Note: Descriptions are shown in the official language in which they were submitted.
CA 02483020 2004-11-03
DESCRIPTION
SULFONATED AMINO ACID DERIVATIVES
.AND METALLOPROTEINASE INHIBITORS CONTAINING THE SAME
Technical Field
This application relates to sulfonated amino acid derivatives and
metalloproteinase inhibitors containing the same.
Background Art
An extracellular matrix consists of collagen, proteoglycan, ete., has a
function
to support tissues, and plays a role in a maintaining of a cell functions ,
for example
propagation, differentiation, adhesion, or the like. Matrix metalloproteinases
(MMP)
such as gelatinase, stromelysin, collagenase, and the like have an important
role in
degradation of an extracellular matrix, and these enzymes work for growth,
tissue
remodeling, etc. under physiological conditions. Therefore, it is considered
that these
enzymes participate in progression of.various kind of diseases involving
breakdown
and fibrosis of tissues, such as osteoarthritis, rheumatoid arthritis, corneal
ulceration,
periodontitis, metastasis and invasion of tumor, and virus infection (for
example, HIV
infection). At the present time, it is not clear which enzyme participates in
the above
diseases seriously, but it is considered that these enzymes at least
participate in tissue
breakdown. As metalloproteinase inhibitors of amino acid derivatives, for
example
hydroxamic acid derivatives of amino acids (JP-A-6-2562939), carboxylic acid
derivatives of amino acid and/or their hydroxamic acid derivatives
(W095135276), etc.
are disclosed.
Disclosure of Invention
If it is able to inhibit the activity of MMP, it is considered that MMP
inhibitors
contribute to an improvement and prevention of the above diseases caused by or
CA 02483020 2004-11-03
related to its activity. Therefore, development of MMP inhibitors has long
been
desired.
In the above situation, the inventors of the present invention found that a
kind of sulfonamide derivatives have strong activity to inhibit MMP.
The present invention relates to a composition for inhibiting
metalloproteinase which contains a compound of the formula I_:
R1
R~-R4-R3-SO2°N~COY
~2
R
wherein Ri is optionally substituted lower alkyl, optionally substituted aryl,
optionally
substituted aralkyl, optionally substituted heteroaryl, or optionally
substituted
heteroarylalkyl; RZ is hydrogen atom, optionally substituted lower alkyl,
optionally
substituted aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, or
optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted
arylene, or
optionally substituted heteroarylene; R4 is a bond, -(CHz)m-, -CH=CH-, -C = G-
, -CO-,
-CO-NH-, -N=N-, -N(R,A)-, -NFi-CO-NH-, -NH-CO-, -O-, -S-, -SOzNH-, -S02-NH-
N=CH-,
I5 or tetrazol-diyi; Rs is optionally substituted lower alkyl, optionally
substituted Ca-Ca
cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or
an
optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or
lower
alkyl; Y is -NHOH or -OH; and m is I or 2; provided Rz is hydrogen atom when Y
is -
NHOH, its optically active substance, their pharmaceutically acceptable salt,
or
hydrate thereof.
Mentioned in more detail, the invention relates to the following a)-b), 1)-
16),
and A)-C).
a) A composition for inhibiting metalloproteinase which contains a compound of
the
formula I:
R5-R4-R3-SO2-N~COY _I
R2
2
CA 02483020 2004-11-03
wherein R1 is optionally substituted lower alkyl, optionally substituted aryl,
optionally
substituted aralkgl, optionally substituted heteroaryl, or optionally
substituted
heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl,
optionally
substituted aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, or
optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted
arylene, or
optionally substituted heteroarylene; R4 is a bond, -(CH2)m-, -CH=CH-, -C '--
C-, -CO-,
-CO-NH-, -N=N-, -N(RA)-, -NH-CO-NH-, -NH-CO-, -O-, -S-, -SOzNH-, -S02-NH-N=CH-
,
or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally
substituted Cs-Ca
cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or
an
optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or
lower
alkyl; Y is -NHOH or -OH; and m is 1 or 2; provided R2 is hydrogen atom when Y
is -
NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl
when R3
is optionally substituted arylene or optionally substituted heteroarylene and
R4 is -
CO-NH- or -NH-CO-, R3 is optionally substituted aryl or optionally substituted
heteroaryl when Rs is optionally substituted arylene or optionally substituted
heteroarylene and R4 is tetrazol-diyl, R5 is lower alkyl, aryl substituted by
lower alkyl
or optionally substituted aryl, or heteroaryl substituted by lower alkyl or
optionally
substituted aryl when Rg is optionally substituted arylene and R4 is a bond,
both of R3
and R4 are not a bond at the same time, and R4 is not -O- when R3 is
optionally
substituted arylene or optionally substituted heteroarylene, its optically
active
substance, their pharmaceutically acceptable salt, or hydrate thereof.
b) A composition for inhibiting metalloprnteinase as mentioned above, which is
a
composition for inhibiting type-IV collagenase.
Preferred embodiment of the present invention are as follows.
1) A compound of the formula I:
R1
R5-R4-R3-S02-N~COY I_
R
wherein Rl is optionally substituted Lower alkyl, optionally substituted aryl,
optionally
3
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substituted aralkyl, optionally substituted heteroaryl, or optionally
substituted
heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl,
optionally
substituted aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, or
optionally substituted heteroarylalkyl; Rg is a bond, optionally substituted
arylene, or
optionally substituted heteroarylene; Rø is a bond, -(CHz)m-, -CH=CH-, -C = C-
, -CO-,
-CO-NH-, -N=N-, -N(R,A)-, -NH-CO-NH-, -NH-CO-, -O-, -S-, -SOzNH-, -SOa-NH-N=CH-
,
or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally
substituted Cs-Cs
cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or
an
optionally substituted non-aromatic heterocyelic grnup; RA is hydrogen atom or
lower
alkyl; Y is -NHOH or -OH; and m is 1 or 2; provided RZ is hydrogen atom when Y
is -
NHOH, Rb is optionally substituted aryl or optionally substituted heteroaryl
when R3
is optionally substituted arylene or optionally substituted heteroarylene and
R4 is -
CO-NH- or -NH-CO- (when R3 is phenylene and R4 is -CO-NH-, Rl is not methyl or
phenyl and Rb is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl),
R~ is lower
alkyl, optionally substituted aryl, or optionally substituted heteroaryl when
R3 is
optionally substituted arylene or optionally substituted heteroarylene and R~
is
tetrazol-diyl, Rb is lower alkyl, aryl substituted with lower alkyl or
optionally
substituted aryl, or heteroaryl substituted with lower alkyl or optionally
substituted
aryl when R3 is optionally substituted arylene and R4 is a bond, both of R3
and R4 are
not a bond at the same time, and R4 is not -O- when R3 is optionally
substituted arylene
or optionally substituted heteroarylene, its optically active substance, their
pharmaceutically acceptable salt, or hydrate thereof.
2) A compound of the formula II:
Rs Rt
R' R6 ~ \ S02-N~COY
-R9 R2
wherein R6 is -CH=CH-, -C '-- C-, -N=N-, -NH-CO-NH-, -S-, -S02NH-, or -SOz-NH-
N=CH-; R' is optionally substituted aryl or optionally substituted heteroaryl;
R$ and R9
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are each independently hydrogen atom, lower alkoxy, or vitro; R1, R2, and Y
are as
defined above, its optically active substance, their pharmaceutically
acceptable salt, or
hydrate thereof.
3) A compound of the formula III:
R8 R~
I
R' R1° ~ ~ SO2-N~COY
Rz
R
wherein Rl° is -(CHa)m-, -CO-, -CO-NH-, -N(R,A)-, -NHCO-, or tetrazol-
diyl; m is 1 or 2;
Rl, R2, R', R8, R9, RA, and Y are as defined above, provided R1 is not methyl
or phenyl
and R~ is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when
Rl° is -NH-
CO-, its optically active substance, their pharmaceutically acceptable salt,
or hydrate
thereof.
4) A compound of the formula IV:
R1
R'-R" ~ ~ sot-nr'~coY
°R2
wherein Ril is a bond, -CH=CH-, or -C = C-; X is oxygen atom or sulfur atom,
R1, R2, R7,
and Y are as defined above, its optically active substance, their
pharmaceutically
acceptable salt, or hydrate thereof.
5) A compound of the formula I_':
',
R
R5~-R~~-R3~-S02-N~COY r_
r 2.
R
wherein R1' is benzyl, (indol-3-yI)methyl, (1-methylindol-3-yl)methyl, (5-
methylindol-
3-yl)methyl, (1-acetylindol-3-yl)methyl, (1-methylsulfonylindol-3-yl)methyl,
(1-
alkoxycarbonyl-3-yl)methyl (for example ethoxycarbonylmethyl), or i-propyl;
R2' is
hydrogen atom, methyl, 4-aminobutyl, or benzyl; R3' is I,4-phenylene; R4' is -
O-; R~' is
phenyl or 4-hydroxy-phenyl; and Y is as defined above, its optically active
substance,
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CA 02483020 2004-11-03
their pharmaceutically acceptable salt, or hydrate thereof.
6) A compound of the formula j'_':
R5"-R4"_R3"-S02-N~COY I_"
i 2"
R
wherein Rl" is 4-thiazolylmethyl, (indol-3-yl)methyl, (5-methoxyindol-3-
yl)methyl, 1-
naphthylmethyl, 2-naphthylmethyl, 4-biphenylylmethyl, 2,2,2-trifluoroethyl, 2-
phenylethyl, benzyl, i-propyl, 4-nitrobenzyl, 4-fluorobenzyl,
cyclohexylmethyl, (I-
methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-ffuoroindol-3-
yI)methyl,
(pyridin-4-yl)methyl, (benzothiazol-2-yl)methyl, (phenyl)(hydroxy)methyl,
phenyl,
carboxymethyl, 2-carboxyethyl, hydroxymethyl, phenylmethoxymethyl, 4-
carboxybenzyl, (benzimidazol-2-yl)methyl, (1-methylsulfonylindol-3-yl)methyl,
or (1-
ethoxycarbonylindol-3-yl)methyl; R2" is hydrogen atom; R~" is 1,4-phenylene;
R4" is a
bond; R~" is phenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-
butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methylthiophenyl, 4-
biphenylyl, 2-thienyl, benzoxazol-2-yl, benzothiazol-2-yl, or tetrazol-2-yl;
and Y is as
defined above, its optically active substance, their pharmaceutically
acceptable salt, or
hydrate thereof.
7) A compound of the formula V:
R~ R~
R'-R12 ~ \ SO2-N~COOH V_
-R9 R2
wherein R12 is -CH=CH- or -C '-- C-; Rl, R2, R7, R8, and R~ are as defined
above, its
optically active substance, their pharmaceutically acceptable salt, or hydrate
thereof.
8) A compound of the formula VI:
6
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R8 R1s
O I ~
R'4-C-N ~ ~ SO2°N~COOH VI
_Rs Rz
wherein R2, R8, and R9 are as defined above, Rls is optionally substituted
lower alkyl,
optionally substituted aryl, optionally substituted aralkyl, optionally
substituted
heteroaryl, or optionally substituted heteroarylalkyl; and R14 is optionally
substituted
aryl, or optionally substituted heteroaryl; provided Rl~ is not methyl or
phenyl and R14
is not 2-ehlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically
active
substance, their pharmaceutically acceptable salt, or hydrate thereof.
9) A compound of the formula VII:
R$ Rt
N N
R7 N. -' / ~ SOz-N ~COOH VII
N L~_ Rz
Rs
wherein R1, R2, R', R8, and R9 are as defined above, its optically active
substance, their
pharmaceutically acceptable salt, or hydrate thereof.
10) A compound of the formula VIII:
Rt
R7 R" ~ p SOz-N~COOH '~Il
Rz
wherein R1, R2, R', and Rii are as defined above, its optically active
substance, their
I5 pharmaceutically acceptable salt, or hydrate thereof.
11) A compound of the formula VIII:
R8 R~
1
R? o ~ \ sot-N''~cooH
Rz
R
wherein R1, R2, R?, R$, and R9 are as defined above, its optically active
substance, their
7
CA 02483020 2004-11-03
pharmaceutically acceptable salt, or hydrate thereof.
12) A compound of the formula X_:
R8 R'
I
R7 R12 ~ ~ S02-N ~COOH
_1_ H _
R9
wherein RIZ is -CH=CH- or -C = C-; Ri, R7, R8, and R9 are as defined above,
its optically
active substance, their pharmaceutically acceptable salt, or hydrate thereof.
13} A compound of the formula Xl:
R8 R13
O I
R14-C-N ~ \ S02-N~COOH XI
H _ _ _.
R9
wherein R8, R9, R13, and Ri4 are as defined above, provided R13 is not methyl
or phenyl
and R'4 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its
optically active
substance, their pharmaceutically acceptable salt, or hydrate thereof.
14) A compound of the formula III:
R8 R1
N N I
R7 N. ~' / ~ SO2-N~COOH ~II_
N 'v:~- H
Rs
wherein R1, R7, R8, and R9 are as defined above, its optically active
substance, their
pharmaceutically acceptable salt, or hydrate thereof.
15) A compound of the formula XI~:
R1
R'-R11 I l So2_N~GOOH
S H
wherein Rl; R7, and Rll are as defined above, its optically active substance,
their
pharmaceutically acceptable salt, or hydrate thereof
8
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16) A compound of the formula HIV:
R8 R~
R7 O ~ \ S02-N'~COOH ITV
H
Rs
wherein R1, R7, R8, and R9 are as defined above, its optically active
substance, their
pharmaceutically acceptable salt, or hydrate thereof.
A compound of the invention is more specifically illustrated below:
A) The compound of any one of above 1) to 16), wherein Rl, Ri', RI", and RI3
are i-propyl,
benzyl, or (indol-3-yl) methyl.
B) The compound of any one of above 1) to 4) and 7) to 16), wherein R5, R7,
and Ri4 are
phenyl optionally substituted with one or more substituents selected from the
group
consisting of alkoxy, alkylthio, and alkyl.
C) The compound of any one of above 1) to 16), wherein a configuration of
asymmetric
carbon atoms bonding with Ra, Ri', Rt", and R13 is R configuration.
Further, this invention relates to a pharmaceutical composition , a
composition for inhibiting metalloproteinase, and a composition fox inhibiting
type IV
collagenase which contain the compound above 1) to I6) and A) to C)
All of compounds of above 1) to 16) and A) to C) have strong metalloproteinase
inhibitory activity, and the following compound is more preferable:
R~
R5-R4-R3-SO2-N~COY ~
R
1) A compound wherein Rl is i-propyl, benzyl, or (indol-3-yl) methyl, RZ is
hydrogen
atom, Rg is 1,4-phenylene, R4 is -C = C-, and R5 is optionally substituted
phenyl.
2) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl) methyl, RZ is
hydrogen
atom, Rg is optionally substituted 2;5-thiophen-diyl, R4 is -C = C-, and R5 is
optionally
substituted phenyl.
3) A compound wherein R' is i-propyl, benzyl, or (indol-3-yl)methyl, R2 is
hydrogen
9
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atom, R3 is 1,4-phenylene, Rø is tetrazol-diyl, and R5 is optionally
substituted phenyl.
The term "alkyl" herein used means Cx-Cio straight or branched chain alkyl,
for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,
tart-butyl, n-
pentyl, i-pentyl, neo-pentyl, tent-pentyl, and the like.
The term "lower alkyl" herein used means Ci-Cs straight or branched chain
alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-
butyl, tart-
butyl, and the like.
The term "Cs-Cs cycloalkyl" herein used is exemplified by cyclopropyl,
eyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term "aryl" herein used means monocyclic or condensed ring aromatic
hydrocarbons. Examples of the aryl are phenyl, naphthyl, and the like.
The term "aralkyl" herein used means the above mentioned alkyl substituted
by the above mentioned aryl at any possible position. Examples of the aralkyl
are
benzyl, phenethyl, phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (a-
naphthylmethyl), anthrylmethyl (9-anthrylmethyl), and the like. Benzyl is
preferred.
The aryl part may optionally be substituted.
The term "heteroaryl" herein used means a 5 to ~ membered aromatic
heterocyclic group which contains one or more hetero atoms selected from the
group
consisting of nitrogen, oxygen and sulfur atoms in the ring and may be fused
with a
carbocyclic ring or other heterocyclic ring at any possible position. Examples
of the
heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 2-indolyl),
carbazolyl (e.g., 3-
carbazolyl), imidazolyl (e.g., 4- imidazolyl), pyrazolyl (e.g., 1-pyrazolyl),
benzimidazolyl
(e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-
indolizinyl),
pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-
isoquinolyl),
acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl),
pyridazinyl (e.g.,
3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-
pyrazinyl),
cinnolinyl (e.g., 3-cinnolinyl), phthalazinyi (e.g., 2-phthalazinyl),
quinazolinyl (e.g., 2-
quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-
benzisoxazolyl),
oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl),
benzoxadiazolyl (e.g., 4-
CA 02483020 2004-11-03
benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g.,
2-
benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-
benzothiazolyl),
furyl (e.g., 3-furyl), benzofuryl (e,g., 3-benzofuryl), thienyl (e.g., 2-
thienyl),
benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. The aryl part
of the above
heteroaryl is optionally substituted.
The term "heteroarylalkyl" herein used means the above mentioned alkyl
substituted with the above mentioned heteroaryl at any possible position.
Examples
of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl),
thiazolylethyl (e.g.,
5-thiazolyl-2-ethyl), indolylmethyl (e.g., 2-indolylmethyl), imidazolylmethyl
(e.g., 4-
imidazolylmethyl), benzothiazolylmethyl (e.g., 2-benzothiazolylmethyl),
benzopyrazolylmethyl (e.g., I-benzopyrazolylmethyl), benzotriazolylmethyl
(e.g., 4-
benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl),
benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 2-
pyridylmethyl), and the like. The aryl part of the above heteroaryl is
optionally
I5 substituted. _.
The term "arylene" herein used is exemplified by phenylene, naphthylene, and
the like. Mentioned in more detail, it is exemplified by 1,2-phenylene, 1,3-
phenylene,
1,4-phenylene, and the like.
The term "heteroarylene" herein used is exemplified by thiophen-diyl, furan-
diyl, pyridin-diyl, and the like, in more detail, by 2,5-thiaphen-diyl, 2,5-
furan-diyl, and
the like.
The term "non-aromatic heterocyclic group" herein used means 5 to 6
membered non-aromatic heterocyclic group which contains one or more hetero
atoms
selected from the group consisting of nitrogen, oxygen and sulfur atoms in the
ring,
and may bind at any possible positin. Examples of the non-aromatic
heterocyclic
group are morpholino, piperidino, pyrrolidino, and the, like.
The term "alkoxy" herein used means alkoxy of which alkyl part is the above
mentioned alkyl. Examples of the alkoxy are methoxy, ethoxy, propoxy, butoxy,
pentyloxy, and the like.
II
CA 02483020 2004-11-03
The term "lower alkoxy" herein used means alkoxy of which alkyl part is the
above mentioned Iower alkyl. Examples of the lower alkoxy are methoxy, ethoxy,
n-
propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tart-butoxy, and the like.
The term "halogen" herein used means fluoro, chloro, bromo, and iodo.
The term "alkylthio" herein used means alkylthio whose alkyl part is the
above mentioned lower alkyl. Examples of the alkylthio are methylthio,
ethylthio,
and the like.
Substituents for "optionally substituted alkyl", "optionally substituted Ca-Ca
cycloalkyl", and "optionally substituted non-aromatic heterocyclic group" are
hydroxy,
alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio),
cycloalkyl
(e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g.,
fluoro, chloro,
bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and
ethoxycarbonyl),
nitrn, cyano, haloalkyl (e.g., trifluoromethyl), substituted or unsubstituted
amino (e.g.,
methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl, benzyloxy,
and the like. These substituents are able to bind them at one or more of any
possible
positions.
Substituents for the aromatic ring of "optionally substituted aryl",
"optionally
substituted aralkyl", "optionally substituted heteroaryl", "optionally
substituted
heteroarylalkyl", "optionally substituted arylene", and "optionally
substituted
heteroarylene" are, for example, hydroxy, alkoxy (e.g., methoxy and ethoxy),
mercapto,
alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl),
halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl
(e.g.,
methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g.,
trifluoromethyl),
aryloxy (e.g., phenyloxy) substituted or unsubstituted amino (e.g.,
methylamino,
dimethylamino, diethylamino, and benzylidenamino), guanidino, alkyl (e.g.,
methyl,
ethyl, n-propyl, i-prapyl, n-butyl, i-butyl, sec-butyl, tart-butyl, n-pentyl,
i-pentyl, neo-
pentyl, and tent-pentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g.,
ethynyl and
phenylethynyl), alkanoyl (e.g., formyl, acetyl, and propionyl), acyloxy (e.g.,
acetyloxy),
acylamino, alkylsulfonyl (e.g., methylsul~onyl), phenyl, benzyl, an azo group
(e.g.,
12
CA 02483020 2004-11-03
phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally
substituted
ureido (e.g., ureido and phenylureido), and the like. These substituents are
able to
bind to it at one or more of any possible position.
Best Mode for Carrying Out the Invention
Compounds (Ia) and (Ib) of the invention are able to be synthesized from the
corresponding a-amino acids represented by the formula (XV) by means of the
following 6 synthetic methods. Generally, it is possible to produce the
compounds of
the invention by means of the method A. Each classified type of the compounds
is
possible to be produced by means of methods the B to F. However, these methods
are
only examples to produce the compounds represented by the formula I. A
compound
represented by the formula I produced by any other method is included in this
invention.
Method A: A general synthetic method of the compound represented by the
formula I.
Method B: A synthetic method of the compound wherein and R3 is optionally
substituted arylene or optionally substituted heteroarylene, R4 is -C=C-, and
R5 is
optionally substituted aryl or optionally substituted heteroaryl.
Method C: A synthetic method of the compound wherein R3 is optionally
substituted arylene or optionally substituted heteroarylene, Rø is a bond, and
R5 is
optionally substituted aryl or optionally substituted heteroaryl.
Method D: A synthetic method of the compound wherein R3 is optionally
substituted arylene or optionally substituted heteroarylene, R~ is -CO-NH-,
and R5 is
optionally substituted aryl or optionally substituted heteroaryl.
Method E: A synthetic method of the compound wherein R3 is optionally
substituted arylene or optionally substituted heteroarylene, R4 is tetrazol-
diyl, and R5
is optionally substituted aryl or optionally substituted heteroaryl.
Method F: A synthetic method of the compound wherein R3 is optionally
substituted arylene or optionally substituted heteroarylene, R4 is -CH=CH-,
and R~ is
13
CA 02483020 2004-11-03
optionally substituted aryl or optionally substituted heteroaryl.
Details of these methods are explained as follows.
(Method A)
R~ R~
Process -1
H2N COORS R5-R4-R3-S02-N COOH
R5-R~-R3-SO2-Hai R2
XV Ia-~
R'
Process 2
Ia-1 --~ R5-R4-R3-S~2-N~CONHOH ~--__
~2
R
Ib-1
R'
Process 3 Process 4
R5-R4-R3-SOz-N CONHOR~s- -
R2
XVI
wherein RI, R2, R3, R~, and RS are as defined above, Rl~ is hydrogen atom or a
carboxy
protective group, Rls is a hydroxy protective group, and Hal is halogen.
Conversion of compound (X'~ to compaund (Ia-1) is sulfonation of an amino
group of the compound (X~ (process 1). If necessary, after this reaction, N-
alkylation,
deprotection of a carboxyl protective group, etc. are carried out. Conversion
of
compound (Ia-1) to compound (Ib-1) is to obtain hydroxamic acid derivatives
from
carboxylic acid derivatives (process 2). To obtain compound (Ib-1) from
compound
(Ia-1), compound (Ia-1) may also be reacted with hydroxylamine having a
hydroxyl
protective group or its acidic salts to give compound (XVI) process 3),
followed by and
deprotection (process 4). Conversion to sulfonyl derivatives and hydroxamic
acid
derivatives are able to be carried out according to an usual method. For
example, an
amino acid represented by the formula (X~ is reacted with a sulfonating agent
such as
sulfonyl halide represented by R3-R4-R3-SOzIial (R.3, R4, and R5 are as
defined above;
and Hal is halogen) and then hydroxylamine. Each process will hereinafter be
described in more detail.
14
CA 02483020 2004-11-03
(Process 1)
Some of amino acids represented by the formula (~ or its acidic salts (e.g.,
hydrochloride, p-toluenesulfonate, and trifluoroacetate) which are starting
materials
are commercially available. The other are able to be synthesized in accordance
with a
method described in Zikkenkagakukoza, vol. 22, IV (nihonkagakukai), J. Med.
Chem.
38, 1689-1?00, 1995, Gary M. Ksander et. al., etc. some of sulfonating agents
are
commercially available and the other are synthesized in accordance with a
method
described Shin-zikkenkagakukoza, vol. 14, 178?, 1978, Synthesis 852-854, 1986,
etc.
A carboxyl protective group is exemplified by esters (e.g., methyl ester ,
tert-butyl ester
and benzyl ester). Deprotection of this protective group may be carried out by
hydrolysis with acid (e.g., hydrochloride and trifluoroacetic acid) or base
(e.g., sodium
hydroxide) depending on the type of the group, or by catalytic reduction,
e.g., under
10% palladium-carbon catalyst condition. To obtain a compound (Ib-1), the
esters
may directly be converted to hydroxamic acid by the method of process 2. When
a
I5 compound (XV) is an amino acid wherein R15 is hydrogen atom, preferable
solvents for
this sulfonylation are dimethylformamide, tetrahydrofuran, dioxane,
dimethylsulfoxide, acetonitrile, water, or mixed solvents thereof. When a
compound
(XV) is an amino acid wherein R15 is a protective group such as an ester, a
solvent for
this sulfonylation is exemplified by the above solvents and mixed solvents of
water-
insoluble solvents (e.g., benzene and dichloromethane) and the above solvents.
A base
to be used in this sulfonylation is exemplified by organic bases such as
triethylamine,
N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide,
potassium
hydroxide, potassium carbonate, and the like. Usually this reaction can be
carried out
at ice-cooling to room temperature. When R1, R3, R4, R5, or R15 of compound
(Ia-1)
contains a functional groups) possibly interfering this sulfonylation (e.g.,
hydroxy,
mercapto, amino, and guanidino), it can previously be protected in accordance
with a
method described in " Protective Groups in Organic Synthesis" ( Theodora W.
Green
(John Wiley & Sons)) and then deprotected at an appropriate process. When R2
is not
hydrogen atom, compound (Ia-I) wherein R2 is hydrogen atom is further reacted
with
CA 02483020 2004-11-03
haloalkyl (e.g., methyl iodide, and ethyl iodide) or haloaralkyl (e.g., benzyl
chloride,
and benzyl bromide) in dino.ethylformamide, tetrahydrofuran, dioxane, and the
like at
a temperature range of ice-cooling to 80 ~, preferably ice-cooling to room
temperature,
for 3-10 hours, preferably 10-20 hours to give the desired N-R2 derivative.
(Process 2)
A hydroxylamine is reacted with compound (Ia-1) or its reactive derivatives to
give hydroxamic acid derivatives (Ib-1). A hydroxylamine is usually used as
its acidic
salts (e.g., hydrochloride, and phosphate, sulfate: commercially available) in
the
presence of a base. A base to be used in this reaction is exemplified by
organic bases
such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, etc. and
inorganic
bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc.
When compound (ta-1) is used as a starting material of conversion to
hydroxamic acid,
this reaction is carried out in the presence of a peptide condensing agent
(e.g.,
dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-
carbonyldiimidazole, or a mixture of one of the above agents with 1-
hydroxybenzotriazole, N-hydroxy sucinicimide, etc.). A salvent for this
reaction may
be dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide,
acetonitrile,
water, and mixed solvent thereof. This reaction is carried out at -20 ~ to 40
°~,
preferably ice-cooling to room temperature, for 1 to 16 hours.
Acid anhydrides (especially, mixed acid anhydrides), acid halides, acid
azides,
and esters can be utilized in this reaction as a reactive derivative of
compound (Ia-1).
These reactive derivatives are produced by usual methods. For example, the
acid
anhydride derivatives can be produced by a reaction of compound øa-1) with
acid
halide derivatives (e.g., ethyl chlorocarbonate) in the presence of a base
(e.g.,
triethylamine), and acid halide derivatives can be produced by a reaction of
compound
(Ia-1) with a halogenation agent (e.g., oxalylchloride, and thionylchloride).
Ester
derivatives may be inactive or active. Sulfonyl derivatives converted from a
compound (X~ wherein R1~ is a carboxyl protective groups (e.g., methyl, tert-
butyl,
and benzyl) at process 1 can he used as inactive esters without deprotection.
Active
16
CA 02483020 2004-11-03
esters can be produced by a reaction of compound (Ia-1), carbodiimide reagents
(e.g.,
dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and
hydroxy derivatives corresponding to the active ester residue such as 1-
hydroxybenzotriazole, N-hydroxysuccinimide, or the like. A reaction condition
of
conversion of the reactive derivatives of compound (Ia-1) to hydroxamic acid
may be
the same as that of conversion of compound (Ia-1) itself to hydroxamic acid .
The
reactions of processes 1 and 2 are able to continuously be carried out in one-
pot
reaction.
(Process 3)
A protected hydroxylamine to be used in this reaction includes O-
benzylhydroxylamine, O-(p-methoxybenzyl)hydroxylamine, O-(tert-
butyl)hydroxylamine, or the like. This reaction condition may be in the same
manner
as that of process 2.
(Process 4)
This process for deprotection is_carried out by catalytic reduction, treatment
with conc. hydrochloric acid, or treatment with trifluoroacetic acid to give
the desired
compound (Ib-1). The compounds of this invention (Ia-1) and (Ib-1) can be
isolated
and purified by usual separation methods and purification methods (e.g.,
chromatography, crystallization, etc.).
(Method B)
1?
CA 02483020 2004-11-03
R' _ Ri
Process 1 ,~ - Process 2
H2N COORS '~" (Hai-~R'~ S02-H COORS --~-
XV X~V
R' R'
Process 3
R~ C=C-R'7 S02-H COOR'S --~ R7 C=C-R'7 SO2-N2 COOH
R
R1
Process 4
~--'' R'-C=C-R1~ SO~-N~CONHOH
R2
Ib-2
wherein R1, R2, R7, R15, and Hal are as defined above, R17 is optionally
substituted aryl
or optionally substituted heteroaryl.
Conversion of compound (X'~ to compound (XVII) is performed by sulfonation
of an amino group of compound (X~ (process 1) in the same manner as that
described
in process 1 of method A. Conversion of compound (XVII) to compound (XVIII) is
performed by Heck reaction (K. Sonogashira, Y. Tohda, and N. Hagihara,
Tetrahedron
Lett., 4467(1975) etc.) wherein halogen of Ri7 is utilized to insert a triple
bond (process
2). Conversion of compound (XVIII) to compound (Ia-2) is N-alkylation,
deprotection
of a carboxyl protective group, etc. (process 3), which can be carried out in
the same
manner as that described in process 1 of method A. Conversion of compound (Ia-
2) to
compound (Ib-2) is that of carboxylic acid derivatives to hydroxamic acid
derivatives
(process 4), which can be carried out in the same manner as those described in
processes 2 to 4 of method A. Each process will hereinafter be described in
more
detail.
(Process 1)
This process may be carried out in the same manner as that described in
process 1 of method A.
(Process 2)
18
CA 02483020 2004-11-03
Compound (XVII) is reacted with optionally substituted aryl or optionally
substituted heteroaryl having an ethynyl group such as ethynylbenzene in a
solvent
such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in
the
presence of a palladium catalyst (e.g., Pd(PhsP)zCl2), a divalent copper
reagent (e.g.,
CuI), and an organic base (e.g., triethylamine, and diisopropylethylamine) to
give a
desired compound (XVIII) (Heck reaction). This reaction is carried out at room
temperature to 100 'C, preferably room temperature to 80 'C. This reaction is
completed for 3 to 30 hours, preferably 10 to 20 hours. When optionally
substituted
aryl or optionally substituted heteroaryl has a substituent(s) interfering
this reaction,
the substituent(s) can previously be protected in accordance with a method of
" Protective Groups in Organic Synthesis " ( Theodora W. Green (John Wiley &
Sons)),
and then deprotected at an appropriate step.
(Process 3)
This process may be carried out in the same manner as that described in
process 1 of method A.
(Process 4)
This process may be carried out in the same manner as those described in
processes 2 to 4 of method A.
(Method C)
R~ R1
(Haf-)R"S02-N~COOR'~ Proces~ R~ RWS02-N~COOR,S
H H
XVII XIX
R1 R1
Process 2 ~ Process 3
-~--~- R' R"S02-N COON ~- R~-R"SO~-N~CONHOH
R2 R2
1~ Ib-3
wherein RI, Rz, R~, R15, R17, and Hal axe as defined above.
Conversion of compound (XVII) to compound (XIX) is performed by Suzuki
reaction (M. J. Sharp and V. Shieckus, Tetrahedron Lett., 26, 5997 (1985)
etc.) wherein
19
CA 02483020 2004-11-03
halogen of R'~ is utilized to introduce aryl or heteroaryl (process 1).
Conversion of
compound (XIX) to compound (Ia-3) is N-alkylation, deprotection of a carboxyl
protective group, etc. (process 2) and this process can be carried out in the
same
manner as that described in process 1 of method A. Conversion of compound (Ia-
3) to
compound (Ib-3) is that of carboxylic acid derivatives to hydroxamic acid
derivatives
(process 3), and this process can be carried out in the same manner as those
described
in processes 2 to 4 of method A. Each process will hereinafter be described in
more
detail.
(process 1)
Compound (XVII) is reacted with optionally substituted aryl or optionally
substituted heteroaryl having a B(OI~2 (otherwise B(Et)z) group such as
phenylboronic
acid in a solvent such as dimethylformamide, toluene, xylene, benzene,
tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(PhsP)a)
and a
base (e.g., potassium carbonate, calcium carbonate, triethylamine, sodium
methoxide
etc.) to give the desired compound (XIX) (Suzuki reaction). This reaction is
carried
out at room temperature to 100 °C, preferably room temperature to 80 ~.
This
reaction is completed for 5 to 50 hours, preferably 15 to 30 hours. When
optionally
substituted aryl or optionally substituted heteroaryl has a substituent(s)
interfering
this reaction, the substituent(s) can previously be protected in accordance
with a
method of " Protective Groups in Organic Synthesis " ( Theodora W. Green (John
Wiley
& Sons)) and then deprotected at an appropriate step.
(Process 2)
This process may be carried out in the same manner as that described in
process 1 of method A.
(Process 3)
This process may be carried out in the same manner as those described in
processes 2 to 4 of method A.
(Method D)
CA 02483020 2004-11-03
R~
R'
Process 1 ~, Process 2
H2N COOR~5 -"(OWN )R17 702 H C~~R~5-- . -
XV XX
R' R'
O
(H2N-)R1~ SO2-N~'COOR~5 PrOCeSS 3 ~ R7_C-N-R'7 SO2-N~COOR15
H H
XXI XXII
R1
Process 4 R7 o-N-R17-S02-N~COOH Process 5~
'2
la-4 R
R1
R' C-N-R~~ S02-N~'CONHOH
R2
wherein Ri, R2, R7, R15, Rm, and Hal are as defined above.
Conversion of compound (X~ to compound (X~ is sulfonation of an amino
group of the compound (X~ (process 1) and this process may be carried out in
the same
manner as that described in process l of method A. Conversion of compound (XX)
to
compound (XXI) is reduction of a vitro group of Ri7 to an amino group (process
2) and
this process can be carried out by catalytic reduction or other reduction
using
hydrochloric chloride - Fe, hydrochloric chloride - Sn, etc. Conversion of
compound
(XXI) to compound (XXII) is performed by usual amide bond formation reaction
wherein an amino group of Rz7 is utilized (process 3). Conversion of compound
(XXII)
to compound (Ia-4) is N-alkylation, deprotection of a carboxyl protective
group, etc.
(process 4) of compound (XXII) and this process can be carried out in the same
manner
as that described in process 1 of method A. Conversion of compound (Ia-4) to
compound (Ib-4) is that of carboxylic acid derivatives to hydroxamic acid
derivatives
(process 5) and this process can be carried out in the same manner as those
described
2i
CA 02483020 2004-11-03
in processes 2 to 4 of method A. Each process will hereinafter be described in
more
detail.
(process 1)
This process may be carried out in the same manner as that described in
process 1 of method A.
(Pracess 2)
Compound (XX) is treated with hydrogen in a salvent such as methanol,
ethanol, ethyl acetate, acetic acid, etc. in the presence of a catalyst (e.g.,
Pd-C, Pt02,
Raney Ni etc.) , under a no-pressure ar pressured condition to give the
desired
compound (XXI). This reaction is carried out at a temperature under ice-
cooling to
80 ~, preferably room temperature to 50 °C, and is completed far 1 to
10 hours,
preferably 2 to 5 hours.
(Process 3)
Compound (XXI) is reacted with optionally substituted aryl or optionally
substituted heteroaryl having an acid halide (otherwise an active ester) group
such as
benzoyl chloride in a solvent such as dimethylformamide, tetrahydrofuran,
dioxane,
dimethylsulfoxide, acetonitrile, xylene, toluene, benzene, dichloromethane,
etc. in the
presence of a base (e.g., triethylamine, N-methylmorpholine, potassium
carbonate etc.)
to give the desired compound (XXII). This reaction is carried out at a
temperature
under ice-cooling to 100 ~, preferably room temperature to 60 ~, and is
completed for
3 to 30 hours, preferably 10 to 25 hours.
(Process 4)
This process may be carried out in the same manner as that described in
process 1 of method A.
(Process 5)
This process may be carried out in the same manner as those described in
processes 2 to 4 of method A.
(Method E)
22
CA 02483020 2004-11-03
R~
Rt
Process 1 ~ Process 2
H2N~COOR~S ~ (CH2=CH-)R'7-S02 H COOR~5
R' _ R'
(OHC-)Rw_S02-N~COOR~S Proce~ R7 S2 N-N-C-R~~ SO2-N~COOR~s
H H
R~
Process 4 N'N ~ Process 5
R~ N,N~R~7 S02-H COOR15
R9 R1
N=N N=N
R? N, ~Rt~ S02-N~'COOH P'~~ R? N, ~--R~~ S02-N~CONHOH
N R2 N R2
I
wherein R1, R2, R7, R15, R~~, and Hal are as defined above.
Conversion of compound (X~ to compound (XXITI) is performed by
sulfonating an amino group of the compound (XV) (process 1) in the same manner
as
that described in process 1 of method A. Conversion of compound (XXIII) to
compound (XXI~ is done by the reduction wherein an ethenyl group of Rl~ is
converted
into an aldehyde group (process 2). Conversion of compound (XXT~ to compound
(:KXVI) is performed by a tetrazole ring formation reaction (processes 3 and
4).
Conversion of compound (XXVI) to compound (Ia-5) is N-alkylation, deprotection
of a
carboxyl protective group, etc. of compound (:KXVI) (process 5), and this
process can be
carried out in the same manner as that described in process 1 of method A.
Conversion of compound (Ia-5) to compound (Ib-5) is that of carboxylic acid
derivatives
to hydraxamic acid derivatives (process 6), which can be carried out in the
same
manner as those described in processes 2 to 4 of method A. Each process will
hereinafter be described in more detail.
(process 1)
This process may be carried out in the same manner as that described in
process 1 of method A.
23
CA 02483020 2004-11-03
(Process 2)
A compound (XXIII) is treated with ozone in a solvent such as
dichloromethane, ethyl acetate, methanol, etc. to form an ozonide, and then a
reagent
such as zinc-acetic acid, triethylphosphate, dimethylsulfide, etc. is added to
this
reaction mixture for reduction to give the desired aldehyde derivatives (XXI~
The
reduction can also be carried out by catalytic hydrogenation. This reaction is
carried
out at -100 ~ to room temperature, preferably -78 'C to a temperature under
ice-
cooling, and is completed for 0.5 to 10 hours, preferably 1 to 3 hours.
(Process 3)
A compound (XXI~ is reacted with benzensulfonylhydrazide in a solvent such
as tetrahydrofuran, ether, etc. mixed with a solvent such as methanol,
ethanol, etc. to
give the desired compound (;~. This reaction is carried out at a temperature
under
ice-cooling to 80 °C, preferably room temperature to 50 ~, and is
completed for 3 to 30
hours, preferably 10 to 20 hours.
(Process 4)
Optionally substituted aryl or optionally substituted heteroaryl having amino
group such as aniline is dissolved in a mixed solvent such as alcohol (e.g.,
ethanol) and
water. To this mixture cone. hydrochloric acid and a diazotizing agent such as
a
sodium nitrite aqueous solution are added at -20 '~ to 10 ~, preferably 0 'C
to 5 ~,
to give a diazonium salt. The reaction time is 5 min to 1 hr, preferably 10 to
30 min.
This reaction mixture is added to a pyridine solution of compound (:~ and
allowed
react for 1 to 10 hr, preferably 2 to 5 hr, at -30 °O to 50 °O,
preferably -15 °C to room
temperature to give the desired compound (X~~~'VI). When optionally
substituted aryl
or optionally substituted heteroaryl has a substituent(s) interfering this
reaction, the
substituent(s) can previously be protected in accordance with a method of "
Protective
Groups in Organic Synthesis " ( Theodore W. Green {John Wiley & Sons)), and
then
deprotected at an appropriate step.
(Process 5)
This process may be carried out in the same manner as that described in
24
CA 02483020 2004-11-03
by an usual method, in a solvent such as toluene, xyleae, tetrahydrofuran,
ether,
dimethylformamide, etc. at -100 ~ to room temperature, preferably -?8 'C to
ice-
cooling for 1 to 20 hours, preferably 1 to 5 hours, to give the desired
compound (XX~VII).
When optionally substituted aryl or optionally substituted heteroaryl has a
substituent(s) interfering this reaction, the substituent(s) can previously be
protected
in accordance with a method of " Protective Groups in Organic Synthesis " (
Theodora
W. Green (John Wiley & Sons)), and deprotected at an appropriate step.
(Process 2)
This process may be carried out in the same manner as that described in
process 1 of method A.
(Process 3)
This process may be carried out in the same manner as those described in
processes 2 to 4 of method A.
The term " compound of the present invention " herein used includes
pharmaceutically acceptable salt or hydrate of the compound. The salt is
exemplified
by a salt with alkali metals (e.g., lithium, sodium, and potassium), alkaline
earth
metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids,
mineral
acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and
sulfuric acid), or
organic acids (e.g., acetic acid, citric acid, mallein acid, fumaric acid,
benzenesulfonic
acid, and p-toluenesulfonic acid). These salts can be formed by the usual
method.
The compound of the present invention is not restricted to any particular
isomers but includes all possible isomers and racemic modifications.
The compound of the present invention has an excellent activity for inhibiting
metalloprateinase, especially activity for inhibiting MMP, and inhibits matrix
dissolution, as described in the following test example. Therefore, the
compound of
the present invention is useful to treat or prevent diseases which are caused
by MMP
and relative enzymes such as TNF-a converting enzyme, etc.
Definitely, the compounds of the present invention are useful in the
prevention or treatment of diseases such as osteoarthritis, rheumatoid
arthritis,
26
CA 02483020 2004-11-03
corneal ulceration, periodontal disease, metastasis and invasion of tumor,
advanced
virus infection (e.g., HIS, arteriosclerosis obliterans, arteriosclerotic
aneurysm,
atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis,
aberrant
angiogenesis, scleritis, multiple sclerosis, open angle glaucoma,
retinopathies,
proliferative retinopathy, neovascular glaucoma, pterygium, keratitis,
epidermolysis
bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease,
gingivitis, tumor
growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever,
hemorrhage, coagulation, cachexia, anorexia, acute infection, shock,
autoimmune
disease, malaria, Crohn disease, meningitis, and gastric ulcer.
When the compound of the present invention is administered to a person for
treatment or prevention of the above diseases, they can be administered by
oral
administration such as powder, granules, tablets, capsules, pilulae, and
liquid
medicine, or by parenterai administration such as injections, suppository,
percutaneous formulations, insufllation, or the like. An effective dose of the
compound of the invention is formulated by being mixed with medicinal
admixture
such as excipient , penetrant, disintegrators, lubricant, and the like if
necessary.
When parenteral injection is prepared, the compound of the invention and an
appropriate carrier are sterilized to prepare it.
An appropriate dosage varies with the conditions of the patients, an
administration route, their age, their body weight and the like and should be
determined by a physician in the end. In the case of oral administration, a
daily
dosage can generally be between 0.1 - 100 mglkglday, preferably 1 - 20
mg/kg/day. In
the case of parenteral administration, the daily dosage can generally be
between 0.01 -
10 mg/kg/day, preferably 0.1 - 1 mg/kg/day. The daily dosage can be
administrated in
one to several divisions.
The following examples are provided to further illustrate the present
invention and are not to be constructed as limiting the scope thereof.
Abbreviations described below are used in the following examples.
p-TsOH : p-toluenesulfonic acid
27
CA 02483020 2004-11-03
DMSO : dimethylsulfoxide
Me : methyl
tBu : tert-butyl
Example 1 (Method A)
~I ~I
Process 1
H2N~COOH ' \ / \ S02-N~COOH
~/ H
Ia-1-1
Process 2 / \ / \ g02-N~CONHOH
~J H
To a suspension of (R)-(+)-phenylalanine (compound XV-1, 1.65g (10 mmol)) in
50 ml of dimethylformamide and 35 ml of water was stirred and treated with
2.78 ml
(20 mmol) of triethylamine under ice-cooling. Then, 2.52g(10 mmol) of 4-
biphenylsulfonyl chloride in 10 ml of dimethylformamide was added dropwise to
the
mixture over 5 min. After the reaction mixture was stirred for 2 h at the same
temperature, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 2.1 g (11
mmol) of
1-ethyl-3-(3-dimethylaminopmpyl)carbodiimide hydrochloride, 3.47 g (50 mmol)
of
hydroxylamine hydrochloride, and 7 mI (50 mmol) of triethylamine were added to
the
mixture. After being stirred for 16 h at room temperature, the reaction
mixture was
poured into water and extracted with ethyl acetate. The organic layer was
washed
with 2N HCI, 5% NaHCOa, and water, and concentrated in vacuo. The residue was
subjected to silica gel column chromatography and the fractions eluting with
CHCIa I
MeOH = 4011 to 20/1 were collected to yield 1.70 g of compound {Ib-1-1) as a
foam.
Yield 43%.. mp. 169-170.
Elemental analysis (%) CziHzoNz04S
28
9.
CA 02483020 2004-11-03
Calcd. : C; 63.62, H; 5.08, N; 7.0?, S; 8.09
Found : C;63.61, H; 5.12, N; 6.98, S; 8.06
IR v max (cm-1) (Nujol) : 3365, 3295, 3266, 16?4, 1320, 1159.
NMR (8 ppm) ds-DMSO : 2.61 (dd, J=8.6, 13.4Hz, 1H), 2.80 (dd, J=6.0, 13.6Hz,
1H), 3.80
(m, 1H).
[ a JD: +18.5 ~ 1.2 (c=0.503 %, 25~.:, DMSO)
Example 1'
Another synthetic method of compound (Ib-1-1)
p-TsOH = _ Process 1~
H2N~C~~CH2Ph ~ ~ ~~SO2-H~'CO~CH2Ph
XV-1,
Ia-1-1'
a
Process 2 ~ ~ / \ ~ Process 3
~S02-H COOH ~- -1-1
-~ Ia-1-1" /
Process 4 ~ l Process 5
S02-N~CONHOCH2Ph
~.l ~J H
XVI-11
Process 1
To a solution of (R)-phenylalanine benzyl ester tosylate (compound XV-1', 2.5
g (5.85 mmol)) in 60 ml of dichloromethane was added triethylamine (1.8 ml,
12.8?
mmol) and 4-biphenylsulfonyl chloride(1.63 g, 6.44 mmol) under ice-cooling.
After
being stirred for 2 h at room temperature, the reaction mixture was washed
with 2N
HCl, 5% NaHCOs and water, and concentrated in vacuo. The residue was subjected
to
silica gel column chromatography and the fractions eluting with CHCIa / MeOH =
40/1
to 2011 were collected and crystallized from dichloromethane / hexane to give
2.32 g of
29
a i~
CA 02483020 2004-11-03
compound (Ia-1-1'). Yield 84.1%. mp. 130-131.
Elemental analysis (%) CasH2sN04S
Calcd. : C; ? 1.32, H; 5.34, N; 2.97, S; 6.80
Found : C; 71.05, H; 5.41, N; 3.00, S; 6.81
IR v max (cm~i) (Nujol) : 3352, 1732, 1341, 1190, 1163.
NMR (b ppm) (CDCIs): 3.06 (d, J=5.8Hz, 2H), 4.30 (dt, J=6.0, 9.OHz, 1H), 4.89
(s, 2H),
5.12 (d, J=9.OHz, 1H), 6.98-7.81 (m, 14H).
[a]n: -I6.4~ 1.1(c=0.506 %, 25~C, MeOH)
Process 2
A solution of compound (Ia-1-1') (2.28 g) which was obtained process 1 in 50
ml
of mixed solvents of methanol I ethyl acetate =IIl, was hydrogenated using 10
% Pd/C
(200 mg) for 25 min. The reaction mixture was filtered off, and the filtrate
was
concentrated in vacuo. The residue was recrystallized from dichloromethane /
hexane
to give 1.83 g of compound (Ia-1-1"). Yield 99.1 %. mp. 146-14790.
Elemental analysis (%) CziHi9N04S
Calcd.: C; 66.12, H; 5.02, N; 3.67, S; 8.41
Found: 0;65.97, H; 5.06, N; 3.61, S; 8.48
IR v max (cmn) (Nujol) : 3408, 3305, 1751, 1325, 1161, 1134.
NMR (b ppm) (CDCIs): 2.97 (dd, J=7.0, 13.8Hz, 1H), 3.14 (dd, J=5.2,
14.OHz,1H), 4.13
(m, 1H), 7.03-7.78 (m, 14H).
[a]n: -4.0~0.4(c=1.000 %, 25'0, MeOH)
Process 3
To a solution of compound (Ia-1-1", L0 g (2.62 mmol)) which was obtained
process 2 in dichloromethane (20 ml} was added 0.33 ml (3.93 mmol) of oxalyl
chloride
and one drop of dimethylformamide. After being stirred for stirred for 1 h at
room
temperature, the reaction mixture was concentrated in vacuo. The residue was
dissolved in 10 ml of tetrahydrofuran. A solution of hydroxylamine
hydrochloride
(911 mg (13.1 mmol)) and NaHCOs 1.54 g (18.34 mmol) in lOml of tetrahydrofuran
and
lOml of water was stirred for 5 min under ice-cooling. To the mixture was
added the
~ .a
CA 02483020 2004-11-03
above solution of acid chloride in tetrahydrofuran and the resulting mixture
was
stirred far 30 min. The reaction mixture was poured into water, and extracted
with
ethyl acetate. The organic layer was washed with 5°r6 NaHCOs, and
water, and
concentrated in vacuo to give compound (Ia-1) (969 mg). Yield 93.3 %.
Process 4
To a solution of compound (Ia-1-1'", 2.0 g, 5.24 mmol) which was obtained
process 2 in dimethylformamide (20 ml) was added 1-hydroxybenzotriazole
hydrate
(0.? g, 5.24 mmol), N-methylmorpholine (2.9 ml, 26.2 mmol), 1-ethyl-3-(3-
diisopropylamino) carbodiimide hydrochloride (8 mmol), and O-
benzylhydroxylamine
hydrochloride (1.67 g, 10.48 mmol}, and the resulting mixture was stirred for
6 h at
room temperature. The reaction mixture was poured into water and extracted
with
ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCOs, and water,
and
concentrated in vacuo. The residue was subjected to silica gel column
chromatography and the fractions eluting with CHzClz I hexane = I/l were
collected
and recrystallized from dichloromethane / hexane to give 2.04 g of compound
(XVI-I).
Yield 80 %. mp. 171-173.
Elemental analysis (%) CzsHzsNz04S
Calcd.: C; 69.I2, H; 5.39, N; 5.76, S; 6.59
Found :C; 68.85, H; 5.46, N; 5.76, S; 6.78
IR v max (cm-1) (Nujol) : 3248, 1661, 1594, I333, 1163.
NMR (8 ppm} (CDCIs): 2.85-3.60 (m, 2H), 3.86 (m, 1H), 4.77 (ABq-Apart,
J=11.4Hz, 1H),
4.82 (ABq-Bpart, J=11.4Hz, 1H), 5.00 (m, 1H}, 6.95-7.70 (m, 19H).
[ a' ]D: -40.2 t 1.6 (c=0.505 %, 25'L, DMSO)
Process 5
A solution of compound (XVI-1) (1.97 g) which was obtained process 4 in a 60
ml of mixed solvents of methanol / ethyl acetate =1/1 was hydrogenated using
10
Pd-C (200 mg) for 3.5 h. The reaction mixture was filtered off, and the
filtrate was
concentrated in vacuo. The residue was recrystallized from dichloromethane /
hexane
to give 1.35 g of compound (Ib-1-1). Yield 84.4 %.
31
CA 02483020 2004-11-03
Example 2 - 91
The compounds which were shown in Tables Z to 22 were synthesized in a
manner similar to those described in Example 1'
32
CA 02483020 2004-11-03
Table 1
~ N = C~7 O ~ pip IV ~ OD n N
tV -~j N N - ~ g N = 0 ~rj N Z N
_~_ _z Z ~ n Z ~r ao
p, ~ $ O x r r ~ = II
O
G' ~ !V Np N N ~ N O IV N ate"; N r T3
i ~~ z~? o
a ~r
~~° r=N ~~ r ~Z t'~
r 'd' N Z_
,~r In Z h" N n ~r O N ~ = N = _ ~ N N
t~ ~j 0 ~ N N ~ O =
~; N ~O ~ ~t 'C r = ~ r ~ E C) '~ T N
r. Z ch N '~ ~ pj r C~ N ~ ~p 'a O GD
II
a0 ~ t0 a0 N O N ~ ~j ~ tp N r t0 '7
N 7 CO CD ~ CV to ~ ~ .Q N' CV ~ ~O II ,Zy
N '7 ~....
M
r.
f~~. ~ tC7 ~ l'Oh C'N~ ~! 3 COp
r r ~ r ' r
v ~ Oi W th r 0 O N
? 1~C~0 (per ~ ~~ O ~tD 00 O~
W r tO r Gg r r r ~ O '~ N r N C'9
r T ~ r T N r
r h. N N t~ Ch r
N O~
tN ~ ~ M ~~ Mr ~ ~ c'~~T 4jcr
~r
Z
Z
U a ea c~ r co
~.~ * n o N at c~c sM.
M N ~ r r r r r
s~- O N M ~ N
N r r r~ r r
ac# '~~~a'~~~'a,'~. x
I
I~ !~ I~ I~ I~ I~ I~ w
Ir
I f I I I I I m
r r r r r r r
Z N
Z U S N
N U N U = N
V =Z / \ V ~ = Uo' U
l \ / \ I r
cn / \ ~ U I
o I
U r
z
a
z N M
>e
I I 1 I ! I I
33
CA 02483020 2004-11-03
Table 2
T c~9 Z
N
O Z N N '!7 ''~Ov.. N ~ OC'~D N
_t~_ ~ Nip ~u~.j ~N ~ ~M_ N=
Z2 ~ zv,= N~ ~!~ ~ cv= TP_
P
N tn P ,C =
o» E E ~ -~ E ~° r- ri ,- r~ cc ~-
N_ N~ _~ _~' _ _~?_
V PP e0 G'7 tn _f'9 M N _~ __ ~ N. N
"~r MN = NM..:
=N N ~~N '~I r= r=N I~~r
~C N O ~ 2 N O r' ~ P ~ ~ P = ~ ~j N
c~x ~"~ ~= O H o~S ~_ ~Z'~ Nice
07 N O ,.
P
C~j ~ ~ ~ ~ tl OTp = ~j ~ T' IV ~ ~N', O
fV ~ O ~ ~ - ~ N 'C t- O = ~ r. P~ O~f 'C
t0 .p' ~ P P .V ~f! ~ ~ II
N ~ 09
~ CO CV t~7 ~ = O = ~ ~ - O !~. ~ ep N = CD
N !~ n, ~ _t'. N '~9 ~ II = II ~ N r !9
N '7 P N 7 ...
C tN~. _
N
c~
P
tsr ~M W ~~ O C'N~ M N
N M M T O O ~ CO P9 C9
r P .- .- r r-
NN NN Of~ Or r
_ ,p ~ O N M tD f0 N tp _tn N (G ci OP
~/ ON rM ~T ~T ~T N'~
N,n- OeP mO Is et t0N c0f~. Nr ct0
Nc~9 Nf~ NfN Nc~~ N~ ~r
M T CAS P (~ T (~ T ('' P (Y~ P
T'
U ~ N n ~ M ~ ~ w
~~ * O i1 r C~ T 1~ !~ T r T
U
Cfl OD '~ CO In N tt
O r ~ r ~ r r
N O, '- '°
.>E x r~ x ~ ~ ~ ~ '~
o ~ ~ ~ ( o 0 0 0 0 0
I~
N
0 0 0 0
N
Z Z I U = w Z U
U U ~ U U = U =Z
N o
rx I o ' .~, ~ ( o U z / \
ti ~ i ~ l \
U
O
c~
Z
a~
C .-~ N c~'~ d' tI~ c0 C
~z
x
W
CA 02483020 2004-11-03
Table 3
tai
°' = n~ o E ~ oyd' °9 ~ °~ c°
i-. N r N t~ Qy et ~ _N p N 7
_ tl N ~
~ r N ~~,- ~C Q~ T 'O
r ~ r ~ r
~ ~t = ~ = tf7 ~ 1I7 ~ ~
n, C7 -N M N _~r _Oj= M=~
r= N= '~ N ~r r
cc= ~ ni E~ tech ~°~ t~=0 ado=V
amo '? ~ o -'- of ~ ''- ri z
T Ch'C= C~j$ OII= ~rU ~~-r
~ N ~ ~ N O N ~ r ~ CO ..~ ~ 4l7 ~
N ~ M ~ _ ~ ~ GV ~ N ~ ~
N "7
'~ O
N
~p m
r r ~ ! r r r ~ r _~ N
O~ ~ ~~ NN t_p~ .ar _~~
~ ..?v ~~ I r ~_M ~~ ~~ O~ Otn
C9 r (h r er C9 N ~
NN U'OD~ CAD t~~ O~ Nr Nr
~. ~° ~ ~ ~ r (~ r
O Mr c'o~
Z
Z
O y
O
* ~ T '' _~ _OOf O
' ~ ~ CO n N
!~' r r
~/ (n r
Ca, '' '' ~ N
I~ \ y
r ~ r r r r I ~ . r
Iw I~ i~ i~ Iw (\ z o
r r r r r
N
U U N U I Z N N
zZ U Z~ =U-Q V
w -'~ ~ I ~ r r
/ \ / \ I , / \ i ~ ~ ~ I ~ I
z
CO 3~ O .-i N M er i.f7
O
.-r .-. N N N N N N
W
CA 02483020 2004-11-03
Table 4
II
Z ~ N
~ Q n r ~ ~ ~ _
.V N n u7 c0 V
N= ~c,~=O ~aD~~ N_IU N_r
Nnp~ _ ~= N~ _..: = E
° W= =rm~ r'~ rr
NO Z=~ N~ Nip
~ e~i = E °~ in ~ ~ s c~ ~ ~ ~ _~°? ~ ~ e?
- p~'ao n co
rN~~ ~ '~ Nm O M _~ aD r
r ~ r r
O N rc9C= Is~= II O N O N
r N
'CSD o~pi=cNO__ ~__~' ~~O ~N
tai -~ N z o .o ~, n co '? tj ~"~
'D r ~ ~ r
'~M ~c=oNniWv°~n: -.raccU ~co
O~ t_i=~ N<~= Cf~ ' ml'.
N ~j ~ ~ aC N c9 aC ca~IN N I~ Z N '7
O
n
m mr N r
M
~D
N r O r r
N M~ i ~ ~ r
r '~ M ~ ~ d N O ~ ~ N ~
r
y.?r O ~ O GO ~' CO N r f'~ r
OM O~' Nr Nr r(p
Nth Nr Ols O~ Or
~m ~M ~r
° C~ r ~ r
cn~~ T
O
_ U ~ _
c~ N
cg ~-~ ~ h O O fp
~C ~ O ~ ~ N ~ ~ 4
z
N CL r r
'~' ~ ~ ~ W ~1
x I ~ I / I / I .~ I / I ~- I / I
Z
u. o ~ i I .- I ,~ I / \ I
CV N
U U N U O U U
U ' _ _ /
cx / / O V O U \ I =Z -
\ I ° o = / v
\i o°
x
cD C~- 00 07 O .--i N M
O
x Z N N N N ~'7 M C9 M
W
36
CA 02483020 2004-11-03
Table 5
T
/~
N
N
'C
N
G?
00
N
N
h
co ~,
O
~O
O N
N~
O C9
O~
(~ Y
A Y
Z b ~'~, ~ r'
Z ''' d'
N C,
x
t
s'
m .,,
U U
- Z
'~.' =Z ZT
a~
6
m m
x
W
37
CA 02483020 2004-11-03
Table 6
~N,-_ .°
o~ _ ~° cMrr _ p ~o ti ~ ,- a
t = N '" ~ t7~ t'' n, = M ~ ap E '~ t~7
.; O _.. M ~ p - o 'fl
'~ nj=~~ ~_~ t~ ~ljj M= T= ~'j
o, zE°-~l°,N zE° ~.., _" zE E~ _= n;'
r. , = r r r .C r
~ N ~ ~ ~ N O r m N ~ = N ~ t!f .~. N ~ 6n
~" pate p~:= t'~ ~_~= t~'~L_'~ et~_rj ~= r
,~-=r = M=~ M= i~: tN07 ~et
N r ~ r T N Z ll
"~ O ~,j = O p t,,~ ~ '~~ nj 11 1~~ nj = - r N '7 N ~
~~=7 ~O~ ~ It ~~' at t'=9 N OZ NN
~O ~~r ~ ~ = OO
~,~~.-nj~ 'Cr - C'Z brr bra (~jpj ~CD ~f~j'~
in -uj' c0 ~ O = tC~ r ~ In 00 ~ ~ ~ O' 11 M - O r _
fi~p~ ~m n"~ ~lt~ w ~~f? ~~ ~= W ~
N '7 .,.... It ~ t1j ... r II z l' II ~p ,N tr1 r ~- r E
CV 7 ~~. C~ '3 r CV 7 v CV 6W ..
O M O eF 1~
M ~ N
r Z w ~ r ~ ~ ~ M
V N
M" ~ M
r r_ O ~ ~ ~ N ~-_._ - o f0 (~ CO ~ r
U ~O
O ~h O CO ~ M CC tt7 ~' r ~ r r r0 O O)
t0 CO M r- t!7 r O ~ ~a' f~ CO O ~ Q) ~ M
... i-r N ~ M v~~ O '~! M r ~ C9 N N N ~ C9 r
Mr Mr Mr Otn
Q M~ MC'' N~ M~ N~
_ U ~
r o~ Ire
v ~ C~O N W N N r !T O
d
.~ C1 tv r ~ t'7
..n T N 00 O N ~ t~ O
r r r
C_D
i~ ~ '~ '"~ x x ~ x
.- .~ .~ i ~ i i w i
x z
i ~ i ~ ,.~ ( ~ w ~ y y -~ ~ i
w w a r i i
Z N
U Z '
N
N U N U ~ = N
=z / \ U W z = v
04 .Z.J TZ ~ / \ / \ ~ ~ V W
</ J co
vo /
U
Z
_d
w
38
CA 02483020 2004-11-03
Table
T
_ _
N ~ ~ r = N r r e.,
N r ~ C~ ~ N = _
N CD C9 N N
nj r Z_ E ~ ~_ ~ _ '°rn ra
U 'N z 7 N ~ C~ ~O ~ O ~ !~ = M et
'4 ~ M i' 'O = t"7 'C '~ e
A N.M-~ ~rj=~ l~ =C~ ~ N= N N
D ~ CC N = N CO ~' ~ E N ~ E
ai z E ~.- co
n ~z cn=o N'' ~= cvi~ o00
E ._'~' ;? ~ T- sz ej _~ M ri y c? t!i
t0 et N ~ ~rj ~ ~ N O ~ m CD N
CO r- O ,- d CO O N N OD N M
N M 'a' n' aij !~ O CD N ~,j
GV "7 Q7
d
O _tn0 C00! C_~JO ~ nP C~7
Pr PP r
Pte' Y 1" P T
_ P_ .- r .- .- r r (» N tC) N (yI7 .-
H et OD et st CO tD et T N M ~ M !- 01 L
N_tn r_N ODN O~t CrJr rt- ~a ptn
r- T M T ~ r C91~ Of t~S OQ OD O
P4' t? tn ~1 Ci O> 1t1 N N M C9 N s? ~ T c0 .-
r ct N O r~ CrJ t'~'~ CD M r C~3 ,- M r O tCl
r-M ehrn Cnc') ~det Nt'~0
M '_' M '' N '°' M '' ~ ~ O O p ~ N ,-
Q Mr MP N~
Q
U ~
M ID ~ MO O T In O
Z ~ '~ N ~ OD r. ,N- N
d i
~v~ r m O n ~ O
N r r r N r r
~_C
li it !~ I~ ii li i~ ii
x
~i 'i ~i I~ !~ !~ ~I ~I
_ Z ~ N
N
Z V U _U = U
U
o U ti z =z =z U z
I i ! / \ / \ i ~ va
/ \ _ / \
N li.
Q
M ~' ~ tD t~ 00 O
C
c~ z ... r, ..., ., ..., ...~ cv cV
w
39
CA 02483020 2004-11-03
Table 8
7 ~ M h N u'1 _
C~ 0 ~.. N ~ ,II ~_
Y O = _ _ '~ _ ~ r Z _E W
~Y
a' Y N T O r" CO Y CO N
I Z ,; N N N N CD N ~ II N Cn ~
r r ~ ~ ~ = N ~ 6'9 =
A N .Z~..~ ~ _ ~ _ ' ~ = N ~ ~ d' T = fj
M ,.~ ~ ~ N N O nj = O ~j = ~ r ~ h n
x ~ _ ~ _ ~° 'd' a ~r' E '° oa ao ~ o~ _ ~ ~t' o~
N ~ N ~ 6p ~ ~ O -9 N il N '? ('.j II
O Z ~ ~ r ~ Y ~ ~ T ? ~ ~ ~ T
r- N Q9 et ~ O ~ O M ~ ~!' ~ ~ h O ~ Q7 ~
CV '7 r ~ N M '7 CD M ~ ~!' CV 7 OD
tN0 CMD
N Ltd CQ (D '- '- M
O r N v- r
~ M M MM ~~ ~O
_ r r r ,- MN Mc'~ O
~ f_9 ' M h
'~' ~l7 C9 ~ LCS O) O O Q M O C~?
_ ~ CNr ~Z ~r0 .h-Or O~ O~
M .- M r M ,_
Mr ~ ~ 6Mn IJ o~ Or
fr7c~ M~- Chr Nr ON O~
Mr M T MT Mr NN NN MCO
NC9 NC9 ~r
0
O
U
p~~ * ~'" eo a~ c~ h
r CV ~ ~ N Qy O
N
r ~_ lf5
N ... T f;! T ~ N
.>E ~ ~ Ix x x x x
Iw iw Iw Iw Iw Iw Iw
0 0 0 0 0 0 0
x
wl wl wl to (o to wl
N N
Z U U
_ =U o W f~ = U o / I
~ ~ O U O w
~ U Z o U
o z z wI o
z
_~
N ~'~7 CO 07 O ~-a N
C
~ ~.r N N N N M M C~7
x
CA 02483020 2004-11-03
Table 9
-o _
"a N
r
~ II
_ '~ r _
~o v~ = coo ~ et
'.. ~ ~'? o Z
A '~_,_ N
r r
II ~ E
~ r ~ P~.
~ r CO r
C7
II =
M 9 r
O 1~.
r
r L
v t~.i OJ r .C
C7 r
~r OCp
'/ r r
Mr
NN Ot'~~
NM
Mr
Nr
Z
U ~
ca co
N r
d
ly N r
a0
oc
'' ~
1
N N
U U
Z
4L~ =Z Z
_n~
a' ~° m
d
m
x
W
41
CA 02483020 2004-11-03
Table 10
~o o°>Nm c°~'r~°
cc r~ cc c6 of of
ire i~ iri iri ui ti~
'A °as oo po:-'
co sci cc cc p v
pZZ pzz Uzz
i I zoo =~0 1 I I ~a°n°~
~ Sri Sri ~ Sri ui yri ui
d ~=S :'__ ~ pZ=
~r9sn ~oc~ o~r~
~r.o. o00 ~o>c~
ZcNDCNe ZcNO.m Z°ic°a
NU U <<""U U ~U U
= v c Z ~ c Z ti c
UUti UU~ UU~
~r .- .~ ~ ~t c~ ~ o o a: eo co n. st m
yn cc o u~ a7 ~ omn er a9 n u~ v o co
v y~, M T tn T It7. T In T C~ in 1- (p f II) !-
T r T T T '1o T 1~ f T T T T T T
N ~ P ~ ~ ~ ~ M M N ~ t
'-' NN f90 00 NN OD CD NP. et0 rM
W h. M t~. et W N P~ f0 ~G ~- t~ M 1~ f~ P M
H T T T T 1~ T r T T 1~ 1~' T T T 1'~ T
r I~
_~ 007 C~~ O~afP7
T C7 T T T T
O GU T 1 1
O °',~° ~ ~ o°~ ~ Q CPO
!' T i Y T T
?a
P»
O
sc
a
(/ I I/ (\ i/ w
/ (
_ /
s / /
/ ( ',- ( ( / o I / ( / ( / ( /
w ~ O ~ U cn /
_ = z
N ~ N
i V ~ ~ U U U U U
Z
_ N _ O _ _ _ _ U
C~ c~ Z U Z =Z =Z ~ =Z ZZ ~ =Z i~~
Z
U
\ / \ / \ S \ ~ ~ ~ \ / \
_a~
0" c0 C- CO 07 O .-., N M
C
1 M ~'7 cY7 C9'7 cr d' d' V'
W
42
CA 02483020 2004-11-03
Table lI
N O~
r ((~
r0 ~ l~ M~ CND
OD CD n 1~ ~ N CC CO
(~ fn fn il3 C7 07 Cn f~
!'~~ N M M ~ OS
.-,~' M C9 6'~5 t9 Z ~ N CV
C ZZ ZZ etao zz
I I ti: ii f I = N o
M~cc Mui~ci toy ~~~ri
ozz ozz ~'" ozz
Sri ui
~a~oa'to ~~~ Zz ~.rno
W O ~ ~ O c~°o c~°o ~..- r.
O cc o5
z .. .. z .. .. orr zmm
~~,UU NUU Z~~ ~jUU
~ zcn ~' ~ ~m
UU
UUti UUti ~~y ~ UUti
U U ti
~m ~ n ~i~D r~3 ~ ~ N
Mr Iwr M tCr M M M M
rr rr r rr r r r r
> eY CC e! et O aD le Qi et ~ T N u7 01 O C7
N N M N P. d' r et t0 CS tp N tn In In
I~ M rw M (D r f~~ M r tD r t~ r f~ r
f"1 r r r r T 1~ r r r r r r r r r r
"'y~1
Gf et 115 n d' ca GD N
r N r r r r r N
1 1
O r
V ~°. ~' ~ ~t ,i ~ ~ aMO aMO
r N r r r r r N
~"~
z
dE P,' P.,' Per t~' Ct~ ~ P'r iY,
O
ao
I
I~ (r (~ Ir i~ I~ it r
r
i
x I r I r I .~ I ~ I w ! s I ~ r
r
r U O U O r
m w I eL z u. z z w I
,
, , , N N
U U U U U U U U
N N N N N _N
M M io M 07 M
U U U U U U I , I i
~r m cc ~ 00 0~ o ..,
0
k Z ~ ~r tr ~r d~ m ~n
W
43
CA 02483020 2004-11-03
Table 12
N f~
lI5 d'
cD ~O ef eF ~ f~'J
r r r r
M F3 ~O ~G ~ N
OzZ ~ZZ
w i i z c~ i ~ ~M~ ~c~V
N ~ t!> O dw? ~ et M
a~ Q = = N= = 0 et ~
O m tLi N GC CG
Z ti') tn z ~f! ~ ~ ~ tl
NU U °°U U z_ r.: n.
Z ~ c 2 ~ c U
UUv° UUii Z ~ c~
U U li
~ c~'o ii c~~~ o .Nrn c°o M
C'9 Ln r Ip r (~ G~ C~ ~ r n
r r r r r r r r r r
rr
? In CO r O ~ f'~ <O e1' C1 tn CO r V~ C9 r Is N
~D Gfl O~ tn ~' N et ~O et c0 -_ __ ~'Q V' N
~r ~~ ~ ~r (ar ~r ~~ ~~!"
r r r r r r r r r r r r r r r
O N tn O O O M
co T o9 a~ r a~ ~t
r r r r r N N
b 47 r ~ ~ ~ Pe ~ N
r ~. ~ O O O N
z
P: P: C~ c~ P~ ~,
O
/ ! ~ I / ~ / y ~~ i y
w w ~ ~ / I
I/ I (/ I/ U ~ /
/
U
Z Z Z
v Z ~ u7 N N
Z ~ ~ _ U U ~ V U
U U U U _ O _
x w w ~ ~ =z xz - ° z =z -
I / p p U _ _ - -
\ / \ / ~ ~ \ /
N M ~Y' ~ c0 t~ 00 cn
C
x ,~., tt) tn ~ ~ tt~ tt7 tf~ t17
W
44
CA 02483020 2004-11-03
Table 13
'wC O '~O,V tJ '~0....~ nj 'gyp... ~ ~ ~ tt'j CPO
M ? Z . Cs
N ~ N N 1~ CV n ~ N Z .~- N
a _~~ _~ _~ ~ _~ r:Zv~ =a E
r r ~"'
ep Tl1 N f~~. ~ N ~ _ ~ _r = f;D _ ~7 ~t N .r IMO. CO
M ? ~ C~ ~ ~ = N _~ _ ~ (Cj = e~. (h
_ ~ _ O r '_fl t~ N
$n' ~ r ~ M
r r r ~G ~ ~D
t- N ~ ° N °' z '°- r°.'' i N
°° ~ ~ ~ a sr m = a r~ ~ ~ ~ -~ n ~
? .~ _ ? ? ~ r M M ~ ? d' ~ c? _
r 'C r r ~ 'd r 1~ ~ ~ r P'
_ _ ~r
~ C ~ ~ O ~ m N c0 O ~ O ~7 ~ _N ~ v_ ~O N
mm~ ~~~ P~M PN PO~ M=P P
II it Z N ~ P ~ M N ' '~ CV r C9 nj -7 <G N ~~
N ~ Ot~ N "~ r
N
P N vt N d~ N et N sf N' M
M ~ 1I~ K ~ t tar MM
tn r
,,r r ~ r ,- rr rr rr
~,In- (MOB ON PN ~N
C'7 M f9 f0 M
r rr rr rr rr rr
~' CV r N t~? <O tn t1D t0 '~'t O tf) 8~ P~~'CO ~ t'N'
Om O ~_f5 ON mCh rN O~ rpp rr
Mr Mr ~~ ~.~- ~r c~tt
C~ r
C~~7 ~
Z
_ U ~ M r
_ r
Z .~~ o ~ I m I I I I
.. ..- v
N GL ~' r
x x ~ x
Iw Iw Iw Iw Iw Iw Iw Iw
i i ~ s i i i
0 0 0 ~ 0 0 0 0
wl w! wl wi l~ I~ I~ I~
_N _N
z V U Z
U U U M
U
U U ~ xz -. v
x 1 ~ =z xz ti ~_z / \ xz ~ ~
/ \ ..- / \ / ~ / \
U
d
o.-iNC~dmncot~
0
ca co co co ~ cc ca ca
W.
CA 02483020 2004-11-03
Table 14
i
'~C~m= ~ o.~ ~ W ~ r ~ W
~ 'n N o co r ao ~" ~ = z E _ao
r
1
~!~~ c~?r=-.g Z '~~ N c''? CD Z S
r = v. f~ r N
W
c, ~ ? ~ °~ ~ oa ~ ~° ~ = E E
oMO :'~ ~ °- r~ ~ ri N
...~ to~'?co N~_'?= ch =_.p Z ~ ~? ri
= N ~"~ N OD
r r CO r z Z N N 1~' O = _ ..~ O
~C ~ N .~ N S = E '~ O = 0,9 r N =
C9Z= h=COD E pj ON~ rte- it1 N
~ c'~ _ ~ ~ Or
~ r n 'p r ~j W ~ N c0 ~D ~'° c0
= II M W Z
CV~W ODN= ~'7 Often NM M? ~~ r
t~ n. pp t0 W W nj N ~ 1~
CV ~ CD CV '7 ~ N ~ ~ _ ~ et M l11 ~ N
M r
N CD
M
cu~''~ ~' ° aWO cMO ~ ~ m~ o~
c~ m ,~n° ~ ~ ~ v I,n v .- m r
rZ r r r r rr rr
~ r
e! CV CV N N M tri M N eF f~ ~t
N W OD oD CO rfi N ~ W h.
iw M ~ 1~ r tn f0 ~ r 1~ r 1L7 r
,~~, '', r r r r r r r r r r r
v~ 00 mr ~N Or ~aD ~"'f~ tflt;C NN
h. M N I!7 N t47 N 01 C~ W N W et et
O O N M P: r t~~ N I~ r N r h r- f~ C7
h"~ ~T ('f'r rr rr rr ('r rr rr
NN et CO ~r ~r triQj ~pr
r('~ LnW 1~M OM rN WCD
d, r' cC ~ C~~ M r c,Ni,~ T ~ M st Cr7 N LA
Nr r Mr Mr
U
,..~ o ~ ~ ~ c~
r I i I N
N ~ ~ O CO O
T' l'r' N
_ab
c~ x c~ x
\ (\ ~\ ~\ ~\ ~\ ~\
s / / / / / / / /
N
N N
U U = V _U U co U
Z
U _ _ UN M _ =Z U
\ =Z ~ U ~_z / \ t ~
/ / \ / \ -- / \ / \
U _ $ L-( U
o ~ cv m yn co
0
e~ z co ca co cca co ca c~ co
t~
46
CA 02483020 2004-11-03
Table 15
(o r
N
N N
r !~
Cj T
I M ~ I
d
N= I
oOhO~
W Z t~pn. ~
N<3 U
c
UUu°.
.~ ON Mr M
tMf7 N f
V i.a
r r r r r
On.
T ~ M r'~ r
r r r r r r r
O
I I
tL *
O
OC
I , w w
i~ I~
0
0 0
I ~ ~ w
I~ I~
0
z
_N ~ _N
U Z
U U Cj U
_ N _ O
- O O
x =z ~z Uz
v o ~ o v o
0
0
~z
x
W
47
CA 02483020 2004-11-03
Table 16
_ __
Z m~U
N ~ r 0
V IV ~ W N ~ NV
.:-, x~x E =m~.
m m NQN
I i CO O~ tf1 :n. ~D N
N ~ N oo cu ~~ o =
a o~i= ~_~ N - o?I:m
C4 p - -,~ - n p r W
M = ch ~. h
"N~ N NZ9 ~r =O'~ I
N PI P x ~ _ ~ I r .- Q
Em
,~', ~~~ _~~ on ~ii~
N "N C~ C7 x 1~ x _N n ~
e~Om~ fO~r Il r x~~
tp CV ~ 11 N V E r
~i_ __ ..~r'~C ~ E ~.
O N N
0~D ~ r~°° ~ ~ C~0 = N
E x o cei x
C n ~ C tV CD tV E Ip
c~j
h
O N
r
COO W ~ NO .S? tN lOl1
... ~ r
I O N I
ooc~ o~ ~V oc~
W.. N .C'7- N ~ p N~ N M
_ N r
N r
N
x C9r Mr ~N C'~r
p M
r
U °'
;~ _ T co
Q _ _
x b ~ °~ .o .n 1 ~ I
N O
N C1.
p
x
!~ ! ~ °_ I~ I
t x
tx N U U
z U U ! i O
p U
N N
N N ()
_ U U U U
=Z / xZ
i ( i ~ i l \ ~ ! l
d
...
a' .~r N tYJ Wit' tf~ cD
C
h n N N n n
W
48
CA 02483020 2004-11-03
Table 17
c~ Z
P r.,
O
P ~ ~
_ CV '~ ~j Of C9 4i
~. ='~D~~ N_
G ~' p. tf7
rQ U~ = CO r N m ~
~ ,~., et ~_ ~7 = ~ r
f'~ _ "O st N u:
,~ P r 6O th ~ r
tn pj In r f~5 O
CO = ~D to ~
~~~_ ~_~
~ r ~ N ~r
N
O ~ ~t
C9 O
N '~ CD ~.. ~ O
N O M
N O
r P1
M~
L r L
r .a
~, O N O aNf7
~ O N r
'-' ~,' N r N s
O
O N O ~
M~ ~r
0
Z
z
U O
~~ * O ~. ~ O
Z .d CO W ~
O
N !3~
N
x
N
Z
U
U U _
SZ
_d
°' ~ oo a~
d
~Z n ~ n
x
W .
49
CA 02483020 2004-11-03
Table 18
,-
~D r. _ ~ ;-~ -i'~ ~ ni 1~ ~rj ~~i = ~_., x ~ n1
wN~- cvi~U ~xU xr ~c'!~- -~xr
CV x N ~ W a = ~ LCD ~ ~ 'O ~ r
,N~'~U r6r7~ ~" .. a 11N ~(~ N
N~aD N~ NaDZ =~~ ~i ~~ 101 pail ~ P
pj II E '~ x .:d O_ tA ~ '3 °7
~ V' I -"D r Rj r ~ x ~ M
o, m u'° ~.t E o?= T~~ Nc~r
G1 t~ ~ ~ ~ CV N ~ Is fp ~ C'7 = x x .~~. O ~ ~ r Q ~ .-r C'r~ m
.:
coG ~o= ~_z~ ~N~ ~=E t's= z== ,x,.o 0
N ..~ N. _!~ '~ '' N COD, r d N N ef- I' ; C- C-
,~ N = x=x =x ~p~~_~p ~p~ ZEN rZ= ri ~CO
_=N MOD ~ !~'Y°~.p r 11 °'_ ~'~~~.ju7 N'"r
I~j M pj CD N C"7 IV N O r x '7 h
=x0! ~.r_~ x~= t~~jr- ~~'= nj~~ Ilx~ G)M
nom ~d r r ~ 'V II r 0a~~ ~~r ~ $ ~;
II ~ _~ r' r E = X11~ V Q? ~ 1I yt ~p 'D M O OvD ~r
~O~ ~~x ~et1! N~~ O~~ ~ '~~~f tDM'~
r w Cr9 v ~ (p P7 ~ J '~O r CO
O~N ~~ r~
C ~ ~T_ O t~ Cx0 O 'CJ x N N N N N N II p y..l
T
_ ~ ~ ~ ~ N ~ !H
N
N O ~ S? ~ ~ r r tC9 CO
s~~ M O ( 7 x ~ : - O C~ sf f~ -_ -. M~ tN ~ N M
,~ U O r OD tf1 C) tn s_' '_~ v ._~
00 ON ~~ TT rr O~- ON M N
~ M ~ .~~- O In N N ,M- ~ O ~ ~~r c0~1 H
_ _ _ _
O M_ O ~' M ~" M r C9 r O I!'1 O r .~.r LO
Nr
x Cph OM ~~ NC7
Nr N.M- Nr Nr
U ~
N
x ~~ r - ~ ~ ~ i i v
z ~,~ r 'o ~ N
N ~ N ~p A ~O
r
E_D
t9
x
N
~ Z
a / N N (n z V
,~ « , ,
z o Ie wl
U U
U U
N N fV
x x r x
2 T ~ U U ~ Z U
_ U U U _ _ U U _
x w w w xz xz i a xz
I ~ I ~ ( ~ / \ / \ ~ I ~ I / \
~ ,.-~ c~ m ~r cc c~. oo cn
d
kZ ~ r' ~ ~ N
W
CA 02483020 2004-11-03
Table I9
,- co
so ~n
eri iri
m n. o~
O~~
I I ~ ~ ~ I I
v
U
Qv~v
Q'U f7
~i
UUu°.
~ yn .- c~ m w ,-
T T T r T T 1~ T
P
T r P" 1'~ T 1~ T T P~ !~
v
p
d ~ _~ N
O b ~ ~ A N Q
U o. .- r- cv ,-.
~!
Z
Z ~ t1,' ~ a; f.~ C
N
~_
0
/ \
a
ti o
o z' o z' cn
f \ / \ / \
m
N N N N
N U U U U
Z
U _ _ _
LL' ~ =Z =Z =Z J SZ I
_ ~ -
\ / \ / \
_a~
A' p .-r N M d'
C
00 00 00 CO 00
k
W
51
CA 02483020 2004-11-03
Table 20
N ~ O N =af
ccr = N
~ r ~ '~" Z
CNO~~'.= ~ ~~ ov'~
r ~ II
NZ~ NOMDCO ~aiv
a Z ~ ~ C~ v Z ~
r
N _
N
= O h N CO 00 cV ~
t0 ~ CO Z v n; = m Z
M = f~ tf) M = ~i H,
Oj ~rj = r ~ N
N _ ~j ~ p o~
CO r.,
,7~= W==O t~iZZ
_~ _
c~ iii ~ ~ ~ ~ E n
v~°r
NC~C'~ fOr~ unyl~~
N in
O
M
M ~ O
M CrC N frD M
~'. ~ ~' r ~ e- (~7 if7
a, O('~~ Or
N r N r O e_t
OcM~ O~
P~ P~ Nr
M M r O et
P tD
Mr
Z
_ O ~ O N P
(L---~ * ~ .. ~ P N
N CD f0
r P COV
N Cv
I\ ~\
Z
ac Z Z ~ S
Z=
Z
\~
Z Z Z
_ U U U
I
/ / \
a~
c.' m ce r.
d
era z o0 0o cc
x
W
52
CA 02483020 2004-11-03
Table 21
~..:~ ~ri~z
v~~= ~~r a
rn '0 M M
II fj O O _ ~.r tp
7 = Qy frj r N O
GV 'C r C~7 ~ Cn
'~a O r
~ CO ~ N ~ Z
ø,~ N~7 rv~ =~O
=O('O~
Q"'' A rj = 1t9 O M ~ T " aj
~ r CO C~ ..~ .~.~ Is 'fl _
N r ~ Z M eh Z
rO
r r
r Ch N
II =
r r L~ r O~ ? T
~ tf7 ~ '~ t' ~ N C~
I° .o
1117
ni u~ ~~?r
N
lO
O
N t0
M
O
r Or
r ~ r r
.Q r ~ Q~ O ~r r
V O ~ n°' ('~
Mr (~rr
''' ~ Mr OM ONO
N IMO. CO~ N (~G
OC~1 N'" NM,°
V'(O
Nr
0
U
~~
v ~ r ~ N
d
N v ~. O O
r N
W_
(\ \
/
z
°_' 2 Z zx
c~ z .- I
zx
~w
/
Z Z
U U U
y ~a i
i i
Q' m :a
c
co co
w
53
CA 02483020 2004-11-03
Table 22
~ca u~
~o
p .,~ p P r r
e~ r ca efi tIj cf)
M 4'~ N N p .a.
r r r r
i. ~ L
1N~' P
m In In ~ 09 CO O apQ' O
.~ZZ zZZ ~c.~t~
C'7 r r
m ~ °~'~'- ~~c~o UOOC~
a a so co p ui ui ,~
Nx x Nx x O C7 In
~ M M ~!n 1n i~ M C?
W O~~ O~a ~~x
z u7 u7 Z ~n tc7 0 ~ tND.
NU U NU U z
x gj C x Lj C ~' st ~
~~ a m~ o °'UU
UUu. UUtL = ti
UUti
v~
r rr r rr
~ N t~ c'~il N tpp C~~ N
t~ N t~. f3 h r P~ C~
~r rr rr rr
O ~ r
r r
f~ CO
U
r
x
z
o ~ x x x
cc
~i ~i
~i ~r
x zx
UO Zx Z
Zx tn0 ~x
w \ ~~ ~ .
m'
N
N
U
N N
fx xZ
U U
\ %
_a~
a. o~ ~ c ..-.
d
~ Z ao co cr: o:
W
54
CA 02483020 2004-11-03
Example 92 (Method B)
HCl = Process 1 ( ( n Process 2
iw. - Br~S02-N COOMe --
H2N COOMe S
XV-2
Me0 ~ ~ - ( ~S02-N~COOMe Process 3
S H
XVIII-1
V
Me0 ~ ~ - ( ( S02-N~COOH
_S_ H
Ia-2-1
Process 1
To a solution of D-valine methylester hydrochloride (XV-2) (755 mg, 4.5 mmol)
in dichloromethane(12 ml) was added N-methylmorpholine (1.49 ml, 3 X 4.5 mmol)
and
5-bromo-2-thiophensulfonyl chloride (1.24 g, 1.05 X 4.5 mmol) was added under
ice
cooling. After being stirred for 15 h.at room temperature, the reaction
mixture was
washed with 2N HCl, 5% NaHCOs, and water. The organic layer was concentrated
in
vacuo, and dried over Na2S~4. The residue was subjected to silica gel column
chromatography and the fractions eluting with ethyl acetate / hexane = 1/3
were
collected and washed with n-hexane to give 1.32 g of the desired compound
(XVII-1).
Yield 82 %. mp. 109-110.
Elemental analysis CioHiaBrNC4S2
Calcd. : C; 33.71 H; 3.96 Br; 22.43 N; 3.93 S;1 8.00
Found : C; 33.75 H; 3.89 Br; 22.43 N; 3.96 S; 17.86
[ c~ ]n : -34.5 t 0.7(c=1.012 CHCla 25°C)
IR(CHCls, v max cm-1) 1737,1356,1164,1138
NMR (CDCIs, b ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz, 3H), 2.00 (m,
1H), 3.60(s,
3H), 3.83(dd, J=5.2, 10.0 Hz, 1H), 5:20(d, J=10.0 Hz, 1H), 7.04(d, J=4.1 Hz,
1H), 7.32(d,
CA 02483020 2004-11-03
J=4.1 Hz, 1H)
Process 2
To a degassed solution of 400 mg (1.12 mmol) of compound (XVII-1) in 5 ml of
dimethylformamide was added 222 mg (1.5 x 1.12 mmol) of 4-
methoxyphenylacetylene
and 21 mg(0.1 x 1.12 mmol) of copper iodide (I) under an argon atmosphere.
Then 39
mg (0.05 x 1.12 mmol) of bis(triphenylphosphine)palladium dichloride (II) and
0.4? ml
(3 x 1.I2 mmol) of triethylamine were added to the reaction mixture. The
resulting
mixture was degassed and stirred overnight under an argon atmosphere at 50
°C.
The reaction mixture was diluted with ethyl acetate. The organic later was
washed
with 1N HCl, 5 % NaHCOs, and water, dried over NazS04, and concentrated in
vacuo.
The resulting residue was column chromatographed on silica gel. The fractions
eluting with n-hexane / ethyl acetate = 2l1 were collected and recrystallized
from ethyl
acetate / n-hexane to give 392 mg of the desired compound (XVIII-1). Yield 86
%. mp.
131-132'C .
Elemental analysis CisHziNOsSz ~ 0.2 Hz0
Calcd. : C; 55.51 H; 5.25 N; 3.41 S; 15.60
Found : C; 55.80 H; 5.I9 N; 3.38 S; 15.36
IR(KBr, v max cm-1) : 3268,2203,1736,1604,1524,1348,1164.
NMR(CDCls, b ppm) : 0.90(d, J=6.6 Hz, 3H), 1.00(d, J=?.0 Hz, 3H), 2.00(m, 1H),
3.60(s,
3H), 3.84(s, 3H), 3.86(dd, J=5.0, 10.2 Hz, 1H), 5.21(d, J=10.2 Hz, 1H),
6.90(d, J=9.0 Hz,
2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).
Process 3
To a solution of 407 mg (1 mmol) of compound (XVII-1) in 8 ml of
tetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH. The
resulting
mixture was stirred for 6 h at 60 'O. The reaction mixture was concentrated in
vacuo
to remove an organic solvent, and the residue was diluted with ethyl acetate.
The
mixture was acidified with aqueous solution of citric acid and extracted with
ethyl
acetate. The organic layer was washed with brine, dried over NaZS04, and
concentrated in vacuo to give 373 mg of compound (Ia-2-1). Yield 100%, mp. 14?-
56
CA 02483020 2004-11-03
148°C .
IR (KBr, v max cm-i) : 1710,1604,1351,1216.
Elemental analysis C18H19N~5S2 a 0.2H20
Calcd. : C; 54.45 H; 4.92 N; 3.53 S; 16.15
Found : C; 54.39 H; 4.93 N; 3.79 5; 15.96
Example 93 - 156
The compounds which were shown in Tables 23 to 30 were synthesized in a
manner similar to those described in Example 92.
57
CA 02483020 2004-11-03
Table 23
mo nco
~ ~r
mm mm mm
v~ cry b~ vi ire ira
'm ~ ~ c'~o, aNO m r°~~
,Wn cri ~ ui ca co
ZZ OZZ OZZ
I ~~ i f I 1 =N~ = o~
'~ef~ ~etsf
,n; ~'~ ~ ~'°o rn '*M ~
W Oiri~ri O'~~ O~'c
mo
2 .. .. Z .. .. Z .. ..
<<""U U NU U ~;,U U
UUt° UUti UUti
o cn ~n co rr oM cap MM
i cN°~ c~~a ii n~ ~~ oc_o c~_~
V r r r-_ r rr rr r_r rr
d'O OM ~~ ll~M mO
Och ehM NM C9 t0 rN N1~ O~ thN
tnr I~r ~.r ~r I~f' 1~(' hM 1~C9
H rr rr 1~r rr rr rr rr rr
v
Z ~ ~ N N rte- COO O p
r r ~ P
M i_p N
O N N r ~ O
r P t- r
a
T
~E p', G~ P.' p.,' W' Q'. 0~ A',
O
cc w ~ .~ ( / ~ ~ ~ \ ~ ~ ( i
U /
/ 6U U IU U IU IU IU
U U U III (~ U
y III / U
U ~ ~ s /
\~ O \~ \I \I \I
z z
V ~ O ~ Z
Z Z
= r Z 2 S Z I Z
U U U U U U U U
f,L =Z =Z ZZ ~ =Z ~ =Z =Z s =Z ~ =Z
~i ~e ~l ~i ~i ~i ~i ~i
o M ~ ~o c~ r. oc o~ a
ca Z a~ c~ a: o~ a~ a~ a~
x .a
w
58
CA 02483020 2004-11-03
Table 24
et P M us
om~ rn a~
to cc n: ri _
i~ in cri fri
~°~ o O ~ r
co co co r:
OZZ OZ~
=o~o~ I i 1 I =~M I I
N d. cY ~- es '~
o== oZ
Omco Oerrs
Zc,PC.~o Z~~
NUU ~UU
_ti _ti
N cC Q ~ c0 O
U U t~ U U u.
CO ~ ~' et OD 09 P CO CD tf9 h P cD N
In UJ et tn P P tp 07 CO th st M
j"WD P (~ tf7 P h P ((~ P tp P
P Y P P P P P~ P P P P P
_a tD GD an O N CV O t0 tn P ~ et W N AD N
M O M C9~ C~7 t~ O M O C~ P et N t~ N 1~
hC9 r.M h.tr3 COM hM PC~ PM PP
H P P P P P P P P P P P P P P P P
i~ M °- ~ ~ ~ coo
V ~ N N N E P N r P
1~ O ~ O ~ P
v N M ('~
N N N N ~ ~ N
~~
Z
# F~' f~ !x 4~' R~' R~ ~,' R;
O
ao
it I / I /° ( / z I '- I ~ I r I
\ \ \
N
U ~U U O IU IU IU IU U
U U U U U U U IU
C4
w I w I w I w I \ I o. I s I
Z IU N O O N Z
g = = O
U U U U
N N N N
fx =z =z =z =z
U U U U
0 0 o r o a o i
a, ~ cV e~ mn ct~ P op
~z ~ ~ o c o ~ 0 0
x .~ .~ .~ .-. .~ '-.~ r, ,-,
W
59
CA 02483020 2004-11-03
Table 25
et N
~.. h h r
tn tn N c~
O O C~ Gh
~~ ZZ
M~
ZZ ~v~
i i =o0 1 I I Oiiu: I
l'~~O NhOQ
= M C'
d r==
' c~ ~O M eh ~
_ ~ M M O
W Q of Ci U3
Z "~? ~!r? 0 eh co
_c""UU Zvv
~U U
UUu°..
UUt°i
tD tn tn W CO 00 O h r t~7 ~' N h N
tn cp sn en N o0 c0 tn t0 O m O N7
(~ r r ~ (~ (~ r (~ T (~ r
rr rr rr rr rr rr rr r
> '~ O Cn ~! t0 ~ O C1 N ~ tf9 CD P. Ln t~ Oi CD N
Nr NCD rOln ChN M!f Nt9 N~ Nh
h (h N~ M h CO r h C9 h. M h M h M h r
I"y rr rr rrr rr rr rr rr rr
w I~
r tNp ~7 M ~ m m
r ~ r r r r r
I I 1
U''~ ahoroo~i ~aMOm
r r r r r r r
oC-
z
z ~ ~ x x x x w x x
N
W_
( ~ ~ I I I ( ~ ~ y
/ I/ / I/ s
111 U ~~ ~ Wii U
U p U U U U iV U
wI ~I wI wI wl wl ~I wl
U O Q O U O
Z Z Z
I
I U Z Z Z I
U" U U U U
M
G~ U U U U I / I / I /
co
Z
U
a~
C, C C7 ~ N M d' ~ CG
~z
.-I r. r-, r.. .. .., ..,
w
CA 02483020 2004-11-03
Table 26
r O
rr
Il1 ~
c0 M M
OZZ
= ON7 ~
N~~
w Z vc1 tn
°' U U
Z ~j C
~~ O
UUu.
~m C~~~ r~ N1! ~T cNOr tnD~ ~N
V O r O r C~ In r
rr_ rr r r
r_r r r r r r r
> O O '~ CO tn C~ tn O et CD r M O) O p'r
NrN(pCOInO'~OMNMNafi t0
h t~3 t~ M u7 r to C9 ~O M 1~ M t~ c~ 1~ M
r"i rr rr rr rr rr rr rr rr
a
a°'o:f c°'c oaNO'~v
~ r r r r r
V'v~'~:-coo I I o°mw
r r r r r r
~~
Z
Z aF i~ tx C~' F.~' tY f~ f~ C~
O
ao
\ \ ~ tn .-, ~ U1 / fn
U ~ IU U tU
IU tU U U U pi tU U
(x U I t I iti N U
O
y i ~ U ~ I z y .i ! y w I
\ ~ \
U ~' O U O
Z ~ S tL Z Z
T Z Z Z x Z
U U U U U U
_ U _ _ _ U
N N
=Z =Z =Z i =Z ZZ =Z Z
U U
/ ~ / ~ / ~ /
t~ 00 Q~ O ~-i N M
N N N N N
~z
.., .-~ ..-~ .-.
w
61
CA 02483020 2004-11-03
Table 27
M P
P N
0 P P
r T T P
fn U3 fl3 Cn N ch
M !9
ZZ
ai ch c7 M
ozz ozz
zr° I i ~'v I a ~ I t I
C, N tn In N ,W t
~xx ~xx ~o
~ ~ O ~ C~e» !~ G~
o CO h o Of ~ Cn ~ ~
WUU ~tUU
z ~0 00
c wn
z ~ = u. .. ..
UUu UUti
U U ti
y°n rnc'~o ii N ~o
V ~ ~ r- M_ _C9 _~C _r-
N ~ O tti tci d' O O d-!P I I I
~- r r r P r~ t r r-
w n
tn tf1 1n ~O tCD
T T T T T
o '~W i ~ ~ r us I I I
U cc an
r P r
~~. a
x
x x c~ x x x x
0
ac
cn ,.- N ~ = cn -~ cn ~' ,~' i \ ' zN
U
tUUtntVUi~~s
U in U V W V
U
V / U ~U , iie
l U
\~ ! \I \) ~ ~ /
\ \ ( ~ ~ = V i
t1. ~ Z LL x
x
Z Z = Z Z ~ Z
U U U U U U U U
N N
U U ~ \ ~ \ ~ \ ~ \ y y
% / / ~ ~ /
d
is, m co N aQ o: o r., N
N N N N N M M M
k ~ ~-n .~ ~ .-r .~ .-~ ..s
W
62
CA 02483020 2004-11-03
Table 28
G
i I I i I I I i
a
a
!~
a
w
I I I I I I I I
...
s~
I i I I I 1 I i
i~
Z
z ~ x rx x ~ c~ sx t~ x
O
_ao
w \ ..-
' 6n / ....- ~. s
\ Z 4 ~ w Cn t//~
s
I -~ U= U= U
U ~U U= U= ~U eU '~j ~U
R.° m U U
U y ~
Z \
U \ \ \ \
io ~ Q
U ~ u. sn U
z
Z Z Z Z Z Z Z Z
U U U U U U U U
\ \ \ \ \ \ \ \
ø, ~ M ~' tf~ Cp h GO Q7 O
M M M M M M M
rr .-~ .--~ .-n ..~ .-~ .--i .--n
W
63
CA 02483020 2004-11-03
Table 29
m
.,.,
m
is
C
m
I I I I I I I I
d
i~
_a>
W
I I I I I I i I
..
ice'
cc
a.
o .-.
t I i I i I I I
..
x
z ~ x t~ x x x tx x
N
r i i
..i ~ \ ~ \ ~ ...r
\ \ ~ \ \
U U
UUUm,C,~,U,V~V
y ,ti y U U ,~ U
el ~ ~I ~/ I ~ I ~I
(
U U
° ~ O 0
w ~ x
i i i i i i z z
U U U U U U U U
I i I i I I ~ I
i i i i i i ~ i
d
p, ~-, N M C" t!7 CO h. 00
m Z ~ ~' ~f' a' C 'd' C' ~f'
X .~ ,.-i .-, ,~ ~ ,--~ .-y ,-i
W
64
CA 02483020 2004-11-03
Table 30
t t I t I t t t
a
a~
w
..
i I ( I i I I t
..
'~ Ci.
I~
o ..
~ ,~~ i i i i i I i i
.r
z
0.'f~t~P~P'.~0.'~.
O
cn r-W- ~ --v
U U
n n ~U ~U 'U U U
U U U U ,U !U
~- ~ r ~ ~ ~ ~ r ~ r
N
m
U U U U U U U U
a ( ~ ~ ~ y y
r r r r , r i r
Or C: O .~w N M ~' t1) c0
C' tf~ lf~ Lf7 tf~ in tl~ tD
.-~ ..-~ .~ .-r ~-~~ ,-t .--i
,,
CA 02483020 2004-11-03
Example 157, 158
Me0 ~ ~ - ~ ~SO -N~COOMe Pr°~ss 1 ~
~S 2 Fi -
XVIII-~
Me0 ~ \ - ~ I S02-N"~COOH
Ia-2-66, a-Ia-I 2-6767
Process 1 (Rz = CHs)
To a solution of 150 mg (0.33 mmol) of compound (XVIII-2) in 2 ml of
dimethylformamide which was synthesized the same manner as those described in
Example 96 was added 227 mg (5 x 0.33 mmol) of potassium carbonate and 0.1 ml
(5 x
0.33 mmol) of methyl iodide, and the resulting mixture was stirred overnight
at room
temperature. The reaction mixture was poured into water and extracted with
ethyl
acetate. The organic layer was washed with water, dried over NazS04, and
concentrated in vacuo to give 373 mg of N-methyl derivative as an oil. Yield
91%.
Elemental analysis C24H23NO5S2
Calcd. : C; 61.39 H; 4.94 N; 2.98 S; 13.66
Found : C; 61.22 H; 5.18 N; 2.93 S; 13.2?
Further, a solution of 140 mg of the above oily compound which was obtained
the above process in 2 ml of methanol was added 0.6 ml of 1N NaOH, and the
resulting
mixture was stirred overnight at room temperature. The reaction mixture was
acidified with 2N HCI and extracted with ethyl acetate. The organic layer was
washed with water, dried over NazS04, and concentrated in vacuo to give 105 mg
of
compound (Ia-2-66) (R= Me). 'Yield 77 %. mp. 185 - 186'C.
Elemental analysis CzsHziNOsS
66
CA 02483020 2004-11-03
Calcd. : C; 60.64 H; 4.65 N; 3.07 S; 14.08
Found : C; 60.56 H; 4.84 N; 3.01 S; 13.94.
IR (KBr, v max cm~i) : 3600-2300br, 3426, 2203, 1710, 1604, 1503, 1344, 1151.
NMR (ds-DMSO, b ppm) : 2.88(s, 3H), 2.93(dd, J=12.0, 10.2 Hz, 1H), 3.19 (dd,
J=14.2,
5.6 Hz, 1H), 3.81(x, 3H), 4.74(dd, J=5.4, 10.2 Hz, 1H), 6.99-7.04(m, 2H), 7.20-
7.35(m,
7H), 7.52-7.56(m, 2H), 6.90(d, J=9.0 Hz, 2H), ?.44(d, J=9.0 Hz, 2H), ?.12(d,
J=4.0 Hz,
1H), 7.44(d, J=4.0 Hz, 1H).
The compound (Ia-2-67) (RZ = CHaPh) was synthesized in the same manner as
those described in Example 157,.
IR(KBr, v max cm-1) : 2200,1722,1340,1151.
NMR (ds-DMSO, 8 ppm) : 2.94(dd, J=7.6, 13.8 Hz, 1H), 3.19(dd, J=7.2, 14.4 Hz,
1H),
3.83(s, 3H), 4.29(d, J=16.2 Hz, 1H), 4.62(d, J=16.2 Hz, 1H) (Only
characteristic peaks
are shown.)
Example 159 (Method C)
V
Process 1
Br I S ~ S02 H COOMe i- Me0 S S02-H COOMe
XVII-1 XIX-11
Process 2
----~~~ Me0 ~ ~ ~ S ~ S02-N~COOH
H
Ia-3-1
Process 1
To a solution of 500 mg (1.4 mmol) of compound(XVII-2) which was obtained
Example 96 in 12 ml of dry tetrahydrofuran was added 387 mg (2 x 1.4 mmol) of
powdery potassium carbonate, 319 mg (1.5x1.4 mmol) of 4-methoxyphenylboronic
acid
and 81 mg (0.05 x 1.4 mmol) of tetrakis(triphenylphosphine)palladium. The
resulting
mixture was stirred under argon atmosphere for 48 h at 75~. The reaction
mixture
was diluted with ethyl acetate. The organic layer was washed with 1N HCI, 5%
NaHCOs aq., and water, dried over NaaS04, and concentrated in vacuo. The
residue
67
CA 02483020 2004-11-03
a
was column chromatographed on silica gel. The fractions eluting with n-hexane
!
ethyl acetate = 3I1 were collected and recrystallized from n-hexane to give
44? mg of
the desired compound (XIX-1). Yield 83 %. mp. 122-123.
Elemental analysis C17H21NO5S2
Calcd. : C; 53.25 H; 5.52 N; 3.65 S; 16.?2
Found : C; 53.26 H; 5.50 N; 3.69 S; 16.63
[ a ]D -21.? ~ 0.6 (c=1.000 DMSO 25'C)
IR (KBr, v max cm-1) : 1735,1605,1505,1350,1167,1136
NMR (CDCIa, b ppm) : 0.90(d, J=7.0 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 2.10(m,
1H), 3.54(x,
3H), 3.85(s, 3H), 3.8?(dd, J=5.0, 10.2 Hz, 1H), 5.20(d, J=10.2 Hz, 1H),
6.94(d, J=9.0 Hz,
2H), ?.52(d, J=9.0 Hz, 2H), 7.11(d, J=4.0 Hz, 1H), 7.49(d, J=4.0 Hz, 1H).
Process 2
To a solution of 390 mg (1.01 mmol) of compound (XIX-1) in 8ml of
tetrahydrofuran and 8ml of methanol was added 5.1 ml of 1N NaOH, and resulting
mixture was stirred at 60'C for 6 h. The reaction mixture was concentrated in
vacuo
to remove an organic solvent. The resulting residue was diluted with ethyl
acetate.
The mixture was acidified with aqueous solution of citric acid and extracted
with ethyl
acetate. The organic layer was washed with brine, dried over NazSO~, and
concentrated in vacuo to give 373 mg of compound (Ia-3-1). 'Yield 100%. mp. :
1?4
176°C
IR(KBr, v max cmw) : 1735, 1503, 1343, 1163.
Example 160 - 1?5
The compounds which were shown in Tables 31 to 32 were synthesized in a
manner similar to those described in Example 159,.
68
CA 02483020 2004-11-03
Table 31
_ O cG T T p~ O)
N ~ ~ ~ N N
Cn U3 op5 O V! CO
°' a~D O
ICJ t0 ~ N ~ (~?
~ZZ NN ZZ
I ~c'~'°,~~ ~ ~ Otn~C! ~O
p p ~t ~ Z In CO et t0
eoZ = T std p
W ~oc~ Q~fd; ~~p
~in~ 'r~~ Z'pd'~
c°vUU Zooi °'UU
.. ..
ti '~ d' cS
UU
UC?ti ~~ ~ UUti
UUU°.
= n. a~ wn P co r~ M sr ao v
~ M t9 O~ CD ~h O ~O ~ O c0 N
~ ~ !7 C'h ~ T t? sn P ~f% 1n P Cp
r !~ P T P 1~ T T T P
> h0 OvR tar ln0 tnC~ M_~ NN Is0
T
cOp~ t~OOr ~c~ ~~ n~ t~.~ Ohm ~:n
r T f~ P T 1'~ r T T 1~ r' 1~ P T t~ 1~
CO ~ r. ~ m h t~ p
~ ~ r r N P r~ r
O ~ ~ CO t~ 07 m ~ p lD 1~.
0 w O tp <O N f~ m ~ O
' T N T t~ T 1~
Q"~ #
\Z
Z~ WC~ 0.'P',A;P~0.'
N
O
m_
/\ / /\ /\ ~, /\
W ~ ' ~ / ~ \ ~ ~.
x ~ \ \ ~ I \ \ I
° ~ i ( ° ° ~ ..~ ~ °
° °
O U cn O U cn
Z Z tL I Z ~ ti S
Z Z Z I
U U U U
_ U U U U
t~ SZ =Z~ =Z ZZ = Z Z Z
U U U U
a ~ e!r a i a i
O. O ~ N M 'Ct' Lf7 cD h~
cp O c0 cD tp cfl O Cb
.-, ,~. .-,
I W I ~ I i ~ L I I
69
CA 02483020 2004-11-03
Table 32
N '~t
CD CO
r e-
~N X000 ~~ 00
!n tn 1f~ tf1 (n fn N N
rr rr ~~ NN
fn !n fn VJ et tD Cn fn
~ CO ~ O N t'~9
Ch fM t'~ ~
ZZ ZZ Oco OZ2
i I i I
~f p d' et O O N et it
0
~ 17 m Cn M h ~ ~' f~ ~ tn
p W C9
w ~ 1WI ~ ~7 t~j Cn = ~ ~ ~ L
Z Z ~ N C9 Z
~UU ~'UU Zctitc °'UU
u»
N l6 p N n3 p ~~ U N c0 Q
UUti UUu. ~c9 ~ UUt~
UUt,°~
~m m~ ~~ ~M
r r_ r_ r r r r I I I I
In p _C~'J CO r In O O Lf)
v
h M t~. M n CO r V' r
rr rr rr rrr
r
CL
O ~
O d ~ co et c~%s I I I I
O v tD lD h. O
r r r N
cc--~ x
z
Z~~ ~C~Q'cY~0.'0.'~CL
O
m
r\ ~" r\ , r\ r
In ~ ~ (n flJ Cn
v
't
1
m
I/ ~/ ~\ I/
Z = 11. Z I ~ ti 2
Z = Z Z Z r Z Z
U U U U U U U U
x W I w ~ w W I w W W W
/ / r i i i i
a . oo a~ o .-~ c~ cr; v~ ~n
~z ~ ~ h r
., .. ,-~ ..., .-a .-. .,
w
CA 02483020 2004-11-03
Example 176 (Method D)
HCl = Process 1 / ~ ,~ t Process 2
H2N~COOtBu "° OzNS02-H COO Bu ~-~-
XV_3 XX-1
~/
H2N ~ \ S02-N~COOtBu Pr°cess 3;
H
XXI-1
MeS ~ \ O N / \ SO2-N~COOtBu ~r°cess 4~
~/ H
XXII-1
O
MeS ~ \ N ~ \ S02°N~COOH
H
Ia-4-1
Process 1
To a solution of 10 g {47.68 mmol) of D-valine tent-butyl ester hydrochloride
(XV-3) in 100 ml of dichloromethane was added 15.7 ml (3 x 47.68 mmol) of N-
methylmorpholine and 14.1 g(1.2 x 47.68 mmol) of 4-nitrobenzenesulfonyl
chloride
under ice-cooling. After being stirred for 5 h at room temperature the
reaction
mixture was washed with 2N HCl, 5% NaHCOs, water. The organic layer was dried
over NazS04 and concentrated in vacuo, and the resulting residue was
recrystallized
from dichloromethane / n-hexane to give 13.38 of the desired compound (XX-1).
Yield
77.8%. mp. 89-90~.
Elemental analysis CisHzzN20sS
Calcd. : C; 50.27 H; 6.19 N; 7.82 S; 8.95
Found : C; 50.04 H; 6.10 N; 7.89 S; 8.84
[cx]D -2.9-~-0.8(c=0.512 DMSO 23~)
IR(KBr, v max cm-1) : 3430br, 3301, 1722, 1698, 1525, 1362, 1348, 1181, 1174,
1159.
71
CA 02483020 2004-11-03
Process 2
A solution of 13.29 g (37.08 mmol) of compound (XX-1) in 200 ml of methanol
was hydrogenated using 10% Pd/C (lg) for 2h at room temperature. The reaction
mixture was filtered off and the filtrate was concentrated in vacuo. The
residue was
recrystallized from acetone / n-hexane to give 11.5g of amine derivative (XXI-
1). Yield
94.4%. mp. 164-166'0
Elemental analysisCisHz4N20~S
Calcd. : C; 54.86 H; 7.37 N; 8«53 S; 9.?6
Found : C; 54.84 H; 7.33 N; 8 63 S; 9.50
IO [ a Jn +10.3 t 1.0(c=0.515 DMSO 23'0)
IR(KBr, v max cm-1) : 3461, 3375, 1716, 1638, 1598, 1344, 1313.
NMR(d-DMSO, b ppm) : 0.80(d, J=6.8 Hz, 3H), 0.82(d, J=6.6 Hz, 3H), 1.23(x,
9H),
1.83(m, 1H), 3.30(m, 1H), 5.86(s, 2H), 6.56(d, J=8.8 Hz, 2H), 7.36(d, J=8.6
Hz, 2H),
7.47(d, J=9.6 Hz, 1H)
Process 3
To a solution of 328 mg (Immol) of compound (XXI-I) in 10 ml of
dichloromethane was added 0.33 ml (3 x 1 mmol) of N-methylmorpholine and 280
mg
(1.5 x 1 mmol) of 4-(methylthio)benzoyl chloride under ice-cooling. The
reaction
mixture was stirred overnight at room temperature. To the reaction mixture was
added ethyl ether and precipitation were collected and washed with ice-water
and
ethyl ether, The solid were recrystallized from acetone / ethyl ether to give
433 mg of
the desired compound (XXII-1). Yield 90.5%. mp. 235-23890.
Elemental analysisCzsHsoN2OsSz
Calcd. : C; 57.72 H; 6.32 N; 5.85 S; 13.40
Found : C; 57.63 H; 6.28 N; 5.86 S; 13.20
[a]n +5.7~0.9(c=0.512 DMSO 25~)
IR(KBr, v max cm-1) : 3366, 3284, 1713, 1667, 1592, 1514, 1498, 1341, 1317.
NMR(ds-DMSO, s ppm) : 0.82(d, J=6.6 Hz, 3H), 0.84(d, J=6.8 Hz, 3H), 1.22(x,
9H),
1.91(m, 1H), 2.55(s, 3H), 3.32(s, 3H), 3.44(dd, J=6.2, 8.6 Hz, 1H), 7.40(d,
J=8.6 Hz, 2H),
72
CA 02483020 2004-11-03
7.73(d, J=8.6 Hz, 2H), 7.90-8.01(m, 5H), 10.48 (s, 1H).
Process 4
To a solution of 405 mg (0.85 mmol) of compound (XXII-1) in 3 ml of
dichloromethane was added 3.3 ml (50 x 0.85 mmol) of trifluoroacetic acid and
resulting mixture was stirred for 2 h at room temperature. The reaction
mixture was
concentrated in vacuo and the resulting residue was washed with ethyl ether to
give
340 mg of the desired compound (Ia-4-1). Yield 94.? %. mp. 231-234'0
IR(KBr, v max cm-1) : 1748, 1655, 1592, 1323, 1161.
Elemental analysis C19H22N2OSS2 ~ 0.lCFsCOOH
Calcd. : C; 53.14 H; 5.13 N; 6.46 S; 14.78
Found : C; 53.48 H; 5.31 N; 6.57 S; 15.06
Example 177 - 208
The compounds which were shown in Tables 33 to 36 were synthesized in a
manner similar to those described in Example 1?6.
?3
CA 02483020 2004-11-03
Table 33
00
0o n
n~ cTn ~~ '~'° taco
Nr Or '~ '~'tC .fn U7 NO
efl cti t0 cC cD c0. eG ct1 m ,Ma, :u :V
Cn fn Cn tn C~ ~ (/j fn
N
~m N~ _.. ~~ n~ ijCOC Zz p0
OO OO
~ZZ Ozz OZZ Ozz _.t_et ~zz
~O)O NetN NmM ~cOO> ~ ': L:
xNt~ xcoN Zit
T ~ /,~,
°' ~xn : x= °_= inNCs omo N=Z
Do~o~ ~s~n~ i ~'a'n~ Ocaoo gist ~uo~~cc~~o~
W ~,ccai O~d; O goo ~=s Own
Z tn In Z In U7 z ~ ~ O r M
g,C?CU NUU '~''UV Zrr ~°''UC)
= ci c x c x c x ti ~ ' ~ ~ Z c
N f6 Q ~t V J t0 V Q N ~ ~ p ~ V 7
N cL3 Q N lC p N U U N Rf p
UUU. UUu. UUti UUu. ~~ c~ UUu.
U U u°.
c~ cn n co a~ rn co c~ o~ to n ao co c~ c~
~ st t0 t!7 n t~3 sf N O !n M tn N <D r 10 N
V y~ Cfl r Cfl t Sp r t0 r CD r CD f'' iD 07 CO C~
r r r t r t r r r t r r r r r r
ci .= co co ri ..: vi o cv of ~ .= o i: o sr aci ci c>
t~7~1' NN Nm rd' MO-._. __M~O N071f~ N~in
ne~~ nc~ nch nco nc~ nint wnr nunr
H rr tt rr rt tr rrt trr trr
td
°' n .~. ao M co ~ oo a~
0 ~ N C~ r r M d' r et'
N N N N N N N
O d ~ tn Ch CD r ~O O In d'
O r r c~~
N N N N N N N N
x
Z~x~~t~f~C~P;i~C~G~
N
O
x I\ \ \ I~ \ ~\
\
I w ~ ( / I ~ ~ / ~ / /
zx
zx zx zx I zx _ zx
Zx UO ~j0 UO UO UO Z UO
'~ UO / ~ ~.~ I / I \ I / ~ ~ O / I
\ ~ \ \
I z
V w ~ U U, ' U
x O ~ x Z
Z Z Z Z Z Z Z Z
U U U U U U U U
xz xz xz xz ~ xZ xZ xZ xz
\ / \ / \ / \ / \ / \ / \ / \ /
d
a, n o5 0~ o -., cJ c~ ~r
n N oD x o0 00 00
r, ~ .~ r. r, .-. .-,
W
74
CA 02483020 2004-11-03
Table 34
NN
m tG M t M t0 m ,~ tt) tn _ O N M P~ h
U) Cn ~ ~ . t0 h. ~O t Cl) V) M C~ ~. N U) Cn
i~ P~ tG CD CD 1~ 'a' 1~ pw n, r r
in lJ7 1n !'n (n VJ ~. ~ ~ ~ = Vj C!) M M
CO c0 t0 ~ M M = N 1n O CO p O N m t0
m tt OOL OCOL. ZZ MM
ZZ c~eo ~ca O~nac~ etm epqp ~t ZZ
CO h. (~ O M O !Y In 07 O
OD1~ ZZ ZZ MZZ O(VCV ZZ ~ZZ NM
Or~r~ ~~ oo Uc°w_~ Ott cc_M Ua~~o- ~v
ap O N tL lL
N tL Il ~ et v 'eh M et ~ ~ m m M M 0 ',t et N
zT ZZ °z= tLN~ z= N=S
C~dv ~~~ ~N~ ~~~ ~r)c' ~sca0o ~07P.. ~'ef
W ~~~ ~oo ~~ad ~nr. N,== ~ricvi O'nn
Oinco Z~m Zyn Z~~ po~co Zm~ '°~~ OrN..
Za~ac ~UCJ ~UU n°,UU zcor~ NUU Z,VU Zoio>
= ci c = ti ~ = cs c '' w ~ _ ~ ~ S c tL wn
O O N- O N- O d1 .. .. co~- O tU
NUU ~m o Nca o Nc~ o o~UU No o Nay o UU
z ~ c t,)-Uti UUti UU~ UUti. UUu. = cv c
UUu°. UUti UUu°.
tM tN Nh CDtn OM mt0 h~ ~-et
In ~7 tn N 1~ N en N h~ M N Of ~O cp M In N
y t0ch t0M t0 t9 COM cDM tou'!t cpM ~DM
tr rt tt tr tt rtr rt rt
> ~ OMt Mgt OMO CONC7 M~-1~ Ni0'd' Nr-r tsC00
MOCO NOCO t01f3 ~O>tf! ~C>t0 tI>1nN et0»D MOCO
htDt h.Mv- f~t0t l~Int l~Ot 1~~OM t~.t0t l~lnt
p".~ t t r' t t r" t t t P t t t 1'~ t t t t t t t T t t
V /~
!t7 O O tf1 M ~t M O
z$~~NN,t-N NNN
p [~ ~ ~ i
p~0 etN NNC_0
() a ~ N N r N N N N
z
x x x c~ x x x x
O
m_
w w w
y Ir p w I I/ I~ y
i
~2~ Z= I s_' Z= ZT
G~ UO UO UO Z UO UO UO
/ ( / UO ' / I UO
W w w I i ( W W w W
. ~- O N m'
O
N
U Z I Z Z = I Z
_ U U U U U U U
c~ zz ~, w ~ w w w w
\ / I ~ I / I / ~ i'~ I ~ I ~ I /
a, ~r: ca ~. ~ a~ o ~., cu
co 00 00 ~ o~ a~ a~ a;
r. ... ... r, ... r,
W
CA 02483020 2004-11-03
Table 35
c~ ago rn° i°°.,
V! Cn ~ (n O C1 T T ~ o N ~ et IL) CO I
,~r. ~ ~ M
ZZ xZZ ON rQ O~~t x~~ rV II CMOMG
T N Q M O ~O CO P P. V ~C t0 O O Z P. 1~ t0 t~.
OMr
a OZZ OZZ ~ZZ 00~ OZZ OZZ
es! 1~ I~ U~P- 1~ NO ~ N("~ O U M r U~~ tf~ NOD tp Nr- CO
x th tfJ x h~ lD P r M Il LL LL = C~ ~ = 1!f ~
V U U ~yri ~ci N _ui ~ti iri ~ci U_ v ~ '" 1I7 Lf~ ~! tn In
e~~i~v °~~ ~~N ~ ~ vix= ov~'~ ins= N~ex~~
~,=x p~''i' ~a>c; Nr~ tn== p~-o ococe
O d' O7 O In tn N <O Cfl N tCa t!7 O M M ~ tC N N 1n 1t? N tn tn
M CO M M r N Z Z Z in lC~ O CD CD Z Z
NU U N(,j U Z M ~ c°vrU V
U .. .. U ._ .. ~ti ~ ~ti ~ I ~ c ~~~ ~ti ~ ~ci ~
Z v ~ _ ~ c UU~i UUu~. tj~j~ x ty c UUu~. UU~
N RS Q N Ctf Q
UUti UUti UU~
W M t0 N N M th t0 t9 tn t9 ~O 1~ O ~- P
h N CD t~3 t(7 N tn N tn N N 01 ~O ~O .-
~~, Cfl M Ct! O'J ~O th CO M t0 M Iw if> ~- ~O !9 t0 !0
TT YET TY PT 1~'T 1~l~P TAT 1~T
>'~ ~hNCO lnNO CDOr ~Nr CpNr O~CON Cprd7 tprUn
NQfln N17~t0 d~O~ID ~fOI~C ~MtD ~cGN NG>47 OOfIn
t~~ tI> r h. tl7 r t~~. In r- P. In r- t~ 119 r 1~ CO f7 N. t0 r- Cp tn N
PrT T1~1~ l~Tr t~l~r . TTr TPr 1~TP 1~P1~
v
x $ ~ N N N N N N N N
O
(] ~ N N N N N N N N
CL
x
# G.' P.~' ~' P~ a; R~ C~ 0.'
O
ao
I w i .- I ~ i ~ l / i w \ I /
~~
zx z= zx zx ~ zx
zx
VO UO _ UO C70 UO ~o Zx UO
I ,r UO
\ z \ z \ \ I \ ( \ I / I \ I
\ O
U z /I
\ ~ Z x
Z Z
_ U U
N N N N N N
\ .~ c~ i~ t~'~ M '~'t~J c7
~, ( / U U U U U U
d
M V' Lf~ c0 I~ 00 Q7 O
O B: O) O: W O~ G7 O
.-., .--t ., ,-i .1 n7
76
CA 02483020 2004-11-03
Table 36
N c0
~ M
t0 tG _
~ ~V N ~ 1~ M O O ~ ~ ~ C~
h h ~ ~ 1~ t~- ~ ~ 1~ h 1~ t~ _
Cn fn ~j uj tn fl3 = V3 N Uj ~ U~ tn
O O tn O
CD O ' Zo Z td) in o ~ N W 1~ ~ h~~
0 0 t p CMp 0 0 U r r 09 ~ ~ 08
p OZZ cm~:cc OZZ ~ZZ ZZ ZZ
~, =c~°p,,~ ,_ ~ ~ =a'~oo ~~c°> ~°n~ ~~ I I
'a' er ef ~ Cd oO '~ ui cc N d. ~ ~~ er et ~
c~~m ~?_= oz= __ =z
O ct ~ ~~ N NO O bN ~ ~~ 1t09
W ~oo ~__ ~cccc O~°~ ~aioo yri~ri
Z u? ua p co er Z en ~ 'd' m an Z ~r? !r? Z in ~n
~UU ~"'~fl NUU o.... o_,UU °'UU
Zeo° ~ m~'f o-° ~ =__ti ~ _ ~ ~ ov ~
UUti ~UU UUu "'~ Q UUu°. UUu°,.
U U u.
t7Uti
OD P. M o3 r 01 M h~ N 07 t17 07 ~ N
c1 CO r C~ In h M !~ C9 CIO r ~ r
V x" ~C C9 <O M t!7 r ~O C9 ~D M <O t0 ~D M
rr r rr rr rr rr rr I
? ~ ~pr(p tClNO O9 CO f~QN ~tfl0 Mltt1' CV CVln
N W t0 N Cn In tn r N C7 ~D r O (p CQ O 1~ M O tn
P. tn r t~ tf1 r 6D f9 IWC7 r I'~ tn r f~. In r I~ In r
rrr rrr rr rrr rrr rrr rrr
to
N O _CD h tt~ ~ O
x $ ~ ~ M M 1w r
N N N N N N N
O U~ _st CO N et Iv I
(J ~ N CN~A N N N N N
ct-~ x
x
Z ~ ~ 0; G'~ i~ P: t~ GY i~
O
_a~
\ \
(/ Is I/ I/ I\ Is 1/ is
zx zx Zx zx / zx zx
UD UO UO VO Z= IZx VO UO
UO
/ / I ~Z UO Zx /
[' ~..-
\ I \ I \ z. I r I ~O i I \ I
U \
o ~ Z ~ Z
o m = x = m i
U U U U U
' N N _fh
t0 M M
U U ~? J J J I
G, ~-V N M V' t1~ ~p ~ . pp
O O O O O O O O
N N N N N N N N
7?
CA 02483020 2004-11-03
Example 209 (Method E)
HCl = Process 1 ~ ~ w Process 2
H2N~'COOtBu -> ~ S02-H'~COOtBu --->
XV_3 XXIII_1
Process 3
OHC ~ ' SOZ-N~COOtBu ------>
H
XXI'V-1
02 H H l o ~ t Process 4
S-N-N=C S02-H COO Bu >
XXV-1
N=N ' Process S
MeS / ~ N,N , ~ S02-H~COOtBu -->
XXVI-1
N=N
MeS ~ \ N~N ~ ~ S02_H'~~'COOH
Ia-5-1
Process 1
To a solution of 20.94 g (99.8 mmol) of D-valine tert-butyl ester
hydrochloride
(XV-3) in 200 ml of dichloromethane was added 22 ml (2 x 99.8 mmol) of N-
methylmorpholine and 20.27 g (99.8 mmol) of p-styrenesulfonyl chloride under
ice-
cooling. After being stirred for 15 h at room temperature, the reaction
mixture was
washed with 2N HCI, 5% NaHCOa, water. The organic layer was dried over Na2S04
and concentrated in vacuo, and the resulting residue was column
chromatographed on
silica gel. The fractions eluting with ethyl acetate / n-hexane I chloroform =
1/3/1 were
collected and washed with n-hexane to give 28.93 g of the desired compound
(XXIII-1).
Yield 85 %. mp. 118-120'C.
78
CA 02483020 2004-11-03
IR(KBr, v max cm-1) : 3419, 3283, 1716, 1348, 1168.
NMR(CDCl3, 8 ppm) : 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 1.21(s, 9H),
2.04(m,
1H), 3.62(dd, J=9.8, 4.5 Hz, 1H), 5.09(d, J=9.8 Hz, 1H), 5.41(dd, J=0.5, 10.9
Hz, 1H),
5.84(dd, J=0.5, 17.6 Hz, 1H), 6.72(dd, J=10.9, 17.6 Hz, 1H), 7.49(d, J=8.4 Hz,
2H),
7.79(d, J=8.4 Hz, 2H).
Process 2
Ozone gas was buhbled through a solution of 5.09 g (15 mmol) of compound
(XXIII-1) in 300 ml of dichloromethane for 15 h at -78°0: To this
solution was added
22 ml (20 x 15 mmol) of methylsulfide, and the reaction mixture was allowed to
warm
to room temperature gradually over 80 min and concentrated in vacuo to give
6.03g
aldehyde derivative (XXIV-1).
IR(CHCIa, v max cmu) : 3322, 1710, 1351, 1170.
NMR(CDCla, 8 ppm) : 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.9 Hz, 3H), 1.22(s, 9H),
2.07(m,
1H), 3.69(dd, J=4.5, 9.9 Hz, 1H), 8.01(s, 4H), 10.08(s, 1H).
Process 3
To a solution of 6.02 g{15 mmol) of compound (XXIV-1) in 60 ml of ethanol and
15 ml of tetrahydrofuran was added 2.72 g (1.05 x 15 mmol) of benzenesulfonyl
hydrazide at room temperature. After being stirred for 2 h, the resulting
mixture was
concentrated in vacuo. The residue which was obtained by concentration in
vacuo
was column chromatographed on silica gel and the fractions eluting with
chloroform
ethyl acetate = 1/4 were collected and recrystallized from ethyl acetate to
give 4.44 g of
the desired compound (XXV-1}. Yield from process 2 60 0, mp. 163-16490.
Elemental analysis CzzHzsNsOsSz
Calcd. : C; 53.32 H; 5.90 N; 8.48 S; 12.94
Found : C; 53.15 H; 5.87 N; 8.32 S; 12.82
[a]n -1L6~ 1.0(c=0.509 DMSO 23.5°0)
IR(KBr, v max cm~l) : 3430, 3274, 1711, 1364, 1343, 1172.
NMR(CDCIs 8 ppm) : 0.84(d, J=6.9 Hz, 3H), 0.99(d, J=6.6 Hz, 3H), 1.19(s, 9H),
2.00(m,
1H), 3.63(dd, J=4.5, 9.9 Hz, 1H), 5.16(d, J=9.9 Hz, 1H), 7_50-7.68(m, 5H),
7,73(s, 1H),
79
CA 02483020 2004-11-03
7.78-7.84(m, 2H), ?.96-8.02(m, 2H), 8.16(brs, 1H).
Process 4
To a solution of 0.14 ml (1.11 x 1 mmol) of 4-(methylmercapto)aniline and 0.3
ml of conc. hydrochloric acid in 3 ml of aqueous 50% ethanol solution was
added a
solution of 78.4 mg (1.14 x 1 mmol) of sodium nitrite in 1 ml of water at 0 to
5 'C of the
internal temperature and the reaction mixture was stirred for 15 min at the
same
temperature. To a solution of 496 mg (1 mmol) of compound (XXV-1) in 5 ml of
dry
pyridine was added the above reaction mixture over 8 min at -25~. This
reaction
mixture was stirred for additional 4 h at -15'C to rt, poured into water, and
extracted
with ethyl acetate. The organic layer was washed with 2N HCl, 5 % NaHCOs, and
water, dried over NaaSO4, and concentrated in vacuo. The residue was column
chromatographed on silica gel and the fractions eluting with chloroform /
ethyl acetate
= ll9 were collected to give 374 mg of the desired compound (~~XVI-1). Yield
74 % .
Elemental analysis C23H29N5O4S2' O.3H2O
Calcd. : C; 54.27 H; 5.86 N; 13.76 S; 12.60
Found : C; 54.25 H; 5.77 N; 13.87 S; 12.52
IR(KBr, v max cm~l) : 3422, 3310, 1705, 1345, 1171.
NMR(ds-DMSO, b ppm) : 0.83(d, J=6.9 Hz, 3H), 0.86(d, J=7.2 Hz, 3H), 1.19(s,
9H),
2.00(m, 1H), 2.59(s, 3H), 3.54(dd, J=6.3, 9.6 Hz, 1H), 7.56(d, J=8.7 Hz, 2H),
8.00(d,
J=8.6 Hz, 2H), 8.10(d, J=8.7 Hz, 2H), 8.33(d, J=9.6 Hz, 2H), 8.34(d, J=8.7 Hz,
2H).
Process 5
A solution of 353 mg of compound (XXVI-1) in 2.5 ml of dichloromethane and
2.5 ml of trifluoroacetic acid was stirred for 3 h at room temperature. The
reaction
mixture was concentrated in vacuo and the resulting residue was washed with
ethyl
ether to give 308 mg of compound (Ia-5-1). Yield 98%. mp. 194 - 195.
IR(KBr, v max cm-1) : 1720, 1343, 1166.
Elemental analysis C19H21N5O4S2 ° l.lHzO
Calcd. : C; 48.83 H; 5.00 N; 14.99 S; 13.72
Found : C; 49.13 H; 5.25 N; 14.55 S; 13.34
CA 02483020 2004-11-03
Example 210 - 251
The compounds which were shown in Tables 3~ to 43 were synthesized in a
manner similar to those described in Example 209.
~1
CA 02483020 2004-11-03
Table 37
n
N CO =
'a r
CD tn
N ~ v~
N II N
~ ~
~ = CD
~p
O
O. (p CD
O N r
r M ~Z
r
Y
r N
M nj Q
",h, e~ Z N
p. W
II r P
N
~ L~ 1
'p ,..
~ N r
a N
N~M
N !5 S
CD ~
~
"' ~ (
D
~ r
LT
.n _.
V i r
_ ~ O 1~
.fl
p'., N r
O~
O G~
h tD
Z
Z
C
t
.d ~ tt
v
N CL r
/ /
s
zZ z
Z ZZ
, ,
N
U
_ U
tx =Z
d
o
o
,~
y~C N N
z
W
82
CA 02483020 2004-11-03
Table 38
a
N
N ~ ~
_ ~ O)
II
S~ = L7
~ !~. = M
ip
Cl~
yr I N
~ ~
CO
~
e'r9
_
_
xi O~ r N
~ ~ ~
_
6~. 'D
Ch =
N ~ tC7
w
MO
M~
C9
-w
~ 'N w
' r-
~1
C~
G~
I - w
~./ o
Y~1
v
Nw
~ N
I
Z ~~ iii
N yr
D
O
\ \
m
L~ Z.ZZ Z,ZZ
\ \
~
N
U
_ U
t~ =Z
a~
o
o -,
%z . N
N
83
CA 02483020 2004-11-03
Table 39
~w
et n ell ~ N tn N n CO n n f'9 O O
M YO ~ (~ Ps O ~ f0 C8 O C'7 '~ O r
Sri ui n ,~ n. n: n n ui Sri ~ sc c~ co
vi c~ co r f~ cri i~ t~ v5 i~ vi in tai vi
y 'yf ~ ~ '°' W 00 N O (O W N N Cb
O N Cf O n f0
~ yn Z Z eo co n n rs r~ c~ mn ui
r Q r r r r r r r r r r
aZZ muy ZZ ZZ OZZ OZZ ZZ
Q' O j, C~ M M 'p' C'O O N ~y ~ N O) O tn CO
LJJ 'O tGl ~ (,L LL O r OD OD ~ ~ ll9 In = N f'~ O r r
~ lfD sf ~ N n tf7 1d7 ~' et ~O °~' !~ N ~ d' N ~
d o== etc~c~ ~_ _= oT= o== =z=
tbo o~cr~ tnry~ W oco got- ~nco ono
~T' ~ U7 ~ ~ ~O 1~ ~C'9 M ~n <O ~O ~ ~r N
W -~c°oc°o yn~' ~,~s~n ours ~cNOCNO ocNncro ~
O
NUU zr~M.'~ ZC7C7 ~IJU M,iJC7 Z,UU NCjU
Z _~ c u_ !n ~? Z ~ c Z ~ c = ~ c Z ~ c = ~ c
c~U ~ o> ~ co- ~ ao- ~ co- ~ ,n
N t0 Q cC Q ftf Q N t0 Q N l0 Q N f6 Q
UUu. ~c, a UUci UUu. UUti UUti UUu_
U U u°.
n co wo era n dno _c~co c~N
r~ c~ a> n o~ n co a>co so o co
M ~ P ~ r ~ ~ ~ r n M
r r rr_ rr r rr rr rr
n~ n~r° nee cory n~ nM nc~~ nerd
r r r r r r r r r r r r r r r r r
v n
N W t N t0 ~ n
N N N N r N N r
r
a~ O ~ N tp c0 6p
O ~ O CV O N et' O N r
(J ~ r N N N r N N r
oc'-~ *
x ~ x
0
\ \ \ \ \ \ \ \
I~ I~ I~ I~ I~ I~ I~ I~
zv zv z~ zv zv zv za zv
ii Z n Z ii Z ie Z ii Z ii Z n Z n Z
Z.Z Z_Z Z_Z Z_Z Z.Z Z.Z Z_Z Z_~
\I \I \I \I \I \~ \I \I
N
z c~J N N U =
_ _ U
LL' U Z U =Z U ~ xz ~ I ~ / \ V =Z U
_ ~ Z - ~ / \
U v
\ / ~ ~ U \ / \
I~
a,
N m er m cn r.. oo a~
k z N N N N N N N N
W
04
CA 02483020 2004-11-03
Table 40
m n
~ ~r
ca ec
°r°~ ~:~ or o~ i~bi
efl cti n: ~ r: n: r: r: ~r° nm
vi iri sr~ cri iii ire iri iri ~: ri
r r i0 O n N n N r r
y N O O n ~tt r ~ r' Z Z
CD ~G CO (~ tf3 tf7 in tn tn N
r r r w- r r r r r
ZZ ZZ OZZ OZZ
iC NN Od Zc0~9~ I NO C') ~ :: :_ I I
= ry r
C et er s87 ct) ~ tc~ tn ~ an tn = m 00
°' _= ZS oSS ~__ °°~0~0
'~W n ~~l~r~ 'np.~- ~en~r QMCh
W ~~~ ~°dvst ~CMC~ O v==
N,U U Z,U U M,f7 U mU U
Z ~ a Z ~ c Z ~ c
u~- ~ o>- a o- ~ o- ~
N fLS Q t$ p N !LS Q N ftS Q
UUti UUu.. UUtL UUci
_ cy c
°° ~ o
U U ti
= rn ~ e~ eo c~ o r N v m ~ co
r cp rn n v~ n o co o ~t
~~ n r (~ r (~ r (~ r (~ (~ ~ n
V r r rr r T r r r r
r rr
~M L~d NCn~ ~p~p ~N COr ODD hr
n co n r~ n r~ n c~ n ~ c°'c :=
rr rr rr rr PP r rr
p n n ~ n CD n tt7
O O O N O O
v ~ r N N ~ CV N N
~ .~ tP~ ct ~ V ~j n d' M
U ~ ~ N N r ~ ~ N N N
~~
Z
~E P'r Q', C~' Q'r R'e P-'W' Q'r
O
m
I i ~.. 1 s I .~ I i I s I ~ I w
i
~Z Z ~Z Z vZ ~ ~Z Z ez z ~Z
-Z z vz 'z z.z -z " .z z ~z
Z.z
z
wl ~I ~I ~I wl ~I wl I
O
z O s z m' z
N N
U U
Z ~ U U U U
c~
tx =Z U ~ ~ io io '~ =Z V
U U V U U
Z Z
U U
m
a. o ~-~ N c~ yn cD r~
N N N N N N N N
N N N N N N N N
CA 02483020 2004-11-03
Table 41
N e'~
OrD O ~ ~O
t0 ~G M tn tp 1~ ~G m r N 07 h. (O N
f~ (O tG SD ~ fn N fn ~ h N t~ ts7 tt7
u5 c0 f/j fn o~D, CAD. ~ ~ '~~j ~ ~ ~C CC cD
r ~ M M '~ ~ ~' '~ 'a' ~ M O ~ O
.., ~ ~- r r r r ~ M n, ~ r O
a~ Z Z co cc Z Z Z Z ~r ~. ri c~~ ,W
r p1 r r C' N n N r r r r r r
°0 pZZ or- rN ~Z~ OZZ OZZ
N 00 N eS" tf' O f~; 1~ N ~ ~ N N 1(! N d ~O
~ f'~ f~ ~ L1. LL N(j (~ Z et = CD M = O r-
r t~7 ~ ~ M = of 07 = r 0 N d. e~' ~:
tOlf) . _= NCO QO~~ r== r== .M==
d ~c~~'? mm~ ~~ COeI' ~Ojc~ fnetM ~r~ ~~1NC~
N = _ ~, ~ ~ o~ '~ v
~'o~ o O = ~ ~n,n m ~
Z .. .. ~or ~~(~ Z ~ Z .. .. Z .. ..
Z~ c'~i c$ mU U Z ~ t~c~ ~ M c~U U c~U V °° U U
~y ~~n N~ ~ ~.. .. U~~ _ ~ c Z ~ c Z ~ c
~UU Nca o UU ~oUU ~~ o Nas o Nra o
_ ~ c UUu- Nti ~ Z ~ c UUu. UUts. UUti
U U t° U U ti V U li
~n n. a~ ~.. r cmn c~ er n. M a r. oo sn
N o co c» co a co o~ co o~ ~ r. o~ co o c~
V ~~, h~~- tf?r Inr efr CGMr tOr (pr
r r r T r r r r r r r T r T r
N ~ ~ N ~ T
MN ~~ MM M _._. _-M~~ M~ MM
1~ r T~ Ch P~ t'0 h. N 1~. M 1~ In C~ i~ C9 1~ CO
H rT r~ rr rr rr rrr rr rr
c' O~ oo ~- 1~ tp I~ _t0 N
N N N N ~r
O ~~ ~ , ,
O ~ ~ ~ oo~ o o N
~y r r- r N N N N r
Z
iE tY. Qi Ow Pr' Qi ~.i C4' Pr'
O
m_
I \ ~'' \ \ \ \ I \ \
/ I/ I/ I/ I/ I/ / I/
Z v Z vZ Z vZ Z Z ~ Z ~Z Z v
°' Z, Z Z.Z Z.Z n Z Z, z Z.Z Z.ZZ Z_ ~Z
\ ( \ I ~~, I I \ I \ I \ I
O U
ap ti O 1i U Z Ue.~ Z
Z
S Z ~ ~ Z ~ Z Z
U U U U U U U U
\ \ '\ ~. \ \ \ \
I/ I/ I/ I/ I/ I/ I/ !/
C. 00 C: O ~-~ N M et' W
N N M M C'~ f0 c~ M
N N N N N N N N
86
CA 02483020 2004-11-03
Table 42
co co
MM
~ci Sri m ~
c~~N ~N ~~ N~
f0 CC lI7 CO - - (n r
p r f0 l69 le i~
!lJ Cl) Cl? Cn ~_P' V_' U7 U Cl) ~lJ tn N
47 OD O et Z Z M A N O
C9 M t~ M p ~p tO ~O CO GD Z Z
r r r r M r r r r r p p
zZ OzZ MM ~ZZ OZZ ~ta~
CO tn N C~ N r r N CL1 0 N O ~h
td M ~ Z in In ~ ~ ~ iW : x tn ~fl Z f' r N~ LL
= m m co ~. ~ yn ui
°i~ oii N°~ i
cn ~ rMM Uo~N ~o~o oeF~r
°' n~ cNOv
in d' ~ ua ~' o N
v= = O O CJ~ ~ Z
Zco o z~c.NO, Ooi. Zus°rW
NUU R;UU zcoac cNVUU n,UU
_~c =~c COvv =tic Sic ~i'on.
~o- ~ ao- ~ ~ in- ~ o_~- ~ co~j U
Nca Q Ncc Q UU N~s Q m Q
UUtL UUu. ~ti j UUti UUu.
UUti UUu°.
co o~ N o ec os ~c o~ c~ re ors o co so ~
N ~ 1~. O In r tt) r N CO h~ V
v ~r rr rr pr ~M ~O M laM
r rr r r rr
> CC ~ O O Es N t0 ~ 09
Mr MN CO~ rM-et ~001~ ~C~ ~C~O strld9
~M PAM 6nN AM 1'~el'r h~M h~r h.l~r
r r r r r r r r r r r r r r r r r r
v n
N N p N O 4 O O
~ r N N N N N
~ $ ~ ~t
N N r N N ~ N N
z
3t x x x ~ G; x x x
O
I ~ I ~ ~ I ~' I ~ w
i z' i I i i i
z 'z ~~ z
z 'z z. Z'z Z 'z Z 'z z 'z Z 'z z '
z.Z z ~ z.~ z. z.Z z.z n z
z z-z
i ~ ~ w I / ~ i i
o W y ~. I ~ I ~ I
m ~I z m'
N N
_ U U U U U U
N N
t'7 N
I ~ I / I r I r C~ U
\ / \
ss. co c~ oo a: o ,-, cu c~
c~c Z n' r= m c~ 'd° ~ ~ d'
N N N N N
~7
CA 02483020 2004-11-03
Table 43
a a~°o ~i m
M M CV CV r r
r r r r r r f~ ~
fn fn fn !n ell Cl~ V? !O
0 0 ~ O 4 0h
rr y~'-.r il~rl~7 N~
oZZ QZZ ~ZZ UZZ
ZOO =NO =OtD N~~tO
r O N ~" c~ r~ .- st ca = O os I i i
~'. ~r= In tt1 p 'cf' ~' r d' tt ~ V' ~
~' NSF N=r N=Z oZZ
't W r ~' f~~ I 1 ~ ~ N ~ ~ !~%.
O~I~CI~ Otlt
Z .. Z .. Z .. Z ..
NUU n,UU ~N"UC) mUU
~fC p Nl0 Q NfC Q ~~ O
UUtL UUu. UUu. UUti
m~
v r r r~ v-_ r_ r r r I I I
tD r O t0 C~1 tt9 OD in O OD h
Q? f~. N ~D lh N r y~. 07 N
t0 r P r h. ~ 1~. '?' r ~D C9
H rr rr e~r rrr rr
R
v
$~Nr~NN
I I
V ~ ~ N ~ N N
t
Z
Z iE fx C' t:,' W' p.'
\ \ \ \ \
I/ I/ I/ Ir I/ I/ I/
\ Z
Z y ~ vZ Z y I Z vz Z
Z,ZZ Z.Z Z_Z Z_Z / Z.Z Z.ZZ
/ / ~ Z y.
I \ I \ I \ I z.= ~ I \ I \ I
_ rn rn tn z cn
U Z Z Z = ~
N N
z = , , ,
U U g
U U U U
N N
Co c~7 \ =Z SZ \ \ \
U U I/ - - I/ I/ I/
~e ~e
a, ~r O cc c~ oo m o
~r rr ~r tr rr mn
N N N N N N N N
CA 02483020 2004-11-03
Example 252 - 266
The compounds which were shown in Tables 44 to 45 were synthesized in a
manner similar to those described in Example 15'7.
89
CA 02483020 2004-11-03
Table 44
=i
BZSZ t=.'==__=NN_
G. C9 = IV t~7 ~ hl nj = ~ N t~'~ = ni N = '- N ~ _ __ O fh v
tp O Z N V~ S ~ CO , ~ N S ~ ~Y Z N 60 ~ N S ~ ~ N N S = Q1
t0 = O rb = ~ ~ _ _ tD ~ ~ m = ~ ~ _ _ V' CD CD = = et et nj
~" ~ fC r tp r t0 In ... r tp r f0 h P7 ~ Q d _
il ~ Z 11 II ~ Z 11 II _ 11 O 11 N ~ I 11 II Z il r. r (p m
~ ~O t9 '~ '? ~O M -7 ~ O ~ ~ (p 7 ? ~C Ch 7 ~ ~ ~ ~! II 11 ~ ~ II li
~~~v ~7 '7-7 C~J
h- h. r m CD CC In N eh ~ N ~ LP7 ~ ~ O ~ ~ CAD n
O C~ r I~ CO OD V' tC9 00 1~ O In CD O 07 CA N ~ 'C ~ 'C (p h~ N
OrN'~ OONCO OOC~ Or~"~ CCLV~ OONd' ~~~ p~p»
OON
N P) ~ ~
.a
0 0 O t0 0 0 O h t0 ~ C~
~nr cpr <nr Or Cco O~ Oret rN
rr rr rr Nr Nr Nr Nrr ~'r
~~Od' NN ~N O.-N O~-Lf7 Of~C9 O~GetN V~'ehr
OODr Or0 Ortn IrNIO7~ OrM
~r CM~r C~~eN~- f~tCN C91~~- COhr ~D/~Wr NPr
(hrr Orr ('err (Qrrr Orr
I1
O /1 ~ O N
r r ( N P7 ' r
r _
"~..C O ~ O N st
r r N C~7 r
r
aE (3.~' P.i' P'., I~.,' CL' ~' Rr' R.i'
O
N
S
S~ * ~ c O o ~ O ~ O O
u' U O O U U U U U
U U
LC
N
Z Z U Z Z ~ U 2
A: U U ~ N U l.) ~ U
ti
w \ w w p' ~ ~ p ' cn
f~ ~~ I~ i i i
°° z ~ z ~ z ~
O O O O z.Z'~ z.~z z.Zz
w
a
z
U U
_ U U U U U ~ U
N N N N N ~ N
N f~ M ~~'7 ~ N ~ M
U U U U U = I / U
U
a~
G. . N M Q' tf~ Cp Ice- 00 Q7
lf.' Lf~ LC~ LCD In In l.t~ LC~
yC ~r N N N N N N N N
CA 02483020 2004-11-03
Table 45
'-~_~'_ ==i
r r r r
~ r ~~ N N N N
O, 0~~117 ~,~Otfl
>a ~U r t~ '~ ~., v ~ tD Vi
_~_'~,''~. °~°~r~fc I I I i I
tGN ~ N»7
!~ t~ S ~! th ~
N dy _ ~~
NQO tpE~D~t~O.
CO ~ ~ Z N lV ch V'
v a-
O et O Itf O
~~M
N r r I I ( I I
wr~ OODr O~Net
Ortn OrOtn
CwO1~hr ~lfh~!nr
r r ~ r r r
/S
1 I I I I I I
0
N
OJ N
O O O V V O O
, , , , , , ,
N = N
°' U = U Z = U Zv
I/ I/ U U I/ U
w ~ v ... O I i i ,~ I i
i i
U U U U
Z= ZS III III III III
\ UO UO U U U U
I / ~ w ~ w w ~ ~, ~ y
i i
U
U
_~
Z S = Z T S
, , ,
Z Z Z Z S
U U U U U U
U
~ N
U I \ I I I I I
-- .~ / / / s /
p. O ~ N M ~' tfJ CD
CO to Cp cp ca O O
k N N N N N C1'I N
~1
CA 02483020 2004-11-03
Example 267
The compounds which were shown in Tables 46 were synthesized in a manner
similar to those described in Example 92.
92
CA 02483020 2004-11-03
Table 46
wo=
r
40 ~ N C9 tn =
r. N 'g [~ ~ 9
c~
=rnoi
u~ _~''i o0
Gr' C~ c'~ Z M ~ = T~3
~- r CO r CV
ef nj t'9 ~j ~f
OD=r ~~CO
~~ N
td
O O M ~ _
GO (G d' h. II i'7
(V '3 CO N ~ 07
O_ ~_
... (Q~- Mr
~N ~N
~t ~r
~N
O l~ p N
MN Nc7
O
V r r
CL--C # ~O ~ CAD
r
N
C_0
O n.'rL
C ~ O
O
O U
U I
I
'-' U U
n~ m
U U
I
N N
_ U v
x Iw Iw
c~ o
M N N
W
93
CA 02483020 2004-11-03
Test examples on the compounds of the present invention are described below.
The test compounds are the ones described in the Examples and Tables.
Test example
(1) Isolation and purification of MMP-9 (92 kDa, gelatinase B)
Type IV collagenase (MMP-9) was purified according to the methods descrived
in the following literature. Scott M. Wilhelm et al., J. Biol. Chem., 264,
17213-17221,
{1989), SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV
Collagenase Which Is Identical to That Secreted by Normal Human Macrophages;
Yasunori Okada et al., J. Biol. Chem., 267, 21712-21719, (1992), Matrix
Metalloproteinase 9 (92-kDa Gelatinase I Type IV Collagenase) from HT 1080
Human
Fibrosarcoma Cells; Robin V. Ward et al., Biochem. J., (1991) 278, 1?9-187,
The
purification of tissue inhibitor of metalloproteinase-2 from its 72 kDa
progelatinase
complex.
MMP-9 is secreted from human fibrosarcoma cell line ATCC HT 1080, into its
culture medium when it is stimulated with 12-tetradecanoylphorbol-13-acetate
(TPA).
The production of MMP-9 in this culture was verified by the gelatin zymography
as
described in the following literature (Hidekazu Tanaka et al., (1993) Biochem.
Biophys.
Res. Commun., 190, ?32-740, Molecular cloning and manifestation of mouse 105-
kDa
gelatinase cDNA). The condition medium of the stimulated HT 1080 was
concentrated and was purified with gelatin-Sepharose 4B, concanavalin A-
sepharose,
and Sephacryl S-200. The purified pro-MMP-9 (92 kDa, gelatinase B) thus
obtained
gave a single positive band in the gelatin zymography. Subsequently, activated
MMP-9 was obtained by treating the pro-MMP-9 with trypsin.
(2) Assay methods of type IV collagenase inhibitors
Collagenase assay was performed using the activated MMP-9 described above
and the substrate supplied in the type IV collagenase activity kit (YAGAI,
inc.),
according to the manufacturer's protocol. The following 4 assays are performed
per
compound (inhibitor).
94
CA 02483020 2004-11-03
(A) substrate (type IV collagenase), enzyme (MMP-9), inhibitor
(B) substrate (type IV collagenase), inhibitor
(C) substrate (type IV collagenase), enzyme (MMP-9)
(D) substrate (type IV collagenase)
According to the manufacturer's protocol, fluorescent intensity was measured
and percent inhibition was determined by the following equation.
Inhibition (%) _ {l - (A - B) l (C - D)} x 100
ICso is a concentration at which the percent inhibition reaches 50 %. The
results are shown in Tables 47 to 54.
CA 02483020 2004-11-03
Table 4?
Exam le No. Com ound No. ICso C ) Com ound No. ICSO t )
1 la-1-1 0 2 4 ib-1-1 0 . 0 3 0
.
2 la-i-2 2 6 lb-1-2 0 . 0 4
.
3 la-1-3 0 1 8 lb-1-3 0 . 0 0 5
.
4 la-1-4 2. 2 5
la-1-5 0 8 1 Ib-1-5 0. 0 4 1
.
6 la-1-6 0 6 8 lb-1-6 0. 0 3 4
7 . 1b-1-? 0. 0 2 8
8 la-I-8 0 lb-1-8 2 . 0
2
.
9 lb-1-9 0. 41
1 0 ib-1-10 2. 1
1 1 ib-1-11 1 . 7
1 2 lb-1-12 0. 0 8 5
1 3 lb-1-13 0. 3 8
1 4 la-1-14 3 7 lb-1-14 0 . 1 1
.
1 5 lb-1-15 0 . 0 2 7
1 6 la-1-16 0. 5 2 Ib-i-16 0. 0 1 0
0 8
1 7 la-1-I? 0. 2 0 Ib-1-1? 0. 0 2 0
5 3
1 8 la-1-18 0. 5 0 lb-1-18 0 . 0 2 8
0 2
2 0 lb-1-20 0 . 1 3 4
2 1 la-1-2I 4. 6 5 lb-1-21 0. 0 0 4
1
2 3 lb-I-23 0. 0 ? 3
2 4 lb-I-24 0 . 2
2 6 ib-1-2fi 1. 3
2 ? lb-1-27 3 . 0
3 0 la-1-30 1 1 6 1b-1-30 0. 2 1 3
3 1 . lb-1-31 0. 0 1 2
9
96
CA 02483020 2004-11-03
Table 48
Exam le No. Com ound ICso ( ) Compound ICso ( )
3 3 No. 0 . 2 4 No. 0 . 0 0 5
la-1-33 lb-1-33
3 5 la-1-35 2. 6 lb-1-35 0 . 0 2 1
6
3 8 la-1-38 0. 0 1 8
4 0 la-1-40 0 . 0 ? 6
4 1 la-1-41 0 . 3 1 2
4 2 la-1-42 0. 0 1 2
3
4 3 la-1-43 0. 6 2 5
4 4 la-1-44 1 . 9 1 0
4 5 la-1-45 0 . 0 4 0
4 6 la-1-46 1 . 1 2
4 7 la-1-47 0 . 3 8 9
4 8 la-1-48 1 . 1 5
4 9 1a-1-49 0. 2 4 9
0 1a-1-50 0 . 5 5 3
5 1 1a-1.51 0 . 1 1 0
5 2 la-1-52 0. 3 2 9
5 3 la-1-53 1 . 8
5 4 1a-1-54 0. 0 ? 5
5 5 1a-1-55 0. 0 3 9
8
6 0 la-1-60 1 . 3 1 lb-1-60 0 . 0 0 1
2
6 1 la-1-61 0 . 2 4 7 lb-1-61 0. 2 4 ?
6 2 lb-1-62 3. 5 0
6 3 la-1-63 1. 0 5 lb-1-63 0. 0 0 0 3
9
6 4 la-1-64 1 . 9 0 lb-1-64 0. 0 0 3 7
6 5 la-1-65 0. 2 9 1 lb-1-65 0. 0 0 3 5
97
CA 02483020 2004-11-03
Table 49
Exam le No. Com ound ICSO (~.M) Com ound ICso ( )
6 7 No. No. 0. 0 0 6 1
la-1-67 lb-1-67
6 8 la-1-68 0-. 2 3 1
8 0 la-1-80 1 . 9 1
8 3 la-1-83 1 . 7 7
8 5 la-1-85 1 . 2 lb-1-85 0. 0 1 3
8 6 la-1-86 0. 3 5 lb-1-86 0. 0 0 5 3
8 7 lb-1-8'7 0 . 9 4 0
9 3 la-2-2 0 . 2 3 7
9 4 la-2-3 0 . 0 1 0
9
9 5 la-2-4 0. 0 7 5
9
9 6 la-2-5 0 . 1 2 3 _
9 7 la-2-6 0 . 0 8 8
98 la-2-'T 0. 0699
1 0 0 la-2-9 0 . 0 5 7
7
1 0 1 la-2-10 0 . 0 2 3
1 0 2 la-2-11 0 . 0 4 7
5
1 0 3 la-2-12 0. 0 9 8
1
1 0 4 la-2-13 3 . 2 8
1 0 5 la-2-14 2 . 9 8
1 0 6 la-2-15 0. 1 3 3
1 0 7 la-2-16 0. 3 2 5
1 0 9 la-2-18 1 . 1 9
1 1 0 la-2-19 0. 2 0 3
1 11 la-2-20 3. 41
1 1 2 la-2-21 3 . 7 4
1 1 4 la-2-23 0. 9 2 9
98
CA 02483020 2004-11-03
Table 50
Exam le No. Com ound ICso (N.M)
No.
11 5 la-2-24 0. 16I
1 1 7 Ia-2-26 1. 1 9
i 1 8 la-2-2 7 0 . 0 8 $
1 1 9 la-2-28 1. 1 1
1 2 0 la-2-29 1. 5 3
1 2 1 la-2-30 0. 0 7 3 6
1 2 2 la-2-31 0 .. 2 2 4
1 2 3 Ia-2-32 0 . 0 2 3
4
1 2 4 la-2-33 0 . 0 2 1
8
1 2 5 la-2-34 0 . 0 I 4
4
1 2 6 la-2-35 0 . 1 5 6
1 2 7 la-2-36 0 . 0 2 4
3
1 2 8 la-2-37 0 . 0 9 2
2
1 2 9 la-2-38 0. 2 2 2
1 6 0 Ia-3-2 0 . 0 4 0
1 6 I la-3-3 0 . 0 1 0
8
1 6 2 la-3-4 0. 8 7 3
1 6 3 la-3-5 0. 0 1 2 6
1 6 4 1a-3-6 0 . 0 9 6
5
1 6 5 1a-3-7 0. 2 3 0
1 6 6 Ia-3-8 1 . 2 8
1 6 7 la-3-9 0. 0 1 4
1 6 8 la-3-10 0 . 0 0 8
3
1 6 9 la-3-11 0. 2 4 4
1 7 0 la-3-12 2. 0 3
1 7 1 la-3-13 0. 0 3 9 5
99
CA 02483020 2004-11-03
Table 51
Exam Ie No. Com ound ICso C )
No.
1 ? 7 la-4-2 0 . 6 8 4
178 la-4-3 0. 0252
1 7 9 la-4-4 2 . 3 6
1 8 0 la-4-5 0 . 0 4 5
1 s 1 la-4-s o . 0 5 3
9
1 8 2 la-4-'7 0 . 0 0 5
9
1 8 3 la-4-8 0 . 0 0 2
?
1 8 4 la-4-9 0 . 0 0 3
2 5
185 la-4-10 0. 0422
186 la-4-11 0.0982
1 8 7 la-4-12 0. 1 7 7
1 8 8 la-4-13 0 . 8 4 3
189 la-4-14 0. 0375
1 9 0 la-4-15 0. 0 5 9 7
__ la-4-16 0 . 0 0 9
1 9 1 5
1 9 2 la-4-1? 0. 3 2 4
1 9 3 la-4-18 0. 7 2 2
1 9 5 1a-4-20 1 . 1
196 la-4-21 0.0573
1 9 7 la-4-22 0. 0 1 6 1
1 9 8 la-4-23 0 . 4 9 3
1 9 9 la-4-24 2 . 0 6
2 0 0 la-4-25 0 . 1 7 3
2 0 1 la-4-26 0 . 2 5 2
2 0 2 la-4-27 0 . 0 1 1
4
2 0 3 la-4-28 0 . 1 7 3
100
CA 02483020 2004-11-03
Table 52
Exam le No. Com ound ICSO ( ) Com ound No. IC3o ( )
No.
2 0 4 la-4-29 3 . 9 5
2 0 7 la-4-30 4 . 4 4
2 1 0 la-5-2 0 . 0 2 4
2 1 1 la-5-3 0 . 2 1 0 1 b - 2 1 1 0 . 0 0 5
fi 5
2 1 2 1a-5-4 0. 3 9 3
2 I 3 la-5-5 0. 1 2 8
2 1 4 la-5-6 0. 8 3 2
2 1 5 la-5- t 0 . 1 1 0
2 1 6 la-5-8 0. 1 0 7
2 1 8 1a-5-10 0 . 7 4 4
2 1 9 la-5-11 0 . 5 7 4
2 2 0 la-5-12 0 . 0 1 6 7
2 2 1 la-5-13 0 . 3 1 6
222 la-5-14 0. 078
2 2 3 la-5-15 0 . 3 4 9
2 2 4 la-1-16 0 . 0 1 0 1
2 2 5 la-5-17 0. 0 1 2 2
2 2 fi la-5-18 0. 1 fi 6
2 2 7 la-5-19 0. 0 1 9 8
2 2 8 la-5-20 0 . 1 0 fi
2 2 9 la-5-21 0 . 2 1 5
2 3 0 la-5-22 0 . 2 8 1
2 3 1 la-5-23 0. 1 9 7
2 3 2 la-5-24 0 . 1 4 4
233 la-5-25 0. 0864
2 3 4 la-5-26 0 . 1 5 3
101
CA 02483020 2004-11-03
Table 53
Exam le No. Com ound ICso ( ) Com~,ou_nd ICso ( )
No. No.
2 3 5 la-5-27 0. 2 6 5
2 3 6 la-5-28 0 . 3 0 4
2 3 7 la-5-29 1. 3 2
2 3 8 la-5-30 2 . 8 5
2 3 9 la-5-31 0 . 2 4 3
2 4 0 la-5-32 0 . 0 0 4
1
2 4 1 la-5-33 0 . 0 1 3
1
2 4 2 la-5-34 0 . 0 2 3
9
2 4 3 la-5-35 0 . 0 5 2
9
2 4 4 la-5-36 0 . 0 1 6
5
2 4 5 la-5-37 0 . 0 0 5
2 4 6 la-5-38 9
2 4 7 la-5-39 0 . 0 1 0
8
0 . 0 0 3
5
2 6 7 la-2-66 1 . 5 lb-2-66 0. 0 1 1
102
CA 02483020 2004-11-03
Table 54
Exam le No. Com ound ICso~)
No.
2 5 2 1-252 0 . 2 4
253 1-253 0. 000039
254 1-254 Oo 00063
2 5 5 1-255 0 . 5 2 9
2 5 6 1-258 0 . 6 0 1
2 5 7 1-25'7 0 . 7 ? 6
2 5 8 1-258 0 . 9 0 8
2 5 9 1-259 0 . 1 3 0
2 6 0 1-260 0 . 1 5 9
2 6 1 I-2so o . 1 8 2
I03
CA 02483020 2004-11-03
The compound of the present invention showed strong activity for inhibiting
type IV collagenase.
Industrial Applicability
It is considered that the compound of the present invention is useful to
prevent or treat osteoarthritis, rheumatoid arthritis, corneal ulceration,
periodontal
disease, metastasis and invasion of tumor, advanced: virus infection (e.g.,
HIV),
arteriosclerosis obliterans, arterioselerotic aneurysm, atherosclerosis,
restenosis,
sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis,
multiple
sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy,
neovascular
glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes,
nephritis,
neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis,
ocular
tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia,
anorexia,
acute infection, shock, autoimmune disease, malaria, Crohn disease,
meningitis, and
gastric ulcer, because the compound of the present invention has strong
inhibitory
activity against metalloproteinase, especially MMP.
104
