JPS6133152A - Renin inhibitive compound - 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 The present invention relates to a novel organic compound that inhibits aurinin, a method for producing this compound, a synthetic intermediate used in this method, and a method for treating hypertension using this compound.

Linin is a proteolytic enzyme that is mainly synthesized and stored in a special part of the kidney called the glomerular apparatus. Three different physiological conditions: (α) a decrease in blood pressure into or within the kidney itself, (b) a decrease in blood volume in the body, or (C)
Decrease in sodium concentration in renal peripheral tubules leads to circulation.
Causes nin release.

When linin is released from the kidneys into the blood, the linin-angiotensin system is activated, causing vasoconstriction and sodium conservation, both of which lead to an increase in blood pressure. Renin acts on the circulating protein angiotensinogen to release a fragment called angiotensin I (AI). AI itself has slightly more pharmacological activity, but after further cleavage by a second enzyme, angiotensin converter enzyme (ACE), it converts into the active molecule angiotensin II (and III). The main pharmacological effects of AI are vasoconstriction and stimulation of the adrenal cortex, leading to sodium retention and release of the cohormone aldosterone. A■ is thus cleaved by aminopeptidase ζ to produce angiotensin ■ (AI[[). AII[ has a weaker vasoconstrictor activity than Al, but is a stronger inducer of aldosterone release.

Renin inhibitors are required as hypertension regulators and as diagnostic agents for identifying hypertension caused by excess renin.

With this goal in mind, the leaning-angiotensin system has traditionally been formulated or treated as an ACE inhibitor. But A.C.
E acts on various substrates other than angiotensin (ICAI), particularly undesirable side effects such as pain, "leaky" tubules, prostaglandin release, and various behavioral and neurological effects. Furthermore, ACE suppression is A
It becomes an accumulation of I. Although Al has a much smaller vasoconstrictor activity than All, its presence negates the hypotensive effects of synthetic occlusion.

Inhibition of other targets in the linin-angiotensin system, such as AI, with compounds such as saralasin, blocks AM activity, but remains intact, possibly enhancing the hypertensive effects of A.

On the other hand, the side effects that occur when linin is inhibited from acting on its substrates are unknown. Thus, considerable research efforts are being undertaken to develop convenient inhibitors of renin. Past research has been directed at substrate congeners such as rinin antibodies, ibustatin, phospholipids and tetrapeptides and octapeptides to tridecapeptides. These inhibitors have shown both weak activity in inhibiting leanin production or weak specificity in inhibiting only leanin. However, Boge et al. (Natu
re + vol. 303, 81, 1983), and 5zel
ke et al. describe polypeptide congeners with non-butide linkages. (Nature, vol. 299, 555
.

(1982) which produces potent renin inhibition and shows a high degree of specificity for this enzyme.

According to the present invention, formula (I): (wherein A represents an N-protecting group, R represents 0 or 1, and B represents hydrogen, hydroxy, NH, lower alkyl or aryl, provided that A is When N-protecting group, B is NH and when n is 0, B is hydrogen, hydroxy, lower alkyl or arylalkyl; R1, X, and R
5 is a lower alkyl or hydrophilic, lipophilic or aromatic amino acid side chain, which may be the same or different. R2, R4, R7
, R8 and Ro are hydrogen or lower alkyl, and may be the same or different: X is NH, 01S, So or SO,
and R6 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, or an N-protecting group, provided that when X is HE, R6 is an N-protecting group. ) is provided.

Preferred compounds are R2, R4, R7, R11 and R9
is hydrogen, R1 is benzyl, α- or β-naphthylmethyl and R5 is inbutyl or cyclohexylmethyl. The most preferred compound is R1
is imidazol-4-yl-methyl, and X is S, S
O, or O and R1 is cyclohexylmethyl.

The center of the chiral CC of the present invention is “R” or S
``S° configuration,'' preferably the S° configuration.

As used herein, "N-protecting group" is used to protect the N-terminus against unfavorable reactions during synthetic procedures, to prevent exopeptidase attack on the final compound, or to increase the solubility of the final compound. sulfonyl, acyl, acetyl, hivaloyl, t-butylacetyl, t-butyloxycarbonyl (CEoc), carbopenzyloxycarbonyl or hachenzoyl group, or L- or D-aminoacyl which itself can be similarly protected. This includes, but is not limited to, remaining funds.

As used herein, "lower alkyl" refers to 1 to 6 carbon atoms.
A straight or branched alkyl group having the following: methyl, ethyl, lepropyl, isopropyl, n-butyl, in-butyl/l/, set-7'fl, 2-methylhexyl, leupentyl, 1 -Methylbutyl, 2,2-
Examples include, but are not limited to, dimethylbutyl, 2-methylinthyl, 2,2-dimethylpropyl, and ruhexyl.

As used herein, "cycloalkyl" refers to alicyclic radicals including, but not limited to, cyclohexyl and cyclozebutyl.

As used herein, "cycloalkylalkyl" refers to an alicyclic residue bonded to an alkyl group, and includes, but is not limited to, cyclohexylmethyl and cyclopentylmethyl.

The term "aryl" as used in is refers to an unsubstituted or substituted aromatic ring, including, but not limited to, phenyl, halophenyl, lower alkylphenyl, naphthyl, and heteroaryl.

As used herein, "arylalkyl" refers to an unsubstituted or substituted aromatic ring attached to an alkyl group, including, but not limited to, benzyl, α- and β-naphthylmethyl, halopencyl, and alkoxybenzyl. It's not a thing.

As used herein, monolipophilic or aromatic amino acid side chain 1 refers to an amino acid side chain that has an affinity for lipids or has an aromatic ring, such as inbutyl, isopropyl, 5ec-butybenzyl, imidasol-4-yl- Examples include, but are not limited to, methyl, p-hydroxybenzyl, alpha- and beta-naphthylmethyl, (pyrazolyl)methyl, (thiazoyl)methyl and cyclohexylmethyl. As used herein, "hydrophilic amino acid side chain" refers to an amino acid side chain that has an affinity for water, including, but not limited to, serine, threonine, allothreonine, homoserine, cysteine, ornithine, arginine, and glutamine. do not have. General examples of amino acid side chains, both in the specification and in the claims, are taken as examples for whether they occur naturally in proteins and for both the D- and L-forms.

A11a", -H4s-, -L as used herein
aw”.

"Phg" indicates alanine, histidine, leucine and phenylalanine, respectively.

The following examples will serve to demonstrate how to make the novel compounds of this invention.

Example 1 3-t-Butyloxycarbonylamino-5-methylhex-1-ene 4-tyltrifhenylphosphonium bromide 1 (L97 g (30,
Butyllithium (19.8 ml of 1,55 M hexane solution) was extracted from a suspension of 70 mmol) at -78° C. (dry ice/acetone bath) for 5 minutes with stirring under an argon atmosphere. . After 10 minutes, the -78°C bath was changed to a 0°C bath, and after 30 minutes, the solution became orange, so it was cooled to -78°C again. The solution was then poured into anhydrous tetrahydrofuran by draining 6.
00 g (27.91 mmol) of the -78 DEG C. stirred solution was added over 30 minutes. 150 g of condensate was added to warm the mixture to room temperature over a period of 3 hours. Hexane 4X 1
The organic phases extracted with 00a/ were combined, washed with 100d of salt solution, dried over Na, SO, and concentrated to give crude 3-1-butyloxycarbonylamino-5-methylhex-1-ene6.
I got 5gQ.

371 g (60%) of 3-1-butyloxycarbonyl-amino-5-methylhex-1-ene were obtained by chromatography using ether/hexane (1/9). Mass spectrum: El, M+-57=156;
C1, (M±ωf=214° Example 2° 3-t-Butyloxycarbonylamino-5-methylhex-1-ene in 20 WJ of dichloromethane 0.43.
9 (2.0 mmol) of m-chlorinated perbenzoin'ff CMCPB480% MCPBA 1.51 g, 7
．． 0 mmol) was added. After 68 hours, the reaction mixture was heated to 0°C.
Cool to 0°C and 10% Na2 while stirring! 10s liquid 5
Added d. After 15 minutes, the mixture was washed and extracted with dichloromethane. Combined organic phase t-0℃1O%N%S0゜6m
2×6 m of saturated NaHCOg and 5 ml of water.

Drying over MfSO, filtration and evaporation afforded 0.42N of crude 3-1-butylox7carbonylamino-5-methyl-1,2-ocunhexane. Pure 3- by chromatography on 840!5011 (hexane/ether, 3/1)
1-butyloxycarbonylamino-5-methyl-1,
0-27 g (59%) of 2-oxohexane was obtained.゛・Mass spectrum: hr+=zz9゜Example 3゜3-t-Butyloxycarbonyl-amino-5-methyl-1,2-oxohexane 20 in 8.7 d of methanol
Cyclohexyl mercaptan 102# (0.87 mmol) and triethylamine 88 rtl (0.87 mmol) were added to a stirred solution of 0.1 mmol (0.87 mmol 1=-P). The resulting solution was refluxed for 2 hours and then evaporated to a residue of 40%
rnSso, 3-t-butyloxycarbonylamino-1-cyclohexylmercapto-2-hydroxy-5-methylhexane 2814 (
94%) t-got. Mass spectrum: M+=a 45
° Analysis calculation value: C, 62-6: H, 10, 2: N, 4.
0° Measured value: c, 6z, ta: H, 1o, 4: y, 3
．． 9°Hexane The method of Example 3 was used, but the cyclohexyl mercapta/ was replaced with 3-phenylpropyl mercaptan to give the desired compound. (Yield 93%) Mass spectrum: M+=
381° analysis calculation value: C, 66,1; ff, 9.3
;N, 3.7.

Measured value: C, 66,3; H, 9,4: N, 3.6
.

Example 5 The method of Example 3 was used, but the cyclohexyl mercaptan was replaced with phenyl mercaptan to yield the desired compound.

(Yield 93%) Mass spectrum: M+ = 339° Example 6° The method of Example 3 was used but cyclohexyl mercapta/
was substituted with β-naphthyl mercaptan to obtain the desired compound.

Yield 65%, mass spectrum: hr+=a-89
Example 7 The method of Example 3 was used but the cyclohexyl mercaptan was replaced with benzyl mercaptan to give the desired compound. Yield 57%, j: 11 quantity Spectrum: M+ = 353゜Example 8゜1-p-bromophenylmercapto-3-t-butyl oxene The method of Example 3 was used, but cyclohexylmercaptan was replaced with p-bromophenylmercaptan. The desired compound was obtained by substitution. Yield 71%. Mass spectrum: M+ = 418° Example 9 3-t-butyloxycarbonylamino-5-methyl-1,2-oxohexane 200° in 8.7 d methanol
■ Phenol 90 in a stirred solution of (o, s 7 mmol)
# (Q96 mmol) and triethylamine 9719 (0
, 96 mmol) was added. The solution was refluxed for 4'4 hours, then evaporated and the residue was treated by the Madograph method (7/3, hexane/ether) to give pure 3-tert-butyloxycarbonylamino-2-hydroxy-5- Methyl-1-phenoxyhexane 711v (
25%). Mass (cuttle: M+ = 323° 200 μm of 3-t-butyloxycarbonylamino-5-methyl-1,2-oxohexane in 10 m methanol
(0.87 mmol) in a stirred solution of aniline (79 μJ) (
0.87 mmol was added. After the solution was refluxed for about 20 hours, the residue obtained by evaporation was chromatographed on Si (
3/2, hexane/ether) to yield 140~(50%) of 3-t-butyloxycarbonylamino-2-hydroxy-5-methyl-1-phenylaminohexane. Mass spectrum: M = 322° Example 11° About 0.75 M methanolic HCIC in a stirred solution of the product compound of Example 3 (about 0.25 mmol) in methanol
10 mg) was added and the opening medium was evaporated for 8-12 hours to yield the desired compound.

This was used without purification.

Example 12 Using the method of Example 11 and using the product compound of Example 4, the desired compound was obtained.

Mercaptohexane Hydrochloride Using the method of Example 11 and the product compound of Example 5, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 6, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 7, the desired compound was obtained.

Droxy-5-methylhexane hydrochloride Using the method of Example 11 and the product compound of Example 8, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 9, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 10, the desired compound was obtained.

Boc-H6s-OH in 3-ml of dry dimethylformamide
A suspension of 7211+9 (0.28 mmol) was heated to -23°C.
Dry dimethylformamide while stirring with
-Amino-1-cyclohexylmercapto-2-hydroxy-5-methylhexane hydrochloride (98 rng, 0.2
8 mmol of 3-1-butyloxycarbonylamino-
1-Cyclohexylmercapto-2-hydroxy-5-
A solution of methylhexane (prepared using the method of Example 11) and N-methylmorpholine 29 (0.28 mmol) was added. Then hydroxybenzotriazole (HOET, 59 Da, 0.43 mmol) and N,N
'-Dicyclohexylcarbodiimide (DCC, 59~
, 0.28 mmol) was added. The mixture was allowed to warm to room temperature for 2 hours. After 22 hours, the mixture was evaporated and partitioned into ethyl acetate 18d and saturated NrtEC. Separate the layers and wash the organic phase with a salt solution for 5 minutes.
, filtered and evaporated solid was chromatographed on 5iOI (9/1. dichloromethane/methanol) to yield the desired compound 86d (63%). Mass spectrum: (M+H)+=483° According to the method of Example 19, 3-amino-1-cyclohekiflumerkabuto 2-
The desired compound was obtained in 62% yield by using 3-amino-2-hydroxy-5-methyl-1-(J-phenylpropylmercapto)hexane hydrochloride in place of human xy-5-methylhexane hydrochloride. Mass spectrum: (M+H
) + = 519 ゜ 」」 − − 夛 夛 夛 ・ ・ ・ ・ ・ ・ ・ ム 主 ム 主 主 ・ 主 主 主 主 主 主 主 主 主 主 主 主 主 主 主 主 見 見 見 見 」」 」」 」」 」見」 」」 The compound was treated with methanolic HCII by the method used in Examples 11-18 and the corresponding deprotected HCII salt was used without purification as described below.

Boc-Phe-OH1 in anhydrous tetrahydrofuran 3N
A -12°C solution of 9,2 # (0,0725 mmol) was stirred and N-methyl mol 7 olein 8.0 μ/(0,0
After removing 725 mmol), 9.4 pl (0.0725 mmol) of inbutyl chloroformate was added.

After 3 minutes, N-methylmorpholine 16.0 μ7 (0,14
A solution of the above ECC base salt in anhydrous tetrahydrofuran containing 5 mmol) at 12 DEG C. was heated for 30 seconds. 1
After 5 minutes, the mixture was warmed to room temperature and the solvent was evaporated. The residue is 20 aJ of ethyl acetate) and saturated NaHCO,
The solution was distributed between 6d and 6d. The layers were separated and the organic layer was washed with 5 d of salt solution, dried over NaJ104 and evaporated. Eli
O.

Treatment by upper chromatography (9/1. dichloromethane/methanol) afforded the desired compound 11 (yield 24%).

Mass spectrum: CM+H)+=630° amide Using the method of Example 21 and replacing Example 19 with Example 20
The desired compound was obtained using the produced compound. Yield 18%,
Mass vector: (M+H)+=666° Example 23
゜3-1-Butyloxycarbonylamino-2-hydroxy-5-methyl-1-phenylmercaptohexane (0,610 mmol) using the method of Example 13
After preparing amino-24)'o4-5-methyl-1-phenylmercaptohexane hydrochloride, add 25 d1 of water to
Partitioned between 4d of salt solution and 10117% of ether. The aqueous phase was brought to pH 8 with 2M NaOH and then chloroform was added.
×7 I went to Sodeyama.

Na11S (h'T!) evaporates to form the corresponding free base (
M+=239) 9111 g (62%) was obtained. This was used next time without purification.

The above free base solution in dimethylformamide was dissolved in anhydrous dimethylformamide 51
Added to a -23°C solution of H153# (0.38 mmol) with stirring. Then hydroxybenzotriazole (HOBT) and then dichlorohexylcarbodiimide (
DCC)' was added.

The mixture was allowed to warm to room temperature for 2.5 hours, and after a further 16 hours the mixture was evaporated in an oven and the residue was partitioned between 20 ml of ethyl acetate and 8 df of saturated NaHCOB. Saturate the organic phase with Na
The white solid, which was washed with 0.8 g of HC (and 8 g of salt solution) and which could be dried and evaporated with Na2SO4, was chromatographed on l1i02 (9515, dichloromethane/methanol) to give the desired compound 1804 (75%). Mass spectrum: (M+Jn = 624° Boc-Phe-Al in amide anhydrous tetrahydrofuran 3-
-12℃ of a-OH4'1.8η (Q142 mmol)
Without stirring the solution, add 15.6μ of N-methylmorpholine.
J (0,142 mmol) and 18.4 pJ (0,142 mmol) of inbutyl chloroformate were added sequentially. Example 12 in anhydrous tetrahydrofuran 2 containing N-methylmorpholine (0,142 ml) after 3 minutes.
A -12° C. solution of the product compound (0,142 mmol) was added. After 10 minutes, the mixture was warmed to room temperature and after another 2 hours, the solvent was evaporated and the residue was mixed with 20 ru of ethyl acetate.
and 5 df of saturated NaHCO were distributed. organic phase to 0.0
Washed sequentially with 1M H, PO43N17 and 5 portions of salt solution. .

Dry with Na2SO2 and evaporate to obtain the desired compound 79■ (93
%) was obtained. Mass (cuttle: CM + H) + = 600
° Analysis calculation value: C, 66, 1; H, 8, 2: N, 7.0
° Measured value: C, 65,9; f, 8.4; N, 6
,9.

Using the method of Example 24 and the product compound of Example 13, the desired compound was obtained. Mass spectrum: (M+H)”
=558°C, H, N30. Analytical value for S'-H,O: Calculated value: C, 62,6: ff, 7.9; N, 7.3° Measured value: C, 62,6; J7.7.7: N, 7. 0.

Using the method of Example 24 and the product compound of Example 16, the desired compound was obtained. NME (300MH2, CDCl
5, pp door): 0.9 (2d, 6N), 1.35 (d,
3ff), 1.2-1.7 (m, 3f), 1.4 (
s, 9B), 2.8-3.2Cm.

5H), 3.55-3.7 Cm, IH), 4.05
(rn, iH), 4.2 4.4 (m, 2H), 4
．． 9Cd, XH), 6.3-6.5C2d, 2
H), 7.15-7.45 (door, 9H).

Using the method of Example 24 and the product compound of Example 14, the desired compound was obtained. NMR (300MHz, CDC
l5, ppm): 0.9 (d, 6H), 1.3
5 (d, 3ff), 1.2-1.7 (m, 3H), 1.
4 (t, 9H), 2.9-3.3 (m,, 5J7)
, 3.6-3.8 (m, IH), 4. I Cm
, IH), 4.25-4.45 (m, 2H), 4. l(
d, xB), 6.4 (d, 2H), 7.2Crn, 2H
), 7-3 (m, 3H), 7.95 (FIL.

3H), 7.8 (m, 4H).

Using the method of Example 24 and the product compound of Example 15, the desired compound was obtained. Mass spectrum: (M+H)”
=572°C, IH4, N30. Analysis value for S-HH,O:
Calculated value: C, 64, I; H, 8, 0:N, 7.2
.

Measured value: C, 64,1: H, 7,9; N, 7.5
.

Using the method of Example 24 and the product compound of Example 11, the desired compound was obtained. Mass S(ctor: (M+l+=
564° Using the method of Example 24 and the product compound of Example 17, the desired compound was obtained. Mass spectrum: CM+H)+-
542° C--N, 06・Ikarasu O analysis value: Calculated value: C, 65,4; H, 8,0; 71/, 7.6° Measured value: c, 65.6; H, 8 , 1; #, 7.6° using the method of Example 24, using the product compound of Example IF3 (which was a dihydrochloride) rather than Example 12, and using 2 equivalents of N-methylmorpholine rather than 1 equivalent. I obtained the desired compound. Mass spectrum: CM+H)+=5
41°C, oH44N, O, -N3 (Analysis value of HtO:
Calculated value: C, 65,5; H, 8,2; N, 10.2° Measured value: C, 65,6: H, 8,1; N, 10.0° Boc using the method of Example 25 The desired compound was obtained by using a 12°C stirred solution of Boc-phg-Tyr-OH in place of -Phe-Ala-OH. xhtEc300MHchiC
DCII,, p win): (L9(yn, 6#), 1.2-
1.5 (rn, 3H),' 1.35 (s.

9H), 2.5-3.3 Cm, 6H), a, 4-
a, 6 (trLt IH), 4.0 (m, IH)
, 4.25 (rlL, Iff), 4.55 (rlL
, 1H), 4.9 (m, IH), 5.6-(br
s, If), 6.1-'6.4 Cbr rn,
2K), 6.7 (d, 2H), 6.9 (d, 2H), 7
．． 1-7-4 Cri, 10H).

Boc-Phg-Ala-OH using the method of Example 25
The desired compound was obtained by using a 12°C stirred solution of Boc-Pha-Phe-OH instead. NMR (300MHz
%CDC1*, ppm): 0.9 (2d, 6
H), 1.2-1.7 (m, , 3H), 1.3(
8°9H), 2.5-3.3 (m, 7H), 3.
5 (m, IH), 4.0 (m, 17f), 4.25 (
m, IH), 4.6 (m,, IH)4,. 9 (br
m, 18), 6.2 (br d, 17
7), 6.3 (brd, IH), 7.0-7.4 (r
n, 15H).

-en The method of Example 1 was used but BoC-leucinal was added to BOC.
-Substitution with phenylalanal gave the desired compound. Mass scale: M+ = 247° The method of Example 1 was used, but BoC-leucinal was replaced by Boc
Substitution with -dicyclohexylalanal gave the desired compound. Mass spectrum: (M+l -254° Example 2
The desired compound was obtained using the product compound of Example 34 using the method of . Mass spectrum: CM+H)+-264° Using the method of Example 2 and the product compound of Example 35, the desired compound was obtained. Mass spectrum: (Af+ff)
+=270° Using the method of Example 3 and the product compound of Example 36, the desired compound was obtained. Mass spectrum: (
M1B)+-3so.

32 Using the method of Example 3 and the product compound of Example 37, but substituting inpropyl mercaptan for cyclohekiflumercaptan, the desired compound was obtained. Mass spectrum:
(M-4-H)+=a46°22 Using the method of Example 3 and the product compound of Example 37, the desired compound was obtained. Mass spectrum: J/'' = 385° - In winter, the product compound of Example 40 was treated with 2.5 equivalents of 3-chloroyloxi-7benzoic acid in dichloromethane and the desired compound was obtained by chromatography. Mass spectrum: (
M+ff) 0=418° The product compound of Example 3 was treated with 1.05 equivalents of 3-chloro4-oxybenzoic acid in dichloromethane to give the desired compound by chromatography. Mass spectrum:
M0 = 361° Using the method of Example 3 and using the product compound of Example 37, but substituting allyl mercaptan for cyclohexyl mercaptan, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 38, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 39, the desired compound 117 was obtained.

Using the method of Example 11 and the product compound of Example 40, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 41, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 42, the desired compound was obtained.

Using the method of Example 11 and the product compound of Example 43, the desired compound was obtained.

Using the method of Example 23 and the product compound of Example 44, the desired compound was obtained by replacing the free base with the amine hydrochloride and 1 equivalent of N-methylmorpholine. Mass spectrum: CM+H)+=664°3-amino-4-cyclohexyl-2-hydroxy-1
Using the method of Example 50 and the product compound of Example 45, the desired compound was obtained. Mass spectrum: (M+l+
=630° Using the method of Example 50 and the product compound of Example 46, the desired compound was obtained. Mass spectrum: CM0H)0 = 670゜'' BOC--Nα-H
4s Amide Using the method of Example 50 and using the product compound of Example 46, but substituting Hoe-Phε-Iris with Eoc-β-7-tylalanine-His, the desired compound was obtained. Mass spectrum: (M+H)+20° Mid. Using the method of Example 50 and the product compound of Example 47, the desired compound was obtained.

Using the method of Example 24 and the product compound of Example 48, the desired compound was obtained. Mass spectrum:, M+=579
The desired compound was obtained using the method of Example 24 and the product compound of Example 49.

Dry tetrahydrofuran (THF) 60! To a -78°C stirred bath solution of Tosyl-LgwCTs-Law) 3-001 (10.5 mmol) was added 23.0 l of a 91.39 M methyllithium solution in ether. The mixture was warmed to room temperature for 1 hour and then poured into IMHc155 at 0°C. Extract with ether and combine the extracts with saturated NaHCO
, and a salt solution, dry and evaporate to obtain the desired compound 2.391
! (80%). Mass spectrum = (M+H)+=
284° in dry THF 7d Product compound of Example 57 1.0
, f (3,5 mmol) in a -78 °C solution of 3 t
-butoxymethyllithium A (E, J., Corey and T.
,M,AICkr zdgg +TgtraAgd-r
onLetters, 3165 (1983)) Q was added. The mixture was warmed to room temperature for 4 hours and then poured into water.

0. Acidified with IME, PO, extracted into ether, washed with salt solution, dried and evaporated to give 1.1 g (85%) of the desired compound.
T-gotta. Mass spectrum: M+ = 371° "Rainbow" I-3-amino-1--4-butyloxy-2,5-dimethyl-2-hydroxyhexane Product compound of Example 58 in liquid NH, BCDt 0 .4
0.25 g (11 mmol) of sodium was added to the solution with stirring. After 5 hours the solvent was evaporated and the residue was partitioned between 40 d of benzene, 10 ml of ethanol and 30 d of water. The layers were separated and the aqueous phase was extracted with ether. Combine the organic layers, dry and evaporate to give the desired compound 0.19
g (79%). Mass vector: M+ -217° Using the method of Example 23 and the product compound of Example 59, the desired compound was obtained.

Example 61゜+-t-Butyloxyamino-2,6-dimethylhept-2-dyne Using the method of Example 1 but replacing methyltriphenylphosphonium bromide with isopropyltriphenylphosphonium bromide, the desired compound was obtained. .

Using the method of Example 11 and the product compound of Example 61, the desired compound was obtained.

Using the method of Example 24 and the product compound of Example 62, the desired compound was obtained.

Example 64 Eoc-Phg-Alα Amide of 4-Amino-2,6-dimethyl-2,3-oxohbutane Using the method of Example 2 and the product compound of Example 63, the desired compound was obtained.

Using the method of Example 3 and using the product compound of Example 64, but substituting inbutyl mercaptan for cyclohexyl mercaptan, the desired compound was obtained.

A suspension of lithium aluminum hydride (1,AH, 4'mi!J mol) in THF'15111 was thoroughly stirred before a solution of the product compound of Example 40 (1 mmol) was added. The mixture was refluxed overnight, cooled and added with 0.161 J of water and 3M
Cooling with 50 tpl of NaOHO, filtration, drying and evaporation afforded the desired compound. Yield 59%.

mm8 Amide Using the method of Example 23 and the product compound of Example 60, the desired compound was obtained.

N(α)-t-butyloxycarbonyl-N(π)-benzylox7methyl-L-histidine (T, Brown
J.H.

Jongs eJ, D, RichcL de ds, J,
Chmrn,! loC,,P'arkin-T
rasaJ, 1゛553 (1882):] J=R,M
cDerrnott and N.L. Benoiton [Ca.
The desired compound was obtained by methylation according to the general method of N. J. Chern, 1915 (1973)).

Using the method of Example 19 and using the product compound of Example 46, the Boc-H4s was replaced with the product compound of Example 6B to yield the desired compound.

Lucy Hiss Dinamide Example 69 product compound 100rR9 was dissolved in IM anhydrous HC4 in anhydrous methanol and hydrogenated with Pd Black 30~ at 3 atmospheres H2 for 8 hours. As luck would have it, 561 ngt of the desired compound was obtained by evaporation. This was used further without purification.

Using the method of Example 21 and the product compound of Example 70 and 2 equivalents of N-methylmorpholine, the desired compound was obtained.

Using the method of Example 3 and using the product compound of Example 37, the cyclohexyl mercaptan was changed to cyclohexyl methyl mercaptan to yield the desired compound. Yield 84%
.

Using the method of Example 11 and the product compound of Example 72, the desired compound was obtained.

H4s Amide Using the method of Example 50 and the product compound of Example 73, the desired compound was obtained.

”≦Example-14-Di“--t-Proxycarbonylamino-2-
Hydroxy-5-methylhexanemethanol 101tldPl The product compound of Example 2 (
A solution of 1,0 mmol) was refluxed for 2 hours with sodium azide (2,4 mmol) and ammonium chloride (1,8 mmol). The solvent was evaporated and the residue was extracted several times with hot chloroform.

The extract was perevaporated and the residue was chromatographed on a Sin-Sin column, eluting with a hexane-ether mixture to give the desired compound. Yield 76%, melting point 50-52°C.

4001 ng of the product compound of Example 75 in methanol I with CHCls was hydrogenated with 10% Pd/c 4 Qq at 3 atmospheres of hydrogen. Filtration and evaporation yielded 30.51 ng of the desired compound.

''2-Example-1L 3-t-Butylox7carbonylamino-2-hydroxychloroform in 10ml of the product compound of Example 76 (
Invaleryl chloride (1.0 mmol) was added to an O°C solution of 1.0 mmol) and triethylamine (2.0 mmol) in 52 ml of CHCl. After 3 hours, the bath was washed sequentially with 10% citric acid, saturated NaHCO, and salt solution. Drying and evaporation gave the desired compound.

Using the method of Example 11 and the product compound of Example 77, the desired compound was obtained.

Boc-Phe-His Amide of 74 Viscous U2I and No-Hydroxy-1-Invalerylamino-5-Methylhexane Using the method of Example 50 and the product compound of Example 78, the desired compound was obtained.

Example 80° Using the method of Example 19 and the product compound of Example 46, the desired compound was obtained. Mass spectrum: CM+H)+=523°CttHa! kO4s l'cNsulf+analytical value: Calculation j
K: c, 62.04: H, 8, 87: N, 10.72° Measured value: C', 61.72; H, 9, 26; N, 10.
59゜Luca-2-hydroxybutane Dba-Hi
The protecting group was removed from the compound of s amide Example 80 by the method of Example 11. A solution of this material in dry dimethylformamide containing 1 equivalent of N-methylmorpholine was prepared using the method of Example 23.
-0H) to give the desired compound. Mass spectrum: M+, 644° The desired compound was obtained using the method of Example 81 and using t-butylacetyl-Phe (Tbty Phe) in place of Dba-OH. Mass spectrum: (f-14) 10 = 668゜Sil--Hi ° Waxy 1- SoA three doro Δ杢三芭! ! Using the method of Example 41 and the product compound of Example 39, the desired compound was obtained. Mass spectrum:
(Analysis value for Af+l+=C1, H3gH□, H: Calculated value: C, 57, 26; H, 9, 34; 71/, 3
．． 71° Measured value: C, 57, 13; H, 9, 57; N,
3.60° Using the method of Example 19 and the product compound of Example 83, the desired compound was obtained. Mass spectrum: M
+=514゜) Lopylsulfonylbutane Boc
-H4tt amide 3-amino-
4-7 Chlohexyl-1-cyclohexylmercapto-
The product compound of Example 84 was used in place of the Boc-His amide of 2-hydrobutane to give the desired compound. Mass scale: (M + H) + = 660° C36H, Analysis value for N7S-3AH20: Calculated value: C, 60, 82: H, 7, 94: N, 9.85° Measured value: C, 60 ,70:H,8,21;N,9.63° The desired compound was obtained using the method of Example 81 and the product compound of Example 84. Mass spectrum: (M-f-H)
+=637° 11 ml t 3-amino-4-cyclohexyl-1-7 chlorohexylmethod According to the method of Example 81, 2,2-dibenzyl acetic acid was replaced with 3-phenylpropion W! Substitution with (Pp-OH) gave the desired compound.

The method of Example 81 was followed, but replacing 2,2-dibenzyl acetic acid with L-3-phenyllactic acid (P)-OH) to yield the desired compound.

The method of Example 81 was used, but 2,2-dibenzyl acetic acid was replaced with 2(8)-methicu-3-phenylpropionic acid CMp.
p-OR) to give the desired compound.

The product compound of Example 83 was converted to methanolic HC! according to Example 11. to give the corresponding deprotected MCI salt, which was used below without further purification.

Boc-8t in 71 ml of freshly dried dichloromethane
-2 of rr-OH601 ng (0,0291 mmol)
N-Methylmorpholine 3 was added sequentially while stirring the solution at 3°C.
3 μj (0.0291 mmol) and 38 μj (0.0305 mmol) of isobutyl chloroformate were added.

5-minute wave hydroxybenzotriazole 10719 (0
. The above HCII salt and N-
Methylmorpholine 33 μJ (0,0305 mmol)
was added as a suspension in dichloromethane ld. The reaction mixture was stirred at -23° C. for 1 hour and at room temperature for 2 hours and partitioned between ethyl acetate and saturated NaHCO. Wash the organic phase sequentially with 10% MCI and salt solutions for 1 min.Nα, 5O4T
: Dry and concentrate in vacuo. The resulting film was chromatographically processed to give the title compound 32 da (yield 26%). Mass quictor: (M+H)+=465° According to Example 21, the desired compound was obtained using the deprotected HCII salt of Example 90. Mass quictor, M+=611°CwH
Analysis calculation values for uNsoas: c, ss, c+o:
H.

8.07; 71/, 6.87° Measured value: C, 58, 86
;H,8,34:N,6.53° The compounds of the invention can be used in the form of salts derived from inorganic or organic acids. These salts include: acetate, azide, alginate, aspartate, benzoate, benzenesulfonate, pisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclointanpropionate, digluconate, dodecyl. Sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemi.

Sulfate, heptonate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-Hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate), difney), versalphate, 3-phenylpropionate, picrate, pivalate, propionate, succinate , tartrate, thiocyanate, tosylate and undecanoate. or basic nitrogen-containing groups: lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and cyamyl sulfate; decyl, lauryl, myristyl and stearyl chloride; Long chain halides such as bromide and iodine can be quaternized with compounds such as aralkyl halides such as benzyl and phenethyl bromide. Water-bathable or oil-soluble or dispersible products can be used.

The novel compounds of the present invention have excellent activity and specificity in the treatment of linin-related hypertension in patients. The ability of the compounds of the present invention to inhibit human kidney renin was demonstrated by testing the selected compounds at various concentrations with human kidney renin without acid proteolytic activity and with human renin substrate (angiotensinogen) at 37°C, p.
It can be demonstrated in vitro by reacting in H6, OfC.

The amount of angiotensin ■ produced at the end of the culture is determined by radioimmunoassay and the percent renin inhibition is calculated. Compounds of the invention when tested by the method described above are shown in Table 1! As shown in Figure 2, it exhibits a high degree of enzyme inhibition.

The total daily dose administered to the patient in single or divided doses is, for example, 90.001 to 10 kg/day, usually 0.01 kg/day.
〜1■. Dosage unit compositions may contain such amounts or submultiples thereof to provide the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the patient being treated and the particular mode of administration.

It depends on a variety of factors, such as method, excretion rate, drug combination, and severity of the particular disease being treated.

The compounds of this invention can be administered orally, parenterally and by inhalation spray and rectally or topically in the form of dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and desired excipients. Parenteral means subcutaneous, intravenous,
Intramuscular or intrafibular injection method.

Injectable compositions, such as continuous injectable aqueous or oily suspensions, may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable composition may also be a sterile injectable solution or suspension in a non-toxic parenteral diluent or solvent, such as a solution in 1,3-butanediol.

Possible excipients and solvents include water (Jlingerf)
solution and isotonic sodium chloride solution. Sterile, fixed oils are also commonly used as a solvent or suspending medium. A variety of fixed oils may be employed for this purpose including synthetic mono- or di-glycerides. Fatty acids, such as olefinic acids, also find use in injectable compositions.

Herbal preparations for rectal administration of this drug contain the drug in a suitable non-irritating excipient such as coconut butter or polyethylene glycol, which is solid at normal temperatures but liquid at rectal temperatures and therefore dissolves in the rectum to release the drug. Can be manufactured by mixing.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In this solid dosage form, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch.

The dosage forms usually also contain additional substances other than inert diluents, such as lubricants such as magnesium stearate.

In the case of capsules, tablets and pills, the dosage form also contains a buffering agent. Additionally, tablets and pills can be manufactured with membranes that are broken down in the intestines.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also contain wetting agents, emulsifying agents, suspending agents, sweetening agents,
Adjuvants such as seasonings and flavors may also be included.

The above description is merely illustrative of the invention and is not intended to limit the invention to the hardware described. Modifications and alterations which are obvious to those skilled in the art are intended to be within the scope and nature of the invention as defined in the claims.

Table 1

Claims (1)

[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents an N-protecting group; n represents 0 or 1; B represents hydrogen, hydroxy, NH, lower alkyl or arylalkyl; provided that if A is an N-protecting group, B
is NH and if n is 0, B is hydrogen, hydroxy, lower alkyl or arylalkyl; R_1,
R_3 and R_5 represent lower alkyl or hydrophilic, lipophilic or aromatic amino acid side chains and may be the same or different; R_2, R_4, R_7, R_8 and R_9 represent hydrogen or lower alkyl and may be the same or different; represents NH, O, S, SO or SO_2; and R_6
represents lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, or an N-protecting group, provided that when X is NH, R_6 is preferably an N-protecting group. Compound. 2, R_1 and R_5 are lower alkyl or lipophilic or aromatic amino acid side chains, and R_2, R_4, R_7, R
A compound according to claim 1, wherein_8 and R_9 are hydrogen. 3. The compound according to claim 2, wherein R_1 is benzyl or α- or β-naphthyl. 4. The compound according to claim 3, wherein R_3 is methyl or imidazol-4-yl-methyl. 5. The compound according to claim 3, wherein R_5 is isobutyl or cyclohexylmethyl. 6. The compound according to claim 3, wherein X is NH, O, S, or SO_2. 7. The compound according to claim 3, wherein R_6 is cyclohexyl or isopropyl. 8. Claim 3 in which X is S, R_1 is benzyl, R_3 is imidazol-4-yl-methyl, R_5 is cyclohexylmethyl or benzyl, and R_6 is isopropyl or cyclohexyl.
Compounds described in Section. 9, X is S, R_1 is β-naphthyl, R_
4. A compound according to claim 3, wherein 3 is imidazol-4-yl-methyl, R_5 is cyclohexylmethyl, benzyl or isobutyl and R_6 is cyclohexyl. 10, X is SO_2, R_1 is benzyl,
R_3 is imidazol-4-yl-methyl, R_
4. A compound according to claim 3, wherein 5 is cyclohexylmethyl and R_6 is cyclohexyl or isopropyl.