JPS63146850A - Renin inhibitor having phenylalanyl-histidine substitute component - 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 provides novel peptides that inhibit the angiotensinogen-cleaving action of the protease renin, a pharmaceutical composition containing the novel peptides of the present invention as an active ingredient,
The present invention also relates to methods for treating and diagnosing hypertension and congestive heart failure using the novel peptides of the present invention.

Renin is an endopeptidase (molecular weight approximately 40,000) produced and secreted by the proximal glomerular cells of the kidney. Edition, 1957, Volume 106, Page 439 (Ske
ggs et'a1. Journal of Expe
riment 26eds 1957.106.439
), the 10th equine temperament (Le
u) and the 11th (Leu) amino acid residue,
or Teuxpreet et al., Circulation, No. 59
．． Volume 60, Special Issue No. 2, Page 132, October 1979 (Tewksbury et al, C1rculati
on59.605Supp, ■: 132.0ct-1
979), it has high specificity for and cleaves the natural plasma glycoprotein angiotensinogen between Leu at position 10 and VaI1 at position 11 of the human renin substrate.

This cleavage of its tetradecapeptide substrate angiotensinogen splits it into the hemodynamically inactive decapeptide angiotensin, which is further converted into an effective pressor octase in the lungs, kidneys, or other tissues by angiotensin-converting enzyme (ACE). It is converted to the peptide angiotensin■.

Next, angiotensin ■ causes contraction of arterioles, but it is also thought to promote the release of aldosterone, a sodium retention hormone, from the adrenal cortex, thereby increasing the amount of extracellular fluid. Thus, the renin-angiotensin system plays an important role in normal cardiovascular homeostasis and in some aspects of increased blood pressure (hypertension).

It has been shown that inhibitors of angiotensin I converting enzyme are used for the regulation of the renin-angiotensin system. As a result, specific inhibitors of the catalytic and rate-limiting enzymatic steps that ultimately regulate angiotensin production, the action of renin on its substrates, are of interest as effective research tools and in the treatment of hypertension and congestive heart failure. It has also been studied as a therapeutic agent.

with an inhibition constant (Ki) in the 10-3 to 10-”M region,
Substrate analogs including renin antibodies, pepstatin (another aspartic protease similar to renin If), phospholipids, and tetrapeptides and ophthaltridecapeptides have been investigated.

Journal of Antibiotics (Tokyo) No. 2
Volume 3, No. 25-262, 1970 (Journal
of Antibiotics (Tokyo) 2
3: 259-262.1970), Ua+ezawa et al. reported that the Actinomyces peptide of pepstatin, an inhibitor of asparatyl proteases such as pepsin, cathepsin D, and renin,
reported on its isolation from the bacterium S. nomyces. Gross et al., Science, vol. 175, p. 656, 1972
Year (Gross et al, 5science 17
5:656.1972) reported that pepstatin reduced blood pressure in vivo after butarenin injection in nephrectomized rats. However, pepstatin has not found wide applicability as an experimental drug due to its limited solubility and inhibition of various other acid proteases, including renin.

Significant efforts have been made to produce specific renin inhibitors based on butarenin substrate analogs because such analogs have a close correlation with and are predictive of human renin inhibitor activity. This is because it has been revealed that it is hollow. The following octapeptide amino acid sequence from histidine-6 to tyrosine-13 was found to have substantially similar kinetic parameters as the complete tetradacapeptide renin substrate.

Kokubu et al., Biochemical Pharmacology, No. 22
@, pages 3217-3223, 1973 (Kokub
u et al,,Biochemical Phar
Macology.

22.3217-3223.1973) is 10-13
Several analogs of the tetrapeptide present between the renin substrates were synthesized, and although inhibitory effects were observed, the inhibition constant was only 1 (on the order of I3M). Analogs are described, for example, in Burton et al., Biochemistry, Vol. 14, No. 38.
92-3898, 1975 (Burton et
al., Biochea+1stry 14:38ri 2-3898.1975) and Paulsen (Pouls
en) et al., Biochemistry, Volume 12, No. 387
7-3882, also synthesized in 1973,
Lack of solubility and weak binding (large inhibition constants) were common.

As a result of modifications to increase solubility, the peptide
It quickly became clear that the inhibitory properties of the various amino acid residues were highly dependent on the hydrophobicity of the various amino acid residues.

In these modifications, increasing solubility by substituting lipophilic amino acids with hydrophilic isosteric residues is counter-productive.
It has also been revealed that the effect of the virus is to be productive. Other approaches to increasing solubility have also reached limits of success.

Modifications designed to increase renin binding have been attempted, but unfortunately have had mixed results.

A series of inhibitors of renin have been disclosed, containing the unnatural amino acid statins: for example, Veber
) et al., U.S. Pat. Nos. 4,384,994 and 4.
No. 478,826: Evans et al.
U.S. Patent No. 4,397,786: Boger
ger) et al., Nature, 1983, Vol. 303, pp. 81-84 and U.S. Pat. No. 4,470,971;
No. 4.485,099, No. 4.663.310 and No. 4.668.770; Matsueda
eda) et al., European Patent Application No. 128762, No. 152
No. 255; Morisawa et al., European Patent Application No. 186977; Rin
iker) et al., European Patent Application No. 111266; Bindra et al., European Patent Application No. 155
Specification No. 809; Stein et al., Federation Proceedings, 1986, Volume 45, Page 869 (
Stein et al., FederationPr.
oceeding, 1986.45.869); and Lolzemann et al., German Patent Publication No. 3,438,545, studies have been carried out to explain the effects of statins. Science, Blenheim Press
Powers et al. (1977), pp. 141-157, observed that the statin in pepstatin occupies a space of two amino acids on either side of the cleavage site of the pepsin substrate. Trends in Biochemical Science, Vol. 1, pp. 205-208, 1976 (T.
rends inBiochemical 5cien
ce, 1:205-208 (1976)) and Journal of Biological Chemistry, Vol. 251, pp. 7088-94, 1976 (Jour
nal of Biological Chen+1s
Lry.

251 Near 088-94.1976) in tongue (
Tang et al. pointed out that the statin residue of pepstatin resembles the transition state during pepsin hydrolysis of a peptide bond.

Renin inhibitors with other peptide bond isosteres, including reduced carbonyl isosteres,
Published European Patent Application Nos. 45665 and 104041; U.S. Patent No. 4.424.207 and Patent Cooperation Treaty International Application Box WO 34/3044; Nature, No. 299@, No. 555 pages, 1982; Hypertension
-sion), Volume 4, Special Issue No. 2, Page 59, 19
In 1981; and in a research publication described in British Patent No. 1.587,809, M.
elke) et al. Peptides, structure and function: Bulletin of the 8th American Peptide Symposium, edited by V.J. Ruby and D.H.Rich No. 57
Peptides, 5 structures, p. 9, Pierce Chemical Co., Rothford, IL, 1983.
and Function:Proceeding o
f the Eighth Ameri-can Pe
ptide Syn+posiun++ed, V, J,
Hruby and D, HoRich, p, 579.
Pierce Chemical Co., Rockf.
ord+IL,.

Suzerk et al. (1983) also showed that isosteric substitution at the Leu-Leu cleavage site resulted in compounds with superior potency.

Other peptide-bonded isosteres are available from Ruhlm
ayer) et al., European Patent Application Nos. 144290 and 1
No. 84550; Bester et al.
European Patent Application No. 173481;
ddatz), European Patent Application No. 161588;
Dunn et al., Biochemical and Biophysical
Research Communications, 1986, No. 13
Volume 4, pp. 71-77 (Dann eL al, Bio
che+++1caland Biophysical
Research Communications,
1986.134.7l-77); Heera (Fuh
Ier) et al., European Patent Application No. 143746;
Kamijo et al., European Patent Application No. 181
No. 110; Tysliphongs et al., Journal
of Medicinal Chemistry, 1985, No. 2
Volume 8, pages 1553-1555 (Thaisrivon
gs et al.

Journal of Medicinal Chem
istry, 1985.28.1553-1555
); Ryono et al., European Patent Application No. 181
No. 071; and Evans et al., US Pat. No. 4,609,641.

Other modifications that have been investigated include, for example, European Patent Publication Nos. 172346 and 172347; Evans et al., Journal of Medicinal Chemistry, 1985, Vol. 28, pp. 1755-1756;
and Bock et al., Peptides, structure and function: Proceedings of the 9th American Peptide Symposium, edited by C.
C0M, Deber et al., No. 751-7
Some make renin inhibitors with a non-peptide C-terminus, as disclosed in P. 54, Pierce Chemical Co., Rockford, IL, 1985. Hypertension, 1985, Volume 7, Special Issue No. 1,
On pages 8-10, Kokubu et al. and Chemistry L.
etters), 1985, No. 1041-1044
Page, European Patent Publication Application No. 128762 and No. 1522
No. 55, Matsueda et al. disclose a peptide aldehyde renin inhibitor, and Biochemical and Biophysical Research.
Communications, 1985, Volume 132, No. 1
55-161, Hanson et al. reported on peptide glycol inhibitors.

All of these various renin inhibitors are generally...A-
consisting of a peptide substrate inhibitor having a sequence of the type B-D-E-F-G-J-1; C-L, ..., where G is a peptide bond mimic; Representative sequences of this type, where A, B, D, ESFSJ, K and L may each be independently absent or represent natural or modified amino acids, include BOC-Pro -Phe-His-5ta-Le
u-Phe,
is or Phe-His.

Substitutions of the Phe (8)-old direct 9) portion of these sequences were described in the above-mentioned literature, where other aromatic amino acids (such as Tyr s Trp) or substituted aromatic amino acids are usually substituted with Phe. is described as a substitute for Additionally, other amino acids (e.g. Lys % L
eu ) has been suggested as a replacement for 1lis, or N11z-C1l(CHt-HeL)COJ (“
1let'' is a - or disubstituted heterocycle) amino acid was used in place of either old S or Phe.

These 8-9 surrogate sequences contain various peptide bonds with N- to stabilize the produced inhibitors from enzymatic degradation.
Some peptides are methylated or reduced. However, no advantage in renin inhibitory efficacy or pharmacological properties was demonstrated or suggested by making such substitutions in the Phe-His sequence.

The present invention discloses renin inhibitors with improved bioavailability, in which novel elements consist of a single component or a novel component linked to histidine or known histidine substitutes. is Phe
(8)-His(9) is conjugated with a statin or other peptide-binding isostere in place of the N-terminal sequence.

In particular, the present invention relates to renin-inhibiting peptides and pharmaceutically acceptable salts of the following formula: IG [wherein A is" (CUt).

R'-(C11□>, -CH-5O1 [In the above formula, R1 and Rta are each independently hydrogen; aryl (aryl is unsubstituted or -, di- or trisubstituted phenyl or naphthyl (substituent is Each independently, C, -
C,-alkyl, amino, mono- or diC1-C
4-fulkylamino, amino-Ct-Ca-alkyl,
hydroxy-CtCa-alkyl, heptano- or di-Cl-C4-alkylamino-C,-C,-alkyl, guanidyl, guanidyl-C,-C,-alkyl,
Hydroxyl, C, -C, -alkoxy, Ch, halogen, CHO, Co□H, Co□-C, -C, -alkyl, -Co□N11! , -CONII-C, -C.

-7JIz$7Lz, NR'R"IIU N(R')z
OAe (R"gt and R& are each independently hydrogen, unsubstituted or monosubstituted Cl-C4-alkyl (substituents are amino, C,-C4-alkylamino, C,-C,-dialkylamino, hydroxyl, CtCg -alkoxy or N(C, -C.

-alkyl)3ΦA1B), where A (B consists of monovalent anions such as chlorine, bromine, nitric acid, perchloric acid, benzoic acid, maleic acid, benzenesulfonic acid, tartaric acid, hemitartrate and acetic acid). Ct
C4-alkyl; C3Ct-cycloalkyl; amino: hydroxyl; thiol; monomoto;
co□-CI Cm-alkyl; C0NRSR'(
R' and R- are as defined above >: C, -C, -alkoxy; or let (Ilet is unsubstituted or -
or a disubstituted 5-16- or 7-membered heterocycle or a benzo-fused 5-16- or 7-membered heterocycle (l or 2
The heteroatoms are each independently N10, S, , No
, 50. selected from the group consisting of SO2 or quaternary N,
The substituents are each independently hydroxyl, thiol, C
I-Ch-alkyl, CF, ,C,-C.

-Alkoxy, halogen, aryl, ary°ruc'
, -c-oalkyl, amino, mono- or di-C,
-C,-alkylamino, amino-C,-C,-alkylamino, amino-CI-Cm-alkyl, hydroxy-CI-Ca-alkyl, di-Cl-C4-alkylamino-C,-C,-alkyl, Guanidyl, guanidyl-CI C4-alkyl, CHO, C0J-, GO!
-Ct-C, -fulki) Lt, NR'R' and NCR
m is O~3; n is θ~3]; CHz) - R'-(CHz)--CH-CO [In the above formula, R', m and n are as defined above; and R2 is Het as defined above (provided that R1 is amino, hydroxyl or mono - or di-C+ Ca-alkylamino, m is other than 0]; (
et; and X is C01SO□ or CI -OH]; (cu
t)-R'-X'-Y-CH-X [in the above formula, R3 is OR'(R' is C, -C4-alkyl or aryl-〇+Ct-alkyl); aryl as defined above; IIetH or NR'R' as defined above
(R'Y is CHt or 0; and R', X and m have the same meanings as above, provided that when X and XI are both CO, Y is other than O; and if Y is CHN or 0, then
R'-(CI+□) is other than hydrogen; or if Y is O and R3 is OR', then X is SOW
]; 171m (cl.

Temporary R1-(C11□), -N-X [In the above formula, R', R''% −
and R''-(CHt), both C+ -Cs -7 Luki 7L/T: Hana]; 21m (CUt) R number Rlk-(CHx)s-Z-(C)It)qcH-X[
In the above formula, R11'' has the same meaning as above; Het has the same meaning as above;
; unsubstituted or monosubstituted CI-Ch-linear or branched alkyl or CS -C,-cycloalkyl (
Substituents are amino, hydroxyl, thio, halogen or mono- or di-Cr C4-alkylaminotear); N(CI-C<-77L4)30Ae(A'
9 C. 11 i? Al); C0tH;
CONR'R'(R' and R' are as defined above); or CI Ca-alkoxy; Z is 0, S, SO, SOx or NR'(R' is hydrogen or Cl-C4-alkyl ); q is θ~2
and R'', X, m and n have the same meanings as above; provided, however, that when Z is 0
or NR' and q is O, then m is O or l
, R”-(C1lz)- is hydrogen or CI-C
or (CHt)-R3-X-Y'-N-X [In the above formula, Yl is CH! or NR'(R' is the above-mentioned and R'', R3, X and n are as defined above]; B is (CHHz,)-K-CH-C0 has the same meaning as above) or C) Iz; R- is unsubstituted or monosubstituted C, -C, -alkyl (substituents are carboxyl, amino, NHCOR'(R' has the same meaning as above), Hydroxyl, guanidino, CI
-Ca-alkoxycarbonyl or thiol);
Hat as defined above; or aryl as defined above; n is defined as defined above]; (cnz)r K -CI-CO [In the above formula, Zl is 0.5SNR', NR'-Co, Co -NR'
, NR'SOt, SO, NR', SO or 5otcR'
is as defined above); r is 1 to 3; and K and R- are as defined above; or Z'-R'' is instead X'R3 (X' and R3 are as defined above); or N-CH2-C0 [In the above formula, R9 is C, -C, alkyl substituted with R1 or Z-R'' (R@ and Z have the same meanings as above)] :; R" is -CUR"R"" Thea 4 [In the above formula, R11 and R1111 are R1 is hydrogen: c, -cs-
Alkyl; Aryl as defined above; 1le as defined above;
t; CI Cs-alkoxy: Ct-Cs-alkylthio; or unsubstituted or disubstituted C5-C? Cycloalkyl (substituents are each independently C, -C, -
Alkyl, trifluoromethyl, hydroxy, CI
selected from the group consisting of Ca-alkoxy and halogen), R'' is hydrogen; or R'' is hydroxy-Cs-Ca-alkyl or amino-CI-
When C4-alkyl, Rl l m is hydrogen or CI Cs-alkyl, and so on; n and R? has the same meaning as above]: and E is CH-G
(In the above formula, W is OH%NH2 or oRlit (Rlm is CI-C-
-alkanoyl or CI-Ca-alkanoyloxy-
C, -C, -alkyl; and G is Q-CO-T-V [in the above formula, Q is a single bond; CH-R13 (R13 is hydrogen; aryl as defined above: CI-Cm-alkyl , C, -C, -cycloalkyl; - or disubstituted Cz Cm-alkyl (each substituent is independently hydroxy: CO to Co
tCI-C4-alkyl; C0NR'R'(R'
and R6 are as defined above); amino; selected from the group consisting of mono- or di-Ct C4 alkylamino and guanidyl, and the substituents are present on the last 1 or 2 carbon atoms of the alkyl chain) or mono- or disubstituted aryl or Cs C'1-cycloalkyl (each substituent is independently CI-C4-alkyl, trifluoromethyl, hydroxy, C, -C4-
selected from the group consisting of alkoxy and halogen); or CI+! -CH-R'3' (Ral- is CHRI41J14'''(Rl' is hydrogen; °amino; hydroxyl; C+-Cs-alkyl; Cs cf
f-Cycloalkyl; Aryl as defined above; Aryl-C1-C,-alkyl; l1et as defined above: H
et-C, -C.

-alkyl; amino-Ct -Ca-alkyl; or guanidyl-CI C4-alkyl, R+4m is hydrogen or CI-Cs-alkyl; hydrogen or C3-
C,-alkyl; and R11 is -(CIlz)w
NR"R" (RI 9 and R16 are each independently hydrogen; same meaning as above) let ; same meaning as above -
unsubstituted or monosubstituted Cl-C4-alkyl (substituents are aryl as defined above, Het as defined above, s
Amino, hydroxyl, mono- or di-Cl-04
-alkylamino, CO□■, 50s)l and C0NR
'R'(R' and R6 have the same meanings as above): W is 1 to 5): -
(C)Iri @ (Ral and R2t are each independently selected from the definition of R'', or R'' and R1 together - (
Hz) a- or -(CHz)s-, Ral
, R10 and W are as defined above); or -(CH,
), -N・CH-NR2lR2* (R!I, Rt
t and W have the same meanings as above); and ■ is 0-(CI), R'' (wherein R'' is hydrogen;
Aryl as defined above; Het as defined above; or unsubstituted or - or disubstituted C, -C, -alkyl,
C2Ct-cycloalkyl or C,-C,-cycloalkyl-C,-C,-alkyl (substituents are each independently amino, hydroxyl, C,-C,-alkoxy, thio, halogen, mono- or di-C+ Ca-alkylamino, CO□H and C0NR'R''(R',
R'' and Ae have the same meanings as above);
7 is hydrogen; aryl as defined above; Wet as defined above
;Unsubstituted or -Mo'C< is disubstituted C, -C, -alkyl, C3C? -cycloalkyl or C, -C, -cycloalkyl -C, -C, -alkyl (substituents each independently amino; hydroxyl: C, -C, -alkoxy; thio: halogen; mono- or di-C, -C4
-alkylamino; COJ: guanidino; mono-, di- or tri-C+ Ca-alkylguar';/
; -N(R')3" Ae and C0NR'R'<R'
, R' and Ae have the same meanings as above), r is O~5, and RI & and U
has the same meaning as above; or R" and R" are combined to form a saturated or unsaturated unsubstituted or - or disubstituted 5- to 7-membered heterocycle or a benzo-fused 5- to 7-membered heterocycle (1- to The three heteroatoms are each independently selected from the group consisting of nitrogen, oxygen and sulfur, and the substituents are each independently CI
-C&-alkyl;hydroxyl;trifluoromethyl; Ct C4-alkoxy; halogen; aryl as defined above; aryl-CI Cm-alkyl; amino; thio; and a group consisting of mono- or di-C,-C4-alkylamino (wherein t is 0 to 2, R', R" and R" have the same meanings as above, or R1& and R1? are combined as above); or 0-CHRlhR” (
In the formula, R1 & and R1? has the same meaning as above or is bonded as above); C, -C, -alkyl (R24 has the same meaning as above); R24 has the same meaning as above; -N
RI9RZ6 , H(H+qRzoR'z+)G) A
e (RI 9, Rzo, Ral, Ral and Ae have the same meanings as above); -CO□H; -5O31 (; is aryl as defined above, or if q is other than O, then 04-alkylamino; q has the same meaning as above); 0-C)l (CHz)q R" (R1!, R24 and q have the same meaning as above); N(
CHz(Hz)zN-R"(R" has the same meaning as above); -N(CHzC)! z)tNR”R””Ae(R”
, R2O and Ae have the same meanings as above); -NH-Het (Het has the same meanings as above);z
3-N-(cl, -RZS (in the formula, 81% is l1et as defined above; or-r as defined above; C+ Ca-alkyl, or y is 0 other than O), then NiNHt, NR”R”, N(
RI'JpOR1I)e A8 or C0NRSR6(R
19, R21, RS, R6 and Ae have the same meanings as above); hydroxyl; CO,)I; or SO, H); or 14m (CHz)s -CH-L-(CL)tR "(In the above formula, RIS is hydrogen; unsubstituted or monosubstituted C+ Ch-alkyl (the substituent is amino or hydroxyl); mono- or di-C,-C,-alkylamino; guanidino: mono-, di- or tri- Ct C4-77
L/ -%-Luguanidzi/ ;-N(R')30^e
(Rs and 7i, e have the same meanings as above); Aryl-C, -C.

-Alkyl (aryl has the same meaning as above); C1C'
r-cycloalkyl-C,-C,-alkyl; cl-C
S-alkenyl; or let as defined above; L is a single bond, S, SQ, So□, NR' or NR' -CO
(R' is as defined above); S is O~2; and R14m and t are as defined above).

Any variable (e.g., aryl, Het sA
e%R', R'%R", R), XI S Z
If S n etc.) occurs more than once in any element or formula (2), its definition at each occurrence is independent of its definition at all other occurrences.

As used herein, "alkyl" refers to both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl and Et is ethyl);
“Alkoxy refers to an alkyl group of the specified number of carbon atoms attached through an oxygen bridge; “C,-C,-cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (Cyh) and cycloheptyl "Alkanoyl" means an alkylcarbonyl group of a specified number of carbon atoms, exemplified by formyl, acetyl, propanoyl, and tanoyl; "alkenyl" means ethynyl, propenyl,
Hydrocarbon chains with one unsaturation, such as butenyl, pentenyl, etc., in a straight or branched configuration, including E and Z types if applicable at any position on the chain. "Arylalkyl" means a group bonded through a straight or branched alkyl group of the specified number of carbon atoms, such as benzyl, phenethyl, 3,3-diphenylpropyl, 3-indolylmethyl, etc. "Halogen" as used herein means fluoro, chloro, bromo and iodo; "counterion" refers to chlorine, bromine, nitric acid,
Used to represent small monovalent anionic species such as acetic acid, perchloric acid, benzoic acid, maleic acid, benzenesulfonic acid, tartaric acid, hemitartrate, and other ions.

As used herein, "aryl°" means, with some exceptions, 1, amino (A■), mono- or di-01-04.
-fulkylamino, amino-C,-C,-alkyl, hydroxy-CI-C4-alkyl, di-C,-C4alkylamino-C,-C,-alkyl, guanidyl, guanidyl-CI-Ca-alkyl, hydroxyl, C,
-C,-alkoxy, CF3, halogen, Cll01
CO□)l, C02R', NR'R'(R', R
' and R6 have the same meaning as above) and N(R')ff"
phenyl (P
h) or naphthyl. "Aroyl" means an arylcarbonyl group exemplified by benzoyl and naphthoyl.

As used herein, the term "1let" means 5, either saturated or unsaturated, consisting of 1 to 3 heteroatoms selected from the group consisting of N, 0, and S, and carbon atoms. -16- or 7-membered heterocycle, the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized or in the form of an N-oxide. It also includes any bicyclic group in which any of the above heterocyclic groups is fused with a benzene ring. In the case of a heterocyclic group having one or more nitrogen atoms, the bonding position is at one of the nitrogen atoms or at any carbon atom. Examples of such heterocyclic elements include piperidyl, piperidinyl, piperazinyl, 2-
Oxopiperazinyl, pyryl, pyrrolinyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl (Pyr), pyrazinyl, pyrimidinyl, pyridazinyl, oxasyl, oxazolidinyl, isoxazolyl, isoxazolyl, Morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,
Quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxacylyl, furyl, chenyl, benzothenyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, azepinyl, 2-oxaazepinyl, 2-oxapyrrolidinyl and 2-oxapi There is peridinyl. Heterocyclic moieties may further optionally include hydroxyl, thiol, C, -C
,-alkyl, CF3, C,-C,-alkoxy, halogen, aryl, aryl-Ct-C4-alkyl,
Amino, mono- or di-Cl-04-alkylamino, amino-C,-C,-alkylamino, amino-C
I-C4-alkyl, hydroxy-C,-C,-alkyl, C,-C,-dialkylaminoCt Cm-alkyl, guanidyl, guanidyl-CI-Ca 7
JLt Kill, CHO, C0JSCOJ', NR'R”
(R', R' and R- have the same meanings as above) or N(
RS) 30^e <RS4;! The group is substituted with 1 to 4 groups independently selected from the group consisting of t't' (as defined above), and Ae is a counterion as defined above.

The following other abbreviations are also used herein: CHPA (3S,4S) -4-amino-
5-cyclohexyl-3-hydroxyvaleric acid Cys cysteine 1 (is D- or L-histidine 11e
L-isoleucine Leu L-leucine Lys L-lysine Orn D- or L-ornithine Phe
L-Phenylalanine Pro Proline Trp L) Liptophan Tyr
l, -Tyrosine BOCt-Butyloxycarbonyl BOM Benzyloxymethyl CBZ
Benzyloxycarbonyl (carbobenzoxy) DNP 2.4-Dinitrophenyl chloride HOT (HOBt) 1-Hydroxybenzotriazole hydrate ■Gold■ DCCI (DCC) Dicyclohexylcarbodiimide DPPA Diphenylphosphoryl azide test-ゑAMP 4 -aminomethylpyridine<80(
:) to di-t-butyl dicarbonate DEAD diethyl azodicarboxylate TFA
) Refluoroacetic acid 1-dish^cOH (HOAc) Acetic acid D? IF Dimethylformamide EtO^c
(E) Ethyl Acetate Etto Ether The A and B components in the renin inhibitor of the present invention have asymmetric centers and exist as racemic mixtures and as individual diastereomers, but all isomers are included in the present invention. included. Generally, the preferred chiral forms of the A and B components are those corresponding to natural L-amino acids. The chiral form of the T component is the form corresponding to an L- or D-amino acid.

Preferred renin inhibitors of the present invention are compounds where E is CH-G (W is OH and G is CHt or CH-CH (R1'' is isopropyl or isobutyl).

Particularly preferred renin inhibitors of the invention include the following compounds: 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-formerly 5-ACIIPA-NH-C)l
(2-Butyl) -CHz-NH-CHt-CHx-N
(CHtGHz)to ;2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-former 5-A
CHPA-NH-C1l (2-buty/L/) -CH
z-NH-CIlg-CHz-N (CHzCl zO
(C1h) 'B C1(9:2-benzyl-5,5-
Dimethyl-4-oxohexanoyl-Hls-8C1 (
P^-NH-CI (i-butyl)-CHl-N(CH
2CHz>zN(CHx)z"CI";N-(
2-(t-butylsulfonylmethyl)-3-phenylpropionyl) -Hls-ACHPA-Nu-CI(i
-butyl)-CL-N)l-(1-ethyl-4,5-dihydroimidazol-2-yl); N-(2-(t-butylsulfonylmethyl)-3-phenylpropionyl-formerly 5-ACHPA- N)l-C1
h-CH(2-butyl)-N(CH,), ;N-(
1-(morpholin-4-yl)sulfonylmethyl-2-
(phenethylsulfonyl) -Hls-AC)IPA-N
H-CHt-CH(2-)+ 7L/) -N (CH
tGHz) s@CIte; N-(1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl) -Hls-ACHPA-NL side, -CH(2-
butyl)-NH-<4.5-dihydroimidazole-2
-yl); N-(1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-former 5-ACHPA-N
H-CHz-C)l(2-butyl)-NH-(1-ethyl4゜5-dihydroimidazol-2-yl);N-
(1-(morpholin-4-yl)sulfonylmethyl-2
-phenethylsulfonyl) -Hls-AC)IPA-
NH-CH(2-butyl) -C1b-(2-hydroxymethylpyrrolidin-1-yl); N-(1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl) -1is-ACHPA
-NH-CH(2-butyl) -CHz-(2-guanidinomethylpyrrolidin-1-yl); N-(1-Cmorpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl) -11is-ACHP
A-NH-C)l(2-butyl)-coz-(2-hydroxymethyl-1-methylpyrrolidinium-1-yl)
0(le.

N-(1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl) -11is-ACHP
A-NH-CH(2-butyl)-CHt-C2-carboxy-1-methylpyrrolidinium-1-yl) inner salt; N-(1-(thiamorpholin-4-yl-3°S-dioxide) ) Sulfonylmethyl-2-phenethylsulfonyl) -Hls-ACIIP^-NH-C11(2-butyl)-cut-(2-1-limethylammoniomethylpyrrolidin-1-yl)l! ICJIC1: N-(1-(thiamorpholin-4-yl-3°S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-former 5-ACHPA-NH-CI(2-butyl)4f
lz-N(Cl(+) 30CLCOze;N-(1-
(thiamorpholin-4-yl-8゜S-dioxide)sulfonylmethyl-2-phenethylsulfonyl) -Hl
s-ACHPA-NH-CI(2-butyl)-CHi(
011) -CHz-N(CHi) (CIIzCHz
) 20@Cf e.

N-(1-(thiamorpholin-4-yl-8°S-dioxide)sulfonylmethyl-2-phenethylsulfonyl) -Hls-ACHPA-NH-CO(2-butyl)
-C1h-(h')dinium-1-yl)'! 'Cl1
e'.

N-(1-(thiamorpholin-4-yl-8°S-dioxide)sulfonylmethyl-2-phenethylsulfonyl) -Hls-8C1(PA-N)l-C1l (2-
Butyl)-CH2-1-/Tylimidazo IJ Lamb-
117L,)” (/!e.

N-(1-(thiamorpholin-4-yl-8°S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-former 5-ACHPA-NH-C)I(2-butyl)-
CHz-N(CHs)zOCIhCH2CO2”;2
-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-formerly 5-ACHPA-NH-2(S)-methylbutyl; 2-benzyl-5,5-dimethyl-4-oxohexanoyl-formerly S-^CIIPA- NH-2(S)-Methylbutyl; N-(benzimidazol-2-yl)sulfonyl-Hls-ACHPA-NH-2(S)-methylbutyl; N-(benzimidazol-2-yl)carbonyl-formerly 5-ACIIPA -Nll-2(S)-methylbutyl; N-(indol-2-yl)carbonyl-11i
s-80) IPA-NH-2(S)-methylbutyl; N
-(2-(t-7'tylsulfonylmethyl)-3-phenylpropionyl) -tlis-ACIIP^-Ni
l-2(S)-Methylbutyl; N (2(i-propylsulfonylmethyl)-3-phenylpropionyl 2(S)-methylbutyl; N-(2-(i-propylsulfonylmethyl)-3-phenylpropionyl) - N Ite-ACIIPA-
Nll-2(S)-methylbutyl; N-(1-(t-butylsulfonylmethyl)-2
-Huenechi JL/Su Jl/Honi) Ii] -His-A
C) IPA-Nil-2(S)-methylbutyl; N-(1-(imidazol-4-yl)sulfonylmethyl-2-phenethylsulfonyl)-11is-A
CHPA-NH-2 (S)-methylbutyl; N- (
1-(1.1-dimethyl-2-carboxyethyl)sulfonylmethyl-2-phenethylsulfonyl) -Hi
s-ACHPA-NH-2(S)-methylbutyl; N-
(1-(p-carboxyphenyl)sulfonylmethyl-2-phenethylsulfonyl) -11is-ACH
PA-NH-2(S)-methylbutyl; N-(1-
(p-aminophenyl)sulfonylmethyl-2-phenethylsulfonyl)-11is-^Cl! PA-NH-2 (S)-methylbutyl; N- (1-thiamorpholin-4-yl-S.S-
(dioxide) sulfonylmethyl-2-phenethylsulfonyl) -His-^CHPA-NH-2(S)-methylbutyl;
Sulfonylmethyl-2-phenethylsulfonyl]-N
It e-ACHPA-NH-2(S)-methylbutyl; N-(N-benzyl-N'-morpholinocarbonylmethyl)carbamoyl-formerly s-ACHr'A-NH-2
(S)-Methylbutyl; N-(N-benzyl-N'-morpholinocarbonylmethyl)sulfonamide-11is-ACIIPA-NH-
2(S)-Methylbutyl; N-(N-benzyl-N'-thiamorpholinocarbonylmethyl-S.S-dioxide)carbamoyl-formerly s-A
CHPA-NH-2(S)-methylbutyl; N-(1-
(N-morpholinocarbonyl)methyl-2-phenethylsulfonyl]-formerly s-ACIIPA-NH-2(S)-
Methylbutyl; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-tylbutyl dihydrochloride; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACIIPA-Ntl-Cl
l(2-butyl)-C)Iz-NH(CI(z
cHz)zO ;2-(N-morpholinocarbonyl)
Methyl-3-phenylpropionyl-formerly 5-ACHPA
-NH-C)I (2-butyl) -CHz-NH(C
HzCHzhSO□; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-formerly 5-ACH
PA-NH-CH (2-butyl) -CI, -N(CH
zCH,)zo(C1l,)” ClC5H2-benzyl-5,5-dimethyl-4-oxohexanoyl-former 5
-ACHPA-Nil-C)I(2-butyl)-CHI
-Ntl (CHzCHz) 2NCH2; 2-benzyl-5,5-dimethyl-4-oxohexanoyl-old 5
-ACHPA-NH-CH(2-butyl)C11□-N
(CHs) (CHzCHz)JC1h■C1e: 2-benzyl-5,5-dimethyl-4-oxohexanoyl-
Former 5-ACHP^-NH-CH (2-butyl) -C)
It-N(C11,)(CH2CH2)25(h”C
1'E': N-(2-(t-butylsulfonylmethyl)-3-phenylpropionyl) -Hls-^CHP
^-NH-C11(2-7”chill)-C1h-NH(C
)lzcTo)J(C)Is)zOC10;N-(2-
(t-butylsulfonylmethyl)-3-phenylpropionyl) -Hls-ACHP^-NH-CH(2-butyl)-CHz-NH(CHzC1l□)zN-Co-
CII+;N-(2-(t-butylsulfonylmethyl)-3-phenylpropionyl(2-butyl)-CHz-N(CHi)z;N-
(2-(t-butylsulfonylmethyl)-3-phenylpropionyl) -11is-ACIIPA-Nll
-Cll(2-buty71z)-Cllz-N(Cf13
):+■Cle;N- (2-(t-butylsulfonylmethyl)-3-phenylpropionyl) -11is
-ACIIPA-N (i-propy71/)-(J
l(2-butyl)-Cllz-N(Clli)i” (
J'3 ; N- (1- (morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-former S-
ACHPA-N (C)13) -Cl (2 - '
7” + Le) -Cllz- N (C113) 3
"Cle;N- (1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl)
- 114s-ACHP^-N(i-butyl)-CI(
(2-Butyl)-Cl+□-K(CH3): l"C
10;N-[1-(morpholin-4-yl)sulfonylmethyl--NH-CH(2-butyl)-CHI-N(CH2C
H2))”Cle;N- (1- (morpholine-4
-yl)sulfonylmethyl-2-phenethylsulfonyl) -His-ACHPA-NH-CH(2-butyl)-C)Iz-Clh-Nl((CHzCL) to
;N-(1-(thiamorpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-CHPA-NH-CH(2-)ethyl)-C)If
-CHI-Nl((CLCHz)zsOl; N-(1-(thiamorpholin-4-yl-S.

S-dioxide)sulfonylmethyl-2-phenethylsulfonyl) -His-ACIIPA-NH-CH(2
-butyl)-CHz-CHz-N(C)lzc)Is)
30Cle; N-(2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-(S-imidazol-4-yl) Cys-Act(PA-NH-CH(
2-butyl)-Clh-CHz-CHz-N(CHz
CH3)z OC le; N-(benzimidazol-2-yl)sulfonyl-formerly s-Ca l (C) l(
OH)CHz) Va1-NH-Cal(2
-butyl)-CHI-NH-(4.5-dihydroimidazol-2-i)v); N-(benzimidazol-2-yl)sulfonyl-formerly s-Ca1(CH(OH)CHz)Val
-NH-CI (2-butyl)-CHz-NH- (
1-ethyl-4,5-dihydroimidazol-2-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal (CII(0)1)C11. )V
a l -NH-Cll (2-butyl)-CHz
-NH- (1-ethyl-pyridinium-4-yl)
■cle; N-(benzimidazol-2-yl)sulfonyl-H
is-Ca 1 (Cll(Oll)Cllz) V
a 1 -NH-Cll (2-butyl)-cuz
-(3-amino-pyrrolidin-1-yl): N-(benzimidazol-2-yl)sulfonyl-formerly s-Ca
1 (CH(OH)CHz) Val-NH-C
ll (2-butyl)-coz-(1-methyl-3
-oxopiperidinium-1-yl)OCJ";N-(2-'(i-propylsulfonylmethyl)-3-
phenylpropionyl) -His-Am ACIIP
A-Nll-CI(2-butyl)-C112~(3-dimethylaminopiperidin-1-yl): N-(2-(i-propylsulfonylmethyl)-3
-phenylpropionyl) -His-Am ACII
PA-Nll-CH(2-butyl)-CH. -(3-
) Limethylammonium-biperidin-1-yl); N-(2-(i-propylsulfonylmethyl)-3-phenylpropionyl) -Hls-(25-i-butyl)AC)IPA-NH-CI (2- butyl)-CHz
-NH-(1,1-dimethylpiperidinium-4-yl)"C1e;N-(2-(i-propylsulfonylmethyl)-3-phenylpropionyl) -Hls-(2S
-Allyl)8CIIPA-NH-CH(2-)'Til)
-CHz-NH-(3,4,5,6-tetrahydropyrazol-2-yl); N-(benzimidazole-2-
yl)sulfonyl-formerly 5-Ca 1 (CH(Nllz
) CJ) Va It -NH-C)I (2-butyl) -CHt-NH-(1-methylazepin-3-yl); N-(2-(t-7"tylsulfonylmethyl)-3
-phenylpropionyl) -Hls-ACHPA-N
ll-CI(2-butyl)-CHt-NH-(1,1-
dimethylazevinyram-3-yl)OCle.

N(2-(i-propylsulfonylmethyl)-3-phenylpropionyl) -Hls-ACHPA-NH-C
H(2-butyl)-CHz-NH-(3-quinuclidinyl); N-(1-(imidazol-4-yl)sulfonylmethyl-2-phenethylsulfonyl) -Hls-A
CHPA-NH-CH(2-butyl)-CHz-N)l
-(N-methyl-kisclidinium-3-yl)I! +
(1e.

N-(1-(1,1-dimethyl-2-carboxyethyl)sulfonylmethyl-2-phenethylsulfonyl) -
Hls-ACHPA-NH-CH(2-butyl)-C
Il□-NH-CHtPh: N-(1-(p-carboxyphenyl)sulfonylmethyl-2-phenethylsulfonyl) -11is-ACH
PA-NH-C)l (2-butyl) -CHz-N
(C113)-Cll□Ph; N-(1-(thiamorpholin-4-yl-S).

5-ACIIPA-NH-CH(2-butyl)-CHz-N (CHs) z-CHzPh”
Cj! ”;N-(1-(4-ethibiperazine-1-
yl)sulfonylmethyl-2-phenethylsulfonyl)
-Nle-ACHPA-NH-C)I(2-butyl)-CHz-Nll-C1lz-(4-pyridyl); N-(N-benzyl-N'-morpholinocarbonylmethyl-butyl)-C)lz -NH-CHz- (1-methylpyridinium-4-yl)OCle; N-(1- (N-morpholinocarbonyl)methyl-2
-phenethylsulfonyl) -His-ACHPA-N
H-C)l (2-butyl)-C)lz-NH-CHz
- (1-ethylpyrrolidin-3-yl); N- (1-(morpholin-4-yl)sulfonylmethyl- -NH-CH(2-butyl)-CHt-NCCIIx)
z” CHzCIIzS(he;N-(1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl)-11is-ACHPA-NH-CH(
2-Butyl)-CHz-N(CH3)zOCIIzC)
IzOll・(zO.

2- (N- (morpholinocarbonyl)methyl-3-
Phenylpropionyl-formerly s-AC liver^-Lys-NH
CII□ (pyridin-4-yl); 2-benzyl-5,5-dimethyl-4-oxohexanoyl-formerly s-ACHPA-NH-Lys-NHCllt
(pyridin-4-yl); N- (benzimidazol-2-yl)sulfonyl-
Old s-ACHPA-Lys-NH (quinuclidine-3-
N-(benzimidazol-2-yl)carbonyl-His-ACIIPA-Lys-NHCHz (
pyridin-2-yl); [N-(indol-2-yl)carbonyl-formerly S-AC)IPA-Lys-NIIC
H(2-butyl)-CH2N(Cl:+) 3) 00
Ace; N-(2 (i-7” lobylsulfonylmethyl)-3-phenylpropionyl) -11is-A
(jlPA-Lys-NIICHz (pyridine-4
-il);.

N-(2-(i-propylsulfonylmethyl)-3-phenylpropionyl) -N 12 e-ACHPA-
Lys-NHCH2 (pyridin-4-yl); N-
(1-(t-butylsulfonylmethyl)-2-phenethylsulfonyl) -His-ACHPA-Lys-N
) l-2(S)-methylbutyl; N-(1-(imidazol-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACflP
A- (N-imidacylin-2-yl)Lys-Nll
-i-Bu; N- (1-(1.1-dimethyl-2-carboxyethyl)sulfonylmethyl-2-phenethylsulfonyl)
-His-ACHPA-(N,N-dimethyl) Lys
-NHGHz (pyridin-4-yl); N-(1-
(p-carboxyphenyl)sulfonylmethyl-2-phenethylsulfonyl) -Hls-ACHP8-NHC
H((C11g)4N)IC(・NCI+3)NH
C113) C0-N)lCH2Ph; N-(1-(p-aminophenyl)sulfonylmethyl-
2-Phenethylsulfoter]-formerly 5-ACHPAα -(N-C1lz)Lys-NH-n-butyl; N-(
1-(thiamorpholin-4-yl-8゜S-dioxide)sulfonylmethyl2-phenethylsulfonyl)-
His-ACHPA-(N-imidacillin-2-yl)
Lys-NH-i-Bu;N-(1-(4-ethylpiperazin-1-yl)sulfonylmethyl-2-phenethylsulfonyl]-N1e-Act(PA-Ly
s-NHz; N-(N-benzyl-N'-morpholinocarboxylmethyl)carbamoyl-flis-ACHPA-(
N-pyridin-4-yl) Lys-N)I-2(S)
-Methylbutyl; N-(N-benzyl-N'-morpholinocarbonylmethyl (pyridin-4-yl)); N- (N-benzyl-N'-thiamorpholinocarbonylmethyl-S.S-dioxide)carbamoyl-His
-ACHPA-Lys-NH-2(S)-methylbutyl; N- (1- (N-morpholinocarbonyl)methyl-2-phenethylsulfonyl) -tlis-ACtl
l'A-Lys-NIICI+□(pyridin-3-yl); (2-(N-morpholinocarbonyl)methyl-3-
Phenylpropionyl-His-ACHPA-arys'
-NHCIlzCHJ(CHs)'Cle; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACIIPA-N
IICII (Cll zcII 2NHPh) QO
NHCHz (pyridin-4-yl); 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-formerly s-ACHPA- (N-CHi3) Lys-N
2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-formerly s-ACIIPA-Lys-NHC
llz (pyridin-4-yl); 2-benzyl-5.5-dimethyl-4-oxohexanoyl-His-AC['A-Lys-NHCHz (piperidin-4-yl); 2-benzyl-5.5 -Dimethyl-4-oxohexanoyl-former s-ACHPA-Lys-NHCHz (pyridin-4-yl>; [2-benzyl-5.5-dimethyl-4-oxohexanoyl-former s-ACHPA-Lys-NO - ((N
- (Clh) -quinuclidin-3-yl)))”c
leHN- (2- (t-butylsulfonylmethyl)
-3-phenylpropionyl) -His-ACHPA
-Lys-Nll-CI (2-butyl) CHJ (CH
s)z :N- (2- <t-butylsulfonylmethyl)-3-phenylpropionyl) -His-ACH
PA-Lys-NH-CH (2-butyl) CHJ(
CHzGHz) to :N-(2-(t-butylsulfonylmethyl)-3-phenylpropionyl) -Hi
s-ACHPA-α (N-Clh)Lys-NHGHz (piperidine-4-
N- (2- <t-butylsulfonylmethyl)-3-phenylpropionyl) -His-ACHP
A-Lys-N((Jb)CHz (piperidine-4
-yl); N- (2- (t-butylsulfonylmethyl)-3-phenylpropionyl) 41is-MCI
(PA-Lys-N(CHi)(Jlt(1-methylpiperidin-4-yl):N-(1-(morpholine-4
-yl)sulfonylmethyl-2-phenethylsulfonyl-formerly S-ACHPA- (N-Ctlz)Lys-N
(CHz) (piperidin-4-yl); N- (1- (morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl-formerly S-^CHPA
-(N-CHs)Lys-N(CH3) (1-ethylpiperidin-4-yl); N- (1- (morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl) -His-ACI
IPA-(N-Clls)Lys-Nll (pyridin-4-yl):N- (1- <thiamorpholine-4-
yl)sulfonylmethyl-2-phenethylsulfonyl)
-11is-8Cl! PA-(N-CHz)Lys-
NH (pyridin-4-yl); N- (1- (thiamorpholin-4-yl-S.

S-dioxide)sulfonylmethyl-2-phenethylsulfonyl) -Hls-ACHPA-Lys-Nil-
2(S)-Methylbutyl; N-(2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-(S-imidazol-4-yl)
Cys-ACHPA-Lys-N(C1ls) (pyridin-3-yl); N-(benzimidazol-2-yl)sulfonyl-formerly 5-Ca1(CI(011)CIlz) Val-L
ys-Nil-2(S)-methylbutyl; N-(benzimidazol-2-yl)sulfonyl-■
5-Ca1(CI(OH)CHz) Val-Lys
-NHCHz(pyridin-4-yl); N-(benzimidazol-2-yl)sulfonyl-H
ls-Cal(CI(On)CHt] Val-(N
-CHs)Lys-N(CHs) (1-ethylpiperidin-4-yl); N-(benzimidazol-2-yl)sulfonyl-formerly 5-Ca1 (CH(OH)CHz
) Vaj2-Lys-NH-n-butyl);
-CHs)Lys-NH(pyridin-4-yl): N-(2-(i-7"ropylsulfonylmethyl)-
3-phenylpropionyl) -H15-Am ACH
PA-Lys; N(2-(i-propylsulfonylmethyl)-3-phenylpropionyl)-11is-Am
AC liver^-Lys-N(CH3) (1-ethylpiperidin-4-yl); N(2-(i-propylsulfonylmethyl)-3-phenylpropionyl) -Hls-
(2S-i-butyl) ACI(PA-Lys-NH
CH:+;N-(2-(i-propylsulfonylmethyl)-3-phenylpropionyl)-Hls-(2
S-Allyl)ACHPA-(N-CIriL31S-NI
ICH2(pyridin-4-yl); N-(benzimidazol-2-yl)sulfonyl-Hls-Cal (C
H(NL)CHz) Val-Lys ;N-(2-(
(t-butylsulfonyl)-3-phenylpropionyl)
-11is-ACHPA-Lys-Nil-CH(2
-butyl) -C1,-NO(1,1-dimethylazepinium-3-yl))OcloH N(2-(i-propylsulfonylmethyl)-3-phenylpropionyl) -Hls-ACHPA-(N-C
)l*)Orn-NllCIIzCHzN (CHtC
Hz) zO;N-((2-butyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-3,S-dioxide)) -AC liver^-NH-
2(S)-Methylbutyl; N-((2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-8,S-di1oxide) -AC
liPA-NH-2(S)-methylbutyl;N-((2
S-butyl-5-(thiamorpholinocarbonyl-3,S
-dioxide)methyl-6-phenyl-4-thiahexanoyl') -ACHPA-NH-2(S)-methylbutyl; N-((IS-butyl-4-(morpholinocarbonyl)
Methyl-5-phenyl-3-thiapentanesulfonyl-
3,S-dioxide) ) -ACHPA-N11-2
(S)-Methylbutyl; N-((IS-butyl-4-(thiamorpholinocarbonyl-3,S-dioxide)methyl-5-phenyl-3-
Thiapentanesulfonyl-3,S-dioxide)〕-〕
Former 5-ACHPA-NH-2S)-methylbutyl; N-(2-(benzimidazol-2-yl)sulfonyl)methylhexanoyl) -ACHPA-NH-CH
i(2-butyl) -C)It-N)l(CHzC)I
t)to;N-(2-(indol-2-yl)sulfonyl)methylhexanoyl) -ACHPA-Ni
l-CH(2-butyl) -C1h-Nll(CthC
Ih) zsOt ; N-(2-(benzimidazol-2-yl)carbonyl)methylhexanoyl) −
ACIIP^-N II-C11(2cobutyl)-C
Hz-N(CHzCHz) zO(CHi)' Cj!
”;N-(2-(indol-2-yl)carbonyl)methylhexanoyl) -ACHPA-NH-C1
1(2-butyl) -CHz-NO(C1hCII□)
,NCI(,.

N-[2-butyl-5-(N-morpholinocarbonyl)
Amino-4-ohesohexanoyl28C) IPA-N
)I-CI(2-butyl)-CHz-N(CHi) (
CIl□CI+□)2NCR, S Cx e.

N-(5-(N-morpholinocarbonyl)amino-4-
oxo-2-phenylthiomethylhexanoyl) -A
CHPA-NH-CH(2-butyl)-CHz-N(
CH3) (CIhCH*) JCLsCIt e;N-
(2-(imidazol-4-yl)methyl-5-(N-
Morpholinocarbonyl)amino-4-oxohexanoyl]-ACOP^-NH-CI(2-butyl)-CHz
-N (CHs) (CHzCh) zsOz” C1
e; N-(2-(S-imidazol-4-yl)thiomethyl-5-(N-morpholinocarbonyl)amino-4-
oxohexanoyl) -ACHPA-NH-CI(2
-butyl)-cuz-s(cus)(cuzcuz)*
sog@cle; N-(5-(t-7'tylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4
-Oxo-6-phenylhexanoylgo-8CHPA-
Nil-CI(2-butyl)-CHz-NH(C)lz
cHt)J(CHs)zlEICl e;N-(5-(
morpholinosulfonyl)methyl-2-(imidazole-
4-yl)methyl-4-oxo-6-phenylhexanoyl) -ACHPA-NH-CH(2-7"thyl')
-CHx-NH(CHzCHt)J(C)Is)z@C
1e; N-(2-n-butyl-5-(L-butylsulfonyl)methyl-4-oxo-6-phenyl-hexanoyl) -ACHPA-NH-CB(2-butyl) -C
112-NH(CHzGHz)J-GO-CHs;
N-(2-(N-benzyl-N'-(morpholinocarbonyl)methyl)sulfonamidomethyl)hexanoyl)
-ACIIPA-Nll-CH(2-butyl) -C
Il□-N(CHs)z: N-(2-n-butyl-5-(t-butylsulfonyl)
Methyl-4-hydroxy-6-phenylhexano-yl) -ACHPA-NH-C)I(2-butyl) -C
11,-N(CHs)s@C1e; N-(5-(t-7”tylsulfonyl)methyl-2-(
(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl) -ACIIPA-Nll-CH
z-CI(2-flLt)-N(CH,CH,), @
(:,le.

N-(5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl) -ACHPA-Nll-, C1h
-CI(2-butyl)-NH-(4,5-dihydroimidazol-2-yl); N-(5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo -6-phenylhexanoyl) -ACHPA-N)l-CHz-
CI(2-butyl)-NH-(1-ethyl-4,5-dihydroimidazol-2-yl); N-(5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl- 4-oxo-6-phenylhexanoyl)-ACHPA-Nll-CH(2
N-(5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6- phenylhexanoyl) -MCIIPA-NH-CI(2
-butyl) -CHz-(2-guanidinomethylpyrrolidin-1-yl): N-(5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexa Noyl) -ACIIPA-NH-CHt(
2-butyl)-CI□-(2-hydroxymethyl-1=
methylpyrrolidinium-1-yl)OC1θ; N-(5
-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl) -ACHPA-NH-CH(2-7”chill)-Cllz-NH(CHzCHt)J( (jls)z
OCj! e; N-(5-(morpholinosulfonyl)
Methyl-2-(imidazol-4-yl)methyl-4-
oxo-6-phenylhexanoyl) -ACHPA-
Nll-CH(27”chill)-CHt-NH(C)lz
cHz)zN(C1h)z”cle;N-(5-(morpholinosulfonyl)methyl-2-(imidazole-4-
methyl-4-oxo-6-phenylhexanoyl) -ACHPA-Nil-CH (2-buty/L, )-
CH2-NH(CHICBri2N(CH3)!”l!e
.

N-(5-(morpholinosulfonyl)methyl-02-(
imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl) -ACHPA-Nil-CI(
2-Butyl)-C1lz-NH(CHxCHz)zN(
C1l:+)z"(Je ; N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl) -A
CHPA-Nll-CH(2-buty/Iz)-CHz-
N) I(CHzCJ) 2N(CH:l)! ” Ci
e;'N-(5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-
6-phenylhexanoyl]-^to CHP-Nll-C
11(2-Butyl)-C)It-NH(CHzClh)
J((Hh) ze C1e ; N-(5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl)
-ACHPA-Nil-C8 (2-7” chi/l/)
-CHz-Nll(CHzCIIz) zN(C)Is
)ze C1e;N-((2S-butyl-5-(morpholinocarbonyl)methyl-6-(phenyl-4-thiahexanoyl-8,S-dioxide)") -AC
HPA-Nll-C1l(2-butyl)-CHt-(2
-) Limethylammoniomethylpyrrolidin-1-yl)
l! +(72e;N-((2S-butyl-5-(morpholinocarbonyl)methyl-6-(phenyl-4-thiahexanoyl-3,S-dioxide)) -MCIIP
A-NH-C11(2-butyl)-CH2-N(C1l
s)z” CH25O2e;N-((2S-butyl-5
-(morpholinocarbonyl)methyl-6-phenyl-4
-thiahexanoyl-3,S-dioxide)]-]C
HP^-NH-CH2-buti71. )-CH(01()
Cut-N (CH3) (CH, CHri 20" C18.

N-((2-imidazol-4-yl)methyl-5-(
morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-8,S-dioxide)
PA-NH-CH(2-butyl) -C1h-(pyridinium-1-yl)eczθ; N-((2-imidazol-4-yl)methyl-5-(
methyl-6-phenyl-4-thiahexanoyl-3,S-dioxide) ) -ACH
PA-NH-CI (2-butyl) -CH, -1-methylimidazolium-1-yl)@C1el.

N-((2-imidazol-4-yl)methyl-5-(
morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-3,S-dioxide)) -ACHP
A-Nil-CI(2-butyl)-CH2-N(C1h
)z(!Icntcuzcoze: N-((2-imidazol-4-yl)methyl-5-(
morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-3,S-dioxide)]-]^CHP
A-NH-CH2-butyl)-CH2-N(C)b)t
@C) IZcI(,SO,e.

N-((2-imidazol-4-yl)methyl-5-(
morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-8,S-dioxyF)) -ACHP
A-Nil-C)l(2-butyl)-CHz-N(CH
s)z"Cl1zC)Izoll・Cl" :N-
((2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-8,S-dioxyF)] -]ACHPA
-Nil-CI2-buty/L/) -C1lz-N(C
1ls)! ”CIIgCHJ(CHz) z・CI
';N-((2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-3,S-dioxide))
-ACHPA-IJII-CI (2-butyl)-C1
h-Nil-CHzC1l□NH-C(=NH)-NH
t ; N-((2-imidazol-4-yl)methyl-
5-(morpholinocarbonyl)methyl-6-phenyl-
4-thiahexanoyl-3,S-dioxide)
-CaIl' (CI(Oll)CL) -VaI
l-NH-CH(2-butyl)-CHt-NH-CH,
CH(NHRCO□lI;N-((2-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-8,S-
Dioxide)]-]A vehicle ACHP 8 to NH-CI 2-
butyl) CH, -NH-CHgCH(COze)N(
CHa)ze;N-((2-imidazol-4-yl)
Methyl = 5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-5,S-dioxide)
)-Ca1(CH(OH)C)It)-VaiN
(i-butyl)-CHz-CHz-N(CH*CHg)
zN(CHz)! "Clθ;N-((2-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-
5,S-dioxide))-(2S-i-butyl)-A
(JIPA-Nll-CI (2-butyl) -CHz
-NH-CHt (pyridin-4-yl-N-oxide)
; N-((2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-3,s-dioxide))-(2S-
Ali/l,) ACHPA-NH-CI (2-butyl)
-CIl□-NH-CB baviridin-2-yl-N-oxide); N-((2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-8,s-dioxyF))-Cal
(CH(Nllz)-CHt) Vaj! -NH-C
ll(2-butyl)-CJ-N)l-CHz (pyridin-2-yl-N-oxide): N-((2-butyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexa Noil-S, S-
) -Call (CIl(OH)C1
12-NH-2(S)-methylbutyl:N-
[(2S-butyl-5-(thiamorpholinocarbonyl-
3,S-dioxide)methyl-6-phenyl-4-thiahexanoyl) -ACIIPA-Lys-NH (quinuclidin-3-yl);
Methyl-5-phenyl-3-thiapentanesulfonyl-
3,S-dioxide) ) -ACHP^-Lys-N
HCHt-(pyridin-2-yl);N-((IS-butyl-4-(thiamorpholinocarbonyl-8,S-dioxide)methyl-5-phenyl-3-thiapentanesulfonyl-3,S-dioxide)) -ACHPA-L
ys-NHCH(2-butyl)CHzN(C1lz)
3) Φcj2e ;N-((2-(imidazole-4-
yl)methyl-5-(morpholinocarbonyl)methyl-
6-phenyl-4-thiahexanoyl-8,S-dioxide) -ACHPA-Lys-NH,;N-((
2-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6=phenyl-4-thiahexanoyl-8,S-dioxide) -ACHPA-
Lys-N(CHdCHz (pyridin-4-yl); N-((2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-3,S-dioxide) -AC
HPA-Lys-NHC)It (pyridin-4-yl);N-((2-(imidazol-4-yl)methyl-
5-(morpholinocarbonyl)methyl-6-phenyl-
(4-thiahexanoi)Lt-3,S-dioxide)
-ACHPA-Lys-NH-2(S)-methylbutyl; N-(5-(morpholinosulfonyl)methyl-2-
(imidazol-4-yl)methyl-4-oxo-6-
phenylhexanoyl]-^CIIPA-(N-imidazolin-2-yl) Lys-NH-i-Bu;
N-(5-(morpholinosulfonyl)methyl-killer 6)
-phenylhexanoyl) -ACIIPA-(N,N
-dimethyl)Lys-NH-CHI(pyridin-4-yl);N-(2-n-butyl-5-(t-butylsulfonyl)methyl-4-hydroxy-6-phenylhexanoyl) -ACHPA-NHCH( (Cllt) 4N
IIC(=NCIIz)-NHC)13) C0-NH
CHzPh; N-(5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoylLys-NO-n-butyl; N-(5-(morpholino sulfonyl)methyl-2-(
(imidazol-4-yl) methyl-4-oxo-6-phenylhexanoyl) -ACHPA-ε (N-imidacillin-2-yl) Lys-Ntl-i
-Bu;N-(5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-^COP^-Ly
s-NHz;N-((2S-butyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S.S-dioxide")) -ACHPA-
(N-pyridin-4-yl) Lys-NH-2(S)
-Methylbutyl;N- [(2S-butyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)) -ACHPA
-Lys-NHCHz (pyridin-4-yl); N- ((2S-butyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S
．． S-dioxide) ) -AC)IPA-Lys-N
H-2(S)-methylbutyl; N-((2S-butyl-5-(morpholinocarbonyl)
Methyl-6-phenyl-4-thiahexanoyl-S,S
-dioki-sito)]-]^CHPA-Lys-NHCH
z (pyridin-3-yl); (N-((2-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl=S
, S-dioxide))-ACHPA-HLys-NHC
)IzCHtGHzN(CHi)z) 0C1e ;N
-((2-(imidazol-4-yl)methyl-5-(
morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-3,S-dioxide) -ACI
IPA-NHCH (CHzCHJHPh) C0NHC
Ilz(pyridin-4-yl); N-(2-(N-benzyl-N'-(morpholinocarbonyl)methyl)sulfonamidomethyl)hexanoyl)
-ACHPA-(N-CHs)Lys-NHCL (
N-(2-(S-imidazol-4-yl)thiomethyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl) -ACHPA-Lys-NHcHz
(Pyridin-4-yl): N-(2-(S-imidazol-4-yl)thiomethyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl) -AC
HPA-Lys-N)lCHz (piperidin-4-yl); N-[2-butyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl) -ACII
PA-Lys-N)lcut (pyridin-4-yl)
;(N-(2-butyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl)-ACHPA-
Lys-(N-CHz-Kinuku'J:,; 7-3-
4 Jl/)) 'C1e; N-(5-N-morpholinocarbonyl)amino-4-oxo-2-phenylthiomethylhexanoyl]-^CHPA-Lys-NH-C
H(2-butyl))CHJ(CH+)z ;N-(5-
(N-morpholinocarbonyl)amino-4-oxo-2
-Phenylthiomethylhexanoyl]-800PA-L
ys-NH-CH (2-butyl) CHIN (Cllt
CHg)to; N-(5-(N-morpholinocarbonyl)amino-4-
oxo-2-phenylthiomethylhexanoyl) -A
CIIPA-(N-CI(3) Lys-NHCHx
(piperidin-4-yl); N-[4-hydroxy-5-(N-morpholinocarbonyl)amino-2-phenylthiomethylhexanoyl)
-ACHPA-Lys-N(CIli)CHz (piperidin-4-yl); N-(5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-funinylhexanoyl N((J13)CL(1-methylpiperidin-4-yl);N-((2-imidazol-4-yl)methyl-
5-(morpholinocarbonyl)methyl-6-phenyl-
4-thiahexanoyl-S. S-dioxide) ) −
ACHPA-(N-CHz)-LVS-N(CHi)(
piperidin-4-yl): N- ((2- (imidazol-4-yl)methyl-
5-(morpholinocarbonyl)methyl-6-phenyl-
4-thiahexanoyl-S,S-dioxide) ) −
AC)IPA-(N-CI(i)Lys-N(Ctlz
) (1-ethylpiperidin-4-yl); N-((2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide) -AC
HPA-Lys-Ntl-2(S)-methylbutyl; N
- ((2-(imidazol-4-yl)methyl-
5-(morpholinocarbonyl)methyl-6-phenyl-
4-thiahexanoyl-S,S-dioxide) )-A
CHPA-Lys-N(CHz)(pyridin-3-yl): N-(2-(indol-2-yl)carbonyl)methylhexanoyl) -Ca l (Cl(Otl)C
Hz) Val-Lys-NH-2(S)-methylbutyl; N-'(2-(indol-2-yl)carbonyl)methylhexanoyl) -Cal (CH(OH)
Hz) Va 1 -Lys-NHCHt (pyridin-4-yl): N-(2-, (benzimidazole-2
-yl)sulfonyl)methylhexanoyl)-Can(
CI(OH)CJ) Va j! -(N-CHa)
Lys-N(CHz) (1-ethylpiperidine-4-
N-(2-(benzimidazol-2-yl)sulfonyl)methylhexanoyl)-Cajl(CH(OH
)CHz) Val-Lys-NH-n-butyl;N-((2-(imidazol-4-yl)methyl-5
-(morpholinocarbonyl)methyl-6-phenyl-4
-thiahexanoyl-8,S-dioxide) -C
al (CH(01()CH2) Vaj+-(N-C
H2) Lys-NO (pyridin-4-yl):N-((
2-Butyl-5-(morpholinocarbonyl)methyl-6
-Phenyl-4-thiahexanoyl-3,S-dioxide) ) -Ao+ ACHPA-Lys;N-[
5-(t-7'tylsulfonyl)methyl=2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl) -A+n ACIIP^-Lys-N
(CI(3) (1-ethylpiperidin-4-yl);
N-(2-(indol-2-yl)sulfonyl)methylhexanoyl)-(2S,-i-butyl)-ACHP
A-Lys-N)ICHs;N-(2-(benzimidazol-2-yl)carbonyl)methylhexanoyl)-Cal(C1l(Nlh)CHz) Val-
Lys; N-(2-(benzimidazol-2-yl)carbonyl)methylhexanoyl) -MCI(PA
-Lys-NH-CH(2-butyl)-CH2-NH-
(1,1-dimethylazevinyram-3-yl)”CI
! e; N-(5-<L-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl) -ACHPAα -(N-CHs)Oral-Nll-C1hC) IJ(
C) IzGHz) tO; N-((1-ethoxycarbonylmethyl-2-phenyl)ethylsulfonyl 2(S)-methylbutyl; N-((1-ethoxycarbonylmethyl-2-phenyl)ethylsulfonyl) -His-ACHPA -L
ys-NHCHg (pyridin-4-yl); N- ((1-ethoxycarbonylmethyl-2-phenyl)ethylsulfonyl) -His-ACHPA-L
ys-NHCH2 (piperidin-4-yl) and N-(
(1-ethoxycarbonylmethyl-1-phenyl)ethylsulfonyl) -His-ACHPA-Lys-NH
-iBue Pharmaceutically acceptable salts of the compound of formula I include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
Citrate, camphorate, camphor sulfonate, cyclopencune propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, Heptanoate, hesanate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate , nicotinate, oxalate, vamocote pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosyl There are acid addition salts such as acid salts and undecanoates. Basic salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and organic bases such as dicyclohexylamine, N-methyl-D-glucamine. There are salts, salts with amino acids such as arginine and lysine, and others. Furthermore, basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl, diethyl, diptyl and cyamyl sulfate; chloride, bromide and , and long chain halides such as decyl, lauryl, myristyl and stearyl iodide; aralkyl halides such as benzyl bromide and phenethyl bromide; and may be quaternized with other reagents. Water- or oil-soluble or dispersible products are thereby obtained. Conventional methods are available for producing these salts.

The present invention further provides a pharmaceutical composition for treating hypertension and congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a peptide of formula (2). 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 treated and the particular route of administration.

Further provided herein is a method of treating hypertension and congestive heart failure comprising administering a therapeutically effective amount of a peptide of Formula I to a patient in need thereof.

The renin-inhibiting peptides of the present invention are also utilized in diagnostic methods to determine the importance of renin as a causative or contributing factor in hypertension or congestive heart failure in a particular patient. For this purpose, the present peptides contain 0.1 to 10
■ Administered in a single dose of / kg body weight.

Both in vivo and in vitro methods are applicable. In the in vivo method, the novel peptides of the invention are preferably administered to the patient by intravenous injection, although other parenteral routes of administration are also suitable, provided that hypotensive doses are used and the single dose is as follows: A temporary decrease in blood pressure occurs. This blood pressure drop is 1
．． If it occurs, it indicates a blood renin level that exceeds the normal range.

Peptide bond mimetics, ie statins or other peptide bond isosteres of Element R, are produced by the following known methods: Buhla+ayer et al., HomoACHPA Structure, European Patent Application No. 184.550-A2
Issue specification; Boger et al., Journal of Medicinal Chemistry, 1985, No. 28
Vol. 1779-1790: Raddatz et al., European Patent Application No. 16
No. 1.588; Skelke et al., Patent Cooperation Treaty International Application No. WO 34103,044; 2-substituted AC:HPA Boger et al., European Patent Application No. 157,409; Veber et al., Biochemical Society Transactions (Biochemical 5
ocietyTransactions), 1984
Year, Volume 12, Pages 956-959; Stein (St.
ein) et al., Federasin Proceedings,
1986, Vol. 45, p. 869; and Plattner et al., European Patent Application No. 172.347.

Some of the peptide coupling operations used in the following routes are carried out through the use of dicyclohexylcarbodiimide; other well-known coupling reagents include DCC/hydroxybenzotriazole (HOBt).
(Takeda et al., Tetrahedron Letters, 198
3, Vol. 24, pp. 4451-54)].

If the unit T consists of an N-alkyl (eg N-methyl) amino acid, methods well known in peptide synthesis are utilized to prepare this amino acid and attach it. Generally, the mixed anhydride method (with pivaloyl chloride and N-methylmorpholine) is used as described by Wenger.
%Helvetica Chimica Acta (l(elvetic)
a Chisica Acta), 1984, No. 6
7, pages 502-525,
or Rich et al., Journal of the American Chemical Society.
American Chemical 5ociety
), 1985, Vol. 107, pp. 4342-43 B
The OP-C1 method is used. N-methylamino acids are produced, for example, by the method of O'Donnell, Tetrahedron Letters, 1984, Vol.・Of Organic Chemistry (Journ)
al of Organic Che+wistry)
, 1983, Vol. 48, pp. 77-81 or Hansen et al., Journal of Organic Chemistry, 1985, Vol. 50, No. 94.
Produced by the method on pages 5-950. N-1j substituted histidines are available from Stillwell.
, Bioorganic Chemistry (Bioorg)
Anic Chemistry), 1975, Vol. 4, pp. 317-325.

The route below is a formula! represents a representative example for the preparation of peptides, similar peptides with other substituents may also be prepared by the routes outlined below, with necessary modifications within the ability of those skilled in the art. .

When component A of the inhibitor of the invention is, for example, a carboxylic acid of formula (1), the production of component A can be carried out by one of two routes: , tLL: aldehyde and diethyl succinate under basic conditions. An alkylidene succinic acid monoester is obtained by condensation of Condensation with an amine, e.g. morpholine gives the corresponding amide ester, which after hydrogenation and then saponification ■
get.

The amide diester is obtained by alkylation of an alkyl diethyl malonate (prepared by alkylation of diethyl malonate) with an electrochloroamide such as chloroacetylmorpholinamide. Then, hydrolysis and decarboxylation of this amide diester yields ①.

The inhibitors of the present invention have element A of formula (1), which is prepared according to the following route: 1(Cl-H,OV- CHsOH-HzOR5-C3-tl; (hH) In the preparation of such inhibitors, the protected form of the B component may be an amino acid of formula ■, which is prepared as described in the following route: IIF Arnold et al., Journal of American Chemical.・Society, 1985, No. 1
Vol. 07, pp. 7105-7109; Fra
Journal of Che+++1cal 5
ociety).

1960, p. 1390 Akaburi
), Bulletin of the Chemical Society of Japan
Chemical Society of Japan)
, 1964, Vol. 37, p. 433: and Kornblam et al., Journal of the American Chemical Society, 1974, No. 9
Volume 6, page 590; or I Melchior et al., Archives of Biochemistry.
chemistry), 1947, Volume 12, No. 3
Page 01; and Wood et al., Journal of Biological Chemistry.
'of Biological Chemistry)
, 1949, vol. 179, p. 529.

In the production of some of the inhibitors of the present invention, it is necessary to prepare a protected form of the B component, which is an amino acid of the formula (1) or (2), and these are produced as follows: ' ↓ (BOC) zO BOC BOC■ Stillwell et al., Bioorganic Chemistry
hemistry), 1975, Volume 4, No. 317-
325 pages.

The A-B component of the present invention may, for example, consist of a urea moiety of formula 1, which is prepared as described in the following route: Peptides of formula (1) with ACHPA as a peptide bond mimetic can be prepared using the following or analogous procedures (as described in p. ) Produced by: In the following operations, the amino acids represented by elements B and T are respectively) AA
' and AA''.

In the following operations, ReO2)1 is a carboxylic acid component, which represents the AB component of formula I.

In this case, component B is not an amino acid (i.e.
element is not NR'). The following R'co'zu is a carboxylic acid component, and this carboxylic acid represents a formula IOA component, and the B component of formula (■) represents an amino acid (i.e., K
corresponds to NR').

Route A: Step A1: BOC-AA' (1) is combined with an amine or alcohol moiety J to form an amide (or ester) 2. The amide (or ester) may be treated with anhydrous TFA to produce 3.

Other reactive functional groups in the amino or alcohol component J are protective groups such as CBZ for amino groups, benzyl ethers for alcohols, and benzyl esters for carboxylic acids in the above steps (and the following steps). )
Medium protected.

Step A2: BOC-ACL(PA-OEt(4)
was treated with anhydrous TFA to remove the BOC protecting group, and A
Generate CHPA-OEt (5).

Step A3: ACHPA-OEL (5
) is combined with RCO□H to produce 8. Alternatively, an amino acid whose N-terminus is protected with a BOC group (BOC-A
A'') is coupled with 5 to produce coupled product 6. Coupled product 6 is conjugated with anhydrous TFA to remove the BOC protecting group.
The resulting product 7 is combined with R'CO□H to produce 8a.

Step A4: The resulting coupling product 8 (or 8a) is treated with methanolic hydrazine to produce the corresponding hydrazine 9 (or 9a).

Step A5: Hydrazine 9 is treated with acidic isoamylnitrile to produce the corresponding acyl azide, which is treated in situ with 3 to produce coupled product 10 (or 10a). Alternatively, the coupled product 8 is treated with sodium hydroxide in THF-HzO and the resulting carboxylic acid derivative is coupled with J to produce 10 (or 10a).

Direct combination of 9 (or 9A) with alcohol or amino component J gives product 12 (or 12a).

Step A6: During the above steps, the reactive functional group present in the side chain of the amino acid component or the J element is retained! protected by These can be CR2 groups in the case of amines, benzyl ethers in the case of alcohols, and benzyl esters in the case of carboxylic acids. In the case of histidine, BOC protection is applied to protect the side chain imidazole ring, but this group is removed in the hydrazine treatment step A4 or the sodium hydroxide treatment step A5. The histidine imidazole ring may then remain unprotected.

Step A7: In cases where a quaternized amino group is introduced into the C-terminal J element of compound 11 (or 11a) or 13 (or 13a), one of the following operations To introduce the groups: Operation 1: The tertiary amine in component J is quaternized by treatment with an alkyl halide and KHcOs in methanol or ethanol or with an alkyl halide in DMF. The resulting quaternary ammonium salt is then treated with anhydrous TFA to remove the BOC protecting group from the amine present in J, and the resulting free amine is used for the preparation of 3 as described in step AI above. . Similarly, the amino acid AA3 with a quaternary ammonium group in the side chain may be used for the preparation of the three.

1 piece! Compounds 10 (or 10a) or 12 (or 12a) are prepared in which the side chain of AA3 or the J element has a tertiary amine, and the tertiary amine is then quaternized by treatment with an alkyl halide in DMF. In the latter case, when histidine is present as an AA' element, it is 10 (or 10
a) or 12 (or 12a) which must first be reprotected as a BOC derivative by treatment with 0 then BOC
The group is dissolved in methanol after step 8 with CO, or DM
It is removed by treating 11 (or 11a) or 13 (or 13a) with F or anhydrous ammonia in methanol.

Step A8: The protecting group is removed by hydrogenolysis to 10 (or 1
0a) or 12 (or 12a) to produce 11 (or 1la) or 13 (or 13a).

Compound Formula % Formula %: -treated with sodium hydroxide in H2O, BOC-AC
Generate HPA.

Step B2: BOC-ACHPA is conjugated with 3 to produce conjugation product 14.

Step B3: Compound 14 is treated with anhydrous TFA to remove the BOC protecting group, producing I5.

Compound 15 is combined with RCO□11 to produce 10. or 15 is combined with BOC-AA' to produce 16. 16 is treated with anhydrous TFA and the resulting product 17 is combined with R' co,u to generate IOa. In step B2, BOC-
Direct combination of ACHPA and amine or alcohol component J and then application of the operations of steps B3 and B4 produce product 12 (or 12a).

1) In cases where a quaternized amino group is introduced into the C-terminal J element of compound 11 (or 1la) or 13 (or 13a), one of the following operations can be used to quaternize To introduce the amino group: Operation 1: The tertiary amine in the J element is quaternized by treatment with an alkyl halide and KHCO3 in methanol or ethanol or with an alkyl halide in DMF. The resulting quaternary ammonium salt is treated with anhydrous TFA to remove the BOC protecting group from the amine present in J, and the resulting free amine is used for the preparation of 3 as described in Route A.

Compounds 10 (or 10a) or 12 (or 12a) where the AA3 or J element has a tertiary amine are prepared, and then the tertiary amine is quaternized by treatment with an alkyl halide in DMF. Ru. In the latter case, when histidine is present as an AA' element,
10 (or 10a) in di-1-butyl dicarbonate
or must first be reprotected as a BOC derivative by treatment with 12 (or 12a).

The BOC group is then dissolved in *CO in methanol after step B6.
s or by treating 11 (or 1la) or 13 (or 13a) with anhydrous ammonia in DMF or methanol.

Step B6: As described above for route A, AA' and AA
The amino acid side chains of 3 as well as the reactive functional groups in the J component are protected during the coupling step.

The protecting group is then removed by hydrogenolysis to form the coupled product 10 (
or removed from 1oa) or 12 (or 12a);
Compound 11 (or 11a) or 13 (or 13a) is produced.

□ Formula % Formula % Peptides of formula I with statins are prepared as described above in Routes A and B, with the exception that BOC-ACHPA
-OEt is replaced with BOC-Sta-OEt. In this way, peptides such as 18.19.20 and 21 are produced.

18 RCO-Sta-AA”-J19
RCO-5ta-J2OR' C0-AA
'-5ta-8A3-J21 R' C0
-AA'-5ta-J Amino-A CHP A (Am
ACHP, A) or amino-sufutin (AmSta)
Peptides of formula I having BOC-ACHPA-OEt are prepared as described above in Routes A and B, with the exception that BOC-ACHPA-OEt
is substituted with BOC-AmACHPA(CBZ)-0E or BOC-AmSta(CBZ)-0Et. The CBZ group of the AmACHPA or Am5ta element is removed by hydrogenolysis in step A8 or B6. In this way, peptides such as 22, 23, 24' and 25 (and the corresponding Am5ta analogs) are produced.

22 RCO-AmACH
P8-AA'-J23 RCO-AmAC
HPA-J24 R'Co-AA'-A
mACIIPA-AA"-J2SR'
Co-AA'-AmACIIPA-J 2-substituted statins or ACH as peptide bond mimics
Peptides of formula 1 containing a PA element are prepared as described above in routes A and B, with the exception that BOC-ACHPA-O
Et is, for example, BOC-(2-allyl)ACHPA-O
A suitably protected 2-substituted ACHPA or 2-substituted statin derivative such as Et or BOC-(2-isobutyl) Sta-OEt is substituted. In this way, 26
．． Peptides such as 27, 28 and 29 are produced.

26 RCO-(2-1sobu tyl
) ACHPA-AA 3-J27 RC
O-(2-isobutyl)^CHPA-J28
R'C0-AA'-(2-allyl)^
CHPA-^^3-J29 R' C0-
AA'-(2-allyl)AC)IPA-Jheftytate binding mimetic Toshi'CCal'(C41(OH)CH
z) Peptides of formula (2) with Val are prepared as described below in routes C and D.

Route C: Step C1:B, the OC protecting group is removed from lactone 25 by treatment with anhydrous TFA to generate lactone 26.

Step C2: Lactone 26 is coupled with RCoffiH to produce 27 or with a terminal BOC protected amino acid (BOC-AA') to produce 28. 28 was treated with anhydrous TFA, and the product 29 was converted to R'
Combination with C0tH generates 30.

Lactone 27 (or 30) is treated with aqueous sodium hydroxide to produce the corresponding hydroxy acid. The hydroxy acid is treated with t-butyldimethylsilyl chloride and imidazole, followed by acetic acid in THF-H2O to produce the protected hydroxy acid 31 (or 32).

Work 1 - Earthwork Compound 31 (or 32) is combined with 3 to produce 33 (or 34). Amino acid side chains or other reactive functional groups in component J are protected with protecting groups such as CBZ for amino and guanidino groups, benzyl ether for alcohols, and benzyl ester for carboxylic acids. When histidine is used as the amino acid component, the side chain imidazole ring may be protected with a BOC protecting group during step C2. This protecting group is removed by TFA treatment and the imidazole ring remains unprotected during the subsequent N-terminal coupling or acylation reaction. Or, histidine is D in step C2.
Optionally protected with an NP protecting group, this group is then removed by potassium hydroxide treatment in step C3.

Step C5: The silyl protecting group is removed from 33 (or 34) by treatment with tetrabutylammonium fluoride in THF-DMF to generate 35 (or 36).

Step C6: In some cases, a quaternized amino group is present in the C-terminal J element of compound 37 (or 38). In such cases, the following procedure is used: Procedure 1: The tertiary amine in the J element is quaternized by treatment with an alkyl halide and KHCO3 in methanol or ethanol or with an alkyl halide in DMF. The resulting quaternary ammonium salt was then treated with anhydrous TFA to remove the BOC protecting group from the amino functionality present in J.
The free salt obtained is used for the preparation of compound 3.

Operation 2: Compound 35 (or 36) having a tertiary amine in the J or AA triad is produced.

If histidine is present as the AA' component, the imidazole ring is then diluted in methanol or DMF.
- protected by treatment with butyl dicarbonate and EtzN. The tertiary amine present in the AA3 or J element is then quaternized by treatment with an alkyl halide in DMF.

Step C7: The protecting group is converted to 35 (or 3
6) to produce 37 (or 38).

25 BOC-Cal [CH(OH)CHz]
Val Lactone 26 Cal [(J!(OH)
CI! ] Val Lactone 27 9CO-Cal
[CII(OH)CHz] Val Lactone 28
BOC-AA'-Cal [CH(OH)C)Ixl
Val Lactone 29 ^A'-Cal [CI
(OB)CHz] Val Lactone 30 R'
C0-AA'-Cal [CI(OH)CHz] Va
t Lactone 31 RCO-Cal [C)l(O
TBDNS)CHz] Val-OH32R' C0-
AA'-Cal [CI((OTBDMS)CH2F
Vat-OH33RCO-Ca1 [CI(OTBDM
S) C1lz] Val-^A3-J34 R' G
o-AA'-Cal [CH(OTBDMS)CH2F
Val-AA"-J35 (37) RCO-Cal
[CH(OH)Ctlzl Val-^A3-J3
6(38) R'CO-^^'-Cal [CH(1
)C)lx] By the same operation as Val-AA3-J,
39 and 40 are produced = 39 RCO-Cal
[CH(OH)CHzl Val-J40 R'
C0-AA'-Cal [CH(OH)CHzl V
Step D1: Lactone 25 is treated with potassium hydroxide to produce the corresponding hydroxy acid 41. hydroxy acid 41
is treated with t-butylmethylsilyl chloride and imidazole, followed by acetic acid in THF-H,O to produce the protected hydroxy acid 42.

Step D2: Protected hydroxy acid 42 is coupled with 3 to generate 43. Other reactive functional groups in component J are protected with protecting groups such as CBZ for amino and guanidino groups, benzyl ether for alcohols, and benzyl ester for carboxylic acids.

Step D3: The BOC protecting group is removed from 43 by treatment with anhydrous TFA to generate 44.

U"LdiA"-Compound 44 can be combined with RCO,H to produce Compound 33, or the N-terminal BOC-retaining group (
Coupling with an amino acid with BOC-AA') generates conjugate product 45.

Step D5: The N-terminal BOC protecting group is removed from 45 by treatment with anhydrous TFA to yield compound 46.

Step D6: Compound 46 is combined with R' CO□H to produce compound 34.

Step D7: Compounds 33 and 34 are treated as described above in Route C to produce compounds 37 and 38.

Compounds 39 and 40 are produced by the same operation as above.

25 BOC-Cal [CI(OH)CHzl
Val Lactone 41 BOC-Cal [CH(
OH) CHzl Val-OH42BOC-Cal
[C1((OTBDNS)CHzl Val-OH43
BOC-Cal [CH(OTBDNS)C)It]
Val-AA3-J44 Cal [CH(
OTBDMS) CHzl Val-＾A”-J45
BOC-AA'-Cal [CH(OTBDMS
)C)l! ] Val-AA3-J46 AA'
-Cal [CH(OTBDMS)CHzl Va
l-AA3-J The novel peptides of the present invention have excellent efficacy in treating hypertension and congestive heart failure in humans and other hyperemic animals such as mice, rats, horses, dogs, cats, etc. , they are also orally active.

For these purposes, the compounds of the invention may be administered orally, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrafibular injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, e.g., as a sterile injectable aqueous or oleaginous suspension, which may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. is prescribed. Sterile injectable preparations include, for example, 1.
It may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 3-butanediol.

Acceptable vehicles and solvents that may be used include water,
There are Ringer's solution and sodium chloride isotonic solutions. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, bland fixed oils may also be employed including synthetic mono- or diglycerides. Furthermore, even fatty acids such as oleic acid can be used as injectable preparations.

The peptides of the invention may be administered as suppositories for rectal administration of the formulation; these compositions are solid at room temperature but liquid at intrarectal temperatures, so that they melt in the rectum. It is manufactured by mixing the drug with a suitable bland excipient, such as cocoa butter or polyethylene glycols, which releases the drug.

In the case of parenteral administration, a dosage of 0.1 to 4.0 g/day is applied for the treatment of the above diseases, but the oral dosage is 3.
~lO times more. For example, renin-related hypertension and hyperaldosteronism are effectively treated parenterally by administering the compound at 1.0-50 w/kg body weight per day. However, the specific dosage for a particular patient will depend on the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, rate of excretion, concomitant drugs, and the amount of time taken during treatment. It will be understood that this will depend on a variety of factors, including the severity of the particular disease.

The present invention provides novel enzyme-inhibiting peptides of formula (1), diuretics, α- and/or β-adrenergic blockers, CNS hypotensive agents, adrenergic nerve blockers, vasodilators, angiotensin I-converting enzyme inhibitors, It also relates to combinations with one or more antihypertensive agents selected from the group consisting of calcium channel blockers and other antihypertensive agents.

For example, the compounds of the invention may be administered in combination with the following compounds or salts or other derivatives thereof: acetazolamide; amiloride; bendroflumethiazide; benzthiazide; bumetanide; chlorothiazide; Chlorthalidone; cyclothiazide; ethacrylic acid; furosemide; hydrochlorothiazide: hydroflumethiazide; benzucrinone (racemic mixture, or (+)
or (-) any single enantiomer, or for example as an artificial ratio of 9:1 of each of said enantiomers); metolazone; methyclothiazide; muzolimine; polythiazide: quinetazine; sodium ethacrylate; sodium nitroprusside; spironolactone; ticlinafene; triamterene; trichlor Methiazide; α-adrenergic blockers: dibenamine; phentolamine, phenoxybenzamine; prazosin; tolazoline; β-adrenergic blockers: atenolol; metoprolol; nadolol; propranolol; butylamino)-2-
Hydroxypropoxy]-2-furananilide) (atenolol): (2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran) 1(J) (
((±')-1-(isopropylamino)-3-(p-
(2-cyclopropylmethoxyethyl)phenoxy)-
2-propranol HC1) ('Betaxolol)
; (1-((3,4-dimethoxyphenethyl)amino)-
3-(m-)Riloxy)-2-propertool H(J)
(Befunolol); (((±)-1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isopropylamino-
(2-propatol) fumarate) (piprolol); (4-(2-hydroxy-3-(4-(phenoxymethyl)-piperidinocopropoxy)indole); (carbazolyl-4-oxy-5,2- (2-methoxyphenoxy)ethylamino-2-propatur): (1-((1,1-dimethylethyl)amino)-3-(
(2-methyl-IH-indol-4-yl)oxy)
-2-propertool benzoate) (Bobbintrol)
; (1-(2-exobicyclo(2,2,1)-hegechy-2-ylphenoxy) -3-((1-methylethyl)
-aminoco-2-propatol H (J) (bornaprolol); (o-[2-hydroxy-3-[(2-indole-
(3-yl-1,1-dimethylethyl)amino]propoxy]benzonitrile) IC1) (pusyntrol); (α-((tert-butylamino)methyl]-7-nityl-2-benzofuranmethanol) (bufuralol)
; (3-(3-acetyl-4(3-(tert-butylamino)-2-hydroxypropyl]phenyl)-1,1
-diethylurea HC1) (celiprolol): ((±”)-2-(2-(3-((1,1-dimethylethyl)aminoco-2-hydroxypropoxy]phenoxy)-N-methylacetamide HCJ) (cetamolol); (2-benzimidazolyl-phenyl (2-isopropylaminopropanol)); ((±)-3'-acetyl-4'-(2-hydroxy-
3-isopropylaminopropoxy)-(methyl-4-
[2-Hydroxy-3-((1-methylethyl)aminopropoxy]]benzenepropanoate HCl1)
(Esmolol); (Erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylamitubucun-2-ol); (1-(tert-butylamino)-3-(o-( 2-
(1-(tert-butylamino)-3-(0-(6-
((-)-2-hydroxy-5-((R)-1-hydroxy-2-((R)-(1-methyl) -3-phenylpropyl)amino)ethyl)benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)propoxy]-7-methyl-5H-furo(3,2-g) (1) benzopyran-5-one) (ibrochlorol); -((-) -5-(tart-butylamino)-2-hydroxypropoxy)-3,4-
Dihydro-1-(2H)-naphthalenone HC1) (repobunorol); (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole) l(J)
; (4(3(tert-butylamino)-2-hydroxypropoxy)-N-methylincarbostyryl)Ic/
); ((±)-N-2-(4-(2-hydroxy-3-isopropylaminopropoxy)phenyl)ethyl-N'-
(isopropylurea) (pafeenolol); (3-(((2-)lifluoroacetamido)ethyl)
(N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2,3-dihydro-3-oxo) -5-pyridazinyl)ethylenediamine); ((±)-N-(3-acetyl-4-[2-hydroxy-3-((1-methylethyl)amino]propoxy]phenyl]butanamide); (( ±) 4'-(3(tert-butylamino)
-2-hydroxypropoxy]spiro[cyclohexane-1,2'-indantu-1'-one) (spilendrol); (7-(3-((2-hydroxy-3-((2-methylindole-4- ((±) -1-tert-butylamino-3-(thiochroman-8-yloxy)-2-propatol);
Tartatrol); ((±) -1-tert-butylamino-3-(2゜3-xylyloxy)-2-propatol HC1) (xibenolol); (8(3(tert-butylamino)-2-hydroxy Propoxy]-5-methylcoumarin) (bucumolol)
; (2-(3-(tert-butylamino)-2-hydroxypropoxy)benzonitrile H1 (bucumolol); ((±) 2' (3(tert-butylamino)-2-hydroxypropoxy-5 '-Fluorobutyrophenone) (butophyllorol); (l-(carbazol-4-yloxy)-3-(isopropylamino)
(5-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyryl HC1
) (carteolol); (1-(tert-butylamino)-3-(2,5-dichlorophenoxy)-2-
propatool) (chloranolol); (1-(inden-4(or 7)-yloxy)-3-
(isopropylamino)-2-propatool H (J)
(indenolol); (1-isopropylamino-3-((2-methylindol-4-yl)oxy-2-propatol) (mepindolol); (1-(4-acetoxy-2,3,5-)limethyl phenoxy)-3-isopropylaminopropan-2-ol) (methipranolol); (l-(isopropylamino)-3-(o-methoxyphenoxy”)-3-(
(1-methylethyl)aminoco-2-propatool)
(moprolol); ((1-tert-butylamino)
-3-((5゜6.7.8-tetrahydro-cis-6,
((S) -1-(2-cyclopentylphenoxy)-
3-((1,1-dimethylethyl)aminoco-2-propatur sulfate (2:1)) (penbutrol); (4'-(1-hydroxy-2-(amino)ethylcomethanesulfonanilide) ( (2-methyl-3-(4-(2-hydroxy-3-tert-butylaminopropoxy)phenyl)-7-medoxyisoquinolin-1-(2H)-one); (2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-isopropylamino-2-
Propatur H14); ((-) -p-(3,4-dimethoxyphenethyl)aminoco-2-hydroxypropoxy]-β-methylcinnamonitrile) (pacrinolol) ;((±) -2-<3 '-tert-butylamino-2'-hydroxypropylthio)-4-(5'
-carbamoyl-2'-chenyl)thiazole H (J)
(arotinolol); )-1-((3-chloro-2-methylindol-4-yl)oxy)-3-((2-phenoxyethyl)aminoco-2-propatol)(indenolol); ((±)-6-( (2-((3-(1)-butoxyphenoxy)-2-hydroxypropyl amino)
(amino)-1,3-dimethyluracil) (pyrepolol); (4-(cyclohexylamino)-1-(1-naphthrenyloxy)-2-butanol; (1-phenyl-3-
(3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy- 2H-
1-benzopyran) and platrol); α and β-adrenaline, : ((±) 1-tert-butylamino)-3-(
o -(2-(3-methyl-5-isoxazolyl)vinyl]phenoxy]-2-propatol)(isoxaprolol); (1-isopropylamino-3-(4-(2-nitroxyethoxy)phenoxy) )-2-propatol H(t; (4-hydroxy-α-((3-(4-methoxyphenyl)-1-methylpropylcoaminomethyl)-3-(methylsulfinyl)benzmethanol MCI) Rufinarol); (5-(1-hydroxy-2-CC2-(o-methoxyphenoxy)ethyl]amino]ethyl]-2-methylbenzenesulfonamide 1-Methyl-3-phenylpropyl)amino)ethyl]salicylamide HC1) (rabechlor); (1-((3-chloro-2-methyl-IH-indol-4-yl)oxy)-3-((2 -phenoxyethyl)amino)-2-propaturmalonate hydrogen salt)
(Inendrol); (4-(2-hydroxy-3-
((1-methyl-3-phenylpropyl)aminocopropoxy)benzeneacetamide) ; (1-(3-((3-(1-naphthoxy)-2-hydroxypropylcoamino)-3,3-dimethylpropyl)
-2-benzimidazolinone): (3-(1-(2-
Hydroxy-2-(4-chlorophenylethyl)-4-
piperidyl)-3゜4-dihydroxy)quinoxaline-
CN5LJflJ: clonidine; methyldopa; adrenergic nerve 21; : guasotidine; reserpine; and other laulphia alkaloids such as recinamine; Enzyme inhibitor: 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2,4-(R,R)-dimethylbutanoyl) ) indoline-2(S)-carboxylic acid); (2-(2-((1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl)-1
,2,3,4-tetrahydro-3-inquinolincarboxylic acid); -LH-indole-2-carboxylic acid H(1); (N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl)thiol-2-methyl-1-oxopropyl)glycine)( ((2R,4R)-2-(2-hydroxyphenyl)-
3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid); (1-(N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-(-3)-alanyl)-cis, syn-octa Hydroindole-2(S)-carvone #H(
J); ((-)-(S)-1-((S)-3-mercapto-2
-Methyl-1-oxopropyl]indoline-2-carboxylic acid); ((1(S),4S)-1-(3-(benzoylthio)
-2-Methyl-1-oxopropyl-4-phenylthio-L-proline; (3-([1-ethoxycarbonyl-3-phenyl-(
IS)-propylcoamino)-2,3゜4.5-tetrahydro-2-oxo-1-(3S)-benzazepine-
1-acetic acid H1); (N-(2-benzyl-3-mercaptopropanoyl)
-5-ethyl-L-cysteine) and S-methyl analogs; (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril); N -[1(S)-ruboxy-3-phenylpropyl]
-L-alanyl-1-proline; N” -(1(S)-
Carboxy-3-phenylpropyl)-L-lysyl-L
-Proline (lisinopril); 2-(N-[(S)-ethoxy'carbonyl-3-phenylpropyl]-L-alanyl-(Is.

(1(S),4S)-1-(3-mercapto-2-methyl-1-oxopropyl)-4- Phenylthio-L-proline-8-benzoyl calcium salt (zofenopril); (1-(+/-)4S)-4-cyclohexyl-1-(
(2-methyl-1-(1-(propoxy)propoxy)
(4-phenylbutyl)phosphinylcoacetyl)-
L-proline sodium salt (phosphopril); Calcium channel 2-blocker 1: nifedepine: nitrendipine; verapamil; diltiazam; saikihuang pressure and engineering niaminophylline; cryptenamine acetate or tannate; deserpidine; meremethoxyline procaine; vargyline; Trimethaphane camsylate; and others, and mixtures and combinations thereof: Typically, the individual daily dosages of these combinations will be compared to the amount when they are administered alone to meet the minimum recommended clinical The amount ranges from about 175 to the maximum recommended amount. At the same time, administration is
This is most easily accomplished by combining the active ingredients into suitable unit dosage forms containing appropriate amounts of each. Of course, other methods of co-administration are also possible.

The following examples are representative and are not intended to be limiting.

ull B o c-ACHPA-NH-2(S)-Methyl B
4 g of oc-ACHPA-0Et was dissolved in methanol (
15a+1) and HzO (5 mN), and the pH was adjusted to l.
:1 PHIO buffer: Adjusted to lO with CHsOH.

2N NaOH (2.1 eq.) was added to the solution and the mixture was stirred for 2 hours. The pH was adjusted again to 1° by addition of INI (Cj!) and the solution was extracted with EtOAC. The solution was then cooled on ice, EtOAc was added and the aqueous layer was acidified to pH 2.5 by addition of 6N HCl. The layers and several aqueous EtOAc extracts were combined and dried.
) L, evaporated to 3.5 g of white brittle foam (93
%) was obtained. TLC (silica gel: 80:10:1:I
CHC113: CH30H: HzO: 1IOAc
Here, a single spot Rf-0,45 is shown.

B, Boc-ACHPA-NH-2(S)-Methylbutyl DMF (25am) Boc-ACHPA
EtJ (
1,6 ml) and DPPA (2,5 ml) were added, and the resulting mixture was diluted with 2(S)-methylbutylamine (1,36 ml).
The reaction mixture was stirred under nitrogen for 30 minutes before addition and allowed to warm to room temperature. After 18 hours, the mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (250ml).

The solution was diluted with INHCj2, nzo, saturated NaHCO*, 8
．． 0 and brine, then dried (NazSO4)
L, the residue after evaporation was subjected to silica gel chromatography (6:
Boc-ACIIPA-NH-(2(S)) as a colorless oil.
-methylbutyl) (3.75 g: 89%) was obtained.

2-benzylacrylic acid in methanol (100 mJ) To a solution of methyl (20 g, 0.113 moJ) at room temperature was added sodium methoxide solution (2N, 171 I11) followed by isopropylthiol (12,56 aj.T).
The reaction was complete after 30 minutes according to LC (4:1 hexane:ethyl acetate).

The reaction mixture is INHCj! acidified with ethyl acetate and 3
The combined organic fractions, extracted twice, were dried over NazSO4, filtered and evaporated under reduced pressure. The crude product was purified by chromatography (silica, 4:1 hexane:ethyl acetate) to yield methyl 3-isopropylthio-2-benzylpropionate.

m-chloroperoxybenzoic acid (45 g, 0.339 mol) was added portionwise to the above compound in chloroform at 0° C. and the reaction was stirred at room temperature for 48 hours.

After TLC (silica, l:l hexane:ethyl acetate) showed the reaction was complete, the reaction mixture was filtered and the filtrate was diluted with saturated Na
Washed thoroughly with HCO, dried with NazSO, filtered and evaporated under reduced pressure.

The crude product was subjected to chromatography (silica, 1:1 hexane:ethyl acetate) to obtain 30 g of methyl 3-isopropylsulfonyl-2-benzylpropionate. T.L.
C (silica, 1:1 hexane:ethyl acetate) Rf=
0.50: NMR (CDC/3) 1.3 (d,
3H), 1.35(d, 3H), 2.8-3.
0 (+m, 2H), 3.0-3.15 (01, 2H)
, 3.3-3.4 (m, 1) 1), 3.4-3.5
(m, IH), 3.7 (s, IH), 7.15-
7.35 (+s, 5H).

The above ester was dissolved in lOAc (20 ml) and concentrated H (J
The reaction mixture was then cooled and extracted three times with ethyl acetate.

The combined organic fractions were dried over Na, SO, filtered and evaporated under reduced pressure. The resulting carboxylic acid (23g) was resolved with R(+)-methylbenzylamine in diethyl ether (400nt) to give the (+) isomer. ((r) o
MeOH = + 11'; NMR (CDC13
) 1.3(d, 3H), 1.35(d, 3)1
), 2.9-3.1(or, 4H), 3.23(
m, IH), 3.35-3.45 (or, 111
), 7.2-7.4 (m, 5H).

Example 3 3-Cyclohexylsulfonyl-2-benzylpropionic acid This compound was prepared according to the procedure of Example 2.

MS, m/e = 310 (M'); NMR (
CDCA'3) 1.1-1.25 (lI, 3H)
, 1.25-1.55 (m, 211), 1.6-1.
75 (brs.

1) 1) , 1.8-2.0 (m, 4B), 2.05
-2.15 (d, IH), 2.7-2.85 (dt,
18), 2.9-3.05 (m, 28), 3.1
5-3.3 (dd.

18)), 3.3-3.5 (m, 2H), 7.2-
7.4 (a+, 5H).

u1 Support 3-N-morpholinocarbonyl-2(R)-(1-naphthylmethyl)propionic acid A, Methyl-3-carboxy-2(R)-(1-naphthylmethyl)propionic acid t-butanol (45+++j Potassium (2,1
5g) dimethyl succinate (14ml) at room temperature.
and 1-naphthaldehyde (7,5mj2) was added dropwise, and the reaction mixture was then heated to reflux for 30 minutes. Afterwards it was cooled to 0°C.

The reaction mixture was HCj! (The reaction mixture was acidified with 5N, 10a+4 and evaporated under reduced pressure. The reaction mixture was partitioned between water and diethyl ether and the combined organic fractions were diluted with NH,OH(IN).
The combined basic fractions were extracted four times with diethyl ether, acidified with HCl (3N) and thoroughly extracted with methylene chloride. The combined organic fractions were dried over Na, SO, filtered and evaporated under reduced pressure.

Without purification, crude methyl 3-carboxy-2-(1-naphthylmethyl)propionate was dissolved in methanol (loO+n
f) and magnesium powder (2.3 g) was slowly added to this solution at 0° C. over 3 hours. After all the magnesium has been consumed, the reaction mixture 'Fr: HC7! (
Carefully, 3N, 150 mf) k:0 reaction mixture was extracted with diethyl ether, dried over Na, SO4,
Filtration and evaporation under reduced pressure gave the title compound as a racemate. This material was partitioned with (+) methylbenzylamine in diethyl ether. As a result, 5.2 g of racemic material was converted to 2.2 g of pure R(+) title compound. [α]
. -148,56 (ErOAc); NMR (
CDCj! s) 2.4-2.5 (dd.

IH), 2.7-2.85 (2d, IH), 3.0
5-3.15 (ABq, IH), 3.55-3.7 (
w, 1) 1) , 3.7 (S, 38), 7.27 (
d, IH), 7.3-7.4 (t, IH), 7.4
5-7.6 (m, 2H), 7.75 (d.

IH), 7.85(d, LH), 8.05(d,
III).

8.3-morpholinocarbonyl-2-(1-naphthylmethyl)propionic acid (Ig, 0.003711Io) in methylene chloride
l), morpholine (0,64+j!, 2 equivalents) and l-
0 in a solution of hydroxybenzotriazole (0,6 g)
The reaction solution with dicyclohexylcarbodiimide (0.92 g) was stirred at 0.degree. C. for 12 hours, after which it was filtered. The filtrate was washed with H (1 IN), saturated NaHCO, dried over Na, SO, filtered and evaporated under reduced pressure.

The crude product was chromatographed (silica, 7:3
EtOAc:hexane) to give the methyl ester of the title compound. TLC (silica, 7:3 EtO
Ac: hexane) Rf=0.46゜methanol (1 m
j) to a solution of this substance in KOH solution (IN, 6.45
ml1) was added. After 3 hours, the reaction mixture was reduced to HC7!
The combined organic fractions, acidified with (3N) and extracted twice with ErOAc, were dried over Na, SOa, filtered and evaporated under reduced pressure to give the title compound (0.78g). NMR
(CDCf 2) 2.4-2.5 (dd, IH), 2
．． 6-2.7 (2d, IH), 3.1-3.3 (n
+, 4H), 3.3-3.4 (+II.

IH), 3.45-3.7 (m, 5H), 3.7
-3.8 (dd, IH), 7.3 (d, IH), 7
．． 4 (t, IH), 7.45-7.6 (second, 2H),
7.75 (d, IH), 7.85 (d, IH)
, 8. Hd, IH).

3-N-morpholinocarbonyl-2(R)-benzylpropionic acid 7 A, methyl-3-carboxy-2(R)-benzylpropionic acid This compound was prepared by the same procedure as in Example 4A. . (cr) a = + 22.9 (MeOH)
.

NMR (CDC13) 2.4-2.5 (dd, lH)
, 2.65-2.85 (m.

2H), 3.05-3.2(m, 2H), 7.1
5-7.4 (m, 5B).

8.3-N-morpholinocarbonyl-2(R)-benzylpropionic acid The title compound was prepared according to the procedure outlined in Example 4B. NMR (CDCf3) 2.3-2.4 (dd
, IFI), 2.6-2.7 (2d, IH), 2.
7-2.85 (ABq, IH), 3.15-3.3
(m, 2H), 3.3-3.4 (o+, 2H), 3
．． 5-3.8 (m, 6H), 7.15-7.35 (steel, 5H).

(4-B o c-piperazin-1-yl)carbonyl-2(R) -benzylpropionic acid The present compound is N
Prepared according to the procedure outlined in Example 4 using -Boc-piperazine.

NMR (CDC13) 1.45 (s, 9H), 2.3
2-2.4 (dd, 01), 2.6-2.7 (m,
18), 2.7-2.85(s, 18),
3.15-3.45 (m, 8)1), 3.5-
4.2 (+*, 2H), 7.15-7.4 (m,
5)1).

St7 3(4-Bo, -c-piperazin-1-yl)carbonyl-2(R,S) -(1-naphthyl)methylpueS]
The compound was prepared according to the procedure of Example 4.

NMR (CDCf3) 1.5 (s, 9H), 2
．． 43-2.55 (dd, LH), 2.6-2.7 (2
d, IH), 3.1-3.3(so, 5), 3
．． 3-3.45 (n.

3H), 3.45-3.645 (school, 2H), 3
．． 7-3.8(dd, 1)1), 7.3(d, 11
), 7.4 (t, IH), 7.45-7.6 (m,
2H), 7.75(d, IH), 7.85(d,
IH), 8.1(d, IH).

Example 8 3-(thiamorpholin-1-yl)carbonyl-2(R
,S)-(1-naphthyl)methylpropionic acid was prepared according to the procedure of Example 4.

NMR2,2-2,5(dd, IH), 2.5-2
．． 7 (o+, 3H), 3.15-3.25 (ABq,
18), 3.3-3.45 (m, 2H)
,, 3.45-3.6 (m.

2H), 3.7-3.9(m, 4)1), 7.3(
d, 18), 7.4(t, IH), 7.5-7.6
(a+, 2H), 7.8 (d, IH), 7.9
(d, II(), 8.1(d, IH).

aN9 Boc -(in+-DNP)His-ACHPA-N
H-2(S)-Methylbutyl Boc-ACHPA-NH-2(S)-methylbutyl (0,85 g.

0,0022 w+ol was dissolved in a saturated solution of HCl in methanol and the reaction was stirred for 1 hour before it was evaporated under full vacuum. Amine hydrochloride in methylene chloride (10111) was treated with triethylamine (1 wall,
3 equivalents) were added. After 15 minutes, Boc-N-is-DN
P-histidine (Ig, 1.1 eq.) was added to the solution followed by l-hydroxybenzotriazole hydrate (0
, 326 g) and dicyclohexylcarbodiimide (0
, 5g) was gradually warmed to room temperature and stirred until the reaction was completed (12 hours).The reaction mixture was filtered to remove dicyclohexylurea, and the filtrate was diluted with INH.
Washed successively with Cl (2x), saturated NaHCOs (2x), dried over NazSOi, filtered and evaporated under reduced pressure. The product was purified by chromatography on silica, E
LOAc) to obtain the title compound (1 g). TLC(
Silica, EtOAc) Rf-0,68-NMR (CDC
Iri 0.85-0.95 (m, 6H), 1.0-1
．． 3 (m, 6H), 1.3-1.7 (im, 9H)
, 1.4 (s, 9), 1.7-1.8 (d, IH)
, 2. t8-2.25 (ad, IH), 2.35-
2.45(01,1)1), 3.0-3.2(a+,
4H), 3.85-4.0(2)1), 4.35-4
．． 45 (ABq, IH), 6.2 (brd, LH)
, 6.48 (brt, 18), 6.55 (d, 1B
) , 6.95(s, 1)1) , 7.65(s,
1) 1), 7.75 (d, 1B), 8.6 (dd,
l1l), 8.85 (dd, IH).

Construction work N-(3-(morpholin-4-yl)carbonyl-2(
R)-benzylpropionyl] His-ACHPA-
NH-2(S)-methylbutyl A, N-(3-(morpholin-4-yl)carbonyl-
2(R)-benzylpropionyl]-(N-io+
GNP) former s -ACHPA -Nil -2(S) HCj of methylbutyl MeOH! 31] Boc-(N
-in+ -DNP) HisACHPA -2(S)
-Methylbutyramide (0.3g.

0.000436+++o1) was stirred for 1 hour, and then the solution was thoroughly evaporated under reduced pressure. Diisopropylethylamine (0,3a+j,3-(morpholine-4-
yl) carbonyl-2(R)-benzylpropionic acid (
To this material in methylene chloride (5 tag) containing 0.12 g) was added benzotriazol-1-yloxytris(dimethylamino)phosiphonium hexafluorophosphate ("BOP") (0.23 g, 1.2 eq.). .

The reaction was stirred for 12 hours, after which it was evaporated under reduced pressure, redissolved in EtOAc and washed with H(J(IN)) and saturated NaHCO.
Dried over SO, filtered and evaporated under reduced pressure. The product was chromatographed (silica, 9:1:0.5
EtOAc (niacetonitrile: MeOH) to give the title compound (0.11 g). TLC (silica, 9
: 1 : 0.5t! tOAc niacetonitrile:
MeOH) Rf = 0.53°B, N-(3-morpholin-4-yl)carbonyl-2
(R)-Benzylpropionyl]-H1s-ACHP
A -NO-2(S)-methylbutylmethanol (11
Thiophenol (0,
Added 05a+4ri.

After stirring for 1 hour, the reaction mixture was thoroughly evaporated.

The product was chromatographed (LH-20, MeOH
) to obtain the title compound (0,045 g). T.L.
C (Silica, 85: 15 HtOAc: MeO
H) Rf = 0.25; MS, ale -682 (M
+2): NMR is consistent with structure.

Oshi ■ Do Do N-(3-(morpholin-4-yl)carbonyl-2(
R)-(1-naphthyl)methylpropionyl]-former S-
^CHPA-NH-2(S)-Methylbutyl The title compound was prepared according to the procedure of Example 10. HPLC (
RP-18,8: 2MeOH:HzO) rt=
16.3 minutes HMS, tale = 731 (M+1
); NMR is consistent with the compound.

N-(3-(thiamorpholin-4-yl)carbonyl-)
2(R,S)-(1-naphthyl)methylpropionyl)
-His-ACHPA-NH=2(S)-Methyl This compound was prepared according to Example 1O. MS: 1
11e =747 (M+1): HPLC (RP-1
8=55:45 0.1% TFA Niacetonitrile)
rt=15.18 min, NMR consistent with compound.

Blood ■Upper N (3-(4-Boc-piperazin-1-yl)carbonyl-2(R)-benzylpropionyl)-His
-AC)IPA -NH-2(S)-Methylbutyl This compound is the 3-(4-Boc-piperazine-
1-yl)carbonyl-2(R)-benzylpropionic acid following the procedure of Example 10. HP
LC (RP-18,70;30 MeOH:HzO)
rt=26.3 minutes; MSSvale=680 (M
+1); NMR is consistent with the compound.

叉台Godoku N -(3-(4-Boc-piperazin-1-yl)carbonyl-2-(l-naphthyl)methylpropionyl)
-Hls-ACHPA-NH-2(S)-Methylbutylpropionic acid of Example 7 was prepared according to the procedure of Example 10 using MS, ale = 830 (M+1): NMR consistent with compound.

Forked dish earthwork N-(3-(piperazin-1-yl)carbonyl-2-
(1-naphthyl)methylpropionyl]-H1s -A
CHPA-Nu-2(S)-Methylbutyl This compound was prepared according to the procedure of Example 10. MS, -/e
-730 (M+1): NMR is consistent with the compound.

1 N-(3-isopropylsulfonyl-2-benzylpropionyl) -Hls-ACHPA-NH-2(S)-
Methylbutyl This compound is prepared according to the procedure of Example 10 using 3-isopropylsulfonyl-2-benzylpropionic acid. MS, s+/e-674(M+1); NMR
is consistent with the compound; HPLC (RP-18,85:
15 MeOH:H2O) rt=10, 48 min.

Example 17 N-(3-cyclohexylsulfonyl-2-benzylpropionyl)-Hls-ACHPA-Lys NH
CHt (Pyridin-4-yl) This compound was prepared by the procedure of Example 10 using 3-cyclohexylsulfonyl-2-benzylpropionic acid.
1), NMR is consistent with the compound. HPLC (RP-
18,80: 25 Meal:H*O).

z韮■Earthwork N-C3-isopropylsulfonyl-2-benzylpropionyl) -Hls-ACHPA-Lys-NHCH
z (pyridin-4-yl) Step A: N-(3-isopropylsulfonyl-2-benzylpropionyl) -Hls-ACHPA-(N -
CBZ) Lys -NHCII* (pyridine-4
-yl) 8oc-(N-ia) in methanol (20mf)
-DNP) Old 5-ACHPA-(N -CBZ)Lys
-NHCHz (pyridin-4-yl) (0,515
g, 0.00053 + aol) solution was saturated with H (J gas) and stirred for 30 min at 0°C. The resulting amine hydrochloride was evaporated to dryness. This material in methylene chloride was dissolved at room temperature in diisopropylethylamine (0 , 5461!, per 6, (+)-3-isopropylsulfonyl-2-benzylpropionic acid (0,157 g, 1.1 eq.) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate -) (0,2
8 g, 1.2 eq) was added. The reaction was stirred for 12 hours, after which it was diluted once with 1N HCl and saturated NaHCl.
Washed twice with COa, dried with NazSOs, filtered through a thin pad of silica and evaporated to dryness. Crude intermediate (TL
C (silica, 9:1:I EtOAc:MeO
Hniacetonitrile) Rr-0,60) was redissolved in methylene chloride (10sjt) and thiophenol (0,60) was redissolved in methylene chloride (10sjt).
, 25 m&litre were added and the reaction mixture was stirred for 4 hours, after which it was thoroughly dried under vacuum.

This substance was purified by chromatography (LH-20, MeOH
) to obtain the title compound (0.17 g) as a solid. TLC (silica, 40:10:ICHCj3:MeO
H:NHz) Rf=0.4: HP LC(R
P-18,1: IMeOH: 0.1% TFA)
rt=12 min (95%): FAB mass spectral data 157 (M+H).

Koodan: N-(3-isopropylsulfonyl-2-benzylpropionyl) -Hls-ACHPAL 5-N
HCHt (pyridin-4-yl)methanol (1 m
A solution of HBr (30%) in acetic acid was added to a solution of the compound (0,075 g) in 11) at 0°C, and the reaction mixture was stirred for 15 minutes at temperature and for 20 minutes at room temperature, and then the reaction mixture was thoroughly diluted. It was evaporated to dryness. The residue was dissolved in MeOH (1 ml).
Redissolve in propylene oxide 20mA! Dilute with
A white hygroscopic solid was obtained. This substance was analyzed by HPLC (RP-1
Purified with 8,1:1 MeOH: 0.1% TFA; rt=7.82 min, FAB gravimetric spectral data:
823 (M+H).

1 Toyosato Joko N-(3-isopropylsulfonyl-2-benzylpropionyl) -Hi's-ACHPA -Lys -N
HCHz(piperidin-4-yl) N-(3-isopropylsulfonyl-2-benzylpropionyl)-His-ACH in MeOH (3++1)
PA-Lys-NHCHx (biliperan-4-yl) (0.2 g, 0.00021 moj solution, HCf (
12N, 0.07mj and palladium hydroxide carbon (2
0%, 0.1 g) was hydrogenated for 24 hours under Hz 401b < ca. Obtained. FAR mass spectral data: 829 (M+H): NMR consistent with compound.

1 11 N-(3-isopropylsulfonyl-2-benzylpropionyl) -Njle-ACHPA-Lys-NHC
Hz(Pyridin-4-yl) The title compound was prepared according to the procedure previously outlined in Example 18A, with the exception that Boc-norleucine was replaced with Boc-
(N-in-DNP) 9 Substituted for Histidine This intermediate was then synthesized to the title compound following the procedure outlined in Example 18.

大挌±11 N-(3-(morpholin-4-yl)carbonyl-2(
R)-benzylpropionyl) -Hls -ACII
P^-Lys-NHCHz (piperidin-4-yl)N-(3-(morpholin-4-yl)carbonyl-2
(R)-benzylpropionyl]-former S- to CIIPA
(N CBZ ) Lys-NHCHz (pyridin-4-yl) is the 3-N-
Prepared according to the procedure of Example 18 using morpholinocarbonyl-2(R)-benzylpropionic acid. T.L.
C (Silica, 80:15:I CHCj!z:Me
OH:HzO) Rf -0,33; MS, tale
=964(M+1). 10%Pd/C (0.15g)
Containing MeOH (5n+j) and HCJ (12N, 0.
This material (0.3g) in 0.51ml was hydrogenated (latm) for 24 hours.The reaction was then filtered and evaporated under reduced pressure to give the title compound (0.2g). F.A.B.
Mass spectral data: 836 (M+1); NMR is consistent with the compound.

11 Ethyl (4-phenyl-2(R,S)-thioacetyl)butyrate (carboethoxymethylene)triphenylphosphorane (24g) in dry THF (200mf).

Add dry THF (50+
Phenylacetaldehyde (5,38g, 4') in
5-soj solution was added and the mixture was refluxed for 4 hours.

The reaction was cooled, evaporated and the residue was dissolved in ethyl acetate (100
+*Il) and the amount of water. The organic layer was washed with water, dried (MgSOn ) and concentrated under reduced pressure to give an oil. The crude material was suspended in hexane with 5% ethyl acetate on silica gel M.
Purified by PLC to obtain two pure isomers E (5,6 g
) and Z (1.9 g) unsaturated esters were obtained. NMR (
CDCj! 3): 1.26 (t, 3B), 3.5
Hd, 2H), 4.2(q, 2B), 5.83(
dd, LH), 7.08-7.40m, 6H).

A solution of the unsaturated ester (E-isomer) (1.9g, 10ms+ol) in absolute ethanol (611It) was dissolved in potassium thioacetate (10mA) in ethanol (10mA).
1.26 g, 11+ moj of solution was added to the solution and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned in ethyl acetate (60 aj and water). The organic phase was dried over Mg5Oa, evaporated and foamed. The product was obtained as a solid.Finally, the product was purified by flash chromatography on silica gel.

Daishikai1YN-(1-(R,S)-ethoxycarbonyl-2-phenylethylsulfonyl)-)1is-ACHPA-
Lys-NHC4h (pyridin-4-yl)ccz
, (containing 10% ethanol) in (4-phenyl-2(
R,S)thioacetyl)ethyl butyrate is reacted with a C1t gas stream at 0<0>C for 2-3 hours.

Removal of the solvent under reduced pressure afforded the corresponding sulbonyl chloride, which was converted to old s (DNP) -ACHPA -Lys
Reaction with (CbZ)-NHGHz (pyridin-4-yl) yields a fully protected peptide. The protecting group is then removed as described in Examples 1O and 18 to provide the title compound.

Daiarashi Spot 1 So N-(3-isopropylsulfonyl-2-benzylpropionyl) -Hls-ACHPA-NH-(N-methyl-kisclidinium-3-yl)00^CO dried in degassed dimethylformamide (DMF) 15111 N
-t-butoxycarbonyl-histidyl-(3
S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoyl hydrazide 931■(1,95a
+a+oj was added and the solution was cooled to -30° C. with stirring under a nitrogen atmosphere.

Freshly prepared Hl(g) tetrahydrofuran solution (4,
56M, 4.28 + jl, 19.5 mmoj were added to the cold reaction mixture and p) I was adjusted to the desired range (0.5-1.5).
Adjusted to.

Isoamylnitrile (287 μl, 2.15 mmo/
) was added in four portions over a period of 2-3 hours at −20 to −18° C., during which time the reaction mixture remained positive on the potassium iodide starch paper test.

After completion of acyl azide formation, 3(S)-aminoquinuclidine dihydrochloride (582 mg, 2.93 mmol) and triethylamine (3,00μ2.23.4mn+oIl)
A pre-chilled (-20 DEG C.) slurry containing was added to the azide while stirring and adjusted to pH 9.0-9.5.

The slurry was stirred vigorously for 1 hour at -20°C and then stored in the refrigerator overnight. DMF is removed by rotary distillation,
The residue was dissolved in chloroform:methanol:ammonia (CMA).
80:20:2) dissolved in 1011Il, insoluble solids were filtered off, and the filtrate was purified by Clark-Steil (C1ar
k5till) Silica gel column (width 3.5al x
Length 3.5ao, 2.30~4.00.230~400
Metsuyufutman (What+++an)060)
added to. The product was fractionated with CMA 80:20:2 from 27 to
45 and after lyophilization from dioxane, N
-t-butoxycarboxy-L-histidyl-(3
S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoyl-3-quinuclidinylamide 87
5■ (yield 80%) was obtained.

Then 50% trifluoro vinegar #/methylene chloride (rt6
t-Boc deprotection using 0 min) and freshly prepared Et
After trituration and filtration with zO, the solid L-histidyl-
(35,4S)-4-amino-5-cyclohexyl-3
-Hydroxypentanoyl-3-quinuclidinyl amide trifluoroacetate was obtained in quantitative yield.

3-Benzyl-2(S)-isopropylsulfonylmethyl-propionic acid (166■, 0.615trrttr
o l) dried degassed DMFl, 25a+j! N-hydroxysuccinimide (70,8■,
Then dicyclohexylcarbodiimide (1,23 raol O, 5 MDCC/methylene chloride) was added. Stir for 4 hours at room temperature over nitrogen and add triethylamine (100 μm, 0.782 veol).
After adjusting the pH to 8.0 by addition, the activated ester was dissolved in DMF3. OO+4! Histidyl (3S,4S)-4-amino-
5-cyclohexyl-3-hydroxypentanoyl-3
- Quinuclidinylamide 3 TFA (368w, 0.
535n+moj2) overnight.

After 17 hours, the reaction mixture was concentrated and the residue was dissolved in CMA85:
MPLC column (width 5.0c) with 15:1.5 eluent
o+X39cm) chromatography. The desired product eluted in fractions 68-98, which was 3-benzyl-2(S)-(isopropylsulfonylmethyl)
Propionyl-histidyl-(3S,4S)-4-
Amino-5-cyclohexyl-3-hydroxypentanoyl-3-quinuclidinylamide 171<i>I was prepared. N
MR (360MHz) and FAB spectral analysis (M
”=709) matched the title structure.rcso=11n
M.

Chloroform 400III! Methyl iodide (13,14all, 0.211mmoj) in /DMF100μE
The above amide (150ag, 0.211mmo
The quaternization of l) proceeded smoothly and the desired salt was obtained after 5 hours at room temperature. After lyophilization, the residue was dissolved in dilute acetic acid and passed through a Bio Rad AC3X 4A column (300 nw). After lyophilization of the eluent, the title compound was isolated (159.5μ, 96% yield) FAB
Mass spectral data (m/e) near 25 (M+1).

Elemental analysis calculation values: C56.85, H7.63, N 9
．． 95 (C3sHstNaOaS"CJsOt-'
Measured value (as CJ*Oz): C99,17, H8,
06, N9.51; Consistent with NMR (360MH2) structure.

Applicant Merck & Co., Ltd.

Claims (1)

[Claims] 1. A peptide of the following formula or a pharmaceutically acceptable salt thereof: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [A in the above formula is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [The above formula R^1 and R^1^a are each independently hydrogen; aryl {aryl is unsubstituted or mono-, di- or trisubstituted phenyl or naphthyl (the substituents are each independently,
C_1-C_7-alkyl, amino, mono- or di-C_1-C_4-alkylamino, amino-C_1-
C_4-alkyl, hydroxy-C_1-C_4-alkyl, mono- or di-C_1-C_4-alkylamino-C_1-C_4-alkyl, guanidyl, guanidyl-C_1-C_4-alkyl, hydroxyl, C_
1-C_4-alkoxy, CF_3, halogen, CHO
, CO_2H, CO_2-C_1-C_4-alkyl,
-CO_2NH_2, -CONH-C_1-C_4-alkyl, NR^5R^6 and N(R^5)_3^■A^
(R^5 and R^6 are each independently hydrogen, unsubstituted or monosubstituted C_1-C_4-alkyl (substituents are amino, C_1-C_4-alkylamino, C_1-C_
4-dialkylamino, hydroxyl, C_1-C_4
-Alkoxy or N(C_1-C_4-alkyl)_3
C_1-C_4-alkyl;
C_3-C_7-cycloalkyl; amino; hydroxyl; thiol; mono- or di-C_1-C_4-alkylamino; halogen; CO_2H:CO_2-C_
1-C_4-alkyl; CONR^5R^6 (R^5 and R^6 are as defined above); C_1-C_4-alkoxy; or Het {Het is unsubstituted or mono- or di-substituted 5-, 6 - or 7-membered heterocycle or benzo-fused 5-, 6- or 7-membered heterocycle (one or two heteroatoms are each independently N, O, S, NO, SO,
selected from the group consisting of SO_2 or quaternary N, each substituent being independently hydroxyl, thiol, C_1-C
_6-alkyl, CF_3, C_1-C_4-alkoxy, halogen, aryl, aryl-C_1-C_4-
Alkyl, amino, mono- or di-C_1-C_4
-alkylamino, amino-C_1-C_4-alkylamino, amino-C_1-C_4-alkyl, hydroxy-C_1-C_4-alkyl, di-C_1-C_4-
Alkylamino-C_1-C_4-alkyl, guanidyl, guanidyl-C_1-C_4-alkyl, CHO,
CO_2H, CO_2-C_1-C_4-alkyl ANR^5R^6 and N(R^5)_3^■A^■(R
^5, R^6 and A^■ have the same meanings as above); m is 0 to 3; n is 0 to 3]; ▲ Formula , chemical formulas, tables, etc. ▼ [In the above formula, R^1, m and n are as defined above; and R^2 is Het as defined above (provided that R^1 is amino, hydroxyl or mono- or di-C_1-C_4-alkylamino, m is other than 0)]; R^2^aX [In the above formula, R^2^a is aryl as defined above, or Het is synonymous with; and X is CO, SO_2 or CH-OH]; ▲ Formula,
There are chemical formulas, tables, etc. ▼ [In the above formula, R^3 is OR^4 (R^4 is C_1-C_4-alkyl or aryl-C_1-C_2-alkyl); Aryl as defined above; Aryl as defined above; Het; or NR^
5R^6 (R^5 and R^6 are the same as above); and R^1, X and m have the same meanings as above, provided that when X and X^1 are both CO, Y is other than O; X^1 is SO_2 and Y is CH_2 or O , then R^1-(CH_2)_m is other than hydrogen; or if Y is O and R^3 is OR^4, then X is S
Other than O_2]; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, R^1, R^1^a, X, m, and n have the same meanings as above, except that when X is CO is R^1-(CH_2
)_m and R^1^a-(CH_2)_n are both C_1
-C_5-Alkyl]; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, R^1^b is aryl as defined above; He as defined above
t; unsubstituted or monosubstituted C_2-C_6-linear or branched alkyl or C_3-C_7-cycloalkyl (substituents are amino, hydroxyl, thio, halogen or mono- or di-C_1-C_4-alkylamino) );N(C_1-C_4-alkyl)_3^
■A^■ (A^■ has the same meaning as above); CO_2H;
CONR^5R^6 (R^5 and R^6 are the same as above); or C_1-C_4-alkoxy; Z is O, S, SO, SO_2 or NR^7 (R^7 is hydrogen or C_1-C_4-alkyl); q is 0 to 2; and R^1^a, X, m and n are as defined above; provided that,
If Z is O or NR^7 and q is 0, then m is not 0 or 1, R^1^b-(CH_2)_m is not hydrogen or C_1-C_5-alkyl, and R^ 1
^a-(CH_2)_n is not hydrogen]; or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, Y^1 is CH_2 or NR^7 (R^7 has the same meaning as above) ; and R^1^a, R^3, is the same as above) or CH_
2; R^8 is unsubstituted or monosubstituted C_1-C_4-alkyl (substituent is carboxyl, amino, NHCOR^1(
R^1 is as defined above), hydroxyl, guanidino, C_1-C_4-alkoxycarbonyl or thiol); Het as defined above; or aryl as defined above; n is defined as defined above] ; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, Z^1 is O, S, NR^7, NR^7-CO, CO-N
R^7, NR^7SO_2, SO_2NR^7, SO or SO_2 (R^7 has the same meaning as above); r is 1 to 3; and K and R^8 have the same meaning as above; Or Z^1-R^8 is instead X^1R^3 (X^1 and R
^3 has the same meaning as above] or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the above formula, R^9 is C_1-C substituted with R^8 or Z-R^8
_4 alkyl (R^8 and Z have the same meanings as above)]; R^1^0 is -CHR^1^1R^1^1^a [
In the above formula, R^1^1 and R^1^1^a are hydrogen;
C_1-C_5-alkyl; Aryl as defined above; Het as defined above; C_1-C_3-alkoxy; C_
1-C_3-alkylthio; or unsubstituted or mono- or disubstituted C_3-C_7 cycloalkyl (where each substituent is independently from the group consisting of C_1-C_4-alkyl, trifluoromethyl, hydroxy, C_1-C_4-alkoxy and halogen) selected), then
R^1^1^a is hydrogen; or R^1^1 is hydroxy-C_1-C_4-alkyl or amino-C_1-
When C_4-alkyl, R^1^1^a is hydrogen or C_1-C_4-alkyl; is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, W is OH, NH_2 or OR^1^2 (R^1^2 is C
_1-C_4-alkanoyl or C_1-C_6-alkanoyloxy-C_1-C_4-alkyl; and G is Q-CO-T-V [in the above formula, Q is a single bond; CH-R^1^3{ R^1^3 is hydrogen; aryl as defined above; C_1-C_8-alkyl; C_
3-C_7-cycloalkyl: mono- or di-substituted C_2
-C_8-alkyl (each substituent is independently hydroxy; CO_2H; CO_2-C_1-C_4-alkyl; CONR^5R^6 (R^5 and R^6 are as defined above); amino; mono- or G-C_1-C_
or mono- or disubstituted aryl or C_3-C_7-cycloalkyl (substituted each group independently selected from the group consisting of C_1-C_4-alkyl, trifluoromethyl, hydroxy, C_1-C_4-alkoxy and halogen}
; or CH_2-CH-R^1^3^a {R^1^3^
a is CHR^1^4R^1^4^a (R^1^4 is hydrogen; amino; hydroxyl; C_1-C_5-alkyl;
C_3-C_7-cycloalkyl; Aryl as defined above; Aryl-C_1-C_4-alkyl; Het as defined above; Het-C_1-C_4-alkyl; Amino-C_1-C_4-alkyl; or guanidyl-C_1
-C_4-alkyl and R^1^4^a is hydrogen or C_1-C_5-alkyl} T is absent or ▲ has a mathematical formula, chemical formula, table, etc. ▼ {the above formula R^1^5 and R^1^5^a are each independently hydrogen or C_1-C_4-alkyl; and R^1^8
Ha-(CH_2)_wNR^1^9R^2^0(R^1
^9 and R^2^0 are each independently hydrogen; Het as defined above; aryl as defined above; unsubstituted or monosubstituted C_1-C_4-alkyl (substituents are aryl as defined above, as defined above) Het, amino, hydroxyl, mono- or di-C_1-C_4-alkylamino, CO_2H, SO_3H and CONR^5R^6(R
^5 and R^6 have the same meanings as above); w is 1 to 5); -(CH_2)_x
N(R^1^9)_3^■A^■(x is 2 to 5,
R^1^9 and A^■ have the same meaning as above); ▲ Formula,
There are chemical formulas, tables, etc. ▼ (R^2^1 and R^2^2 are each independently R^1
selected from the definitions of ^9 or R^2^1 and R
^2^2 came together -(CH_2)_4- or -(
CH_2)_5-, where R^1^9, R^2^0 and w have the same meanings as above); or -(CH_2)_w-
N=CH-NR^2^1R^2^2(R^2^1, R^
2^2 and w have the same meanings as above)}: and V is O-(CH_2)_uR^1^6 {wherein, R^1^
6 is hydrogen; aryl as defined above; Het as defined above
; or unsubstituted or mono- or di-substituted C_2-C_4-
Alkyl, C_3-C_7-cycloalkyl or C_2
-C_7-cycloalkyl-C_1-C_4-alkyl (each substituent is independently amino, hydroxyl, C_7-cycloalkyl-C_1-C_4-alkyl
_1-C_4-alkoxy, thio, halogen, mono- or di-C_1-C_4-alkylamino, CO_2
H and CONR^5R^6 (R^5, R^6 and A^■
is selected from the group consisting of (same meaning as above), and u is 0 to 5}; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1^7 is hydrogen; Aryl as defined above; Het as defined above; unsubstituted or mono- or di-substituted C_
2-C_4-alkyl, C_3-C_7-cycloalkyl or C_3-C_7-cycloalkyl-C_1-C_
4-Alkyl (each substituent is independently amino; hydroxyl; C_1-C_4-alkoxy; thio; halogen; mono- or di-C_1-C_4-alkylamino; CO_2H; guanidino; mono-, di- or tri-C_1 -C_4-alkylguanidino;-N(R^
5)_3^■A^■ and CONR^5R^6 (R^5,
or R ^1^6 and R^1
^6 is a bonded saturated or unsaturated unsubstituted or mono- or disubstituted 5- to 7-membered heterocycle or a benzo-fused 5- to 7-membered heterocycle (1 to 3 heteroatoms are each independently nitrogen,
selected from the group consisting of oxygen and sulfur, each substituent being independently C_1-C_6-alkyl; hydroxyl; trifluoromethyl; C_1-C_4-alkoxy;
Halogen; Aryl as defined above; Aryl-C_1-
(selected from the group consisting of C_4-alkyl; amino; thio; and mono- or di-C_1-C_4-alkylamino); ~2, R^7, R^1^6 and R
^1^7 has the same meaning as above, or R^1^6 and R
^1^7 are combined as above}; or O
-CHR^1^6R^1^7 {In the formula, R^1^6 and R
^1^7 has the same meaning as above or is combined as above}; ▲There are numerical formulas, chemical formulas, tables, etc.▼ {In the formula, R^2^3 is hydrogen, C_1-C_4-alkyl or aryl-C_1-C_4-alkyl (aryl is as defined above); R^2^4 is Het as defined above; -NR^1^9R^2^0, -N(R^1^ 9
R^2^0R^2^1)^■A^■▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^1^9, R^2^0, R^2^1, R^2^2 and A^■ has the same meaning as above);-CO_2H;-SO
_3H; Aryl as defined above, or di-C_1-C_4-alkylamino when q is other than 0; q is as defined above}; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ {R^2^3, R^2^4 and q have the same meanings as above}
;-N(CH_2CH_2)_2N-R^1^9{R^
1^9 has the same meaning as above};-N(CH_2CH_2
)_2NR^1^9R^2^0^■A^■＾＾1^9
, R^2^0 and A^■ have the same meaning as above}; -NH-Het {Het has the same meaning as above}; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ {In the formula, R^2^ 5 is Het as defined above; aryl as defined above; C_1-C_4-alkyl, or NH_2 when y is other than 0; NR^1^9R^2^
0, N (R^1^9R^2^0R^2^1)^■A^■
or CONR^5R^6 (R^1^9, R^2^1, R
^5, R^6 and A^■ have the same meanings as above); hydroxyl; CO_2H; or SO_3H}; or ▲
There are mathematical formulas, chemical formulas, tables, etc.▼ (In the above formula, R^1^5 is hydrogen; unsubstituted or monosubstituted C_1-C_
6-alkyl (substituent is amino or hydroxyl); mono- or di-C_1-C_4-alkylamino; guanidino; mono-, di- or tri-C_1-
C_4-alkyl-guanidino;-N(R^5)_3^
■A^■ (R^5 and A^■ have the same meanings as above); Aryl-C_1-C_4-alkyl (Aryl has the same meaning as above); C_5-C_7-cycloalkyl-C_
1-C_4-alkyl; C_1-C_5-alkenyl;
or Het as defined above; L is a single bond, S, SO, SO_2, NR^7 or NR^
7-CO (R^7 has the same meaning as above); s is 0
~2; and R^1^4^a and t have the same meanings as above]]
]. 2. E is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [W is OH
and G is Q-CO-T-V (Q is CH_2 or ▲Mathematical formula, chemical formula, table, etc.▼ (R^1^3^a is isopropyl or isobutyl))]. , the peptide according to claim 1. 3,2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-NH-CH
(2-Butyl)-CH_2-NH-CH_2-CH_2
-N(CH_2CH_2)_2O; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-H
is-ACHPA-NH-CH(2-butyl)-CH_
2-NH-CH_2-CH_2-N(CH_2CH_2
)_2O(CH_3)^■Cl^■;2-benzyl-5
,5-dimethyl-4-oxohexanoyl-His-A
CHPA-NH-CH(i-butyl)-CH_2-N(
CH_2CH_2)_2N(CH_3)_2^■Cl^
■;N-[2-(t-butylsulfonylmethyl)-3-
phenylpropionyl]-His-ACHPA-NH-
CH(i-butyl)-CH_2-NH-(1-ethyl-
4,5-dihydroimidazol-2-yl); N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-NH-CH
_2-CH(2-butyl)-N(CH_3)_2;N-
[1-(morpholin-4-yl)sulfonylmethyl-2
-phenethylsulfonyl]-His-ACHPA-NH
-CH_2-CH(2-butyl)-N(CH_2CH_
3) 3^■Cl^■N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-H
is-ACHPA-NH-CH_2-CH(2-butyl)-NH-(4,5-dihydroimidazol-2-yl); N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl] -His-ACHPA-
NH-CH_2-CH(2-butyl)-NH-(1-ethyl 4,5-dihydroimidazol-2-yl); N-
[1-(morpholin-4-yl)sulfonylmethyl-2
-phenethylsulfonyl]-His-ACHPA-NH
-CH(2-butyl)-CH_2-(2-hydroxymethylpyrrolidin-1-yl); N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
NH-CH(2-butyl)-CH_2-(2-guanidinomethylpyrrolidin-1-yl); N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
NH-CH(2-butyl)-CH_2-(2-hydroxymethyl-1-methylpyrrolidinium-1-yl)＾■
Cl^■; N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
NH-CH(2-butyl)-CH_2-(2-carboxy-1-methylpyrrolidinium-1-yl) inner salt; N-[1-(thiamorpholin-4-yl-S,S-dioxide) Sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-CH(2
-butyl)-CH_2-(2-trimethylammoniomethylpyrrolidin-1-yl)^■Cl^■; N-[1-(thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl-2-phenethyl sulfonyl]-His-ACHPA-NH-CH(2
-butyl)-CH_2-N(CH_3)_3^■CH_
2CO_2^■;N-[1-(thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl-2-phenethylsulfonyl)-His-ACHPA-NH-CH
(2-Butyl)-CH(OH)-CH_2-N(CH_
3) (CH_2CH_2)_2O^■Cl^■;N-[
1-(thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-H
is-ACHPA-NH-CH(2-butyl)-CH_
2-(pyridinium-1-yl)^■Cl^■;N-[
1-(thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-H
is-ACHPA-NH-CH(2-butyl)-CH_
2-1-methylimidazolium-1-yl)^■Cl^
■N-[1-(thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-CH (2-butyl)
-CH_2-N(CH_3)_2^■CH_2CH_2
CO2^■;2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-N
H-2(S)-methylbutyl; 2-benzyl-5,5-dimethyl-4-oxohexanoyl-His-ACHPA-NH-2(S)-methylbutyl; N-(benzimidazol-2-yl)sulfonyl- H
is-ACHPA-NH-2(S)-methylbutyl; N
-(benzimidazol-2-yl)carbonyl-Hi
s-ACHPA-NH-2(S)-methylbutyl; N-
(Indol-2-yl)carbonyl-His-ACHPA-NH-2(S)-methylbutyl; N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-NH-2
(S)-Methylbutyl; N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-NH-2
(S)-Methylbutyl; N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-Nle-ACHPA-NH-2
(S)-Methylbutyl; N-[1-(t-butylsulfonylmethyl)-2-phenethylsulfonyl]-His-ACHPA-NH-2(
S)-Methylbutyl; N-[1-(imidazol-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA
-NH-2(S)-methylbutyl; N-[1-(1,1
-dimethyl-2-carboxyethyl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
NH-2(S)-methylbutyl; N-[1-(p-carboxyphenyl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA
-Ni-2(S)-methylbutyl; N-[1-(p-aminophenyl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-2(S)-methylbutyl; N-[1-thiamorpholine -4-yl-S,
S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-2(S)-methylbutyl; N-[1-(4-ethylpiperazin-1-yl)sulfonylmethyl-2-phenethylsulfonyl]- Nle-A
CHPA-NH-2(S)-methylbutyl; N-(N-
Benzyl-N'-morpholinocarbonylmethyl)carbamoyl-His-ACHPA-NH-2(S)-methylbutyl;N-(N-benzyl-N'-morpholinocarbonylmethyl)sulfonamide-His-ACHPA-NH-2(
S)-Methylbutyl;N-(N-benzyl-N'-thiamorpholinocarbonylmethyl-S,S-dioxide)carbamoyl-His-
ACHPA-NH-2(S)-methylbutyl; N-[1
-(N-morpholinocarbonyl)methyl-2-phenethylsulfonyl]-His-ACHPA-NH-2(S)
-Methylbutyl; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-NH-2(S)
-Methylbutyl dihydrochloride; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-NH-CH(2
-butyl)-CH_2-NH(CH_2CH_2)_2
O;2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-NH-CH
(2-Butyl)-CH_2-NH(CH_2CH_2)
_2SO_2; 2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-
NH-CH(2-butyl)-CH_2-N(CH_2C
H_2)_2O(CH_3)^■Cl^■; 2-benzyl-5,5-dimethyl-4-oxohexanoyl-Hi
s-ACHPA-NH-CH(2-butyl)-CH_2
-NH(CH_2CH_2)_2NCH_3; 2-benzyl-5,5-dimethyl-4-oxohexanoyl-H
is-ACHPA-NH-CH(2-butyl)CH_2
-N(CH_3)(CH_2CH_2)_2NCH_3
^■Cl^■; 2-benzyl-5,5-dimethyl-4-
Oxohexanoyl-His-ACHPA-NH-CH
(2-Butyl)-CH_2-N(CH_3)(CH_2
CH_2)_2SO_2^■Cl^■;N-[2-(t
-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-NH-CH(2-butyl)
-CH_2-NH(CH_2CH_2)_2N(CH_
3)_2^■Cl^■;N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-
ACHPA-NH-CH(2-butyl)-CH_2-N
H(CH_2CH_2)_2N-CO-CH_3;N-
[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-NH-CH(2
-butyl)-CH_2-N(CH_3)_2;N-[2
-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-NH-CH(2-butyl)-CH_2-N(CH_3)_3^■Cl^■;
N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-N(i-propyl)-CH(2-butyl)-CH_2-N(CH_
3)_3^■Cl^■;N-[1-(morpholine-4-
yl)sulfonylmethyl-2-phenethylsulfonyl]
-His-ACHPA-N(CH_3)-CH(2-butyl)-CH_2-N(CH_3)_3^■Cl^■;
N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHP
A-N(i-butyl)-CH(2-butyl)-CH_2
-N(CH_3)_3^■Cl^■; N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
NH-CH(2-butyl)-CH_2-N(CH_2C
H_3)_3^■Cl^■;N-[1-(morpholine-
4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-CH(2-butyl)
-CH_2-CH_2-NH(CH_2CH_2)_2
ON-[1-(thiamorpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACH
PA-NH-CH(2-butyl)-CH_2-CH_2
-NH(CH_2CH_2)_2SO_2; N-[1-(thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-CH(2-butyl)-
CH_2-CH_2-N (CH_2CH_3)_3^■
Cl^■;N-[2-(t-butylsulfonylmethyl)
-3-phenylpropionyl]-(S-imidazole-
4-yl)Cys-ACHPA-NH-CH(2-butyl)-CH_2-CH_2-CH_2-N(CH_2C
H_3)_3^■Cl^■; N-(benzimidazol-2-yl)sulfonyl-His-Cal [CH(OH
)CH_2]Val-NH-CH(2-butyl)-CH
_2-NH-(4,5-dihydroimidazol-2-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2]Val-NH-
CH(2-butyl)-CH_2-NH-(1-ethyl-
4,5-dihydroimidazol-2-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2]Val-NH-
CH(2-butyl)-CH_2-NH-(1-ethyl-
pyridinium-4-yl)^■Cl^■; N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2)Val-NH-
CH(2-butyl)-CH_2-(3-amino-pyrrolidin-1-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2)Val-NH-
CH(2-butyl)-CH_2-(1-methyl-3-oxopiperidinium-1-yl)^■Cl^■; N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]- His-Am ACHPA-N
H-CH(2-butyl)-CH_2-(3-dimethylaminopiperidin-1-yl); N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-His-Am ACHPA-N
H-CH(2-butyl)-CH_2-(3-trimethylammonium-piperidin-1-yl); N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-His-(2S-i- butyl)
ACHPA-NH-CH(2-butyl)-CH_2-N
H-(1,1-dimethylpiperidinium-4-yl)^
■Cl^■;N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-His-(2S-
Allyl)ACHPA-NH-CH(2-butyl)-CH
_2-NH-(3,4,5,6-tetrahydropyrazol-2-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(NH_2)CH_2]Val-N
H-CH(2-butyl)-CH_2-NH-(1-methylazepin-3-yl); N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-NH-CH
(2-Butyl)-CH_2-NH-(1,1-dimethylazepinium-3-yl)^■Cl^■; N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-His -ACHPA-NH-C
H(2-butyl)-CH_2-NH-(3-quinuclidinyl); N-[1-(imidazol-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-A
CHPA-NH-CH(2-butyl)-CH_2-NH
-(N-methyl-quinuclidinium-3-yl)^■C
l^■;N-[1-(1,1-dimethyl-2-carboxyethyl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-CH (2-butyl)
-CH_2-NH-CH_2Ph; N-[1-(p-carboxyphenyl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA
-NH-CH(2-butyl)-CH_2-N(CH_3
)-CH_2Ph;N-[1-(Thiamorpholine-4-
yl-S,S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NH-C
H(2-butyl)-CH_2-N(CH_3)_2-C
H_2Ph^■Cl^■;N-[1-(4-ethypiperazin-1-yl)sulfonylmethyl-2-phenethylsulfonyl]-Nle-ACHPA-NH-CH(2-butyl)-CH_2-NH-CH_2- (4-pyridyl)
; N-(N-benzyl-N'-morpholinocarbonylmethyl)carbamoyl-His-ACHPA-NH-CH (
2-butyl)-CH_2-NH-CH_2-(1-methylpyridinium-4-yl)^■Cl^■; N-[1-(N-morpholinocarbonyl)methyl-2-
Phenethylsulfonyl]-His-ACHPA-NH-
CH(2-butyl)-CH_2-NH-CH_2-(1
-ethylpyrrolidin-3-yl); N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
NH-CH(2-butyl)-CH_2-N(CH_3)
_2^■CH_2CH_2SO_3^■; N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
NH-CH(2-butyl)-CH_2-N(CH_3)
_2^■CH_2CH_2OH・Cl^■; 2-(N-(morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-Lys-NH
CH_2 (pyridin-4-yl); 2-benzyl-5,5-dimethyl-4-oxohexanoyl-His-ACHPA-NH-Lys-NHCH_
2(pyridin-4-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-ACHPA-Lys-NH (quinuclidine-3-
N-(benzimidazol-2-yl)carbonyl-H
is-ACHPA-Lys-NHCH_2 (pyridine-
2-yl); [N-(indol-2-yl)carbonyl-His-
ACHPA-Lys-NHCH(2-butyl)-CH_
2N(CH_3)_3〕＾■OAc＾■；N-[2-(
i-propylsulfonylmethyl)-3-phenylpropionyl]-His-ACHPA-Lys-NHCH_2
(pyridin-4-yl); N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-Nle-ACHPA-Lys-
NHCH_2 (pyridin-4-yl); N-[1-(t-butylsulfonylmethyl)-2-phenethylsulfonyl]-His-ACHPA-Lys-N
H-2(S)-methylbutyl; N-[1-(imidazol-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA
-(N-imidazolin-2-yl)Lys-NH-i-
Bu; N-[1-(1,1-dimethyl-2-carboxyethyl)sulfonylmethyl-2-phenethylsulfonyl]-H
is-ACHPA-(N^ε, N^ε-dimethyl)Ly
s-NHCH_2 (pyridin-4-yl); N-[1-
(p-carboxyphenyl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-NHCH
[(CH_2)_4NHC(=NCH_3)NHCH_
3]CO-NHCH_2Ph; N-[1-(p-aminophenyl)sulfonylmethyl-
2-Phenethylsulfonyl]-His-ACHPA-(
N-CH_3)Lys-NH-n-butyl; N-[1-
(Thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl]-2-phenethylsulfonyl]-Hi
s-ACHPA-(N^ε-imidazolin-2-yl)
Lys-NH-i-Bu; N-[1-(4-ethylpiperazin-1-yl)sulfonylmethyl-2-phenethylsulfonyl]-Nle-ACHPA-Lys-NH_2
;N-(N-benzyl-N'-morpholinocarbonylmethyl)carbamoyl-His-ACHPA-(N^ε-
pyridin-4-yl)Lys-NH-2(S)-methylbutyl; N-(N-benzyl-N'-morpholinocarbonylmethyl)sulfonamide-His-ACHPA-LysNH
CH_2 (pyridin-4-yl); N-(N-benzyl-N'-thiamorpholinocarbonylmethyl-S,S-dioxide)carbamoyl-His-
ACHPA-Lys-NH-2(S)-methylbutyl; N-[1-(N-morpholinocarbonyl)methyl-2-
Phenethylsulfonyl]-His-ACHPA-Lys
-NHCH_2(pyridin-3-yl); [2-(N-
morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-HLys-NHCH_2C
H_2N(CH_3)_3〕＾■Cl＾■;2-(N-
morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-NHCH(CH_2CH_
2NHPh)CONHCH_2(pyridin-4-yl)
;2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-(N^α-C
H_3) Lys-NHCH_2 (pyridin-4-yl)
;2-(N-morpholinocarbonyl)methyl-3-phenylpropionyl-His-ACHPA-Lys-NH
CH_2 (pyridin-4-yl); 2-benzyl-5,5-dimethyl-4-oxohexanoyl-His-ACHPA-Lys-NHCH_2 (piperidin-4-yl); 2-benzyl-5,5-dimethyl- 4-oxohexanoyl-His-ACHPA-Lys-NHCH_2 (pyridin-4-yl); [2-benzyl-5,5-dimethyl-4-oxohexanoyl-His-ACHPA-Lys-NH-[(N-
(CH_3)-quinuclidin-3-yl)]]＾■Cl
^■;N-[2-(t-butylsulfonylmethyl)-3
-phenylpropionyl]-His-ACHPA-Ly
s-NH-CH (2-butyl) CH_2N (CH_3)
_2; N-[2-(t-butylsulfonylmethyl)-3
-phenylpropionyl]-His-ACHPA-Ly
s-NH-CH(2-butyl)CH_2N(CH_2C
H_2)_2O; N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-ACH
PA-(N^α-CH_3)Lys-NHCH_2(piperidin-4-yl); N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-
ACHPA-Lys-N(CH_3)CH_2(piperidin-4-yl);N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-His-AC
HPA-Lys-N(CH_3)CH_2(1-methylpiperidin-4-yl);N-[1-(morpholine-4
-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-(N^α-CH_3)Lys
-N(CH_3)(piperidin-4-yl); N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
(N^α-CH_3)Lys-N(CH_3) (1-ethylpiperidin-4-yl); N-[1-(morpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-ACHPA-
(N^α-CH_3)Lys-NH (pyridin-4-yl); N-(1-(thiamorpholin-4-yl)sulfonylmethyl-2-phenethylsulfonyl]-His-A
CHPA-(N^α-CH_3)Lys-NH(pyridin-4-yl); N-[1-(thiamorpholin-4-yl-S,S-dioxide)sulfonylmethyl-2-phenethylsulfonyl]-His- ACHPA-Lys-NH-2(S)-methylbutyl; N-[2-(t-butylsulfonylmethyl)-3-phenylpropionyl]-(S-imidazol-4-yl)
Cys-ACHPA-Lys-N(CH_3)(pyridin-3-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2]Val-Lys
-NH-2(S)-methylbutyl; N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2)Val-Lys
-NHCH_2(pyridin-4-yl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2]Val-(N-
CH_3) Lys-N(CH_3) (1-ethylpiperidin-4-yl); N-(benzimidazol-2-yl)sulfonyl-His-Cal[CH(OH)CH_
2) Val-Lys-NH-n-butyl); N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(OH)CH_2)Val-(N^
ε-CH_3)Lys-NH (pyridin-4-yl); N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-His-Am ACHPA-L
ys; N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl]-His-Am ACHPA-L
ys-N(CH_3)(1-ethylpiperidin-4-yl); N-[2-(i-propylsulfonylmethyl)-
3-Phenylpropionyl]-His-(2S-i-butyl)ACHPA-Lys-NHCH_3;N-[2-
(i-propylsulfonylmethyl)-3-phenylpropionyl]-His-(2S-allyl)ACHPA-(
N-CH_3)Lys-NHCH_2(pyridine-4-
N-(benzimidazol-2-yl)sulfonyl-H
is-Cal[CH(NH_2)CH_2]Val-L
ys;N-[2-(t-butylsulfonyl)-3-phenylpropionyl]-His-ACHPA-Lys-N
H-CH(2-butyl)-CH_2-NH(1,1-dimethylazepinium-3-yl)]^■Cl^■; N-[2-(i-propylsulfonylmethyl)-3-phenylpropionyl ]-His-ACHPA-(N-C
H_3) Orn-NHCH_2CH_2N(CH_2C
H_2)_2O;N-[(2-butyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-NH-
2(S)-Methylbutyl; N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-NH-2(S)-methylbutyl; N-[(2S-butyl-5-(thiamorpholinocarbonyl-S,S-dioxide)methyl-6-phenyl-4-
thiahexanoyl)] -ACHPA-NH-2(S)-methylbutyl; N-[
(1S-butyl-4-(morpholinocarbonyl)methyl-5-phenyl-3-thiapentanesulfonyl-S,S
-dioxide)]-ACHPA-NH-2(S)-methylbutyl;N-[(1S-butyl-4-(thiamorpholinocarbonyl-S,S-dioxide)methyl-5-phenyl-3-thiapentanesulfonyl-S ,S-dioxide)]-His-ACHPA-NH-2(S)-methylbutyl; N-[2-(benzimidazol-2-yl)sulfonyl)methylhexanoyl]-ACHPA-NH-CH(
2-butyl)-CH_2-NH(CH_2CH_2)_
2O;N-[2-(indol-2-yl)sulfonyl)methylhexanoyl]-ACHPA-NH-CH(2
-butyl)-CH_2-NH(CH_2CH_2)_2
SO_2;N-[2-(benzimidazol-2-yl)carbonyl)methylhexanoyl]-ACHPA-N
H-CH(2-butyl)-CH_2-N(CH_2CH
_2)_2O(CH_3)^■Cl^■;N-[2-(
indol-2-yl)carbonyl)methylhexanoyl]-ACHPA-NH-CH(2-butyl)-CH_
2-NH(CH_2CH_2)_2NCH_3;N-[
2-Butyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl]-ACHPA-NH-CH
(2-Butyl)-CH_2-N(CH_3)(CH_2
CH_2)_2NCH_3^■Cl^■; N-[5-(N-morpholinocarbonyl)amino-4-
Oxo-2-phenylthiomethylhexanoyl]-AC
HPA-NH-CH(2-butyl)-CH_2-N(C
H_3) (CH_2CH_2)_2NCH_3^■Cl
^■;N-[2-(imidazol-4-yl)methyl-
5-(N-morpholinocarbonyl)amino-4-oxohexanoyl]-ACHPA-NH-CH(2-butyl)-CH_2-N(CH_3)(CH_2CH_2)_
2SO_2^■Cl^■;N-[2-(S-imidazol-4-yl)thiomethyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl]-ACHP
A-NH-CH(2-butyl)-CH_2-N(CH_
3) (CH_2CH_2)_2SO_2^■Cl^■;
N-[5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH(2-butyl)-CH_2-NH( CH_2CH_2)_2N(
CH_3)_2^■Cl^■;N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)
Methyl-4-oxo-6-phenylhexanoyl]-A
CHPA-NH-CH(2-butyl)-CH_2-NH
CH_2CH_2)_2N(CH_3)_2^■Cl^
■;N-[2-n-butyl-5-(t-butylsulfonyl)methyl-4-oxo-6-phenyl-hexanoyl]-ACHPA-NH-CH(2-butyl)-CH_2
-NH(CH_2CH_2)_2N-CO-CH_3;
N-[2-(N-benzyl-N'-(morpholinocarbonyl)methyl)sulfonamidomethyl)hexanoyl]
-ACHPA-NH-CH(2-butyl)-CH_2-
N(CH_3)_2; N-[2-n-butyl-5-(t-butylsulfonyl)
Methyl-4-hydroxy-6-phenylhexanoyl]
-ACHPA-NH-CH(2-butyl)-CH_2-
N(CH_3)_3^■Cl^■;N-[5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]
-ACHPA-NH-CH_2-CH(2-butyl)-
N(CH_2CH_3)_2^■Cl^■;N-[5-
(t-Butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH_2-CH(2-butyl)-NH-(4,5- Dihydroimidazole-2-
N-[5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH_2-C
H(2-butyl)-NH-(1-ethyl-4,5-dihydroimidazol-2-yl); N-[5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl- 4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH(2-butyl)-CH_2-(2-hydroxymethylpyrrolidin-1-yl); N-[5-(t-butylsulfonyl)methyl-2 -(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH(2-butyl)-CH_2-(2-guanidinomethylpyrrolidin-1-yl); N-[5 -(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH(2-butyl)-CH_2-(2-hydroxymethyl- 1-methylpyrrolidinium-1-yl)^■Cl^■;N-[5
-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH(2-butyl)-
CH_2-NH(CH_2CH_2)_2N(CH_3
)_2^■Cl^■;N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-
4-oxo-6-phenylhexanoyl]-ACHPA
-NH-CH(2-butyl)-CH_2-NH(CH_
2CH_2)_2N(CH_3)_2's ^■l^■;N
-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-CH(2-butyl)-CH_2-NH(CH_2CH_2)_2N (C
H_3)_2^■Cl^■;N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-AC
HPA-NH-CH(2-butyl)-CH_2-NH(
CH_2CH_2)_2N(CH_3)_2^■Cl^
■;N-[5-(morpholinosulfonyl)methyl-2-
(imidazol-4-yl)methyl-4-oxo-6-
phenylhexanoyl]-ACHPA-NH-CH(2
-butyl)-CH_2-NH(CH_2CH_2)_2
N(CH_3)_2^■Cl^■;N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]
-ACHPA-NH-CH(2-butyl)-CH_2-
NH(CH_2CH_2)_2N(CH_3)_2^■
Cl^■;N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-NH-C
H(2-butyl)-CH_2-NH(CH_2CH_2
)_2N(CH_3)_2^■Cl^■;N-[(2S
-butyl-5-(morpholinocarbonyl)methyl-6-
(Phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-NH-CH(2-butyl)-CH
_2-(2-trimethylammoniomethylpyrrolidica|1-yl)^■Cl^■;N-[(2S-butyl-
5-(morpholinocarbonyl)methyl-6-(phenyl-4-thiahexanoyl-S,S-dioxide)]-A
CHPA-NH-CH(2-butyl)-CH_2-N(
CH_3)_2^■CH_2SO2^■;N-[(2S
-butyl-5-(morpholinocarbonyl)methyl-6-
phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-NH-CH(2-butyl)-CH(
OH)CH_2-N(CH_3)(CH_2CH_2)
＿2O^■Cl^■;N-[(2-imidazole-4-
yl)methyl-5-(morpholinocarbonyl)methyl-
6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-NH-CH(2-butyl)-C
H_2-(pyridinium-1-yl)^■Cl^■;N
-[(2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-
NH-CH(2-butyl)-CH_2-1-methylimidazolium-1-yl)^■Cl^■;N-[(2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6 -Phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-NH-CH(
2-butyl)-CH_2-N(CH_3)_2^■CH
_2CH_2CO_2^■;N-[(2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-
Dioxide)]-ACHPA-NH-CH(2-butyl)-CH_2-N(CH_3)_2^■CH_2CH_
2SO_3^■;N-[(2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-
phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-NH-CH(2-butyl)-CH_
2-N(CH_3)_2^■CH_2CH_2OH・C
l^■;N-[(2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-A
CHPA-NH-CH(2-butyl)-CH_2-N(
CH_3)_2^■CH_2CH_2N(CH_3)_
2.Cl^■;N-[(2-imidazol-4-yl)
Methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxy)]-ACHPA-NH-CH(2-butyl)-CH_
2-NH-CH_2CH_2NH-C(=NH)-NH
_2;N-[(2-imidazol-4-yl)methyl-
5-(morpholinocarbonyl)methyl-6-phenyl-
4-thiahexanoyl-S,S-dioxide)]-Ca
l[CH(OH)CH_2]-Val-NH-CH(2
-butyl)-CH_2-NH-CH_2CH(NH_2
)CO_2H;N-[(2-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-
phenyl-4-thiahexanoyl-S,S-dioxide)]-Am ACHPA-NH-CH(2-butyl)C
H_2-NH-CH_2CH(CO_2^■)N(CH
_3)_3^■;N-[(2-imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-
phenyl-4-thiahexanoyl-S,S-dioxide)]-Cal[CH(OH)CH_2]-Val-N(
i-butyl)-CH_2-CH_2-N(CH_2CH
_2)_2N(CH_3)_2^■Cl^■;N-[(
2-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-(2S-i-butyl)-ACHPA-NH-CH (2-butyl)-CH_
2-NH-CH_2 (pyridin-4-yl-N-oxide); N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-(2S-
Allyl)ACHPA-NH-CH(2-butyl)-CH
_2-NH-CH_2 (pyridin-2-yl-N-oxide); N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-Cal[
CH(NH_2)-CH_2] Val-NH-CH(2
-butyl)-CH_2-NH-CH_2(pyridine-2
-yl-N-oxide); N-[(2-butyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-
Dioxide)]-Cal(CH(OH)CH_2)Va
l-NH-2(S)-methylbutyl; N-[(2S-butyl-5-(thiamorpholinocarbonyl-S,S-dioxide)methyl-6-phenyl-4-thiahexanoyl]-ACHPA-Lys-NH (quinuclidin-3-yl);N-[(1S-butyl-4-(morpholinocarbonyl)methyl-5-phenyl-3-thiapentanesulfonyl-S,S-dioxide)]-ACHPA-Lys-
NHCH_2-(pyridin-2-yl);N-[(1S
-butyl-4-(thiamorpholinocarbonyl-S,S-
methyl-5-phenyl-3-thiapentanesulfonyl-S,S-dioxide)]-ACHPA-L
ys-NHCH (2-butyl)CH_2N(CH_3)
＿３〕＾■Cl＾■；N-[(2-(imidazole-4
-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-Lys-NH_2;N-[(
2-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-Ly
s-N(CH_3)CH_2(pyridin-4-yl); N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-Lys-NHCH_2(pyridin-4-yl); N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-Lys-NH-2(S)-methylbutyl; N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-(N -imidazolin-2-yl)Lys-NH-i-Bu; N-[5-(morpholinosulfonyl)methyl-2-(imidazole-4
-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-(N,N-dimethyl)Lys-NH
-CH_2(pyridin-4-yl); N-[2-n-butyl-5-(t-butylsulfonyl)
Methyl-4-hydroxy-6-phenylhexanoyl]
-ACHPA-NHCH [(CH_2)_4NHC(=
NCH_3)-NHCH_3]CO-NHCH_2Ph
;N-[5-(t-butylsulfonyl)methyl-2-(
imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-N^α-CH_3
) Lys-NH-n-butyl; N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)
Methyl-4-oxo-6-phenylhexanoyl]-A
CHPA-(N^ε-imidazolin-2-yl)Lys
-NH-i-Bu; N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4
-Oxo-6-phenylhexanoyl]-ACHPA-
Lys-NH_2; N-[(2S-butyl-5-(morpholinocarbonyl)
Methyl-6-phenyl-4-thiahexanoyl-S,S
-dioxide)]-ACHPA-(N^ε-pyridine-
4-yl)Lys-NH-2(S)-methylbutyl; N-[(2S-butyl-5-(morpholinocarbonyl)
Methyl-6-phenyl-4-thiahexanoyl-S,S
-dioxide)]-ACHPA-Lys-NHCH_2
(pyridin-4-yl);N-[(2S-butyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-Lys-NH-2(S)-methylbutyl; N-[(
2S-butyl-5-(morpholinocarbonyl)methyl-
6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-Lys-NHCH_2(pyridin-3-yl); [N-[(2-(imidazole-4-
yl)methyl-5-(morpholinocarbonyl)methyl-
6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA-HLys-NHCH_2CH_
2CH_2N(CH_3)_3]^■Cl^■; N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-NHCH(CH_2CH_2NHPh)CONHC
H_2(pyridin-4-yl); N-[2-(N-benzyl-N'-(morpholinocarbonyl)methyl)sulfonamidomethyl)hexanoyl]-ACHPA-(N^
α-CH_3)Lys-NHCH_2(pyridine-4-
N-[2-(S-imidazol-4-yl)thiomethyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl]-ACHPA-Lys-NHCH_2
(pyridin-4-yl); N-[2-(S-imidazol-4-yl)thiomethyl-5-(N-morpholinocarbonyl)amino-4-oxohexanoyl]-ACHP
A-Lys-NHCH_2 (piperidin-4-yl);
N-[2-butyl-5-(N-morpholinocarbonyl)
Amino-4-oxohexanoyl]-ACHPA-Ly
s-NHCH_2 (pyridin-4-yl); [N-[2
-butyl-5-(N-morpholinocarbonyl)amino-
4-oxohexanoyl]-ACHPA-Lys-(N
-CH_3-quinuclidin-3-yl)]^■Cl^■
; N-[5-N-morpholinocarbonyl)amino-4-oxo-2-phenylthiomethylhexanoyl]-ACH
PA-Lys-NH-CH(2-butyl))CH_2N
(CH_3)_2; N-[5-(N-morpholinocarbonyl)amino-4-
Oxo-2-phenylthiomethylhexanoyl]-AC
HPA-Lys-NH-CH(2-butyl)CH_2N
(CH_2CH_2)_2O; N-[5-(N-morpholinocarbonyl)amino-4-
Oxo-2-phenylthiomethylhexanoyl]-AC
HPA-(N^α-CH_3)Lys-NHCH_2(
piperidin-4-yl); N-[4-hydroxy-5-(N-morpholinocarbonyl)amino-2-phenylthiomethylhexanoyl]-
ACHPA-Lys-N(CH_3)CH_2(piperidin-4-yl); N-[5-(morpholinosulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]- ACHPA-Lys-N(CH_
3) CH_2(1-methylpiperidin-4-yl); N-[(2-imidazol-4-yl)methyl-5-(
morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-ACHPA
-(N^α-CH_3)-Lys-N(CH_3)(piperidin-4-yl); N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-(N^α-CH_3)Lys-N(CH_3)(1
-ethylpiperidin-4-yl); N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-Lys-NH-2(S)-methylbutyl; N-[(2-(imidazol-4-yl)methyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-ACHP
A-Lys-N(CH_3)(pyridin-3-yl); N-[2-(indol-2-yl)carbonyl)methylhexanoyl]-Cal[CH(OH)CH_2]V
al-Lys-NH-2(S)-methylbutyl; N-[
2-(indol-2-yl)carbonyl)methylhexanoyl]-Cal(CH(OH)CH_2]Val-
Lys-NHCH_2 (pyridin-4-yl); N-[
2-(benzimidazol-2-yl)sulfonyl)methylhexanoyl]-Cal[CH(OH)CH_2)
Val-(N^α-CH_3)Lys-N(CH_3)
(1-ethylpiperidin-4-yl); N-[2-(benzimidazol-2-yl)sulfonyl)methylhexanoyl]-Cal[CH(OH)CH
_2] Val-Lys-NH-n-butyl; N-[(2
-(imidazol-4-yl)methyl-5-(morpholinocarbonyl)methyl-6-phenyl-4-thiahexanoyl-S,S-dioxide)]-Cal[CH(OH
)CH_2) Val-(N^α-CH_3)Lys-N
H(pyridin-4-yl); N-[(2-butyl-5-
(morpholinocarbonyl)methyl-6-phenyl-4-
Thiahexanoyl-S,S-dioxide)]-Am A
CHPA-Lys; N-[5-(t-butylsulfonyl)methyl-2-(imidazol-4-yl)methyl-4-oxo-6-phenylhexanoyl]-Am ACHPA-Lys-N(
CH_3) (1-ethylpiperidin-4-yl); N-[2-(indol-2-yl)sulfonyl)methylhexanoyl]-(2S-i-butyl)-ACHPA
-Lys-NHCH_3;N-[2-(benzimidazol-2-yl)carbonyl)methylhexanoyl]-
Cal[CH(NH_2)CH_2]Val-Lys;
N-[2-(benzimidazol-2-yl)carbonyl)methylhexanoyl]-ACHPA-Lys-NH
-CH(2-butyl)-CH_2-NH-(1,1-dimethylazepinium-3-yl)]^■Cl^■; N-[5-(t-butylsulfonyl)methyl-2-(imidazole) -4-yl)methyl-4-oxo-6-phenylhexanoyl]-ACHPA-(N^α-CH_3
)Orm-NH-CH_2CH_2N(CH_2CH_
2)_2O;N-[(1-ethoxycarbonylmethyl-
2-phenyl)ethylsulfonyl]-His-ACHP
A-NH-2(S)-methylbutyl; N-[(1-ethoxycarbonylmethyl-2-phenyl)ethylsulfonyl]-His-ACHPA-Lys-
NHCH_2(pyridin-4-yl); N-[(1-ethoxycarbonylmethyl-2-phenyl)ethylsulfonyl]-His-ACHPA-Lys-NHCH_2(
piperidin-4-yl) and N-[(1-ethoxycarbonylmethyl-2-phenyl)ethylsulfonyl]-H
Claim 1 selected from the group consisting essentially of is-ACHPA-Lys-NH-iBu
Peptides described in Section. 4. A composition containing a therapeutically effective amount of the peptide according to claim 1 and a pharmaceutical carrier. 5, Diuretics: Acetazolamide; Amiloride; Bendroflumethiazide; Benzthiazide; Bumetanide; Chlorothiazide; Chlorthalidone; Cyclothiazide; Ethacrylic acid; Furamide; Hydrochlorothiazide; Hydroflumethiazide; Indacrinone (racemic mixture, or (
+) or (-) single enantiomer,
or for example as a population ratio of 9:1 of each of said enantiomers); metolazone; methyclothiazide, muzolimine; polythiazide, quinetazone; sodium ethacrylate; sodium nitroprusside; spironolactone; ticlinafen; triamterene; trichlormethiazide; : dibenamine; phentolamine; phenoxybenzamine; prazosin; torazoline; β-adrenergic blocker ￥: atenolol; metoprolol; nadolol; propranolol; timolol; ((±)-2-[3-(tert-butylamino)- 2
-Hydroxypropoxy]-2-furananilide (ancarolol); (2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran HCl) (befunolol); ((±)-1-(isopropylamino)- 3-(p-(
2-cyclopropylmethoxyethyl)phenoxy)-2
-properanol HCl) (betaxolol); (1-[(3,4-dimethoxyphenethyl)amino]-
3-(m-triloxy)-2-propanol HCl) (
(((±)-1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isopropylamino-
(2-propanol) fumarate) (bisoprolol); (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidino]propoxy)indole); (carbazolyl-4-oxy-5,2-(2-methoxy) phenoxy)ethylamino-2-propanol); (1-((1,1-dimethylethyl)amino)-3-(
(2-methyl-1H-indol-4-yl)oxy)
-2-propanol benzoate) (bopindolol)
; (1-(2-exobicyclo[2.2.1]-heptyl-
2-ylphenoxy)-3-[(1-methylethyl)-
Amino]-2-propanol HCl) (bornaprolol); (O-[2-hydroxy-3-[(2-indole-3
-yl-1,1-dimethylethyl)amino]propoxy]benzonitrile HCl) (bucindolol); (α-[(tert-butylamino)methyl]-7-ethyl-2-benzofuranmethanol) (bufuralol)
; (3-[3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropyl]phenyl]-1,
((±)-2-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenoxy]-N-methylacetamide HCl) ) (cetamolol)
; (2-Benzimidazolyl-phenyl (2-isopropylaminopropanol)); ((±)-3'-acetyl-4'-(2-hydroxy-
3-isopropylaminopropoxy)-(methyl-4-
[2-Hydroxy-3-[(1-methylethyl)aminopropoxy]]benzenepropanoate HCl (esmolol); (erythro-
DL-1-(7-methylindan-4-yloxy)-
(1-(tert-butylamino)-3-[O-(2-
propynyloxy)phenoxy]-2-propanol (
(1-(tert-butylamino)-3-[O-(6-
((-)-2-hydroxy-5-[(R)-1-hydroxy-2-[(R)-(1-methyl -3-phenylpropyl)amino]ethyl]benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)propoxy]-7-methyl 5H-furo[3,2-g][1] (benzopyran-5-one) (iprochlorol); ((-)-5-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-1-(2H)-naphthalenone HCl) (levobunolol) (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole HCl); (4-[3-(tert-butylamino)-2-hydroxypropoxy]-N-methyliso Carbostyril HC
l); ((±)-N-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]]ethyl-N'
-isopropylurea) (pafenolol); (3-[[(2-trifluoroacetamido)ethyl]
(N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2,3-dihydro-3-oxo- ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl)butanamide)(acebutolol); ((±) )-4'-[3-(tert-butylamino)-
2-Hydroxypropoxy]spiro[cyclohexane-
1,2'-indan]-1'-one) (spilendrol); (7-[3-[[2-hydroxy-3-[(2-methylindol-4-yl)oxy]propylamino]butyl ] Thiophylline) (Theoprolol)
((±)-1-tert-butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tartatrol); ((±)-1-tert-butylamino-3-(2,3
-xylyloxy)-2-propanol HCl) (xibenolol); (8-[3-(tert-butylamino)-2-hydroxy-propoxy]-5-methylcoumarin) (bucumolol); -butylamino)-2-hydroxypropoxy)benzonitrile HCl) (bunitrol); ((±)-2'-[3-(tert-butylamino)-
2-hydroxypropoxy-5'-fluorobutyrophenone) (butophyllorol); (1-(carbazole-
4-yloxy)-3-(isopropylamino)-2-
propanol) (carazolol); (5-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyryl HCl
)(cartiolol); (1-(tert-butylamino)-3-(2,5-dichlorophenoxy)-2-propanol)(chloranolol); (1-(inden-4(or 7)yloxy) -3-isopropylamino)-2-propanol HCl) (indenolol); (1-isopropylamino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindolol); (1-( 4-acetoxy-2,3,5-trimethylphenoxy)-3-isopropylaminopropan-2-ol) (methipranolol); (1-(isopropylamino)-3-(o-methoxyphenoxy)-3-[ (1-
methylethyl)amino]-2-propanol)(moprolol); ((1-tert-butylamino)-3-[(5,6,
7,8-tetrahydro-cis-6,7-dihydroxy-
1-naphthyl)oxy]-2-propanol) (nadolol); ((S)-1-(2-cyclopentylphenoxy-3-
[(1,1-dimethylethyl)amino]-2-propanol sulfate (2:1)) (penbutrol); (4'-[1-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol) ; (2-methyl-3-[4-(2-hydroxy-3-te
rt-butylaminopropoxy)phenyl]-7-methoxy-isoquinolin-1-(2H)-one); (1-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-isopropylamino- 2-
Propanol HCl); ((-)-p-[3-[(3,
4-dimethoxyphenethyl)amino]-2-hydroxypropoxy]-β-methylcinnamonitrile) (pacrinolol); ((±)-2-(3'-tert-butylamino-2'
-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole HCl) (arotinolol); ((±)-1-[p-[2-cyclopropylmethoxy)
Ethoxy]phenoxy]-3-(isopropylamino)
-2-propanol) (cycloprolol); ((±)-1-[(3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)amino]-2- propanol) (indopanolol)
; ((±)-6-[[2-[[3-(p-butoxyphenoxy)-2-hydroxypropyl]amino]ethyl]amino]-1,3-dimethyluracil) (pirepolol)
(4-(cyclohexylamino)-1-(1-naphthrenyloxy)-2-butanol; (1-phenyl-3-
[2-[3-(2-cyanophenoxy)-2-hydroxypropyl]aminoethyl]hydantoin HCl); (3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy- 2H-
1-benzopyran) (nipradolol); ￥ α- and β-adrenergic blocker: ￥ ((±)-tert-butylamino)-3-[o-[2
-(3-Methyl-5-isoxazolyl)vinyl]phenoxy]-2-propanol)(isoxaprolol); (1-isopropylamino-3-(4-(2-nitroxyethoxy)phenoxy)-2-propanol HCl)
; (4-hydroxy-α-[[3-(4-methoxyphenyl)-1-methylpropyl]aminomethyl]-3-(methylsulfinyl)benzmethanol HCl) (sulfinarol); (5-[1 -Hydroxy-2-[[2-
(o-methoxyphenoxy)ethyl]amino]ethyl]
-2-methylbenzenesulfonamide HCl); (5-
[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]salicylamide HCl) (
labetalol);(1-((3-chloro-2-methyl-
1H-indol-4-yl)oxy)-3-((2-
phenoxyethyl)amino)-2-propanol hydrogen malonate) (ifendrol); (4-(2-hydroxy-3-[(1-methyl-3-phenylpropyl)amino]propoxy)benzeneacetamide); 1-[3-[[3-(1-naphthoxy)-2-hydroxypropyl]amino]-3,3-dimethylpropyl]
-2-Benzimidazolinone); (3-(1-(2-hydroxy-2-(4-chlorophenylethyl)-4-piperidyl)-3,4-dihydroxy)quinoxalin-2(1H)-one); ¥ CNS agonists: clonidine; methyldopa; adrenergic neuroleptics: guanethidine; reserpine; and other rhauorphic alkaloids such as recinamine; vasodilators: diazoxide; hydralazine; minoxidil; angiotensin I-converting enzyme Inhibitor ￥: 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2,4 (R,R)-dimethylbutanoyl) Indoline-2 (S
)-carboxylic acid); (2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1
,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid); ((S)-1-[2-[[1-ethoxycarbonyl)-
3-phenylpropyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid H
Cl); (N-cyclopentyl-N-(3-2,2-dimethyl-
((2R,4R)-2-(2-hydroxyphenyl)-
3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid); (1-(N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis, syn-
Octahydroindole-2(S)-carboxylic acid HCl
); ((-)-(S)-1-[(S)-3-mercapto-2
-Methyl-1-oxopropyl]indoline-2-carboxylic acid); ([1(S),4S]-1-[3-(benzoylthio)
-2-methyl-1-oxopropyl]-4-phenylthio-L-proline; (3-([1-ethoxycarbonyl-3-phenyl-(
1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxy-1-(3S)-benzazepine-
(N-(2-benzyl-3-mercaptopropanoyl)-5-ethyl-L-cysteine) and S-methyl analogs; (N-(1(S)-ethoxycarbonyl-3- Phenylpropyl)-L-alanyl-L-proline maleate) (enalapril); N-[1(S)-carboxy-3-phenylpropyl]
-L-alanyl-1-proline; N^2-[1(S)-
Carboxy-3-phenylpropyl]-L-lysyl-L
-Proline (lisinopril); 2-[N-[(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl- (1S,3S,5S)-2-azabicyclo[3.3.0
]Octane-3-carboxylic acid; [1(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenylthio-L-proline-S-benzoyl calcium salt (diphenopril) ; [1-(+/-)4S]-4-cyclohexyl-1-[
[2-methyl-1-(propoxy)propoxy] (4-
Phenylbutyl)phosphinyl]acetyl-L-proline sodium salt (phosphofuryl); ￥Calcium channel blockers￥: Nifedepine; Nitrendipine; Verapamil; Diltiazam; ￥Other antihypertensive agents: Aminophylline; Cryptenamine acetate or tannate; ; meremethoxylinprocaine; pargyline; trimethaphan camsylate; and others, as well as mixtures and combinations thereof; A composition according to scope item 4. 6. A method for treating renin-related hypertension or renin-related congestive heart failure, comprising administering to a patient in need of such treatment a therapeutically effective amount of the peptide according to claim 1. 7. The patient is a human and the therapeutically effective amount is 0.1 to 40 g.
7. The method of claim 6, wherein: /day.