CA2045578A1 - Anaphylatoxin-receptor ligands - Google Patents

Anaphylatoxin-receptor ligands

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Publication number
CA2045578A1
CA2045578A1 CA002045578A CA2045578A CA2045578A1 CA 2045578 A1 CA2045578 A1 CA 2045578A1 CA 002045578 A CA002045578 A CA 002045578A CA 2045578 A CA2045578 A CA 2045578A CA 2045578 A1 CA2045578 A1 CA 2045578A1
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alkyl
amino
group
lysyl
cyclohexylpropanoyl
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French (fr)
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Megumi Kawai
Yat S. Or
Paul E. Wiedeman
Jay R. Luly
Mikel P. Moyer
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/472—Complement proteins, e.g. anaphylatoxin, C3a, C5a
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Veterinary Medicine (AREA)
  • Toxicology (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Oligopeptide compounds or oligopeptide analogue compounds of the formula A-B-D-E-G-J-L-M-Q-T are ligands for the anaphylatoxin receptor and are useful in the treatment of inflammatory disease states. Also disclosed are anaphylatoxin receptor ligand compositions and a method for modulating anaphylatoxin activity.

Description

,'J

ANAHYI,~J--REC~;PTOR LIG~,~D~S

C~osc-~ef~ _ This application is a continuation-in-part of copend n~
patent application Serial No. 304,693 filed 31 January ~589.

T e ~ .~ F; eld This nvention relates ~o organic compounds that modulate anaphylatoxin activity. It also relates to methocs and compositions for modulating anaphylatoxin aCtivity in human and animal hosts in need or such treatment.

~ackg-ou~d o~ the T~ve~l ; on A wide variety of conditions including infection by bacteria, viruses or fungi, infiltration by cancer cells, allergic or autoimmune disorders and physically- or chemically-induced trauma causes an inflammatory response in humans. In all of these diseases and conditions in man and in most mammals, activation of the complement system ~a se~
of proteins, regulatory factors and ?roteolytic enzymes) via either the classical or the alternative pathway results in the generation of biologically active peptides which serve to 25 amplify and exacerbate the resulting inflammation. The ost active peptide, anaphylatoxin CSa, a 74-amino acid polypeptide, is generated by cleavage of the alpha-cha~n o-native C5 at a specific site by convertases (proteolytic enzymes) of the blood complement system as well as by enzymes of the coagulation system. CSa exis-s in vivo in two biologically active forms. Once it is liberated from C5, _se carboxyl terminal arginine of CSa is rapidly removed by 20~57~ 2 carboxypeptidase-N, leaving the des-Arg derivative. Al~hough C5a des-Arg is less active than C5a, both are potent inflammatory mediators at concentrations li~ely to be generated in vivo (Fernandez, H. N.; Henson, P. M.; Otanl, A.; Hugli, T. E. J. Immunol . 1978, 120, 1 09 . ) . Togethe~, these peptides along with C3a, C4a, and their des-Arg degradation products, collectively described herein zs anaphylatoxin, are capable of triggering diverse infla~-2-o-i reactions.
Among the various cell types, the neutrophil response _G
C5a is the best defined. Cell surface receptors spec f_c r--C5a have been demonstrated on the neutrophil (Chenoweth, D.
E.; Hugli, T. E. P~oc. Natl. Acad. Sci. U.S.A . 1978, 75, 3943-3947. Huey, R.; Hugli, T. E. J. Immunol. 1985, 135, 2063-2068. Rollins, T. E.; Springer, M. S. J. Biol. ~hem.
1985, 260, 7157-7160.), and the ligand-receptor interaction promotes human polymorpho-nuclear leukocyte (PMN) migration in a directed fashion (chemotaxis), adherence, oxidative burst, and granular enzyme release from these cells (Hugli, T. E. Springer Semin. Immunopathol . 1984, 7, 193-219.). The interaction of C5a with PMN and other target cells and tissues results in increased histamine release, vascular per.meability, smooth muscle contraction, and an ir.flux nto tissues of inflammatory-cells, including neutrophils, eosinophils, and basophils (Hugli, T. E. Springer Semin .
~mmunopathol . 1984, 7, 193-219.). C5a may also be impor~an_ in mediating inflammatory effects of phagocytic mononuclea-cells that accumulate at sites of chronic inflammation (Allison, A. C.; Ferluga, J.; Prydz, H.; Scherlemmer, H. U.
Agents and Actions 1978, 8, 27.). C5a and CSa des-Arg can induce cAemotaxis in monocytes (Ward, P. A. J. Exp. ~ed.
1958, 128, 1201. Snyderman, R.; Shin, H. S.; Dannenberg, ..

2 ~ r~

C. J. Immunol. 1972, 109, 896.) and cause them to release lysosomal enzymes (McCarthy, K.; Henson, P. S. J. Immu~o7.
1979, 123, 2511.) in a manner analogous to the neut-ophil responses elicited by these agents. Recent studies sugge-^~
S that CSa may have an immunoregulatory role by enhancing antibody particularly at sites of inflammation (Morgzn, ~.
L.; Weigle, W. O.; Hugli, T. E. J. Exp. Med. 1982, 155, 14:2.
Weigle, W. 0.; ~organ, E. L.; Goodman, M. G.; Chenoweth, 3.
_.; Hugli, T. E. Federation Proc. 1982, 41, 3099. Morgan, ~.
L~; Weigle, W. O.; Hugli, T. E. ~ederation Proc. 1984, 43, 2543.).
CSa and C5a des-Arg play important roles in hos_ defenses against bacterial infections and possibly in the mediation of some pathologic lesions such as the leu~ocyte infiltration seen in tne lungs during acute respiratory distress syndrome. This mechanism seems to play a role in different pathological situations like pulmonary distress during hemodialysis, leukophoresis, cardiopulmonary bypass, and in acute myocardial infarction. Complement activation has been postulated to play an important pathological role in rheumatoid arthritis, serum sickness, systemic lupus erythematosus, ulcerative colitis, and forms of hepatic cirrhosis, chronic hepatitis, and glomerulonephritis, in certain shock states, during hemodialysis, and cardiopulmonary bypass, acute pancreatit-s, myocardial infarction (which may be worsened by C5z-induced leuko-embolization following the interaction of complement with atheromatous plaques), asthma, bronchoconstriction, some auto-allergic diseases, transplant rejection, and post-virzl encephalopathies.

WO90/09162 PCT/US90/002g6 2 ~

By serving as antagonists by binding to and bloc~ing the anaphylatoxin receptor, certain compounds of the present invention can reduce or prevent anaphylatoxin~mediated inflammation. Other compounds of the present invention are agonists that mimic anaphylatoxin activity, ar.d assis. the body in building its defense mechanism against invasion by infectious agents and malignancy. Additionally, these compounds may influence the immunoregulatory effects o_ anaphylatoxin. The possible involvement of anaphylatoxin in a wide range of diseases, as indicated by these exzmples, suggests that anaphylatoxin receptor ligands could have clinical applications for the treatment and prevention of the above-mentioned pathological conditions.

Su~ o ~ =ent;o~
In accordance with the principal embodiment of the present invention, there are provided anaphylotoxin activity modifying compounds of the formula A-B-D-E-G-J-~-M-Q-T
and the pharmaceutically acceptable salts, esters, or amides thereof.
In the generic formula given above, the groups A through T have the following values:
A is Rl-R2-R3;
B is selected from R4-Rs-R6r R31, R32, R35 and R37;
D is selected from R7-R8-Rg~ R31, R32, R35 and R37;
E is selected from Rlo-Rll-Rl2~ R31, R32, R35 and R37;
G is selected from R13-R14-R1s, R31, R32, R35 and R37;
J is selected from R16-R17-R1g, R31, R32, R35 and R37;
1 is selected from R1g-R20-R2lr R31, R32, R35 and R37;
M is selected from R22-R23-R24r R31~ R32~ ~35 and ~37;
Q is selected from R2;-R26-R27r i~31r R32~ ~35 and R37;

WO90tO9162 ~CT/US90/00296 ~ J , T is R28-R29-R3o;

B and D, taken together, optionally represent a g-oup selected from R33, R34, R3g, R3g, R40, R41, R42, an~;
R43;
D and E, taken together, optionallv re?resent a g-~?
selected from R33, R34, R3g, R3g, R40, R41, R42, znd R43i E and G, taken together, optionally re?resent a grou?
1 0 selected from R33, R34, R3g, R33, R40, R41, R42, and R43i G and J, taken together, optionally re?resent a group selected from R33, R34, R3g, R3g, R40, R41, R42, and R43;
1 5 J and L, taken together, optionally represent a g-oup selected from R33, R34, R3g, R3g, R40, R41, R42, and R43;
L and M, taken toqether, optionally represent a group selected from R33, R34, R3g, R3g, R40, R41, R42, and 2 0 R43; and M and Q, taken together, optionally represent a group selected from R33, R34, R3g, R3g, R40, R41, R42, and R43, and one or more of the groups R5-R6-~7; ~8-R9-~1Oi 2 5 R11-R12-R13; R14-R15-R16; Rl7-~13-R19; R20-R21-R22;
- R23-R24-R2s; or R26-R27-R2g~ independently optionally represent R36-Tne group R1 is selected from the g~oup consisting of amino, (lower alkyl)amino, dialkylamino, (arylalkyl)amino, 3 0 hydroxy, alkoxy, aryloxy, arylalkoxy, acetamido, thioalkoxy, halogen, aryl, lower alkyl, arylalkyl, (heterocyclic)alcyl, heterocyclic, arylamino, and hydrogen.

WO90/09162 PCT/US9~/~0296 7 ~ 6 R2 is selected from the group consisting of >cRs9~0a, >C=CRgsRg6, existing in either the Z- or E~configuration, oxygen, amino, and alkylamino, with the proviso that when ~2 is oxygen, amino or alkylamino, Rl is S aryl, lower alkyl, arylalkyl or (heterocyclic)alkyl.
R3 is selected from the group consisting of >C=0, ~ 2, >C=S, and >S02, with the proviso that when R3 is >C:-.2 5- >S~'2 ~hen R2 cannot be oxygen, amino or alkylamino.
R4 is seiected from the group consisting of >CH2r ~0, >S, and >NR~ol where Rlol is hydrogen, lower alkyl, ary al'~.y , alkenyl, hyd-oxy or alkoxy, with the proviso that wher. R~ -s >0 or >S then Rl, R2 and R3 taken together represent a grou_ selected from lower alkyl, arylalkyl, aryl or hydroger..
Rs is selected from the group consisting of >CR201R202 >NR203, >C=C~205R206~ existing in either the Z- or E-configuration, and substituted cyclopropyl of the ~ R~n formula R~2.
R6, Rg, R12, R15, R18, R2l~ and R24 are independently selected from the group consisting of >C=O, >CH2, -CH2C~O)-, -NHC(O)-, >C-S, >S02, and >P(O)X where X is selected from hydroxy, alkoxy, aminoj alkylamino and dialkylamino.
R7, Rlo, R13, R16, Rlg, R22~ R2s are independently selected from >CH2 and >NRso where Rso is selected from the g-oup consisting of hydrogen, lower alkyl, arylalkyl, z-yl, hyd-oxy and alkoxy.
R8 is selected from the group consisting of >cR2lo~2llt >NR213, >C=CR21sR216, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ,~R2.0 R21- ~

WO90/09162 PCT/US90/0~296 R11 is selected from the group consisting of >CR22~R2~1, >NR223, >C=C~225R226, existing in either the Z- or ~-configuration, and substituted cyclopropyl of the fo-mula ~,R220 R~1 .
R14 is selected from the group consist-ng Oc >C~230~2~ r >NR233, >C=C~23SR236r existing in either the Z- or _-conflguration, and substituted cyclopropyl of the ~ Rz~
formula R231.
R77 is selected from the group consisting of >cR30~?~3o2r >NR303, >c=cR3osR3o6~existing in either the Z- or ~-conflguration, and substituted cyclopropyl of the ~ R~
for.,.ula R~2.
R20 is selected from the group consisting of ~CR310R3 >NR313, >C=CR31sR316, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula \~R310 --` R3.1 .
R23 is selected from the group consisting f >C~320~32', >N~323, >C=C~325R326~ exlsting in either the Z- or E-configuration, and substituted cyclopropyl of the formul 2 R3~
O R321 .
R26 is selected from the group consistlng of ~C~330~33 >C=CR33sR336, existing in either the Z- or E-configurztlon, ~ R~
znd substituted cyclopropyl of the formula R331.
R27 is selected from the group consisting of >C=O, >CH2, -C:-2C(O)-, >C=S, >SO2, and >P(O)X wnere X is selected frcm hy~roxy, alkoxy, amino, alkylamino and dialkylamino.

R28 is selected from the group consisting o4 >0/ >S, >CH2, and >NRlog where Rlog is selected from hydrogen, Lowe_ alkyl, (heterocyclic)alkyl, and arylalkyl, with the proviso that when R27 is >SO2 or >P(O)X, then R28 is >O or >NR~og-R29 is selected f-om the group consisting of hyc-oge^., lowe- alkyl, arylalkyl, and >N~llo where R11o is selec~ed ^-o~
hydrogen, lower alkyl, aryl, and arylalkyl, with the ?rov- os t:~at (i) when R28 is >O, or >S then R29 is lower alkyl or arylalkyl, and (ii) when R29 is hydrogen, lower alkyl, or a-ylalkyl then R30 is absent.
R30 is selected from the group consisting of hydrogen, a-yl, lower alkyl, and arylalkyl.
R31 is a group having the structure (CH2) H ~ (CH2)m where m and n are integers independently selected from 0, 1 and 2.
R32 is a group having the structure ~N(CHz)p ~

w:nere p and q are integers independently selected from 0, 1 and 2.

~ ~J' !,t; ~ ,J

R33 is a group having the structure s~S~N~
H ~ --(CH ~ ~

where t and v are intege_s independently selected f-om 0, :, 2 and 3.
R34 is a group having the structure s~
l~ (CH2~

where r and s are ir.tegers independently selected from 0, 1, 0 2 and 3.
R3s is a group having the structure R
rl /X
(CH
~ 1 where f is and integer of 0 to 3, X is selected from ~C=0 and -CH2-. R is selected from hydrogen and lower alkyl, with the provisos that (i) when f is 0, X is at C-2 and R is at C-3 o-C-4; (ii) when f is 1, X is at C-2 and R is at C-3, C-4 or C-5 and C-3,4 are saturated or unsaturatedi (iii) when f is 2, X is at C-2, C-3 or C-4 and R is at C-2, C-3, C-4, C-5 o-C-6 when the position is unoccupied by X and C-3,4 or C-4,5 are saturated or unsaturated; and (~v) when f is 3, X is a-C-2, C-3 o_ C-4 and R is at C-2, C-3, C-4, C-5, C-6 or C-7 WO90/09162 PCT~US90/002g6 2~ 7~

when the position is unoccupied by X and C-3,4 or C-4,~ or C-5,6 are saturated or unsaturated.
R3~ is a group having the structure (C/ 2) ~ ~ N~

S O
where g is an integer of from 0 to 3.
R37 is a group having the structure o where h is 0 or 1 and j is 0 or 1 with the proviso that either h or j must be 1.
R38 is a group having the structure H3C ~ S ~CH3 N

R39 is a group having the struc~ure H ~ O

~0 WO 90/09162 PCT/~S90/002~

R40 is a divalent group having the structure ,~3 H~N H

R41 is a divalent g-oup having the structure C~=
~" N
'2, N ~

R42 is a divalent group having the structure ~ N ~
N ~ ~J
' o ~
R43 is a divalent group having the structure (CH2~f where k is an integer of f-om zero to two.

R1 and R2, taken together, optionally may re?resen~ 2 g-oup selected from aryl, heterocyclic, or hydrogen.

WO90/09l62 P~T/US90/00296 2~5 7~

R6 and R7; Rg and Rlo; R12 and R13; Rls and R16; R18 a~d Rlg; R21 and R22; and R24 and R2s; each pair taken together, may optionally and independently represent a gro p S selected from >CH2, -(CH2)3-, -CH=CH-, -C-C-, -C(=C:i2)CH2-, -CH(OH)CH2-, -C(O)O-, -C(O)S-, -CH2C(O)O-, -CH2C(O)S-, -CH2O-, -CH2S-, and -NHC(O)-; wi_h he provisos that (i) when ~; is >NR2o3 or >C=C~205~206~ ~6 a~d ~,, taken together, represent -C(O)NH- or -C~O)NC:-.3-; (li) when ?.
is >N~213 ~ >C=CR215R216~ Rg and Rlo, taken togethe_, represent -C(O)NH- or -C(O)NCH3-; (iii) when ~11 is >NR223 o->C=CR22sR226, R12 and R13, taken together represent -CONH- o~
-CONC~3-; (iv) when R14 is >NR233 or >c=cR23sR236~ Rls and R16, taken together, represent -C(O)NH- or -C(O)NC~.3-; (v) when Rl7 is >NR303 or >c=c~3osR3o6~ Rlg and Rlg, taken together, represent -C(O)NH- or -C(O)NCH3-; (vi) when R20 is >NR313 or >C=CR31SR316, R21 and R22, taken together, represent -CONH- or -CONCH3-; (vii) when R23 is >NR323 or >c=cR32sR326~ R24 and R25, taken together, represent -C(O)NH- or -C(O)NCH3-.
R2g and R30, taken together, optionally represent a group selected from hydrogen, hydroxy, or alkoxy, with tne proviso that when R28 is >O or >S then R2g and R30, taken together, represent hydrogen.
Rl, R2 and R3, taken together, optionally represent a group selected from lowe- alkyl, arylalkyl, alkenyl, a-yl, hydroxy, alkoxy, hydrogen, an N-termln21 protecting group o-peptide fragment of 1-8 residues similarly protected wherei each of the amino acids com.prising the peptide fragment is independently selected from the 20 naturally occuring amino acids.

WO 90/09162 PCT/~S90/00296 R1, R2, R3 and R4, taken together, optionally re?res~n~
a group selected from hydrogen, lower alkyl, a ylalky}, a_yl, heterocyclic, or H2NC(O)-, with the proviso that when 2, J
>CH2 then R1, R2, R3 and R4, taken together, may not De hydrogen.
R27, R28, R29 and R30, taken togethe-, optionally represent a group selected from hydrogen, lowe- alkyl, 2--,tl, or arylalkyl.
R1, R2, R3, R4 and R5, taken together, o?tionally 0 re~resent an aryl or heterocyclic g-oup.
R95, Rs6, R205, R206, R215, R216r R225, R226, R235, R236, R305, R306, R31s, R316, R33s and R336 are independently selected from the grou? consisting of hydrogen, lower alkyl, aryl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxyamido)alkyl, ureidoalkyl, (heterocyclic)alkyl, and halosubstituted alkyl.
R99, R202, ~211, R221r R231, R302, R311r R321 and R331 are independently selected from hydrogen and lower alkyl.
R1oo is selected from the group consisting of hydrogen, lower alkyl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (heterocyclic)alkyl, (_hioalkoxy)alkyl, arylalXoxy, and sulfhydrylalkyl.
R201 is selected from the grou_ consisting of hydrosen., lower alkyl, alkenyl, aryl, arylalkyl, ~cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, (carboxyhyd-azino)alkyl, ureidoalkyl, (he~_erocyclic)alkyl, (_hioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alYyl, (t;~ioarylalkoxy)alkyl, protected su' hydrylalkyl, and halosubstituted alkyl.

WO90/09162 PCT/US90/ ~ g6 2~57~ 14 R203, R213, R223, R233, R303, and R313 are independently selected from the group consisting of hyd-ogen, lower alkyl, alkenyl, arylaLkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hyd-oxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, (carboxyhydrazino)alk ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, or protected sulfhydrylalkyl ~ith ~ ~
proviso that none of the groups R203~ R213, R223, R233, ?~3^3~ __ R313 may be a vinyl group or have a hete-oatom di-ec~'y attached to the nitrogen or separated from it by one methylene unit.
R210 is hydrogen, lower àlkyl, alkenyl, aryl, a-ylalXy_, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, ureidoalkyl, ~carboxyhydrazino)alkyl, (heterocyclic)alkyl, ~thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfhydrylalkyl, or halosubs, tuted alkyl.
R220, R230, R301, R310, and ~330 are independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, (carboxyhydrazino)alkyl, ureidoalky', (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, protec~_ed sulfhydrylalkyl, or halosubstituted alkyl.
R32~ and ~323 are selected from the group consis' n5 c-hydrogen, lower alkyl, alkenyl, aryl, benzyl, (cycloalkyl)alkyl, -(alkylene)-C(O)NR340R34l~
-(alkylene)-NR342R343, -(alkylene)-NR344C~O)R345, hydroxyalk._, WO90/09~62 PCT/~S9~/002 2 ~ d ~

-(alkylene)-NR342R343, -(alkylene)-NR344C(O)R34;, hydroxy21.~y1, guanidinoalkyl, carboxyalkyl, (carboxyhyd_azino)alkyl, ureldoalkyl, heterocyclic substituted methyl, (thioalkoxy)alkyl, sulfhyd-ylalkyl, (aminothioalkoxy)alky', protected sulfhydrylalkyl, and halosubstl uted alky , ~ e-e R340, R341-R342, and R343 are independently selected f-om hydrogen and lower alkyl, and R344 and R34s are indepence.-l-;
selected from hydrogen, lower alkyl, and halosubs~ ed lower alkyl, with the proviso that R323 may not be a vl-.yl 1 0 group or have a hete-oatom directly attached to the -. --~^e-.
or separated from it by one methylene un-..
R325 and R326 are independently selected from the C-~?
consisting of hydrogen, lower alkyl, aryl, (cycloalkyl)c':cyl, -(alkylene)-NR344C(O)R34s, (carboxyamido)alkyl, ureidoalcyl, lS (heterocyclic)alkyl, and halosubstituted alkyl, where R344 ar.d R345 are as defined above.
R201 and R202, R210 and R211, R220 and R221, R230 and R231, R301 and R302, R310 and R311, R320 and R321, znd R330 and R331, each pair taken together, independently may 2 0 optionally represent -(CH2)z- where z is an integer o- ._om 2 to 6.
All of the foregoing definitions are with the prov-cos that, in the compounds of the present invention, (i) when more than one sulfhydrylalkyl is present in the compour.d, .-.e 2 5 compound exists in the oxidized disulfide form producing a cyclic molecule, or the two sulfhydryl moieties are connecre~
by a C2 to C3 alkylene chain and (ii) when the compound con.ains a free amino group and carboxyl grou?, they can ~e cyclized to give the corresponding lactam.

WO90/09162 PCT/U'S90/00296 Detailed Description As discussed above, CSa is the most active of a class o biologically active-peptides which serves to amplify and exacerbate inflammation. While CSa contains 74 amino acid 5 residues, it has been found in accordance with the preser..
invention that oligopeptides containing as few as eighr am~r.o acid residues are also actively bound by CSa recep.ors.
~oreover, it has been found that peptidomimetic compounds (i.e. compounds which mimic the activity of peptides) in which certain groups replace the ~-carbon, carbonyl group, and amide-nitrogen group of the individual amino acids in oligopeptides are also actively bound by C5a receptors.
The chemical structures of the compounds of the present invention are best understood by reference to the follow ng structural formula in which it is understood that the segments are joined serially at the free valence bonds to form the compound A-8-D-E-G-J-L-M-Q-T.

Rl R2 R3 R4 R, R8 R7 R8 Rg CH~CH2 ~ NH2 02¦_~o~. _ Rloo R202 52 R2ll SO2 >P(O)X :~P(O)X
'7 0 ~A ~ ~ D -- ~

WO gO/09162 PCr/USgO/00296 Rto R" R-2 R" R,~ R1s R,~ 7 R1a '~C=O - ;C-O - ;C=O
{~`NR 03 ¦ 1 220 'CH,C(O) { NR04 ¦--~ 'CH,C(O) 1 1~ ~CH C(O

P(O)X P(O)X P(O)X
¦ ~ E ~ ¦ ~ G ¦ ~ J ~ ¦

R19 R20R2l R22 R23R24 R25 R25R2 ;C~O - ;C=O -~C=O
~CH2 R320 ~CH2 R330 >CH2 --¦~CH2 }~ ',CNcHH,2Cs((OO))' ' ~NRl07~' NHC(O)~ ~[~CH2 ~1--i,C5H 5C(O)-~
~52 ~SO2 P(O)X
_,P(O~X ~P(O)X
¦ ~ L ¦ ~ M ~
s ~NR1os ~NR1,o -H
- ~ ~ ~ ~ H -Ary I
_ ~S~ (Lower alkylr , -(Lower alkyl) ~CH2 -(Arylalkyl) -(Arylalkyl) ¦~T ~ .¦

As used throughout this specification and the appended 0 claims, the following terms have the meanings specified.
The term "alkyl" as used herein refers to monovalent straight chain or branched chain groups o' 1 to 12 carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isop-opyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the l~ l ke.

20~5 7~ 18 The term "lower alkyl" as used herein refers to stra g;~t or branched chain alkyl groups containing from ~ to 8 carson atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, r-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "alkylene" as used herein refe-s to divale-.t groups of from one to twelve carbon atoms derlved by the removal of two hydrogen atoms from straight o- branched saturated hydrocarbons. Examples include -CH2-, -C~(C:.3)-, -C(C~3)2-~ -C~(C2~S)-~ -CH2CH2-, -CH2C;~(CH3)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and the like.
The term "alkenyl" as used herein refers to straight or branched chain groups of 2 to 12 carbon atoms containing a carbon-carbon double bond, including, but not limited to ethenyl, l-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
The term "halosubstituted alkyl" refers to an alkyl group as described above substituted with one or more halogens, including, but not limited to chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like. The terms "halo" and "halogen" are used r.erein to mean groups derived from the elements fluorine, chlorine, bromine, o.
iodine.
The term "cycloalkyl" as used herein refers to cyclic groups, of 3 to 8 carbons, including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "(cycloalkyl)alkyl" as used herein refers to a cycloalkyl group appended to a lower alkyl group, includir.~, but not limited to cyclohexylmethyl -nd cyclohexylethvl.

WO90/09162 PCT/US90/002g6 The term "alkoxy" as used herein refers to an 21kyl group as defined above, attached to the remzinder of the molecule through an oxygen atom. Alkoxy groups include, _or example, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butox isobutoxy, te-t-butoxy, and the like.
The term "sulfhydrylalkyl" as used herein refe-s .o a -S~. group appended to a lower alkyl group, as ?reviously defined.
The term "protected sulfhydrylalkyl" refe-s to 2 sulfhydrylalkyl group, as previously defined, whicA :.as se_n transformed to the corresponding S-acetamidome~hyl (S-Ac-") _~
other similar protecting group, including, but not limited tO
S-phenacetamidomethyl.
The term "thioalkoxy" as used herein refe-s to an alky' group, as previously defined, attached to the remainder of the molecule through a sulfur atom. Examples of thioalkoxy groups include, but are not limited to, thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy, sec-thiobutoxy, isothiobu'oxy, tert-thiobutoxy and the like.
The term "(thioalkoxy)alkyl" as used herein refe-s to a thioalkoxy group, as just defined, appended to a lower alky group.
The term "(thioarylalkoxy)alkyl" as used herein refers to a group of the structure R420-S- appended to a lower alky' where R420 is an arylalkyl group as defined below.
The term "aryl" as used herein refers to subs~i.uted znd unsubstituted carbocyclic aromatic groups including, but no_ limited to p~.enyl, 1- or 2-naphthyl, fluorenyl, (1,2)-dihydronaphthyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, indanyl, and the like, wherein the aryl grou? may be subs~itu~ed with 1, 2, or 3 substituen~s inde?enden-ly 2~5~78 20 selected from halo, nitro, cyano, Cl to C12 alkyl, alkox~f, aroyl and halosubstituted alkyl.
The term "arylalkyl" as used herein refers to an aryl group, as previously defined, appended to an alkyl group, including, but not llmited to benzyl, 1- and 2-naphthylmethyl, halobenzyl, alkoxybenzyl, hydroxybe?.zyl, aminobenzyl, nitrobenzyl, guanidinobenzyl, phenylmethyl(benzyl), l-phenylethyl, 2-phenylethyl, l-naphthylethyl, and the like.
The term "benzyl" as used herein refers specifically tO
to phenyl substituted methyl in which the phenyl grou? may be substituted with l, 2, or 3 substituents independently selected from halo, nitro, cyano, alkyl of from one to twelve carbon atoms, alkoxy, aroyl, and halosubstituted alkyl, znd the like.
The term "aryloxy" as used herein refers to an aryl group as previously defined, attached to the parent molecular moiety through an oxygen atom. Aryloxy includes, but is not llmited to phenoxy, 1-naphthoxy, 2-naphthoxy and the llke The term "arylalkoxy" as used herein refers to an arylalkyl group as previously defined, attached to the parent molecular moiety through an oxygen atom. Arylalkoxy includes, but is not limited to benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy and the like.
The term "aroyl" as used herein refers to an aryl group as defined above, attached to the parent molecule through a carbonyl group. Examples include benzoyl and substituted benzoyl.
The term "alkylamino" as used herein refers to a group having the s.ructure -NH(alkyl) ~he-e the alkyl por_lon .s as defined above. Alkylamino groups i..clude, for example, methylamino, ethylamino, isopropylamino and the like.

WO90/09162 PC~/~'S9~/~02g6 ~,~

The term "dialkylamino~ as used herein refers to a g o~p having the structure -N(alkyl)(alkyl) where the two alkyl groups may be the same or different and are as previousiy defined.
The term "aminoalkyl" as used herein refe-s to a ~-~2 having the structure -NR342R343 appended to a lowe- alkyl g-oup, as previously defined. The groups R342 and R343 a-e independently selected from hydrogen, lower alkyl, aryl and arylalkyl. Additionally, R342 and R343 taken togethe-, .may 10 ` optionally be ~(CH2)mm- where mm is an integer of from 2 ,o 6.
The term "amidoalkyl" as used herein refers to a 5-oU?
having the structure -NR344C(O)R345 appended to a lower alkyl grou?, as previously defined. The groups R344 and R34; a-e independently selected from hydrogen, lower alkyl, aryl, arylal}cyl, and halosubstituted alkyl. Additionally, R344 and R345 taken together may optionally be -~CH2) kk- where kk is ~-.
integer of from 2 to 6.
The term "(aminothioalkoxy)alkyl" as used herein refers to H2N-Rx-S-Ry- where Rx and Ry are alkylene groups, as previously defined, and may be the same or different.
The te-m "carboxyalkyl" as used herein refers to a carboxyl group, -CO2H, appended to a lower alkyl group, as previously defined.
The term "(carboxyamido)al~yl" as used herein re-e~s to a group of the formula -C(O)NR340R341, appended to a lower alkyl group, as previously defined. The groups R,40 and R
are lndependently selected from hydrogen, lower alkyl, aryl and arylalkyl. Alternatively, R340 and R341 taken together may optionally be -(CH2)?p- wherein 2P is an integer of -om ^~
to 6.

20~57~ 22 The term "~carboxyhydrazino)alkyl" as used herein refers to a grou? having the structure -C~O)NR425NHR430 appended to z lower al~yl group, as previously defined. The groups ~42~ ~~5 R430 are independently selected from hydrogen, lower alkyl, S aryl and arylalkyl.
The term "guanidinoalkyl" as used herein re4ers to -group of the structure -NR346C(=NR347)NHR34g appended to a lower al~yl group, as previously de4ined. R346, R347, ans ?~-are independently selected from hydrogen, lower alkyl, a?.d aryl.
The .erm "ureidoalkyl" as used herein refers to a 5rou3 having the structure -NHC(O)NH2 appended to a lower al~yl group, as previously defined.
The term "heterocyclic" as used herein refers to any _-or 6-membered ring containing from one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the S-membered ring has 0 to 2 double bonds and the 6-membered ring has 0 to 3 double bonds, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, wherein the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any c_ the above heterocyclic rings is fused to a benzene ring.
Representative heterocycles include, but are not limite- to pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidlnyl, pyridazinyl, oxazoyl, oxazolidinyl, soxazolyl, isoxazolldinyl, morpholinyl, indolyl, quinolinyl, thizzolv_, thiazolidinyl, isothiazolyl, isothiazolidinyl, isoquinol nyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, .hieni , and benzo~hienyl.

WO90/09162 PCT/~SgO/00296 The term "(heterocyclic)alkyl" as used herein re~e-s tO
a heterocyclic group, as previously defined, appended tO an alkyl group as previously defined.
The term "hydroxyalkyl" as used herein refers to -O-S appended to a lower alkyl group.
The term "naturally occuring amino ac ~" refe-s to a.
amino acid selected from the group consisting of alan ~.e, 2rginine, zsparagine, aspartic acid, cysteine, gluta~ ~.e, glutamic acid, glycine, histidine, isoleucine, leucine, I 0 lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
The term "N-terminal protecting group" refers ~o those groups intended to protect the N-terminus against undes rab e reactions during synthetic procedures or to prevent the I 5 a;tack or^ exopeptidases on the final compou~ds or to i..c-ezse the solubility of the final compounds and includes, but is not limited to acyl, acetyl, pivaloyl, tert-butylacetyl, tert-butyloxycarbonyl (Boc), carbobenzyloxycarbonyl (Cbz), benzoyl groups or an L- or D-aminoacyl residue, which may itself be N-protected similarly.
The term "anaphylatoxin" is used herein to mean C5a, C4a, C~a, or the corresponding des-Arg degradation products.
The term "pharmaceutically acceptable salt" refers to non-toxic acid addition salts such as salts formed with 2~ inorganic acids such as hydrochloric acid, hydrobromic acld, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, malic acid, tartaric acid, citric acid, succ-nic zcid o-malonic acid. Other pharmaceutically acceptable salts include inorganic nitrate, sulfate, acetate, malate, formate, lactate, tartrate, succinate, ci;rate, ?-toluenesulConate, and the li~e, including, but not li.mited to cations based o-.

2~57~ 24 the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine catio^.s, including, but not limited to ammonium, tetramethyla~..on~
tetraethylammonium, methylamine, dimethylamine, .rime;hyla.m.ine, triethylamine, ethylamine, and the l ke.
_xamples of pharmaceutically acceptable, non-toxi_ esters of the compounds of this invention include Cl o C~
alkyl esters wherein the alkyl group is straight or branc;.e~
chain. Acceptable esters also include C; to C7 cyclo2l kyl esters as well as arylalkyl esters such as, but not 1 m t-d to benzyl. Cl to C4 alkyl esters are preferred. Este-s o the compound of formula I may be prepared according ~o conventional methods.
Examples of pharmaceutically acceptable, non-tox c amides of the compounds of this invention include amides derived from ammonia, primary Cl to C6 alkyl amines and secondary Cl to C6 dialkyl amines wherein the alkyl groups zre straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived rrom ammonia, Cl to C3 alkyl primary amides and Cl to C2 d-alkyl secondary amides are preferred. Amides of the compound of formula I may be prepared according to conventional methods.
Numezous asymmetric centers may exist in the compounds of the present invention. The present invention contemplates the various stereoisomers and mixtures thereof. In particula-, chiral centers can exist at R2, Rs, Rg, Rll, Rl4, R17, R20, R23 and R26. When these groups comprise the a-carDon a-om o~ an a-amino acid, the natural configuration is ?-eferred. However, compounds of the present inver.~ion ~ ~ J'; ~ ~ ~ 'J

containing up to three ~-amino acid residues of non-natura~
configuration have also been found to be effective as modulators of anaphylotoxin activity.
Particular stereoisomers are prepared by seLecting the starting amino acids or amino acid analogs having the des-~e-s~erec_h~mis~ri a-.d react,.,~ ...êsc atar~ ng ~ua~er ~ G ~ ~ by methods detailed below. Starting compounds of particula-stereochemistry are either commercially available or are .,.zd-by the methods detailed below and resolved by techni~ues well known in the organic chemical arts.
One class of preferred compounds of the present invention are those in which the groups R4, R7, Rlo, R13, ~
Rlg, R22, and R2s are independently selected from >NH and >N-(lower alkyl).
In another class of preferred compounds of the preser.~
invention, the groups R6, Rg, Rl2~ R15, R18, R21~ R24, and R27 are independently selected from >C-O and >CH2.
The group Rs is preferably selected from >CR201R202;
>NR203; >C=CR20sR2o6~ existing in the Z- or E-configuration;
~ R~1 and substituted cyclopropyl of the formula R~2 where where R201 is selected from lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxyamido)alkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfhydrylalkyl, and halosubstituted alkyl. R202 and R205 are selected from the group consisting of hydrogen and lower alkyl; R2a3 is selec.ed ^ro~ the group consisting of lower alkyl, alkenyl, arylalkyl, ~cycloalkyl)alkyl, amidoalkyl, ~carboxyamido)alkyl, (heterocyclic)alkyl, tthioalkoxy)alkyl, (thioarylalkoxy)-alkyl, and protected sulfhydrylalkyl, with the proviso that R203 ~2y not be a vinyl group or have a heteroatom directly 2 ~ 3 7 ~

attached to the nitrogen or separated from it by one methylene group. R206 is selected from the group consistL.g of lower alkyli aryl; arylalkyl; (cycloaLkyl)alkyl;
amidoalkyl; (carboxyamido)alkyl; (heterocycl c)alkyl; and halosubstituted alkyl.
R8 is preferebly selected f-om the grou? cor.sis~ing o >CR210~211; >NR213; >C=CR215R216; and subs; tu.ed cyclo?-o--~
\~R2lo of the formula ~--~R2l1. R210 is selected f-om the grou?
consisting of arylalkyl; aminoalky!; guanidi?.oalkyl;
(heterocyclic)alkyl; (aminothioalkoxy)alkyl. R211 and ~215 selected from hydrogen and lower alkyl; ~213 is selected - o-.
the group consisting of arylalkyl; aminoalkyl;
guanidinoalkyl; (heterocyclic)alkyl; and (aminothioalkoxy)alkyl; with the proviso tha- ~213 ~.ay no-have a herteroatom directly attached to the nitrogen or separated from it by one methylene unit; and R216 is selected from arylalkyl and (heterocyclic)alkyl.
R26 is preferably selected from the group consisting o^
>CR330R331; >C=CR335R336~ existing in either the Z- or ~-configuration; and substituted cyclopropyl of the formula ,~R330 R33.; where R33s is selected from hydrogen and lower alkyl. R336 is selected from arylalkyl and (heterocyclic~-alkyl; R330 is selected from the group consis.ing of arylalkyl, aminoalkyl, guanidinoalkyl, (heterocyclic)alkyl and (aminothioalkoxy)alkyl; and R331 is hydrogen or lower alkyl.

WO 90/09162 PCr/US90/0~2g6 2 7 2 ~

MQtho~ Of TrQ~t.m~n~
The compounds of the present invention serve to mccul~e the activity of anaphylatoxin. Certain compounds of _he present invention function as anaphylatoxin antagonis~s, while others function as agonists. The antagonis; co-?ou^.~~
of the present invention block the anaphylatoxin recepto~ z-.~
prevent anaphylatoxin activity, which makes those compounds useful in the treatment and prevention of injurious conditions or diseases in which anaphylatoxin may be 0 involved. Disease states in which anaphylatoxin is in-iol ved include asthma, bronchial allergy, ch_onic in_lammat- 0?., systemic lupus erythematosus, vasculitis, serum sickness, angioedema, rheumatoid arthritis, osteoarthritis, gout, bullous skin diseases, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, immune complex-mediated glomerulonephritis, psoriasis, allergic rhinitis, adult respiratory distress syndrome, acute pulmonary disorders, endotoxin shock, hepatic cirrhosis, pancreatitis, inflammatory bowel diseases ~including Crohn's disease and ulcerative colitis), thermal injury, Gram-negative sepsis, necrosis in myocardial infarction, leukophoresis, exposure ~3 medical devices (including but not l-mited to hemodialyze_ membranes and extracorpeal blood circulation equipment), chronic hepatitis, transplant rejec~ion, post-viral encephalopathies, and/or ischemia induced myoca-diai o- ~-a_~.
injury. These compounds may also be used as prophylac.ics for such condition~ as shock accompanying Dengue feve_. In addltion, a combination of antibiotic and anti-infla~,ato y agent such as corticosteroids ~e.g., methylprednisolone) anc one or more of the above mentioned compounds may be em?1 O~Q- .
Certain compounds of the invent on are useful therapeutic agents because of their ability to mimic or WO~/09162 PCT/US90/00296 7 ~ 28 promote anaphylatoxin activity and are therefore useful n stlmulating the inflammatory response and immune response -n mammals who are deficient in this regard. These agonist compounds may be used to assist the body in building irs defense mechanism against invasion by infectious mic_oorg2.isms or other stress. Interac;ion by these agonists at the anaphylatoxin receptor makes them usefu~
treating conditions or diseases including, but not 1 mi~ed :_ cancers (-ncluding but not limited lung carcinoma), immunode ciency diseases, and severe infections.
In some cases this will involve preventing the underlying cause of the disease state and in other cases, while the underlying disease will not be affected, the compounds of this invention will have the benefit of ameliorat ng the symptoms or preventing the manifesta-io..s o the disease.
The compounds of the present lnvention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intrasternal, intra-arterial injection or infusion techniques, without limitation. The term "topically" encompasses administration rectally 2nd by inhalation spray, as well as by the more common routes of the skin and the mucous membranes of the mouth and nose.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to aAAieve the desired therapeutic response for a parricula- patient, compositions, and mode of administra~_c...

WO90/09162 PCT/US90/002g6 29 h~

The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated.
~owever, it is within the skill of the art to start doscs c_ the compound at levels lower than required for to achleve ~he desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 0.001 mg to about lOC
mg, more typically from about 0.1 mg to about 20 mg, of active compound per kilogram of body weight per day are administered daily to a mammalian host. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.

- Formulation of Pharmaceutical ComDosition Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aaueous and nonaqueous cariers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectabie organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance cc th~
_equired pa-.icle size in the case of dispersions, and bv t.-' use of surfactants.

WO90/09162 PCr/US90/On296 2 ~ 7 ~

These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of varlous antibacte_ial and antifungal agents, for example, paraben, chlorobu;anol, phenol, sorbic acid, and the like. I~ ~ay also be desirable to include isotonic agents such as susars, sodium chloride, and the like, Prolonged absorption of t:~e injectable pharmaceutical form may be brought about by the inclusion of agents which delay abdorption such as alu.-inum monostea-ate and gelatin.
If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filte_, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at 2~ least one inert, pharmaceutically accept2ble excipient o-carrier such as sodium citrate or dicalcium phosphate and/o-a) fillers or extenders such as starches, lactose, suc_ose, glucose, mannitol, and silicic acid, b) binders such as, fo.
example, carboxyme~hylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c~ humectants suc.
as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca szarch, alginic acid, WO90/09162 PCT/~'S90/002~6 ~, certain silicates, and sodium carbonate, e) so~ution retarding agents such as paraffin, f) absorp~ion accele~ato_s such as quaternaryammonium compounds, g) wet~ing ager.ts suc:~
as, for example, cetyl alcohol and glyce_ol monostea-2te, :^) zbsorben~s such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sul^~
and mixtures thereof. In the case of capsules, tablets ar.~
pills, the dosage fo-m may also comprise buf_ering agen.s.
0 Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin cz?sules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, 1~ pills, and granules can be prepared witA coatings and sr.ells such as enteric coatings and other coatings well ~nown i~. the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient~s) only, or preferentially, i-;
a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which cz-.
be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-ment or.ed excipients.
Liquid dosage forms for oral acministrz~ion include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the zct ve compounds, the liquid dosage forms may contain inert diluen.s com~only used in the art such as, Çc- example, water or othe-solvents, solubilizing agents and e...-lsifiers such as e~^y:
alcohol, lsopropyl alcohol, ethyl carbonate, ethyl ace~a~e, ~ 32 benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mix~u-es thereof.
Besides inert diluents, the oral compos-tions czn also include adjuvants such as wetting agents, emulsifying zr.d suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and so-sitan esters, microcrystalline cellulose, aluminum metahyd-oxlde, bentonite, agar-agar, and tragacanth, and mix~ures thereGf.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carrier~ such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Dosage forms for topical administration of a compound o-this invention include powders, s?rays, ointments andinhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and a-.y needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders a-.d so7utions are also contemplated as being within the scope O r this invention.

WO90/09162 PCT/USgO/0~296 Anaphylatoxin Receptor Binding Ki Determination Specific inhibition of C5a binding activity o4 representztive compounds of the present inventlon was measured using 0.03-1 nM 125I-C5a with 2.5-2; ug/mL of S purified P~NL membrane fragments (Borregaard, N.; :-.e ?'e, J.M.; S-mons, E.R.; and Clark, R.A. ~. Cell. ~iol. 1983, 97, 52-61.). Free and membrane-bound ligand were separa~ec by f-ltrat on. Binding potencies for representative exa-.? __ of compounds of this invention are listed in Table 1 Table In vitro C5a Receptor Binding Potency of Compounds of this Invention.
.__,_______________________.__~.__.___~____...______________J___~_~,~,=
~xample Ki uM Example Ki u:
_____________________________________________________________ 2 0.098 249 0.11 13 0.85 279 4.0 23 2.4 282 0.023 31 0.09 295 3.3 91 0.485 296 0.012 106 0.042 305 0.17 111 0.65 316 0.17 117 0.55 338 0.5 131 0.17 348 0.14 150 0.11 377 1.8 165 0.042 402 0.0;1 182 0.3 404 C.13 188 0.21 409 3.8 202 0.87 421 3.2 213 0.33 424 0.48 220 0.22 432 0.03 WO90/0916Z PCT/US90/002g6 2 ~ 7 ~ 34 (Table 1 concluded) 229 0.033 445 0.26 245 0.052 455 0.017 247 0.33 460 0.021 !:~ynth~,~C~Un~
The novel compounds and salts thereof or the inventior.
can be utilized effectively as therapeutic agents.
Accordingly, the present invention fu-the- relates to therapeutic compositions comprising a novel compound having the general formula I or salts thereof as an active component.
The compounds of the invention may be prepared by a IS synthetic method of elongation of a peptide chain throusr.
condensation of one amino acid by one, or by a method of coupling fragments consisting of two or several amino acids, or by a combination of these methods in accordance with conventional peptide syntheois methods.
The condensation of two amino acids, the condensation o~
an amino acid with a peptide or the condensation of one peptide with another peptide may be effected in accordance with conventional condensation methods such as azide method, mixed acid anhydride method, symmetrical anhydride method, DCC (dicyclohexylcarbodiimide) method, active ester method (p-nitrophenyl ester method, N-hydroxysucc~nimide ester method, cyanomethyl ester method and the like), Woodward reagent K method, DCC-~OBT~1-hydroxy-benzot_iazole) method and the like. These condensation reactions may be done by either solution methods or solid phase synthetic methods.
~nen the pe?tide chain is elongated ~y ~he solid phase method, the C-terminal amino acid is linked to an insol~b e .J, carrier. As the insoluble carrier, any that can produce a detachable bond by reacting with a carboxyl group in a C-terminal amino acid may be used, and the examples the_eof involve, for example, halomethyl resins such as chlorome~:n~L
resin, bromomethyl resin and the like, hyd-oxy-methyl res~r., benzhyd-ylamine resin, and t-alkyloxycarbonyl hydrazide resin.
As conventional ?olypeptide synthesis, branched cha_n amino ar.d carboxyl groups at alpha and omega positions n amino ac ds ~ay be protected/deprotected if necessa-y. ~he protecting groups for amino g-oups which can be used involve, for example, benzyloxycarbonyl (Z), o-chlorobenzyloxycarbonyl ((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxy-benzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (3OC), t-amyloxyca-bonyl (Aoc), isobornyloxycarbonyl, admantyloxycarbonyl, 2-(4-biphenyl)-2-propyloxycarbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxycarbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl (~Jps), diphenylphosphinothioyl (Ppt), and dimethylphosphinothioyl (Mpt).
The examples of protecting groups for carboxyl groups involve, for example, benzyl ester (OBn), cyclohexyl ester, 4-nitrobenzyl ester (OBnNO2), t-butyl ester (OtBu), 4-picoly:
ester (OPic) and the like.
In the course of the synthesis of the present novel compounds, specific amino acids having functional sroups other than amino and carboxyl groups in the branched chain such as arginine, cysteine, serine, and the like may be protected, if necessary, with sultable protecting group. It is preferable that for example, the guanidino group (NG) n argir.ine may be protected with nitro, p-toluenesulfonyl 7 ~ 36 (Tos), benzyloxycarbonyl ~Z), adamantyloxycarbonyl ~Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2,6-dimethylbenzene-sulfonyl (Mds), 1,3,5-trimethylphenylsulfonyl (~ts) and t:~e like, and the thiol group in cysteine may be protected w~
benzyl, p-methoxybenzyl, triphenylmethyl, acetzmidomet~yl, ethylcarbamyl, 4-methylbenzyl (4-MeBn), 2,4,6-~rimethyl~e?.z-,l (Tmb) and the like, and the hydroxyl group in serine ~.ay be protected with benzyl (Bn), t-butyl, acetyl, tetrahydropyranyl and the like.
0 N-Acetylated peptides were prepared in analogy to rxam,ple 9~. The following literature procedures we-e used -3 prepare N-alkyl- or N,N-dialkyl-amino acid derivatives.
Lovett, J. A.; Portoghese, P. J. Med. Chem. 1987, 30, 1144-1149. Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, '573-1674. :~ansen, D. W.; Pilipauskas, 3. J. Org. ~hem.
1985, 50, 945-950. Grieco, P. A.; Bashas, A. J. Org. Chem.
1987, 52, 5746-5749. Shuman, R. T.; Smithwick, E. L.;
Smiley, D. L.; Brooke, G. S.; Gesellchen, P. D. "Peptide:
Structure and Function", Proceedings of the Eighth ~..erican Peptide Symposium, 1984; p 143-146. Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 906-910. These reactions we_e carried out either on the elongated peptide-resin or on Zmi?.G
acid derivatives and then incorporated into the peptide-resin.
The following literature procedures were used to pre?are (2'S,3S)-3-amino-2-oxo-1-pyrrolidine-{2'-~4'-~.ethyl)}-pentanoic acid, (2'R,3S)-3-amino-2-oxo-1-pyrrolidine-~2'-(4'-methyl)~-pentanoic acid, and (2'R/S,3S)-3-amino-2-oxo-1-azepine-2'-pentanoic acid: Freidinger, R. M.; Perlow, D. S.;
Veber, D. F. J. Org. Chem. 1982, 47, 104-109. The ?-e?aration of ~2R,S)-2-amino-5-phenylpentanoic acld is des_-ibed i-.: Greenstein, J p ; r~inl tz, M. "C~.emistry o. ~~.

37 2~ 7~

Amino Acids"; John Wiley and Sons, Inc.: New York, 1961; V51 III, p.2387. Perhydroindolecarboxylic acid was synthesized according to the following procedure: Vincer.;, M .; Remon~, G.; Portevin, B.; Serkiz, B.; Laubie, M. Tetrahedron Lett.
1982, 23, 1677-1682.
(2S)-2-Amino-4-cyclohexylbutanoic acid: A solution o-(2S)-2-amino-4-phenylbutanoic acid (5 g) in 10~ HOAC--2O (~0 m~) was hydrogenated at room temperature a~ 5 atms with platinum oxide (0.1 g). Removal of catalyst by filtra_ior.
and evaporation yielded 4.9 g of product. 3-(2'-Pe-hydronaphthyl)~alanine and 3-(1'-pe-hydronaphthyl)}ala.. ne were prepared similarly from L-3-(2'-naphthyl)}alanine and ~-3-~1'-naphthyl)}alanine, respectively.
The following literatùre procedures were used to pre?2-~
N-guanid no substituted arginine derivatives: Mathias, L.
J., Synthesis 1979, 561-576; Maryanoff, C. A.; Stanzione, R.
C.; Plampin; J. M.; Mills, J. E. J. Org. Chem. 1986, 51, 1882-1884; Nestor, J. J.; Ho, T. L.; Simpson, R. A.; Horner, B. L.; Jor.es, G. P..; McP~ae, G. I.; Vickery, P. H. J. Med.
Chem. 1982, 25, 795-801. The obtained arginine derivative3 were at.ached to Merrifield resin as described in: Stewar~, J. M.; You~g, J. D."Solid Phase Peptide Synthesis", 2nd edition; Pierce Chemical Co.: ~ockford, Illinois, 1984; p 7'-72. The amino acid resin obtained was used to construct the peptide, followed by cleavage and purification to yield the desired peptide analog.

WO90/09162 PCT/US90/002g6 The following fragments are prepared as descri~ed ~n t~
literature:
O O
H C \\~

O H
Fragment l Fragment-2 ~N~ [~SCH3 ~
Fragment-3 Fragment 4 CH3 ~7~1 (CH2~--~S~

'~ ~N~
Fragment-5 Fragment-6 k=C,1,2 References:
1. Fiegel, M. J. Am. Chem. Soc. lg86, 108, 181.
0 2. :~emp, D. S.; McNamara, P. _. J. Org. Chem. 1985, 50, 5834.

WO90/09162 PCT/~'SgO/~296 ~ r, ~ - ' ,'~ "J

3. 3elanger, P. C.; Dufresne, C.; Scheigetz, J.; Yang, R.N.; Springer, J. P.; Dmitrienko, G. I. Can. J. Chem, 1982, 60, 1019.
4. :~.stenansky, J. L.; Baranowdki, R. L.; Currie, ~. _ 5 Biochem. 3iophys. Res. '~ornmu~. 1982, 109, 1368.
5. A;twood, M. R.; Francis, R. ~.; Hassall, C. H.;
~rohn, ~.; Lawton, G.; Natoff, I. L.; Nixon, J. S.; Redsha~, S.; Thomas, W. A. ~E~S Lett. 1984, 165, 201.
6. (a)Nagai, U.; Sato, X. Tetrahedron Lett . 1985, 6~7.
(~)Baldwin, J.; Lee, E. Tetrahedron Lett . 1986,42, 6;51.
The co~pounds of the invention were prepared by s~ændz~~
solid phase peptide synthesis conditions as described in "Solid Dhase Peptide Synthesis" by J. M. Stewart and J. D.
Young, Second Edition (1984) and illustrated in Examples 1 ar.d 2 in ~r.e experimental section.
The compounds of the invention may also be prepared by partial solid phase synthesis, fragment condensation methods and classical solution methods as exemplified by the methods described in "Peptide Synthesis", Second Edition, M.
Bodanszky, Y. S. Xlausner, and M. A. Ondetti (1976).
The standard chirality descriptors "R" and "S" are used to indicate an isomerically pure center, "RS" to indicate a mixture, and "R/S" to indicate a single pure isomer of undetermined configuration. The descriptor "i" refers to a d,l mixture of amino acids at the indicated residue. The descriptor ~{X~ indicates the group, X, that is 2 replacemen~
for the s~andard peptide bond, -C(O)NH-. The descriptor "*"
or "**" when written in a chemical name indicates the site c a disulfide or amide linkage, respectively.
The foregoing may be better understood by reference to the following examples which are provided for illustratlon and not li.~.l_ation of the practice o~ the invention. Unlecs WO 90/09162 PCI-lUSgO/00296 r ~ 40 2~5~ ~

otherwise indicated, the standard peptide method~ descri~ed above and in examples 1 and 2 were used to assemble che different products, using the precursors indicated by tne specific peptide sequence. The product was at least g5 S pure, and gave NMR and mass spectra consis~ent with the proposed structure.

Exa~ple H-Phenylalanyl-Lysyl(N-epsilon-Cbz)-Alanyl-~2S)-2-Amino-~-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-D-Alanyl-Arginyl(N-guanidino-Tos)-Merrifield Resir.
Boc-A_g(N-guanidino-Tos)-Merrifield resin (0.4-1.0 g) was placed in a solid phase peptide synthesis vessel and amino acids were attached to the resln sequentially in the following order: Boc-D-Alanine, Boc-Leucine, Boc-(2S)-2-Amino-3-cyclohexylpropanoic acid, Boc-(2S)-2-Amino-3-cyclohexylpropanoic acid, Boc-Alanine, (N-alpha-Boc,N-epsilon-Cbz)Lysine, Boc-Phenylalanine, according to the protocol outlined in Agenda A to yield the protected peptide resin: H-Phenylalanyl-Lysyl(N-epsilon-Cbz)-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-D-Alanyl-Arginyl(N-guanidino-Tos)-Merrifield resin. Following the synthesis, the protected peptide resin was removed from the reaction vessel by washing the resin three times with 20 mL DMF into a 30-60 mL sintered glass funnel, followed by washing the resin three times with 20 mL methylene chloride. The resin was dried at leas~ L ive hours, then weighed.

2 ~ ~

~ae~da ~
l. Deblock : 45% trifluoroacetic acid (TFA) in metnylsne chloride containing 2.5% anisole ~v/v/v).
2. Neutralization : 10% diisopropylethylamine (DI_~) in methylene chloride (v/v) 3. Single Coupling : 0.2-0.4M Boc-amino zc_d de-ivz~_-;s in N,N-dimethylformamide (DMF), 0.2-0.4M
diisopropylcarbodiimide (DIC) in methylene chlo_ide, -ezc~ _~
time, 60 minutes.
4. Resin base washing : l0~ DIEA in methylene chlor ce (v/v) .
5. Single Coupling repeated : same as Step 3.
6. Go to next amino acid residue (go back to Step l).
7. Upon attachment of the final amino acid to the growing pep~ide chain, the protecting group ('-3OC) s removed as in Step l.

Example 2 H-Phenylalanyl-Lysyl-Alanyl-{l2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
The protected peptide resin of Example l (0.6 g) was treated with l.0 mL anisole and l0 mL hydrogen rluoride (~
for 60 minutes at 0C. The HF and anisole were removed ~~
vacuo at 0C, and the mixture of the peptide and resin was washed with diethyl ether (2 x 25 mL). The crude peptide w25 extracted frGm th~ mixture by treatment with portions o. 20 aqueous acetic acid (4 x 25 mL), lyophilized to a dry amorphous powder, and purified by high performance liquid chromatography (HPLC) (column: 21.4 mm ID x 25 cm or 41.4 mm ID x 25 cm, Dynamax (Rainin), 8um silica, Cl8 reverse-?hase column}. The sample was purified by gradient elution ~f-Gm 2~S70' 42 20 to 60~ (80% acetonitrile in water with 0.1%
- trifluoroacetic acid)~ at a flow rate of 15-45 mL/min.
FAB+ MS: (M+H)+=1011 Amino Acid Anai.: Phe (0.91~, Lys (1.01), Ala (2.06), Cha (1.96), Leu (0.91), Arg (1.04) s Examplo 3 Ac-Histidyl-Lysyl-Asparaginyl-Methionyl-Glutaminyl-~eucyl-Glycyl-Arsinyl-OH
FAB+ MS: (M+H)+=1025 Amino Acid Anal.: Asx (0.98), Glx (~.07), Gly (0.97), Met (0.96), Leu (1.0;), His (0.97), Lys (0.98), Arg (1.04) Example 4 Ac-Histidyl-Lysyl-Aspartyl-Methionyl-Phenylalanyl-Leucyl-Glycyl-A_ginyl-OH
FAB+ MS: (M+H~+=1045 - Example S
(N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-(Fragment-1)-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH

~xample 6 Ac-Histidyl-Lysyl-Aspartyl-~(2S)-2-Aminohexanoyl}-{(2S)-2-Aminohexanoyll-{(2S)-2-Aminohexanoyl}-Glycyl-Arginyl-OH
E~3+ MS: (M+H)+= 993 Amino Acid Anal.: Asx (0.96), Gly (0.98), His (0.84), Lys (1.01), Arg(1.05), Nle (3.07) Example 7 H-:~lstidyl-Lysyl-Aspartyl-Methionyl-{(2'5,3S)-3-Amino-2-oxo-1-pyrrolidine-{2'-~4'-methyl)}-pentanoyl}-Glycyl-Arginyl-OH
FA3+ MS: (M+H)+-939 WO90/09162 PCT/US90/002g6 '~JJ~ J

Examplo 8 Ac-Histidyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-~2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-3-Aminopropanoyl-Arginyl-OH
FAB+ MS: (M+H)+=1087 ~mino Acid Anal.: Asx (1. al), Leu (0.99), Cha (1.98), His (0.93), Lys (1.01), A-g(1.03) Example 9 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-~(2S)-2-Am~no-3-cyclohexylpropanoyl~-Glycyl-(Fragment-2)-A-~lnyl-OH

Examplo 10 Ac-Histidyl-Lysyl-Aspartyl-Methionyl-Threonyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+:i)+=999 Amino Acid Anal.: Asx ~0.96), Th_ (0.78), Gly ~1.02), Met ~0.84), Leu (1.05), His (0.95), Lys (0.84), Arg (1.03) Exa~pl~ 1 1 Ac-Histidyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Isoleucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1087 Example 12 Ac-Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DMethionyl-Arginyl-OH
FAB+ MS: (M+H)+31147 Amino Acid Anal.: His (1.10), Lys (0.94), Asp t0.96, Cha (1.84), Leu ~1.01), Met t0.96), Arg (1.03) WO90/09162 PCT/US90/002g6 2 ~ 7 () 44 Exampl~ 13 Ac-Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-~mino-3-cyclohexylpropanoyl~-Leucyl-Pipecolyl(+)-Arginyl-OH
FAB+ MS: (M+H)+=1127 Amino Acid Anal.: His (1.19), JyS
(1.04), Asp (1.09), Cha (1.71), Leu (1.04), A-g (0.92) Example 14 -Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-(Fragment-3)-Leucyl-(~-Methyl)DAlanyl-Arginyl-OH

~xa~pl 15 Ac-Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-4-cyclohexylbutanoyl}-{(2S)-2-Amino-4-cyclohexylbutanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H) +31115 Example 16 H-6-Aminohexanoyl-Aspartyl-{(25)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+3893 Example 17 Ac-Histidyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1043 WO9~/09t62 PCT/US9~/00296 Exa~ple 18 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-~2S)-2-Amino-3-cyclonexylpropanoyl~-(Fragment-4)-(N-Methyl)DAlanyl-Arginyl-OH
s Exa~ple 19 Ac-Histidyl-Lysyl-Aspartyl-Cysteinvl(Acm)-Cyste~nyl(Acm)-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+31129 Example 20 Ac-Histidyl-Lysyl-Aspartyl-DTryptophyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1120 l S
Examplq 21 Ac-Histidyl-Lysyl-Aspartyl-Methionyl-Histidyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1049 Example 22 Ac-Y.istidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-DTryptophyl-Leucyl-DAlanyl-Arsinyl-OH
FAB+ MS: (M+H)+=1120 Example 23 Ac-Histidyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Y.istidyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)~=1071 ~0 20~7~ 46 Example 24 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-((25)-2-Am.ino-3-cyclohe~ylpropanoylJ-(Fragment-5)-~N-Methyl)DAlanyl-Arginyl-OH

Exa~ple 25 Ac-Histidyl-Lysyl-Aspartyl-Cysteinyl*-Cystei~yl*-~eucyl-DAlanyl-Arsinyl-OH
FAB+ MS: (M+H)+=985 Exa~ple 26 Ac-Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Valyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1073 Amino Acid Anal.: J'' S (1.17), Lys (1.00), Asp (0.93), Cha (1.71), Val (1.00), Ala (0.90), Arg (0.97) Example 27 Ac-Histidyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-~2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DSeryl-Arginyl-OH
FAB+ MS: (M+H)+=1103 Amino Acid Anal.: His (1.06), Lys (1.19), Asp (0.83), Cha (1.93), Leu (1.04), Se- (0 ~0), Arg (0.91) Exa~ple 28 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-(Fragment-6)-(N-Methyl)3Alanyl-Arginyl-OH

WO 90/09162 PCT/USgO/00296 47 ~ 4 ~,j J

Exampl- 29 Ac-Histidyl-Lysyl-Aspartyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoy11-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1172 Amino Acid Anal,: ;-.is ('.03), ys (0.97), Asp (0.93), Cha (1.74), Leu (0.95), Arg (1.96j Example 30 Ac-Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl)-{(2'S,3S)-3-Amino-2-oxo-1-pyrrolidine-{2'-(4'-methyl)l-pentanoyl}-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1017 Example 31 Ac-(4-NO2)Phenylalanyl-Lysyl-Aspartyl-{(25)-2-Amino-3-cyclohexylpropanoyll-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1142 Exa~plo 32 H-Phenylalanyl-{(2S)-2Amino-6-trifluoroacetamidohexanoyll-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-O~.

Example 33 Ac-Histidyl-Lysyl-Glutaminyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-l(2S)-2-Amino-3-cyclohexylpropanoyll-Leucyl-DAlanyl-Arginyl-OH
FAB~ MS: (M+H) +allOO

WO gO/09162 PCr/US90/~02g6 2OL~7 (~ 48 Example 34 Ac-Histidyl-Lysyl-Cysteinyl~Acm)-((2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl}
Leucyl-DCysteinyl(Acm)-Arginyl-OH
FAB+ MS: (M+H)+=1249 ~xamplQ 35 H-Dhenylalanyl-{(2S)-2-Amino-6-formamidohexanoyl}-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylo-opanoyl}-Leucyl-DAlanyl-Arginyl-OH

Exa~pl- 36 Ac-Histidyl-Lysyl-Aspartyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1005 Exampl~ 37 Ac-Histidyl-(N-delta-iPr)Ornithyl-Asparaginyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1114 Amino Acid Anal.: Ala ~1.00), Leu (1.01), His (1.11), Cha (1.79), Arg (1.01) Example 38 Ac-~istidyl-Lysyl-Asparaginyl-l(2S)-2-Amino-3-cyclohexylpropanoyll-((2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-NHNH2 N-Acetyl-Histidyl-Lysyl(N-epsilon-Cbz)-Asparaginyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-D-Alanyl-Arginyl(N-guanidino-Tos)-OResin (0.62g) was suspended in 10 mL of N,N-dlmethylfor..amide (DMF), and 1 mL of anhydrous nydrazine was 2~ J 7 added. The mixture was stirred at room temperature for 4 days and filtered. The resin was washed with an add7tionaL la mL of DMF, and the combined DM~ solution was poured into 100 mL of diethylether. Upon cooling the mixture, it gradually solidified. The solid was collected by filtration, wzshed with 50 mL of water and dried. The dry solid obtained (approximately 160 mg) was treated with HF and anisole, as described in Example 2. After lyophilization, 1;3 ms o-crude peptide was obtained which was purified by HPLC
(Example 2) to yield 35.6 mg of pure peptide that gave NM~
and mass spectra consistent with the desired p-oduc~.
FAB+ MS: (MIH) +3 1099 Examplo 39 Ac-Histidyl-Lysyl-Aspartyl-~2S)-2-Amino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyl}-(~2S)-2-Aminopentanoyl}-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+=1189 Amino Acid Anal.: Ala ~1.00), His ~1.11), Cha ~1.89), Lys ~0.98), Arg ~1.01) ~xa~ple 40 ~N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amir.o-3-cyclohexylpropanoyl}-Glycyl-Leucyl-~N-Methyl)DAlanyl-Arginyl-Glycyl-Giycyi-OH

2~ 3 so Example 41 Ac-Histidyl-Lysyl-Asparaginyl-~(2S)-2-Amino-3-cyclohexyl?ropanoyl}-f~2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OCH3 FAB+ MS: (M+H)+=1100 Amino Acid Anal.: Asx (0.91), Alz (0.90), Leu (0.96), ~is (1.08), Cha (1.65), Lys (0.97), Arg (O'. 95) Example 42 Ac-Histidyl-Lysyl-Aspa-tyl-{(2R)-2-Amino-3-cyclohexyl?ropanoyl}-{(2R)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1087 Amino Acid Anal.: Asx (0.99), Ala (0.95), Leu (1.02), His (1.07), Cha (1.80), Lys (1.03), Arg (1.02) Example 43 Ac-Alanyl-Arginyl-Asparaginyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+31048 Amino Acid Anal.: Asx (1.01), Ala (1.94), Leu (1.02), Cha (1.88), Arg (2.08) Fxample 44 Ac-Lysyl-Lysyl-Asparaginyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1077 Amino Acid Anal.: Asx S0.98), Ala (0.93), Leu (1.01), Cha (1.87), Lys (2.01), Arg (1.01) WO90/09162 PCT/USgO/Oo2g6 f, Example 45 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-~ .o-3-cyclor.exylpropanoyl}-Glycyl-Leucyl-(N-Methyl)DAlanyl-~(4~)-(4-Ethyl)Agmatine~
N-alpha-30c-N-guanidino-Tosyl-Arginine is converte~ to its aldenyde which is reacted with methylenet~ipnenyl-phosphorane using a modified literature procedure (Luly, J.
R.; Dellaria, J. F.; Plattner, J. J.; Sode-quist, J. L.; Y , N. J. Org. Chem. 1987, 52, 1487) followed by hydrogena._on c-.
Pd/C to yield (4R)-N-alpha-30c-N-guanidino-Tosyl-(4-Ethyl)Agmatine. The protected peptide: N-30c-(N-Methyl)Phenylalanyl-N-epsilon-Cbz-Lysyl-(N-~.ethyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Gylcyl-Leucyl-(N-Methyl)DAlanine is synthesized according to the procedu~e o Example No. 303. The above agmatine derivatlve is trea;ed with 4N-HCl/Dioxane, and the resulting salt is coupled with the protected peptide using a DCC/HOBT mediated coupling procedure. The protecting groups are removed by treatmer.t with liquid HF/anisole according to the procedure of Example 2.

Example 46 H-Lysyl-Phenylalanyl-Aspartyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+- 1055 WO90/09162 ~CT/US90/0~296 2 ~ 7 ~ 52 ~xampl~ 47 H-3henylalanyl-Lysyl-4-Aminobutanoyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=872 Amino Acid Anal.: Phe (0.99), Lys (1 01), Gaba (0.97), Cha (0.94~, Leu (1.06), Ala (1.00), ~.r ( 1 . 00) Example 48 H-DPhenylalanyl-DLysyl-DAspartyl-DMethionyl-DGlu~amlnyl-0 DLeucyl-Arginyl-DAr~inyl-OH
FAB+ MS: (M+H)+=1093 Amino Acid Anal.: Asp (O.S7), ~lx (1.05), Met (0.61), Leu (1.03), ~he (0.97), Lys (0.94), ~~g (2.04) Exa~ple 49 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-~N-Methyl)DAlanyl-(NH~alpha)Phenethyl~R/S)) The protected peptide: N-Boc-~N-Methyl)Phenylalanyl-N-epsilon-Boc-Lysyl-~N-Methyl)Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Gylcyl-Leucyl-~N-Methyl)DAlanine s prepared by the method described below. The peptide chaln is elongated by the same method described in Example 1, exce?t that after N-alpha-Fmoc-N-epsilon-30c-Lysine is coupled, the sequence is stopped at agenda A-step 5. The obtained N-alpha-Fmoc-N-epsilon-Boc-Lysyl-peptide resin is treated with DMF:piperidine ~1:1) for 30 minutes at room temperature.
After the peptide resin is washed with DMF and methyLene chloride, the next synthetic protocol (rxample 1, agenda ~-step 3) is initiated with the exception that the N-terminal protecting group is not removed at the end of the synthes s.
The fully ?-otected peptide is obtalned by the procedure c-2 ~ 3 ~ v' Example 309. The prote~cted peptide is coupled with alpha-phenethylamine using DCC/HO3T. The protecting groups z-e removed by treatment with 4N-HCl/dioxane to give the de~i-eA
compound.

Example 50 H-Phenylalanyl-Lysyl-Prolyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+-1037 Amino Acid Anal.: Phe (1.01), Lys (1.01), Pro (1.02), Cha (1.96), Leu (1.09), Ala (0.88), A-g (1.04) Example 51 H-Phenylalanyl-Histidyl-Lysyl-Alanyl-((2S)-2-~mino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1148 Amino Acid Anal.: Phe (0.95), His (1.07), Lys (0.98), Ala (1.64), Cha (1.76), Leu (1.02), Arg (0.98) 2xample 52 Hydrocinnamoyl-Lysyl-Aspartyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1040 Amino Acid Anal.: Lys (0.64), Asp (0.73), Cha (1.93), Leu (1.04), Ala (0.82), Arg (1.04) 2 ~ 7 ~ ~

~xampl~ 53 (N-Methyl)Phenylalanyl-Lysyl-~N-Methyl)Alanyl-((2S)-2-~ino-3-cyclohexylpropanoyl~-Glycyl Leucyl-(N-Methyl)DAlanyl-{(4~)-(4-(beta-Phenethyl))Agmatine) (4R)-N-alpha-Boc-N-guanidino-Tosyl-(4-(beta-Phenethyl))Agmatine is synthesized by the method descri~e~
Example 45 with the exception that benzyltriphenyl-phosphorane is used instead of methylenetri?henylphospho-zne.
The Boc group is remo~ed by treatment with 4N-:~C1/dioxane, and the resulting amine salt is coupled wi.h the p-otected heptapeptide (cited in ~xample 45) using DCC/H03T. The protecting groups are removed by treatment with liquid HF/anisole to give the desired compound.

~xample 54 H-Phenylalanyl-Lysyl-DProlyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+31037 Amino Acid Anal.: (Phe (1.00), Lys (1.01), Pro (1.06), Cha (1.94), Leu (1.09), Ala (0.86), Arg (1.04) Exa~l- 55 H-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2'S,3S)-3-Amino-2-oxo-1-pyrrolidine-{2'-(4'-methyl)}-pentanoyl}-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=985 Amino Acid Anal.: Phe ~0.98), Lys (0.94), Asp (1.01), Cha (0.95), Ala (1.06), Arg (1.07) WO90/09162 PCT/US90/~96 ,,, " ; ,~

~xample 56 H-Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexyl?ropanoyl}-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-Leucyl-DProlyl-Arginyl-OH
FA3+ MS: (~+H)+= 1037 Amino Acid Anal.: Phe (0.9g), L~--(0.93), Ala (0.93), Cha (1.94), Leu (1.09), ~-o (0.83), A:g (1.07) Examplo 57 H-Phenylalanyl-Histidyl-Lysyl-{(2S)-2-Amino-3-cyclohexylp_opanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoylJ-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H) +5 1077 Example 58 Ac-(4-NH2)Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M~H)+=1112 Amino Acid Anal.: (4-NH2)Phe (0.75), Lys (1.02), Asp (0.98), Cha (1.90), Leu (1.09), Ala (0.99, Arg (1.03) Example 59 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-~N ~ethyl)DAlanyl-Arginyl-SCH2CH3 N-alpha-3Oc-Arginine is reacted with ethylmercaptan, according to the procedure described by Yamada, S.;
Yokoyama, Y.; Shioiri, T. J. Org. Chem. 1974, 39, 3302. T'n ester obtained is treated with 4N-HCl/dioxane and coupled with the protected heptapeptide (ci;ed in ~ample 49). -i-.a:

~ 56 deprotection is carried out by treatment with 4N-HCl/diox~ne to give the desired product.

Examplo 60 Ac-Phenylalanyl-Lysyl-Asparaginyl-Histidyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Tryptophyl-OH
FAB+ MS: (M+H)+=1110 Example 61 H-Phenylalanyl-Lysyl-6-Aminohexanoyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=900 Amino Acid Anal.: Phe (0.98), Lys (0.99), Cha (0.94), Leu (1.07), Ala (1.01), Arg (1.02) Exa~ple 62 H-!4-I)Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+-1137 Exa~pl- 63 H-T.yrosyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl;-~t2s~-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Argin OH
FAB+ MS: (M+H)+31027 Amino Acid Anal.: Tyr (0.32), Lys (1.00), Ala (1.89), Cha (1.45), Leu (1.19), Arg (1.12) ~ ~J ~ ~J ~

Example 64 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-NHCH2CH3 N-alpAa-Boc-Arginine is coupled with ethylamine ~si.~
mlxed anhydride method conditions. Deprotection o .he product wlth 4N-HCl/dioxane yields arginine ethylamide dihydrochloride which is coupled with the protected heptapeptide (cited in Example 49) using DCC/HOBT. The 10 protecting groups are removed by treatment with 4N-HCl/dioxane to give the desired product.

Ex~mple 65 H-Phenylalanyl-Arginyl-Aspartyl-{(2S)-2-Amino-3-15 cyclohexylp-opanoyl}-{(2S)-2-Amino-3-cyclohexylpropar.oyl;-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1083 Amino Acid Anal.: Phe (0.94), Arg (1.98), Asp ~1.07), Cha (2.01), Leu (1.14), Ala (0.82) Exampl~ 66 H-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~973 ~xa~pl~ 67 :i-(4-CX3)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FABi MS: (M+H)+-1025 Amino Acid Anal.: (4-Me)Phe (0.7v), Lys (0.99), Ala (1.71), Cha (1.92), Leu (1.07), Arg (1.02) WO90/09162 PCT/US90/002g6 2B4~7 8 ~ xa~ple 68 ~-(4-F)Phenylalanyl(R/S)-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropaQoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~+~)+-1029 Example 69 (N-Methyl)Phenylalanyl-Lysyl-~N-Methyl)Alanyl-((25)-2-~m~no-3-cyclohexylpropanoyl}-Glycyl-Leucyl-(N-Methyl)DAlanyl-10 Arginyl-NHCH2C6Hs This compound is prepared by the same met;~od desc_i~ed in Example 64 with the exception that ~enzylamine is used instead of ethylamine.

Example 70 H-(4-F)Phenylalanyl(R/S)-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-l(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1029 Amino Acid Anal.: (4-F)Phe (0.96), Lys (1.03), Ala (1.94), Cha (1.96), Leu (1.07), Arg ~1.00) Exampl- 71 H-(3-F)Phenylalanyl(R/S)-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1029 Amino Acid Anal.: (3-F)Phe (0.84), Lys (1.00), Ala (1.84), Cha (1.98), Leu (1.03), Arg (0.99) WO90/09162 PCT/US~0/00296 2 ~ 7 ~

Examplo 72 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-(~2S)-2-Am~no-3-cyclohexylpropanoyl~-Glycyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-NH(2-Pyridyl)methyl This compound is synthesized by the same method describe~ in Example 64 ~ith the exception that (2-pyridyl)methylamine is used instead of ethylamine.

Exa~ple 73 H-(3-F)Phenylalanyl(R/S)-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-((2S)-2-Amino-3-cyclohexylpropanoyll-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1029 Amino Acid Anal.: (3-F)Phe (0.85), Lys (0.99), Ala (0.84), Cha (1.98), Leu (1.03), Arg (1.00) Example 74 H-(2-F)Phenylalanyl(R/S)-Lysyl-Alanyl-(~2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1029 Amino Acid Anal.: (2-F)Phe (1.01), Lys (1.00), Ala (1.95), Cha (2.02), Leu (1.08), Arg (1.04) Example 75 H-t2-F)Phenylalanyl(R/S)-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1029 Amino Acid Anal.: (2-F)Phe (0.99), Lys (0.99), Ala (1.84), Cha (1.98), Leu (1.03), Arg (l.OG

2~4~7~, 60 Example 76 (N-Methyl)Phenylalanyl-Lysyl-~N-Methyl)Alanyl-{~2S)-2-Amino-3-cyclohexyl?ropanoyl)-Giycyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-NRNHc6Hs The compound is prepared in analogy to Example 38.

Example 77 H-ehenylalanyl-Lysyl-Alanyl-Leucyl-Leucyl-Leucyl-DAlanyl-Histidyl-OH
FAB+ MS: (M+:~)+=912 Exampl- 78 H-(4-NO2)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1056 Amino Acid Anal.: (4-NO2)Phe (0.69), Lys (0.99), Ala (1.83), Cha (1.94), Leu (1.07), Arg ( 1 . 00 ) Exa~plo 7g H-Phenylalanyl-Lysyl-Phenylalanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1087 Example 80 Phenoxyacetyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H) +D998 WO90/09162 PCT/US90/OO~g6 ~ ~,,, 7 ,, ~

Example 81 ~N-Methyl)Phenylalanyl-Lysyl-~N-Methyl)Alanyl-{(2S)-2-~mino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-~N-Methyl)DAlanyl-Arginyl-N(-cH2c6Hs)NH2 The compound is prepared in analogy to Example 3~.

Example 82 H-Tryptophyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=1050 Example 83 H-Phenylalanyl-Lysyl-Histidyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoy'~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: UM+H)+~1077 Example 84 H-{3-(2'-Naphthyl)alanyl}-Lysyl-Alanyl-{(2S)-2-Amino-3 cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1061 Ex~mple 85 (N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-.~mlno-3-cyclohexylpropanoyl}-Glycyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OCH2C6Hs N-alpha-Boc-Arginine is converted to its benzyl ester, accordina to the procedure described by Wang, S.-S.; Gisin, 3. F.; '~inter, ~. P.; Makofske, R.; Kulesha, I. D.;
Tzougraki, C. and Meienhofer, J. J. Org. Chem. 1977, 42, WO90/09162 PCT/USgO/002~6 2 ~ 7 ~ 62 1286. The compound obtained is treated with 4N-HC1/dioxane and coupled with the protected heptapeptide (cited i~ Exa~p1e 45) using DCC/HOBT . - The protecting groups are removed ~y treatment with 4N-HCl/dioxane to give the desired product.

Example 86 H-{3-~ Naphthyl)alanyl}-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylp-opanoylj-{(25)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1061 ~ xampl- 87 H-(3-F)Phenylalanyl(R/S)-Lysyl-DAlanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl)-DAlanyl-Leucyl-DAlanyl-Arginyl-OH
I 5 ~A3+ MS: (M+~)+=947 Exa~pl- 88 H-Phenyialanyl-Lysyl-~(2S)-2-Amino-3-cyclohexylpropanoyi}-3-(Aminomethyl)benzoyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+3920 Example 89 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl}-2~ Leucyl-DPipecolyl-Arginyl-OH
FAB+ MS: (M+H)+-1051 Exampl~ 9O
(N-Methyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-NP.OCH3 The compound is prepared in analogy to Example 38.

WO90/09l62 PCT/US90/00296 Exa~ple 91 H-Phenylalanyl-Lysyl-Asparaginyl-Phenylalanyl-2henylalanyl-Leucyl-DAlanyl Arginyl-OH
FAB+ MS: (M+H)+~1042 Example 92 H-Phenylalanyl-Lysyl-Alanyl-Phenylalanyl-?henylalanyl-_eucy -DAlanyl-A_ginyl-OH
~AB+ MS: (M+H)+=999 Example 93 H-Phenylalanyl-Lysyl-Phenylalanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Histidyl-OH
FAB+ MS: (M+H)+=1068 Fxample 94 .-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-(~2S)-2-Amino-4-pentenoyl}-Leucyl-Glycyl-Arginyl-OH

~xample 95 Ac-Histidyl-Lysyl-Asparaginyl-t2-CH3)PhenylalanyltR/S)-t2 CH3)Pheny~alanyltR/S)-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: tM+H)+=1102 Amino Acid Anal.: Asx ~1.01), Leu ~0.97), His t0.89), Ala ~1.00), Lys ~1.01), Arg (1.04) Example 96 Ac-Histidyl-Lysyl-Asparaginyl-(4-CH3)Phenylalanyl(R/S)-~4-CH3)PhenylalanyltR/S)-Leucyl-DAlanyl-Arginyl-OH
cAB+ MS: (M+~)+=1102 Pcr/~sso/oo2s6 2 ~ 7 ~

Example 97 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexyipropanoyl}-(2-Amino-2-methyl-propanoyl}-Leucy t _ DAlanyl-Arginyl-OH
s Exampl~ 98 Ac-Arginyl-Lysyl-Asparaginyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cycLohexylpropznoyl}-Leucyl-DAlanyL-Arginyl-OH
FAB+ MS: (M+H)+-1105 Amino Acid Anal.: Asx (0.97), A12 (0.98), Leu (1.02), Cha (1.88), Lys (1.01), Arg (2.02) ~xampl~ 99 Ac-Aspartyl-Lysyl-Asparaginyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
The trifluoroacetic acid salt of Aspartyl(beta-Benzyl)-Lysyl(N-epsilon-Cbz)-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-cyclohexylpropanoyl}-Leucyl-D-Alanyl-Arginine(N-guanidino-Tos)-OResin (0.56 g) was prepared according to the procedure described in Example 1. The peptide-resin obtained was washed with 10%-diisopropylethylamine ~DIEA) in methylene chloride (3 x 15 mL, 45 seconds each) and methylene chloride (4 x 15 mL).
10%-DIEA in methylene chloride (15 mL) was introduced into the reaction vessel and acetic anhydride (0.47 mL, 5 mmole) was added. It wa-q reacted at room temperature for 1 hour ar.
repeated if neccesary (until Kaiser test was negative). The N-acetyl-peptide-resin was treated with HF and anisole to yield 127.3 mg of dried powder. A portion of the powder (75 mg) was pur-fied by HPLC, according to the procedure WO90/09162 PCT/US90/0~2~6 ~ t ~"'1 ~; rl '~ ~

mentioned in Example 2 to yield 40.4 mg of pure produc.
consistent with proposed structure.
FAB+ MS: (M+H)+21064 Amino Acid Anal.: Asx (1.8~), ALa ~1.04), Leu ~1.08), Cha ~1.89), Lys (0.96), Arg (1,07) s Exa~ple 100 H-((2R)-2-Amino-3-cyclohexylpropanoyl)-DLysyl-DAsparty t _ ~2R)-2-Amino-3-cyclohexylpropanoyl}-{~2R)-2-Amino-3-cyclohexylpropanoyl}-DLeucyl-Alanyl-DArginyl-OH
10~ FA3+ MS: ~M+~)+=1061 Exa~pl~ 101 H-Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{Aminocyclopropyl-l-carbonyl}-Le~cyl-DAlanyl-Arginyl-OH

Example 102 H-Phenylalanyl-Lysyl-Lysyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1068 Example 103 H--{3-(2'-Thienyl)alanyl( )}-Lysyl-Histidyl-{(2S)-2-~ino-3-cycIohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1084 Exa~ple 104 H-Phe~ylalanyl-Lysyl-Alanyl-(4-I)Phenylalanyl-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1049 WO90/09162 PCT/US90/002g6 2 ~ 66 Example 105 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{Aminocyclohexyl-l-carbonyl~-Leu DAlanyl-Arginyl-OH

Example 106 H-Phenylalanyl-Lysyl-Alanyl-{(25)-2-Amino-4-cyclohexylbutanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-O~
FAB+ MS: (M+H)+-943 Example 107 H-Phenylalanyl-Lysyl-Alany~-(3-F)Phenylalanyl(R/S)-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB- MS: (M-H)-=939 Exampl- 108 H-Phenylalanyl-Lysyl-Alanyl-(3-F)Phenylalanyl(R/S)-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~941 Example 109 H-Phenylalanyl-Lysyl-Alanyl-{(25)-2-Amino-4-phenylbutanoyl~-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~937 Ex ~pl- 110 Ac-{(lR/S)t2R/S)((Z)-1-Amino-2-phenylcyclopropyl)-1-carbonyl}-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
The C-terminal heptapeptide is prepared under standa-^
solid phase peptide synthesis conditions. The epsilon WO90/09162 PCT/US90/0~2g6 2~ ~J~

nitrogen of lysine is protected as its Fmoc derivative wr-ch remains intact through the acidic cleavage of the heptapeptide from the resin. Racemic ((Z)-l-Acetamido-2-phenylcyclopropane)-l-carboxylic acid is prepared 4rom Z-acetamidocinnamic acid according to the methodology g-ven ~n, Schmidt, U.; Lieberknecht, A.; Wild, J. S~nthesis 1988, 1;3-172, and the references cited therein. This amino ac ~ ~s then coupled in solution phase to the heptapeptide by the mixed acid anhydride method, and the Fmoc group is removed with pipe-idine. Separation of the diaste-eome-ic ?-cc-c_s by HPLC fu-nishes the final product.

Exampl- 111 H-Isoleucyl-Seryl-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropas._yl,-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1255 2xampl- 112 H-Phenylalanyl-Lysyl-Alanyl-{(2R/S)-2-Aminooctanoyl~-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=917 Example 113 H-Phenylalanyl-Lysyl-Alanyl-{(2R/S)-2-Aminooctanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+~)+-917 ~xampl- 114 H-Phenylalanyl-Lysyl-Alanyl-(3-(2'-Thienyl)alanyl~RtS)}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+~929 2 ~
Example 115 Ac-{(Z)-2-Amino-3-phenyl-2-propenoyl~-Lysyl-Alanyl-(~2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-Glycyl-Arginyl-OH
The C-terminal heptapeptide is prepared using standard 5 solid phase peptide synthesis techniques. The lysine is incorporated with the epsilon nitrogen protec;ed wi.h cmoc which survives HF cleavage of the peptide from the reslr. z..~
removal of the other protecting groups. Z-Acetamidocinnam~c acid is coupled to the heptapeptide in solution phase employing the mixed acid anhydride method. The Fmoc ~_ou? _s subsequently removed with piperidine, and the crude pe?tide is pu-ified by HPLC.

Example 116 1 5 H-Alanyl-Asparaginyl-Isoleucyl-Seryl-Phenylalanyl _T y5y 1 _ Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1440 Example 117 H-Phenylalanyl-Lysyl-Alanyl-Phenylseryl-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-939 Example 118 H-Phenylalanyl-Lysyl-Leucyl-{(2S)-2-~ino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leu-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1053 ~J~

Exampl- 119 (N,W-Dimethyl)Alanyl-(N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-~ethyl)DAlanyl-Arginyl-OH

Example 120 H-3henylalanyl-Lysyl-Alanyl-l(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-(omega-N, omega'-N-diethyl)Arginyl-OH
rA3+ MS: (M+H)+=1081 Amino Acid Anal.: Ala (1.9'), ~e~
(1.09), Phe (0.96), Cha (1.98), Lys (0.96) Example 121 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl'-Leucyl-DAlanyl-(omega-N-phenyl)Arginyl-OH
FAB+ MS: (M+H)+~1087 Amino Acid Anal.: Ala (1.86), Leu (0.98), Phe (1.07), Cha (1.98), Lys (1.11) .

Example 122 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-(omega-N-methyl)Arginyl-OH
FAB+ MS: (M+H)+-1025 Amino Acid Anal.: Ala (1.90), Leu (1.25), Phe (0.95), Cha (2.25), Lys (1.08), Arg (1.08) Example 123 (N-Methyl)Phenylalanyl-(N-Methyl)Phenylalanyl-Lysyl-Alany'-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH

W090/09162 PCT/US90/002g6 2 ~ 3 5 7 ~
Example 124 Ac-~istidyl-Lysyl-Asparaginyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-1(2S)-2-Amino-3-cyclohexylpropanGyl~-Leucyl-DAlanyl-Arginyl-NHOH
The com?ou~d was prepared in analogy to _xample 38 FABI MS: (M+H) +=i101 Example 125 Ac-Phenylalanyl-Lysyl-Glutamyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropar.ctl}-Leucyl-DAlanyl-Arginyl-OH
The synthesis, deprotection and cleavage of the resin-bound peptide was carried out as outlined in Examples 1 anc 2 except for the acetylation of the N-terminus which occu_-ed between the synthesis and deprotection/cleavage steps. .e acetylation was carried out as described in "Solid Phase Peptide Synthesis" by John M. Stewart and Janis D. Young, Second Edition (1984), p. 73.
FAB+ MS: (M+H) +
Exa~ple 126 H-Phenylalanyl-Lysyl-Glutamyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAE+ MS: ~M+H)+~1069 Example 127 ~N-Benzyl)Glycyl-~N-Methyl)Dhenylalanyl-Lysyl-Alanyl-l(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyi-Arginyl-OH

WO90/09162 . PCT/US90/00296 ~J ~ '_, ,J ~, i~ ,' Example 128 H-Phenylalanyl-Ornithyl-Alanyl-{(2S)-2-Amino-3-cyclohexyipropanoyl}-(t2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=997 Examp~ 129 H-Phenylalanyl-Lysyl-Alanyl-1(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Lysyl-DAlanyl-Arginyl-OH
FAg+ MS: (M+H)+=1026 Example 130 H-Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl)-{(2S)-2-Amino-3-cyclohexylpro?anoyl~-Glutamyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1027 Example 131 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Threonyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H) +3999 ~xample 132 (N-Phenyl)Glycyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH

WO90/09162 PCT/US9~/002g6 , .
2 ~ 72 Ex~mpl- 133 H-Leucyl-A;ginyl-Alanyl-Asparaginyl-Isoleucyl-Seryl-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1709 Example 134 H-Phenylalanyl-Glutaminyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylp.opanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1055 ExamplQ 135 H-Phenylalanyl-Alanyl-Aspartyl-(~2S)-2-Amino-3-cyc~ohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~+H)+=998 ~xa3pl~ 136 Alpha-Hydrazinohistidyl-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~N-Methyl)DAlanyl-Argi~.yl-OH

~xa~pl~ 137 2-Pyridylacetyl-Lysyl-Histidyl-{~2S)-2-Amino-3-cyclohexylpropanoyl~-{~2S)-2-Amino-3-cyclohexylpropanoy~
Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~1049 WO90/09162 PCT/~S90/00296 2 ~ 7 a Examplo 138 H-{(2S)-2-Amino-4-phenylbutanoyl}-Lysyl-Histidyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1091 Example 139 (5-Dimethylamino-l-naphthalenesulfonyl)-Lysyl-Histidy -~(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1163 Example 140 Methoxyacetyl-(N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-Methyl)DAlany -Arginyl-OH

Example 141 {1,2,3,4-Tetrahydroisoquinolin-3-carbonyl(_)}-Lysyl-Histidyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1089 Example 142 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DPhenylalanyl-Arginyl-OH
FABi MS: (M+H)+=1087 WO90/09162 PCT/US90/~0296 2 ~ L~ 5 7 ~ 74 Example 143 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropar.oyl'~-Glycyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=95S Amino Acid Anal.: Phe (1.01), Lys (1.07), Ala (1.90), Cha (2.10), Arg (1.06), Gly (.g7) Example 144 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-l(2S)-2-Amino-3-cycloAexylpropanoyi,-Alanyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+a969 Amino Acid Anal.: Phe (1.03), Lys (1.01), Ala (2.86), Cha (2.11), Arg (1.10) Example 145 H-Phenylalanyl-{(2S)-2-Amino-5-ureidopentanoyl}-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1040 Example 146 Hydroxyacetyl-(N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH
Example 147 H-Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-Lysyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=986 2 ~J3 f~

Example 148 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glutamyl-Leucyl-DAlanyl-Arginyl-O~:
FAB+ MS: (M+H)+=987 S
Example 149 H-Phenylal2nyl-Lysyl-Histidyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-{~2'R/S,3S)-3-Amino-2-oxo-1-azeplne-2'-pentanoyl)-DAlanyl-Arginyl-OH
FAB+ MS: (~+H)+=1021 Exa~ple 150 H-Phenylalanyl-Lysyl-Histidyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-{(2'R/S,3S)-3-Amino-2-oxo-1-azeplr.e-2'-pentanoyl~-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1021 Example 151 beta-Phenylethyl-oxy-acetyl-(N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~N-Methyl)DAlanyl-Arginyl-OH

Example 152 H-Phenylalznyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-{(2~/S)-2-Amino-4,4,4-trifluorobutanoyl)-Arginyl-OH
FAB+ MS: (M+H)+=1079 Example 153 H-?henyla'anyl-Lysyl-Alanyl-{3-(2'-?erhyd-ona?h.thyl)alznyl~-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=983 WO90/09162 PCT/US90/~96 - 2 ~ 76 Exa~ple 154 H-Phenylalanyl-Lysyl-Alanyl-{3-(2'-Naphthyl)alanyl}-Alany~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+=973 s Example 155 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoy'}-Leucyl-{(2R/S)-2-Amino-4,9,4-trifluorobutanoyl~-Arginyl-O:i FAB+ MS: (M+H)+=1079 Exa~ple 156 2-Methylthioacetyl-(N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH

Example 157 H-Phenylalanyl-Lysyl-Alanyl-(3-(1'-Naphthyl)alanyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=973 Example 158 H-Phenylalanyl-Lysyl-Alanyl-{3-(2'-(5'-tert-Butylthienyl))alanyl(R/S)}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=985 Example 1S9 H-Phenylalanyl-Lysyl-Alanyl-{3-(2'-(5'-tert-Butylthienyl))alanyl(R/S)~-Alanyl-Leucyl-DAlanyl-Arginyi-OH
FAB+ MS: (M+H)+=985 2 ~ ~ 5 .5 7~, Example 160 H-Phenylalanyl-Lysyl-Alanyl-(3-(2'-Thienyl)alanyl(R/S)}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=929 Example 161 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2'RS,3S)-3-Amino-2-oxo-1-pyrrolidl^.e-{2'-(4'-methyl)}-pentanoyll-DProlyl-Arginyl-OH
FAB+ MS: (M+H)+=967 Example 162 4-Phenylbutyryl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arg -.y'-OH

~ Example 163 H-Phenylalanyl-Lysyl-Alanyl-{3-(1'-Perhydronaphthyl)alanyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=983 Example 164 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Threonyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=9S9 Example 16S
H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-.~mino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (U+H)+=915 Amino Acid Anal.: Phe (.99), Lys (l.C~), Ala (1.92), Cha (1.00), Leu (1.07), .~rg (1.02), Gly (.9/j 2 ~ 78 Example 166 H-Phenylalanyl-Lysyl-Alanyl-Lysyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+=986 Example 167 Phenylacetyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(~-Methyl)DAlanf'~ g_^.yl-OH
Example 168 H-Phenylalanyl-Lysyl-Alanyl-Glutamyl-~2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=987 Examplo 169 H-{(2S)-2-Amino-4-phenylbutanoyl~-Lysyl-Alanyl-{(2S)-2-~mino-4-phenylbutanoyl~-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=951 Examplo 170 H-Phenylalanyl-Lysyl-Alanyl-~2S)-2-Amino-4-phenylbutanoyl~-Alanyl-Alanyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+3895 Example 171 Pyrazylcarbonyl-Lysyl-Histidyl-{(2S)--2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanovl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1036 WO90/09162 PCT/US9~/00296 2 ~

Exa~ple 172 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-~2S)-2-P~ino-3-cyclohexylpropanoyl}-(N-Hydroxy)Asparaginyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OY.

Exa~ple 173 3-Cyclopentylpropanoyl-Lysyl-Histidyl-{(2S)-2-Amlno-3-cyclohexylpropanoyl~-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FA + MS: (M+H)+-1054 Example 174 (3-Benzoyl)benzoyl-Lysyl-Histidyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropar.oyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1138 Example 175 {1,2,3,4-Tetrahydronaphthyl-carbonyl(+)~-Lysyl-Histidyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+Na)+-1110 ~xa3ple 176 (N-~ethyl)Phenylalanyl-Lysyl-Glycyl-~{CH2CO-NH}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-Methyl)DAlar.yl-Arginyl-OH

WO90/09162 PCT/US90/002g6 2 ~ , 80 Example 177 H-Phenylalanyl-Lysyl-Nipecotyl~+)-1~2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyt~-Leucyl-3Alanyl-Arginyl-OH
FA3+ MS: (M+H)+=1051 Example 178 4-Phenylbutanoyl-Lysyl-Histidyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropancyl}-Leucyl-DAlanyl-Arginyl-OH
-A3+ MS: (M+H)+= 1076 Example 179 H-~henylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-4-phenylbutanoyl'-~minocyclohexyl-3-carbonyl(R/S)}-DAlanyl-Arginyl-OH
FA~+ MS: ~M+H)+- 878 Example 180 H-Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-4-phenylbutanoyl}-{Aminocyclohexyl-3-carbonyl~R/S)}-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+=878 Exa3ple 181 ~N-Methyl)Phenylalanyl-Lysyl-Glycyl-~{S~O)2-NH~-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~N-Methyl)DAlan.yl-Arginyl-OH

Example 182 H-Phenylalanyl-Lysyl-Alanyl-Threonyl-{~2S)-2-Amino-3-cyclohexylpropanoyl)-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: ~M+H)+=959 WO90/09162 PCT/US90/~0296 81 2 ~ 7 ~

Exa~pl~ 183 ~-Phenylalanyl-Lysyl-Alanyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=929 Amino Acid Anal.: Phe (1.05), Lys ( 9'), Ala (2.69), Cha (.93), Leu (1.20), Arg (1.03) Exa~ple 184 H-Phenylalanyl-Lysyl-Alanyl-Glycyl-{(2S)-2-Amlno-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=915 Amino Acid Anal.: Phe (1.10), Lys (1.04), ~la (1.93), Cha ~1.01), Leu (1.23), Arg (1.08), - y (.95) Exa~ple 185 :i-Phenylalanyl-Lysyl-DAlanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1011 Example 186 (N-Melhyl)Phenylalany-l-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-~{C¦C}-Glycyl-Arginyl-O:~.
The Boc-Leu-Gly-OH alkyne isostere is prepared in analogy to the procedure described in the literature (`van Marsenille, M.; Gysen, C.; Tourwe, D.; van ~inst, G. Bull.
Soc. Chim. Belg. 1986, 108, 825. ) and incorporated into ~ne peptide by classical solution methods as exemplified by ~he methods described in "Peptide Synthesis", Second Editio~
Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

WO90/09162 PCT/USgO/00296 20~73 82 Example 187 H-Alanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyL}-{(25)-2-Amino-3-cyclohexylpropanoylJ-Leucyl-DAlanyl-Arginy'-OH
FAB+ MS: (M+H)+~935 Amino Acid Anal.: Lys ~.39), Ala (2.
Cha (1.74), Leu (1.03), Arg (.98) Example 188 ~-Phenylalanyl-Lysyl-Alanyl-i(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexyl?ropanoyl~-Leucyl-Alanyl-Arg~nyl-OH
FAB+ MS: (M+H)+ 1011 Example 189 H-Phenylalanyl-Lysyl-Glycyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~997 Amino Acid Anal.: Phe (.99), Lys (1.01), Ala (.73), Cha (1.80), Leu (1.06), Arg (.99), Gly (.95) ~xample 190 H-Glycyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=921 Amino Acid Anal.: Phe (.97), Lys (1.03), Ala ~1.70), Cha ~1.85), Leu ~1.09), Arg (1.00) WO90/09162 PCT/US9n/00296 Example 191 (N-Methyl)Phenylalanyl-Lysyl-Glycyl-~{C(=S)-NH}-((2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(~J-Methyl)3Alanyl-Arginyl-OH
The Boc-Glycyl-~{C(=S)-~H}-{~2S)-2-~mino-3-cyclohexylpropanoyl}-OH dipeptide is p-epared ln analocy -o the procedure described in the litera~ure (Maziak, L.;
Lajoie, G.; 3elleau, 3. J. Am. Chem. Soc. 1986, 108, 82.
and incorporated into the peptide by c!assical so}_tion O methods as exemplified by t~.e met~.ods descr oed in "?~p- _G
Synthesis", Second Edition, M. 30danszky, Y.S. :~lausne-, z-.d M.A. Ondetti (1976).

Example 192 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Aml?.o-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=997 Amino Acid Anal.: Phe ~.97), Lys ('.CO), Ala (.98), Cha (1.82), Leu (1.07), Arg (.98), Gly (.80) ~xamplo 193 H-Penicillaminyl*-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Cysteinyl*-Leucyl-DAlanyl-Arginyl-O:H
The compound was prepared in analogy to Example 334.
FAB+ MS: (M+H)+=943 - -Exa~ple 194 H-DPenicillaminyl*-Lysyl-Alanyl-{(2S)-2-Amino-3-cycloAexylpropanoyl~-Cysteinyl~-Leucyl-DAlanyl-Arginyl-O:-.
The compound was prepared in analogy to Example 334.
FA + MS: (M+H)+=943 w~90/OYl62 PCT/US90/0~296 2 ~ j 5 7 o Examplo 195 Benzoyl-2enicillaminyl*-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Cysteinyl~-Leucyl-DAlanyl-Arg nyl-O:
The compound was prepared in analogy to Example 334.
FAB+ MS: (M+H)+-1047 Example 196 Benzoyl-DPenicillaminyl~-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl)-Cysteinyl*-Leucyl-DAlanyl-Argir.yl-O:.
0 The compound was prepared in analogy to Example 334.
FA3+ MS: (M+H)+=1047 Examplo 197 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-DLysyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+-986 Example 198 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~{CH2-0~-Glycyl-Arginyl-O:.
The Boc-Leucyl-~{CH2-0}-Glycyl-OH dipeptide is prepa-ed in analogy to the procedure described in the literature (Rubini, E.; Gilson, C.; Selinger, Z.; Chorev, M. Tetranedron 1986, 42, 6039.) and incorporated into the peptide by classical solution methods as exemplified by the methods described in "Peptide Synthesis", Second Edition, M.
Bodanszky, Y.S. ~lausner, and M.A. Ondetti (1976).

Examplo 199 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-DAlanyl-Leucyl-DAlanyl-Arginyl-OH
~3~ ~S: (~+:-.)+=929 WO90/09162 PCr/~S90/00296 ~ s~ - 7 Example 200 H-Phenylalanyl-Lysyl-Alanyl-((25)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropar.oyl,-Leucyl-3~1anyl-~4-NH2)Phenylalanyl-OH
FA3+ MS: (M+H)+=1011 Exa~ple 201 H-?henylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl)-~(2R)-2-Amino-3-cyclohexylpropanoyi}-Le~cyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=1011 Example 202 H-~henylalanyl-Lysyl-Alanyl-{(25)-2-Amino-3-cyclohexyl-ropanoyl}-((2S)-2-.~mino-3-cyclohexyl?ropa?.o;: -DAlanyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=969 Exampl~ 203 H-Phenylalanyl-Lysyl-Alanyl-Phenylalanyl-Alanyl-Leucyl-DAlanyl-A;ginyl-OH
FA3+ MS: (M+~)+=923 Example 204 H-{2-Aminooctanoyl(+)}-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl]-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+~1196 WO90/09t62 PCT/US90/00296 2 ~
Example 205 H-Phenylalanyl-Lysyl-Alanyl-~(R/S)-Perhydroindole-2-carbonyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=927 Ex~ple 206 (N-Methyl)2henylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-~{CH2-S~-Glycyl-A-g~nyl-O:-.
The Boc-Leucyl-~{CH2-5~-Glycyl-OH dipeptide s p_epz~e~
in analogy to the procedure described in the literature (Spatola, A.; Anwer, M.; Rockwell, A.; Gierasch, L. J. ~
Chem. Soc. 1986, 108, 825.) and incorpo-ated into the pe?.ide by classical solution methods as exempliried by the methods desc-ibed in "Peptide Synthesis", Second Edition, M.
30d2nszky, Y.S. :Ylausner, and M.A. Onde~~i (1970).

Exampl- 207 H-Phenylalanyl-Lysyl-Alanyl-((R/S)-Perhydroindole-2-carbonyl~-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=927 Exampla 208 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: ~M+H)+-929 Exa~ple 209 H-Phenylalanyl-Lysyl-Alanyl-{(2R/S)-2-Amino-5-phenylpentanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+-951 2 ~

~ xa~ple 210 H-Phenylalanyl-Lysyl-Alanyl-((2~/S)-2-Amino-5-phenylpentanoyl~-Alanyl-Leucyl-~Alanyl-Arginyl-OH
FAB+ MS: (M+H)+=951 Example 211 ~-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexy'?ropanoyl'-Leucyl-DAlanyl-Arginyl-Glycyl-OH
FAB+ MS: (M+H)+=1068 Exa~ple 212 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-~2S)-2-Am-no-3-cyclohexylsropanoyl~-Alanyl-Leucyl-~{C(=O)-OJ-Glycyl-Argl-.~1-OH
The Boc-Leucyl-~{C(=O)-O~-Glycyl-OH dipeptide is prepared in analogy to the procedure described in the literature (Roy, J.; Gazis, D.; Shakman, R.; Schwartz, I.:.
Int. J. Peptide Protein Res. 1982, 20, 35.) and incorpora-e~
into the peptide by classical solution methods as exempl_ -ec by the methods described in "Peptide Synthesis", Second Edition, M. Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

~xampl~ 213 ~-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-~ino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexy'propanoyl~-Leucyl-DAlanyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=1068 WO90/09162 PCT/USg~/00246 2~ J~o 88 Example 214 ~-Phenylalanyl-Lysyl-Alanyl-{(trans-3-propyl)Prolyl~R/S)~-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)~=915 Example 215 H-Phenylalanyl-Lysyl-Alanyl-~(trans-3-propyl)Prolyl ~/â), -Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=915 .xample 216 H-Phenylalanyl-Lysyl-(3,5-di-I)Tyrosyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1273 Exa~ple 217 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoylJ-DTryptophyl-Leucyl-DAlanyl-Arginyi-O~.
FAB+ MS: ~M+H)+-1044 Example 218 H-Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Tryptophyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+~)+~1044 Example No. 219 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoylJ-Alanyl-Leucyl-~{C(=O)-S}-Glycyl-Arginyl-OH
The 8Oc-Leucyl-~{C(~O)-S}-Glycyl-OH dipeptide is prepared by standard coupling of Boc-leucine mixed anhy~
wlth th olacetic acid and incorporated into the peptide bi WO90/09162 PCT/US90/002g6 89 ~ 3 classical solution methods as exemplified by the methods described in "Peptide Synthesis", Second Edition, M.
Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

Example 220 ~-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-DPhenylalanyl-Leucyl-DAlanyl-Arginyl~
FAB+ MS: (M+H)+=1005 Amino Acid Anal.: Phe (2.00), L~s (1.04), Ala (1.86), Cha (1.26), Leu (1.07), Arg (1.04) Example 221 H-Phenylalanyl-Lysyl-Alanyl-DTryptophyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+S1044 Exampl~ 222 H-Phenylalanyl-Alanyl-DLysyl-{(25)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+- 929 Example 223 H-Phenylalanyl-Lysyl-(3-I)Tyrosyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M-H)--1145 Example 224 H-Phenylalanyl-Lysyl-Alanyl-Alanyl-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (MtH)+= 847 W090/09162 PCT/US~0/00296 2 ~ 90 Example 225 Iodoacetyl-Phenylalanyl-Lysyl-Lysyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-AlanyL-Leucyl-D~lanyl-Arginyl-O:-FAB+ MS- (M+H)+=1154 s Exampl- 226 H-Phenylalanyl-Lysyl-Alanyl-(4-NO2)Phenylalanyl-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=968 Example 227 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-~{CH2C(=O)-O~-Glycyl-Arginyl-OH
The Boc-Leu-~{CH2C(-O)~-OH is prepared by A--.d~-~is-e--synthesis as described in the literature ( Wakamiya, T.;
Uratani, H.; Teshima, T.; Shiba, T. ~ull. Chem. ~oc Jpn.
1975, 48, 2401.) Boc-Leucyl-~{CH2C(=O)-O~-Glycyl-O~. is prepared in analogy to Example 212. The peptide s prepared by classical solution methods as exemplified by the me~hods described in "Peptide Synthesis", Second Edition, M.
Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

Example 228 H-Phenylalanyl-Lysyl-Alanyl-~4-NH2)Phenylalanyl-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FA~+ MS: (M+FI) +~938 Example 229 H-Phenylalanyl-Lysyl-Alanyl-(~2S)-2-Amino-3-cyclohexyl?ropanoyl~-{(2S)-2-Amino-3-cyclohexyl?ro?ar.cyl}-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH

7 'J

FAB+ MS: (M+H)+=1025 Amino Acid Anal.: Ala ~1.01), Leu (0.99), Phe (0.96), Cha (1.97), Lys ~1.04), Arg (1.02) Examplo 230 H-~henylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexyl?ropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-(`.-Methyl)Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+X)+-1025 Amino Acid Anal.: Ala (1.94), ~he (1.00), Cha (2.00), Lys (1.03), Arg (1.04) Exa~ple 231 H-~henylalanyl-Lysyl-Cysteinyl*-{(2S)-2-Amlno-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoylJ-Penicillaminyl*-DAlanyl-Arginyl-OH
The compound was prepared in analogy to _xample 33~.
FAB+ MS: (M+H)+- 1059 Example 232 H-Phenylalanyl-Lysyl-Cysteinyl*-((2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoylJ-DPenicillaminyl*-DAlanyl-Arginyl-OH
The compound was prepared in analogy to Example 334. -FAB+ MS: (M+H)+=1059 Amino Acid Anal.: Ala (0.85), ~:~e (1.00), Cha (1.98), Lys (0.99), Arg (1.03) Example 233 H-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (~+H)+=1017 Amino Acid Anal.: Ala (1.88), Leu (1.07), Cha (2.78), Lys (1.02), A-g (1.04) WO90/09162 PCT/US90/~2g6 2 ~ 92 Example 234 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~{CH2C(-O)-S~-Glycyl-Arginyl-OH
The Boc-Leucyl-~{CH2C(=O)-S}-Glycyl-OH dipept~de s prepared by standard coupling of Boc-Leu-~{CH2C(=O)~-G~
which is prepared as described in Example 227, mixed anhydride with thiolacetic acid and incorporated into ~he peptide by classical solution methods as exemplified by -he methods described in "Peptide Synthesis", Second Edi~ion, M.
Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

Ex~mple 235 H-Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyi -Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1025 Exampl- 236 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DArginyl-Arginyl-OH
FA8+ MS: (M+H)+~1096 ~xa~ple 237 Dhenoxyacetyl-Lysyl-Lysyl**-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl**
FAB+ MS: (M+H)+= 1037 2 ~

Exa~pl~ 238 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{~3,4-dehydro)Prolyl(R/S)~-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=953 ~ xa~pl~ 239 H-~henylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexyi?ropanoyl}-{(3,4-dehydro)P:olyl(R/S)}-Leucyl-0 DAlanyl-A-ginyl-OH
FABt MS: (M+H)+~953 Exa2pl- 240 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-I 5 cyelohexyl?-o?anoyl}-Alanyl-Leucyi-~{CH=CH~-Glycyl-Arg_..y'-^:
The Boc-Leucyl-~{CH-CH}-Glycyl-OH ethylenic isoste_e is prepared in analogy to the procedure described in the literature (Spaltenstein, A.; Carpino, P.; Miyake, F.;
Hopkins, P. Tetrahedron Lett. 1986, 27, 2095.) and incorporated into the peptide by classical solution methods as exemplified by the methods described in "Peptide Synthesis", Second Edition, M. Bodanszky, Y.S. ~lausne-, and M.A. Ondetti ~1976).

Exa~ple 241 H-Phenylalanyl-Lysyl-{(3,4-dehydro)Prolyl(R/S)}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-C:-FAB+ MS: (M~H)+-953 ~ ~ ~3 ~ 7 ~
Example 242 H-Phenylalanyl-Lysyl-l(3,4-dehydro)Prolyl(R/S)~-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DAlanyl-A-gi?.yL-5:H
FAB+ MS: (M+H)+=953 ~ xample 243 henylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DArginyl-Glycyl-OH
FA3+ MS: (M+H)+=915 Exa~pl~ 244 H-Phenylalanyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl;-Leucyl-DArginyl-Arginyl-OH
FA3+ MS: (M+H)+=1140 Example 245 H-Phenylalanyl-Lysyl-Alanyl-Tryptophyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1044 2x~mpl- 246 H-Phenylalanyl-Lysyl-Alanyl-((2~)~2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl,~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1011 Example 247 H-Phenyl21anyl-Lysyl-Alanyl-DAlanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+3929 WO90/09162 PCT/US90/002g6 2 ~ 3 ~, Example 248 ~N-~ethyl)Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~{CH2-CH2}-Glycyl-Arginyl-OH
The Boc-Leucyl-~{CH2-CH2}-Glycyl-OH isostere ls prepa_e~
by hydrogenating 30c-Leucyl-~{CH=CH}-Glycyl-O:J, which ~s prepared as described in Example 240, with palladium-ca_~o~, and incorporated into the peptide in analogy to the synthes 3 of Example 2.

Example 249 H-Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-DTryptophyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-988 ~xa~pl- 250 H-Histidyl-Lysyl-Phenylalanyl-Tyrosyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1087 Example 251 H-Phenylalanyl-Lysyl-Glycyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=901 Amino Acid Anal.: Phe (1.00), Lys (1.17), Cha (1.07), Leu (1.08), Ala (.94), Arg (1.07), Gly (1 . 91) Exam~l- 252 H-(4-N02)Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (~+H)+=1185 W090/09162 PCT/US90/~0296 Example 253 H-((2S)-2-Amino-3-cyclohexylpropanoyl}-Lysyl-Aspartyl-{(2S~-2-Amino-3-cyclohexylpropanoyl)-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DArginyl-Arginyl-OH
S FAB+ MS: (M+H)+-1146 ~xamplo 254 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~{C(=O)-CH2)-Glycyl-Arglnyl-OH
The 3Oc-Leucyl-~{C(=O)-CH2~-Glycyl-OH isostere ls prepared in analogy to the procedure described in the literature (McMurray, J.; Dyckes, D. J. Org. Chem. 198S, i0, 1112.) and incorporated into the peptide by class cal solut on ~ethods as exemplified by the methods desc-ised "Peptide Synthesis", Second Edition, M. Bodanszky, Y.S.
Klausner, and M.A. Ondetti (1976).

Exampl- 255 H-(3-NO2)Tyrosyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+~1201 Exa~pl- 256 H-Tryptophyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+~1179 WO90/09162 PcT/Us~O/OO~g6 2 ~ 7 3 Exam~le 257 H-{3-(2'-Thienyl)alanyl(~/S)~-Lysyl-Aspartyl-{(25)-2-~ino-~-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylp-opanoyL'-Leucyl-DArginyl-Arginyl-OH
FA3+ MS: (M+H)+=1146 ~ xample 258 r.-~ 3-(2'-Thienyl)alanyl(R/S)~-Lysyl-Aspartyl-{(25)-2-.~-.ino-_-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexyl?-opar.oyl'-Leucyl-~Arginyl-Arginyl-OH
~A3+ ~S: (M+H)+=1146 Exa3ple 259 ~.-(4-CH3)Phenylalanyl-Lysyl-Aspartyl-l(2S)-2-Amino-3-cyc or.exylpropanoyl~-{(2S)-2-~mino-3-cyclohexy'pro?zr.oy:,-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+-1154 Exa~ple 260 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-~{CH(-OH)-CH2}-Glycyl-Arginyl-OH
The Boc-Leucyl-~{C(=O)-CH2~-Glycyl-OH isostere is prepared in analogy to the procedu_e described in tAe literature (McMurray, J.; Dyckes, D. J. Org. Chem... 1985, 50, 1112.), reduced to Boc-Leucyl-~{CH(-OH)-CH2}-Glycyl-OH
sodium borohydride in methanol and incorporated into the peptide by classical solu~ion met~.cds as exemplified by t~.e methods described in "Peptide Synthesis~', Second Edition, M.
3~ Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

WO90/0916t PCT/US90/002g6 2~a;~0 Example 261 H-{3-(2'-(5'-tert-Butylthienyl))alanyl~l)}-Lysyl-AspartyL-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-~-cyclohexylpropanoyl}-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1202 Example 262 H-?henyl21anyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-Glycyl-Arginyl-OY
F.~B+ MS: (M+H)+=901 Amino Acid Anal.: ?he (1.07), Lys (.~'), Ala (1.10), Cha (1.05), Gly (1.64), Leu (1.06), Arg (1.1-) Example 263 H-Histidyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpro-2r.oyl}-(4-~2)?henylalanyl-Leucyl-~A12nyl-(4-~r2)?he~.yl212ny'-O:-~
FAB+ MS: (M+H)+=1016 Exa~ple 264 H-(4-NH2)Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1155 Example 265 H-(3-NH2)Tyrosyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amlno-3-cyclohexylpropanoyl}-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H}+=1171 99 ',~J' _;~

Example 266 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Phenylalanyl-Leucyl-DAlanyl-Ar~ir.y7-O'i FAB+ MS: (M+H)+=1005 Amino Acid Anal.: Phe (1.98), Lys (1.00), Ala (1.90), Cha (1.07), Leu (1.07), Arg (1.04) Ex~ple 267 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-~{C(=CH2)-CH2~-Glycy'-Arginyl-OH
The 3Oc-Leucyl-~{C(=CH2)-CH2~-Glycyl-OH sostere ls prepared by condensing methylenetriphenylphosphorane and Boc-Leucyl-~{CO-CH2)-Glycyl-OH which is prepared as descr bed in the literature (McMurray, J.; Dyckes, D. J. Org. Chem.
1985, 50, 1112.), and ncorporated into the pep~ide by classical solution methods as exemplified by the methods described in "Peptide Synthesis", Second Edition, M.
Bodanszky, Y.S. Klausner, and M.A. Ondetti ~1976).

Exa3pl- 268 H-Phenylalanyl-Lysyl-Alanyl-Phenylalanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-O:i FAB+ MS: (M+H)+~1005 Amino Acid Anal.: Phe (1.98), Lys ~1.00), Ala (1.89), Cha ~1.10), Leu (1.08), Arg (1.05) ~xample 269 H-(l-CH3)Histidyl-Lysyl-Aspartyl-{~2S)-2-Amino-3-cyclohexylpropanoyl)-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: ~M+H)+=1144 Ex~ple 270 H-(3-CH3)Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)~=1144 Exampla 271 H-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glutaminyl-Leucyl-&lycyl-Arginyl-C:-.
FAB+ MS: (M+H)+=1016 Example 272 Ac-Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glutaminyl-Leucyl-DAlanyl-Arginyl-O:-.
FAB+ MS: (M+H)+=1062 Amino Acid Anal.: His (0.95), _rs (1.00), Asp (0.97), Cr.a (0.9), Gln (1.03), Leu (1.05), .'.:-(0.97), Arg (1.03) Example 273 H-Phenylalanyl-Lysyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-929 Amino Acid Anal.: Phe (1.00), Lys (1.01), Cha ~0.96), Ala (2.92), Leu ~1.0~), Arg (1.02) Example 274 H-2henylalanyl-Lysyl-Alanyl-{(2S)-2-Methylamino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl`-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1025 Amino Acid Anal.: Ala (1.63), ~u (1.04), ~ne (0.96), Cha (0.95), Lys (0.97), Arg (1.03) 2Q~J78 Example 275 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-~{C(=O)-N(OMe)}-Glycyl-Arginyl-OH
The Boc-N(OMe)-Glycyl-OH is prepared as desc--Ded ~.
the literature (Ottenheijm, H.; Herscheid, J. Chem, Rev.
1986, 86, 697.), and incorporated into the peptide ~y classical solution methods as exemplified by the methods descri~ed in "Peptide Synthesis", Second ~d~t-on, M.
Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

Example 276 Benzoyl-Penicillaminyl*-Lysyl-Alanyl-~(2S)-2-.~mino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DC~steinyl*-Arginyl-OH
The compound was prepared in analogy to Example 334.
FAB+ MS: (M+H)+-1129 Amino Acid Anal.: Ala (0.98), Leu (1.01), Cha (1.90), Lys (0.99), Arg (1.03) Exa3ple 277 H-DPenicillaminyl*-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl;-Leucyl-DCysteinyl*-Arginyl-OH
FAB+ MS: (M+H)+=1025 ~xample 278 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-!(2S)-2-Methylamino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-1025 Amino Acid Anal.: Ala (1.89), Leu (1.04), Phe (0.95), Cha (0.99), Lys (l.C0), Arg (1.58) 2~ 7~ 102 Exa~ple 279 Benzoyl-DPenicillaminyl*-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyll-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DCysteinyl~-Arginyl-OH
S FAB+ MS: (M+H)+=1129 Amino Acid Anal.: Ala (0.84), :eu (0.88), Cha (2.01), Lys (1.01), Arg (1.04) Example 280 :-.-Dhenylalanyl-Lysyl-Glycyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-Glycyl-Arginyl-OH
~A3+ MS: (M+H)+=887 ~ino Acid Anal.: Phe (1.02), Lys (1.02), Cha (1.03), Leu (1.09), Arg (1.05), Gly (2.82) Example 281 (N-~,~ethyl)Phenylalanyl-Lysyl-Alanyl-{(25)-2-Amino-3-cyclohexylpropanoyl}-Gly-~{PO(OH)-NH~-Leucyl-Gly-Arginyl-OY.
The Cbz-Gly-~{PO(OH)-NH}-Leucyl-Gly-OH is prepared 2S
described in the literature (Bartlett, P.; Marlowe, C.
Biochemistry 1987, 26, 8554.), and incorporated into the peptide by classical solution methods as exemplified by the methods descri~ed in "Peptide Synthesis", Second Editi~n, M.
Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

Example No. 282 H-Phenylalanyl-Lysyl-Alanyl-DPhenylalanyl-Glycyl~Leucyl-DAlanyl-Arginyl-OH
~AB+ MS: (M+H)+~909 Amino Acid Anal.: Phe (1.93), Lys (.99~, Ala (2.00), Gly (.98), Leu (1.08), Arg (1.03) W~90/09162 PCTIUS90/00296 2 ~

Examplo 283 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Phenylalanyl-DAlanyl-Arginyl-O:~
FAB+ MS: (M+H)+=949 Amino Acid Anal.: Phe (2.14), Lys (.
Ala (1.77), Cha (1.04), Gly (.99), Arg (1.13) Lxample 284 H-~henylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-DPhenylalanyl-DAlanyl-Arginyl-O:-' FA3+ MS: (M+.H)+=949 Amino Acid Anal.: Phe (1.96), Lys (1.00), Ala (2.01), Cha (1.02), Gly (1.00), A-g (1.03) Example 285 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amir.o-3-cyclohexyl?.opanoyl}-Glycyl-Tryptophyl-DAlanyl-Arginy~
FAB+ MS: (M+H)+~988 Amino Acid Anal.: Phe (1.02), Lys (1.04), Ala (1.84), Cha (1.04), Arg (1.11), Gly (.82), T-p (.75) ~xa~ple 286 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl'~-Leucyl-Alanyl-DArginyl-OH
FAB+ MS: (M+H)+=1011 Examplo 287 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl3-Gly-~{PO(OMe)-NH~-Leucyl-Gly-Arginyl-Gk The Cbz-Gly-~{PO(O~.e)-NH~-Leucyl-Gly-OH is prepared i-.
analogy to the procedure described in the literature (~ar.le_~, ?.; Ma-lowe, C. 9iocheml3try 1987, 26, 85~
and inco--o-ated into the peptide by classic2l solu_ior.

W090/09162 PCT/US90/~0296 2 ~L1~ 7 ~ 104 methods as exemplified by the methods described in "~ept~de Synthesis", Second Edition, M. Bodanszky, Y.S. Xlausne-, ar.d M.A. Ondetti ~1976).

Example 288 H-Phenylalanyl-Lysyl-~(2R)-2-Amino-3-cyclohexylpro?anoyl~-Alanyl-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB MS: (M+H)+=929 Example 289 H-Phenylalanyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucy1-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+~994 Amino Acid Anal.: Phe (0.91), Lys (1.06), Asp (0.94), Met (0.85), Gln (1.02), Leu (1.07), Gly (0.99), Arg (1.02) Exa~ple 290 Ac-Histidyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=1048 ~ xa~pl- 291 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-D(4-NO2)Phenylalanyl-Arginyl-OH
FAB+ MS: (M+H)+=1050 Amino Acid Anal.: Phe (0.67), Lvs (0.66), Ala (1.59), Cha (0.93), Leu (1.00), D(4-NO2)Phe (0.92), Ar~ (1.00) WO90/09162 PCT/US9~J/00296 .3 7 ~

Example 292 H-Phenylalanyl-Lysyl-{(2~/S)-2-Amino-5-phenylpentanoyl~-{(25)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-3Alanyl-Arginyl-OH
FAB+ MS: (M+H)+=1033 Amino Acid Anal.: Phe (0.3.), _y, (1.00), hhPhe (0.82), Cha (0.93), Ala (2.00), Leu (1 04), 3.-(1 .01) Example 293 0 H-2henylalanyl-Lysyl-{(2R/S)-2-Amino-5-phenylpent2noyl;-{(2S)-2-~ino-3-cyclonexylpropanoyl~-Alanyl-Leucyl-3A12-iy'-Arginyl-OH
FAB+ MS: (M+H)+=1033 Example 294 H-Phenylalanyl-Alanyl-Lysyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FABT MS: (M+H)+=929 Example 295 H-Phenylalanyl-Lysyl-Alanyl-Alanyl-Leucyl-Alanyl-DAlanyl-A~ginyl-OH
FABI MS: (M+H)+-847 Example 296 r.-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-.~mino-3-cyclohexylpropanoyl)-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+'943 Amino Acid Anal.: Ala (1.94), Leu (1.06), Phe (0.96), Cha ~0.94), Lys (0.96), Arg (1.02) WO90/09162 PCT/US~0/0029~

~ 7 ~ 106 Example 297 Formyl-~NH-CO~-DPhenylalanyl-~{NH-CO~-DLysyl-~NP.-CO~Glycyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-NMeDAla-Arginyl-OH
The Formyl-~{NH-CO~-DPhenylalanyl-~{NH-CO}-DLysyl-~{N'-CO~Glycyl-OH fragment is prepared by classical solut or.
methods (exemplified by the methods described n "Peptice Synthesis", Second Edition, M. Bodanszky, Y.S. :~lausne_, ar.c M.A. Ondetti 1976. ) and is incorpe-ated into the peptlde n analogy to Example 2.
S~S
Ex~mplo 298 H-Phenylalanyl-Lysyl-Penicillaminyl*-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl'-Le--cyl-DCysteinyl*-Arginyl-OH
The compound was prepared in analogy to Example 334.
FAB+ MS: ~M+H)+=1101 Example 299 H-Phenylalanyl-Lysyl-Asparaginyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-NCH3NH2 The compound was prepared in analogy to Example 38.
FAB+ MS: ~M+H)+=1082 Amino Acid Anal.: Asx (1.02), Ala (0.94), Leu (1.05), Phe (0.98), Cha (1.96), Lys (0.97), Arg (1.06) WO90/09162 PCT/US90/002g~
2 ~

Example 300 H-Phenylalanyl-Lysyl-Asparaginyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-~(2S)-2-Amino-3-cyclohexylpropanoy'~-Leucyl-3Alanyl-Arginyl-NHNH2 The compound was prepared in analogy to _xample 38.
FA3+ MS: (M+H)+=1068 Amino Acid Anal.: Asx (0.98), ,'.12 (0.99), Leu (1.08), Phe (1.00), Cha (1.97), Lys (1.03), A-g (1.04) Example 301 (~-.Methyl)~(2S)-2-Amino-3-cyclohexylproDanoyl~-Lysyl-Alz^.y'-~(2S)-2-~mino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1031 Amino Acid Anal.: Ala (1.87), Le (1.06), Cha (1.96), Lys (1.01), Arg (1.06) Example 302 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Argin~l-OU
FAB+ MS: (M+H)+=1025 Amino Acid Anal.: Ala (1.87), `~.e?he (0.87), Leu (1.06), Cha (1.92), Lys (0.98), Arg (1.04) Example 303 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylproDanoyl}-Alanyl-Glycyl-Arginyl-O~
FAB+ MS: (M+H)+-955 Amino Acid Anal.: Phe (.99), Lys (1.03), Ala (1.98), Cha (2.14), Gly (.91), A_g (1.09) 2 ~ 7 ~ 108 Example 304 H-Phenylalanyl-Lysyl-Glycyl-~2S)-2-Amino-3-cyclohexylpropanoyl}-~(25)-~-Amino-3-cyclohexylpropanoyl~-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+:i)+=983 Amino Acid Anal.: Phe (1.00), Lyâ
(1.06), Cha (2.18), Gly (1.79), Leu (1.07), Arg (1.08) Examplo 305 Ac-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DAlanyl-Tyrosyl-O~
FAB+ MS: (M+~)+=978 Exa~ple 306 H-Phenylalanyl-Lysyl-Tyrosyl-{(2S)-2-Amino-3-cyclohexyl?-opanoyl~-Alanyl-Leucyl-DAlanyl-Arg nyl-G:{
FAB+ MS: (M+H)+-1021 Examplo 307 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Gly-~PO(NHMe)-NH}-Leucyl-Gly-Arginyl-O:-.
The Cbz-Gly-~{PO(OH)-NH}-Leucyl-Gly-OtBu is prepared in analogy to the procedure described in the literatuze (Bartlett, P.; Marlowe, C. ~iochemistry 1987, 26, 8554 ) , coupled with methyl amine and deprotected to give Cbz-Gly-~{PO(NHMe)-NH}-Leucyl-Gly-OH. Cbz-Gly-~{PO~NHMe)-NH}-Leucy -Gly-O~ is incorporated into the peptide by classical solut on methods as exemplified by the methods described in "Pept-de Synthesis", Second Edition, M. Bodanszky, Y.S. Klausne~
M.A. Ondetti (1976).

WO90/09162 PCT/US~0/002g6 2 ~

Example 308 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-DLeucyl-DAlanyl-Arglnyl-OH
FAB+ MS: (M+H)+=1011 Exa~ple 309 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexyl?ropanoyl~-Leucyl-DAlanyl-Agmatine The peptide was synthesized 'ollowir.g the ?roced~lre described in Example 1 with the exception that the N-term~?.zl protecting group was not removed at the end of the syr.thesls.
Cleavage of the peptide from the resin was accomplished Dy _ranses.e-ification'with metnanol as desc-i~ed in "Solid Phase Peptide Synthesis" by John M. Stewart and Janis D.
Young, Second Edition (1984), p.91. The methyl ester was hydrolyzed with sodium hydroxide and the peptide then coupled with agmatine sulfate using a DCC mediated coupling procedure. The protecting groups were removed by treatment with liquid HF/anisole.
FAB+ MS: (M+H)+-967 Example 310 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-.~mino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexyl?ropanoy!~-Sarcosyl-DAlanyl-Arginyl-OH
FAB+ MS (M+H)+-969 Amino Acid ~nal.: Ph.e (1.01), Lys (1.04), Ala (1.87), Cha (1.94), Arg (1.08), Sa- (1.10) Pcr/usso/002s6 2 ~ l o Example ~11 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Sarcosyl-Leucyl-DAlanyl-Arginyl-O:-.
rAB+ MS: (M+H)+=929 Amino Acid Anal: Phe (.97), Lys ( .00), Ala (1.98), Cha (1.02), Leu (1.04), Arg (1.01), Sar (1.'') Example 312 H-Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexyl?~opanoyl~-{l2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-Sa-cosyl-Arginyl-OH
FAB+ MS: (M'H)+=1011 Amino Acid Anal.: Phe (.97), _ys (1.00), Ala (.96), Cha (1.93), Leu (1.04), Arg (1.03), Sar (.93) Example 313 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Gly-~{PO(NMe2)-NH~-Leucyl-Gly-Arginyl-5H
The Cbz-Gly-~{PO~OH)-NH~-Leucyl-Gly-OtBu is prepared i?.
analogy to the procedure described in the literature (3artlet~ P.; Ma.low~, C. Biochemistry 1987, 26, 8554.), coupled with dimethyl amine and deprotected to give Cbz-Gl~-~{PO(NMe2)-NH)-Leucyl-Gly-OH. Cbz-Gly-~{PO(N~e2)-NH~-Le cyl-Gly-OH is incorporated into the peptide by classical sol-_tio~.
methods as exemplified by the methods described in "Pe?tide Synthesis", Second Edition, M. Bodanszky, Y.S. Klausner, a~.d M.A. Ondetti (1976).

WO90/09162 PCT/US90/002g6 ~>~ /'J

~xample 314 H-Phenylalanyl-Lysyl-Sarcosyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl~-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
5 FAB+ MS: (M+H)+=1011 Amino Acid Anal.: 2he (.9g), _'yâ
(1.02), Le-~ (1.07), Ala (.86), Cha (2.12), Arg (1.05), âz_ (1.13) Example 315 H-Phenylalanyl-Lysyl-Alanyl-Sarcosyl-~(2S)-2-Amino-3-cyclohexyl?ropanoyl~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~929 Amino Acid Anal.: Phe (.99), Lys (1.04), Ala (1.83), Cha (1.06), Leu (1.08), Arg (1.06), Sar (1.11) Exampla 316 H-Phenylalanyl-Lysyl-DPhenylalanyl-~(2S)-2-Amino-3-cyclohexylpropanoyll-Glycyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=991 Amino Acid Anal.: Phe (2.00), Lys (1.03), Cha (1.08), Gly (.95), Leu (1.10), Ala (.86), Arg (1.07) Example 317 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexyl~ropanoylJ-Glycyl-Leucyl-DPhenylalanyl-Arginyl-OX
FAB+ MS: (M+H)+~991 Amino Acid Anal.: Phe (1.95), Lys (.95), Ala (1.02), Cha (1.04), Gly (.92), Leu (1.07), Arg (1.05) Exam~le 318 (N-Methyl)Dhenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-Gly-~{PO(NH2)-NH~-Leucyl-Gly-Arginyl-O:-The C~z-Gly-~{?O(OX)-NH}-Leucy'-Gly-OtBu is prepa-ec analogy tc the procedure described in the literature WO90/09162 PCT/~S9~/00296 2 ~ U; 3 ~ 7 ~ 112 (Bartlett, P.; Marlowe, C. 8iochemistry 1987, 26, 85~4 . ) , coupled with ammonia and deprotected to give Cbz-Gly-~{PO(NH2)-NH~-Leucyl-Gly-OH. Cb~-Gly-~{PO(NH2)-~H~-Leucyl-Gly-OH is incorporated into the peptide by classicaL solutlor.
methods as exemplified by the methods desc-ibed in "Pe?t_ce Synthesis", Second Edition, M. Bodanszky, Y.S. :~lausne-, a^.~
M.A. Ondet.i (1976).

Exampl- 319 ;~-~henylalanyl-Lysyl-Phenylalanyl-{(2S)-2-Amir.o-3-cyclohexylpropanoyl}-Glycyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-991 Amino Acid Anal.: Phe (1.95), Lys (0.97), Gly (0.92), Leu (1.07), Ala (0.93), Arg (1.00) Example 320 H-Phenylalanyl-Lysyl-Alanyl-l(2S)-2-Amino-3-cyclohexylpropanoyll-Glycyl-Leucyl-Tryptophyl-Arginyl-OH
FAB+ MS: (M+H)+=1030 2~ Example 321 H-Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyll-Glycyl-Leucyl-Phenylalanyl-Arginyl-C'i FAB+ MS: (M+H)+-991 Amino Acid Anal.: Phe (1.94), Lys (.99), Ala (1.02), Gly (.96), Leu (1.07), Arg (1.0~) Example 322 Ac-Phenylalanyl-Lysyl-((2R/S)-2-Amino-5-?henylpentanoyll-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alar.yl-Le--cyl-DAl2r.yl-A_ginyl-OH
FAB+ MS: (M+H)+=1075 WO90/09162 PCT/~S9~/002g6 Example 323 Ac-Phenylalanyl-Lysyl-{~2R/S)-2-Amino-5-phenylpentanoyl}-~(2S)-2-Ar,lno-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DAl2n~_-Arginyl-O:~
FAB+ MS: (~+.~.)+-1075 Example 324 Formyl-~{~.i-CG}-DPhenylalanyl-~{NH-CO}-DLysyl-~{NH-CG-NHIGlycyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Le-~_y:-NMeDAla-Arginyl-OH
The B-3Lysyl-DPhenalanyl-NH2 f-agment is prepareA by classical solution methods (exempli^ied by the methods described in "Peptide Synthesis", Second Edition, M.
Bodansz~y, Y.S. Klausner, and M.A. Ondett 1976. ) and s coupled with methyl isocyanoacetate ,o gi-~e ~or-,.yl-~{~
DPhenylalanyl-~{NH-CO}-DLysyl-~{NH-CO-NH}Glycyl-OMe. I t i S
then hydrolyzed to the corresponding carboxylic acid and incorporated into the peptide by classical solution methocs as exempli'ied by the methods described in "Peptide Syrthesi3", Second ~dition, M. Bodanszky, Y.S. Klausner, and M.A. Ondetti (1976).

Example 325 H-Valyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyll-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H) +=881 Amino Acid Anal.: Ala (2.93), Val (1.03), Le-~ (1.02), Cha (0.97), Lys (1.01), Arg (1.01) WO90/09162 PCT/US9~/00296 : 114 2 ~ 7 ~

Exa~ple 326 H-Phenylalanyl-Sarcosyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyL,-Leucyl-DAlanyl-Arginyl-OH
F.~a+ MS: (M+H)+-954 Amino Acid Anal.: Phe (1.00), Ala (1.91), Cha (1.98), Leu (1.0?), Arg (1.0;), Sa- (.o3) Exampl- 327 H-Sarcosyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropa..oyl'~-10 {(2S)-2-.~mino-3-cyclohexylpropanoyll-Leucyl-DAlanyl-Arg_nyL-OH
FA3+ MS: (M+H)+-935 Amino Acid Anal.: Lys (1.12), Ala (1.48), Cha (2.16), Leu (1.17), Arg (1.23), Sar (.63) ~xample 328 H-Phenylalanyl-Lysyl-((2R/S)-2-Amino-5-phenylpentanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+-1019 ~xa~pl- 329 ~-Phenylalanyl-Lysyl-((2R/S)-2-Amino-5-phenylpentanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=1019 Exa~pl- 330 Y.-Phenylalanyl-Lysyl-((2R/S)-2-Amino-5-pnenylpentanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-Glycyl-Arginyl-OH
~+ ~S (~.+'J.) +=1005 WO90/09162 PCT/US90/002~6 1 1 5 ~ s~ ~ 3i Example 331 Hydrocinnamoyl-(N-Methyl)Phenylalanyl-Lysyl-Alanyl-~(2S~-2-Amino-~-cyclohexylpropanoyl~-Alanyl-Leucyl-(N-Methyl)~AlJ?.yl-Arginyl-OH

Example 332 :i-?henylalanyl-Lysyl-{(2R/S)-2-Amino-5-phenylpentanoyl~-((2S)-2-~ino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-Glycy -Arginyl-OH
.-AB+ MS: (~+~)+=1005 Example 333 (N-Methyl)Dhenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amlno-3-cyclohexylpropanoyl}-Glycyl-Leucyl-(N-~ethyl)DAlanyl-A-ginyl-C:-.
EAB+ MS: (M+H)+3957 Example 334 N-Benzoyl-DPenicillaminyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DCysteinyl-Arginine Cyclic disulfide N-3e~zoyl-DPenicillaminyl(S-4-methylbenzyl)-Lysyl(~-epsilon-Cbz)-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoly}-Leucyl-DCycteinyl(5-4-methylbenzyl)-Arginyl(N-guanidino-Tos)-OResin (0.6 g) w25 prepared by the method of Example 1 and was treated with :i~-and anisole as illustrated in Example 2. After extrac.ior.
o' the c-ude peptide by treatment with 2 x 25 mL of degassed 20% a~ueous acetic acid, it was then dilu~ed to l,500 mL with degassed, distilled water. The p~ of the solution was zdjusted :o 8.0 _y _he zddition o^ concent-ated am~.onlum hydroxide. Potassium fe-ricyanide a-ueous solu ion (0.0'~) WO90/09162 PCT/USgO/00296 2 ~ 7 3 was added dropwise to the stirred solution untiL a yelLcw color zppeared. The resultant solution was stirred for ar.
additional 30 minutes at room temperature, and the p~ was adjusted to 5.0 with glacial acetic acid. Packed Bio-~ad anion exchange resin AGX-4 (10 mL, Cl form) was added, sti-red for 30 minutes and filtered. The filt-a~e W25 applied to 2 column containing 150 g XAD-16 molecula-adsorbent resin. The sample was desalted by fi-st washing the column with 1 L of distilled water and then elutir.g --5.-.
the column with 1 L of 50% aoueous ethanol. The co,.~ineA
ethanol fractions were concent-ated to approxi.~ately 100 .-_ ;~ v~ o and lyophilized to a dried powder. The crude peptide was then purified by HPLC as described in Example 2.
The compound obtained (12 mg) gave NMR and mass spectra consistent with the proposed structure.
FAB+ MS: (M+H)+=1129 Example 33S
H-Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-DPhênyldlanyl-D~nenylalanyl-Arginyl-OH
FAB+ MS: (M+H)+~1025 Amino Acid Anal.: Phe (2.92), _ys (1.01), Ala (1.01), Gly (1.00), Arg (1.06), Cha (1.04) ~xampl- 336 r.-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DArginyl-Arsinyl-OH
FAB+ MS: (M+H)+=1058 wo go/09162 PCJ~/US90/0~296 Example 337 H-Phenylalanyl-Lysyl-{~2R/S)-2-Amino-5-phenylpentanoyl}-~(2S)-2-Amino-3-cyclohexy7propanoyl}-Glycyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=1019 Example 338 H-Tryptophyl(N-formyl)-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoy~;-Leucyl-3Alanyl-Arginyl-OH
FAB+ MS: (M+H)+sl078 Ex~mple 339 H-Phenylalanyl-Lysyl-{(2R/S)-2-Amino-5-phenylpentanoyl~-((25)-2-Amino-3-cyclohexylpropanoyl)-Glycyl-Leucyl-DAlzny -Arginyl-OH
FAB+ MS: (M+H)+~1019 Example 340 H-Phenylalanyl-Lysyl-{(2R/S)-2-Amino-5-pAenylpentanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DArgi..yl-Arginyl-OH
FAB+ MS: (M+H)+~1118 Example 341 H-Phenylalanyl-Lysyl-~(2R/S)-2-Amino-5-p;qenylpentanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DArglnyl-Arginyl-OH
FAB+ MS: (M+H)+=1118 WO90/09162 PC~/US90/00296 Example 342 H-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-Arginyl-Arginyl-OH
rAB+ MS: (M+H)+=1140 Example 343 H-?henylalanyl-Lysyl-Aspartyl-Alanyl-{(2S)-2-A.~no-3-cyclohexyl?ropanoyl~-Leucyl-DArginyl-Arginyl-OH
FA3+ MS: (M+H)+=1058 Exampl- 344 H-Phenylalanyl-Lysyl-Aspartyl-Alanyl-Alanyl-Leucyl-DArginyl-Arginyl-OH
~A3+ MS: (M+H)+=976 ~ xampl~ 345 H-((2S)-2-Amino-3-cyclohexylpropanoyl~-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
2~ FAB+ MS: (M+H)+=1000 Example 346 H-Phenylalanyl-Lysyl-Alanyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=950 Example 347 H-?henylalanyl-Lysyl-Alanyl-{(2S)-2-.amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-D~zyptophyl-Arginyl-oH
FAB+ MS: (M+H)+=1030 WO90/09l62 PCT/US90/00296 119 ~ ~J

Exacple 348 H-Phenylalanyl-~S-2-Aminoethyl)Cysteinyl-Alanyl-{(2S)-2-~mino-3-cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylp-opanoyl}-Leucyl-DAlanyl-Arginyl-OH
The synthesis, deprotection and cleavage of the -es~n-bound peptide ~as carried out as oulined in Examples 1 2~.C ~.
The 5-(2-aminoethyl)-L-cys~eine residue was p-otected as t:-e N-alpha 8OC, N-epsilon Cbz derivative prior to inco-po-atic-into the peptide.
F.~3+ MS: (~+H)+=1029 Example 349 Y.-Phenylalanyl-Lysyl-Alanyl-Alanyl-{(2S)-2-Amino-3-cyclohexylp-opanoyll-Leucyl-DArginyl-Arginyl-OH
FA3+ ~S: (`~tH) +=1014 Ex~ple 350 Y.-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-(~2Sj-2-Amino-3-cyclohexylpropanoyl J -~0 Leucyl-DHistidyl-Arginyl-OH
FAB+ MS: (M+H)+=1121 Example 351 H-Phenylalanyl-Lysyl-Aspartyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylpro?anoyl~-Leucyl-DAspartyl-Arginyl-OH
FA3+ MS: (M+H)+=1099 Example 352 H-Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclo'nexvlp-~pznoyl}-.~lanyl-~eucyl-~A-glnyl-A-ginyl-O~
FAB+ MS (M~.)+=1014 WO 90/09162 PCT/US90/0~2g6 Example 353 H-Phenylalanyl-Lysyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Aianyl-Alanyl-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1014 s Example 354 :.-Phenylalanyl-Lysyl-Aspartyl-Methionyl-~lutaminyl-Leucy'l-DAlanyl-A-ginyl-OH
FAB+ MS: (M+H)+=1008 Example 355 H-2henylalanyl-Lysyl-Alanyl-(N-Methyl)Alanyl-Sarcosyl-Leucy -DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=861 1 ~
Exampl- 356 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl~-(N-Methyl)Alanyl-Sarcosyl-DAlanyl-Arginyl-OH
FAB~ MS: (M+H)+=901 Example 357 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyll-~(2s)-2-Amino-3-cyclohexylpropanoyl~-(N
Methyl)Alanyl-Sarcosyl-Arginyl-OH
~AB+ MS: (M+H)+=983 Ex~mple 353 (N-(2-pnenyi)ethyl)Phenylalanyl-Lysyi-Alanyl-i(2S)-2-Amlno-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
rA~+ MS (`A+H)+=1033 WO90/09162 PCT/US90/~296 2~5 ~

Example 359 H-?henylalanyl-Lysyl-Alanyl-Alanyl-Alanyl-Leucyl-DArgir.y'-Arginyl-OH
FA3+ MS: (M+H)+s932 3xample 360 H-?henylalanyl-Lysyl-Aspartyl-((2S)-2-Amino-3-cyclohexyl?ropanoyl}-Glutaminyl-Leucyl-DAlanyl-A_sinyl-O:-FA3+ MS: (M+H)+=1030 Example ~61 Ac-Phenylalanyl-Lysyl-Aspartyl-Leucyl-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FA3+ MS: (M+H)+=1018 1 ~ .
Example 362 Ac-Phenylalanyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucyl-DAlanyl-A-ginyl-OH
FA3+ MS: (M+H)+=1050 'O
Example 363 Ac-?henylalanyl-Lysyl-Aspartyl-Leucyl-Glutaminyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: ~M+H)+=1032 ~ xample 364 H-?henylalanyl-Lysyl-Aspartyl-((25)-2-Amino-3-cyclohexylpropanoyl~-Prolyl-Leucyl-DArginyl-Arginyl-OH
FA2t MS: (M+H)+-1084 WO90/09162 PCT/US9~/002g6 2&~3~`~ 122 Example 365 H-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Arginyl-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1143 Example 366 :--Dhenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoyi}-Leucyl-Arginyl-DArginyl-OH
1 0 rA3+ MS: (M+H)+=1140 Example 367 H-Phenylalanyl-Lysyl-Aspartyl-~2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoylJ-I S Leucyl-~A-s nyl-~A-ginyl-OH
FAB+ MS: (M+H)+=1140 Example 368 H-(1-CH3)Histidyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Arginyl-GH
FAB+ MS: (M+H)+=998 Exa~pl~ 369 H-(3-CH3)Histidyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=998 Examplo 370 :-'-P~,enyla'anyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Glutaminyl-Leucyl-DArginyl-Arginyl-OH

F,~r MS: (~+-S) +=1115 WO90/09162 PCT/US90/002g6 2~ ~ c~ .7~

Exa~ple 371 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpro~anoyl}-Glycyl-Leucyl-DArginyl-A-~inyl-OH
FAB+ MS: (M+H)+=1000 Example 372 H-Phenylalanyl-Lysyl-Aspartyl-Methionyl-Gluta.T.lnyl-Leucyt-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+-1093 Example 373 H-Phenylalanyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2'R/S,3S)-3-Amino-2-oxo-1-pyrrolidine-{2'-{4'-methyl)}-pentanoyl~-DArginyl-Arginyl-OH
FA3+ MS: (M+:) =1070 Exampl- 374 H-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-~(2'R/S,3S)-3-Amino-2-oxo-1-py..rolidine-~0 ~2'-(4'-methyl)}-pentanoyl}-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1070 3xampl~ 375 H-Phenylalanyl-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-~5 cyclohexylpropanoyl~-{(2S)-2-Amino-3-cyclohexylpropanoyl}-DLeucyl~DArginyl-OH
FAB+ MS: (M+H)+=1087 Examplo 376 H-{3-(1'-Naphthyl)alanyl~-Lysyl-Aspartyl-Methionyl-Gluzaminyl-Leucyl-Glycyl-Arginyl-O'.i P~+ MS: (M+H)+=10a3 WO90/09162 PCT/Us90/002~6 2~ '~5~ 124 Example 377 H-~3-(2'-~Japhthyl)alanyl~-Lysyl-Aspartyl-Me_hionyl-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=1043 Exa3ple 378 H-i3-(2~-~hienyl)alanyl(R/s)~-Lysyl-Aspartyl-Methion Glutaminyl-Leucyl-Glycyl-Arginyl-OH
F.~B+ MS: (~+H)+=1000 Example 379 H-{3-(2'-Thienyl)alanyl(R/S)~-Lysyl-Aspartyl-Methionyl-.
Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FA3+ MS: (~.+H)+=1000 Exampl- 380 H-{(2S)-2-Amino-4-phenyl~utanoyl~-Lysyl-Alanyl-{~25)-2-~mino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DArginyl-Arginyl-On . FAB+ MS: (M+H) +=1028 Example 381 H-{(2R/S)-2-Amino-5-phenylpentanoyl~-Lysyl-Alanyl-[(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DArginyl-Arginyl-OH
~AB+ MS: (M+H) +alO42 Exa~ple 382 H-{(2R/S)-2-Amino-5-phenylpentanoyl}-Lysyl-Alanyl-{(2â)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-_eucyl-DArginyl-Arginyl-OH
,3+ uS (`~-J) +=1042 WO90/09162 PCT/~'S9~/002g6 2 ~ ~'J'~

Example 383 4-Phenylbutanoyl-Lysyl-Alanyl-~2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DArginyl-Arginyl-C:-FAB+ MS: (M+H)+=1013 ~xample 384 '.-Phenyl212nyl-~{C..2-Nr.}-Lysyl-Alanyl-((25)-2-.~-?.o-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DAlanyl-Arginyl-O:-The compound was prepared in analogy to Example 413.
~AB+ ~S: ~M+H)+3915 Amir.o Acid Anal.: Ala (2.97), Le_ (1.02), Cha (0.89), Arg (1.01) Example 385 (N-Methyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-~mino-3-cy-lohexyl?ropanoyl}-Alanyl-Leucyl-(`i-`.~e~yl)5A'ar.y OH
FA3+ MS: (M+H)+-957 Amino Acid Anal.: Ala (2.04), Leu (1.05), MePhe (0.87), Cha (0.98), Lys (1.03), Arg (l.Oi) Example 386 (N-alpha-(2-phenyl)ethyl)Lysyl-Alanyl-~2S)-2-Amino-3-cyclohexyl?ropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyl-A-~ nt -OH
FAB+ MS: (M+H)+=900 2~
Example 387 ~.-Phenylalanyl-Lysyl-Aspartyl-DMethlonyl-Glutaminyl-Leucyl-DArginyl-Arginyl-OH
FA~+ MS: (M+H)+=1093 Amino Acid Anal.: Asp (0.53), G:;~
(1.06), Met (0.68), Leu (1.07), Phe (0.97), Lys (0.92), A-g (2.06) 2~ 7 126 Example 388 H-Phenylalanyl-Lysyl-Aspartyl-Methionyl-DGlutaminy'-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1093 Amino Acid Anal.: Asp ~0.g5), Glx.
(1.07), Met (0.61), Leu (1.05), Phe (0.98), Lys ~0.3'), E--(2.04) Example 389 H-?henylalanyl-Lysyl-Aspartyi-Me~hionyl-Glutaminyl-Leucyl-0 DArginyl-DArginyl-OH
FAB+ MS: (M+H)+=1093 Amino Acid Anal.: Aso (0.97), ~-lx (1.06), Met (0.68), Leu (1.05), Phe (0.97), Lys ~0.92), Ar, (2.03) Exampls 390 H-Phenylalanyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-DLeucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1093 Amino Acid Anal.: Asp (0. sa), Glx (1.05), Met (0.57), Leu (1.06), Phe (0.97), Lys (0.S2), Arg (2.02) Example 391 Phenoxyacetyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1001 Example 392 Phenoxypropanoyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alznyl-Leucyl-DArginyl-Arginyl-On FAB+ MS: (M+H)+=1015 WO90/09162 PCT/~S9~/002g6 2 ~ "

~ xample 393 H-Phenylalanyl-Lysyl-Glycyl-Aspartyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-~(2S)-2-Amino-3-cyclohexylpropanoJ ~-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H)+=1197 Example 394 3-Phenylpropanoyl-Lysyl-Alanyl-{t2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: (M+H~+=999 Exampl- 395 H-Phenylalanyl-Lysyl-3-Aminopropanoyl-((2S)-2-P,mino-3-cyclohexylpropanoyl)-{(2S)-2-Amino-3-cyclohexylpropanoyl'~-Leucyl-3A-ginyl-Argi~,yl-OH
FAB+ MS: ~M+H)+-1096 Example 396 H-Phenylalanyl-(N-Methyl)Alanyl-Alanyl-{(2S)-2-Pmino-3-cyclohexylpropanoyl}-((2S)-2-Amino-3-cyclohexylpropanoyi~-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+~968 Example 397 H-Phenylalanyl-Lysyl-Aspartyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-{~2S)-2-Amino-3-cyclohexylpropanoy:,-Leucyl-DLysyl-Arginyl-OH
FAB+ MS: (M+H)+~1112 2~5~3 Exa~ple 398 H-Phenylalanyl-Lysyl-Aspartyl-(~2S)-2-Amino~3-cyclohexylpropanoyl~-((2S)-2-Amino-3-cyclohexyl?ropar.oyl~-Isoleucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1055 Example 399 H-Phenylalanyl-Lysyl-Aspartyl~Alanyl-Alanyl-Isoleucyl-DAlanyl-Arginyl-OH
F.~B+ MS: (M+H)~=891 Exa~ple 400 H-Phenylalanyl-Lysyl-DAspartyl-Methionyl-Glutaminyl-Leu-y~-DArginyl-Arginyl-OH
-~+ MS: (M~H)+=1093 Amino Acid Anal.: AS? (0 37)~ --(1.04), Met (0.59), Leu ~1.06), Phe ~0.94), Lys ~0.89), Arg (2.09) Exampl- 401 H-DPhenylalanyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucyl-DArginyl-Arginyl-OH
FAB+ MS: ~M+H)+=1093 Amino Acid Anal.: As? (0.95), Glx ~1.05), Met ~0.5g), Leu ~1.05), Phe (0.97), Lys ~0.93), Arg ~2.07) Exa~ple 402 (N-Ethyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-~ethyl)DAlanyl-Argin O~i FAB+ MS: ~M+H)+-971 Amino Acid Anal.: Ala ~2.02), Leu ('.03), Ch2 (0.97), Lys (1.01), A_g (0.99) W090/09162 PCT/USgO/002g6 2 ~ 7 ~

Example 403 (N-Methyl)?henylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-~ethyl)DALanyl-A_g--.y'-The compound was prepared in analogy to Example 38.
FA3+ MS: (~+H)+=971 Amino Acid Anal.: Ala (2.01), Me?he (0.85), Leu (1.02), Cha (0.33), Lys (0.98), A-g (0.93) Example 404 te; t -3utyloxycarbonyl-~henylalanyl-Lysyl-Alanyl-((2S)-2-.~mino-3-cyclohexylpropanoyl~-Alanyl-_eucyl-DAlanyl-Arg ..y~
FA3+ MS: (M+H)+=1029 Exampla 405 (~- ?-)?he.~lalanyl-Lysyl-Ala?.yl-{(2a)-2-Amir.o-3-cyclohexylpropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arglryl-OH
FA3~ MS: (M+H)+=985 Amino Acid Anal.: Ala (2.07), Leu (0.96), Cha (0.97), Lys (0.99), Arg (0.98) EYample 406 H-D(N-Methy!)Phenylalanyl-Lysyl-Alanyl-~(25)-2-.~mino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyl-Argl?.y'-OH
FAB+ MS: (M+H)+~957 Amino Acid Anal.: Ala (1.97), Leu (1.04), Cha (0.93), Lys (0.97), Arg (1.02) ?,~ g?

Example 407 H-Phenylalanyl-Lysyl-Aspartyl(NHNH2)-{(2S)-2-L~ino-3-cyclohexylpropanoyl~-{(25)-2-Amino-3-cyclohexylpropanoy}~-Leucyl-(N-Methyl)DAlanyl-Arginyl-NHNH2 The compound was prepared in analogy to _xample 3~, F.~B+ MS: (M~H)+=1083 Example 408 Y.-~henylalanyl-Lysyl-Aspartyl(NCH3NH2)-~(2S)-2-Amino-3-cyclohexyl?.opanoyl~-((2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-(N-~.ethyl)DAlanyl-Arginyl-NCH3NH2 The compound was prepared in analogy to Example 38.
FAB+ MS: (M+H)+=1111 I S Example 409 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-~{CH2-NH~-Leucyl-DAlanyl-Arginyl-OH
The compound was prepared in analogy to Example 413.
FAB+ MS: (M+H)+=915 Amino Acid Anal.: Ala (1.97), ~he (0.99), Cha (1.79), Lys ~1.02), Arg (1.01) Exa~plo 410 H-Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl- Leucyl-~{CH2-NH~-DAlanyl-Arginyl-OH
The compound was prepared in analogy to Example 413.
FA3+ MS: (M+H)+-915 Amino Acid Anal.: Ala (2.02~, ~he (0.97), CAa (0.94), Lys (1.01), Arg (0.82) W090/09162 PCT/US90/0~2g6 y~

Example 411 ~-Phenylalanyl-Lysyl-Alanyl-~{CH2-NH}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-A_ginyl-GH
The compound was prepared in analogy to ~xample 413 FAB+ MS: (M+:~)+=915 Amino Acid Anal.: Ala (2.06), Leu (1.05), Pr.e (0.94), Lys (0.99), Arg (0.95) Example 412 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-0 cyclohexylpropanoyl}-~{CH2-NH}-Alanyl-Leucyl-DAlanyl-A-- ny -OH
The compound was prepared in analogy to Example 413.
FAB+ MS: (M+H)+-915 Amino Acid Anal.: Ala (2.00), Leu (1.02), Phe (0.97), Lys (1.02), Arg (1.02) ~xample 413 H-Phenylalanyl-Lysyl-~{CH2-NH~-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
Commercially available N-alpha-Boc-Lysine(N-epsilon-Cbz) was converted to its N,O-dimethylhydroxamate, which was reduced with lithium aluminum hydride to yield N-alpha-30c-N-epsilon-Cbz-Lysinal, according to the literature: Nahm, S.;
Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. The pepti~^
chain was then elongated by the method described in Exzm?le 1, except that after Boc-Alanine was coupled, the sequence was stopped at agenda A-step 2. N-alpha-Boc-N-epsilon-C~z-Lysinal (235 mg, 3.5 equivalent mole) in 10 mL of DMF
containing 0.1% glacial acetic acid was added, followed 2y sodium cyanoborohydride (404 mg, 10 equivalent mole) . The rea~tion was allowed to proceed at rGGm temperature .Gr ..ou-. A_~e- the peptide resin ob~a-ned ~as ~ashed ~3 x 10 mL) and methylene chloride (3 x 10 "~T ) ~ I :-e ?.

WO90/09162 PCT/US90/0~296 2 ~ 7 ~ 132 synthetic protocol (Example 1, Agenda A step 2) was initiated. The peptide-resin was then treated as desc ~be~
in Example 2 to yield 27.8 mg of pure product consistent proposed structure.
S rAB+ MS: (M+H)+=915 Amino Acid Anal.: Ala (1.99), Le--(1.01), Phe (0.94), Cha (0.93), Arg (1.06) Othe; amino aldehydes (Boc-Phenylalanal, 3Oc-(2S)-2-amino-3-cyclohexylpropanal, 3Oc-Alanal, Boc-Leucinal ar.d ~
D-Alanal were prepared by literature methods: ~nhoury, ~.. _.;
A-ic.~x, M.; Crooy, P.; De Neys, R.; Eliaers, J. J. Chem.
Soc. Perk~n l 1974, 191; Hamada, Y.; Shioir-, T. Cr.e.~.
Pharm. Bull. 1982, 30, 1921.

Example 414 :H-?henylalanyl-Lysyl-Aspartyl-M.ethiony!-Gluta.~. nyl-Le-_cy_-Glycyl-DArginyl-OH
FAB+ MS: (M+H)+'994 Amino Acid Anal.: Asp (0.95), Glx (1.08), Gly (0.77), Met (0.56), Leu (1.04), Phe ~0.97), Lys (0.94), Arg (1.03) ~xa3plo 415 H-Phenylalanyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-DLeucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+'994 Amino Acid Anal.: Asp (0.96), Glx 2~ (0.93), Gly (0.67), Met (0.54), Leu (1.06), Phe (0.97), Lys (0.88), A-g (1.05) WO90/09162 PCT/~S90/00296 2 ~

Exa~ple 416 H-?henylalanyl-Lysyl-Aspartyl-Methionyl-DGlutaminyl-_eucyl-Glycyl-Argi~.yl-OH
FA3+ MS: (M+H)+=994 Amino Acid Anal.: Asp (0.97), Glx ~1.08), Gly (0.67), Met (0.61), Leu (1.04), ?he (C.93), _;s (C.88), A-g (1.05) Example 417 H-?henylalanyl-Lysyl-Aspartyl-DMethionyl-Glutaminyl-Le~cyl-Glycyl-Arg~nyl-OH
FA3+ MS: (M+.~)+=994 Amino Acid Anal.: Asp (0.47), Gl r (0.32), Gly (0.68), Met (0.64), Leu (1.00), Phe (0.27), Lys (0.30), Arg (1.00) Example 418 H-Phenylalanyl-Lysyl-DAspartyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+:.)+=994 Amino Acid Anal.: Asp (0.46), Glx (0.28), Gly (0.68), Met (0.59), Leu (1.00), Phe (0.24), Lys (0.29), Arg (1.00) 7-xampl~ 419 H-~henylalanyl-DLysyl-Aspartyl-Methionyl-Glutaminyl-Le~cy'-Glycyl-Arginyl-OH
F~3+ MS: (M+:~)+-994 Amino Acid Anal.: Asp (0.47), Glx (0.31), Gly (0.84), Met (0.53), Leu (1.04), Phe (0.22), Lys (0.26), A g (0.g6) WO90/09162 PCT/US90/002g6 2~3~7~ 134 Example 420 H-Phenylalanyl-Lysyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-3-Aminopropanoyl-Leucyl-DArginyl-Arginyl-OH
5 F~B+ MS: (M+H)+=1058 ~ xamplQ 421 H-Phenylalanyl-Lysyl-Alanyl-{(25~-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-DAlanyl-~{CY2-N:i~-A-, -.y:-OH
The compound was prepared in analogy to Example ~13.
FA3+ MS: (M+H)+=915 Amino Acid Anal.: Ala (1.80), Leu (1.02), Phe (1.02), Cha (1.00), Lys (0.97) Example 422 (N~(3-Phenyl)propyl)Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arg-nyl-OH
FAB+ MS: (M+H)+=914 ~xa~plQ 423 (N,N-di-(3-Phenyl)propyl)Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1032 Amino Acid Anal.: Ala (2.10), Le~
(1.06), Cha (0.97), Lys (0.93), Arg (1.04) WO90/09162 PCT/US90/0029~

135 2 ~

Exampl~ 424 H-Phenylalanyl-Lysyl-Aspartyl-Methionyl-Arginyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=1022 Amino Acid Anal.: Asp (0.62), G'y (0.99), Met (0.49), Leu (1.13), Phe (0.30), Lys (0.35), A_-(1.88) Example 425 H-Phenylalanyl-Lysyl-Arginyl-Methionyl-Glutam-nyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=1035 Amino Acid Anal.: Glx (0.38), Gly(0.83), Met (0.91), Leu (1.13), Phe (0.27), Lys (0.27), Arg (1.96) Example 42~
H-Phenylalanyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Lysyl-OH
FAB+ MS: (M+H)+=966 Amino Acid Anal.: Asp(0.70), Glx (0.32), Gly (0.94), Met ~0.66), Leu (1.19), Phe (0.35), Lys (1.89) Example 427 H-Phenylalanyl-Ornithyl-Aspartyl-Methionyl-Glutaminyl-Le-_cyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+-980 Amino Acid Anal.: Asp (0.49), Glx (0.32), Gly (0.71), Met (0.65), Leu (1.00), Phe (0.33), (0.25), Arg (1.00) WO90/09162 PCT/US90/002g6 2 ~ o) 136 Example 428 H-DPhenylalanyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+=994 Amino Acid Anal.: Asp (0.45), Glx (0.30), Gly (0.70), Met (0.68), Leu (1.00), Phe (0.30), L;-(0.43), A-g (1.00) Example 429 H-Phenylalanyl-Lysyl-Aspartyl-~(2S)-2-Amino-3-cyclohexylpropanoyll-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-Glycyl-Arginyl-Arginyl-OH
FA~+ MS: (M+H)+=1197 Ex~mple 430 H-Phenyla_anyl-Lysyl-Aspartyl-((2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl;-Leucyl-Glycyl-Arginyl-DArginyl-OH
FAB+ MS: (M+H)+=1197 Example 431 3-Phenylpropanoyl-Lysyl-Aspartyl-Methionyl-Glutaminyl-Leucy_-Glycyl-Arginyl-OH
FAB+ MS: (M+H)+-979 ~xampl~ 432 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Arginyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=1014 Amino Acid Anal.: Ala (1.86), T~U
(1.04), Phe (1.00), Cha (0.96), Lys (0.99), Arg (1.97) WO90/09162 PCT/USg0tn0296 137 2 ~ 7 ~

Example 433 (N-Allyl)?henylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexyl?ropanoyl}-Alanyl-Leucyl-(N-Methyl)DAlanyl-A--inyl-OH
S ~AB+ MS: (M+H)+-983 Amino Acid Anal.: Ala (1.98), Leu (1.04), C;~a (0.94), Lys (0.96), Arg (1.02) Example 434 (N,N-di-~.e:hyl)Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexvl?ropanoyl~-Alanyl-Leucyl-(N-Methyl)DAlanyl-A-g nr OH
FAB+ MS: (M+H)+~971 Amino Acid Anal.: Ala (2.01), Leu (1.06), Cha (0.88), Lys (0.91), Arg (1.03) Example 435 Pyrazylcarbonyl-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=1035 Zxampl~ 436 3enzoyl-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
FA3+ MS: (M+H)+=1033 Examplo 437 2-Pyridylacetyl-Phenylalanyl-Lysyl-Alanyl-((2S)-2-Amino-3-cyclohexyl?ropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-OH
r A8+ MS: !M+H)+=1048 W~90/0sl62 PCT/US90/0~96 2 ~ 138 Example 438 Ac-Phenylalanyl-Lysyl-Alanyl-1(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-DAlanyl-Arginyl-O~
FAB+ MS: (M+H)+=971 s Example 439 H-Phenylalanyl-Lysyl-Alanyl-1(2S)-2-.~mino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-(N-Bn)Glyc-yl-A-ginyl-C:-.
FAB+ MS: (M+H)+=1005 Example 440 1(3R/S)-1,2,3,4-Tetrahydroisoquinolin-3-carbonyl)-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-DAlanyl-Arginyl-OH
cA3+ MS: (~ =927 Amino ~cid Anal.: Gly (C.90), Lys (1.01), Ala (1.78), Cha (0.98), Leu (1.00), Arg (1.02) Example 441 ~(3R/S)-1,2,3,4-Tetrahydroisoquinolin-3-carbonyl~-Lysyl-Alanyl-l(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=927 Amino Acid Anal.: Gly (0.92), Lys (1.02), Ala (1.90), Cha (0.99), Leu (1.07), Arg ~1.04) Fxample 442 H-~henylalanyl-Lysyl-~(3R/S)-1,2,3,4-Tetrahydroisoquinol~
carbonyl~-1(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Le-cyl-(N-Methyl)~.~lanyl-Arginyl-OH
FAB+ MS: (M+H)+=1003 WO90/09162 PCT/US90/002~6 139 2 ~ .fi.

Example 443 H-Dhenylalanyl-Lysyl-{(3R/S)-1,2,3,4-Tetrahydroisoquinol r-~-carbonyl}-((2S)-2-Amino-3-cyclohexylpropanoyl~-&lycyl-Leucy -(N-Methyl)DAlanyl-Arginyl-OH
FAB+ MS: (M~) +=1003 Amino Acid Anal.: Phe (0.97), ys (0.94), Ala (0.80), Gly (1.00), Leu (1.06), Arg (1.04) Example 444 H-Phenylalanyl-Lysyl-Alanyl-{(3R/S)-1,2,3,4-Tetrahydroisoquinolin-3-carbonyl~-Glycyl-Leucvl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+- 921 Amino Acid Anal.: Phe (0.96), ~ys (0.97), Ala (1.82), Gly (0.96), Leu (1.05), Arg (1.03) Example 445 H-Phenylalanyl-Lysyl-Alanyl-{(3R/S)-1,2,3,4-Tetrahydroisoquinolin-3-carbonyl~-Glycyl-Leucyl-DAlanyl-Arginyl-OH
FAo+ MS: (MiH)+~921 Amino Acid Anal.: Phe (1.01), Lys ~1.00), Ala ~1.99), Gly ~0.93), Leu ~1.13), Arg (1.09) Exa~pls 445 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(3R/S)-1,2,3,4-Tetrahydrolsoquinolin-3-carbonyl}-Leucyl-DAlanyl-Arginyl-OH
FA8+ MS: (M+H)+=1017 Amino Acid Anal.: Phe (0.99), Lys (0.96), Ala (1.69), Cha (0.99), Leu (1.06), Arg (1.00) WO90/09162 PCT/US90/002g6 Example 447 H-Phenylalanyl-Lysyl-Alanyl-(~2S)-2-Amino-3-cyclohe~ylpropanoyl}-~(3R/S)-1,2,3,4-Tetrahydroisoquino~ n-3-carbonylJ-Leucyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+:)+=1017 Amino Acid Anal.: Phe (1.01), _y_ (~.02), ~la (1.79), Cha (0.99), Leu (1.10), Arg (1.0~) Example 448 ~ henyialanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohe.Yylorooanoyl~-Glycyl-l(3R/S)-1,2,3,4-Tetrahyd_oisoquinolin-3-carbonyl)-DAlanyl-Arginyl-O:J.
FAB+ MS: (M+H)+=961 Amino Acid Anal.: Phe (0.99), Lys (1.04), Ala (1.94), Gly (1.03), Leu (1.07), Arg (1.08) ~xa~ple 449 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoylJ-Glycyl-((3R/S)-1,2,3,4-Tetrahyd-oisoquinolin-3-carbonyl)-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+=961 Amino Acid Anal.: Phe (1.00), Lys (1.03), Ala (2.01), Gly (0.94), Leu (1.07), Arg (1.02) Exa~ple 450 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-{(3R/5)-1,2,3,4-Tetrahydroisoquinolin-3-carbonylJ-Arginyl-OH
FA3+ MS: (M H)+=1003 Amino Acid Anal.: ~he (0.90), _~s (0.9~ .12 ~1.02~, Gly (0.98" Leu (1.021, Arg ~1.06j WO90/09162 PCT/US90/~02g6 2 ~ 7 ~

Example 451 H-Phenylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-{~3R/S)-1,2,3,4-Tetrahydroisoquinolin-3-carbonyl}-Arginyl-OH
FA3+ MS: (M+~)+=1003 Examplo 452 (N, N-di-Allyl)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-(N-Methyl)DAllny'-A_ginyl-O;~
FA3+ MS: (~+H)+sl023 Amino Acid Anal.: Lys (0.91), ~:~a (0.98), Gly (0.99), Leu (1.05), Arg (0.99) Exa3ple 453 (N-Allyl)?henylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-~m5-,-3-cyclohexylpropanoyl}-Glycyl-Leucyl-(N-Methyl)DAlanyl-Azslnyl-OH
FAB+ MS: (M+H)+=983 Amino Acid Anal.: Lys (0.93), Cha (0.90), Gly (0.91), Leu ~1.05), Arg ~1.02) ExYmplo 454 2-Indolylcarbonyl-Lysyl-(N-Methyl)Alanyl-{~2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-(N-Methyl)DAlanyl-Ar~ nyl-OH
FA3+ MS: ~M+H)+-939 Amino Acid Anal.: Lys (0.86), Cha (0.97), Gly (1.01), Leu (1.03), Arg (0.96) Examplo 455 (N,N-di-Methyl)~henylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Glycyl-Leucyl-(N-Methyl)DAlanyl-A-ginyl-C:-~P~+ MS: ('.~U)-=971 ?.9~ :37~ 142 Example 456 Ac-(Z-dehyd_o)Phenylalanyl-Lysyl-(N-Methyl)Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycyl-Leucyl-(N-Methyl)CAlanyl-Arginyl-OH
,-A3+ MS: (M-H)+=983 Amino Acid Anal.: Lys (1.02), G7y (l.Oi), Cha (0.94), Leu (1.01), A-g (0.97) Example 457 ?ivaloyl-Phenylalanyl-Lysyl-Alanyl-l(25)-2-Amino-3-cyclohexylp-opanoyl}-Alanyl-Leucyl-DAlanyl-Arg_nyl-O:
F.~3+ MS: (M+H)+-1013 Example 458 :i-Phenylalanyl-Arginyl-Arginyl-Methionyl-51utaminyl-Le~_-yl-1 5 ~ c ~ . y l -O:~I
FAB+ MS: (M+H)+-1063 Amino Acid Anal.: Glx ~0.31), Gly (0.84), Met (0.82), Leu ~1.11), Phe (0.33), Arg (2.23) ~xampl- 459 H-Phenylalanyl-Lysyl-Arginyl-Methionyl-Glutaminyl-Leucyl-Glycyl-Alanyl-OH
~AB+ MS: (M+~)+-950 Amino Acid Anal.: Glx (0.35), Gly (1.02), Ala (1.45), Met (0.97), Leu (1.31), Phe (0.26), Lys (0.30), Arg (1.00) Example 460 ~ -Me~hyijphenyiaianyi-Lysyi-Arginyi-Melhionyl-Glu~amin Leucyl-51ycyl-Arginyl-OH
~ MS: (M~H)+=1049 Amino Acid Anal.: G_x (0.38), G:i (0.79), Met (0.91), Leu (0.92), Lys (0.14), Arg (1.67) WO90/09162 PCT/USgO/002g6 Example 461 H-Phenylalanyl-Lysyl-Alanyl-~(2S)-2-Amino-3-cyclohexylpropanoyl}-Alanyl-Leucyl-Azaglycyl-A-ginyl-O:-.
FA3+ MS: (U+H)+=917.
Thls peptide was prepared using methodoiogy similar .c that desc-ibed in: Dutta, A. S.; Giles, M. ~.; Willizms, _ C. J. Chem. Soc., Perkin Trans. 1 1986, 165;-64; Dut~a, A.
S.; Giles, M. ~.; Gormley, J. J.; Williams, J. C.; Kusne , ~
J. J. Chem. Soc., Perkin Trans. 1 1987, 111-120.

Example 462 H-Phenylglycinyl-Lysyl-Alanyl-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Glycinyl-Leucyl-DAlanyl-Arginyl-OH

~xa~pl~ 463 H-Phenylalanyl-Lysyl-Cysteinyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-~H
The protected peptide resin: H-Phenylalanyl-Lysyl(N-epsilon-Cbz)-Cysteinyl(S-4-methylbenzyl)-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl(N-guanidino-Tos)-Merrifield resir. is prepared as described in Example 1. The peptide is cleaved from the resin as described in Example 2 with the followins precautions: the peptide is extracted with degassed 20~
aaueous acetic acid following cleavage with H~; and HPLC
purification is accomplished using helium saturated solven~s WO90/09162 PCr/U590/002g6 2~ 7'~ 144 Example 464 H-Phenylalanyl-Lysyl-(S-Benzyl)Cysteinyl-((2S)-2-Amlno-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl~-Leucyl-DAlanyl-Arginyl-OH
The octapeptide prepared in Example 463 ls dissolved _~.
methanol saturated with ammonia to make a 0.03 M solu_ on under a nitrogen atmosphere, and the resultant solution ls chilled to 0 C. Benzyl bromide (1.3 equivalents) is introduced neat, and the reaction mixture is stirred for 1 hour at 0 C. The entire reaction mixture ls ?oured ln~o water followed by trifluoroacetic acld addition to ob.a-n 2 pH of 2. The product is subsequently isolated by HPLC usi-.g solvents saturated with helium.

~xampl~ 46~
2-Acetamidoacryloyl-Phenylalanyl-Arginyl-Aspartyl-{(2S)-2-Amino-3-cyclohexylpropanoyl}-{(2S)-2-Amino-3-cyclohexylpropanoyl}-Leucyl-DAlanyl-Arginyl-OH
Excess 2-acetamido acrylic acid isobutyl mixed anhyd-ice in tetrahydrofuran, prepared from 2-acetamido acryllc ac-d - and isobutyl chloroformate by the standard method, is adde~
into a stirred 0 C solution of the peptide prepared in Example 65 in 0.1 N aqueous sodium bicarbonate containing sufficient acetonitrile to produce a homogenous solution.
After stirring for 6 hours at 0 C, ;he reaction mixture ls brought to pH 2, and the peptide is purified by reverse phzse HP~C followed by lyophilization.

The foregoing examples are merely illustrative of tke 3~ invention and are not intended to limit the invention to t:-e scloseA c-m?our.ds. V2-ia~ions ar.d changes ~:-ich a-e obvious to one skilled ln the art are lr.:ended to be w~

2~ 7~

the scope and nature of the invention which is defined i~ e~
appended claims.

Claims (8)

1. An anaphylotoxin activity modulating compound of the formula:
A-B-D-E-G-J-L-M-Q-T
and the pharmaceutically acceptable salts, esters, of amides thereof wherein the groups A through T have the values:

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, R32, R35 and R37;
E is selected from R10-R11-R12, R31, R32, R35 and R37;
G is selected from R13-R14-R15, R31, R32, R35 and R37;
J is selected from R16-R17-R13, 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 selected from R25-R26-R27, R31, R32, R35 and R37;
T is R28-R29-R30;
B and D, taken together, optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42, and R43;
D and E, taken together, optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42, and R43;
E and G, taken together, optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42, and R43;
G and J, taken together, optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42, and R43;

J and L, taken together, optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42, and R43;
L and M, taken together, optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42, and R43;
M and Q, taken together, optionally represent a group selected from R33, R34, R38, R39, R40, R41, R42, and R43, and one or more of the groups R5-R6-R7, R8-R9-R10, R11-R12-R13, R14-R15-R16, R17-R18-R19, R20-R22-R22, R23-R24-R25, or R26-R27-R28, independently may optionally represent R36; wherein (a) R1 s selected from the group consisting of amino, (lower alkyl)amino, dialkylamino, (arylalkyl)amino, hydroxy, alkoxy, aryloxy, arylalkoxy, acetamido, thioalkoxy, halogen, aryl, lower alkyl, arylalkyl, (heterocyclic)alkyl, heterocyclic, arylamino, and hydrogen;

(b) R2 is selected from the group consisting of >CR99R100, >C=CR95R96, existing in either the Z- or E-configuration, oxygen, amino, and alkylamino, with the proviso that when R2 is oxygen, amino or alkylamino, R1 is aryl, lower alkyl, arylalkyl or (heterocyclic)alkyl;

(c) R3 is selected from the group consisting of >C=O, >CH2, >C=S, >SO2, with the proviso that when R3 is >CH2 or >SO2 then R2 cannot be oxygen, amino 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, with the proviso that when R4 is >O or >S then R1, R2 and R3 taken together represent a group selected from lower alkyl, arylalkyl, aryl or hydrogen;

(e) R5 is selected from the group consisting of >CR201R202, >NR203, >C=CR205R206, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(f) R6, R9, R12, R15, R18, R21, and R24 are independently selected from the group consisting of >C=O, >CH2, -CH2C(O)-, -NHC(O)-, >C=S, >SO2, and >P(O)X where X is selected from hydroxy, alkoxy, amino, alkylamino and dialkylamino;

(g) R7, R10, R13, R16, R19, R22, R25 are independently selected from >CH2 and >NR50 where R50 is selected from the group consisting of hydrogen, lower alkyl, arylalkyl, aryl, hydroxy and alkoxy;

(h) R8 is selected from the group consisting of >CR210R211, >NR213, >C=CR215R216, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(i) R11 is selected from the group consisting of >CR220R221, >NR223, >C=CR225R226, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(j) R14 is selected from the group consisting of >CR230R231, >NR233, >C=CR235R236, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(k) R17 is selected from the group consisting of >CR301R302, >NR303, >C=CR305R306, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(l) R20 is selected from the group consisting of >CR310R311, >NR313, >C=CR315R316, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(m) R23 is selected from the group consisting of >CR320R321, >NR323, >C=CR325R326, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(n) R26 is selected from the group consisting of >CR330R331, >C=CR335R336, existing in either the Z- or E-configuration, and substituted cyclopropyl of the formula ;

(o) R27 is selected from the group consisting of >C=O, >CH2, -CH2C(O)-, >C=S, >SO2, and >P(O)X
wherein X is selected from hydroxy, alkoxy, amino, alkylamino and dialkylamino;

(P) R28 is 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, then R28 is >O or >NR109;

(q) R29 is selected from the group consisting of hydrogen, lower alkyl, arylalkyl, and >NR110 where R110 is selected from hydrogen, lower alkyl, aryl, and arylalkyl, with the provisos that (i) when R28 is >O, or >S then R29 is lower alkyl or arylalkyl, and (ii) when R29 is hydrogen, lower alkyl, or arylalkyl then R30 is absent;

(r) R30 is selected from the group consisting of hydrogen, aryl, lower alkyl, and arylalkyl;

(s) R31 is where m and n are integers independently selected from 0, 1 and 2;
(t) R32 is where p and q are integers independen?ly selected from 0, 1 and 2;

(u) R33 is where t and v are integers independently selected from 0, 1, 2 and 3;
(v) R34 is where r and s are integers independently selected from 0, 1, 2 and 3;

(w) R35 is where f is and integer of 0 to 3, X is selected from >C=O and -CH2- and R is selected from hydrogen and lower alkyl, with the provisos 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 and R
is at C-3, C-4 or C-5 and C-3,4 are saturated or unsaturated;
(iii) when f is 2, X is at C-2, C-3 or C-4 and R is at C-2, C-3, C-4, C-5 or C-6 when the position is unoccupied by X
and C-3,4 or C-4,5 are saturated or unsaturated; and (iv) when f is 3, X is at C-2, C-3 or C-4 and R is at C-2, C-3, C-4, C-5, C-6 or C-7 when the position is unoccupied by X
and C-3,4 or C-4,5 or C-5,6 are saturated or unsaturated;

(x) R36 is where g is an integer of from 0 to 3;
(y) R37 is wherein h is 0 or 1 and j is 0 or 1 with the proviso that either h or j must be 1;

(z) R38 is ;

(aa) R39 is ;

(ab) R40 is ;

(ac) R41 is ;

(ad) R42 is ;

(ae) R43 is where k is an integer or from zero to two;

(af) R1 and R2, taken together, optionally represent a group selected from aryl, heterocyclic, or hydrogen;

(ag) R6 and R7; R9 and R10; R12 and R13;
R15 and R16; R18 and R19; R21 and R22; and R24 and R25; each pair taken together, optionally and independently represent a group selected from >CH2, -(CH2)3-, -CH=CH-, -C?C-, -C(=CH2)CH2-, -CH(OH)CH2-, -C(O)O-, -C(O)S-, -CH2C(O)O-, -CH2C(O)S-, -CH2O-, -CH2S-, and -NHC(O)-, with the provisos that (i) when R5 is >NR203 or >C=CR205R206, R6 and R7, taken together, represent -C(O)NH- or -C(O)NCH3-;
(ii) when R8 is >NR213 or >C=CR215R216, R9 and R10, taken together, represent -C(O)NH- or -C(O)NCH3-;
(iii) when R11 is >NR223 or >C=CR225R226, R12 and R13, taken together represent -C(O)NH- or -C(O)NCH3-;
(iv) when R14 is >NR233 or >C=CR235R236, R15 and R16, taken together, represent -C(O)NH- or -C(O)NCH3-;
(v) when R17 is >NR303 or >C=CR305R306, R18 and R19, taken together, represent -C(O)NH- or -C(O)NCH3-;
(vi) when R20 is >NR313 or >C=CR315R316;
R21 and R22, taken together, represent -C(O)NH- or -C(O)NCH3-;
(vii) when R23 is >NR323 or >C=CR325R326, R24 and R25, taken together, represent -C(O)NH- or -C(O)NCH3-;

(ah) R29 and R30, taken together, optionally;

represent a group selected from hydrogen, hydroxy, or alkoxy, with the proviso that when R28 is >O or >S then R29 and R30, taken together, represent hydrogen;

(ai) R1, R2 and R3, taken together, optionally represent a group selected from lower alkyl, arylalkyl, alkenyl, aryl, hydroxy, alkoxy, hydrogen, an N-terminal protecting group or peptide fragment of 1-8 residues similarly protected wherein each of the amino acids comprising the peptide fragment is independently selected from the 20 naturally occuring amino acids;

(aj) R28, R29 and R30, taken together, optionally represent a group selected from an amino acid or dipeptide selected from from the 20 naturally occuring amino acids;

(ak) R1, R2, R3 and R4, taken together, optionally represents a group selected from hydrogen, lower alkyl, arylalkyl, aryl, heterocyclic, or H2NC(O)-, with the proviso that when R5 is >CH2 then R1, R2, R3 and R4, taken together, may not be hydrogen;

(al) R27, R28, R29 and R30, taken together, optionally represent a group selected from hydrogen, lower alkyl, aryl, or arylalkyl;

(am) R1, R2, R3, R4 and R5, taken together, optionally represent an aryl or heterocyclic group;

(an) R95, R96, R205, R206, R215, R216, R225, R226, R235, R236, R305, R306, R315, R316, R335 and R336 are independently selected from the group consisting of hydrogen, lower alkyl, aryl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxyamido)alkyl, ureidoalkyl, (heterocyclic)alkyl, and halosubstituted alkyl;

(ao) R99, R202, R211, R221, R231, R302, R311, R321 and R331 are independently selected from hydrogen and lower alkyl;

(ap) R100 is selected from the group consisting of hydrogen, lower alkyl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, arylalkoxy, and sulfhydrylalkyl;

(aq) R201 is selected from the group consisting of hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, (carboxyhydrazino)alkyl, ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfhydrylalkyl, and halosubstituted alkyl;

(ar) R203, R213, R223, R233, R303, and R313 are independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, (carboxyhydrazino)alkyl, ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, or protected sulfhydrylalkyl with the proviso that none of R203, R213, R223, R233, R303, or R313 may be a vinyl group or have a heteroatom directly attached to the nitrogen or separated from it by one methylene unit;

(as) R210 is hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, ureidoalkyl, (carboxyhydrazino)alkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfhydrylalkyl, or halosubstituted alkyl;

(at) R220, R230, R301, R310, and R330 are independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido)alkyl, (carboxyhydrazino)alkyl, ureidoalkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfhydrylalkyl, or halosubstituted alkyl;

(au) R320 and R323 are selected from the group consisting of hydrogen, lower alkyl, alkenyl, aryl, benzyl, (cycloalkyl)alkyl, -(alkylene)-C(O)NR340R341, -(alkylene)-NR342R343, -(alkylene)-NR344C(O)R345, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyhydrazino)alkyl, ureidoalkyl, heterocyclic substituted methyl, (thioalkoxy)alkyl, sulfhydrylalkyl, (aminothioalkoxy)alkyl, protected sulfhydrylalkyl, and halosubstituted 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 halosubstituted lower alkyl, with the proviso that R323 may not be a vinyl group or have a heteroatom directly attached to the nitrogen or separated from it by one methylene unit;

(av) R325 and R326 are independently selected from the group consisting of hydrogen, lower alkyl, aryl, (cycloalkyl)alkyl, -(alkylene)-NR344C(O)R345, (carboxyamido)alkyl, ureidoalkyl, (heterocyclic)alkyl, and halosubstituted 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 ard R311, R320 and R321, and R330 and R331, each pair taken together, independently may optionally represent -(CH2)z- where z is an integer of from 2 to 6;

all of the foregoing with the provisos that (i) when more than one sulfhydrylalkyl is present in the compound, the compound exists in the oxidized disulfide form producing a cyclic molecule, or the two sulfhydryl moieties are connected by a C2 to C8 alkylene chain and (ii) when the compound contains a free amino group and carboxyl group, they can be cyclized to give the corresponding lactam.
2. A compound as defined by Claim 1 wherein R4, R7, R10, R13, R16, R19, R22, and R25 are independently selected from >NH and >N-(lower alkyl).
3. A compound as defined by Claim 1 wherein R6, R9, R12, R15, R18, R21, R24, and R27 are independently selected from >C=O and >CH2.
4. A compound as defined by Claim 1 wherein R5 is selected from >CR201R202; >NR203; >C=CR205R206, existing in the Z-or E-configuration: and substituted cyclopropyl of the formula ;

where R201 is selected from lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxyamido)alkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, (thioarylalkoxy)alkyl, protected sulfhydrylalkyl, and halosubstituted alkyl;

R202 and R205 are selected from the group consisting of hydrogen and lower alkyl;

R203 is selected from the group consisting of selected from the group consisting of lower alkyl, alkenyl, arylalkyl, (cycloalkyl)alkyl, amidoalkyl, (carboxyamido)alkyl, (heterocyclic)alkyl, (thioalkoxy)alkyl, (thioarylalkoxy)alkyl, or protected sulfhydrylalkyl, with the proviso that R203 may not be a vinyl group or have a heteroatom directly attached to the nitrogen or separated from it by one methylene group;
and R206 is selected from the group consisting of lower alkyl; aryl; arylalkyl; (cycloalkyl)alkyl;
amidoalkyl; (carboxyamido)alkyl;
(heterocyclic)alkyl; and halosubstituted alkyl.
5. A compound as defined in Claim 1 wherein R8 is selected from the group consisting of >CR210R211; >NR213;
>C=CR215R216, existing in either the Z- or E
configuration;

and substituted cyclopropyl of the formula ;
where R210 is selected from the group consisting of arylalkyl; aminoalkyl; guanidinoalkyl;
(heterocyclic)alkyl; (aminothioalkoxy)alkyl;

R211 and R215 selected from hydrogen and lower alkyl;

R213 is selected from the group consisting of arylalkyl; aminoalkyl; guanidinoalkyl;
(heterocyclic)alkyl; and (aminothioalkoxy)alkyl; with the proviso that R213 may not have a herteroatom directly attached to the nitrogen or separated from it by one methylene unit; and R216 is selected from arylalkyl and (heterocyclic)alkyl.
6. A compound as defined by Claim 1 wherein R26 is selected from the group consisting of >CR330R331; >C=CR335R336, existing in either the Z- or E-configuration; and substituted cyclopropyl of the formula ; where 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. A method for modulating anaphylatoxin activity in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1.
8. An anaphylatoxin modulating composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.
CA002045578A 1989-01-31 1990-01-16 Anaphylatoxin-receptor ligands Abandoned CA2045578A1 (en)

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US5190922A (en) * 1991-06-04 1993-03-02 Abbott Laboratories Terminally modified tri-, tetra- and pentapeptide anaphylatoxin receptor ligands
WO1994007518A1 (en) * 1992-09-25 1994-04-14 Abbott Laboratories Anaphylatoxin receptor ligands containing lipophilic residues
US5837499A (en) * 1993-12-06 1998-11-17 Ciba-Geigy Corporation DNA encoding C5A receptor antagonists having substantially no agonist activity and methods of expressing same
US5807824A (en) * 1993-12-06 1998-09-15 Ciba-Geigy Corporation C5A receptor antagonists having substantially no agonist activity
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CN103599523B (en) * 2013-11-25 2016-08-17 中国人民解放军第二军医大学 Pentapeptide metabolite application in preparing anti-inflammatory drug

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