LIGANDS RECEPTEURS DE L'ANAPHYLATOXINE

ANAPHYLATOXIN-RECEPTOR LIGANDS

Abrégé anglais

2045578 9009162 PCTABS00001
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.

Revendications

WO 90/09162 PCT/US90/00296
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WE CLAIM:
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;

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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;

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(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
<IMG>;
(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;

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(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
<IMG>;
(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
<IMG>;
(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
<IMG>;
(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
<IMG>;

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(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
<IMG>;
(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
<IMG>;
(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 <IMG>;
(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;

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

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

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(w) R35 is
<IMG>
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;

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(x) R36 is
<IMG>
where g is an integer of from 0 to 3;
(y) R37 is
<IMG>
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
<IMG>;
(aa) R39 is
<IMG>;

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(ab) R40 is
<IMG>;
(ac) R41 is
<IMG>;
(ad) R42 is
<IMG>;
(ae) R43 is
<IMG>
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;

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(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;

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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,

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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,

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(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;

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(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

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161
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).

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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 <IMG>;
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

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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 <IMG>;
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.

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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 <IMG>; 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.

Description

WO 90/09162 PCI-/US90/00296
,'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

WO90/09162 PCT/US90/00296
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, ..

WO90/09162 PCT/US90/00296
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.

WO 90/09162 PCT/US90/00296
73 8
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
0
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.

WO 90/09162 PCT/US90/00296
~ ~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
1 0
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~
1 1
R40 is a divalent group having the structure
,~3
H~N H
SCH3
R41 is a divalent g-oup having the structure
C~=
~" N
'2, N ~
H3C CH3
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
13
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.
3 0

WO90/09162 PCT/U'S90/00296
16
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
17
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
R28 R29 R30
~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.

WO90/09162 PCT/US90/00296
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
19
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

WO90/09162 PCT/US90/00296
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
~,~
21
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.

WO 90/09162 PCT/US90/00296
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
23
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-.

W090/09162 PCT/US90/00296
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

WO90/09162 PCT/US90/00296
~ ~ 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

WO90/09162 PCT/US90/00296
26
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
~,
31
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,

WO90/09162 PCT/US90/00296
~ 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
33
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

WO90/09162 PCT/US90/00296
.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

WO90/09162 PCT/US90/00296
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. ~~.

WO90/09162 PCT/US90/00296
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
7 3 38
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
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
39
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.

WO90/09162 PCT/US90/00296
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

WO90/09162 PCT/US90/00296
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
43
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

WO90/09162 PCT/US90/00296
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

WO90/09162 PCT/US90/00296
2~ J 7
49
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

WO90/09162 PCT/US90/00296
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,
51
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-

WO90/09162 PCT/US90/00296
2 ~ 3 ~ v'
53
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)

WO90J09162 PCT/US90/00296
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:

WO90/09162 PCT/US90/00296
~ 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)

WO90/09162 PCT/US90/00296
~ ~J ~ ~J ~
57
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)
1 5
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

WO90/09162 PCT/US90/00296
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 ,, ~
61
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
63
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
WO90/09162
64
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~
67
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

WO90/09162 PCT/US90/0U296
68
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

WO90/09162 PCT/US90/00296
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69
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
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71
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
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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

WO90/09162 PCT/US90/00296
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

WO90/09162 PCT/US90/00296
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

WO90/09162 PCT/US90/00296
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 ~
79
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
83
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
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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
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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

WO90/09162 PCT/US90/00296
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87
~ 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
1 5
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
1 0
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

WO90/09162 PCT/US90/00296
7 'J
91
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

WO90/09162 PCT/US90/00296
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

WO9O/09162 PCT/US90/00296
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~ ~ ~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
1 0
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.
1 0
Example 249
H-Phenylalanyl-Lysyl-Alanyl-{~2S)-2-Amino-3-
cyclohexylpropanoyl}-Glycyl-DTryptophyl-DAlanyl-Arginyl-OH
FAB+ MS: (M+H)+-988
1 5
~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
96
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
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97
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
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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

WO90/09162 PCT/US90/00296
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

WO90/09162 PCT/US90/00296
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7 0
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)

WO90/09162 PCT/US90/00296
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101
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)

WO90/09162 PCT/US90/00296
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
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103
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
2S
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
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105
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~
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107
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)

WO90/09162 PCT/US90/00296
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 ~
109
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
WO90/09162
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
1 1 1
~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
113
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
116
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
1 17
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
7 3 118
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
73 120
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 ~
121
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~
123
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
1 0
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'~
125
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)

WO90/09162 PCT/US90/00296
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 ~ "
127
~ 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

WO90/09162 PCT/US90/00296
128
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 ~
129
Example 403
(N-Methyl)?henylalanyl-Lysyl-Alanyl-{(2S)-2-Amino-3-
cyclohexylpropanoyl}-Alanyl-Leucyl-(N-~ethyl)DALanyl-A_g--.y'-
NHNH2
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)

W090/09162 PCT/US90/00296
130
?,~ 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~
131
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 ~
133
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
1 0
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 ~
141
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

WO90/09162 PCT/US90/00296
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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
143
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.
1 0
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~

WO90/09162
PCT/US90/00296
2~ 7~
145
the scope and nature of the invention which is defined i~ e~
appended claims.