Note: Descriptions are shown in the official language in which they were submitted.
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
NOVEL COMPOUNDS AND COMPOSITIONS AS CATHEPSIN INHIBITORS
THE INVENTION
This Application relates to compounds and compositions for treating diseases
associated with cysteine protease activity, particularly diseases associated
with activity of
cathepsin S.
DESCRIPTION OF THE FIELD
Cysteine proteases represent a class of peptidases characterized by the
presence of
a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are
associated
with the normal degradation and processing of proteins. The aberrant activity
of cysteine
proteases, e.g., as a result of increase expression or enhanced activation,
however, rnay
have pathological consequences. In this regard, certain cysteine proteases are
associated
with a number of disease states, including arthritis, muscular dystrophy,
inflammation,
tumor invasion, glomerulonephritis, malaria, periodontal disease,
metachromatic
leukodystrophy and others. . An increase in cathepsin S activity contributes
to the
pathology and/or symptomatology of a number of diseases. Accordingly,
molecules that
. inhibit the activity of cathepsin S protease are useful as therapeutic
agents in the treatment
of such diseases.
1
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
SUMMARY OF THE INVENTION
This Application relates to corn'pounds of Formula I:
R3
R4 X1
O O
I
in which:
X' is -NHC(Rl)(Rz)Xz or -NHX3;
Xz is cyano, -C(R')(R8)X3, -C(R')(R8)CF3, -C(R')(R$)CF2CF2R9 -CH=CHS(O)zRs,
-C(O)CF2C(O)NRSRS, -C(O)C(O)NRSR6, -C(O)C(O)ORS, -C(O)CH20R5,
-C(O)CH2N(R6)S02R5 or -C(O)C(O)R5; wherein RS is (Cl_4)alkyl,
(CS_lo)aryl(Co_6)alkyl or
(CS_lo)heteroaryl(Co_6)alkyl; R6 is hydrogen or (Cl_6)alkyl; R' is hydrogen or
(Cl~,)alkyl and
R$ is hydroxy or R' and Rg together form oxo; R9 is hydrogen, halo,
(Cl~)alkyl,
(Cs-lo)~'Yl(Co-6)alkyl or (CS_lo)heteroaryl(Co_6)alkyl;
X3 comprises a heteromonocyclic ring containing 4 to 6 ring member atoms or a
fused heterobicyclic ring system containing 8 to 14. ring member atoms and any
carbocyclic ketone, iminoketone or thioketone derivative thereof;
wherein within R5, Xz or X3 any alicyclic or aromatic ring system may be
substituted further by 1 to 5 radicals independently selected from
(Gl_6)alkyl,
(Cl_6)alkylidene, cyano, halo, halo-substituted(Cl_4)alkyl, vitro, -X4NRIZRIZ,
_Xa~lzC(o)Rlz, -Xa~lzC(O)OR12~ -~r4~12G(O)~12R12' _X4~lzC~l2)~1zR12'
2~ -X4ORlz, -X4SRlz, -X4C ~ ORIZ, -X4C(O)R12~ -X40C(O)R12~ _X~al~Cl(~O)~12R12'
-X4S(~)2~12R12' -X4~12S(O~2R12' -X4p(O)(~R'z)ORIZ, -X40P(O)(ORIZ)ORIZ,
-Xa~lzC(O)Rls, -XøS(O)R13 and -X4S(O)zRl3 and/or 1 radical selected from -R14,
-XøOR14,
-X4SR1~, -X4S(O)R14' -X4S(O)2RI4' -X4C(O)R14' _X4~,(O)OR14, -X40C(O)R14' -
X4~14R12?
-X4~12G(O)R14' _Xa~lzC O OR'4 -X4C O NR'zRlz~ _~4s(~~2~14R12' -X4~12s(O)2R14'
-X4NRIZC(O)NRl4Rlz ~d _xa~lzC(~lz)~1aR12~ Wherein X4 is a bond or (Cl_6)alkyl;
Rlz
at each occurrence independently is hydrogen, (Cl_6)allcyl or halo-
substituted(Cl_6)alkyl; R13
is (Cl_6)alkyl or halo-substituted(C1_6)alkyl; and R14 is
(C3_lo)cycloalkyl(Co_6)alkyl,
2
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
hetero(C3_lo)cycloalkyl(Co_3)alkyl, (C6_lo)aryl(Co_6)alkyl,
hetero(CS_lo)~Yl(Co-s)a~'1,
(C9_lo)bicycloaryl(Co_6)alkyl or hetero(C$_lo)bicycloaryl(Co_6)alkyl;
Rl is hydrogen, halo or (C1_6)alkyl and Rz is selected from a group consisting
of
hydrogen, cyano, halo, -X4~l2Rlz~ -X4~12C(O)Rlz, _X4~12C(O)OR12~
Jr -X4~12Gr(Q)~12R12' _X4~12C~12)~12R12' -X4QR12' -X4SR12, -X4C 0 ORl ,
-X4~(Q)Rlz' -X4QC(Q)R12' _X\4lC~l(~Q)~1zR12' _X4f(~)z~lzRlz' -X4~12~r(Q)2R12'
-X4P(O)(OR12)ORlz, -X40P(O)(ORIZ)OR12, -X4NRI2C(0)R13, -X4S(0)R13' -
X4S(Q)2R13'
-R14' -X4QR14' -X4'~'~R14' -X4Sr(Q)R14' -x4s(Q)2R14~ -X4C(Q)R147 -X4C(Q)QRI4' -
X40C(O)R14~
-X4~14R12' -X4~12~(Q)R14' _X4~12Gr(Q)OR14, -X4C(0)NRlzRlz' _X4S(O)z~l4Rlz'
-X4NR12S(O)ZR14, -X4~12~(Q)~l4Rlz ~d -X4~12~~12)~14R12' wherein X4, R12~ R13
and R14 are as defined above; or R' and R2 taken together with the carbon atom
to which
both R' and Rz are attached form (C3_8)cycloalkylene or
(C3_8)heterocycloalkylene; wherein
within said Rz any heteroaryl, aryl, cycloalkyl, heterocycloalkyl,
cycloalkylene or
heterocycloallcylene is optionally substituted with 1 to 3 radicals
independently selected
from (Cl_6)alkyl, (Cl_6)alkylidene, cyano, halo, halo-substituted(Cl~,)alkyl,
vitro,
-X4~lzRlz' -X4~lzC(Q)Rlz' -X4~lz~(Q)QRlz' -~r4~12C(Q)~12R12'
_X4~12C~12)~12R12' -X4QR12' _X4~rR12' -X4C(O OR12, -X4C(O)R12~ _X40C(O)R12~
-X4C(O)~ll~llz~Rlz~ -X4S(Q)z~12R12' -X4~lzs(0)zRl2a -X4p(O)(OR12)ORIZ,
-X40P(0)(ORIZ)OR12, -X4NRIZC(0)Rl3a ,X4S(O)R13~ -X4s(O)2R13 ~d X4C(O)R13,
wherein
X4, R12 and R13 are as defined above;
R3 is -C(R6)(R6)X5, wherein R6 is as defined above and XS is selected from
-X4~I2R12~ -X4~IZC(Q)RIZ' -X4~I2C(Q)QR12' -X4~iZ~(Q)~12Ri2'
-X4~12Gr~12)~12R12' -X4QR12' -X4~rR12' -X4w(Q)QR12' -X4~(O)R12' -X4QC(Q)R12'
-X4C(O)~11~112~R12~ _X4f(O)z~lzRlz~ -X4~lzs(O)zRlz~ -X4p(O)(OR12)ORIZ, _X4Rlz~
-X40P 0 OR1Z OR1Z, -X4C(0)R13' -X4~12~(Q)R13' -X4~r(Q)R13 and -X4s(0)ZR13' -
R14'
-X4QR14' -X4SR14' -X4s(Q)R14' -X4s(Q)2R14' _X4~(O)R14' -X4C(Q)QR14' -
X4QC(Q)R14'
-X4~14R12' -X4~12~(Q)R14' -X4~12~(~)QR14' -X4~r(Q)~14R12' -~4S(Q)2~14RI2'
-X4~IZS(Q)ZR14' -X4~12~(Q)~1L4VRt1~2 ~d -X4~lzC( l~~ 1z) ~V~1~14R12 wherein
X4, Rlz, R13
and R14 are as defined above;
R4 is NR6R6, NR6R14a _~sRls or NR6XSC(O)R14 wherein R6, XS and R14 are
as described above and Rls is hydrogen, -(Cl_6)alkyl or -XSOR6 wherein XS is
as described
3
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
above; or R6 and Rls together with the nitrogen atom to which R6 and Rls are
attached form
hetero(C3_lo)cYcloalkyl, hetero(CS_lo)aryl or hetero(C8_lo)bicycloaryl;
wherein within R3 and R4 any alicyclic or aromatic ring system may be
substituted
further by 1-5 radicals independently selected from (C1_6)alkyl,
(Cl_6)allcylidene, cyano,
halo, halo-substituted(CI_4)allcyl, nitro, -X4NRIZRIZ, -X4NRIZC(O)Rlz, -
X4NR12C(O)ORIZ,
-X4~12~(O)~12R12' -X4~12~~12)~12R12' -X40R12' -X4SR12' -X4C(O)OR12'
-x4l~Vr(i~O)R12' 1V-1X~4O~r(O)RI21'Vt~-X4\~~r(~lO~)~1V11~2RI2' -
X4~r(O)2~IZRI2' -X4~12~(O)2R12'
-X4P(O)(OR12)ORIZ, -X40P(O)(ORIZ)ORIZ, -X4NRI2C(O)R13~ -X4S(O)RI3~ -X4C(O)RIS
~d
-X4S(O)2R13 and/or 1 ~ radical selected from -R'4, -X4OR14, -X4SRI4, -
X4S(O)R14,
-X4S(O)2R14' -X4C(O)RI4~ -X4C(O)OR14, -X4OC(O)R14, -X4NR14R12~ -X4~12C(O)R14~
-X4~12C(O)OR14' -X4Gr(0~~14R12' _X4~,(O)2~14R12' -X4~12~r(O)2R14'
-X4~12G(O)~14RI2 ~d -X4~12C~12)~14R12; and within R3 and R4 any aliphatic
moiety may be substituted further by 1-5 radicals independently selected from
cyano, halo,
IlltrO, -NR12R12' ~lz~(O)RI2, -~lz~(O)ORIZ' -~lz~(O)~1zR12' -~1z~~12)~lzRlz'
-ORIZ, -SRIZ, -C(O)ORIZ, -C(O)R12~ -OC(O)Rlz~ -C(O)~l2RIZ~ -S(O)2~12R12~
-~125(O)zRlz~ -p(p)(OR12)ORIZ, -OP(O)(ORIZ)ORIZ, _NRIZC(O)R13~ -S(O)RIS ~d _
S(O)2R13; wherein X4, Rlz, RI3 and R14 are as described above;
with the proviso that only one bicyclic ring structure is present within R3 or
R4; and
the N oxide derivatives, prodrug derivatives, protected derivatives,
individual isomers and
mixtures of isomers thereof; and the pharmaceutically acceptable salts and
solvates (e.g.
hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives,
protected
derivatives, individual isomers and mixtures of isomers thereof.
A second aspect of the invention is a pharmaceutical composition which
contains
a compound of Formula I or a N oxide derivative, individual isomer or mixture
of isomers
thereof, or a pharmaceutically acceptable salt thereof, in admixture with one
or more
suitable excipients.
A third aspect of the invention is a method for treating a disease in an
animal in
which inhibition of cathepsin S can prevent, inhibit or ameliorate the
pathology and/or
symptomatology of the disease, which method comprises administering to the
animal a
therapeutically effective amount of compound of Formula I or a N oxide
derivative,
individual isomer or mixture of isomers thereof; or a pharmaceutically
acceptable salt
4
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
thereof.
A fourth aspect of the invention is the processes for preparing compounds of
Formula I and the N oxide derivatives, prodrug derivatives, protected
derivatives,
individual isomers and mixtures of isomers thereof; and the pharmaceutically
acceptable
salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
Unless otherwise stated, the following terms used in the specification and
claims
are defined for the purposes of this Application and have the following
meanings.
"Alicyclic" means a moiety characterized by arrangement of the carbon atoms in
closed non-aromatic ring structures having properties resembling those of
aliphatics and
may be saturated or partially unsaturated with two or more double or triple
bonds.
"Aliphatic" means a moiety characterized by a straight or branched chain
arrangement of the constituent carbon atoms and may be saturated or partially
unsaturated
with two or more double or triple bonds.
"Alkyl" represented by itself means a straight or branched, saturated or
unsaturated,
aliphatic radical having the number of carbon atoms indicated (e.g.,
(CI_6)alkyl includes
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tent-butyl,
vinyl, allyl,
1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl,
ethynyl,
1-propynyl, 2-propynyl, and the like). Alkyl represented along with another
xadical (e.g.,
as in arylalkyl) means a straight or branched, saturated or unsaturated
aliphatic divalent
radical having the number of atoms indicated or when no atoms are indicated
means a bond
(e.g., (C6_lo)aryl(Co_3)alkyl includes phenyl, benzyl, phenethyl, 1-
phenylethyl
3-phenylpropyl, and the like).
"Alkylene", unless indicated otherwise, means a straight or branched,
saturated or
unsaturated, aliphatic, divalent radical having the number of carbon atoms
indicated (e.g.,
(C,_6)alkylene includes methylene (-CHZ ), ethylene (-CHzCH2 ), trimethylene
(-CHZCHZCHz ), tetramethylene (-CHZCHZCH~CHz ) 2-butenylene (-CHzCH=CHCHZ ),
5
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
2-methyltetramethylene (-CHZCH(CH3)CHZCHz ), pentamethylene
(-CHzCH2CH2CH2CH2-) and the like).
"Alkylidene" means a straight or branched saturated or unsaturated, aliphatic,
divalent radical having the number of carbon atoms indicated (e.g.
(C,_6)alkylidene
S includes methylidene (=CHz), ethylidene (=CHCH3), isopropylidene (=C(CH3)z),
propylidene (=CHCHZCH3), allylidene (=CH-CH=CHz), and the like).
"Amino" means the radical -NH2. Unless indicated otherwise, the compounds of
the invention containing amino moieties include protected derivatives thereof.
Suitable
protecting groups for amino moieties include acetyl, test-butoxycarbonyl,
I O benzyloxycarbonyl, and the like.
"Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits,
cattle,
horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds,
and the like).
"Aromatic" means a moiety wherein the constituent atoms make up an unsaturated
ring system, all atoms in the ring system are spz hybridized and the total
number of pi
1 S electrons is equal to 4n+2.
"Aryl" means a monocyclic or fused bicyclic ring assembly containing the total
number of ring carbon atoms indicated, wherein each ring is comprised of 6
ring carbon
atoms and is aromatic or when fused with a second ring forms an aromatic ring
assembly.
For example, optionally substituted (C~lo)aryl as used in this Application
includes, but is
20 not limited to, biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl, 2-
bromo-
S-fluorophenyl, 4-tent-butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-
nitrophenyl,
2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl, 4-
chlorocarbonylphenyl,
2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-
chloro-
2-nitrophenyl, 2,6-dibromophenyl, 2,3-dichlorophenyl, 2,S-dichlorophenyl,
2S 3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,S-dimethylphenyl,
2-ethoxycarbonylphenyl, 2-fluorophenyl, 2-iodophenyl, 4-isopropylphenyl,
2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-
methylphenyl,
S-methyl-2-nitrophenyl, 4-methylsulfonylphenyl, naphth-2-y1, 2-nitrophenyl,
3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl,
30 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-
trifluoromethoxyphenyl,
2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
6
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
2-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, and the
like. Optionally
substituted (C6_,o)arYl as used in this Application includes 3-acetylphenyl,
3-tent-butoxycarbonylaminomethylphenyl, biphenyl-4-yl, 3-hydroxyphenyl,
4-hydroxyphenyl, 3-methoxyphenyl, naphth-2-yl, 3-phenoxyphenyl, phenyl, and
the like.
"Bicycloaryl" means a bicyclic ring assembly containing the number of ring
carbon
atoms indicated, wherein the rings are linked by a single bond or fused and at
least one of
the rings comprising the assembly is aromatic, and any carbocyclic ketone,
thioketone or
iminoketone derivative thereof (e.g., (C9_lo)bicycloaryl includes
cyclohexylphenyl,
1,2-dihydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl,
1,2,3,4-tetrahydronaphthyl, and the like).
"Carbamoyl" means the radical -C(O)NHz. Unless indicated otherwise, the
compounds of the invention containing carbamoyl moieties include protected
derivatives
thereof. Suitable protecting groups for carbamoyl moieties include acetyl,
tent-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected
and
protected derivatives fall within the scope of the invention.
"Carbocyclic ketone derivative" means a derivative containing the moiety
-C(O)-.
"Carboxy" means the radical -C(O)OH. Unless indicated otherwise, the
compounds of the invention containing carboxy moieties include protected
derivatives
thereof. Suitable protecting groups for carboxy moieties include benzyl, tey~t-
butyl, and the
like.
"Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused
bicyclic
or bridged polycyclic ring assembly containing the number of ring carbon atoms
indicated,
and any carbocyclic ketone, thioketone or iminoketone derivative thereof
(e.g.,
(C3-~o)cYcloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexenyl,
2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl,
oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl,
and the
like).
"Cycloalkylene" means a divalent saturated or partially unsaturated,
monocyclic
ring or bridged polycyclic ring assembly containing the number of ring carbon
atoms
indicated, and any carbocyclic ketone, thioketone or iminoketone derivative
thereof. For
7
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
example, the instance wherein "R' and RZ together with the carbon atom to
which both RI
and R2 are attached form (C3_8)cycloalkylene" includes, but is not limited to,
the following:
-~ N C=N y N C=N -~ N C=N
"Disease" specifically includes any unhealthy condition of an animal or part
thereof
and includes an unhealthy condition that may be caused by, or incident to,
medical or
veterinary therapy applied to that animal, i.e., the "side effects" of such
therapy.
"Halo" means fluoro, chloro, bromo or iodo:
"Halo-substituted alkyl", as an isolated group or part of a larger group,
means
"alkyl" substituted by one or more "halo" atoms, as such tenors are defined in
this
Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl,
trihaloalkyl,
perhaloalkyl and the like (e.g. halo-substituted (C,_3)alkyl includes
chloromethyl,
dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
perfluoroethyl,
2,2,2-trifluoro-1,1-dichloroethyl, and the like).
"Heteroatom moiety" includes -N=, -NR-, -O-, -S- or -S(O)z-, wherein R is
hydrogen, (C,_6)alkyl or a protecting group.
"Heterocycloalkylene" means cycloalkylene, as defined in this Application,
provided that one or more of the ring member carbon atoms indicated, is
replaced by
heteroatom moiety selected from -N=, -NR-, -O-, -S- or -S(O)S-, wherein R is
hydrogen or
(C~-s)alkyl. For example, the instance wherein Rl and RZ together with the
carbon atom to
which both R' and RZ are attached form hetero(C3_8)cycloalkyl" includes, but
is not limited
to, the following:
-~-N C=N -~ N C=N -~-N C=N -~ N C=N
N y
O R O~ SAO
8
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
in which R is hydrogen, (C,_6)alkyl, or a protecting group.
"Heteroaryl" means aryl, as defined in this Application, provided that one or
more
of the ring carbon atoms indicated are replaced by a heteroatom moiety
selected from -N--,
-NR-, -O- or -S-, wherein R is hydrogen, (C,_6)alkyl, a protecting group or
represents the
free valence which serves as the point of attachment to a ring nitrogen, and
each ring is
comprised of 5 or 6 ring atoms. For example, optionally substituted
hetero(CS_,o)aryl as
used in this Application includes, but is not limited to, 4-amino-2-
hydroxypyrimidin-5-yl,
benzothiazol-2-yl, 1H benzoimidazol-2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-
yl,
4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl, 5-carboxy-2,6-dimethylpyrid-3-
yl,
3,5-dimethylisoxazol-4-yl, S-ethoxy-2,6-dimethylpyrid-3-yI, 5-fluoro-
6-hydroxypyrimidin-4-yl, fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl,
8-hydroxy-
5,7-dimethylquinolin-2-yl, 5-hydroxymethylisoxazol-3-yl, 3-hydroxy-6-
methylpyrid-2-yl,
3-hydroxypyrid-2-yl, 1H imidazol-2-yl, IH imidazol-4-yl, 1H indol-3-yl,
isothiazol-4-yI,
isoxazol-4-yl, 2-methylfur-3-yl, 5-methylfur-2-yl, 1-methyl-1H imidazol-2-yl,
5-methyl-
3H imidazol-4-yl, 5-methylisoxazol-3-yl, 5-methyl-ZH pyrazol-3-yl, 3-
methylpyrid-2-yl,
4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylpyrid-3-
yl,
2-methylthiazol-4-yl, 5-nitropyrid-2-yl, ZH pyrazol-3-yl, 3H pyrazol-4-yl,
pyridazin-3-yl,
pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2H [1,2,4]triazol-3-yl,
pyrimidin_4-yl,
pyrimidin-5-yl, 1H pyrrol-3-yl, quinolin-2-yl, 1H tetrazol-5-yl, thiazol-2-yl,
thiazol-5-yl,
thien-2-yl, thien-3-yI, ZH [1,2,4]triazol-3-yl, 3H [1,2,3]triazol-4-yl,
5-trifluoromethylpyrid-2-yl, and the like. Suitable protecting groups include
tart-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-
nitrobenzyl, and the
like. Optionally substituted hetero(CS_,o)aryl as used in this Application to
define R4
includes benzofur-2-yl, fur-2-yl, fur-3-yl, pyrid-3-yl, pyrid-4-yl, quinol-2-
yl, quinol-3-yl,
thien-2-yl, thien-3-yl, and the like.
"Heterobicycloaryl" means bicycloaryl, as defined in this Application,
provided
that one or more of the ring carbon atoms indicated are replaced by a
heteroatom moiety
selected from -N=, -NR-, -O- or -S-, wherein R is hydrogen, (Cl_~)alkyl, a
protecting group
or represents the free valence which serves as the point of attachment to a
ring nitrogen,
and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For
example,
optionally substituted hetero(C8_,o)bicycloaryl as used in this Application
includes, but is
9
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, and the like. In
general, the term
heterobicycloaryl as used in this Application includes, for example,
benzo[1,3]dioxol-5-yl,
3,4-dihydro-2H [1,8]naphthyridinyl, 3,4-dihydro-2H quinolinyl, 2,4-dioxo-3,4-
dihydro
2H quinazolinyl, 1,2,3,4,5,6-hexahydro[2,2')bipyridinylyl, 3-oxo
S 2,3-dihydrobenzo[1,4]oxazinyl, 5,6,7,8-tetrahydroquinolinyl, and the like.
"Heterocycloalkyl" means cycloalkyl, as defined in this Application, provided
that
one or more of the ring carbon atoms indicated are replaced by a heteroatom
moiety
selected from -N=, -NR-, -O- or -S-, wherein R is hydrogen, (C,$)alkyl, a
protecting group
or represents the free valence which serves as the point of attachment to a
ring nitrogen,
and any carbocyclic ketone, thioketone or iminoketone derivative thereof
(e.g., the term
hetero(CS_,~)cycloalkyl includes imidazolidinyl, morpholinyl, piperazinyl,
piperidyl,
pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like). Suitable protecting
groups include
tart-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-
nitrobenzyl, and the
like. Both the unprotected and protected derivatives fall within the scope of
the invention.
"Hydroxy" means the radical -OH. Unless indicated otherwise, the compounds of
the invention containing hydroxy radicals include protected derivatives
thereof. Suitable
protecting groups for hydroxy moieties include benzyl and the like.
"Iminoketone derivative" means a derivative containing the moiety -C(NR)-,
wherein R is hydrogen or (C,_6)alkyl.
"Isomers" mean compounds of Formula I having identical molecular formulae but
differ in the nature or sequence of bonding of their atoms or in the
arrangement of their
atoms in space. Isomers that differ in the arrangement of their atoms in space
are termed
"stereoisomers". Stereoisomers that are not mirror images of one another are
termed
"diastereomers" and stereoisomers that are nonsuperimposable mirror images are
termed
"enantiomers" or sometimes "optical isomers". A carbon atom bonded to four
nonidentical
substituents is termed a "chiral center". A compound with one chiral center
has two
enantiomeric forms of opposite chirality is termed a "racemic mixture". A
compound that
has more than one chiral center has 2"-' enantiomeric pairs, where n is the
number of chiral
centers. Compounds with more than one chiral center may exist as ether an
individual
diastereomers or as a mixture of diastereomers, termed a "diastereQmeric
mixture". When
one chiral center is present a stereoisomer may be characterized by the
absolute
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
configuration of that chiral center. Absolute configuration refers to the
arrangement in
space of the substituents attached to the chiral center. Enantiomers are
characterized by
the absolute configuration of their chiral centers and described by the R- and
S-sequencing
rules of Calm, Ingold and Prelog. Conventions for stereochemical nomenclature,
methods
for the determination of stereochemistry and the separation of stereoisomers
are well
known in the art (e.g., see "Advanced Organic Chemistry", 4th edition, March,
Jerry, John
Wiley & Sons, New York, 1992). It is understood that the names and
illustration used in
this Application to describe compounds of Formula I are meant to be
encompassed all
possible stereoisomers. Thus, for example, the name N [I-(1-Benzylcarbamoyl-
methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-phenyhnethanesulfonyhnethyl-
butyramide
is meant to include N [(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-
4-yl-4-
oxo-2-phenylinethanesulfonylinethyl-butyramide and N [(R)-1-(1-Benzylcarbamoyl-
methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-phenylinethanesulfonylinethyl-
butyramide
and any mixture, racemic or otherwise, thereof.
"Ketone derivative" means a derivative containing the moiety -C(O)-. For
example, in this Application X3 can be 2-acetoxy-azetidin-3-yl. The
"carbocyclic ketone
derivative" of this example of X3 would be 2-acetoxy-4-oxo-azetidin-3-yl (see
Table 3,
C32).
"Nitro" means the radical -NO2.
"Optional" or "optionally" means that the subsequently described event or
circumstance may or may not occur, and that the description includes
instances~where the
event or circumstance occurs and instances in which it does not. For example,
the phrase
"wherein within R3 and R4 any alicyclic or aromatic ring system may be
substituted further
by 1-5 radicals..." means that R3 and R4 may or may not be substituted in
order to fall
within the scope of the invention.
"Oxoalkyl" means alkyl, as defined above, wherein one of the number of carbon
atoms indicated is replaced by an oxygen group (-O-), e.g., oxo(Cz_6)alkyl
includes
methoxymethyl, etc.
"N oxide derivatives" means derivatives of compounds of Formula I in which
nitrogens are in an oxidized state (i.e., O-N) and which possess the desired
pharmacological activity.
11
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
"Pathology" of a disease means the essential nature, causes and development of
the
disease as well as the structural and functional changes that result from the
disease
processes.
"Pharmaceutically acceptable" means that which is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and neither
biologically nor
otherwise undesirable and includes that which is acceptable for veterinary use
as well as
human pharmaceutical use. '
"Pharmaceutically acceptable salts" means salts of compounds of Formula I
which
are pharmaceutically acceptable, as defined above, and which possess the
desired
pharmacological activity. Such salts include acid addition salts formed with
inorganic
acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric
acid, and the like; or with organic acids such as acetic acid, propionic acid,
hexanoic acid,
heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,
lactic acid,
malonic acid, succinic acid, malic acid, malefic acid, fumaric acid, tartatic
acid, citric acid,
benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic
acid,
2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2~oct-2-ene-1-carboxylic acid, glucoheptonic acid,
4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid,
trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid,
gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and
the like.
Pharmaceutically acceptable salts also include base addition salts which may
be
formed when acidic protons present are capable of reacting with inorganic or
organic
bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate,
potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable
organic
bases include ethanolamine, diethanolamine, triethanolamine, tromethamine,
N methylglucamine and the like.
"Prodrug" means a compound which is convertible in vivo by metabolic means
(e.g. by hydrolysis) to a compound of Formula I. For example an ester of a
compound of
Formula I containing a hydroxy group may be convertible by hydrolysis in vivo
to the
I2
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
parent molecule. Alternatively an ester of a compound of Formula I containing
a carboxy
group may be convertible by hydrolysis in vivo to the parent molecule.
Suitable esters of
compounds of Formula I containing a hydroxy group, are for example acetates,
citrates,
lactates, tartrates, malonates, oxalates, salicylates, propionates,
succinates, fumarates,
maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di p-toluoyltaxtrates, methanesulphonates, ethanesulphonates,
benzenesulphonates,
p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of
compounds
of Formula I containing a carboxy group, are for example those described by
F.J.Leinweber, Drug Metab. Res., 1987, I8, page 379. An especially useful
class of esters
of compounds of Formula I containing a hydroxy group, may be formed from acid
moieties
selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32,
page
2503-2507, and include substituted (aminomethyl)-benzoates, for example,
dialkylamino-
methylbenzoates in which the two alkyl groups may be joined together and/or
interrupted
by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an
alkylated nitrogen
atom, more especially (morpholino-methyl)benzoates, e.g. 3-. or 4-
(morpholinomethyl)-
benzoates, and (4-alkylpiperazin-I-yl)benzoates, e.g. 3- or 4-(4-
alkylpiperazin-1-yl)-
benzoates.
"Protected derivatives" means derivatives of compounds of Formula I in which a
reactive site or sites are blocked with protecting groups. Protected
derivatives of
compounds of Formula I are useful in the preparation of compounds of Formula I
or in
themselves may be active cathepsin S inhibitors. A comprehensive list of
suitable
protecting groups can be found in T.W. Greene, Protecting Groups in Organic
Synthesis,
3rd edition, John Wiley & Sons, Inc. 1999.
"Therapeutically effective amount" means that amount which, when administered
to an animal for treating a disease, is sufficient to effect such treatment
for the disease.
"Thioketone derivative" means a derivative containing the moiety -C(S)-.
"Treatment" or "treating" means any administration of a compound of the
present
invention and includes:
(1) preventing the disease from occurnng in an animal which may be predisposed
to
the disease but does not yet experience or display the pathology or
symptomatology of the
disease,
13
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
(2) inhibiting the disease in an animal that is experiencing or displaying the
pathology
or symptomatology of the diseased (i.e., arresting further development of the
pathology
and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying
the
pathology or symptomatology of the diseased (i.e., reversing the pathology
andlor
symptomatology).
Nomenclature:
The compounds of Formula I and the intermediates and starting materials used
in
their preparation are named in accordance with ICTPAC rules of nomenclature in
which the
characteristic groups have decreasing priority for citation as the principle
group as follows:
acids, esters, amides, etc. Alternatively, the compounds axe named by AutoNom
4.0
(Beilstein Information Systems, Inc.). For example, a compound of Formula I in
which
X' is NHC(R')(Rz)Xz (R' and Rz are each hydrogen), Xz is cyano, R3 is
cyclohexylinethyl,
and R4 is phenylamino; that is, a compound having the following structure:
N
N N
O O
is named N cyanomethyl-2-c cly ohex l~yl-N-phenyl-malonamide.
Presently Preferred Embodiments:
While the broadest definition of the invention is set forth in the Summary of
the
Invention, certain aspects of the invention are preferred. For example, Xl is -
NHC(R')(Rz)Xz or NHX3; Xz is cyano, -C(O)X3, -C(O)CF3, -C(O)CFZCFzR9, -
CH=CHS(O)zRS, -C(O)CFzC(O)NRSRS, -C(O)C(O)NRSR6, -C(O)C(O)ORS, -
C(O)CHzORs, -C(O)CHzN(R6)SOZRS or -C(O)C(O)R5; wherein RS and R6 are as
described
14
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
above; X3 comprises a heteromonocyclic ring containing 4 to 6 ring member
atoms or a
fused heterobicyclic ring system containing 8 to 14 ring member atoms and any
carbocyclic ketone, iminoketone or thioketone derivative thereof; wherein
within R5, X2
or X3 any alicyclic or aromatic ring system may be substituted further by 1 to
5 radicals
independently selected from (C,_6)alkyl or -X40C(O)R12 and/or 1 radical
selected from -R14,
-X4C(O)R14 or -X40C(O)R14; wherein X4, R12 and R14 are as described above; R'
is
hydrogen ar (C,_6)allcyl and R2 is hydrogen, -X4OR12,
(CS_,o)heteroaryl(Co_6)alkyl,
(CS_,o)aryl(Co_6)alkyl, (CS_lo)cycloalkyl(Co_6)alkyl,
(CS_,o)heterocycloalkyl(Co-6)alkyl or
(C,_6)alkyl; or Rl and R2 taken together with the carbon atom to which both R'
and R2 are
attached form (C3_8)cycloalkylene or (C3_$)heterocycloalkylene; wherein within
said R2 any
heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or
heterocycloalkylene is
optionally substituted with 1 to 3 radicals independently selected from
(C,_6)alkyl and
hydroxy; R3 is -CH2X5, wherein XS at each occurrence independently is selected
from
-X4SR12' -X4C(O)~12R12' -X4S(O)2R13' -X4~-r(~~R13' -~4~rR14' -X4R12' -R14' -
X4~r~O)2R14'
-X4C(O)R'4, -X4C(O)NR14R12, wherein X4, R12, R'3 and R14 are as defined above;
R4 is -
~6R6' ~6R14' ~6Rls Or ~6X5~(~)R14 wherein R6, XS and R14 are as described
above and R15 is hydrogen, -(C,_6)allcyl or -XSOR6 wherein XS is as described
above; or R6
and Rls together with the nitrogen atom to which R6 and Rls are attached form
hetero(C3_
lo)cYcloalkyl, hetero(CS_,o)aryl or hetero(C8_,o)bicycloaryl; wherein within
R3 and R4 any
alicyclic or aromatic ring system may be substituted further by 1-5 radicals
independently
selected from (C,_6)alkyl, cyano, halo, vitro, halo-substituted(C,~,)alkyl, -
X4OR12,
-X4C(O)OR12, -X4C(O)R13, -X4~(O)~12R12' -~r4~12s(O)2R12 ~~or 1 radical
selected
from -R14, -X4OR'4 and -X4C(O)NR14R12; within R3 and R4 any aliphatic moiety
may be
substituted further by 1-5 radicals independently selected from cyano; wherein
X4, R12, Rls
and R14 are as described above; with the proviso that only one bicyclic ring
structure is
present within R3 or R4.
In particular, X' is NHC(Rl)(R2)X2 or NHX3; X2 is cyano, -C(O)X3, -CF3,
-CF2CF3, (E)-2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl,
1-benzylcarbamoyl-methanoyl, 1-benzyloxy(oxalyl), 2-benzyloxy-acetyl,
2-benzenesulfonylamino-ethanoyl or 2-oxo-2-phenyl-ethanoyl; X3 is
1H benzoimidazol-2-yl, pyrimidin-2-yl, benzooxazol-2-yl, benzothiazol-2-yl,
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
pyridazin-3-yl, 3-phenyl-[1,2,4]oxadiazol-5-yl, 3-ethyl-[1,2,4]oxadiazol-5-yl,
2-methyl-4-oxo-tetrahydro-furan-3-yl, 2-ethyl-4-oxo-tetrahydro-furan-3-y1,
4-oxo-1-(1-phenyl-methanoyl)-pyrrolidin-3-yl or (S)-2-Acetoxy-4-oxo-azetidin-3-
yl; Rl
is hydrogen or methyl and Rz is hydrogen, methoxymethyl, (Cl_6)alkyl,
phenethyl,
thiophen-2-yl or 5-methyl-furan-2-yl, or (ii) R' and RZ taken together with
the carbon atom
to which both R' and RZ are attached form cyclopropylene, tetrahydro-pyran-4-
ylene or
methyl-piperidin-4-ylene.
R3 more preferably is thiophene-2-sulfonylmethyl,
3-chloro-2-fluoro-phenylinethanesulfonylinethyl, benzenesulfonylmethyl,
IO phenylmethanesulfonylmethyl, 2-(1,1-difluoro-methoxy)-
phenylmethanesulfonylmethyl,
2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-
sulfonyl)-ethyl,
2-phenylmethanesulfonyl-ethyl, oxy-pyridin-2-ylmethanesulfonylmethyl,
prop-2-ene-1-sulfonylmethyl, 4-methoxy-phenyhnethanesulfonylmethyl,
p-tolyhnethanesulfonylinethyl, 4-chloro-phenyhnethanesulfonylmethyl,
o-tolylmethanesulfonylinethyl, 3,5-dimethyl-phenylinethanesulfonylmethyl,
4-trifluoromethyl-phenylmethanesulfonylmethyl,
4-trifluoromethoxy-phenylmethanesulfonylmethyl,
2-bromo-phenylmethanesulfonylmethyl, pyridin-2-ylinethanesulfonylinethyl,
pyridin-3-ylinethanesulfonylinethyl, pyridin-4-ylmethanesulfonylmethyl,
naphthalen-2-ylinethanesulfonylmethyl, 3-methyl-phenylmethanesulfonylmethyl,
3-trifluoromethyl-phenylmethanesulfonylmethyl,
3-trifluoromethoxy-phenylmethanesulfonylmethyl,
4-fluoro-2-trifluoromethoxy-phenylmethanesulfonylinethyl,
2-fluoro-6-trifluoromethyl-phenylmethanesulfonylinethyl,
3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenyhnethanesulfonylmethyl,
2-trifluoro-phenylinethanesulfonylmethyl, 2-cyano-phenyhnethanesulfonylmethyl,
4-tent-butyl-phenylmethanesulfonylmethyl,
2-fluoro-3-methyl-phenylmethanesulfonyhnethyl, 3-fluoro-
phenyhnethanesulfonyhnethyl,
4-fluoro-phenylmethanesulfonylmethyl, 2-chloro-phenyhnethanesulfonylinethyl,
2,5-difluoro-phenylrnethanesulfonylmethyl, 2,6-difluoro-
phenylmethanesulfonyhnethyl,
2,S-dichloro-phenylmethanesulfonylinethyl, 3,4-dichloro-
phenylmethanesulfonyhnethyl,
16
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
2-( 1,1-difluoro-methoxy)-phenylmethanesulfonylmethyl,
2-cyano-phenylmethanesulfonylmethyl, 3-cyano-phenylinethanesulfonylinethyl,
2-trifluoromethoxy-phenylmethanesulfonylmethyl,
2,3-difluoro-phenylrnethanesulfonylinethyl, 2,5-difluoro-
phenylinethanesulfonylinethyl,
biphenyl-2-ylmethanesulfonylmethyl, cyclohexylmethyl,
3-fluoro-phenylmethanesulfonylmethyl, 3,4-difluoro-
phenyhnethanesulfonylmethyl,
2,4-difluoro-phenyhnethanesulfonyhnethyl, 2,4,6-trifluoro-
phenyhnethanesulfonylinethyl,
2,4,5-trifluoro-phenylmethanesulfonylmethyl,
2,3,4-trifluoro-phenylmethanesulfonyhnethyl,
2,3,5-trifluoro-phenylmethanesulfonylmethyl,
2,5,6-trifluoro-phenylmethanesulfonylmethyl,
2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2-methyl-propane-1-
sulfonyl,
2-fluoro-3-trifluoromethylphenylinethanesulfonylinethyl,
2-fluoro-4-trifluoromethylphenylinethanesulfonyhnethyl,
2-fluoro-5-trifluoromethylphenylinethanesulfonylmethyl,
4-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl,
2-methoxy-phenylmethanesulfonylmethyl, 3,5
bis-trifluoromethyl-phenylmethanesulfonylinethyl,
4-difluoromethoxy-phenylmethanesulfonylinethyl,
2-difluoromethoxy-phenylmethanesulfonylinethyl,
3-difluoromethoxy-phenyhnethanesulfonylmethyl,
2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylinethyl,
3,5-dimethyl-isoxazol-4-ylmethanesulfonylmethyl,
5-chloro-thiophen-2-ylmethanesulfonylmethyl,
2-[4-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl,
2-[2-( 1,1-Difluoro-methoxy)-b enzenesulfonyl]-ethyl,
2-[3-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl,
2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl,
2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl,
2-(2-trifluoromethoxy-benzenesulfonyl)-ethyl, (cyanomethyl-methyl-carbamoyl)-
methyl,
butyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-benzenesulfonyl-
ethyl,
17
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl,
cyclohexylinethanesulfonylinethyl,
2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylinethyl,
2-trifluoromethyl-benzylsulfanylmethyl, 5-bromo-thiophen-2-ylinethyl,
phenylsulfanyl-ethyl and cyclopropylmethanesulfonylmethyl.
R4 more preferably is phenylamino, benzylamino, 4-phenoxy-phenylamino,
phenethylamino, 3-phenyl-propylamino, morpholin-4-yl, cyclohexylamino,
naphthalen-1-
ylmethyl-amino, pyridin-3-ylamino, 6-methoxy-pyridin-3-ylamino,
diisobutylamino, 4-
nitro-benzylamino, 2-thiophen-2-yl-ethylamino, 3-phenoxy-phenylamino,
cyanomethyl-
amino, (pyridin-3-ylmethyl)-amino, 5,6,7,8-tetrahydro-naphthalen-1-ylamino, 2-
pyridin-2-
yl-ethylamino, 2,3-dihydro-indol-1-yl, 3,4-dihydro-1H-isoquinolin-2-yl,
cyclohexylmethyl-amino, 2-methoxy-benzylamino, 1-phenyl-ethylamino, (pyridin-4-
ylmethyl)-amino, benzyl-methyl-amino, 3-nitro-benzylamino, 4-methoxy-
phenylamino,
3-carbamoyl-phenylamino, 4-carbamoyl-phenylamino, (tetrahydro-furan-2-
ylmethyl)-
amino, 3,4-dihydro-2H-quinolin-1-yl, dimethylamino, butylinethylamino,
diisopropylamino, propylinethylamino, 1-(benzooxazole-2-carbonyl)-propylamino
and
isobutylmethylamino.
Reference to the preferred embodiments set forth above is meant to include all
combinations of particular and preferred groups.
Particular compounds of the invention are selected from the compounds formed
by joining the acyl carbon atom (C*) of one of the fragments (Al to A37) shown
in
Table 1 to the methine carbon atom (*CH*) of one of the fragments (B 1 to B88)
shown
in Table 2, and joining the methine carbon atom (*CH*) of one of the fragments
(B 1 to
B88) shown in Table 2 to the acyl carbon atom (C*) of one of the fragments (C1
to
C36) depicted in Table 3.
The following tables are intended to provide guidance to better carry out the
present invention. However, they do not limit the scope of the invention.
People of
ordinary skill may selectively make particular compounds by joining of one of
the
fragments shown in Table 1 to any one of the fragments shown in Table 2, and
then
joining the fragments shown in Table 2 to the any of one of the fragments
Table 3.
18
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
TALE 1
1 \ N * A2 / A3 ~ HOC
N
\C o~
I I
o ~ \II* I \ o
0
4 ~ 5 6
N~C* / I H O
IO \ N\C* ~N\
/ ~° I I*
0
/ 9
\II* \ I \ \II*
O ~ O
/ H N
N~
C*
O
\ N\C* 11 12
II ~N /
0
\ ~ O N
O N N~ \ ~C*
of
13 \ N\C* 14 \ o \ N\c* 15 H -
II ~ / ~ / o~ NON\II*
S O
O
16 r 17 18 N N
\ ~ \C*
N \ I N\ ~ N~C* OI
oI* , / to i
19 ~ 20 ~ 21
/ I H
N\C* N\C*
N\ II II
C* O O
I I
O
19
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
22 23 / A24 N
° I H I H
I N ~ N\C* ~ N\II*
\C* 0I 0
O
25 / 26 0~ ~ 27
N\ I \ oI
C* / ~o /
II , I H
O ~ N\C
Ii
0
28 0 29 H 30
N
H \
C* H
N I ~ N\C* N
II N / Oi o \C*
/ o ~ of
0
31 / 2 I 33
/N\C* N\C*
~C*
O
34 35 I 36
~N\C* N\C* NBC
oI I~I
37 °
H
N
\ ~C*
o,
TABLE 2
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
Bl B2 ~l B3 ~
s I \ F
*CH* OaS
oas ' / oasl
*CH*
*CH*
4 ~ ~ 5 ~ ~ OCHFa 6
/ / /
OZS
Oas1 OaSI
*CH* *CH* *CH*
7 /~ 8 wN 9 w
02S ~ N Oa6 ~ / ~ /
as
*CH* *CH*
*CH*
~ N+,o 11 I 12 oH3o \
/ ~/
oas~ oas l
*CH*
*CH* *CH*
13 ~H3 ~ 14 C1 ~ 15 ~ eH3
~ / I / , ~ /
oas\ oas\ oas\
*CH* *CH* *CH*
16 oH3 17 F3o I ~ 18 F3oo
\ / /
CH3 OaS\ 02S\
025 1I 1I~
*CH* *CH*
*CH*
s
21
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
19 I \ Br B20 I ~ 21
/ \ /
OzS ~ / OaS
1 ~ 1
*CH* OzS~ *CH*
*CH*
22 N \ B23 ~ ~ 24 ci
/ I / Cl \
(/
OZS~ oZS l 1
*CH* *CH* zS
*CH*
25 cH3 26 cF3 2~ ocF3
\ I \
O S O S O S
*CH* *CH* *CH*
28 c1 29 \ F 30 \ ci
\
ozs~ O2S\
*CH* . *CH*
*CH*
B31 rsu ~ B32 I \ CF3 33 ~ \ CN
/ /
O S OzS OzS
*cx* . *cH* *eH*
34 cH3 35 F 36 \ F
\ F . I ~ ~ /
F
/ /
OZS\
OzS\ OZS ,I~
,I * CH*
*CH* *CH*
22
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
B37 F I ~ 38 i \ c~ ~ 39
Br
S
/ Cl / *CH*
02S' F OaS\
*CH* *CH*
B40 CN 4I NC ~ 42 ~ ocF3
i \ I / i /
oas\ oas~
OaS~ *CH* *CH*
*CH*
43 F 44 ~ 45
F
\ /
i
/ I *CH*
/
*CH*
O2~'~ O2$~
*CH*
B46 F i \ B47 F 48 F ( ~ F
F
/ I\ /
/
os os
os
*CH* a *CH*
*CH*
49 F i ~ F 50 F i ~ F 51 F
F \ F
/ F / i
/
F oas\ oas\
oas\
*CH* *CH*
*CH*
52 I \ C1 53 S4
CF3 / 1 F /
os
OS a F OS
a ~ *CH* a
*CH* *CH*
23
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
B55 CFa 56 CF3 ~ ~ F 5~ ~ \ CF3
F
/ /
/
OaS~ F OaS
OaS\
1I *CH* *CH*
*~*
58 F B59 I ~ F 6p F I ~ cF3
F
/ /
CF3
F OaS 02S\
- OaS
*CH* *CH*
*CH*
B6.1 cF3 62 ~ ocH3 63 cF3
F'w
/ /
OzS CFs
OS OS
a ~ *CH* a
*CH* *CH*
B64 FaCHO ~ 65 ocHFa 66 ~ ci
/ W ~ /
os ~ ci os
a~ os a1
*CH* a *CH*
*CH* '
67 / B68 N CH3 69 ci
s
/ o ~ ~
CH3 O
1 OaS1 .
*CH* ~ H*
*CH*
gyp I ~ ocHFa ~1 Faxeo I ~ ~2 ocHFa
oas / oas /
Oas /
*CH* *CH*
*CH*
24
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
B73 ~ \ OCF3 B74 CFsO ~ \ ~ B75 OCF3
OzS- v OzS
~2$ /
*cH* *cH*
*cH*
76 o B77 \ 78 0
NC~N~ ~ / N
I/
CH3 *CH* ~ *CH*
\ *CH*
79 80 / 81
s
s\
*cH*
*cH* *cH*
82 83 , 84
\)
*cH*
OZ
*CH* *CH*
B85 / 86 / c~'3 87
w ~ W
o2s\
s\ s~ *cH*
*CH* *CH*
88
*CH*
TABLE 3
Cl ~N\ C2 N C3 N ~~N
~ N ~
N
*c * ~
/ ~ *
O O
O
O
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
C4 H N C5 H N C6 °
~N C ,N C H H
*II *II ~N N
*C
° °~ p NJ ° ~ N r ~
I
CH3
C7 H o C8 H o C9 H o
~N~ ,N N ~N N
*iI CF3 *C ~ ~ *C N
O~ O/i N~ Orj
C10 H ~N Cll H ~N C12
* ~N C ~ *C.rN C ~ N O
p II *~
O /~ O / O O N r
S
C13 ° C14 H °s~° C15
*CiN~O *CiN\~S \ *CiN~O
I I
OI N r ~ ° ~ / O N r
/
C16 x °o o° C17 ° ~ C18 0 .
*CrN~s \ N N \ ~ *CiN S
p1 * C _ I I
II ~ o N r
° j ° /
C19 ° C20 H ° C21 °
rN O N O H H
*II ~ ~ *C~ ~ rN N \
0 N II
O N
O 0
C22 ° / C23 ° ~ C24
x
*crN \ ~ *C N~O \ ~ *C~N CF CF3
of ~ of j o. /
C25 H o o C26 H ° C27 x °
I iN~~~i~~N/ * ~N * ~N
* C I I
O j F F ~ O ° O °
26
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
C28 C29 C30
N~O \ N N~ \ ~N N~ \
*II *II ~S~ *c ~S\~
o j o o~ ~o o ~ 0 0
C31 H ° C32 ~Nj,, ° C33 H o
N
i *C N
*II II ~ *C~ H
o ° of
0
o ~ ~ ~o
C34 of C35 x ° C36 H o
~,N~O ~ ~
N *C *CiN~NiO\
*C~ O 0 N ~ ~ lol
0
~~
Thus, for example, in table 4 the compound denoted as A2-B45-C35 is the
product of the combination of group A2 in Table l and B45 in Table 2 and C35
in
Table 3, namely N [1-(1-benzooxazol-2-yl-methanol-3-phen,~-prop,~~l]-N-benz,~-
cyclohex,~lmeth,~malonamide:
Further preferred are compounds of Formula I selected from a group consisting
of
2-butyl-N cyanomethyl-N-phenyl-malonamide (Compound 1; denoted as Al-
B88-C1);
N Cyanomethyl-2-c ~clohex lmethyl-N=phenyl-malonamide (Compound 2;
denoted as Al-B45-C1);
N Cyanometh ly~-2-c_ cl~_ ohex 1y meth~phenethyl-malonamide (Compound 3;
denoted as A4-B45-C1);
27
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
N C anomethyl-2-c cl~ ohexvlmethyl-N-~yridin-4-vlmethyl-malonamide
(Compound 4; denoted as A24-B45-C1);
N [1-(Benzooxazole-2-carbon~~3-phen ~~1-props]-N-benz
c clohexvlmethyl-malonamide (Compound 5; denoted as A2-B45-C35);
N Cyanometh~-N-c clue ohexyl-2-cyclohex~lmethyl-malonamide (Compound 6;
denoted as A7-B45-C1);
N Benz~yanomethyl-2-cyclohex l~rnethyl-malonamide (Compound 7;
denotes as A2-B45-C 1 );
N Cyanomethyl-2-cyclohexylmethyl-N-(4-phenox, -~phen~)-malonamide
(Compound 8; denoted as A3-B45-C1);
N Cyanometh.~yclohexylmeth.~~3-phenyl-prop,~~ll-malonamide
(Compound 9; denoted as A5-B45-C1);
N Cyanomethyl-2-cyclohexylmethyl-3-morlaholin-4-yl-3-oxo-nropionamide
(Compound 10; denoted as A6-B45-C1);
N Cyanometh~yclohexvlmethyl-N-naphthalen-1 ~lmethyl-malonamide
(Compound 11; denoted as A8-B45-C1);
N Cyanomethyl-2-cyclohexylmethyl-N ~yridin-3-yl-malonamide (Compound
12; denoted as A9-B45-C 1 );
N Cyanometh~cyclohexylmethyl-NLN-diisobut~-malonamide (Compound
13; denoted as A11-B45-Cl);
N Cyanometh~ cl~ex l~thyl-N,N-diisopropyl-malonamide (Compound
14; denoted as A36-B45-C1);
N Cyanometh~yclohex 1~ methyl-N-(6-methoxy-pyridin-3-~)-malonamide
(Compound 15; denoted as A10-B45-C1);
N Cyanomethyl-2-c clue ohex 1y meth~~2-thio~hen-2-yl-ethyll-malonamide
(Compound 16; denoted as A13-B45-C1);
N Cyanometh~-c~lohex 1~~~3-phenox~phenyl~ malonamide
(Compound 17; denoted as A14-B45-C1);
N Cyanometh~l-2-c cly ohex 1~~-N~4-nitro-benzXl~malonamide
(Compound 18; denoted as A12-B45-C1);
N,N-Bis-cyanomethYl-2-cyclohexylmethyl-malonamide (Compound 19;
28
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
denoted as A1S-B4S-C1);
N Cyanomethyl-2-cyclohex )y meths(5,6,7,8-tetrah~naphthalen-1-yll-
malonamide (Compound 20; denoted as A17-B45-C1);
N Cyanometh,~yclohex lmeth,yl-N-(2-pyridin-2-yl-ethyl)-malonamide
S (Compound 21; denoted as A18-B4S-C1);
N Cyanometh~l-2-c cy lohex )y methyl-3-(2,3-dihydro-indol-1-~~-3-oxo-
propionamide (Compound 22; denoted as A19-B4S-Cl);
N Cyanometh 1~-2-cyclohex l~ 1-~3-(,3,4-dihydro-1H-isoquinolin-2-yl)-3-
oxo-propionamide (Compound 23; denoted as A20-B45-C1);
N Cyanomethyl-2.N-bis-c~clohexylmethyl-malonamide (Compound 24;
denoted as A21-B45-C1);
N Cyanometh.~yclohex,1~,~2-method-benz~lLmalonamide
(Compound 2S; denoted as A22-B4S-C1);
N Cy_anomethyl-2-c;~clohex~meth~-N;~ 1 ~hen,~l-ethyl-malonarnide
1 S (Compound 26; denoted as A23-B4S-C 1);
N Benzyl-N-cyanometh,~-2-cyclohexylmethyl-N methyl-malonamide
(Compound 27; denoted as A2S-B4S-Cl);
N Cyanomethyl-2-cyclohex 1~ methyl-N-(3-nitro-benz~)-malonamide
(Compound 28; denoted as A26-B4S-C1);
N Cyanomethyl-2-cyclohex,1~,~-N~4-methoxy-benz,~~l)-malonamide
(Compound 29; denoted as A27-B4S-C1);
N (3-Carbamo ~~1-phenyl)-N-c, a~ ethyl-2-cyclohex l~yl-malonamide
(Compound 30; denoted as A28-B4S-C1);
N Cyanomethvl-2-c clohex l~methXl-N-pyridin-3-vlmethyl-malonamide
2S (Compound 31; denoted as A16-B4S-Cl);
N (4-carbamoylphen~ -N'-c~anometh~2-c~clohex~methylmalonamide
(Compound 32; denoted as A29-B45-Cl);
N cyanometh~-2-c c~~lmethyl-N'-tetrahydrofur-2-~methylmalonamide
(Compound 33; denoted as A30-B4S-C1);
N cyanometh~ cy lohex )y methXl-3-(3,4-dihydro-2H quinolin-1-
oxopropionamide (Compound 34; denoted as A31-B4S-C1);
29
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
N test-butyl-N-cvanometh~ clohexylmethyl-N methylmalonamide
(Compound 35; denoted as A35-B45-Cl);
N cyanomethyl-2-cyclohex ly~methyl-N-methyl-N-propylmalonamide
(Compound 36; denoted as A34-B45-C1);
N butyl-N-cyanomethyl-2-c clohexylmethyl-N methylmalonamide
(Compound 37; denoted as A33-B45-C1);
N cyanomethyl-2-cyclohex~methyl-N.N-dimethylmalonamide (Compound 38;
denoted as A32-B45-C1);
N benzyl N-c~anometh~(2-phen~sulfan~~~malonamide (Compound
3 9; denoted as A2-B 80-C 1 );
2~2~hen 1sY ulfonylethyll-N benzyl-N-c~anomethylmalonamide (Compound
40; denoted as A2-B6-C 1 );
2-(2-Benzenesulfon~y~-N [(S~(1-benzooxazol-2-yl-methanol-pent]-
N-benz;rl-malonamide (Compound 41; denoted as A2-B6-C12);
N.N-Bis-[(Sl-1-(1-benzooxazol-2-yl-methanoyl~~ropyl]-2-cyclohex 1y meth ~~1-
malonamide (Compound 42; denoted as A37-B45-C13);
and the N-oxide derivatives, prodrug derivatives, protected derivatives,
individual
stereoisomers and mixtures of isomers thereof; and the pharmaceutically
acceptable salts
and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives,
prodrug
derivatives, protected derivatives, individual isomers and mixtures of isomers
thereof..
Pharmacology and Utility:
The compounds of the invention are selective inhibitors of cathepsin S and, as
such, are useful for treating diseases in which cathepsin S activity
contributes to the
pathology and/or symptomatology of the disease. For example, the compounds of
the
invention are useful in treating autoimmune disorders, including, but not
limited to,
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves'
disease,
myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and
Hashimoto's
thyroiditis, allergic disorders, including, but not limited to, asthma, and
allogeneic immune
responses, including, but not limited to, organ transplants or tissue grafts.
Cathepsin S also is implicated in disorders involving excessive elastolysis,
such as
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis,
excessive airway
elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease
such as
plaque rupture and atheroma. Cathepsin S is implicated in fibril formation
and, therefore,
inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.
The cysteine protease inhibitory activities of the compounds of the invention
can
be determined by methods known to those of ordinary skill in the art. Suitable
ira vitro
assays for measuring protease activity and the inhibition thereof by test
compounds are
known. Typically, the assay measures protease induced hydrolysis of a peptide
based
substrate. Details of assays for measuring protease inhibitory activity are
set forth in
Examples 6-9, infra.
Administration and Pharmaceutical Compositions:
In general, compounds of Formula I will be administered in therapeutically
effective amounts via any of the usual and acceptable modes known in the art,
either singly
or in combination with one or more therapeutic agents. A therapeutically
effective amount
may vary widely depending on the severity of the disease, the age and relative
health of
the subject, the potency of the compound used and other factors. For example,
therapeutically effective amounts of a compound of Formula I may range from
about 1
micrograms per kilogram body weight (pg/kg) per day to about 1 milligram per
kilogram
body weight (mg/kg) per day, typically from about 10 p,g/kg/day to about 0.1
mglkg/day.
Therefore, a therapeutically effective amount for a 80 kg human patient may
range from
about 100 p,g/day to about 100 mg/day, typically from about 1 pg/day to about
10 mg/day.
In general, one of ordinary skill in the art, acting in reliance upon personal
knowledge and
the disclosure of this Application, will be able to ascertain a
therapeutically effective
amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions
by one of the following routes: oral, systemic (e.g., transdermal, intranasal
or by
suppository) or parenteral (e.g., intramusculax, intravenous or subcutaneous).
Compositions can take the form of tablets, pills, capsules, semisolids,
powders, sustained
release formulations, solutions, suspensions, elixirs, aerosols, or any other
appropriate
composition and are comprised of, in general, a compound of Formula I in
combination
31
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
with at least one pharmaceutically acceptable excipient. Acceptable excipients
are
non-toxic, aid administration, and do not adversely affect the therapeutic
benefit of the
active ingredient. Such excipient may be any solid, liquid, semisolid or, in
the case of an
aerosol composition, gaseous excipient that is generally available to one of
skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose,
lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate,
sodium stearate,
glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid
and
semisolid excipients may be selected from water, ethanol, glycerol, propylene
glycol and
various oils, including those of petroleum animal, vegetable or synthetic
origin (e.g.,
peanut oil, soybean oil, mineral oil, sesame oil, and the like). Preferred
liquid carriers,
particularly for injectable solutions, include water, saline, aqueous dextrose
and glycols.
The amount of a compound of Formula I in the composition may vary widely
depending upon the type of formulation, size of a unit dosage, kind of
excipients and other
factors known to those of ,skill in the art of pharmaceutical sciences. In
general, a
1 S composition of a compound of Formula I for treating a given disease will
comprise from
0.01 %w to 10%w, preferably 0.3%w to 1 %w, of active ingredient with the
remainder
being the excipient or excipients. Preferably . the pharmaceutical composition
is
administered in a single unit dosage form for continuous treatment or in a
single unit
dosage form ad libitum when relief of symptoms is specifically required.
Representative
pharmaceutical formulations containing a compound of Formula I are described
in
Example I0.
Chemistry:
Processes for Making Compounds of Formula I:
Compounds of the invention may be prepared by the application or adaptation of
known methods, by which is meant methods used heretofore or described in the
literature,
for example those described by R.C. Larock in Comprehensive Organic
Transformations,
VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive
functional groups, for example hydroxy, amino, imino, thio or carboxy groups,
where these
32
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
are desired in the final product, to avoid their unwanted participation in the
reactions.
Conventional protecting groups may be used in accordance with standard
practice, for
examples see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic
Chemistry" John Wiley and Sons, 1991.
S Compounds of Formula I, where X' is NHC(R')(RZ)Xz, can be prepared by
proceeding as in the following Reaction Scheme 1:
Reaction Scheme 1
R3
R4 OH
O O
2
NHZCR1RZX2
R3
H
R4 N XZ
R2
O
I
in which X2, R', R2, R3 and R4 are as defined in the Summary of the Invention.
Compounds of Formula I can be prepared by condensing an acid of Formula 2 with
a compound of formula NHZCR1RZX2. The condensation reaction can be effected
with an
appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidino-
phosphonium
hexafluorophosphate (PyBOP~), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTI~, 1,3-dicyclohexyl-carbodiimide (DCC), or the like)
and
optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-
hydroxy-7-
azabenzotriazole (HOAt), or the like) and non-nucleophillic base (e.g., N
methylmorpholine, triethylamine, or the like, or any suitable combination
thereof) in a
suitable solvent (N methylpyrrolidinone, or the like) at ambient temperature
and requires
33
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
3 to 10 hours to complete the reaction. A detailed description for the
synthesis of a
compound of Formula I by the processes in Reaction Scheme 1 is set forth in
the
Examples, infra.
Compounds of Formula I, where X' is NHX3, can be prepared by proceeding
as in the following Reaction Scheme 2:
Reaction Scheme 2
R3
R4 OH
O O
2
2x3
R3
H
R N~Xs
O O
I
in which X3, R3 and R4 are as defined in the Summary of the Invention.
~ Compounds of Formula I can be prepared by condensing an acid of Formula 2
with
a compound of formula NH2X3. The condensation reaction can be effected with an
appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidino-
phosphonium
hexafluorophosphate (PyBOP~), I-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTI~, 1,3-dicyclohexyl-carbodiimide (DCC), or the like)
and
optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-
hydroxy-7-
azabenzotriazole (HOAt), or the like) and non-nucleophillic base (e.g., N
methylmorpholine, triethylamine, or the like, or any suitable combination
thereof) in a
suitable solvent (N methylpyrrolidinone, or the like) at ambient temperature
and requires
34
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
3 to 10 hours to complete the reaction. A detailed description for the
synthesis of a
compound of Formula I by the processes in Reaction Scheme 1 is set forth in
the
Examples, infra.
Additional Processes for Preparing Compounds of Formula I:
A compound of Formula I can be prepared as a pharmaceutically acceptable acid
addition salt by reacting the free base form of the compound with a
pharmaceutically
acceptable inorganic or organic acid. Alternatively, a pharmaceutically
acceptable base
addition salt of a compound of Formula I can be prepared by reacting the free
acid form
of the compound with a pharmaceutically acceptable inorganic or organic base.
Inorganic
and organic acids and bases suitable for the preparation of the
pharmaceutically acceptable
salts of compounds of Formula I are set forth in the definitions section of
this Application.
Alternatively, the salt forms of the compounds of Formula I can be prepared
using salts
of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared
from the corresponding base addition salt or acid addition salt form. For
example, a
compound of Formula I in an acid addition salt form can be converted to the
corresponding
free base by treating with a suitable base (e.g., ammonium hydroxide solution,
sodium
hydroxide, and the like). A compound of Formula I in a base addition salt form
can be
converted to the corresponding free acid by treating with a suitable acid
(e.g., hydrochloric
acid, etc).
The N oxides of compounds of Formula I can be prepared by methods known to
those of ordinary skill in the art. For example, N oxides can be prepared by
treating an
unoxidized form of the compound of Formula I with an oxidizing agent (e.g.,
trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid,
meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic
solvent (e.g., a
halogenated hydrocarbon such as dichloromethane) at approximately 0°C.
Alternatively,
the N oxides of the compounds of Formula I can be prepared from the N oxide of
an
appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N oxides of
compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur
dioxide,
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus
trichloride,
tribromide, or the like) in an suitable inert organic solvent (e.g.,
acetonitrile, ethanol,
aqueous dioxane, or the like) at 0 to 80°C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods
known to those of ordinary skill in the art (e.g., for fiuther details see
Saulnier et a1.(1994),
Bioorganic ahd Medicinal Chemistry Letters, Vol. 4, p. 1985). For example,
appropriate
prodrugs can be prepared by reacting a non-derivatized compound of Formula I
with a
suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate;para-
nitrophenyl
carbonate, or the like).
Protected derivatives of the compounds of Formula I can be made by means known
to those of ordinary skill in the art. A detailed description of the
techniques applicable to
the creation of protecting groups and their removal can be found in T.W.
Greene,
Protecting Groups ira Organic Synthesis, 3'~ edition, John Wiley ~Z Sons, Inc.
1999.
Compounds of the present invention may be conveniently prepared, or formed
during the
process of the invention, as solvates (e.g. hydrates). Hydrates of compounds
of the present
invention may be conveniently prepared by recrystallisation from an
aqueous/organic
solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or
methanol.
Compounds of Formula I can be prepared as their individual stereoisomers by
reacting a
racemic mixture of the compound with an optically active resolving agent to
form a pair
of diastereoisomeric compounds, separating the diastereomers and recovering
the optically
pure enantiomer. While resolution of enantiomers can be carried out using
covalent
diasteromeric derivatives of compounds of Formula I, dissociable complexes are
preferred
(e.g., crystalline diastereoisomeric salts). Diastereomers have distinct
physical properties
(e.g., melting points, boiling points, solubilities, reactivity, etc.) and can
be readily
separated by taking advantage of these dissimilarities. The diastereomers can
be separated
by chromatography or, preferably, by separation/resolution techniques based
upon
differences in solubility. The optically pure enantiomer is then recovered,
along with the
resolving agent, by any practical means that would not result in racemization.
A more
detailed description of the techniques applicable to the resolution of
stereoisomers of
compounds from their racemic mixture can be found in Jean Jacques Andre
Collet, Samuel
H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc.
(1981).
36
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
In summary, the compounds of Formula I are made by a process which comprises:
(A) reacting a compound of Formula 2:
R3
R4 ~ OH
O O
2
S with a compound of formula NHZCR'RZXz, in which R', RZ, R3 , R4 and XZ are
as defined in the Summary of the Invention for Formula I; or
(B) reacting a compound of Formula 2 with a compound of Formula NHZX3, in
which R3 , R4 and X3 are as described in the Summary of the Invention for
Formula I; and
(C) optionally converting a compound of Formula I into a pharmaceutically
acceptable salt; °
(D) optionally converting a salt form of a compound of Formula I to non-salt
form;
(E) optionally converting an unoxidized form of a compound of Formula I into a
pharmaceutically acceptable N oxide;
(F) optionally converting an N oxide form of a compound of Formula I its
unoxidized form;
(G) optionally resolving an individual isomer of a compound of Formula I from
a
mixture of isomers;
(H) optionally converting a non-derivatized compound of Formula T into a
pharmaceutically prodrug derivative; and
(I) optionally converting a prodrug derivative of a compound of Formula I to
its
non-derivatized form.
Examples:
2S The present invention is further exemplified, but not limited by, the
following
examples that illustrate the preparation of compounds of Formula I (Examples)
and
intermediates (References) according to the invention.
37
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
REFERENCE 1
2-Phen. l~carbamoyl-hexanoic acid
A solution of aniline (5.47 ml, 60 mmol) and triethylamine (8.36 ml, 60 mmol)
in methylene chloride (150 ml) was cooled to -20°C and treated with
methylmalonylchloride (8.36 ml, 60mmol) in methylene chloride (20 ml). The
reaction
mixture was allowed to warm to ambient temperature for 3 hours and then poured
into
cold 1N HCI. The organic layer was separated and washed with aqueous sodium
bicarbonate then brine and dried over magnesium sulfate and evaporated to give
methyl
2-phenylcarbamoylacetate.
A mixture of methyl 2-phenylcarbamoylacetate (1.1598, 6 mmol) lithium
hydroxide (0.438, 18 mmol) and 1-iodobutane (0.91 ml, 8 mW o1) in N
methylpyrrolidinone
(10 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture
was poured
into ice water, extracted with ethylacetate (twice, 50 ml each). The combined
extracts were
washed with brine, dried over magnesium sulfate and evaporated. The residue
was
purified by flash chromatography on silica gel eluting with 20%
ethylacetate/hexane to
give methyl 2-phenylcarbamoylhexanoate (0.7158, 48% yield).
A solution of methyl 2-phenylcarbamoylhexanoate (0.988 3.9 mmol) in methanol
(10 ml) was treated with sodium hydroxide (4 ml, 4 mmol) at ambient
temperature for 17
hours. The methanol was removed under reduced pressure and the residue was
treated with
IN HCl and extracted with ethylacetate (twice, 50 ml each). The organic layers
were
washed with brine, dried over magnesium sulfate and evaporated to give 2-
phenylcarbamoylhexanoic acid (0.68 g, 2.9 mmol, 74% yield).
REFERENCE 2
2-C clohex l~yl-N phenyl-malonamic acid
A mixture of methyl 2-phenylcarbamoylacetate (prepared as in reference Example
1) (4.39 g, 22.7 mmol), lithium hydroxide (1.08 g, 45 mmol) and
bromomethylcyclohexane
(3.76 ml, 27 mmol), in N methylpyrrolidinone (25 ml) was stirred at ambient
temperature
38
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
for 17 hours. The reaction mixture was poured into ice water and extracted
with ether
(three times, 100 ml each). The extracts were washed with water then brine,
dried over
magnesium sulfate and evaporated. The residue was purified by flash
chromatography on
silica gel eluting with 10% ethylacetate (hexane) to give methyl 2-
cyclohexylmethyl-N
S phenyl malonamate (1.89 g, 6.5 mmol, 29% yield). The aqueous layer above was
cooled
on ice and acidified to pH 2 with IN HCI. The aqueous layer was extracted with
ether (3
times, 100 ml each) and the extracts were washed with water, then brine, dried
over
magnesium sulfate and evaporated to give 2-cvclohexylmethyl-N phenyl malonamic
acid
(1.12 g, 18% yield).
REFERENCE 3
2-C, cly ohexylmethyl-N phenethyl-malonamic acid
Sodium (6.9 g, 0.3 mol), dissolved in ethanol (300 ml), and then
diethylinalonate
(50.3 ml, 0.3 mol) was added. Bromomethylcyclohexane (46 ml, 0:33 mol) was
added and
the reaction mixture was heated at 70°c for 14 hours. The reaction
mixture was cooled and
the ethanol removed by evaporation. The resulting mass was dissolved in ice
water and
then extracted with ethylacetate. The organic layers were washed with water,
then brine
and dried over magnesium sulfate. The solvents were removed under reduced
pressure to
give diethylcyclohexyl malonate.
A solution of diethylcyclohexylmalonate (12.8 g, 0.05 mol) in ethanol (100 ml)
was
treated with a solution of lithium hydroxide (1.2 g, 0.05 moles) in water (50
ml) and then
stirred at ambient temperature for 15 hours. The ethanol was removed at
reduced pressure
and water (50 ml) was added to the residue. The reaction mixture was extracted
with ether,
cooled on ice and acidified to pH 1.5 with HCI. The aqueous phase was
saturated with
NaCI and extracted with ethylacetate (twice, 150 ml each). Drying over
magnesium sulfate
and evaporating the solvent gave ethyl 2-cyclohexylmalonate (8.52 g, 37 mmol,
74%
yield).
The ethyl 2-cyclohexylinalonate (8.52 g, 37 mmol) in ethylacetate (80 ml) was
cooled to 0° C and treated with dimethylformade (SOIL) and then
oxalylchloride (3.93 ml,
45 mmol). The reaction temperature was raised to room temperature and after 2
hours the
39
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
solvents were removed under reduced pressure to give ethyl 2-
cyclohexylinalonyl chloride.
The malonylchloride above was diluted to 28 ml volume with ethylacetate and 2
ml of that solution was added to a solution of phenethylamine (0.376 ml, 3
mmol) and N
methylmorpholine (0.40 g, 4 mmol) in ethylacetate (4 ml) at -20°c.
After 15 minutes the
reaction mixture was allowed to warm to ambient temperature overnight. The
reaction
mixture was diluted with ethylacetate (5 ml) and ice water (5 ml). The organic
layer was
separated and washed with cold 0.05 N HCI, then aqueous NaHC03, then brine,
dried over
magnesium sulfate and evaporated under reduced pressure. The residue was
purified by
radial chromatography to give ethyl 2-cyclohexylmethyl-N phenethyl malonamate
(0.366
g, 1.10 mmol, 42% yield).
The ester above (0.366 g, 1.10 mmol) in ethanol (10 ml) was treated at ambient
temperature with aqueous sodium hydroxide (1.3 ml of IN) for 2.5 hours. The
reaction
mixture was diluted with water (30 ml) and washed with ether (3 times, 30 ml
each). The
aqueous layer was cooled, acidified with 1N HCl (2 ml) and extracted with
ethylacetate
(3 times, 30 ml each). The ethylacetate extracts were washed with brine, dried
over
magnesium sulfate and evaporated to give 2-cyclohexylmethyl-N phemethyl
malonamic
acid (0.138 g, 0.46 mmol, 42% yield).
REFERENCE 4
2-C, cy lohexylmethyl-N ~yridin-4-ylmethyl-malonamic acid
Ethyl 2-cyclohexylmethylmalonyl chloride, prepared as in Reference 3 (0.307 g,
1.25 mmol), was condensed with 4-aminomethyl pyridine using the method of
Reference
3 to give ethyl 2-cyclohexylmethyl-4-pyrin-4-ylinethylmalonamate (0.237 g,
0.74 mmol,
58% yield).
This ester was hydrolyzed with sodium hydroxide using the method of Reference
3 to give 2-c cl~yhnethyl-N pyridin-4- l~ethylmalonamic acid (0.041 g, 0.14
mmol,
19% yield).
Proceeding as in the above referenced examples provided the following
compounds:
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
N Benzyl-2-cyclohexylinethyl-malonamic acid;
2-Cyclohexylmethyl-N (4-phenoxy-phenyl)-malonamic acid;
2-Cyclohexylmethyl-N (3-phenyl-propyl)-malonamic acid;
2-Cyclohexyhnethyl-3-morpholin-4-yl-3-oxo-propionic acid;
N Cyclohexyl-2-cyclohexylmethyl-malonamic acid;
2-Cyclohexylmethyl-N naphthalen-1-ylmethyl-malonamic acid;
2-Cyclohexylmethyl-N pyridin-3-yl-malonamic acid;
2-Cyclohexylmethyl-N,N diisobutyl-malonamic acid;
2-Cyclohexylmethyl N (6-methoxy-pyridin-3-yl)-malonamic acid;
2-Cyclohexylmethyl-N (2-thiophen-2-yl-ethyl)-malonamic acid;
2-Cyclohexylmethyl-N (3-phenoxy-phenyl)-malonamic acid;
2-Cyclohexylmethyl-N (4-nitro-benzyl)-malonamic acid;
N Cyanomethyl-2-cyclohexylmethyl-malonamic acid;
2-Cyclohexyhnethyl-N (5,6,7,~-tetrahydro-naphthalen-1-yl)-malonamic acid;
2-Cyclohexylmethyl-N (2-pyridin-2-yl-ethyl)-malonamic acid;
2-Cyclohexylmethyl-3-(2,3-dihydro-indol-1-yl)-3-oxo-propionic acid;
2-Cyclohexylmethyl-3-(3,4-dihydro-1H isoquinolin-2-yl)-3-oxo-propionic acid;
2,1V Bis-cyclohexylmethyl-3-oxo-butyramide;
2-Cyclohexylmethyl-N (2-methoxy-benzyl)-3-oxo-butyramide;
2-Cyclohexylmethyl-N (1-phenyl-ethyl)-malonamic acid;
N Benzyl-2-cyclohexylmethyl-N methyl-malonamic acid;
2-Cyclohexylmethyl-N (3-nitro-benzyl)-3-oxo-butyramide;
2-Cyclohexylmethyl N (4-methoxy-benzyl)-malonamic, acid;
N (3-Carbamoyl-phenyl)-2-cyclohexylmethyl-malonamic acid;
2-Cyclohexylinethyl-N pyridin-3-ylmethyl-malonamic acid;
N (4-Carbamoyl-phenyl)-2-cyclohexyhnethyl-malonamic acid;
2-Cyclohexylmethyl-N (tetrahydro-furan-2-ylinethyl)-malonamic acid;
2-Cyclohexylmethyl-3-(3,4-dihydro-2H quinolin-1-yl)-3-oxo-propionic acid;
N tent-Butyl-2-cyclohexylmethyl-N methyl-malonamic acid;
2-Cyclohexylmethyl-N methyl-N propyl-malonamic acid;
N Butyl-2-cyclohexylinethyl N methyl-malonamic acid;
41
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
2-Cyclohexylmethyl-N,N dimethyl-malonamic acid;
(R)-2-Benzylcarbamoyl-4-phenylsulfanyl-butyric acid; and
4-Benzenesulfonyl-2-benzylcarbamoyl-butyric acid;
S
EXAMPLE 1
2-but~-N cyanomet~l-N'-~henylmalonamide
(Compound 1 )
H H
N N~C'N
O O
A solution comprised of 2-Phenylcarbamoyl-hexanoic acid (188g, 0.8mmol),
prepared as in Reference l, in DMF (S.OmL) was°treated with PyBOP~ (42S
0.8mmo1),
aminoacetonitrile bisulfate (140mg, 0.9 mmol) and triethylamine (600p,L,
4.3mmol). The
mixture was stirred for 3 hours and then partitioned between water (20 mL) and
ethyl
acetate (SO rnL). The organic layer was separated and washed with 1 M
saturated sodium
bicarbonate solution, 1 M hydrochloric acid solution and water, dried (MgS04)
and
concentrated. Product was purified from the residue by flash column on silica
gel (60°A)
with SO% ethyl acetate in hexane to provide 2-but ~~N-cXanomethyl-N'-
phenyhnalonamide
(12S mg, S7% yield). . 'H NMR: (DMSO) 10.01 (s, 1H), 7.59 (d, J=8Hz, 2H), 7.31
(t,
J=7Hz, 2H), 7.06 (t, J=7Hz, 1H), 4.13 (d, J=6Hz, 2H), 3.32 (t, J=BHz, 1H),
1.80 (m, 2H),
1.25 (m, 4H), 0.86 (t, J=7Hz, 3H). MS: m/e 273.9.
EXAMPLE 2
N Cyanomethyl-2-cyclohex~th~-N-phenyl-malonamide
(Compound 2);
N42 N eN
w
i o
42
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
A solution comprised of 2-Cyclohexyhnethyl-N phenyl-malonamic acid (350 mg,
1.2 mmol), prepared as in Reference 2, EDCI (250 mg, 1.3 mmol), HOBt hydrate
(199 mg,
1.3 mmol), amino acetonitrile bisulfate (200 mg, 1.3 mmol) and N-
methylinorpholine (0.30
S ml, 2.7 mmol) in N, N dimethylpyrrolidinone (S ml) was stirred at ambient
temperature for
15 hours. The reaction mixture was poured into cold IN HCl and extracted with
ethylacetate. The organic phase was washed with aqueous saturated sodium
bicarbonate
and then brine (SO ml each) dried over magnesium sulfate and evaporated. The
residue
was purified by radial chrorrxatography using 50% ethylacetate/hexane as
eluent to rp ovide
N-Cyanometh~yclohex l~~phenyl-malonamide (179 mg, 48% yield). 1H
NMR: (DMSO) 10.01 (s, 1H), 8.47 (t, J=SHz, 1H), 7.59 (d, J=7Hz, 2H), 7.31 (t,
J=8Hz,
2H), 7.07 (t, J=7Hz, 1H), 4.13 (d, J=SHz, 2H), 3.47 (t, J=7Hz, 1H), 1.6 (m,
7H), 1.1 (m,
4H), 0.9 (m, 2H). MS: m/e 313.2.
EXAMPLE 3
N cyanometh.~!1-2-c clue ohexylmeth~-N'-phenethylmalonamide
(Compound 3)
H H / N
N N~,C
O O
A solution comprised of 2-Cyclohexylinethyl-N phenethyl-malonic acid (138 mg,
0.46 mmol), prepared as in Reference 3, EDCI (115 mg, 0.60 mmol), HOBt hydrate
(92
mg, 0.60 mmol), N methylinorpholine (0115 ml, 1.38 mmol) in N,N dimethyl
pyrrolidimone (4 mI) was stirred at ambient temperature for 10 min.
Aminoacetonitrile
bisulfate (106 mg, 0.69 mmol) was added. The reaction mixture was stirred at
ambient
temperature for 2 hours, then poured into cold IN HCl and extracted twice with
ethylacetate (SO ml each). The organic phase was washed with aqueous sodium
bicarbonate and then brine (50 ml each), dried over magnesium sulfate and
evaporated.
43
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
The.residue was purified by radial chromatography using 50%
ethylacetate/hexane as
eluent to provide N c~nomethyl-2-c clohexylometh~phenethyhnalonamide (56 mg,
36% yield). 1H NMR: (DMSO) 8.38 (t, J=SHz, 1H), 7.98 (t, J=6Hz, 1H), 7.25 (m,
SH),
4.10 (d, J=6Hz, 2H), 3.2 (m, 3H), 2.71 (t, J=7Hz, 2H), 1.6 (m, 7H), 1.1 (m,
4H), 0.85 (m,
2H). MS: n~/e 342.10.
EXAMPLE 4
N cyanomethvl-2-c clue l~yl-N'-p ~~ l~methylmalonamide
(Compound 4)
N~ I I
N N
N
O O
A solution comprised of 2-Cyclohexylmethyl-N pyridin-4-yhnethyl-malonic acid
(41 mg, 0.14 mmol), prepared as in Reference 4, was coupled to
aminoacetonitrile as
described in Example 3 to provide N cyanomethyl-2-cyclohex l~~pyrid-4-
ylinethylinalonamide (13 mg, 28% yield). 'H NMR: (DMSO) 8.5 (m, 4H), 7.20 (d,
J=6Hz,
2H), 4.3 (m, 2H), 4.13 (d, J=SHz, 2H), 3.3 (m, 1H),1.6 (m, 7H), 1.1 (m, 4H),
0.83 (m, 2H).
MS: m/e 329.08.
EXAMPLE 5
N [1-(1-Benzooxazol-2-yl-methanoyl~ 3-phenyl-props]-N-benz~_2-
c clue lmethyl-malonamide
(Compound 5)
44
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
A mixture of N benzyl-2-cyclohexylmethyl-malonamic acid (200mg,
0.69mmol), HOBt (159mg, 1.04mmo1), EDC (146mg, 0.76mmo1), 2-amino-1-
benzooxazol-2-yl-4-phenyl-butan-1-one (195mg, 0.69mmol), dichloromethane (3mL)
and triethylamina (106p,L, 0.76mmo1) was allowed to stir 2 hour. The product
was
extracted into ethyl acetate (60mL) and washed with two lSmL portions of 1N
HCI,
and two lSmL portions of saturated NaHS03, dried over MgSO~ and concentrated.
Ethyl acetate (SmL) was added and a white precipitate formed and was collected
to give
N [1-(1-benzooxazol-2-yl-1-hydroxy-methyl)-3-phenyl-propyl]-N-benzyl-2-
cyclohexylmethyl-malonamide (8lmg, 0.12mmol, 21% yield).
N [1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-3-phenyl-propyl]-N-benzyl-2-
cyclohexylinethyl-malonamide (70mg, 0.126mmo1) was dissolved in 0.6mL
dichloromethane and treated with Dess Martin periodinane (107mg, 0.253mmo1).
The
mixture was stirred for 2 hours, then 8mL of 0.26M NaS2O3 in saturated NaHS03
was
added and the mixture was extracted with two lSmL portions of ethyl acetate
and
washed with two 4mL portions of saturated NaHSO3. The organic layer was dried
over
MgSOø and concentrated. The product was recrystallized from ethyl acetate and
hexane
to give N ![1-(1-Benzooxazol-2-yl-methanoyll-3-phenyl-props]-N-benzyl-2-
c clohexylinethyl-malonamide (40mg, 0.072mmo1, 57% yield);'H NMR: (DMSO)
7.88 (m, 1H), 7.68-7.40 (m, 3H), 7.35-7.10 (m, 10H), 6.90 (m, 1H), 5.65 (m,
1H), 4.43
(d, J=5.7Hz, 2H), 3.25 (m, 1H), 2.74 (t, J=B.OHz, lI-I), 2.46 (m, 1H), 2.17
(m, 1H), 1.77
(t, J=7.4Hz, 1H), 1.64 (m, 7H), 1.22 (m, 4H), 0.87 (m, 2H); MS: (M+-t-1)
552.8; 551.68.
The following compounds of Formula I were provided by proceeding as in the
above Examples:
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
N cyanomethyl-N'-c~clohex~vclohexxlmeth~namide (Compound 6); IH
NMR(DMSO): 8.31 (t, J=6Hz, 1H), 7.82 (d, J=8Hz, 1H), 4.10 (d, J=8Hz, 2H), 3.52
(m,
1H), 3.20 (t, J=7Hz, 1H), 1.d (m, 12H), 1.I (m, 9H), 0.83 (m, 2H); MS (m/e)
=320.11;
N benz~yanometh~-c c~ lohex~lmethylmalonamide (Compound 7); 'H
NMR(DMSO): 8.45 (m, 2H), 7.3 (m, 5H), 4.33 (dd, J=6,15Hz, 1H), 4.23 (dd,
J=6,15Hz,
1H), 4.12 (d, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS
(m/e) = 328.15,
M.Wt. = 327.43;
N cyanometh~ cly ohex 1~~~4-phenoxyphen~~malonamide
(Compound 8);1H NMR(DMSO): 10.1 (s, 1H), 8.50 (t,J=SHz, 1H), 7.61 (d, J=7Hz,
2H),
7.37 (t, J=7Hz, 2H), 7.11 (t,J=7Hz, IH), 7.0 (m, 4H), 4.14 (d, J=SHz, 2H),
3.47 (t,J=7Hz,
IH), 1.7 (m, 7H), I.I (m, 4H), 0.92 (m, 2H); MS (m/e) = 406.10, M.Wt. =
405.49;
N cyanometh~vclohexylmethyl-N'~'3-phen~lpropvl~malonamide (Compound
9); 'H NMR(DMSO): 8.38 (t, J=6Hz, 1H), 8.00 (t,J=6Hz, 1H), 7.2 (m, 5H), 4.10
(d,
J=SHz, 2H), 3.23 (t,J=7Hz, 1H), 3.1 (m, 2H), 2.5 (m, 2H), 1.6 (m, 9H), 1.1 (m,
4H), 0.85
(m, 2H); MS (m/e) = 356.02;
N cyanometh 1-~2-c_ clue ohex~lmethyl-3-morpholin-4-yl-3-oxopropionamide
(Compound 10);'H NMR(DMSO): 8.54 (t, J=4Hz, 1H), 4.12 (d, J=SHz, 2H), 3.5 (m,
8H),
1.65 (m, 8H), 1.15 (m, 4H), 0.85 (m, 2H); MS (m/e) = 308.05;
N cyanometh~ cl~~ 1-~phth-1-ylmethylmalonamide (Compound
11); 'H NMR(DMSO): 8.53 (t, J=SHz, 1H), 8.43 (t,J=6Hz, 1H), 8.04 (m, 1H), 7.94
(m,
IH), 7.86 (d,J=BHz, 1H), 7.5 (m, 4H), 4.85 (dd, J=6,15Hz, 1H), 4.65 (dd,
J=5,15Hz, 1H),
4.12 (d, J=3Hz, 2H), 3.3 (m, 1H), 1.6 (m, 8H), 1.0 (m, 5H); MS (m/e) = 378.18,
M.Wt.
377.18;
N cyanometh~-2-c clohexylmethXl-N'-pyrid-3 ylmalonamide (Compound 12);
'H NMR(DMSO): 10.24 (s, 1H), 8.75 (s, 1H), 8.54 (t, J=SHz, IH), 8.29 (d,
J=SHz, 1H),
8.04 (d,J=7Hz, 1H), 7.36 (m, IH), 4.I3 (d, J=SHz, 2H), 3.49 (t, J=7Hz, 1H),1.7
(m, 7H),
1.1 (m, 4H), 0.9 (m, 2H); MS (m/e) = 314.91;
N cvanometh~c cly ohexylinethyl-N,N-diisobutyhnalonamide (Compound 13);
'H NMR(DMSO): 8.50 (t, J=4Hz, 1H), 4.09 (m, 2H), 3.63 (t, J=7Hz, 1H), 3.2 (m,
2H),
3.05 (m, ZH), 1.9 (m, 2H), I.6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 14H); MS (m/e) =
350.08,
M. Wt. 349.51;
46
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
N cyanomethyl-2-cyclohex~lmethyl N,N-diisopropylinalonamide (Compound 14);
'H NMR(DMSO): 8.45 (t, J=SHz, 1H), 4.1 (rn, 3H), 3.55 (t, J=7Hz, 1H), 3.46 (m,
1H),1.6
(m, 7H), 1.27 (d, J=7Hz, 6H), 1.11 (m, 10H), 0.85 (m, 2H); MS (m/e) = 321.99,
M.Wt.
321.24;
N cyanomethyl-2-cyclohex 1~~(6-methoxyp '~~lmalonamide
(Compound 15);'H NMR(DMSO): 10.04 (s, 1H), 8.50 (t, J=SHz, 1H), 8.35 (s,1H),
7.88
(d, J=9Hz, 1H), 6.80 (d,J=9Hz, 1H), 4.13 (m, 2H), 3.81 (s, 3H), 3.44 (t,
J=8Hz, 1H), 1.7
(m, 7H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e) = 345.01, M.Wt. 344.18;
N c~anomethyl-2-c cly_ ohex~ 1-~~--(2-thien-2-ylethyl)malonamide (Compound
16);'H NMR(DMSO): 8.40 (t, J=SHz, 1H), 8.07 (t, J=SHz, 1H), 7.33 (d,
J=SHz,1H), 6.95
(m, 1H), b.87 (m, 1H), 4.10 (d, J=SHz, 2H), 3.3 (m, 3H), 3.21 (t, J=7Hz; 2H),
1.6 (m, 7H),
1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 348.09, M.Wt. 347.48;
N cyanomethyl-2-c~hexylmethyl-N'-(3-phenoxyphenyl)malonamide
(Compound 17);'HNMR(DMSO): 10.1 (s,1H), 8.45 (t, J=SHz, 1H), 7.41 (t, J=8Hz,
2H),
7.33 (m, 3H), 7.16 (t, J=7Hz, 1H), 7.03 (d, J=BHz, 2H), 6.73 (m, 1H), 4.1 (m,
2H), 3.42
(t, J=7Hz, IH),1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 406.04,
M.Wt. 405.49;
N c ay nometh,~yclohexylmethvl-N'-l4-nitrobenz~)mal~namide (Compound
18);1H NMR(DMSO): 8.61 (t, J--6Hz, 1H), 8.53 (t, J--6Hz, 1H), 8.17 (d, J--9Hz,
2H), 7.47
(d, J=9Hz, 2H), 4.41 (d, J=6Hz, 2H), 4.14 (d, J=6Hz, 2H), 3.3 (m, 1H), 1.6 (m,
7H), 1.1
(m, 4H), 0.87 (m, 2H); MS (m/e) = 373.02, M.Wt. 372.42;
N,N'-biscyanometh~ cly ohex l~meth~malonamide (Compound 19); 'H
NMR(DMSO): 8.59 (t, J=SHz, 2H), 4.14 (d, J=6Hz, 4H), 3.28 (t, J=8Hz, 1H), 1.6
(m, 7H),
1.1 (m, 4H), 0.86 (m, 2H); MS (m/e) = 276.99, M.Wt. 276.34;
N cyanomethyl-2-c cl~~yl-N'-(5,6,7,8-tetrah~dronaphth-1-~lmalonamide
(Compound 20);'H NMR(DMSO): 9.28 (s,1H), 8.57 (t, J=6Hz, 1H), 7.21 (d,
J=8Hz,1H),
7.05 (t, J=8Hz, 1 H), 6.90 (d, J=7Hz, 1 H), 4.16 (d, J=6Hz, 2H), 3.49 (t,
J=7Hz, 1 H), 2.7 (m,
2H), 2.5 (m, 2H), 1.7 (m, 11H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e) = 368.04,
M.Wt.
367.48;
N c~anometh ~~1-2-c cl~xylmethyl-N'-(2-pxrid-2-~eth~)malonamide
(Compound 21);'H NMR(DMSO): 8.49 (m, lI~, 8.40 (t, J=6Hz, 1H), 8.00 (t,
J=SHz,1H),
7.68 (dt, J=2,8Hz, 1H), 7.2 (m, 2H), 4.09 (d, J=6Hz, 2H), 3.42 (m, 2H), 3.17
(t, J=8Hz,
47
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
1H), 2.85 (t, J=7Hz, 2H), 1.6 (m, 7H), 1.07 (m, 4H), 0.83 (m, 2H); MS (m/e) =
343.04,
M.Wt. 342.44;
N cyanometh~yclohex l~yl-32,3-dihydroindol-1-~ -3-oxopropionamide
(Compound 22); 'H NMR(DMSO): 8.73 (t, J=SHz, 1H), 8.06 (d, J=8Hz, IH), 7.24
(d,
J=7Hz, 1H), 7.15 (t, J=7Hz, 1H), 7.00 (t, J=7Hz, 1H), 4.15 (d, J=SHz, 2H), 4.1
(m, 2H),
3.66 (t, J=7Hz, 1 H), 3.14 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H); MS
(m/e) _
340.07, M.Wt. 339.19;
N cyanomethyl-2-cyclohexylmethy~3,4-dihydro-1H isoduinolin-2-~)-3-
oxopropionamide (Compound 23); 'H NMR(DMSO): 8.64(t, J=SHz, 1H), 7.15 (s, 4H),
4.65 (m, 2H), 4.11 (t, J=6Hz, 2H), 3.77 (m, 2H), 2.8 (m, 2H), 1.7 (m, 7H), 1.1
(m, 4H),
0.89 (m, 2H), 3.54 (m, 1H); MS (mle) = 354.05, M.Wt. 353.46;
N cyanomethyl-2,N-bisc cl~ohexylmethylmalonamide (Compound 24); 1H
NMR(DMSO): 8.34 (t, J=SHz, 1H), 7.93 (t, J=SHz, 1H), 4.09 (d, J=6Hz, 2H), 3.23
(dd,
J=7,9Hz, 1H), 3.0 (m, 1H), 2.8 (m, IH), 1.6 (m, I2H), 1.4 (m, 1H), 1.1 (m,
7H), 0.86 (m,
4H); MS (m/e) = 334.00, M.Wt. 333.47;
N cyanometh,~ cly ohex l~hyl-N' ~2-methox~~lmalonamide
(Compound 25); 'H NMR(DMSO): 8.44 (t, J=SHz, 1H), 8.27 (t, J=6Hz, 1H), 7.24
(dt,
J=2,7Hz, 1H), 7.10 (dd, J=2,7Hz, 1H), 6.96 (d, J=7Hz, 1H), 6.88 (dt, J=7,lHz,
1H), 4.30
(dd, J=6,16Hz, 1H), 4.20 (dd, J=5,16Hz, 1H), 4.12 (d, J=6Hz, 2H), 3.79 (s,
3H), 3.3 (m,
1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 358.03, M.Wt. 357.45;
N cyanomethyl-2-c cl~ohe_x l~methyl-N'_(1-phen~~)malonamide (Compound
26); 'H NMR(DMSO): 8.25 (m, 1H), 7.4 (m, SH), 4.02 (m, ZH), 3.18 (s, 3H), 3.25
(m,
1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.7 (m, 2H); MS (m/e) = 328.08, M.Wt. 327.42;
N benz~-N'-c~anometh~ c~lohex~linethyl-N methylmalonamide (Compound
27);1H NMR(DMSO): 8.62 (m, 1H), 7.3 (m, SH), 4.5 (m, 2H), 4.13 (d,J=6Hz, 2H),
3.7 (rn,
1H), 2.93 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.88 (m, 2H); MS (m/e) = 342.09,
M.Wt.
341.45;
N cyanometh~yclohex l~yl-N'-(3-nitrobenzyl)malonamide (Compound
28); IH NMR(DMSO): 8.6 (t, 1H), 8.5 (t, 1H), 8.1 (m, 2H), 7.6 (m, 2H), 4.1 (m,
2H), 1.6
(m, 7H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e) = 373.07, M.Wt. 372.42;
N cvanomethyl-2-oyclohexylmeth~(4-methoxybenz~lmalonamide
48
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
(Compound 29); 'H NMR(DMSO): 8.42 (t, J=SHz, 1H), 8.38 (t, J=6Hz, 1H), 7.14
(d,
J=9Hz, 2H), 6.86 (d, J=9Hz, 2H), 4.25 (dd, J--6,15Hz, 1H), 4.15 (dd, J=7,16Hz,
1H), 3.71
(s, 3H), 3.27 (t, J=8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.84 (m, 2H), 4.11
(d,J=6Hz, 2H);
MS (m/e) = 356.97, M.Wt. 357.45;
N (3-carbamoylphen~rlZN'-cyanomethyl-2-cyclohex l~methylmalonamide
(Compound 30);'H NMR(DMSO): 10.14 (s, 1H), 8.48 (t, 1H), 8.03 (s, 1H), 7.75
(d,1H),
7.54 (d, IH), 7.35 (m, 2H), 4.12 (d, 2H), 3.4 (t, 1H), 1.6 (m, 7H), 1.1 (m,
4H), 0.9 (m, 2H),
3.29 (s, 3H); MS (m/e) = 357.11, M.Wt. 356.42;
N-cyanomethyl-2-c, c~hex~hneth,~~ 'yrid-3-3-, l~ylmalonamide (Compound
31);'H NMR(DMSO): 8.4 (m, 4H), 7.55 (d, 1H), 7.25 (dd, 1H), 4.28 (dd, 1H),
4.18 (dd,
1H), 4.05 (d, 2H), 3.2 (m, 1H), 1.6 (m, 7H); 1.01 (m, 4H), 0.78 (m, 2H); MS
(m/e) _
329.03, M.Wt. 328.41;
N (,4-carbamo~~hen~ll-N'-cyanomethyl-2-c~clohex l~methylmalonamide
(Compound 32);'H NMR(DMSO): 10.22 (s, 2H), 8.50 (t, J=6Hz, 1H), 7.83 (d, J=9Hz
2H),
7.64 (d, J=9Hz, 2H), 7.52 (s, 1H), 4.13 (d, J=6Hz, ZH), 3.48 (t, J=7Hz, 1H),
1.7 (m, 7H),
1.1 (rn, 4H), 0.9 (m, 2H); MS (mle) = 357.04, M.Wt. 356.42;
N cyanometh,~-2-c, cl~ylmethyl-lV'-tetrahydrofur-2-, l~ylmalonamide
(Compound 33); 'H NMR(DMSO): 8.38 (t, J=SHz, 1H), 7.98 (t, J=4Hz, 1H), 4.10
(d,
J=6Hz 2H), 3.8 (m, 2H), 3.6 (m, 1H), 3.2 (m, 4H), 1.8 (m, 3H), 1.6 (m, 7H),
1.1 (m, 4H),
0.85 (m, 2H); MS (m/e) = 322.02, M.Wt. 321.41;
N cyanomethyl-2-c cl~ohex lmeth~(3,4-dihydro-2H quinolin-1-~)-3
oxopropionamide (Compound 34);'H NMR(DMSO): 8.5 (m, 1H), 7.35 (m, 1H), 7.2
(m,.
4H), 4.1 (m, 2H), 3.82 (dd, 1H), 2.78 (t, 1H), 2.72 (t, 1H), 2.59 (m, 1H), 1.8
(m, 2H), 1.5
(m, 7H), 1.0 (m, 4H), 0.7 (m, 2H); MS (m/e) = 354.02, M.Wt. 353.46;
N tent-but~yanomethyl-2-c clue 1y methyl-N methyl_malonamide
(Compound 35); 'H NMR(DMSO): 8.41 (t, J=SHz, 1H), 4.09 (d, J=SHz, 1H), 3.56
(t,
J=7Hz, 1H), 2.86 (s, 3H), 1.6 (m, 7H), 1.31 (s, 9H), 1.1 (m, 4H), 0.8 (m, 2H);
MS (m/e)
= 308.04, M.Wt. 307.43;
N cyanometh~ clue l~methyl-N'-meth~propyhnalonamide (Compound
36); 1H NMR(DMSO): 8.5 (m, 1H), 4.10 (m, 2H), 3.60 (t, J=7Hz, 1H), 3.2 (m,
2H), 2.96
(s, 3H), 1.65 (m, 7H), I.45 (m, 2H), I.l (m, 4H), 0.8 (m, SH); MS (m/e) =
294.02, M.Wt.
49
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
293.40;
N butyl-N'-cyanometh.~_2-cyclohexxlmeth,~~l-N methylmalonamide (Compound
37); 'H NMR(DMSO): 8.5 (m, 1H), 4.10 (d, J=SHz, 2H), 3.60 (t, 1H), 3.3 (m,
2H), 2.95
(s, 3H), 1.6 (m, 7H), 1.4 (m, 2H), 1.1 (m, 6H), 0.8 (m, 5H); MS (m/e) =
308.01, M.Wt.
307.43;
N cyanometh.~yclohex. l~methyl-N,N-dimethyhnalonamide (Compound 38);
1H NMR(DMSO): 8.55 (t, J=SHz, 1H), 4.11 (d, J=7Hz, 2H), 3.62 (t, J=8Hz, 1H),
2.99 (s,
3H), 2.81 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 266.01,
M.Wt.
265.18;
N bent,~~l-N-~anometh,~l-2-~-nhen~sulfanyleth,~~l)malonamide (Compound 39);
'H NMR(DMSO): 8.56 (t, J=6Hz, 1H), 8.49 (t, J=6Hz, 1H), 7.3 (m, 10H), 4.29 (d,
J=6Hz,
2H), 4.14 (d, J=6Hz, 2H), 3.40 (t, J=7Hz, 1H), 2.86 (t, J=8Hz, 2H), 2.05 (m,
2H); MS
(m/e) = 368.02, M.Wt. 367.14; and
2-(2-phen lsulfonylethyl -N benz~l-N-cyanomethyhnalonamide (Compound 40);
'H NMR(DMSO): 8.56 (t, J=6Hz, 1H), 8.43 (t, J=6Hz, 1H), 7.86 (d, J=7Hz, 2H),
7.79 (t,
J=SHz, 1H), 7.68 (t, J=8Hz, 2H), 7.25 (m, 5H), 4.26 (d, J=6Hz, 2H), 4.13 (d,
J=6Hz, 2H),
3.36 (m, 1H), 3.19 (m, 2H), 2.00 (m, 2H); MS (m/e) = 400.04, M.Wt. 399.47;
~2-Benzenesulfonyl-eth~ll-N [fS~-1-(1-benzooxazol-2-yl-methano~2pent~] N'-
benzyl-malonamide (Compound 41)'H NMR(DMSO): 8.56 (d, J=6Hz, 1H), 8.2 (m, 1H),
20~ 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H), 4.24 (t, J=6Hz, 2H), 3.41
(t, J=7Hz, 1H),
3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H),1.30 (m, 4H), 0.82 (m, 3H); MS (m/e)
= 576.27,
M.Wt. 575.21; and
N,N-Bis-[(Sl-1-(1-benzooxazol-2-yl-methanol)~ro~yll-2-cyclohexylmeth ,~l-
malonamide (Compound 42)'H NMR(DMSO): 8.41 (d, J=6Hz, 2H), 8.00 (d, J=BHz,
2H),
7.89 (d, J=8Hz, 2H), 7.65 (t, J=7Hz, 2H), 7.53 (t, J=BHz, 2H), 5.19 (m, 2H),
3.42 (t,
J=8Hz, 1H), 1.98 (m, 2H), 1.74 (m, 2H), 1.52 (m, 7H), 0.94. (m, l OH), 0.77
(m, 2H); MS
(m/e) = 572.26, M.Wt. 573.4.
E~~AMPLE 6
Cathepsin S Assay
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
Solutions of test compounds in varying concentrations were prepared in 10 ~,L
of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ~.L,
comprising: MES,
50 mM (pH 6.5); EDTA, 2.5 mM; and NaCI, 100 rnM). Human cathepsin S (0.158
pMoles
in 25 ~L of assay buffer) was added to the dilutions. The assay solutions were
mixed for
5-10 seconds on a shaker plate, covered and incubated for 30 minutes at
ambient
temperature. Z-Val-Val-Arg-AMC (9 nMoles in 25 ~L of assay buffer) was added
to the
assay solutions and hydrolysis was followed spectrophotometrically at (7~ 460
nm) for 5
minutes. Apparent inhibition constants (K;) were calculated from the enzyme
progress
curves using standard mathematical models.
EXAMPLE 7
Cathepsin B Assay
Solutions of test compounds in varying concentrations were prepared in 10 p,L
of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ~,L,
comprising: N,N
bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6);
polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM).
Human
cathepsin B (0.025 pMoles in 25 ~L of assay buffer) was added to the
dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated
for 30
minutes at ambient temperature. Z-FR-AMC (20 nMoles in 25 pL of assay buffer)
was
added to the assay solutions and hydrolysis was followed
spectrophotometrically at (~, 460
nm) for 5 minutes. Apparent inhibition constants (K;) were calculated from the
enzyme
progress curves using standard mathematical models.
EXAMPLE 8
Cathepsin I~ Assay
Solutions of test compounds. in varying concentrations were prepared in 10 ~,L
of
51
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 p.L,
comprising: MES,
50 rnM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906
pMoles in 25 p.L of assay buffer) was added to the dilutions. The assay
solutions were
mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes
at ambient
temperature. Z-Phe-Arg-AMC (4 nMoles in 25 p,L of assay buffer) was added to
the assay
solutions and hydrolysis was followed spectrophotornetrically at (?~ 460 nm)
for 5 minutes.
Apparent inhibition constants (K;) were calculated from the enzyme progress
curves using
standard mathematical models.
EXAMPLE 9
Cathepsin L Assay
Solutions of test compounds in varying concentrations were prepared in 10 p,L
of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL,
comprising: MES,
50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles
in 25 p,L of assay buffer) was added to the dilutions. The assay solutions
were mixed for
5-10 seconds on a shaker plate, covered and incubated for 30 minutes at
ambient
temperature. Z-Phe-Arg-AMC (1 nMoles in 25 pL of assay buffer) was added to
the assay
solutions and hydrolysis was followed spectrophotometrically at (~, 460 nm)
for 5 minutes.
Apparent inhibition constants (K;) were calculated from the enzyme progress
curves using
standard mathematical models.
Compounds of the invention were tested according to the above-described assays
for protease inhibition and observed to exhibit selective cathepsin S
inhibitory activity.
For example, the compounds of the invention were found to inhibit cathepsin S
protease
activity at concentrations that are least 50 fold less than those
concentrations required to
produce an equiactive inhibition of cathepsin K protease activity. The
apparent irxhibition
constants (K~ for compounds of the invention, against Cathepsin S, were in the
range from
about 10-'°M to about 10-'M.
52
CA 02449021 2003-11-27
WO 02/098406 PCT/US02/17922
EXAMPLE 10
Representative Pharmaceutical Formulations Containing a Compound of
Formula I
ORAL FORMULATION
Compound of Formula I 10-100 mg
Citric Acid Monohydrate 105 mg
Sodium Hydroxide 18 mg
Flavoring
Water q.s. to 100
mL
INTRAVENOUS FORMULATION
Compound of Formula I 0.1-10 mg
Dextrose Monohydrate q.s. to make
isotonic
Citric Acid Monohydrate 1.05 mg
'Sodium Hydroxide 0.18 mg
Water for Injection q.s. to 1.0
mL
TABLET FORMULATION
Compound of Formula I 1
Microcrystalline Cellulose 73%
Stearic Acid 25%
Colloidal Silica 1%.
53
