JPS63295541A - Novel peptides, manufacture and use - Google Patents

Abstract

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

Description

[Detailed description of the invention] [Industrial use! F1 The present invention relates to novel renin inhibitors, to pharmaceutical compositions containing them, as well as to their preparation and use.

DESCRIPTION OF THE INVENTION The present invention provides compounds of formula (I).

[wherein A is an acyl group such as BOC-proline or peptide, where R1 is optionally (Cl-
8) Straight-chain or branched (Cs-+.) optionally substituted by alkoxy or (Cs-+.)aryloxy
t. ) alkyl group, (C3-1°) cycloalkyl group,
'(Cs-+.)cycloalkyl-(Cl-1)alkyl group, (Cs-s.)aryl group, with one or two nitrogen atoms, oxygen or sulfur atoms or one nitrogen atom and one oxygen atom a 5- or 6-membered heteroaryl group containing one sulfur atom or both, or a 5- or 6-membered heteroaryl group containing one or two nitrogen, oxygen or sulfur atoms or one heteroaryl-(C+-S)alkyl group, straight-chain or branched (C+-s)alkoxy group or (Ca-+) containing a nitrogen atom and/or one oxygen atom and one sulfur atom; .)aryl-(C,-S)alkoxy group, or with the formula R+5O(CHICH,O)n(CH
z) m- (where RIs are straight or branched chains (C+-S
) means an alkyl group, n is an integer of 1 to 20, and m
is an integer from 1 to 5), R1 and R, independently mean a hydrophilic or hydrophobic side chain, R2 means a hydroxyl or amino group, and R1 represents a hydrogen group. or R8 and R3 together represent an oxo group, B represents the formula (wherein R, has the same meaning as R1, R7 and R
, has the same meaning as R2 and R1, and R9 and R
1° each independently represents hydrogen or fluorine; Ro and Rlt are the same or different groups, each representing hydrogen, a straight-chain or branched (C+-s) alkyl group;
(Cs-+.)Aryl-(C+-S)alkyl group or heteroaryl group is 5- or 6-membered and has one or two
denotes a heteroaryl-(C+-S)alkyl group containing one nitrogen atom, oxygen or sulfur atom, or one nitrogen atom and one oxygen atom and/or one sulfur atom [in the formula ,RI! means a straight chain or branched chain (Ct-i) alkyl group or a straight chain or branched chain (Cl-1) hydroxyalkyl group, R1
, is a hydroxyl group, straight or branched (C+-s)
means a group in which the alkoxy group, amino or alkyl group is a straight chain or branched chain (Ct-S) alkylamino group, aminomethylpyridyl group or benzyl group), and C means a bond; 10-1-N- also stands for hydrogen or fluorine, or R.

or B is of the formula (wherein R, , R, and R have the meanings given above and D is -N- or -CH-) means a group represented by ] An asymmetrically substituted carbon atom may be in the R- or S-configuration. The configuration represented by the following formula (I') is preferred.

Preferred compounds represented by formula (1) are those having formula (I').

[In the formula, A' means benzyloxycarbonyl, tertiary butoxycarbonyl, pivaloyl, benzoyl or adamantylcarbonyl, R1v means cyclohexylmethyl, phenylmethyl, isobutyl, and R1 and R1' together represent oxo or R,f means hydrogen, R,' means hydroxyl, R4y is phenylmethy/butyl, isobutyl,
B' means isopropyl, pyridylmethyl, 2-butenyl or methylthiomethyl, and B' is of the formula R,
t means a hydroxyl group, R, F means hydrogen, or when R, F and R10' each represent fluorine, R
7v and R, F together mean an oxo group)
C' is a bond or a group represented by the formula (wherein R11' and RIF are fluorine, or the sound Oj-(dimension, R,,', R4v) is 1. ．．
P means a group represented by -71-1*pot*), R11' means hydrogen or methyl, and R12ν is hydrogen, methyl, isopropyl, imbutino-2-butyl or ' is isobutyl and R14' is aminomethylbiridyl].

In formula (1), R6 is straight-chain or branched alkyl having 1-10 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2,2
-dimethylethyl, pentyl, hexyl, etc., meaning especially methyl, tertiary butyl and 2,2-dimethylethyl; when substituted by aryloxy it is especially phenoxymethyl or 1- or 2-naphthyloxymethyl, preferably is l-naphthyloxymethyl,
When cycloalkyl has 3-10 carbon atoms,
When cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl is (Cs-+a)cycloalkyl-(Cl-1)alkyl, cycloalkyl may have the above meaning; The group is in particular 2-cyclohexylethyl- or 2-(1-adamantyl)ethyl, in which R6 is (Cs
-+. )-aryl, especially phenyl or l-
or 2-naphthyl, preferably l-naphthyl,
When it is a heteroaryl group, in particular pyridyl, chenyl or furyl, and when it is a heteroarylalkyl group, the heteroaryl and alkyl groups preferably have the meanings given above, and are straight-chain or branched alkoxy groups. Sometimes it means especially ethoxy or tertiary butoxy,
When (Ca-1°)aryl-(C+-2)-alkoxy it has the meaning given especially in the case of aryl and alkyl, and benzyloxy is preferred.

In the group R110(CHICH20)n(CHx)11-, R11 preferably means methyl, n is an integer from 4 to 12, preferably 7, and m is l
It is preferable that

Hydrophobic side chains mentioned for R1 and R4 are, for example, n-butyl, isobutyl, benzyl, 2-butenyl,
It may be a 2-methylthioethyl or cyclohexylmethyl group, and the hydrophilic side chains mentioned for R1 and R4 may be, for example, 4-imidazolylmethyl, pyridylmethyl or hydroxyalkyl groups.

R11 and RI2 are (Ca-+.)aryl-(C+
-5) When referring to an alkyl group, they represent phenyl-(C
+-5)-Alkyl, especially a benzyl group, is preferably meant; when they denote a heteroarylalkyl group, a heteroaryl group is especially meant a pyridyl, chenyl or furyl group, alkyl including the groups mentioned above.

When R11 and R12 represent (Cl-4)alkyl,
Alkyl has the meaning given above in relation to Rs, restricted to 1-5 carbon atoms.

When R+s represents a (C+-a)alkyl group, alkyl means the groups mentioned above, but in particular isopropyl, n-butyl, isobutyl and 2-methylbutyl. Preferably, hydroxyalkyl means hydroxymethyl or hydroxyethyl. When R14 means aminomethylpyridyl, it is preferably aminomethyl-2-pyridyl.

The method for producing a compound represented by formula (I) includes: a) reacting a compound represented by formula (n) with a compound represented by 2H-B [wherein B is described above]; b) Formula (I)1
oxidizing a compound represented by the formula [E] [wherein R7 and R1 together form an oxo group], C) A compound of formula (I) [wherein R2 and R1 together form an oxo group] is reduced to form a compound of formula (I).
) forming a compound of the formula [wherein R,=OH and R,-H], d) reducing the multiple bonds found in the side chains R4, R, or R17, or e) converting the protecting group (I) [wherein A is t-BOC]
The method consists of eliminating the compound represented by the formula and further acylating the free amine.

The method of step a) comprises converting the acid of formula (U) by methods known in peptide chemistry, e.g. This is preferably carried out by reaction with an amine of the formula H-B using a method in the presence of hexylcarbodiimide (with addition of 1-hydroxybenzotriazole).

The method of step b) is carried out by oxidation of the alcohol of formula (I) with CrOs.Pyz (choline reagent) in a solvent such as methylene chloride or DMF to form the corresponding ketone. It will be done.

The method of step C) is preferably reduced with NaBHa in a solvent such as methanol so that the ketone of formula (I) forms the corresponding alcohol.

The method of step d) is preferably carried out at a temperature of room temperature - 60°C, l-
It is carried out at a hydrogen pressure of 5 atmospheres in a solvent such as ethanol with palladium (10% on activated carbon) as catalyst.

The reaction of process step e) is preferably carried out such that the t-B OC group is cleaved in the presence of trifluoroacetic acid at a temperature of 0-5°C, and the free amine is cleaved with an active acid in a solvent such as methylene chloride. Preference is given to acylation with derivatives such as hydroxy-succinimide esters.

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

The compound represented by formula (I) produced according to the present invention is:
Racemates and/or mixtures of diastereoisomers, which can be separated and purified by known methods, can be separated by known methods. When containing groups, these compounds can also optionally form salts, for example metal salts such as sodium salts or acid addition salts such as hydrochloric acid salts.

In the examples given below, all temperatures are in degrees Celsius;
It is uncorrected.

The compounds shown in the examples in the form of abbreviations are all listed in claim 3 in the order given in the examples.

In the examples presented below, the following abbreviations are used:

HF, CHaOH (3R,4S)-4-amino-5-cyclohexyl-2
,2-difluoro-3-hydroxy-valeric acid HFxCho 0H (4S)-4-amino-5-cyclohexyl-2゜2-
Difluoro-3-oxo-valeric acid H-Cha(OH)A(2a-OH (2R14S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-methyl-caproic acid H-Cha(OH )N(2e -OH (2R,4S,5S)-5-amino-2-butyl-6-
Cyclohexyl-4-hydroxy-caproic acid H-Cha(0)Nffa -OH (2R,5S)-5-amino-2-butyl-6-cyclohexyl-4-oxo-caproic acid H-Cha(OH )
BI2y -OH (23,4S,53)-5-amino-2-(E -2-
butenyl)-6-cyclohexyl-4-hydroxy-caproic acid H-Cha(0)B12. -0H (2R,5S)-5-Amino-2-(E -2-butenyl)-6-cyclohexyl-4-oxo-caproic acid H-Cha(OH)Phe-OH (2R,4S,53) -5-amino-2-benzyl-6
-Cyclohexyl-4-hydroxy-caproic acid H-Cha(○)Phe-OH (2R,5S)-5-amino-2-benzyl-6-cyclohexyl-4-oxo-caproic acid H-L eu (O
Meu -OH (2R,5S)-5-amino-2-ynbutyl-7-methyl-4-oxo-caprylic acid OC Tertiary-butyloxycarbonylbenzyloxocarbonyl [α]D Always measured at 20 °C .

Example 1, tB OCCha(0)B Iy
F2Cha-N H1Bu FzChaNHtBu was incubated at 0 °C for 2 h, then at room temperature for 24 h.
t-BOC-C in 2 mQ of tetrahydrofuran in the presence of 120 mg of hydroxybenzotriazole and N,N'-dicyclohexyl tribodiimide F97u.
React with 70 rng of ha(0)Bly-OHl.

The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was purified with silica gel using 50% ether/hexane.
Apply to chromatography. [alD=-7,3°(C
-0,4, methylene chloride).

Example 2, t-BOC-Cha(0)Bly
-F 2Ch.

-N HiBu The product 22+119 described in Example 1 was dissolved in 1.8 mQ of methylene chloride and choline reagent (Cro3*P
Yz) 84mg. After 3-0 minutes, ethyl acetate is added, the mixture is filtered through Hyflo and silica gel, and the filtrate is lyophilized under benzene. [alD-+4.6' (C-0,17, methylene chloride).

Example 3, t-BOC-Cha(0)NQe
-F zchaNHiBu The product 12+119 described in Example 1 was dissolved in 1°2 of ethanol.
ml and hydrogenated for 4 hours in the presence of 1.4 mg of palladium on carbon. The catalyst is filtered off and the filtrate is concentrated by evaporation. [σ]D=-5.7°(C-0,
14, methylene chloride) Example 4, t-B OC-Leu(0)Leu
-F 2Cha-Leu-2-picoline F, Cha-Leu-2-picoline 115u, t
-BQC-Leu(0)Leu-OH 78mg, hydroxybenzotriazole 601119 and N,N''-
Example 1 Dicyclohexylcarbodiimide 47119
React in the same way. The crude product is chromatographed on silica gel using ether. [α]D-
+8.0° (C-0,2, methylene chloride).

Example 5, t-BOC-Cha(0)Phe
-Cha(OH)Phe-NHBu Cha(OH)Phe-NHBu34ray, t-BO
40 m+9 of C-Cha(0)Phe-OH, 25 m9 of hydroxybenzotriazole and 20 m9 of N,N'-dicyclohexylcarbodiimide are reacted in the same manner as in Example 1. The crude product was dissolved in ether (4
0-100%) on silica gel. [σID-+13.7° (C-0,11 methylene chloride).

Example 6, t-B OC-Cha(0)B(ly
-Cha(OH)Bgy-NHBu Cha(OH)BQy -N HBo37uCha(0
) BI2y-OH4019, 17TRg of hydroxybenzotriazole and 2211g of N,N'-dicyclohexylcarbodiimide are reacted in the same manner as in Example 1.

The crude product is chromatographed using ether in hexane. [σID−−11.4°(C−〇,
methylene chloride).

Example 7, t-BOC-Cha(0)NI2e
-Cha(OH)? 1e-NHBu The product 30+9 described in Example 6 is dissolved in 2 mQ of ethanol and hydrogenated for 3 hours in the presence of palladium on carbon 3+119. [σID--13,0° (C-0,1°methylene chloride).

Example 8, t-BOC-Cha(OH)BQy
-Cha(OH)BQy-NHBu Product 101119 described in Example 6 was dissolved in methanol 0°5
m12 and reacted with 5 mg of sodium borohydride. After half an hour, the solution is diluted with ether and washed with aqueous tartaric acid (2N) solution, the organic phase is dried over magnesium sulphate and concentrated by evaporation. The product is obtained as an approximately 2:l mixture of diastereoisomers.

Example 9, 2-Cha(0)Bffy-Cha(
OH)BI2yNHBu The product 301119 described in Example 6 was dissolved in a l:l mixture of trifluoroacetic acid and methylene chloride (0°5
mff) for 1 hour, thereby cleaving the protecting groups. The mixture was then diluted with methylene chloride, extracted with aqueous soda (2N) and the organic phase was dried over potassium carbonate, concentrated by evaporation and diluted with 0.5 m
React with N-(benzyloxycarbonyloxy)-succinimide 151119 in Q at 50°C. The crude product is dissolved in ether, washed with water, dried and concentrated by evaporation. [σ]D--14.6°(C-0,05
, methylene chloride).

Example 10, L-B OC-Leu(0)Leu
-F 2Cha-Leu-2-picoline The product 651119 described in Example 4 is reacted analogously to Example 2 with 150 mg of Choline reagent. [σID-16,2° (C-0,1, methylene chloride) of the title compound.

intermediate product.

t-BOC-Cha(0)BQy-OHt-BOC-C
ha(OH)B (293 mg of 2y-OH is dissolved in 7 mQ of dimethylformamide and reacted with 1.54 g of choline reagent. The reaction mixture is partitioned between ether and aqueous potassium bisulfate, the organic phase is extracted with water and magnesium sulfate is added. and concentrated by evaporation.

Example 11, BOC-Cha(0)BI2y-
Cha(0)1)B(Ly -Leu -a-picoline H-Cha(OH)B(2y -Leu -a-picoline 66 mg, BOC-Cha(0)BI2y OH5
2 mg of hydroxybenzotriazole and 30 mg of N,N'-synchrohexylcarbodiimide are reacted in the same manner as in Example 1. The crude product is chromatographed using 3% methanol in methylene chloride. [αID--26,0°(C-0.

1. Methylene chloride).

Example 12. BOC-Cha(○)B Qy-C-A
QaHBu H-Cha(OH)AQa-NHBuo, 84g5BO
1.09 g of C-Cha(0)Bf2y-○H, 0.5 g of hydroxybenzotriazole, and 0.6 g of N,N'-dicyclohexylcarbodiimide are reacted in the same manner as in Example 1. Convert the crude product into ether and methylene
Chromatograph on silica gel using chloride (20-60%). [σ]D−-16°9°(C=0
．． 2, methylene chloride).

The compounds of formula (I) exhibit pharmaceutical activity and are therefore useful as medicines.

Those compounds are inhibitors of renin activity and have been shown, for example, by Cumin et al. (F, Cum1n et al.
al), C Biochemistry Eto Biophysica Acta (B 1ochev+1ca-B 1ophys-
Acta) Vol. 913, pp. 10-19 (1987) 1
or in a renin binding assay, inhibits the enzymatic activity of pure human renin by 50%.

Poulsen and Jirgensen (K, Poulsen
and J. rgensen), [Journal Op.
Clinical Endocrinology and Metabolism (J.

Cl1n, Endocrin-Metab) Vol. 39, pp. 816-825 (1974) 1, these compounds inhibit human plasma renin activity at concentrations of 10-'M-10-''M.

The compounds of the invention are therefore useful for the prevention and treatment of conditions characterized by enzymatic dysfunction or for which inhibition of enzymatic activity is indicated.

As renin inhibitors they are suitable for example for the prevention and treatment of hypertension and cardiac dysfunction ('congestive heart failure').

Preferred compounds for the prevention and treatment of hypertension and cardiac dysfunction are Examples 1 and 4-12, especially Examples 5.6.
and 8-1O1, particularly the title compounds shown in Examples 5.6.8 and 10, most preferably the compound shown in Example 8.

The title compound shown in Example 8 is a preferred compound for renin inhibition, such as a minimum inhibitory concentration of 0.15 nmoles/litre, a maximum inhibitory concentration of 15 nmoles/liter, and a 50% inhibitory concentration of 1.5 nmoles/liter. This was tested in an antibody capture test, thus showing that the compound shown in Example 8 can be administered to large mammals such as humans at a daily dose of 1 m9 to 10 mg.

The compounds of the invention also exhibit antiretroviral activity;
It is therefore useful for the treatment of diseases caused by retroviruses, including HTLV-IN and 1. This activity is
FeLV cat type [Cete + Essex (Cerny +
E 5sex), CRC Press (CRC-pr
ess), pp. 233-256 (1979); Cockerell et at., Journal of the National Cancer Institute) (
J, NatL Cancer, I n5t) No. 57
Volume, pp. 1095-1099 (1976), Kotel et al.
Cotterat al), Journal of the American Veterinary Medicine Association (
J, A+a.

Vet, med, As5oc) Volume 66, 449-45
3 (1975), Essex et al.
al), Science Volume 190,
790-792 (1975)] (can be demonstrated by a disease model for human AIDS).

3°-azido-3'-deoxy-thymidine 3 for 14 days
Treatment with 01119 could show a 10-fold reduction in FeLV-titer, but no cure was achieved, as shown for example (25th ICAAC in Minneapolis, September 3).
0 days - 1 October 2 days). By administering the compounds according to the invention, eradication of the virus can be observed.

The dosage range for antiretroviral activity is that conventionally used, for example within the range of 5-20 mg/kg/day.

For the above indications, the dosage administered will vary depending on the particular compound and the intended treatment. In general, satisfactory results were obtained when compound
When administered at a daily dose of 9/kg body weight. For large mammals, such as humans, suitable daily doses are from about 1 m9 to about 500 mg, e.g. up to 4 times daily in divided doses, in doses of I; It is preferable to administer the drug directly.

The compounds of the invention may be administered in free form or, if acidic or basic groups are present, in the form of medically acceptable salts. Such salt forms have the same degree of activity as the free form and can be produced by known methods. The present invention
It likewise concerns pharmaceutical formulations containing the compounds of the invention in free form or in the form of pharmaceutically acceptable salts, optionally together with pharmaceutical auxiliaries and/or carrier substances. be. Such formulations may be formulated for enteral, preferably oral administration, eg, as a tablet, or for parenteral administration, eg, as an injection solution or suspension.

Claims (11)

[Claims] (1) Compound represented by formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, A is an N-protected amino acid group, or the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. An acyl group represented by ▼,
Here, R_6 is a straight or branched chain (C_1_-_6) optionally substituted with (C_1_-_6) alkoxy or (C_6_-_1_6) aryloxy.
_1_0) alkyl group, (C_3_-_1_8) cycloalkyl group, (C_3_-_1_0) cycloalkyl-
(C_1_-_5) alkyl group, (C_6_-_1_0
) an aryl group, a 5- or 6-membered heteroaryl group containing one or two nitrogen, oxygen or sulfur atoms or one nitrogen atom and one oxygen and/or sulfur atom; or a heteroaryl group in which the heteroaryl group is 5- or 6-membered and contains one or two nitrogen atoms, oxygen or sulfur atoms, or one nitrogen atom and one oxygen atom and/or one sulfur atom; (C_1_-_5) Alkyl group, straight chain or branched chain (C_1_-_5) Alkoxy group or (C_8_-_1_0) aryl-(C_1_-_5)
alkoxy group, or formula R_1_6O(CH_2CH_
2O)_n(CH_2)_m- (wherein R_1_5 means a straight chain or branched chain (C_1_-_5) alkyl group, n is an integer of 1 to 20, and m is an integer of 1 to 5. R_1 and R_4 independently represent a hydrophilic or hydrophobic side chain; R_2 represents a hydroxyl or amino group; R_3
means hydrogen, or R_3 and R_4 together represent an oxo group, and B
is a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_6 has the same meaning as R_1, R_7 and R_8 have the same meaning as R_2 and R_3,
R_9 and R_1_0 each independently represent hydrogen or fluorine, and R_1_1 and R_1_2 are the same or different groups, each representing hydrogen, a straight or branched chain (C_1_-_
5) Alkyl group, (C_6_-_1_0)aryl-(
C_1_-_5) The alkyl group or heteroaryl group is 5- or 6-membered and has one or two nitrogen atoms, oxygen or sulfur atoms, or one nitrogen atom and/or both one oxygen atom and one sulfur atom. Heteroaryl- (C_1_-_5) alkyl group containing one of the above means a group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1_3 is a straight chain or Branched chain (C_1_-
_5) Alkyl group or straight chain or branched chain (C_1_
-_5) hydroxyalkyl group, R_1_4 is a hydroxyl group, straight chain or branched (C_1_-_5
) means a group in which the alkoxy group, amino or alkyl group is a straight or branched chain (C_1_-_6) means an alkylamino group, aminomethylpyridyl group or pencil group), where C means a bond or -O-,-
N- or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula,
R_1_6 and R_1_7 independently represent hydrogen or fluorine, or have the meaning indicated in R_4), or B is a formula ▲ a mathematical formula, a chemical formula, a table, etc. ▼ (in the formula, R_4, R_5, R_7 and R_1_2 have the above meanings, and D is -N- or -CH
means a group represented by -. ] (2) Formula (Iy) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Iy) [In the formula, A^y means benzyloxycarbonyl, tertiary butoxycarbonyl, bivaloyl, benzoyl or adamantylcarbonyl, R_1^y is cyclohexylmethyl, phenylmethyl,
means isobutyl, R_2^y and R_3^y together mean oxo group, or R_2^y means hydrogen, R_3^y
means hydroxyl, R_4^y means phenylmethyl, n-butyl, isobutyl, isopropyl, pyridylmethyl, 2-butenyl or methylthiomethyl;
By has ▲mathematical formula, chemical formula, table, etc.▼ (In the formula, R_6^y is isobutyl, benzyl or cyclohexylmethyl, and when R_9^y and R_1_0^y each represent hydrogen, R_7^y represents a hydroxyl group. Meaning, R_8^
y means hydrogen, or when R_9^y and R_1_0^y each represent fluorine, R_7^y and R_8^y together mean an oxo group), and C ^y is a bond or a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1_6^y and R_1_7^y are fluorine, or R_1_8^y has the meaning of R_4^y, means hydrogen), R_1_1^y means hydrogen or methyl, R_1_
2^y is hydrogen, methyl, isopropyl, isobutyl, 2
-Butyl or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1_3^y is isobutyl, R_1_
4^y is aminomethylpyridyl). A compound according to claim 1. (3) (3R,4S,7R,10S)-5-aza-7-
(E-2-butenyl)-10-tert-butyloxycarbonylamino-11-cyclohexyl-4-cyclohexylmethyl-2,2-difluoro-3-hydroxy-6
,9-dioxo-undecanoic acid-isobutyramide. (4S,7R,10S)-5-aza-7-(E-2-butenyl)-10-tert-butyloxycarbonylamino-11-cyclohexyl-4-cyclohexylmethyl-
2,2-difluoro-3,6,9-trioxo-undecanoic acid-isobutyramide. (3R,4S,7R,10S)-5-aza-7-butyl-10-tert-butyloxycarbonylamino-11-
Cyclohexyl-2,2-difluoro-3-hydroxy-6,9-dioxo-undecanoic acid-isobutyramide. (2S,6R,7S,10R,13R)-3,8-diaza-2,10-diisobutyl-13-tert-butyloxy-carbonylamino-7-cyclohexylmethyl-5
,5-difluoro-6-hydroxy-15-methyl-4
,9,12-trioxo-valmitic acid-2-picolylamide. (2R,4S,5S,8R,11S)-6-aza-2,
8-dibenzyl-11-tert-butyloxycarbonylamino-12-cyclohexyl-5-cyclohexylmethyl-4-hydroxy-7,10-dioxo-lauric acid-butyramide. (2R,4S,5S,8R,11S)-6-aza-2,
8-di(2-butenyl)-11-tert-butyloxycarbonylamino-12-cyclohexyl-5-cyclohexylmethyl-4-hydroxy-7,10-dioxo-
Lauric acid-butyramide. (2R,4S,5S,8R,11S)-6-aza-2,
8-dibutyl-11-tert-butyloxycarbonylamino-12-cyclohexyl-5-cyclohexylmethyl-4-hydroxy-7,10-dioxo-lauric acid-butyramide. (2R, 4S, 5S, 8R, 10RS, 11S)-6-
Aza-2,8-di(2-butenyl)-11-tert-butyloxycarbonylamino-12-cyclohexyl-5
-Cyclohexylmethyl-4,10-dihydro-7-oxo-lauric acid-butyramide. (2R,4S,5S,8R,11S)-6-aza-11
-benzyloxycarbonylamino-2,8-di(2-
butenyl)-12-cyclohexyl-5-cyclohexylmethyl-4-hydroxy-7,10-dioxo-lauric acid-butyramide. (2S,7S,10R,13S)-3,8-diaza-2
, 10-diisobutyl-13-tert-butyloxycarbonylamino-7-cyclohexylmethyl-5,5-difluoro-15-methyl-4,6,9,12-tetraoxo-valmitic acid-2-picolylamide. (2S, 5R, 7S, 8S, 11R, 14S) -3,9
-Diaza-5,11-di(E-2-butenyl)-14-
tertiary butyloxycarbonylamino-8,14-di(
cyclohexylmethyl)-7-hydroxy-2-isobutyl-4,10,13-trioxo-tetradecanoic acid-
2-picolylamide. (2R,4S,5S,8R,11S)-6-Aza-8-
(2E-Butenyl)-11-tert-butyloxycarbonylamino-12-cyclohexyl-5-cyclohexylmethyl-4-hydroxy-2-methyl-7,10-dioxo-lauric acid-butyramide. A compound according to claims 1 and 2 selected from. (4) a) Formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, A, R_1 and R_4 are described before] A compound represented by the formula H-B [In the formula , B is as previously described]; b) a compound of formula (I) [wherein R_7=OH and R_8=H
] by oxidizing the compound represented by the formula [I] [wherein R_7
and R_8 together form an oxo group], and c) produce a compound represented by formula (I) [wherein R_2 and R_3 together form an oxo group]. d) reducing the multiple bonds found in the side chains R_4, R_1_6 or R_1_7, or e) protecting groups. A method for producing a compound represented by formula (I), which comprises removing from the compound represented by formula (I) [wherein A is t-BOC], and further acylating the free amine. . (5) The compound according to any one of claims 1 to 3, which is for pharmaceutical use. (6) The compound according to any one of claims 1 to 3, which is used as a renin inhibitor. (7) The compound according to any one of claims 1 to 3, which is used for antihypertension or anticardiac dysfunction. (8) A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 in a confectionery-acceptable form together with a confectionery carrier or diluent. (9) Use of the pharmaceutical composition according to claim 6, which is for the manufacture of a medicament for treating hypertension or congestive heart failure. (10) Use of the pharmaceutical composition according to claim 6, which is for producing a medicament for treating diseases caused by retroviruses. (11) The compound according to any one of claims 1 to 3, which is for pharmaceutical use.