cyclohexylmethyl-2(R,S)-
hirroxy3-(1-methyliotasol-2-yl)propylamine 4(S)-cyclohexylmethyl-5-(1-methylimidazol-2-yl-methyl)-1,3-oxazolidine-゛2- On 790 ■ 2N lithium hydroxide in methanol/water 1:1 331! / and heated the solution under reflux for 3 hours, then 150ff of water! and extracted three times with 50 methylene chloride. Drying over sodium sulfate and concentration under vacuum affords the above title compound as a colorless oil, which is used for further purification.

Rf(Ryadan eOH) = 0.11 c) 4(s)-cyclohexylmethyl-5-(R,s
) -(1-methylimidazol-2-yl-methyl)
-1,5-oxazolidin-2-one dissolved in tetrahyplofuran 70-*1.2-dimethylimidazole3.
21.5W11 of a 1.6 M n-butyllithium solution in hexane is added dropwise to 23t at -40°C. 40 at 0℃
After stirring for a minute, z-cyclohexylalaninal 4.51 f [rs
Synthesis J, page 676 (1983)] is added dropwise at -30°C. The reaction mixture is allowed to warm to room temperature and is stirred into 100 ml of saturated aqueous sodium bicarbonate solution. The tetrahydrofuran is removed under vacuum and the aqueous phase is extracted three times with 100 d of ethyl acetate. (M'rBAeOH 9:1
) to give the above title compound as a colorless oil.

Rf (MTB/MeOH8: 1) = 0.17
; Me (FAB): 278 (M+1) 270 M
'H NMR spectra measured at Hz demonstrated that the above title compound was entirely consistent with the displayed structure.

The compounds of Examples 8 to 12 are prepared in the same manner as in Example 1.

Example 8 Boc-Pha-Hls-ACHPA-11e-NH
2Rf(EIVMeOH1: 1)=0.2; M
S(FAB): 698(M+1) Example 9 Iva-Thi-Cys(Me)-ACHPA(le
-NH2Rf (acetyl/H2010: 1) = 0.
1;Me(FAB):66B(M+1) Example 10 Ac-3-(1-naphthyl)-alanyl-Hls-
AcHPA-Ile-MHz Rf(MeOH/'H2010: 1) = 0.1
; MS (FAB): 690 (M+1) Example
11 7 l- 2-(8)-Phe-Hia
-ACHPA-11e -MHz Rf (acetone/H2os:1)=o, 1;Ms(
FAB): sy.

(M+1)・Example 12 2-Hirroxy5-(1-naphthyl)frozeo-Rue Hls-ACHPA-IIs-NF(2Rf(acetone/H205: 1)=0.1:MS(FAB
): 649(M+1) 2-hydroxy-3-(1-naphthyl)zolopionic acid is r J, Agric, Chem, Soc, Japan
J Vol. 19, p. 39.43 (1945).

Example 13 Etoc-Phe-)11g-1(s)-cyclohexylmethyl-2(R,J)-hydroxyProxy3-(4,4
-dimethyloxazolin-2-yl)propylamide P Reference Example 1 Etoc-Phe-Hl
s(DNP)-1(S)-cyclohexylmethyl-2-
HyProxy5- (4,4-dimethyloxazoline-
Reaction of 2-yl)propylamide F'' with thiophenol provides the title compound above.

Rf (acedratrile/water 10:1) 0.2: MS
(FAB) :625(M+1) a) Etoc-Phe-Hls(DNP) -1(s
)-Cyclohexylmethyl-2(R,8)-hyProxy3-(·4,4-dimethyloxazolin-2-yl)
Propylamide Example 1Boc-His(DNp) as in b)
-1(s)-cyclohexylmethyl-2-hydroxy-
3-(4,4-dimethyloxazolin-2-yl)propylamide 490■ Etoc -Phe 1<S9#
react with.

Rf(IM/MsOH10:1)=0.4; M
e (FAB) Near 89 (M+1) b) Boe4is
(DNP) -1(s)-cyclohexylmethyl-2(
BOC-1(8)-cyclohexylmethyl-2-hydroxy- 3-(4,4-dimethyloxazolin-2-yl)propylamine P 260 I
f is reacted with Boc-Hls(DNP)=OR299 cape.

Rf(EA)=Q,! l;MS(FAB): 6
70 (M+1)c) Boc=1 (8)-cyclohexylmethyl-2(R,S)-hydroxy-3-(
4,4-dimethyloxazolin-2-yl)propylamide Meyers [Mr. Meyers r J, Org, Ch
Boc-cyclohexylalaninal 1.4f was converted to 2.4.4-)dimethyloxazoline 1 as described by Em.
．． React with 4-. The two diastereomers are 1:1
It is obtained by the ratio of

D 1: Rf (MTB//i, :/propyl ether 1:1) = o, 15; M8: 369 (M+1) D2: P, f (MTB/i) propyl x-fl 1
: 1) == 0.10; MS: 369 (M+
1) Dl is further processed to prepare the title compound of Example 13.

Compounds of Examples 14 and 15 are prepared similarly to Example 13.

Example 14 Etoc-Phe-Hls -1(S)-cyclohexylmethyl-2(R,S)-hydroxy-3-[4(S,
8)-Sect-butyl-oxazolin-2-yl]zolopyramide Rf (acetonitrile/water 10:1) = 0.3
;MS(EA3):+553(M+1) Example 15 Iva-Thi-His-1(8)-cyclohexylmethyl-2(R,8)-hydroxy-3-C4(s,s
)-2f-thyl-oxazolin-2-yl]propylamide R (acetonitrile/water 10:1) = 0.2
; Ms(FAB): 671 (M+1) The oxazoline used in Examples 14 and 15 is obtained as follows.

a) 4(8,8)-2F thyl-2-methyloxazoline 2-acetylamino-3-methylpentanol 15F
was dissolved in methylene chloride 200°C and heated to 0°C under argon.
And thionylchlori? Add 3.5 txJ and stir the mixture at 0° C. for 3 hours. The reaction solution is poured into 200 ml of saturated aqueous sodium carbonate solution, and the mixture is extracted three times with 100 ml of ethyl acetate. Drying over sodium sulfate and concentration under vacuum affords the above title compound and bis(2-acetylamino-3-methylpentyl) sulfite, which can be converted to the above title compound by heating at 110° C. in toluene. It can also be converted to .

Rf (MTB/A7ton 10:1) = 0.3;
Me: 142(M+1')b) 2-acetylamino-3-methylpentanol Ac-IIs-OMe 2
2.4 t are dissolved in 200 d of tetrahydroffuran, 8.9 t of lithium aluminum hydride are added at 0° C. and the mixture is stirred at 0° C. for 1 hour. Approximately 90 g of the tetrahydrofuran is removed under vacuum, 100 g of aqueous potassium bisulfate are added, and the mixture is extracted three times with 200 g of ethyl acetate. Drying over sodium sulfate and concentration under vacuum followed by chromatography on silica gel (mobile phase MTB/acetone 10:1) gives the title compound as a colorless oil.

Rf (MTB/7 set 710: 1) = Q, 1;
M8:16o(M+1) Example 16 Iva-Thi-Hla-1(8)-cyclohexylmethyl-2(R,8) -Ya+C4-C4-(8
,8)-Sect-butyloxazolin-2-yl)f tylaminr Similarly to Reference Examples 1 a) and 1 b),
1(8)-cyclohexylmethyl-2(s)-hydroxy-4-(4(8,8)-sec-butyl-oxazoline-
2-yl)butylamine 260 cape is attached to the N-terminal di(putide).

Rf (7cetonitrile/water 10:1)=0.2
; Me(FAB): 1585 (M+1) a) 1(S)-cyclohexylmethyl-2(R,S)
-Hydroxy-4-(4(s,s)-sec-notyloxazolin-2-yl)butylamine 3-Boa-4(B
)-cyclohexylmethyl-2,2-cy)thyl-5(S
)-C2-(4(B,8)-sec-butyl-oxazolin-2-yl)ethyl]oxazolidine 570η is protected from the protecting group and reacted further without purification.

b)! l -BOC-4(8)-cyclohexylmethyl-2,2-dimethyl-s (R,8) -C2-(4
(8,8)-Sect-butyloxazolin-2-yl)ethyl]oxazolidine 4 (8,8)-Sect-zotyl-2-methyloxazoline 3.76 f and N,N,N',N'-tetramethylethylenediamine 4.0 is dissolved in 100 of tetrahyrofuran and at -78 DEG C. 14.9 d of a 1.6 M solution of n-zotyllithium in hexane are added dropwise. The mixture was stirred at this temperature for 30 minutes and then 3-Boc-4(8)-cyclohexylmethyl-2,2-dimethyl-5(R,8) in 10 wLl of tetrahypfuran
-m-Tomethyloxazolidine i, 15f is added dropwise.

The reaction solution is stirred for 1 hour at room temperature, poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted three times with ethyl acetate. After drying over sodium sulphate and concentration under vacuum, chromatography on silica gel (mobile phase MTB/diisozorobyl ether 1:1) is carried out. The above title compound is obtained as a colorless oil.

Rf (1 in MTB/diisopropyl ether); α6;
M8 (FAB): 451 (M+1)c) 3-
Boc-4(8)-silaelhexylmethyl-2.2
-dimethyl-5(R,8)-iodomethyloxa'
Sylysine Boc-2-cyclohexyl-1(8)-oxira8
61-2 (R,8)-ylethylamine 2.4f, sodium iodine 1.3t and trimethylsilyl chloride 1. Dissolve i gJ in 100 d of acetonitrile and stir the solution for 1.5 hours at room temperature. Next, tetrabutylammonium fluoro-P in tetrahy-P rofuran
8.7 d of a 1M solution of and 5.5 d of dimethoxyethane
inject. The mixture was stirred at room temperature for 2.5 hours, then 200 d of saturated aqueous sodium bicarbonate solution was added and the mixture was dissolved in methyl tert-butyl ether.
Extract 3 times at 0-. After drying over sodium sulfate and concentration in vacuo, chromatography on silica gel (mobile phase MTB/diisoprolether 1:2) gives the title compound as a colorless oil.

Rf (MTB/diisopropyl ether 1:2)
=0.5;Me:422(M-CHg) d) Boc-2-SilaOhexyl-1(B)-oxirane-2(R,8)-ylethylamine Boc-1(8)-cyclohexylmethylprobar 2
-en-1-ylamine 2.6 f t-methylene chloride) '50 dIC dissolved and methylene chloride 50
1.9 f of m-chloroperbenzoic acid in d is added dropwise at 0°C. The reaction solution is stirred at room temperature for 66 hours and then extracted first with 5% aqueous sulfite solution (100 ml) and then with saturated aqueous carbonic acid solution (100 d). After drying over sodium sulfate and concentration in vacuo, chromatography on silica glu (mobile phase MTB/cyclohexane 1:1) affords the above title compound as a colorless oil, with diastereomeric ratios ranging from 3:1. 5:1
It is.

Mixture of diastereomers Rf (MTB/cyclohexane 1:1) = 0.4
; Me(FAB): 270 (M+1) e) BoC-1(8)-cyclohexylmethylprop-2-en-1-ylamine 5.4 t of methyltriphenylphosphonium bromide was suspended in 10011 J of tetrahydrofuran, and Al Potassium tertiary detylate 17f is added at room temperature under a tank. The mixture is stirred at room temperature for 2 hours, cooled to 0 DEG C. and 3.9 t of Boc-silalohexylalanyl in 50 tJ of tetrahydrofuran are added dropwise. The mixture is then stirred for 50 minutes at 0 DEG C., 100 g of water is added dropwise and the tetrahydrofuran is removed under vacuum. Add 100+4 of saturated aqueous sodium bicarbonate solution;
The mixture is then extracted three times with 100 d of methylene chloride. After drying over sodium sulfate and concentrating under vacuum, chromatography on silica glu (mobile phase MTB
/cyclohexane 1:3) to give the above title compound as a colorless oil.

Rf (MTB/cyclohexane 1:3)=0.4
:Me: 254 (M+1) The compounds of Examples 17 to 19 are produced in the same manner as Example 6.

Example 17 Iva-Phe-Hla-1(8)-cyclohexylmethyl-2(R,B)-hydroxy-3-(2-benzoxasilyl)brolamide Rf(EAAleOH5:1)=0.3;Me(
FAB)-657(M+1) Example 1B Iva-Pha-Hls-1(8)-cyclohexylmethyl-2-hyProxy 3-(4-zeridyl)-propylamide First diastereomer Rf (EA/ MeOH5: 1) = α2; M
e(FAB) = 617 (M+1) Example 19 Iva-Phe-Hls -1(S)-cyclohexylmethyl-2-hyProxy 3-(4-pyridyl)-propylami r Second diastereomer Rf(EA /M130H5: 1)=0.1;Me
(FAB)=617(M+1) Example 20 Iva-Phe-Hls-1(s)-cyclohexylmethyl-2(R,8)-hyproxy3-, aminopropylamide Similar to Reference Example 1 , Iva-Phe-H1s'
-1(S)-cyclohexylmethyl-2(R,S)-
Hydrogenate 100 Mg of HyProxy 3-benzyloxycarbonylaminopropyl amine.

Rf(MeOH)-0,1; M8=555 (M+
1) a) Iva-Phe-His-1(S)-cyclohexylmethyl-2(R,S)-hyproxy-3-benzyloxycarbonylaminopropylamine P Analogously to Reference Example La), Iva-Phe -Hl
5(DNP)-1(8)-cyclohexylmethyl-
2(R,8)-hyProxy 3-benzyloxycarbonylaminopropylamine P250 is reacted with thiophenol.

Rf (E ~ eOH) = 0.65; M8 = 689 (
M+1)b) Iva-Phe-Hls(DNP)
-1(s)-Cyclohexylmethyl-2(R,8)-hyProxy3-penzyloxycarbonylaminopyramiP The above title compound was prepared analogously to Reference Example 1 b) by Iva-Phe- Hls(DNP)-OH28
0If and 1 (1-cyclohexylmethyl-2(R
,8)-hyProxy-3-benzyloxycarbonylaminoprobylamine from 160 wg.

Rf(EA/MeOH10:1) -0,5; M
S(FAB) = 855 (M+1)c)1(8)
-Cyclohexylmethyl-2(R,-8)-hydroxy-3-benzyloxycarbonylaminoprobylamine The above title compound was prepared analogously to Reference Example 1 c).
It is prepared from 220 ml of Boc-1(8)-cyclohexylmethyl-3-benzyloxycarbonylaminoprobylamine and is used in its "crude" form for the next reaction step.

d) Boc-1(S)-cyclohexylmethyl-2'
(R,8)-hydroxy-3-benzyloxycarbo'
Nylaminopropylamine Example 1 Similarly to g), BCl3-'1 (8)
-cyclohexylmethyl-3-aminopropylamine 1
．． 5f is reacted with zo-succinimide 1.39.

Rf (toluene/EA2:1)=0. ! l ;
MS(FAB)=421(M+1).

e) Boc-1(S)-cyclohexylmethyl-2
(R,S)-hyProxy 3-aminopropylamine B
OC-1(8)-cyclohexylmethyl-2(R,8)
1.4 f of monohydroxy-3-nitropropylamine are hydrogenated in 100 d of ethanol/glacial acetic acid (10:1) using Raney nickel at 50° C. and 50 par for 6 hours. The catalyst is filtered off with suction, the KF solution is concentrated, the residue is dissolved in methylene chloride, and the solution is washed twice with saturated sodium carbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sulfuric acid and then evaporated, and the resulting oil is used for further purification in the next step.・Rf(MeOH) = α3 f) Boa -1'(8)-cyclohexylmethyl-
2(R,'8)-Hydroxy-3-nitropropylamine BOc-cyclohexylalaninal 5001v and tetramethylguanidine 25·da (approximately 0.1 mol)
Stir in 10°C of nitromethane at 0°C for 16 hours. The reaction solution is then concentrated and purified on silica gel using toluene/ethyl acetate 4:1 as eluent.

Rf (toluene/EA4: 1) = 0.25;
M8=316 Example 21 Etoc-Thi-Hls -1(S)-cyclohexylmethyl-'2(R,8)-hyproxy-3-aminopropylamide The above title compound was synthesized in the same manner as in Example 1. be done.

Example 22 Iva-Phe-Hls -1(S)'-cyclohexylmethyl-2(R,s)-hydroxy-4-(2-pylJdyl)butyramide The above title compound is similar to Reference Example 1 a) Then I
va-Phe-Hls(DNP)-1(s)-cyclohexylmethyl-2(R,S)-hydroxy-4-(2-
It is synthesized by reacting 400 m of pyridyl)butyramide with thiophenol. 'Rf(HA/
MeOH5: 1) = α15; Me(FAB)
=631 (M+1)a) Iva-Phe-Hl
s(DNP)-1(8)-cyclohexylmefk-2
(R,8)-Hi)'*l/-4-(2-pyridyl)butyramiP The above title compounds are based on Reference Examples 1 b) and 1 c
) in the same manner as Iva-Phe-Hls(DNP)-0
Manufactured from H552QF Oyohi Boe-1(S)-cyclohexylmethyl-2(currently 8)-hydroxy-4-(2-pyridyl)butylamine 400 If.

Rf (gA/MeOH10: 1) = 0-25 e
MB (FAB) ”797(M+1) b) BoC-1(8)-cyclohexylmethyl-2(
R, El) HyProxy 4-(2-pyridyl)butylamine Example 6 c) 220 μl of 2-picoline
c2 equivalent) is deprotonated. Next, 300 parts of BoC-2-cyclohexyl-1(s)-oxirane-2(R,S)-ylethylamine in tetrahydrofuran are added at -60°C. After 1 hour water is added and the mixture is extracted three times with ethyl acetate. sulfuric acid (organic phase)
Dry over IJum, then concentrate and isolate the above title compound by chromatography on silica gel using ethyl acetate/hexane 2:1 as eluent.

Rf(EIV′H2: 1) = O13; MB(F
AB)=365(M+1>Example 23 Iva-Phe-Hls-1(8)-cyclohexylmethyl-2(8)-hyproxy5-(2-pyridyl)
-Pentylamide The above title compound was prepared analogously to Reference Example 1 a).
Iva-Phe-Hls(DNP)-1(S)-cyclohexylmethyl-2(8)-hydroxy-5-(2-1
'lysyl) pentyl amine r 11oq is prepared by treating it with thiophenol.

R (acetonitrile/water 8:1)=O13:M
B(FAB)=645(M+1) a) Iva-Phe-Hls(DNP) -1(B)
-cyclohexylmethyl-2(S)nihiProxy5-
(2-pyridyl)-t! Iva-Phe-Hls(DNP)-OH
263W Oyohi 3-BoC-4 (8)-Cyclohexylmethyl-2,2-dimethyl-5-(3-(2-pyridyl)propyl)oxazolidine is synthesized from 200 μl.

Rf(EA/MeOH)=α4:MS(F'AB)=
811 (M+1)b) 3- Boc-4(8)-
Cyclohexylmethyl-2,2-dimethyl-5-(3-
(2-Pyridyl)zolopyl)oxazolidine 367μ of 2-picoline is deprotonated analogously to Example 6c). This deep red solution was added to 3-Boc-4(8)- in 10 d of tetrahydrofuran at -50 °C.
cyclohexylmethyl-2,2-dimethyl-5-(2-
Add 500 Da of oxazolidine (bromoethyl). 15
After a minute, water is added and the mixture is extracted three times with ethyl acetate.

The organic phase is dried with sulfuric acid), then concentrated,
It is then subjected to silica gel chromatography (eluent: toluene/ethyl acetate 3:1).

Rr (toluene/gA 3 : 1) = 0.25;
M8=417(M+1)c) 3-Boa-1(8
)-cyclohexylmethyl-2,2-dimethyl-5-(
3-Boa-1(2-bromoethyl)-oxazolidine methylene chloride in 15 Wtl
S)-cyclohexylmethyl-2,2-dimethyl-5-
(2-hydroxymethyl)oxazolidine <59019
,) Diethylazodicarboxylate 16- is added dropwise to liphenylphosphine 2.62 and pyridinium bromide t6f at 20° C. under argon. After 16 hours at room temperature, water is added and the mixture is diluted with methylene chloride 1004. The organic phase is washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried with sulfuric acid) and
Concentrate, dissolve the residue in a little ethyl acetate and remove triphenylphosphine tF. Purification on silica glu gives the above title compound (eluent: ≠A15
:1) Rr(IL/Koshiki 15:1)=0.3;Me 40
4(M)d) 3-Boc-1(8)-cyclohexylmethyl-2,2-dimethyl-5-(2-hydroxymethyl)oxazolidine Boc-ACHPA-OBt1 [1t, p=
) 500 μl of toluene sulfonic acid and 7.2 d of dimethoxypropane were added to toluene at 80° C. under argon in 60° C.
Time heating. This mixture is then concentrated. The residue is added dropwise at 0° C. to a suspension of 2f of lithium aluminum hydride in 200d of tetrahydrofuran.

After 2.5 hours at 0 DEG C., 100 ml of 5% sodium hydrogen sulfate solution is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution.

After drying with sodium sulfate, it is concentrated and chromatographed (eluent: HAA 2:1).

Rt (φA 4 : 1)=0.1; MS=34
2(M+1) Examples 24-27 are synthesized in the same manner as Example 23.

Example 24 -Iva-Phe-H1-1(s)-cyclohexylmethyl-2(S)-hydroxy-5-(4-pyridyl)-
Pentylamine P Rr (acetonitrile/water 10:1) = 0.1
; Ms=644 (M) Example 25 Iva-Phe-Hls -1(8)-cyclohexylmethyl-2(S)-hyproxy5- (4(8,8)
-2nd f tyloxazolin-2-yl)pentylamide Rf (acetonitrile/water 10:1) = 0.1
; M8(FAB) -i3(M+1) Example 26 Eva-Phe-H1a -i (8)-cyclohexylmethyl-2(8)-hydroxy-5-(2-ethyl-
4-pyridyl)pentylamide Rf (methylene chloride/methanol/acetic acid/water 80
:20:1:1)=0.5;M8(FAB):6
73(M+1) Example 27 Iva-Phe-Hls -1(S)-cyclohexylmethyl-2(8)-hydroxy-5-(4-ethyl-2
-pyridyl)pentylamide Rf (acetonitrile/water 10:1) = 0.3
;MEI(FAB):673(M+1) Example 28 Iva-Phe-Hlg-1(s)-cyclohexylmethyl-2(8)-hyProxy5-(4-piperidinyl)-pentylamine P The above title compound is , Reference Examples 1 and 1a) to 1c
) is prepared from Boc-1(8)-cyclohexylmethyl-2(S)-hyProxy5-(4-benzyloxycarbonylpiperidinyl)-(antylamide P).

Rf (acetonitrile/water 2:1)=13;M
S(FAB)=651(M+1) a) Boc-1(S)-cyclohexylmethyl-2(
8) -Hyroxy5(4-benzyloxycarbonylpiperidinyl)pentylamide P3-Boc-4(8)-cyclohexylmethyl-2
, 2-dimethyl-5-(3-(4-pyridyl)propyl)oxazolidine 265 Wfl is hydrogenated in 5° of ethanol using 5-tyrodium charcoal powder 4011 at 100° C. and 100 par for 3.5 hours.

The catalyst is then removed from the oven and the filtrate is concentrated.

Dissolve the residue in dimethylformamide (5-, 2-0-
160 mg of succinimr is added and the mixture is stirred at room temperature for 16 hours. It was concentrated and chromatographed on silica gel (eluent: HβA4:
Attached to 1).

Rf(HβA)=α4; MS=541 (M-OH
M) Example 29 Bis(1-7thylmethyl)acetyl-Hls-1(
8)-Cyclohexylmethyl-2(8)-hyproxy5-(2-ethyl-4-pyridyl)pentylamide The above title compound was prepared analogously to Reference Example 1 a) by preparing bis(1-naphthylmethyl)acetyl -Hls(I)NP
) -1(8) -cyclohexylmethyl-2(S)
-Produced by treating Roxy-5-(2-ethyl-4-pyridyl)intylamide P with thiophenol.

Rr (methylene chloride) 4/methanol/acetic acid/water 80
:20:1:1)-0,6;Me(FAB
)=764 (M+1)a) Bis-(1-naphthylmethyl)acetyl-Hls(DNP)-1(s)-cyclohexylmethyl-2(S)-hydroxy-5-(2-
Ethyl-4-pyridyl)pentylamine P The above title compound was prepared analogously to Example 1 b) by bis(
1-naphthylmethyl)acetic acid [rLiebLgsAnn,
J Vol. 468, p. 302] and Boa-Hls(DNP)-1(8)
-cyclohexylmethyl-2(8)-hyproxy5
Synthesized from -(2-ethyl-4-t'IJdyl)-pentylamine P.

Rf(E~%eOH10:1)=α5; Me(
FAB) = 930(M+1)b) Boc-Hl
s(DNP)-1(8)-cyclohexylmethyl-2
(8)-Hydroxy-5-(2-ethyl-4-pyridyl)intylamide The above title compound was prepared analogously to Reference Example 1 b).
oc-Hls(DNP)-0H and 1(s)-cyclohexylmethyl-2(S)-hyProxy5-(2
-ethyl-4-pyridyl)pentylamine, which is synthesized analogously to Reference Example 1c) and Example 23b).

Rf(3AAleOH10:1)=0.3; M
S(FAB)=708(M+1) Examples 30 and 31
The compound is prepared in the same manner as in Example 23.

Example 50 Etoc-Phe-Hls-1(S)-cyclobexylmethyl-2(S)-hyProxy5-(4,4-dimethyloxazolin-2-yl)hentylami)! Rf
(acetonitrile/water 10:1)=0.1;
Me(F'A3): 653 (M+1) Example 31 1va-Phe-Hls -1(S)-cyclohexylmethyl-2(S)-hydroxy-5-(4,5-dimethyloxazol-2-yl)pentylamide P Rf (EAAleOH5: 1) = 0.2; Me
(FAB): 663 (M+1) Patent applicant
Proceedings filed by two persons other than Beckist Akchengesellschaft September 7, 1988 Director General of the Patent Office Kunio Ogawa 1. Indication of the case 1987 Patent Application No. 187879 2. Title of the invention: Zee which inhibits renin and Tripeptides and their production methods 30. Relationship with the case of the person making the amendment Patent applicant Address: Frankfurt am Main, Federal Republic of Germany (no address) Name: Beckist Akziengesellschaft 4, Agent 5, Date of amendment order (voluntary) Contents of Z amendment 1) The scope of patent claims will be amended as shown in the attached sheet.

2) Add the following statement between the third and second lines from the bottom of page 23.

r R2 is hydrogen, (01-c1o)-alkyl, (04
~c7)-cycloalkyl, (04-c7)-cycloalkyl-(01-c4)-alkyl, (06-c14)
-7 Riru or (06-c14) -Ori-ru (01
~C4)-alkyl, R3 is hydrogen, (01~c1o)-alkyl, (06~c1o)-alkyl,
14) -oryl or (06-c14)-aryl-
Represents (C1-C4)-alkyl, Claims 1) Formula ■ (In the formula, R1 is al) is absent or represents hydrogen, C2) Hydroxyl, (c1-c' 7)-alkoxy, (01~
C7)-alkanoyloxy, carboxyl 1. (C
i-C7)-alkoxycarbonyl, (01-C3)-
Alkanoyloxy, chlorine, bromine, amino, (01-c
7)-alkylamino, di(01-C7)-alkyl/
optionally by 1, 2 or 6 identical or different groups selected from the group consisting of l/7mino, (01-c5)-alkoxycarbonylamino or (C7-, -011)-aralkyloxycarbonylamino represents a di-substituted (01-C20)-alkyl or (
C3~cB)-cycloalkyl, (03~CB)-cycloalkyl-(cl~C1,o), +alkyl, or optionally in its aryl moiety fluorine, chlorine,
Bromine, hydroxyl, (01-C7)-alkoxy, (
(01-c7)-disubstituted by one or two identical or anisotropic groups selected from the group consisting of alkyl, (01-c7)-alkoxycarbonyl, amine or trifluoromethyl; c14)-71 reel-(C
1 to cB)-alkyl, or C3) formula ■ Ra -w-(n) (in the Tatashi formula, W is -co-1-〇-C〇-1-so2
- or -NH-CO-, and Ra is hydrogen;
optionally having one or two unsaturated bonds and optionally hydroxyl, (01-C7)-alkoxy, (01-C7)-alkanoyloxy, carboxyl, (01-C7)-alkoxycarbonyl, chlorine, Bromine, amino, (c1-C7)-alkylamino, di(
Up to three selected from the group consisting of 01-C7)-alkylamino, (C, ~c5)-alkoxycarbonylamino, (c7-C15)-aralkoxycarbonylamino and 9-fluorenylmethoxycarbonylamino (01-C1o) disubstituted by the same or different groups of
-alkyl or (C3-c6)-cycloalkyl, (05-C3)-cycloalkyl-(01-
C6)-Alkyl, optionally fluorine, chlorine, bromine, iodine, hydroxyl, (01-C7)-alkoxy, (C1
~c7)-alkyl, (01-C7)-alkoxycarbonyl, amine, optionally one or two selected from the group consisting of anilino and trifluoromethyl di-substituted with up to two halogens. represents (Cs-C14)-aryl disubstituted by the same or different groups, or optionally in the aryl moiety, fluorine, chlorine, bromine, iodine, hydroxyl, (01-07)-alkoxy, ( 01-C7)-alkyl, (01-C7)-alkoxycarbonyl, amine, (01-C7)-alkylamino, di(01-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)
)-alkyl, (01-C7)-alkylamino-(0
1-C7)-alkyl, di(01-C7)-alkylamino-(01-C7)-alkyl, (01-C7)-
(Cs-C14)- substituted with one or two identical or different groups selected from the group consisting of alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (01-C7)-alkoxysulfonyl, sulfo- and guanidinomethyl represents aryl-(01-C6)-alkyl or at least one carbon atom, 1
~4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring atoms, and optionally the above a.
2) mono-, di- or tri-substituted 5- or 6-membered as defined for (06-c14)-aryl
represents a group of a monocyclic, 9- or 1o-membered bicyclic aromatic heterocyclic compound, represents (c1-C4)-alkyl, and R4 is of the formula -X-(CH2) GoR70V) [wherein X is absent or represents oxygen or sulfur, n' may be 0, 1.2, '5 or 4, and R7 is hydrogen, hydroxyl, amino or partially -CH-(CH2)p-Y- (CH2), -R10(■
) (wherein, R9 is hydrogen, (Ci-C7)-alkyl, or hydroxyl, (C1-C3)-alkoxy, (01-C3)-alkylthio, carboxyl, (C
1-C3)-alkoxycarbonyl, fluorine, chlorine, bromine, iodine, (01-C5)-alkylamino, di(01
~C3)-alkyl7mi/s (01~C3)-
Alkoxycarbonylamino or (C7=C1s)-
monosubstituted by aralkoxycarbonylamino (
01-C7)-alkyl, R10 represents hydroxyl or amino, Y represents absent H or -CH-, p and q are not zero) , and A is bl)2■a (wherein n and m are the same or different, and 0.
1.2.3 or 4, and R5 and R6 are the same or different, phenyl, 2- or 3-chenyl, 2
-16- or 4-pyridyl, 1-12- or 4-imidazolyl, 1- or 2-naphthyl, 2-0c is 3-
or b2) phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine,
Asparagine, aspartic acid, β-2-f enylalanine, β-3-chenylalanine, β-2-furylalanine, β-6-furylalanine, lysine, ornithine,
Valine, alanine, 2.4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone,
Methionine sulfoxyr, 2-pyridylalanine, 3-
' Lysylalanine, cyclohexylalanine, cyclohexylglycine, -methylhistidine, 0-methyltyrosine, 0-benzyltyrosine, 0-tert-butyltyrosine, phenylchrysine, 1-naphthylalanine, 2
-Naphthylalanine, 4-nitrophenylalanine, β
-2-penz [b] chenylalanine, β-6-denzo) [b] chenylalanine, 2-fluorophenylalanine, 6-fluorophenylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methylcis nine, 1.2.3.4-tetrahydroisoquinoline-6-carboxylic acid, homophenylalanine, DOPA
% O-dimethyl Y-noξ, 2-amino-4-(2-chenyl)butyric acid, 2-amino-4-(3-chenyl)butyric acid, 3-(2-chenyl)serine, norvaline, (Z)-
N of selected amino acids in the group consisting of dehydrophenylalanine and (E)-7"hydrophenylalanine
-terminus is bonded to R1, and its C-terminus is B
, B represents a group of amino acids as defined in b2), or R4 represents a group of formula V [wherein R8 is hydrogen, partially or completely hydrogen]; The added heteroaryl (heteroaryl represents a group of an aromatic heterocyclic compound defined in a3 above) or the group "represents the group 2) above", and A and B are the same or With different words, the groups A and B (
7) On the other hand, among the group consisting of 1'iβ-2-chenylalanine, β-3-chenylalanine, β-2-benzo[b]chenylalanine and β-3-benzo[b]chenylalanine, and the physiologically acceptable salts thereof; and the other is as defined under b2) above.

2) R1 is absent, represents hydrogen, or (0
1-C1o)-alkyl, cyclopentyl, cyclohexyl, cyclopen5-(C1-C1o)-alkyl, cyclohexyl-(01-C'1o)-alkyl, optionally substituted phenyl-(ci-C5)- Alkyl, H2N-'(01-Cl0)-alkyl, T
-10-CC1-Cl0)-alkyl, (Ci-C4)
-Alkoxy-(01~C1o) -7#*ru, (C1
~C4)-Alkoxycarbonyl-(01-C1o)-
alkyl, carboxy-(01-C1o)-alkyl,
Preferably, the 2-hydroxypropylbutyryl is 2-hydroxy-3-methylbutyryl or (01-C3)-
Compounds of formula 1 according to claim 1 and physiologically acceptable salts thereof, which represent alkanoyloxy-(01-c1o)-alkyl.

3) R1 is (C1-C11)-alkanoyl, preferably n-decanoyl, formyl, acetyl, pivaloyl, isovaleryl or isobutyryl, optionally protected amino-(01-C11)-alkanoyl, preferably 4-aminobutyryl, 5 -aminopentanoyl, 6-aminohexanoyl, 4-N-tert-butoxycarbonylaminobutyryl, 5-N-6-butoxycarbonylaminobencnoyl or 6-N-tert-butoxycarbonylaminohexanoyl, di(01 ~C7)-Alkylamino-(C2-C11)'' Alkanoyl preferably dimethylaminoacetyl, (04-C9)-cycloalkylcarbonyl preferably hacyclobrolcarbonyl, cyclobutylcarbonyl, cyclobentylcarbonyl matahcyclohexylcarbonyl , (06-C1o)-aryl-(02-C11)-alkanoyl-11,<
fd Phenylacetyl, phenylpropanoyl or phenylpukunoyl, 2-(2',6-dichloroanilino)phenylacetyl, 2-(N-benzyl-2,6-dichloroanilino)phenylacetyl, case niyoυhaO Dan, (C1-C7)-alkyl, (-c1-C7)-
benzoyl substituted by alkoxy or (C1-C7)-alkoxycarbonyl, preferably 4-chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxypenzoyl, 2-pyrrolylcarbonyl 3 m HJzylcarbonyl, Benzenesulfonyl, (01-Cl0)-alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, (01-Cl0)-alkoxycarbonyl, preferably 2,2.2-) di-substituted with halogen, IJ dichloro Toxycarbonyl or 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, (06-C14)-aryl(
01-C6)-Alkoxydicarbonyl, preferably benzyloxycarbonyl or 9-fluorenylmethylcarbonyl, and their physiologically acceptable salts.

4) Compounds of formula I and physiologically acceptable salts thereof according to any one of claims 1 to 3, wherein R2 represents isobutyl, benzyl or cyclohexylmethyl.

5) Compounds of formula I according to any one of claims 1 to 4 and physiologically acceptable salts thereof, wherein R3 represents hydrogen, isopropyl or isobutyl.

6) Claim 1, in which R4 is defined as in claim 1, with the proviso that Rln represents an amine.
A compound of formula (1) according to any one of items 1 to 5 and a physiologically acceptable salt thereof.

7) R5 and R675Z are the same or different, phenyl, 2-chenyl, 2-vinyl, 1-1-butyl,
2-Pen:/' [bl Compounds of formula I according to any one of claims 1 to 6 and physiologically acceptable salts thereof, representing chenyl, hydroxyl or hydrogen.

8) A and B are the same or different, phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asno ξ lagine, asno ξ lagine, β-2-chenylalanine, β-3-
Chenylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, norvaline,
β-2-furylalanine, methionine sulfoxide, 2
-Pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, ■-Methylhistidine, O-methyltyrosine, 〇-benzyltyrosine, 〇-tert-butyltyrosine, phenylglycine, 1-
Naphthylalanine = /% 2-naphthylalanine, 4-nitrophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3.4-tetrahyr-lysoquinoline-3-carboxylic acid, homophenylalanine, 2-
Compounds of formula I according to any one of claims 1 to 7, representing amino-4-(2-chenyl)butyric acid, (Z)-dehydrophenylalanine ma'cld(E)-dehydrophenylalanine and its physiologically acceptable salts.

9) Compounds of the formula I according to any one of claims 1 to 7 and physiologically acceptable salts thereof, wherein A represents the group 2) according to claim 1.

10) Coupling of a fragment with a terminal carboxyl group or its reactive derivative with a suitable fragment with a free amino group, if appropriate with a temporarily introduced 1 or 10. The method according to claim 1, which comprises removing a plurality of protecting groups and, if appropriate, converting the resulting compound into its physiologically acceptable salt. Methods of Preparing Compounds of Formula I.

11) Use of the compound according to any one of claims 1 to 9 as a pharmaceutical.

12. Use of the compound according to any one of claims 1 to 8 as a pharmaceutical for treating hypertension.

13) A drug containing the compound according to any one of claims 1 to 9.

Procedural amendment dated 28th lθ, 1985 Kunio Ogawa, Commissioner of the Patent Office1, Indication of the case, Patent Application No. 187879, filed in 19872, Name of the invention, G- and tripeptides inhibiting renin and their production method3, Relationship with the case of the person making the amendment Patent applicant name Bächst Akchengesellschaft 4, Agent 7 Contents of amendment 1) r-2 (S
)-J is corrected as r-2-(R,S)-J.

2) Page 75, line 4, r-5-J to r-5(R,5)-
Correct it with J.

3) Correct r-2-j in line 2 of page 79, line 14 of the same page, and line 7 of page 80 to r-2(R,5)-J.

4) Replace r-2(S)-J on page 84, line 10 with “2
Correct it as -(R,5)-J.

5) Change r-5(S)-J on page 85, lines 3-4 to [-5(
Correct R, 5) - J.

6) “Methyl-3” on page 93, lines 2-3 and line 10
-” is corrected to “methyl-2(R,S)-hydroxy-3-”.

7) Page 99, line 13, page 99, line 16, and page 10.
Correct rl(S,)J on page 0, line 15 to "4(S)".

that's all

Claims (1)

[Claims] 1) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) {However, in the formula, R^1 is a_1) absent or represents hydrogen, or a_2) hydroxyl, (C_1~ C_7)-alkoxy, (C_1-C_7)-alkanoyloxy, carboxyl, (C_1-C_7)-alkoxycarbonyl,
(C_1-C_8)-alkanoyloxy, chlorine, bromine, amino, (C_1-C_7)-alkylamino, di-
(C_1-C_7)-alkylamino, (C_1-C_
5)-Alkoxycarbonylamino or (C_7-C
_1_1)-aralkyloxycarbonylamino optionally substituted with 1, 2 or 3 same or different groups selected from the group consisting of (C_1 to C_2
_0)-alkyl or (C_3 to C_8
)-cycloalkyl, (C_3-C_8)-cycloalkyl-(C_1-C_1_0)-alkyl, or optionally in its aryl part fluorine, chlorine, bromine, hydroxyl, (C_1-C_7)-alkoxy, (C_
(C_6-C_1_4)-aryl substituted by one or two identical or different groups selected from the group consisting of 1-C_7)-alkyl, (C_1-C_7)-alkoxycarbonyl, amino or trifluoromethyl; -(C_1~C_8)-alkyl or a_3) Formula II R^a-W-(II) (wherein, W is -CO-, -O-Co-, -SO_
2- or -NH-CO-, and R^a is hydrogen, optionally having one or two unsaturated bonds, and optionally hydroxyl, (C_1-C_7)-alkoxy, (C_1-C_7 )-alkanoyloxy,
Carboxyl, (C_1-C_7)-alkoxycarbonyl, chlorine, bromine, amino, (C_1-C_7)-alkylamino, di-(C_1-C_7)-alkylamino, (C_1-C_5)-alkoxycarbonylamino,
represents (C_1-C_1_0)-alkyl substituted with up to three same or different groups selected from the group consisting of (C_7-C_1_5)-aralkoxycarbonylamino and 9-fluorenylmethoxycarbonylamino; , or (C_3-C_8)-cycloalkyl, (C_3-C_8)-cycloalkyl-(C_1-C
_6)-Alkyl, optionally fluorine, chlorine, bromine, iodine, hydroxyl, (C_1-C_7)-alkoxy, (
C_1-C_7)-alkyl, (C_1-C_7)-alkoxycarbonyl, amino, one or two identical or Substituted with different groups (C_6-C_1_4)
- represents aryl or optionally in the aryl moiety fluorine, chlorine, bromine, iodine, hydroxyl, (C
_1-C_7)-alkoxy, (C_1-C_7)-alkyl, (C_1-C_7)-alkoxycarbonyl,
Amino, (C_1-C_7)-alkylamino, di-(
C_1-C_7)-alkylamino, carboxyl, carboxymethoxy, amino-(C_1-C_7)-alkyl, (C_
1-C_7)-alkylamino-(C_1-C_7)-
Alkyl, di-(C_1-C_7)-alkylamino-
(C_1-C_7)-alkyl, (C_1-C_7)-
(C_6-C_1_4)- substituted with four or two identical or different groups selected from the group consisting of alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (C_1-C_7)-alkoxysulfonyl, sulfo- and guanidinomethyl Aryl-(C_1~
C_6)-alkyl or contains at least one carbon atom, 1 to 4 nitrogen atoms and/or one sulfur or oxygen atom as ring atoms, and optionally represents (C_6-) of a_2) above. C_1_4) - 5- or 6-membered monocyclic or 9- or 1-membered mono-, di- or tri-substituted as defined for aryl
represents a group of a 0-membered bicyclic aromatic heterocyclic compound), and R^4 represents a group of the formula IV -X-(CH_2)_n'-R^7(IV) [wherein X is present or represents oxygen or sulfur, n' may be 0, 1, 2, 3 or 4, and R^7 is hydrogen, hydroxyl, amino or partially or fully hydrogenated hetero aryl (wherein, heteroaryl represents a group of an aromatic heterocyclic compound defined in a_3) above), or formula VI ▲ Numerical formula, chemical formula, table, etc. ▼ (VI) (However, in the formula, ^9 is hydrogen, (C_1-C_7)-alkyl, or hydroxyl, (C_1-C_5)-alkoxy, (C_1-C_5)-alkylthio, carboxyl, (C_1-C_5)-alkoxycarbonyl,
Fluorine, chlorine, bromine, iodine, (C_1-C_5)-alkylamino, di-(C_1-C_5)-alkylamino,
represents (C_1-C_7)-alkyl monosubstituted by (C_1-C_5)-alkoxycarbonylamino or (C_7-C_1_5)-aralkoxycarbonylamino, R^1^0 represents hydroxyl or amino, and Y represents It does not exist or ▲There is a mathematical formula, chemical formula, table, etc.▼, and p and q each independently represent 0, 1, 2, 3, or 4, provided that Y ▼If q is not 0), A represents b_1) Formula III ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (However, in the formula, n and m are the same or different, 0,
represents 1, 2, 3 or 4, and R^5 and R^6 are the same or different, phenyl, 2- or 3-chenyl, 2-, 3- or 4-pyridyl, 1-, 2- or 4
- imidazolyl, 1- or 2-naphthyl, 2- or 3-benzo[b]chenyl, hydroxyl or hydrogen), or b_2) phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine,
Asparagine, aspartic acid, β-2-chenylalanine, β-6-chenylalanine, β-2-furylalanine, β-3-furylalanine, lysine, ornithine,
Valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone,
Methionine sulfoxide, 2-pyridylalanine, 3-
Pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-pencyltyrosine, O-tert-butyltyrosine, phenylglycine, 1-naphthylalanine, 2-
naphthylalanine, 4-nitrophenylalanine, β-
2-benzo[b]chenylalanine, β-3-benzo[
b] Chenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA ,
O-dimethyldopa, 2-amino-4-(2-chenyl)butyric acid, 2-amino-4-(3-chenyl)butyric acid, 3-
The N-terminus of an amino acid selected from the group consisting of (2-chenyl)serine, norvaline, (Z)-dehydrophenylalanine and (E)-dehydrophenylalanine is bonded to R^1, and the C-terminus represents a group such that is bonded to B, and B represents an amino acid group as defined in b_2), or R^4 is a formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (V) [In the formula, R^8 represents hydrogen, partially or completely hydrogenated heteroaryl (where heteroaryl represents a group of an aromatic heterocyclic compound as defined in a_3) above), or the above-mentioned represents a group of formula VI], A and B are the same or different, and one of the groups A and B is β-2-chenylalanine, β-3-chenylalanine, β-2-benzo [ b] Chenylalanine and β-
represents an amino acid group selected from the group consisting of 3-benzo[b]chenylalanine, and the other is b_ as defined above.
2) and physiologically acceptable salts thereof. 2) R^1 is absent, represents hydrogen, or (
C_1-C_1_0)-alkyl, cyclopentyl, cyclohexyl, cyclopentyl-(C_1-C_1_0
)-alkyl, cyclohexyl-(C_1 to C_1_0
)-alkyl, optionally substituted phenyl-(C_
1-C_8)-alkyl, H_2N-(C_1-C_1
_0)-alkyl, HO-(C_1~C_1_0)-alkyl, (C_1~C_4)-alkoxy-(C_1~
C_1_0)-alkyl, (C_1-C_4)-alkoxy-carbonyl-(C_1-C_1_0)-alkyl, carboxy-(C_1-C_1_0)-alkyl, preferably 2-hydroxypropionyl or 2-hydroxy-3-methylbutyryl or (C_1 ~C_8)-
Compounds of the formula I according to claim 1 and their physiologically acceptable salts, which represent alkanoyloxy-(C_1-C_1_0)-alkyl. 3) R^1 is (C_1-C_1_1)-alkanoyl, preferably n-decanoyl, formyl, acetyl, pivaloyl, isovaleryl or isobutyryl, optionally protected amino-(C_1-C_1_1)-alkanoyl, preferably 4-aminobutyryl, 5 -aminopentanoyl, 6-aminohexanoyl, 4-N-butoxycarbonylaminobutyryl, 5-N(tert-butoxycarbonylaminopentanoyl or 6-N-tert-butoxycarbonylaminohexanoyl, di-(C_1~ C_7)-
Alkylamino-(C_2-C_1_1)-alkanoyl preferably dimethylaminoacetyl, (C_4-C_
9)-Cycloalkylcarbonyl, preferably cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl, (C
_6~C_1_0)-aryl-(C_2~C_1_1
)-alkanoyl preferably phenylacetyl, phenylpropanoyl or phenylbutanoyl, 2-(2,6-dichloroanilino)phenylacetyl, 2-
(N-benzyl-2,6-dichloroanilino)phenylacetyl, optionally halogen, (C_1-C_7)-
Alkyl, (C_1-C_7)-alkoxy or (C
_1 to C_7)-Alkoxycarbonyl-substituted benzoyl, preferably 4-chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxybenzoyl, 2-pyrrolylcarbonyl, 3-pyridylcarbonyl, benzenesulfonyl, ( C
_1 to C_1_0)-alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, substituted by halogen (C_1
~C_1_0)-alkoxycarbonyl preferably 2,
2,2-trichloroethoxycarbonyl or 1,1-
Dimethyl-2,2,2-trichloroethoxycarbonyl, (C_6-C_1_4)-aryl-(C_1-C_
6) Compounds of formula I according to claim 1 and their physiologically acceptable salts, which represent -alkoxycarbonyl, preferably benzyloxycarbonyl or 9-fluorenylmethylcarbonyl. 4) Compounds of formula I and physiologically acceptable salts thereof according to any one of claims 1 to 3, wherein R^2 represents isobutyl, benzyl or cyclohexylmethyl. 5) Compounds of formula I and physiologically acceptable salts thereof according to any one of claims 1 to 4, wherein R^3 represents hydrogen, isopropyl or isobutyl. 6) The formula according to any one of claims 1 to 5, wherein R^4 is defined as in claim 1, but R^1^0 represents amino. Compounds of I and their physiologically acceptable salts. 7) R^5 and R^6 are the same or different, phenyl, 2-chenyl, 2-pyridyl, 1-naphthyl, 2-
Compounds of formula I according to any one of claims 1 to 6 and physiologically acceptable salts thereof, representing benzo[b]chenyl, hydroxyl or hydrogen. 8) A and B are the same or different, phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-chenylalanine, β-3-chenylalanine, lysine, ornithine, Valine, Alanine, 2
, 4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, norvaline, β-2-
Furylalanine, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O
-Tertiary butyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homo Formula I according to any one of claims 1 to 7, representing phenylalanine, 2-amino-4-(2-chenyl)butyric acid, (Z)-dehydrophenylalanine or (E)-dehydrophenylalanine compounds and their physiologically acceptable salts. 9) Compounds of formula I according to any one of claims 1 to 1 and physiologically acceptable salts thereof, wherein A represents a group of formula III according to claim 1. 10) Coupling of a fragment with a terminal carboxyl group or its reactive derivative with a suitable fragment with a free amino group, if appropriate with a temporarily introduced 1 or 10. The method according to claim 1, which comprises removing a plurality of protecting groups and, if appropriate, converting the resulting compound into its physiologically acceptable salt. Method of Preparing Compounds of Formula I. 11) Use of the compound according to any one of claims 1 to 9 as a pharmaceutical. 12) Use of the compound according to any one of claims 1 to 8 as a pharmaceutical for treating hypertension. 13) A drug containing the compound according to any one of claims 1 to 9.