COMBINATIONS OF INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

COMBINAISONS D'INHIBITEURS DE FARNESYL-PROTEINE TRANSFERASE

English Abstract

The present invention relates to compositions comprising amounts of at least
two therapeutic agents selected from a group consisting of a farnesyl protein
transferase inhibitor which is an effective inhibitor of the enzyme because it
is competitive with respect to the protein substrate of the enzyme and a
farnesyl protein transferase inhibitor which is an effective inhibitor of the
enzyme because it is competitive with respect to farnesyl pyrophosphate.
Further contained in this invention are methods of inhibiting farnesyl-protein
transferase and treating cancer in a mammal, which methods comprise
administering to said mammal, either sequentially in any order or
simultaneously, amounts of at least two therapeutic agents selected from a
group consisting of a farnesyl protein transferase inhibitor which is an
effective inhibitor of the enzyme because it is a competitive inhibitor with
respect to the protein substrate of the enzyme and a farnesyl protein
transferase inhibitor which is an effective inhibitor of the enzyme because it
is a competitive inhibitor with respect to farnesyl pyrophosphate, in amounts
sufficient to achieve an additive or synergistic therapeutic effect. The
invention also relates to methods of preparing such compositions.

French Abstract

L'invention concerne des compositions comprenant des quantités d'au moins deux agents thérapeutiques choisis dans un groupe constitué d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il se trouve en concurrence par rapport au substrat protéique de l'enzyme, et d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il se trouve en concurrence par rapport au farnésylpyrophosphate. L'invention concerne également des procédés d'inhibition de farnésyl-protéine transférase et de traitement du cancer chez un mammifère, lesquels procédés consistent à administrer audit mammifère, soit séquentiellement dans n'importe quel ordre soit simultanément, des doses d'au moins deux agents thérapeutiques choisis dans un groupe constitué d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il est un inhibiteur concurrentiel par rapport au substrat protéique de l'enzyme, et d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il est un inhibiteur concurrentiel par rapport au farnésyle pyrophosphate en des doses suffisantes pour obtenir un effet thérapeutique ou synergique. L'invention concerne en outre des procédés de préparation de ces compositions.

Claims

- 389 -
WHAT IS CLAIMED IS:
1. A method for achieving an additive or synergistic
therapeutic effect in a mammal in need thereof which comprises
administering to said mammal amounts of at least two therapeutic agents
selected from a group consisting of:
a) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
the protein substrate of the enzyme and
b) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
farnesyl pyrophosphate;
wherein the amount of a) alone and the amount of b) alone is
insufficient to achieve said therapeutic effect.
2. The method according to Claim 1 wherein an amount
of a protein substrate-competitive inhibitor and an amount of a farnesyl
pyrophosphate-competitive inhibitor are administered simultaneously.
3. A method for achieving a synergistic therapeutic
effect in a mammal in need thereof which comprises administering to
said mammal amounts of at least two therapeutic agents selected from a
group consisting of:
a) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
the protein substrate of the enzyme and
b) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
farnesyl pyrophosphate;

- 390-
wherein the amount of a) alone and the amount of b) alone is
insufficient to achieve said therapeutic effect; and
wherein said therapeutic effect of the amounts of the therapeutic agents
administered is greater than the sum of the therapeutic effects of the
amounts of the amounts of the individual therapeutic agents
administered.
4. The method according to Claim 3 wherein an amount
of a protein substrate-competitive inhibitor and an amount of a farnesyl
pyrophosphate-competitive inhibitor are administered simultaneously.
5. The method according to Claim 1 wherein the
protein substrate-competitive inhibitor is selected from:
a) a peptide that comprises the amino acids CA1A2X, wherein:
C = cysteine;
A1 = an aliphatic amino acid;
A2 = an aliphatic amino acid; and
X = any amino acid;
b) Cys - Xaa1 - Xaa2 - Xaa3 - NRR1, wherein
Cys = cysteine;
Xaa1 = any amino acid in the natural L-isomer form;
Xaa2 = any amino acid in the natural L-isomer form; and
Xaa3 - NRR1 = an amide of any amino acid in the natural
L-isomer form, wherein R and R1 are independently
selected from hydrogen, C1-C12 alkyl, aralkyl, or
unsubstituted or substituted aryl;
c) Cys - Xaa1 - Xaa2 - Xaa3, wherein
Cys = cysteine;
Xaa1 = any amino acid;
Xaa2 = the amino acid phenyl alanine or a
p-fluorophenylalanine; and

- 391 -
Xaa3 = any amino acid;
d) Cys - Xaa1 - dXaa2 - Xaa3, wherein
Cys = cysteine;
Xaa1 = any amino acid in the natural L-isomer form;
Xaa2 = any amino acid in the natural L-isomer form; and
Xaa3 = any amino acid in the natural L-isomer form;
e)
<IMG>
wherem:
X, Y, and Z are independently H2 or O, provided that at least one
of these is H2;
R1 is H, an alkyl group, an acyl group, an alkylsulfonyl group
or aryl sulfonyl group, wherein alkyl and acyl groups
comprise straight chain or branched chain hydrocarbons
of 1 to 6 carbon atoms, or in the alternative, R1NH may
be absent;
R2, R3 and R4 are the side chains of naturally occurring amino
acids, or in the alternative may be substituted or
unsubstituted aliphatic, aromatic or heteroaromatic
groups, such as allyl, cyclohexyl, phenyl, pyridyl,
imidazolyl or saturated chains of 2 to 8 carbon atoms,
wherein the aliphatic substitutents may be substituted with
an aromatic or heteroaromatic ring; and

- 392 -
R5 is H or a straight or branched chain aliphatic group, which
may be substituted with an aromatic or heteroaromatic
group;
<IMG>
wherein:
X and Y are independently H2 or O, provided that at least one of
these is H2;
R1 is H, an alkyl group, an acyl group, an alkylsulfonyl group
or aryl sulfonyl group, wherein alkyl and acyl groups
comprise straight chain or branched chain hydrocarbons
of 1 to 6 carbon atoms, or in the alternative, R1NH may
be absent;
R2 and R3 are the side chains of naturally occurring amino acids,
or in the alternative may be substituted or unsubstituted
aliphatic, aromatic or heteroaromatic groups, such as
allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated
chains of 2 to 8 carbon atoms, wherein the aliphatic
substitutents may be substituted with an aromatic or
heteroaromatic ring;
Z is O or S;and
n is 0, 1 or 2;
g)

- 393 -
<IMG>
wherein:
X and Y are independently H2 or O, provided that at least one of
these is H2;
R1 is H, an alkyl group, an acyl group, an alkylsulfonyl group
or aryl sulfonyl group, wherein alkyl and acyl groups
comprise straight chain or branched chain hydrocarbons
of 1 to 6 carbon atoms, or in the alternative, R1NH nnay
be absent;
R2 and R3 are the side chains of naturally occurring amino acids,
or in the alternative may be substituted or unsubstituted
aliphatic, aromatic or heteroaromatic groups, such as
allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated
chains of 2 to 8 carbon atoms, wherein the aliphatic
substitutents may be substituted with an aromatic or
heteroaromatic ring;
Z is O or S; and
n is 0, 1 or 2;
h)
<IMG>
wherein:

- 394 -
X and Y are independently H2 or O;
R1 is an alkyl group, hydrogen, an acyl group, an alkylsulfonyl
group or arylsulfonyl group, wherein alkyl and acyl groups
comprise straight chain or branched chain hydrocarbons of
1 to 6 carbons atoms, which alternatively may be
substituted with an aryl group;
R2 is the side chains of naturally occurring amino acids, or in the
alternative may be substituted or unsubstituted aliphatic,
aromatic or heterocyclic groups, such as allyl, cyclohexyl,
phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8
carbon atoms which may be branched or unbranched,
wherein the aliphatic substituents may be substituted with an
aromatic or heteroaromatic ring;
R3 is an aromatic or heteroaromatic ring or in the alternative an
alkyl group or an aryl or heteroaryl substituted alkane,
wherein the aromatic ring is unsubstituted or in the
alternative, substituted with one or more groups which may
be alkyl, halo, alkoxy, trifluoromethyl, or sulfamoyl
groups, and which may be polycyclic;

- 395 -
<IMG>
I
<IMG>
II
<IMG>
III
or
<IMG>
IV
wherein:
R1 and R5a are independently selected from:
hydrogen, a C1-C6 alkyl group, a C1-C6 acyl group, an
aroyl group, a C1-C6 alkylsulfonyl group, C1-C6
aralkylsulfonyl group or arylsulfonyl group

- 396-
wherein the alkyl group and acyl group is optionally
substituted with substituted or unsubstituted aryl or
heterocycle;
R2, R3 and R4 are independently selected from:
a) a side chain of naturally occurring amino acids,
b) an oxidized form of a side chain of naturally occurring
amino acids selected from methionine sulfoxide and
methionine sulfone,
c) substituted or unsubstituted C1-C8 alkyl, C3-C8
cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups,
wherein the aliphatic substituent is optionally substituted
with an aryl, heterocycle or C3-C9 cycloalkyl;
R5b is a C1-C6 alkyl group, a C1-C6 acyl group, an aroyl group,
a C1-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group
or arylsulfonyl group
wherein the alkyl group and acyl group is optionally
substituted with substituted or unsubstituted aryl or
heterocycle;
R6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic
group, wherein the aliphatic substituent is optionally
substituted with an aryl or heterocyclic ring; and
n is 0, 1 or 2;

- 397 -
j)
<IMG>
I
<IMG>
II
<IMG>
III
or
<IMG>
IV
wherein:
R1 is selected from:
hydrogen, a C1-C6 alkyl group, a C1-C6 acyl group, an
aroyl group, a C1-C6 alkylsulfonyl group, C1-C6
aralkylsulfonyl group or arylsulfonyl group

- 398 -
wherein the alkyl group and acyl group is optionally
substituted with substituted or unsubstituted aryl or
heterocycle;
R2, R3 and R4 are independently selected from:
a) a side chain of naturally occurring amino acids,
b) an oxidized form of a side chain of naturally occurring
amino acids selected from methionine sulfoxide and
methionine sulfone,
c) substituted or unsubstituted C1-C8 alkyl, C3-C8
cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups,
wherein the aliphatic substituent is optionally substituted
with an aryl, heterocycle or C3-C8 cycloalkyl;
X is CH2CH2 or trans CH=CH;
R6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic
group, wherein the aliphatic substituent is optionally
substituted with an aryl or heterocyclic ring; and
n is 0, 1 or 2;

- 399 -
k)
<IMG>
I
<IMG>
II
<IMG>
III
or
<IMG>
IV
wherein,
R1 is hydrogen, an alkyl group, an aralkyl group, an acyl group,
an aracyl group, an aroyl group, an alkylsulfonyl group,

- 400 -
aralkylsulfonyl group or arylsulfonyl group, wherein alkyl
and acyl groups comprise straight chain or branched chain
hydrocarbons of 1 to 6 carbon atoms;
R2, R3 and R5 are
the side chains of naturally occurring amino acids,
including their oxidized forms which may be methionine
sulfoxide or methionine sulfone, or in the alternative may
be substituted or unsubstituted aliphatic, aromatic or
heteroaromatic groups, such as allyl, cyclohexyl, phenyl,
pyridyl, imidazolyl or saturated chains of 2 to 8 carbon
atoms which may be branched or unbranched, wherein the
aliphatic substituents may be substituted with an aromatic or
heteroaromatic ring;
R4 is hydrogen or an alkyl group, wherein the alkyl group
comprises straight chain or branched chain hydrocarbons of
1 to 6 carbon atoms;
R6 is a substituted or unsubstituted aliphatic, aromatic or
heteroaromatic group such as saturated chains of 1 to 8
carbon atoms, which may be branched or unbranched,
wherein the aliphatic substituent may be substituted with an
aromatic or heteroaromatic ring;
T is O or S(O)m;
m is 0, 1 or 2; and
n is 0, 1, or 2;

- 401 -
<IMG> A
<IMG> B
<IMG> C
wherein:
X is O or H2;
m is 1 or 2;
n is 0 or 1;
t is 1 to 4;
R and R1 are independently selected from H, C1-4 alkyl, or aralkyl;

- 402 -
R2, R3, R4, and R5 are independently selected from: H; C1-8 alkyl,
<IMG> or <IMG> ,
alkenyl, alkynyl, aryl, heterocycle,
unsubstituted or substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)tOR6,
c) (CH2)tNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
5) -NR6R7 ,
6) <IMG> ,
7) <IMG> ,

- 403 -
8) <IMG> ,
9) <IMG> ,
10) <IMG> ,
11) <IMG> ,
12) <IMG> ,
13) <IMG> , or
14) <IMG> ;
and any two of R2, R3, R4, and R5 are optionally attached to the
same carbon atom;
Y is aryl, heterocycle, unsubstituted or substituted with one or
more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
2) aryl or heterocycle,
3) halogen,
4) OR6,

- 404 -
5) NR6R7,
6) CN,
7) NO2, or
8) CF3;
W is H2 or O;
Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl,
arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle, or
e) HO,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2, or
8) CF3;
R6, R7 and R8 are independently selected from: H; C1-4 alkyl, C3-6
cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,
heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,

- 405 -
e) <IMG> ,
f) <IMG> , or
g) NRR1, wherein
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring; and
R9 is C1-4 alkyl or aralkyl;
m)
<IMG>
I
<IMG>
II

- 406 -
<IMG>
III
or
<IMG>
IV
wherein:
R1 is selected from:
a) hydrogen,
b) R8S(O)2-, R8C(O)-, (R8)2NC(O)- or R9OC(O)-,
and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl, R8O-,
R8S(O)m-, R8C(O)NR8-, CN, (R8)2N-C(NR8)-,
R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)NR8-;
R2a and R2b are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstituted or substituted by alkenyl,
R8O-, R8S(O)m-, R8C(O)NR8-, CN, (R8)2N-C(NR8)-,
R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)NR8-,
c) aryl, heterocycle, cycloalkyl, alkenyl, R8O-,
R8S(O)m-, R8C(O)NR8-, CN, NO2,
(R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or
R9OC(O)NR8-, and

- 407 -
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl;
R3 and R4 are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone, and
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F,
Cl, Br, N(R8)2, NO2, R8O-, R8S(O)m-,
R8C(O)NR8-, CN, (R8)2N-C(NR8)-,
R8C(O)-, R8OC(O)-, N3, -N(R8)2,
R9OC(O)NR8- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl; or
R3 and R4 are combined to form -(CH2)s -;
R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
N(R8)2, NO2, R8O-, R8S(O)m-, R8C(O)NR8-, CN,

- 408 -
(R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3,
-N(R8)2, R9OC(O)NR8- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl; or
R5a and R5b are combined to form - (CH2)s - wherein one of
the carbon atoms is optionally replaced by a moiety selected
from: O, S(O)m, -NC(O)-, and-N(COR8)-;
R6 is
a) substituted or unsubstituted C1-8g alkyl, wherein the
substituent on the alkyl is selected from:
1) aryl,
2) heterocycle,
3) -N(R9)2,
4) -OR8, or
b)
<IMG>;

- 409 -
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;
R7a is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl;
R7b is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,

- 410 -
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted cycloalkyl,
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl,
f) a carbonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocycle,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or
an unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl, and
g) a sulfonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocycle,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or
an unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl;
R8 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
R10 is independently selected from hydrogen and C1-C6 alkyl;
R11 is independently selected from C1-C6 alkyl;
Z1 and Z2 are independently H2 or O, provided that Z1 is not O
when
X-Y is - C(O)N(R7a)-;
m is 0, 1 or 2;
q is 0, 1 or 2;
s is 4 or 5; and
t is 3, 4 or 5;

- 411 -
n)
<IMG>
I
wherein:
R1 is selected from:
a) hydrogen,
b) R5S(O)2-, R5C(O)-, (R5)2NC(O)- or R6OC(O)-,
and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl, R5O-,
R5S(O)m-, R5C(O)NR5-, CN, (R5)2N-C(NR5)-;
R5C(O)-, R5OC(O)-, N3, -N(R5)2, or R6OC(O)NR5-;
R2a and R2b are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, R5O-, R5S(O)m-,
RSC(O)NR5-, CN, (R5)2N-C(NR5)-, R5C(O)-,
R5OC(O)-, N3, -N(R5)2, or R6OC(O)NR5-, and
c) aryl, heterocycle, cycloalkyl, alkenyl, R5O-,
R5S(O)m-, R5C(O)NR5-, CN, NO2, (R5)2N-C(NR5)-,
R5C(O)-, R5OC(O)-, N3, -N(R5)2, or R6OC(O)NR5-,
R3 is selected from:
a) unsubstituted or substituted aryl,
b) unsubstituted or substituted heterocycle,
c) unsubstituted or substituted cycloalkyl, and

- 412 -
d) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl;
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;
R4a is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl;

- 413 -
R4b is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted cycloalkyl,
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl,
f) a carbonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocycle,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or
an unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl, and
g) a sulfonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocycle,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or
an unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl;
R5 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R6 is independently selected from C1-C6 alkyl and aryl;
Z is independently H2 or O;
m is 0, 1 or 2, provided that m is O when R5 = hydrogen;
n is 0, 1, 2, 3 or 4; and
t is 3, 4 or 5;

- 414 -
P)
<IMG> A
<IMG> B
<IMG> C
<IMG> D
wherein:
X and Y are independently O or H2;
m is 1 or 2;
n is 0 or 1 ;
p is 1, 2 or 3;
q is 0, 1 or 2;
t is 1 to 4;
R, R1 and R2 are independently selected from: H, C1-6 alkyl, or C1-6
aralkyl;

- 415 -
R3 and R4 are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl,
R6O-, R5S(O)q-, R7C(O)NR6-, CN, N3, R6OC(O)NR6-,
R6R7N-C(NR6R8), R6C(O)-, R7R8NC(O)O-,
R7R8NC(O)-, R6R7N-S(O)2-, -NR6S(O)2R5, R6OC(O)O-,
-NR6R7, or R7R8NC(O)NR6-,
c) unsubstituted or substituted cycloalkyl, alkenyl,
R6O-, R5S(O)q-, R6C(O)NR6-, CN, NO2,
R6R7N-C(NR8)-, R6C(O)-, N3, -NR6R7,
halogen or R7OC(O)NR6-, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl;
W is -CHR9- or -NR9-;
Z is unsubstituted or substituted C1-8 alkyl, unsubstituted or
substituted C2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted
or substituted heterocycle;
wherein the substituted group is substituted with one or more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2, or
9) CF3;

- 416 -
R5 is C1-4 alkyl or aralkyl;
R6, R7 and R8 are independently selected from: H, C1-4 alkyl, C3-6
cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,
heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) <IMG> ,
f) ~SO2R5, or
g) -NR6R7, or
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring;
R9 is selected from: H, C1-4 alkyl, C3-6 cycloalkyl, heterocycle and
aryl, unsubstituted, monosubstituted or disubstituted with
substituents independently selected from:
a) C1-4 alkyl,
b) C1-4 alkoxy,
c) aryl or heterocycle,
d) halogen,
e) HO,
f) <IMG> ,
g) ~SO2R5 , and
h) -NR6R7;

- 417 -
V is selected from: -C(R11)=C(R11), -C~C-, -C(O)-, -C(R11)2-,
C(OR11)R11, CN(R11)2R11, -OC(R11)2, -NR11C(R11)2-,
C(R11)2O, C(R11)2NR11, -C(O)NR11, NR11C(O)-, O,
-NC(O)R11, -NC(O)OR11, -S(O)2N(R11), -N(R11)S(O)2-, or
S(O)m;
R10 and R11 are independently selected from hydrogen, C1-C6 alkyl,
C2-C4 alkenyl, benzyl and aryl;

- 418 -
q)
<IMG>
I
<IMG>
II
<IMG>
III
or
<IMG>
IV

- 419 -
R1 is selected from:
a) heterocycle, and
b) C1-C10 alkyl, which is substituted with heterocycle and
which is optionally substituted with one or more of C1-C4
alkyl, hydroxy or amino groups;
R2a and R2b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
NO2, R8O-, R9S(O)m-, R8C(O)NR8-, CN, (R8)2N-
C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2,
R9OC(O)NR8- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R2a and R2b are combined to form -(CH2)s-;
R3 and R4 are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone, and
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,

- 420 -
wherein the substituent is selected from F, Cl, Br,
N(R8)2, NO2, R8O-, R9S(O)m-, R8C(O)NR8-,
CN, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3,
-N(R8)2, R9OC(O)NR8- and C1-C20 alkyl,, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl; or
R3 and R4 are combined to form -(CH2)s-;
R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
N(R8)2, NO2, R8O-, R9S(O)m-, R8C(O)NR8-,
CN, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3,
-N(R8)2, R9OC(O)NR8- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl; or
R5a and R5b are combined to form -(CH2)s- wherein one of the
carbon atoms is optionally replaced by a moiety selected from: O,
S(O)m, -NC(O)-, and-N(COR8)-;
R6 is
a) substituted or unsubstituted C1-C8 alkyl, wherein the
substituent on the alkyl is selected from:
1) aryl,

- 421 -
2) heterocycle,
3) -N(R9)2,
4) -OR8, or
b) <IMG> ;
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;
R7a is selected from
a) hydrogen,

- 422 -
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocyclic,
d) unsubstituted or substituted cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl;
R7b is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocyclic,
d) unsubstituted or substituted cycloalkyl,
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl,
f) a carbonyl group which is bonded to an unsubstituted or
substituted group selected from aryl, heterocyclic,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl, and
g) a sulfonyl group which is bonded to an unsubstituted or
substituted group selected from aryl, heterocyclic,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl;
R8 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
R10 is independently selected from hydrogen and C1-C6 alkyl;
R11 is independently selected from C1-C6 alkyl;

- 423 -
Z is independently H2 or O;
m is 0, 1 or 2;
n is 0, 1 or 2; and
s is 4 or 5;
r)
<IMG>
I
<IMG>
II
<IMG>
III
and
<IMG>
IV
wherein:

- 424 -
V is CH2, O, S, HN, or R7N;
R2, R3, R4 and R5 are independently the side chains of naturally
occurring amino acids, including their oxidized forms
which may be methionine sulfoxide or methionine sulfone,
or in the alternative may be substituted or unsubstituted
aliphatic, aromatic or heteroaromatic groups, such as allyl,
cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains
of 2 to 8 carbon atoms which may be branched or
unbranched, wherein the aliphatic substituents may be
substituted with an aromatic or heteroaromatic ring;
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;

- 425 -
R6 is a substituted or unsubstituted aliphatic, aromatic or
heteroaromatic group such as saturated chains of 1 to 8
carbon atoms, which may be branched or unbranched,
wherein the aliphatic substituent may be substituted with an
aromatic or heteroaromatic ring;
R7 is an alkyl group, wherein the alkyl group comprises straight
chain or branched chain hydrocarbons of 1 to 6 carbon
atoms, which may be substituted with an aromatic or
heteroaromatic group;
Z is H2 or 0;
m is 0, 1 or 2;
n is 0, 1 or 2; and
o is 0, 1, 2 or 3;

- 426 -
s)
<IMG>
I
<IMG>
II
<IMG>
III
and
<IMG>
IV
wherein:
R1a is selected from:
a) hydrogen,
b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl,
(R10)2N-C(NR10), R10C(O)-, or R10OC(O)-, and

- 427 -
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-,
R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10-;
R1b is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, cycloalkyl, alkenyl,
alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-,
and
c) C1-C6 alkyl unsubstituted or substituted by
unsubstituted or substituted aryl, cycloalkyl, alkenyl,
alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
provided that R1b is not R10C(O)NR10- when R1a is alkenyl,
V is hydrogen and X-Y is -C(O)NR7a-;
R2a and R2b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or

- 428 -
R2a and R2b are combined to form -(CH2)s-;
R3 and R4 are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R3 and R4 are combined to form -(CH2)s-;
R5a and R5b independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
NO2, R10O-, R11S(O)m, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and

- 429 -
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R5a and R5b are combined to form -(CH2)s- wherein one of
the carbon atoms is optionally replaced by a moiety selected
from: O, S(O)m, -NC(O)-, and-N(COR10)-;
R6 is
a) substituted or unsubstituted C1-C8 alkyl, wherein the
substituent on the alkyl is selected from:
1) aryl,
2) heterocycle,
3) -N(R11)2,
4) -OR10, or
b) <IMG> ;

- 430 -
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;
R7a is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocyclic,
d) unsubstituted or substituted cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl;
R7b is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,

- 431 -
c) unsubstituted or substituted heterocyclic,
d) unsubstituted or substituted cycloalkyl,
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl,
f) a carbonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocyclic,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or
an unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl, and
g) a sulfonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocyclic,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or
an unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl,
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NR10-, CN, NO2, R102N-C(NR10)-,
R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl,
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NH-;
R9 is selected from:
hydrogen, C1-C6 alkyl, R10O-, R11S(O)m-,
R10C(O)NR10-, CN, NO2, N3, -N(R10)2, and
R11OC(O)NR10-;

- 432 -
provided that R9 is not R10C(O)NR10- when R1a is alkenyl, V
is hydrogen and X-Y is -C(O)NR7a-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl
and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen and C1-C6 alkyl;
R13 is C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle; or
c) hydrogen;
W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-,
-N(R7a)- or -N[C(O)R7a]-;
Z is independently H2 or O;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ~ 0 when V is hydrogen and W
is
-S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ 0 when R9 is not hydrogen or
C1-C6 lower alkyl;
q is 0, 1 or 2;
r is 0 or 1;
s is 4 or 5; and
t is 0, 1 or 2, provided that t = 0 when V is hydrogen;

- 433 -
t)
<IMG>
I
<IMG>
II
<IMG>
III
and
<IMG>
IV
wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
R2a and R2b are independently selected from:

- 434 -
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-
C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2,
R10OC(O)NR9- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R2a and R2b are combined to form -(CH2)s-;
R3 and R4 are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-
C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2,
R10OC(O)NR9- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R3 and R4 are combined to form -(CH2)s-;

- 435 -
R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-
C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2,
R10OC(O)NR9- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R5a and R5b are combined to form -(CH2)s- wherein one of the
carbon atoms is optionally replaced by a moiety selected from: O,
S(O)m,-NC(O)-, and-N(COR9)-;
R6 is
a) substituted or unsubstituted C1-C8 alkyl, wherein the
substituent on the alkyl is selected from:
1) aryl,
2) heterocycle,
3) -N(R10)2,
4) -OR9, or
b) <IMG>;

- 436 -
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
I
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;
R7a is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl;
R7b is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted cycloalkyl,

- 437 -
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl,
f) a carbonyl group which is bonded to an unsubstituted or
substituted group selected from aryl, heterocycle,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl, and
g) a sulfonyl group which is bonded to an unsubstituted or
substituted group selected from aryl, heterocycle,
cycloalkyl and C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and cycloalkyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN,
R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-,
N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl,
heterocycle or C1-C20 alkyl substituted with aryl or
heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl,
provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;
R13 is C1-C6 alkyl;
<IMG> is aryl or 1,2,3,4-tetrahydronaphthyl;

- 438 -
Z is independently H2 or O;
m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1;
q is 0, 1 or 2; and
s is 4 or 5;
u)
<IMG>
I
<IMG>
II
<IMG>
III
or
<IMG>
IV

- 439 -
wherein:
R1 is independently selected from:
a) hydrogen,
b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl,
R10O-, R11S(O)m, R10C(O)NR10-, CN, NO2,
(R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-,
R11S(O)m, R10C(O)NRl0-, CN, (R10)2N-C(NR10)-,
R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10;
R2a and R2b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R2a and R2b are combined to form -(CH2)s-;
R3 and R4 are independently selected from:
a) a side chain of a naturally occurring amino acid,

- 440 -
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R3 and R4 are combined to form -(CH2)s-;
R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally
occurring amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20
alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or

- 441 -
R5a and R5b are combined to form -(CH2)s- wherein one
of the carbon atoms is optionally replaced by a moiety
selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R6 is
a) substituted or unsubstituted C1-C8 alkyl, wherein the
substituent on the alkyl is selected from:
1) aryl,
2) heterocycle,
3) -N(R11)2,
4) -OR10, or
b) <IMG> ;

- 442 -
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;
R7a is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocyclic,
d) unsubstituted or substituted cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl;
R7b is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,

- 443 -
c) unsubstituted or substituted heterocyclic,
d) unsubstituted or substituted cycloalkyl,
e) C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocyclic and cycloalkyl,
f) a carbonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocyclic,
cycloalkyl and C1-C6 alkyl substituted with hydrogen
or an unsubstituted or substituted group selected from
aryl, heterocyclic and cycloalkyl, and
g) a sulfonyl group which is bonded to an unsubstituted
or substituted group selected from aryl, heterocyclic,
cycloalkyl and C1-C6 alkyl substituted with hydrogen
or an unsubstituted or substituted group selected from
aryl, heterocyclic and cycloalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl,
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NR10-, CN, NO2, R102N-C(NR10)-,
R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl,
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NH-;
R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-

-444-
C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-
R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen and C1-C6 alkyl;
R13 is independently selected from C1-C6 alkyl;
A1 and A2 are independently selected from: a bond, -CH=CH-,
-C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-,
-NR10C(O)-, -S(O)2N(R10)-, -N(R10)S(O)2- or
S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 non-terminal
carbon atoms are replaced with a a heteroatom selected
from O, S, and N, and
e) C2-C20 alkenyl;
provided that V is not hydrogen if A1 is S(O)m and V is not
hydrogen if A1 is a bond, n is 0 and A2 is S(O)m or a bond;
W is a heterocycle;
Z is independently H2 or O;

- 445 -
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
s is 4 or 5;

- 446 -
v)
<IMG>
I
<IMG>
II
<IMG>
III
<IMG>
IV
wherein:
R1a and R1b are independently selected from:
a) hydrogen,

- 447 -
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
NO2,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6
alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)-NR10-;
R2a and R2b are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl,
R10O-, R11S(O)m, R10C(O)NR10-, CN, N3, (R10)2N-
C(NR10), R10c(O)-, R10OC(O)-, -N(R10)2, or
R11OC(O)NR10-,
c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-
, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-
, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10-, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl;
R3 and R4 are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl,
C3-C10 cycloalkyl, aryl or heterocyclic group,

- 448 -
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R3 and R4 are combined to form -(CH2)s-;
R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl,
C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
CF3, N(R10)2, NO2, R10O-, R11S(O)m-,
R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and
C1-C20 alkyl, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3- C10 cycloalkyl; or
R5a and R5b are combined to form -(CH2)s - wherein one of the
carbon atoms is optionally replaced by a moiety selected from: O,
S(O)m, -NC(O)-, and -N(COR10)-;

- 449 -
R6 is
a) substituted or unsubstituted C1-C8 alkyl, substituted or
unsubstituted C5-C8 cycloalkyl, or substituted or
unsubstituted cyclic amine, wherein the substituted alkyl,
cycloalkyl or cyclic amine is substituted with 1 or 2
substituents independently selected from:
1 ) C1-C6 alkyl,
2) aryl,
3) heterocycle,
4) -N(R11)2,
S) -OR10, or
b) <IMG> ;
X-Y is
a) <IMG> ,
b) <IMG> ,
c) <IMG> ,
<IMG>

- 450 -
d) <IMG> ,
e) <IMG> , or
f) -CH2-CH2-;
R7a is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted C3-C10 cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an unsubstituted
or substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl;
R7b is selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted C3-C10 cycloalkyl,
e) C1-C6 alkyl substituted with hydrogen or an unsubstituted
or substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl,
f) a carbonyl group which is bonded to an unsubstituted or
substituted group selected from aryl, heterocycle, C3-C10
cycloalkyl and C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and C3-C10 cycloalkyl, and
g) a sulfonyl group which is bonded to an unsubstituted or
substituted group selected from aryl, heterocycle, C3-C10

- 451 -
cycloalkyl and C1-C6 alkyl substituted with hydrogen or an
unsubstituted or substituted group selected from aryl,
heterocycle and C3-C10 cycloalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6
alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, or R10OC(O)NH-;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-
C-(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from H, C1-C6 alkyl, benzyl, substituted
aryl and C1-C6 alkyl substituted with substituted aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is hydrogen or C1-C6 alkyl;

- 452 -
R13 is C1-C6 alkyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-,
-S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a a heteroatom selected from O, S, and N,
and
e) C2-C20 alkenyl,
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
Z is independently H2 or O;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5;
t is 3, 4 or 5; and
u is 0 or 1 ;

- 453 -
w)
<IMG>
I
<IMG>
II
<IMG>
III
<IMG>
IV
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10O-,
R11S(O)m, R10C(O)NR10-, CN, NO2,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10- ,

- 454 -
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-,
R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)-NR10-;
R2a and R2b are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-,
R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-,
c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, NO2,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl;
R3a and R3b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone, and
c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl,
C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
and

- 455 -
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3- C10 cycloalkyl; or
R3a and R3b are combined to form -(CH2)S- wherein one of the
carbon atoms iis optionally replaced by a moiety selected from: O,
S(O)m, -NC(O)-, and-N(COR10)-;
R4 and R5 are independently selected from:
a) hydrogen, and
b)
<IMG> ;
R6 is
a) substituted or unsubstituted C1-C8 alkyl or substituted or
unsubstituted C5-C8 cycloalkyl, wherein the substituent on
the alkyl is selected from:
1) aryl,
2) heterocycle,
3) -N(R11)2,
4) -OR10, or
b)
<IMG> ;
R7 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and

- 456 -
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,
Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN,
H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R10OC(O)NH-;
R8 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m, R10C(O)NR10-, CN, NO2,
(R10)2N-C-(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen and C1-C6 alkyl;
R13 is independently selected from C1-C6 alkyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-,
-S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,

- 457 -
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a a heteroatom selected from O, S, and N,
and
e) C2-C20 alkenyl,
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
Z is independently H2 or O;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5; and
u is 0 or 1;

- 458 -
<IMG>
II
<IMG>
III
<IMG>
IV
wherein:
R1a and R1b are independently selected from:
a) hydrogen,

- 459 -
b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10O-,
R11S(O)m, R10C(O)NR10-, CN, NO2,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-,
R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)-NR10-;
R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone, and
c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl,
C3-C10 cycloalkyl, aryl or heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3- C10 cycloalkyl; or
R2 and R3 are combined to form -(CH2)S-; or
R2 or R3 are combined with R6 to form a ring such that

- 460 -
<IMG> is <IMG> ;
R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-,
R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-,
c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, NO2,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl;
R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
amino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone,
c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl,
C3-C10 cycloalkyl, aryl or heterocycle group,
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3- C10 cycloalkyl; or

- 461 -
R5a and R5b are combined to form -(CH2)S- wherein one of the
carbon atoms is optionally replaced by a moiety selected from: O,
S(O)m, -NC(O)-, and -N(COR10)-;
R6 is independently selected from hydrogen or C1-C6 alkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,
Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-
C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R10OC(O)NH-;
R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10)-,
R10C(O)-, R10OC(O)-, N3, -N(R10)2, or
R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;

- 462 -
R12 is
a) substituted or unsubstituted C1-C8 alkyl or substituted or
unsubstituted C5-C8 cycloalkyl, wherein the substituent on
the alkyl or cycloalkyl is selected from:
1) aryl,
2) heterocycle,
3) -N(R11)2,
4) -OR10, or
b)
<IMG> ;
R13 is independently selected from hydrogen and C1-C6 alkyl;
R14 is independently selected from C1-C6 alkyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-,
-S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or
bicyclic ring system, wherein the non-nitrogen containing ring may be
an aromatic ring, a C5-C7 saturated ring or a heterocycle;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a a heteroatom selected from O, S, and N,
and
e) C2-C20 alkenyl,

- 463 -
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is O and A2 is S(O)m;
W is a heterocycle;
X, Y and Z are independently H2 or O;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5;
t is 3, 4 or 5; and
u is 0 or 1;

- 464 -
y)
<IMG>
A
<IMG>
B
<IMG>
C
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6
alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN,

- 465 -
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)-NR10-;
R2 and R3 are independently selected from: H; unsubstituted or
substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl,
unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
<IMG> or <IMG> ,
unsubstituted or substituted heterocycle,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
5) -NR6R7 ,
6) <IMG> ,
7) <IMG> ,

- 466 -
8) <IMG> ,
9) <IMG> ,
10) <IMG> ,
11) <IMG> ,
12) <IMG> ,
13) <IMG> , or
14) <IMG> , or
R2 and R3 are attached to the same C atom and are combined to form
-(CH2)u- wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R4 is selected from H and CH3;
and any two of R2, R3 and R4 are optionally attached to the same
carbon atom;
R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6
cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,
heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy,

- 467 -
b) aryl or heterocycle,
c) halogen,
d) HO,
e) <IMG> ,
f) -SO2R11 , or
g) N(R10)2; or
R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;
R8 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10OC(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6
alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10OC(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, or R10OC(O)NH-;
R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NR10-, CN, NO2,
(R10)2N-C-(NR10), R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;

- 468 -
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-,
-S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
G is H2 or O;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a a heteroatom selected from O, S, and N,
and
e) C2-C20 alkenyl,
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
X is -CH2-, -C(=O)-, or -S(=O)m-;
Y is aryl, heterocycle, unsubstituted or substituted with one or
more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,

- 469 -
e) HO,
f) -S(O)mR6, or
g) -C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3;
9) -S(O)mR6,
10) -C(O)NR6R7, or
11) C3-C6 cycloalkyl;
Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl,
arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) -S(O)mR6, or
g) -C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3;
9) -S(O)mR6,
10) -C(O)NR6R7, or

- 470 -
11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and
u is 4 or 5;
z)
<IMG>
I
wherein:
R1a is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl,
C2-C20 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocyclic, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C20
alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)-NR10-;
R1b is independently selected from:
a) hydrogen,

- 471 -
b) substituted or unsubstituted aryl, substituted or unsubstituted
heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C20
alkynyl, R10O-, R11S(O)m-, CN, NO2, (R10)2N-C(NR10)-,
R10C(O)-, R10OC(O)-, N3 or -N(R10)2,
c) C1-C6 alkyl unsubstituted or substituted by substituted or
unsubstituted aryl, substituted or unsubstituted heterocyclic,
C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl,
R10O-, R11S(O)m-, CN, (R10)2N-C(NR10)-, R1OC(O)-,
R10OC(O)-, N3 or -N(R10)2;
R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid,
b) an oxidized form of a side chain of a naturally occurring
annino acid which is:
i) methionine sulfoxide, or
ii) methionine sulfone, and
c) substituted or unsubstituted C1-C20 alkyl, substituted or
unsubstituted C2-C20 alkenyl, substituted or unsubstituted
C3-C10 cycloalkyl, substituted or unsubstituted aryl or
substituted or unsubstituted heterocyclic group,
wherein the substituent is selected from F, Cl, Br,
N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,
and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl; or
R2 and R3 are combined to form -(CH2)S-; or
R2 or R3 are combined with R7 to form a ring such that

- 472 -
<IMG> is <IMG> ;
R4, R5, R13a and R13b are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstitued or substituted by C2-C20 alkenyl,
R10o-, R11S(O)m-, R10C(O)NR10-, CN, N3,
(R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-,
c) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl,
C2-C20 alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-,
CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, N3,
N(R10)2, or R11OC(O)NR10-, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl;
R6 is selected from:
a) hydrogen,
b) substituted or unsubstituted aryl, substituted or
unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20
alkenyl, C2-C20 alkynyl, C1-C20 perfluoroalkyl, allyloxy,
F, Cl, Br, R10O-, R11S(O)m, R10C(O)NR10-, CN, NO2,
R102N-C(NR10)-, R10C(O)-, N3, -N(R10)2,
(R12)2NC(O)- or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by substituted or
unsubstituted aryl, substituted or unsubstituted heterocycle,
C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl,
C2-C20 perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,
R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, N3,
-N(R10)2, or R10OC(O)NH-;

- 473 -
R7 is independently selected from
a) hydrogen,
b) unsubstituted or substituted aryl,
c) unsubstituted or substituted heterocycle,
d) unsubstituted or substituted C3-C10 cycloalkyl, and
e) C1-C6 alkyl substituted with hydrogen or an unsubstituted
or substituted group selected from aryl, heterocycle and
C3-C10 cycloalkyl;
R8 is selected from:
a) hydrogen,
b) substituted or unsubstituted aryl, substituted or
unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20
alkenyl, C2-C20 alkynyl, C1-C20 perfluoroalkyl, allyloxy,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-,
-S(O)2NR10 2, CN, NO2, R102N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by substituted or
umsubstituted aryl, substituted or unsubstituted heterocycle,
C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2-C20
perfluoroalkyl, F, Cl, Br, R10O, R11S(O)m-,
R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-,
N3, -N(R10)2, or R10OC(O)NH-;
R9 is selected from:
a) hydrogen,
b) C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2,
(R10)2N-C-(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by C2-C20
perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,

- 474 -
R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-,
R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl and aryl, or
(R12)2 forms -(CH2)s-;
A1, A2 and A3 are independently selected from: a bond, -CH=CH-,
-C~C-, -C(O)-, -C(O)NR7-, -NR7C(O)-, O, -N(R7)-,
-S(O)2N(R7)-, -N(R7)S(O)2-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a a heteroatom selected from O, S, and N,
and
e) C2-C20 alkenyl,
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
Z is independently H2 or O;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1, 2, 3 or 4;

- 475 -
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5; and
t is 3, 4 or 5;
or
aa)
<IMG>
I
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, unsubstituted or substituted C3-C6
cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O-,
R9S(O)m-, R8C(O)NR8-, CN, NO2, (R8)2N-C(NR8)-,
R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)NR8-,
c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
unsubstituted or substituted C3-C6 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, R8O-, R9S(O)m-, R8C(O)NR8-,
CN, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2,
or R9OC(O)-NR8-;
R2a, R2b and R3 are independently selected from:
a) hydrogen,
b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl,
R8O-, R9S(O)m-, R8C(O)NR8-, CN, N3, (R8)2N-C(NR8)-,
,R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(O)NR8-,

- 476 -
c) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, unsubstituted or
substituted cycloalkyl, alkenyl, R8O-,
R9S(O)m-, R8C(O)NR8-, CN, NO2,
(R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3,
-N(R8)2, halogen or R9OC(O)NR8-, and
d) C1-C6 alkyl substituted with an unsubstituted or
substituted group selected from aryl, heterocyclic and
C3-C10 cycloalkyl;
R4 and R5 are independently selected from:
a) hydrogen, and
b)
<IMG> ;
R6 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, unsubstituted or substituted C3-C6
cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
perfluoroalkyl, F, Cl, Br, R8O-, R9S(O)m-, R8C(O)NR8-,
CN, NO2, R82N-C(NR8)-, R8C(O)-, R8OC(O)-, N3,
-N(R8)2, or R9OC(O)NR8-, and
c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or
substituted aryl, unsubstituted or substituted heterocycle,
unsubstituted or substituted C3-C6 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br,
R8O-, R9S(O)m-, R8C(O)NH-, CN, H2N-C(NH)-, R8C(O)-
, R8OC(O)-, N3, -N(R8)2, or R8OC(O)NH-;
R7 is selected from:
a) hydrogen,

- 477 -
b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
Cl, Br, R8O-, R9S(O)m-, R8C(O)NR8-, CN, NO2,
(R8)2N-C-(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or
R9OC(O)NR8-, and
c) C1-C6 alkyl unsubstituted or substituted by C1-C6
perfluoroalkyl, F, Cl, Br, R8O-, R9S(O)m-, R8C(O)NR8-,
CN, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2,
or R9OC(O)NR8-;
R8 is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted
aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
R10 is independently selected from hydrogen, C1-C6 alkyl, substituted
or unsubstituted C1-C6 aralkyl and substituted or
unsubstituted aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR8-, -NR8C(O)-, O, -N(R8)-,
-S,(O)2N(R8)-, -N(R8)S(O)2-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a a heteroatom selected from O, S, and N,
ar,ld
e) C2-C20 alkenyl,
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;

- 478 -
W is a heterocycle;
Y is selected from: a bond, -C(R10)=C(R10)-, -C~C-, -C(O)-, -C(R10)-
2-, -C(OR10)R10-, CN(R10)2R10-,-OC(R10)2-,-NR10C(R10)2-,
-C(R10)2O-, -C(R10)2NR10-, -C(O)NR10-, -NR10C(O)-, O,
-NC(O)R10-, -NC(O)OR10-, -S(O)2N(R10)-, -N(R10)S(O)2-, or
S(O)m;
Z is H2 or O;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
u is 0 or 1 ;
or a pharmaceutically acceptable salt thereof.
6. The method according to Claim 5 wherein the
protein substrate competitive inhibitor is selected from:
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-propyl-
3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-methyl-
3,4-E-octenoyl-homserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-ethyl-3,4-
E-octenoyl-homserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-i-propyl-
3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,

- 479 -
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-butyl-
3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-s-butyl-
3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-t-butyl-
3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-
cyclohexyl-3,4-E-octenoyl-homoserine, and the corresponding
homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-
cyclopentyl-3,4-E-octenoyl-homoserine, and the corresponding
homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-benzyl-
3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6-methyl-2(R)-i-propyl-3,4-
E-octenoyl-homoserine, and the corresponding homoserine lactone,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-i-propyl-
3,4-E-octenoyl-methionine, and the corresponding methyl ester,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-butyl-
3,4-E-octenoyl-methionine, and the corresponding methyl ester,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-benzyl-
3,4-E-octenoyl-methionine, and the corresponding methyl ester,
5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-propyl-
octanoyl-homoserine, and the corresponding homoserine lactone,

- 480 -
5(S)-[2(R)-amino-3-mercaptopropylarnino]-6(S)-methyl-2(R)-benzyl-
octanoyl-homoserine, and the corresponding homoserine lactone,
N-(3-phenyl-2(S)-(mercaptopropionylamino)prop-1-yl)isoleucyl-
methionine,
N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine,
N-(3-mercaptopropyl)isoleucyl-phenylalanyl-methionine,
N-(3 -mercaptopropyl)valyl-isoleucyl-methionine,
N-(2(R)-amino-3-mercaptopropyl)valyl-isoleucyl-methionine,
N-(3-methyl-2(S)-(cysteinylamino)but-1-yl)phenylalanyl-methionine,
N-(3-methyl-2(S)-(mercaptopropionylamino)but-1-yl)-phenylalanyl-
methionine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)methylpentyl]-
phenylalanyl-methionine,
N-[2(S)-(3-mercaptopropylamino)-3(S)methylpentyl]-phenylalanyl-
methionine,
N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-(methionine
sulfone),
N-(2(R)-amino-3-mercaptopropyl)isoleucyl)-(p-iodophenylalanyl)-
methionine,
N-[2(R)-(cysteinyl-isoleucylamino)-3(S)-methylpentyl]-methionine,

- 481 -
N-[2(R)-(N'-(2(R)-amino-3-mercaptopropyl)-isoleucylamino)-3-phenyl-
propyl]methionine,
N-[2(R)-(N'-(2'(R)-amino-3-mercaptopropyl)-isoleucylamino)-3(S)-
methylpentyl]methionine,
N-(3-mercaptopropyl)valyl-isoleucyl-methionine methyl ester,
N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine
ethyl ester,
N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine
benzyl ester,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-phenethylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-benzylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-3-methylbutylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-3-phenylpropylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucyl-L-phenylalaninol,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-N'-methylbenzylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-
methoxybenzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dichloro-
benzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-trifluoromethyl-
benzyl)amide,

- 482 -
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dichloro-
phenethyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2-benzimidazol-
ylmethyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(1-indanyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dimethyl-
benzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dichloro-
benzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-sulfamoyl-
benzyl)arnide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucineanilide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dimethyl-
phenyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dimethyl-
phenyl)amide,
L-Cysteinyl-L-isoleucine-phenethylamide,
N-[2(S)-[2(R)-Amino-3-mercaptopropylamino]-3-methylpentyl]-
phenethylamide,
N-(2(R)-Amino-3-mercaptopropyl)-L-alaninebenzylamide,
N-Benzyl-[2(S)-2(R)-Amino-3-mercaptopropyl)-amino]butyramide,

- 483 -
N-(2(R)-Amino-3-mercaptopropyl)-L-norleucinebenzylamide,
N-(2(R)-Amino-3-mercaptopropyl)-L-norvalinebenzylamide,
N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homoserine,
N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homoserine,
N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homoserine
lactone,
N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homoserine
lactone,
N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homocysteine
lactone,
N-[2(S)-(2(R)-Amino-3-mercaptopropyl)-3(S)-methylpentyl]-isoleucyl-
homoserine lactone,
N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl]-3(S)-
amino-tetrahydropyran-2-one,
N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl]-3(S)-amino-
tetrahydropyran-2-one,
N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homocysteine
lactone,
N-[2(S)-(2(R)-Amino-3-mercaptopropylamino)-3(S)-methyl
pentyl]isoleucyl-homoserine,

- 484 -
N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl]-3(S)-
amino-4-hydroxypentanoic acid,
N- [N'-(2(R)-Amino-3 -mercaptopropyl)isoleucyl-isoleucyl]-3(S)-amino-
4-hydroxypentanoic acid,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-isoleucyl-homoserine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-isoleucyl-homoserine lactone,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-phenylalanyl-homoserine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-phenylalanyl-homoserine lactone,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methyl-butyl]-N-
methyl-phenylalanyl-homoserine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methyl-butyl]-N-
methyl-phenylalanyl-homoserine lactone,
3(S)-{N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methyl-
pentyl]-N-methyl-isoleucylamino}-3-methyltetra-hydropyran-2-one,
2(S)-{N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methyl-
pentyl]-N-methyl-isoleucylamino}-2-methyl-5-hydroxypentanoic acid,
2(S)-{N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-
methylpentyl]-N-methyl-isoleucylamino}-5-methyl-5-hydroxyhexanoic
acid,

- 485 -
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-norvalyl-homoserine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-norvalyl-homoserine lactone,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-isoleucyl-methionine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-isoleucyl-methionine methyl ester,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-phenylalanyl-methionine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-phenylalanyl-methionine methyl ester,
3(S)-{N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methyl-
pentyl]-N-methyl-isoleucylamino}-6,6-dimethyl-tetrahydropyran-2-one,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-norvalyl-methionine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-norvalyl-methionine methyl ester,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-D-norvalyl-homoserine,
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-
methyl-D-norvalyl-homoserine lactone,

- 486 -
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-phenylpropionyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3 -phenylpropionyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-2-methyl-3-phenylpropionyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-2-methyl-3-phenylpropionyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-4-pentenoyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-4-pentenoyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxypentanoyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxypentanoyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-4-methylpentanoyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-4-methylpentanoyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-methylbutanoyl-homoserine lactone,

- 487 -
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-methylbutanoyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-phenylbutanoyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-phenylbutanoyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentylthio-2-methyl-3-phenylpropionyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-phenylpropionyl-methionine methyl ester,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-phenylpropionyl-methionine,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester,
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-phenylpropionyl-methionine sulfone,

- 488 -
2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone methyl ester,
2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone,
2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone methyl ester,
2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone,
2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-methybutanoyl-methionine methyl ester,
2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-
pentyloxy-3-methybutanoyl-methionine,
Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-
methyl]pentyloxy-3-phenylpropionyl-homoserine lactone,
Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-
methyl]pentyloxy-3-phenylpropionyl-homoserine,
Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-
methyl]pentyloxy-3-methylbutanoyl-methionine methyl ester.
1-[2-(R)-Amino-3-mercaptopropyl]-2(S)-(1-butyl)-4-(2,3-dimethyl-
benzoyl)piperazine dihydrochloride
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(n-butyl)-4-(1 -
naphthoyl)piperazine

- 489 -
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-benzyl-4-[1-(2,3-
dimethyl)benzoyl]piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-methoxy)ethyl-4-[1-(2,3-
dimethyl)benzoyl]piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-methylthio)ethyl-4-[1-(2,3-
dimethyl)benzoyl]piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(n-butyl)-4-[7-(2,3-
dihydrobenzofuroyl)]piperazine
1-(2(R)-Amino-3-mercaptopropyl)-4-(1-naphthoyl)-2(S)-
pyridinylcarboxyl-4-piperazine dihydrochloride
Methyl 4-(2(R)-amino-3-mercaptopropyl)-1-(1-naphthyl-
methyl)piperazine-2-carboxylate hydrochloride
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-methoxyethyl)-4-(1-
naphthoyl)piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-n -butyl-4-(8-
quinolinylcarbonyl)piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-(1-propoxy)ethyl)-4-(1-
naphthoyl)piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(3-methoxy-1-propyl)-4-(1-
naphthoyl)piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-(1-propoxy)ethyl)-4-(8-
quinolinoyl)piperazine
1-[2(R)-Amino-3-mercaptopropyl]-2(S)-[(3-pyridyl)methoxyethyl)]-4-
(1-naphthoyl)piperazine

- 490 -
1-[2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2-phenylsulfonyl-
ethyl)piperazine dihydrochloride
bis-1,1'-[2(R)-Amino-3-(2(S)-(2-methoxyethyl)-4-naphthoyl-1-
piperazinyl)]propyl disulfide tetrahydrochloride
bis-1,1'-[2(R)-Amino-3-(4-naphthoyl-2(S)-(2-phenylsulfonylethyl)-1-
piperazinyl)]propyl disulfide tetrahydrochloride
1-[2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2-
cyclopropyloxyethyl)piperazine dihydrochloride
1-[2(R)-Amino-3-mercaptopropyl]-4-(1-naphthoyl)-2(S)-(4-
acetamidobutyl)piperazine dihydrochloride
1-[2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2-
cyclopropylmethylsulfonylethyl)piperazine dihydrochloride
Pyroglutamyl-valyl-phenylalanyl-methionine
Pyroglutamyl-valyl-phenylalanyl-methionine methyl ester;
Pyroglutamyl-valyl-isoleucyl-methionine;
Pyroglutamyl-valyl-isoleucyl-methionine methyl ester;
Nicotinoyl-isoleucyl-phenylalanyl-methionine;
Nicotinoyl-isoleucyl-phenylalanyl-methionine methyl ester;
N-[2(S)-(L-Pyroglutamylamino)-3-methylbutyl]phenylalanyl-
methionine;

- 491 -
N-[2(S)-(L-Pyroglutamylamino)-3-methylbutyl]phenylalanyl-methionine
methyl ester;
N-[5(S)-(L-Pyroglutamylamino)-6(S)-methyl-2(R)-butyl-3,4(E)-
octenoyl]-methionine;
N-[5(S)-(L-Pyroglutamylamino)-6(S)-methyl-2(R)-butyl-3,4(E)-
octenoyl]-methionine methyl ester;
N-[5(S)-((Imidazol-4-yl)acetylamino)-6(S)-methyl-2(R)-butyl-3,4(E)-
octenoyl]-methionine;
N-[5(S)-((Imidazol-4-yl)acetylamino)-6(S)-methyl-2(R)-butyl-3,4(E)-
octenoyl]-methionine methyl ester;
N-[5(S)-((Imidazol-4-ylcarbonylamino)-6(S)-methyl-2(R)-butyl-3,4(E)-
octenoyl]-methionine;
N-[5(S)-((ImidaLzol-4-ylcarbonylamino)-6(S)-methyl-2(R)-butyl-3,4(E)-
octenoyl]-methionine methyl ester;
N-[2(S)-(2(S)-(Imidazol-4-yl)acetylamino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine;
N-[2(S)-(2(S)-(Imidazol-4-yl)acetylamino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine methyl ester;
N-[2(S)-(2(S)-Pyroglutamylamino-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine;
N-[2(S)-(2(S)-Pyroglutamylamino-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine methyl ester;

- 492 -
N-[2(S)-(2(S)-Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine;
N-[2(S)-(2(S)-Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine methyl ester;
N-[2(S)-(2(S)-((3-Picolinyl)amino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine;
N-[2(S)-(2(S)-((3-Picolinyl)amino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine methyl ester;
N-[2(S)-(2(S)-((Histidyl)amino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine;
N-[2(S)-(2(S)-((Histidyl)amino)-3(S)-methylpentyloxy)-3-
phenylpropionyl]-methionine methyl ester;
N-Benzyl-N-[2(S)-((Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyl]-
glycyl-methionine;
N-Benzyl-N-[2(S)-((Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyl]-
glycyl-methionine methyl ester;
N-Benzyl-N-[2(S)-((Imidazol-4-ylacetyl)amino)-3(S)-methylpentyl]-
glycyl-methionine;
N-Benzyl-N-[2(S)-((Imidazol-4-ylacetyl)amino)-3(S)-methylpentyl]-
glycyl-methionine methyl ester;
N-Benzyl-N-[2(S)-((Pyroglutamyl)amino)-3(S)-methylpentyl]-glycyl-
methionine;

- 493 -
N-Benzyl-N-[2(S)-((Pyroglutamyl)amino)-3(S)-methylpentyl]-glycyl-
methionine methyl ester;
N-(1-Naphthylmethyl)-N-[2(S)-((imidazol-4-ylcarbonyl)amino)-3(S)-
methylpentyl]-glycyl-methionine;
N-(1-Naphthylmethyl)-N-[2(S)-((imidazol-4-ylcarbonyl)amino)-3(S)-
methylpentyl]-glycyl-methionine methyl ester;
N-(1 -Naphthylmethyl)-N-[2(S)-((imidazol-4-ylacetyl)amino)-3(S)-
methylpentyl]-glycyl-methionine;
N-(1-Naphthylmethyl)-N-[2(S)-((imidazol-4-ylacetyl)amino)-3(S)-
methylpentyl]-glycyl-methionine methyl ester;
N-(1-Naphthylmethyl)-N-[2(S)-((pyroglutamyl)amino-3(S)-methyl-
pentyl]-glycyl-methionine; and
N-(1 -Naphthylmethyl)-N-[2(S)-((pyroglutamyl)amino-3(S)-methyl-
pentyl]-glycyl-methionine methyl ester;
N-[1-(Pyroglutamylamino)cyclopent-1-ylmethyl]-N-(1-naphthylmethyl)-
glycyl-methionine methyl ester
N-[1-(Pyroglutamylamino)-cyclopent-1-ylmethyl]-N-(1-naphthyl-
methyl)-glycyl-methionine
N-(2(S)-L-Histidylamino-3(S)-methylpentyl)-N-(benzylmethyl)glycyl-
methionine methyl ester
N-(2(S)-L-Histidylamino-3(S)-methylpentyl)-N-(benzylmethyl)glycyl-
methionine

- 494 -
N-(2(S)-L-Histidylamino-3(S)-methylpentyl)-N-(1-naphthylmethyl)-
glycyl-methionine methyl ester
N-(2(S)-L-Histidylamino-3(S)-methylpentyl)-N-(1-naphthylmethyl)-
glycyl-methionine
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-
methylbutanoyl-methionine methyl ester
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-
methylbutanoyl-methionine
2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-
methylbutanoyl-methionine methyl ester
2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-
methylbutanoyl-methionine
N-(Benzyl)-N-[2(S)-(2-oxopyrrolidin-5(R,S)-ylmethyl)amino-3(S)-
methylpentyl]-glycyl-methionine methyl ester
N-(Benzyl)-N-[2(S)-(2-oxopyrrolidin-5(R,S)-ylmethyl)amino-3(S)-
methylpentyl]-glycyl-methionine
N-(Benzyl)-N-{2(S)-[((D,L)-2-thiazolyl)alanyl)amino]-3(S)-
methylpentyl}-glycyl-methionine methyl ester
N-(Benzyl)-N-{2(S)-[((D,L)-2-thiazolyl)alanyl)amino]-3(S)-
methylpentyl}-glycyl-methionine
N-(Benzyl)-N-[2(S)-(3-pyridylmethyl)amino-3(S)-methylpentyl]-glycyl-
methionine methyl ester
N-(Benzyl)-N-[2(S)-(3-pyridylmethyl)amino-3(S)-methylpentyl]-glycyl-
methionine

- 495 -
2(S)-[2(S)-(2-Oxopyrrolidin-5(S)-ylmethyl)amino-3(S)-
methylpentyloxy]-3-phenylpropionyl-methionine methyl estr
2(S)-[2(S)-(2-Oxopyrrolidin-5(S)-ylmethyl)amino-3(S)-methyl-
pentyloxy]-3-phenylpropionyl-methionine
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(1 -
naphthyl)propionyl-methionine sulfone methyl ester
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(1-
naphthyl)propionyl-methionine sulfone
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(2-
naphthyl)propionyl-methionine sulfone methyl ester
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-(2-
naphthyl)propionyl-methionine sulfone
2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(1-
naphthyl)propionyl-methionine sulfone methyl ester
2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(1-
naphthyl)propionyl-methionine sulfone
2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(2-
naphthyl)propionyl-methionine sulfone methyl ester
2(S)-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3-(2-
naphthyl)propionyl-methionine sulfone
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-quinolyl-
methyl)glycyl-methionine methyl ester

- 496 -
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-quinoly-
Imethyl)glycyl-methionine
N-(Benzyl)-N-[2(S)-(tetrazol-1-ylacetyl)amino-3(S)-methylpentyl]-
glycyl-methionine methyl ester
N-(Benzyl)-N-[2(S)-(tetrazol-1-ylacetyl)amino-3(S)-methylpentyl]-
glycyl-methionine
N-(Benzyl)-N-[2(S)-nicotinoylamino-3(S)-methylpentyl]-glycyl-
methionine methyl ester
N-(Benzyl)-N-[2(S)-nicotinoylamino-3(S)-methylpentyl]-glycyl-
methionine
N-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-
naphthylmethyl)-glycyl-methionine sulfoxide methyl ester
N-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-
naphthylmethyl)-glycyl-methionine sulfoxide
2(S)-{2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)-
methylpentyloxy}-3-phenylpropionyl-methionine sulfone methyl ester
2(S)-{2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)-
methylpentyloxy}-3-phenylpropionyl-methionine sulfone
2(S)-{2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)-
methylpentyloxy}-3-phenylpropionyl-methionine sulfone methyl ester
2(S)-{2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)-
methylpentyloxy}-3-phenylpropionyl-methionine sulfone

- 497 -
N-{2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-methyl-
pentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester
N-{2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-
methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine
N-{2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-methyl-
pentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester
N-{2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-
methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine
N-{2(S)-[(Imidazol-4-yl)methyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)-glycyl-methionine methyl ester
N-{2(S)-[(Imidazol-4-yl)methyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)-glycyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-
naphthylmethyl)glycyl-methionine isopropyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-methionine t-butyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(4-quinolyl-
methyl)glycyl-methionine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(4-quinolyl-
methyl)glycyl-methionine
N-{2(S)-[3-(Imidazol-4-yl)propyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine methyl ester

- 498 -
N-{2(S)-[3-(Imidazol-4-yl)propyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-norleucine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-norleucine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-glutamine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-glutamine t-butyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-[5-(dimethyl-
amino)naphthylsulfonyl]glycyl-methionine methyl ester
N-[2(S)-(3-pyridylmethyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-methionine
2(S)-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)-methylpentyloxy}-3-
phenylpropionyl-methionine sulfone methyl ester
2(S)-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)-methylpentyloxy}-3-
phenylpropionyl-methionine sulfone
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-serine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-(D,L)-serine

- 499 -
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-(L,D)-serine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-homoserine lactone
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-homoserine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(cinnamyl)-
glycyl-methionine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(cinnamyl)-
glycyl-methionine
N-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine methyl ester
N-{2(S)-[2-(Imidazol-4-yl)ethyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-alanine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-alanine
N-[2(S)-(D-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-methionine methyl ester
N-[2(S)-(D-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-methionine

- 500 -
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-phenyl-
propionyl-methionine sulfone methyl ester
2(S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-phenyl-
propionyl-methionine sulfone
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-methyl-
enedioxybenzyl)glycyl-methionine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-
methylenedioxybenzyl)glycyl-methionine
N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-(2,3-
dihydrobenzofuran-7-ylmethyl)glycyl-methionine methyl ester
N-[2(S)-(Imidazol-4-ylacetyl)amino-3 (S)-methylpentyl]-N-(2,3-
dihydrobenzofuran-7-ylmethyl)glycyl-methionine
N-{2(S)-[3-(3-indolyl)propionyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine methyl ester
N-{2(S)-[3-(3-indolyl)propionyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine
N-{2(S)-[3-(1-indolyl)propionyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine methyl ester
N-{2(S)-[3-(1-indolyl)propionyl]amino-3(S)-methylpentyl}-N-(1-
naphthylmethyl)glycyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-
naphthylmethyl)glycyl-histidine methyl ester

- 501 -
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-histidine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(cyclo-
propylmethyl)glycyl-methionine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-
(cyclopropylrnethyl)glycyl-methionine
N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-
(cyclopropylmethyl)glycyl-methionine methyl ester
N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-
(cyclopropylmethyl)glycyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-
dihydrobenzofuran-7-ylmethyl)glycyl-methionine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-
dihydrobenzofuran-7-ylmethyl)glycyl-methionine
2(S)-[2(S)-N-(L-Pyroglutamyl)-N-methylamino-3(S)-methylpentyloxy]-
3-phenylpropionyl-methionine methyl ester
2(S)-[2(S)-N-(L-Pyroglutamyl)-N-methylamino-3(S)-methylpentyloxy]-
3-phenylpropionyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-
naphthylmethyl)glycyl-O-methylserine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1 -
naphthylmethyl)glycyl-O-methylserine
N-(1-Naphthylmethyl)-N-[2(S)-(N'-(L-pyroglutamyl)-N'-methylamino)-
3(S)-methylpentyl]-glycyl-methionine methyl ester

- 502 -
N-(1-Naphthylmethyl)-N-[2(S)-(N'-(L-pyroglutamyl)-N'-methylamino)-
3(S)-methylpentyl]-glycyl-methionine
N-[1-(Pyroglutamylamino)cyclopent-1-ylmethyl]-N-(1-naphthylmethyl)-
glycyl-methionine methyl ester
N-[1-(Pyroglutamylamino)-cyclopent-1-ylmethyl]-N-(1-
naphthylmethyl)-glycyl-methionine
N-[2(S)-(Pyridin-2-on-6-ylcarbonyl)amino-3(S)-methylpentyl]-N-(1-
naphthylmethyl)glycyl-methionine methyl ester
N-[2(S)-(Pyridin-2-on-6-ylcarbonyl)amino-3(S)-methylpentyl]-N-(1-
naphthylmethyl)glycyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-chloro-
benzyl)glycyl-methionine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-chloro-
benzyl)glycyl-methionine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-O-methylhomoserine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-O-methylhomoserine
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-dimethyl-
benzyl)glycyl-methionine methyl ester
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(2,3-dimethyl-
benzyl)glycyl-methionine

- 503 -
N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-(2-thienyl)alanine methyl ester
N- [2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(1-naphthyl-
methyl)glycyl-(2-thienyl)alanine
N-[2(S)-(pyrrolidin-2-on-1-yl)-3-methylbutanoyl]-isoleucyl-methionine;
or
N-[2(S)-(piperidin-2-on-1-yl)-3-methylbutanoyl]-isoleucyl-methionine;
or a pharmaceutically acceptable salt or optical isomer thereof.
7. The method according to Claim 5 wherein the
protein substrate competitive inhibitor is selected from:
Compound A:
<IMG>
Compound B:

- 504 -
<IMG> .
and Compound E:
<IMG> .
or a pharmaceutically acceptable salt or optical isomer thereof.
8. The method according to Claim 1 wherein the
farnesyl pyrophosphate-competitive inhibitor is selected from:
bb)

- 505 -
<IMG>
or
<IMG>
wherein:
X - X is: CH = CH (cis);
CH = CH (trans); or
CH2CH2;
R1 and R2 are each independently selected from:
a) H;
b) C1-5 alkyl;
c) C1-5 alkyl substituted with a member of the group
consisting of:
i) phenyl;
ii) phenyl substituted with methyl, methoxy, halogen
(Cl, Br, F, I) or hydroxy;
or a pharmaceutically acceptable salt of a compound of formula (I) in
which at least one of R1 and R2 is hydrogen;
cc)

- 506-
<IMG>
I
or
<IMG>
II
wherein:
R1 and R2 are each independently selected from:
a) H;
b) C1-5 alkyl;
c) C1-5 alkyl substituted with a member of the group
consisting of:
i) phenyl;
ii) phenyl substituted with methyl, methoxy, halogen
(Cl, Br, F, I) or hydroxy;
or a pharmaceutically acceptable salt of a compound of formula (I) in
which at least one of R1 and R2 is hydrogen;
dd)

- 507 -
<IMG>
or
<IMG>
wherein:
X - X is: CH = CH (cis);
CH = CH (trans); or
CH2CH2;
R1 and R2 are each independently selected from:
a) H;
b) C1-5 alkyl;
c) C1-5 alkyl substituted with a member of the group
consisting of:
i) phenyl;
ii) phenyl substituted with methyl, methoxy, halogen
(Cl, Br, F, I) or hydroxy;
or a pharmaceutically acceptable salt of a compound of formula (I) in
which at least one of R1 and R2 is hydrogen;
ee)

- 508 -
<IMG>
I
or the pharmaceutically acceptable salts, hydrates, esters or amides
thereof, wherein:
n is: 0 to 4,
R1 and R3 independently are C0-4 alkyl, substituted with substituents
selected from the group consisting of:
a) aryl, which is defined as phenyl or naphthyl,
unsubstituted or substituted with one, two, three or four substituents
selected from the group consisting of:
i) F,
ii) Cl,
iii) Br,
iv) nitro,
v) cyano,
vi) C1-8 alkoxy,
vii) C1-8 alkylthio,
viii) C1-8 alkylsulfonyl,
ix) sulfamoyl, or
x) C1-8 alkyl; or
b) heteroaryl, which is defined as indolyl, imidazolyl or
pyridyl, unsubstituted or substituted with one, two, three or four
substituents selected from the group consisting of:
i) F,
ii) Cl,
iii) Br,

- 509 -
iv) nitro,
v) cyano,
vi) C1-8 alkoxy,
vii) C1-8 alkylthio,
viii) C1-8 alkylsulfonyl,
ix) sulfamoyl, or
x) C1-8 alkyl;
R2 is: C0-6 alkyl, which is unsubstituted or substituted with a substituent
selected from the group consisting of:
a) unsubstituted or substituted aryl, as defined in R1(a),
b) unsubstituted or substituted heteroaryl, as defined in
R1 (b),
c) C3-8 cycloalkyl,
d) C1-8 alkylthio,
e) C1-8 alkylsulfonyl,
f) C1-8 alkoxy, or
g) aryl C1-8 alkyl sulfonyl; and
R4 is: H;
ff)
<IMG>
wherein:
X is CH2, CH(OH), C=O, CHCOR, CH(NH2), CH(NHCOR), O, S(O)p,
NH, NHCO,
<IMG> , <IMG>
p is 0, 1 or 2;
Y is PO3RR1 or CO2R;

- 510 -
R is H, lower alkyl, or CH2CH2N+Me3A-;
R1 is H, lower alkyl, or CH2CH2N+Me3A-;
A is a pharmaceutically acceptable anion;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3;
gg)
<IMG>
wherein each of
<IMG>, <IMG>, <IMG> and <IMG>
which are the same or different, is an aryl group or a heteroaromatic
ring group; A is a C2-8 saturated or unsubstituted aliphatic hydrocarbon
group which may have substituent(s) selected from the group consisting
of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group,
a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group,
an aryl group and an aralkyl group; each of X and Y which are the same
or different, is an oxygen atom, a sulfur atom, a
carbonyl group or a group of the formula -CHRa- (wherein Ra is a
hydrogen atom or a lower alkyl group) or -NRb (wherein Rb is a
hydrogen atom or a lower alkyl group), or X and Y together represent
a vinylene group or an ethynylene group; each of R1, R2, R3, R8 and R9
which are the same or different, is a hydrogen atom, a halogen atom, a

- 511 -
hydroxyl group, a lower alkyl group or a lower alkoxy group; each of
R4 and R5 which are the same or different, is a hydrogen atom, a
halogen atom, a hydroxyl group, an amino group, a nitro group, a
cyano group, a carboxyl group, a lower alkoxycarbonyl group, a
carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a
lower hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy
group; R6 is a lower alkyl group; and R7 is a hydrogen atom or a lower
alkyl group, provided that when one of X and Y is an oxygen atom, a
sulfur atom or a group of the formula -NRb- (wherein Rb is as defined
above), the other is a carbonyl group or a group of the formula -CHRa-
(wherein Ra is as defined above);
or
hh)
<IMG>
wherein each of
<IMG>
<IMG> and
which are the same or different, is an aryl group or a heteroaromatic
ring group; A is a C2-8 saturated or unsaturated aliphatic hydrocarbon
group which may have substituent(s) selected from the group consisting
of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group,

- 512 -
a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group,
an aryl group and an aralkyl group; Q is a group of the forrnula
-(C1-12)m- (wherein m is an integer of from 1 to 6) or -(CH2)n-W-(CH2)p-
(wherein W is an oxygen atom, a sulfur atom, a vinylene group or an
ethynylene group; and each of n and p which are the same or differentf
is an integer of from 0 to 3); R1 is a hydrogen atom, a halogen atom, a
hydroxyl group, a lower alkyl group, a lower alkoxy group, or an aryl
or heteroaromatic ring group which may have substituent(s) selected
from the group consisting of a halogen atom, a lower alkyl group and a
lower alkoxy group; each of R2,
R7 and R8 which are the same or different, is a hydrogen atom, a
halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy
group; each of R3 and R4 which are the same or different, is a
hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a
nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl
group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl
group, a lower hydroxyalkyl group, a lower fluoroalkyl group or a
lower alkoxy group; R5 is a lower alkyl group; and R6 is a hydrogen
atom or a lower alkyl group;
or a pharmaceutically acceptable salt thereof.
9. The method according to Claim 8 wherein the
farnesyl pyrophosphate-competitive inhibitor is selected from:
3-Hydroxy-7,11,15 -trimethylhexadeca-6,10,14-trienoic acid,
[2- Oxo-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonic acid
[2- Hydroxy-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonic acid
[1- Acetyl-4,8,12-trimethylpentadeca-3,7,11-trienyl]phosphonic acid

- 513 -
[2-[(E,E)-3,7, 11-Trimethyl-2,6, 10-dodecatrienylamino]-2-oxo-
ethyl]phosphcnic acid
[(E,E)-4,8,12-Trimethyl-3,7,11 -tridecatrienyl]thiomethyl-phosphonic
acid
3-[(E,E)-3,7,11-Trimethyl-2,6, 10-dodecatrienylamino]-3-oxo-propionic
acid
[2-[(E,E)-3,7,11-Trimethyl-2,6,10-dodecatrienylamino]-2-oxo-
ethyl]phosphonic acid monomethyl ester
[2-[(E,E)-3,7,11 -Trimethyl-2,6, 10-dodecatrienylamino]- 1 -oxo-
methyl]phosphonic acid
[1-Hydroxy-(E,E)-3,7,11 -trimethyl-2,6, 10-dodecatrienyl]-phosphonic
acid
[1-Hydroxy-(E,E)-5,9, 13-trimethyl-4,8, 12-tetradecatrienyl]-phosphonicacid
[1-Hydroxy-(E,E)-4,8, 12-trimethyl-3,7,11-tridecatrienyl]-phosphonic
acid
[2-Acetamido-(E,E)-4,8, 12-trimethyl-3,7, 11-tridecatrienyl]-phosphonicacid,
[2-Hydroxy-(E,E)-4,8, 12-trimethyl-3,7, 11-tridecatrienyl]-phosphonic
acid
N- {(1RS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-4-
pentenyl} -N-(2-naphthylmethyl)-carbamoylmethylsuccinic acid

- 514 -
N-{(1RS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-(1-naphthyl)-4-
pentenyl}-N-(2-naphthylmethyl)-carbamoylmethylsuccinic acid
N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)pentyl}-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-4-(2-naphthoxy)butyl}-N-
(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-4-(2-naphthyl)butyl}-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-6-(2-naphthyl)hexyl} -N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-5-phenyl-4-pentynyl} -N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-2-(4-methoxyphenyl)-1-methyl-5-(2-naphthyl)-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-1-methyl-2-(4-methylphenyl)-5-(2-naphthyl)-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-1-methyl-5-(2-naphthyl)-2-(4-nitrophenyl)-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-2-(4-fluorophenyl)-1-methyl-5-(2-naphthyl)-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-1-methyl-5-(2-naphthyl)-2-(4-trifluoromethylphenyl)-
4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid

- 515 -
N-{(1RS,2RS,4E)-1-methyl-5-(2-naphthyl)-2-phenyl-4-pentenyl}-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-1-methyl-2-(6-methyl-3-pyridyl)-5-(2-naphthyl)-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,6E)-2-(4-chlorophenyl)-1-methyl-7-phenyl-6-heptenyl}-N-
(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,6E)-2-(4-chlorophenyl)-1-methyl-7-(2-naphthyl)-6-
heptenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-4-
pentenyl}-N-(3-quinolylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-4-
pentenyl}-N-(3,4-difluorobenzyl)carbamoylmethylsuccinic acid
N-(2-benzoxazolylmethyl)-N-{(1RS,2RS,4E)-2-(4-chlorophenyl)-1-
methyl-5-(2-naphthyl)-4-pentenyl }carbamoylmethylsuccinic acid
N-(2-benzo[b]thienylmethyl)-N-{(1RS,2RS,4E)-2-(4-chlorophenyl)-1-
methyl-5-(2-naphthyl)-4-pentenyl}carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-1-methyl-2-(3,4-methylenedioxyphenyl)-5-(2-
naphthyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic
acid
(2R*)-2-[N-{(1S*,2S*,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-
4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethyl]succinic acid
(2R*)-2-[N-{(1R*,2R*,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-
naphthyl)-4- pentenyl}-N-(2-naphthylmethyl)carbamoylmethyl]succinic
acid

- 516 -
(2S*)-2-[N-{(1R*,2R*,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-
4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethyl]succinic acid
(2S*)-2-[N-{(1S*,2S*,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-
4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethyl]succinic acid
5-[N- {(1RS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-4-
pentenyl}-N-(2-naphthylmethyl)carbamoyl]pentanoic acid
(2R*)-2-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)-
carbamoylmethyl]succinic acid
(2R*)-2-[N-{(1RS,2RS,4Z)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)-
carbamoylmethyl]succinic acid
(2R*)-2-[N-(2-benzo[b]furanylmethyl)-N-{(1RS,2RS,4E)-5-(2-
benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl}carbamoylmethyl]succinate
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-{(1RS,2RS,4E)-5-
(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl}carbamoylmethyl]succinic acid
(2R*)-2-[N-[(1RS,2RS,4E)-5-(2-benzoxazolyl)-2-{3,4-
bis(methoxycarbonyl)phenyl}-1-methyl-4-pentenyl]-N-(2-
naphthylmethyl)carbamoylmethyl]succinic acid
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-{(1RS,2RS,4E)-5-
(2-benzoxazolyl)-2-(4-methoxycarbonylphenyl)-1-methyl-4-
pentenyl}carbamoylmethyl]succinic acid

- 517 -
(2R*)-2-[N-(2-benzo[b]furanylmethyl)-N-{ (1RS,2RS,4E)-5-(2-
benzoxazolyl) -2-(4-methoxycarbonylphenyl)-1-methyl-4-
pentenyl}carbamoylmethyl]succinic acid
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N- {(1RS,2RS,4E)-5-(2-
benzoxazolyl)-2-(4-cyanophenyl)-1-methyl-4-
pentenyl}carbamoylmethyl]succinic acid
(2R*)-2-[N-(5-benzo[b]thienylmethyl)-N-{(1RS,2RS,4E)-5-(2-
benzoxazolyl)-2-(4-methoxycarbonylphenyl)-1-methyl-4-
pentenyl}carbamoylmethyl]succinic acid
N- {(1RS,2RS,4E)-5-(3-chloro-4-methylphenyl)-2-(4-chlorophenyl)-1-
methyl-4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4Z)-5-(3-chloro-4-methylphenyl)-2-(4-chlorophenyl)-1-
methyl-4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-5-(2-benzo[b]furanyl)-2-(4-chlorophenyl)-1-methyl-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4Z)-5-(2-benzo [b]furanyl)-2-(4-chlorophenyl)-1-methyl-4-
pentenyl}-N-(7-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-2-(4-chlorophenyl)-1-methyl-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4Z)-5-(2-benzoxazolyl)-2-(4-chlorophenyl)-1-methyl-4-
pentenyl}-N-(7-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-5-(2-benzimidazolyl)-2-(4-chlorophenyl)-1-methyl-4-
pentenyl}-N-(7-naphthylmethyl)carbamoylmethylsuccinic acid

- 518 -
N- {(1RS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-5-(2-benzothiazolyl)-2-(4-chlorophenyl)-1-methyl-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-2-(4-cyanophenyl)-1-methyl-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
1,2,3-butanetricarboxylic acid
3-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
1,2,2-propanetricarboxylic acid
(2S,3R)-4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-
(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-
naphthylmethyl)carbamoylmethyl]-3-carboxy-2-hydroxybutanoic acid
4-[N-((1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-carboxy-4-methoxybutanoic acid
5-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl]-
4-carboxy-3-carboxymethylpentanoic acid
1-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-2-(4-methoxycarbonylphenyl)-
1-methyl-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-1,2,3-
propanetricarboxylic acid

- 519 -
(3R*)-4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-methoxybutanoic acid
(3S*)-4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-methoxybutanoic acid
N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-2-(4-carboxyphenyl)-1-methyl-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-{4-(N-
methylcarbamoyl)phenyl}-4-pentenyl]-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
(2R*)-2-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-2-(4-hydroxy-3-
methoxyphenyl)-1-methyl-4-pentenyl}-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-2-(4-hydroxymethylphenyl)-1-methyl-5-(2-naphthyl)-
4-pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-{(1RS,2RS,4E)-2-(4-aminophenyl)-1-methyl-5-(2-naphthyl)-4-
pentenyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
disodium (3RS.4RS)-4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-
2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-
naphthylmethyl)carbamoyl]-3-carboxy-4-hyroxybutanoate
N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)-5-
oxotetrahydrofuran-2-carboxyamide

- 520 -
sodium 4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)]carbamoyl-
4-hyroxybutanoate
4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
2-oxotetrahydrofuran-3-yl-acetic acid
(2R*)-2-[N-{(1R*,2R*,4E)-5-(2-benzoxazolyl)-2-(4-
methoxycarbonylphenyl)-1-methyl-4-pentenyl}-N-(2-
naphthylmethyl)carbamoylmethyl]succinic acid
(2R*)-2-[N-{(1S*,2S*,4E)-5-(2-benzoxazolyl)-2-(4-
methoxycarbonylphenyl)-1-methyl-4-pentenyl}-N-(2-
naphthylmethyl)carbamoylmethyl]succinic acid
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-{(1S*,2S*,4E)-5-
(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl}carbamoylmethyl]succinic acid
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-{(1R*,2R*,4E)-5-
(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl }carbamoylmethyl]succinic acid
(2R*)-2-[N-{(1RS,2RS)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)pentyl}-N-(2-
naphthylmethyl)carbamoylmethyl]succinic acid
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-{(1RS,2RS)-5-
(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-
pentyl}carbamoylmethyl]succinic acid

- 521 -
(2R*)-2-[N-{(1R*,2R*)-5-(2-benzoxazolyl)-2-(4-
methoxycarbonylphenyl)-1-methylpentyl}-N-(2-
naphthylmethyl)carbamoylmethyl]succinic acid
disodium (3S,4S)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-
(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-
naphthylmethyl)carbamoyl]-3-carboxy-4-hyroxybutanoate (Compound
D)
<IMG>
sodium (3S,4S)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-ethoxycarbonyl-4-hyroxybutanoate
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-tert-butoxycarbonyl-4-hydroxy-3-butenoic acid
<IMG>

- 522 -
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl]-
4-hydroxy-3-methoxycarbonyl-3-butenoic acid
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
4-hydroxy-3-isopropoxycarbonyl-3-butenoic acid
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-cyclohexyloxycarbonyl-4-hydroxy-3-butenoic acid
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
4-hydroxy-3-(2-methoxyethoxy)carbonyl-3-butenoic acid
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-benzyloxycarbonyl-4-hydroxy-3-butenoic acid
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
3-cyclopentyloxycarbonyl-4-hydroxy-3-butenoic acid
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
4-hydroxy-3-(3-tetrahydrofuranyloxycarbonyl)-3-butenoic acid
4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
4-hydroxy-3-(2-hydroxy-1-hydroxymethylethoxycarbonyl)-3-butenoic
acid

- 523 -
3 allyloxycarbonyl-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-
(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-
naphthylmethyl)carbamoyl]-4-hydroxy-3-butenoic acid
4-[N- {(1R,2R,4E)-5-(2-benzoxazolyl)-2-(3,4-methylenedioxyphenyl)-1
methyl-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-3-
carboxymethylcarbonyl-4-hydroxy-3-butenoic acid
5-[N- {(1R,2R, 4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
4-ethoxycarbonyl-5-hydroxy-4-pentenoic acid
5-N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl]-
4-tert-butoxycarbonyl-5-hydroxy-4-pentenoic acid
4-N-{ (1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-
4-hydroxy-3-hydroxymethyl-3-butenoic acid
4-[N- {(1RS,2RS,5E)-6-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-5-hexenyl }-N-(2-naphthylmethyl)carbamoyl]-3-
tert-butoxycarbonyl-4-hydroxy-3-butenoic acid
(2S*,3R*)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl]-
1,2,3-butanetricarboxylic acid
(2R*,3S*)-4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl]-
1,2,3-butanetricarboxylic acid

- 524-
N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3- {5-(phenylcarbamoyl)-2-
furyl}propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-3- {5-(3,4-dimethoxyphenylcarbamoyl)-2-furyl}-1-methyl-
2-(4-nitrophenyl)propyl] -N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-3-{5-(2-hydroxyphenylcarbamoyl)-2-furyl}-1-methyl-2-
(4-nitrophenyl)propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic
acid
N-[(1RS,2RS)-1-methyl-3- {5-(N-methylphenylcarbamoyl)-2-furyl}-2-(4-
nitrophenyl)propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3- {5-(3-pyridylcarbamoyl)-2-
furyl}propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3- {5-(4-
pyridylcarbamoyl) -2-furyl} propyl] -N- (2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3- {5-(5-
pyrimidinylcarbamoyl)-2-furyl }propyl]-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3- {5-(2-thiazolylcarbamoyl)-
2-furyl}propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-{5-(phenylcarbamoyl)-2-
furyl}propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N- {(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(3-
phenylcarbamoylphenyl)propyl}-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid

- 525 -
N-[(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3- {3-(phenylcarbamoyl)-5-
isoxazolyl}propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-{4-(phenylcarbamoyl)-2-
pyridyl}propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-[(1RS,2RS)-1-methyl-2-(3,4-
methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-
furyl}propyl]carbamoylmethyl]succinic acid
(2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-[(1RS,2RS)-1-
methyl-2-(3,4-methylenedioxyphenyl)-3- {5-(3-pyridylcarbamoyl)-2-
furyl}propyl]carbamoylmethyl]succinic acid
monopivaloyloxymethyl (2R*)-2-[N-(2-benzo[b]thienylmethyl)-N-
[(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3- {5-
(phenylcarbamoyl)-2-furyl}propyl]carbamoylmethyl]succinate
(2R*)-2-[N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(3-
phenoxymethylphenyl)propyl} -N-2-
naphthylmethyl)carbamoylmethyl]succinic acid
(2R*)-2-[N-[(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-
methyl-3- {3-(phenoxymethyl)-5-(1,2,4-oxadiazolyl)} propyl]-N-(2-
naphthylmethyl)carbamoylmethyl]succinic acid
(2R*)-2-[N-[(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{(E)-
3-styrylphenyl }propyl]-N-(2-naphthylmethyl)carbamoylmethyl]succinic
acid
(2R*)-2-[N-[(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{3-(2-
phenylethyl)phenyl}propyl]-N-(2-naphthylmethyl)-
carbamoylmethyl]succinic acid

- 526 -
N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)-
propyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid
N-[(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3- {(E)-3-
styrylphenyl}propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic
acid
N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(5-
phenoxymethyl-2-furyl)propyl }-N-(2-
naphthylmethyl)carbamoylmethylsuccinic acid
4-[N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-
(phenylcarbamoyl)-2-furyl }propyl]-N-(2-naphthylmethyl)carbamoyl]-
1,2,3-butanetricarboxylic acid
disodium (3RS,4RS)-3-carboxylato-4-hydroxy-4-[N-[(1RS,2RS)-1-
methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl }propyl]-N-
(2-naphthylmethyl)carbamoyl]butanoate
disodium (3SR,4SR)-3-carboxylato-4-hydroxy-4-[N-[(1RS,2RS)-1-
methyl-2-(4-nitrophenyl)-3- {5-(phenylcarbamoyl)-2-furyl } propyl]-N-
(2-naphthylmethyl)carbamoyl]butanoate
3-tert-butoxycarbonyl-4-hydroxy-4-[N-[(1RS,2RS)-1-methyl-2-(4-
nitrophenyl)-3- {5-(phenylcarbamoyl)-2-furyl} propyl]-N-(2-
naphthylmethyl)carbamoyl]-3-butenoic acid
3-tert-butoxycarbonyl-4-hydroxy-4-[N-[(1RS,2RS)-1-methyl-2-(3,4-
methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl }propyl]-N-(2-
naphthylmethyl)carbamoyl]-3-butenoic acid
3-tert-butoxycarbonyl-4-hydroxy-4-[N-{(1RS,2RS)-1-methyl-
2-(4-nitrophenyl)-3-(3-phenoxymethylphenyl)propyl}-N-(2-

- 527 -
naphthylmethyl)carbamoyl]-3-butenoic acid
4-hydroxy-3-methoxycarbonyl-4-[N-[(1RS,2RS)-1-methyl-2-(3,4-
methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl] -N-(2
naphthylmethyl)carbamoyl]-3-butenoic acid
3-allyloxycarbonyl-4-hydroxy-4-[N-[(1RS,2RS)-1-methyl-2-(3,4-
methylenedioxyphenyl)-3- {5-(phenylcarbamoyl)-2-furyl}propyl]-N-
(2-naphthylmethyl)carbamoyl]-3-butenoic acid
5-hydroxy-4-isopropylcarbonyl-5-[N-[(1RS,2RS)-1-methyl-2-(4-
nitrophenyl)-3- {5-(phenylcarbamoyl)-2-furyl }propyl]-N-(2-
naphthylmethyl)carbamoyl]-4-pentenoic acid or
3-tert-butoxycarbonyl-4-{N-(2,3-dichlorobenzyl)-N-[(1RS,2RS)-1-
methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-
furyl}propyl]carbamoyl]-4-hydroxy-3-butenoic acid
or a pharmaceutically acceptable salt or optical isomer thereof.
10. The method according to Claim 8 wherein the
farnesyl pyrophosphate-competitive inhibitor is selected from:
sodium 4-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl]-
3-tert-butoxycarbonyl-4-hydroxy-3-butenoate (Compound C)
<IMG>

- 528 -
or
disodium (3RS.4RS)-4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-
2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-
naphthylmethyl)carbamoyl]-3-carboxyl-4-hyroxybutanoate (Compound
D)
<IMG>
or a pharmaceutically acceptable salt or optical isomer thereof.
11. The method according to Claim 1 wherein the
protein substrate-competitive inhibitor is:
Compound E:
<IMG>
or a pharmaceutically acceptable salt or optical isomer thereof
and the farnesyl pyrophosphate-competitive inhibitor is:

- 529 -
disodium (3RS.4RS)-4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-
2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-
naphthylmethyl)carbamoyl]-3-carboxyl-4-hyroxybutanoate (Compound
D)
<IMG>
12. A pharmaceutical composition for achieving an
additive or synergistic therapeutic effect in a mammal in need thereof
which comprises amounts of at least two therapeutic agents selected
from a group consisting of:
a) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
the protein substrate of the enzyme and
b) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
farnesyl pyrophosphate;
wherein the amount of a) alone and the amount of b) alone is
insufficient to achieve said therapeutic effect.
13. The pharmaceutical composition according to Claim
12 comprising an amount of a protein substrate-competitive inhibitor
and an amount of a farnesyl pyrophosphate-competitive inhibitor.
14. A pharmaceutical composition for achieving a
synergistic therapeutic effect in a mammal in need thereof which

- 530 -
comprises amounts of at least two therapeutic agents selected from a
group consisting of:
a) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
the protein substrate of the enzyme and
b) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
farnesyl pyrophosphate;
wherein the amount of a) alone and the amount of b) alone is
insufficient to achieve said therapeutic effect; and
wherein said therapeutic effect of the pharmaceutical composition is
greater than the sum of the therapeutic effects of the amounts of the
amounts of the individual therapeutic agents administered.
15. The pharmaceutical composition according to Claim
14 comprising an amount of a protein substrate-competitive inhibitor
and an amount of a farnesyl pyrophosphate-competitive inhibitor.
16. A method of preparing a pharmaceutical composition
for achieving an additive or synergistic therapeutic effect in a mammal
in need thereof which comprises mixing amounts of at least two
therapeutic agents selected from a group consisting of:
a) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
the protein substrate of the enzyme and
b) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
farnesyl pyrophosphate;
wherein the amount of a) alone and the amount of b) alone is
insufficient to achieve said therapeutic effect.

- 531 -
17. The method of preparing a pharmaceutical
composition according to Claim 16 comprising mixing an amount of a
protein substrate-competitive inhibitor and an amount of a farnesyl
pyrophosphate-competitive inhibitor.
18. A method of preparing a pharmaceutical composition
for achieving a synergistic therapeutic effect in a mammal in need
thereof which comprises mixing amounts of at least two therapeutic
agents selected from a group consisting of:
a) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
the protein substrate of the enzyme and
b) a farnesyl protein transferase inhibitor which is an effective
inhibitor of the enzyme because it is competitive with respect to
farnesyl pyrophosphate;
wherein the amount of a) alone and the amount of b) alone is
insufficient to achieve said therapeutic effect; and
wherein said therapeutic effect of the pharmaceutical composition is
greater than the sum of the therapeutic effects of the amounts of the
amounts of the individual therapeutic agents administered.
19. The method of preparing a pharmaceutical
composition according to Claim 18 comprising mixing an amount of a
protein substrate-competitive inhibitor and an amount of a farnesyl
pyrophosphate-competitive inhibitor.

Description

~A 0 2 2 2 5 2 5 5 19 9 7 - i 2 - 18 ~
DEMANDES C)U ~3REV~S VOLUMINEUX
LA PRÉSENTE PARTlt- DE CETTE DEMANDE OU C~ BREVET
COMPREND Pl US D'IUN TOME.
CE~CI EST LE TOME ~ --DE_~/
NOTE: Pour ~es tomes addil:ionels, veuillez c~ln~ac~r le Bureau canadien des
b~evets
JUIVIBO APPL~CATIONS/PATENTS
lHIS SECTION ¢3F THE APPLICATION/PATENT CONTAINS MORE
~HAN ONE VOLUME
T~IS IS VOI UIVIE ~ OF
,
NO~E: For addit~-ona1 ~c~umes please cr~ntact ~he Canadian Patent Off~c~

CA 02225255 1997-12-18
WO 97/0127~i PCTJUS96/II1122
- 201 -
SCHEME S (con*nlle-l)
Ar~\~CH2CO2H Ra _~
~N +HCI H N N
XXIII Rb
Vlll
EDC- HCI
HOBt
DMF
~ HCI
XXIV

CA 02225255 1997-12-18
WO 97/0127S PCT/US96/11022
- 202 -
SCHEME 6
~=~ NaBH(OAc)3
Ra ~3Et3N, CICH2CH2CI
HCI ~ N N~ BnOl
Rb BocNH CHO
Vlll
XXV
BnO ~N N~ 20% Pd(OH)2 H2
y O CH30H
NHBoc Rb CH3C02H
XXVI
HO N N$~3 CICOCOCI
DMSO CH2CI2
NHBoc Rb (C2H~j)3N
XXVII

-
CA 02225255 1997-12-18
WO 97/~1275 PCT/USg6/11022
- 203 -
SCHEME 6 (CONTINUED)
R~ ~ ~ 1. R'MgX
~N N~/ (C2H5)2o
\ < o 2.TFA,
HNHBoc Rb CH2CI2
XXVIII
R~
HO~N~N
R' NH2 Rb
XXIX

CA 02225255 1997-12-18
WO 97/0127S PCT/US96/11022
- 204 -
SCHEME 7
Ra /=
~ ~ CF3C02H
HO ~NyN~ CH2CI2
NHBoc Rb
XXVII
R~ ~ ~3 R'CHO
HO~NyN~ NaBH(OAc)3
NH2 Rb CICH2CH2CI
XXX
R~
HO ~N N
NH Rb
R'CH2
XXXI

CA 02225255 l997- l2- l8
WO 97/01275 PCTJUS96;J11~22
- 205 -
SCHEME 8
H rN
RA ~3 o2
H0 ~--N N
~~ \ < O NaH, DMF0~C
NHBoc Rb
XXVII
RA~ ~ _~ R'SH
b ~ CH30H
H R
XXXII
RA> , ~3
R'S~ ~N N
NH2 Rb
XXXIII

CA 02225255 1997-12-18
WO 97/0127S PCT/US96/11022
- 206 -
SCHEME 9
HO~ 1) Boc2O, K2C~3 HO~
~/ THF-H20
2) CH2N2, EtOAc ~1~
H2NCO2H BocNH CO2CH3
XXXIV
XXXV
HO~
LiAlH4 ~ R'CH2X
THF 1 Cs2CO3
0-20~C BocNH CH2OH DMF
XXXVI
R'CH20 R'CH20
~J DMSO J~
BocNH CH2OH 20~C BocNH CHO
XXXVII XXXVIII

CA 02225255 1997-12-18
WO 97/0127S PCTrUS96/11022
- 207 -
- SCHEME 9 (contim
R'CHzO~
+ HCI N N
Boc:NH CHO \ <Rb
XXXVIII Vlll
NaBH(OAc)3
CICH2CH2CI
R'CH2o~N~3
NHBoc Rb
XXXIX \ HCI
ETOAc
1) 20% Pd(C)H)2
CH30H, ~H3CO2H / R~
R'CH20/~ N~N O
" 1 NH2 Rb
~~ Ra~ XLI
NH2 Rb
XL

CA 02225255 1997-12-18
WO 97/01275 PCT/US96/11022
- 208 -
SCHEME 10
CO2R
n( S~~ 1) LAH, Et20
HN N 2) Boc20
O ~
XLII
R60
HO ~
R61 ~ n ( < )
n( S~ NaH, DMF ~o~N~
XLIV
XLIII
S SCH~ME 1 1
Rb
ArNH2 + Cl~ )2NH HCI
XLV Ra
XLVI
Ra Rb
n - butanol >~
ArN NH HCI
reflux >~
Ra Rb
XLVII

CA 02225255 1997-12-18
wo 97~alz7s PCT/US961~1~)22
- 209 -
SCHEME 12
.i
>~ J~ Ra CH3NHOCH3 HCI
O N~ EDC . HCI, HOBT
H o DMF, Et3N, pH 7
I
O Ra
O N~N(CH3)0CH3 LAH, Et20
XLVIII
>~ ~ R NaBH(OAc)3
H o CICH2CH2CI
XLIX pH 6
O Ra 1) BrCH2COBr
>~JI~N~NHCH2Ar EtOAc, H20, NaHCO3
H 2) NaH,THF, DMF
L

CA 02225255 1997-12-18
W O 97/0127S PCT~US96/11022
- 210 -
SCHEME 12 (CONT'D)
R ~ ~ 1 ) TFA, CH2C12
~0 ~~ Ar
o
Ll
Ra
~,
HN N~
\~ Ar

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- 211 -
- ~CHEME 13
NaBH(OAc)3
ArCHO + NH2CH2CH(Oc2H~)2
Lll Llll o Ra
Ar CH2NHCH2CH(Oc2Hs)2>~0~ N ~
LIVEDC . HCI, HOBT
DMF, Et3N, pH 7
O R ~ 6N HCI
>~C)~ N ~N~CH(Oc2Hs)2 THF
H o
LV
Ra O H2 1 0%Pd/C
N N~ CH30H
0 \=/ Ar
LVI
Ra o
~~ ~
~0 \ J Ar
LVII

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PCT/US96/1 1022
WO 97/01275
- 212 -
SCHE~IE 14
Rb
1) CF3C02H, CH2C12, N NH ArCO2H
2) NaHCO3 ~ y EDC HCI
. ~ HOBT, DMF
LVIII
Rb Rb
N N~ 10% Pd / C ~ HN N~
;IX Ar H2 CH30H R-XY Ar

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- 213 -
SCHEME 15
~ PhcH2NHcH2co2c2H5
BocNH C02H DCC, CH2C12
LXI
a) TFA, CH2C12
BocNH~N~CO2C2H~ b) NaHCO3
0 LXII
H N~N~C02C2Hs (cH3)3A
LXIII
~u~O
HN,~N~3 LiAlH4 . HN N~
LXIV / \ LXV
Boc20 BocN N~ H2 Pd/C
CH2CI2 ~ CH30H
LXVI

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WO 97/01275 PCT/US96/11022
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SCHEME 15 (continued)
COCI
~>\ ~ -
BocN NH
NaHCO3 EtOAc
LXVII
~'
a) TFA, CH2C12
BocN N~ /=\ b) NaBH(OAc)3
LXVIII ~3C(=O)H
CPh3
< u >
/ \ ,0
rN N~=~ TFA CH2C12
(c2H5)3siH
CPh3
LXIX
~>\
_~N N--
H 2TFA
LXX

CA 02225255 1997-12-18
WO 9710~275 PCTnJS96~11022
- 215 -
c SCHEME 16
BocNHlCHO NaBH(OAc)3 N~Ar
CICH2CH2CI
Xl_IX LXXI
O R
Cl~J~CI BocNH N-Ar
EtOAc / H20 ~;
NaHCO3 Cl O
LXXII
NaH ~\ HCI
BocN N-Ar
Dl~,AF \~ EtOAc
o
LXXIII
-

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- 216 -
SCHEME 16 (continued)
CHO
R ~ R
~ N
HCIHN N--Ar C(Ph)3 . N~ \~
O NaBH(OAc)3 ~N~ ~
LXXIV pH 5-6 ~Ph)3C
LXXV
Ar ~ ~ N N--Ar
ArCH2X N~ \~
CH3CN ~ o
N (3 (3
(Ph)3c X
LXXVI
MeOH )~
or Ar~ _~N~N--Ar
TFA, CH2CI ~N~ ~
(c2H5)3siH
LXXVII
The compound of the formula (gg) of the present invention
5 can be prepared, for example, by the following process 1, 2, 3, 4, 5 or
6.

CA 0222~2~ 1997-12-18
WO 97/0127~ PCI-/US96/lIaZZ
- 217 -
Process 1
The compound of the formula (gg) can be prepared by
S reacting a compound of the formula (II):
R3P R8P
~r1 xp_yp~ H2 R7 ~A~
~Ar3/ ~NH
R4P ~) H ¦ 6
R5P
wherein each of
Cr C~2- ' C~3 and Cr4
which are the same or different, is an aryl group or a heteroaromatic
ring group; each of XP and YP which are the same or different, is an
oxygen atom, a sulfur atom, a carbonyl group or a group of the formula
-CHRa- (wherein Ra is a hydrogen atom or a lower alkyl group) or
lS -NRbP- (wherein RbP is a hydrogen atom, a lower alkyl group or an
imino-protecting group), or XP and YP together represent a vinylene
group or an etllynylene group; each of RlP, R2P, R3P, R8P and R9P
which are the same or different, is a hydrogen atom, a halogen atom, a
hydroxyl group which may be protected, a lower alkyl group or a lower
20 aLkoxy group; each of R4P and R5P which are the same or different, is a
hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower
alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl
group, a lower alkyl group, a lower fluoroalkyl group, a lower alkoxy
group or a hydroxyl, amino, carboxyl or lower hydroxyalkyl group
25 which may be protected; R6 is a lower alkyl group; and R7 is a

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WO 97/01275 rCT/US96/11022
- 218 -
hydrogen atom or a lower aL~yl group, provided that when one of XP
and YP is an oxygen atom, a sulfur atom or a group of the formula
-NRbP- (wherein RbP is as defined above), the other is a carbonyl
group or a group of the formula -CHRa- (wherein Ra is as de~med
S above), with a carboxylic acid of the formula (III) or its reactive
derivative:
HO AP-CO2RP
~ (111)
wherein AP is a C2 g saturated or ~ln~tllrated aliphatic hydrocarbon
group which may have substituent(s) selected from the group consisting
10 of a lower aL~yl group, a lower aL~oxy group, an aryl group, an araL~yl
group, and hydroxyl, lower hydroxyaL~cyl, carboxyl and lower
carboxyaL~yl groups which may be protected; and RP is a hydrogen
atom or a carboxyl-protecting group, to obtain a compound of the
formula (IV):
R3P R8P
~~rl XP _yp ~r2_ CH2 7 /A~
R2P Cl~ CH (IV)
R4P~)r3/ >~N~AP-CO2RP
R5P
Cr ~ Cr2 , Cr , Cr
wherein
AP, XP, YP, RlP, R2P, R3P, R4P, RSP, R6, R7, R8P, R9P and RP are as
defined above, and, if necessary, removing any protecting group.
As the reactive derivative of the carboxylic acid of
20 the formula (III), an acid halide, a mixed acid anhydride, an active ester
or an active amide may, for example, be used. When the carboxylic
acid of the formula (III) is used, it is preferred to conduct the reaction
in the presence of a condensing agent such as N,N'-

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WO 97/01275 PCT/US96/11022
- 219 -
dicyclohexylcarbo-liimirle, l-ethyl-3-(3-
dimethylaminopropyl)carbodii~ide or 2-chloro-1,3-dimethylimidazolyl
chloride.
ThLe reaction of the compound of the formula (II)
with the carbo~ylic acid of the formula (III) or its reactive derivative, is
conducted usua~lly by using 1 mol or an excess molar amount, preferably
from 1 to 5 mols, of the carboxylic acid of the formula (III) or its
reactive derivative, per mol of the compound of the formula (II).
The reaction is conducted usually in an inert solvent. The inert solvent
may, for example, be a halogenated hydrocarbon such as methylene
chloride, chloroform, carbon tetrachloride, dichloroethane or
trichloroethylene; an ether such as ethyl ether, tetrahydrofuran or
dioxane; an aromatic hydrocarbon such as benzene, toluene,
chlorobenzene or xylene; an aprotic polar solvent such as
dimethylformamide, acetonitrile, acetone, ethyl acetate or
hexamethylphosphoric triamide, or a mixture of such solvents.
The reaction temperature is usually from -70~C to the
boiling point o~ the solvent used for the reaction, preferably from -20~C
to 100~C.
The reaction tirne is usually from S minutes to 7 days, preferably from
10 minutes to 24 hours.
Th~e above readtion can be conducted in the presence
of a base to facilitate the reaction.
As such a base, it is preferred to conduct the reaction in the
presence of an inorganic base such as sodium hydroxide, potassium
hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate
or sodium hydrogen carbonate, or an organic base such as
triethylamine, N-ethyldiisopropylamine, pyridine, 4-
dimethylaminopyridine or N,N-dimethylaniline.
Such a base is used usually in an amount of 1 mol or
-~ an excess mola.r amount, preferably from 1 to 5 mols, per mol of the
reactive derivative of the carboxylic acid of the formula (III).
The acid halide of the compound of the formula (III) can be
obtained by reacting the carboxylic acid of the formula (III) with a

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- 220 -
halogenating agent in accordance with a conventional method. As the
halogenating agent, thionyl chloride, phosphorus trichloride,
phosphorus pentachloride, phosphorus oxychloride, phosphorus
tribromide, oxalyl chloride or phosgene may, for example, be used.
S The mixed acid anhydride of the compound of the formula
(III) can be obtained by reacting the carboxylic acid of the formula (III)
with an aLkyl chlorocarbonate such as ethyl chlorocarbonate or with an
aliphatic carboxylic acid chloride such as acetyl chloride, in accordance
with a conventional method. Further, an intramolecular acid anhydride
may be formed between carboxyl groups at both terminals, or when in
the formula (III), a carboxyl group is present on the saturated or
Im~tllrated aliphatic hydrocarbon group for AP, an intramolecular acid
anhydride may be formed between such a carboxyl group and a
carboxyl group to be involved in the reaction, to constitute a reactive
derivative of the carboxylic acid.
The active ester of the compound of the formula (III) can
be prepared by reacting the carboxylic acid of the formula (III) with an
N-hydroxy compound such as N-hydroxysuccinimide, N-
hydroxyphth~limide or 1-hydroxybenzotriazole, or a phenol compound
such as a 4-
nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol or
pentachlorophenol, in the presence of a condensing agent such as N,N'-
dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide in accordance with a conventional method.
The active amide of the compound of the formula (III) can be prepared
by reacting the carboxylic acid of the formula (III) with e.g. 1,1'-
carbonyldiimidazole or 1,1'-carbonylbis(2-methylimidazole) in
accordance with a conventional method.
When a hydroxyl group is present on the group of the
formula
R3P
~ ~ R8p~
R2p R9P

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WO 97/01275 PCT/US96/11022
- 221 -
when a hydroxyl group, a lower hydroxyaL~yl group, a carboxyl group
or a lower carboxyaLlcyl group is present on the saturated or lln~tllrated
aliphatic hydrocarbon group represented by AP, and when a hydroxyl
group, an amino group, a carboxyl group or a lower hydroxyaL~yl
5 group is present on the group of the formula
R4P~
~,3_
R5P
it is preferred ta, conduct the reaction after protecting such a hydroxyl
group, a lower hydroxyaL~yl group, an amino group, a carboxyl group
or a lower carboxyaL~yl group aL~ opriately by a hydroxyl-protecting
10 group, an amino-protecting group or a carboxyl-protecting gtoup and
removing the protecting group after the reaction. Further, in a case
where one of XP and YP is a group of the forrnula -NRbP- (wherein
RbP is as defined above), and the other is a group of the forrnula
-CHRa- (wherein Ra is as defined above), RbP is preferably a lower
15 aL~yl group or an imino-protecting group, and when RbP is an
iminoprotecting group, it is preferred to remove such a protecting
group after the reaction.
The hydroxyl-protecting group may, for example, be a
lower aL~ylsilyl group such as a trimethylsilyl group or a tert-
20 butyldimethylsilyl group; a lower aLkoxymethyl group such as amethoxymethyl group or a 2-methoxyethoxymethyl group; a
tetrahydropyranyl group; an aralkyl group such as a benzyl group, a p-
methoxybenzyl group, a p-nitrobenzyl group or a trityl group; or an
acyl group such as a formyl group or an acetyl group. Particularly
25 preferred is a methoxymethyl group, a tetrahydropyranyl group, a trityl
group, a tent-bultyldimethylsilyl group or an acetyl group.
The amino- or imino-protecting group may, for example,
be an araL~yl group such as a benzyl group, a p-methoxybenzyl group, a
p-nitrobenzyl group, a benzhydryl group or a trityl group; a lower
30 aL~anoyl group such as a formyl group, an acetyl group, a propionyl

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
- 222 -
group, a butyryl group or a pivaloyl group; a lower haloaL~anoyl group
such as a trifluoroacetyl group; a lower aL~oxycarbonyl group such as a
methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl
group or a tert-butoxycarbonyl group; a lower haloalkoxycarbonyl
5 group such as a 2,2,2-trichloroethoxycarbonyl group; an
aLkenyloxycarbonyl group such as a 2-propenyloxycarbonyl group; an
aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a p-
nitrobenzyloxycarbonyl group; or a lower aL~ylsilyl group such as a
trimethylsilyl group or-a tert-butyldimethylsilyl group. Further the
10 amino-protecting group may, for example, be an aralkylidene group
such as a benzylidene group, a p-chlorobenzylidene group or a p-
nitrobenzylidene group. Particularly preferred is an acetyl group, a
trifluoroacetyl group, a tert-butoxycarbonyl group or a
benzyloxycarbonyl group.
The carboxyl-protecting group may, for example, be a
lower alkyl group such as a methyl group, an ethyl group, a propyl
group, an isopropyl group or a tert-butyl group; a lower haloalkyl
group such as a 2,2,2-trichloroethyl group; a lower alkenyl group such
as 2-propenyl group; or an aralkyl group such as a benzyl group, a p-
20 methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group or
trityl group. Particularly preferred is a methyl group, an ethyl group, a
tert-butyl group, a 2-propenyl group, a benzyl group, a p-
methoxybenzyl group or a benzhydryl group.
After completion of the reaction, conventional treatment is
25 conducted to obtain a crude product of the compound of the formula
(IV). The compound of the formula (IV) may or may not be purified in
accordance with a conventional method, and if necessary, reactions for
removing protecting groups such as a hydroxyl group, an amino group
and a carboxyl group, are a~ liately conducted to obtain a
30 compound of the formula (gg).
Removal of protecting groups may vary depending upon
their types, but can be-conducted in accordance with the methods
disclosed in a literature (Protective Groups in Organic Synthesis, T.W.
Greene, John Wiley & Sons (1981)) or methods ~imil~r thereto, for

CA 02225255 1997-12-18
WO 9710127S PCT/US96/11022
- 223 -
example by solvolysis employing an acid or a base, by chemical
reduction employing a metal hydride complex or by catalytic reduction
employing a p~ rn-carbon catalyst or Raney nickel.
S Process 2
A compound of the formula (gg-a):
R3 R8
--Xa-Ya~ I R7~CH ~ (gg-a)
4 ~1r3 H>~ ~
R5
wherein
Cr~ Cr2 C C
A, Rl, R2, R3, R4, RS, R6, R7, R8 and R9 are as defined above, and
xa and ya are as defined below, can be prepared by reacting a
compound of the formula (V):
R1P
~~r1 Xa_z
R2p (V)
wherein Xa is a carbonyl group or a group of the formula -CHRa-
(wherein Ra is as defined above), Z is a leaving group; and
C
R' lp and R2P are as defined above, with a compound of
the formula (Vl):

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WO 97/0127S PCT/US96/11022
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R3P R8p
H--ya~r--¦H2 R7 ~A~ (Vl)
R4P--~Ir3/ ~N~AP-CO2RP
R5P
wherein ya is an oxygen atom, a sulfur atom or a group of
the formula -NRb- (wherein Rb is as defined above); and
Cr2- Cr3 ' Cr4
AP, R3P, R4P, R5P, R6, R7,
R8P, R9P and RP are as defined above, to obtain a
compound of the formula (IV-a):
R3P R3P
~~r1 xa--ya~r2--CH /A
R2p Cl~ I
R4P ~r3/ >~N~AP-CO2RP
R5P
10 wherein
Cr - , Cr - ~ Cr ~ Cr4-- ~
AP, xa, ya, Rlp
R2P, R3P, R4P, R5P, R6, R7, R8P, R9P and RP are as defined above,
and, if necessary, removing any protecting group.
Process 2 is a process for preparing a compound of the
15 formula (gg) wherein -X-Y- is a group of the formula -COO-, -COS-,

CA 0222~2~ 1997-12-18
WO 97~aI2?S PCTf~JS96/~1022
- 225 -
-CONRb-, -C]~IRaO-, -CHRaS- or -CHRaNRb- (wherein Ra and Rb are
as defined above) i.e. a compound of the formula (gg-a).
The reaction of the compound of the formula (V) with a
compound of the formula (VI) is carried out usually by using 1 mol or
an excess molar amount, preferably from 1 to 3 mols, of the compound
of the formula (V), per mol of the compound of the formula (VI).
The reaction is conducted usually in an inert solvent. The
inert solvent nnay, for example, be a halogenated hydrocarbon such as
methylene chloride, chloroform, carbon tetrachloride, dichloroethane
or
trichloroethylene; an ether such as ethyl ether, tetrahydrofuran or
dioxane; an aromatic hydrocarbon such as benzene, toluene,
chlorobenzene or xylene; an aprotic polar solvent such as
dimethylform lmitle, acetonitrile, acetone, ethyl acetate or
hexamethylphosphoric tri~micle, or a mixture of such solvents.
The reaction temperature is usually from -70~C to the
boiling point of the solvent used for the reaction, preferably from -20~C
to 100~C.
The reaction time is usually from 5 minntes to 7 days,
preferably fro~m 10 minlltes to 24 hours.
The above reaction is preferably conducted in the presence
of a base to facilitate the reaction. Especially when ya in the formula
(VI) is not a group of the formula -NRb-, it is necessary to carry out
the reaction in the presence of an inorganic base such as sodium
hydride, n-butyl lithium, sodium hydroxide, potassium hydroxide,
calcium hydroxide, sodium carbonate, potassium carbonate or sodium
z hydrogen carbonate, or an organic base such as triethyl~mine, N-
ethyldiisoprop~yl~mine, pyridine, 4-dimethylaminopyridine or N,N-
dimethyl~niline.
The base is used usually in an amount of 1 mol or an
~r excess molar amount, preferably from 1 to 5 mols, per mol of the
compound of the formula (V).
The leaving group represented by Z in the formula (V)
..

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WO 97/0127S PCT/US96/11022
- 226-
may, for example, be a halogen atom such as a chlorine atom, a bromine
atom or an iodine atom, or an organic sulfonyloxy group such as a
methanesulfonyloxy group, a p-toluenesulfonyloxy group or a
benzenesulfonyloxy group.
When a hydroxyl group is present on the group of the
formula
~r1 ~r2 or ~r4
R2p R9P
when a hydroxyl group, a lower hydroxyalkyl group, a
carboxyl group or a lower carboxyalkyl group is present on the
10 saturated or nnc~tllrated aliphatic hydrocarbon group represented by
AP, and when a hydroxyl group, an amino group, a carboxyl group or a
lower hydroxyalkyl group is present on the group of the formula
R4P
(~ Ar3
R5P
it is preferred to conduct the reaction after protecting such a hydroxyl
group, a lower hydroxyalkyl group, an amino group, a carboxyl group
or a lower carboxyalkyl group a~lo~liately by a hydroxyl-protecting
group, an amino-protecting group or a carboxyl-protecting group and
20 removing any protecting group after the reaction.
The hydroxyl-protecting group, the amino-protecting
group and the carboxyl-protecting group may be the protecting groups
mentioned above with respect to process 1.
After completion of the reaction, a usual treatment is
25 carried out to obtain a crude product of the compound of the formula
(IV-a). The compound of the formula (IV-a) thus obtained may or may
not be purified by a conventional method, and if necessary, reactions for
removing the hydroxyl-, amino- and carboxyl-protecting groups may be

CA 02225255 1997-12-18
WO 97/01275 PCT/US96/II022
- 227 -
carried out in a proper combination to obtain a compound of the
for,mu~a (gg-a).
The method for removing a protecting group var,ies
depending upc,n the type of the protecting group and the stability of the
5 desired compound (gg-a). However, removal of protecting groups can
be a~ro~liatelly conducted in accordance with the methods disclosed in
the
above-mentioned literature or methods simil~r thereto.
Process 3
A compound of the formula (gg-b):
R3 R5
~~r1- xb-Yb~r ¦ H2 R7 /A~ (g~-b)
R4~r3 >~N~A-CO2H
R5
wherein
Cr Cr ' Cr3 ' Cr--
A, Rl, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above, and
xb and yb are as defined below, can be prepared by reacting a
compound of the formula (VII):
R1P
~~r1 Xb ~ H
~/
R2P (VII)

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WO 97/01275 PCT/US96/11022
- 228 -
wherein Xb is an oxygen atom, a sulfur atom or a group of the formula
~~r1
-NRb- (wherein Rb is as defined above); and ~/ RlP and
R2P are as defined above, with a compound of the forrnula (VIII):
R3P R8P
f 2 R7 ~A(~
R4P~r3/ >~N~n,AP-co2Rp
R5P
(VIII)
wherein yb is a carbonyl group or a group of the formula -CHRa-
(wherein Ra is as defined above); and
Cr2 ' Cr3 ' ~r4 -
, AP, Z, R3P, R4P, R5P, R6, R7
R8P, R9P and RP are as defined above, to obtain a compound of the
formula (IV-b):
R3P R5P
~~r1 Xb_yb_~r2_fH A~
R2p ~CH
rAr3 >~,N~AP-CO2RP
R4P ~) H R6 ~
R5P
(IV-b)

CA 0222~2~ 1997-12-18
WO 97tO127~i pcT/rrs96n~ozz
- 229 -
Cr1 C2 C13 Cr4-
wherein
AP, Xb, yb, Rlp, R2p, R3P, R4P, R5P, R6, R7, R8P, R9P and RP are
as
defined above, and, if necessary, removing any protecting
S group.
Process 3 is a process for preparing a compound of the
formula (gg) wherein -X-Y- is a group of the formula -OCO-, -SCO-,
-NRbCO-, OCHRa-, -SCHRa- or -NRbCHRa- (wherein Ra and Rb are
as defined above) i.e. a compound of the formula (I-b).
This process can be conducted usually in an inert solvent,
preferably in the presence of a base, by using 1 mol or an excess molar
arnount, preferably from 1 to 3 mols, of the compound of the formula
(VII), per mol of the compound of the formula (VIII). The types of the
inert solvent and the base as well as the reaction conditions may be the
15 same as described above with respect to process 2. Accordingly, the
reaction and the post-treatment after the reaction may preferably be
carried out all in accordance with process 2.
Further, in the above processes 2 and 3, when xa or
yb is a carbonyl group, a compound wherein the group corresponding
20 to Z is a hydroxyl group i.e. a compound wherein Z and the adjacent
xa or yb together represents a carboxyl group, can be used. In such a
case the reaction conditions, etc. are preferably in accordance with the
reaction condiitions for the reaction of the compound of the formula (II)
with the compound of the formula (III) in the above process 1.
Process 4
A compound of the formula (gg-c):

CA 02225255 1997-12-18
W O 97101275 PCTrUS96/11022
- 230 -
R3 R8
~~r1--C--CH~rZ--I Hz A~R~
R2 ~CH H
~5
gg-c
Crl Cr2- Cr3-- Cr4--
S wherein
A, Rl, R2, R3, R4, RS, R6, R7, R8 and R9 are as defined above, and
Rla and R2a are as defined below, can be prepared by reacting a
compound of the formula (IX):
R1P
~r1--R--R1a
R2P O (IX)
wherein Rla is a hydrogen atom or a lower alkyl group; and
Cr1
, RlP and R2P are as defined above, with a compound of
the formula (X):

CA 02225255 l997- l2- l8
WO 97/0127S PCT/US96~11022
- 231 -
'
R3P R3P
Q-CH~ H2 R7 /A~
~~Ar3/ ~N~AP-CO2RP
R4P--~ R6
R5P
wherein Q is a triphenylphosphonio group, a dimethoxyphosphoryl
S group or a diethoxyphosphoryl group; R2a is a hydrogen atom or a
Cr Cr--' Cr
lower aL~cyl group; and , AP,
R3P, R4P, R5P, R6, R7, R8P, R9P and RP are as defined above, to
obtain a compound
of the formula (XI):
R3P R3P
r 1 2 R7~ /(~
R4p~r3/ ~>~N~Ap-co2Rp
R5P
(XI)
wherein
Cr1 Cr2 Cr3 Cr4--
AP, RlP, R2P, R3P, R4P, R5P, R6, R7, R8P, R9P, RP, Rla and R2a are
15 as defined above, and, if necessary, removing any protecting group.

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
- 232 -
Process 4 is a process for preparing a compound of the
formula (gg) wherein -X-Y- is -CHRlaCHR2a- (wherein each of Rla
and R2a which are the same or different, is a hydrogen atom or a lower
alkyl group) i.e. a compound of the formula (gg-c).
The reaction of the compound of the formula (IX) with
a compound of the formula (X) is carried out usually by employing
equimolar amounts of the two reactants or using a slightly excess
amount of one of them.
The reaction is carried out usually in an inert solvent. Such
an inert solvent may, for example, be an ether such as ethyl ether,
tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene,
toluene, chlorobenzene or xylene; an aprotic polar solvent such as
dimethylform~micle, acetonitrile, acetone, ethyl acetate or
hexamethylphosphoric triamide; or a mixture of such solvents.
The reaction temperature is usually from -100~C to the
boiling point of the solvent used for the reaction, preferably from -70~C
to 50~C.
The reaction time is usually from 5 minutes to 7 days,
preferably from 10 minntes to 24 hours.
Further, the above reaction can be conducted in the
presence of a base to facilitate the reaction. Especially when Q in the
formula (X) is a triphenylphosphonio group, the reaction is preferably
conducted in the presence of a base such as sodium hydride, n-butyl
lithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide
or potassium hydroxide.
Such a base is used in an amount of 1 mol or an excess
molar amount, preferably from 1 to 5 mols per mol of the compound
wherein Q is a triphenylphosphonio group.
The reaction of reducing the compound of the formula
(XI) obtained in the above step is usually preferably conducted by
catalytic reduction employing a palladium carbon catalyst, a Raney
nickel catalyst or a platinum catalyst in an inert solvent.
The inert solvent may, for example, be an alcohol
such as methanol, ethanol or propanol, or acetic acid.

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WO 97/0127S PCT/US96111022
- 233 -
The reaction temperalule is usually from -20~C to
100~C, preferably from 0~C to room temperature.
The reaction time is usually from 5 minutes to 7
days, preferably from 10 minlltes to 24 hours.
The hydrogen pressure in the catalytic reduction
reaction is usually preferably from atmospheric pressure to S atm, and
the amount of the catalyst is usually from 0.01 to 1 mol, preferably
from 0.05 to 0.2 mol, per mol of the starting material compound (XI).
After completion of the reaction, the product is subjected to
10 a usual treatment after removing any protecting group if such a
protecting group is present or directly if no such protecting group is
present, to
obtain a compound of the formula (gg-c).
Removal of the protecting group and the post
15 treatment may b~e conducted by the methods described with
respect to the above process 1.
Process 5
A compound of the formula (gg-c):
R
R2 /CH
>~N~AP-C02H
gg-c
Cr1_, Cr2--' Cr3--' Cr4

CA 0222~2~ 1997-12-18
WO 97101275 PCT/US96/11022
- 234-
A Rl, R2, R3, R4, RS, R6, R7, R8 and R9, Rla and R2a are as defined
above, can be obtained by reacting a compound of the formula (XII):
R1P
~~r1--CH -Q
~ I
R2p R1a (XII)
s
Cr1
wherein , Q, RlP, R2P and Rla are as defined above, with
a compound of the fo~nula (XIII):
R3P R8P
C C, H
R4p~r3/ ~>~N~AP-CO2RP
R5P
10 (XIII)
~r2 C~r3 Cr4--
wherein , Al?, R3P, R4P, RSP, R6,
R7, R8P, R9P, RP and R2a are as defined above, to obtain a compound
of the formula (XI):

CA 02225255 1997-12-18
WO g7/0127S 1 ~ .U11022
- 235 -
R3P R~P
~~r1--C=c~r2--CH2 7 ~A~
R2PR1a R2a Cl~ CH
rAr3/ >,,N~AP-CO2RP
R4P--~'' R6
R5P
~ )
wherein
C C C C
S AP, R1P, R2P.~ R3P, R4P, RSP, R6, R7, R8P, R9P, RP, R1a and R2a are
as rlefint-~l above, then reducing the compound of the formula (XI), and,
if necessary, removing any protecting group.
Like process 4, process S is a process for producing
a compound of the form~ (gg) wherein -X-Y- is -CHRlaCHR2a
(wherein R1a and R2a are as defined above) i.e. a compound of the
formula (gg-c).
Process S is equal to the reaction of process 4 wherein
staring material compounds (IX) and (X) are replaced by the
compounds (XIII) and (XII), respectively. Accordingly, the manner
and conditions of the reaction may be all in accordance with process 4.
Further, a compound of the formula (gg-d):
R3 R3
~~r1--C = C ~r--CI H2 R~7 /A~ (gg-d)
R4~~r3/ ~N~A-CO2H
R5

CA 02225255 l997- l2- l8
WO 97/0127S PCT/US96/11022
- 236 -
Cr1 Cr--'Cr ' Cr
wherein , A, Rl,
R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above, can be
obtained by removing a protectin~ group, as the case requires, from a
5 compound of the formula (XI-a):
R3P R3P
~~rl_Cl =CI ~r2--CH2 A~
R2P H H Cl~ CH
R4P~3/ ~N~AP-CO2RP
R5P
(XI-a)
Cr--' Cr ' Cr3 ' Cr4
R2P, R3P, R4P, R5P, R6, R7, R8P, R9P and RP are as defined above,
10 i.e. a compound of the formula (XI) wherein both Rla and R2a are
hydrogen atoms, among compounds of the formula (XI) obtainable as
intermediates in the above processes 4 and 5.
Process 6
A compound of the formula (gg-e):

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WO 97/01275 PCT/US96/11022
- 237 -
_~,Rl
Ar1 R8
X~r2--CH2 R\ /A~R9 (gg-e)
CH R12
R4~)3/ >~ ~ ( 2)p 8 C_ (CH2)q~CH~(CH2)rCO2~
R5 R R13
~~r1 Cr2 Cr3-- Cr4
R1, R2, R3, R4, RS, R6, R7, R8, R9, R12, R13, p, q and r are as
5 defined above, can be prepared by oxidizing a compound of the formtla
(IV-e):
Rl2P
~ RlP
Ar 3p R8P
YP~ Ar2--CH2 R\7 /A~R9P
CH Rl2p
/C ~N~ (CH2)p~(CH2)q-cH-(cH2)rCO2R
R4P~ R6 OH Rl3p
R5P
(IV-e)
wherein R12P is a hydrogen atom or a lower hydroxyaLkyl or carboxyl
10 group which may be protected, R13P is a hydrogen atom or a hydroxyl
or carboxyl group which may be protected;
Cr1--- Cr2 Cr3-- Cr4
and , XP, YP, R1P,

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R2P, R3P, R4P, R5P, R6, R7, R8P, R9P, RP, p, q and r are as defined
above, and, if necessary, removing any protecting group.
Process 6 is a process for ~re~a~ g a compound of the
5 formula (gg) wherein A is a group of the formula (b):
~12
-(CH2)p--C=C--(CH2)q~CH~(CH2)r
OH R13 (b)
wherein R12, R13, p, q and r are as defined above, i.e. a compound of
the formula (gg-e).
The reaction of oxidizing the compound of the formula
(IV-e) is usually preferably carried out in an inert solvent by using so-
called Dess-Martin oxidation employing 12-I-5 triacetoxyperiodinane;
so-called Swern oxidation employing oxalyl chloride and dime~yl
sulfoxide; a sulfur trioxide-pyridine complex; pyridinium
lS chlorochromate; active m~ng~nese dioxide; or tetra-n-propylammonium
perruthenate.
The inert solvent may, for example, be a halogenated
hydrocarbon such as methylene chloride, chloroform or dichloroethane;
an ether such as ethyl ether, tetrahydrofuran or dioxane; an aprotic
20 polar solvent such as acetonitrile, acetone, ethyl acetate or dimethyl
sulfoxide; or a mixture of such solvents.
The reaction temperature varies depending upon the type of
the oxidizing agent, etc. However, it is usually from -100~C to the
boiling point of the solvent used for the reaction, preferably from -70~C
25 to 100~C.
The reaction time is usually from 5 minlltes to 7 days,
preferably from 10 minutes to 24 hours.
After completion of the reaction, the product is subjected to ~'
usual treatment after removing a protecting group when such a
30 protecting group is present, or directly when no such protecting group
is present, to obtain the compound of the formula (gg-e).

CA 02225255 1997-12-18
WO 97/0127S PCT/US96/11022
- 239 -
The removal of the protecting group and the post-treatment
may be contlllcted in the same manner as described above with respect to
process 1.
Further, a compound corresponding to the compound of the
S formula (IV-e) to be used as the starting material in the above process 6,
can be prepared, for example, by hydrolyzing a compound of the
formula (IV-e- 1):
Ar1-Xp-Yp~rz--CH~ ~ ~A~ O
R2p R4P--~Ir H~ ~ Rf2P I l~p
R5P
(IV-e- 1 )
Cr Cr Cr-- Cr
wherein , XP, YP,
RlP, R2P, R3P, R4P, R5P, R6,R7, R8P, R9P, R12P, R13P, p, q and r are
as defined above, in the presence of a base, to obtain a compound of the
15 formula (IV-e-2),

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- 240 -
R2p
~P
yp~r2--fH~ R~ ~/A~
r~ .. l
~ N~(CH2)p--C~CIH (cH2)q-cH-(cH2)rco2M
R4P~ R6 R12p Rl3P
R5P
(IV-e-2)
wherein M is a hydrogen atom or an aL~ali metal
Cr1 C12 Cr3 Cr4
5 atom; and , XP.
YP, R1P, R2P, R3P, R4P, R5P, R6~R7~ R8P, R9P, R12P, R13P, p, q and
r are as defined above, then reacting thereto a diazo compound of the
formula
10 RPP-N+--N
wherein RPP is a lower aLkyl group, a lower aLkenyl group, an araL~cyl
group or a lower aL~coxycarbonylaLkyl group, or an aLkylating agent of
the formula RPP-Z1, wherein RPP and zl are as defined above.
Isolation and purification of the compound of the formula
(gg), (gg-a), (gg-b), (gg-c), (gg-d) or (gg-e), obtained by the above
process can be conducted by a single use or a proper combination of
conventional separating means such as column chromatography
employing silica gel, adsorbent resin, etc., liquid chromatography,
20 solvent extraction and recryst~lli7~tion-reprecipitation.
The compound of the formula (gg), (gg-a), (gg-b), (gg-c),
(gg-d) or (gg-e) can be converted to a ph~ ceutically acceptable salt
or ester by a conventional method. Reversely, the conversion from the

CA 02225255 1997-12-18
WO 97101275 PCT~lJS96/llOZZ
- 241 -
salt or ester to a free carboxylic acid can also be conducted by a
collvtxllional method.
The compounds of the form~ (II), (III), (V), (VI), (VII),
(VIII), (IX), (X), (XII) and (XIII) may be commercially available or
5 can be prepared in accordance with the methods disclosed in literatures
(J. Med. Chem., 10, 717 (1967); ibid., 725; J. Chem. Soc. Perkin I,
1636 (1978); Chem. Lett., 191 (1980); ibid., 375 (1984); J. Chem. Soc.
Chem. Comm~m, 579 (1984); J. Am. Chem. Soc., 104, 5716 (1982)) or
methods ~imil~r thereto, or in accordance with the following processes
10 or the rnethods disclosed in Examples.

CA 02225255 1997-12-18
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Process A
R4P
~~r3--
R5P
R4P~
(>~r3--CH2--ICl_R6
R5P 4
R3P
~~rl Xp-yp~r2--CH2-~
R2P 5
R3P
R1P~ k--
~r1 XP-YP~r2--CH2 6
R2P ~CH R6
R4P--~) O
R5P

CA 02225255 1997-12-18
WO 97/~11275 PCT/US96/11022
- 243 -
-
R8P R7
~r4--I H2 NH2
R9P 7
2) reduction
~ .
R3P R8P
~~rl----XP-YP~r2--¦ H2 R7 //A~
R2P /Cl~ CH
~~Ar >~'
R4P~) H 16
R5P
In the above forrnulas, Ql is a cyano group, a carboxyl
group, a lower alkoxycarbonyl group, a chloroforrnyl group or an N-
S methoxy-N-methylcarbamoyl group; Q2 is a halogen atom; zl is a
leaving group selected from the group consisting of a chlorine atom, a
bromine atom, an iodine atom, a trifluoroacetoxy group, a
methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a
p-toluenesulfonyloxy group; and
Cr Cr2 C~3-- Cr4--
RlP, R2P, R3E~, R4P, RSP~ R6~R7~ R8P, R9P are as defined above.
By this process, the desired compound (II) can be prepared
- by reacting a nitrile or a carboxylic acid derivative of the formula 1
15 with an aLkyl ].ithium of the formula 2 or an aLkyl Grignard reagent (or
an aLkyl Gilman reagent) of the formula 3 to obtain a ketone compound
_, then reacting an aLkylating agent of the formula S to the ketone

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96111022
- 244-
compound _ to produce a compound of the formula 6, then re~ctin~ the
compound 6 with an amine compound of the formula 7, followed by
reduction.
The above reaction steps will be described in detail
referring to suitable reaction conditions, etc.
The first step of preparing the ketone compound 4 is
conducted usually by reacting 1 mol or an excess molar arnount,
preferably from 1 to 5 mols of the aLkyl lithium reagent 2 or the alkyl
Grignard reagent (or the alkyl Gilman reagent in the case where the
10 substituent Ql of the compound 1 is a chloroformyl group) 3 to 1 mol of
the starting material compound 1 in a solvent inert to the reaction such
as tetrahydrofuran, ethyl ether or benzene, if necessary followed by
hydrolysis under an acidic condition.
The reaction temperature is usually from -80~C to the
15 boiling point of the solvent used for the reaction, preferably from -70~C
to 50~C. The reaction time is usually from S minutes to 48 hours,
preferably from 30 minlltes to 24 hours.
When the substituent Ql in the formula of the starting
material compound 1 is a cyano group, it may be necessary to conduct a
20 hydrolytic reaction under an acidic condition after completion of the
reaction, and such a hydrolytic reaction is conducted in e.g. methanol,
ethanol, tetrahydrofuran or a solvent mixture thereof with water in the
presence of an acid such as hydrochloric acid, sulfuric acid or p-
toluenesulfonic acid.
The reaction temperature is usually from O~C to the boiling
point of the solvent used for the reaction, and the reaction time is from
30 minutes to 24 hours.
The step of preparing the compound of the formula 6 from
the ketone compound _, can be conducted by reacting an equimolar
30 amount or an excess molar amount, preferably from 1 to 2 mols, of the
alkylating agent of the formula 5 to the ketone compound _ in the
presence of a base in an inert solvent which does not adversely affect the
reaction or without using any solvent.

CA 0222~2~ 1997-12-18
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- 245 -
The inert solvent may, for example, be an ether such as
ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such
as benzene, tolllene or xylene; an aprotic polar solvent such as
dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric
S triamide, or a nnixture ofsuch solvents.
The base to be used for this reaction, may, for example, be
an aL~ali metal hydride such as sodium hydride, lithium hydride or
potassium hydride; a lithillm amide such as lithium amide, lithium
diisopropyl~mi~le or lithium bis(trimethylsilyl)amide; an aL~yl lithillTn
10 such as methyl lithium, butyl lithium or tert-butyl lithium; an alkali
metal aL~oxide such as sodium methoxide, sodium ethoxide or potassium
tert-butoxide; or an aL~ali metal hydroxide such as sodium hydroxide,
potassium hydroxide or lithium hydroxide.
The base is used usually in an amount of 1 mol or an excess
15 molar amount, preferably from 1 to 5 mols, per mol of the starting
material aL~ylal;ing agent 5.
The reaction temperature is usually from -100~C to the
boiling point oiF the solvent used for the reaction, preferably from -80~C
to 100~C. The reaction time is usually from lO minutes to 48 hours,
20 preferably frorm 30 minlltes to 24 hours.
The step of preparing the desired compound (II) from the
compound of the formula 6 can be conducted usually in an inert solvent
such as methanol, ethanol, benzene, ethyl ether or tetrahydtofuran by
reacting 1 mol or an excess molar amount, preferably from l to 2 mols,
25 of the amine compound of the formula 7 to l mol of the compound of
the formula 6 to prelimin~rily form an imine, which is subsequently
reduced.
The reaction temperature in the process for forming the
above imine is usually from 0~C to the boiling point of the solvent used
30 for the reaction, preferably from room temperature to 100~C. The
reaction time is usually from 5 minlltes to 48 hours, preferably from 30
minutes to 24 hours. After the formation of the imine, the reaction
solution may be used as it is to the subsequent step of the reduction
reaction, or the reaction solution may be distilled or subjected to a

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
- 246 -
conventional separation means to isolate the imine compound, which is
then subjected to the subsequent reduction.
The reduction can be carried out by using a metal hyd~ide
complex such as sodium borohydride, sodium cyanoborohydride or
lithium aluminum hydride, or by catalytic reduction employing a
palladium-carbon catalyst or a Raney nickel catalyst.
When a metal hydride complex is used as a reducing agent,
the reducing agent is used usually in an amount of 1 mol or an excess
molar amount, preferably from 1 to 5 mols, per mol of the above
10 imine.
For the reduction, an inert solvent, for example, an alcohol
such as methanol or ethanol; an ether such as dimethyl ether, ethyl
ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane,
tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane,
15 hexane, heptane or cyclohexane; or an aromatic hydrocarbon such as
benzene or toluene; or a mixture of such solvents, can be used
a~ro~liately as a solvent depending upon the type of the reducing
agent.
The reaction temperature is usually from 0~C to room
20 temperature, and the reaction time is usually from 1 hour to 6 hours.
Further, in this process, it is also possible to react an
aL~ylating agent of the formula S to the nitrile or carboxylic acid
derivative of the formula 1 to prelimin~rily produce an aL~yl compound
and then to react an aL~yl lithium of the formula 2 or an aL~cyl Grignard
25 reagent (or an aL~yl Gilman reagent) of the formula 3 to the aL~yl
compound to obtain a compound of the formula 6. Such a reaction can
be conducted under the conditions ~imil~r to the above Process A.
Accordingly, the reaction conditions described for the above Process A
may all be used as the reaction conditions for this reaction.
The compounds of the formulas 1, 2, 3, 5 and 7 may be
commercially available or can be produced by a proper combination, as
the case requires, of the methods disclosed in Fx~mples, or conventional
methods or methods .simil~r thereto.

CA 02225255 l997- l2- l8
WO 97/0127S PCT~US96~11022
- 247 -
Process B
J ~~r1---XP-YP~ f H2
R2P R4P~~ 3 CH R6
reduction Rsp O
R3P
~~r1----XP-YP~ fH2
R2P R4P~r3--CI~OH 8
5PR R6
1 ) CH3SO2CI/TEA (or PBr3)
R3P R7
~r4--CH2-NH2
R9P 7
3 R8p
rlXP-YP~r2--fH /~R9P
R2P CH CH
~A 3/ >~NH [Il]
R4P--~ H l 6
R5P
S In the above formulas,

CA 0222~2~ l997- l2- l8
WO 97/01275 PCT/US96/11022
- 248 -
Cr ~ Cl2 ' Cr3 , /~~r4
XP, Yp, RlP
R2P, R3P, R4P, R5P, R6, R7, R8P and R9P are as defined above.
According to this process, the desired compound (II) can be
S prepared by reacting a reducing agent such as a metal hydride complex
to a compound of the formula 6 to obtain an alcohol compound 8 and
reacting an amine compound of the formula 7 to the alcohol compound
.
The above reaction steps will be described in detail
referring to suitable reaction conditions, etc.
The reaction for reducing the compound of the formula 6
to the alcohol compound 8 can be conducted usually by using a metal
hydride complex such as sodium borohydride, diisobutyl al-lminllm
hydride, lithium alllminuTn hydride or lithium tri-sec-butylborohydr~de
(L-selectrideTM), or by catalytic reduction employing e.g. a palladium-
carbon catalyst or a Raney nickel catalyst, in an inert solvent which does
not adversely affect the reaction.
When the metal hydride complex is used as the reducing
agent, such a reducing agent is used usually in an amount of 1 mol or an
excess molar amount, preferably from 1 to 5 mols, per mol of the
starting material compound 6.
The inert solvent to be used in this reaction may be suitably
selected depending upon the type of the reducing agent.
For example, when the reducing agent is sodium
borohydride, an inert solvent, such as an alcohol such as methanol or
ethanol; an ether such as dimethoxyethane, dioxane, tetrahydrofuran or
diglyme; an aprotic polar solvent such as dimethylformamide or
dimethylacetamide, or water, or a solvent mixture thereof, may be used,
and particularly preferred is an alcohol such as methanol or ethanol.
For example, when the reducing agent is diisobutyl
minum hydride, an inert solvent, such as an ether such as dimethyl
ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane,

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/IJS96/11022
- 249 -
dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as
pentane, hexane, heptane or cyclohexane; an aromatic hydrocarbon such
as benzene or toluene; methylene chloride, or a solvent mixture thereof
may be used, and particularly preferred is toluene or methylene
S chloride.
For example, when the reducing agent is lithium al1lminllm
hydride or lithium tri-sec-butylborohydride, an inert solvent, such as an
ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl
ether, dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an
aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane;
or an aromatic hydrocarbon such as benzene or toluene, or a solvent
mixture thereof, may be used, and particularly preferred is ethyl ether
or tetrahydrofuran.
For the catalytic reduction, the solvent is preferably an
alcohol such as methanol or ethanol.
The reaction temperature and the reaction time vary
depending upon the stability and the susceptibility to the reduction
reaction of the starting material ketone compound 6, the type of the
reducing agent and the type of the solvent. However, the reaction
temperature is usually from -80~C to 100~C, preferably from -70~C to
40~C, and the reaction time is usually~from S minlltes to 2 days,
preferably from 30 minutes to 24 hours.
The step of preparing the desired compound (II) from
a compound of the formula 8 can be carried out by reacting a
sulfonating agent such as meth~n~sulfonyl chloride to the alcohol
compound of the forrnula 8 in the presence of a base, or reacting a
halogenating agent such as thionyl chloride or phosphorous tribrornide
thereto, to convert the hydroxyl group in the formula to a leaving
group, followedL by reacting an amine compound of the forrnula 7.
The reaction for introducing the leaving group can be
- conducted usually by reacting 1 mol or an excess molar amount,
preferably from 1 to 2 mols, of a sulfonating agent and a base such as
triethyl~min~ to 1 mol of the a]Lcohol compound 8 in an inert solvent
such as methylene chloride, chloroform, benzene, tetrahydrofuran ~r

CA 0222~2~ l997- l2- l8
WO 97/01275 PCT/US96/llOZ2
- 250 -
ethyl ~cet~te, or using 1 mol or an excess molar amount, preferably
from 1 to 5 mols, of a halogenating agent.
The reaction tempelalule is usually from -70~C to the
boiling point of the solvent used for the reaction, preferably from -20~C
to 80~C, and the reaction time is usually from 5 minlltes to 48 hours,
preferably from 30 minutes to 24 hours.
Then, the step of reacting an amine compound _ to the
compound having the leaving group intro~ ce~l, obtained by the above
reaction, can be conducted usually by employing 1 mol or an excess
10 molar amount, preferably from 1 to 50 mols, of the amine compound 7
per mol of the starting compound having the leaving group, in an inert
solvent such as methylene chloride, chloroform, benzene, ethyl ether or
tetrahydrofuran .
If necessary, this reaction can be conducted in the presence
15 of a base other than the amine compound of the formula 7.
As such a base, an inorganic base such as sodium
hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,
potassium carbonate or sodium hydrogencarbonate, or an organic base
such as triethyl~mine, N-ethyldiisopropyl~mine, pyridine or N,N-
20 dimethyl~niline may, for example, be mentioned.
Such a base is used usually in an amount of 1 mol or an
excess molar amount, preferably from 1 to 5 mols, per mol of the
starting material compound.
The reaction temperature is usually from -50~C to 150~C,
25 preferably from -20~C to 100~C, and the reaction time is usually from 5
minutes to 7 days, preferably from 10 minlltes to 24 hours.

CA 02225255 l 997 - l 2 - l 8
WO 97/01275 PCT/US96~11022
- 251 -
Process C
R3P
R1P~_~ ~
(~r1--XP-YP~I~ Cl H2 8
R2P R4p~A,3 CH OH
~ H >~
R5P R6
1 )DEAD Ph P Phthalimide (or HN3 or DPPA)
) Cl~3~02CI, TEA
~ ii) Phthalimide (or NaN3)
2) NH2NH2 (or reduction)
R3P
R1p~ ~
5~r1---XP-YP~ ~ Cl H2 9
R2P R4P~r3 CH NH2
R5P R6
R8P o
1 ) ~r4--IC-R7 10
R9P
2) reduction
R8P
R3~ R9P
R2P rA 3/ >~NH [Il]
R4P ~ H R6
R5P

CA 0222~2~ 1997-12-18
WO 97/01275 PCT/US96/11022
- 252 -
In the above fonn~
Ar , (~~r2 Cr3-- f Ar
XP, Yp, RlP
R2P, R3P, R4P, R5P, R6, R7, R8P and R9P are as ~lefîne-l above.
According to this process, the desired compound (II) can be
pre~aled by firstly reacting diethyl azodicarboxylate,
triphenylphosphine and phth~limide (or hydrogen azide or
diphenylphosphoryl azide) or reacting a sulfonylation agent such as
methanesulfonyl chloride in the presence of a base such as triethylamine,
then reacting phth~limi(1e (or sodium azide) in the presence of a base, to
the alcohol compound of the formula 8, to obtain a phth~limide-
protected form (or an azide compound) of the amine compound 2, then
reacting hydrazine (or a reducing agent) to remove the phth~limicle
group (or reduce the azide group) to obtain an amine product of the
formula 9. and finally re~-ting a compound of the formula 10 to the
compound 2, followed by reduction.
The above reaction steps will be described in detail
referring to suitable reaction conditions, etc.
For the step of producing the amine compound of the
formula 2 from the alcohol compound 8, various synthetic methods and
reaction conditions well known in organic synthetic chemistry for
converting alcohol compounds to amines, may be employed. For
example, it is preferred to employ a Mitsunobu reaction using diethyl
azodicarboxylate, triphenylphosphine and phth~limide (or hydrogen
azide or diphenylphosphoryl azide) or a method which comprises
sulfonylation with a sulfonylation agent such as methanesulfonyl
chloride in the presence of a base such as triethylamine, then reacting
phth~limide (or sodium azide) in the presence of a base, and ~en
treating the obtained phth~limide compound with hydrazine (or
reducing the azide compound).
The above reactions are conducted usually in a solvent inert
to the reaction. The inert solvent may,for example, ~lefel~bly be
tetrahydrofuran,dimethoxyethane, benzene or toluene in the case of the
above-mentioned Mitsunobu reaction; methylene chloride, chloroform,

CA 0222~2~ l997- l2- l8
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- 253 -
tetrahydrofuran, benzene, ethyl acetate or dimethylform~mi~le in the
case of the sulfonylation followed by the reaction with phth~limicle (or
sodium azide); ~m alcohol such as methanol or ethanol in the next step of
the phth~limi~le-removing reaction with hydrazine; an ether such as
5 ethyl ether or tetrahydrofuran in the case where a metal hydride
complex is used as the reducing agent in the reduction reaction of the
azide compouncl; water-cont~inin~ tetrahydrofuran in the case where
phosphine reduction is conducted with triphenylphosp-h-ine or the like;
and an alcohol such as methanol or ethanol in the reduction by catalytic
1 0 reduction.
Wi~h respect to the amounts of the reagents to be used, in
the above Mitsunobu reaction, each of diethyl azodicarboxylate,
triphenylphosph!ine and phth~limide (or hydrogen azide or
diphenylphosphoryl azide) is used in an amount of 1 mol or an excess
15 molar amount, preferably from 1 to 5 mols, per mol of the starting
material alcoho]L compound 8. In the reaction with the phth~limide (or
sodium azide) after the sulfonylation, the sulfonylation agent such as
methanesulfonyl chloride is used in an amount of 1 mol or an excess
molar amount, ~lefel~bly from 1 to 2 mols, per mol of the alcohol
20 compound 8, and the base such as triethylamine used at that time is
usually in an amount of 1 mol or an excess molar amount, preferably
from 1 to 2 mols, per mol of the sulfonylation agent. In the next step of
the reaction with phth~limicle (or sodium azide) in the presence of a
base, 1 mol or an excess molar amount, preferably from 1 to 5 mols of
25 each of phth~limide and the base (or sodium azide) is used per mol of
the starting material sulfonylation agent. Here, the base to be used
together with phth~limide is preferably sodium carbonate or potassium
carbonate. Otherwise, without using such a base, a sodium salt or a
potassium salt of phth~limicle may be used by itself. Then, in the
30 reaction for removing the phth~limide group with hydrazine, hydrazine
is used in an amount of 1 mol or an excess molar amount, preferably
from 1 to 10 mols, per mol of the phth~limide compound as the starting
material compound. In the reduction of the azide compound with a
~ metal hydride complex or with triphenylphosphine, the reducing agent

CA 0222~2~ 1997-12-18
WO 97/01275 1 ~_ l/U~;' .S/11022
- 254 -
is used usually in an amount of 1 mol or an excess molar amount,
preferably from 1 to 2 mols, per mol of the azide compound.
In the case of the above Mitsunobu reaction, the
reaction temperature is usually from -70~C to 100~C, preferably from
-20~C to 50~C, and the reaction time is usually from 5 minlltes to 48
hours, preferably from 30 minutes to 24 hours. In the reaction for
removing the phth~limille group by hydrazine, the reaction temperature
is usually from 0~C to the boiling point of the solvent used for the
reaction, preferably from room temperature to 100~C, and the reaction
time is usually from 5 minntes to 48 hours, preferably from 30 minutes
to 24 hours. In the reaction for converting the azide compound to the
amine compound by reduction, when a metal hydride complex is used as
the reducing agent, the reaction temperature is usually from -70~C to
150~C, preferably from -20~C to 50~C, and the reaction time is usually
from 5 minutes to 48 hours, preferably from 10 minutes to 10 hours.
When triphenylphosphine is used as the reducing agent, the reaction
temperature is usually from room temperature to the boiling point of
the solvent used for the reaction, preferably from 30~C to 100~C, and
the reaction time is usually from 10 minutes to 48 hours, preferably
from 30 minutes to 24 hours. Further, in the case of the reduction by
catalytic reduction, the reaction temperature is usually from 0~C to
100~C, preferably from room temperature to 50~C, and the reaction
time is usually from 10 minutes to 48 hours, preferably from 10
minutes to 24 hours.
The step for producing the desired compound (II) from
the compound of the formula 9 is carried out usually by prelimin~rily
forming an imine by reacting 1 mol or an excess molar amount,
preferably from 1 to 2 mols of the compound of the formula 10 to 1
mol of the compound of the formula 9 in an inert solvent such as
30 methanol. ethanol, benzene, ethyl ether or tetrahydrofuran, and then
reducing it. -
This step can be carried out in the same manner as the step
for producing the desired compound (II) from the compound of the

CA 02225255 1997-12-18
WO 97/0127S PCTIUS96/11022
- 255 -
formula 6 in the above process A. Accordingly, with respect to the
reaction conditions, etc., .simil~r conditions may be employed.
Further, the compound of the formula 10 may be
commercially available or can be produced by a proper combination, as
S the case requires, of the methods disclosed in Examples, or conventional
methods or mel:hods similar thereto.

CA 02225255 1997-12-18
WO 97/0127S PCT/US96/11022
- 256 -
Process D
R4P
O
R5P R3P
R14_ya~r2--CH2-~
1 1 base
R3P
R!4_ya~,~ Cl H2 12
/CH R6
R4P~Ar3 ~
~ ~
R5P
1) reduction
2) CH3SO2CI, TEA, NaN3
(or DEAD, Ph3P, DPPA)
3) reduction
R3P
R14_yp~r2--fH2 13
/CH--CH-NH2
rAr3 R6
R4P~
R5P

CA 02225255 l997- l2- l8
WO 97/01275 PCT/US96J11022
- 257 -
.
~r4--C - R7
R9P
1 ~)
2) reduction
R3P R8P
R14_ya~Ar2--Cl H2 R
C~ CH
rAr3/ >~NH 14
R4P--~ R6
IR5P
1) HO - C -AP- COORP [Ill]
2) selective removal of
protecting groups
R3P ~ R8P
H _Ya~r2--CH2 7 /A~ R9P
~Ar3/ >~N~AP-COORP
R5P
in the above form~ .c, R14 means a hydroxylprotecting group when ya
- is an oxygen atom; a mercapto-protecting group when ya is a sulfilr
5 atom; or an amino- or imino-protecting group when ya is a group of
the formula -NRb- (wherein Rb is as defined above); and

CA 0222~2~ 1997-12-18
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- 258 -
C~ C~ Cr4
AP ya, Zl, R3P, R4P, RSP, R6, R7, R8P, R9P and RP are as defined
above.
According to this process, the desired compound (VI) can
S be prepared by firstly reacting an alkylating agent of the forrnula 11 to
a ketone compound of the formula 4 to obtain a compound of the
formula 12, reacting a reducing agent such as a metal hydride complex
to the compound 12 to obtain an alcohol compound, then reacting
diethyl azodicarboxylate, triphenylphosphine and phth~limi~1e (or
10 hydrogen azide or diphenylphosphoryl azide) or reacting a sulfonylation
agent such as methanosulfonyl chloride in the presence of a base such as
triethyl~minP, and then reacting phth~limide (or sodium azide) in the
presence of a base, to obtain a phthz~limide-protected form (or an azide
compound) of the amine compound 1~, then reacting hydrazine (or a
15 reducing agent) to remove the phth~limide group (or reduce the azide
group) to obtain an amine compound of the formula 13, reacting a
compound of the formula 10 to the compound 13, followed by reduction
to obtain a compound of the formula 14, reacting a carboxylic acid of
the formula (III) or its reactive derivative to the compound 14, and
20 finally selectively removing the protecting group represented by R14.
The step of producing a compound of the formula 12 from
a ketone compound of the formula 4, can be carried out in the same
manner as the step of producing the compound of the formula 6 from
the ketone of the formula_ in the above process A. Accordingly, with
25 respect to the reaction conditions, etc., similar conditions may be
employed.
When R14 is a hydroxyl-protecting group, such a
hydroxyl-protecting group may be the one disclosed above with respect
to process 1.
When R14 is a mercapto-protecting group, the hydroxyl-
protecting group disclosed above with respect to process 1 can be used
as such a mercapto-protecting group.

CA 0222~2~ 1997-12-18
WO 97~0127~; PCT~U596/IIllZZ
- 259 -
When R14 is an amino- or imino-protecting group, such an
amino- or imino-protecting group may be the amino- or imino-
protecting group disclosed above with respect to process 1.
In the step of producing the amine compound of the
S formula 13 after reacting a reducing agent such as a metal hydride
complex to the compound of the formula 12 to obtain an alcohol
compound, the step of converting the compound of the formula 12 to
the alcohol compound can be carried out in the same manner as the step
of reducing the compound of the formula 6 to the alcohol compound 8
in the above process B. Accordingly, with respect to the reaction
conditions, etc.~ .cimil~r conditions may be employed. Further, the step
of producing an amine compound of the formula 13 from the obtained
alcohol, can be carried out in the same manner as in the step of
producing the amine compound 2 from the alcohol compound of the
formula 8 in the above process C. Accordingly, with respect to the
reaction conditions, etc., .~imil~r conditions may be employed.
The step of producing a compound of the formula 14 from
the amine compound of the formula 13, can be carried out in the same
marmer as in the step of producing a compound of the formula (II) from
the amine of the formula 9 in the above process C. Accordingly, with
respect to the reaction conditions, etc., simil~r conditions may be
employed.
In 1he step of producing the desired compound (VI) from
the compound of the formula 14, the reaction of the compound of the
formula 14 with the carboxylic acid of the formula (III) or its reactive
derivative, can be carried out in the same manner as the reaction of the
compound of the formula (II) with the carboxylic acid of (III) or its
reactive derivative in the above process 1. Accordingly, with respect to
the reaction conditions, etc., .~imil~r conditions may be employed.
For the step of selectively removing the protective group
- represented by R14 from the compound obtained by the above reaction,
various methods may suitably be selected depending upon the type and
the characteristics of the protecting group. Namely, ~ltili7ing the
difference in the stability against an acid, a base or reduction between

CA 0222~2~ l997- l2- l8
WO 97/0127S PCT/US96/11022
- 260 -
R14 and other protecting groups, the protecting group can selectively be
removed by a conventional means such as an acid, a base or reduction.
With respect to specific conditions for such a reaction, the methods
disclosed in known literatures, such as "Protective Groups in Organic
5 Synthesis, T.W. Greene, John Siley & Sons (1981)", may, for example,
be used.
Further, the compound of the formula 11 may be
commercially available, or may be produced by a proper combination.
as the case requires, of the methods disclosed in Examples, or
10 conventional methods or methods .cimil7~r thereto.

CA 02225255 1997-12-18
WO 97101~75 PCT/US96/1~022
- 261 -
Process E
R4P
~~r- CH2-liC-R6 4
R5P R3P
R15,~ CH2-Z1/
/ base
1 S
R3P
R15~'~ CH2
16
/CH R6
R4P ~Ar3 ~
~) ~
R5P
1~ reduction
2) CH3SO2CI, TEA, NaN3
(or DEAD, Ph3P, DPPA)
3) reduction
R3P~
R1s~r2--fH2 17
/CH--CH-NH2
rA~3 R6
R4P~
R5P

CA 02225255 1997-12-18
WO 97tO127S PCT/US96/11022
- 262 -
R3P o
,~ C-R7
1 0
2) reduction
R3P R3P
R1s~r2--CH2 R7 /A~
CH~ CH
rAr3/ >~NH 18
R4P ~J H R6
R5P
1) HO - C -AP- COORP [Ill]
2) selective removal of
protecting groups
R3P ~ R8P
Rl6_co~ f R7'CH/ ~
CH
rAr3 >,,N~AP-COORP
R4P~' R6 19
R5P

CA 02225255 1997-12-18
WO 97/01275 PCT/USg6~0Z2
- 263 -
~!
reduction
R3P ~ R8P
HC~r~--I H2 R7 /A~R9P
R4P--~r3/ ~N~AP-COORP
R5P
introduction of leaving group
R3P ~ R3P
CH CH
R4P~ H>l~6 ~ ~ a]
In the above formulas, R15 is a protected carboxyl group or a group of
the formula Ra-C(ORPl)(ORP2)- (wherein each Of Rpl and RP2 which
S are the same or different, is a methyl group or an ethyl group, or RP 1
and RP2 together represent an ethylene group, and Ra is as defined
above); R16 is a hydroxyl group or a group of the formula Ra (wherein
Ra is as defined above); and

CA 0222~2~ 1997-12-18
WO 97/01275 PCT/US96/11022
- 264 -
C~ ' C~ Cr4
AP Z, zl, R3P, R4P, R5P, R6, R7, R8P, R9P, Ra and RP are as defined
above.
According to this process, the desired compound (VIII-a)
S can be prepared by firstly reacting an alkylating agent of the formula 15
to a ketone compound of the formula _ to obtain a compound of the
formula 16, reacting a reducing agent such as a metal hydride complex
to the compound 16 to obtain an alcohol compound, then reacting
diethyl azodicarboxylate, triphenylphosphine and phth~limide (or
10 hydrogen azide or diphenylphosphoryl azide), or reacting a
sulfonylation agent such as methanesulfonyl chloride in the presence of a
base such as triethyl~mine and then reacting phth~limide (or sodium
azide) in the presence of a base, to obtain a phth~limide-protected form
(or an azide compound) of the amine compound 17, then reacting
15 hydrazine (or a reducing agent) to remove the phth~limide group (or
reduce the azide group) to obtain an arnine compound of the formula
17, reacting a compound of the formula 10 to the compound 17,
followed by reduction to obtain a compound of the formula 18, reacting
a carboxylic acid of the formula (III) or its reactive derivative to the
20 compound 18, then selectively removing the protecting group at R15 to
obtain a compound of the formula 19, reacting a reducing agent to the
compound 19 to obtain a compound of the formula 20, and finally
introducing a leaving group to the compound 20.
The respective steps up to the production of the compound
25 of the formula 19 from the ketone compound of the formula 4 can be
carried out in the same manner as the respective steps for the production
of the compound of the formula (VI) from the ketone compound of the
formula 4 in the above process D. Accordingly, with respect to the
reaction conditions, etc., the same conditions as in the corresponding
30 respective steps can be employed.
The step of reacting a reducing agent to the compound of
the formula 19 to obtain the compound of the formula 20, can be

CA 02225255 1997-12-18
WO 97J ~1275 PCT~'(JS96~1~022
- 265 -
conducted in t~he same manner as the reduction method employing e.g.
sodium bor~rd~ide as a reducing agent in the step of reducing the
compound of the formula 6 to an alcohol compound 8 in the above
process B. Accordingly, with respect to the reaction conditions, etc.,
S .simil~r conditions can be employed.
Tlle step of producing the desired compound (VIII-a) by
introducing a leaving group to the compound of the formula 20 can be
carried out in the same manner as in the method of introducing a
leaving group ItO the compound of the formula 8 in the above process B
10 by using, for e~ample, a halogenating agent such as thionyl chloride,
phosphorus trichloride, phosphorus pentachloride, phosphorus
oxychloride, plhosphorus tribrornide, oxalyl chloride or phosgene, or a
sulfonating agent such as methanesulfonyl chloride, p-toluenesulfonyl
chloride or benzenesulfonyl chloride. Accordingly, with respect to the
15 reaction conditions, etc., ,cimil~r conditions may be employed.
Further, the compound of the formula 15 may be
commercially available, or can be produced by a proper combination, as
the case requires, of the methods disclosed in Examples, or conventional
methods or methods simil~r thereto.
Process F
-

CA 02225255 1997-12-18
WO 97/01275 PCT/US96/11022
- 266 -
R3P R8p
H02C ~r ¦ H2 R7 ~A~ RgP
R4P ~)r3/ ~N~AP-COORP
R5P
introduction of leaving group
R3P ~ R3P
Z~ ¦ R7~CH/ ~
R4P ~3/ >~N~AP-COORP
R5P
In the above formulas,
Cr2 Cr3 Cr4--
AP, Z, R3P, R4P, R5P, R6, R7, R8P, R9P and RP are as defined above.
According to this process, the desired compound (VIII-b)
can be prepared by introducing a leaving group to the compound of the
formula l9-a in the same manner and conditions as the method of
introducing a leaving group to the compound of the forrnula 20 in the
above process E.
Process G

CA 02225255 1997-12-18
WO 9-7J0~2'J~i PCT/US96/11022
- 267 -
R3P R3P
HC~r2--I H2 7 A~R9P
rAr3 / ~ N~ AP-COORP
R4P~ 6 [Vlll-a]
R5P
PPh3 or P(OMe)3 or P(OEt)3
R3P ~ R3P
Ra/ ~ I H2 R7 /A~
rAr~/ ~N~AP-COORP
R4P ~) ~6 [X]
R5F)
In the above formulas,
C C Cr--
AP, Q, Z, R3P, R4p, RSP, R6, R7, R8P, R9P, Ra and RP are as defined
~~ above.
According to this process, the desired compound (X)
can be prepared by reacting triphenylphosphine, trimethyl phosphite or
triethyl phosphite, to the compound of the formula (VIII-a).

CA 0222~2~ 1997-12-18
WO 97/01275 PCT/US96/11022
- 268 -
When a triphenylphosphine is reacted, the above reaction is
carried out usually in an inert solvent which does not affect the reaction.
As such an inert solvent, toluene or xylene is, for example, preferred.
The triphenylphosphine is used usually in an amount of 1
S mol or an excess molar amount, preferably from 1 to 5 mols, per mol
of the compound (VIII-a).
The reaction temperature is usually from room temperature
to the boiling point of the solvent used for the reaction, preferably from
80~C to 150~C. The reaction time is usually from S minutes to 7 days,
10 preferably from 1 hour to 24 hours.
Likewise, when trimethyl phosphite or triethyl phosphite is
reacted to the compound (VIII-a), the above reaction is conducted
usually in an inert solvent which does not affect the reaction, or more
preferably, an excess trimethyl phosphite or triethyl phosphite is used as
15 both the solvent and the reactant.
The reaction temperature is usually from room temperature
to the boiling point of the solvent for the reaction, preferably from
80~C to 150~C, and the reaction time is usually from 5 minutes to 7
days, preferably from 1 hour to 24 hours.
A compound of the formula (XII):
RlP
Ar1--CH - Q (Xll)
R2P~<J R1a
Cr1
wherein Q, RlP, R2P and Rla are as defined above, can
be prepared from a compound of the formula (XIV):

CA 02225255 1997-12-18
WO 97~01275 PCT/US96/11022
R1P - 269 -
>~
Arl--CH - Z (XIV)
R2p~ 1 1
,. Ra
Crl ,
wherein Z, R1P, R2P and Rla are as defined above, in
accordance with process G.
Further, the compound of the formula (XIV) may be
commercially available, or can be prepared by a proper combination, as
the case requires, of the methods disclosed in Examples, or conventional
methods or methods similar thereto.
Further, the formula (XIII):
R3P R8P
~~r2 I H2 R7 ~A~R9P (Xlll)
R4p~lr3/ >~N~AP-COORP
R5P
Ar2 (3r3 ~ 4
wherein ~ , AP, R3P, R4P,
RSP, R6, R7, R8P, R9P, RP and R2a are as defined above, is
15 subst~nti~lly the same as the formula 19 in the above process E, wherein
R16 is a group of the fonnula Ra. Accordingly, the compound of the
formula (XIII) can be prepared by the above process E.
-

CA 0222~2~ 1997-12-18
WO 9710127S PCT/US96/11022
- 270 -
Process H
R19~ ,COOR20
Rl7CH2 - COOR18 + Cl base
;21 COOR21
R17 R19
deprotection
R18 OOC-CH-CIH- R--COOR20
COOR2l
Rl7 R19
H-OOC-CH-Cr--C--COOR20 [Ill-a]
COOR21
In the above formulas, each of R17 and Rl9 which are the
same or different, is a hydrogen atom, a lower aL~yl group, an aryl
group or an aralkyl group; each of R20 and R21 which are the sarne or
different, is a carboxyl-protecting group; and R18 is a tert-butyl group,
a benzyl group, a benzhydryl group or a trityl group.
Process H is a process for preparing a carboxylic acid
derivative of the formula (III-a) among the compounds of the above
formula (III).
According to this process, the desired carboxylic acid
derivative (III-a) can be prepared by conducting a so-called Michael
addition reaction which comprises reacting a maleic acid derivative or a
fumaric acid derivative of the formula ~ to an ester derivative having a
readily removable carboxyl-protecting group R18, represented by the
formula 21, in the presence of a base, and then removing the carboxyl-
protecting group Rl8 from the obtained Michael addition product 23
under a mild condition.
As the carboxyl-protecting group for R20 and R21, a

CA 0222~2~ l997- l2- l8
WO 97/Oli7S PCT/US96/11022
t - 271 -
lower aL~yl group such as a tert-butyl group, or a benzhydryl group, is
preferred.
Thle protecting group R18 is preferably the one which
can readily be removed under a mild condition of catalytic reduction or
5 wealcly acidic condition and which is stable under the Michael addition
reaction condition, such as a tert-butyl group, a benzyl group, a
benzhydrylgrol1p or a trityl group.
The above Michael addition reaction can be conducted by
reacting the co]mpound of the formula 22 in an amount of 1 mol or an
10 excess molar aimount, preferably from 1 to 2 mols, to 1 mol of the
compound of the formula 21 in the presence of a base such as sodium
hydride, butyl lithium, lithium diisopropylamide or lithium
bis(trimethylsilyl)amide usually in an inert solvent such as benzene,
ethyl ether or l:etrahydrofuran.
Such a base is used-usually in an amount of 1 mol or a
slightly excess molar amount, preferably from I to 1.5 mols, per mol of
the compound of the formula 22.
The reaction temperature is usually from -100~C to 100~C,
preferably frorn -80~C to room temperature, and the reaction time is
usually from 5 minutes to 24 hours, preferably from 10 minutes to 10
hours.
The reaction conditions for the reaction for removing the
protecting group from the compound of the formula 23 to form the
desired carboxylic acid derivative (III-a), vary depending upon the type
of the protecting group, etc. For example, when the protecting group is
~ a tert-butyl group, a benzhydryl group or a trityl group, a method may
be employed wlherein the compound is treated with an acid such as acetic
acid, formic acid, trifluoroacetic acid or hydrochloric acid, preferably
within a temperature range of from -20~C to 50~C for from 10 minutes
to 24 hours in t~he absence of a solvent or usually in an inert solvent such
- as methylene chloride, anisole, tetrahydrofuran, methanol or ethanol or
a solvent mixture thereof with water.
For example, when the protecting group is a benzyl group,
a benzhydryl group or a trityl group, a method may be employed

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
- 272 -
wherein the compound is catalytically reduced with a catalyst such as a
p~ m-carbon catalyst or a Raney nickel catalyst preferably under a
hydrogen pressure of from 1 to 20 kg/cm2 preferably within a
tempelaLule range of from 0~C to 40~C for from 10 minutes to 24
S hours usually in an inert solvent such as methanol, ethanol, dioxane,
water or acetic acid, or a solvent mixture thereof.
Among compounds of the formula (III-a), an optically
active compound of the formula (III-b1):
H-OOC-CH2~ CH2-COORl9 (Ill-bl)
H COORl 8
or the formula (III-b2):
H-OOC-CH2--C-CH2-COORl9 (lll-b2)
~ \
H COORl8
wherein each of R18 and R19 which are the same or different, is a
carboxyl-protecting group, can be obtained by reacting a racemic
mixture of the compound of the formula (III-b):
H-OOC- CH2- Cr CH2- COOR1 9 (Ill-b)
COORl8
wherein R18 and R19 are as defined above, with cinchonidine or
quinine to obtain a mixture of two diastereomers, then separating and
25 collecting either one of the diastereomers by lltili7ing the difference in
the solubility as between the two diastereomers, followed by recovering
the free carboxylic acid by treating with an acid.
Separation of the diastereomer mixture may be conducted
in an organic solvent such as carbon tetrachloride or isopropyl ether.
30 Usually, the mixture of the diastereomers is dissolved in a solvent in a

CA 02225255 1997-12-18
WO 97101275 ~CTrUS96111022
- 273 -
hot state, and t~he solution is gradually cooled to utilize the solubility
diLrel~llce for separation of the diastereomers.
Further, either one of the diastereomers thus obtained is
treated with an acid such as hydrochloric acid to obtain an optically
S active compou:nd of the formula (III-bl) or (III-b2).
The compounds of the formula 21 and 22 may be
commercially available or can be produced by a proper combination, as
the case requires, of the methods disclosed in Examples, or conventional
methods or methods simil~r thereto.

CA 02225255 l997- l2- l8
WO 97/01275 PCT/US96/11022
- 274 -
Process I
R3P J~
~ Rs OCORt
W~r2 Cl H2
CH - CH - OH
R4P~r3/ R6
R5P
R3P R3P
(R) ~ CH2 (S)
R4P~ CH - CH - OCORt /CH - CIH - OCORt
R5P R5P
2~ Z
R3P R3P
W ~r2 CH2 (R) W ~r2 CH2 (R)
/CH - CH - OCORt CH - CH - OH
R4P~r3 R hydrolysis ~)r3/ R6 r
R5P R5P
~ ;~ _

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R1P
R2p ~r~ XP-YP-
In the above formulas, W is (wherein
(~~rl
--~/ , XP, YP, RlP and R2P are as defined above), R14-Ya-
(wherein ya and Rl4 are as defined above) or Rl5 (wherein Rl5 is as
de~med above)l; RS is a hydrogen atom or a methyl group; Rt is a lower
S alkyl group, an aryl group or a lower aL~enyl group; and
(~r2-, (~r3
, R3P, R4P, R5P and R6 are as defined above.
Process I is a process for preparing an optically active
substance 27 or 28 of an alcohol compound 24 obtainable as the above
lO formula 8 or a reduction product of the formula 12 or 16.
According to this process, the desired optically active
alcohol compounds 27 and 28 can be prepared by reacting a vinyl ester
derivative of the formula ~S to a racemic alcohol derivative of the
formula 24 in the presence of a lipase, separating the obtained optically
15 active ester derivative 26 and the optically active alcohol derivative, and
then hydrolyzing the ester group with respect to the optically active
ester derivative 26.
Rt of the vinyl ester derivative of the formula 25 is
preferably a lower alkyl group such as a methyl group or an ethyl
20 group; an aryl group such as a phenyl group or a naphthyl group; or an
araL~yl group such as a benzyl group or a 2-phenylethyl group.
Particularly preferred is a methyl group, i.e. a case wherein the
compound of tb~e forrnula 25 is vinyl acetate or isopropenyl acetate.
Th~e above optical resolution reaction by lipase can be
25 conducted usua]Lly in an inert solvent such as methylene chloride,
- chloroform, ethyl ether, tetrahydrofuran, benzene, toluene, hexane,
heptane or acetonitrile, or by using the starting material vinyl ester
derivative of the formula 25 itself as the solvent.
-

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The vinyl ester derivative 25 is used usually in an amount
of 1 mol or in a large excess molar amount, preferably from 1 to 100
mols, per mol of the starting material compound 24, and the amount of
the lipase as the catalyst is from 0.01 to 100%, preferably from 0.1 to
5 20%, by weight, relative to the compound 24.
The type of the lipase is preferably a lipase derivative from
Pseudomonas sp. such as Toyothium LIPTM (manufactured by Toyobo).
Further, the above enzymatic reaction tends to be
accelerated, when the reaction is carried out in the presence of a base.
10 As a base to be used for this purpose, an organic base such as
triethylamine or diisopropylethylamine, is preferred.
The base is used usually in an amount of 0.01 mol or
slightly excess molar amount, preferably from 0.1 to 1.5 mols, relative
to the starting material compound 24.
The reaction temperature is usually from 0~C to 50~C,
preferably from room temperature to 40~C. The reaction time is
usually from 30 mimltes to 7 days, preferably from 1 hour to 48 hours.
The hydrolytic reaction of the ester of the formula 26 can
be conducted by a common method well known in the organic synthetic
20 chemistry under an acidic or basic condition.

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Th.e compound of the formula (hh) of the present invention
can be prepared, for example, by the following process 1, 2, 3, 4, ~, 6
or 7.
S Process 1
The compound of the formula (hh) can be prepared by reacting a
compound of tlle formula (II):
RlP R7P
R2~)~r1 Q--I H2 R6 ~A~
rAr2/ ~ NH
R3P--~'' H R5
R4P
Cr~- ~ Cr2--and Cr3
wherein each of which
are the same or different, is an aryl group or a heteroaromatic ring
group; Q is a group of the formula -(cH2)m- (wherein m is an integer
of from 1 to 6) or-(cH2)n-w-(cH2)p- (wherein W is an oxygen atom, a
15 sulfur atom, a ~inylene group or an ethynylene group; and each of n and
p which are the same or different, is an integer of from 0 to 3); RlP is a
hydrogen atomy a halogen atom, a hydroxyl group which may be
protected, a lower alkyl group, a lower aL~oxy group, or an aryl or
heteroaromatic ring group which may have substituent(s) selected from
20 the group consisting of a halogen atom, a lower alkyl group and a lower
aLkoxy group; each of R2P, R7P and R8P which are the same or
different, is a hydrogen atom, a halogen atom, a hydroxyl group which
may be protected, a lower alkyl group or a lower alkoxy group; each of
R3P and R4P which are the same or different, is a hydrogen atom, a
25 halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl

CA 0222~2~ 1997-12-18
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group, a carbamoyl group, a lower aL~ylcarbamoyl group, a lower aL~yl
group, a lower fluoroaL~yl group, a lower aL~oxy group or a hydroxyl,
amino, carboxyl or lower hydroxyaL~yl group which may be protected;
R5 is a lower aLkyl group; and R6 is a hydrogen atom or a lower aL~yl
5 group, with a carboxylic acid of the formula (III) or its reactive
derivative:
HO~AP-CO2RP (111)
10 wherein AP is a C2-8 saturated or lm.~hlrated aliphatic hydrocarbon
group which may have substituent(s) selected from the group consisting
of a lower aL~yl group, a lower aL~oxy group, an aryl group, an araL~yl
group, and hydroxyl, lower hydroxyaL~yl, carboxyl and lower
carboxyaL~cyl groups which may be protected; and RP is a hydrogen
15 atom or a carboxyl-protecting group, to obtain a compound of the
formula (IV):
R1P R7P
R5~CH/~ (IV)
rAr2/ ~N~AP - COORP
R3P ~ R5 ~
R4P
Crl-- Cr2 Cr3
wherein AP, Q, RlP, R2p
R3P, R4P, R5, R6, R7P, R8P and RP are as defined above, and, if
20 necessary, removing any protecting group.
As the reactive derivative of the carboxylic acid of the
formula (III), an acid halide, a mixed acid anhydride, an active ester or
an active amide may, for example, be used.

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Wlhen the carboxylic acid of the formula (III) is used, it is
preferred to conduct the reaction in the presence of a condensing agent
such as N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-
~! dimethylaminopropyl)carbodiimide or 2-chloro- 1 ,3-dimethylimi(1~7olyl
chloride.
The reaction of the compound of the formula (II) with the
carboxylic acid of the formula (III) or its reactive derivative, is
conducted usually by using 1 mol or an excess molar amount, preferably
from 1 to 5 mols, of the carboxylic acid of the formula (III) or its
reactive derival:ive~ per mol of the compound of the formula (II).
The reaction is conducted usually in an inert solvent. The
inert solvent may, for example, be a halogenated hydrocarbon such as
methylene chloride, chloroform, carbon tetrachloride, dichloroethane
or trichloroethylene; an ether such as ethyl ether, tetrahydrofuran or
dioxane; an aromatic hydrocarbon such as benzene, toluene,
chlorobenzene or xylene; an aprotic polar solvent such as
dimethylformamide, acetonitrile,
acetone, ethyl acetate or hexamethylphosphoric triamide, or a mixture
of such solvents.
The reaction temperature is usually from -70~C to the
boiling point oi~ the solvent used for the reaction, preferably from -20~C
to 100~C.
The reaction time is usually from 5 minutes to 7
days, preferabl~y from 10 minutes to 24 hours.
The above reaction can be conducted in the presence of a
base to facilitate the reaction. As such a base, it is preferred to conduct
the reaction in the presence of an inorganic base such as sodium
hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,
potassium carbonate or sodium hydrogen carbonate, or an organic base
such as triethyl~mine, N-ethyldiisopropylamine, pyridine, 4-
-. dimethylaminopyridine or N,N-dimethyl~niline.
Such a base is used usually in an amount of 1 mol or
an excess molar amount, preferably frorn 1 to 5 mols, per mol of the
reactive derivative of the carboxylic acid of the formula (III).

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The acid halide of the compound of the formula (III) can be
obtained by reacting the carboxylic acid of the formula (III) with a
halogenating agent in accordance with a conventional method. As the
halogenating agent, thionyl chloride, phosphorus trichloride, t
5 phosphorus pentachloride, phosphorus oxychloride, phosphorus
tribromide, oxalyl chloride or phosgene may, for example, be used.
The mixed acid anhydride of the compound of the
formula (III) can be obtained by reacting the carboxylic acid of the
formula (III) with an aL~yl chlorocarbonate such as ethyl
10 chlorocarbonate or with an aliphatic carboxylic acid chloride such as
acetyl chloride, in accordance with a conventional method. Further, an
intramolecular acid anhydride may be formed between carboxyl groups
at both terminals, or when in the formula (III), a carboxyl group is
present on the saturated or lln~tllrated aliphatic hydrocarbon group for
15 AP, an intramolecular acid anhydride may be formed between such a
carboxyl group and a carboxyl group to be involved in the reaction, to
constitute a reactive derivative of the carboxylic acid.
The active ester of the compound of the formula (III) can
be prepared by reacting the carboxylic acid of the formula (III) with an
20 N-hydroxy compound such as N-hydroxysuccinimi~le, N-
hydroxyphth~limide or l-hydroxybenzotriazole, or a phenol compound
such as a 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol or
pentachlorophenol, in the presence of a condensing agent such as N,N'-
dicyclohexylcarbodiimide or l-ethyl-3-(3-
25 dimethylaminopropyl)carbodiimide in accordance with a conventionalmethod.
The active amide of the compound of the formula (III) can
be prepared by reacting the carboxylic acid of the formula (III) with
e.g. 1,1'-carbonyldiimidazole or l,1'-carbonylbis(2-methylimidazole) in
30 accordance with a conventional method.
When a hydroxyl group is present on the group of the -
formula

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WO 97/01275 PCT/US96~ OZ2
- 281 -
.~
RlP~C~ R7P~
Ar1__ (~ Ar3
>L~ ~
.. R2P R8P
when a hydroxyl group, a lower hydroxyaL~yl group, a carboxyl group
or a lower carboxyalkyl group is present on thLe saturated or lln~ lrated
aliphatic hydrocarbon group represented by AP, and when a hydroxyl
5 group, an aminLo group, a carboxyl group or a lower hydroxyalkyl
group is present on the group of thLe formula
R4P
it is preferred to conduct the reaction after protecting such a hydroxyl
10 group, a lower hydroxyaL~yl group, an amino group, a carboxyl group
or a lower carboxyaL~yl group a~ro~liately by a hydroxyl-protecting
group, an amino-protecting group or a carboxyl-protecting group an
removing the plrotecting group after the reaction.
The hydroxyl-protecting group may, for example, be a
15 lower aL~ylsilyil group such as a trimethylsilyl group or a tert-
butyldimethyls;lyl group; a lower aL~oxymethLyl group such as a
methoxymethy] group or a 2-methoxyethoxymethyl group; a
tetrahydropyranyl group; an arailkyl group such as a benzyl group, a p-
methoxybenzyl group, a p-nitrobenzyl group or a trityl group; or an
20 acyl group such as a formyl group or an acetyl group. Particularly
preferred is a methoxymethyl group, a tetrahydropyranyl group, a trityl
group, a tert- butyldimethylsilyl group or an acetyl group.
The amino-protecting group may, for example, be an
- araL~ylidene group such as a benzylidene group, a p-chlorobenzylidene
25 group or a p-nitrobenzylidene group; an araL~yl group such as a benzyl
group, a p-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl
group or a trityl group; a lower aL~anoyl group such as a formyl group,
an acetyl group, a propionyl group, a butyryl group or a pivaloyl

CA 0222~2~ 1997-12-18
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group; a lower haloaL~anoyl group such as a trifluoroacetyl group; a
lower aL~oxycarbonyl group such as a methoxycarbonyl group, an
ethoxycarbonyl group, a propoxycarbonyl group or a tert-
butoxycarbonyl group; a lower haloaL~oxycarbonyl group such as a
2,2,2-trichloroethoxycarbonyl group; an alkenyloxycarbonyl group such
as a 2-propenyloxycarbonyl group; an aralkyloxycarbonyl group such as
a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group; or a
lower alkylsilyl group such as a trimethylsilyl group or a tert-
butyldimethylsilyl group. Particularly preferred is an acetyl group, a
trifluoroacetyl group, a tertbutoxycarbonyl group or a
benzyloxycarbonyl group.
The carboxyl-protecting group may, for example, be a
lower alkyl group such as a methyl group, an ethyl group, a propyl
group, an isopropyl group or a tert-butyl group; a lower haloaL~yl
group such as a 2,2,2-trichloroethyl group; a lower aLkenyl group such
as 2-p~ ellyl group; or an araL~yl group such as a benzyl group, a p-
methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group or
trityl group. Particularly preferred is a methyl group, an ethyl group, a
tert-butyl group, a 2-propenyl group, a benzyl group, a p-
methoxybenzyl group or a benzhydryl group.
After completion of the reaction, conventional
treatment is conducted to obtain a crude product of the compound of the
formula (IV). The compound of the formula (IV) may or may not be
purified in accordance with a conventional method, and if necessary,
reactions for removing protecting groups such as a hydroxyl group, an
amino group and a carboxyl group, are a~l~ro~liately conducted to
obtain a compound of the formula (hh).
Removal of protecting groups may vary depending upon v
their types, but can be conducted in accordance with the methods
30 disclosed in a literature (Protective Groups in Organic Synthesi~, T.W.
Greene, John Wiley & Sons (1981)) or methods similar thereto, for
example by solvolysis employing an acid or a base, by chemical
reduction employing a metal hydride complex or by catalytic reduction
employing a palladium-carbon catalyst or Raney nickel. t

CA 02225255 1997-12-18
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-
Proçess 2
A compound of the formula (hh-l):
r-~ ~r1_Q1--I H2 6 ~A~ (hh-l)
R ~ >~5 0
5 wherein Ql is -~cH2)n-cH=cH-(cH2)p- (wherein n and p are as defined
~ Ar~ r2 (~3
above); and ~ A, Rl, R2, R3, R4
R5, R6, R7 and R8 are as defined above, can be prepared by reactimg a
cornpound of the formula (V):
R1P
~~r1 (CH2)n-C H (V)
R2P ~
Cr1
wherein RlP, R2P and n are as de~med above, with a
compound of the formula (VI):

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WO 97/0127S PCT/US96/11022
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R7P
P
T- CH2 - (CH2)p--l H2 6 ArJ (Vl)
R3P~)r2/ ~,N~AP - COORP
R4P '
wherein T is a triphenylphosphonio group, a dimethoxyphosphoryl
(~~r2 (~~r3
group or a diethoxyphosphoryl group; and ~' ~'
AP, p, R3P, R4P, R5, R6, R7P, R8P and RP are as defined above, to
obtain a compound of the formula (IV-l):
R7P
R1P~ ~,R8P
(~L~rl (CH2)n CH = CH - (CH2)p--I H2 R6 ~Ar~;) (IV-I)
~~Ar2/ ~,N~,~AP - COORP
R3P~~) Rs ~
R4P
Crl--' ~r2 '
wherein AP, n, p, RlP, R2p
R3P, R4P, R5, R6, R7P, R8P and RP are as defined above, and, if
10 necessary, removing any protecting group.
Process 2 is a process for preparing a compound of the
formula (hh) wherein Q is -(cH2)n-cH=cH-(cH2)p- (wherein n and p ,~
are as defined above) i.e. a compound of the formula (hh-13.
The reaction of the compound of the formula (V) with a
15 compound of the formula (VI) is carried out usually by employing

CA 0222~2~ l997- l2- l8
WO 97JO1275 ~ /lIO22
- 285 -
equimolar amolLmts of the two re~ct~nt~ or using a slightly excess
amount of one of them.
The reaction is carried out usually in an inert solvent. Such
,, an inert solvent may, for example, be an ether such as ethyl ether,5 tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene,
toluene, chlorol~enzene or xylene; an apratic polar solvent such as
dimethylformamide, acetonitrile, acetone, ethyl acetate or
hexamethylphosphoric triamide; or a n~ixture of such solvents.
The reaction temperature is usually from -100~C to the
10 boiling point of the solvent used for the reaction, ~lcfelably from -70~C
to 50~C.
The reaction tilme is usually from 5 minlltes to 7 days,
preferably fromL 10 minlltes to 24 hours. Further, the above reaction
can be conducted in the presence of a base to facilitate the reaction.
15 Especially when T in the formula (VI) is a triphenylphosphonio group,
the reaction is preferably concl~lctecl in the presence of a base such as
sodium hydride, n-butyl lithium, sodium methoxide, potassium tert-
butoxide, sodiuim hydroxide or potassium hydroxide.
Such a base is used in an amount of one mol or an excess
20 molar amount, ]preferably from 1 to 5 mols per mol of the compound
wherein T is a lriphenylphosphonio group. When a hydroxyl group is
present on the group of the formula
R1P R7P
~r1_ or ~
R2P R8P
25 when a hydroxyl group, a lower hydroxyaLkyl group, a carboxyl group
or a lower carboxyaLkyl group is present on the sahlrated or lln~hlrated
aliphatic hyclroc,arbon group represented by AP, and when a hydroxyl
group, an amino group, a carboxyl group or a lower hydroxyaLkyl
group is present on the group of the formula
,.

CA 0222~2~ l997-l2-l8
W O 97/0127S PCTrUS96/11022
- 286 -
R3P
R4P
it is preferred to carry out the reaction after protecting such a hydroxyl
group, a lower hydroxyaL~yl group, an amino group, a carboxyl group
or a lower carboxyaL~yl group appr~,iately by a hydroxyl-protecting
5 group, an amino-protecting group or a carboxyl-protecting group, and
removing any protecting group after the reaction.
The hydroxyl-protecting group, the amino-protecting
group and the carboxyl-protecting group may be the protecting groups
mentioned above with respect to process 1.
After completion of the reaction, a conventional treatment
may be carried out to obtain a crude product of the compound of the
formula (IV-l). The compound of the formula (IV-l) thus obtained
may or may not be purified by a conventional method, and if necessary,
reactions for removing hydroxyl-, amino- and carboxyl-protecting
15 groups may be carried out in a proper combination to obtain a
compound of the formula (hh-l).
The method for removing a protecting group varies
depending upon the type of the protecting group and the stability of the
desired compound (hh-l). However, removal of protecting groups can
20 be suitably conducted in accordance with the methods disclosed in the
above-mentioned literature or methods .~imil~r thereto.
Process 3
A compound of the formula (hh-l):

CA 02225255 1997-12-18
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- Rl R7
R~r1--Q1--CH2 A~ R8
R6~ / (hh-l)
CH
N~A - COOH
C~r1 , Cr2 , (~r3--
wherein A, Ql, Rl, R2, R3,
R4, R5, R6, R7 and R8 are as defined above, can be obtained by
reacting a compound of the formula (VII):
R1P~
~r1 (CH2)n -CH2 - T (Vll)
R2P
~r1
wherein T, n, RlP and R2P are as defined above, with a
compound of th~e formula (VIII):
R7P
~, R8P
H-l'-(CH2)P--IH2 R6 /Ar~) (Vlll)
~Ar2/ ~N~AP - COORP
R3P--~) R5 ~
R4P

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WO 97/0127S PCT/US96/11022
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Cr- ~ Cr3--
wherein AP, p, R3P, R4P, R5, R6, R7P, R8P
and RP are as defined above, to obtain a compound of the formula (IV-
1):
R7P
R1P;~rl (CH2)n CH = CH - (CH2)p I H2 R6~ /~ (IV-I)
R3P~rl2/ ~,N~AP - COORP
R4P
S
/~~r1 /~~r2 ~3
wherein ~/ ~~ AP, n, p, RlP, R2p
R3P, R4P, R5, R6, R7P, R8P and RP are as defined above, and, if
necessary, removing any protecting group.
Like process 2, process 3 is a process for producing
10 a compound of the formula (hh) wherein Q is -(CH2)n-CH=CH-(CH2)p-
(wherein n and p are as defined above) i.e. a compound of the formula
(hh-l).
Process 3 is equal to the reaction of process 2 wherein
starting material compounds (V) and (VI) are replaced by the
15 compounds (VIII) and (VII), respectively. Accordingly, the manner
and conditions of the reaction may be all in accordance with process 2.
Process 4
20 A compound of the formula (hh-2):

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WO 97/0127S PCT/US96/11022
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- R1 R7
R~ ~r1_Q2--CH2 A(;~R3
R6~ / (hh-2)
~/ ~çN~A - COOH
wherein Q2 is -(CH2)m- (wherein m is as defined above);
C~r1_ ~r2 ~3
arld A, Rl, R2, R3, R4, R5,
R6, R7 and R8 a~re as defined above, can be obtained by reducing a
S compound of the formula (IV-l'):
R7P
R1p~ 1 ~R8P
5~,r (CH2tnÇ~H = CH - (CH2)p1--CH2 6 Ar~ (IV-I~)
R3P~Ir2/ >~N~AP - COORP
R4P
wherein each of n1 and P1 which are the same or different, is an integer
C~r~ r2 ' Cr3
of from O to 3; and
10 AP RlP, R2P, R3P, R4P, R5, R6, R7P, R8P and RP are as defined above
(provided that the sum of n1 and Pl does not exceed 4), and, if
-. necessary, removing any protecting group.
Process 4 is a process for producing a compound of the
formula (hh) wh~erein Q is -(cH2)m- (wherein m is as defined above)
15 i.e. a compound of the formula (hh-2).

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
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The reaction of reducing the compound of the formula (IV-
1') is usually preferably conducted by catalytic reduction employing a
palladium-carbon catalyst, a Raney nickel catalyst or a pl~tinllm catalyst
in an inert solvent.
S The inert solvent may, for example, be an alcohol such as
methanol, ethanol or propanol, or acetic acid.
The reaction temperature is usually from -20~C to 100~C,
preferably from 0~C to room temperature.
The reaction time is usually from S minutes to 7 days,
preferably from 10 minutes to 24 hours.
The hydrogen pressure in the catalytic reduction reaction is
usually preferably from atmospheric pressure to S atm, and the amount
of the catalyst is usually from 0.01 to 1 mol, preferably from 0.05 to
0.2 mol, per mol of the starting material compound (IV-l').
After completion of the reaction, the product is subjected to
a usual treatment after removing any protecting group if such a
protecting group is present or directly if no such protecting group is
present, to obtain a compound of the formula (hh-2).
Removal of the protecting group and the post treatment
may be conducted by the methods described with respect to the above
process 1.
Process S
A compound of the formula (hh-3);
R1 R7
R~ ¦ R6~ ~ ~ (hh-3)
CH CH
--~)4 Rs

CA 0222 72 7 7 1997 - 12 - 18
WO 97~1~12','5 PCT/US96/11022
- 291 -
.
wherein Q3 is -(cH2)n-wl-(cH2)p- (wherein n, p and Wl are as de~med
C Ar1 C~r2- C~
above); and ~ A, Rl, R2, R3
R4, R5, R6, R7 and R8 are as defined above, can be prepared by
reacting a compound of the formula (IX):
R1P~~ '
5~_9r1 (CH2)n -W1 - H (IX)
R2P
wherein Wl is an oxygen atom or a sulfur atom; and
Cr
n, RlP and R2P are as defined above, with a compound of the formula
(X):
R7P
~, R3P
Z1 _ (CH2)p--CH2 6 Al-~ (X)
~Ar2/ ~N~AP COORP
R3P--~) R5 ~
R4P
C C
- 15 wherein zl is a leaving group, and AP, p,
R3P, R4P, R5, R.6, R7P, R8P and RP are as defined above, to obtain a
compound of the formula (IV-3);
,.

CA 0222~2~ l997- l2- l8
WO 97/0127S PCT/US96/11022
- 292 -
R7P
R1P~ ~,R8P
R2p5~rl- (CH2)n ~ Wl - (CH2)p I H2 R6 /Ar3~ (IV-3)
R3P.~I H>fs o
, R4P
Crl--' Cr2 ' ~r3
wherein AP, n, p, Wl, RlP
R2P, R3P, R4P, R5, R6, R7P, R8P and RP are as defined above, and, if
necessary, removing any protecting group.
Process 5 is a process for preparing a compound of the
formula (hh) wherein Q is -(cH2)n-wl-(cH2)p- (wherein n, p and W
are as defined above) i.e. a compound of the formula (hh-3).
The reaction of the compound of the formula (IX) with
a compound of the formula (X) is carried out usually by using 1 mol or
an excess molar amount, preferably from 1 to 3 mols, of the compound
of the formula (IX), per mol of the compound of the formula (X).
The reaction is conducted usually in an inert
solvent. The inert solvent may, for example, be a halogenated
hydrocarbon such as methylene chloride, chloroform, carbon
tetrachloride, dichloroethane or trichloroethylene; an ether such as ethyl
ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as
benzene, toluene, chlorobenzene or xylene; an aprotic polar solvent such
as dimethylformamide, acetonitrile, acetone, ethyl acetate or
hexamethylphosphoric triamide, or a mixture of such solvents.
The reaction temperature is usually from -70~C to the
boiling point of the solvent used for the reaction, ~Jrefel~bly from -20~C
to 100~C.
The reaction time is usually from 5 minutes to 7 days,
preferably from 10 minutes to 24 hours.

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ThLe above reaction is preferably conducted in the presence
of a base to facilitate the reaction. Such a base may, for exarnple, be an
inorganic base such as sodium hydride, n-butyl lithium, sodium
hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,
5 potassium carbonate or sodium hydrogencarbonate, or an organic base
such as triethylamine, N- ethyldiisopropylamine, pyridine, 4-
dimethylaminopyridine or N,N-dimethylaniline.
The base is used usually in an amount of 1 mol or an excess
molar amount, preferably from 1 to 5 mols, per mol of the compound
10 of the formula (IX).
The leaving group represented by zl may, for example,
be a halogen atom such as a chlorine atom, a bromine atom or an iodine
atom, or an organic sulfonyloxy group such as a methanesulfonyloxy
group, a p-toluenesulfonyloxy group or a benzenesulfonyloxy group.
~hen a hydroxyl group is present on the group of the
formula
R1P~ R7P~
(~r1 or ~3_
R2P R3P
when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group
20 or a lower carboxyalkyl group is present on the saturated or nnc~tllrated
aliphatic hydrocarbon group represented by AP, and when a hydroxyl
group, an amino group, a carboxyl group or a lower hydroxyalkyl
group is present on the group of the formula
R3P
R4P
~, it is preferred to conduct the reaction after protecting such a hydroxyl
group, a lower hydroxyalkyl group, an amino group, a carboxyl group
or a lower alkoxyalkyl group appropriately by a hydroxyl-protecting
group, an amino-protecting group or a carboxyl-protecting group and

CA 0222~2~ 1997-12-18
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removing any protecting group after the reaction.
The hydroxyl-protecting group, the amino-protecting
group and the carboxyl-protecting group may be the protecting groups
mentioned above with respect to process 1.
After completion of the reaction, a usual treatment is
carried out to obtain a crude product of the compound of the formula
(IV-3). The compound of the formula (IV-3) thus obtained may or may
not be purified by a conventional method, and reactions for removing
the hydroxyl-, amino- and carboxyl-protecting groups may be carried
10 out in a proper combination, to obtain a compound of the formula (hh-
3). The method for removing a protecting group varies depending upon
the type of the protecting group and the stability of the desired
compound (hh-3). However, removal of protecting groups can be
ap~ fiately conducted in accordance with the methods disclosed in the
15 above-mentioned literature or methods similar thereto.
Process 6
A compound of the formula (hh-3):
R1 Ar~--Q3--CH2 6 A~ (hh-3)
R ~~ >~5 0
Cr1 Cr2 Cr3
20 wherein A, Q3, R 1, R2
R3, R4, R5, R6, R7 and R8 are as defined above, can be prepared by
reacting a compound of the formula (Xl):

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R1P ,C~
~L ,9r1 (CH2)n ~ Z1 (Xl)
R2P
(~r~- ,
wherein ~~ n, zl, RlP and R2P are as defined above, with a
S compound of the: formula (XII):
R7P
~" R3P
H _~\/1 (CH2)p--I H2 R6 /Ar~) (Xll)
R3P~Ir2/ ~,N~AP - COORP
R4P
wherein C AP, p, Wl, R3P, R4P, R5, R6,
R7P, R8P and RP are as defined above, to obtain a compound of the
formula (IV-3):
R7P
R1p~1-(CH2)n - W - (CH2)p I H2 R6 ~A~ (IV-3)
R3P--~)r2/ >~N~AP - COORP
R4P

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Cr1 , ~r2, Cr3
wherein AP, n, p, Wl, RlP
R2P, R3P, R4P, R5, R6, R7P, R8P and RP are as defined above, and, if
necessary, removing any protecting group.
Like the above process 5, process 6 is a process for
5 preparing a compound of the formula (hh) wherein Q is -(CH2)n-Wl-
(CH2)p- (wherein n, p and Wl are as defined above) i.e. a compound of
the formula (hh-3).
This process can be conducted usually in an inert solvent,
preferably in the presence of a base, by using 1 mol or an excess molar
10 amount, preferably from 1 to 3 mols, of the compound of the formula
(XI), per mol of the compound of the formula (XII). The types of the
inert solvent and the base as well as the reaction conditions may be the
same as described above with respect to process 5. Accordingly, the
reaction and the post-treatment after the reaction may preferably be
15 carried out all in accordance with process 5.
Process 7
A compound of the formula (hh-4):
R1 R6 ~ R8
R~r1--Q--ICH2 ~ /Ar3J R11 (hh-4)
,~ .. l I
~ N~(CH2)V--~C=C--(cH2)w-cH-(cH2)xco2
R3--~,) R5 ~ HO Rl2
R4
(~rl (~r2~
wherein ~/ ~~ Q, Rl, R2, R3, R4
R5 R6, R7, R8, Rl 1, R12, v, w and x are as defined above, can be
prepared by oxidizing a compound of the formula (IV-4):

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- 297 -
RZp~r1-Q-c~H2 R\, /A~ R11p (IV-4)
2/ ~N~ (CH2)V--7H - C - (CH2)w~CH~(CH2)xC02RP
R3P~ Rs ~ HO R12p
R4P
wherein Rl lp is a hydrogen atom or a lower hydroxyalkyl or carboxyl
S group which may be protected, R12P is a hydrogen atom or a hydroxyl
or carboxyl group which may be protected; and
~r1 , ( Ar2-- Cr3
Q, RlP, R2P, R3P, R4P, RS,
R6, R7P, R8P, RP, v, w and x are as defined above, and, if necessary,
removing any protecting group.
Process 7 is a process for preparing a compound of the
formula (hh) wherein A is a group of the formula (b):
F~1 1
-(CH2)v--C=C--- (CH2)W-CH-(CH2)X
OH R12 (b)
wherein Rl 1, R12, v, w and x are as defined above, i.e. a compound of
the formula (hh-4).
s The reaction of oxidizing the compound of the formula
(IV-4) is usually preferably carried out in an inert solvent by using so-
called Dess-Martin oxidation employing 12-I-S triacetoxyperiodinane;
so-called Swern oxidation employing oxalyl chloride and dimethyl
sulfoxide; a sulfur trioxide-pyridine complex; pyridinium
chlorochromate; active manganese dioxide; or tetra-n-propylammonium
perruthenate.

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The inert solvent may, for example, be a halogenated
hydrocarbon such as methylene chloride, chloroform or dichloroethane;
an ether such as ethyl ether, tetrahydrofuran or dioxane; an aprotic
polar solvent such as acetonitrile, acetone, ethyl acetate or dimethyl
5 sulfoxide; or a rnixture of such solvents.
The reaction temperature varies depending upon the type of
the oxidizing agent, etc. However, it is usually from -100~C to the
boiling point of the solvent used for the reaction, preferably from -70~C
to 100~C.
The reaction time is usually from 5 minutes to 7 days,
preferably from 10 minutes to 24 hours.
After completion of the reaction, the product is subjected to
usuai treatment after removing a protecting group when such a
protecting group is present, or directly when no such protecting group
15 is present, to obtain the compound of the formula (hh-4).
The removal of the protecting group and the post-treatment
may be conducted in the same manner as described above with respect to
process 1.
Further, a compound corresponding to the compound of the
20 formula (IV-4) to be used as the starting material in the above process
7, can be prepared, for example, by hydrolyzing a compound of the
formula (IV-4a):
R7P
RlP ~, R8P (IV-4a)
R2p~r1-Q- CH2 R\ /Ar~ ¦ ~
Ar2/ ~ N~ (CH2)V HC--CIH-(cH2)w-cH-(cH2)x
R3P~ Rs ~ Rl lp Rl2p
R4P

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- 299 -
~r~ r2- ~r3--
wherein ~' ~/ ~' Q, RlP, R2P, R3P
R4P RS, R6, R7P, R8P, Rl lp, Rl2P~ v, w and x are as defined above,
in the presence of a base, to obtain a compound of the formula (IV-4b):
R2p~r-Q-C,H2 \ /A~ HO (IV-4b)
CH
/C,H N~(CH2)v CH--CH-(CH2)W-CH-(cH2)xco2
R3P~ Rs ~ R1 'p Rl2p
S R4P
wherein M is a hydrogen atom or an aLkali metal atom; and
~r1 , ( Ar2 ~ Cr3
Q, RlP, R2P, R3P, R4P, R5,
R6, R7P, R8P, R~ 1 lp, R12p, v, w and x are as defined, then re~tin~;
thereto a diazo compound of the formula
RPP - N+ _ N
wherein RPP is a lower aLkyl group, a lower aLkenyl group, an araLkyl
group or a lower aLkoxycarbonylaLkyl group, or an aLkylating agent of
the formula RPP-Z wherein RPP and Z are as defined above.
Isolation and purification of the compound of the
formula (hh), (hh-I), (hh-2), (hh-3) or (hh-4), obtained by the above
process can be conducted by a single use or a proper combination of
conventional separating means such as column chromatography
J employing silica gel, adsorbent resin, etc., liquid chromatography,
solvent extraction and recryst~lli7~tion-reprecipitation.
The compound of the formula (hh), (hh-I), (hh-2), (hh-3)
or (hh-4) can be converted to a ph~ ceutically acceptable salt or ester

CA 02225255 1997-12-18
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by a conventional method. Reversely, the conversion from the salt or
ester to a free carJooxy~ic acid can also be cor~ucted by a conventional
method.
Further, compounds of the present invention can all be
S prepared by a process ~imil~r to the above processes by using the
starting materials corresponding to the desired compounds.
The compounds of the formulas (II), (III), (V), (VI),
(VII), (VIII), (IX), (X), (XI) and (XII) may be commercially available
or can be prepared in accordance with the methods disclosed in
10 literatures (J. Med. Chem., 10, 717 (1967); ibid., 725; J. Chem. Soc.
Perkin 1, 1636 (1978); Chem. Lett., 191 (1980); ibid., 375 (1984); J.
Chem. Soc. Chem. Commun., 579 (1984); J. Am. Chem. Soc., 104,
5716 (1982)) or methods .~imil~r thereto, or in accordance with the
following processes or the methods disclosed in Examples.
Process A
R3P (or R5MgX, R52CuLi 3)R
~~~r2--CH2-Y . ~r2--CH2--C-R
R4P 1 R4P
R1P~C~
;~/base ~~r1 - Q fH2
~ R2p /CH R5
rAr2'
R3P~ ~
R4P ~ -

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WO 97~01275 PCT/US96/11~22
- 301 -
R7P R6
CH-NH2
8P 7
2) reduction
R7P
R1 p~ ~, R8P
5~r1--~ CH2 6 A~
rAr2/ ~ NH [Il]
R3P~ H 15
R4P
~r~ C~-
In the above fonmulas,
Q RIP, R2P, R3P, R4P, R5, R6, R7P and R8P are as defined above; X
5 is a halogen atom; Y is a cyano group, a carboxyl group, a lower
aLkoxycarbonyl group, a chlorofonmyl group or an N-methoxy-N-
methylcarbamoyl group; Z is a leaving group selected from the group
consisting of a chlorine atom, a bromine atom, an iodine atom, a
trifluoroacetoxy group, a methanesulfonyloxy group, a
10 trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxy group.
By this process, the desired compound (II) can be prepared
by reacting a nitrile or a carboxylic acid derivative of the fonmula 1
with an alkyl lit~hium of the formula 2 or an alkyl Grignard reagent (or
an alkyl Gilman reagent) of the formula 3 to obtain a ketone compound
-, 15 4, then reacting .an alkylating agent of the fornnula 5 to the ketone
compound 4 to produce a compound of the formula 6, then reacting the
compound 6 with an amine compound of the fonmula 7, followed by
reduction.
The above reaction steps will be described in detail

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referring to suitable reaction conditions, etc.
The first step of preparing the ketone compound _ is
conducted usually by reacting 1 mol or an excess molar amount,
preferably from 1 to 5 mols of the alkyl lithium reagent 2 or the alkyl
5 Grignard reagent 3 (or the alkyl Gilman reagent in the case where the
substituent Y of the compound 1 is a chloroformyl group) to 1 mol of
the starting material compound 1 in a solvent inert to the reaction such
as tetrahydrofuran, ethyl ether or benzene, if necessary followed by
hydrolysis under an acidic condition.
The reaction temperature is usually from -80~C to the
boiling point of the solvent used for the reaction, preferably from -70~C
to 50~C. The reaction time is usually from 5 minutes to 48 hours,
preferably from 30 minutes to 24 hours.
When the substituent Y in the formula of the starting
material compound 1 is a cyano group, it may be necessary to conduct a
hydrolytic reaction under an acidic condition after completion of the
reaction, and such a hydrolytic reaction is conducted in e.g. methanol,
ethanol, tetrahydrofuran or a solvent mixture thereof with water in the
presence of an acid such as hydrochloric acid, sulfuric acid or p-
toluenesulfonic acid.
The reaction temperature is usually from O~C to the
boiling point of the solvent used for the reaction, and the reaction time
is from 30 minutes to 24 hours.
The step of preparing the compound of the formula 6 from
the ketone compound 4, can be conducted by reacting an equimolar
amount or an excess molar amount, preferably from 1 to 2 mols, of the
alkylating agent of the formula S to the ketone compound 4 in the
presence of a base in an inert solvent which does not adversely affect the
reaction or without using any solvent.
The inert solvent may, for example, be an ether such as
ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such ~-
as benzene, toluene or xylene; an aprotic polar solvent such as
dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric
triamide, or a mixtute of such solvents.

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~.
The base to be used for this reaction, may, for
example, be an aL~ali metal hydride such as sodium hydride, lithium
hydride or potassium hydride; a lithium amide such as lithium ~micle,
~ lithium diisopropylamide or lithium bis(trimethylsilyl)amide; an aL~yl
S lithium such as methyl lithium, butyl lithium or tert-butyl lithium; an
aL~ali metal aL~oxide such as sodium methoxide, sodium ethoxide or
potassium tert-butoxide; or an aL~ali metal hydroxide such as sodium
hydroxide, potassium hydroxide or lithium hydroxide.
The base is used usually in an amount of 1 mol or an excess
10 molar amount, preferably from 1 to 5 mols, per mol of the starting
material alkylating agent 5.
The reaction temperature is usually from -100~C to the
boiling point of the solvent used for the reaction, preferably from -80~C
to 100~C. The reaction time is usually from 10 minutes to 48 hours,
15 preferably fronn 30 minutes to 24 hours.
The step of preparing the desired compound (II) from the
compound of t]he formula 6 can be conducted usually in an inert solvent
such as methanol, ethanol, benzene, ethyl ether or tetrahydrofuran by
reacting 1 mol or an excess molar amount, preferably from 1 to 2 mols,
20 of the amine compound of the formula 7 to 1 mol of the compound of
the formula 6 to prelimin~rily form an imine, which is subsequently
reduced.
The reaction temperature in the process for forming the
above imine is usually from 0~C to the boiling point of the solvent used
25 for the reaction, preferably from room temperature to 100~C. The
reaction time is usually from 5 minutes to 48 hours, preferably from 30
rninutes to 24 ]:lours. After the formation of the imine, the reaction
solution may be used as it is to the subsequent step of the reduction
reaction, or the: reaction solution may be distilled or subjected to a
30 conventional separation means to isolate the imine compound, which is
~., then subjected to the subsequent reduction.
The reduction can be carried out by using a metal hydride
complex such as sodium borohydride, sodium cyanoborohydride or

CA 0222~2~ 1997-12-18
WO 97/01275 PCT/US96/11022
- 304-
lithium alllminllm hydride, or by catalytic reduction employing a
palladium-carbon catalyst or a Raney nickel catalyst.
When a metal hydride complex is used as a reducing agent,
the reducing agent is used usually in an amount of 1 mol or an excess
5 molar amount, preferably from 1 to 5 mols, per mol of the above
imine.
For the reduction, an inert solvent, for example, an alcohol
such as methanol or ethanol; an ether such as dimethyl ether, ethyl
ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane,
10 tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane,
hexane, heptane or cyclohexane; or an aromatic hydrocarbon such as
benzene or toluene; or a mixture of such solvents, can be used
~plo~liately as a solvent depending upon the type of the reducing
agent.
The reaction temperature is usually from 0~C to room
temperature, and the reaction time is usually from 1 hour
to 6 hours.
Further, in this process, it is also possible to react an
alkylating agent of the formula 5 to the nitrile or carboxylic acid
20 derivative of the formula I to prelimin~rily produce an alkyl compound
and then to react an alkyl lithium of the formula 2 or an alkyl Grignard
reagent (or an alkyl Gilman reagent) of the formula 3 to the alkyl
compound to obtain a compound of the formula 6. Such a reaction can
be conducted under the conditions ~imil~r to the above Process A.
25 Accordingly, the reaction conditions described for the above Process A
may all be used as the reaction conditions for this reaction.
The compounds of the formulas 1, 2, 3, 5 and 7 may be
commercially available or can be produced by a proper combination, as
the case requires, of the methods disclosed in Examples, or conventional
30 methods or methods similar thereto.

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Process B
RlP
~~r1--Q f H2 reduction
R3P.~ 2~CH R5
R1P~
Arl--al CH2 1 ) CH3SO2CI/TEA (or PBr3)
R ~ Rs R~P~
R7P
R1P C~rlQ--fH ~R3P
R2p~ CH C, H
2/ >~ [Il]
R4P
Cr~ r2 ~r3
SIn the above formulas, Q,
~. R1P, R2P, R3P, ]R4P, R5, R6, R7P and R8P are as defined above.
According to this process, the desired compound (II) can be
prepared by reacting a reducing agent such as a metal hydride complex
to a compound of the formula 6 to obtain an alcohol compound 8 and

CA 0222~2~ 1997-12-18
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reacting an amine compound of the formula 7 to the alcohol compound
The above reaction steps will be described in detail
referring to suitable reaction conditions, etc.
The reaction for reducing the compound of the formula 6
to the alcohol compound 8 can be conducted usually by using a metal
hydride complex such as sodium borohydride, diisobutyl aluminum
hydride, lithium aluminum hydride or lithium tri-sec-butylborohydride
(L-selectrideTM), or by catalytic reduction employing e.g. a p~ um-
carbon catalyst or a Raney nickel catalyst, in an inert solvent which does
not adversely affect the reaction.
When the metal hydride complex is used as the reducing
agent, such a reducing agent is used usually in an amount of 1 mol or an
excess molar amount, preferably from 1 to 5 mols, per mol of the
starting material compound 6.
The inert solvent to be used in this reaction may be suitably
selected depending upon the type of the reducing agent.
For example, when the reducing agent is sodium
borohydride, an inert solvent, such as an alcohol such as methanol or
ethanol; an ether such as dimethoxyethane, dioxane, tetrahydrofuran or
diglyme; an aprotic polar solvent such as dimethylformamide or
dimethylacetamide, or water, or a solvent mixture thereof, may be used,
and particularly preferred is an alcohol such as rnethanol or ethanol.
For example, when the reducing agent is diisobutyl
aluminum hydride, an inert solvent, such as an ether such as dimethyl
ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane,
dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as
pentane, hexane, heptane or cyclohexane; an aromatic hydrocarbon such
as benzene or toluene; methylene chloride, or a solvent mixture thereof,
may be used, and particularly preferred is toluene or methylene
chloride. ~~
For example, when the reducing agent is lithium aluminum
hydride or lithium tri-sec-butylborohydride, an inert solvent, such as an
ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl

CA 0222~2~ 1997-12-18
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- 307 -
ether, dimetho~:yethane, dioxane, tetrahydrofulan or diglyme; an
aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane;
or an aromatic ]hydrocarbon such as benzene or toluene, or a solvent
mixture thereof, may be used, and particularly preferred is ethyl ether
5 or tetrahydrofuran.
For the catalytic reduction, the solvent is preferably an
alcohol such as methanol or ethanol.
The reaction temperature and the reaction time vary
depending upon the stability and the susceptibility to the reduction
10 reaction of the starting material ketone compound 6, the type of the
reducing agent and the type of the solvent. However, the reaction
temperature is usually from -80~C to 100~C, preferably from -70~C to
40~C, and the reaction time is usually from 5 minutes to 2 days,
preferably from~ 30 minutes to 24 hours.
The step of preparing the desired compound (II) from
a compound of the formula 8 can be carried out by re~ctin~ a
sulfonating agent such as methanesulfonyl chloride to the alcohol
compound of the formula 8 in the presence of a base, or reacting a
halogenating agent such as thionyl chloride or phosphorus tribromide
20 thereto, to convert the hydroxyl group in the formula to a leaving
group, followed by reacting an amine compound of the formula 7.
The reaction for introducing the leaving group can be
conducted usually by reacting 1 mol or an excess molar amount,
preferably from 1 to 2 mols, of a sulfonating agent and a base such as
25 triethyl~mine to 1 mol of the alcohol compound 8 in an inert solvent
such as methylene chloride, chloroform, benzene, tetrahydrofuran or
ethyl acetate, or using 1 mol or an excess molar amount, preferably
from 1 to 5 molls, of a halogenating agent.
The reaction temperature is usually from -70~C to the
30 boiling point of the solvent used for the reaction, preferably from -20~C
~~ to 80~C, and the reaction time is usually from 5 minutes to 48 hours,
preferably from 30 minutes to 24 hours.
Then, the step of reacting an amine compound 7 to the
li

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
- 308 -
compound having the leaving group introduced, obtained by the above
reaction, can be conducted usually by employing 1 mol or an excess
molar amount, preferably from 1 to 50 mols, of the amine compound 7
per mol of the starting compound having the leaving group, in an inert
5 solvent such as methylene chloride, chloroform, benzene, ethyl ether or
tetrahydrofuran .
If necessary, this reaction can be conducted in the presence
of a base other than the amine compound of the formula 7.
As such a base, an inorganic base such as sodium
10 hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,
potassium carbonate or sodium hydrogencarbonate, or an organic base
such as triethyl~mine, N-ethyldiisopropylamine, pyridine or N,N-
dimethylaniline may, for example, be mentioned.
Such a base is used usually in an amount of 1 mol or an
15 excess molar amount, preferably from 1 to 5 mols, per mol of the
starting material compound.
The reaction temperature is usually from -50~C to
150~C, preferably from -20~C to 100~C, and the reaction time is usually
from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.

CA 02225255 1997-12-18
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Process C
RlP 1 )DEAD, Ph3P,
c R2P~r1--Q l H2Phthaiimide (or HN3 or DPPA)
R3P~Ar2 C~oHor ( i) CH3SO2CI, TEA
~'J H Iii) Phthalimide (or NaN3)
R4P 8 R52) NH2NH2 (or reduction)
R2p~r1----Q--CH2 1) ~r7 - C-
R3P~ Ar2 CH~ NH2
~J H/¦ 2) reduction
R4P R5
Rlp ~ R8P
~r1 Q--I H2 R6 /Ar_~
~A~/ ~NH [Il]
R3P~ H R5
R4P
In tlhe above forrnulas,
Cr1--, ( Ar2 Cr3

CA 0222~2~ 1997-12-18
WO 97/01275 PCT/US96/11022
- 310-
Q, RlP, R2P, R3P, R4P, R5, R6, R7P and R8P are as defined above.
Accoraing to this process, the desired compound (II)
can be prepared by firstly reacting diethyl azodicarboxylate,
triphenylphosphihe and phth~limide (or hydrogen azide or i'
5 diphenylphosphoryl azide) or reacting a sulfonylation agent such as
methanesulfonyl chloride in the presence of a base such as triethylamine,
then reacting phth~limi~le (or sodium azide) in the presence of a base, to
the alcohol compound of the formula 8, to obtain a phth~limide-
protected form (or an azide compound) of the amine compound 2, then
10 reacting hydrazine (or a reducing agent) to remove the phth~limide
group (or reduce the azide group) to obtain an amine product of the
formula 2, and finally reacting a compound of the formula 10 to the
compound 2, followed by reduction.
The above reaction steps will be described in detail
15 referring to suitable reaction conditions, etc.
For the step of producing the amine compound of the
formula 2 from the alcohol compound 8, various synthetic methods and
reaction conditions well known in organic synthetic chemistry for
converting alcohol compounds to ~mines, may be employed. For
20 example, it is preferred to employ a Mitsunobu reaction using diethyl
azodicarboxylate, triphenylphosphine and phth~limide (or hydrogen
azide or diphenylphosphoryl azide) or a method which comprises
sulfonylation with a sulfonylation agent such as methanesulfonyl
chloride in the presence of a base such as triethylamine, then reacting
25 phth~limide (or sodium azide) in the presence of a base, and then
treating the obtained phth~limide compound with hydrazine (or
reducing the azide compound).
The above reactions are conducted usually in a
solvent inert to the reaction. The inert solvent may, for example,
30 preferably be tetrahydrofuran, dimethoxyethane, benzene or toluene in
the case of the above-mentioned Mitsunobu reaction; methylene ~-
chloride,
chloroform, tetrahydrofuran, benzene, ethyl acetate or
dimethylformamide in the case of the sulfonylation followed by the

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- 311 -
reaction with phth~limide (or sodium azide); an alcohol such as
methanol or et]:lanol in the next step of the phth:~limide-removing
reaction with hydrazine; an ether such as ethyl ether or tetrahydrofuran
in the case where a metal hydride complex is used as the reducing agent
5 in the reduction reaction of the azide compound; water-cont~inin~
tetrahydrofuraIl in the case where phosphine reduction is conducted with
triphenylphosphine or the like; and an alcohol such as methanol or
ethanol in the reduction by catalytic reduction.
With respect to the amounts of the reagents to be usedL, in
10 the above Mitsunobu reaction, each of diethyl azodicarboxylate,
triphenylphosphine and phthzllimide (or hydrogen azide or
diphenylphosphoryl azide) is used in an amount of 1 mol or an excess
molar amount, preferably from 1 to 5 mols, per mol of the starting
material alcohol compound 8. In the reaction with the phth~limide (or
15 sodium azide) after the sulfonylation, the sulfonylation agent such as
methanesulfonyl chloride is used in an amount of 1 mol or an excess
molar amount, preferably from 1 to 2 mols, per mol of the alcohol
compound 8, and the base such as triethylamine used at that time is
usually in an amount of 1 mol or an excess molar amount, preferably
20 from 1 to 2 mols, per mol of the sulfonylation agent. In the next step of
the reaction with phth~limide (or sodium azide) in the presence of a
base, 1 mol or an excess molar amount, preferably from 1 to 5 mols of
each of phth~limide and the base (or sodium azide) is used per mol of
the starting material sulfonylation agent. Here, the base to be used
25 together with phth~limide is preferably sodium carbonate or potassium
carbonate. Otherwise, without using such a base, a sodium salt or a
potassium salt of phth~limide may be used by itself. Then, in the
reaction for re]moving the phth~limide group with hydrazine, hydrazine
is used in an alrnount of 1 mol or an excess molar amount, preferably
30 from 1 to 10 mols, per mol of the phth~limide compound as the starting
~, material compound. In the reduction of the azide compound with a
metal hydride complex or with triphenylphosphine, the reducing agent
is used usually in an amount of 1 mol or an excess molar amount,
preferably frorn 1 to 2 mols, per mol of the azide compound.

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WO 97/01275 PCT~S96/11022
- 312 -
In the case of the above Mitsunobu reaction, the reaction
tempeld~ e is usually from -70~C to 100~C, preferably from -20~C to
50~C, and the reaction time is usually from 5 minutes to 48 hours,
preferably from 30 minutes to 24 hours. In the reaction for removing
S the phth~limide group by hydrazine, the reaction temperature is usually
from 0~C to the boiling point of the solvent used for the reaction,
preferably from room tempela~u,e to 100~C, and the reaction time is
usually from 5 minutes to 48 hours, preferably from 30 minutes to 24
hours. In the reaction for converting the azide compound to the amine
compound by reduction, when a metal hydride complex is used as the
reducing agent, the reaction temperature is usually from -70~C to
150~C, preferably from -20~C to 50~C, and the reaction time is usually
from S minutes to 48 hours, preferably from 10 minutes to 10 hours.
When triphenylphosphine is used as the reducing agent, the reaction
temperature is usually from room temperature to the boiling point of
the solvent used for the reaction, preferably from 30~C to 100~C, and
the reaction time is usually from 10 minutes to 48 hours, preferably
from 30 minutes to 24 hours. Further, in the case of the reduction by
catalytic reduction, the reaction temperature is usually from 0~C to
100~C, preferably from room temperature to 50~C, and the reaction
time is usually from 10 minutes to 48 hours, preferably from 10
minutes to 24 hours.
The step for producing the desired compound (II)
from the compound of the formula 2 is carried out usually by
prelimin~rily forming an imine by reacting 1 mol or an excess molar
amount, preferably from 1 to 2 mols of the compound of the formula
10 to 1 mol of the compound of the formula 2 in an inert solvent such as
methanol, ethanol, benzene, ethyl ether or tetrahydrofuran, and then
reducing it.
This step can be carried out in the same manner as
the step for producing the desired compound (II) from the compound of g
the formula 6 in the above process A. Accordingly, with respect to the
reaction conditions, etc., simil~r modes may be employed.
Further, the compound of the formula 10 may be

CA 02225255 l997- l2- l8
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- 313 -
commercially available or can be produced by a proper combination, as
the case requires, of the rnethods disclosed in Examples, or conventional
methods or methods .~imil~r thereto.

CA 02225255 1997-12-18
W O 97/01275 PCT~US96/11022
- 314 -
Process D
RP1 OCH2(CH2)pCH2-Z
R3P C~ 11
~r--CH2-llC-R base
R4P 4
RP1 OCH2(CH2)pCH2
1) reduction
CH Rs
r2/ ~ 2) CH3SO2CI, TEA, NaN3
R3P~ 3 ~ (orDEAD, Ph3P, DPPA)
12 3) reduction
R4P
RP1 OcH2(cH2)pcH2 R7P o
/CH--CH-NH2 R8p~Ar3--C- R6
R3P--~) 2) reduction
R4P 1 3
R7P
RPl OCH2(CH2)pCH2 A~ R8p
CH CH 1 ) HO - C -AP - COORP
~Ar2/ ~NH 2) selective removal of
R3P--~'' H R5 protecting groups
R4P 1 4

CA 02225255 1997-12-18
WO 97/01275 PCTIUS96/11022
- 315 -
-
R7P
HocH2(cH2)~cH2 ~R8p Introduction of a
R6 /Ar / leaving group
~. . CH
R3P~r2/ ~N ~AP-COORP
R4P
R7P
CH C, HR3P PPh3 or P(OMe)3 or
R3P~ NAP-COORP
R4P
R7P
CH C, HR8p
R3P~ N~ AP-COORP
R4P
In the above fon:nulas, RlP means a hydroxyl-protecting group;
Cr , Cr
and AP, p, T, z, zl, R3P, R4P, R5, R6, R7P,
R8P and RP are as defined above.
According to this process, the desired compound (VI) can
be prepared by fïrstly reacting an aLkylating agent of the formula 11 to
a ketone compolmd of the formula _ to obtain a compound of the
formula ~, reacting a reducing agent such as a metal hydride complex
to the compound 12 to obtain an alcohol compound, then reacting
10 diethyl azodicarlboxylate, triphenylphosphine and phth~limide (or

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
- 316 -
hydrogen azide or diphenylphosphoryl azide) or reacting a sulfonylation
agent such as methanesulfonyl chloride in the presence of a base such as
triethylamine, and then reacting phthalimide (or sodium azide) in the
presence of a base, to obtain a phthalimide-protected form (or an azide
5 compound) of the amine compound 13, then reacting hydrazine (or a
reducing agent) to remove the phthalimide group (or reduce the azide
group) to obtain an amine compound of the formula 13, reacting a
compound of the formula 10 to the compound 13, followed by reduction
to obtain a compound of the formula 14, reacting a carboxylic acid of
10 the formula (III) or its reactive derivative to the compound 14, then
selectively removing the protecting group represented by Rpl to obtain
a compound of the formula 15, then introducing a leaving group to the
compound 15 to obtain a compound of the 16, and finally reacting
triphenylphosphine, trimethyl phosphite or triethyl phosphite to the
15 compound 16.
The hydroxyl-protecting group of Rpl may be the
hydroxyl-protecting groups mentioned above with respect to process 1.
The step of producing a compound of the formula 12
from a ketone compound of the formula 4, can be carried out in the
20 same manner as the step of producing the compound of the formula 6
from the ketone of the formula 4 in the above process A. Accordingly,
with respect to the reaction conditions, etc., similar conditions may be
employed.
In the step of producing the amine compound of the
25 formula 13 after reacting a reducing agent such as a metal hydride
complex to the compound of the formula 12 to obtain an alcohol
compound, the step of converting the compound of the formula 12 to
the alcohol compound can be carried out in the same manner as the step
of reducing the compound of the formula 6 to the alcohol compound 8
30 in the above process B. Accordingly, with respect to the reaction
conditions, etc., ~imilar conditions may be employed. Further, the step ~~
of producing an amine compound of the formula 13 from the obtained
alcohol, can be carried out in the same manner as in the step of
producing the amine compound 9 from the alcohol compound of the

CA 0222~2~ 1997-12-18
WO 97/01275 PCT/US96/11022
- 317 -
,
formula 8 in the above process C. Accordingly, with respect to thLe
reaction conditions, etc., ~imil~r conditions may be employed.
The step of producing a compound of thLe formula 14 from
the amine compound of the formLula 13, can be carried out in the same
m~nner as in the step of producing a compound of the formula (II) from
thLe amine of the formula 2 in thLe above process C. Accordingly, withL
respect to the re,action conditions, etc., ~imil~r conditions may be
employed.
In thLe step of producing a compound of the formula 15
from the compound of the formula 14, the reaction of the
compound of thLe formula 14 with thLe carboxylic acid of the formula
(III) or its reactive derivative, can be carried out in the same m~nner as
the reaction of lhe compound of the formula (II) with the carboxylic
acid of the formula (III) or its reactive derivative in thLe above process
1. Accordingly, with respect to the reaction conditions, etc., ~imil~qr
conditions may be employed.
For thLe step of selectively removing thLe protectiive group
represented by RPl from the compound obtained by the above reaction,
various methods may suitably be selected depending upon thLe type and
the characteristiics of thLe protectin~ group. Namely, lltili7ing thLe
difference in the stability against an acid, a base or reduction between
Rpl and other protecting groups, the protecting group can selectively be
rernoved by a conventional means such as an acid, a base or reduction.
With respect to specific conditions for such a reaction, the methods
disclosed in known litelalures, such as "Protective Groups in Organic
Synthesis, T.W. Greene, John Siley & Sons (1981)", may, for example,
be used.
Thle step of producing a compound of the formula 16 by
introducing a leaving group to the compound of the formula 15 can be
-. 30 carried out in the same m~nner as in the method of introducing a
leaving group to the compound of the formula 8 in the above process B
by using, for example, a halogen~tin~ agent such as thionyl chloride,
phosphorus trichloride, phosphorus pentachloride, phosphorus
oxychloride, phosphorus tribromide, oxalyl chloride or phosgene, or a

CA 0222~2~ 1997-12-18
WO 97/01275 PCT/US96/11022
- 318 -
sulfonating agent such as methanesulfonyl chloride, p-toluenesulfonyl
chloride or benzenesulfonyl chloride. Accordingly, with respect to the
reaction conditions, etc., .~imil~r conditions may be employed.
The step of producing the desired compound (VI) from the
S compound of the forrnula 16, can be carried out by reacting
triphenylphosphine, trimethyl phosphite or triethyl phosphite, to the
compound of the formula 16.
When a triphenylphosphine is reacted, the above reaction is
carried out usually in an inert solvent which does not affect the reaction.
10 As such an inert solvent, toluene or xylene is, for example, preferred.
The triphenylphosphine is used usually in an amount
of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per
mol of the compound 16.
The reaction temperature is usually from room
15 temperature to the boiling point of the solvent used for the reaction,
preferably from 80~C to 150~C. The reaction time is usually from 5
minlltes to 7 days, preferably from 1 hour to 24 hours.
Likewise, when trimethyl phosphite or triethyl
phosphite is reacted to the compound 16, the above reaction is conducted
20 usually in an inert solvent which does not affect the reaction, or more
preferably, an excess trimethyl phosphite or triethyl phosphite is used
as both the solvent and the reactant.
The reaction temperature is usually from room temperature
to the boiling point of the solvent for the reaction, preferably from
25 80~C to 150~C, and the reaction time is usually from S minutes to 7
days, preferably from 1 hour to 24 hours.
Further, the compound of the formula 11 may be
commercially available, or may be produced by a proper combination,
as the case requires, of the methods disclosed in Examples, or
30 conventional methods or methods similar thereto.

CA 02225255 1997-12-18
WO 97101275 PCTlUS96/llU22
- 319 -
Process E
~ RP20
R3P 3 ,CH(cH2)pcH2-z
~~r2--~H2-lCI-R5 base
RP 4
RP2o~
3 ,CH(c1-l2)pcH2
CH R5 1 ) reduction
R3P ~Ar2~ ~ 2) CH3S02CI, TEA, NaN3
~J O (orDEAD, Ph3P, DPPA)
R 18 3) reduction
RP2o~
p3 ,CH(CH2~lp ICH2 R7P~ 3_ 1~
Ar2/ Rs R3P~ 10
R3P ~) 2) reduction
R4P 1 9
R7P
RP2o ~\ R5P
RP3O, ( 2)pl 2 R6 /Ar~1) HO - C-AP- COORP
Ar2~ NH 2) selective removal of
R3P--~' H R5 protecting groups
'~ R4P

CA 0222~2~ 1997-12-18
WO 97tO1275 PCT/US96/11022
- 320-
R7P
H-ll -(CH2)p IcH2 6 ~A~ R8p
~Ar2/ >~N~AP-COORP
R3P~ ) R5 ~ [Vlll]
R4P
In the above formulas, each of Rp2 and RP3 which are the same or
different, is a methyl group or an ethyl group, or Rp2 and RP3 together
S represent an ethylene group;
C C
and AP, p, Z, R3P, R4P, R5, R6, R7P
R8P and RP are as defined above.
According to this process, the desired compound (VIII) can
be prepared by firstly reacting an aL~ylating agent of the formula 17 to
10 a ketone compound of the formula 4 to obtain a compound of the
formula 18, reacting a reducing agent such as a metal hydride complex
to the compound 18 to obtain an alcohol compound, then reacting
diethyl azodicarboxylate, triphenylphosphine and phth~limide (or
hydrogen azide or diphenylphosphoryl azide), or reacting a
15 sulfonylation agent such as methanesulfonyl chloride in the presence of a
base such as triethylamine and then reacting phth~limide (or sodium
azide) in the presence of a base, to obtain a phth~limide-protected form
(or an azide compound) of the amine compound 19, then reacting
hydrazine (or a reducing agent) to remove the phth~limide group (or
20 reduce the azide group) to obtain an amine compound of the formula
19, reacting a compound of the formula 10 to the compound 19,
followed by reduction to obtain a compound of the formula 20, reacting
a carboxylic acid of the formula (III) or its reactive derivative to the
compound 20, and then selectively removing the protecting groups
25 represented by Rp2 and RP3.

CA 0222~2~ 1997-12-18
WO 9711)1275 ~CT/US96/1102
- 321 -
Removal of such protecting groups is usually preferably
conducted in the presence of an acid s;~ch as hydrochloric acid, sulfuric
acid or p-toluenesulfonic acid in a solvent such as water-cont~inin~
. methanol, water-cont~ining ethanol or water-cont~ining
5 tetrahydrofuran.
The reaction temperature is usually from -20~C to 100~C,
preferably from 0~C to 50~C, and the reaction time is usually from S
minlltes to 48 hours, preferably from 10 minutes to 24 hours.
The respective steps up to the production of the desired
10 compound (VIII,~ from the ketone compound of the formula 4 can be
carried out in the: same manner as the respective steps for the production
of the compound of the formula 15 from the ketone compound of the
formula 4 in the above process D. Accordingly, with respect to the
reaction conditions, etc., the same conditions as in the corresponding
15 respective steps c an be employed.
Further, the compound of the formula 17 may be
commercially available, or can be produced by a proper combination, as
the case requires, of the methods disclosed in Examples, or conventional
methods or methods .~imil~r thereto.

CA02225255 1997-12-18
WO 97/0127~i PCT/US96/11022
- 322-
Process F
RP4-W1-(CH2)pCH2-Z
R3P~ 21
~rCH2-1CI-R base
R4P 4
RP4_W1 -(cH2)pcH2
1) reduction
CH Rs
R3P ~Ar2/ ~f 2) CH3SO2CI, TEA, NaN3
~ ) O (orDEAD, Ph3P, DPPA)
R4P 22 3) reduction
R -W -(CH )plCH 2 R~p~Ar3--C - R6
R3P ~) 2) reduction
R4P 23
R7P
RP4-W1-(CH2)pCH2 /~ R8p
R6 /Ar 1 ) HO - C -AP - COORP
CH , O [Ill]
rAr2/ >~NH 2) selective removal of
R3P--~'' H R5 protecting groups
R4P
24

CA 0222~2~ 1997-12-18
WO 9'JJ0~2'TS PCT/US5~6~IIaZ2
- 323 -
R7P
H-W -(cH23pl H2 A~ R8P
~A~/ >,,N~AP-COORP
R3P--~) 15 ~ [Xll]
R4P
In the above formulas, RP4 represents a hydroxyl-protecting group
S when W1 is an oxygen atom; or a mercapto-protecting group when W
C C
is a sulfur atom; and AP, p, Wl, Z, R3P,
R4P, R5, R6, R7P, R8P and RP are as defined above.
According to this process, the desired compound (XII) can
be prepared by i-lrstly reacting an aL~ylating agent of the formula 21 to
10 a ketone compound of the formula 4 to obtain a compound of the
formula 22, reacting a reducing agent such as a metal hydride complex
to the compound 22 to obtain an alcohol compound, then reacting
diethyl azodicarlboxylate, triphenylphosphine and phth~limide (or
hydrogen azide or diphenylphosphoryl azide), or reacting a
15 sulfonylation agent such as methanesulfonyl chloride in the presence of a
base such as triethylamine and then reacting phth~limide (or sodium
azide) in the presence of a base, to obtain a phth~limide-protected form
(or an azide compound) of the amine compound 23, then reacting
hydrazine (or a reducing agent) to remove the phth~limide group (or
20 reduce the azide group) to obtain an amine of the formula 23, reacting a
compound of the formula 10 to the compound 23, followed by reduction
to obtain a compound of the formula 24, reacting a carboxylic acid of
the formula (III,~ or its reactive derivative to the compound 24, and then
selectively removing the protecting group represented by RP4.
J

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/US96/11022
- 324-
When RP4 is a hydroxyl-protecting group, as such a
hydroxyl-protecting group, the nydroxyl-protecting groups disclosed
above with respect to process 1 may be employed.
When RP4 is a mercapto-protecting group, as such a
5 mercapto-protecting group, the hydroxyl-protecting groups disclosed
above with respect to process 1 can be employed.
The respective steps up to the production of the desired
compound (XII) from the ketone compound of the formula 4 can be
carried out in the same manner as the respective steps for the production
10 of the compound of the formula 15 from the ketone compound of the
formula 4 in the above process D. Accordingly, with respect to the
reaction conditions, etc., the same conditions as in the corresponding
respective steps can be employed.
Further, the compound of the formula 21 may be
lS commercially available, or can be produced by a proper combination, as
the case requires, of the methods disclosed in Examples, or conventional
methods or methods similar thereto.

CA 02225255 l997-l2-l8
W O 97/01275 PCTrUS96/11022
- 325 -
Process G
R7P
HO-(CH2)F,CH2A~R8p Introduction of a
R6~c / J leaving group
rAr2/ >~N~AP-COORP
R3P~) I 5 ~ [Xll - a]
R4P
R7P
Z1-(C'H2)pCH2 1~ R8P
rAr2/ >~,N~ AP-COORP
R3P--~ Rs ~ [X]
R4P
Cr ' Cr
In the above form~ , AP, p,
5zl, R3P, R4P, R5, R6, R7P, R8P and RP are as defined above.
According to this process, the desired compound (X) can be
prepared by introducing a leaving group to the compound of the
formula (XII-a).
This step can be carried out in the same manner as the
10 method of introducing a leaving group to the compound of the formula
lS in the above process D. Accordingly, with respect to the reaction
conditions, etc., ~imil~r conditions may be employed.
A compound of the formula (VII):
R1P ~
~~ 9rl (CH2)n -CH2 - T (Vll)
, R2P

CA 02225255 1997-12-18
WO 97/0127!i PCT/US96111022
- 326-
Cr1
wherein n, T, RlP and R2P are as defined above, can be
prepared from a compound of the formula (XIII):
R1P
~~rl (CH2)n-CH2 Z1 (Xlll)
R2P
f ~rl
wherein ~/ n, zl, RlP and R2P are as defined above, in
accordance with the method for producing a compound of the formula
(VI) from the compound of the formula 16 in process D.
Further, the compound of the formula (XIII) may be
10 commercially available, or can be prepared by a proper combination, as
the case requires, of the methods disclosed in Examples, or conventional
methods or methods .~imil~r thereto.

CA 02225255 1997-12-18
WO 9711~127S PCT/US96~IIOZ2
- 327 -
Process H
wx CH2
(R)
CH - CH - OCORt
Wx--fll2 RsJ~OCORt ~2 R5
CltCHOH 29 4p 30
R3P ~Ar2~ I R
~) R5
R4P/ wx f H2 (s)
~ CH-CH-OH
R3P~~Ar2/ R5
~ ) 31
R4P
WY fH2 (R) WY fH2 (R~
CH - CH - OCORt /CH--CHOH
R3p~2/ R hydrolysis ~Ir2 R5
R4P R4P
;~
R1P
R2P~r1--Q -
S In the above formulas, WX is (wherein
Cr1_,
Q, R1P and R2P are as defined above),
RP4-Wl-(CH2)pl- (wherein p' is an integer of from O to 4;and RP4 and
wl are as de~med above) or

CA 0222.72.7.7 1997 - 12 - 18
WO 97/0127S PCT/US96111022 --
- 328 -
..
RP2o
RP3O (wherein RP2, RP3 and p are as defined above); RS is a
hydrogen atom or a methyl group; Rt is a lower aL~yl group, an aryl r
Cl2 ~
group or a lower alkenyl group; and R3P, R4P and R5 are
as defined above.
S Process H is a process for preparing an optically active
substance 31 or 32 of an alcohol compound 28 obtainable as the above
formula 8 or a reduction product of the formula 12, 18 or 22.
According to this process, the desired optically active
alcohol compounds 31 and 32 can be prepared by reacting a vinyl ester
derivative of the formula 29 to a racemic alcohol derivative of the
formula 28 in the presence of a lipase, separating the obtained optically
active ester derivative 30 and the optically active alcohol derivative, and
then hydrolyzing the ester group with respect to the optically active
ester derivative 30.
Rt of the vinyl ester derivative of the formula 29 is
preferably a lower aL~yl group such as a methyl group or an ethyl
group; an aryl group such as a phenyl group or a naphthyl group; or an
araL~yl group such as a benzyl group or a 2-phenylethyl group.
Particularly preferred is a methyl group, i.e. a case wherein the
20 compound of the formula 29 is vinyl acetate or isopropenyl acetate.
The above optical resolution reaction by lipase can be
conducted usually in an inert solvent such as methylene chloride,
chloroform, ethyl ether, tetrahydrofuran, benzene, toluene, hexane,
heptane or acetonitrile, or by using the starting material vinyl ester
25 derivative of the formula 29 itself as the solvent.
The vinyl ester derivative 29 is used usually in an
amount of 1 mol or in a large excess molar amount, preferably from 1
to 100 mols, per mol of the starting material compound 28, and the
arnount of the lipase as the catalyst is from 0.01 to 100% preferably
30 from 0.1 to 20%, by weight, relative to the compound 28.

CA 0222~2~ 1997-12-18
WO 97/0127S PCT/lJS96tllO22
- 329 -
Th~e type of the lipase is preferably a lipase derivative from
Pseudomonas sp. such as Toyothium LIPTM (manufactured by Toyobo).
Further, the above enzymatic reaction tends to be
accelerated, when the reaction is carried out in the presence of a base.
5 As a base to be used for this purpose, an organic base such as
triethylamine or diisopropylethylamine, is preferred.
ThLe base is used usually in an amount of 0.01 mol or
slightly excess molar amount, preferably from 0.1 tol.5 mols, relative
to the starting material compound 28.
Thle reaction temperature is usually from 0~C to 50~C,
preferably from room temperature to 40~C. The reaction time is
usually from 30 minlltes to 7 days, preferably from 1 hour to 48 hours.
The hydrolytic reaction of the ester of the formula
30 can be conducted by a common method well known in the
lS organic synthel:ic chemistry under an acidic or basic
condition.
The compositions of this invention inhibit Ras farnesyl
transferase which catalyzes the first step in the post-translational
20 processing of Ras and the biosynthesis of functional Ras protein. These
compositions are useful as pharmaceutical agents for m~mm~
especially for hnm~n~. These compositions may be ~lmini~tered to
patients for use in the treatment of cancer. Examples of the type of
cancer which may be treated with the compositions of this invention
25 include, but are not limited to, colorectal carcinoma, exocrine
pancreatic carcinoma, and myeloid leukemias.
The compositions of this invention are also useful for
inhibiting proliferative diseases, both benign and malignant, wherein
Ras proteins are aberrantly activated as a result of oncogenic mutation
30 in other genes (i.e., the Ras gene itself is not activated by mutation to an
~~ oncogenic form) with said inhibition being accomplished by the
~lrnini~tration of an effective amount of the compositions of the
invention to a m~mm~l in need of such treatment. For example, the
benign proliferative disorder neurofibromatosis, or tumors in which the

CA 0222~2~ 1997-12-18
W O 9710127S PCTrUS96/11022
- 330 -
Ras is activated due to mutation or overexpression of tyrosine kinase
oncogenes (e.g., neu, src, abl, lck, and fyn) may be inhibited by the
compositions of this invention.
In practicing the methods of this invention, which comprise
S ~lminictering, simultaneously or sequentially or in any order, two or
more of a protein substrate-competitive inhibitor and a farnesyl
pyrophosphate-competitive inhibitor, such ~lmini~tration can be orally
or parenterally, including the intravenous, intramuscular,
intraperitoneal, subcutaneous, rectal and topical routes of
10 ~tlmini~tration. It is preferred that such ~1mini~tration be orally. It is
more preferred that such ~lminictration be orally and simultaneously.
When the protein substrate-competitive inhibitor and farnesyl
pyrophosphate-competitive inhibitor are ~clmini.stered sequentially, the
~lmini~tration of each can be by the same method or by different
15 methods.
The compositions of this invention may be ~lminictered to
m~mm~l~, preferably humans, either alone or, preferably, in
combination with ph~rm~c.eutically acceptable carriers or diluents,
optionally with known adjuvants, such as alum, in a pharmaceutical
20 composition, according to standard pharmaceutical practice.
For oral use of a chemotherapeutic composition according
to this invention, the selected composition may be ~-lmini.stered, for
example, in the form of tablets or capsules, or as an aqueous solution or
suspension. In the case of tablets for oral use, carriers which are
25 commonly used include lactose and corn starch? and lubricating agents,
such as magnesium stearate, are commonly added. For oral
~lministration in capsule form, useful diluents include lactose and dried
corn starch. When aqueous suspensions are required for oral use, the
active ingredient is combined with emulsifying and suspending agents.
30 If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, ~-
sterile solutions of the active ingredient are usually prepared, and the pH
of the solutions should be suitably adjusted and buffered. For

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intravenous use, the total concentration of solutes should be controlled
in order to render the preparation isotonic.
Suitable compositions of this invention include aqueous
solutions comprising compounds of this invention and
5 pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g.,
7.4. The solutions may be introduced into a patient's intramuscular
blood-stream by local bolus injection.
When a composition according to this invention is
z~lmini~tered into a human subject, the daily dosage will normally be
10 determined by the prescribing physician with the dosage generally
varying according to the age, weight, and response of the individual
patient, as well as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of
composition is ~flmini~tered to a m~mm~l undergoing treatment for
15 cancer. A-lmini~tration occurs in an amount of a composition that
comprises between about 0.1 mg/kg of body weight to about 40 mg/kg
of ~ody weight per day, preferably of between 0.5 mg/kg of body
weight to about 20 mg/kg of body weight per day of a protein substrate-
competitive inhibitor and an amount between about 0.1 mg/kg of body
20 weight to about 40 mg/kg of body weight per day, preferably of
between 0.5 mg/kg of body weight to about 20 mg/kg of body weight
per day of a farnesyl pyrophosphate-competitive inhibitor.
EXAMPLE~S
E~:amples provided are intended to assist in a further
underst~ncling of the invention. Particular materials employed, species
and conditions are intended to be further illustrative of the invention
and not limit~tive of the reasonable scope thereof.
EXAMPLE 1
Preparation of N-{ (lRS,2RS,4E)-2-(4-chlorophenyl)-1 -methyl-5-(2-
naphthyl)-4-pemtenyl }-2-naphthylmethylamine

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(1) Preparation of (E)-3-(4-chlorophenyl)-6-(2-naph~yl)-5-
hexen-2-one
2.56 g of p-chlorophenylacetone was dissolved in a mixed
solution of S ml of dimethylformamide and S ml of benzene, and a
S dimethylformamide 8 ml/benzene 8 ml solution cont~ining 0.62 g of
60% oily sodium hydride and 3.50 g of (E)-3-(2-naphthyl)-2-propenyl
bromide, was added under cooling with ice with stirring, followed by
stirrin,e~ at room temperature for 2 hours. The reaction solution was
acidified by an addition of lN hydrochloric acid and extracted by an
10 addition of water and ethyl ether. Then, the organic layer was washed
with a saturated sodium chloride aqueous solution and then dried over
anhydrous magnesium sulfate. The drying agent was filtered off, and
then, the solvent was distilled off under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/ethyl acetate
15 5/1) to obtain the above-identif1ed compound.
(2) Preparation of (2RS,3SR,5E)-3-(4-chlorophenyl)-6-(2-
naphthyl)-5-hexen-2-ol
4.78 g of (E)-3-(4-chlorophenyl)-6-(2-naphthyl)-5-hexen-
20 2-one was dissolved in 30 ml of tetrahydrofuran, and 14.3 ml of a lM
tetrahydrofuran solution of lithillm tri-sec-butyl borohydride was added
at -78~C under cooling with stirring, followed by stirring at the same
temperature for 2 hours. To the reaction solution, 10 ml of a 2N
sodium hydroxide aqueous solution was added under cooling with ice
25 with stirrin~, and then, 15 ml of a 30% hydrogen peroxide aqueous
solution was gradually dropwise added, followed by stirring at room
temperature for one hour. The reaction solution was extracted by an
addition of ethyl ether and water. The organic layer was washed with a
saturated sodium thiosulfate aqueous solution and a saturated sodium
30 chloride aqueous solution and then dried over anhydrous m~gnesium
sulfate. The drying agent was filtered off, and then, the solvent was .~
distilled off under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 15/1 to 5/1) to
obtain the above-identified

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compound.
(3) Preparation of (lRS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-
5 -(2-naphthyl)-4-pentenylamine
4.06 g of (2RS,3SR,5E)-3-(4-chlorophenyl)-6-(2-naphthyl)-
5-hexen-2-ol was dissolved in 30 ml of tetrahydrofuran, and 4.77 g of
triphenylphosphine, 2.89 ml of diethyl azodicarboxylate and 4.77 g of
diphenylphosphoryl azide were added under cooling with ice wit]h
stirring, followed by stirring at room temperature for 30 minutes. The
10 reaction solution was evaporated to dryness under reduced pressure.
Then, the residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 50/1 to 30/1). The obtained azide product was
heated and reflu,xed together wit]h 3.2 g of triphenylphosphine in 100 ml
of 10% water-cont~inin~ tetrahydrofuran. The reaction solution was
15 evaporated to dryness under reduced pressure. Then, the residue was
purified by silica gel column chromatography (methylene
chloride/methanol = 50/1 to 20/1) to obtain the above-identified
compound.
(4) Preparation of N-{ (IRS,2RS,4E)-2-(4-chlorophenyl)-1-
met]hyl-5-(2-naphthyl)-4-pentenyl ~-2-naphthylmethylamine
0.75 g of (lRS,2RS,4E)-2-(4-chlorophenyl)-l-methyl-5-(2-
naphthyl)-4-pentenylamine was dissolved in 10 ml of methanol, and 0.34
g of 2-naphthoaldehyde was added thereto, followed by stirring at room
temperature overnight. To the reaction solution, 10 mg of
tetrahydrofuran was added to dissolve the forrned precipitate, and 84
mg of sodium borohydride was added thereto, followed by stirring at
b room temperature for 2 hours. The reaction solution was extracted by
an addition of ethyl ether and water. The organic layer was washed
with a saturated sodium chloride aqueous solution and then dried over
-~ anhydrous magnesium sulfate. The drying agent was filtered off, and
then, the solvent was distilled off under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/ethyl acetate
= 7/1 to 3/1) to obtain the above-identified compound.

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The reaction was carried out in the same manner as in
Example 1 except that instead of the p-chlorophenylacetone and/or (E)-
3-(2-naphthyl)-2-propenylbromide and/or 2-naphthoaldehyde, used as
5 the starting material in the above reaction, the corresponding
arylacetone derivative and/or halide and/or arylaldehyde derivative, was
used to obtain N{(lRS,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-(1-
naphthyl)-4-pentenyl } -2-naphthylmethylamine, N- { (lRS,2RS)-2-(4-
chlorophenyl)-l-methyl-5-(2-naphthyl)-4-pentyl }-2-
10 naphthylmethylamine, N-{(lRS,2RS)-2-(4-chlorophenyl)-1-methyl-4-(2-
naphthoxy)butyl }-2-naphthylmethylamine, N- { (lRS,2RS)-2-(4-
chlorophenyl)-l-methyl-4-(2-naphthyl)butyl }-2-naphthylmethyl~mine,
N- { (lRS,2RS)-2-(4-chlorophenyl)-1-methyl-6-(2-naphthyl)hexyl } -2-
naphthylmethyl~mine, N-{(lRS,2RS)-2-(4-chlorophenyl)-1-methyl-5-
phenyl-4-pentynyl }-2-naphthylmethylamine, N-{ (lRS,2RS,4E)-2-(4-
methoxyphenyl)-l-methyl-5-(2-naphthyl)-4-pentenyl }-2-
naphthylmethylamine, N-{(lRS,2RS,4E)-2-(4-methylphenyl)-1-methyl-5-
(2-naphthyl)-4-pentenyl } -2-naphthylmethylamine, N- { ( 1 RS ,2RS ,4E)-l-
methyl-5-(2-naphthyl)-2-(4-nitrophenyl)-4-pentenyl }-2-
naphthylmethylamine, N- { (lRS,2RS,4E)-2-(4-fluorophenyl) 1 -methyl-5-
(2-naphthyl)-4-pentenyl }-2-naphthylmethylamine, N- { (lRS,2RS,4E)-l-
methyl-5-(2-naphthyl)-2-(4-trifluoromethylphenyl)-4-pentenyl }-2-
naphthylmethylamine, N-{(lRS,2RS,4E)-l-methyl-5-(2-naphthyl)-2-
phenyl-4-pentenyl }-2-naphthylmethylamine, N- { (lRS,2RS,4E)-l-methyl-
2-(6-methyl-3-pyridyl)-5-(2-naphthyl)-4-pentenyl }-2-
naphthylmethylamine, N-{(lRS,2RS,6E)-2-(4-chlorophenyl)-1-methyl-7-
phenyl-6-heptenyl)-2-naphthylmethylamine, N-{(lRS,2RS,6E)-2-(4-
chlorophenyl)-l-methyl-7-(2-naphthyl)-6-heptenyl)-2-
naphthylmethylamine, N- { (lRS,2RS,4E)-2-(4-chlorophenyl)- 1 -methyl-
5-(2-naphthyl)-4-pentenyl }-3-quinolylmethylamine, N- { (lRS,2RS,4E)-
2-(4-chlorophenyl)- 1-methyl-5-(2-naphthyl)-4-pentenyl }-3,4- ~ -
difluorobenzylamine, N-(2-benzoxazolylmethyl)-{(lRS,2RS,4E)-2-(4-
chlorophenyl)-l-methyl-5-(2-naphthyl)-4-pentenyl}amine, N-(2-
benzo[b]thienylmethyl)- { (lRS ,2RS,4E)-2-(4-chlorophenyl)-1-methyl-5-

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(2-naphthyl)-4-pentenyl }amine, N- { (lRS,2RS,4E)-l-methyl-2-(3,4-
methylenedioxyphenyl)-5-(2-naphthyl)-4-pentenyl }-2-
naphthylmethylamine, N-{(lRS,2RS)-4,4-diethoxy-1-methyl-2-(3,4-
methylenedioxyphenyl)butyl}-2-naphthylmethyl~mine, N-(2-
5 benzo[b]furanylmethyl)-{ (lRS,2RS)-4,4-diethoxy-1-methyl-2-(3,4-
methylenedioxyphenyl)butyl}amine, N-(2-benzo[b]thienylmethyl)-
{ (lRS,2RS)-4,4-diethoxy-1-methyl-2-(3,4-
methylenedioxyphenyl)butyl}annine, N-[(lRS,2RS)-4,4-diethoxy-1-
methyl-2- { (3,4 -bis(methoxycarbonyl)phenyl }butyl]-2-
10 naphthylmethylamine, N-(2-benzo[b]thienylmethyl)- { (lRS,2RS)-4,4-
diethoxy-2-(4-methoxycarbonylphenyl)-l-methylbutylannine, N-(2-
benzo[b]furanylmethyl)- { (lRS ,2RS)-4,4-diethoxy-2-(4-
methoxycarbonylphenyl)- 1 -methylbutyl }amine, N-(2-
benzo[b]thienylmethyl)- { (lRS ,2RS)-2-(4-cyanophenyl)-4,4-diethoxy-1-
15 methylbutyl }annine, N-(5-benzo[b]thienylmethyl)-{ (lRS,2RS)-4,4-
diethoxy-2-(4-rnethoxycarbonylphenyl)-1-methylbutyl}amine, N-
{ (lRS,2RS)-2-(4-chlorophenyl)-4,4-diethoxy-1-methylbutyl }-2-
naphthylmethylamine, N-{(lRS,2RS)-2-(4-cyanophenyl)-4,4-diethoxy-1-
methylbutyl } -2-naphthylmethylamine, N- { (lRS,2RS)-2-(4-
20 cyanophenyl) -4 ,4-diethoxy-1-methylbutyl } -2-naphthylmethylamine, N -
{ (lRS,2RS)-4,4-diethoxy-2-(4-methoxycarbonylphenyl)-1-methylbutyl }-
2-naphthylmethylamine, N-{(lRS,2RS,4E)-2-(4-
methoxycarbonylphenyl)-l-methyl-5-(2-naphthyl)-4-pentenyl }-2-
naphthylmethylamine and N-[(lRS,2RS)-5-(1,3-dioxolan-2-yl)-1-methyl-
25 2-(3,4-methylenedioxyphenyl)butyl]-2-naphthylmethylamine.
FXAMPLE 2
Preparation of 1,2-di-tert-butyl 1, 2, 3-propanetricarboxylate and its
30 optical resoluti,on
13.1 n[ll of a 1.5M cyclohexane solution of lithium
diisopropylamide was dissolved in 10 nnl of tetrahydrofuran, and a
tetrahydrofuran solution (10 ml) cont~ining 2.96 g of benzyl acetate was
35 added under cooling to -70~C with stirring, followed by stirring at the

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same temperature for 30 minutes. Then, a tetrahydlorul~n solution (10
ml) cont7~ininp: 2.96 g of di-tert-butyl maleate, was dropwise added
thereto, followed by stirring at the same temperature for 30 minutes.
The reaction solution was extracted by an addition of 20 ml of water
S and 50 ml of ethyl ether. The organic layer was separated, then washed
with a saturated sodium chloride aqueous solution and dried over
anhydrous magnesium sulfate. Then, the solvent was distilled off under
reduced pressure. The residue was dissolved in 50 ml of dioxane, and
0.4 g of a 10% palladium carbon catalyst was added thereto, followed
by catalytic reduction for 20 hours at room temperature under
hydrogen atmospheric pressure. The catalyst was filtered off, and then,
the solvent was distilled off under reduced pressure. The residue was
treated with hexane, whereupon the precipitate thereby obtained was
collected by filtration and then dried to obtain the above-identified
compound as colorless crystalline powder, mp 55-57~C.
12.97 g of the di-tert-butyl ester thus obtained and 13.24 g
of cinchonidine was dissolved under heating in l liter of carbon
tetrachloride. Then, seed crystals were added thereto, and the mixture
was left to stand at room temperature for 24 hours. The crystals were
collected by filtration and then again dissolved under heating in 1 liter
of carbon tetrachloride, and seed crystals were added thereto, and the
mixture was left to stand for 24 hours. This operation was further
repeated twice to obtain a cinchonidine salt of the above-identified
compound, which is named as the (S*)-isomer for the sake of
convenience, [a] 20D -62.7~(c 1.0, chloroform) .
The cinchonidine salt thus obtained was dissolved in a
mixed solution of ethyl ether and lN hydrochloric acid under cooling
with ice, and the organic layer was separated and then post-treated in
accordance with a conventional method to obtain the (S * )-isomer of
the above-identified compound as colorless oily s~lbstance, [a] 20D
+4.44~(c 0.92, chloroform).
The fraction cont~inin,P a large amount of the other mirror
image isomer obtained in the above optical resolution operation, was
converted to a free acid, and then, the same operation was carried out in

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isopropyl ether using quinine, whereby the mirror image isomer nanned
as the (R*)-isorner for the sake of convenience, was obtained.
FXAMPLE 3
s
Preparation of (2RS,3RS)-3-tert-butoxyc:arbonyl-5-
oxotetrahydrofuran-2-carboxylic acid
(1) Preparation of (2RS,3SR)-2 diphenylmethoxycarbonyl-5-
oxotetrahydrofuran-3-carbo~;ylic acid
262 mg of (2RS,3SR)-5-oxotetrahydrofuran-2,3-
dicarboxylic acid was dissolved in 5 ml of acetone, and 291 mg of
diphenyldiazomethane was added thereto, followed by stirring at room
15 temperature for 20 minutes. The reaction solution was evaporated to
dryness under reduced pressure. The residue was purified by silica gel
column chromatography (chloroform/methanol = 100/1 to 10/1) to
obtain the above-identified compound as white powder.
(2) Preparation of 3-tert-butyl 2-diphenylmethyl (2RS,3RS)-5-
oxotetrahydrofuran-2 ~3 -dicarboxylate
163 mg of (2RS,3SR)-2-diphenylmethoxycarbonyl-5-
oxotetrahydrofi~ran-3-carboxylic acid, 55~ mg of 4-
dimethylaminopyridine and 36 mg of terl:-butanoL were dissolved in 4
ml of methylene chloride, and 110 mg of 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride was added thereto,
followed by stirring at room temperature for 13 hours. The reaction
solution was diluted with methylene chloride, then sequentially washed
with a 10% CitIiC acid aqueous solution, a saturated sodium
hydrogencarbonate aqueous solution and a saturated
~, sodium chloride aqueous solution and dried over anhydrous magnesium
sulfate. The drying agent was filtered off, and then, the solvent was
distilled off under reduced pressure. The residue was puri~led by silica

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gel column chromatography (hexane/ethyl acetate = 10/1) to obtain the
above-identified compound as colorless oily substance.
(3) Preparation of (2RS,3RS)-3-tert-butoxycarbonyl-5-
oxotetrahydrofuran-2-carboxylic acid
148 mg of 3-tert-butyl 2-diphenylmethyl (2RS,3RS)-5-
oxotetrahydrofuran-2,3-dicarboxylate was dissolved in 4 ml of ethyl
acetate, and 15 mg of a 10% p~ m-carbon catalyst was added
thereto, followed by catalytic reduction for 15 hours at room
temperature under hydrogen atmospheric pressure. The catalyst was
filtered off, and then, the solvent was distilled off under reduced
pressure. The residue was washed with benzene to obtain the above-
identified compound as white crystalline powder.
EXAMPLE 4
Preparation of (2R*)-2-[N-{(lRS,2RS,4E)-5-(2-
benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl }-N-(2-naphthylmethyl)carbamoylmethyl]succinic
acid and (2R*)-2-[N-{ (lRS,2RS,4Z)-5-(2-benzoxazolyl)- 1-methyl-2-
(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-
n~?hthylmethyl)carbamoylmethyllsuccinic acid
(1) Preparation of di-tert-butyl (2R*)-2-[N- { (lRS ,2RS)-4,4-
diethoxy-1-methyl-2-(3,4-methylenedioxyphenyl)butyl }-N-
(2-naphthylmethyl)carbamoylmethyll succinate
436 mg of N-{(lRS,2RS)-4,4-diethoxy-l-methyl-2-(3,4-
methylenedioxyphenyl)butyl }-2-naphthylmethylamine
obtained in a manner .cimil~r to Example 1, 346 mg of 1,2-di-tert-butyl
(R*)-1,2,3-propanetricarboxylate obtained in Example 2 and 122 mg of
4-dimethylaminopyridine, were dissolved in 5 ml of methylene chloride, ,-
and 249 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride was added thereto, followed by stirring at room
temperature for 14 hours. The reaction solution was diluted with ethyl

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acetate, then, sequentially washed with lN hydrochloric acid, saturated
sodium hydrogen carbonate aqueous solution and a saturated sodium
chloride aqueouls solution and dried over anhydrous magnesium sulfate.
The drying agent was filtered off, and then, the solvent was distilled off
5 under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 10/1 to 5/1) to obtain the
above-identifiecl compound as a colorless foam.
(2) Preparation of di-tert-butyl (2R*)-2-[N-{ (lRS,2RS)-3-
formyl-l-methyl-2-(3,4-methylenedioxyphenyl)propyl }-N-
(2-naphthylmethyl)carbamoylmethyll succinate
636 mg of di-tert-butyl (2R*)-2-[N-{(lRS,2RS)-4,4-
diethoxy-l-methyl-2-(3,4-methylenedioxyphenyl)butyl }-N-(2-
naphthylmethyl)carbamoylmethyl]succinate was dissolved in 12 ml of
15 tetrahydrofuran, and 3 ml of 2N hydrochloric acid was added thereto,
followed by stirring at room temperature for 3 hours. To the reaction
solution, a saturated sodium hydrogencarbonate aqueous solution was
added, and the mixture was extracted with ethyl acetate. Then, the
organic layer was washed with a saturated sodium chloride aqueous
20 solution and dried over anhydrous magnesium sulfate. The drying agent
was filtered off, and then, the solvent was distilled off under reduced
pressure to obtain the above-identified compound as colorless oily
substance.
(3) Pre:paration of di-tert-butyl (2R*)-2-[N-{(lRS,2RS,4E)-5-
(2-benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)-
4-pentenyl }-N-(2-naphthylmethyl)carbamoylmethyl]-
succinate
53 mg of 60% oily sodium hydride was suspended in 5 ml
30 of tetrahydrofuran, and 634 mg of 2-benzoxazolylmethyl
. triphenyl)phosp~honium bromide was added thereto, followed by stirring
at room temperature for 30 minutes. 5 ml of a tetrahydrofuran solution
cont~ining 563 mg of di-tert-butyl (2R*)-2-[N-{(lRS,2RS)-3-formyl-l-
methyl-2-(3,4-rnethylenedioxyphenyl)propyl }-N-(2-

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naphthylmethyl)carbamoylmethyl]succinate was added thereto, followed
by stirring at room temperature for 12 hours. Then, water was added
to the reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was washed with a saturated sodium chloride
S aqueous solution and then dried over anhydrous magnesium sulfate.
The drying agent was filtered off, and then, the solvent was distilled off
under reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate = 10/1 to 5/1) to obtain the
above-identified E isomer compound and Z-isomer of the above-
10 identified compound, respectively, as a colorless foam.
(4) Preparation of (2R*)-2-[N-{(lRS,2RS,4E)-5-(2-
benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl } -N-(2-naphthylmethyl)carbamoylmethyl]succinic
acid
486 mg of di-tert-butyl (2R*)-2-[N-{(lRS,2RS,4E)-5-(2-
benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-
(2-naphthylmethyl)carbamoylmethyl]succinate was dissolved in 10 ml of
formic acid, followed by stirring at room temperature for 12 hours.
20 Then, formic acid was distilled off under reduced pressure to obtain the
above-identified compound as white solid.
lH-NMR(CDC13) o;0.91-1.00(3H, m), 2.30-3.70(8H, m),
4.20-5.30(3H, m), 5.90-5.94(2H, m), 6.43(1H, d, J=15.7Hz), 6.57-
6.76(4H, m), 7.26-7.84(1 lH, m) FAB-MS:635(M+H)
By the same treatment as above except that di-tert-butyl (2R*)-2-[N-
{ (lRS,2RS,4Z)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-
methylenedioxyphenyl)-4-pentenyl }-N-(2-
naphthylmethyl)carbamoylmethyl]succinate was used, Z-isomer of the
30 above-identified compound was obtained.

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- 341 -
EXAMPLE 5
Preparation of disodium (3RS,4RS)-4-[N-{(lRS,2RS,4E)-5-(2-
benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-
5 (2-naphthylmethyl)carbamoyll-3-carboxy-4-hydroxybutanoate
(1) Preparation of (2RS,3RS)-2-[N-{(lRS,2RS,4E)-5-(2-
benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl }-N-(2-naphthylmethyl)carbamoyl]-5-
oxotetrahydrofuran-3-carboxylic acid.
47 IIlg of tert-butyl (2RS,3RS)-2-[N-{(lRS,2RS,4E)-5-(2-
benzoxazolyl)-l-nnethyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-
(2-naphthylmethyl) carbamoyl]-5-oxotetrahydrofuran-3-carboxylate
prepared in a malmer ~imil~r to Fx~mple 4 except that (2RS,3RS)-3-
15 tertbutoxycarbon~yl-5-oxotetrahydrofuran-2-carboxylic acid obtained in
Example 3 was used, instead of the 1,2-di-tert-butyl (R*)-1,2,3,-
propanetricarbox~late in Example 4, was dissolved in 1 ml of formic
acid, and the solution was left to stand at room temperature overnight.
The reaction solution was distilled under reduced pressure. Then,
20 toluene was added to the residue, followed by clistillation again. The
product was puri~led by silica gel column chromatography (hexane/ethyl
acetate = 2/1 to ch~oroform/methanol = 50/1) to obtain the above-
identified compolmd as white solid.
lH-NMR(CDC13)~:0.99 and l.lO(total 3H, each d, J=6.2Hz, 6.3Hz),
25 2.50-3.10(5H, m), 4.15-4.25 and 4.37-4.47(total lH, each m), 4.50-
5.35(4H, m), 5.73, 5.75, 5.88 and 5.94(total 2H, each s), 6.07 and
6.36(total lH, each d, each J=15.8Hz), 6.60-6.75(4H, m), 7.25-
. 7.82(11H, m)
FAB-MS:633(M~H)
-" (2) Disodium (3RS,4RS)-4-[N-{(lRS,2RS,4E)-5-(2-benzoxazolyl)-1-
methyl-2-(3,4-methylenedioxyphenyl }-4-pentenyl)-N-(2-
naphthylmethyl)carbamoyll-3-carboxy-4- hydroxybutanoate

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8 mg of the lactone thus obtained was dissolved in a II~ixed
solution of 1 ml of methanol and 1 ml of tetrahydrofuran, and 26 ,ul of
a lN sodium hydroxide aqueous solution was added under cooling with
ice with stirring, followed by stirring at room temperature for 10
S minlltes. The reaction solution was evaporated to dryness under
reduced pressure to obtain the above-identified coInpound as white
solid.
lH-NMR(CDC13)~:0.91 and 1.03(total 3H, each d, J=6.0Hz
10 and 6.7Hz), 2.35-3.40(6H, m), 4.60-5.10(4H, m), 5.86 and 5.90(total
2H, each s), 5.90-6.95(5H, m), 7.28-8.01(11H,m)
FAN-MS :695(M+H)
FXAMPLE 6
Preparation of disodium (3S, 4S)-4-[N-{ lR,2R,4E)-5-(2-benzoxazolyl)-
1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthyl-
methyl)carbamoyll-3-carboxy-4-hydroxybutanoate (Compound D)
(1) Preparation of N-[(lR,2R)-4,4-diethoxy-1-methyl-2-(3,4-
methylenedioxyphenyl)butyl }-2-naphtylmethylamine
(1-1) Preparation of 5,5-diethoxy-3-(3,4-
methylenedioxyphenyl)pentan-2-one
11.7 g of (3,4-methylenedioxyphenyl)acetone was dissolved
in 100 ml of dimethylformamide, and 2.76 g of 60% oily sodium
hydride and 20.9 g of 2,2-diethoxyethyliodide was added under cooling
with ice with stirring, followed by stirring at room tempelalule for 2
30 hours. The reaction solution was poured into 100 ml of water and
extracted with diethyl ether. Then, the organic layer was washed with a
saturated sodium chloride aqueous solution and then dried over
anhydrous magnesium sulfate. The drying agent was ~lltered off, and
then the solvent was distilled off under reduced pressure. The residue

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-
was purified by silica gel column chromatography (hexane/ethyl acetate
= 15/1 to 10/1) to obtain the above-identified compound.
(1-2) Preparation of (2RS,3SR)-5,5-diethoxy-3-(3,4-
methylenedioxyphenyl)pentan-2-ol
18.3 g of (3,4-methylenedioxyphenyl)acetone was dissolved
in 200 ml of tetrahydrofuran, and 65 ml of a 1.0 M tetrahydrofuran
solution of lithium tri-sec-butyl borohydride was added at -78~C under
cooling with stirring, followed by stirring at the same temperature for 2
hours. To~the reaction solution, 130 ml of a lN sodium hydroxide
aqueous sl)lution was added under cooling with stirring, and then 150 ml
of a 30% hydrogen eroxide aqueous solution was gradually dropwise
added, followed by stirring at room temperature of one hour. The
reaction s(~lution was extracted by an addition of ethyl ether and water.
The orgamc layer was washed with a saturated sodium chloride aqueous
solution and a saturated sodium thiosulfate aqueous solution and water
then driedjover anhydrous magnesium sulfate. The drying agent was
filtered of:[, and then the solvent was distilled off under reduced
pressure. The residue was purified by silica gel column
chromatography- (hexane/ethyl acetate = 15/1 to 10/1 to 3/1) to obtain
the above-identified compound.
(1-3) Preparation of (2S,3R)-5,5-diethoxy-3-(3,4-
mel:hylenedioxyphenyl)pentan-2-ol
31.98 g of (2RS,3SR)-5,5-diethoxy-3-(3,4-methylenedioxy-
phenyl)pelitan-2-ol was dissolved in 320 ml of vinyl acetate, and 15.1 ml
of triethyLlmine was added thereto. Then 1.0 g of immobilized lipase
(Toyothium LIP') was added thereto, followed by stirring at 30~C for 16
hours. Further, 0.9 g of immobilized lipase was added thereto,
followed by stirring at the same temperature for 4~ hours. Then,
~~, insoluble Inatters were filtered off. The filtrate was diluted with ethyl
acetate, thl~n sequentially washed with lN hydrochloric acid, a saturated
. sodium hy~drogencarbonate aqueous solution and a saturated sodium
h chloride a~iueous solution and dried over anhydrous magnesium solfate.

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The drying agent was filtered off, and then the solvent was distilled off
under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate - 5/1 to 1/1) to obtain the above-
identified compound, [a]D20-3l.8o (c 1.0, methanol) as colorless oily
5 substance and (2R,3S)-2-acetoxy-5,5-diethoxy-3-(3,4-
methylenedioxyphenyl)pentane as colorless oily substance. Further, the
absolute configuration of the above-identified compound was detered by
Mosher method (J. Am. Chem. Soc., Vol. 113, p. 4092 (1991)).
(1-4) Preparation of (lR,2R)-4,4-diethoxy-1-methyl-2-(3,4-
methylenedioxyphenyl)butylamine
4.19 g of (2S,3R)-5,5-diethyl-3-(3,4-
methylenedioxyphenyl)pentan-2-ol was dissolved in 45 ml of ethyl
acetate, and 1.64 ml of methanesulfonylchloride and 3.93 ml of
15 triethyl~mine were added under cooling with ice thereto, followed by
stirring under cooling with ice for 30 minutes. To the reaction solution,
50 ml of a saturated sodium hydrogen carbonate solution was added,
followed by stirring at room temperature for 4~ minutes. The reaction
solution was extracted by an addition of ethyl acetate and water. The
20 organic layer was washed with a saturated sodium chloride aqueous
solution and dried over anhydrous magnesium sulfate. the drying agent
was filtered off, and then the solvent was distilled off under reduced
pressure. The residue was dissolved in 40 ml of dimethylformamide,
and 4.58 g of sodium azide was added thereto, followed by stirring at
120~C for 30 minutes. The reaction solution was a saturated sodium
chloride aqueous solution and dried over anhydrous magnesium sulfate.
The drying agent was filtered off, and then the solvent was distilled off
under reduced pressure. The residue was dissolved in a mixed solution
of 40 ml of tetrahydrofuran, and 4 ml of water was added, followed by
stirring at 90~C for 4.5 hours. The reaction solution was distilled under
reduced pressure. Then, the residue was purified by silica gel column
chromatography (ethyl acetate/methanol = 9/1) to obtain the above-
identified compound.

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(1-5) Preparation of N-{ (lR,2R)-4,4-diethoxy-1-methyl-2-(3,4-
methylene-dioxyphenyl)butyl }-2-naphtylmethylamine
150 mg of (lR,2R)-4,4-diethoxy-1-methyl-2-(3,4-
methylene-dioxyphenyl)butyl }-2-naphtylmethylamine was dissolved in 2
5 ml of methanol, and 79 mg of naphthoaldehyde was added thereto,
followed by stirring at 60~C for 2 hours. To the reaction solution, 28
mg of sodium borohydride was added under cooling with ice thereto,
followed by stirring under cooling with ice for 2 hours. The reaction
solution was exltracted by an addition of ethyl ether and water. The
10 organic layer was washed with a saturated sodium chloride aqueous
solution and then dried over anhydrous magnesium sulfate. The drying
agent was filtered off under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/ethyl acetate = 5/1 to 3/1)
to obtain the above-identified compound.
(2) Preparation of (2S,3S)-3-tert-butoxycarbonyl-5-
oxotetrahydrofuran-2-carboxylic acid
(2-1 ) Preparation of 3-tert-butyl 1 ,2-diethyl( 1 S,2R)- 1 -hydroxy-
1.2~3-propanetricarboxylate
31 ml of a 1.69 M hexane solution of n-butyl lithium
was dissolved in 30 ml of tetrahydrofuran, and 7.1 ml of
diisopropylamine was added under cooling with ice, followed by
stirring at the same temperature for 30 minutes. Then the mixture
25 was cooled to -78~C. 20 ml of a tetrahydrofuran solution cont~ining
4.94 g of diethyl (S)-malate was dropwise added at a temperature of
not higher than -50~C, followed by stirring at -20~C for 1.5 hours.
The reaction so]ution was cooled to -78~C, and 20 ml of a
tetrahydlorulan solution containing 5.58 g of tert-butyl promoacetate
30 and 4.66 g of hexamethylphosphoric triamide was dropwise added
' ~ thereto at a temperature of not higher than -50~C, followed by
stirring at room temperature for one hour. The reaction solution
was poured into 150 ml of 0.5 N hydrochloric acid and extracted
.~ with diethyl ether. Then the organic layer was washed with a

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saturated sodium hydrogencarbonate aqueous solution and a saturated
sodium chloride aqueous solution and then dried over anhydrous
m~hnesium sulfate. The drying agent was filtered off, and then the
solvent was distilled off under reduced pressure. The residue was
5 purified by silica gel column chromatography (hexane/ethyl acetate =
5/1 to 4/1) to obtain the above-identified compound as yellow oily
substance.
(2-2) Preparation of (2S,3R)-5-oxotetrahydrofuran-2,3-
dicarboxylic acid
16.49 g of 3-tert-butyl 1,2-diethyl (lS,2R)-l-hydroxy-
1,2,3-propanetricarboxylate, 100 ml of acetic acid and 50 ml of
concentrated hydrochloric acid were mixed and stirred at 70~C for 12
hours. Acetic acid and hydrochloric acid were distilled off under
15 reduced pressure. Then the residue was again dissolved in 100 ml of
acetic acid and 50 ml of concentrated hydrochloric acid and stirred at
70~C for 12 hours. Acetic acid and hydrochloric acid were distilled off
under reduced pressure. Then 100 ml of trifluoroacetic acid was added
to the residue, followed by stirring at 60~C for 5 hours. Trifluoroacetic
20 acid was distilled off under reduced pressure, and the residue was
distilled off under reduced pressure, and the residue was crystallized
from hexane-ethyl acetate to obtain the above-identified compound as
white powder.
(2-3) Preparation of (2S,3R)-2-benzyloxycarbonyl-5-
oxotetrahydrofuran-3-carboxylic acid
5.2 of (2S,3R)-5-oxotetrahydrofuran-2,3-dicarboxylic
acid was dissolved in 88 ml of acetone, and 6.5 g of 1,1'-
dicyclohexylcarbodiimide was added thereto, followed by stirring at
room temperature for 2 hours. 3.26 ml of benzyl alcohol was added
to the reaction solution, and stirred at the same temperature for 12
hours. Insoluble mattes were filtered off, and the filtrate was
~ concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate - 4/1 to

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chloroform.methanol - 50/1) to obtain the above-identi~le-1
compound as yellow solid.
(2-4) Prep~aration of 2-benzyl 3-tert-butyl (2S,3S)-5-
oxotetrahydrofuran-23-dicarboxylate
7.93 g of (2S-3R)-2-benzyloxycarbonyl-5-
oxotetrahLydrofuran-3-carboxylic acid was dissolved in 75 ml of
chloroform,. and 5.5 g of 4-dimethylaminopyridine, 8.6 g of 1-
ethLyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 5.7
ml of tert-butyl alcohol were sequentially added thereto, followed by
stirring at room temperature for 60 hours. The reaction solution
was poured into IN hydrochloric acid cooled with ice, and extracted
with ehtyl acetate. The organic layer was dried over anhydrous
magnesium sulfate. The drying agent was filtered off, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate =
5/1) to obtain the above-identified compound as white solid.
(2-5) Preparation of (2S,3S)-3-tert-butoxycarbonyl-5-
oxot,etrahydrofuran-2-carboxylic acid
6.4 g of 2 benzyl 3-tert-butyl (2S,3S)-S-
oxotetrahydrofur~m-2,3-dicarboxylate was dissolved in 80 ml of
ethyl acetate, and 640 mg of a 10% palladium-carbon catalyst was
added thereto, followed by catalytic reduction for 3 hours at room
25 temperature under hydrogen atmospheric pressure. The catalyst was
filtered off, and the filtrate was evaporated to dryness under reduced
pressure to obtain the above-identified compound as white solid.
(3) Preparation of ter-butyl (2S,3S)-2-[N- ~ 1 R,2R)-4,4-
diethLoxy- 1 -methyl-2-(3,4-methylenedioxyphenyl)butyl } -N-
. (2-naphtylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-
carboxylate
61 mg of N-{(lR,2R)-4,4-diethoxy-1-methLyl-2-(3,4-
methylenedioxyphenyl)butyl}-2-naphtylmethylamine, 35 mg of

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(2S ,3S)-3-tert-buthoxycarbonyl-5-oxotetrahydrofuran-2-carboxylic
acid and 83 ,ul of triethylamine, were dissolved in 2 ml of
chloroform, and 0.5 ml of a chloroform solution cont~ining 34 mg
of 2-chloro-1,3-dimethylimidazolinium chloride was added thereto
5 under cooling with ice followed by stirring at the same temperature
of 30 minlltes. The reaction solution was poured into water and
extracted with ethyl acetate. The extract solution was dried over
anhydrous magnesium sulfate. The drying agent was filtered off,
and the solvent was distilled off under reduced pressure. The residue
10 was purified by silica gel column chromatography (hexane/ethyl
acetate = 1/3) to obtain of the above-identified compound as colorless
oily substance.
(4) Preparation of tert-butyl (2S,3S)-2-[N-{(lR,2R)-3-formyl-
1-methyl-2-(3,4-methylenedioxyphenyl)propyl }-N-(2-
naphtylmethyl)carbamoyl] -5 -oxotetrahydrofuran-3 -
carboxylate
490 mg of tert-butyl (2S,3S)-2-[N-{ lR,2R)-4,4-
diethoxy- 1 -methyl-2-(3,4-methylenedioxyphenyl)butyl } -N-(2-
20 naphtylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was
dissolved in 15 ml of tetrahydrofuran, and 5 ml of 1 N hydrochloric
acid was added thereto, followed by stirring at room temperature for
24 hours. To the reaction solution, a saturated sodium
hydrogencarbonate aqueous solution was added, and the mixture was
25 extracted with ethyl acetate. Then the organic layer was washed with
a saturated sodium chloride solution and dried over anhydrous
magnesium sulfate. The drying agent was filtered off, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel column chromatography (Hexane/ethyl acetate
30 = 5/1) to obtain the above-identified compound as colorless oily
substance.
(5) Preparation of tert-butyl (2S,3S)-2-[N-{(lR,2R4E)-5-(2-
benzoxazolyl)- 1 -methyl-2-(3,4-methylenedioxyphenyl)-4-

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pentenyl }-N-(2-naphtylmethyl)carbamoyl]-5-
oxol:etrahydrofuran-3-carboxylate.
29 nng of 60% oily sodium hydride was suspended in 15
" ml of tetrahydro~furan, and 389 mg of 2-
5 benzoxazolylmethyl(triphenyl)phosphonium bromide was added
thereto, followed by stirring at room temperature for 2 hours. 5 ml
of a tetrahydrofuran solution cont~inin~ 319 mg of tert-butyl
(2S ,3S)-2-[N- { ( ] R,2R)-3-formyl- 1 -methyl-2-(3,4-
methylenedioxyphenyl)propyl }-N-(2-naphthylmethyl)carbamony]-5
10 oxotetrahydrofuran-3-carboxylate was added thereto, followed by
stirring at room temperature overnight. Then water was added to
the solution, and the mixture was extracted with diethyl ether. The
organic layer was washed with a saturated sodium chloride aqueous
solution and then dried over anhydrous magnesium sulfate. The
15 drying agent was filtered off, and then the solvent was distilled off
under reduced pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate - 3/1) to obtain the above-
identified compound as a colorless foam.
(6) Preparation of (2S,3S)-2-[N-{(lR,2R,4E)-5-(2-benzoxazolyl)-1-
methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-
naphtylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylic acid.
295 mg of tert-butyl (2S,3S)-2-[N-{(lR,2R,4E)-5-(2-
benzoxazolyl)- l-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-
(2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was
dissolved in 5 ml of formic acid, and the solution was left to stand at
room temperature overnight. The reaction solution was distilled under
reduced pressure. The product was purified by silica gel column
chromatography (chloroform/methanol - 50/1) to obtain the above-
identified compound as white solid.
L lH-NMR(CDCl3)~:0:99 and 1.10 (total 3H, each d, J=6.2 Hz, 6.3 Hz),
2.50-3.10 (SH, m), 4.15-4.25 and 4.37-4.47 (total lH, each m), 4.50-
5.35 (4H, m) 5.73, 5.75, 5.88 and 5.94 (total 2H, each s), 6.07 and 6.36

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(total lH, each d, each J-15.8Hz), 6.60-6.75 (4H, m), 7.25-7.82 (1 lH,
m) FAB-~S:~33 ~Mt~)
(7) Preparation of disodium (2S,3S)-2-[N-{(lR,2R,4E)-5-(2-
benzoxazolyl)- 1-methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl } -N-(2-naphthylmethyl)carbamoyl]-3-carboxy-4-
hydroxybutanoate
262 mg of the lactone thus obtainea was dissolved in a
mixed solution of 10 of methanol and 5 ml of water, and 0.91 ml of
10 a lN sodium hydroxide aquous solution was added under cooling
with ice with stirring, followed by stirring at room temperature
overnight. The reaction solution was evaporated to dryness under
reduced pressure. The residue was cryst~li7ecl from 2 rnl of
methanol and 10 ml of diethyl ether to obtain the above-identified
15 compound as white solid.
1H-NMR(CD30D)o:0.83-1.08 (3H, m), 2.30-3.20 (6H, m), 4.53-
5.10(4H, m), 5.85 and 5.89 (total 2H, each s), 5.80-6.95 (4H, m),
7.20-8.06 (12H, m)
FAB-MS :695(M+H)
EXAMPLE 7
P,G~alation of sodium 4-[N-{(lR,2R,4E)-5-(2-benzoxazolyl)-1-methyl-
2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)-
25 carbamoyl]-3-tert-butoxycarbonyl-4-hydroxy-3-butenoate (Compound
C)
(1) Preparation of methyl (3S,4S)-4-[N-{(lR,2R,4E)-5-(2-
benzoxazolyl)- 1 -methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl }-N-(2-naphthylmethyl)carbomoyl]-3-tert-
butoxycarbonyl -4-hydroxybutanoate ~ '
193 mg of tert-butyl (2S,3S)-2-[N-{(lR,2R,4E)-5-(2-
benzoxazolyl)- l-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-
(2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was

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dissolved in a mixed solution of 5 ml of tetrahydrofuran and 2 ml of
water, and 0.31 IIll of a lN sodium hydroxide aqueous solution was
added thereto, followed by stirring at room temperature for 15 hours.
The reaction solution was acidified (about pH4) by an addition of lN
5 hydrochloric acid and then extracted with ethy acetate. The extract
solution was dried over anhydrous magnesium solfate. The drying
agent was filtered off, and then the solvent was distilled off under
reuced pressure. The obtained carboxylic acid was dissolved in ethyl
acetate, and a slightly excess amount of diazomethane was added at room
10 temperature. Thle solvent was distilled off under reduced pressure, and
the residue was purified by silica gel column chromatography
(hexane/ethyl acetate - 2/1) to obtain the above-identified compound as
colorless oily substance.
(2) Preparation of methyl 4-[N-{(lR,2R,4E)-5-(2-
benzoxazolyl)- 1 -methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl }-N-(2-naphthylmethyl)carbamoyl }-3-tert-
butoxycarbonyl-4-hydroxy-3-butenoate
36 mg of methyl (3S,4S)-4-[N-{(lR,2R,4E)-5-(2-
20 benzoxazolyl)- 1 -methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-
(2-naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4-
hyudroxybutanoaite was dissolved in 2 ml of chloroform, and 42 mg of a
Dess-Martin reagent (periodenane) was added thereto, followed by
stirring at room temperature for 1 hour. The reaction solution was
25 poured into a mixed solution of a saturated sodium hydrogencarbonate
aqueous solution and a saturated sodium thiosulfate aqueous solution and
extracted with ethyl acetate. The organic layer was washed with a
saturated sodium chloride aqueous solution and dried over anhydrous
magnesium sulfate. The drying agent was filtered off, and then the
30 solvent was disti]led off under reduced pressure. The residue was
, purified by silica gel thin layer chromatography (KieselgelTM 60F254AI-tTM 5744; hexane/ethyl acetate - 3/2) to obtain the above-identified
compound as colorless oily substance.

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(3) Preparation of 4-[N-{ (lR,2R,4E)-5-(2-benzoxazolyl)-1-
methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-
naphthylmethyl)carbamoyl] -3 -tert-butoxycarbonyl-4-
hydroxy-3-butenoic acid
9.9 mg of methyl 4-[N-{(lR,2R,4E)-5-(2-benzoxazolyl)-
1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-
naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4-hydroxy-3-
butenoate was dissolved in a mixed solution of 3 ml of
tetrahydrofuran and 1 ml of water, and 140 111 of a lN sodium
hydroxide aqueous solution was added thereto, followed by stirring
at room temperature for 4 hours. The reaction solution was
acidified by an addition of lN hydrochloric acid and extracted with
ethyl acetate. The extract solution was dried over anhydrous
magnesium sulfate. The drying agent was filtered off, and then the
solvent was distilled off under reduced pressure. The residue was
purified by silica gel thin layer chromatography (Kieselgel TM
60F254~ ArtTM 5744; chloroform/methanol = 10/1) to obtain the
above-identified compound as a colorless foam.
lH-NMR(CDC13) o:0.96-1.06 (3H, M), 1.41-1.51 (9H, m), 2.30-3.29
(5H, m), 4.15-4.98 (4H, m), 5.88-6.34 (3H, m), 6.41-6.74 (4H, m),
7.21-7.88 (llH, m)
FAB-MS:705(M+H)
(3) Preparation of sodium 4-[N-{(lR,2R,4E)-5-(2-
benzoxazolyl)- 1 -methyl-2-(3,4-methylenedioxyphenyl)-4-
pentenyl }-N-(2-naphthylmethyl)carbamoyl]-3-tert-
butoxycarbonyl-4-hydroxy-3-butenoate
850 mg of 4-[N-{(lR,2R,4E)-5-(2-benzoxazolyl)-1-
methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-
30 naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4-hydroxy-3-
butenoic acid, prepared as described in Step (3), was dissolved in 25 ~'
ml of methanol, and sodium methoxide was added thereto. The
solvent was distilled off under reduced pressure. The residue was

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" solidified from e~er and hexane to obtain the above-identified
compound as a ~vhite powder.
H-NMR(CD3C~D) o:0.99-1.10 (3H, m), 1.45-1.53 (9H, m), 2.16-
3.53 (SH, m), 4.19-5.22 (4H, m), 5.50-6.33 (3H, m), 6.37-6.86 (4H,
m), 7.22-8.15 (llH, m)
FAB-MS :727(M~Na)
EXAMPLE 8
Preparation of 2(S )- [2(S)- [2(R)-Amino-3 -mercapto] -propylamino-
3(S)-methyl]penlyloxy-3-phenylpropionyl-homoserine lactone and
2(S)-[2(S)-[2(R)- Amino-3-mercapto]-propylamino-3(S)-
methyllpentyloxy-3-phenyl-propionyl-homoserine
Step A: Preparation of N-(o~-chloroacetyl)-L-isoleucinol
To a stirred solution of L-isoleucinol (20 g, 0.17 mol)
and triethyl~mine (28.56 ml, 0.204 mol) in CH2C12 (500 ml) at -78~C
was added chloroacetyl chlLoride (16.3 ml, 0.204 mol) over 5 minutes.
The cooling bath was removed and the solution allowed to warm to
-20~C. The mixture was diluted with EtOAc and washed sequentiallLy
with 1 M HCl, and brine and dried (Na2SO4). Evaporation in vacuo
afforded the amide title compound (35 g, 100%).
Rf = 0.3 CH2Cl2: MeOH (95:5);
lH NMR (CDCl3) o 6.80 (lH, brd, J = 5 Hz), 4.10 (2H, s), 3.84 (lH,
m), 3.79 (2H, m)l, 2.65 (lH, brs), 1.72 (lH, m), 1.55 (lH, m), 1.17
(lH, m), 0.96 (3H, d, J = 6Hz) 0.90 (3H,t, J=6 Hz).
~ Step B: Preplaration of 5(S)-[l(S)-methyl]propyl-2,3,5,6-tetra-
hydro-4H- 1 ~4-oxazin-3-one
To a stirred solution of N-(a-chloroacetyl)-L-isoleucinol
'~ (7.4 g, 0.038 mo]L) in THF (125 ml) under argon at 0~C was slowly
added sodium hydride (2.2 g of a 60% dispersion in mineral oil,
0.055 mol) with c oncomitant gas evolution. After completing the
s addition, the mixture was warmed to room temperature (R.T.) and

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stirled for 16 hr. Water (2.8 ml) was added and the solvents
evaporated in vacuo. The residue was dissolved in CHCl3 (70 ml)
and washed with water saturated NaCl solution. The organic layer
was dried (Na2S04) and evaporated in vacuo. The residue was
S chromatographed using silica gel eluting with CH2C12:MeOH (96:4)
to afford the lactam title compound (4.35 g, 72%) as a white solid.
Rf = 0.35 CH2Cl2:MeOH (95:5);
lH NMR o (CDCl3) 6.72 (lH, brs), 4.20 (lH, d, J = 14.5 Hz), 4.10
(lH, d, J = 14.5 Hz), 3.88 (lH, dd, J = 9 and 3.5 Hz), 3.58 (lH, dd, J
10 = 9 and 6.5 Hz), 3.45 (lH, brqt, J = 3.5 Hz), 1.70-1.45 (2H, m), 1.34
- 1.15 (lH, m), 0.96 (3H, t, J = 6.5 Hz), 0.94 (3H, d, J = 6.5 Hz).
Step C: Preparation of N-(tert-butoxycarbonyl)-5(S)-[l(S)-
methyllpropyl-2~3.5.6-tetrahydro-4H- 1.4-oxazin-3-one
5(S)-[1 (S)-Methyl]propyl-2,3,5,6-tetrahydro 4H- 1,4-
oxazin-3-one (12.2 g, 0.0776 mol) and DMAP (18.9 g, 0.155 mol)
were dissolved in methylene chloride (120 ml) under argon at R.T.
Boc anhydride (33.9 g, 0.155 mol) was added to the stirred solution
in one portion, with concomitant gas evolution and the mixture was
20 stirred at R.T. for 16 hr. The solvent was evaporated in vacuo and
the residue was taken up in ethyl acetate and washed sequentially with
10% citric acid, 50% NaHCO3 and finally brine. The organic extract
was dried (Na2SO4) and evaporated in vacuo. Chromatography of
the residue over silica gel eluting with 20% EtOAc in hexanes
25 afforded the title compound as a white solid.
Rf = 0.75 EtOAc:hexanes (20:80); mp 59-60~C
Anal. Calc'd. for C13H2304N: C, 60.68; H,9.01; N, 5.44. Found: C,
60.75; H, 9.01; N, 5.58.
lH NMR (CDC13) o 4.25 (lH, d, J = 15 Hz), 4.15 (lH, d, J = 15 Hz),
30 4.15 - 4.00 (2H, m), 3.73 (lH, dd, J = 10 and 2 Hz), 1.88 (lH, qt, J =
6 Hz), 1.55 (9H, s), 1.50 - 1.36 (lH, m), 1.35 - 1.19 (lH, m) 1.00
(3H,d,J=6Hz)0.95(3H,d,J=6.5Hz).

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-
Step D: Pre]paration of N-(tert-Butoxycarbonyl)-2(S)-benzyl-
5(S)-[1 (S)-methyl]propyl-2,3,5,6-tetrahydro-4H- 1,4-
oxazin-3-one
A solution of N-(tert-butoxycarbonyl)-5(S)-[l(S)-
methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one (5.75 g, 22.34
mmol) in DME (100 ml) under argon was cooled to -60~C. The cold
solution was transferred via canula to a second flask cont~inins~
sodium bis~trimethylsilyl)amide (24.58 ml of a lM solution in THF,
24.58 mmol) at -78~C under argon. After stirring for 10 minutes,
benzyl bromide (2.25 ml, 18.99 3mmol) was added over 5 minutes and
the resulting mixture was stirred at -78~C for 3 hours. After this
time, the reaction rnixture was transferred via cannula to another
flask cont~ining sodium bis(trimethylsilyl)amide (24.58 ml of a lM
solution in THF, 24.58 mmol) a~: -78~C, under argon. After stirring
for a further 5 mLinutes, the reaction was quenched by the addition of
saturated aqueous ammonium chloride solution (24.6 ml) and allowed
to warm to room temperature. l'his mixture was diluted with brine
(50 ml) and water (20 ml) and then extracted with ethyl acetate (2 x
100 ml). The organic extracts were washed with brine (50 ml) and
evaporated in vacuo to afford an oil. Chromatography of the residue
over silica gel (230-400 mesh, 300 g) eluting with 10-20% ethyl
acetate in hexanes afforded the title compound as a clear oil.
Rf = 0.25 EtOAc:Hexanes (20:80);
lH NMR (CDCl3) ~ 7.35 - 7.15 (5H, m), 4.31 (lH, dd, J = 6 and 2
Hz), 4.03 (lH, d, J = 12 Hz), 3.8% (lH, dd, J = 6 and 1 Hz), 3.66 (lH,
dd, J = 12 and 2 Hz), 3.29 (lH, dLd, J = 12 and 3 Hz), 1.54 (9H, s),
3.12 (lH, dd, J = 12 and 7 Hz), 1.47 (lH, m), 1.25 (lH, m), 1.10
(lH, m), 0.83 (31H, d, J = 6 Hz), 0.80 (3H, t, J = 6 Hz).
Step E: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)-
amimo-3(S)-methyllpentyloxy-3-phenyl-propionic acid
To a stirred solution of N-(tert-butoxycarbonyl)-2(S)-
benzyl-5(S)-[1 (S)-methyl]-propyl-2,3,5,6-tetrahydro-4H- 1,4-oxazin-
s 3-one (5.1 g, 14.7 mmol) in TH~ (150 ml) and water (50 ml) at 0~C

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was added hydrogen peroxide (15 ml of a 30% aqueous solution, 132
mmol) and lithium hydroxide (3.0 g, 63.9 mmol). After stirring for
30 minlltes, the reaction was quenched with a solution of sodium
sulfite (28.25 g, 0.224 mol) in water (70 ml). The THF was
5 evaporated in vacuo and the aqueous phase was acidified to pH 3-4 by
addition of 10% citric acid solution and extracted with EtOAc. The
organic extracts were dried (Na2so4)~ evaporated in vacuo and the
residue purified by chromatography over silica gel eluting with 4%
MeOH in CH2Cl2 to give the lactam 2(S)-benzyl-5(S)-[l(S)-
methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one and then with
20% MeOH in CH2Cl2 to afford the title compound (4.03 g, 75%) as
a viscous oil.
Rf = 0.4 MeOH:CH2Cl2 (5:95) + 0.3% AcOH;
lH NMR (d6 DMSO) o 7.35 - 7.10 (5H, m), 6.68 (lH, br, s), 3.75
15 (lH,dd,J=7.5and2.5Hz)3.54(1H,m),3.5-3.2(2H,m)2.99
(lH, dd, J = 12.5 and 2.5 Hz), 2.75 (lH, dd, J = 12.5 and 7.5 Hz),
1.50 - 1.35 (llH, m), 0.98 (lH, sept, J = 6 Hz), 0.78 (3H, t, J = 6 Hz),
0.65 (3H, d, J = 6 Hz);
FAB MS 366 (MH+) 266 (MH2+ - CO2tBu).
Step F: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)-
amino-3(S)-methyl]-pentyloxy-3-phenyl-propionyl-
homoserine lactone
To a stirred solution of N-(tert-butoxycarbonyl)-2(S)-
[2(S)-amino-3(S)-methyl]-pentyloxy-3-phenylpropionic acid (0.53 g,
1.45 mmol) and 3-hydroxy-1,2,3,-benzotriazin-4(3H)-one (HOOBT)
(0.26 g, 1.6 mmol) in DMF (15 ml) at room temperature was added
EDC (0.307 g, 1.6 mmol) and L-homoserine lactone hydrochloride
(0.219 g, 6.0 mmol). The pH was adjusted to pH= 6.5 by addition of
NEt3 (the pH was monitored by application of an aliquot of the
reaction mixture to a moist strip of pH paper). After stirring at room
temperature for 16 hr, the reaction was diluted with EtOAc and
washed with saturated NaHCO3 and then brine and dried (NaSO4).
Evaporation in vacuo (sufficient to remove DMF) and

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chromatography over silica gel eluting with 5% acetone in CH2C12
afforded the title compound as a white solid, mp 115-117~C.
Rf = 0.3 Acetone: CH2C12 (5:95)-
ç lH NMlR (CDC13) o 7.73 (lH, brd, J=5 Hz), 7.40-7.15 (SH, m), 4.68
(lH, dt, J=9 and 7.5 Hz), 4.65-4.35 (2H, m), 4.33-4.18 (lH, m), 4.20
(lH, dd, J=7 andL 3 Hz), 3.78 (lH, m), 3.49 (lH, dd, J=7.5 and 4.0
Hz), 3.37 (lH, dd, J=7.5 and 6.5 Hz), 3.15 (lH, dd, J=ll.S and 2 Hz),
2.86 (lH, dd, J=11.5 and 7.5 Hz), 2.68 (lH, m) 2.11 (lH, q, J=9 Hz),
1.55-1.30 (1 lH, m), 1.07 (lH, m), 0.87 (3H, t, J=6.3 Hz), 0.79 (3H,
d, J=6 Hz).
Step G: Preparation of 2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-
3-phenylpropionyl-homoserine lactone hydrochloride
Anhydrous HCl gas was bubbled through a cold (0~C)
solution of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-
methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (3.0 g, 6.7
mmol) in ethyl acetate (120 ml) until a saturated solution was
obtained. The resulting mixture was stirred at 0~C for 1 hr. The
solution was purged with nitrogen and the mixture concentrated in
vacuo to afford the title compound as a sticky foam which was used
without further purification.
lH NMR (d6 D~/ISO) o 8.60 (lH, d, J=7 Hz), 8.08 (3H, brs), 7.35-
7.15 (SH, m), 4.60 (lH, qt, J=8 Hz), 4.36 (lH, t J=7.5 Hz), 4.22 (lH,
q, J=7.5 Hz), 4.lS-3.95 (2H, m), 3.64 (lH, dd, J=9 and 2.5 Hz), 3.15-
3.00 (2H, m), 2.92 (lH, dd, J=12.5 and 5.0 Hz), 2.40-2.15 (2H, m),
1.65 (lH, m), 1.43 (lH, m), 1.07 (lH, m), 0.82 (3H, t, J=6 Hz), 0.72
(3H, d, J=6.0 Hz).
Step H: Preparation of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-
amino-3-triphenylmethylmercap-to]propylamino-3(S)-
methyl]-pentyloxy-3-phenylpropionyl-homoserine
lact~ne
2(S)-[2(S)-Amino-3(S)-methyl]pentyloxy-3-phenyl-
,~ propionyl-homoserine hydrochloride (6.7 mmol) and N-(tert-butoxy-

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carbonyl)-S-triphenylmethylcysteine aldehyde (0.74 g, 7.5 mmol)
(prepared from N-(tert-butoxycarbonyl)-S-triphenylmethylcysteine
by the procedure of Goel, O.P.; Krolls, U.; Stier, M.; Keston, S. Org.
Svn. 1988, 67, 69.) and potassium acetate (3.66 g, 8.2 mmol) were
dissolved in methanol (48 ml). Activated 4A molecular sieves (6g)
and then Na(CN)BH3 (0.70 g, 10.7 mmol) were added and the
resulting slurry was stirred under argon at room temperature for 16
hr. The solids were removed by filtration and the filtrate evaporated
in vacuo. The residue was dissolved in EtOAc and washed
sequentially with saturated aqueous NaHCO3 and brine and then dried
(Na2SO4). Evaporation in vacuo afforded an oil which was purified
by chromatography over silica gel eluting with a gradient of 30-50%
EtOAc in hexane to afford the title compound cont~rnin~fed with a
small amount of the corresponding methyl ester.
lH NMR (CD30D) o 7.60-7.05(20H, m), 4.64 (lH, d, J=9.OHz), 4.39
(lH, br t, J=9Hz), 4.25(1H, m), 3.93 (lH, m), 3.75-3.60(1H, m), 3.55
(lH, dd, J=9.0 and 2Hz), 3.20 (lH, dd, J=9.0 and 6.0 Hz), 3.04 (lH,
dd, J=15.0 and 5.0 Hz), 2.85 (lH, dd, J=15.0 and 9.0 Hz), 2.60 (lH,
dd, J=12.0 and 5.0 Hz), 2.50-2.15 (7H, m), 1.45 (9H, s), 1.40-1.20
(lH, m), 1.07 (lH, m), 0.87 (3H, t, J=6 Hz), 0.67 (3H, d, J=6.0 Hz).
Step I: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-
propylamino-3 (S)-methyl]pentyloxy-3 -phenylpropionyl-
homoserine lactone
To a stirred solution of 2(S)-[2(S)-[2(R)-(tert-butoxy-
carbonyl)amino-3-triphenylmethylmercapto]-propylamino-3(S)-
methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (2.72 g,
3.49 mmol) in CH2C12 (90 ml) was added HSiEt3 (2.16 ml, 13.5 "
mmol) and TFA (43.2 ml, 0.56 mol) and the solution was stirred at
R.T. under argon for 2 hrs. The solvent was evaporated in vacuo and
the residue partitioned between 0.1% aqueous TFA (200 ml) and
hexanes (100 ml). The aqueous layer was separated and washed with
hexanes (20 ml) and then lyophilised. The resulting white lyophilate
was chromatographed in 5 equal portions over a Waters Prepak

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cartridge (C-18, 15-20 mM 100 A) eluting with a gradient of 95:5 to
5:95 0.1% TFA in H20: 0.1% TFA in CH3CN at 100 ml/min over 60
min. The desired compound eluted after 19 min. The CH3CN was
evaporated in vacuo and the aqueous solution lyophilised to afford ~e
title compound (1.95 g, 77%) as the TFA salt.
The salt is hygroscopic and is prone to disulphide
formation if left in solution and exposed to air.
lH NMR o (CD30D) 7.40-7.15 (SH,m), 4.55-5.40 (2H, m), 4.33 (lH,
m), 4.18 (lH, m), 3.90-3.62 (3H, m), 3.53 (lH, dd, J=10.5 and 4.0
Hz), 3.37 (lH, d~, J=10.5 and 6.0 Hz), 3.23 (lH, m), 3.15-2.95 (2H,
m), 2.88 (lH, dd, J=12.5 and 5.0 Hz), 2.55-2.25 (2H, m), 1.92 (lH,
m), 1.49 (lH, m'~, 1.23 (lH, m), 0.94 (3H, t, J=6 Hz), 0.90 (3H, d,
J=6Hz).
FAB MS 873 (2~-H+) 438 (MH+) 361 (MH~tPh)
Anal. calc'd for C22H36O4N3S 2.6 TFA:C, 43.58; H, 5.25; N, 5,82.
Found: C, 43.62, H, 5.07; N, 5.80.
Step J: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-
propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-
hom~oserine
2(S)-[2(S)-[2(R)-Amino-3-mercapto]propyl-amino-3(S)-
methyl]pentylox~y-3-phenylpropionyl-homoserine lactone (0.00326
mmol) was dissolved in methanol (0.0506 ml) and lN sodium
hydroxide (0.0134 ml) was added followed by methanol (0.262 ml).
The conversion of the lactone to the hydroxy-acid was confirmed by
HPLC analysis and NMR.

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FXAMPLE 9
Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-
3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl
5 çster (Compound 5)
Step A: Preparation of Methionine sulfone methyl ester
Thionyl chloride (2.63 ml, 36 mmol) was added
dropwise to a stirred solution of N-Boc-Met sulfone (5 g, 18 mmol)
10 in methanol (40 ml) cooled at 0~C. After the completion of the
addition, the resulting mixture was warmed to room temperature and
stirred overnight. The reaction mixture was recooled to 0~C and
slowly treated with solid sodium bicarbonate to adjust the pH to 7.
The mixture was concentrated in vacuo to remove methanol and the
15 residue was dissolved in a minimllm amount of water (solution pH ca.
10) and extracted with ethyl acetate four times. The combined
extracts were dried (Na2so4) and concentrated to give the title
compound (1.5 g). NMR (CD30D) ~ 2.04 (H, m), 2.21 (H, m), 2.98
~3H, s), 3.23 (2H, t, J=7Hz), 3.63 (H, d of d, J=8.6Hz), 3.77 (3H, s).
Step B: Preparation of N-(tert-Butoxycarbonyl)-2(S)-[2(S)-
amino-3(S)-methyl]-pentyloxy-3-phenyl-propionyl-
methionine sulfone methyl ester
The title compound was prepared in the same fashion as
that described in F.x~mple 8, Step F, but using methionine sulfone
methyl ester in place of homoserine lactone hydrochloride. NMR
(CD30D) o 0.80 (3H, d, J=6Hz), 0.88 (3H, t, J=6Hz), 1.12 (H, m),
1.47 (9H, s), 2.10 (H, m), 2.32 (H, m~, 2.93 (3H, s), 3.5~3.7 (2H, m),
3.74 (3H, s), 4.01 (H, d of d, J=7.4Hz), 4.60 (H, d of d, J=9.SHz),
6.60 (H, d, J=8Hz), 7.25 (5H, m).
Step C: Preparation of 2(S)-[2(S)-Amino-3(S)-methyl]-
pentyloxy-3-phenylpropionyl-methionine sulfone methyl
ester hydrochloride

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The title compound was prepared in the same fashion as
that described in Fx~mple 8, Step G, but using N-(tert-
butoxycarbonyl)l-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-
phenylpropionyl-methionine sulfone methyl ester in place of N-(tert-
S butoxycarbonyl)-2(S)-[2(S)-a~ino-3(S)-methyl]pentyloxy-3-
phenylpropiony]-homoserine lactone. NMR (CD30D) o 0.85 (3H, d,
J=6Hz), 0.94 (3]~I, t, J=6Hz), 1.20 (H, m), 1.52 (H, m), 1.72 (H, m),
2.14 (H, m), 2.38 (H, m), 2.98 (3H, s), 3.57 (H, d of d, J=12, 6Hz),
3.73 (H, d of d, J=12, 9Hz), 3.78 (3H, s), 4.15 (H, d of d, J=8.6Hz),
10 4.63 (H, d of d, J=8.5Hz), 7.30 (5H, m).
Step D: Pre]paration of 2(S)-[2(S)-[2(R)-(tert-Butoxy-carbonyl)-
amino-3-triphenylmethylmercapto]-propylamino-3(S)-
methyl]pentyloxy-3-phenyl-propionyl-methionine sulfone
methyl ester
The title compound was prepared in a similar fashion as
that described in Example 8, Step H, but using 2(S)-[2(S)-amino-3(S)-
methyl]pentyloxy-3-phenyl-propionyl-methionine sulfone methyl
ester hydrochloride in place of 2(S)-[2(S)-amino-3(S)-
20 methyl]pentyloxy-3-phenylpropionyl-homoserine lactone
hydrochloride. NMR (CD30D) ~o 0.70 (3H, d, J=6Hz), 0.88 (3H, t,
J=6Hz), 1.10 (H, m), 1.47 (9H, s), 2.15 (H, m), 2.67 (H, m), 2.92
(3H, s), 3.67 (H, m), 4.68 (H, d of d, J=10, 6Hz), 7.15~7.45 (20H,
m).
Step E: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-
propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-
methionine sulfone methyl ester
The title compound was prepared in a ~imil~r fashion as
30 that described in Example 8, Step I, but using 2(S)-[2(S)-[2(R)-(tert-
butoxycarbonyl)lamino-3-triphenylmethylmercapto]propylamino-3(S)-
methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone methyl
ester in place of 2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl)-amino-3-
triphenyl-methylmercapto]propylamino-3(S)-methyl]pentyloxy-3-

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phenyl-propionyl-homoserine lactone. NMR (CD30D) ~ 0.83 (3H, d,
J=6Hz), 0.93 (3H, t, J=6Hz), 1.20 (H, m), 1.51 (H, m), 1.80 (H, m~,
2.22 (H, m), 2.43 (H, m), 3.00 (3H, s), 3.78 (3H, s), 4.20 (H, d of d,
J=8.4Hz), 4.72 (H, d of d, J=10, 6Hz), 7.30 (5H, m).
5 FABMS m/z 532 (MH+).
EXAMPLE 10
Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-
10 3 (S)-methyl] -pentyloxy-3-phenylpropionyl-methionine sulfone
isopropyl ester (Compound A)
HS
H2N --~~ ~~
/~ O
o2s\
CH3
The title compound was prepared using methods A-E
from Example 9, except for Method A. Methionine sulfone isopropyl
ester was prepared by coupling t-butyloxycarbonyl-methionine
sulfone with isopropyl alcohol using dicyclohexylcarbodiirnide (DCC)
and 4-dimethylaminopyridine (DMAP) followed by deprotection with
HCl in EtOAc. NMR (CD30D) o 0.83 (3H, d, J = 6 Hz), 0.94 (3H, t,
J = 6 Hz), 1.11-1.56 (2H, m), 1.28 (6H, d, J = 6 Hz), 1.8-1.96 (lH, r
m), 2.12-2.27 (lH, m), 2.89-3.0 (2H, m), 3.01 (3H, s), 3.06-3.3 (4H,
m), 3.42 (lH, dd, J = 6, 13 Hz), 3.65 (lH, dd, J = 6,13 Hz), 3.68-3.91
(3H, m), 4.2-4.27 (lH, m), 4.61-4.7 (lH, m), 4.96-5.12 (2H, m),
7.19-7.44 (5H, m). Anal. Calc'd. for C26H45N3O6S2 ~ 2 CF3CO2H:
C, 44.07; H, 5.67; N, 4.97; Found C, 44.35; H, 5.68; N, 5.23

CA 0222~2~ 1997-12-18
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F~AMPLE 11
1 -(2(R)-Amino-3 -mercaptopropyl)-4-(2,3 -dimethylbenzoyl)piperazine
dihydrochloride
Step A: tert-I3utyl 4-(2,3-dimethylbenzoyl)piperazine-1-
carboxylate
tert -]3utyl piperazine-l-carboxylate (0.50 g, 2.6 mmol),
2,3-dimethylbenzoic acid (0.44 g, 2.9 mmol), l-hydroxybenzotriazole
10 (HOBT) (0.45 g, Z.9 mmol) and 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide hydrochloride (EDC ~ HCl) (0.56 g, 2.9 rr~nol)
were added to dry, degassed dimethylform~mi~le (7 mL). The pH of the
reaction was adjusted to 7 with triethylamine, and the reaction stirred
for 2 h. The dimethylformamide (DMF) was distilled in vacuo, and the
15 residue partitioned between ethyl 2cet~te and water. The organic phase
was washed with 2% aqueous potassium hydrogen sulfate, saturated
sodium bicarbonate solution, saturated sodium chloride solution, and
dried over magnesium sulfate. The crude product was
chromatographed on silica gel using 30% ethyl acetate in hexane as
20 eluant. The title compound was obtained as a white solid, NMR
(CDC13, 300 MHz;) o 7.17 (lH, d, J=7 Hz), 7.13 (lH, t, J=7 Hz), 6.98
(lH, d, J=7 Hz), 3.77 (2H, m), 3.51 (2H, m), 3.32 (2H, t, J=5 Hz), 3.19
(2H, m), 2.28 (3H, s), 2.18 (3H, s), 1.45 (9H, s).
25 Step B: N-Methoxy-N-methyl 2(R)-tert -butoxycarbonylamino-3-
triphenylmethylthiopropionamide
The title compound was synthesized essentially according to
the procedure described by O. P. Goel, U. Krolls, M. Stier, and S.
Kesten in Organic Syntheses, 1988, 67, 69-75. Thus N,O-dimethyl-
30 hydroxylamine hydrochloride (1.05 g, 10.82 mmol) and N-methyl-
, morpholine (1.22 mL, 11.14 mmol) were stirred in dichloromethane (6
mL) under nitrogen at 0 C for 30 min. In a separate flask, 2(R)-tert -
butoxycarbonylam~ino-3-triphenylmethyl-thiopropionic acid (5.02 g,
10.82 mmol) in tetrahydrofuran (11.5 mL, dry) and methylene chloride

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(45 mL) were cooled to -20 C, and N-methylmorpholine (1.22 mL,
11.14 mmol) and isopropylchloroformate (10.82 mL of lM solution in
toluene) were added via syringe, m~int~ining the temperature less than
-15 C. The reaction was stirred at -30 C, and the suspension of N,O-
5 dimethylhydroxyl~mine hydrochloride and N-methylmorpholine in
methylene chloride added all at once. The cooling bath was rernoved
and the reaction allowed to warm to room temperature over 4 h. The
reaction was cooled to 0 C and quickly washed with two portions of 0.2
N hydrochloric acid, two portions of 0.5 N sodium hydroxide, and
10 saturated sodium chloride solution. The organic phase was dried over
magnesium sulfate, filtered and reduced in vacuo to obtain the title
compound as a clear gum. NMR (300 MHz, DMSO-d6) o 7.30 (lSH,
m), 4.43 (lH, br s), 3.56 (3H, s), 2.99 (3H, s), 2.30 (2H, m), 1.36 (9H,
s).
Step C: 2(R)-tert -Butoxycarbonylamino-3-triphenylmethyl-
thiopropanal
The title compound was synthesized essentially according to
the procedure described by O. P. Goel, U. Krolls, M. Stier, and S.
Kesten in Organic Syntheses, 1988, 67, 69-75. Thus lithium alllminllm
hydride (0.451 g, 11.90 mmol) and diethyl ether (40 mL) were stirred
at 20~C under nitrogen for 1 h, then cooled to -45~C. N-Methoxy-N-
methyl 2(R)-tert -butoxycarbonylamino-3-triphenylmethylthio-
propionamide (5.50 g, 10.82 mmol) in diethyl ether (20 mL) was added
in a steady stream, m~int~inin~ the temperature less than -35 C. The
cooling bath was removed and the reaction warmed to 5 C, then cooled
to -35 C. A solution of potassium hydrogen sulfate (2.94 g, 21.64
mmol) in water (50 mL) was added slowly, m:~in~ining the temperature
less than 0 C. The reaction was warmed to 20 C over 1 h, and filtered
through Celite. The filtrate was washed with 10% citric acid, saturated
sodium chloride solution, and dried over magnesium sulfate. After .
filtration, the solvents were removed in vacuo and the title compound
obtained as a foam.

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., Step D: 1-(2~R)-tert -Butoxycarbonylamino-3-triphenylmethyl-
thiopropyl)-4-(2.3-dimethylbenzoyl)piperazine
The product from step A (0.480 g, 0.86,0 mrnol) was
dissolved in methylene chloride (4 mL) and trifluoroacetic acid was
added (2 mL). ~e reaction was stirred for 30 min. at 20 C, then
evaporated to dr~ness. The crude trifluoroacetate salt was taken up in
dimethylformamide and the pH adjusted to 6 by the addition of
briethy~ ne. To this solution was added sodium triacetoxyboro-
hydride (0.331 g, 1.56 mmol), and crushed molecular sieves (0.5 g),
and the reaction cooled to 0 C under nitrogen. 2(R)-N-tert -butoxy-
carbonylamino-3-triphenylmethylthiopropanal (0.350 g, 0.782 mmol) in
dimethylformamide was added slowly dropwise. The reaction was
stirred at 20 C ullder nitrogen for 2 h. The dimethylformamide was
removed in vacuo and the residue partitioned between saturated sodium
bicarbonate and ethyl acetate. The organic phase was washed with
saturated sodium chloride and dried over magnesium sulfate. Filtration
and evaporation gave the title compound as a white foam. NMR
(CDC13, 300 MH.z) ~ 7.0-7.6 (18H, m~, 5.60 (lH, br s), 4.4-4.9 (lH[,
m), 2.1-3.9 (12H, m), 2.25 (3H, s), 2.15 (3H, br s), 1.40 (9H, s).
Step E: 1-(2(R)-Amino-3-mercaptopropyl)-4-(2,3-dimethyl-
benzoyl)piperazine dihydrochloride
The product from step D and triethylsilane (0.54 mL, 3.4
mmol) were dissolved in methylene chloride (6 mL). To this solution
was added trifluoroacetic acid (3 mL) and the reaction stirred at 20 C
for 30 min. The reaction was evaporated to dryness and partitioned
between hexane and water. The aqueous phase was injected onto a 40 X
100 mm Waters PrepPak(~) reverse phase HPLC column (Delta-PakTM
Clg 15 ,um, 100 A), and pure product isolated by gradient elution using
100% Solvent A (0.1% trifluoroacetic acid in water) to 50% Solvent
~, A/50% Solvent B (0.1 % trifluoroacetic acid in acetonitrile) over 50
min at a flow rate of 40 mL/min. Combined fractions were evaporated,
dissolved in water and passed through a Biorad AG(~ 3X4 ion exchange

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resin column (100-200 mesh, Cl- form). The colurnn eluant was
lyophilized to give the title compound as a white powder.
Analysis calculated for C16H25N3OS ~ 2.4 HCl - 1.4 H20:
C, 45.76; H, 7.25; N; 10.01.
Found: C, 45.73, H; 7.25; N, 10.01.
EXAMPLE 12
1 -[2(R)-Amino-3-mercaptopropyl]-4(S)-(2,3-dimethylbenzoyl)-2-
mçthylpiperazine dihydrochloride
Step A: 1- Benzyl-3(S)-methylpiperazine-2.5-dione
The title compound was prepared according to the
procedure described by John S. Kiely and Stephen R. Priebe in Organzc
Preparations and Procedures Int., 22 (6), 761-768 (1990). Thus 100
mL of a stock solution of dicyclohexylcarbodiimide in methylene
chloride (0.5 M) was added to methylene chloride (250 mL). This
solution was cooled to 0 C under nitrogen and Boc-L-alanine (9.46 g,
50.00 mmol) was added. The resulting slurry was stirred for 5 min,
and then ethyl N-benzylglycinate (9.37 mL, 50.00 mmol) was added.
The reaction was stirred for 2 h at 0 C, then at 20 C overnight. The
precipitate was removed by filtration, and hydrogen chloride gas
bubbled through the methylene chloride solution for 2-4 h, until the
reaction was shown to be complete by tlc. The solvent was removed in
vacuo, and the residue partitioned between ethyl acetate (150 rnL) and
saturated sodium bicarbonate solution (42 mL). The organic phase was
washed with saturated sodium chloride, dryed over magnesium sulfate,
filtered and evaporated. The crude product was recrystallized from
toluene to give the title compound as white crystals. NMR (300 MHz,
CDC13) â 7.30-7.38 (3H, m), 7.22-7.30 (2H, m), 6.94 (lH, br s), 4.59
(2H, s), 4.14 (lH, q, J=7 Hz), 3.84 (2H, s), 1.52 (3H, d, J=7 Hz).
Step B: 4-Benzyl-l-tert-butoxycarbonyl-2(S)-methylpiperazine
The product from Step A (5.88 g, 27.00 mmol) was
dissolved in THF (200 mL) and cooled under nitrogen to 0 C with

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mechanical stirring. Lithium alllminllm hydride (3.69 g, 0.097 mol)
was added slowl~y. The reaction was refluxed for 18 h, cooled to 0 C,
and quenched by the sequential slow addition of S mL H20, 5 rnL 10%
sodium hydroxide solution and 5 mL H2O. The reaction was stirred for
5 30 min and filtered. The solvent was removed in vacuo, the crude
product taken up in methylene chloride and dried over magnesium
sulfate. The drying agent was removed by filtration, and the filtrate
treated with di-tert -butyl dicarbonate (6.03 g, 27.6 mmol). After 2 h at
20 C, saturated sodium bicarbonate was added. The layers were
10 separated, and the organic phase washed with saturated sodium chloride
solution, then dried over nnagnesium sulfate. Filtration and evaporation
gave the crude product which was purified by column chromatography
on silica gel, eluting with 5% ethyl acetate in hexane. The title
compound was obtained as a foam. NMR (300 MHz, CDC13) o 7.25
(5H, m), 4.18 (lH, br s,), 3.80 (lH, d, J=12 Hz), 3.46 (2H, AB q, J=14
Hz), 3.11 (lH, dt, J=4, 12 Hz), 2.75 (lH, d, J=10 Hz), 2.58 (lH, d, J=10
Hz), 2.12 (lH, dd, J=4, 12 Hz), 2.00 (lH, dt, J=4, 12 Hz), 1.45 (9H, s),
1.23 (3H, d, J--7 Hz).
20 Step C: l-tert -Butoxycarbonyl-2(S)-methylpiperazine
The product from Step B (5.28 g, 18.2 mmol) was
dissolved in methanol (75 mL) in a Parr bottle, and the vessel pllrged
with argon. To this was added 10 % palladium on carbon (1.0 g) and
the reaction hydrogenated under 60 psi hydrogen for 24 h. The catalyst
25 was removed by ~lltration through Celite, and the filtrate evaporated in
vacuo to give the title compound as an oil. NMR (300 MHz, CDCl3) o
4.15 (lH, m), 3.77 (lH, d, J=12 Hz), 2.85-3.06 (3H, m), 2.75 (lH, d,
J=12 Hz), 2.64 (]LH, dt, J=4, 12 Hz), 2.13 (lH, s), 1.45 (9H, s), 1.40
(3H, d, J=7 Hz).
Step D: l-te~t -Butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-
m ethylpiperazine
The product from Step C (1.00 g, 5.00 mmol) wasconverted to the title compound according to the procedure described in

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Example 11, Step A using 2,3-dimethylbenzoic acid (0.750 g, 5.00
mmol), HOBT (0.765 g, 5.00 mmol), EDC ~ HCl (0.958 g, 5.00 mmol)
and triethylamine to adjust the pH to 7. The title compound was
obtained as a pale yellow solid.
s
Step E: 1-[2(R)-N-terf -Butoxycarbonylamino-3-triphenylmethyl-
thiopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-methyl-
piperazine
The title compound was obtained from the product of Step
D (0.390 g, 1.17 mmol) according to the procedure described in
Example 11, Step D. Thus, l-tert -butoxycarbonyl-4-(2,3-dimethyl-
benzoyl)-2(S)-methylpiperazine (0.390 g, 1.17 mmol) was first treated
with trifluoroacetic acid (3 mL) in methylene chloride (6 mL) for 30
min. The reaction was evaporated to dryness, and the crude product
reacted with sodium triacetoxyborohydride (0.331 g, 1.56 mmol) and
2(R)-N-tert -butoxycarbonylamino-3-triphenylmethylthiopropanal
(0.350 g, 0.782 mmol) in the presence of crushed molecular sieves (0.5
g) in DMF at pH 6 and 0-20 C overnight. The title compound was
obtained as a foam.
Step F: 1 - [2(R)-Amino-3-mercaptopropyl] -4-(2,3-dimethyl-
benzoyl)-2(S)-methylpiperazine dihydrochloride
The product from Step E (0.370 g, 0.55 mmol) was
converted to the title compound according to the procedure described
for Step E? Example 11 using triethylsilane (0.350 mL, 2.20 mmol) and
trifluoroacetic acid (4.5 mL) in methylene chloride (9 mL).
Purification by preparative HPLC (gradient elution: 100% Solvent A to
50% Solvent A/50% Solvent B, 50 min) and ion exchange provided the
title compound as a white powder.
Analysis calculated for C 17H27N3OS ~ 2.7 HCl ~ 1.1 H20:
C, 46.47; H, 7.32; N; 9.56. "~
Found: C, 46.40, H, 7.31, N, 9.39.

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EXAMPLE 13
1 -[2(R)-Amino-3-mercaptopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-(2-
methoxyethyl)piperazine dihydrochloride
Step A: l-Benzyl-3(S)-cyclohexoxycarbonylmethylpiperazine-2,
S-dio]ne
The title compound was ~rel~aled according to the
procedure described in Fx~rnple 12, Step A, except using Boc-L-
aspartic acid, ,13-c~rclohexyl ester (6.15 g, 19.5 mmol), ethyl N-
benzylglycinate (3.76 g, 19.5 mmol) and dicyclohexylcarbodiimide (39
rnL, 0.5 M in dich~loromethane, 19.5 mmol). The title compound was
obtained as a white powder. NMR (CD30D, 300 MHz) ~i 7.3 (SH, m),
4.77 (lH, d, J=15 Hz), 4.73 (lH, m), 4.48 (lH, d, J=15 Hz), 4.35 (lH, t,
J=5 Hz), 3.96 (lH, dd, J=l, 17 Hz), 3.87 (lH, dd, J=l, 17 Hz), 3.06 (lH,
dd, J=4, 17 Hz), 2.81 (lH, dd, J=5, 17 Hz), 1.78 (4H, m), 1.54 (lH, m),
1.35 (SH, m).
Step B: 4-Benzyl-l-tert -butoxycarbonyl-2(S)-(2-hydroxy-
ethyl)piperazine
The title compound was prepared according to the
procedure described in Example 12, Step B, except using l-benzyl-3(S)-
cyclohexoxycarbonylmethylpiperazine-2,5-dione (1.5 g, 4.36 mmol) and
lithium al-lminllm hydride (0.76 g, 20.1 mmol), followed by di-
tert -butyl dicarbonate (1.04 g, 4.77 mmol). The crude product was
purified by column chromatography on silica gel, eluting with 30%
ethyl acetate in hexane. The title compound was obtained as a clear oil.
NMR (CD30D, 300 MHz) o 7.3 (SH, m), 4.20 (lH, m), 3.86 (lH, dm,
J=13 Hz), 3.55 (l]~I, d, J=13 Hz), 3.46 (2H, m), 3.39 (lH, d, J=13 Hz),
3.08 (lH, t, J=12 Hz), 2.80 (lH, d, J=12 Hz), 2.73 (lH, d, J=12 Hz),
2.04 (3H, m), 1.84 (1 H, sextet, J=7 Hz), 1.45 (9H, s).
Step C: 4- Benzyl- 1 -tert -butoxycarbonyl-2(S)-(2-methoxy-
ethyl~piperazine

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A solution of 4-benzyl-1-tert -butoxycarbonyl-2(S)-(2-
hydroxyethyl)piperazine (0.322 g, 1.00 mmol) in dry, degassed
dimethylform~mi~e (4 mL) was cooled under nitrogen to 0 C. Sodium
hydride was added (0.052 g, 60% dispersion in oil, 1.30 mmol)
followed by methyl iodide (0.88 mT-, 1.41 mmol). After 3 h, the c
reaction was quenched with saturated ammonium chloride. The solvent
was removed in vacuo and the residue partitioned between ethyl acetate
and saturated sodium bicarbonate. The ethyl acetate was washed with
water, saturated sodium chloride solution, and dried over magnesium
sulfate. The crude product was chromatographed on silica gel with 40%
ethyl acetate in hexane to obtain the title compound as a clear oil. NMR
(CD30D, 300 MHz) o 7.3 (SH, m), 4.19 (lH, m), 3.85 (lH, dm, J=13
Hz), 3.56 (lH, d, J=13 Hz), 3.16 (lH, d, J=13 Hz), 3.28 (2H, m,
partially obscured by solvent), 3.23 (3H, s), 3.08 ( lH, t, J=13 Hz), 2.80
(lH, d, J=l l Hz), 2.70 (lH, d, J=l l Hz), 2.03 (3H, m), 1.86, (lH, sextet,
J=6 Hz), 1.45 (9H, s).
Step D: l-tert -Butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine
The title compound was prepared according to the
procedure described in Example 12, Step C, except using 4-benzyl-1-
tert-butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine (0.280 g, 0.83
mmol) and 10% palladium on carbon (80 mg). The title compound was
obtained as an oil. NMR (CD30D, 300 MHz) o 4.17 (lH, m), 3.81
(lH, dd, J=3, 13 Hz), 3.38 (2H, t, J=6 Hz), 2.82-3.02 (2H, m), 2.77 (2H,
ABq, J=4, 13 Hz), 2.59 (lH, dt, J=4, 7 Hz), 2.04 (lH, m), 1.84 (lH, m),
1.46 (9H, s).
Step E: l-tert -Butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2-
methoxyethyl)piperazine
The title compound was prepared according to the
procedure described for Example 11, Step A except using l-tert -
butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine (0.179 g, 0.73 mmol),
2,3-dimethylbenzoic acid (0.115 g, 0.75 mmol), HOBT (0.098 g, 0.73
mmol), EDC-HCl (0.153 g, 0.80 mmol) in methylene chloride (5 mL).

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Triethylamine was added to adjust the pH to 7. Chromatography on
silica gel with 4()% ethyl acetate in hexane afforded the title compound
as a clear oil. NMR (CDC13, 300 MHz) ~ 6.9-7.2 (SH, m), 4.70 (lH,
m), 3.8-4.5 (9H, mm), 2.0-2.3 (6H, mm), 1.9 (2H, m), 1.59 (9H, s).
s
Step F: 1-[2'(R)-N-tert -Butoxycarbonylamino-3-triphenyl-
methylthiopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-(2-
methoxyethyl)piperazine
The title compound was prepared according to the
procedure described in Example 11, Step D, except using l-tert -
butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2-methoxyethyl)piper-
azine (0.222 g, 0.590 mmol) and trifluoroacetic acid (3 mL) in
methylene chloriide (7 mL). The trifluoroacetate salt was reacted with
2(R)-N-tert -butoxycarbonylamino-3 -triphenylmethylthiopropanal
(0.316 g, 0.710 ]mmol), sodium triacetoxyborohydride (0.565 g, 2.65
mmol) in the presence of crushed molecular sieves in dichloroethane.
The title compound was isolated after chromatography on silica gel with
50% ethyl acetate in hexane.
Step G: 1-[2(R)-Amino-3-mercaptopropyl]-4-(2,3-dimethyl-
ben:zoyl)-2(S)-(2-methoxyethyl)piperazine dihydrochloride
The title compound was obtained according to the
procedure described for Step E, Example 11 except using 1-[2(R)-N-
tert -butoxycarbonylamino-3 -triphenylmethylthiopropyl] -4-(2,3-
dimethylbenzoyl)-2(S)-(2-methoxyethyl)piperazine (0.247 g, 0.349
mmol), triethylsilane (0.22 mL, 1.39 mmol) and trifluoroacetic acid
(3.5 mL) in methylene chloride (7 mL). Purification by preparative
HPLC (gradient elution: 95% Solvent A to 30% Solvent A/70% Solvent
B, 60 rnin) and ion exchange provided the title compound as a white
powder.
'- ~ Analysis calculated for ClgH31N3OS ~ 3.80 HCl - 0.6 H20:
C, 44.39; H, 7.06; N, 8.17.
Found: C, 44.46; H, 7.07; N, 8.00.

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EXAMPLE 14
1 -t2(R)-Amino-3-mercaptopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-(2-
5methylthioethyl)piperazine dihydrochloride s
Step A: 1 -Benzyl-3(S)-(2-methylthioethyl)piperazine-2.5-dione
The title compound was prepared according to the
procedure described in Fx~mple 12, Step A, except using Boc-L-
10 methionine (10.0 g, 40.0 mmol), ethyl N-benzylglycinate (7.75 g, 40.0
mmol), HOBT (5.41 g, 40.0 mmol) and EDC ~ HCl (7.68 g, 40.00
mmol) in dimethylformamide. Upon completion of the reaction, the
dimethylformamide was removed in vacuo and the crude product
partitioned between ethyl acetate and water. The organic phase was
15 washed with water and saturated sodium chloride solution, then dried
over sodium sulfate. The solvent was removed in vacuo and the
residue taken up in methylene chloride (200 mL). Trifluoroacetic acid
(100 mL) was added and the reaction stirred at 20 C for 2 h. The
volatiles were removed in vacuo and the residue partitioned between
20 ethyl acetate and saturated sodium bicarbonate solution.. The organic
phase was washed with saturated sodium chloride solution and dried
over magnesium sulfate. The title compound was obtained as a white
solid. NMR (CHC13, 300 MHz) ~ 7.4-7.2 (6H, m); 4.60 (2H, AB q, J=
13 Hz), 4.24 (lH, m); 3.85 (2H, AB q, J= 18 Hz); 2.63 (2H, t, J= 7Hz);
252.3-2.1 (2H, m); 2.1 (3H, s).
Stçp B: 4- Benzyl-1-tert-butoxycarbonyl-2(S)-(2-methyl-
thioethyl)piperazine
The title compound was prepared according to the
30 procedure described in Example 12, Step 13, except using 1-benzyl-3(S)-
(2-methylthioethyl)piperazine-2,5-dione (9.08 g, 32.6 mmol) and
lithium aluminum hydride (4.40 g, 0.115 mmol), followed by di-tert -
butyl dicarbonate (7.64 g, 35.0 mmol). The crude product was puri~led
by column chromatography on silica gel, eluting with 5% ethyl acetate

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in hexane. The title compound was obtained as a clear oil. N~R
(CHC13, 300 MH:z) ~ 7.35-7.25 (5H, m); 4.18 (lH, br s); 3.90 (lH, lbr
d); 3.55 (lH, d, J= 13Hz); 3.40 (lH, d, J= 13Hz); 3.07 (lH, t, J= 12 Hz);
2.72 (2H, m); 2.40 (2H, m); 2.10 (3H, s); 1.48 (9H, s).
Ste~ C: l-tert - Butoxycarbonyl-2(S)-(2-methylthio-
ethyl)piperazine
To a solution of the product from Step B (6.63 g, 18.9
mmol) in 20 mL methylene chloride was added 2.15 mT (20 mmol) of
10 l-chloroethyl chloroformate (ACE-Cl) dropwise with stirring. The
tempe,~Lule rose from 25 ~C to 32 ~C. After 90 min was added another
0.20 mL of ACE-Cl and 2.4 g of solid potassium carbonate. After 90
min the mixture was diluted with ethyl acetate and washed ~llcces~ively
with 10% sodium bicarbonate and brine. The solution was dried
15 (sodium sulfate) ~md evaporated to afford 8.4 g of an oil. The oil was
dissolved in 500 mL methanol. The mixture was stirred at room
tempel~Lule for 3 h and placed in the refrigerator overnight. The
solution was treated with 100 mL of water and the methanol was
evaporated. The ~solution was washed with ethyl ~cet~e to remove
20 nonbasic iln~ es. The aqueous phase was neutralized with 10%
sodium bicarbona!te and extracted with methylene chloride. The extract
was dried (potassium carbonate) and evaporated to give 4.0 g of l-tert-
butoxycarbonyl-2(S)-(2-methylthioethyl)piperazine. NMR (CHC13, 300
MHz) ~ 4.17 (lH, br s); 3.89 (lH, br d); 2.92 (4H, m); 2.70 (lH, dt, J=
25 4,12 Hz); 2.6-2.4 (2H, m); 2.10 (3H, s); 1.88 (lH, m); 1.48 (9H,s).
Step D: l-tert -Butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2-
methylthioethyl)piperazine
The l:itle compound was prepared according to the
30 procedure described for Example 11, Step A except using l-tert -
butoxycarbonyl-2(S)-(2-methylthioethyl)piperazine (1.87 g, 7.19
mmol), 2,3-dimethylbenzoic acid (1.08 g, 7.19 mmol), HOBT (0.970 g,
7.19 mmol), EDC-HCl (1.64 g, 8.62 mmol) in methylene chloride (50
mL). Triethyl~ e was added to adjust the pH to 7. Chromatography

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on silica gel with 30% ethyl acetate in hexane afforded the title
compound as a clear oil. NMR (DMSO-d6, 300 MHz) ~ 6.9-7.3 (3H,
m), 4.22-4.50 (2H, mm), 3.62-4.06 (2H, mIn), 2.66-3.24 (4H, mm), 2.4
(lH, m), 2.24 (3H, s), 1.92-2.18 (6H, ms),1.4-1.8 (2H, m), 1.39 (9H, s).
Step E: 1 - [2(R)-N-tert -Butoxycarbonylamino-3-triphenylmethyl-
thiopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-(2-methylthio-
ethyl)piperazine
The title compound was prepared according to the
10 procedure described in Example 11, Step D, except using 1-tert -
butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2-methylthio-
ethyl)piperazine (0.465 g, 1.18 mmol) and trifluoroacetic acid (3 mL)
in methylene chloride (7 rnL). The trifluoroacetate salt was reacted
with 2(R)-N-tert -butoxycarbonylamino-3-triphenylmethylthiopropanal
15 (0.400 g, 0.890 mmol), sodium triacetoxyborohydride (0.302 g, 1.42
mmol) in the presence of crushed molecular sieves in dichloroethane.
The title compound was isolated as a foam after chromatography on
silica gel with 50% ethyl acetate in hexane.
Step F: 4-[2(R)-Amino-3-mercaptopropyl]-1-(2,3-dimethyl-
benzoyl)-2(S)-(2-methylthioethyl)piperazine
dihydrochloride
The title compound was obtained according to the
procedure described for Step E, Example 11 except using 1-[2(R)-N-
tert-butoxycarbonylamino-3-triphenylmethylthiopropyl]-4-(2,3-
dimethylbenzoyl)-2(S)-(2-methylthioethyl)piperazine (0.465 g, 0.656
mmol), triethylsilane (0.420 mL, 2.63 mmol) and trifluoroacetic acid
(3.5 mL) in methylene chloride (7 mL). Purification by preparative
HPLC (gradient elution: 95% Solvent A to 20% Solvent A/80% Solvent
B, 60 min) and ion exchange provided the title corripound as a white
powder.
Analysis calculated for ClgH31N3OS2 ~ 2.80 HCl - 0.8 H2O:
C, 45.85; H, 7.17; N, 8.44.
Found: C, 45.85; H, 7.14; N, 8.32.

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~X~MPLE 15
.
1-[2(R)-Amino-3-merca~loL,ro~yl]-4-(1-naphthoyl)-2(S)-(2-
metho~yethyl)piperazine dihvdrochloride (Compound E)
., 5
Step A: 4-Berlzyl-1-[2(R)-tert-butoxycarbonylamino-3-triphenyl-
methylthiopropyll -2(S)-(2-methoxyethyl)piperazine
4-Benzyl- l-tert -butoxycarbonyl-2(S)-(2-methoxyethyl)-
piperazine from Example 13, step C (1.17 g, 3.50 mmol) was dissolved
in methylene chlo]ride (20 mL). To this solution was added
trifluoroacetic acid (10 mL) and the reaction stirred at 20~C for 1 h.
The volatiles were removed in vacuo and the residue taken up in
dichloroethane (40 mL). Triethylarnine was added to attain pH 7. To
this solution was a.dded crushed molecular seives (1 g), sodium
triacetoxyborohydride (1.2 g, 5.3 mmol) and the reaction cooled to
-15~C with ice-methanol. A solution of 2(R)-tert-butoxycarbonyl-
amino-3-triphenylmethylthiopropanal (1.72 g, 3.85 mmol) in
dichloroethane (lS mL) was added slowly dropwise. The reaction was
stirred at 20~C overnight then quenched with saturated sodium
bicarbonate. The organic phase was washed with saturated sodium
chloride solution, and dried over magnesium sulfate. The crude product
(2.52 g) was chrornatographed on silica gel with 30% ethyl acetate in
hexane using medium pressure liquid chromatography (MPLC). The
title compound (Rf 0.21) was isolated as a gum. NMR (CHCl3, 300
MHz) o 7.2-7.4 (20 H, m), 4.70 (lH, d, J=8 Hz), 3.63 (lH, br s), 3.50
(lH, d, J= 13 Hz), 3.36 (lH, d, J=13 Hz), 3.2-3.35 (SH, m), 2.75 (lH,
m), 2.0-2.6 (10 H, m), 1.75 (2H, m), 1.42 (9H, s). A diastereomeric
minor product (Rf 0.14) was also isolated.
Step B: 1-[2(R)-tert -Butoxycarbonylamino-3-triphenylmethyl-
thiopropyll-2(S)-(2-methoxyethyl)piperazine
The title compound was obtained by treating the product of
step A (0.884 g, 1.33 mmol) with l-chloroethyl chloroformate (0.151
mL, 1.39 mL) and potassium carbonate (0.200 g, 1.45 mmol) in

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dichloromethane (15 mL) according to the procedure described in
Example 14, step C. The crude product was chromatographed on silica
gel with 5-10% methanol in chloroforrn. The title compound was
isolated as a foam. NMR (CHC13, 300 MHz) o 7.2-7.45 (lSH, m), 4.66
(lH, d, J=8 Hz), 3.65 (lH, m), 3.35 (2H, m), 3.28 (3H, s), 2.94 (lH, dd,
J=12, 3 Hz), 1.7-2.9 (13H, m), 1.42 (9H, s).
Step C: 1-[2(R)-ter~ -Butoxycarbonylamino-3-triphenylmethyl-
thiopropyl]-2(S)-(2-methoxyethyl)-4-(1 -naphthoyl)-
piperazine
The title compound was prepared from the product of Step
B (0.422 g, 0.733 mmol), l-naphthoic acid (0.120 mg, 0.698 mmol),
EDC ~ HCl (0.154 mg, 0.806 mmol), HOBT (0.099 g, 0.733 mmol) in
DMF at pH 7 according to ~e procedure described in Example 11, Step
A. The crude product was chromatographed on silica gel with 30-40%
ethyl acetate in hexane (Rf 0.50, 40% ethyl acetate/hexane). The title
compound was isolated as a gum.
Step D: 1-[2(R)-Amino-3-mercaptopropyl]-2(S)-(2-methoxyethyl)-
4-(1 -naphthoyl)piperazine dihvdrochloride
The title compound was prepared from the product of Step
C (0.438 g, 0.600 mmol), triethylsilane (0.383 mL, 2.4 mmol),
trifluoroacetic acid (10 mL) in dichloromethane (20 mL) according to
the procedure described in Example 11, Step E. The crude product was
purified by preparative HPLC (gradient: 85% Solvent A/15% Solvent B
to 65% Solvent A/35% Solvent B). After ion exchange and
lyophili7~tion, the title compound was obtained as a white powder.
Analysis calculated for C2lH29N3o2s ~ 2.95 HCl - 0.05 H20:
C, 50.85; H, 6.51; N, 8.47.
Found: C, 50.86; H, 6.12; N, 8.31.

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EXAMPLE 16
Preparation of N-l2(S)-N'-(1-(4-Nitrophenylmethyl)-lH-imi~1~7ol-4-
ylacetyl)amino-3(S)-methylpentyl]-N- l -naphthylmethyl-glycyl-
5 methionine bis trifluoro~et~te and N-[2(S)-N'-(1-(4-
Nitrophenylmethyl)- lH-imicl~ol-5-ylacetyl)amino-3(S)-methylpentyl]-
N- 1 -naphthylmethyl-glycyl-methionine bis trifluoroacetate
Step A: Preparation of 1-(4-Nitrophenylmethyl)-lH-imidazol-4-
ylace~:ic acid methyl ester and 1-(4-Nitrophenylmethyl)-lH-
imidazol-5-ylacetic acid methyl ester (3:1mixture~
To a solution of sodium hydride (60% in mineral oil, 99
mg, 2.5 mmol) in ,dimethylforrn~mide (2 ml) cooled to 0~C was added,
via cannula, a solution of lH-imi~ ole-4-acetic acid methyl ester
hydrochloride (200 mg, 1.13 mmol) in dimethylformamide (3 ml).
This suspension was allowed to stir at 0~C for 15 min. To this
suspension was added 4-nitrobenzyl bromide (244 mg, 1.13 mmol) and
stirred at room ternperature for 2 h. After this time, the mixture was
quenched with sat. aq. sodium bicarbonate (15 ml) and water (20 ml)
and extracted with methylene chloride (2 x 50 ml). The combined
organic extracts were washed with brine (20 ml), dried (MgSO4),
filtered and the solvent was evaporated in vacuo. The residue was
purified by flash chromatography using acetonitrile as eluent to give the
title compounds as a yellow oil.
lH NMR (CDC13, 400 MHz) o 8.20 (2H, d, J=8.5 Hz), 7.49 (lH, s),
7.27 (2H, d, J=8.5 Hz), 7.03 (0.25H, s), 6.87 (0.75H, s), 5.28 (0.5H, s),
5.18 (l.SH, s), 3.70 (2.25H, s), 3.65 (l.SH, s), 3.61 (0.75H, s) and 3.44
" (O.SH, s) ppm.
Step B: Preparation of 1-(4-Nitrophenylmethyl)-lH-imidazol-4-
- ylacetic acid hydrochloride and 1-(4-Nitrophenyl-methyl)-
lH-i~idazol-5-ylacetic acid (3: lmixture)
To a solution of a mixture of 1-(4-Nitrophenylmethyl)-lH-
imidazol-4-ylacetic acid methyl ester and 1-(4-Nitrophenylmethyl)-lH-

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imidazol-5-ylacetic acid methyl ester (3:1mixture, 216 mg, 0.785 mmol)
in methan~ (3 ml) and tetrahydrofuran (3 ml) under argon was added
1.0 M sodium hydroxide (1.18 rnl, 1.18 mmol) and stirred for 18 h.
After this time, 1.0 N hydrochloric acid (2.36 ml, 2.36 mmol) was
5 added and the mixture evaporated in vacuo to give the title compounds.
lH NMR (CDC13, 400 MHz) o 9.04 (0.75H, s), 8.83 (0.25H, s), 8.28
(2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.54 (0.75H, s), 7.43 (0.25H,
s), 5.61 (0.5H, s), 5.58 (l.SH, s), 3.84 (0.SH, s) and 3.82 (l.SH, s) ppm.
10 Step (:~: Pr~alation of N-[(2S)-N'-(1-(4-Nitrophenylmethyl)-lH-
imi(l~7ol-4-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -
naphthylmethyl-glycyl-methionine methyl ester bis
trifluoroacetate and N-[2(S)-N'-(1-(4-Nitrophenyl-methyl)-
lH-imic~ol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -
naphthylmethyl-glycyl-methionine methyl ester bis
trifluoroacetate
To a solution of 1-(4-nitrophenylmethyl)-lH-imic1~7ol-4-
ylacetic acid hydrochloride and 1-(4-nitrophenylmethyl)-lH-imidazol-
5-ylacetic acid hydrochloride (3:1 mixture, 153 mg, 0.392 mmol), N-
20 [2(S)-amino-3(S)-methylpentyl]-N-naphthylmethyl-glycyl-methionine
methyl ester bis hydrochloride (209 mg, 0.392 mmol) and 3-hydroxy-
1,2,3-benzotriazin-4(3H)-one (HOOBT, 64 mg, 0.39 mmol) in
methylene chloride (10 ml) was added 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC, 75.2 mg, 0.392 mmol) and
25 triethylamine (219 ,ul, 1.57 mmol) and the mixture stirred overnight at
room temperature. After this time, sat. aq. sodium bicarbonate (10 ml)
was added and the mixture was extracted with methylene chloride. The
combined extracts were washed with sat. aq. sodium bicarbonate (10 ml)
and the solvent evaporated in vacuo. The regioisomers were separated
30 by Prep HPLC using a Nova Prep 5000 Semi preparative HPLC system
and a Waters PrepPak cartridge (47 X 300mm, C18, 15 ~lm, 100A)
eluting with S - 95% acetonitrile/water (0.1% TFA) at 100 ml/min
(chromatography method A ) to give after lyophili7~tl0n Compounds
F and G.

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F:
lH NMR (CD3OD, 400 MHz) ~i 8.96 (lH, s), 8.17 (lH, m), 8.23 (2~,
d, J=8.7 Hz), 7.92 (2H, d, J=8.9 Hz), 7.61 (lH, d, J=6.9 Hz), 7.56 (2H,
d, J=8.9 Hz), 7.50 (2H, m), 7.44 (2H, m), 5.52 (2H, s), 4.70 (lH, d,
J=9.4 Hz), 4.49 (lH, d, J=l l.9 Hz), 4.38 (lH, dd, J=4.7 and 8.9 Hz),
4.13 (lH, m), 3.67 (3H, s), 3.65 (4H, m), 3.30 (lH, m), 3.06 (lH, m),
2.31 (lH, m), 2.23 (lH, m), 1.97 (3H, s), 1.94 (lH, m), 1.71 (lH, m),
1.57 (lH, m), 1.42 (lH, m), 1.17 (lH, m), 0.90 (3H, d, J=6.9 Hz) and
0.87 (3H, t, J=7.4 Hz) ppm.
Anal. Calcd for C37H46N6o6s-2.4o TFA-0.25 H20: C, 51.18; H,5.02;
N, 8.57. Found: C, 51.17; H, 5.03; N, 8.80.
FAB MS calcd for C37H47N6o6s 703 (MH+), found 703.
G:
lH NMR (CD30D, 400 MHz) ~ 8.91 (lH, s), 8.26 (lH, d, J=12.8 Hz),
8.21 (2H, d, J=10.7 Hz), 7.91 (2H, m), 7.65-7.36 (7H, m), 5.51 (2H, s),
4.72-3.99 (4H, m), 3.66 (3H, s), 3.66-3.24 (4H, m), 3.20-2.85 (2H, m),
2.29 (lH, m), 2.20 (lH, m), 1.96 (3H, s), 1.91 (lH, br s), 1.70 (lH, d,
J=16 Hz), 1.56 (lH, m), 1.38 (lH, m), 1.13 (lH, m) and 0.88 (6H, m)
ppm.
FAB HRMS exact mass calcd for C37H47N6o6s 703.32778 (MH+),
found 703.32852.
Step D: Preparation of N-[2(S)-N'-(1-(4-Nitrophenylmethyl)-lH-
imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -
napht]hylmethyl-glycyl-methionine bis trifluoroacetate
To a solution of N-[2(S)-N'-(1-(4-nitrophenylmethyl)-lH-
imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- 1-naphthylmethyl-
glycyl-methionine methyl ester bis trifluoroacetate (F, 21 mg, 0.023
mmol) in methanol (1 ml ) at room temperature was added l.ON lithium
hydroxide (135 ,ul, 0.135 mmol). This solution was stirred for 4 h and
treated with trifluoroacetic acid (100 ,ul). This mixture was purified by

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preparative HPLC using chromatography method A to give the title
compound.
lH NMR (CD30D, 400 MHz) o 8.86 (lH, s), 8.23 (2H, d, J= 8.8Hz),
8.22 (lH, m), 7.90 (2H, dd, J=7.3 Hz), 7.55 (2H, d, J=8.4 Hz), 7.44-
7.28 (SH, m), 5.50 (2H, s), 4.53 (lH, m), 4.35 (2H, m), 4.12 (lH, m),
3.79-3.25 (4H, m), 3.26-2.86 (2H, m), 2.27 (lH, m), 2.18 (lH, m), 1.96
(3H, s), 1.9 (lH, m), 1.67 (lH, m), 1.57 (lH, m), 1.42 (lH, m), 1.15
(lH, m), 0.90 (3H, d, J=6.9 Hz) and 0.86 (3H, t, J=7.3 Hz) ppm.
FAB HRMS exact mass calcd for C36H45N606S 689.31213 (MH+),
found 689.31262.
Step E: Preparation of N-[2(S)-N'-(1-(4-Nitrophenylmethyl)-lH-
imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -
naphthylmethyl-glycyl-methionine bis trifluoroacetate
To a solution of N-[2(S)-N'-(1-(4-nitrophenylmethyl)-lH-
imi~l~7.ol-5-ylacetyl)amino-3(S)-methylpentyl]-N-l-naphthylmethyl-
glycyl-methionine methyl ester bis trifluoroacetate (29 mg, 0.031
mmol) in methanol (1 ml ) was added l.ON lithium hydroxide (187
0.187 mmol). This solution was stirred for 4 h and treated with
trifluoroacetic acid (100 ,ul). This mixture was purified by preparative
HPLC using chromatography method A to give the title compound.
lH NMR (CD30D, 400 ~Hz) o 8.89 (lH, s), 8.25 (lH, m), 8.21 (2H,
d, J= 9.0Hz), 7.89 (2H, m~, 7.64-7.34 (7H, m), 5.52 (2H, s), 4.59-3.88
(4H, m), 3.77-3.38 (4H, m), 3.18-2.75 (2H, m), 2.27 (lH, m), 2.18 (lH,
m), 1.96 (3H, s), 1.9 (lH, m), 1.67 (lH, m), 1.57 (lH, m), 1.42 (lH,
m), 1.15 (lH, m), 0.89 (6H, m) ppm.
FAB HRMS exact mass calcd for C36H4sN6o6s 689.31213 (MH+),
found 689.31135.
EXAMPLE 17
.
Regioselective preparation of N-[2(S)-N'-(1 -(4-Nitrophenylmethyl)- lH-
imidazol-5-ylacetyl)amino-3 (S)-methylpentyl]-N- 1 -naphthylmethyl-
~lycyl-methionine methyl ester bis trifluoroacetate

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-
Ste~ A: Preparation of 1 -(Triphenylmethyl)- lH-imic1~7ol-4-ylacetic
acid rnethyl ester
To a suspension of lH-imi-1~7.ole-4-acetic acid methyl ester
hydrochloride (7.48, 42.4 mmol) in methylene chloride (200 ml) was
added triethyl~min~ (17.7 ml, 127 mmol) and triphenylmethyl bromide
(16.4 g, 50.8 mmo:l) and stirred for 72 h. After this time, reaction
mixture was washed with sat. aq. sodium bicarbonate (100 ml) and
water (100 ml). The organic layer was evaporated in vacuo and
purified by flash chromatography (30-100% ethyl ~cet~te/hexanes
gradient elution) to provide the title compound as a white solid.
lH NMR (CDC13, 400 MHz) ~ 7.35 (lH, s), 7.31 (9H, m), 7.22 (6H,
m), 6.76 (lH, s), 3.68 (3H, s) and 3.60 (2H, s) ppm.
Step B: Preparation of 1-(4-Nitrophenylmethyl)-lH-imidazol-5-
ylacetic acid methyl ester
To a solution of l-(triphenylmethyl)-lH-imidazol-4-ylacetic
acid methyl ester fi-om Step A (274 mg, 0.736 mmol) in acetonitrile (10
ml) was added 4-nitrobenzylbromide (159 mg, 0.736 mmol) and heated
to 55~C for 16 h. After this time, the reaction was cooled to room
temperature, treated with ethyl acetate (20 ml) and the resulting
precipitate was filtered. The filtrate was concentrated to dryness in
vacuo and the residue was redissolved in acetonitrile (4 ml) and heated
to 65~C for 3 h. After this time, the reaction mixture was evaporated to
dryness and combined with initial precipitate. This residue was
dissolved in methanol (5 ml ) and heated to reflux for 30 min. The
resulting solution was evaporated in vacuo and the residue was purified
by flash chromatography (2-5% methanol/methylene chloride gradient
elution ) to provide the title compound.
lH NMR (CDC13, 400 MHz) o 8.20 (2H, d, J=8.8 Hz), 7.53 (lH, s),
7.19 (2H, d, J=8.8 Hz), 7.03 (lH, s), 5.28 (2H, s), 3.61 (3H, s) and 3.44
(2H, s) ppm.

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Step C: Preparation of 1-(4-Nitrophenylmethyl)-lH-irnidazol-5-
ylacetic acid hydroc~lo~
1 -(4-Nitrophenylmethyl)- l H-imi~ ol-5-ylacetic acid
methyl ester (0.115 g, 0.42 mmol ) was dissolved in l.ON hydrochloric
5 acid (10 ml ) and heated at 55~C for 3 h. The solution was evaporated in
vacuo to give the title compound as a white solid.
lH NMR (CD30D, 400 MHz) â 9.06 (lH, s), 8.27 (2H, d, J=8.8 Hz),
7.61 (lH, s), 7.55 (2H, d, J=8.8 Hz), 5.63 (2H, s) and 3.81 (2H, s) ppm.
~0 Step D: Preparation of N-[2(S)-N'-(1-(4-Nitrophenylmethyl)-lH-
imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -
naphthylmethyl-glycyl-methionine methyl ester bis
trifluoroacetate
Following the procedure described in Example 16, Step C,
15 but using the 1-(4-nitrophenylmethyl)-lH-imidazol-5-ylacetic acid
hydrochloride, prepared as described in Step C provided the title
compound.
EXAMPLE 18
Preparation of N-[2(S)-N'-(1 -(4-Cyanophenylmethyl)- 1 H-imidazol-5-
ylacetyl)amino-3(S)-methylpentyl]-N- 1-naphthylmethyl-glycyl-
methionine bis trifluoroacetate (Compound B)
~5 Step A: Preparation of N-[2(S)-N'-(1-(4-Cyanophenylmethyl)-lH-
imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -
naphthylmethyl-glycyl-methionine methyl ester bis
trifluoroacetate
Following the procedure described in Example 17, Steps B-
30 D, but using a-bromo-p-tolunitrile in place of 4-nitrobenzylbromide
provided the title compound.
1H NMR (CD30D, 400 MHz) o 8.92 (lH, s), 8.31 (lH, m), 8.01 (lH,
d, J=8 Hz), 7.96 (lH, m), 7.75 (2H, d, J=8 Hz), 7.62 (lH, s), 7.58-7.48
(3H, m), 7.45 (lH, m), 7.41 (2H, d, J=8 Hz), 5.51 (2H, s), 4.97 (lH, m),

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4.76 (lH, m), 4.41 (lH, m), 4.10 (lH, m) 3.92 (2H, m), 3.75-3.47 (3H,
m), 3.6~ ~3H, s), 3.25 (lH, m~, ~.37 (lH, m), 2.30 (lH, m), 2.00 (3H,
s), 1.97 (lH,m), 1.79 (lH, m), 1.58 (lH, m), 1.43 (lH, m), 1.19 (lH,
m) and 0.91 (6H, m) ppm.
~ S Anal. Calcd for C38H46N604S-2.40 TFA-l.90 H20: C, 51.89; H, 5.31;
N, 8.48. Found: C, 51.88; H, 5.29; N, 8.72.
FAB HRMS exact: mass calcd for C38H47N6o4s 683.337951 (MH+),
found 683.33843 ~'.
EXAMPLE 19
In vitro inhibition of ras farnesyl transferase
Assays of farnesy~-protein transferase. Partially purified bovine FPTase
and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) is prepared as
15 described by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),
Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS
U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase is assayed in
a volume of 100 ,u~l cont~ining 100 mM N-(2-hydroxy ethyl) piperazine-
N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12~ ~ mM
20 dithiothreitol (DTT), 100 rnM [3H]-farnesyl diphosphate ([3H]-FPP; 740
CBq/mmol, New lFngl~nd Nuclear), 650 nM Ras-CVLS and 10 ,ug/ml
FPTase at 31~C for 60 min. Reactions are initiated with FPTase and
stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates are collected
onto filter-mats using a TomTec Mach II cell harvestor, washed with
25 100% ethanol, dried and counted in an LKB ~-plate counter. The assay
is linear with respect to both substrates, FPTase levels and time; less
than 10% of the [-3H]-FPP is utilized during the reaction period.
Individual purified protein substrate-competitive inhibitor and/or
farnesyl pyrophosphate-competitive inhibitor and compositions of the
30 invention that comprise at least one of a protein substrate-competitive
- inhibitor and a famesyl pyrophosphate-competitive inhibitor are
dissolved in 100% dimethyl sulfoxide (DMSO) and are diluted 20-fold
into the assay. Percentage inhibition is measured by the amount of
incorporation of radioactivity in the presence of the test compound

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when compared to the amount of incorporation in the absence of the test
co~ oulld.
Human FPTase is prepared as described by Omer et al.,
Biochemistry 32:5167-5176 (1993). Human FPTase activity is assayed
5 as described above with the exception that 0.1 % (w/v) polyethylene
glycol 20,000, 10 ,UM ZnCl2 and 100 nM Ras-CVIM are added to the
reaction mixture. Reactions are performed for 30 min., stopped with
100 ,ul of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed
as described above for the bovine enzyme.
Comr~ on is made between the inhibitory activity of a
composition of the instant invention and the inhibitory activities of
individual compounds that make up the composition in the assay.
EXAMPLE 20
In vivo ras farnesylation assay
The cell line used in this assay is a v-ras line derived from
either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The
assay is performed essentially as described in DeClue, J.E. et al., Cancer
20 Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of
solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at
37~C, the cells are labelled in 3 ml methionine-free DMEM
supplemented with 10% regular DMEM, 2% fetal bovine serum and 400
25 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the
cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5
mM MgC12/lmM DTT/10 ~g/ml aprotinen/2 ,ug/ml leupeptin/2 ~g/ml
antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at
100,000 x g for 45 min. Aliquots of lysates cont~ining equal numbers
30 of acid-precipitable counts are bought to 1 ml with IP buffer (lysis
buffer lacking Dl-r) and immllnoprecipitated with the ras-specific
monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304,
(1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a
25~o suspension of ~lotei" A-Sepharose coated with rabbit anti rat IgG

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.
- 385 -
is added for 45 miin. The imm~lnoprecipitates are washed four times
with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA~1% Triton X-
100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE
sample buffer and loaded on 13% acrylamide gels. When the dye front
reached the bottorn, the gel is fixed, soaked in F~nlip;htening~ dried and
autoradiographed. The intensities of the bands corresponding to
farnesylated and nonfarnesylated ras proteins are compared to
determine the percent inhibition of farnesyl transfer to protein.
Comparison is made between the inhibitory activity of a
composition of the instant invention and the inhibitory activities of
individual compoLmds that make up the composition in the assay.
FXAMPLE 21
In vivo ras farnes~lation assay
The cell line used in this assay is a H-ras line derived from a
NIH3T3 cells, whi,ch expressed cellular Ha-ras p21. The assay is
performed essentially as described in Ana Maria Garcia et al., The
Journal of Biological Chemistry 268:18415-18418, (1993). Cells in 3.3
cm dishes at 50-7S% confluency are treated with the test compound
(final concentration of solvent, dimethyl sulfoxide, is 0.1%). After 24
hours the cells are lysed in lysis buffer (1% NP40/20mM HEPES, pH
7.5/5mM MgCk/l ,ug/ml aprotinin/2 ,ug/ml leupeptin/2 ,ug/ml
antipain/O.SmM PMSF). The lysate was separated by centrifugation at
13000rpm for 5 min and the supernatant used as cell extract. Total
protein was separated by SDS-polyacrylamide gel electrophoresis in
~ 12% acrylamide gels. After transfer to nitrocellose, the blots were
probed with NCC-RAS-004 mouse monoclonal antibody to H-ras
(Nihonkayaku). A.ll Western blots were developed using enhanced
- chemiluminescence reagents (Amersham Corp.). The intensities of the
bands corresponding to farnesylated and nonfarnesylated ras proteins
are compared to determine the percent inhibition of farnesyl transfer to
protein.

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Comparison is made between the inhibitory activity of a
composition of instant of instant invention and the inhibitory activities
of individual compounds that make up the composition in the assay.
s
EXAMPLE 22
In vil~o ~rowth inhibition assay
To determine the biological consequences of FPTase
inhibition, the effect of examples of compositions of the instant
invention on the anchorage-independent growth of Ratl cells
transformed with either a v-ras, v-raf, or v-mos oncogene in
comparison with the effect of the individual components of such
compositions on the same growth was tested. Cells transformed by v-
Raf were included in the analysis to evaluate the specificity of instant
compounds for Ras-induced cell transformation. Cells transformed by
v-Mos may also be included in an analysis.
Rat 1 cells transformed with either v-ras or v-raf were
seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a
0.3% top agarose layer in medium A (Dulbecco's modified Eagle's
medium supplemented with 10% fetal bovine serum) over a bottom
agarose layer (0.6%). Both layers contained 0.1% methanol or an
a~plo~liate concentration of the instant composition or the individual
component compounds (dissolved in methanol at 1000 times the final
concentration used in the assay). The cells were fed twice weelcly with
O.S ml of medium A containing 0.1% methanol or the concentration of
the instant compound. Photomicrographs were taken 9 days after the
cultures are seeded and comparisons are made between treated and
untreated plates.
The results of the assay are shown in Table 1. The extent
of inhibition of the cell growth was inferred from the subjective
quantitization of the colony growth. Wild type (vehicle only) colony
growth is designated "+/++", less than wild type growth is designated
"+", much less than wild type growth is designated "+/-" and no visually

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WO 97101275 PCT/US96/11022
- 387 -
detectable colonies is cle~si~n~te~ ". The assay was run against
individual protein substrate-competitive FPTase inhibitors (Compounds
A and B) and a farnesyl pyrophosphate-competitive FPTase inhibitor
(Compound C) to establish minimllm concentrations where wild type or
S less than wild type growth was observed. The compositions cont~ining
both the protein substrate-competitive and farnesyl pyrophosphate-
competitive inhibitors were then tested in the assay at those
concentrations of ~e FPTase inhibitors that showed such non-inhibitory
or minim~lly inhibitory effects for the individual compounds.

CA 02225255 1997-12-18
WO 97/01275 PCT/US96/11022
- 388 -
TABLE 1
CompoundConc.,uM Ras Raf
MeOH +/++ +/++
Compound A2.5 +/- +/++
+/ +/++
0.25 +/++ +/++
Compound B2.5 +/++
- +t++
0.25 + +/++
Compound C10 + +/++
2.5 +/++ +1++
+/++ +1++
CompoundC at 2.5 and +/- to + +/++
Compound A at 0.25
CompoundC at 2.5 and - to +/- +1++
Compound B at 0.25

, ~ ' ., 7. , . ~., _ ' . . . ', . ' . _ ' ~-~ ' CA 0 2 2 2 5 2 5 5 1 9 9 7 - 1 2 - i 8 ~ Y~ ~ ,;r, ~ ' - ' ''-~'~ '~ '-~ :~ ~ ' =, ~ ",
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CECI EST LE ~OME ~ --DE~
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