JPH04503073A - anaphylatoxin receptor ligand - 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] Anaphycytoxin receptor ligand Industrial applications The present invention relates to organic compounds that modulate anaphylatoxin activity. The present invention is based on this to modulate anaphylatoxin activity in human and animal patients requiring such treatment. It also relates to methods and compositions for.

Background of the invention Infection by bacteria, viruses or fungi, infiltration by cancer cells, allergies or autoimmunity A wide variety of conditions, including epidemic disorders, and physically or chemically induced disorders, causes an inflammatory response in patients. of these diseases and conditions in humans and most mammals. For all, the classical view of the complement system (a set of proteins, regulators and proteolytic enzymes) generation of biologically active peptides via activation 1; , and plays a role in expanding and aggravating the inflammation that it causes. A very active pen Anaphylatoxin C,5a is a polypeptide consisting of 74 amino acids. The α-chain of C5, which is the origin of C5, is a converting enzyme (C0fi protein) of the blood complement system. c++1+c) (proteolytic enzyme) and coagulation system enzymes to specific sites. It is generated by being cleaved at C5a exists in two biologically active forms in vivo.

When released from C5, the carboxy-terminal arginine of C5a becomes carboxypep It is rapidly removed by Tidase N, leaving behind dss-Ar (derivative. C3ade+ -Arg is less active than C5m, but both are present at concentrations that are likely to occur in vivo. Both are strong inflammatory mediators (B, N, Fe+ntndes, P, M, [l5nson, A, 01tni, T, E, Bs1li, 1eI m+uno1. 1978. 120.　10'9. ). These peptides are C3a　5C4a and their deI-A4 decomposition products are collectively included in this book. We will describe it as an anaphylatoxin, and it is responsible for various inflammatory reactions. It can become a drag.

Among the various cell types, the neutrophil response to C5a is the most distinct. C Cell surface receptors specific for 5a have been demonstrated on neutrophils (D, E ,　Chenow＊jh,　T,　E,HBli.

Proc, Ns, ^cod, Sei, U, S, A, 1978. 75. 39 43-3947. It.

Hie7. T, E, llB11. J, Ims++no1. 19!15 ．． H5, 20637206B.

T, E, Rolli+s, M, S, Springy, T, Bio l, Chu+, 19g5.2611°7175~? +60. ). Ligand-receptor The body interaction is the controlled movement (chemotaxis) of human polymorphonuclear leukocytes (PMNs). properties), adhesion, oxidative burst, and release of microenzymes from these cells. (T, ε, Hugli, Sp+iBe’+ 5tffiin, IIllwu oopxjhol, 1984°7, 193-219. ). PMN and other marks The interaction of C5a with human cells and tissues affects histamine release, vascular permeability, and smooth muscle aggregation. shrinkage and increased influx of inflammatory cells into tissue fibers, including neutrophils, eosinophils, and basophils. (T, E, )Iugli, Sp+1nHr 5tain.

1mmunop*1ho1. 19N, 7. 193-219. ), C5 a further mediates the inflammatory effects of phagocytic mononuclear cells that accumulate at sites of chronic inflammation. may also be important (＾, C, Al1 mouth on, 1. Ferlugt, 11. P+7+l+, H.

Il, 5che+1lIIer, A s+++’s sad Actions 197g, 8,27. ). C5a and C5a deI-Arg migrate to mononuclear cells. (P, 'A, W*+d, 1. Etp, 1 led,' 1961-128. I201. R, SBdtrmtn, tl , S, 5hin, A, C, DinunbeB, 1. Immanoi, 1 972. +19. -896,), and the neutrophil responses elicited by these substances. Similar to the above, the release of lysosomal enzymes occurs in mononuclear cells (LMcCx order by.

P, S, tl! n+on J, I+++uno1. +979. -123.　 2511.1゜Recent research shows that C5a enhances antibodies, especially at sites of inflammation. (E, L, MorH) In.

W,O,Wtille,T,E,Hagli,],E! p, Msd, 1982 155. 1412゜1, O, Weigle, E, L, Mor(sn, M, G, Goodmxa, D, E.

Cheaov NhyT, E, HBli, Federljion ProC, 19 g! ,41,3099,E,L,MorHa,W,’O,Wtigle,T,E. , HBli, Fede+N1on Ptoc.

19g4. 43. 2543,).

C5a and C5a deI-Arg are involved in host defense against bacterial infections and possibly acute It plays an important role in pathological disorders such as leukocyte infiltration in the lungs in cases of respiratory distress syndrome. Play the wari. This mechanism includes hemodialysis, leukophoresis (Icnkophores), Useful in various pathological situations such as pulmonary distress in case of cardiopulmonary bypass and acute myocardial infarction. It seems like he is acting. Complement activation is associated with linymatous arthritis, serum sickness, and systemic disease. Lithematosus, ulcerative colitis, and conditions of liver cirrhosis, chronic hepatitis, and glomerulonephritis , certain chronic conditions during hemodialysis and cardiopulmonary bypass, acute pancreatitis, peristalsis infarction (complement Following the interaction of the atherosclerotic plaques, C5a-induced leukocyte embolization (lewko7, eabol++rt+oa), asthma, bronchoconstriction, some symptoms plays an important pathological role in autoallergic diseases, graft rejection, and postviral encephalopathy. Acting is a prerequisite.

Certain compounds of the invention have the ability to bind to and block anaphylatoxin receptors. and serve as an antagonist to reduce or prevent anaphylatoxin-mediated inflammation. can do. Other compounds of the invention mimic anaphylatoxin activity An agent that regulates the body's defense mechanisms against invasion by pathogens and malignant tumors. It is an agonist that helps build up. Furthermore, these compounds have been shown to be effective against anaphylatoxins. May affect immunomodulatory effects.

These examples demonstrate the role of anaphylatoxins in a wide range of diseases. A possible involvement is that anaphylatoxin receptor ligands are involved in the pathological condition. This suggests that it may have clinical application in treatment and prevention.

Summary of the invention As a main embodiment of the invention, Anaphylatoxin activity-modifying compounds and their pharmaceutically acceptable salts, esters or offers amides.

In the above general formula, the groups A to T have the following meanings.

^ is R1-R, 噌1; B is selected from R-R5-R6, R21R29R3 and R37; D is R7''-R8-R9' Select from R31, R32, R35 and R37 E is R -R-RRSRSelect from R37 10 11 B111 32 35 is; G is selected from R13-RR4-R1s' RH' R32' R35 and R37 J is selected from R-R-R, R, R, R and R3fu 16 1fu II! 1’4 2 35; L is selected from R-R-RSR, RSR and R31 II 20 HH32!5 is; M is selected from Rll''-RH-RH%R31' RH' Rll and R37 ; Q is selected from R-R-R, R, R, R and R3 25 N 27 31 H35 is; T is R21R29''-R3; B and D together, depending on the case, R33, R34, R3 Hatake, R31'RR, R and R43; 4・ゝ　41　4! D and E together optionally represent R1, R34, R21R29, R, R, R and represents a group selected from R43 and R43; 4, 41, 42 E and G together, optionally Rll, R34, R31, R39, RRSR and represents a group selected from R43; 4・ゝ　41　42 G and J are together, depending on the case, R33, R21R29, R39, R46' represents a group selected from R41, R42 and R43; J and L taken together, RB, R34, R21R29, R411' R41, Rll and R4 as the case may be represents a group selected from 3; L and M taken together, optionally R21R29; , RH5R39, RSR, R and R43; 4.41 42 M and Q together, depending on the case, "H1R34, R38, R1I'R40" R41' represents a group selected from Rll and R43; and a group Rs -Ri -R? ;　Ra　-Rt　-Rl・'　R11-RH-R13'Rth-R15 -RH; R17-R18-Rl9' R26-"1l-R22'R-R-R; is one or more of Rll-R27-R21 independently N242S Optionally represents R31.

The group R1 is amiha (lower alkyl) amihata dialkylamino, (arylalkyl) ) Amino, hydroxy, alkoxy, aryloxy, aryl aluma, Acetamide, thioalkoxy, halogen, aryl, lower alkyl, aryl Groups consisting of alkyl, (heterocycle)alkyl, heterocycle, arylamino, and hydrogen. selected from the loop.

RIt, >CRR, >C-CR,,R,, (Z-or It　E　-any configuration selected from the group consisting of oxygen, amino, and alkylamino provided that when R2 is oxygen, amino or alkylamino, R1 is aryl, lower alkyl, arylalkyl or (bicyclic) alkyl.

R is selected from the group consisting of >Cm01>CH2, >C-1s and >S02. However, when R is >CM or >S02, R2 is oxygen, amino or It cannot be alkylamino.

R is >CM, >O, >S and >NR (R11114 here! 101 is hydrogen, lower alkyl, arylalkyl, alkenyl, hydroxy or alcohol ), with the proviso that R4 is 〉O or 〉S In this case, R1, R2 and R3 are lower alkyl, arylalkyl, selected from aryl or hydrogen.

, >NR>C-CR, .

The trap is -> CR2a t Rt・2% 2nd ~ R (Z- or E-configuration ) and a group consisting of a substituted cyclopropyl of the formula △ζ= be done.

R' R' R12' R15' R1g' R2+ and R24 are >C-0° >CH2, -CH2C(0)-1-NHC(0)-1>cs.

〉So2 and ＞P (0) X (where X is hydroxy, alkoxy, amino , alkylamino and dialkylamino) independently selected.

R7, RIO, R13, R16, R19, R22, R25 are >CH2 and > NR (here, R2O is hydrogen, lower alkyl, arylalkyl, aryl, hydrogen (selected from the group consisting of droxy and alkoxy) Ru.

R is 〉CR210R211, ＞N　R213, ＞C-CR2゜C(z- or Substituted cyclopropylene of the formula, \ to ζ R is selected from the group consisting of >CHR, >NR223, >C-CR,2 5II 220 221 R (present in either the Z- or E-configuration), and 226° To the bar.

R selected from the group consisting of substituted cyclopropyl of formula >CRR, >NR, >CR235R (present in Z- or E-configuration) and formula, N;

selected from the group consisting of substituted cyclopropyl.

R is >CRR, >NR>C5-CR, o.

F 3G1 302 303' R306 (present in either the Z- or E-configuration), and selected from the group consisting of a set of substituted cyclopropyl.

R is >CR310R311, >NR313, >C so-called CR31SR (Z- or E - existing in either configuration), and pekko.

R selected from the group consisting of substituted cyclopropyl of formula >CRR, >NR3 ,3,>C helmet CR3252332032+ R326 (present in either Z- or E-configuration), and Rit>CRR ,>C,CRR(Z- or 2a 336 3'H3353N Meζ.

E-configuration), ゛ and the position R27 of the formula is 〉C50, > CH2, -CH2C(0)-': >C-9, >So2 and >P (0) X (where X is hydroxy, alkoxy, amino, alkylamino and dialkyl selected from the group consisting of (selected from amino).

RIt, >O, >S, >CH and >NR(, :, :l, :, 28 2 N19 RIN is from hydrogen, lower alkyl, (heterocyclic) alkyl and arylalkyl ), where R > So and 1t > P (0) If XC' is present, R28 is >0 or >N R109.

R29 represents hydrogen, lower alkyl, arylalkyl, and >NR (where R110 is hydrogen, lower alkyl, aryl and 1G selected from the group consisting of arylalkyl), with the proviso that When R is 〉O or 〉S, R29 is lower alkyl or arylalkyl. and (iilR29 is hydrogen, lower alkyl or arylalkyl) There is no R2O.

R30 is a group consisting of hydrogen, aryl, lower alkyl and arylalkyl. selected from the list.

R31 is the structure ).

R32 is the structure (where p and q are integers independently selected from 0.1 and 2) It is the basis.

R33 is the structure (where and V are integers independently selected from 0.1.2 and 3). This is the basis for

R34 is the structure (where r and S are integers independently selected from O, l, 2 and 3). This is the basis for

R3S is a structure -0 and -〇H2-, and R is selected from hydrogen and lower alkyl. , However, if (il　f is 0, X is C-2 and R is C-3 or C- 4; (If iilf is 1, X matches C-2, R matches C-3, C- 4 or C-5, and C-3,4 is saturated or unsaturated; (iii) f is 2, then X is at C-2, C-3 or C-4, and k is the position X occupies. If not, it is in C-2, C-3, C-4, C-5 or C-6, and C-3, 4 or C-4,5 is saturated or unsaturated, and (it) f is 31', X It is in C-2, ca or C-4, and R is occupied by X If not, it is located at C-2, C-3, C-4, C-5, C-6 or C-7, and C-3, 4 or C-4,5 or C-5,6 is saturated or unsaturated.

R3-Structure (here, g is an integer of θ to 3).

R17 is the structure, (Here, h is 0 or 1, and j is 0 or 1, provided that.

RlB has the structure: It is a group having

R3 is a structure It is a group having

It is a divalent group having

It is a divalent group that grows.

R42 is the structure It is a divalent group having

R43 is the structure (herein, k is an integer of 0 to 2).

Both R and R2 optionally represent a group selected from aryl, heterocycle or hydrogen. can be expressed.

R and R; R and R, R and R13; RIs and R16', R18 and R19; R2 and R22 and R24 and R25 each pair together are >C H, -(CH2) 3-1-CH-CH-1-c = c-1-C(-CH2) CH2-1-CH(OH)CH2,-1-C(0)O-1-C(0)S-1-C HC(0)O-1-CH2C(0)S-1-CH20-1-CH,, S- and - A group selected from NHC(0)- may optionally and independently be represented. however , (1) If Rs is > N R2a s or > C-CRR, R6 and R7 together represent -C(0)NH- or -C(0)NCH,-, (■) If R is > N R or > C-CR21S R216, R and Rlo are Together they represent -C(0)NH- or -c(o)NCHs-, and (i iI) When R11 is >N R223 or >c-CR22S R226, R12 and R13 taken together, -CONH- or it -CON CH- represents; (it) R, 4 > NR or > ClllICR235C236 In some cases, RIs and R16 are together T knee C(0) NH- or 1t-C(0 ) NCH3-8 representation; (Ma) R17 is > N Rs o a or > C-CR3 If it is G5 R306, Rls and CF Rt 9 ka * ni natte, -C ( 0) NH- or -C(0)NCH-; fwilR2o is > N R3 If t 3 or > C tength CR315R316, R21 and R22 are together, t) L, (tii) R When 23 is >N R323 or "-CR325R326, R24 and R 25 together represent C(0)NH- or -0(0)NCH3-.

R and 'R3o both represent hydrogen, hydroxyl or alkoxy, as the case may be. However, if R2B is 〉O or 〉S, both R and R2O represent hydrogen. represent.

Both R, R and R optionally represent lower alkyl, arylalkyl, alkenyl. Nyl, aryl, hydroxy, alkoxy, hydrogen, N-terminal protecting group or similarly protected A peptide fragment consisting of 1 to 18 protected residues (herein, a peptide fragment consisting of 1 to 18 protected residues) Each of the amino acids that make up the fragment consists of the 20 naturally occurring amino acids R, R, R and and R4 both optionally represent hydrogen, lower alkyl, arylalkyl, aryl. represents a group selected from R, heterocycle or H2SO(0)-, provided that R is 2, R-' R2, 'R3 and R4 are both hydrogen and the I don't get it.

Both R, R, R and R30 are optionally hydrogen, lower 27 2B 29 Represents a group selected from alkyl, aryl, or arylalkyl.

R1, R2, R3, R4 and R5 are all optionally a, aryl or hetero Represents a ring group.

RSR, RSR, RSR"225~ R, R, R, RSRSR, R.

R and R336 are hydrogen, lower alkyl, aryl, arylalkyl, (cyclo (roalkyl)alkyl, amidoalkyl, (carboxamido)alkyl, ure from the group consisting of idoalkyl, (heterocyclic)alkyl and halo-substituted alkyl independently selected.

99　202　”　”　’ R'　''　'　R211'　R221'　R231302311R and R331 are independently selected from hydrogen and lower alkyl.

R100 is hydrogen, lower alkyl, arylalkyl, (cycloalkyl)alkyl Kyl, aminoalkyl, (alkylamino)alkyl, hydroxyalkyl, group Anidinoalkyl, carboxyalkyl, (heterocyclic)alkyl, (thioalkyl) C) Glue consisting of alkyl, arylalkoxy and sulfhydryl alkyl selected from the list.

R21ll is hydrogen, lower alkyl, alkenyl, aryl, arylalkyl (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxy Sialkyl, guanidinoalkyl, carboxyalkyl, (carboxamide) Alkyl, (carboxyhydrazino)alkyl, ureidoalkyl, (heterocycle) Alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothi oalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfuryl selected from the group consisting of drillalkyl and halo-substituted alkyl.

R%R, R, R%R and R3!3 are water 2.3 H! ! ! ! ! 31 81 elementary, lower alkyl, alkenyl, arylalkyl, (cycloalkyl)alkyl aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl carboxyalkyl, (carboxamido)alkyl, (carboxyhydra) dino)alkyl, ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy) Alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, a group consisting of oarylalkoxy)alkyl or protected sulfhydrylalkyl Selected independently from the loop. However, R, R, R, R, Rm! 11 222 R33.3 or none of the groups of R813 can be a vinyl group and can also be bonded directly to the nitrogen or - having a heteroatom separated from it by one methylene unit 1# Key;=Catfish-No.

Rtto is hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxya alkyl, guanidinoalkyl, carboxyalkyl, (carboxamido)alkyl Kyl, ureidoalkyl, (carboxyhydrazino)alkyl, (heterocyclic)alkyl Kyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioa alkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfhydryl alkyl, or halo-substituted alkyl.

R, R, R%R3, and R33 are hydrogen, lower 20 2N 311 Alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl Kyl, aminoalkyl, amidoalkyl, his(carboxamido)alkyl, ( carboxyhydrazino)alkyl, ureidoalkyl, (heterocyclic)alkyl, ( thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy) ) alkyl, (thioarylalkoxy)alkyl, protected sulfhydryl alkyl independently selected from the group consisting of halo- or halo-substituted alkyl.

R and R323 are hydrogen, lower alkyl, alkenyl, a32. Ryl, benzyl, (cycloalkyl)alkyl, -(alkylene) -C(0 ) N R340R341, -(alkylene)-NRR, -(alkylene)-N R,4,C(o)R3,5,342ro3 Hydroxyalkyl, -(alkylene)"-NRlHR343' -(alkylene) ) -NRC(0) R, hydroxyalkyl, guanidinoalkyl, carbo xyalkyl, (carboxyhydrazino)alkyl, ureidoalkyl, heterocycle Substituted methyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (amino thioalkoxy)alkyl, protected sulfhydrylalkyl, and halo-substituted alkyl (Here, R%R, R and 34・341 3B R is independently selected from hydrogen and lower alkyl' and R345 are independently selected from hydrogen, lower alkyl and muro-substituted lower alkyl. selected from the group consisting of However, R3゜ cannot be a vinyl group, or Also, a nitrogen bonded directly to the nitrogen or separated from it by one methylene unit. It is not necessary to cultivate terrorist atoms.

R3!5 and R326 are hydrogen, lower alkyl, aryl, (cycloalkyl) Alkyl, -(alkylene) -NR344C(0)R, (carboxamide) Alkyl, ureido alkyl! 45 (heterocyclic)alkyl, and halo-substituted alkyl (where R344 and R345 are (same as defined above).

R and R, R and R, R and R221, 2012N H601220 k and R, R and R, R and R311, 23112031113J2 He R and k 1 and R and R331 are the respective pairs 3N 01 330 together and independently -(CH2)z- (where 2 is an integer from 2 to 6) may be expressed as the case may be.

For the entirety of the above definitions, the compounds of the invention include (i) more than one sulfur group; When a dryalkyl is present in a compound, the compound can be oxidized to produce a cyclic molecule. or the two sulfhydryl groups are present in the form of a 02-C8 alkyl (ii) the compound has free amino groups and carboxyl chains; If they contain a boxy group, they can be cyclized to form the corresponding lactam The condition is that.

detailed description As discussed above, C5m is a bioactive peptide that plays a role in expanding and exacerbating inflammation. It is the most active of its kind. C5a contains 74 amino acid residues, but 8 Oligopeptides containing few amino acid residues also actively bind to C5a receptors. was found by the present invention. Moreover, the α-carbon of the individual amino acids of the oligopeptide , peptides in which the carboxyl group and the amide nitrogen group are replaced by certain groups Mimetic (pzplido-aim+1is) compounds (i.e., those that inhibit the activity of the peptide) A mimetic compound) was also found to bind actively to the C5a receptor.

The chemical structure of the compounds of this invention is best understood by reference to the following structural formula: be done. In the formula, segments are connected sequentially at free valence bonds to form a compound. It is understood to form the entity A-B-D-E-G-J-L-M-Q-T.

R, R2R1R4RI RI R? %”True n’I11.FTlI’+s1m RH Town 4IJyRHt-'--Peeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeehmmmmmmmms--a-1111111" Sunichi,’-・・zu1san”HFllll’h! Fhs’ya’hs’ h@　RnRlI　Flu　Flss Throughout this specification and the appended claims, the following terms have specific meanings.

The term "alkyl" in this document refers to a monovalent straight or branched chain of 1 to 12 carbon atoms. Refers to groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 'HC -butyl, isobutyl, +111-butyl, and the like, but are not limited to these.

In this document, the term "lower alkyl" refers to a straight or branched chain containing 1 to 8 carbon atoms. Refers to alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, 5ec-but2,2-dimethylbutyl, 2-methylpentyl, 2. Uses herein include, but are not limited to, 2-dimethylpropyl, n-hexyl, etc. The term "alkylene" refers to the removal of two hydrogen atoms from a straight or branched saturated hydrocarbon. Refers to a divalent group of 1 to 12 carbon atoms derived as follows. As an example, -CH2 -1-CH(CH)-1-C(CH3) 2-1-CH(CH)-1CH2CH 2-1 -CH,CH(CH3)-1 -C(CH) C(CH3) 2-1 -CH2C1 (2CH2-, etc. are included).

The term "alkenyl" in this book refers to 2 to 12 carbon atoms containing a carbon-carbon double bond. Refers to straight chain or branched chain groups, such as ethynyl, nopropenyl, 2-propenyl, Including 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. chloromethyl, trifluoromethane, etc. ethyl, 2.2.2-)lichloroethyl, and the like. This book The terms "/\mouth" and "norogen" refer to the elements fluorine, chlorine, bromine or iodine. means a group derived from

The term "cycloalkyl" in this document refers to a cyclic group of 3 to 8 carbon atoms, Includes lopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It is not limited to these.

In this book, the term "(cycloalkyl)alkyl" refers to the cycloalkyl group attached to a lower alkyl group. Indicates a chloroalkyl group, including cyclohexylmethyl and cyclohexylethyl However, it is not limited to these.

The term "alkoxy" in this book refers to the above-mentioned group attached to the rest of the molecule through an oxygen atom. Refers to an alkyl group. Alkoxy groups include, for example, methoxy, ethoxy, and Ropoxy, n-butoxy, 1ee-butoxy, imbutoxy, j! +1-Butoki Including shi etc.

The term "sulfhydryl alkyl" in this book refers to lower alkyl as defined above. Refers to the -5iH group attached to the group.

The term "protected sulfhydryl alkyl" refers to the corresponding S-acetamidomethyl ( S-Acm) or other similar protecting groups as defined above; Refers to drillalkyl groups, including but not limited to S-phenacetamidomethyl. do not have.

The term ``thioalkoxy'' in this book refers to a molecule attached to the rest of the molecule through a sulfur atom. , refers to an alkyl group as defined above. An example of a thioalkoxy group is thiomethoxy. cy, thioethoxy, thioisopropoxy, n-thiobutoxy, $IC-thiobutoxy Including, but not limited to, Not possible.

In this book, the term "(thioalkoxy)alkyl" refers to a group attached to a lower alkyl group. Refers to a thioalkoxy group as defined above.　'Terms in this book “(Thioarylalkoxy "alkyl" refers to the structure R42O-8- (herein, R 4! O refers to a group (which is an arylalkyl group defined later).

The term "aryl" in this document refers to substituted and unsubstituted carbocyclic aromatic groups; Nyl, 1- or 2-naphthyl, fluorenyl, (1,2)-dihydronaphthyl, Contains (1,2,3,4)-tetrahydronaphthyl, indenyl, indanyl, etc. However, it is not limited to these. In this case, the aryl group is halo, nitro, siahaC1 ~CI! independently selected from alkyl, alkoxy, aroyl and alkyl substituted with Cf may be substituted with one, two or three substituents selected.

The term "arylalkyl" in this document refers to the aryl group as defined above attached to an alkyl group. benzyl, 1- and 2-naphthylmethyl, halobenzyl, alco xybenzyl, hydroxybenzyl, aminobenzyl, nitrobenzyl, guani Dinobenzyl, phenylmethyl (benzyl), 1-phenylethyl, 2-phenyl Examples include, but are not limited to, ruethyl, 1-naphthylethyl, and the like.

The term "benzyl" in this document refers specifically to phenyl-substituted methyl; The group is halo, nitro, cyano, alkyl of 1 to 12 carbon atoms, alkoxy, independently selected from aroyl, halo-substituted alkyl, and the like. 1.2 or 3 substitutions may be substituted with groups.

The term "aryloxy" in this book refers to aryloxy, which is linked to the parent molecular skeleton through an oxygen atom. It also refers to the aryl group defined above. Aryloxy includes phenoxy, 1-naph including, but not limited to, toxy, 2-naphthoxy, and the like.

In this book, the term “arylalkoxy J” refers to arylalkyl group as defined above. For arylalkoxy, benzene 2-7enethyloxy, 1-naphthylmethyloxy, etc. It is not limited to these.

In this book, the term "aroyl" refers to refers to an aryl group as defined above. Examples include benzoyl and substituted benzoyl. Ru.

As used herein, the term "alkylamino" refers to a structure in which the alkyl moiety is the same as defined above. -Nl (refers to a group having (alkyl). An alkylamino group includes, for example, methyl These include ruamino, ethylamino, isopropylamino, and the like.

As used herein, the term "dialkylamino" refers to a group in which two alkyl groups are the same or can be winged. , and a group having the structure -N(alkyl)(alkyl) as defined above Point.

As used herein, the term "aminoalkyl" refers to the term "aminoalkyl" attached to a lower alkyl group as defined above. Refers to a group having the structure -NR30R343. Groups R342 and R343 are water independently selected from aryl, lower alkyl, aryl and arylalkyl. Furthermore , R342 and R are - together, optionally -(CH2)-1 (where - is 2 to may be an integer of 6).

In this book, the term "amidoalkyl" refers to a lower alkyl group as defined above. Refers to a group having the structure -NR(0)R,4. Groups R and R345 are hydrogen, lower independently selected from alkyl, aryl, arylalkyl and halo-substituted alkyl It will be done. Furthermore, R344 and R345 may be combined together to -(CH2)kk- (herein, ■ is an integer from ±2 to 6).

The term "(aminothioalkoxy)alkyl" in this document means that kX and R7 are defined above. H2N-Rx-8 is an alkylene group as defined above, and is the same or can occur -R3'-.

The term "carboxyalkyl" in this book refers to the term "carboxyalkyl" attached to a lower alkyl group as defined above. Refers to the carboxy group, -〇〇2H.

The term "(carboxamido)alkyl" in this book refers to the lower alkyl group defined above. Formula attached to -〇　(O) NR340R341 monol and arylalkyl? selected independently. Instead, R340 and R341 together may optionally - (CH2), , - (where pP is an integer from 2 to 6).

The term "(carboxyhydrazino)alkyl" in this book refers to lower alkyl as defined above. Refers to a group having the structure -〇(0)　N　RusNHR attached to the Ru group. group R4 25 and R430 are hydrogen, low ll independently selected from alkyl, aryl and arylalkyl.

In this book, the term "guanidinoalkyl" refers to the lower alkyl group defined above. Structure-NR346C (Snow N R347) refers to the group of NHR. R, R and R348 is hydrogen, low 3.48 346 347 independently selected from alkyl and aryl.

The term "ureidoalkyl" in this book refers to the structure attached to the lower alkyl group defined above. -NHC (0) Refers to a group having NH2.

In this document, the term "heterocyclic" refers to Refers to a 5- or 6-membered ring containing 1 to 3 selected heteroatoms, where the 5-membered ring is O- 2 (grows 1 double bond, the 6-membered ring has 0 to 3 double bonds. Its nitrogen and Sulfur heteroatoms can optionally be oxidized and nitrogen heteroatoms can optionally be quaternized. obtain. In addition, a bicyclic group in which one of the above heterocycles is fused to a benzene ring included. Typical heterocyclic groups include pyrrolyl, pyrrolisdinyl, pyrazolyl, and pyrolyl. Zolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl , pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyrida Dinyl, oxasilyl, oxazolidinyl, isoxasilyl, inoxazoli Dinyl, morpholinyl, indolyl, quinolinyl, thiazolyl, thiazolidinyl , inthiazolyl, isothiazolidinyl, inquinolinyl, benzimidazolyl , benzothiazolyl, benzoxacylyl, furyl, chenyl and pentucheni including but not limited to.

The term "(heterocyclic)alkyl" in this document refers to the above-mentioned group attached to the alkyl group defined above. Refers to a defined heterocyclic group.

The term "hydroxyalkyl" in this book refers to 1OH attached to a lower alkyl group. vinegar.

The term "naturally occurring amino acids" includes alanine, arginine, asparagine, and asparagus. Gic acid, cysteine, glutamine, glutamic acid, glycine, histidine, iso Leucine, leucine, lysine, methionine, phenylalanine, proline, seri valine, threonine, tryptophan, tyrosine and valine. Refers to the amino acid selected.

"N-terminal protecting group" is a group that protects the N-terminus from undesirable reactions during synthetic procedures; or prevent the final compound from being attacked by exopeptidases, or prevent the final compound from being attacked by exopeptidases. refers to a group whose purpose is to increase the solubility of acyl, acetyl, hivaloyl , +++1-butylacetyl, le+t-butyloxycarbonyl (Boc ), carboxybenzyloxycarbonyl (Cbz), benzoyl group or itself contain N-protected or D-aminoacyl residues, but these Not limited.

The term "anaphylatoxin" in this book refers to C5a s C4a.

means C3a or the corresponding de+-Aug degradation product.

The term "pharmaceutically acceptable salts" refers to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and Inorganic acids such as perchloric acid, or acetic acid, sinioic acid, maleic acid, malic acid, tartaric acid , non-toxic formed using organic acids such as citric acid, succinic acid or malonic acid Refers to acid addition salts. Other pharmaceutically acceptable salts include inorganic nitrates, sulfates, vinegar acid salt, malate, formate, lactate, tartrate, succinate, citrate, p- Examples include toluene sulfinate, sodium, lithium, potassium, calcium cations based on alkali metals and alkaline earth metals such as and ammonium, tetramethylammonium, tetraethylammonium, Methylamine, dimethylamine, trimethylamine, triethylamine, ethyl Non-toxic ammonium, quaternary, including but not limited to amines etc. Contains, but is not limited to, ammonium and amine cations.

Examples of pharmaceutically acceptable, non-toxic esters of compounds of the invention include Examples include 01-C6 alkyl esters in which the alkyl group is linear or branched. permission Compatible esters include benzyl as well as 05-C7 cycloalkyl esters. It also includes, but is not limited to, aryl alkyl esters.

Cl"" C4 alkyl ester is preferred. Esters of compounds of formula I are commonly It can be manufactured by the method.

Examples of pharmaceutically acceptable and non-toxic amides of the compounds of the invention include ammonia, A. Primary C to C alkylamines whose alkyl groups are straight or branched and secondary Amides derived from secondary C-C6 dialkylamines are mentioned. Second class ami In the case of obtain. Amides derived from ammonia, 01-C alkyl primary amides and C -02 dialkyl secondary amide is preferred. Amides of compounds of formula I can be prepared in a conventional manner. It can be manufactured more easily.

Many asymmetric centers may exist in the compounds of the present invention. In the present invention, the stereogenic substance is A mixture of that is expected. In particular, the chiral centers are R2' R5' R8' R11 '　R14'　R17'　R20' Can be applied to R23 and R26. Wear. When these groups contain the a-carbon atom of an α-amino acid, the natural configuration is preferable. However, if it contains up to three α-amino acid residues in a non-natural configuration, The compound of the present invention was also found to be effective as a modulator of anaphylatoxin activity. It's clear.

Individual stereoisomers are obtained by selecting amino acids or amino acid analogs exhibiting the desired stereochemistry. and is produced by reacting these starting materials according to the method described below. Ru. Starting compounds of specific stereochemistry are either commercially available or prepared by the methods described below. They are prepared and separated by means well known in the organic chemistry art.

One type of preferred compounds of the present invention is R4, R7, R1o1R13, R16, R 19, R22 and R25 groups are independently selected from >NH and >N-(lower alkyl) It is a compound that is selected. .

In another class of preferred compounds of the invention, R6, R9, R12, R15, Rt g' R21% R24 and [27 groups are independently selected from It will be done.

The group R is preferably >CRR; >NR; >c -CR2I15R206 (z- or E-configuration); and formula R201 is lower alkyl, alkenyl, ali aryl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxyl) ruboxiamido)alkyl, (wl ring)alkyl, (thioalkoxy)alkyl (thioarylalkoxy)alkyl, protected sulfhydrylalkyl and substituted alkyl.

R202 and R2O5 are selected from the group consisting of hydrogen and lower alkyl; RIH is lower alkyl, alkenyl, arylalkyl, (cycloalkyl)a alkyl, amidoalkyl, (carboxamido)alkyl, (heterocyclic)alkyl , (thioalkoxy)alkyl, (thioarylalkoxy)alkyl and protection selected from the group consisting of sulfhydrylalkyl, or one methylene It cannot grow a heteroatom separated from it by a group. R2O3 is lower alkyl ;Aryl;Arylalkyl;(Cycloalkyl)alkyl;Amidoalkyl Lu: (Selected from the group consisting of Kaalkil.

R is preferably selected by >CRR; >NR; >c votes. R210 is arylal Kyl; Aminoalkyl; Guanidinoalkyl; (Heterocyclic)alkyl: (Aminoalkyl) selected from the group consisting of (notioalkoxy)alkyl; R211 and R 215 is selected from hydrogen and lower alkyl, R2H is arylalkyl, amino Noalkyl; guanidinoalkyl, (heterocyclic)alkyl and (aminothioalkyl) (xy)alkyl, with the proviso that R213 is directly bonded to nitrogen. a heteroatom attached to or separated from it by one methylene unit. I don't get it. R216 is selected from arylalkyl and (heterocyclic)alkyl.

R (present in either the Z- or E-configuration); R3 here 35 is selected from hydrogen and lower alkyl. R336 is arylalkyl and selected from (heterocyclic)alkyl; R330 is arylfurkyl, aminoalkyl; R331 is hydrogen or class alkyl.

Method of treatment The compounds of the invention are used to modulate the activity of anaphylatoxins. Main departure Some light compounds function as anaphylatoxin antagonists, while others Functions as an agent.

Antagonist compounds of the invention block anaphylatoxin receptors and inhibit anaphylatoxin. anaphylatoxins, thereby preventing these compounds from inhibiting anaphylatoxin activity. be useful in the treatment and prevention of disordered conditions or diseases. Involves anaphylatoxin Disease conditions include asthma, bronchial allergies, chronic inflammation, systemic lupus erythematosus, Vasculitis, serum sickness, angioedema, linymatoid arthritis, osteoarthritis, gout, varicella skin disease, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, postimmune syndrome Combined mediated gastritis, psoriasis, allergic rhinitis, adult respiratory distress syndrome, acute lung disorders, endotoxin depletion, liver cirrhosis, pancreatitis, inflammatory bowel disease (Crohn's disease and ulcerative enterocolitis), burns, Gram-negative sepsis, myocardial infarction, leukophoresis (1 koph o + @), medical equipment (including but limited to hemodialysis membranes and extracorporeal blood circulation devices) (not determined), chronic hepatitis, graft rejection, viral infection of the brain. injury and/or ischemia-induced myocardial or brain damage. these The compound may also be used as a prophylactic against medical conditions such as dengue fever-associated symptoms. Ru. Additionally, antibiotic drugs and corticosteroids (e.g. methylprednisolone) anti-inflammatory drugs such as ron) as well as combinations of one or more of the aforementioned compounds may be used. .

Certain compounds of the invention may mimic or enhance anaphylatoxin activity. It is a useful therapeutic agent because it is capable of The body uses this defense against invasion by microorganisms or other insults due to the animal's inflammatory response and immunity. Can be used to assist in building dishes. at anaphylatoxin receptors The involvement of these agonists may lead to cancer (including but not limited to lung cancer), immune Symptoms or diseases, including but not limited to debilitating diseases and severe infections, can be effectively treated. be treated.

In some cases this may involve controlling the underlying cause of the disease condition, and in others In cases where the underlying disease is not affected, the compounds of the invention improve symptoms and or may have the benefit of preventing the development of a disease.

The compounds of this invention can be carried out using any desired conventional non-toxic pharmaceutically acceptable carriers, adjuvants (gd. iuvxfi+) as a dosage unit preparation for oral, parenteral, inhalation spray, and direct use. It may be administered enterally or topically.

In this document, the term "parenteral" refers to subcutaneous, intravenous, intramuscular, intrasternal, intraarterial injection or Including, but not limited to, injection. The term "topical" refers to rectal and inhalation sprays. as well as administration by the more traditional routes of the skin and mucous membranes of the mouth and nose.

The actual dosage levels of active ingredients in the pharmaceutical compositions of the invention will vary depending on the individual patient, composition and The mode of administration may be varied to achieve the desired therapeutic response. Selected pitch Drug levels depend on the individual compound, the route of administration, the severity of the condition being treated, and the This will vary depending on the patient's condition and previous medical history. However, as the state of the art the lowest level of the compound needed to achieve the desired therapeutic effect. Starting at a dose of 1, the dosage is gradually increased until the desired effect is achieved.

Generally, it is about 0.0% per body weight per day. ON■ ~ about 100■, more typically about 0 ．． Dosage levels of 1 to about 20 μ of active compound are administered to mammalian hosts daily.

If desired, an effective single dose may be administered in multiple doses, e.g. 2 to 4 times per day. It can be divided into several parts.

Formulation of medical compositions The pharmaceutical compositions of the present invention for parenteral injection can be prepared in pharmaceutically acceptable sterile aqueous or non-aqueous formulations. Sterile injectable solutions immediately before use, including liquid solutions, dispersions, suspensions, or emulsions. or consisting of a sterile powder for reconstitution into a dispersion. Suitable aqueous and non-aqueous carriers Examples of diluents, solvents or excipients include water, ethanol, polyols (e.g. glycerol, propylene glycol, polyethylene glycol, etc.) and these suitable mixtures of, vegetable oils (e.g. olive oil), as well as ethyl oleate. Injectable organic esters. For example, coati like lecithin The use of a It is possible to maintain appropriate fluidity.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. I can see it. Prevention of the action of microorganisms can be achieved by using various antibacterial and antifungal agents, such as parabens. This can be achieved by containing , chlorobutanol, phenol, sorbic acid, etc. sugar, It may also be desirable to include isotonic agents such as sodium chloride and the like. injectable pharmaceutical form Prolonging absorption can be achieved by using absorbent substances such as aluminum monostearate and gelatin. may be brought about by the inclusion of drugs that delay the

sustained or targeted release such as limer matrices, liposomes and microspheres It can be prepared in the following manner:

The injectable preparation is made using a bacteria-retaining filter (b1cte+1xl-+eHiniB1 It! er) or by formulating the sterilizing agent into a sterile solid composition; It can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. It can be sterilized in this way.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. . Such solid dosage forms contain the active compound in sodium citrate or diphosphate. at least one inert pharmaceutically acceptable excipient such as calcium or carrier and/or 1) starch, lactose, sucrose, glucose, mannitol and silicic acid; b) fillers or extenders such as carboxymethyl cellulose, such as ruginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic binders, humectants such as cl-glycerin, d) agar, calcium carbonate, barley Tsudenbun or tapioca starch, alginic acid, certain silicates and sodium carbonate Disintegrants such as thorium, dissolution retarders such as paraffin, f) quaternary ammonium M) absorption enhancers such as sodium compounds, e.g. cetyl alcohol and monosodium compounds; humectants such as glyceryl tearate; h) wetting agents such as kaolin and bentonite clay; Absorbent, and i) Talc, Stearin-san Calcium, Stearin-san Magne solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. Mix with a lubricant such as a compound. In the case of capsules, tablets and emulsions, the mesh Buffers may also be included.

Similar forms of solid compositions include high molecular weight polyethylene as well as lactose or milk sugar. soft-filled and hard-filled gelatin sepsels using excipients such as Recall, etc. It can also be used as a filler.

Solid mesh tablets, dragees, capsules, emulsions and granules are commonly used in pharmaceutical formulation technology. With skins and skins such as known enteric coatings and other coatings It can be manufactured as follows. These may optionally contain opacifying agents. They are It is also preferable to administer the active ingredient only or preferentially to a certain part of the intestinal tract, as the case may be. It is also possible to create compositions with delayed release. Available embeddings (<sbed Examples of ding) compositions include polymeric substances and waxes.

The active compounds can be microencapsulated, if appropriate with one or more of the excipients mentioned above. It can also be converted into

Liquid forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and Includes drops and elixirs.

In addition to the active compound, in liquid network form, it is possible to combine Diluents, solubilizers and emulsifiers commonly used in the art, such as ethyl alcohol, Isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, rest Benzyl fragrant, propylene glycol, ester, 3-butylene glycol, dimethyl Formamide, oil (bean oil, cottonseed oil, peanut oil, corn oil, germ oil) tmaro + I), olive oil, castor oil, and sesame oil), glycerin, tetrahedron Drofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters stel, as well as mixtures thereof.

Besides inert diluents, oral compositions can also include wetting agents, emulsifying agents, and suspending agents. Adjuvants, sweetening agents, flavoring agents, and flavoring agents may also be included.

Suspensions contain, in addition to the active compound, e.g. ethoxylated instearyl alcohol. polyoxyethylene sorbitol and sorbitan esters, microcrystalline cells loin, aluminum metahydroxide, bentonite, agar, and gum tragacanth Suspending agents such as as well as mixtures thereof may be included.

For compositions for rectal or vaginal administration, suppositories are preferred, which contain compounds of the invention. with a suitable non-irritating excipient or carrier, such as cocoa powder, polyethylene glycol Alternatively, it can be prepared by mixing with suppository wax. These are solid at room temperature However, it is a liquid at body temperature and therefore melts in the rectum or vaginal cavity, releasing the active compound. put out

Forms for topical administration of the compounds of this invention include powders, sprays, ointments and inhalants. Examples include agents. The active compound is added under sterile conditions to a pharmaceutically acceptable carrier and as required. Mix with preservatives, buffers, or propellants if necessary. Ophthalmic preparations, ophthalmic ointments , ophthalmic powders and ophthalmic solutions are also considered within the scope of this invention.

Anaphylatoxin receptor binding Ki determination C5a binding activity of representative compounds of the present invention For details on the inhibition of purified PMNL membrane fragments at 2.5-25 ug/d. It was measured using 0.03-1 nM 125I-C5a (N.

Rorr*g*trd; 1. M, He1plt; E, R, Simons ; and R, A, C1erk.

J, Ce11. Biol, 19g3.97.52-61), free ligand and membrane-bound ligands were separated by filtration. Binding strength of representative examples of compounds of the present invention are shown in Table 1.

Table 1 In vitro C5a receptor binding ability of the compound of the present invention Ki uM Example K i uM2 0.09g 249 0.11 NO, H2794,0 232,42820,0N 31 0.0G 295 3.3 91 0.486 296 0. H2 1060,1423050,17 I11 165 316 11.17 117 0.55 338 0.5 131 0.17 3411 0.14150 0.11 377 1.8 (Continued from Table 1) 165 0.042 4G2 0.0111N O, 34G4. O, 13 1880,214093,8 2G2 0.87 421 3.2 2+3 0.33 424 0.48 220 0.22 432 0.03 229 0.033 445 G, 26245 G, 052 455 0.01 ? 247 0.33 460 0.021 Synthesis of compound The novel compounds of the present invention and their salts can be effectively used as therapeutic agents.

Therefore, the present invention further provides a novel compound having general formula 1 or a salt thereof as an active ingredient. Therapeutic compositions comprising:

The compound of the present invention is a synthetic method for elongating a peptide chain by condensation of one amino acid at a time. or a combination of these methods by synthetic methods from two or several amino acids It can be manufactured by

Condensation of two amino acids, condensation of an amino acid and a peptide, or condensation of one peptide and another Condensation of one peptide can be carried out using conventional condensation methods, e.g. azide method, mixed acid anhydride method. method, symmetrical anhydride method, DCC (dicyclohexylcarbodiimide) method, activated Es ter method (p-nitrophenyl ester method, N-hydroxysuccinimide ester method) method, cyanomethyl ester method, etc.), Woodward reagent method, DCC-HOBT (1-hydroxy-benzotriazole) method, etc. These contractions The synthesis reaction can be carried out by either a solution method or a solid phase synthesis method. Peptide chains are prepared using solid phase method. If extended, the C-terminal amino acid is followed by an insoluble carrier. As an insoluble carrier In this case, a bond that can be released by reacting with the carboxyl group of the C-terminal amino acid is Anything that can occur can be used, examples include Halomethyl resins, hydroxyl resins such as lolomethyl resins, bromomethyl resins, etc. C-methyl resin, benzhydrylamine resin, and t-alkyl oxycal Bonyl hydrazide resin is mentioned.

Conventional polypeptide synthesis involves the addition of branched chain amino acids in the α and ω positions of amino acids. Groups and carboxyl groups may be protected/deprotected if necessary. For amino groups that can be used Protecting groups include, for example, benzyloxycarbonyl (Z), o-chlorobenzyl xycarbonyl ((2-CI)Z), p-nitrobenzyloxycarbonyl ( Z (No2H1p-methoxybenzyloxycarbonyl (Z (OMe)), t-Butoxycarbonyl (Boc), t-amyloxycarbonyl (AOC)% Isobornyloxycarbonyl, adamantyloxycarbonyl, 2-(4-bicarbonyl) phenyl)-2-propyloxycarbonyl (Bpoc), 9-fluorenyl -methoxycarbonyl (Fmoc), methylsulfonylethoxycarbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenyl Sulfenyl (Nps), diphenylphosphinothioyl (Ppt) and dimethylene Ruphosphinothioyl (Mpt) is mentioned.

Examples of carboxyl group protecting groups include benzyl ester (OBn), Cyclohexyl ester, 4-nitrobenzyl ester (OBnNO2) , t-butyl ester (OtBu), 4-picolyl ester (PPic), etc. included.

In the case of synthesis of the novel compounds of the present invention, such as arginine, cysteine, serine, etc. Certain amino acids that develop functional groups other than amino and carboxy groups in their branched chains are If necessary, protection can be achieved using a suitable protecting group. For example, guani in arginine Dino group (NG) is nitro, p-toluenesulfonyl (Tos), benzyloxy Carbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxy Benzenesulfonyl, 4-methoxy-2,6-dimethoxybenzenesulfonyl ( Md　s), 1゜3.5-trimethylphenylsulfonyl (Mts), etc. can be protected. Thiol groups in cysteine are benzyl, p-methoxybenzyl, Triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylben Using Zyl (4-MeBn), 2゜4.6-drimethylbenzyl (Tmb), etc. can be protected.

The hydroxyl groups in serine are benzyl (Bn), t-butyl, acetyl, and tetra It can be protected using hydropyranyl and the like.

N-acetylated peptide was produced in the same manner as in Example 99.

N-alkyl- or N,N-dialkyl-amino acid derivatization using the following literature procedure: manufactured the body.

], A, Lovelt, P, Po+togbs+s, 1.11+d, Chew, +987. Yuhong 1144-1I49. R, F, Bosch, A.1. Hr+sid, 1. Org, Chew.

91985, 50. 945-950. P, A, Grieco, A, Bs5 h*s.

J, Or, Ch! M, LH? , 52. 5741i ~ 5749. R,T , Sbam*n, E, L.

5iilkvick, D, L, 5siley, G, S, Brook T, P, D, Gti! 1lcbe+.

“Peptides: Structure and Function”, Proceedings of the 8th American Peptide Conference.

■984; Pages 143-146, S, T, C15tB, N, L, 1len oHoa.

Cue, J, Chew, 19f 7.55. 906-91G, these reactions is carried out on extended peptide-resin or on amino acid derivatives and then peptide - Mixed with resin.

Using the following literature procedure, (2'S,3S)-3-amino-2-oxo-1- Pyrrolidine-(2'-(4'-methyl))pentanoic acid, (2'R,3S)- 3-Amino-2-oxo-1-pyrrolidine-(2'-(4'-methyl))beta acid and (2'R/S,3S)-3-amino-2-oxo-1-azepine-21 - produced pentanoic acid. RM, Fre+d+Bs+, DS.

Pcrlot, D, F, Veber, ), Ore, Chtm, 19 $1', 47.1114-1119゜(2R,S)-2-amino-5-phene There is the following description in the production of nilpentanoic acid: lP, 1rzs++5leia M, tieH3r Amino Acid Chemistry J Iahn Wils7 s++d Soa + Publishing, New York, 1961, Volume II, 2387 pages. Perhydroy Endolecarboxylic acid was synthesized by the following procedure. M, Viac! +l, G , Lmoid, B, Forjevin, B, 5srkH, M, L*ab i! , Trfr8h*dron Lsth, 19B2. 23.　1677〜16 82° (25)-2-amino-4-cyclohexylbutanoic acid = (2S)-2-amino- 4-phenylbutanoic acid (5g) was added to 10% HOA c-H20 (50ml). A solution was prepared and hydrogenated using platinum oxide (1 g) at 5 atm at room temperature. filter Removal of the catalyst by filtration and evaporation gave 4.9 g of product. 3- (2’ -perhydronaphthyl)alanine and 3-(1'-perhydronaphthyl)alani Similarly, L-3-(2'-naphthyl)alanine and L-3-( 1'-naphthyl) alanine.

N-guanidino substituted arginine derivatives were prepared using the following literature procedure: L , J, M*lhi*s, 5yajhtsis 1NG, 51i1~57 g.

CA, M*B*nof+, R, CHsmt+oa*, IM Pl*mp im J, E.

Mills, J. Or, Chit 1986.51. 1882-188 4.　L　I.

N5slor, T.L., Ho, R.A., Simpson, B.L., [Ioras r, G, H.

Jones, G., 1. McRss, B, 11. ViCk! r7.1. Msd, Chew, 19H+25, 795-801. The obtained arginine The conductors were bonded to Mer++I+eld resin as described in the following references: ], 11.5lev*r+, J, D.

Yeah, "Solid Phase Peptide Synthesis" 2nd edition; Pierce Chemics 1 Publisher, Roekford, Illinois, 1984, pages 71-72. Obtained The peptides were constructed using the synthesized aminoshun resin, and then cleaved and purified to achieve the desired results. The desired peptide analog was obtained.

The following fragments were prepared as described in the literature.

References 1, M, FiBtl, J, At CheIl, Soc, 1986.1 08.181゜2, D, S, Ksmp, P, E, McN*m*r* , l, O? g, Chew, 19B5゜50, 5834゜ 3, P, C, Be1xB*r, C, Du+r! sne, J, Scbei gClr, R,N.

hH, J, P, Sp100Be+lG, 1. l1mH+1rako, Csn, J, Chtm.

1982, 60.1019° 4,], L, K+5lea*■kY, R, L, B*r*aovdki, B, L, C++rrie.

8iachem, Biopb7s, Bs3 Comraaa, 19N, 1 119.1368゜5, M, R, A eyes vood, R, J, F + * acis, C ,H,H*5stll,A.

Krohn, G, L*v+on, 1. L, Ns+o+! , J, S , N1xoe, S, Rsdsb*v.

W, A, ↑hom*+, FEBS Lef+, 19g4.165.201゜ 6, (sl U, 1lIBi, K, 5slo, Tslrxhed+oI ILed, 1985°647, (b) 1. BxldviIl, E, L! e, Teth 1hedroo L*th, 1986. 42゜6551゜ The compound of the present invention was prepared as follows:] 1M, 5lev*r+ and 1. D, You++1 Phased Peptide Synthesis, 2nd Edition, (104), and Example 1 and Example 1 in the experimental section thereof. and 2 by standard solid phase peptide synthesis methods.

The compounds of the present invention can be synthesized using partial solid-phase synthesis, fragment condensation, and "peptide synthesis." 2nd edition, M, Bod■s+7. 'I, S, Kltasnsr and M, A , 0nds Kui II (1976). It can also be manufactured by

Standard chirality symbols “R” and “S” are used to indicate isomerically pure centers; rRl indicates a mixture; rR/SJ indicates a single, pure substance of unconfirmed configuration. Indicates isomer. The symbol "±" refers to the dI mixture of amino acids of the designated residue . The symbol W (Xl) is an alternative to the standard peptide bond -C(0)NH- Indicates the group X.

When the symbol “ne” or “this book” is included in a chemical name, it indicates a disulfide or an atom, respectively. The position of the mid linkage is shown.

The foregoing may be better understood by reference to the following examples, which are given by way of illustration only. This is not intended to limit the implementation of the present invention. unless instructed otherwise , using the standard peptide method described above and in Examples 1 and 2, Different products were synthesized using the precursors indicated by the sequences. less product NMR and mass spectra both 95% pure and consistent with the proposed structure. showed that.

Example I H-phenylalanyl-lysyl (N-ε-Cbly-7ranyl ((23)-2- Amino-3-cyclohexylpropanoyl)-((23)-2-amino-3-cyclo chlorhexylpro/<noyl)-isoyl-D-alanyl-arginyl (N-g Anidino-Tom)-Merrifield Resin BOC-AH (N-guanidino-cho+)-Merrifield resin (0,4-1 ．． 0g) into a solid-phase peptide synthesizer and sequentially bind amino acids to the resin in the following order: did: i.e.: Boc-D-alanine, Boc-oisine, RoC-(2S) -2-amino-3-cyclohexylpropanoic acid, Boe-(2S)-2-a Mino-3-cyclohexylpropanoic acid, Boc-alanine, (N-α-Boc, N-ε-Cb lysine, Boc-phenylalanine, and the bond is according to method A. Following the abbreviated experimental guidelines, the following resin, which is a protected peptide resin, is produced. :H-phenylalanyl-lysyl(N-ε-Cbt)-alanyl-((2S)- 2-amino-3-cyclohexylpropanoyl)-[(29)-2-amino- 3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl (N -guanidino-Tom)-Merrifield resin. Following synthesis, the protected peptide Take out the resin from the reactor and put it into a sintered glass funnel of 30-6G theory 1. Wash the resin three times using 20 ml of F, followed by 20 ml of methylene chloride. The resin was washed three times. The resin was weighed after at least 5 hours.

1111A 1. Deprotection: Trifluoroacetic acid (T FA) 45% solution (V/V/V).

2. Neutralized diisopropylethylamine (DrEA) 10% methylene chloride solution (v/v).

3. Single coupling: 0.2-0.4M Boe-amino acid derivative N,N- Dimethylformamide (DMF) solution, 0.2-0.4M diisopropylcal Bodiimide (DEC) in methylene chloride solution, reaction time 60 minutes.

4. Resin base material cleaning; lO% DTEA methylene chloride solution (V/V).

5. Same as step 3 for single coupling repetition.

6. Proceed to next amino acid residue (return to step 1).

7. After bonding the final amino acid to the elongating peptide chain, a protecting group (t-Boc ) according to step 1.

Example 2 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc ((2S)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-alanyl-D-alanyl-arginyl-OH The protected peptide resin (0.6 g) of Example 1 was added to 1.0 ml of anisole and fluoride. It was treated with hydrogen hydride (HF) lhl at 0° C. for 60 minutes.

The HF and anisole were removed under vacuum at 0°C and the peptide and resin mixture was diluted with diethyl chloride. ether (2 times, 25 ml).

The crude peptide was treated with aliquots of 20% aqueous acetic acid (4 times, 251). extracted from the mixture by lyophilization to a dry amorphous powder, and ROMATOGRAPHY () I P L C’) (Column: 21.4 mm I D x 25%m or 41.4mm ID x 25cm.

DHn1a+1xfRtinin), 8■silica, C18 reverse phase column) Purified. Samples were subjected to gradient elution (20-60% (with addition of 0.1% trifluoroacetic acid) Purification was carried out using acetonitrile (80% aqueous solution)) at a flow rate of 15-45 ml/min.

FAB MS: (M+H) +=1011 Amino acid analysis value: Phe (0 ,911,Ly+(1,[1,AI+(2,06),Cbt(1,96 ), Leu (0,91), Att (1,04) Example 3 Ac-Histidyl-Lysyl-Asparaginyl-Methionyl-Glutaminleuroy Cyl-glycyl-arginyl-0HFAB MS: (M+H)“-1025a Mino acid analysis value: Ast (11, H), ell! 1.07), Gly (o, 9)), Met (0,96), Lei (1,05), His (0,97) .

Lr, s (0,981, Art (1,114) Example 4 Ac-Histidyl-lysyl-aspartyl-methionyl-phenylalanyl-ro isyl-glycyl-arginyl-OH+ FARMS: (M+H)+cap 1145 Example 5 (N-methyl)phenylalanyl-lysyl=(N-methyl)alanyl-(flag Mento-1)-isoyl-(N-methyl)D-alanyl-arginyl-OH Example 6 Ac-Histidyl-lysyl-aspartyl-((2S)-2-aminohexanoyl ) -((25)-2-aminohexanoyl)-((23)-2-aminohexanoyl Sanoyl)-glycyl-arginyl-0H FAB MS: (M+H) -993 Amino acid analysis value: Al1 (0,96) , Glr (0,98), His (0,84), LFS (1,01 ), Art (1,051, mouth t (3,0V1 Example 7 H-Histidyl-lysine-aspartyl-methionyl-((2'S, 38)- 3-amino-2-oxo-1-pyrrolidine-(2'(4'-methyl))-pe (antanoyl)-glycyl-arginyl-OH FAB Ms: (M+H) 939 Example 8 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-((2s)-2-amino-3-cyclohexylpropanoyl) Panoil)-Kouchisil-3-7 Minotsuku Panoil-Arginyl-0HFAB M S: (M+H) -1087 Amino acid analysis value: Al1 [1, ell, L ee (0, H), Ckg (1,98), His (0, H), Lts (1,・1), Atg (1,03j Example 9 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-glycyl (fragment -2)-Arginyl-OH Example 10 Ac-Histidyl-lysyl-aspartyl-methionyl-threonyl-leucyl -Glycyl-Arginyl-〇HFAB MS: (M+H) Lord 999 Ami Noic acid analysis values: Asx (0,96), Thr (0,781, Gly (1,0 2), Mu (0,84), Lts (1, O5), [Ii+ (0,9 T1.

Lys (11, Hl, ^rl (1,031 Example 11 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc ((23)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-isoleucyl-D alanyl-arginyl-OH FAB MS: (M+H) = 1087 Example work 2 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cy (23) -2-amino-3-cyclohexy (propanoyl)-isoyl-D-methionyl-arginyl-0H FAB+MS: (M+H)” -+147 Amino Shun analysis value: H mouth (1,1 0), Lts (0,94), Asp (0,96), Ckg [+, 841. Lee (1,011, Met (1P, Hl.

Art(1,031 Implementation N15 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc ((23)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-leucilupivecolyl(±)-arginyl-OH + FAB MS: (M+H)” -1127 Amino acid analysis value: 1lis( 1,19), Lrs (1,04), Asp (1,09), Ckg (1,71), Lts (1,041, Art (0, X2) Example 14 (N-methyl)-phenylalanyl-lysyl-(N-methyl)alanyl-(furanyl) gment-3)-isoyl-(N-methyl)D-alanyl-arginyl-OH Example 15 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-4-cyc (2S)-2-amino-4-cyclohexylbutanoyl) -((2S)-2-amino-4-cyclohexylbutanoyl) (noyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) =ll15 Example 1G H-6-7minohexanoyl-asbarthyl-((28)-2-amino-3-silyl) chlorohexylpropanoyl)-((2S)-2-amino-3-cyclohexylp lopanoyl)-alanyl-D-alanyl-arginyl-OH FAB MS: (M+H) -H3 example 17 Ac-Histidyl-lysyl-alanyl-((2S)-2-amino-3-cycloto xylpropanoyl) -((2S)-2-amino-3-cyclohexylpropanoyl (noyl)-isoyl-D alanyl-arginyl-0H FA, B MS: (M+H) -1043 Example 18 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-(fragment-4)- (N-methyl)D-alanyl-arginyl-OH Example 19 Ac-Histidyl-lysyl-aspartyl-cysteinyl-cysteinyl (Ac ml-isoyl-D-alanyl-arginyl-OH FAB” MS: (M+H)” lB9 Example 20 Ac-histidyl-lysyl-aspartyl-D tryptopyl-((23)-2 -amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arg Nil-OHFAB” MS: (M+H)” 11211 Example 21 Ac-Histidyl-lysyl-aspartyl-methionyl-histidyl-leucyl -D Alanyl-Arginyl-OHFAB MS: (M+H) +-1049 + Example 22 Ac-Histidyl-lysyl-aspartyl-((28)-2-amino-3-cyc lohexylpropanoyl)-D)ributofyl-leucil-Dalanyl-argyl Nyl-OHFAB” MS: (M+H) +==1120 Example 23 Ac-Histidyl-lysyl-aspartyl-(C25)-2-amino-3-cy (chlorohexylpropanoyl)-histidyl-leucyl-D-alanyl-arginyl -0) (FAB MS: (M+H) + Tomi 1071 Example 24 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-(fragment-5)- (N-methyl)D alanyl-arginyl-OH Example 25 * Ac-Histidyl-lysyl-aspartyl-cysteinylcysteinyl"- Icyl-D alanyl-arginyl-OHFAB MS: (M+H) 98 5 Example 26 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc lohexylpropanoyl) - ((2S) -2-amino-3-cyclohexy (propanoyl)-valyl-D alanyl-arginyl-OH FAB+MS: (M=H) +-1073 Amino acid analysis value・8 mouths (1. 17), L! l (1. Off), Alp (0.93), Chx (1. 71), Vtl (1, 001. Ahl (G. 9G).

Arg (0.97) Example 27 Ac-Histidyl-lysyl-7spartyl((29)-2-amino-3-cyc ((2S)-2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl) (ropanoyl)-isoyl-Dseryl-arginyl-OH FAB MS: (M+H)” -1103 Amino acid analysis value: Old 2+ (1.06), Lrs f+. 191, ^19 (0. 831, Ch x (1, 931, Le++ (1, 04), Ser i0. Sol.

Arg (D.91) Example 28 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((23 )-2-amino-3-cyclohexylpropanoyl)-(fragment-6)- (N-methyl)D alanyl-arginyl-OH Example 29 Ac-Histidyl-lysyl-aspartyl-((23)-2-amino-3-cyc lohexylpropanoyl)-((2S)-2-amino-3-cyclohexyl (propanoyl)-isoyl-D-arginyl-alkynyl-OH FAB MS: (M+H) +1172 Amino acid analysis value: Ir1s+ (1,・9), Lu (tl, 97), ^sp (0,93), Ck* (1, 74), L@a (0,951, Arg (1,961 Example 3G Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-((2'S,3S)-3-amino-2-oxo- 1-pyrrolidine-(2'-(4'-methyl))pentanoyl)-Dalanyl-a Luginil 0H FAB MS: (M-1-H) + proverb 1/1 example 31 Ac-(4-No2)phenylalanyl-lysyl-aspartyl-((2S)- 2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino- 3-cyclohexylpropanoyl)-isoyl-D alanyl-arginyl-OH + FAB MS: (M+H) +=1142 Actual 12 H-phenylalanyl-((2S)-2-amino-6-dolifluoroacetamide dohexanoyl)-alanyl-((25)-2-amino-3-cyclohexylp lopanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl)- leucyl-D alanyl-arginyl-OH Example 33 Ac-Histidyl-lysyl-glutaminyl ((28)-2-amino-3-cyc ((2S)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) 1100 Example 34 Ac-Histidyl-lysyl-cysteinyl(^ζ■)-((28)-2-amino -3-cyclohexylpropanoyl)-((28) to-2-amino-3-cyclo xylpropanoyl)-leucyl-Dcysteinyl(AC■)-arginyl-0 HFAB MS: (M+H) 109 Example 35 H-phenylalanyl-((2S)-2-amino-6-formamidehexanoyl )-alanyl-((2S)-2-amino-3-cyclohexylpropanoyl) -((28)-2-amino-3-cyclohexylpropanoyl)-leucyl- D-alanyl-arginyl-OH -2-amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-a Luginyl-0H FAB” MS: (M+H)”-1005 Example 3 Ac-Histidyl-(N-δ-1Pr) ornithylu-asparaginyl-((2 S)-2-amino-3-cyclohexylpropanoyl)-((23)-2-a mino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl -0HFAB MS: (M+)I)” = 1114 Amino acid analysis value: A 11 (1,001, Lc* (1,01), H mouth f1.11), Ch heat [1, 79), Arg(t, 1ll) Example 3B Ac-Histidyl-lysyl-asparaginyl-((2S)-2-amino-3-cy chlorohexylpropanoyl)-((2S)-2-amino-3-cyclohexylp lopanoyl)-isoyl-D-alanyl-arginyl-NHNH2 N-acetyl-histidyl-lysyl (N-ε-Cbtl-7 sparaginyl (( 2S)-2-aminol 3-cyclohexylpropanoyl)-((28)-2- Amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arg Nyl(N-guanidino-TO8)-0 resin (0.62g) was mixed with 10ml of N, Suspended in N-dimethylformamide (DMF) and added 11 anhydrous hydrazine. Ta. The mixture was stirred at room temperature for 4 hours and filtered. Add resin DM F 10 Wash with 11 ml of DMF solution and pour into 100 ml of diethyl ether. did. When the mixture cooled, it gradually solidified. Collect solids by filtration, 501 of water and dried. The dry solid obtained (approximately 160 cm1) was obtained from Example 2. with HF and anisole as described in . After freeze-drying, the obtained 153it of crude peptide was purified by HPLC (Example 2) to give 35.6mg The pure peptide was obtained. The NMR and mass spectra of this product indicate the desired production. matched the object.

FAB MS: (M+H)”=1099 Example 39 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc ((2S)-2-amino-3-cyclohexylpropanoyl) lopanoyl) -((23)-2-aminopentanoyl)-D alanyl-arg Nil-oH+ FAB MS: (M+H) Tomi 1189 Amino acid analysis value: AfI (1, H), Hat fl N), Cbs (1, H), LFJ [0,98) , Art fl, 0+) Example 40 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((29 )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl) D alanyl-arginyl-glycyl-glycyl-OH Example 41 Ac-Histidyl-lysyl-asparaginyl-((2S)-2-amino-3-cy chlorohexylpropanoyl)-((2S)-2-amino-3-cyclohexylp lopanoyl)-isoyl-D-alanyl-arginyl-oCH3 + FAB MS: (M+H) = IIN Amino acid analysis value: Human 11 (0,91 ), ^Is (0,9G), Lea fO,961,His (1,0g), Chx (1,651, LF$ (Q, 97j.

Arg(0,95) Example 42 Ac-Histidyl-lysyl-aspartyl-((2R)-2-amino-3-cyc (2R)-2-amino-3-cyclohexylpropanoyl) -[(2R)-2-amino-3-cyclohexylp lopanoyl)-leucyl-D alanyl-arginyl-〇CH.

FAB MS: (M+H)”-1087 Amino acid analysis value: AII (0 , 99), AIl (D, 95), Leg (1, 02), old 1 fl, 0 fl ), Cbs (1,80), Lts (1,03).

Arg(1,02) Example 43 Ac-alanyl-arginyl-asparagyl, nyl-((2S)-2-amino-3 -cyclohexylpropanoyl)-((25)-2-amino-3-cyclohexy (propanoyl)-isoyl-〇alanyl-arginyl-0H FAB" MS = (M+H) -1848 amino acid analysis value; AII (1, O f), AII (1,94), Lt++ (1,02), Chs (1,8 g1. Arg (2,08) Example 44 Ac-lysyl-lysyl-asparaginyl-((2S)-2-amino-3-cyclo hexylpropanoyl) -((2S)-2-amino-3-cyclohexylpropanoyl) panoyl)-isoyl-D alanyl-arginyl-0H FAB” MS: (M+H) So 1077 Amino acid analysis value = AI (0,9 8), AIl (0,93), Leg (1,011, CI+* (1, H l, Lrs (2,011, Art (1, Of■ Example 45 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)D alanyl-((4R)-(4-ethyl)agmatine)N-α-H oe-N-guanidinosyl-arginine is converted to its aldehyde and modified. Literature method (1, R, La1r, 1.F.

Dells+mouth, 1. ], PltHne+, ], L, 5odtrquis+, N , Yi;1. Org, Cbst19117, 52.1487) and convert it to reaction with methylenetriphenylphosphorane followed by hydrogenation over Pd/C, (4R)-N-α-Boc-N-guanidinothyl-(4-ethyl)a.

Got Gumatin. The protected peptide N-Boc-(N-methyl)phenyla Nyl-N-ε-Cbx-lysyl-(N-methyl)alanyl-((23)-2-a mino-3-cyclohexylpropanoyl)-glycyl-loinru(N-methyl ) D-alanine was synthesized by the method of Example 309. The above agmatine derivative 4N-NCI/dioxane and the resulting salt was treated with DCC/HOBT-mediated Coupling method was used to couple to the protected peptide. Protecting group Example 2 It was removed by treatment with liquid HF/anisole according to the method described in .

Example 46 H-lysyl-phenylalanyl-aspartyl-((2s)-2-amino-3- cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexyl propanoyl)-leucyl-D alanyl-arginyl-0H FAB MS: (M+H)”=1055+ Example 47 H-phenylalanyl-lysyl-4-aminobutanoyl-((25)-2-amino (-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl- 0HFAB" MS: (M+t()" -872 Amino acid analysis value: Pb @(0,99), LFI (1,Of), Gtb heat (0,97), Cht (0,941, Llm[1,06), Ale (1,00+, AII (1,0 01 Example 48 ) T-D Phenylalanyl-Rysine-D Aspartyl-D Methionyl-D Glue Taminyl D leucyl-arginyl-D arginyl-0H FAB MS: (M+H)”=1093 Amino acid analysis value: A+p+ fe, H), GIX fl, 05), 1lel (0,611,Llm (1,031,Phe (0,97),i” (0,941K ^H(2,04> Example 49 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl) D-alanyl-(NH(α)phenethyl (R/S)) Protected peptide N-Boc-(N-methyl)phenylalanyl-N-ξ-1 1oc-lysyl-(N-methyl)alanyl-((28)-2-amino-3-cyc lohexylpropanoyl)-glycyl-leucyl-(N-methyl)D-alanine It was manufactured by the method described below. The peptide chain was extended by the same method as described in Example 1. However, the coupling of N-a-Fmoc-N-8-60C-lysine After that, the chain was interrupted at Step 5 of Procedure A. Obtained N-α-F*ot-N-ε- B.C-lysyl-peptide resin was incubated with DMF:piperidine (1:1). Treated at room temperature for 30 minutes. Wash the peptide resin using DMF and methylene chloride. , the following synthetic guideline (Example 1. Procedure A Step 3) was started, but the N-terminal protecting group The exception is that it is not removed at the end of the synthesis. The fully protected peptide is shown in Example 3. Obtained by the procedure of 09.

Coupling the protected peptide with α-phenethylamine using DCC/HOBT did. The protecting groups were removed by treatment with 4N-HCI/dioxane. , the desired compound was obtained.

Example 50 H-phenylalanyl-lysyl-prolyl-((23)-2-amino-3-cyc lohexylpropanoyl) -((28)-2-amino-3-cyclohexylp lopanoyl)-leucyl-D alanyl-arginyl-0H FAB+MS: (M+H)-IN amino acid analysis value: t’he(1, 01), LFS (1, l1l), Pro (1, OH, Ck (1, [1, L sm (1, III), Als (0, H).

Artfl, N) Implementation #’151 H-phenylalanyl-histidyl-lysyl-alanyl-((23)-2-ami -3-cyclohexylpropanoyl)-((23)-2-amino-3-cyclo lohexylpropanoyl)-leucyl-D-alanyl-arginyl-0HFAB MS: (M+H) -1148 Amino acid analysis value: Phe (11,95), l1is (1,07), Lu (0, H), Aft (1, H), Ck* ( 1,76), Let (1,02).

ArH(0,981 Example 52 Hydrocinnamoyl-lysyl-aspartyl-((2S)-2-amino-3-sil chlorohexylpropanoyl) -((28)-2-amino-3-cyclohexyl propanoyl)-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) -11140 Amino acid analysis value: L7s (0, 641, Asl (0,73), Cb Hatake (1,90, Llm (1,041, A lr (0, ε21. A+1 (1,04) Example 53 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)D-alanyl-((4R)-(4-(β-7enethyl))agmatine ) (4R) -N-a-Boe-N-guanidino-tosyl-(4-β-7enethi ) Agmatine was synthesized by the method described in Example 45, with the exception that methylene Benzyltriphenylphosphorane instead of benzyl in triphenylphosphorane used. The Boc group was removed by treatment with 4N-HC1/dioxane, resulting in The protected porcine peptide (cited in Example 45) was purified using DCC/HOBT. ) was coupled. Protecting groups are removed by treatment with liquid HF/anisole. The desired compound was obtained.

Example 54 H-phenylalanyl-lysyl-Dprolyl-((28)-2-amino-3-cy chlorohexylpropanoyl) -((2S)-2-amino-3-cyclohexyl propanoyl)-leucyl-D alanyl-arginyl-0H FAB MS: (M+H)”-1037 Amino acid analysis value: He(1, 00), Lrs (1,01), Pry fl, O6), Cht fl, 91) , Ls++ [1, H), Aft [0,116).

Ate (1,041 Example 55 H-phenylalanyl-lysyl-aspartyl-((23)-2-amino-3- cyclohexylpropanoyl) -((2'S.

3S)-3-amino-2-oxo-1-pyrrolidine-((2'-(4'-methyl ))-pentanoyl)-D alanyl-arginyl-0H FAB MS: (M+H) 985 Amino acid analysis value: Pbt (0,98 ), LteK (0,94n, Asp (1,01), Ch&!11.95), A11 fl, 08>, Art fl, 07) Example 56 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc ((28)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-isoyl-Dprolyl-arginyl-0)( + FAB MS: (M+H) +-1037 Amino acid analysis value: Phe (0, 99), Lys (0,99>, All [0,93), Cbx (1, 94), Lu+ (1,09), Pro (0, W3).

Arg(1,07) Example 57 H-phenylalanyl-histidyl-lysyl-((2S)-2-amino-3-lysyl Chlorhexylpropanoyl 1-((25)-2-amino-3-cyclohexyl propanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H)”=1077 Example 58 A c (4N H2) phenylalanyl-lysyl-aspartyl-r (2S) -2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino -3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl-0 HFAB MS: (M+H)” 1112 Amino acid analysis value = (4-child NH2) Ph5f0.75), Lys(1,0ri, Asp(0,98), C h katsu(1,90), Let(+,09), Algfo,99), Arg(1, 03) Example 59 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)D alanyl-arginyl-8CH2CH3 N-α-Boc-arginine with ethyl mercaptan S, Ysmsd5Y, Y oko71t, T, 5hioiri, ], Or1. Chsm, 1974.3 9.3302. The reaction was performed according to the procedure described by. The obtained ester 4N to HCI/dioxane to transform the protected heptopeptide (example 49). Quote) was coupled. Final deprotection was performed using 4N-HCl/dioxane. Ac-phenylalanyl-lysyl-aspartic acid Laginyl-histidyl-((23)-2-amino-3-cyclohexylpropano MS: ( M+H)”=lllG Example 61 H-phenylalanyl-lysyl-6-aminohexanoyl ((23)-2-a mino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl -OH+ FAB MS: (M+H)”-900 Amino acid analysis value: Pbt (0, 9g), Lr+ (0,991, Cbx (0,94), LeIl (1, 071, AI & (1,011, Arg (1,021 Example 62 )! -(41) Phenylalanyl-lysyl-7ranyl[2S)-2-amino- 3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclo xylpropanoyl)-leucyl-D alanyl-arginyl-〇H FAB+MS: (M,-)T)-1137 Example 63 H-tyrosyl-lysyl-alanyl-((2S)-2-amino-3-cyclohexy -((23)-2-amino-3-cyclohexylpropanoyl) )-isoyl-D alanyl-arginyl-0H FAB' MS: (M+H) = 1027 Amino acid analysis value Nicho 7r (0, 32), LFl (1,001, Aft (1,89), Chz [1,451 , Lea (+, +91.Arg (1,121 Example 64 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)Dalanyl-arginyl-NHCH2CH3 N-α-Boc-arginine was prepared with ethylamine and carbon using mixed anhydride method conditions. I connected. The product was deprotected using 4N-HCl/dioxane and Ninethylamide dihydrochloride was obtained, which was converted to the protected pig peptide (cited in Example 49). ) was coupled by using DCC/HOBT. Protecting group with 4N-HCl /dioxane treatment to yield the desired compound.

Example 65 H-phenylalanyl-arginyl-aspartyl-((25)=2-amino- 3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexyl silpropanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+yH) 1083 Amino acid analysis value: Pht (11 ,94), ArI (1,H), AH (1,07), Cht (2,Oll , Lsm (1, 14), Als (tl, Hj Example 66 H-phenylalanyl-lysyl-aspartyl-((2S)-2-amino-3- cyclohexylpropanoyl)-7 ranylleucilyl-D alanyl-arginyl -0HFAB” MS: (M+H) 173 Example 67 H-(4-CH,)phenylalanyl-lysyl-alanyl-((2S)-2-a mino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclo lohexylpropanoyl)-leucil-D alanyl-arginyl-0HFAB MS: (M+H) San 1025 Amino acid analysis value: (4-Me) P he [0,761, Lrs (0,99), Als (1,71), Ch s (1, H), Lsm (1,07).

Ale (1,02) Example 68 H-(4-F)phenylalanyl(R/S)-lysyl-alanyl-((23)- 2-amino-3-cyclohexylpropanoyl)-((23)-2-amino- 3-cyclohexylpropanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+1()-100 Example 69 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((23 )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)Dalanyl-arginyl-NHCH,C,Hs This compound was prepared as follows, except that benzylamine was used instead of ethylamine. Prepared by the same method as described in Example 64.

Example 70 H-(4-F)phenylalanyl(R/S)-lysyl-alanyl-((2S)- 2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino- 3-cyclohexylpropanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) = ll129 7mi J Shun analysis value: (4-F) Ph#(11,98), Lrt(1,113), A11[1,j4), Hs [I. 96), Ltifl, 0f).

ArI(1,00) Ru((28)-2-amino-3-cyclohexylpropanoyl)-((2S )-2-amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl- Arginyl-0) IF, AB MS: (M+)i) 1029 amino acid content Analysis values: (3-F) pHe (0,84), Lys (1,00), Al s(1,84), Chs(1,981,L!of1.03).

ArI (0,991 Implementation N72 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((23 )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)Dalanyl-arginyl-NH(2-pyridyl)methylThis compound is , except that (2-pyridyl)methylamine is used instead of ethylamine. Synthesized by the same method as described in Example 64.

Example F3 H-(3-F)phenylalanyl(R/S)-lysyl-alanyl-((2S)- 2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3 -cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl-0HF AB MS: (M+H) = 1029 Amino acid analysis value = (3-F) Ph @ (0,85), Lys (0,99), Aft (L 84), Cb@(1,981,Lee(1,03).

Arl fl, 01l) Example 74 H-(2-F)phenylalanyl(R/S)-lysyl-alanyl-((2S)- 2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3 -cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl-0HF AB MS: (M+H) Gosu 1029 Amino acid analysis value = (2-F) Phe (1, all, LFI (1,001, Aft (1,95), Ch s(2, Hl, Le++(1,08).

Ar((1,N) Example F5 1(-(2-F)phenylalanyl(R/S)-lysyl-alanyl-((2S) -2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino- 3-Schiff ahexylpropanoyl)-leucyl-D alanyl-arginyl-0H FAB” MS: (M+H) = 1029 Amino acid analysis value: (2-F ) Pbgfo, 99), Lrs (0,99), Als fl, 84 ), Chs (1,981, Lti (1,03) B Arg (1,00) Example 76 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((23 )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)Dalanyl-arginyl-NHNI(C6H5 This compound was produced in the same manner as in Example 38.

Example 77 H-phenylalanyl-lysyl-alanyl-leucyl-leucyl-leucyl-D Alanyl-Histidyl-〇HFAB MS: (M+H) 912 Example 78 H-(4-No2'Iphenylalanyl-lysyl-alanyl-((2S)-2- Amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclo chlorohexylpropanoyl)-isoyl-D-alanyl-arginyl-0HFAB +MS: (M+H) = 1056 Amino acid analysis value: (4-N O2) Phe (0,691, Lr + fO, 99), mountain (1,83), Cbz ( 1,94), Lta f+, 07).

Person 11 (1,00) Example 79 H-722alanylrulysilufenylalanyl((2S)-2-amino- 3-cyclohexylpropanoyl)-((28)-2-amino-3-cyclohexyl silpropanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) -1ON Example 80 Phenoxyacetyl-lysyl-alanyl-((23)-2-amino-3-cyclo hexylpropanoyl) -((2S)-2-amino-3-cyclohexylpropanoyl) panoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) So-called 998 Example 81 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpro/(noyl)-glycyl-leucyl- (N-methyl)Dalanyl-arginyl-N(-CHCH)NH2 This compound was produced in the same manner as in Example 38.

Example 82 H-4Lyptophyllurisilylalanyl-((23)-2-amino-3-cyclo hexylpropanoyl) -((23)-2-amino-3-cyclohexylpropanoyl panoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H)” = 105G Example 83 H-phenylalanyl-lysyl-histidyl-((23)-2-amino-3-cy chlorohexylpropanoyl) -((23)-2-amino-3-cyclohexyl propanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H)”-1077 Example 84 H-(3-(2' naphthyl)alanyl)-lysyl-alanyl-[(2S)-2 -amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3- cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl-0HFA B+MS: (M+H)"-1061 Example 85 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpro/<noyl)-glycyl-leucyl- (N-methyl)D alanyl-al-1'yl-0CH2Cs f(5N-α-B oc-arginine as S, S, WInπ, B, F, Gi+in, D, P.

Winter, R, Mtkot+, 1. D, Llesh*, C, TroB rIki, and], Meieoho! t+, ], OB, Chem, 1977, 4 2. 1286. It was converted to its benzyl ester by the procedure described in .

The obtained compound was treated with 4N-HCI /')O*+Nwo'7: Where! 1L, DCC /Coupling with the protected pig peptide (cited in Example 45) using HOBT did. The protecting groups were removed by treatment with 4N-HC1/dioxane to yield the desired product. I got something.

Example 86 H-(3-(1' naphthyl)alanyl)-lysylalani,ru-((25)- 2-amino-3-cyclohexylpro, (/yl)-((23)-2-amino- 3-cyclohexylpronocinoyl)-leucyl-D alanyl-arginyl-0 HFAB” MS: (M+H) +-1061 Example 87 H-(3-F)phenylalanyl(R/S)-lysyl-Dalanyl-((2S) -2-amino-3-cyclohexylpropanoyl)-D alanyl-leucyl-D Alanyl-arginyl-OH FAB+MS: (M+H)”-947 Example 88 H-phenylalanyl-lysyl-((2S)-2-amino-3-cyclohexyl propanoyl)-3-(aminomethyl)benzoyl-leucyl-D-alanyl- Arginyl-0HFAB” MS: (M+H) +-N.

Example 89 H-phenylalanyl-lysyl-alanyl-((28)-2-amino-3-cyc lohexylpropanoyl) -((25) -2-amino-3-cyclohexyl Propanoyl)-Pipecolyl-Arginyl-0H FAB” MS: (M+H) = 1051 Example 90 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((2S )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl)Dalanyl-arginyl-NHOCH3 This compound was produced in the same manner as in Example 38.

Example 91 H-phenylalanyl-lysyl-asparaginyl-phenylalanyl-phenyl alanyl-leucyl-D alanyl-arginyl-OH FAB+MS: (M+H)” 1042 Example 92 H-phenylalanyl-lysyl-alanyl-phenylalanyl-phenylalanyl leucyl-D alanyl-arginyl-OH FAB" MS: (M+)I)" -999 Example 93 H-phenylalanyl-lysyl-phenylalanyl-((25)-2-amino- 3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexyl silpropanoyl)-isoyl-D alanyl-histidyl-0H FAB MS: (M+H) 106g Example 94 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl) -((28)-2-amino-4-pentenoyl)- leucyl-glycyl-arginyl-OH Example 95 Ac-Histidyl-lysyl-asparaginyl-(2-CH3)phenylalanyl (R/S)-(2-CH3”)phenylalanyl(R/S)-isoyl-DA Ranyl-arginyl-0HFAB MS: (M+H) = 1102 amino Acid analysis value: ＾S! (1, Oll, L!w (0,971, old s [0,891, Alt (1,00), Lys (1, oll, Att (1,04) Example 96 Ac-Histidyl-lysyl-asparaginyl-(4-CH3)phenylalanyl (R/S)-(4-CH3)phenylalanyl(R/S)-isoyl-D-alani Ru-Arginyl-0HFAB MS: (M+H)”=11021102 fruit -phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyclo lohexylpropanoyl)-(2-amino-2-methyl-propanoyl)- Syl-D-alanyl-arg-Ac-arginyl-lysyl-asparaginyl-((2 S)-2-amino-3-cyclohexylpropanoyl)-((28)-2-amino Nor-3-cyclohexylpropanoyl)-leucyl-D-alanyl-arginyl- 0H FAB MS: (M+H) -1105 Amino acid analysis value: Ast (0,97 ), Att (0,981, Lsu (1,021, Ch* (1,88), Lr+fl, 01), Arg (2,0Q) Example 99 Ac-aspartyl-lysyl-asparaginyl-((2S)-2-amino-3- cyclohexylpropanoyl) -((2S)-2-amino-3-cyclohexy leucyl-D-alanyl-arginyl-OH Aspartyl (β-benzyl)-lysyl (N- t-Cbsl-((2S)-2-amino-3-cyclohexylpropanoy )-((2S)-2-amino-cyclohexylpropanoyl)-isoyl- Trifle of D-alanyl-arginine (N-guanidino-Toil-0 resin) The oroacetate (0.56 g) was produced. The obtained peptide resin was dissolved in methylene chloride. Medium diisopropylethylamine (DtEA) 10% solution fi (3 times.

151, 45 seconds each time) and methylene chloride (4 times, 15 ml). Ta. A 10% DIEA solution in methylene chloride (15 ml) was introduced into the reactor and anhydrous vinegar was added. Acid (0.47 ml. 5 mmol) was added. The reaction was carried out at room temperature for 1 hour, and further Repeat if necessary (until KI eye e+ test is negative). N-acetyl pepti The resin was treated with HF and anisole to obtain 127.3 mg of dry powder. Ta. A portion (75 mg) of the powder was analyzed by HPLC according to the procedure described in Example 2. Purification yielded 40.4 mg of a pure product consistent with the proposed structure.

FAB MS: (M-1-H) + Gourd 1064 Amino acid analysis value: Al! + 1.851. ^lx　(1,041,Leo(1,081,C)u　(1,89 ), Lys (0,961, AH (1,,07) Example 10G H-((2R)-2-amino-3-cyclohexylpropanoyl l-D lysyl D-aspartyl-((2R)-2-amino-3-cyclohexylpropanoyl) -((2R)-2-amino-3-cyclohexylpropanoyl)-D leucyl -alanyl-D arginyl-0H FAB MS: (M+H) Tomi 1061 Example +01 H-phenylalanyl-lysyl-alanyl-((23)-2-amino-3-cyc lohexylpropanoyl)-(aminocyclopropyl-1-carbonyl)- Sil-D alanyl-arginyl-OH Example! 02 H-phenylalanyl-lysyl-lysyl-((2S)-2-amino-3-cyclo hexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl (noyl)-isoyl-D alanyl-arginyl-OH FAB MS: (M+H) -1068 Example 103 H-(3-(2'-chenyl)alanyl(±))-lysyl-histidyl-((2 3)-2-amino-3-cyclohexylpropanoyl)-((23)-2-amino (-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl- 0HFAB MS: (M+H)”-1084 Example 104 H-phenylalanyl-lysyl-alanyl-(4-f)phenylalanyl-ara Nyl-leucyl-D alanyl-arginyl-OH FAB MS: (M+H) +=1049 Example 105 H-phenylalanyl-lysyl-alanyl-((25)-2-amino-3-cyc lohexylpropanoyl)-(aminocyclohexyl-1-carbonyl)- Sil-D alanyl-arginyl-OH Example 106 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-4-cyc lohexylbutanoyl)-alanyl-leucyl-D alanyl-arginyl-0H FAB" MS: (M-'H)" = 943 Example 107 H-phenylalanyl-lysyl-alanyl=(3-F)phenylalanyl (R/ S)-alanyl-leucyl-D alanyl-arginyl-0H FAB-MS: (MH)--939 Example 108 H-phenylalanyl-lysyl-alanyl-(3-F)phenylalanyl (R/ S)-alanyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+H)-941 Example 109 H-phenylalanyl-lysyl-7ranyl((23)-2-amino-4-phenylene) nylbutanoyl)-alanyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) = 937 Example 110 Ac-((IR/5)(2R/5)((Z)-1-7 minnow 2-phenylcyclo propyl)-1-carbonyl)-lysyl-alanyl-((2S)-2-amino- 3-cyclohexylpropanoyl) -((23)-2-amino-3-cyclo xylpropanoyl)-alanyl-arginyl-0HC-terminated The peptides were prepared under standard solid phase peptide synthesis conditions. ε nitrogen of lysine Protected as its FIIoe derivative, it was During cleavage - remained inert throughout. 2-acetamidocinnamic acid to υ, S chmidl, A, Li@btrke@chl, 1. Wild, 571hc +is 198g, 159-172, and the references cited therein. The method provides racemic ((z)-1-7cetamido-2-phenylcyclopropane )-1-carboxylic acid was produced. Then, the amino acid was extracted by the mixed acid anhydride method. was coupled to the heptapeptide in solution phase, and the Free group was added using piperidine. Removed. Diastereomeric products were separated by HPLC to obtain the final product. .

Example 111 H-Isoleucyl-seryl-phenylalanyl-lysyl-aspartyl-((2 S)-2-amino-3-cyclohexylpropanoyl)-((23)-2- Amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-argini Le-0HFAB MS: (M+H) 1255 Example 112 H-phenylalanyl-lysyl-alanyl-((2R/5)-2-aminoocta (noyl)-alanyl-leucyl-D alanyl-arginyl-0H FAB” MS: (M+H) Tomi 917 Example + 13 H-phenylalanyl-lysyl-alanyl-((2R/S)-2-aminooc (Tanoyl)-alanyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) = 917 Example 114 H-phenylalanyl-lysyl-alanyl-(3-(2'-+engineyl)-ara Nyl (R/5))-7 ranyl-leucil-D alanyl-arginyl-0H FAB MS: (M+H) Bulk 929 example + 15 AC((Z)-2-amino-3-phenyl-2-propenoyl)-lysyl-ara Nyl-((2S)-2-amino-3-cyclohexylpropanoyl)-alanyl -Leucyl-glycyl-arginyl-0H C-terminal peptides were prepared using standard solid phase peptide synthesis techniques.

The ε-nitrogen of lysine was protected using Free, which is the f( It was left in place until after F cleavage and removal of other protecting groups. mixed acid anhydride Coupling 2-acetamidocinnamic acid to heptapeptide in solution phase using a physical method. I clicked. Subsequently, the Free group was removed using piperidine and the crude peptide was purified by HP Purified by LC.

Example 116 H-alanyl-asparaginyl-isoleucyl-seryl-phenylalanyl-ly syl-aspartyl-((23)-2-amino-3-cyclohexylpropanoyl )-((23)-2-amino-3-cyclohexylpropanoyl)-isoyl -D alanyl-arginyl-0H FAB MS: (M+H) = 14401440 implementation H-Phenylalanyl luricyl-alanilu-phenylseryl-alanyl-leuci LuD alanyl-arginyl-OHFABMS2(M+H)-939 Example 11g H-phenylalanyl-lysyl-leucyl-((2S)-2-amino-3-cycyl ((2S)-2-amino-3-cyclohexylpropanoyl), -((2S)-2-amino-3-cyclohexylpropanoyl) lopanoyl) -Lta -D alanyl-arginyl-OH FAB MS・(M+H)-1053 Example 119 (N,N-dimethyl)alanyl-(N-methyl)phenylalanyl-lysyl-a Ranyl-((23)-2-amino-3-cyclohexylpropanoyl)-arani leucyl-(N-methyl)D-alanyl-arginyl-OH Example 120 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc ((28)-2-amino-3-cyclohexylpropanoyl)-((28)-2-amino-3-cyclohexylpropanoyl) panoyl)-alanyl-D-alanyl-(ω-N, ω’-N-diethyl)argini Ru-0HFAB” MS: (M+H)”-11181 Amino acid analysis value: A11 (1,91), Le++ (1,09), Pht (0,961, Cbt jl, 981, Lts (fl, 96) Example 121 H-phenylalanyl-lysyl-7ranyl((2S)-2-amino-3-cyc ((23)-2-amino-3-cyclohexylpropanoyl)-((23)-2-amino-3-cyclohexylpropanoyl) panoyl)-alanyl-D-alanyl-(ω-N-phenyl)arginyl-OHF AB MS: (M+H) = 1087 Amino acid analysis value: Aft (1,, 861, Lea (0,98), Phe fl, 0? ), Cht (1 ,981,LrI (1,11) Example 122 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc ((23)-2-amino-3-cyclohexylpropanoyl) (ropanoyl)-isoyl-D-alanyl-(ω-N-methyl)arginyl-0HF AB MS: (M+H) Mo1025 Amino acid analysis value 2 A11 (1,90 ), Leg (1,251, Phe to, 951. Chl (2,25) , LrI (1,08), Aug (1,08j Example 123 (N-methyl)phenylalanyl-(N-methyl)phenylalanyl-lysyl- Alanyl-((2S)-2-amino-3-cyclohexylpropanoyl)-ara Nyl-leucyl-(N-methyl)D-alanyl-arginyl-OH Example +24 Ac-Histidyl-lysyl-asparaginyl-((2S)-2-amino-3-cy chlorohexylpropanoyl)-((2S)-2-amino-3-cyclohexylp (ropanoyl)-isoyl-D-alanyl-arginyl-NHOH This compound was produced in the same manner as in Example 38.

FAB+MS: (M+H) = llO1ll side 125 Ac-phenylalanyl-lysyl-glutamyl-((2S)-2-amino-3- cyclohexylpropanoyl)-((25)-2-amino-3-cyclohexyl propanoyl)-alanyl-D-alanyl-arginyl-OH Synthesis, deprotection and cleavage of resin-bound peptides were performed as outlined in Examples 1 and 2. It was. However, N-terminal acetylation may be performed between the synthesis and deprotection/cleavage steps. except that Acetylation is Job++ M,! 1nver+ and Jsnis D, ToaB fr Solid Phase Peptide Synthesis, 2nd edition (1984), page 73 It was carried out according to the description.

FAB MS: (M+H) 1111 Example + 26 H-phenylalanyl-lysyl-glutamyl-((2S)-2-amino-3-sil chlorohexylpropanoyl) -((2S) = 2-amino-3-cyclohexy FAB MS: (M+H) -1069 Example 12 (N-benzyl)glycyl-(N-methyl)phenylalanyl-lysyl-arginyl -((2S)-2-amino-3-cyclohexylpropanoyl)-alanyl-leucyl-(N-methyl)D-alanyl-arginyl-OH Example 128 H-phenylalanyl-olnityl-alanyl-((25 )-2-amino-3-cyclohexylpropanoyl) -((29)-2-amino-3-cyclohexyl FAB MS: (M+H) = 997 Example 129 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-alanyl) cyclohexylpropanoyl) -((2S)-2=amino-cyclohexylpropanoyl) lopanoyl)-lysyl-D alanyl-arginyl-0H FAB MS: (M+H) = l [126 Example 130 H-phenylalanyl-lysyl-alanyl-((23)-2-amino-3-cyclo ((23)-2-amino-3-cyclohexylpropanoyl) -((23)-2-amino-3-cyclohexylp (ropanoyl)-glutamyl-D alanyl-arginyl-0H FAB MS: (M+H) + =1027+ Example 131 H-phenylalanyl-lysil-alanyl-((25)-2-amino-3-cyclo (2S)-2-amino-3-cyclohexylpropanoyl) -((2S)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-threonyl-D alanyl-arginyl-Of(FAB" MS: (M+H)" = 999 Example 132 (N-phenyl)glycyl-lysyl-alanyl-((2S)-2-amino-3-cyclohexyl propanoyl)-alanyl-leucyl-(N-methyl)D-alani -Arginyl-OH Example 133 H-Leucyl-arginyl-alanyl-asparaginyl-isoleucyl-seryl-phenylalanyl-lysyl-aspartyl-((2S)-2-amino-3-silyl chlorohexylpropanoyl)-((2,9)-2-amino-3-cyclohexylpropanoyl)-leucyl-D alanyl-arginyl-0HFAB MS: CM+H) = 17091709 Fragment H-phenylalanyl-glutaminyl Ruaspartyl-1(2S)-2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl)-alanyl-D alanyl-arginyl-0H FAB MS: (M+H) -, 1055 Example 135 H-phenylalanyl-alanyl-aspartyl-((2S)-2-amino-3-cyclohexylpropanoyl)-((23)-2-amino-3 -cyclohexy lysyl-alanyl-((28)-2-amino-3-cyclohexylpropanoyl) Noyl)-alanyl-leucyl-(N-methyl)D-alani -Arginyl-OH Example 137 2-Pyridylacetyl-lysyl-histidyl-((23)-2-amino-3- chlorohexylpropanoyl) -((28)-2-amino-3-cyclohexylpropanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) Akebono 1049 Example 138 H-((25)-2 -Amino-4-phenylbutanoyl)-lysyl-histidyl-((2S)-2-amino-3-4cyclohexylpropanoyl) -((2g) -2-amino-3-cyclohexylpropanoyl) -Isyl-D-alanyl -Arginyl-OH FAB MS; (M+H) -1091 Example 139 (5-dimethylamino-1-naphthalenesulfonyl)-lysyl-histidyl- ((2S)-2-amino-3-cyclo hexylpropanoyl) -((2S)-2-amino-3-cyclohexylpropanoyl) dileucil-D-alanyl Guinyl-0HFAB MS: (M+)I)ll! 111N Example 14G Methoxyacetyl-(N-methyl)phenylalamol-lysyl-alanyl-((2S)-2-ami,no-3-cyclohexylpropanoyl)-alanyl-leuci -(N-methyl)Dalanyl-arginyl-OH Practice N141 C1,2,3,4-tetrahydroisoquinoline-3-carbonyl(±))-lysyl Ruhi, stidyl-((2S)-2-amino-3-cyclohexylpropanoyl)-((28)-2-amino-3-cyclohexylpropanoyl)-alanyl-D alanyl-arginyl-0H FAB MS: (M+H) 1089 Example 142 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyclo ((28)-2-amino-3-cyclohexylpropanoyl)-((28)-2-amino-3-cyclohexylpropanoyl) Panoyl)-Phenylalanyl-Arginyl-〇H FAB MS: (M+H) Proverb 1087 Trap 1'' 1 So L Amino-3-cyclohexylpropanoyl)-((2! 9) -2-Amino-3-cyclohexylpropanoyl)-glycyl-D alanyl-arginyl-0H FAB MS: (M+H) Iris 955 Amino acid analysis value: Pb*(1, Ol I, Lys (1,07) , AI & (1,911), Chs (2,10 1, Atx (1, H), Gly (,97) Example 144 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3 −Siku ((23)-2-amino-3-cyclohexylpropanoyl) -((23)-2-amino-3-cyclohexylp (lopanoyl)-alanyl-Dalanyl-arginyl-0H FAB MS: (M+H)-969 Amino acid analysis value: I'l+s(1,031,Lrs(1,0il,Aft(2,1161,Chs(2,II)) Ate (1,l1l) Example 145 H-phenylalanyl-((2S)-2-amino-5-ureidopentanoyl)-alanyl-((28)-2-amino-3-cyclohexylpropanoyl) - ((23)-2-amino-3-cyclohexylbropanoyl)-isoyl-D-a ranyl-arginyl-0f(+FAB MS: (M+H)” 1040 Example 146 Hydroxyacetyl-(N-methyl)phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyclohexylpropan (noyl)-alanyl-leuci -(N-methyl)D-alanyl-arginyl-OH Example 147 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyclo H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3- Siku H-phenylalanyl-lysyl-histidyl-((2S)-2-amino-3-histidyl)-glutamyl-leucyl-D-alanyl-arginyl-0HFAB MS: (M+H) +-987+ Example 149 chlorohexylpropanoyl) -((2' R/S, 3S)-3-amino-2-oxo-1-azepine-2'-pentanoyl)-D alanyl-arginyl-0H FAB MS: (M+H)" = 102t+ Example +50 H-phenylalanyl-lysyl-histidyl-[(2S)-2-amino-3-cy chlorohexylpropanoyl) -((2'R/S,3S)-3-amino-2-oxo-1-azepine-2'-pentanoyl)-D alanyl-arginyl-OH FAB MS: (M+H) + =1021 Example 151 β-phenylethyl-oxy-acetyl-(N-methyl)phenylalanyl-ly Sil-alanyl-((2S)-2-amino-3-cyclohexylpropanoyl)-alanyl-leucyl-(N-methyl)D-alanyl-arginyl-OH Example 1. 52 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc (2S)-2-amino-3-cyclohexylpropanoyl) -((2S)-2-amino-3-cyclohexylpropanoyl) FAB MS: (M+H) = 1079 Example 153 H- Phenylalanyl-lysyl-alanyl-(3-(2'-perhydronaphthi) H-phenylalanyl-phosphorus-alanyl-(3-(2'-naphthyl)alani) )-alanyl-leucyl-Dalanyl-arginyl-0H FAB MS. isyl = ((2R/S)l -2-amino-4,4,4-trifluorobutanoyl )-Arginyl-OH FAB MS: (M+H) +=1079+ Example 156 2-Methylthioacetyl-(N-methyl)phenylalanyl-lysyl-alanyl-((23)-2-amino-3-cyclohexylpropanoyl )-alanil-ro Isyl-(N-methyl)Dalanyl-arginyl-OH Example 157 H-phenylalanyl-lysyl-7ranyl-(3-(1'-naphthyl)alani) )-alanyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) +=973+ Example 158 H-phenylalanyl-lysyl-alanyl-(3-(2'-(5'-n++-butylchenyl) )alanyl (R/S)) -alanyl-leucyl-D-alani FAB MS in L-arginyl-OH: (M+H)” =91159115 performed H-phenylalanyl-lysyl-alanyl-(3-(2'-(5'-feat-butylchenyl))alanyl (R/5)) -alanyl-leucil-D-alani-arginyl-0HFAB” MS: (M+H) -9115 Example 16 0 H-phenylalanyl-lysyl-alanyl-(3-(2'-chenyl)alanyl (R/S)) -alanyl -Leucyl-D alanyl-arginyl-0H FAB MS: (M+H)'' -90 Example 161 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl) -((2' R8゜3S)-3~amino-2-ox So-1-pyrrolidine-(2'-(4'-methyl))-pentanoyl-D prolyl-arginyl 0H FAB MS: (M+H)" -967 Example 162 4-phenylbutyryl-lysyl-alanyl-((23 )-2-amino-3-cyc (hexylpropanoyl)-alanyl-leucyl-(N-methyl)Dalanyl-arginyl-OHExample 163 (28)-2-amino-3- Siku ((28)-2-amino-3- Siku lohexylpropanoyl)-glycyl-leucyl-D alanyl-arginyl-0 1(+ FAB MS: (M+H)” = 915 Amino acid analysis values: Ph5 (, 99), Lts (1, H), Aft (1,92 ), Ch heat (1, Go), L ea (1,071, Arg (1,021°G17F, 971 hexylpropanoyl)-leucyl-D alanyl-arginyl-0H FAB MS: (M+H)+-986+ Example 167 Phenylacetyl-lysyl-alanyl-((28)-2-amino-3-cyclohe xylpropanoyl)-alanyl-leucyl-(N-methyl)Dalanyl-al Ginyl-OH Example 1611 H-phenylalanyl-lysyl-alanyl-glutamyl-((2S)-2-ami Nor-3-cyclohexylpropanoyl 1-isoyl-D-alanyl-arginyl-0HFAB+MS: (M+H) -987 Example 169 H-((2S)-2-amino-4-phenylbutanoyl)-lysyl-alanyl - ((23)-2-amino-4-phenylbutanoyl)-alanyl-leucyl-D alanyl-arginyl-OH FAB MS: (MfH) -951 Example 170 H-phenylalanyl-lysyl-alanyl- ((23)-2-amino-4-phene Nylbutanoyl 1-7 Ranyl-7 Ranil-D Alanyl-arginyl-0H FAB+MS: (M+H) -895 Example 1 F1 Biradylcarbonyl-lysyl-histidyl-((25)-2-amino-3-cyc lohexylpropanoyl) -((2S)-2-amino-3-cyclohexylp (lopanoyl)-leucyl-D alanyl-arginyl-OH + FAB MS: (M+H)” = 1036 Example 172 (N-methyl)phenylalanyl-lysyl-alanyl-1(2S)-2-amino-3-cyclo xylpropanoyl)-(N-hydroxy)asparaginyl-ro Isyl-(N-methyl)Dalanyl-arginyl-OH Example 1 F3 3-cyclopentylpropanoyl-lysyl-histidyl-((23)-2-amino Nor-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl)-isoyl-D alanyl-arginyl-0HFAB MS: (M+H) 1054 Example 174 (3 -benzoyl)benzoyl-lysyl-histidyl-i[2s)-2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl -Arginyl-0H FAB MS: (M+H)” -1118 Example 175 (1,2,3,4-tetrahydronaphthyl-carbonyl (±))-lysyl-his Tidyl-((23)-2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl)-tidyl-D-arani -Arginyl-OH FAB+MS: (M+Na)” =llIG Example 176 (N-Methyl)phenylalanyl-lysyl-glycyl-W (CH2Co-NH) -((2S)-2-amino-3-cyclohexyl Propanoyl)-alanyl-leucyl-(N-methyl)Dalanyl-arginyl-OH Example 177 -3-cyclohexylpropanoyl) -((23)-2-amino-3-cyclo 4-phenylbutanoyl-lysyl-histidyl-((2S)-2-amino-3-cyclo xylpropanoyl)-((23)-2-amino-3-cyclohexylpropanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) +=1076+ Example+79 H-phenylalanyl-lysyl -Alanyl-((23)-2-amino-4-phene nylbutanoyl)-(aminocyclohexyl-3-carbonyl(R/S))-D alanyl-arginyl-OH FAB MS: (M+H) =878 Example 180 H-phenylalanyl-lysyl-alanyl-((2S)-2 -Amino-4-fe nylbutanoyl)-(aminocyclohexyl-3-carbonyl(R/S))-Dalanyl-arginyl-OH FAB MS: (M+H)” -878 Example 181 (N-methyl)phenylalanyl-lysil-glycyluma (S (0)2 MH I ((2S) 2 7mi/3'/cyclohexylpropanoyl-alanyl-leucyl-(N-methyl)D alanyl-arginyl-OH Example 182 H-phenylalanyl-lysyl-alanyl-threonyl -((2S)-2-ami Nor-3-cyclohexylpropanoyl)-isoyl-Dalanyl-arginyl-0HFAB MS: (M+H) = 959 Example 183 H-phenylalanyl-lysyl-alanyl-alanyl-1(23)-2-amino-3 -cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl-0H FAB MS: (M+H) -929 Amino acid analysis value: Phe(1,05 1,Lri (,9)1.AIl (2,691, Chx (,93), Lea (1,20), Arg (1,03) Example 184 H-phenylalanyl-lysyl-alanyl-glycyl-1(25)-2-amino-3-cyclohexylpropanoyl )-Isyl-D alanyl-arginyl-0H FAB MS: (M+H) = 915 Amino acid analysis values: Phe (1,1 01, LTI (1,04), Aft (1,93), Chx (1,01) ), Lee (1,23), Arg (1,0W).

H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl) -((2S)-2-amino-3-cyclohexyl propanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) = IQ11 Example 186 (N-methyl)phenylalanyl-lysyl-alanyl-((29)-2-amino -3-cyclohexylpropanoyl)-alanylleuciluma (C/　C)- Glycyl-arginyl 0H Boc-Lea-GI7-OH alkyne isostere is described in literature (M, tsaM grteail! ,C,GTIll,D,Tosrv@,G,? 111 Bi nN, Ba11. Soe.

S + is engineering 1 Yu 121N6.108.1125. ) in the same way as described in "Peptide Synthesis Method J, 312th Edition, M, Bodussk 7. Y, S , KI*wsmtr, and the method described in M.A.O*d*mei (1979) Peptides were incorporated by the classical solution method exemplified by.

Example 187 H-alanyl-lysyl-alanyl-((2S)-2-amino-3-cycloheteisi) (23)-2-amino-3-cyclohexylpropanoyl )-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) +=935 Amino acid analysis value: LH (, 99 ), Al * (2,48), Chs (1,741, Le++ (1,0 31, Arg! , H) Example 188 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc ((23)-2-amino-3-cyclohexylpropanoyl)-((23)-2-amino-3-cyclohexylpropanoyl) Panoyl 1-leucyl-alanyl-arginyl-01 ( FAB MS: (M+)I) Proverbs 1011 Examples 189 H-phenylalanyl-lysyl-glycyl-((23)-2-amino-3-cycyl ((2S)-2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl) panoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) -197 Amino acid analysis value: Ph5 (,99) , Lrt(1,01), Ale(,)31. Cht (1,80), Ltm (1,06), Art (,991°Glr(,95) Example 190 H-glycyl-lysyl-alanyl-((2S)-2-amino-3-cyclohexy -((23)-2-amino-3-cyclohexylpropanoyl) )-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) -121 Amino acid analysis value: Ph! (,97) , Lts (1,031, Aft (1,7i1), Chs (1,0>, Leg (1,119), Art (+, g) Example 191 (N-methyl)phenylalanyl-lysyl-glycyl-v(c(cod5)-NH) -([28)-2-amino-3-cyclohexylpropanoyl)-alanyl- leucyl-(N-methyl)D alanyl-arginyl-0H Boc-glycyl-ma(C(-8)-NH)-((23)-2-amino-3- cyclohexylpropanoyl) -OH dipeptide as described in the literature (L, Mcsitk ,G,L*1oit,B,Ilellctw,1. At Ches.

Soc Engineering 19g6.108.182. ) is manufactured in the same manner as described in Petido synthesis method JjllR version, M, Bods++5tky, Y, S, Kl *Wsntr and M, A, Ond *By the method described in 1st author (1976) Incorporated into peptides by classical solution methods as exemplified by

Example 192 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-silyl chlorohexylpropanoyl) -l5)-2-amino-3-cyclohexylpropanoyl panoyl)-leucyl-glycyl-arginyl-0H FAB MS: (M+H) Kasu997 amino acid analysis value: Phe (,97), Lys (1,0D, Ala (,91), Cha (1,82), Leu (1,07), Arg(,9B).

G　I　y　(,8G) Example 193 H-benicillaminyl★-lysylalanyl-((2S)-2-amino-3-sic lohexylpropanoyl)-cysteinyl★-leucyl-D alanyl-argini This compound was prepared in the same manner as in Example 334.

FAB MS: (M+H) + Proverb 943 Example L94 H-D penicillaminyl★-lysyl-alanyl-(+28)-2-amino-3- cyclohexylpropanoyl)-cysteinyl pre-0 isyl-D alanyl-al Guinyl-OH This compound was prepared in the same manner as in Example 334.

FAB" MS: (M+H) -943 Example 195 Penzoylpenicillaminyl★-lysyl-alanyl-((2S)-2-amino- 3-cyclohexylpropanoyl)-cysteinyl★-leucylalanyl-a Luginyl-OH This compound was prepared in the same manner as in Example 334.

+ FAB MS: (M+H) +=1047 Example 196 Penzoyl 〇 Benicillaminyl ★-lysyl-7 ranyl ((2S)-2-amino -3-cyclohexylpropanoyl)-cysteinyl★-leucyl-D-alanyl -Arginyl-OH This compound was prepared in the same manner as in Example 334.

FAB+MS: (M+H) +-1047 Example 197 H-phenylalanyl-lysyl-alanyl-((29)-2-amino-3-cyc lohexylpropanoyl)-D-lysyl-leucyl-D-alanyl-arginyl-0 H FAB MS: (M+H) +-986+ Example 198 (N-methyl)phenylalanyl-lysyl-alanyl-(+23)-2-amino -3-cyclohexylpropanoyl)-alanylleuciluma (CH2-0) -glycyl-arginyl-0HBoc-leucyl-1F (CH2-0) -g The lysyl-OH dipeptide has been described in the literature (E, Robini, C, Gil+on, L5eliBt+, manufactured by 11°, "Peptide Synthesis Method" 2nd edition, M, Bodrnsxk7. L S.

Described in Kl*s+ner and M, A, 0nde+til (1976) was incorporated into the peptide by the classical solution method exemplified by the method of .

Example 199 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-silyl (chlorohexylpropanoyl)-D-alanyl-leucyl-D-alanyl-arginyl -0H FAB MS: (M+H)”=929+ Example 200 H-phenylalanyl-lysyl-alanyl-((28)-2-amino-3-cyc -(+23)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-isoyl-D-alanyl-(4-NH2)phenylalanyl-OH + FAB MS: (M+H)”=1011 Example 201 H-phenylalanyl-lysilyl-alanyl-((23)-2-amino-3-silyl chlorohexylpropanoyl) -((2R)-2-amino-3-cyclohexy (propanoyl)-alanyl-D-alanyl-arginyl-OH ゛　＋ FAB MS: (M+H)” = 1011 Example 202 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-silyl chlorohexylpropanoyl) -((2S)-2-amino-3-cyclohexyl propanoyl)-D-alanyl-D-alanyl-arginyl-0H FAB+MS: (M+H) 969 Example 203 H-Phenylalanylrulyciluaraniluroy Silu D alanyl-arginyl-0HFAB+MS: (M+H) +-92 3 Example 204 H-(2-aminooctanoyl(±))-phenylalanyl-lysyl-aspar Thyl-((2S)-2-amino-3-cyclohexylpropanoyl)-(f2s )-2-amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl- arginyl-OH FAB MS: (M+H)”-1196 Example 205 H-phenylalanyl-lysyl-alanyl-((R/S)-perhydroindole (2-carbonyl)-alanyl-leucyl-D alanyl-arginyl-oH FAB MS: (M+H) -927 Example 206 (N-methyl)phenylalanyl-lysyl-alanyl-((23)-2-amino -3-cyclohexylpropanoyl)-alanylulloinluma (CH, -3) -glycyl-arginyl-0HBoa-oisyl W (CH2-3) -g Lysyl-OH dipeptide in literature (human, Sps+o1g, 11.A mouth ver. , A., Rockvell, L.

Gis+x+eh, ], Am, Chtm, Soc, 1986. 108. 82 Produced in the same manner as described in 5.1, "Peptide Synthesis Method" 2nd edition 1M.

Written by Bodsns+ky, Y, S, KI■+oe+ and M, ^, 0ndelli (1976) by the classical solution method. Incorporated.

Example 207 H-phenylalanyl-lysyl-alanyl-((R/5)-7<-hydroindo alanyl-2-carbonyl)-alanyl-leucyl-D alanyl-arginyl-01 ( FAB MS: (M+H)” -927+ Example H8 H-phenylalanyl-lysyl-alanyl-[3)-2-amino-3-cyclo hexylpropanoyl)-alanyl-leucyl-D alanyl-arginyl-OH + FAB MS: (M+14)”-90 Example 2N H-phenylalanyl-lysil-alanyl-((2R/S)-2-amino-5 -phenylpentanoyl)-alanyl-leucyl-D alanyl-arginyl-0 H FAB MS: (M1H) +is1+ Example 2111 H-phenylalanyl-lysyl-alanyl = ((2R/s)-2-amino-S -phenylpentanoyl)-alanyl-leucyl-D alanyl-arginyl-O H FAB MS: (M+H)” i51+ Example 211 H-phenylalanyl-lysyl-alanyl-(+23)-2-amino-3-silyl chlorohexylpropanoyl) -((28)-2-amino-3-cyclohexyl propanoyl)-isoyl-D alanyl-arginyl-glycyl-0H FAB MS: (M+H) Dew 1G6g Example 212 (N-methyl)phenylalanyl-lysyl-alanyl-((Is)-2-amino -3-cyclohexylpropanoyl)-alanylleuciluma (C(-0)- 0)-glycyl-arginyl-OH Boc-leucyluma (C(-0)-01-glycyl-OH dipeptide was described in literature ( J, Ito7. D, G5X1@, R, Sh*kisa, 1. L.

5chvt+js, L, 11. J, P@pth ds Ptoltte Res, 1 N2.20. 35. ) is produced in the same manner as described in "Peptide Synthesis Method". 2nd edition.

M, Badttrttky, Y S, E11tr*vy and M, A, Lad@mouth 11F (1976) by the classical solution method. Incorporated into Petide.

Example 2N H-phenylalanyl-lysilyl-alanyl-(+28)-2-amino-3-silyl (chlorohexylpropanoyl)-(+28)-2-amino-3-schiffa hexylp (ropanoyl)-isoyl-D alanyl-glycyl-arginyl-〇H FAB MS: (M+H) +-100+ Example 214 H-phenylalanyl-lysyl-alanyl-((lru++-3-propyl)propyl) lolyl (R/5))-alanyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+H)” 915 Example 215 H-phenylalanyl-lysyl-alanyl-((lru+5-3-propyl)propyl) lolyl (R/S)) -alanyl-leucyl-D alanyl-arginyl-01 ( FAB MS: (M+H)” 115 Example 216 H-phenylalanylurisilyl-(3,5-di-l)tyrosyl-((23)-2 -amino-3-cyclohexylpropanoyl)-alanyl-leucyl-D-alani Le-arginyl-0HFAB MS: (M+H)”-1273 Example 2 17 H-phenylalanyl-lysil-alanyl-((H)-2-amino-3-cyclo hexylpropanoyl)-Dtryptophyl-leucyl-Dalanyl-argini Lou0HFAB+ Example 218 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3- cyclohexylpropanoyl)-tryptophyl-leucyl-D-alanyl-al Guinyl-0HFAB+MS: (M+H) Feather 1044 Example 219 (N-methyl)phenylalanyl-lysyl-alanyl-((2S)-2-ami No-3-cyclohexylpropanoyl)-alanylleuciluma (C(- 0)-8)-glycyl-arginyl-OH Boc-er isyl-(C(-0)-3)-glycyl-OH dipeptide Produced by standard mixed anhydride coupling of Boa-leucine and 1,000-ol acetic acid "Peptide Synthesis Method" 2nd edition, M. Bod*auky, Y. S.　 K11asn*r and M. A. As stated in Oad*Ni if (1976) Incorporated into peptides by the classical solution method exemplified by Methods.

Example 220 H-phenylalanyl-lysilyl-alanyl-((28)-2-amino-3-cyc (hexylpropanoyl)-Dphenylalanyl-aisyl-Dalanyl-al Guinyl-○HFAB MS: (M+H) +=10050 Amino acid analysis values: Phe (2,00), Lys (1,04), Ala (1 ,86), Ch a (1,26), L e u (1,07), Ar g(1,04) Example 221 H-phenylalanyl-lysilyl-alanyl-D tryptopyl-((13)-2 -amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arg Nil-OH+ FAB MS: (M+H)” = 1044 Example 222 H-phenylalanyl-alanyl-D-lysyl-(f2s)-2-amino-3- cyclohexylpropanoyl)-alanyl-leucyl-D alanyl-arginyl -0H FAB MS: (M+H)” = 929 children Example 223 H-phenylalanyl-lysyl-(3-1)tyrosyl-((23)-2-amino -3-cyclohexylpropanoyl)-alanyl-leucyl-D-alanyl-al Guinyl-0HFAB MS: (M-H)-Proverb 1145 Example 224 D Alanyl-arginyl-0HFAB MS: (M+H) 847 Example 225 iodoacetyl-phenylalanyl-lysyl-lysyl-((23)-2-amino -3-cyclohexylpropanoyl)-alanyl-leucyl-D-alanyl-al Guinyl-0HFAB MS: (M+H) Tomi 1154 Example 226 H-phenylalanyl-lysyl-alanyl-(4-No2)phenylalanyl- Alanyl-leucyl-D Alanyl-arginyl 0H FAB MS: (M+H) -96g Example 227 (N-methyl)phenylalanyl-lysyl-alanyl-((2S)-2-amino -3-cyclohexylpropanoyl)-alanyl-leucyl-v (cH2c) (=o)-0)-glycyl-arginyl-0H Boc-Leu-ma(C)12C(=O))-OH in the literature (T, Wxktmi 7t, H, [l+xltni, T, Te+him*, T, +hibs, L soil LC hem: Soc, Ipn, 1975. Yu8. It was listed in 240+,) Sea urchin was produced by Arunto ice tilt synthesis. Boc-Kuchi-Ishiru-1F (CH2C(-0)-0)GIJC)L, -OH are the same as in Example 212. Manufactured by Peptide is "Peptide Synthesis Method" 2nd edition.

M, Bodsn+sk7. Y, S, Htaine+ and M, A, O++ del Produced by the classical solution method exemplified by the method described in +i (1976) did.

Example 228 H-phenylalanyl-lysyl-alanyl-(4-Nl2), phenylalanyl -alanyl-leucyl-D alanyl-arginyl 0H FAB MS: (M+H)' -93g Example 229 H-phenylalanyl-lysyl-alanyl-((23)-2-amino-3-cyc lohexylpropanoyl) -([23)-2-amino-3-cyclohexylp lopanoyl)-isoyl-(N-methyl)D-alanyl-arginyl-0HFAB +MS: (M+)I) +-1025 Amino acid analysis value: AIa (1,01 ), Leu (0,99), Phe (0,96), Cha (1,97), Lys (1,04), Arg (1,02) Example 230 H-phenylalanyl-lysyl-alanyl-((28)-2-amino-3-silyl chlorohexylpropanoyl)-((2S)-2-amino-3-cyclohexylp lopanoyl)-(N-methyl)leucyl-D-alanyl-arginyl-0HFAB "MS: (M+H)" = 1025 Amino acid analysis value: A1a (1,94 ), Phe (1,00), Cha (2,00), Lys (1, 03), A r g (1,04) implementation M23+ H-phenylalanyl-lysyl-cysteinyl★-((23)-2-amino-3 -cyclohexylpropanoyl)-((23)-2-demino 3-cyclohexyl silbolobanoyl)-penicillaminyl★-D alanyl-arginyl-OH conversion The compound was prepared in the same manner as in Example 334.

FARMS: (M+Ff) -1659 Example 232 H-phenylalanyl lysyl cysteinyl ★-(+!5)-2-amino-3 -cyclohexylpropanoyl) -K5) -2-amino-3-cyclohexyl This compound is Produced in the same manner as Example 334.

FAB MS: (M+H) 105! Amino acid analysis value: AIa (0,H) , Pha (1, Oa), Cha (1,9g), Lys (0,91) , A r g (1, OD Example 233 H-((23)-2-amino-3-cyclohexylpropanoyl)-lysyl-a Ranyl-(+25)-2-amino-3-cyclohexylpropanoyl)-( (23)-2-amino-3-cyclohexylpropanoyl)-isoyl-Dara Nyl-arginyl-OH FAB MS: (M+H) Tomi 1017 amino acid analysis value: A1a (1,8 0, Leu (1,07), ChaC2,18), Lys (1, OD , A r g (1, +14) Example 234 (N-methyl)phinylalanyllysilylalanyl-((23)-2-amino -3-Cyclohexylpropanoyl)-alanyl-leucyl-ma(CH2C(Tomi) 0)-8)-Glycyl-arginyl-0H Boa-o isiluma (CH2C(-0)-3)-glycyl-OH dipeptide Boa-Leu-ma (CM2C) prepared as described in Example 227. -0))-OH by standard coupling of mixed anhydrides using thiol acetic acid. ``Peptide synthesis method'' M2 version, M1ods++5xky , TS.

K1n5m@ and the method described in M, A, 0udtHiiF C1976) was incorporated into the peptide by the classical solution method exemplified by.

Example 235 H-phenylalanyl-lysyl-(N-methyl)alanyl-((2S)-2- Amino-3-cyclohexylpropanoyl)-(+23)-2-amino-3-cyclo (chlorohexylpropanoyl)-leucyl-D-alanyl-arginyl-0HFAB MS: (M+H) = 1025 Example 236 H-phenylalanyl-lysyl-alanyl-((28)-2-amino-3-silyl chlorohexylpropanoyl) -([28)-2-amino-3-cyclohexy (propanoyl)-isoyl-D-arginyl-arginyl-OH FAB MS: (M+H)” 1Oj6 Example 237 Phenoxyacetyl-lysyl-lysyl★★-([)-2-amino-3-cyclo hexylpropanoyl) -(+23)-2-amino-3-cyclohexylpropanoyl panoyl)-alanyl-D-alanyl-arginyl★★ FAB MS: (M〒〒　H)　=1037 Example 238 H-phenylalanyl-lysyl-alanyl-(+23)-2-amino-3-silyl hexylpropanoyl)-([3,4-dehydro)prolyl (R/5)) -Icyl-D alanyl-arginyl-FAB MS: (M+H) = H3 Example 239 H-phenylalanyl-lysyl-alanyl-[29)-2-amino-3-cyclo hexylpropanoyl) -[3,4-dehydro)prolyl (R/S)) -ro isyl-D alanyl-arginyl-OH FAB" MS: (M1H) -953 Example 240 (N-methyl)phenylalanyl-lysyl-alanyl-(+29)-2-amino -3-cyclohexylpropanoyl)-7 ranylleuciluma (CH-Cl -glycyl-arginyl-0HBoc-0 isiluma (CH-CI()-glycyl The sil-OH ethylene isostere is described in the literature fA, 5111tnstzin, P , C*rpino, F.

MiY*ke, P, Lpkir+t, TNrshtdrom Ltth, +986 ．． 27. 2095. ) is produced in the same manner as described in ``Peptide Synthesis''. Law” 2nd edition.

M, Bod*n5sky, Y, S, K11isae+ and fellow, A, 0nd by the classical solution method, exemplified by the method described in I1F (1976). and incorporated into the peptide.

Example 241 H-phenylalanyl-lysyl-((3,4-dehydro)prolyl (R/S)) -((2S)-2-amino-3-cyclohexylpropanoyl)-alanyl- leucyl-D alanyl-arginyl 0H FAB MS: (M+H) + Fable953+ Example 242 H-phenylalanylurisilyl ((3,4-dehydro)prolyl (R/S)) -((29)-2-amino-3-cyclohexylpropanoyl)-alanyl- leucyl-D alanyl-arginyl OH + FAB MS: (M+H)”=953 Example 243 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-silyl (chlorohexylpropanoyl)-alanyl-leucyl-D-arginyl-glycyl- 0H FAB” MS: (M+H)” = 915 Example 244 H-phenylalanyl-lysyl-aspartyl-((29)-2-amino-3- cyclohexylpropanoyl) -((23)-2-amino-3-cyclohexy (propanoyl)-isoyl-D-arginyl-arginyl-0H FAB" MS: (M+H) + Fable 1140 Example 245 H-phenylalanyl-lysyl-alanyl-tryptophyl-((23)-2- Amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-argini Le-0HFAB” MS: (M+H)” 1044 Example 246 H-phenylalanyl-lysyl-alanyl-(+2R)-2-amino-3-sil chlorohexylpropanoyl) -((2S)-2-amino-3-cyclohexy (propanoyl)-leucyl-D alanyl-arginyl-0H FAB+MS: (M+H)” 1011 Example 247 H-phenylalanyl-lysyl-alanyl-D-alanyl-((2S)-2-ami (-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl- 0H FAB MS: (M+)I)”-929 Example 248 (N-methyl)phenylalanyl-lysyl-alanyl-((2S)-2-amino -3-Cyclohexylpropanoyl)-alanyl-leucyl-IF (CH-C H2) -glycyl-arginyl-OH Boc-leucyl-su(CH-CHI-G) prepared as described in Example 240 By hydrogenating lysyl-OH with palladium-carbon, BOC- Sil-v(CH2-CH2)-glycyl-OH was produced and used in the synthesis of Example 2. It was incorporated into a peptide in the same manner as the synthetic method.

Example 249 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-glycyl-D-tryptopyl-D-alanyl-argyl Nil-0HFAB MS: (Mshi H)” = 988+ Example 250 H-Histidyl-lysyl-phenylalanyl-tyrosyl-((2S)-2-ami Nor-3-cyclohexylpropanoyl)-leucyl-D-alanyl-arginyl- 0H FAB MS: (M+H) -1087 Example 251 H-phenylalanyl-lysyl-glycyl-((2S)-2-amino-3-silyl (chlorohexylpropanoyl)-glycyl-leucyl-D-alanyl-arginyl- 0H FAB MS・(M+H)+=901 Amino acid analysis value: Phe (1,00 ), Lys (1,17), Cha (1,07), Leu (1,08), Ala (,94), Arg (1,07).

H(4N02) Phenylalanyl-lysyl-aspartyl ((23)-2-ami nor-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclo hexylpropanoyl)-isoyl-D-arginyl-arginyl-0HFAB MS: (M+H) = lll15 Example 253 H-(f23)-2-amino-3-cyclohexylpropanoyl)-lysyl-a Spartyl-((23)-2-amino-3-cyclohexylpropanoyl)- (+23)-2-amino-3-cyclohexylpropanoyl)-leucyl-D a Luginyl-arginyl-0H FAB MS: (M+H) Tomi 1146 Example 254 (N-methyl)phenylalanyl-lysyl-alanyl-(+28)-2-amino -3-cyclohexylpropanoyl)-alanyl-leucyl-ma(C(-0)- CH2) -glycyl-arginyl-OH Boc-o isiluma (C(-0)-CH2)-glycyl-OH isostere Literature (+, McM * rr * 1. D, I) tckss, Mu'mouth' Engineering C hew, 19g5. Produced in the same manner as described in So, +112), "Peptide Synthesis Method" 2nd edition, M, l1odtsstk7. Y, S, II* by the method described in w+nst and M, A, 0ndttji (1976). Incorporated into peptides by classical solution methods as exemplified by

Example 255 H-(3-No2)tyrosyl-lysyl-aspartyl-(+23)-2-ami -3-cyclohexylpropanoyl)-, ((29)-2-amino-3-cyclo lohexylpropanoyl)-leucyl-D arginyl-arginyl-0H FAB MS: (M+H) 1201 Example 256 H-)ribtophyl-lysyl-alpartyl-([28)-2-amino-3-sil (chlorohexylpropanoyl)-((23)-2-amino-3-cyclohexylp lopanoyl)-leucyl-D arginyl-arginyl-0H FAB MS: (M+H)” 1179 Example 257 H-13-+2'-chenyl)alanyl (R/S))-lysyl-aspartyl -((25)-2-amino-3-cyclohexylpropanoyl] -((!S) 　-2-amino-3-sif-a-hexylpropanoyl)-acyl-D-arginyl -Arginyl-0HFAB MS: (M+H)” 114! Example 25g H-13-(2'-chenyl)alanyl(R/5))-lysyl-aspartyl- (+23)-2-amino-3-cyclohexylpropanoyl) -(f’s) -2-amino-3-cyclohexylpropanoyl)-isoyl-D-arginyl- Arginyl-○HFAB MS: (M+H)-1148 Example 259 H-(4-CH3)phenylalanyl-lysyl-aspartyl-((29)- 2-amino-3-cyclohexylpropanoyl)-((28)-2-amino-3 -cyclohexylpropanoyl)-leucyl-D arginyl-arginyl-0H FAB MS: (M+H)”-1154 Example 26G (N-methyl)phenylalanyl-lysyl-alanyl-((28)-2-amino -3-cyclohexylpropanoyl)-alanyl-leuciluma (CI((-O H)-CH2)-glycyl-arginyl-0H Boc-Leucyluma (C(0)-CH2)-glycyl-OH isostere is Literature (+, McMsrrH, D, DrCkss, Mul” Engineering Chsm, 1 9B5. 50. 1+12. ), boron hydride Boc-leuciluma (CH(-OH)- CH2)-glycyl-OH, "Peptide Synthesis Method" 2nd edition, M, Il+dgasrky Y, S.

11■5aer and those listed in 0ndC++if (1976) Incorporated into peptides by the classical solution method exemplified by the method.

Example 261 H-13-(2'-Is'-te-butylchenyl))alanyl (±)) -lysyl-aspartyl-(+23)-2-amino-3-cyclohexylpropyl ((28)-2-amino-3-cyclohexylpropanoyl)-((28)-2-amino-3-cyclohexylpropanoyl)- Sil-D arginyl-arginyl-0H FAB MS: (M1H)”-1202 Example 262 H-phenylalanyl-lysyl-alanyl-us)-2-amino-3-cyclo xylpropanoyl)-glycyl-leucyl-glycyl-arginyl-0H FAB MS: CM+H) +9tll Amino acid analysis value: Phe (1,0 7), Lys (,97), Ala (1,10), Cha (1,05), Gly (1,54), Leu (1,116).

A r g (+15) Implementation M 263 H-Histidyl-lysyl-alanyl-(+23)-2-amino-3-cyclohexyl silpropanoyl)-+4-NH2)phenylalanylleucilyl-D-alanyl -(4-NH2)phenylalanyl-0H FAB MS: (M+H) = IO16 Example 264 H-(4-NH2)phenylalanyl-lysyl-aspartyl-((2S)-2 -amino-3-cyclohexylpropanoyl)-((23)-2-amino-3- cyclohexylbronoyl)-isoyl-D arginyl-arginyl-0H FAB MS: (M+H) Collection 1155 Example 265 H-(3N H2)Tyrosyl-lysyl-aspartyl-((29)-2-amino -3-cyclohexylpropanoyl) -([23)-2-amino-3-cyclo hexylpropanoyl)-isoyl-D arginyl-arginyl-0H FAB MS: (M+H) = 11711171 implementation H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-silyl (chlorohexylpropanoyl)-phenylalanyl-leucyl-D-alanyl-al Guinyl-0HFAB MS: (M+I() +=1005+ Amino acid analysis values: Phe (1,911), Lys (1,00), Ala ( 1,90), Cha (1,Q?), Le u (1,07), Ar g (1,04) Example 267 (N-methyl)phenylalanyl-lysyl-alanyl-((23)-2-amino -3-cyclohexylpropanoyl)-alanylleuciluma (C(-CH) -CH2) -glycyl-arginyl-0H BoC-Glycyl-IF (C(-CH)-CH2)-Glycyl-OH etc. power distribution The parent body is methylenetriphenylphosphorane, and the literature (J, McMwrrB, D , J. Jekes, 1. Org, Chew, 190.50°1112, 1 Boa-glycyl-V(Co-CH2)-glycyl prepared as described in -OH and is produced by condensation with "Peptide Synthesis Method" 2nd edition, M, Bo d■■ky, T, S.

Those described in K15w1ner and M, A, Ondelli (1976) The peptides were incorporated by classical solution methods as exemplified by the method.

Example 268 H-phenylalanyl-lysyl-alanyl-phenylalanyl-((2S)-2 -amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arg Nil-0HFAB MS: (M+H)-1005 Amino acid analysis value: Phe (1,98), Lys (1,0fl), Aha (1,89), Cha (1, IQ), Leu (1,08), Arg (1,05) Example 26 9 H-[1-CH)Histidyl-lysyl-aspartyl-((2S)-2-amino -3-cyclohexylpropanoyl) -(f2s)-2-amino-3-cyclo hexylpropanoyl)-leucyl-D arginyl-arginyl-0H FAB MS: (M+H)-1144-2-amino-3-cyclohexyl propanoyl)-((23)=2-amino-3-cyclohexylpropanoyl) -Loin-RouD Arginyl-Arginyl-0H FAB MS: (M+H)’-1141 Example 271 H-phenylalanylurisyl-as/glutyl-((2S)-2-amino-3 -cyclohexylbronoyl)-glutaminyl-leucyl-glycyl-al Guinyl-0HFAB MS: (M+H)”=1016 Example 272 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-glutaminyl-leucyl-D-alanyl-arginyl -0HFAB MS: (M1H) +1062 Amino acid analysis value: His ( 0,95), Lys (1, H), Asp (0,97), Cha (0,9) , Gln (1,03), Leu (1,05).

A I a (0,97), A r g (1,03) Example 273 H-phenylalanyl-lysyl-((23)-2-amino-3-cyclohexyl propanoyl)-alanyl-alanyl-leucyl-D alanyl-arginyl-0 H FAB MS: (M+) -929 Amino acid analysis value: Phe (1,00 ), Lys (1,01), Cha (0,96), Ala (2,92) , Leu (1,05), Arg (1,02) Example 274 H-phenylalanyl-lysyl-alanyl-(f23)-2-methylamino- 3-cyclohexylpropanoyl) -((23)-2-amino-3-cyclo xylpropanoyl)-isoyl-D-alanyl-arginyl-OH + FAB MS: (M+H) + Dew 1025 Amino acid analysis value: Ala (1,6 3), Leu (1,04), Phe (0,96), Ch a (0, 95), L y s (0,91), A r g (1,0 Example 275 (N-methyl)phenylalanyl-lysyl-alanyl-(+23)-2-amino -3-cyclohexylpropanoyl)-alanylleuciluma(C(=O)- N (OMe))-glycyl-arginyl-OH Literature (H, ONtmhtiii, J, 1lzrscb!id,], Chss , ltw, 198L116, 697. ) as described in Boc-N ( OMe)-glycyl-OH was produced and "Peptide synthesis method" 2nd edition, 11°Bo d*n5xky, Y, S, KI■set, r and 11. A, 0ndt Peptide by the classical solution method, exemplified by the method described in Jli (106). Incorporated into Petide.

Implementation M 1!78 Penzoylpenicillaminyl★-lysyl-alanyl-(+29)-2-amino -3-cyclohexylpropanoyl) -((2S)-2-amino-3-cyclo hexylpropanoyl)-leucyl-〇cysteinyl★-arginyl-OH conversion The compound was prepared in the same manner as in Example 334.

FAB MS: (M+H)” = 11291129 amino acid A1a (0 ,911), Leu (1,01), Cha (1,90), Lys (0,99)', A r g (1,03) Example 277 H-D penicillaminyl★-lysyl-alanyl-((28)-2-amino-3-silyl chlorohexylpropanoyl) -((28)-2-amino-3-cyclohexyl propanoyl)-cysteinyl-D-cysteinyl★-arginyl-OH FAB” MS: (M+H)+Hayabusa IN! Implementation Tsuba 278 H-phenylalanyl-lysil-alanyl-us)-2-amino-3-cyclo xylpropanoyl) -Is) -2-methylamino-3-cyclohexylp (ropanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H) -1025 Amino acid analysis value: AIa (1,H ), Leu (1,04), Phe (0,9D, Cha (0,99), L F# (1,011), Arg (1,08) Example 27g Benzoyl-Dbenicillaminyl★-lysyl-alanyl-((2S)-2-amino -3-cyclohexylpropanoyl)-[2S)-2-amino-3-cyclohexyl silpropanoyl)-acyl-Dcysteinyl★-arginyl-0HFAB MS: (M+H) = 11291129 amino acid A1a (0,84), Leu (0,88), Cha (2,01), Lys (1,01) , A r g (1,04) Example 211G H-phenylalanyl-lysyl-glycyl-(+28)-2-amino-3-cyc lohexylpropanoyl)-glycyl-leucyl-glycyl-arginyl-0H FAB" MS: (M+H) -887 Amino acid analysis value: Phe (1, 02), Lys (1,0D), Cha (1,03), Leu (1,09 ), Arg (1,05), Gly (2,H) Example 281 (N-methyl)phenylalanyl-lysyl-alanyl-((23)-2-ami nor-3-cyclohexylpropanoyl)-glycyluma (PO(OH)-Nl( )-Leucyl-glycyl-arginyl-0H Cbz-Gly-Ma(PO(OH)-NH)-oIshiruG I Y-OH Literature (P, BgNltH, C, M*rlov@, Biochemi+jr7 1987, 26. 8554. ) as described in ``Peptide Synthesis''. Law” 2nd edition, M, BodInsky, Y, S, KI*w+nsr and ,A.

by the classical solution method, exemplified by the method described by 0ndNli (1976). was incorporated into the peptide.

Example 282 H-phenylalanyl-lysyl-alanyl-D-phenylalanyl-glycyl-lo Isyl-D alanyl-arginyl-0HFAB MS: (M+H)'- 909 amino acid analysis values: Phe (1,93), Lys (,99), Ala ( 2, IIQ), Gly (,9g), Leu (1, Og), Arg (1,03) Example 283 H-phenylalanyl-lysyl-alanyl-(+23)-2-amino-3-silyl chlorohexylpropanoyl)-glycylupheni FAB MS: (M+H) =949 Amino acid analysis values: Phe (2,14), Lye (,97), Al a (1,77), Cha (1,04), Gly (,99)', Ar g (1,N) Example 284 H-phenylalanyl-lysyl-alanyl-((23)-2-amino-3-cyc (hexylpropanoyl)-glycyl-D-phenylalanyl-D-alanyl-al Guinyl-OH+ FAB MS: (M+H)” 949 Amino acid analysis value: Phe (1,96) , Ly s (1,00), A l a (2,01), Ch, a ( 1,02), Gl y (1,00), Arg (1,03) Example 2 85 H-phenylalanyl-lysyl-alanyl-((29)-2-amino-3-silyl (chlorohexylpropanoyl)-glycyl-tryptophyl-D-alanyl-arg Nil-0HFAB MS: (M+H)”-988 Amino acid analysis value: Ph e (1,02), Lys (1,04), Ala (1, N), Cha ( 1,04), Arg (1,11), Gly (.82).

Trp (,75) Example 286 H-7 22-alanyl-lysil-alanyl-((2;)-2-amino-3-silyl (chlorohexylpropanoyl) -(f29) -2-amino-3-cyclohexy (propanoyl)-leucyl-alanyl-D-arginyl-0H FAB” MS: (M+H)” = 1011 Example 287 (N-methyl)phenylalanyl-lysyl-alanyl-((2B>-2-amino -3-cyclohexylpropanoyl)-glycyluma (PO(OMe)-NH) -Leucyl-glycyl-arginyl-0H Cbz-glycyl-ma(PO(OMe)-NH)-oylglycyl-OH Literature (P, BgrlliN, C, Mtrlovc.

Biocbemi+Iry 1987.26. 8554. ). "Peptide Synthesis Method" Grave 2nd Edition, M. BodznItkl, Y. S.

By the method described in Kl■5ntr and LA, O+deguchi 1 (1976). Incorporated into peptides by classical solution methods as exemplified by

Example 288 H-phenylalanyl-lysyl-((2R)-2-amino-3-cyclohexyl propanoyl)-alanyl-alanyl-leucyl-Dalanyl-arginyl~O H + FAB MS: (M+H)”=929 Example 289 H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminirulo Isyl-glycyl-arginyl-0HFAB MS: (M+H)””9 94+ Amino acid analysis fil: Phe (11,91), Lys (1,06), Asp (0,94), Met (0,85), Gln (1,02 ), Leu (1,07).

G I Y ([99), A r g (1,02) Example 290 Ac-Histidyl-lysyl-aspartyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-glutaminyl-leucyl-glycyl-arginyl- 0H FAB + MS + (M + H)' = 1048 Example 291 H-phenylalanyl-lysyl-alanyl-([2S)-2-7 minnow 3- cyclohexylpropanoyl)-alanyl-leucyl-D (4N O2) Nylalanyl-arginyl-〇HFAB MS: (M+H)”=105 0+ Amino acid analysis values: Phe (0,67), Lys (0,66), Ala ( 1,59), Cha (0,93), Leu (1,00), D (4-N o2) P h e (0,92), A r g (1,0G) Example 292 H-phenylalanylurisyl-(f2R/S)-2-amino-5-phenylpene ((2S)-2-amino-3-cyclohexylpropanoyl) -alanyl-loin-D alanyl-arginyl-0H FAB” MS: (M+H) = 1033 Amino acid analysis value: Ph e ( 0,94), Lys (1,001, hhPh e(0,82), Cha ([1,93), Ala (2,0G), Leu (1,04).

H-phenylalanylurisilyl(f2R/S)-2-amino-5-phenylpene ntanoyl-((2S)-2-amino-3-cyclohexylpropanoyl )-alanyl-leucyl-D alanyl-arginyl-〇H FAB MS: (M+H)”=1033+ Example 294 H-phenylalanyl-alanyl-lysyl-((25)-2-amino-3-cyc lohexylpropanoyl)-alanyl-leucyl-D alanyl-arginyl-0 H FAB MS: (M+H) -929 Example 295 H-Finylalanyl-lysil-alani-alanyl-leucil-alani-D Alanyl-arginyl-0HFAB+MS: (M+H)”-847 Example 296 H-phinylalanyl-lysilylalanyl-((2s)-2-amino-3-cyc lohexylpropanoyl)-alanyl-leucyl-(N-methyl)D-alanyl- Arginyl-OH+ FAB MS: (M+H) +-943 (0,96), Cha (0, 94), Lys (0,96), Arg (1,02) Example 297 Formyl-IF (NH-co)-D Phenylalaniluma (NH-Co)-D Lysyluma (NH-Co) glycyl-((2S)-2-amino-3-cyclohexyl silpropanoyl)-alanyl-leucyl-NMeD alanyl-arginyl-O H-Formyluma (NH-Co)-D Phenylalaniluma (NI(-Co)- D. lysyluma (NH-Co) glycyl-01 (fragment was prepared using the classical solution method (“ Peptide Synthesis Method” 2nd edition.

M,Ilodsmssk7. Ma, S, Kltw+l1sr and M, A, 0a dstt+IF (exemplified by the method described in 1976), It was incorporated into a peptide in the same manner as in Example 2.

Example 2g8 H-phenylalanylurisilupenicillaminyl★-(+23)-2-amino- 3-cyclohexylpropanoyl) to -(+28)-2-amino-3-cyclo xylpropanoyl)-acyl-Dcysteinyl★-arginyl-OH compound The product was manufactured in the same manner as in Example 334.

ten FAB MS: (M+H)”-1101 Example 299 H-phenylalanyl-lysyl-asparaginy-((2S)-2-amino-3 -cyclohexylpropanoyl) -(+28) to -2-amino-3-cyclo xylpropanoyl)-〇isyl-D alanyl-arginyl-NCH3NH2 pieces The compound was produced in the same manner as in Example 38.

FAB MS: (M+H) -100 Amino acid analysis value: Asx (1,02 ), Ala (0,94), Leu (1,05), Phe (0,98 ), Cha (1,96), Lye (0,97).

A r g (1,08) Example 300 H-phenylalanyl-lysyl-asparaginyl-((25)-2-amino-3 -cyclohexylpropanoyl) -((23) to -2-amino-3-cyclo xylpropanoyl)-isoyl-D-alanyl-arginyl-NHNH2 This compound was produced in the same manner as in Example 38.

FAB MS: (M+)I)” -1068 Amino acid analysis value: Asx ( 0,98), Ala (0,99), Leu (L[18), Phe ( 1,00), Cha (1,97), Lys (1,03).

A r g (1,04) Example 301 (N-methyl')((2S)-2-amino-3-cyclohexylpropanoyl) -lysyl-alanyl-((2S)-2-amino-3-cyclohexylpropanoyl )-((25)-2-amino-3-cyclohexylpropanoyl)-mouth Lu-D alanyl-arginyl-OH FAB MS: (M+H) Lou 1031 amino acid analysis value: A1a (1,8 7), Leu (1,06), Cha (1,96), Lys (1, 01), A r g (1,06) Example 3N (N-methyl)phenylalanyl-lysyl-alanyl-((H)-2-amino- 3-cyclohexylpropanoyl)-18)-2-amino-3-cyclohexyl propanoyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M1H)” = 1025 Amino Shun analysis value: A1a (1, 87), MePhefo, 87), Leu (1,06), Cha (1,92) ), Lys (0,98), Arg (1,04) Example 303 H-phenylalanyl-lysyl-alanyl-(+2S)-2-amino-3-cyc lohexylpropanoyl) -([23)-2-amino-3-cyclohexylp Ropanoyl)-7 ranyl-glycyl-arginyl-OH FAB" MS: (M+H) -955 Amino acid analysis value: Phe (,99) , Lys (1,03), Ala (1,98), Cha (2,14), Gl y(,91), Arg (1,09) Example 304 H-phenylalanyl-lycyl-glycyl ((23)-2-amino-3-cycyl ((23)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-leucyl-glycyl-arginyl-OH FAB MS: (M+H)” 983 Amino acid analysis value: Phe (1, 00), Lys (1,06), Cha (2,18), Gly ( 1,79), Leu (1,07), Arg (1,08) Example 305 Ac-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3- cyclohexylpropanoyl)-alanyl-leucyl-D alanyl-tyrosyl- 0H FAB MS: (M+H) = 978 Example 306 H-phenylalanyl-lysyl-tyrosyl-((23)-2-amino-3-cyc lohexylpropanoyl)-alanyl-leucyl-D alanyl-arginyl-0 H FAB MS: (M+H) Tomi 1021 Example 307 (N-methyl)phenylalanyl-lysyl-alanyl-(f2s)=2-amino -3-cyclohexylpropanoyl)-glycyluma (PO(NHMe)-NH ) -o isyl-glycyl-arginyl-0H Cbz-glycylluma (PO(OH)-NH) -CI isylglycyllum 0t Bu in the literature (p, 9*Nlemouth, C, l1trlove.

BioChemiNB 1987. 26.8554. ) as described in Cbz-glycyluma was produced by coupling with methylamine and deprotection. (PO(NHMe)-NH)-leucyl-glycyl-OH was obtained. Cbz-G Lyciluma (PO(NHMe)-NH)-leucyl-glycyl-OH is a Tide Synthesis Method” 2nd edition, M, Bodsas! ky, Y, S, KItw+nsr and and the classic method exemplified by the method described in M. A. Onde1.1 (1976). It was incorporated into the peptide by the standard solution method.

Example 308 H-phenylalanyl-lysyl-alanyl-((23,)-2-amino-3- cyclohexylpropanoyl) -(f2s) -2-amino-3-cyclohexyl Cylpropanoyl l-D leucyl-D alanyl-arginyl-0H FAB” MS: (M+H)”1ull Example 309 H-phenylalanyl-lysyl-alanyl-((28)-2-amino-3-cyc ((23)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-alanyl-D-alanyl-agmatine The peptide was as described in Example 1, except that the protecting groups were not removed at the end of the synthesis. It was synthesized according to the procedure. Cleavage of peptides from resin is carried out using the solid phase peptide synthesis method. J Iohn M, Slew*r+ and l5nis D, Young, Vol. As described on page 91 of the 2nd edition (19114), make the ester using methanol. This could be done by exchange reaction.

The methyl ester was hydrolyzed using sodium hydroxide, followed by DCC-mediated oxidation. The peptide was coupled with agmatine sulfate using the pulling method. protecting group was removed by treatment with liquid HF/anisole.

FAB MS: (M+H) = 967 Example 31G H-phenylalanyl-lysyl-alanyl-((29)-2-amino-3-cyc lohexylpropanoyl) -((H) -2-amino-3-cyclohexylp lopanoyl)-sarcosyl-D alanyl-arginyl-0H FAB" MS: (M+H) +-969 Amino acid analysis value: Phe (1, 01), Lys (1,04), Ala (1,87), Cha (1,9 4), Ar g (1, QIl), Sa r (1, 10) Example 311 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-silyl (chlorohexylpropanoyl)-sarcosyl-leucyl-D-alanyl-arginyl -0H FAB MS: (M+H) +=929 Amino acid analysis value: Phe (,97) , Lys (1,00), Ala (1,98), Cha (1,02) , Leu (1,04), Arg (1,01).

S a r (1, 13) Example 312 H-phenylalanyl-lysyl-alanyl-(f28)-2-amino-3-silyl Chlorhexylpropanoyl -((2S)-2-amino-3-cyclohexyl propanoyl)-isoyl-sarcosyl-arginyl-OH + FAB MS: (M+H)”=lO11 Amino acid analysis value: Phe(,9 7), Lys (1,00), Ala (,96), Cha (1,93), L eu (1,04), Arg (1,03).

S a r (,93) Example 3N (N-methyl)phenylalanyl-lysyl-alanyl-((23)-2-amino -3-cyclohexylpropanoyl)-glycyl-”I (PO(NMI!2 ) -NH) -o-in-glycyl-arginyl-0H Cbz-glycylluma (PO(OH)-NH)-o-in-glycyl-0tB u to literature (P, L+Ntth, C, Mltl+vs.

BiochemiNr71987.26. 8554. ) as described in Cbz-glycyl- (PO(NMe2)-NI-leucyl-glycyl-OH was obtained.C bz-glyciluma (PO(N M e 2)-NI()-leucyl-g) Lysyl-OH is from "Peptide Synthesis Method" 2nd edition, M, l1odsn+rky, Y, S, KIras++tr and M, A, Qadsjli 1 (1176) Peptides were incorporated by classical solution methods exemplified by the methods described.

Example 314 H-phenylalanyl-lysyl-sarcosyl-(f23)-2-amino-3- cyclohexylpropanoyl) -((2S)-2-amino-3-cyclohexy (propanoyl)-leucyl-D alanyl-arginyl-0H FAB" MS: (M+H) -1011 Amino acid analysis value: Phe(,9 9), Lys (1,02), Leu (1,07), Ala (,86) , Cha (2,12), Arg (1,05).

S a r (1, 13) Example 315 H-phenylalanyl-lysilyl-alanyl-sarcosyl ((23)-2-ami (-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl- 0HFAB+MS: (M+H) -929 Amino acid analysis value: Phe[,9G ), Lys (1,04), Ala (1,83), Cha (1,06 ), Lau (1, OD, Arg (1,06).

S a r (1, 11) Example 316 H-phenylalanyl-lysyl-〇phenylalanyl-((2S)-2-amino -3-cyclohexylpropanoyl)-glycyl-leucyl-D-alanyl-al Ginyl-0HFAB” MS: (M+H)-991 Amino acid analysis value: Ph e (2,00), Lys (1,03), Cha (1,08), Gay (,95), Leu (1,10), Ala (,86).

A r g (1,07) Example 317 H-phenylalanyl-lysyl-alanyl-((23)-2-amino-3-silyl (chlorohexylpropanoyl)-glycyl-leucyl-〇phenylalanylal Guinyroux 0HFAB MS: (M+)I)” -991 Amino acid analysis value: Phe (1,95), Lysf, 99), Ala (1,02), Ch a (1,04), Gly (,92), Leu (1,07).

A r g (1,05) Example 318 (N-methyl)phenylalanyl-lysyl-alanyl-(f23)Cbz-gly Sciluma (PO(OH)-NH)-oinruglycyl-0tBu in literature (P , BsNI@H,C,M*+1ovt.

Biochtmis H71987, 26, 8554,) Cbz-glycyluma (P O(NH2')-NH)-leucyl-glycyl-OH was obtained. Cbz-Glyshi Luma(PO(NH2)-NH)-leucyl-glycyl-OH is a 2nd edition.

M. Bodsnuk7. Y, S, KI*wsezt and M, A, 0nde Peptide by the classical solution method, exemplified by the method described in Mei (1976). Incorporated into Chido.

Example 319 H-phenylalanyl-lysyl-phenylalanyl-(f2s)-2-amino- 3-cyclohexylpropanoyl)-glycyl-leucyl-D-alanyl-arg Nyl-0HFAB MS: (M+H) = 991 Amino acid analysis value: Phe (1,95), Lys (0,97), Gly (6,92), Leu (1 , Q, ), Al a (0,93), Arg (1,00) Example 32 0 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc (hexylpropanoyl)-glycyl-leucyl-tryptophyl-arginyl -○HFAB MS: (M+H) Proverbs 1030 Examples 321 H-phenylalanyl-lysyl-alanyl-[29)-2-amino-3-cyc lohexylpropanoyl)-glycyl-leucyl-phenylalanyl-argini Lu-〇l4FAB MS: (M+H) 991 amino acid analysis value: Phe (1,94), Lys(,99), Ala(1,02), Gly(,96 ), Leu (1,07), Arg (1,03) Example 322 Ac-phenylalanyl-lysyl-((2R/S)-2-amino-5-phenyl pentanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl) -alanyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) = I075 Example 323 Ac-phenylalanyl-lysyl-((2R/S)-2-amino-5-722 Rubentanoyl) -((2S)-2-amino-3-cyclohexylpropano yl)-alanyl-leucyl-D alanyl-arginyl-0H FAB” MS: (M+H)” 1075 Example 324 Formyluma (NH-Co) -D phenylalanyl-IF (NH-Co) -D lysyluma (NH-Co-NH) -glycyl ((23)-2-amino-3 -cyclohexylpropanoyl)-alanyl-leucyl-NMeD alanyl-a The luginyl-0HH-D lysyl-D phenylalanyl-NH2 fragment was Classical solution method (“Peptide Synthesis Method” 2nd edition, M, Bod*ns! 7.T.

Written by S. Kl*Il+ns+ and M. A. OndξHi (1976). methyl isocyanoacetate and coupling formyl-IF (Nl(-Co)-D phenylalanyl-tF (N H-Co)-D! Jsil-11(NH-Co-NH)-glycyl-〇Me was obtained . Then, it is hydrolyzed to the corresponding carboxylic acid and used in "Peptide Synthesis Method" No. 2. Edition, M, [lod*e++ to 7°T, S, Kltasner and colleagues, ^, 0 by the classical solution method, exemplified by the method described by Ndelli Hashi (1976). was incorporated into the peptide.

Example 325 H-valyl-lysyl-alanyl-((2S)-2-amino-3-cyclohexy (propanoyl)-alanyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+1()-881 Amino acid analysis value: Ala (2,9 3), Val (1, H), Leu (1,02), Cha (0,97) , Lys' (1, H), Arg (1,01) Example 326 H-phenylalanyl-sarcosyl-alanyl-((23)-2-amino-3- Cyclohexylpropanoyl -((2S)-2-amino-3-cyclohexyl silpropanoyl)-isoyl-D alanyl-arginyl-0H FAB” MS + (M+H) = 954 Amino acid analysis value: Phe (1,0 G), Ala (1,91), Cha (1,98), Leu (1,07) , Arg (1,05), Sa r (,63) Example 327 H-Sarkosyl-lysyl-alanyl-([2S)-2-amino-3-cyclo xylpropanoyl) -([23)-2-amino-3-cyclohexylpropanoyl (noyl)-isoyl-D alanyl-arginyl-0H FAB MS: (M+H)” -935+ Amino acid analysis value: Lys (1,12), Ala (1,48) , Cha (2,16), Leu (1,17), Arg (1,23) , Sa r (,63) Example 328 H-phenylalanyl-lysyl-((2R/S)-2-amino-5-phenyl pentanoyl)’-((2S)-2-amino-3-cyclohexylpropanoyl )-alanyl-leucyl-glycyl-arginyl-0H FAB MS: (M+H) +=1019+ Example 329 H-phenylalanyl-lysyl-((2R/S)-2-amino-5-phenyl pentanoyl) -((2s)-2-amino-3-cyclohexylpropanoyl )-alanyl-leucyl-glycyl-arginyl-OH + FAB MS: (M+H)”=1019 Example 330 H-phenylalanyl-lysyl-IR/S)-2-amino-5-phenylpenta ((25)-2-amino-3-cyclohexylpropanoyl)- Glycyl-leucyl-glycyl-arginyl-OH + FAB MS: (M+1()”-1005 Example 331 Hydrocinnamoyl-(N-methyl)phenylalanyl-lysyl-alanyl-( [23)-2-amino-3-cyclohexylpropanoyl)-7 ranyl leuci Ru(N-methyl)D alanyl-arginyl-OH Example 332 H-phenylalanyl-lysyl-((2R/S)-2-amino-5-phenylpene -(+28)-2-amino-3-cyclohexylpropanoyl) -glycyl-leucyl-glycyl-arginyl-OH ÷ FAB MS: (M+H)+1005 Example 333 (N-methyl)phenylalanyl-lysyl-(N-methyl)alanyl-((23 )-2-amino-3-cyclohexylpropanoyl)-glycyl-leucyl-( N-methyl) D alanyl-arginyl-0H FAB MS: (M+H)”=H7 Example 334 N-benzoyl-Dbenicillaminylurisyl-alanyl-(+28)-2-a mino-3-cyclohexylpropanoyl)-((28)-2-amino-3-cyclo lohexylpropanoyl)-cysteinyl-Dcysteinyl-arginine cyclic disulfide N-benzoyl-D penicillaminyl (S-4-methylbenzyl)-lysyl (N -tt-Cbz)-alanyl-(+28)-2-amino-3-cyclohexylp -(+28)-2-amino-3-cyclohexylpropanoyl) -Isyl-D cysteinyl (S-(-methylbenzyl)-arginyl (N-g) Anidino-Tos)-0 resin (0.6 g) was prepared by the method of Example 1, Treated as described in Example 2 using HF and anisole. Degassed acetic acid 2 Crude peptides were extracted by treatment with 2×25 ml of 0% aqueous solution. Thereafter, it was diluted to 1.500 ml using degassed distilled water. concentrated ammonium hydroxide The pH of the solution was adjusted to 8.0 by addition of silica. While stirring the solution, add ferric acid. pII was adjusted to 5.0 using Prefilled Bio-Rad Anion Exchange Resin A GX-N10w+I, CI form) was added, stirred for 30 minutes, and filtered. filtrate was passed through a column containing 150 g of XAD-16 molecule adsorbent resin. beginning Wash the column with 11 parts of distilled water and then 11 parts of 50% aqueous alcohol. The sample was desalted by eluting from the column using ethanol flux The mixture was concentrated under vacuum to approximately IG Om+ and lyophilized to form a dry powder. I made it. The crude peptide was then purified by HPLC as described in Example 2. Ta. The obtained compound (12■) has NMR and mass spectra consistent with the proposed structure. showed the tor.

FAB" MS: (M+H) -1129 Example 335 H-phenylalanyl-lysilyl-alanyl-(tls)-2-amino-3-silyl (chlorohexylpropanoyl)-glycyl-〇phenylalanyl-D phenylalanyl Nyl-arginyl-0HFAB MS: (M+H) + 1025 amino acids Analysis values: Phe (2,92), Lys (1,H), Alm (1,01 ), G 1 y (1,00), Arg (1,06), Cha (1, 04) Example 336 H-phenylalanyl-lysyl-aspartyl-((2S)-2-amino-3 -cyclohexylpropanoyl)-alanyl-leucyl-D-arginyl-arg Nyl-0HFAB” MS: (M+H)-1058 Example 337 H-phenylalanyl-lysyl-(f2R/S)-2-amino-5-phenylpene ntanoyl 1-((28)-2-amino-3-cyclohexylpropanoyl )~glycyl-leucil-D alanyl-arginyl-0H FAB MS: (M+H) = l (IN Example 338 H-tryptophyl(N-formyl)-lysyl-alanyl~(+23)-2-a mino-3-cyclohexylpropanoyl)-[8)-2 to amino-3-cyclo xylpropanoyl)-isoyl-D-alanyl-arginyl-0HFAB MS : (M+H)""Ion Example 339 H-phenylalanyl-lysyl-((2R/S)-2-amino-5-phenylpene ntanoyl) -((23) -2-amino-3-cyclohexylpropanoyl )-glycyl-leucyl-D alanyl-arginyl-OH + FAB MS: (M+H)”=ffl19 Example 34G H-phenylalanyl-lysyl-((2R/5)-2-amino-5-phenylpene (antanoyl)-us)-2-amino-3-cyclohexylpropanoyl)-ara Nyl-leucyl-D arginyl-arginyl-OH + FAB MS: (M+H) + Lou 1118 Example 341 H-phenylalanyl-lysyl-((2R/S)-2-amino-5-phenylpene ((2S)-2-amino-3-cyclohexylpropanoyl) -alanyl-leucyl-D arginyl-arginyl-0H FAB MS: (M+H)” -1118+ Example 342 H-phenylalanyl-lysyl-aspartyl-((28)-2-amino-3 -cyclohexylpropanoyl) -[2S)-2-amino-3-cyclohexy (propanoyl)-leucyl-arginyl-arginyl-0H FAB+MS: (M+H) +-100 Example 343 H-phenylalanyl-lysyl-aspartyl-alanyl-((28)-2-a Mino-3-cyclohexylpropanoyl)-〇Isil-D arginyl-argini Le-0HFAB MS: (M+H)” = 1058+ Example 344 H-phenylalanyl-lysyl-aspartyl-alanyl-alanyl-leucyl -D arginyl-arginyl-0HFAB MS: (M+H) + = 97 6+ Example 345 H-((2s)-2-amino-3-cyclohexylpropanoyl)-lysyl-a Spartyl-methionyl-glutaminyl-leucyl-glycyl-arginyl-0 H FAB MS: (M+H) +=1000 Example 346 H-Phenylalanyl-lysyl-alanyl-methionyl-glutaminyl leuci Le-glycyl-arginyl=OHFAB MS: (M-i-H)-950 Example 347 H-phenylalanyl-lysyl-alanyl-([28)-2-amino-3-cyc (hexylpropanoyl)-glycyl-leucyl-〇tryptophyllu-argini Roux HFAB MS: (M+H) = 1030 Example 348 H-phenylalanyl-(S-2-aminoethyl)cysteinyl-alanyl-( (2S)-2-amino-3-cyclohexylpropanoyl -((2S)-2 -amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arg Synthesis, deprotection and cleavage of Nyl-〇H resin-bound peptides are outlined in Examples 1 and 2. I did as I did. Prior to incorporation into the peptide, 5-(2-aminoethyl) -L-cystine residue N-αBoc.

It was protected as a N-6CbZN conductor.

FAB MS: (M+H) Tomi 102S Example 349 H-phenylalanyl-lysyl-alanyl-alanyl-(+28)-2-amino -3-cyclohexylpropanoyl)-isoyl-D-arginyl-arginyl- 0r( FAB MS: (M+H)”-1014 Example 350 H-phenylalanyl-lysyl-aspartyl-((28)-2-amino-3 -cyclohexylpropanoyl) -((23)-2-amino-3-cyclohexyl silpropanoyl)-isoyl-D histidyl-arginyl-0H FAB MS: (M+H) +-1121 Example 351 H-phenylalanyl-lysyl-aspartyl-((2S)-2-amino-3- cyclohexylpropanoyl) -((2S)-2-amino-3-cyclohexyl silpropanoyl)-isoyl-D aspartyl-arginyl-0H FAB MS: (M+)I) = ION Example 352 H-phenylalanyl-lysyl-alanyl-(+29)-2-amino-3-cyc lohexylpropanoyl)-alanyl-leucyl-D-arginyl-arginyl- 0H FAB MS: (M+H)”-1014 Example 353 H-phenylalanyl-lysyl-(+23)-2-amino-3-cyclohexyl propanoyl)-alanyl-alanyl-leucyl-D-arginyl-arginyl- 0H FAB MS: (M+H)” -1014+ Example 354 H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminirulo isyl-D alanyl-arginyl-OH+ FAB MS: (M+H)” 100g Example 355 H-phenylalanyl-lysyl-alanyl-(N-methyl)alanyl-sarkosy leucyl-D alanyl-arginyl-OH + FAB MS: (M+H)”=861 Example 356 H-phenylalanyl-lysyl-alanyl-((23)-2-amino-3-silyl Clohexylpropanoyl)-(N-methyl)alanyl-sarcosyl-D-alani Le-arginyl-0HFAB MS: (M+H) Proverb 9111 Example 357 H-phenylalanyl-lysyl-alanyl-(+2S)-2-amino-3-cyc ((28)-2-amino-3-cyclohexylpropanoyl) lopanoyl)-(N-methyl)alanyl-sarcosyl-arginyl-〇HFAB MS: (M+H) = 983 Example 358 (N-(2-phenyl)ethyl)phenylalanyl-lysyl-alanyl-((2 3) -2-Amino-3-cyclohexylpropanoyl)-alanyl-royniru -D alanyl-arginyl-0HFAB MS: (M+H) 1033 implementation Example 359 D Arginyl-Arginyl-0HFAB MS: (M+H) Tomi932 Example 3 stones O H-phenylalanyl-lysyl-aspartyl-((2S)-2-amino-3- cyclohexylpropanoyl)-glutaminyl-leucyl-D-alanyl-argyl Nyl-0HFAB MS: (M+)I) = 1030 Example 361 Ac-phenylalanyl-lysyl-aspartyl-leucyl-glutaminirulo Isyl-glycyl-arginyl-0HFAB MS: (M+H) Dew 101B Example 362 Ac-phenylalanyl-lysyl-aspartyl-methionyl-glutaminyl Leucyl-D alanyl-arginyl-0HFAB” MS: (M+H) Father-in-law 1ose example 363 AC-Finirualanyl leucilyl-asbarthyl leucil-glutaminullo Isilu D alanyl-arginyl-0HFAB” MS: (M+H) = 1 032 Example 364 H-phenylalanyl-lysil-aspartyl-((2S)-2-amino-3 -cyclohexylpropanoyl)-prolyl-leuleucyl-D-arginyl-a Luginyl-OH+ FAB MS: (M+H) + proverb 1084-amino-3-cyclohexylpro panoyl)-arginyl-leucyl-D arginyl-arginyl-0HFAB MS: (M+H) +=1143 Example 366 H-phenylalanyl-lysyl-aspartyl-(+2S)-2-amino-3 -cyclohexylpropanoyl) -([28) -2-amino-3-cyclohe xylpropanoyl)-leucyl-arginyl-D-arginyl-OH ＋　＋ FAB MS: (M+1() Wing 11411 Example 36T H-phenylalanyl-lysil-aspartyl-((23)-2-amino-3- cyclohexylpropanoyl) -(+23) -2-amino-3-cyclohexyl silpropanoyl)-isoyl-D-arginyl-D-arginyl-0H FAB MS: (M+H) +=l140+ Example 368 H-(1-CH3)Histidyl-lysyl-aspartyl-methionyl-glutami Nylleucyl-glycyl-arginyl-0HFAB MS: (M+)f) +=998÷ Example 369 H(3-CH,)Histidyl-lysyl-aspartyl-methionyl-glutamini Leulocyl-glycyl-arginyl-0HFAB” MS: (M+H)” iN Example 370 H-phenylalanyl-lysyl-aspartyl-((2S)-2-amino-3- cyclohexylpropanoyl)-glutaminyl-leucyl-D-arginyl-al Guinyl-0HFAB” MS: (M+H) + Proverb 1115 Example 371 H-phenylalanyl-lysyl-7ranyl((2S)-2-amino-3-cyc lohexylpropanoyl)-glycyl-leucyl-D-arginyl-arginyl- 0H FAB+MS: (M+H)=1000 Example 372 H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminirulo Isyl-D arginyl-arginyl-0HFAB MS: (M+H)” =1093 Example 3 F3 H-phenylalanyl-lysyl-aspartyl-((28)-2-amino-3 -cyclohexylpropanoyl) -((2' R/S.

38) -3-amino-2-oxo-1-pyrrolidine-(2'-(4'-methyl) )-pentanoyl)-D arginyl-arginyl-0H FAB” MS: (M+H) +=1070-amino-1-cyclohexyl propanoyl) -((2' R/S, 3S)-3-amino-2-oxo-1- Pyrrolidine-(2'-(4'-methyl))-pentanoyl)-D-arginyl-a Luginyl-0H FAB MS: (M+)() = 1070 cases 375 H-phenylalanyl-phenylalanyl-lysyl-alanyl-((23)-2 -amino-3-cyclohexylpro/gnoyl)-((2S)-2-amino-3 -cyclohexylpro-I)-D-leucyl-D-arginyl-0H FAB MS: (M+H) -1087 Example 376 H-13-(1'-naphthyl)alanyl)-lysyl-as! <Rutile-methiony Leu-glutaminyl-leucyl-glycyl-arginyl-〇H FAB MS: (M+H) -1043 Example 377 H-+3- (2'-naphthyl)alanyl)-lysyluas/<rutyl-methio Nyl-glutaminyl leucyl-glycyl-arginyl-0H FAB MS: (M+H) = 1043 Example 378 H-+3-+2'-chenyl)alanyl(R/S))-lysyl-asparti Ru-methionyl-glutaminyl-leucyl-glycyl-arginyl- FAB MS: (M+H) Error 1000 Examples 379 H - +3- (2'-chenyl) alanyl (R/S)) - lysyl asba Rutile-methionyl-glutaminyl-leucil-glycyl-fulginyl-OH FAB Ml (M+H) San 1G011 Example 31H H-((23)-2-amino-4-phenylbutanoyl)-lysyl-ara Nyl-(US)-2-amino-3-cyclohexylpropanoyl)-alanyl -Leucyl-D Arginyl-Arginyl-〇H FAB MS: (M-1-H) Tomi 1G2B Example 381 H-((2R/S)-2-amino-tophenylpentanoyl)-lysyl -alanyl-(+23)-2-amino-3-cyclohexylpropanoyl)- Alanyl-leucyl-D arginyl-arginyl-OH FAB MS: (M+H) 1042 Example 382 H-((2R/S)-2-amino-5-phenylpentanoyl)-lysyl-ara Nyl-CC25)-2-amino-3-cyclohexylpropanoyl)-arani leucyl-D arginyl-arginyl-0H FAB MS: (M+H) = 1042 Example 383 4-F-style nylbutanoyl-lysyl-alanyl-((28)-2-amino-3- cyclohexylpropanoyl)-alanyl-leucyl-D-arginyl-argini Le-0HFAB MS: (M+H) = 1ON implementation M 384 H-phenylalanyluma(OH2-NH)-lysyl-alanyl-(f’s)- 2-amino-3-cyclohexylpropanoyl)-alanylleucilyl D-ara Nyl-Arginyl-OH This compound was prepared in the same manner as Example 4N.

FAB MS: (M+H) -915 Amino acid analysis value: Ala (2,97 ), Leu (1,02), Cha (tl, 89), A r g (1,0 1) Example 385 (N-methyl)phenylalanyl-lysyl-alanyl-((28)-2-amino -3-cyclohexylpropanoyl)-7 ranylleucilyl(N-methyl)D Alanyl-arginyl-0HFAB MS: (M+H)-957 amino acid Analysis values: A1a (2,04), Leu (1,1151, MePhe (0,87) , Cha (0,98), Lys (1,03), Arg (1 , 111) Implementation N 38g (N-α-(2-phenyl)ethyl)lysyl-alanyl-((28)-2-amino Nor-3-cyclohexylpropanoyl)-alanyl-leucyl-(N-methyl) D Alanyl-Arginyl-0HFAB MS: (M+H) 19110 Trap g H-phenylalanyl-lysyl-aspartyl-D-methionyl-glutaminyl Leucyl-D arginyl-fulginyl-0HFAB MS: (M+H) Tomi 1 093 amino acid analysis values: Asp (0,93), Glx (1,06), M, et (0,68), Leu (1,07), Phe (0,97), Lys (0,H).

A r g (2,06) Example 388 H-phenylalanyl-lysyl-aspartyl-methionyl-D-glutaminyl Leucyl-D arginyl-arginyl-0HFAB MS: (M+H) = ID93 Amino Shun analysis value: A11) (0,95), Glx (1,07), Met (0,61), Leu (1,05), Phe (0,911 ), Lys (0,91).

A r g (2,04) Example 389 H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminirulo isyl-D-arginyl-D-arginyl-0HFAR” MS: (M+H)” ION amino acid analysis values: Asp (0,97), Glx (1,06), Met (0,611), Leu (1,05), Phe (0,H), Lys (0,92).

A r g (2,03) ° Example 390 H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminyl D Leucyl-D arginyl-arginyl-0HFAB MS: (M+H)” -11193 Amino acid analysis value: Asp (G, H), Glx (1,05) , Met (0,57), Leu (1,06), P,, he, (0,9 7), Lys (0,92).

A　r　g　C2,02) Example 391 Phenoxyacetyl-lysyl-7ranyl(f's)-2-amino-3-cyc lohexylpropanoyl-alanyl-leucyl-D-arginyl-arginyl- OH Example 392 Phenoxypropanoyl-lysyl-alanyl-((29)-2-aminol 3- cyclohexylpropanoyl)-alanyl-leucyl-D-arginyl-argini Ru-01 (FAB MS: (M+H) 1015 Example 393 H-phenylalanyl-lysyl-glycyl-aspartyl-(+28)-2-a mino-3-cyclohexylpropanoyl)-([23)-2-amino-3-cyclo lohexylpropanoyl)-isoyl-D-arginyl-arginyl-0HFAR MS: (M +) i) -1497 Example 394 3-phenylpropanoyl-lysyl-alanyl-((23)-2-amino-3 -cyclohexylpropanoyl)-7ranylleucilyl-D-arginyl-arginyl Nyl-0HFAB MS: (M+H) Tomi 999 Example 395 H-phenylalanyl-lysyl-3-aminopropanoyl-((29)-2- Amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclo chlorohexylpropanoyl)-isoyl-D-arginyl-arginyl-0HFA B MS: (M+H) -1096 Example 396 H-phenylalanyl-(N-methyl)alanyl-alanyl-(f2S)-2 -amino-3-cyclohexylpropanoyl)-((23)-2-amino-3- cyclohexylpropanoyl)-isoyl-D-alanyl-arginyl-0HFA B MS: (M+H) = 968 Example 397 H-phenylalanyl-lysyl-aspartyl-(+29)-2-amiso 3-cyclohexylpropanoyl)-([H)-2-amino-3-cyclo xylpropanoyl)-lysyl-〇lysyl-arginyl-0H FAB MS: (M+H) -1112 Example 398 H-phenylalanyl-lysyl-aspartyl-((23)-2-amino-3 -cyclohexylpropanoyl) -((28)-2-amino-3-cyclohexyl silpropanoyl)-isoleucyl-D alanyl-arginyl-0H FAB MS: (M+H)” 1G55 Example 399 H-phenylalanyl-lysyl-aspartyl-alanyl-alanyl-isoroy Sil-D alanyl-arginyl-0HFAB MS: (M+H) +-89 1 Example 40G H-phenylalanyl-lysyl-〇aspartyl-methionyl-glutaminyl- Leucyl-D arginyl-arginyl-0HFAB” MS: (M+H) +-1093 amino acid analysis value: Asp ((1,97), Glx (1,04) , Met (0,59), Leu (1,06), Phe (0,94) , Lys (0,89).

A r g (2,09) Example 401 H-D Phenylalanyl-lysyl-aspartyl-methionyl-glutaminyl Leucyl-D arginyl-arginyl-0HFAB MS: (M+H) Tomi 1 093 amino acid analysis value: Alp (0,95), Glx (1,05), M et (0,59), Leu (1,05), Pha (11,97), L ys (0,90.

A r g (2, Q7) Example 402 (N-ethyl)phenylalanyl-lysyl-alanyl-Is)-2-amino-3 -cyclohexylpropanoyl)-alanyl-leucyl-(N-methyl)Dara Nyl-arginyl-0HFAB MS: (M+H) 971 amino acid analysis value :A1 a (2,02), Leu (1,03), Cha (197) , L y s (1,01), A r g (0,91) Example 403 (N-methyl)phenylalanyl-lysyl-alanyl-((2S)-2-amino -3-cyclohexylpropanoyl)-alanyl-leucyl-(N-methyl)D Alanyl-arginyl-HNH2 This compound was produced in the same manner as in Example 38.

FAB MS: (M+H) +=971 Amino acid analysis value: AIm (2,0 1), MePhe (0, H).

Leu (1,02), Cha (0,93), Lys (0,98), Arg+@N-butyloxycarbonyl-phenylalanyl-lysyl-arani Ru-([29)-2-amino-3-cyclohexylpropanoyl)-alanyl- leucyl-D alanyl-arginyl-H FAB" MS: (M+H)" -1t129 Example 405 (N-iPr)phenylalanyl-lysyl-alanyl-US)-2-amino-3 -cyclohexylpropanoyl)-alanyl-leucyl-(N-methyl)Dara Nyl-Arginyl-0HFAB Ml (M+H) Tomi■5 Amino acid analysis values: A1m (2,07), Leu (19ri), Cha (0,97 ), L y s (0,99), A r g (0,98) Example 406 H-D(N-methyl)phenylalanyl-lysyl-alanyl-((2S)-2- Amino-3-cyclohexylpropanoyl)-7 ranylleucilyl(N-methy ) D alanyl-arginyl 0H FAB" MS: (M+H) + FAB957 amino acid analysis value: A1a (1,9 7), Leu (1,04), Cha (0,93), Lys ( 0,97), A r g (1,02) Example 4G? H-phenylalanyl-lysyl-aspartyl (Nf(NH2)-[[23)- 2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3 -cyclohexylpropanoyl)-isoyl-(N-methyl)D-alanyl-al Guinyl-HNH2 This compound was produced in the same manner as in Example 38.

FAB MS: (M+H)”-1083 Example 408 H-phenylalanyl-lysyl-aspartyl (NC)1 aNH2)-([ 2S)-2-amino-3-cyclohexylpropanoyl)-l5)-2-amino -3-cyclohexylpropanoyl)-isoyl-(N-methyl)D-alanyl- Arginyl-NCH3NH2 This compound was produced in the same manner as in Example 38.

FAB” MS: (M+H) = 11111111 implementation H-phenylalanyl-lysilyl-alanyl-((28)-2-amino-3-silyl chlorohexylpropanoyl)-7ranyl-W(CH2-NH)-isoyl-p Alanyl-Arginyl-OH This compound was prepared in the same manner as Example 4N.

FAB MS: (M+H) Rich 915 amino acid analysis value: Ala (1,97) , Phe (0,99), Cha (1,79), Lys (1,02 ), A r g (1,01) Example 410 H-phenylalanyl-lysyl-alanyl-C(2s)-2-amino-3-sil chlorohexylpropanoyl)-alanylleuciluma (CH2-NH)-D Alanyl-Arginyl-OH This compound was prepared in the same manner as Example 4N.

FAB" MS: (M+H)"-91'5 Amino acid analysis value: AIa (2, 02), Phe (0,97), Cha (0,94), Lys (1, 01), A r g (0,82) Example 411 H-phenylalanylurisilylalaniluma(CH2-NH)-((28)- 2-amino-3-cyclohexylpropanoyl)-alanylleucilyl D-ara Nyl-Arginyl-OH This compound was prepared similarly to Example 4H.

FAB M! 3: (M-1-H) -915 Amino acid analysis value: A1a (2 ,06),Leu(1,Q5),Phe(0,94),Lys (0,99), A r g (0,95) Example 4!2 H-phenylalanyl-lysyl-alanyl-((25)-2-amino-3-cyc lohexylpropanoyl)-ma(C)12-NH)-alanylleucilyl D-a Ranyl-arginyl-OH This compound was prepared in the same manner as in Example 413.

FAB “MS”: (M+H)+Ag 9!5 Amino acid analysis value: Ala (2,00 ), Leu (1,02), Phe (0,97), Lys (1,02) , A r g (1, H) s Example 4N H-phenylalanylurisiluma(CH2-NH)-alanyl-((28)- 2-Amino-3-cyclohexylpropanoyl)-alanyl-leucyl-Dara N-a7Boc-lysine (N-z-C bz) to its N,O-dimethylhydroxamate, which is described in the literature: i 1t1ha, S, M, 1leiareb, Ttrrxhtdrom Ls N, using lithium aluminum hydride according to 19111.22°3815 Reduction gave N-a-Boa-N-z-Cbz-ricinal. Then Boa - except that after coupling alanine, the chain is stopped in Procedure A step 2. Then, the peptide chain was extended by the method described in Example 1. N-a-BoC- N-ε-Cbz-ricinal (235 μm, 3.5 equivalent mole) was added to 0.1% glacial acetic acid. Containing D M F lGm1, then add sodium cyanoborohydride (404■.

1a equivalent mole) was added. The reaction was allowed to stand at room temperature for 1 hour. Obtained peptide The resin was mixed with DMF, (3 times, 1lal) and methylene chloride C, 3 times, 111 After washing with m1), the next synthesis step (Example 1゜Procedure A Step 2) was started. I got it. The peptide resin was then treated as described in Example 2 to create the display structure. 27.8 ml of pure product was obtained, consistent with the structure.

FAB+MS: (M+H) 915 amino acid analysis value: A1a (1,99 ), Leu (1,01), Phe (0,94), Ch a (0,93) , A r g (1,06) other aminoaldehydes (Boc-phenylalanar Boc-(2S)-2-amino-3-cyclohexylpropanal, Boc -aranal, Boc-leucinal and Boc-D-aranal) using literature methods. : l11. L, Aahow+7. M, Ar+ckX, P.

H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminirulo Isyl-glycyl-D-arginyl-0HFAB MS: (M+H)”- 994+ Amino acid analysis values: Asp (0,95), Glx (1,08), Gly ( 0,7)), Met (0,56), Leu (1,04), Phe ( 0,97).

L y s (0,94), A r g (1,03) Example 415 H-Phenylalanyl-lysyl-7 subalthyl-methionyl-glutaminyl-D Leucyl-glycyl-arginyl-0HFAB MS: (M+H) Fable 994 Amino acid analysis values: Asp (0,96), Glx (0,93), Gly ( 0,67), Met (0,54), Leu (1,06), Phe (0,97).

L　y　s　(0,8D　,　A　r　g　(1,05) Example 416 H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminyl Leucylglycyl-arginyl-0HFAB+MS: (M+H) +-9 94 amino acid analysis values: Asp (0,97), Gig (1, H), Gly [0,67), Mel(0,61).

Lee (1,114), Phe (0,18), Lr5 (0, Hl, Art (1,115) Example 41 H-phenylalanyl-lysyl-aspartyl-D-methionyl-glutaminyl Leucyl-glycyl-arginyl-0HFAB MS: (M+H) + 99 4 Amino acid analysis value: ＾uf0.4f), Glf (・, 32), Gly (0,61), 1lej(11,64).

Lee fl, Go), Phe (・, 21), LFI (010) , Art (1,001 Examples 418 H-phenylalanyl lysilyl D aspartyl-methionyl-glutaminyl Leucyl-glycyl-arginyl-0HFAB+MS: (M+H)+Tomi99 4 Amino acid analysis value: A+p (0,46), Glf (0,28), Gl r (0,681, MetfO, 59).

Lee (1,00), Phe (0,24), Ly+(0,291, Ar t(1,0G) Example 419 H-phenylalanyl-lysyl-aspartyl-methionyl FAB” MS : (M+H)+th994 Amino acid analysis value: ^+p(0,471, Glx(0 ,31), Glf(0,84), M@j(0,531.

Lee (1,04), Pbt (0,221, Lr5 (0,26), Ar t(0,961 Example 420 H-phenylalanyl-lysyl-aspartyl-((25)-2-amino-3- cyclohexylpropanoyl)-3-aminopropanoyl-leucyl-D-algyl Nyl-arginyl-01 (FAB MS: (M+H) Tomi 1058 Example 4 21 H-phenylalanyl-lysyl-alanyl-((23)-2-amino-3-silyl (chlorohexylpropanoyl)-alanyl-leucyl-D alanyluma (0M2- NH)-Arginyl-OH This compound was prepared in the same manner as Example 413.

FAB+MS: (M+H)”-915 Amino acid analysis value: A11 (1,11 0), Lee (1,02), Phe (1, Hl, Chs (1,00 ).

(N-(3-phenyl)propyl)lysyl-alanyl-((2S)-2-amino -3-cyclohexylpropanoyl)-alanyl-leucyl-(N-methyl)D Alanyl-arginyl-OH FAB MS: (M+H) Tomi 914 Example 423 (N,N-di(3-phenyl)propyl)lysyl-alanyl-((28)-2 -amino-3-cyclohexylpropanoyl)-alanyl-leucyl-(N-methane) chill) D alanyl-arginyl-0H FAB+MS: (M+H)"-1ON Amino acid analysis value: Todoroki 11 (!, 1it), Lee (i, 61, Chs (mouth,!7), LYt( +1.93).

ATE (1,041 Example 424 H-phenylalanyl-lysyl-aspartyl-methionyl-arginyl-roy Cyl-glycyl-fulginyl-0HFAB" MS: (M+H) -100 Amino acid analysis values: Asp (062), Glt [0,991, Met (0,4 9), Lem(1,13).

Pbe (0,301, Lu full, 351, Arg [1,88) real Example 425 H-Phenylalanyl-lysyl-arginyl-methionyl-glutaminyl-roy Cyl-glycyl-arginyl-0HFAB MS: (M+H)”-10 35 amino acid analysis values: GIF (0,38), Glr (0,833, MsNo. , 91), Lsw (1, 13).

Phe (0,271, LH (0,27), Ar’g (1,961 examples) 426 H-phenylalanyl-lysyl-aspartyl-methionyl-glutaminirulo isyl-glycyl-lysyl-0HFAB” MS: (M+H) = 956 Amino acid analysis value: Anfl, 70), GIxfOj2), Glyfl , 94), Mtj (11, 66).

Le++ fl, 19), Pbe (If, 351, Lts (1 , 891 Example 42] H-phenylalanyl-ornithylu-asvarthyl-methionyl-glutaminyl - Leucyl-glycyl-arginyl-0HFAB MS: (M+H) -9 110 amino acid analysis value: As1l (0; 491, GItfO, 32), GIF (0,71), Mu (0,65).

Lew[1,00), Pbe(0,33), 0rfi(0,25), Arg(1,00) Example 428 H-D Phenylalanyl-lysyl-aspartyl-methionyl-glutaminyl Leucyl-glycyl-arginyl-0HFAB MS: (M+H)-99 4 amino acid analysis values: Asp (0,45), Glx (0,301, Gly (0 ,761,Tot(0,gllll.

Lem(1,0(11, Ph5(fl, 301, Lr+, (il,, 43) , Arrfl, OO) Example 429 H-phenylalanyl-lysyl-aspartyl-(, (2S)-2-amino-3 -cyclohexylpropanoyl)-((28)-2-amino-3-cyclohexy (propanoyl) = leucyl-glycyl-arginyl-arginyl-0HFAB MS: (M+H) -1197H-phenylalanyl-lysyl-aspar thyl-[(2S)-2-amino-3-cyclohexylpropanoyl)-((2S )-2-amino-3-cyclohexylpropanoyl)-leucyl-glycyl-a Luginyl-D Arginyl-〇HFAB” MS: (M+H) +-119? Example 431 H-Phenylprobanoyl-lysyl-asbarthyl-methionyl-glutaminyl - Leucyl-glycyl-arginyl-0HFAB + MS: (M+H) + -979 Example 432 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-arginyl-leucyl-D-alanyl-arginyl- 0HFAB” MS: (M+H)” = 1014 Amino acid analysis value: Alt fl, 86), Ltw (1, ◎4), Pht (1,00), Ch* (0,96).

L7s(0,991, Ar((1,971 Example 433 (N-allyl)phenylalanyl-lysyl-alanyl-((2S)-2-amino -゛3-cyclohexylprono(noyl)-ara Example 43.0 Nyl-leucyl-(N-methyl)D alanyl-arginyl-0HFAB MS : (M+H) Lou 983 Amino acid analysis value: Al*(1,98), Let( 1, +14), Ch Hatake fO, 94), Lts (0,96).

Arπ+1.021 Example 434 (N,N-dimethyl)phenylalanyl-lysyl-alanyl-((23)-2- Amino-3-cycloheicylpropanoyl)-alanyl-leucyl-(N-methy ) D alanyl-arginyl-0H FAB MS: (M+H) = 971 Amino Shun analysis value: A1 Todoroki (2,01 ), L@w (1,061, Ch Hatake (,0,,88), LFI (0, 91).

Arr(1,03) Example 435 biradylcarbonyl-phenylalanyl-lysyl-ara,nyl-((2S)-2 -amino-3-cyclohexylpropano-)-alanylleucilyl D-ara Nyl-teruginyl-0HFAB MS: (M+H) 710j5 Example 43 6 Benzoyl-phenylalanyl-lysyl-alanyl-((25)-2-amino- 3-cyclohexylpropanoyl)-alanyl-leucyl-D alanyl-arg Nil-0HFAB” MS: (M+H)”-1033 Example 437 2-Pyridylacetyl-phenylalanyl-lysyl-alanyl-((2S)-2 -amino-3-cyclohexylpropanoyl)-alanyl-leucyl-D-alani Ru-arginyl-0f (FAB MS: (M+H)-1048 Example 43 8 Ac-phenylalanyl-lysyl-alanyl-((28)-2-amino-3-cy (chlorohexylpropanoyl)-alanyl-leucyl-D alanyl-arginyl- 〇HFAB MS: (M+H) +=971 Example 439 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cylo hexylbropanoyl)-alanyl-leucyl-(N-Bn)glycyl-al Guinyl-0HFAB M! 3: (M+H)” -1005+ Example 440 ((3R/J)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl )-lysyl-alanyl-((23)-2-amino-3-cyclohexylpropano yl)-glycyl-leucyl-D alanyl-arginyl-0H FAB" MS: ('M+H) +-927 Amino acid analysis value: Gly (0, 901, LH (+, 011, Ah kick (1,7g), Ch & (0,98) .

Leg (1,001, Art (1,02) Example 441 ((3R/5)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl )-lysyl-alanyl-((2S)-2-amino-3-cyclohexylpropano yl)-glycyl-leucyl-D alanyl-arginyl-0H FAB MS: (M+H) +-92’l Amino acid analysis value: + Glr(0,92), LyI(1,021, Alt(1,901, Ch@( 0,99).

Lea(1, (171, Art(1,041 Example 442 H-phenylalanyl-lysyl ((3R/5)-L 2,3°4-tetrahydro isoquinoline-3-carbonyl)-((2S)-2-amino-3-cyclohexyl silpropanoyl)-glycyl-leucyl-(methyl)D-alanyl-arginyl -0HFAB+MS: (M+H) -1003 Example 443 H-phenylalanyl-lysyl ((3R/5)-1,2,3°4-tetrahydro isoquinoline-3-carbonyl) -((23)-2-amino-3-cyclohexyl silpropanoyl)-glycyl-leucyl-(methyl)D-alanyl-arginyl -0HFAB MS: (M+H) +=1003 Amino acid analysis value: Phe (0,97), Lr5 (0,94), A11 (0,80), Glr (1,00).

Leg (1,06), A+g (1,04) Example 444 H-phenylalanyl-lysyl-alanyl-((3R/5)-1,2,3,4- Tetrahydroisoquinoline-3-carbonyl)-glycyl-leucyl-D-arani Le-arginyl-0HFAB MS: (M+H) = 921 Amino acid analysis Value: Pbc (0,96), Lts (0,971,, Ah (1,82), Gly (tl, 96).

Let fl, 05), ArM (1, f131 Example A45 H-phenylalanyl-lysyl-alanyl-((3R/5)-1,2,3,4- Tetrahydroisoquinoline-3-carbonyl)-glycyl-leucyl-D-arani Le-arginyl-0HFAB+MS: (M+H)+Feg921 Amino acid analysis Value: Phe (1,01), Lr+(1,00), Alt (1,99), Glr(0,93).

Lzi (+, H), Arg (1,09) Example 446 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl) -((3R/5)-1,2,3,4-tetrahydro Isoquinoline-3-carbonyl)-alanyl-D-alanyl-arginyl-0HF AB MS: (M+H) +=IQ17 Amino acid analysis value: + Ph5 (0,99), Lr5 (0,96), Alt (1,69), Cbi (0,99).

Law (!, 66), Art (1, Go) Example 447 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl) -((3R/5)-1,2,3,4-tetrahydro isoquinoline-3-carbonyl)-alanyl-D-alanyl-arginyl-0HF AB MS: (M+1 () Proverb 1017 Amino acid analysis value: Phe (1,01 ), Lysfl, 02), Ala(1,79), ChI(fl, 9 91.

LFI (1,10), Arl (1,081 examples 448 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-glycyl-((3R/5)-1,2,3,4-tet lahydroisoquinoline-3-carbonyl)-D-alanyl-arginyl-0HFA B+MS: (M+H)”=961 Amino acid analysis value: Phe (0,99) , Lys(1,04), AII(1,94j), GIr(1,03) .

Le++ fl, 071, Art (1,08) Example 449 H-phenylalanyl-lysyl-alanyl-((2S)-2-amino-3-cyc lohexylpropanoyl)-glycyl-((3R/5)-1,2,3,4-tet lahydroisoquinoline-3-carbonyl)-Dalanyl-arginyl-0)IF AB+MS: (M+H)” 961 Amino acid analysis value: Ph5 (1,00) , , Lr5 (1,03), Al8 (2,011, Glr[0,94) .

LFI (1,0?), Arg (1,02) H-phenylalanyl-lysyl -alanyl-((2S)-2-amino-3-cyclohexylpropanoyl)-g Lysyl-((3R/5)-1,2,3,4-tetrahydroisoquinoline-3-ka (M+)I)”-10 03 amino acid analysis value: Phe [0,90), LFI (0,91,), A ll+1.021, Glr(0,98).

Lta[1,02,,), 4+t(ly,06)fl H-phenylalanyl-lysilyl-alanyl-((28)-2-amino-3-cyc lohexylpropanoyl)-glycyl-leucyl-((3R/5)-1,2,3 ,4-tetrahydroisoquinoline-3-carbonyl)-arginyl-0HFAB MS: (M+1() Fable 111113, Example 452 (N,N-di-allyl)phenylalanyl-lysyl-(N-methyl)alanyl- ((2S)-2-amino-3-cyclohexylpropanoyl)-glycyl-leu sil-(N-methyl)D alanyl-arginyl-〇H FAB MS: (M+H) Tomi 1023 Amino acid analysis value: Lts (0,9 1), ChI (0,98), GIF (0,99)', Leg (1,05) .

ArH(0,99) Example 453 (N-allyl)phenylalanyl-lysyl-(N-methyl)alanyl-((23 )-2-amino-3-cyclohexylpro/<noyl)-glycyl-leucyl- (N-methyl)D alanyl-arginyl-0H FAB+MS: (M+)i)”-90 Amino acid analysis value: Lys(0,93 ), Chr (G, 90), GIF+0.91), Lewfl, 05).

ArH(1,02) Example 454 2-Indolylcarbonyl-lysyl-(N-methyl)alanyl-((2S)-2 -amino-3-cyclohexylpropanoyl)-glycyl-leucyl-(N-methyl chill) D alanyl-arginyl-0H FAB"MS: (M+H) + proverb 939 Amino acid analysis value: Lys (0,86 1, ChI (0,9?), Gly (1,01), Lewfl, 03),.

Itt (0,96) Example 455 (N,N-di-methyl)phenylala, nyl-lysyl-(N-methyl)alanyl -((28)-2-amino-13-cyclohexylpropanoyl)-glycyl- leucyl-(N-methyl)D alanyl-arginyl-0H FAB MS: (M+H) -971 Example 456 Ac-(Z-dehydro)phenylalanyl-lysyl-(N-methyl)alanyl- ((23)-2-amino-3-cyclohexylpropanoyl)-glycyl-leu Sil-(N-methyl)D alanyl-arginyl-0H FAB MS: (M+)I) 983 Amino acid analysis value: Lr5(1,H ), Gly(1,01), C15(0,94), Lta(1,, O l).

Arg (0,97) Example 457 Piparoy roof ÷ Nylalanyl-lysyl-alanyl-(,(,2S)-2-ami -3-cyclohexy, lupropanoyl) Arginyl-OH+ FAB MS: (M+H)”-10H Example 458 H-phenylalanyl-arginyl-arginyl-methionyl-glutaminyl Leucyl-glycyl-arginyl-0HFAB+MS: (M+H)+Tomi 106 3 Amino acid analysis values: Glx (0,31), Gly (0,84), MU (0,821, Lsa(1,111.

Phs (0,331, Arg (2,23) Example 459 H-Phenylalanyl-lysyl-arginyl-methionyl-glutaminyl-roy Cyl-glycyl-alanyl-OH+ FAB MS: (M+H) +-950 Amino acid analysis value: GIF (035) , GIF(102), Aft(1451, Met(0,9?).

Lsa(lull, Pb*fO, 261, Lrs[0,30), A+t (1,00) Example 460 (N-methyl)phenylalanyl-lysyl-arginyl-methionyl-glutami Nylleucyl-glycyl-arginyl-OH FAB MS: (M+H) +1049 Amino Shun analysis value: 10 GIxfo, 38), Gly (0,79), Met (0,911, Lt n(0,92).

L41 (0,14), 5 rl (1,671 Example 461 H-phenylalanyl-lysyl-7ranyl((2S)-2-amino-3-cyc lohexylpropanoyl)-alanyl-leucyl-azaglycyl-arginyl- 〇HFAB MS: (M+H) -917゜This peptide is A, S, D ullt, M, B, G11es.

J, C, f111m5. J, Chst SaC, Perkin Trea t, 119g6゜1655~64;^, S, Dint, M, B, G11 t+, J, J, GormlB, J, C.

Willi■1.　E,J,l■ter,J,Cbem,Set,,Perki n　TrsIlg, 11987, 111-120. Manufactured using.

Example 462 H-phenylglycinyl-lysyl-alanyl-((28)-2-amino-3-silyl (chlorohexylpropanoyl)-glycinyl-leucyl-D-alanyl-arginyl -OH Example 463 H-phenylalanyl-lysylcystinyl-((25)-2-amino-3- cyclohexylpropanoyl) -((2S)-2-amino-3-cyclohexy (propanoyl)-alanyl-D-alanyl-arginyl-OH Protected peptide resin H-phenylalanyl-lysyl (N-e-Cbz)- Cysteinyl(S-4-methylbenzyl)-((29)-2-amino-3-cyc ((2S)-2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino-3-cyclohexylpropanoyl) Panoilun〇Isil〇alanyl-arginyl (N-guanidino-Tos)- Merrifield resin was prepared as described in Example 1. Peptides are actually The resin was cleaved as described in Example 2, with the following precautions taken. That is, , cleavage with HF followed by extraction of the peptide using degassed 20% aqueous acetic acid. and HPLC purification was performed using helium saturated solvent.

Example 464 H-phenylalanyl-lysyl-(S-benzyl)cysteinyl-((2S)- 2-amino-3-cyclohexylpropanoyl)-((2S)-2-amino- 3-cyclohexylpropanoyl)-isoyl-D alanyl-arginyl-OH The octapeptide produced in Example 463 was dissolved in methanol saturated with ammonia. The solution was dissolved to form a 0031 solution under a nitrogen atmosphere, and the resulting solution was cooled to 0°C. Base bromide 1.3 eq.) was introduced neat and the reaction mixture was stirred at 0° C. for 1 h.

The entire reaction mixture was poured into water followed by the addition of trifluoroacetic acid to bring the pH to 2. did. The product was then isolated by HPLC using a helium saturated solvent. Ta.

Example 465 Acetamide acryloyl-phenylalanyl-arginyl-aspartyl-( (25)-2-amino-3-cyclohexylpropanoyl)-((28)-2 -amino-3-cyclohexylpropanoyl)-isoyl-D-alanyl-arg 2-acetamidoacrylic acid and isobutyl chloroformate by standard method Excess isobutyl 2-acetamidoacrylate mixed anhydride prepared from 0, IN bicarbonate as a solution in trihydrofuran and containing sufficient acetonitrile. The peptide produced in Example 65 was dissolved in an aqueous sodium solution and stirred at 0°C. The above solution was added thereto to make a homogeneous solution. After stirring at 0°C for 6 hours, the reaction The mixture was brought to pH 2 and the peptide was purified by reverse phase HPLC followed by lyophilization. did.

The foregoing examples are merely illustrative of the present invention and are intended to illustrate the present invention with respect to the exemplified compounds. It is not intended to be limited to.

Modifications and variations that are obvious to those skilled in the art may be made to the invention as defined in the appended claims. shall be included within the scope and substance.

Claims (1)

[Claims] 1. An anaphylatoxin activity modulating compound of formula A-B-D-E-G-J-L-M-Q-T and its pharmaceutically acceptable salts, esters or amides. [In the above general formula, the groups from A to T have the following meanings. A is R1-R2-R3; B is selected from R4-R5-R6, R31, R32, R35 and R37; D is selected from R7-R8-R9, R31, 32, R35 and R37; E is R10-R11-R12, R31, R32, R35 and R37; G is selected from R13-R14-R15, R31, R32, R35 and R37; J is R16-R17-R18, R31, R32, R35 and R37; L is selected from R19-R20-R21, R31, R32, R35 and R37; M is selected from R22-R23-R24, R31, R32, R35 and R37; Q is R25-26-R27 , R31, R32, R35 and R37; T is R28-R29-R30; B and D together are optionally selected from R33, R34, R38, R39, R40, R41, R42 and R43. D and E together optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42 and R43; E and G together represent optionally represents a group selected from R33, R34, R38, R39, R40, R41, R42 and R43; i; G and J together optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42 and R43; J and L together represent Therefore, R33, R34, R38, R39, R40, R41, R42 and and M together optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42 and R43; M and Q together optionally represents a group selected from R33, R34, R38, R39, R40, R41, R42 and R43; R5-R6-R7; R8-R9-R10; R11-R12-R13; -R15-R16; R17-R18-R19; R20-R21-R22; R23-R24-R25; or R26-R27-R28 independently optionally represents R35; vinegar. Here, (a) the group R1 is amino, (lower alkyl)amino, dialkylamino, (aryl) (alkyl) amino, hydroxy, alkoxy, aryloxy, aryla selected from the group consisting of alkoxy, acetamido, thioalkoxy, halogen, aryl, lower alkyl, arylalkyl, (heterocycle)alkyl, heterocycle, arylamino, and hydrogen. (b) R2 is a group consisting of >CR99R100, >C=CR95R96 (present in either the Z- or E-configuration), oxygen, amino, and alkylamino. provided that when R2 is oxygen, amino or alkylamino, R1 is aryl, lower alkyl, arylalkyl or (heterocyclic)alkyl. Ru. (c) Is R3 a group consisting of >C=O, >CH2, >C=S and >SO2? provided that R3 is >CH2 or >SO2, R2 is oxygen, It cannot be mino or alkylamino. (d) R4 is selected from the group consisting of >CH2, >O, >S and >NR101, where R101 is hydrogen, lower alkyl, arylalkyl, alkenyl, hydroxy or alkoxy, provided that R4 is > When O or >S, R1, R2 and R3 together represent a group selected from lower alkyl, arylalkyl, aryl or hydrogen. (e) R5 consists of >CR201R202, >NR203, >C=CR205R20 6 (present in either Z- or E-configuration) and a substituted cyclopropyl of the formula selected from the group. (f) R6, R9, R12, R15, R18, R21 and R24 are >C=O, >CH2, -CH2C(O)-, -NHC(O)-, >C=S, >SO2 and >P (O)X, where X can be selected from hydroxy, alkoxy, amino, alkylamino and dialkylamino. (g) R7, R10, R13, R16, R19, R22, R25 are >CH2 and >NR50 (here, R50 is hydrogen, lower alkyl, arylalkyl, aryl (selected from the group consisting of alcohol, hydroxy and alkoxy). (h) R8 is selected from the group consisting of >CR210R211>NR213, >C=CR215C216 (present in either Z- or E-configuration) and substituted cycloproles of the formula be done. (i) R11 consists of >CR220R221, >NR223, >C=CR225R2 26 (present in either Z- or E-configuration), and a substituted tsukpropyl of the formula ▲ selected from the group. (j) R14 consists of >CR230R231, >NR233, >C=CR235R2 36 (present in either the Z- or E-configuration) and a substituted cyclopropyl of the formula ▲ selected from the group. (k) R17 is a group consisting of >CR301R302, >NR303, >C=CR305C306 (present in either Z- or E-configuration) and a substituted tsukpropyl of the formula selected from. (l) R20 is >CR310R311, >C=CR313, >C=CR315 R316 (present in either Z- or E-configuration) and substituted cyclopropyl of the formula ▲ has a mathematical formula, chemical formula, table, etc. selected from the group consisting of. (m) R23 is >CR320R321, >C=CR323, >C=CR325 R326 (present in either Z- or E-configuration) and substituted cyclopropyl of the formula ▲ has a mathematical formula, chemical formula, table, etc. selected from the group consisting of. (n) R26 is selected from the group consisting of >CR330R331, >C=CR335R336 (present in either Z- or E-configuration) and substituted cyclopropyl of the formula Ru. (o) R27 is >C=O, >CH2, -CH2C(O)-, >C=S, >SO2 and >P(O)X (where X is hydroxy, alkoxy, amino, alkyla selected from the group consisting of (selected from amino and dialkylamino). (p) R28 can be selected from the group consisting of >O, >S, >CH2, and >NR109, where R109 is selected from hydrogen, lower alkyl, (heterocyclic) alkyl, and arylalkyl, with the proviso that When R27 is >SO2 or >P(O)X, R28 is >O or >NR109. (q) R29 represents hydrogen, lower alkyl, arylalkyl and >NR110 (this Here R110 can be selected from hydrogen, lower alkyl, aryl and arylalkyl. (i) when R28 is >O or >S, R29 is lower alkyl or arylalkyl; (ii) when R29 is hydrogen, lower alkyl or arylalkyl; In some cases, R30 is not present. (r) R30 is a group consisting of hydrogen, aryl, lower alkyl and arylalkyl. selected from the loop. (s) R31 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (where m and n are integers independently selected from 0, 1, and 2). (t) R32 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (where p and q are integers independently selected from 0, 1, and 2). (u) R33 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (where t and v are integers independently selected from 0, 1, 2, and 3). Ru. (v) R34 is ▲a mathematical formula, a chemical formula, a table, etc.▼ (where r and s are integers independently selected from 0, 1, 2, and 3). Ru. (w) R35 has ▲a mathematical formula, a chemical formula, a table, etc.▼, where f is an integer from 0 to 3, and X is selected from >C=0 and -CH2-. and R is selected from hydrogen and lower alkyl, provided that (i) when f is 0, X is at C-2 and R is at C-3 or C-4; (ii) ) when f is 1, X is at C-2, R is at C-3, C-4 or C-5, and C-3, 4 is saturated or unsaturated; (iii) f is 2, then x is at C-2, C-3 or C-4, and R is C-2, C-3, C-4, C-5 or C-6, C-3, 4 or C-4, 5 is saturated or unsaturated; (iv) f is 3; , X is at C-2, C-3 or C-4 and R is C-2, C-3, C-4, C-5, C- if X does not occupy that position. 6 or C-7, and C-3, 4 or C-4, 5 or C-5, 6 is saturated or unsaturated. Ru. (x) R36 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (here, g is an integer from 0 to 3). (y) R37 has ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (here, h is 0 or 1) and j is 0 or 1, provided that either h or j must be 1). (z) R38 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (aa) R39 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (ab) R40 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (ac) R41 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (ad) R42 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (ae) R43 has ▲mathematical formulas, chemical formulas, tables, etc.▼(Here, k is an integer from 0 to 2. is a number). (af) Both R1 and R2 optionally represent a group selected from aryl, heterocycle or hydrogen. (ag) R6 and R7; R9 and R10; R12 and R13; R15 and R16; R18 and R19; -CH=CH-, -C≡C-, -C(=CH2)CH2-, -CH(OH)CH2-, -C(O)O-, -C(O)S-, -CH2C(O) It optionally and independently represents a group selected from O-, -CH2C(O)S-, -CH2O-, -CH2S- and -NHC(O)-. However, (i) when R5 is >NR203 or >C=CR205R206, R6 and R7 together represent -C(O)NH- or -C(O)NCH3-, and (ii) R8 is >NR213 or >C=CR215R216, R9 and and R10 together represent -C(O)NH- or -C(O)NCH3-, and (iii) when R11 is >NR223 or >C=CR225R226, R12 and R13 together represent -C(O)NH- or -C(O)NCH3-; represents -CONH- or -C(O)NCH3- (iv) When R14 is >NR233 or >C=CR235C236, R15 and R16 together represent -C(O)NH- or -C(O)NCH3-; (v) When R17 is >NR303 or >C=CR305R306, R18 and R19 together represent -C(O)NH- or -C(O)NCH3-; (vi) When R20 is >NR313 or >C=CR315R316, R21 and R22 together represent -C(O)NH- or -C(O)NCH3-; (vii) When R23 is >NR323 or >C=CR325R326, R24 and R25 together represent -C(O)NH- or -C(O)NCH3-. (ab) R29 and R30 are both hydrogen, hydroxy or alkyl, as the case may be. represents a group selected from koxy, provided that when R28 is >0 or >S, R29 and R30 both represent hydrogen; (ai) R1, R2 and R3 are all lower alkyl, aryl, as the case may be; Peptide fragments consisting of 1 to 8 residues with alkyl, alkenyl, aryl, hydroxy, alkoxy, hydrogen, N-terminal protecting group, or similarly protected, where each amino acid making up the peptide fragment is one of the 20 naturally occurring amino acids. A that occurs in (independently selected from amino acids). (ai) R28, R29 and R30 together optionally represent 20 naturally occurring represents a group selected from dipeptides or amino acids selected from dipeptides. (ak) R1, R2, R3 and R4 all optionally represent a group selected from hydrogen, lower alkyl, arylalkyl, aryl, heterocycle or H2NC(O)-, provided that when R5 is >CH2 , R1, R2, R3 and R4 are both This cannot be the case with hydrogen. (al) R27, R28, R29 and R30 are all optionally hydrogen, lower atom represents a group selected from alkyl, aryl, or arylalkyl. (am) R1, R2, R3, R4 and R5 each represent an aryl group or a heterocyclic group, as the case may be. (an) R95, R96, R205, R206, R215, R216, R225, R226, R235, R236, R305, R306, R315, R313 are hydrogen, lower alkyl, aryl, arylalkyl, (cycloalkyl) Groups consisting of alkyl, amidoalkyl, (carboxamido)alkyl, ureidoalkyl, (heterocyclic)alkyl and halo-substituted alkyl. selected independently from the group. (ao) R99, R202, R211, R221, R231, R302, R311, R321 and R331 are independently selected from hydrogen and lower alkyl. (ap)R100 is hydrogen, lower alkyl, arylalkyl, (cycloalkyl) )alkyl, aminoalkyl, (alkylamino)alkyl, hydroxyalkyl selected from the group consisting of: (aq) R201 is hydrogen, lower alkyl, alkenyl, aryl, aryl alkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydro Roxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamidine) de)alkyl, (carboxyhydrazino)alkyl, ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (amidoalkyl) Notioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfur selected from the group consisting of hydrylalkyl and halo-substituted alkyl. (ar) R203, R213, R223, R233, R303 and R313 are hydrogen, lower alkyl, alkenyl, arylalkyl, (cycloalkyl)alkyl; Kyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoal Kyl, carboxyalkyl, (carboxamido)alkyl, (carboxyhydro) independently selected from the group consisting of radino)alkyl, ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, or protected sulfhydrylalkyl. However, none of the groups R203, R213, R223, R233, R303 or R313 can be a vinyl group and have a heteroatom bonded directly to the nitrogen or separated from it by one methylene unit. I don't get it. (as) R210 is hydrogen, lower alkyl, alkenyl, aryl, aryl alkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydro Roxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamidine) de)alkyl, ureidoalkyl, (carboxyhydrazino)alkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (amidoalkyl) Notioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfur Fuhydryl alkyl or halo-substituted alkyl. (at) R220, R230, R301, R310 and R330 are hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl; Kyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guazinoalkyl carboxyalkyl, (carboxamido)alkyl, (carboxyhydradino)alkyl, ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy)alxy, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioalkyl) oarylalkoxy)alkyl, protected sulfhydrylalkyl or halo-substituted alkyl selected independently from a group consisting of Rukiru. (au)R320 and R323 are hydrogen, lower alkyl, alkenyl, aryl, benzyl, (cycloalkyl)alkyl, -(allene)-C(O)NR34 0R341, -(alkylene)-NR342R343, -(alkylene)-NR 344C(O)R345, hydroxyalkyl, guanidinoalkyl, carboxy Sialkyl, (carboxyhydrazino)alkyl, ureidoalkyl, heterocyclic ring methyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothi oalkoxy)alkyl, protected sulfhydrylalkyl, and halo-substituted alkyl (where R340, R341, R342 and R343 are independently selected from hydrogen and lower alkyl, and R344 and R345 are independently selected from hydrogen, lower alkyl and halo-substituted lower alkyl) selected from the group consisting of However, R323 cannot be a vinyl group, and must be directly bonded to nitrogen or have one methyl cannot have a heteroatom separated from it by an ion unit. (ar) R325 and R326 are hydrogen, lower alkyl, aryl, (cycloa (alkyl)alkyl, -(alkylene)-NR344C(O)R345, (carbo (xamido)alkyl, ureidoalkyl, (heterocyclic)alkyl, and halo-substituted alkyl, where R344 and R345 are as defined above. (aw) R201 and R202, R210 and R211, R220 and R221, R230 and R231, R301 and R302, R310 and R311, R320 and R321, and R330 and R331, each pair taken together, independently - (CH2)2- (herein or an integer from 2 to 6) may optionally be represented. For all of the foregoing, (i) if more than one sulfhydryl alkyl is present in the compound, The compound exists in the form of an oxidized disulfide resulting in a cyclic molecule, or in the form of two sulfides. The hydryl groups are linked by C2-C8 alkylene chains, and (ii) If the compounds contain free amino and carboxy groups, it is provided that they can be cyclized to give the corresponding lactams. ]2. Compounds according to the definition of claim 1, wherein R4, R7, R10, R13, R16, R19, R22 and R25 are independently selected from >NH and >N-(lower alkyl) thing. 3. A compound according to the definition of claim 1, wherein R6, R9, R12, R15, R18, R21, R24 and R27 are independently selected from >C=O and >CH2. 4. Claim 1, wherein the group R5 is selected from substituted cyclopropyl of >CR201R202; >NR203; >C=CR205R206 (present in Z- or E-configuration); Compound by definition. Here, R201 is lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxamido)alkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, (thioarylalkyl) c) Select from alkyl, protected sulfhydryl alkyl, and halo-substituted alkyl Ru. R202 and R205 are selected from the group consisting of hydrogen and lower alkyl; R203 is lower alkyl, alkenyl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxamido)alkyl, (heterocyclic)alkyl; (thioalkoxy)alkyl, (thioarylalkoxy)alkyl or selected from the group consisting of protected sulfhydryl alkyl, with the proviso that R203 is It cannot be a nyl group and cannot have a heteroatom directly attached to the nitrogen or separated from it by a methylene group. R206 is lower alkyl; ary arylalkyl; (cycloalkyl)alkyl; amidoalkyl; selected from the group consisting of boxamido)alkyl, (heterocyclic)alkyl, and halo-substituted alkyl. ]5. >CR210R211; >NR213; >C=CR215R216 (present in either Z- or E-configuration), and A compound according to the definition of claim 1, selected from substituted cyclopropyl with the formula ▲, which has a mathematical formula, a chemical formula, a table, etc. [Here, R210 is a group consisting of arylalkyl; aminoalkyl; guanidinoalkyl; (heterocyclic)alkyl; (aminothioalkoxy)alkyl. selected from. R211 and R215 are selected from hydrogen and lower alkyl. R213 is selected from the group consisting of arylalkyl; aminoalkyl; guanidinoalkyl, (heterocyclic)alkyl and (aminothioalkoxy)alkyl. provided that R213 is directly linked to nitrogen or linked to it by one methylene unit. cannot have a heteroatom separated from it. R216 can be selected from arylalkyl and (heterocyclic)alkyl. ]6. R26 is selected from the group consisting of >CR330R331; >C=CR335R336 (present in either the Z- or E-configuration); and a substitution of the formula ▲ cyclopropyl; A compound according to the definition of claim 1. [wherein R330 is selected from the group consisting of arylalkyl, aminoalkyl, guanidinoalkyl, (heterocyclic)alkyl and (aminothioalkoxy)alkyl; , R331 and R335 are independently selected from hydrogen or lower alkyl, and R336 is selected from arylalkyl and (heterocyclic)alkyl. ]7. An anaphyla toxin modulating composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.