JPH01199983A - Novel silicon-containing peptides, their production methods and uses - Google Patents

Abstract

NEW MATERIAL: Silicon-containing renin inhibitors.

EXAMPLE: (2R,4S,5S,8S,11R)-6,9,12-triaza-2-(2-E-butenyl)-8-butyl-5- cyclohexymethyl-4-hydroxy-15,15-dimethyl-11-trimethylsilylmethyl-14-oxa-7,10,13- trioxo-hexadecanicacidbutylamide.

USE: Medicaments useful for prevention and treatment of hypertension and cardiac insufficency.

PROCESS: Renin inhibitor of formula VI is obtained by allowing the compound of formula I [R₁ is 1-5C alkyl; A is N-amino-protecting group, peptide or the like; B is formula II or III (R₇ is H or 1-5C chain alkyl; R₃ is hydrophilic or lipophilic amino, acid side chain)] to react with the compound of formula H-D [D is formula IV or V (X is O, S, or the like; R₉ is R₈; R₁₀ is OH or amino; R₁₁ is H or the like; R₁₂ and R₁₃ are each F or H; R₁₄ and R₁₅ are each H, 1-6C chain alkyl or the like)].

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to silicon-containing renin inhibitors, their production methods, their uses and pharmaceutical compositions containing them.

DISCLOSURE OF THE INVENTION In particular, this invention relates to a compound of the formula A straight-chain or branched (C,-,.)argyl group which may be substituted by (Cz-s)alkyl or (Cs-+.)aryloxy, one or two nitrogen atoms, oxygen preferably a sulfur atom or 1
nitrogen atoms and one oxygen atom and/or tg
a 5- or 6-membered heteroaryl group containing a sulfur atom,
Or the heteroaryl part is 5-like but 6-membered, and 1
A heteroaryl (C,-5)alkyl group containing preferably 2 nitrogen atoms, preferably sulfur atoms or 1 nitrogen atom and 1 oxygen atom and/or 1 sulfur atom, straight-chain or branched (C,-5)alkoxy group or (C8-to)aryl-(C1-S)alkoxy group], or A means a group represented by the formula XR3-O-(
CI, C11, -0)m-(CH2)n-W-C-[wherein, W is -〇-1NR? -or-CII, (where R
7 means hydrogen or a straight-chain or branched (C,-5) alkyl group), and R3 is hydrogen, a straight-chain or branched (C,-,O) alkyl group, or bonded as a glycoside. optionally substituted, saturated or unsaturated, linear or branched (Ct-s.) alkylcarbonyl groups, (C3-S) polyhydroxyalkylcarbonyl, phosphoroyl, bis-(dimethylamino) ) Bosporoil,
sulfo, amyl, hete[1a[1yl, arylalkyl, arylalkylcarbonyl or heteroarylalkylcarbonyl group, or biotinoyl group, or R3 is of the formula (wherein R14 is hydrogen or D-like !, - is the side chain of an amino acid, and Ra and R6 are the same or different and each represents hydrogen, (C
, -S)alkyl, (Ct-S)hydroxyalkyl or (C,-,)aminoalkyl), or R3 represents a group of the formula (wherein R1 and R11 are p is an integer from 0 to 5, 1ε means a bond or a group -C-), or R1 is 2F-(CH,)p-E- (wherein p and E have the above meanings, and I? represents a group represented by the formula (in the formula, R7 has the above meanings), m represents 1- is an integer of 20, n is an integer of 0 to 5], 13 is a group represented by the formula, or formula R9 has the above meaning, R8 is hydrophilic or lipophilic means an amino acid side chain], D is a group represented by the formula [wherein, and rat is hydrogen or R1° and Ro together form an oxo group, R1! and R13 independently of each other mean fluorine or hydrogen, RI4 and R15 are the same or different , each hydrogen,
Straight-chain or branched (C,-a)alkyl group, or R1,
means a straight-chain or branched (Ct-S) alkyl group or a straight-chain or branched <c, -s) hydroxyalkyl group, R1, is a hydroxyl group, a straight-chain or branched (Ct-S) ,
-S)alkoxy group, amino or (Ct-S)alkylamino group, aminomethylbilidyl group, benzyl group or a protected or unprotected amino acid), Y means a bond, or -〇-1-N-(in the formula,
Tl la and R,, independently of each other represent hydrogen or fluorine, or each has the same meaning as R8 above, or D represents a group of the formula (wherein R8, R, , R, and n have the above meanings)
A silicon-containing renin inhibitor is provided.

The renin inhibitor according to the invention contains trimethylsilyl-substituted amino acids as a component. Surprisingly, the presence of this trimethylsilyl substituted amino acid confers significant stability to the peptide molecule against the proteolytic activity of chymotrypsin. This surprisingly leads to a great improvement in the bioavailability of the compounds according to the invention.

Hereinafter, the above-mentioned compounds will be referred to as compounds of the present invention.

In formula (1), A especially means BOC-proline and R, especially means ethyl, propyl or isobutyl. If R2 is straight-chain or branched alkyl having 1 to 10 carbon atoms, it stands in particular for methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2
．． 2-dimethylethyl, pentyl, hexyl, etc., especially methyl, 1-butyl and 2,2-dimethylethyl. If it is substituted with aryloxy, it is especially phenoxymethyl or! - or 2-naphthyloxymethyl, preferably 1-naphthyloxymethyl. Heteroaryl means in particular pyridyl, thienyl or furyl. In the heteroarylalkyl group, the heteroaryl and alkyl moieties preferably have the meanings given above. A straight-chain or branched alkoxy group means in particular ethoxy or L-butoxy, (C
,-+o)aryl-(C,-3)-alkoxy group is
In particular it has the meanings given above for aryl and alkyl, preferably benzyloxy.

A is a group X R, -〇-(CLCL-0)m-(CL)n-W-C-
, R4 is straight-chain or branched alkyl,
In particular alkyl having 1 to 5 carbon atoms, in particular ethyl, propyl or isobutyl, the sugar group bound as a glycoside is e.g. glucopyranosyl which can optionally be 0-acylated, e.g. A nosyl optionally substituted saturated or unsaturated (Ct-3°) alkylcarbonyl group is especially the corresponding CCa-x. ) is an alkylcarbonyl group, such as a valmitoyl, oleyl, linolyl, stearoyl or piparoyl group (although the alkylcarbonyl group may be substituted by a cyclopentaphenanthrene group and may represent a cholyl group);
) polyhydroxyalkylcarbonyl groups, such as optionally substituted glycerinoyl or gluconoyl groups (which may represent, for example, penta-0-acetylgluconyl or dibutyroylglycerinoyl groups), aroyl groups,
For example, a benzoyl group, a heteroaroyl group, such as 2-13
- or 4-pyridinoyl group, arylalkyl group,
For example benzyl, phenethyl, naphthylmethyl, p-chlorophenoxy-probyl-2 groups, arylalkylcarbonyl groups such as phenylacetyl, bis(I-naphthylmethyl)acetyl or p-chlorophenoxy-1
, 1-dimethylacetyl group, heteroarylalkylcarbonyl group, such as bis-(3-pyridylmethyl)acetyl or bis(4-quinolinylmethyl)acetyl group. In R4, the D- or L-amino acid side chain is
In particular methyl, isopropyl, isobutyl, benzyl, hydroxy(C+-S)alkyl, 4-aminobutyl or 2-carboxyethyl.

Hydrophilic or lipophilic amino acid side chains in the sense of R8 can be, for example, n-butyl, isobutyl, benzyl, 4-imidazolylmethyl, 2-methylthioethyl, trimethylsilylmethyl, cyclohexylmethyl or pyridylmethyl groups.

Hydroxyalkyl having 1 to 5 carbon atoms in the zero flavor of R18 is preferably hydroxyethyl or hydroxypropyl, RI? 1~ in the color of
Alkoxy having 5 carbon atoms preferably means methoxy or ethoxy.

Preferred compounds among the compounds of the present invention are those of formula (IY)AY
means a group of the formula (wherein XY means S or 0 and R8Y represents t-butyloxy, benzyloxy, 5-aminopentyl or isobutyl), or AY represents a group of the formula % (Formula %) (In the formula, xY has the above meaning, R3Y represents hydrogen, methyl, glucopyranosyl, pyridinoyl, 3,4.5-trimethoxybenzoyl, ■ means an integer of 2-7, n means an integer of 0-2), BY means a group represented by the formula (wherein, R7Y represents hydrogen or methyl, R8Y represents n-butyl, isobutyl, 2-butenyl, phenylmethyl, 4-imidazolylmethyl, pyridinemethyl or trimethylsilylmethyl), DY is [wherein, RaY is isobutyl, benzyl or cyclohexylmethyl, and R+tY and R+ a Y each represent hydrogen] If not shown, R
1°Y means a hydroxy group, R++Y means hydrogen, or when R1, Y and R13Y each represent fluorine, ne
oY and R1,Y together form an oxo group, 1'? +-Y means hydrogen, R+sY represents hydrogen, methyl, i-propyl, i-butyl or the formula R+ a Y represents i-butyl or 2-butyl, R
1, Y represents aminomethylpyridyl), YY represents a bond or the formula R1° and R1.Y each represent fluorine, or R11Y represents n-butyl, isobutyl, 2- butenyl,
It means methyl, methyldiomethyl, benzyl, isopropyl or chlorine, and RIY represents hydrogen).

The method for producing the compound represented by formula (I) is as follows: a) A compound represented by formula (11) (wherein A, B and R1 are the above-mentioned meanings), or b) a compound of the formula (In) (wherein R1, B and D are as defined above) is reacted with a compound of the formula A -OI-1 (wherein R1, B and D are as defined above). , A means na), or C) by oxidizing a compound represented by formula ([) (wherein R8° is a hydroxyl group and Ro is hydrogen), It is characterized by obtaining a compound represented by (I) (wherein RIo and Ro together form an oxo group).

The method according to step a) is preferably carried out using methods well known in the art of peptide chemistry, such as e.g. N,N'-dicyclohexylcarbodiimide, in a suitable solvent, e.g. (adding DCCXI-hydroxybenzotriazole (HOBT)), a compound of formula (n) is reacted with an amine of formula HD.

The method according to step b) is carried out under the same conditions as the method according to step a).

The method according to step C) involves producing the corresponding ketone by oxidizing the alcohol of the compound of the present invention using a chromium trioxide/dipyridine complex (Cr Oa/Pyt = Collins reagent) in a methylene chloride or dimethylformamide solvent, for example. It is done in a way that

The starting compounds used in the above process are known or can be prepared by known methods, such as those described in the examples below.

Compounds of formula (1) produced according to this invention can be isolated and purified by known methods. Racemic and/or diastereomeric mixtures may be separated using known methods.

If the compounds of formula (1) contain acidic or basic groups, they may optionally also form salts, such as metal salts, such as sodium salts or acid addition salts, such as hydrochlorides.

In the examples below, all temperatures are in degrees Celsius and are uncorrected. Optical activity was measured at 20°C.

Compounds given in abbreviations in the examples are fully described in claim 3 in the order of the examples.

Hereinafter, the following abbreviations will be used in the examples.

H-Bly-OH: (2S)-2-amino-hexa=
(4)-enecarboxylic acid.

7EG-OH: 2, 6.9, 12, 15.1 B, 2
1.24-octaoxa-pentacosanoic acid.

3EG-OH: 3.6.9.12-tetraoxatridecanoic acid.

H-Chatin-OH: (3S,45)-4-amino-5-cyclohexyl-3-hydroxyvaleric acid.

H-FgChatin-OH: (3R,45)-4-
Amino-5-cyclohexyl-2,2-difluoro-3
-Hydroxy-5valeric acid.

H-PtChaton-OH: (4S) 4-amino-5-cyclohexyl-2,2-difluoro-3-oxo-valeric acid.

Tm5al: (2R) 2-amino-3-trimethylsilyl-propionic acid.

H.-Aca-OH: 6-aminocaproic acid.

Niacin-OH: 3-pyridinecarboxylic acid.

H-3eg-OH: 2,5,8.11-tetraoxaundecanoic acid.

H-2eg-OH: 2,5.8-)rioxaoctanoic acid.

H-Cha(OH)Bly-OH: (2R,4S,5
S)-5-amino-2-(E-2-butenyl)-6-cyclohexyl-4-hydroxycaproic acid.

HOBT: 1-hydroxybenzotriazole.

H'-'Cha(OH)Ala-OH: (2R,4S
, 55) -5-amino-6-cyclohexyl-4-hydroxy-2-methylcaproic acid.

α-Pie: 2-aminomethyl-pyridine.

4-PySAc: (4-pyridylthio)acetyl.

Tmpac-OH: (3,4,5-)dimethoxy)phenylacetic acid.

H-Cha (O)I)CHtCHCl 0H:
(2R.

4S, 5S)-5-amino-2-chloro-6-cyclohexyl-4-hydroxycaproic acid.

MPA: 3-(4-morpholinyl)propylamine.

H-2egs-OH: 2,5.8-)rioxaoctanethionoic acid.

H-Cha-(Otl)CFtCFtCFs: (4
S, 5S)-5-amino-6-cyclohexyl-1,1
゜1.2,2,3.3-hebutafluoro-4-hydroxyhexanoic acid.

HCha CFtCFtCFs: (5S) 5
-amino-6-cyclohexyl-1,1,1,2,2,
3゜3-Heptafluoro-4-oxo-hexanoic acid.

H-Leu-(S)-a-Pie: (2S)-2-
Amino-4-methyl-pentanethionic acid α-picolylamide.

3EGS-OH: 3,6,9.12-tetraoxa-
Tridecanethionic acid.

7EGS-OH: 2.6.9, 12, 15, 18°2
1.24-octaoxa-pentacosanthionic acid.

H-Leu-R-Tmsal-Of-1: (2R,5
S)-5-amino-3-aza-7-methyl-2-trimethylsilylmethyl-octanoic acid.

[(-Cha(OH)Thiobly-OH: (2R
,4S.

5S)-5-amino-2-(E-2-butenyl)-6-
Cyclohexyl-4-hydroxy-thionocaproic acid.

EDCI: N-ethyl-No-(dimethylaminopropyl)carbodiimide.

[Example] (intermediate product) L-N-BOC-β-trimethylsilylalanine.

Dissolve 24+y of (2R)-2,5-dihydro-3,6-simethoxy-2-isopropylpyrazine in 400xQ of tetrahydrofuran. 82i12 of n-butyllithium was added dropwise at -70°C, stirred for 15 minutes, 30g of iodotrimethylsilane was added, and the mixture was left at room temperature overnight.

The reaction solution is partitioned between ether and sluice, washed to neutrality, dried (MgSQ, ), evaporated and chromatographed on silica gel using 7% ether in hexane.

The product (24g) was dissolved in 2001 methanol and 0
Mix Ite 2011Q with concentrated hydrochloric acid in 5 ole of water at -5° and stir for 2 hours. The product is then concentrated under reduced pressure, and the residue is dissolved in methylene chloride and extracted with 2N soda solution. The organic phase is dried (K t cO8) and concentrated by evaporation. Dissolve the residue in tetrahydrofuran and add 3
It is mixed with 5 g of di-tert-butyl dicarbonate, left overnight at room temperature and then concentrated by evaporation. The residue is dissolved in methanol (1,512) and mixed with a solution consisting of 1.59 sodium hydroxide and +00Rd H10/methanol (1:l) while cooling with water. After 3 hours, the methanol was distilled off and the residue was dissolved in ether and water and 40%
g of phosphoric acid (85%). Dry the organic phase (Mg
SO4) evaporate and concentrate. Title compound and D
36 g of a 1:l mixture of -BOC-valine are obtained. This mixture is used for dipeptide synthesis without further purification.

BOC-Tmsal-His-OH0 29g of acid mixture (BocTmsal-OH+D-BO
Dissolve C-Vat-OH) in 100x (j dimethylformamide. 19.29 H-HisOCHs 2H
CQ was added, the mixture was cooled for 0-5 °ζ and mixed with 50 g of N-methyl-morpholine, then 52 x Q of propane phosphoric anhydride (50%, in CHt CI e) was added.
Drip at 5°. After 15 hours at room temperature, the product is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The crude product is subjected to silica gel chromatography using methanol/methylene chloride (2-5%). Dissolve 10g of this methyl ester in methanol and add 10g of barium hydroxide 8H2.
Add a solution consisting of 0 and 1003112 water. After 2 hours at room temperature, an aqueous solution containing 3.2 FM concentrated sulfuric acid is added, the barium sulfate is removed by centrifugation, the remaining solution is concentrated to dryness, and the residue is crystallized from methanol/methylene chloride/ether.

BOC-Tmsal-Nle-OH Similar to the example above, a mixture of 259 acids in 1003112 dimethylformamide and 19 g H-Nle
OCHs HCQ is reacted with 551 N-methylmorpholine and 70 molecules propane sulfuric anhydride. In this example, the methyl ester can also be hydrolyzed with aqueous sodium hydroxide.

Example I H warm B OC-Tl1lsal -Nle -Cha(OH
) BOC-Tisal- of B IyNBu166jIg
Nle-OH 150 Shoulder 2 H-CHa(OH)Bly
Dissolve in methylene chloride with NHBu and 100% hydroxybenzotriazole. 961 g of dicyclohexylcarbodiimide are added at O-5°. The mixture is stirred at room temperature for 15 hours, the precipitated dicyclohexylurea is filtered, and the crude product is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. Dry the organic phase (Mg
SO, )t, evaporate and concentrate. The residue is recrystallized from methylene chloride/hexane.

[αcoD=-39.1 (c=0.2, in cHacts)
.

Example 2H BOC-Tm5al-Nle-Cha(OH)
Nle-NBu.

The title compound of Example 1 is dissolved in ethanol and hydrolyzed over a palladium on carbon catalyst at normal pressure for 3 hours. The catalyst is filtered off, the residue is concentrated by evaporation and crystallized from methylene chloride/hexane.

[αcoD=-30.9° (c=0.2, CHf
fiCl, medium).

Example 3 B OC-To+5al-Nle-Ft-Chati
n-NH-1Buc+200 in the same manner as in Example 1
Phantom BOC-Tmsal-Nle-OH and 163o
of HF, -Chatin-NHiBu is reacted with 1441 g of hydroxybenzotriazole and 113o of dicyclohexylcarbodiimide.

[α] o = 20, 1'' (c = 1, 5, CH1
During C1t).

Example 4 BOC-Tmsal-Nle-Ft-Chaton-N
H-iBu.

331 g of the alcohol from Example 3 is dissolved in 1×Q dry methylene chloride and mixed with 200° CrOs.Pyt (Collins Reagent). Stir for 20 minutes at room temperature, precipitate the chromium salt by adding ethyl acetate, and filter the product using Hyflo and silica gel. The filtrate is concentrated by evaporation and the residue is lyophilized from benzene.

[a] o-35, 8° (c=0.35, CHtC1w
During).

Example 5 B OC-Tm5al -Nle -Chatin-
Leu-a-Pic.

In the same manner as in Example 1, a 200 m9 BOC-Tms
al-Nle-OH and 223,5J! H- of g
Chatin-Leu-a-Pic 140H
of hydroxybenzotriazole and IllIIg glue are reacted with cyclohexylcarboimide. The product is crystallized from methylene chloride/hexane.

[αID = 12, 9° (c = 0.15, ct-tt
c+1).

Example 6 BOC-Tmsal-His-Cha(OH)Bly-
NHBua In the same manner as in Example 1, 230 m9 BOC-Tms
al7 His-OH and 195H H-Cha (
01-1) BlyNHBu in dimethylformamide 1
50 hydroxybenzotriazoles and 1201
g with synchhexylcarbodiimide. The product is crystallized from methylene chloride/methanol/ether.

[α]o-32, 5° (c=o, 11MeOH/CHz
(J!i:1).

Example 7 BOC-Tmsal-His-Cha(OH)Nle-
NH-Bu.

25 mg of the title compound of Example 6 in the same manner as in Example 2
is dissolved in 2 mQ of alcohol and hydrogenated with 3 mg of palladium on carbon catalyst (3%).

[αID = 38, 6° (c = 0.1, M e OH
/CHtC12tl:l).

Example 8 BOC-Tmsal-Bly-Fz-Chatin-N
H-iBu0 248 mg of BOC-Tms in the same manner as in Example 1
al-Bly-OH and 204x9 H-F', -C
hatin-N H-iBu is reacted with 1821 g of hydroxybenzotriazole and 14119 of synchhexylcarbodiimide. The crude product is chromatographed on silica gel using methylene chloride/ether 8:2 and lyophilized from benzene.

[α], = -29.8° (c = 0.5, CH, C1ff
1).

Example 9 BOC-TIIlsal-Bly-Ft-Chaton
-NH-iBu0 Alcohol 29R of Example 8 in the same manner as Example 4
9 is oxidized with 25019 Collins reagent.

[α]o = 47, 9° (c = 0.24, CHtel
! During).

Example 10 7 EG-Tmsal-Bly-Ft-Chatin-
NH-jBu.

In the same manner as in Example 7, HT m5a of 59jI9
1-Bly-Ft-Chatin-NH-iBu and 43-order 9 7E G -OH are reacted with 29-hydroxybenzotriazole and 231Rg dicyclohexylcarbodiimide. The crude product is purified on silica gel with methylene chloride/ether 8:2.

[α]o = 18, 8° (c = 1.8, CHt Cl
inside).

Example 11 7EG-Tmsal-Bly-Ft-Chaton-N
H-Bua Alcohol 23R of Example 10 in the same manner as in Example 4
9 is oxidized with Collins reagent 13019.

[α] o-20, 6° (c=0.34, CHtClt
l).

Example 12 3EG-Tmsal-Iris-Cha(OH)-Bl
y-NI-1-Bu.

In the same manner as in Example 1, 206J! 9 EG-0) [
and 500u of H-Tm5al-His-Cha
(OH) -Bly-NH-Bu is reacted with 0.144 MQ of diisopropylcarbodiimide in dimethylformamide. The crude product is subjected to silica gel chromatography using 2-1θ% methanol/methylene chloride.

[α1D=-27,6° (c=0.L in CHtC1t).

Example 13 7EG-Tmsal-His-Cha(OH)-Bly
-NH-nBuo In the same manner as in Example 7, 7EG-OH of 338 and 500. W9's H-Tlllsal-His-Cha
(OH)Bly-NH-nBu is reacted with 110 Jtg of hydroxybenzotriazole and 0.13xQ of diisopropylcarbodiimide in dimethylformamide. The product is crystallized from methylene chloride/ether/hexane.

[α]o:=21,0°(c=0.1.CHtC1
(during t).

Example I4 B OC-Tm5al -His -Chatin-
Leu -a -ic0 In the same manner as in Example 1, 2,99 BOC-Tm5a
l -His -OH and 3.1 g of II -Cha
Lin -Leu-α-Pic was dissolved in 2 g of hydroquinohenecitriazole and 1.2 m
To avoid reaction with diisoprobyl sulfodiimide of Q, chromatography on silica gel with methanol/methylene chloride 0-10% is carried out.

[ff]D--27,2° (c=0.2, CL(, CI
,During).

Example! 5 Me -3eg -Tm5al -His -Chat
in -Leu-aPic0 350m9 of Me-3sg-p-nitrophenol and 700 of H-Tmsal-His-Chatin-
Dissolve LeU-α-Pie in trimethylformamide.

After 3 hours, the solution is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase is dried, evaporated and the residue is chromatographed on silica gel using methanol/methylene chloride 0-10%. The title compound is [α], -26°5° (c=0.2, CHfC1
t).

Example 16 Me-3sg-Tmsal-(me-3sg)-His
-Chatin-Leu-a -Pico The diacylated compound of this example can be isolated from Example 15 as a by-product.

[α]D--4.7° (c=0.2, in CH, C12)
.

Example 17 BOC-Aca-Tmsal-His-Chatin-
Leu-α-Pic0 In the same manner as in Example 15, 300xy BOC-Ac
a-p-nitrophenol and 600iy H-Tm
sal -His-Chatin-Leu-Ct
-Pic 100II! 9 in the presence of imidazole.

The crude product is chromatographed with methanol/methylene chloride 0-12%.

[αko −21,5° (c=0.2, CHt
(in CII).

Example 18 H-Aca-Tm5al-H1s-Chatin-
Leu-a-Pic ・3) IC(!.

Title compound of Example 17 500II! 9 is treated with trifluoroacetic acid/methylene chloride 1.1 for 1 hour.

The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. Separate the organic phase, dry,
Mix with 3 mQ of concentrated hydrochloric acid and concentrate to dryness. t the residue
- Lyophilization from butanol.

[α]o = 23, 4° (c = 0.2, M e OH
/ CI (te12i:1).

Example 19 Niacin-2sg-Tmsal-Nle-Ft-C
hatin-NH-iBuo In the same manner as in Example 15, 381 mg of Nyan-2
eg-p-nitrophenol and 523 mg H-T
msal-Nle-Pa-Chatin-NH-iBu
react.

[α]D=-24,5° (c=0.1.CH, CI)
.

Example 20 Niacin-2sg-Tmsal-Nle-F, -Ch
aton-NH-iBuo Alcohol 50z of Example 19 in the same manner as in Example 4
g is oxidized with Collins reagent 241xip.

[α]' = -31,6° (c = 0.4, CHfC1t
During).

Example 21 BOC-Δca-Tmsal-Nle-Chatin-
Leu-α-Pie0 275 mg of N-”t-[
'30C-6-aminocaproic acid-p-nitrophenyl ester and 500 Tm5al-Nle-C
hatin-Leu''a-Pic. The crude product is crystallized from ethyl acetate/ether.

[αcoD = -47,0° (C=0.1.C
l-1, C1, middle).

Example 22 H-Aca-Tm5al-Nle-Chatin
-Leu -a-Pic2HC (io In a similar manner to Example 18, the title compound of Example 2I was deprotected with trifluoroacetic acid/methylene chloride,
) convert to hydrochloride.

[α]D-15,4° (c=0.2, in CH2Cl2)
.

Example 23 7 E G-Tmsal -N le -Chatin
-Leu -a -r'ic0 In the same manner as in Example 1, 400M9 H-TTIIS
al-Nle-Chatin-Leu-a-Pic 2
60mg of 7EG-OH1801119 HOB
React with T and 130 m of DCC. The crude product is chromatographed using methi 12209195% methanol.

[α]D = 3, 9° (c = 0.8, in CH2Cl)
.

Example 24 Niacin-2eg-Tmsal-N le -Cha
tin -seu-α-Pic0 H-Tmsal at 500° in the same manner as in Example I5
-DMF Nle-Chatin-Leu-a-Pie
'Middle school 300J! 9 with niacin-2eg-p-nitrophenol. The crude product was converted into methylene chloride/
Crystallizes from ether.

[α]D = 27, 2° (c = 0.25, CH,
during CL).

Example 25 H-2eg -Tm5al -N le -Chati
Dissolve n-Leu-aPie0 50J19 nicotinic acid ester (Example 24) in methanol and add approximately 50+g of NaOH.

■ After 5 minutes, redistribute between water and methylene chloride. The organic phase is separated, dried (MgSO4) and concentrated. The residue is crystallized from methylene chloride/ether/hexane.

[α]D=-15,5° (c=0.1, CH, CI, medium).

Example 26 4-PyS Ac-Tm5al-Nle-Ft
-Chatin -NH+BIJ+ In the same manner as in Example 1, H-Tn+5 of 511119
al-Nle-Pt-Chatin-NH-iBu,
40m (155zy (4-pyridylthio)acetic acid in 1 DMF, 245mg HOBT and 197mg DC
React with C.

[α]D=-38, pi (c=0.1, in methanol).

Example 27 Biotinoyl Tm5al-Nle-Ft-Chati
n −N[−(−iBu.

In the same manner as in Example 1, 244 mg of (+) biotin was added to 560 mg of H-Tmsal-Nle-F't-Ch.
atin-NH-iBu, 269J! 9 HOBT
and 215 mg of DCC.

[a] D = 22, 9° (c = 0.33, CH, C
during It).

Example 28 H-2eg-Tmsal-Nle-Chaton-NH
-iBu.

The title compound 32119 of Example 20 is dissolved in methanol and hydrolyzed with 4 ypti of NaOH. The reaction mixture is partitioned between aqueous sodium bicarbonate and methylene chloride, the organic phase is dried and concentrated.

[α] p = 2 l pi (c = 0.6, CHx CI
inside).

Example 29 Tmpac -2eg -Tm5al -N le -
F2-Chatin-NH-iI'3u0 In the same manner as in Example 15, 440m9 of H=Tmsa
l-Nle-F 2-Chatin-Nl-1-iBu
is reacted with 3707?9 H-Tmpac-2eg-p-nitrophenol. The crude product is purified by silica gel chromatography.

[α]o -19,3@ (in c-0,1-CHtCI2).

Example 30 Tmpac-2eg-Tm5al-Nle-F
x-Chaton -NH-iBuo In the same manner as in Example 4, the title compound 20 of Example 29 was prepared.
oxidize with 100 mg of Collins reagent.

[αcoD=-2t, 0° (c=0.2, CH
2Cl, medium).

Example 31 BOC-Tmsal-Nle-Cha(OH)CHtC
HCl-NHBuo 636.7y,g BOC-Tmsal-Nle-OH
and 479.8 m9 of Ht N CH (Chm)
a-Chloa-lactone KCl2 in DMF 1.05x
ff of N-ethylmorpholine and 1. 14io2 of propane phosphoric anhydride (50% in CHzClt). The reaction solution was concentrated and the residue was dissolved in ethyl acetate and 2N
Partition between hydrochloric acid. The organic phase was washed once with saturated aqueous sodium carbonate solution and twice with saturated aqueous sodium chloride solution,
Dry with N at SO and concentrate. The residue is subjected to silica gel chromatography using hexane/ethyl acetate (2:I).

The resulting pure OC-Tmsal-Nle-NHCH
(C1un)-Cl-chlorolactone followed by 3,6
m(1) with n-butylamine at room temperature. The reaction solution is concentrated and the residue is crystallized from methylene chloride/hexane.

[α]o-38, 9° (c=0.48 in MeOH).

Example 32 BOC-Tmsal-Nle-Cha(01()Ala
=NH-Bu.

Similar to Example 1, I, 5Li BOC-Tm5a
l -Nle-OH+ I, 29 H-Cha (
OH)Ala-NH-Bu and 0.79 HOBT are reacted in methylene chloride. The crude product is crystallized from methanol/methylene chloride/ether.

[α]D-39, 5° (c=0.2, CH, pull, medium).

Example 33 3EG-Tmsal-Nle-Cha(OH)Thio
bly-NHnBu.

3EG-0 of 117.8H)! and 350JIIF H-T m5al-N le -Cha(OH)Thi
obly -NH=nBuT)iF/DMF(1:
1) with 105.5x9 of hydroxybenzotriazole and 111.811!9 of EDCI. Concentrate the reaction mixture, add saturated aqueous sodium carbonate solution at 5° and take up the mixture in ethyl acetate. The organic phase is washed with dilute hydrochloric acid and dried over Mg5Oa. The crude product is chromatographed on silica gel with ethyl acetate/alcohol (99:1).

[α]D=-18.4° (c=0.5, CH, CI, medium).

Example 34 3Eg-Tm5al-N1e-Cha(OH)
B ly -N Hu0 In the same manner as in Example 1, H-Tmsal of 502+9
-Nle-Cha(O)()Bly-NHBu 2.3
Niji no Tetrahydrofuran/DMF (1:1) 2,8
u HOBT, 15+1 3EG-OH and 143
Next, react with N-ethyl-N"-(3-dimethylaminopropyl)carbodiimide.HCe in 9. The crude product is crystallized from methylene chloride/hexane [α]o-3
1,4' (c=0,5,cH7c+tl).

Example 35 Me-3egs-Tm5al-His-Cha
(OH)B ly -N HB u.

1751 g of the methyl xanthate of triethylene glycol monomethyl ether was dissolved in 400×9 H-Tmsal-I (is
-Cha(O)[)Bly-NF(React with Bu.

After 15 hours, the reaction mixture was diluted with ethyl acetate, washed with water and the crude product was dissolved in methanol (2-1
0%) on silica gel.

[a] o-49, 8° (c=0.2, CHt Cbl
).

Example 36 3EG-Tmsal-Nle-Cha(OIl)CH,
CHC(l-NI4Bu.

In the same manner as in Example 1, 338H H-T m5al
-Nle-Cha(Of()CH,CHC?!-NI-
[Bu-HCf2 at 127 mg HOBT, 0.086
2 shoulder g of N-ethyl morpoline, 184119 of 3EG
-OH and 11 mg of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide.HCl2. The crude product is chromatographed using methanol/water (8:2) or on Clobrep PR-18.

[(Z]D = 22, 8' (c = 0, 6, CHt
Cl, medium).

Example 37 4-PyCH,OCS-Tmsal-Nle-F, -C
hakin -N H-iB u0 In the same manner as in Example 35, 4101N9 H-T m5al -N Ie-
React with F, -Chatin-NHiBu. The crude product is methanol/methylene chloride! Chromatography with −5%.

[a] o-53, Oo (c = 0, 1, CH
2CL).

Example 38 MPA-C3-Tmsal-Nle-Chatin-L
eu-α-Pie0 400 shoulder y H-Tm5al -N le -Chat
In -Leu-α-Pic is reacted with 115 u of the isothiocyanide of 3-(4-morpholino)propylamine in DMP. After 2 hours the reaction mixture is diluted with ethyl acetate, ether is added and the precipitated product is filtered.

Ca]D = 68, 6° (c = 0.2, CHtC
I inside).

Example 39 4-PyCH,OCS-Tmsal-Nle-F*-C
hanon-NH-iBu.

Dissolve 300 t7 of the alcohol from Example 37 in DMSO/benzene ■:I. Add 443 mg DCC and 171 g dichloroacetic acid at 0-5°. After 24 hours, 200 pg of oxalic acid dissolved in methanol are added, and after 1 hour the mixture is filtered and the filtrate is partitioned between ethyl acetate and saturated sodium carbonate solution. Dry the organic phase (MgSO,)
L. Concentrate.

[α]D = 19.1 (c = 0.1q CH, C1, medium).

Example 40 Niacin-2egs-Tm5al-Nle-
P * -Chatin -N H-iB u0 In the same manner as in Example 35, 514 m9 of H-T + m5
al-Nle-Ft-Chatin-NH-iBu 4
It is reacted with 3021 g of methylxanthate of diethylene glycol mononicotinic acid ester in the presence of dimethylaminopyridine of 0rn9.

[ff]D-71.2° (c=0.1.CHtC1t
During).

Example 41 Niacin-2egs-Tmsal-Nle-P, -C
haton-N H-iB u.

Similarly to Example 39, alcohol 28 of Example 4o
R9 was oxidized with 35119(7) DCC and 0.5 equivalents of dichloroacetic acid.

[α=0=-13,5° (c=0.05, CH
, CI, in).

Example 42 Tmpac-2egs-Tmsal-Nle-F2-
Chatin-NH-iBuo 610xy H-Tm5a in the same manner as in Example 35
l-Nle-F2-Chatin-NH-iBu, I
After adding dimethylaminopyridine of oomy, it is reacted with 500y of methylxanthate of diethylene glycol mono(3,4,5-trimethoxy)phenylacetate.

[α]o-49,1 (c=0.1. in CHtC1t).

Example 43 Tmpac-2egs-Tm5al-NIe
-Ft-ChatonNH+BLI.

Similarly to Example 39, alcohol 300z of Example 42
y is oxidized with 33 tries of DCC and I, 5 tries of dichloroacetic acid.

[α]D=+1.8° (c=0.1. in CHtC1t)
.

Example 44 BOC-Tmsal-Nle-Cha(OH)CFtC
FtCP,.

In the same manner as in Example 1, 94 mg of (4R,5S)-
5-amino-6-cyclohexyl-1,1,1°2.2
．． 3.3-heptafluoro-4-hexanol 108
mg BOC-Tmsal-Nle-OH, 78 Takumi H
React with DCC of OB T and 61 shoulder 9.

[a] o-28, 9° (c=2.0, CI-i,'
CI, CF)).

Example 45 Niacin-2egs-Tmsal-Nle-Cha (
OH)-CFtCF, CF3゜T-BOC- of Example 44 in the same manner as Example 35
251 g of the deprotected product are reacted with 15 mg of the methylxanthate of diethylene glycol mononicotinate in the presence of 5J19 dimethylaminopyridine.

[α]D--38.5° (c=0.7, in CH, C12).

Example 46 3EG-Tmsal-Nle-Cha(OH)CF20
F.

C.F.

In the same manner as in Example 1, 55 positions of the L-BOC-deprotected product of Example 44 were converted to 20z9(1)3EG-0■], 1
React with 2m9 HOBT and 18mg DCC.

[α=0=-26,8° (c=0.2, CH,
CI, middle).

Example 47 3EG Tm5al Nle Cha CF2
Crj2CFs.

In the same manner as in Example 4, the title compound 30 of Example 46 was prepared.
oxidize my with Collins reagent.

[αcoD −t5.8° (c=O, l,
in CH7CIt).

Example 48 3EGS-Tm5al-Nle-Cha
(OH)Thiobly-NH-nBuo 3EGS-OEt of 380319 and H of 790 shoulder 9
-Tmsal-Nle -Cha(OH)-Thiob
ly-NH-nBu in methylene chloride for 15.8J!
9 with N-dimethylaminopyridine (DMAP).

After 1.5 hours at room temperature, the mixture is heated to reflux for 1.5 hours. The reaction mixture was further diluted with methylene chloride and IN
Wash once with sodium bisulfate solution, once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution and dry over pJ a 2 S Oa. After filtration and concentration, the resulting residue is subjected to silica gel chromatography using hegisan/ethyl acetate (30 Nia 0-0:100).

[α]D--56.8° (c=0.5, CHtCl
inside).

Example 49 BOC-Tmsal-Nle-Chatin-Leu (
S) -α-Pic0 In the same manner as in Example 1, 235 m9 of H-Chati
n -Leu(S) -a -Pic to 210m9 BOC-Tmsal-Nle-OH, 90H HOBT
and 115 mg of DCC. The crude product is chromatographed with 0.5-3% methanol in methylene chloride.

[α']o = 13, 0° (c = 0.2, CHlCl
,During).

Example 50 3 EG'; -Tm5al -Nle -Chat
in -Leu(S)-α-Pie0 135 mg of H-Tmsal-Nle-Chatin-
Leu(S)-α-Pie in methylene chloride at 80 m
g of 3EGS-OEt. 24 hours later,
The reaction mixture is chromatographed with 0.5-5% methanol in methylene chloride.

[αcoD=-66,7° (c=0.1,
in CHtCL).

Example 51 7 EGS-Tmsal-Nle-Chatin-Le
u(S)-α-Pie0 Similarly to Example 50, H-T+n5a of L35m9
l -N le -Chatin -Leu(S)
-a-Pic 120J119 7EGS-OEt
I reacted.

[α几=-58,3° (c=0.2, in CHt CIt).

Example 52 BOC-Leu-R-Tmsal-Nle-Chati
n-Leu-a-Pic.

H-Tm5al-NIe-Chatin-Le
u -a -P 1c550 Takumi,) evening) -le 1.6+1
To a solution consisting of 2 and 0.93x (1 (1) 5N-HC (2 in methanol), 18011 g of BOC-Loynal and 0,6x (l) of methanol, followed by 31x9 of cyanoborohydride Sodium is added and the resulting mixture is stirred at room temperature for 24 hours.

The reaction mixture is poured into ice water, made alkaline with 2N aqueous sodium bicarbonate solution, and subsequently extracted with methylene chloride. The organic phase is dried and concentrated, and the resulting residue is subjected to silica gel chromatography using 5% ethanol in methylene chloride. The title compound is [α]D=-
33,1' (c=0.38 in ethanol).

Example 53, H-Leu-R-Tmsal-Nle-Chatin
-Leu-α-Pic.

250η BOC-Leu-R-Tmsal-Nle
-Chatin-Leu-a-Pic, 10
31 tI2 of concentrated hydrochloric acid (in glacial acetic acid) was added at 0°C. Heat the resulting mixture to room temperature. After 3 hours, the mixture is concentrated. The residue is partitioned between saturated aqueous sodium bicarbonate and 5% ethanol (in methylene chloride). The organic phase is dried and concentrated and the residue is chromatographed on silica gel using IO% ethanol in 1% concentrated ammonia solution. The title compound has [α]D=-25,0°(
c=0.34 in ethanol).

``Effects of the Invention The compounds of the present invention exhibit pharmacological activity and are therefore useful as medicines.

They are, for example, inhibitors of renin activity towards human tetradecapeptide substrates, and they can be used in the method of Cumin et al.
och, Biophys, Acta) 913, IO
~19 (1987)] or C-nin binding bond-Oite1
A concentration of 0-'M-10-''M inhibits pure human renin enzyme activity by 50%.

Antibody trapping method of Bolsen and Jorgensen [[J Tarino Endocrine Metab J (J,
Cl1n, Endocrin, Metab,)
, 39, (1974) 816-825], they inhibit human plasma renin activity at concentrations of I 0-5M-10-■M.

The compounds of the invention are therefore useful in the prevention and treatment of conditions characterized by enzyme dysfunction and requiring inhibition of enzyme activity.

As renin inhibitors they are suitable for use, for example, in the prevention and treatment of hypertension and heart failure ("congestive heart disease").

Preferred compounds for the prevention and treatment of hypertension and heart failure are Examples 1122.23.24.35 and 51;
In particular, the title compounds of Examples 22 and 23.

The title compound of Example 23 is the most preferred compound with respect to renin inhibition; for example, its measurement results in an antibody trapping test show that the lowest inhibition layer/ff10, +51-
1 mol/12, the highest inhibitory concentration! 5 nanomol/Q,,IC
s. =1.5 nanomol/12. Therefore, Example 2
Compound 3 is large for mammals, such as humans! Shoulder g~
It has been shown that it can be administered at a daily dose of 10 mg.

Furthermore, the compounds of the present invention exhibit antiretroviral activity and are therefore useful in the treatment of diseases caused by retroviruses, including HTLV-1 and HTLV-1. This activity is F
eLV Cat Model U Cerny and Essex, Sea
R.C. Press, 1979, pp. 233-256, Kotzkarel et al., Journal of National
Cancer Institute J (J, Natl.
, Cancer Inst.

), 57, 1095-1099 (1976), Kotter et al.
, Yet, med, As5oc,) I 66.
449-453 (1975), Essex et al. [Science J (Sc 1ence), +9O-1790-7
92 (1975)] - can be demonstrated in a disease model of human AIDS.

It has been reported that treatment with 3°-azido-3′-deoxythyminone for 14 days 3 (Jtg) could show a 10-fold reduction in FeLV titers but did not lead to cure (e.g. 25th ICAAC1 in Minneapolis
September 30th - October 2nd).

Upon administration of the compounds of the invention, eradication of the virus can be observed. Dosage ranges for antiretroviral activity are conventional ranges, for example in the range of 5-20 x9/kti/day.

In the case of the above-mentioned indications, the doses to be administered will depend in each case on the compound used, the type of administration and the desired treatment.

Generally, the compound is 0.02ttrg/kl? ~about 20R
Satisfactory results are obtained when administered at a daily dose of 9/9 (animal body weight). Large animals are mammals, such as humans,
Directions - The daily dose is from about 1t9 to about 50 (JRg), conveniently administered orally in doses of up to four times a day, eg from 0.25 yrg to about 50011 g, eg in divided or sustained release form.

The compounds of the invention may be administered in free form, or in the form of pharmacologically acceptable salts when acidic or basic groups are present. Their salt forms have the same order of activity as the free form and can be prepared by known methods. In addition, this invention
It relates to pharmaceutical formulations containing the free or pharmaceutically acceptable salt forms of the compounds of the invention, optionally together with pharmaceutical adjuvants and/or carrier substances.

These pharmaceutical preparations may be formulated enterically, preferably for oral administration, eg as a tablet, or for parenteral administration, eg as an injectable solution or suspension. Furthermore, intranasal administration of the compounds of the present invention is also possible. Suitable arithmetic sprays can be produced in a manner known per se.

Claims (14)

[Claims] (1) Silicon-containing renin inhibitor. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R_1 means (C_1-_5) alkyl, A is N
- is a protected amino acid group or a peptide, or has the formula ▲ mathematical formula, chemical formula, table, etc. ▼ [wherein X represents O, S or H_2, and R_2 is optionally amino, hydroxy or (C_2-_5)
Straight-chain or branched (C_1-_1
_0) an alkyl group, a 5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms, oxygen or sulfur atoms or 1 nitrogen atom and 1 oxygen atom and/or 1 sulfur atom, or the heteroaryl moiety is 5 or 6 members and has 1 or 2 nitrogen atoms,
a heteroaryl (C_1-_5) alkyl group, a straight-chain or branched (C_1-_5) alkoxy group, containing an oxygen or sulfur atom or one nitrogen atom and one oxygen atom and/or one sulfur atom; (C_6-_
1_0) Aryl-(C_1-_5) alkoxy group] or A means a group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, W is -O-, NR_7 -or-CH_2 (however,
R_7 is hydrogen or linear or branched (C_1-_5
) means an alkyl group), and R_3 is hydrogen, straight chain or branched (C_1-_2_
0) Sugar group bonded as an alkyl group or glycoside, optionally substituted, saturated or unsaturated, linear or branched (C_2-_3_0) alkylcarbonyl group, (C_3-_6) polyhydroxy is an alkylcarbonyl, phosphoroyl, bis-(dimethylamino)phosphoroyl, sulfo, aroyl, heteroaroyl, arylalkyl, arylalkylcarbonyl or heteroarylalkylcarbonyl group, or a biotinoyl group, or R_3 is a formula ▲ mathematical formula, chemical formula, table etc.▼ (In the formula, R_4 is hydrogen or a side chain of a D- or L-amino acid, and R_5 and R_6 are the same or different and each represents hydrogen,
(C_1-_5) alkyl, (C_2-_5) hydroxyalkyl or (C_2-_5) aminoalkyl) or R_3 is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_5 and R_6 have the above meanings, p is an integer from 0 to 5, and E means a bond or a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼) or R_3 is the formula F-(CH_2)p-E- (where p and E have the above meanings, F is the formula ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_7 represents the group shown above), m is an integer from 1 to 20, and n is from 0 to B means a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_7 is the above-mentioned meaning, R_8 means a hydrophilic or lipophilic amino acid side chain], D is a group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ [wherein, X is the above-mentioned R_8 has the same meaning as R_6, R_1_0 is hydroxyl or amino group, R_8 has the same meaning as R_6, R_1_0 is hydroxyl or amino group,
1_1 is hydrogen, or R_1_0 and R_1_1 together form an oxo group, R_1_2 and R_1_3 independently of each other mean fluorine or hydrogen, R_1_4 and R_1_5 are the same or different and each represents hydrogen, Straight chain or branched (C_1-6) alkyl group, or each formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1_6 is a straight chain or branched (C_1-_5) alkyl group or straight chain or a branched (C_1-_5) hydroxyalkyl group, and R_1_7 is a hydroxyl group, a linear or branched (C_1-_5) hydroxyalkyl group,
C_1-_5) alkoxy group, amino or (C_1-_5)
_5) means a group represented by an alkylamino group, an aminomethylpyridyl group, a benzyl group, or a protected or unprotected amino acid), where Y means a bond, or -O-, ▲ mathematical formula, chemical formula, table, etc. ▼ or ▲ There is a mathematical formula, chemical formula, table, etc. ▼ (In the formula, R_1_6 and R_1_8 independently represent hydrogen or fluorine, or each has the same meaning as R_8 above.) or D means a group represented by the formula ▲ which may be a mathematical formula, a chemical formula, a table, etc. ▼ (wherein R_9, R_1_0, R_1_1 and n have the above meanings)] 1. The renin inhibitor according to 1. (3) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼( I ＾Y) [In the formula, A＾Y is a formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X＾Y is S or O means, R_2^Y is t-butyloxy, benzyloxy, 5
- denotes aminopentyl or isobutyl), or A^Y means a group represented by the formula ▲ Numerical formula, chemical formula, table, etc.▼ (wherein, X^Y has the above meaning, R_3^ Y represents hydrogen, methyl, glucopyranosyl, pyridinoyl, 3,4,5-trimethoxybenzoyl, m means an integer of 2-7, n means an integer of 0-2) Meaning, B^Y is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. , 4-imidazolylmethyl, pyridinemethyl or trimethylsilylmethyl), and D^Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_9^Y is isobutyl, benzyl or When R_1_2^Y and R_1_3^Y each represent hydrogen, R_1_0^Y means a hydroxyl group, and R_
1_1^Y means hydrogen, or when R_1_2^Y and R_1_3^Y each represent fluorine, R_1_0^Y and R_1_1^Y together form an oxo group, and R_1_4^Y means hydrogen. and R_1_5^Y is hydrogen, methyl, i-propyl, i-
Butyl, 2-butyl or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1_6^Y represents i-butyl or 2-butyl,
R_1_7^Y represents aminomethylpyridyl), Y^Y is a bond or a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1_8^Y and R_1_9^Y each represent fluorine or R_1_8^Y means n-butyl, isobutyl, 2-butenyl, methyl, methylthiomethyl, benzyl, isopropyl or chlorine, and R_1_\9\\Y represents hydrogen) The compound according to claim 1 or 2, which means: (4) (2R, 4S, 5S, 8S, 11R)-6,9,
12-triaza-2-(2-E-butenyl)-8-butyl-5-cyclohexylmethyl-4-hydroxy-15
,15-dimethyl-11-trimethylsilylmethyl-1
4-Oxa-7,10,13-trioxo-hexadecanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-2,8-dibutyl-5-cyclohexylmethyl-4-hydroxy-15,15-dimethyl-11-trimethylsilylmethyl-14-oxa-7,10,13
-trioxo-hexadecanoic acid butyramide, (3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-
difluoro-3-hydroxy-14,14-dimethyl-
10-trimethylsilylmethyl-13-oxa-6,9
, 12-trioxo-pentadecanoic acid isobutyramide, (4S,7S,10R)-5,8,11-triaza-7
-Butyl-4-cyclohexylmethyl-2,2-difluoro-14,14-dimethyl-10-trimethylsilylmethyl-13-oxa-3,6,9,12-tetraoxo-pentadecanoic acid isobutylamide, (3S,4S,7S ,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-3-hydroxy-14,14-dimethyl-10-trimethylsilylmethyl-13-oxa-6,9,12-trioxo-
Pentadecanoyl-(L)-leucine-α-picolylamide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-2-(2-E-butenyl)-5-cyclohexylmethyl-4-hydroxy-8-(4-imidazolyl)-methyl-15,15-dimethyl-11-trimethylsilylmethyl-14-oxa-7,10, 13-Trioxo-hexadecanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-2-butyl-5-cyclohexylmethyl-4
-Hydroxy-8-(4-imidazolyl)-methyl-1
5,15-dimethyl-11-trimethylsilylmethyl-
14-oxa-7,10,13-trioxo-hexadecanoic acid butyramide, (3R,4S,7S,10R)-
5,8,11-triaza-7-(2-E-butenyl)-
4-cyclohexylmethyl-2,2-difluoro-3-
Hydroxy-14,14-dimethyl-10-trimethylsilylmethyl-13-oxa-6,9,12-trioxo-pentadecanoic acid isobutyramide, (4S,7S,10R)-5,8,11-triaza-7
-(2-E-butenyl)-4-cyclohexylmethyl-
2,2-difluoro-14,14-dimethyl-10-trimethylsilylmethyl-13-oxa-3,6,9,1
2-Tetraoxo-pentacarboxylic acid isobutyramide, (3R,4S,7S,10R)-5,8,11-triaza-7-(2-E-butenyl)-4-cyclohexylmethyl-2,2-difluoro-3 -Hydroxy-10-trimethylsilylmethyl-14,17,20,23,26
, 29,32,35-octaoxa-6,9,12-trioxo-hexatriacontanoic acid isobutyramide, (4S,7S,10R)-5,8,11-triaza-7
-(2-E-butenyl)-4-cyclohexylmethyl-
2,2-difluoro-10-trimethylsilylmethyl-
14,17,20,23,26,29,32,35-octaoxa-3,6,9,12-tetraoxa-hexatriarontanoic acid isobutyramide, (2R,4S,5S,8S,11R)-6,9 ,12-
Triaza-2-(2-E-butenyl)-5-cyclohexylmethyl-4-hydroxy-8-(4-imidazolyl)-methyl-11-trimethylsilylmethyl-15,1
8,21,24-tetraoxa-7,10,13-trioxo-pentacosanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-2-(2-E-butenyl)-5-cyclohexylmethyl-4-hydroxy-8-(4-imidazolyl)-methyl-11-trimethylsilylmethyl-15,1
8,21,24,27,30,33,36-octaoxa-7,10,13-trioxo-heptatricontanoic acid butyramide, (3S,4S,7S,10R)-5,8,11-triaza-4- cyclohexylmethyl-3-hydroxy-7-
(4-imidazolyl)methyl-14,14-dimethyl-
10-trimethylsilylmethyl-13-oxa-6,9
, 12-trioxopentadecanoyl-(L)-leucine-α-picolylamide, (3S,4S,7S,10R
)-5,8,11-triaza-4-cyclohexylmethyl-3-hydroxy-7-(4-imidazolyl)methyl-10-trimethylsilylmethyl-13,16,19,
22-Tetraoxa-6,9,12-trioxotricosanoyl-(L)-leucine-α-picolylamide, (
3S,4S,7S,10R)-5,8,11-triaza-4-cyclohexylmethyl-3-hydroxy-7-[
4-(1-(2,5,8,11-tetraoxa-lauroyl))-imidazolyl]methyl-10-trimethylsilylmethyl-13,16,19,22-tetraoxa-
6,9,12-trioxo-tricosanoyl-(L)-
Leucine-α-picolylamide, (3S,4S,7S,10R)-5,8,11,18-
Tetraaza-4-cyclohexylmethyl-3-hydroxy-7-(4-imidazolyl)methyl-21,21-dimethyl-10-trimethylsilylmethyl-20-oxa-6,9,12,19-tetraoxo-docosanoyl-
(L)-leucine-α-picolylamide, (3S,4S,7S,10R)-17-amino-5,8
, 11-triaza-4-cyclohexylmethyl-3-hydroxy-7-(4-imidazolyl)methyl-10-trimethylsilylmethyl-6,9,12-trioxo-heptadecanoyl-(L)-leucine-α-picolylamide, (3S ,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-
Difluoro-3-hydroxy-19-nicotinoyl-1
0-Trimethylsilylmethyl-13,16,19-trioxa-6,9,12-trioxo-nonadecanoic acid-isobutyramide, (4S,7S,10R)-5,8,11-triaza-7
-Butyl-4-cyclohexylmethyl-2,2-difluoro-19-nicotinoyl-10-trimethylsilylmethyl-13,16,19-trioxa-3,6,9,1
2-tetraoxo-nonadecanoic acid-isobutyramide, (3S,4S,7S,10S)-5,8,11,18-
Tetraaza-4-cyclohexylmethyl-7-butyl-
3-hydroxy-21,21-dimethyl-10-trimethylsilylmethyl-20-oxa-6,9,12,19
-Tetraoxo-docosanoyl-(L)-leucine-α
-Picolylamide, (3S,4S,7S,10R)-1
7-amino-5,8,11-triaza-7-butyl-4
-Cyclohexylmethyl-3-hydroxy-10-trimethylsilylmethyl-6,9,12-trioxoheptadecanoyl-(L)-leucine-α-picolylamide, (3S,4S,7S,10R)-5,8,11 -triaza-7-butyl-4-cyclohexylmethyl-3-hydroxy-10-trimethylsilylmethyl-14,17,
20,23,26,29,32,35-octaoxa-
6,9,12-trioxo-hexatriacontanoyl-(L)-leucine-α-picolylamide, (3S,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl- 3-Hydroxy-19-nicotinoyl-10-trimethylsilylmethyl-13,16,19-trioxa-6,9,12
-trioxo-nonadecanoyl-(L)-leucine-α
-Picolylamide, (3S,4S,7S,10R)-5
,8,11-triaza-7-butyl-4-cyclohexylmethyl-3-hydroxy-10-trimethylsilylmethyl-13,16,19-trioxa-6,9,12-
trioxo-nonadecanoyl-(L)-leucine-α-
Picolylamide, (3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-
Difluoro-3-hydroxy-10-trimethylsilylmethyl-6,9-dioxo-11-(4-pyridylthio)acetyl-undecanoic acid-isobutyramide, (3R,4S,7S,10R)-5,8,11-triaza- 7-Butyl-4-cyclohexylmethyl-2,2-
Difluoro-3-hydroxy-10-trimethylsilylmethyl-6,9-dioxo-11-biotinoyl-undecanoic acid-isobutyramide, (4S,7S,10R)-5,8,11-triaza-7
-butyl-4-cyclohexylmethyl-2,2-difluoro-10-trimethylsilylmethyl-13,16,1
9-trioxa-3,6,9,12-tetraoxononadecanoic acid-isobutyramide, (3R,4S,7S,1
0R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-3-hydroxy-19-(3,4,5-trimethoxyphenyl)-
Acetyl-10-trimethylsilylmethyl-13,16
, 19-trioxa-6,9,12-trioxo-nonadecanoic acid-isobutyramide, (4S,7S,10R)-5,8,11-triaza-7
-butyl-4-cyclohexylmethyl-2,2-difluoro-19-(3,4,5-trimethoxyphenyl)acetyl-10-trimethylsilylmethyl-13,16,
19-trioxa-3,6,9,12-tetraoxo-
Nonadecanoic acid-isobutyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-2-chloro-8-butyl-5-cyclohexylmethyl-4-hydroxy-15,15-dimethyl-1
1-trimethylsilylmethyl-14-oxa-7,10
, 13-trioxo-hexadecanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-8-butyl-5-cyclohexylmethyl-4
-Hydroxy-2,15,15-trimethyl-11-trimethylsilylmethyl-14-oxa-7,10,13
-trioxo-hexadecanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-11-trimethylsilylmethyl-2-(E-
2-Butenyl)-5-cyclohexylmethyl-8-butyl-4-hydroxy-7,10,13-trioxo-1
5,18,21,24-tetraoxa-pentacosanthionate butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-11-trimethylsilylmethyl-2-(E-
2-Butenyl)-5-cyclohexylmethyl-8-butyl-4-hydroxy-7,10,13-trioxo-1
5,18,21,24-tetraoxa-pentacosanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-2-(2-E-butenyl)-5-cyclohexylmethyl-4-hydroxy-8-(4-imidazolyl)methyl-11-trimethylsilylmethyl-14,17
,20,23-tetraoxa-7,10-dioxo-1
3-thioxo-tetracosanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-11-trimethylsilylmethyl-2-chloro-5-cyclohexylmethyl-8-butyl-4-hydroxy-7,10,13-trioxo-15,18,21
,24-tetraoxa-pentacosanoic acid butyramide, (3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-
Difluoro-3-hydroxy-10-trimethylsilylmethyl-13-oxa-6,9-dioxo-14-(4
-pyridyl)-12-thioxo-tetradecanoic acid isobutyramide, (3S,4S,7S,10R)-5,8,11,13-
Tetraaza-7-butyl-4-cyclohexylmethyl-
3-hydroxy-10-trimethylsilylmethyl-16
-(4-morpholinyl)-6,9-dioxo-12-thioxo-hexadecanoyl-(L)-leucine-α-
Picolylamide, (4S,7S,10R)-5,8,11-triaza-7
-butyl-4-cyclohexylmethyl-2,2-difluoro-10-trimethylsilylmethyl-13-oxa-
3,6,9-trioxo-14-(4-pyridyl)-1
2-thioxo-tetradecanoic acid isobutyramide, (3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-
Difluoro-3-hydroxy-19-nicotinoyl-1
0-Trimethylsilylmethyl-13,16,19-trioxa-6,9-dioxo-12-thioxo-nonadecanoic acid isobutyramide, (4S,7S,10R)-5,8,11-triaza-7
-Butyl-4-cyclohexylmethyl-2,2-difluoro-19-nicotinoyl-10-trimethylsilylmethyl-13,16,19-trioxa-3,6,9-trioxo-12-thioxo-nonadecanoic acid isobutyramide, (3R ,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-
Difluoro-3-hydroxy-19-(3,4,5-trimethoxyphenyl)acetyl-10-trimethylsilylmethyl-13,16,19-trioxa-6,9-dioxo-12-thioxo-nonadecanoic acid isobutyramide, ( 4S,7S,10R)-5,8,11-triaza-7
-butyl-4-cyclohexylmethyl-2,2-difluoro-19-(3,4,5-trimethoxyphenyl)acetyl-10-trimethylsilylmethyl-13,16,
19-trioxa-3,6,9-trioxo-12-thioxo-nonadecanoic acid isobutyramide, (4R,5S,8S,11R)-6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1, 1,
1,2,2,3,3-heptafluoro-4-hydroxy-12-t-butyloxycarbonyl-11-trimethylsilylmethyl-7,10-dioxododecanoic acid butyramide, (4R,5S,8S,11R)- 6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1,1,
1,2,2,3,3-heptafluoro-4-hydroxy-11-trimethylsilylmethyl-14,17,20-
Trioxa-7,10-dioxo-13-thioxo-
20-nicotinoyl-eicosanoic acid butyramide, (4R,5S,8S,11R)-6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1,1,
1,2,2,3,3-heptafluoro-4-hydroxy-11-trimethylsilylmethyl-15,18,21,
24-Tetraoxa-7,10,13-trioxo-pentacosanoic acid butyramide, (5S,8S,11R)-
6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1,1,1,2,2,3,3-heptafluoro-11-trimethylsilylmethyl-15,18,2
1,24-tetraoxa-4,7,10,13-tetraoxo-pentacosanoic acid butyramide, (2R,4S,5S,8S,11R)-6,9,12-
Triaza-11-trimethylsilylmethyl-2-(E-
2-butenyl)-5-cyclohexylmethyl-8-butyl-4-hydroxy-13-thioxo-7,10-dioxo-15,18,21,24-tetraoxa-pentacosanthionate butyramide, (2S,6S,7S , 10S, 13R)-3, 8, 11
,14-tetraaza-10-butyl-7-cyclohexylmethyl-6-hydroxy-2-isobutyl-17,1
7-dimethyl-13-trimethylsilylmethyl-16-
Oxa-4,9,12,15-tetraoxo-octadecationocarboxylic acid-α-picolylamide, (2S,6S,7S,10S,13R)-3,8,11
,14-tetraaza-10-butyl-7-cyclohexylmethyl-6-hydroxy-2-isobutyl-13-trimethylsilylmethyl-17,20,23,26-tetraoxa-4,9,12-trioxo-15-thioxo-hepta Cosanthionocarboxylic acid-α-picolylamide, (2S,6S,7S,10S,13R)-3,8,11
, 14-tetraaza-10-butyl-7-cyclohexylmethyl-6-hydroxy-2-isobutyl-13-trimethylsilylmethyl-17,20,23,26,29
, 32,35,38-tetraoxa-4,9,12-trioxo-15-thioxo-nonatriacontanethionic acid-α-picolylamide, (3S,4S,7S,10
R)-5,8,11,14-tetraaza-7-butyl-
4-Cyclohexylmethyl-3-hydroxy-13-isobutyl-10-trimethylsilylmethyl-14-t-
Butyloxycarbonyl-6,9-dioxo-tetradecanoyl-(L)-leucine-α-picolylamide, (
3S,4S,7S,10R)-5,8,11,14-tetraaza-7-butyl-4-cyclohexylmethyl-3
-Hydroxy-13-isobutyl-10-trimethylsilylmethyl-6,9-dioxotetradecanoyl-(L
)-leucine-α-picolylamide. (5) A method for producing a compound represented by formula (I), comprising a) formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (wherein A, B and R_1 are claims 2 or b) formula (III) ▲ mathematical formula, chemical formula, table, etc. ▼(III) A compound represented by the formula A-OH (wherein R_1, B and D have the meanings as defined in claim 2) is converted into a compound represented by the formula A-OH (wherein A has the meaning as defined in claim 2) or c) by oxidizing a compound of formula (I), where R_1_0 is a hydroxyl group and R_1_1 is hydrogen. forming an oxo group). (6) The compound according to any one of claims 1 to 4, which is used as a medicine. (7) The compound according to any one of claims 1 to 4, which is used as a renin inhibitor. (8) The compound according to any one of claims 1 to 4, which is used for hypertension and heart failure. (9) A pharmaceutical composition containing a pharmaceutically acceptable form of the compound according to any one of claims 1 to 4 together with a pharmacologically acceptable adjuvant and/or diluent. (10) Use of the hydrophilic renin inhibitor according to any one of claims 1 to 4 in the manufacture of a medicament for treating hypertension and heart failure. (11) Use of the hydrophilic renin inhibitor according to any one of claims 1 to 4 in the manufacture of a medicament for treating diseases caused by retroviruses. (12) Use of the pharmaceutical composition according to claim 10 in the manufacture of a medicament for treating hypertension and congestive heart disease. (13) Use of the pharmaceutical composition according to claim 10 in the manufacture of a medicament for treating diseases caused by retroviruses. (14) The compound according to any one of claims 1 to 4, which is used as a medicine.