Note: Descriptions are shown in the official language in which they were submitted.
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SPiRO=PYRfMIDfNE-2.4.6-TRIONE METALLOPROTEtNASEINHIBITORS
t3ackaround of the invention
The present invention relates to 5-spiro-pyrimidine-2,4,6-triune
metalloproteinase
inhibitors and to pharmaceutical compositions and methods of treatment of
inflammation,
cancer and other disorders.
The compounds of the present invention are inhibitors of zinc
metalloendopeptidases,
especially those belonging to the class of matrix metalloproteinases (also
ca;led MMP or
matrixin).
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1,
MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14,
MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP's are most well known
for their role in regulating the turn-over of extracellular matrix proteins
and as such play
important roles in normal physiological processes such as reproduction,
development and
differentiation. In addition, the MMP's are expressed in many pathological
situations in which
abnormal connective tissue turnover is occurring. For example, MMP-13 an
enzyme with
potent activity at degrading type II collagen (the principal collagen in
cartilage), has been
demonstrated to be overexpressed in osteoarthritic cartilage (Mitchell, et
al., J. Clin. Invest.,
97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also
overexpressed in osteoarthritic cartilage and inhibition of some or all of
these MMP's is
expected to slow or block the accelerated loss of cartilage typical of joint
diseases such as
osteoarthritis or rheumatoid arthritis.
It is recognized that different combinations of MMP's are expressed in
different
pathological situations. As such, inhibitors with specific selectivities for
individual MMP's may
be preferred for individual diseases.
Matrix metalloproteinase inhibitors are well known in the literature.
Hydroxamic acid
MMP inhibitors are exemplified in European Patent Publication 606,046,
published July 13,
1994. Several pyrimidine-2,4,6-triune MMP inhibitors are referred to in PCT
publication WO
98158925, published December 30, 1998. PCT publication WO 00147565, published
August
17, 2000 refers to certain aryl substituted pyrimidine-2,4,6-triune MMP
inhibitors. United
States Non-provisional application 09/635156, filed August 9, 2000 (which
claims priority to
United States Provisional application 601148547 filed August 12, 1999) refers
to heteroaryl
substituted pyrimidine-2,4,6-triune MMP inhibitors. United States Provisional
Application
entitled "Pyrimidine-2,4,6-triune Metalloproteinase Inhibitors", filed October
26, 2000, refers to
certain pyrimidine-2,4,6-triunes. Barbituric acids and methods for their
preparation are well
known in the art, see for example Goodman and Gilman's, "The Phamacological
Basis of
Therapeutics," 345-382 (Eighth Edition, McGraw Hill, 1990). Each of the above
referenced
publications and applications is hereby incorporated by reference in its
entirety.
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Summary of the Invention
The present invention relates to compounds of the formula:
O X-Y-Z-G
N
O
N A
O I
wherein said "A" is a 5-7 membered heterocyclic ring selected from the group
consisting of:
X-Y-Z-G X-Y-Z-G X-Y-Z-G
a) ~ O b) I O c) I O
Ra R3
N R4 ~ N R4 N ~ Ra
R3 Rs ' R~
,,
''~ ~ ~' Rz . R~ Rs . ~Rs ,
R ' R2 Re , R R R ,
d) X-Y-Z-G e) X-Y-Z-G f) X-Y-Z-G 9
O l/0 O R
N~ -R9 N~N~R N N Rio
R~1 R
> > > . ~ - ~ s Rs
R R . R Rz Rio . R Rz R
,
X-Y-Z-G
g) X Y Z G h) I-Y-Z-G i) a
R
N-SOz R4 N.SOz R4 N SOz ' Rs
,, Rs y Re
Rs ~ Rs . R~ .
R~ Rz ; R, Rz Rs , R~ Rz Rs ~ Rs ,
X-Y-Z-G X-Y-Z-G
X-Y-Z-G k I ) " 10
11 ) R~~ R1o R RRIs
1p 8 12
R R
N Rs N , R7 N ,, Ra
r~ ~ ;
v R5 s ; w R~
1 z ; R' R ; R' Rs
R R R2 R R2 R5 ,
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-3-
m) X-Y-Z-G n) X-Y-Z-G o) X-Y-Z-G
"
// O R 'o
''~ R
N~N'R9 ~ N N'Rs and ~ N H
~~SO ~ R'2
O O
wherein each of R', R2, R3, Rd, R5, Rs, R', R8, Rs, R'°, R", F2'2 and
R'3 is
independently selected from the group consisting of hydrogen, (C,-C4)alkyl,
(C,-C4)alkenyl,
(C,-C4)alkynyl, (C6-C,o)aryl, (C,-C,°)heteroaryl, (C3-C8)cycloalkyl and
(C,-C,°)heterocyclyl;
wherein each of said (C,-C4)alkyl, (C6-C,°)aryl, (C,-
C,°)heteroaryl, (C3-C8)cycloalkyl and (C,-
C,°)heterocyclyl may be optionally substituted on any of the ring
carbon atoms capable of
forming an additional bond with 1-3 substituents per ring independently
selected from halo,
(C,-C4)alkyl, (C,-C4)alkoxy, -CN, -OH and -NHa;
X is (C6-C,o)aryl or (C,-C,o)heteroaryl;
Y is selected from the group consisting of a bond, oxygen, sulfur, >C=0, >S02,
>S=0,
-CHZ-, -CH~O-, -O(CH2)~ , -CH2S-, -S(CHZ)~ , -CHzSO-, -CH~SOZ-, -SO(CHZ)~ ,
-SOz(CHz)r; , -NR'4, -NR'4(CH~)~ , -CH2[N(R,a)]-, -CHZ(CHZ)~ , -CH=CH-, -C---C-
, -[N(R,a)]-SOZ-
and -SOZ[N(R'4)]-;
n is an integer from one to four;
R'4 is hydrogen or (C,-C4)alkyl;
Z is selected from the group consisting of (C6-C,o)aryl, (C3-C$)cycloalkyl,
(C,-
C,o)heterocyclyl and (C,-C,°)heteroaryl; wherein one or two carbon-
carbon single bonds of
said (C3-C8)cycloalkyl or (C,-C,°)heterocyclyl may optionally be
replaced by carbon-carbon
double bonds;
wherein each of said X or Z may be independently optionally substituted on any
of the
ring carbon atoms capable of forming an additional bond by one or two
substituents per ring
independently selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-
C4)perfluoroalkyl, (C,-
C4)perfluoroalkoxy, (C,-C4)alkoxy and (C3-C8)cycloalkyloxy;
G is R'S-(CR'6R")p ; wherein G is a substituent on any ring carbon atom of Z
capable
of forming an additional bond and is oriented at a position other than alpha
to the point of
attachment of the Z ring to Y;
p is an integer from 0 to 4;
R'S is independently selected from the group consisting of halo, -CN, -NO2,
OH, (C,
C4)alkenyl, (C,-C4)alkynyl, (C,-C4)perfluoroalkyl, perfluoro(C,-C4)alkoxy, R'8-
, R'8-O-, R'8-(C,
C4)alkyl-O-, R'8-(C=O)-, R'8-(C=O)-O-, R'8-O-(C=O)- R'8-S-, R~-(S=O)-, R'8-
(SOZ)-, R~
(SOZ)-(NRz')- R's-(C=0)-(NRZ')- R22-0-(C=0)-(NR2,)- (R,sRzo)N-, (R'sRzo)N-
(SOz)-,
(R'sR2o)N-(C=0)_; (R,sRao)N-(C=0)-(NRz,)- and (R'sRzo)N-(C=0)-0_;
each of R'6 and R" is independently selected from hydrogen and (C,-C4)alkyl;
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or R'6 and R" may optionally be taken together with the carbon to which they
are
attached to form a 5 to 10-membered carbocyclic ring;
R'8, R'9, RZ° and R2' are independently selected from the group
consisting of
hydrogen, (C~-C4)alkyl, (C6-C~°)aryl, (C3-Ce)cycloalkyl, (C~-
C~°)heteroaryl and (C~
C~°)heterocyclyl; wherein said (Cs-C,°)aryl, (C3-C8)cycloalkyl,
(C~-C,°)heteroaryl and (C,
C,°)heterocyclyl moieties may be optionally substituted on any of the
ring carbon atoms
capable of forming an additional bond by one to three substituents per ring
independently
selected from F, CI, Br, CN, OH, (C~-C4)alkyl, (C,-C4)perfluoroalkyl, (C~-
C4)perfluoroalkoxy,
(C~-C4)alkoxy, amino, (C~-C4)alkyl-NH-, [(CT-C4)alkyl]2-N- and (C3-
C8)cycloalkyloxy; wherein
said (C3-C8)cycloalkyl and (C~-C,°)heterocyclyl moieties may also
optionally be substituted by
oxo; wherein said (C,-C,°)heteroaryl and (C,-C,°)heterocyclyl
moieties may optionally be
substituted on any ring nitrogen atom, able to support an additional
substituent by one to two
substituents per ring independently selected from the group consisting of (C~-
C4)alkyl and (C~-
C4)alkyl-(C=O)-;
or R'9 and RZ° may optionally be taken together with the nitrogen to
which they are
attached to form a 3 to 8-membered heterocyclic ring;
or R'9 and RZ' may optionally be taken together with the nitrogen, the carbon
or the
oxygen to which they are attached to form a 3 to 8-membered heterocyclic ring;
R~2 is selected from the group consisting of (C~-C4)alkyl, (C6-
C~°)aryl, (C3
C8)cycloalkyl, (C~-C,°)heteroaryl and (C~-C1°)heterocyclyl;
wherein said (C6-C~°)aryl, (C3
C8)cycloalkyl, (Ci-C~°)heteroaryl and (C~-C~°)heterocyclyl
moieties may be optionally
substituted on any of the ring carbon atoms capable of forming an additional
bond by one to
three substituents per ring independently seVected from F, CI, Br, CN, OH, (C~-
C4)alkyi, (C~
C4)perfluoroalkyl, (C~-C4)perfluoroalkoxy, (C~-C4)alkoxy, amino, (C~-C4)alkyl-
NH-, [(C~
C4)alkyl]2-N- and (C3-C8)cycloalkyloxy; wherein said (C3-C8)cycloalkyl and (C~-
C~°)heterocyclyl
moieties may also optionally be substituted by oxo; wherein said (C1-
C~°)heteroaryl and (Ct-
C,°)heterocyclyl moieties may optionally be substituted on any ring
nitrogen atom able to
support an additional substituent by one to two substituents per ring
independently selected
from the group consisting of (C~-C4)alkyl and (C,-C4)alkyl-(C=O)-;
or R~' and R~ may optionally be taken together with the nitrogen, the oxygen
or the
sulfur to which they are attached to form a 3 to 8-membered heterocyclic ring;
or the pharmaceutically acceptable salts thereof.
The present invention also relates to the pharmaceutically acceptable acid
addition
salts of compounds of the formula I. The acids which are used to prepare the
pharmaceutically acceptable acid addition salts of the aforementioned base
compounds of this
invention are those which form non-toxic acid addition salts, i.e., salts
containing
pharmacologically acceptable anions, such as the hydrochloride, hydrobromide,
hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,
citrate, acid citrate,
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tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate,
benzoate,
methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and
pamoate
[i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical
bases that
may be used as reagents to prepare pharmaceutically acceptable base salts of
those
compounds of formula I that are acidic in nature are those that form non-toxic
base salts with
such compounds. Such non-toxic base salts include, but are not limited to
those derived from
such pharmacologically acceptable cations such as alkali metal cations (e.g.,
potassium and
sodium) and alkaline earth metal cations (e.g., calcium and magnesium),
ammonium or water
soluble amine addition salts such as N-methylglucamine (meglumine) and the
lower
alkanolammonium and other base salts of pharmaceutically acceptable organic
amines.
The term "a bond", as used herein in the group Y, means that the groups X and
Z are
directly connected through a carbon-carbon bond so as to form pendent aryl
rings such as
diphenyl.
The dashed lines as used in each of the heterocyclic ring "A" of formulae a),
b), c), g),
h), i), k) and I) refer to optional double bonds. The exact positions of the
optional double
bonds for each of the heterocyclic ring "A" of formulae a), b), c), g), h),
i), k) and I) are as
defined in the specification. Whenever the dashed line extends over two carbon
atoms, one
skilled in the art will understand that two carbons are tetravalent and that
the extra
substituent(s) (i.e., any of R', R2, R3, R4, R5, Rs, R', R8, R'°, R",
R'z, or R'3) may be absent.
The term "alkyl", as used herein, unless otherwise indicated, includes
saturated
monovalent hydrocarbon radicals having straight, branched moieties, or
combinations thereof.
Alkyl groups, wherever they occur, may be optionally substituted by a suitable
substituent.
The term "alkenyl", as used herein, unless otherwise indicated, includes
hydrocarbon
radicals containing at least one olefin linkage and having straight, branched
moieties, or
combinations thereof.
The term "alkynyl", as used herein, unless otherwise indicated, includes
hydrocarbon
radicals containing at least one carbon-carbon triple bond linkage and having
straight, branched
moieties or combinations thereof.
The term "cycloalkyl", as used herein, unless otherwise indicated, includes a
mono or
bicyclic carbocyclic ring (e.g., cyclopropyl, cyciobutyf, cycfopentyl,
cycfohexyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl,
bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing
f or 2 double bonds
and optionally substituted by 1 to 3 suitable substituents as defined below
such as fluoro,
chloro, trifluoromethyl, (C,-Ca)alkoxy, (C6-C~°)aryloxy,
trifluoromethoxy, difluoromethoxy or
(C,-Ca)alkyl, more preferably fluoro, chloro, methyl, ethyl and methoxy.
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The term "a(koxy", as used herein, includes O-alkyl groups wherein "alkyl" is
as defined
above.
The term "halo", as used herein, unless otherwise indicated, includes
fluorine, chlorine,
bromine or iodine, preferably fluorine or chlorine.
The term "aryl", as used herein, unless otherwise indicated, includes an
organic radical
derived from an aromatic hydrocarbon by removal of one or more hydrogens, such
as phenyl or
naphthyl, optionally substituted by 1 to 3 suitable substituents such as
fluoro, chloro, cyano, vitro,
trifluaromethyl, (C~-C6)alkoxy, (C6-C~o)aryfoxy, (C3-C8)cycloalkyloxy,
trifluoromethoxy,
difiuoromethoxy, or (C~-Cs)aikyl.
The term "heteroaryl", as used herein, unless otherwise indicated, includes an
organic
radical derived from an aromatic heterocyclic compound by removal of one or
more
hydrogens, such as benzimidazofyi, benzofurany(, benzafurazanyi, 2H-1-
benzopyranyi,
benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl,
benzoxazolyl, chromanyl,
cinnolinyl,-furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indoiinyl,
indofizinyl, (ndoiyl, 3H-
indolyl, isoindolyl, isoquinolinyl, isothiazofyi, isoxazo(y1, naphthyridinyl,
oxadiazo(yi, oxazo(y(,
phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyf, pyridinyl,
pyrimidinyt, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl, quinoxafinyf, tetrazolyi, thiazolyl, thiadiazolyl,
thienyl, triazinyl and
triazolyi, wherein said IC,-C,o}heteroaryl is optionally substituted on any of
the ring carbon
atoms capable of forming an additional band by one or tv~o substituents
independently
selected from F, C(, Bc, CN, OH, (C~-Ca)alky(, (C,-C4)perfluoroalkyl, (C1-
C4)perfluoroalkoxy,
(C,-C4)a(koxy and (C3-C&)cycloalkyloxy. The foregoing groups, can be C-
attached or N-
attached where such is possible. For instance, pyrrolyl can be pyrrol-1-yl (N-
attached) or
pyrrol-3-yl (C-attached).
The term "heterocyciyl", as used herein, unless otherwise indicated, includes
an organic
radical derived from a non-aromatic heterocyclic compound by removal of one or
more
hydrogens, such as 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl,
azetidinyl,
dihydrofuranyl, dihydropyranyl, dihydrothienyi, dioxanyl, 1,3-dioxolanyl, 1,4-
dithianyl,
hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl,
isoxazolidinyl,
marpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4N-pyranyl,
pyrazolidinyl,
pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyi, quinoliziny(,
tetrahydrofuranyi,
tetrahydropyranyl, 1,2,3,fi-tetrahydropyridiny(, tetrahydrothienyl,
tetcahydcothiopyranyl,
thiomorpholinyl, thioxanyl and trithianyl. The foregoing groups, can be C-
attached or N-attached
where such is possible. For example, piperidinyl can be piperidin-1-yl (N-
attached) or piperidin-4-
yl (C-attached). The foregoing groups, as derived from the compounds listed
above, can be
optionally substituted where such is possible by a suitable substituent, such
as oxo, F, Cl, Br,
CN, OH, (C,-C~)alkyl, (C,-Ca)perfiiuoroalkyl, (C~-C4)perfluoroalkoxy, (C~-
C4}alkoxy, or (C3-
C$)cycloalkyloxy.
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_7_
The phrase "a suitable substituent" is intended to mean a chemically and
pharmaceutically acceptable functional group i.e., a moiety that does not
negate the inhibitory
activity of the inventive compounds. Such suitable substituents may be
routinely selected by
those skilled in the art. Illustrative examples of suitable substituents
include, but are not limited
to halo groups, perffuoroalkyl groups, perfluoroalkoxy groups, alkyl groups,
hydroxy groups, oxo
groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl
groups, aryloxy or
heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or
heteroaralkoxy groups, carboxy
groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,
alkylcarbonyl groups,
alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups,
arylcarbonyl
groups, aryloxycarbonyl groups, alkylsulfonyl groups, an arylsulfonyl groups
and the like.
The phrase "at a position other than alpha to the point of attachment of the Z
ring to
Y", as used herein, unless otherwise indicated, is intended to mean a
chemically and
pharmaceutically acceptable orientation of the bond connecting group Z to G (Z-
G bond)
relative to the bond connecting group Y to Z (Y-Z bond). Such relative
orientation may be
meta, wherein the Z-G bond is in the 1,3 position relative to the Y-Z bond.
Another relative
orientation may be para, wherein the Z-G bond is in the 1,4 position relative
to the Y-Z bond.
Some compounds of formula I contain chiral centers and therefore exist in
different
enantiomeric forms. This invention relates to all optical isomers,
enantiomers, diastereomers
and stereoisomers of the compounds of formula I and mixtures thereof. The
compounds of
the invention also exist in different tautomeric forms. This invention relates
to all tautomers of
formula I. Those skilled in the art are well aware that the pyrimidine-2,4,6-
trione nucleus
exists as a mixture of tautomers in solution. The various ratios of the
tautomers in solid and
liquid form is dependent on the various substituents on the molecule as well
as the particular
crystallisation technique used to isolate a compound.
In one embodiment of the invention, the heterocyclic ring "A" of the compounds
of the
formula I is selected from the formulae a) or b):
X-Y-Z-G X-Y-Z-G
a) ~ O b) ~ O
R4 ~ N Ra
R3 or ~ Rs
R~ , Rz R~Rz Rs Rs ;
wherein X is (Cs-C~o)aryl, preferably phenyl. Within this embodiment, Y is
selected from the
group consisting of a bond, oxygen, >C=0, -CHz-, -CH20-, -O(CH2)~ , -CHZCHz-, -
CH=CH-
and -C=C-; wherein n is 1 or 2; preferably Y is selected from the group
consisting of oxygen,
-OCHz- and -CH20-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formulae a)
or b), wherein X is (C6-C~o)aryl, preferably phenyl. Within this embodiment, Y
is selected from
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_g_
the group consisting of sulfur, >S02, >S=0, -CHZS-, -S(CHZ)~ , -CHZSO-, -
CHZSOZ-, -SOCH2-
and -SOZ(CHZ)~ ; wherein n is 1 or 2; preferably Y is sulfur or >S02.
In another embodiment of the invention, the heterocyclic ring "A" has the
formulae a)
or b), wherein X is (C6-C,o)aryl, preferably phenyl. Within this embodiment, Y
is selected from
the group consisting of CHZ[N(R'4)]-, >NR'4, -NR"(CHZ)~-, -SOZ[N(R'4)]- and -
[N(R'4)]-SOz-,
wherein R'4 is hydrogen or methyl; and n is 1 or 2.
In another embodiment of the invention, the heterocyclic ring "A" has the
formulae a)
or b), wherein X is (C~-C~o)heteroaryl selected from the group consisting of
benzimidazolyl,
benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine,
benzothiazinyl,
benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,
furazanyl, furopyridinyl,
furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl,
pteridinyl, purinyl,
pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl,
quinoxaliriyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and
triazolyl, wherein said (G~-
C,o)heteroaryl is optionally substituted on any of the ring carbon atoms
capable of forming an
additional bond by one or two substituents independently selected from F, CI,
Br, CN, OH, (C~-
C4)alkyl, (C~-C4)perfluoroalkyl, (C~-C4)perfluoroalkoxy, (C1-C4)alkoxy and (C3-
C8)cycloalkyloxy;
preferably X is selected from the group consisting of imidazolyl,
isothiazolyl, isoxazolyl,
oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and
pyrazolyl; more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is
pyridinyl. Within this
embodiment, Y is a bond, oxygen, sulfur, -CHZ-, >S02, -OCHZ- or -CH20-;
preferably Y is
oxygen, -OCHZ- or -CH~O-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formulae a)
or b), wherein X is (C~-C,o)heteroaryl selected from the group consisting of
benzimidazolyl,
benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine,
benzothiazinyl,
benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,~
furazanyl, furopyridinyl,
furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl,
pteridinyl, purinyl,
pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl,
quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and
triazolyl, wherein said (C~-
C~o)heteroaryl is optionally substituted on any of the ring carbon atoms
capable of forming an
additional bond by one or two substituents independently selected from F, CI,
Br, CN, OH, (C~-
C4)alkyl, (C,-C4)perfluoroalkyl, (C,-C4)perfluoroalkoxy, (C~-C4)alkoxy and (C3-
C8)cycloalkyloxy;
preferably X is selected from the group consisting of imidazolyl,
isothiazolyl, isoxazolyl,
oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and
pyrazolyl; more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is
pyridinyl. Within this
embodiment, Y is selected from the group consisting of sulfur, >S02, >S=0, -
CH?S-, -S(CH2)
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_g-
-CHZSO-, -CH2S02-, -SOCHZ- and -SO~(CHZ)~ ; wherein n is 1 or 2; preferably Y
is sulfur or
>S02.
In another embodiment of the invention, the heterocyclic ring "A" has the
formulae a)
or b), wherein X is (C~-C~o)heteroaryl selected from the group consisting of
benzimidazolyl,
benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine,
benzothiazinyl,
benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,
furazanyl, furopyridinyl,
furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl,
pteridinyl, purinyl,
pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl,
quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and
triazolyl, wherein said (C,-
C,o)heteroaryl is optionally substituted on any of the ring carbon atoms
capable of forming an
additional bond by one or two substituents independently selected from F, CI,
Br, CN, OH, (C~-
C4)alkyl, (C~-Cd)perfluoroalkyl, (Ci-C4)perfluoroalkoxy, (C~-C4)alkoxy and (C3-
C8)cycloalkyloxy;
preferably X is selected from the group consisting of imidazolyl,
isothiazolyl, isoxazolyl,
oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and
pyrazolyl; more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is
pyridinyl. Within this
embodiment Y is selected from the group consisting of CHI[N(R'4)]-, >NR", -
NR'4(CHZ)~ , -
SOZ[N(R'~)]- and -[N(R'4)]-SO2-, wherein R'4 is hydrogen or methyl; and n is 1
or 2.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula a),
wherein X is (C~-C,o)heteroaryl selected from the group consisting of
benzimidazolyl,
benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine,
benzothiazinyl,
benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,
furazanyl, furopyridinyl,
furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl,
pteridinyl, purinyl,
pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl,
quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and
triazolyl, wherein said (C~-
C~o)heteroaryl is optionally substituted on any of the ring carbon atoms
capable of forming an
additional bond by one or two substituents independently selected from F, CI,
Br, CN, OH, (C~-
C4)alkyl, (C~-C4)perfluoroalkyl, (C~-C4)perfluoroalkoxy, (C~-C4)alkoxy and (C3-
C8)cycloalkyloxy;
preferably X is selected from the group consisting of imidazolyl,
isothiazolyl, isoxazolyl,
oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and
pyrazolyl; more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is
pyridinyl. Within this
embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,
-CHZ-, >S02,
-OCHz- and -CHZO-; preferably Y~ is oxygen, -OCH~- or -CH20-; more preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula a),
as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A"
the dashed line is a
double bond.
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In another embodiment of the invention, the heterocyclic ring "A" has ohe
formula b),
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
benzimidazolyl,
benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine,
benzothiazinyl,
benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,
furazanyl, furopyridinyl,
furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl,
pteridinyl, purinyl,
pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl,
quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and
triazolyl, wherein said (C~-
C~o)heteroaryl is optionally substituted on any of the ring carbon atoms
capable of forming an
additional bond by one or two substituents independently selected from F, CI,
Br, CN, OH, (C~-
C4)alkyl, (C,-C4)pertluoroalkyl, (C,-C4)perfluoroalkoxy, (C,-C4)alkoxy and (C3-
C8)cycloalkyloxy;
preferably X is selected from the group consisting of imidazolyl,
isothiazolyl, isoxazolyl,
oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and
pyrazolyl; more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is
pyridinyl. Within this
embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur,
-CHI-, >S02,
-OCHz- and -CHZO-; preferably Y is oxygen, -OCH2- or -CHzO-; more preferably Y
is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula b),
as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A"
the dashed line is a
double bond.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula c):
X-Y-Z-G
c R' Rs
N ~, Rs
R
R~ R/~'Rs .
wherein X is (C,-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is selected from the group consisting of pyrazinyl, pyridazinyl,
pyridyl and
pyrimidinyl; more preferably X is pyridinyl. Within this embodiment, Y is
selected from the
group consisting of a bond, oxygen, sulfur, -CHz-, >S02, -OCHz- and -CH20-;
preferably Y is
oxygen, -OCHZ- or -CH20-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula c),
wherein in the heterocyclic ring "A" the dashed line is a double bond, such
that the
heterocyclic ring "A" of formula c is selected from the group consisting of:
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X-Y-Z-G X-Y-Z-G
O
c,) ~ Ra c2) O Rags
N ~ and N
~~ r~ Ry~ x~ R~
R~ RZ Rs Rs R, RZ Rs
In another embodiment of the invention, the heterocyclic ring "A" has the
formula d):
d) ~-Y-Z-G
//O
NON-Rs
"
R R
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >S02, -OCHa- and -CH20-; preferably Y is oxygen, -OCH~- or -CHzO-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula e):
X-Y-Z-G
a
O
N~N~Rs
R"
R' Rz Rio
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyi, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHa-, >S02, -OCH~- and -CH20-; preferably Y is oxygen, -OCHZ- or -CHzO-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula f):
X-Y-Z-G
f) ( O s
R
N~N R"
R,o
R~ R~ Rs Rs .
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wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CH20-; preferably Y is oxygen, -OCHz- or -CH20-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula g):
X-Y-Z-G
g)
N_SOz R4
. ~ Rs
R, Rz
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CHzO-; preferably Y is oxygen, -OCHz- or -CHzO-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula g),
as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A"
the dashed line is a
double bond.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula h):
h)
X-Y-Z-G
N.SOz R4
Rs
'
Rs
' ~s
R Rz R
wherein X is (C~-C,o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CH20-; preferably Y is oxygen, -OCHz- or -CH20-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula h),
as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A"
the dashed line is a
double bond.
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In another embodiment of the invention, the heterocyclic ring "A" has the
formula l):
X-Y-Z-G
l)
Ra
N,SOz Rs
o R8
\ R'
R, ~ ~ ~ Rs
R2 Rs
wherein X is (C,-C,o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CHzO-; preferably Y is oxygen, -OCHz- or -CH20-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula l),
wherein in the heterocyclic ring "A" the dashed line is a double bond, such
that the
heterocyclic ring "A" of formula l) is selected from the group consisting of:
X-Y-Z-G iz) X-Y-Z-G
4
I S R 3 I SO Rs
N. Oz R N. z
R~ and ~ R~
R~ Rz RS Ri Rz RS ~ Rs
In a preferred embodiment of the invention, the heterocyclic ring "A" has the
formula
selected from the group consisting of
X-Y-Z-G
R" ~ o
X-Y-Z-G X-Y-Z-G I R
j) R» k) ( R" Rio ) R~z
Rio R8 N '. Ra
N-
N R8 ~ R~ l
/~ R
R Rs R,~Rs
z Rs
R' Rz ; R~ Rz RS ; and R
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl,
pyridinyl, pyrimidinyl and
pyrazolyl; preferably X is pyrazinyl, pyridazinyl, pyridy! and pyrimidinyl;
more preferably X is
pyridinyl. Within this embodiment, Y is selected from the group consisting of
a bond, oxygen,
sulfur, -CHz-, >SOz, -OCHz- and -CH20-; preferably Y is oxygen, -OCHz- or -
CH20-; more
preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula j):
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X-Y-Z-G
J) ~ R»
~o
Rs
~ Rs
R'~R2
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CHzO-; preferably Y is oxygen, -OCHz- or -CHzO-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula k):
X-Y-Z-G
k). ~ R" Rio
Ra
' R'
Rs
R, Rz R5
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CH20-; preferably Y is oxygen, -OCHz- or -CHZO-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula k),
as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A"
the dashed line is a
double bond.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula I):
X-Y-Z-G
R" Rio
I) R~s
R~z
Ra
R'
R~ Rs
Rz Rs .
wherein X is (C,-C,o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
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preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CH20-; preferably Y is oxygen, -OCHz- or -CH20-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula I),
wherein in the heterocyclic ring "A" the dashed fine is a double bond, such
that the
heterocycfic ring "A" of formula I is selected from the group consisting of:
X-Y-Z-G X-Y-Z-G
) Ri~ R,o (z) ~ Rn Riot's
R~ 3 R
N R,z N s
Rs and ~ R
s
R~ Rs R ~~ R
Rz R R
In another embodiment of the invention, the heterocyclic ring "A" has the
formula m):
m) X-Y-Z-G
//O
N~ ,Rs
N
~~SOz
;
wherein X is (C,-C~o)heteroaryf selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridy! and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CH20-; preferably Y is oxygen, -OCHz- or -CH20-; more
preferably
Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the
formula n):
X-Y-Z-G
O
N N_Rs
O
wherein X is (C~-C~o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more
preferably X is pyridinyl.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHz-, >SOz, -OCHz- and -CHzO-; preferably Y is oxygen, -OCHz- or -CH20-; more
preferably
Y is oxygen.
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In another embodiment of the invention, the heterocyclic ring "A" has the
formula o):
o) X-Y-Z-G
R"
R,o
H
R,2
O
wherein X is (C,-C,o)heteroaryl selected from the group consisting of
imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl and pyrazolyl;
preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyi; more
preferably X is pyridinyf.
Within this embodiment, Y is selected from the group consisting of a bond,
oxygen, sulfur,
-CHZ-, >S02, -OCHz- and -CH~O-; preferably Y is oxygen, -OCHZ- or -CH20-; more
preferably
Y is oxygen.
In another embodiment of the invention, each of R', R2, R3, R4, R'°,
R", R'2 and R'3
is selected from the group consisting of hydrogen, (C,-C4)alkyl, (C,-
C4)aikenyl, (C~-C4)alkynyl,
(C6-C,°)aryl, (C,-C,o)heteroaryl, (C3-CB)cycloalkyl and (C,-
C,°)heterocyciyl; and wherein each
of said (C~-C~)aikyl, (C6-C~o)aryl, (C~-C~°)heteroaryl, (C3-
C$)cycloatkyl and (C~-C~°}heterocyciyl
may be optionally substituted on any of the ring carbon atoms capable of
forming an additional
bond with 1-3 substituents independently selected from halo, (C~-Ca)afkyl, (C~-
C4)alkoxy, -CN,
-OH and -NHZ.
A generic or sub-generic embodiment of each of the foregoing embodiments are
those compounds wherein each of Ft', RZ, R3, R4, R~, R6, R', R8, R9,
R'°, R", R'2 and R'3 is
selected from the group consisting of hydrogen, (C~-C4)alkyl, (Cs-C~o)aryl,
(C~-C,o)heteroaryl,
and (C3-C8)cycloalkyl.
A preferred generic or sub-generic embodiment is directed to those foregoing
embodiments wherein each of R', R2, R3, R4, R5, R6, R', R8, R9, R'°,
R", R'2 and R'3 is
selected from hydrogen and (C1-C4}alkyl, such as methyl.
In another embodiment of the invention, each of R5, R6, R7 and R8 is selected
from the
group consisting of hydrogen, (C,-CQ)alkyl, (C,-Ca)alkenyl, (Ct-Ca)alkynyl,
(Cs-C~°)aryl, (C~-
C~o)heteroaryl, (C3-Ca)cycloalkyl and (C1-C,°)heterocyclyl; and wherein
each of said (C~-
C~}alkyl, (C6-Cio)aryt, (C~-C~ojheteroaryl, (C3-C8}cycloalkyl and (C,-
C,o)heterocyclyl may be
optionally substituted on any of the ring carbon atoms capable of forming an
additional bond
with 1-3 substituents independently selected from halo, (C,-Ca)alkyl, (C~-
C4}alkoxy, -CN, -OH
and -NH2.
tn another embodiment of the invention, one or two of R5, R6, R' and R8 is/are
a group
other than hydrogen.
In another embodiment of the invention, R9 is independently selected from
hydrogen,
(C~-C4)alkyl, (C6-C~b)aryl, (C,-C,°)heteroaryl, (C3-C$)cycloalkyl and
(C,-C~o)heterocyclyi.
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In another embodiment of the invention, R9 is independently selected from
hydrogen
and (C,-C4)alkyl, such as methyl.
In another embodiment of the invention, Z is a (C3-C8)cycloalkyl or a (C,
C,o)heterocyclyl, selected from the group consisting of cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-3-azetidinyl,
piperazinyl, piperidinyl,
1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-2,4-dion-5-yl, 4,5-dihydro-1,2-
oxazolidin-3-on-4-yl, 1,3-
thiazolidin-4-on-5-y1, 1,3-thiazolidin-2,4-dion-5-yl, 1,3-imidazolidin-4-on-5-
yi, 1,3-imidazolidin-
2,4-dion-5-yl, 1,2-pyrazolidin-3-on-4-yl, tetrahydro-1,3-oxazin-4-on-5-yl,
tetrahydro-1,3-oxazin-
2,4-dion-5-yl, morpholinyl, morpholin-3-on-2-yl, morpholin-3,5-dion-2-yl, 2,3-
dihydro-1,4-
oxazin-3-on-2-yl, tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-2,4-
dion-5-yl,
thiomorpholinyl, thiomorpholin-3-on-2-yl, thiomorpholin-3,5-dion-2-yl, 2,3-
dihydro-1,4-thiazin-3-
on-2-yl, hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-pyridazin-3-on-4-yl,
hexahydro-1,3-
diazin-2,4-dion-5-yl, piperazin-2-on-3-yl, piperazin-2,6-dion-3-yl, tetrahydro-
1,3,4-thiadiazin-5-
on-6-yl, 5,6-dihydro-1,3,4-thiadiazin-5-on-6-yi, 1,3,4-oxadiazin-5-on-6-yl,
5,6-dihydro-1,2,4-
oxadiazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-
6-yl, tetrahydro-
1,2,4-axadiazin-5-on-6-yl, 5,6-dihydro-1-2,4-oxadiazin-5-on-6-yl, 1,2,4-
oxadiazin-3,5-dion-6-yl
and 1,2,4-triazin-6-on-5-yl. Within this embodiment, preferably Z is selected
from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
tetrahydrofuranyl,
tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, N-
methylpiperidinyl and
morpholinyl. Within this embodiment, more preferably Z is selected from the
group consisting
of cyclopropyf, cyclobutyl, cyclopentyi, cyclohexyl, tetrahydrofuranyl and
tetrahydropyranyl.
Within this embodiment, most preferably Z is selected from the group
consisting of
cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.
In another embodiment of the invention, Z is a (C,-C,o)heteroaryl selected
from the
group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-
benzopyranyl,
benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl,
benzoxazolyl, chromanyl,
cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl,
indolizinyl, indolyl, 3H
indolyl, isoindolyl, isoquinofinyl, isothiazolyl, isoxazolyl, naphthyridinyl,
oxadiazolyl, oxazolyi,
phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl,
thienyl, triazinyl and
triazolyl, more preferably pyridinyl, pyrazinyl, pyridazinyl and pyrazolyl,
wherein said (C,-
C,o)heteroaryl is optionally substituted on any of the ring carbon atoms
capable of forming an
additional bond by one or two substituents independently selected from F, CI,
Br, CN, OH, (C,-
C4)alkyl, (C,-C4)perfluoroalkyl, (C,-Ca)perftuoroaikoxy, (C,-Ca)alkoxy and (C3-
C8)cycioalkyloxy.
fn another embodiment of the invention, either X or Z is substituted on any of
the ring
carbon atoms capable of forming an additional bond by one or two substituents
independently
selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-C4)perfluoroalkyl, (C,-
Ca)perfluoroalkoxy,
(C,-C4)alkoxy and (C3-C8)cycloalkyloxy.
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In another embodiment of the invention, both X and Z are substituted on any of
the
ring carbon atoms capable of forming an additional bond by one or two
substituents
independently selected from F, Cl, Br, CN, OH, (C~-C4)alkyl, (C~-
C4)perffuoroalkyl, (C~-
C4)perfluoroalkoxy, (C,-C4)alkoxy and (C3-C8)cycloalkyloxy.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 0;
R'S is
selected from the group consisting of halo, -CN, and R'8; wherein said R'8 is
selected from the
group consisting hydrogen, (C,-C4)alkyl, (C6-C,°)aryl, (C3-
C8)cycloalkyl, (C,-C,°)heteroaryl and
(C~-C,°)heterocyclyl; wherein said (C6-C,°)aryl, (C3-
C8)cycloalkyl, (C~-C~°)heteroaryl and (C~-
C1°)heterocyclyl moieties may be optionally substituted on any of the
ring carbon atoms
capable of forming an additional bond by one to three substituents per ring
independently
selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-C4)perfluoroalkyl, (C,-
C4)perfluoroalkoxy,
(C1-C4)alkoxy, amino, (C,-C4)alkyl-NH-, [(C,-C4)alkyl]z-N- and (C3-
C8)cycloalkyloxy; wherein
said (C3-C8)cycloalkyl and (C~-C~°)heterocyclyl moieties may also
optionally be substituted by
oxo; wherein said (C~-C~°)heteroaryl and (C~-C,°)heterocyclyl
moieties may optionally be
substituted on any ring nitrogen atom able to support an additional
substituent by one to two
substituents per ring independently selected from the group consisting of (C~-
Cd)alkyl and (C~-
C4)alkyl-(C=O)-.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 0 to
4,
preferably 1 to 2; R'S is selected from the group consisting of halo, -CN, -
NOz, OH, (C~
C4)alkenyl, (C~-C4)alkynyl, (C~-C4)perfluoroalkyl, perfluoro(C~-Ca)alkoxy, R'8-
, R'8-O-, R'8-(C~
C4)alkyl-O-, R'8-(C=O)-, R'e-(C=O)-O-, R'8-O-(C=O)- R'8-S-, Rzz-(S=O)-, R'8-
(SOz)-, Rzz-
(SOz)-(NRz~)- R,s-(C=O)-(NRz,)- Rzz-O-(C=O)-(NRz~)-~ (R~sRzo)N-. (R~sRzo)N-
(SOz)_,
(R'9Rz°)N-(C=O)-; (R'9Rz°)N-(C=O)-(NRz')- and (R'9Rz°)N-
(C=O)-O; each of R's and R" is
independently hydrogen or (C,-C4)alkyl; R'8 is selected from the group
consisting hydrogen,
(C~-C4)alkyl, (C6-C,°)aryl, (C3-C8)cycloalkyl, (C,-
C,°)heteroaryl and (C~-C~°)heterocyclyl;
wherein said (C6-C,°)aryl, (C3-C8)cycloalkyl, (C~-C~°)heteroaryl
and (C~-C,°)heterocyclyl
moieties may be optionally substituted on any of the ring carbon atoms capable
of forming an
additional bond by one to three substituents per ring independently selected
from F, CI, Br, CN,
OH, (C~-C4)alkyl, (Ci-C4)perfluoroalkyl, (C~-C4)perfluoroalkoxy, (C~-
C4)alkoxy, amino, (C~-
C4)alkyl-NH-, [(C~-C4)alkyl]z-N- and (C3-C8)cycloalkyloxy; wherein said (Cs-
C8)cycloalkyl and
(C~-C~°)heterocyclyl moieties may also optionally be substituted by
oxo; wherein said (C~-
C,°)heteroaryl and (C,-C,°)heterocyclyl moieties may optionally
be substituted on any ring
nitrogen atom able to support an additional substituent by one to two
substituents per ring
independently selected from the group consisting of (C~-C4)alkyl and (C,-
Ca)alkyl-(C=O)-.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1;
R'S is
(R'9Rz°)N-; each of R'6 or R" is independently hydrogen; and each of
R'9 and Rz° is hydrogen
or (C,-C,°)heteroaryl, such as 2-oxazolyl, 2-pyrazolyl, or 3-pyrazolyl.
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In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1;
R'S is
(R'9Rz°)N-(C=O)-(NRZ')-; each of R's or R" is independently hydrogen;
each of R'9 and RZ° is
(C~-C4)alkyl and are taken together with the nitrogen to which they are
attached to form a 3 to
8-membered ring; and wherein R~3 is selected from the group consisting of
hydrogen and (C~-
C4)alkyl.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1;
R'S is
RZZ-O-(C=O)-(NR~')-; each of R's or R" is independently hydrogen; RZ' is
selected from the
group consisting of hydrogen and (C~-C4)alkyl; and wherein R~Z is selected
from the group
consisting of (C~-C4)alkyl and (C3-C$)cycloalkyl, such as methyl, ethyl,
propyl, butyl or
cyclobutyl.
In another embodiment of the invention G is R'S-(CR'6R")p ; wherein p is 1;
R'S is
R'9-(C=O)-(NR2'); each of R'6 and R" is independently hydrogen or (C~-
C4)alkyl; R'9 and Rz'
are taken together with the carbon or the nitrogen to which they are attached
to form a 3 to 8
membered heterocyclic ring.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1;
R'S is
(R'9R2°)N-(C=O)-(NR~'); each of R'6 and R" is independently hydrogen or
(C,-C4)alkyl; R'9
and RZ' are taken together with the nitrogen to which they are attached to
form a 3 to 8
membered heterocyclic ring.
In another embodiment of the invention, G is R'S-(CR'6R")P ; wherein p is 1;
R'S is
R22-O-(C=O)-(NRz')-; each of R'6 and R" is independently hydrogen or (C~-
Cd)alkyl; RZ' and
R~Z are taken together with the nitrogen or the oxygen to which they are
attached to form a 3
to 8 membered heterocyclic ring.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1 to
4,
preferably 1; R'S is selected from the group consisting of halo, -CN and R'8;
each of R's and
R" is independently hydrogen or (C,-C4)alkyl; said R'8 is selected from the
group consisting of
hydrogen, (C~-C4)alkyl, (C6-C,°)aryl, (C3-C8)cycloalkyl, (C~-
C~°)heteroaryl and (C~-
C~°)heterocyclyl; wherein said (C6-C,°)aryl, (C3-C8)cycloalkyl,
(C,-C,°)heteroaryl and (C~-
C~°)heterocyclyl moieties may be optionally substituted on any of the
ring carbon atoms
capable of forming an additional bond by one to three substituents per ring
independently
selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-C4)perfluoroalkyl, (C~-
C4)perfluoroalkoxy,
(C~-C4)alkoxy, amino, (C~-C4)alkyl-NH-, [(C~-C4)alkyl]Z-N- and (C3-
C8)cycloalkyloxy; wherein
said (C3-C8)cycloalkyl and (C,-C,°)heterocyclyl moieties may also
optionally be substituted by
oxo; wherein said (C~-C~°)heteroaryl and (C~-C~°)heterocyclyl
moieties may optionally be
substituted on any ring nitrogen atom able to support an additional
substituent !:~y one to two
substituents per ring independently selected from the group consisting of (C~-
C4)alkyl and (C~-
C4)alkyl-(C=O)-.
In another embodiment of the invention, G is R'S-(CR'6R")pi; wherein p is 1 to
4,
preferably 1; R'S is selected from the group consisting of R'8; each of R'6
and R" is
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independently hydrogen or (C~-Ca)alkyl; wherein said R'8 is selected from the
group consisting
of hydrogen and (C~-Ca)alkyl.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1 to
4,
preferably 1; R'S is selected from the group consisting of (R'9R2°)N-,
(R'9R2°)N-(C=O),
(R'9Rz°)N-(SOZ); (R'9R2°)N-(C=O)-(NRz')- and (R'9Rz°)N-
(C=O)-O; each of R'6 and R" is
independently hydrogen or (C~-Ca)alkyl; and wherein R'9 and Ra° are
taken together with the
nitrogen to which they are attached to form a 3 to 8-membered heterocyclic
ring.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1 to
4,
preferably 1; R'S is selected from the group consisting of R'9-(C=O)-(NRZ')-,
(R'9R2°)N-(C=O)
(NR2'), -NR'9Rz°, (R'9R2o)N-(C=O)-(NRZ')-; Rzz(S=O)-; R~z(S02)-(NRZ')-;
Rzz-0-(C=O)-(NRZ')_
and (R'9R2°)N-(C=O)-O-; each of R'6 and R" is independently hydrogen or
(C~-Ca)alkyl;
wherein each of R'9, Rz° and Rz' is independently selected from the
group consisting of
hydrogen, (C,-Ca)alkyl, (C6-C,°)aryl, (C3-C8)cycloalkyl, (C,-
Ci°)heteroaryl and (C,-
C~°)heterocyclyl; wherein the (C6-C~°)aryl, (C3-C8)cycloalkyl,
(C~-C~°)heteroaryl and (C~-
C,°)heterocyclyl moieties may be optionally substituted on any of the
ring carbon atoms
capable of forming an additional bond by 1-3 substituents independently
selected from F, CI,
Br, CN, OH, (C~-Ca)alkyl, (C~-Ca)perfluoroalkyl, (C~-Ca)perfluoroalkoxy, (C~-
Ca)alkoxy, amino,
(C~-Ca)alkyl-NH-, [(C1-Ca)alkyl]2-N- and (C3-C8)cycioalkyioxy; wherein said
(C3-C8)cycioalkyi
and (C,-C,°)heterocyclyl moieties may also optionally be substituted by
oxo; wherein said (C,-
C~°)heteroaryl and (C~-C~°)heterocyclyl moieties may optionally
be substituted on any ring
nitrogen atom able to support an additional substituent by one to two
substituents per ring
independently selected from the group consisting of (C,-Ca)alkyl and (C,-
Ca)alkyl-(C=O)-; and
wherein R~ is selected from the group consisting of (C,-Ca)alkyl, (C6-
C~°)aryl, (C3-
C8)cycloalkyl, (C,-C,°)heteroaryl and (C~-C,°)heterocyclyl;
wherein the (C6-C,°)aryl, (C3-
C8)cycioalkyi, (C,-C,°)heteroaryl and (C,-C,°)heterocyciyl
moieties may be optionally
substituted on any of the ring carbon atoms capable of forming an additional
bond by 1-3
substituents independently selected from F, CI, Br, CN, OH, (C~-Ca)alkyl, (C~-
Ca)perfluoroalkyl,
(C~-Ca)perfluoroalkoxy, (C~-Ca)alkoxy, amino, (C~-Ca)alkyl-NH-, [(C~-
Ca)alkylJa-N- and (C3-
C8)cycloalkyloxy; wherein said (C3-C8)cycloalkyl and (C~-
C~°)heterocyclyl moieties may also
optionally be substituted by oxo; wherein said (C~-C~°)heteroaryl and
(C~-C~°)heterocyclyl
moieties may optionally be substituted on any ring nitrogen atom able to
support an additional
substituent by one to two substituents per ring independently selected from
the group
consisting of (C~-Ca)alkyl and (C,-Ca)alkyl-(C=O)-.
In another embodiment of the invention, G is R'S-(CR'6R")P ; wherein p is 1 to
4,
preferably 1; R'S is selected from the group consisting of R'9-(C=O)-(NRZ')-,
R'9-O-(C=O)
(NR2')- and (R'9R2°)N-(C=O)-(NRZ'); each of R's and R" is independently
hydrogen or (C~
Ca)alkyl; wherein R'9 and RZ' are taken together with the nitrogen, the carbon
or the oxygen to
which they are attached to form a 3 to 8 membered heterocyclic ring.
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In another embodiment of the invention, G is R'5-(CR'6R")p ; wherein p is 0;
and G is
oriented at a position other than alpha to the point of attachment of the Z
ring to Y.
In another embodiment of the invention, G is R'S-(CR'sR")p ; wherein p is 0;
and G is
oriented at a position meta to the point of attachment of the Z ring to Y.
In another embodiment of the invention, G is R'S-(CR'6R")p ; wherein p is 1 to
4,
preferably 1; and G is oriented at a position other than alpha to the point of
attachment of the
Z ring to Y.
In another embodiment of the invention, G is R'S-(CR'6R")P ; wherein p is 1 to
4,
preferably 1; and G is oriented at a position meta to the point of attachment
of the Z ring to Y.
In another preferred embodiment of the invention, one or two of R', Rz, R3,
R4, R'°,
R", R'z and R'3 is a group other than hydrogen.
In a more preferred embodiment of the invention, each of R', Rz, R3, R4, R5,
R6, R',
R8, R9, R'°, R", R'z and R'3 is hydrogen.
in another preferred embodiment of the invention, either X or Z is not
substituted by
any optional substituents.
In another preferred embodiment of the invention, both X and Z are not
substituted by
any optional substituents.
In another preferred embodiment of the invention, G is R'S-(CR'6R")p ; wherein
p is 0;
R'S is selected from the group consisting of halo, -CN and (C~-C~o)heteroaryl.
More preferably,
R'5 is bromo, f(uoro, -CN or oxadiazolyl, preferably [1,3,4] oxadiazol-2-yl.
In another preferred embodiment of the invention, G is R'S-(CR'6R")P ; wherein
p is 0
or 1; R'S is R'8; each of R'6 and R" is hydrogen; and R'8 is independently
hydrogen or (C,-
C4)alkyl; preferably methyl.
in another preferred embodiment of the invention, G is R'5-(CR'6R")p ; wherein
p is 0
or 1; wherein G is oriented at a position para to the point of attachment of
the Z ring to Y.
In another preferred embodiment of the invention, G is R'S-(CR'sR")P ; wherein
p is 1;
R'S is R'9-(C=O)-(NRz')-; each of R'6 or R" is independently hydrogen; R'9 is
(C~-C4)alkyl,
more preferably methyl, ethyl, or butyl; or (C3-C$)cycloalkyl, more preferably
cyclobutyl; and
Rz' is hydrogen.
In another preferred embodiment of the invention, G is R'S-(CR'6R")p ; wherein
p is 1;
R'S is (C,-C,°)heteroaryl, such as 2-pyrazolyl; and wherein each of R'6
and R" is
independently hydrogen.
In another preferred embodiment of the invention, the heterocyclic ring "A"
has the
formula a) or b):
X-Y-Z-G X-Y-Z-G
a) I O b) O
Q ~ 4
N R ~.r N R
' Rs or ~ Rs
R~ ,, Rz ~ ,, s
R Rz Rs R
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wherein X is (C,-C,o)heteroaryl selected from the group consisting of
pyrazinyl, pyridazinyl,
pyridyl and pyrimidinyl; more preferably X is pyridinyl; and Y is selected
from the group
consisting of a bond, oxygen, sulfur, -CHz-, >SOz, -OCHz- and -CHzO-; more
preferably Y is
oxygen, -OCHz- or -CH20-; most preferably Y is oxygen.
Other preferred compounds of the invention include compounds of formula I,
wherein
the heterocyclic ring "A" has the formula a) or b), as defined above; X is (C,-
C,o)heteroaryl
selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and
pyrimidinyl; more
preferably X is pyridinyl; most preferably wherein the pyridinyl together with
the "A" ring and
the group Y-Z-G has the formula:
Y-Z-G Y-Z-G
N ~ N ~
I 1
a..) i ~ b") i
O O
N R4 ~ N Ra
R3 or .' Rs
R~ ~ Rz , ~ s
R Rz Rs R
wherein Y is a bond, oxygen, sulfur, -CNz-, >SOz, -OCHz- or -CHZO-; preferably
Y is oxygen,
-OCHz- or -CHzO-; more preferably Y is oxygen.
Other preferred compounds of the invention include compounds of formula I,
wherein
the heterocyclic ring "A" has the formula a) or b), as defined above; X is
pyridinyl, most
preferably wherein the pyridinyl together with the "A" ring and the group Y-Z-
G has the formula
a") or b") as defined above; Y is oxygen; Z is (Cs-C,o)aryl, preferably
phenyl; G is R'S-
(CR'sR")p ; wherein p is 1; R'S is (C,-C,o)heteroaryl, such as 2-pyrazolyl;
each of R's and R"
is independently hydrogen or (C,-C4)alkyl, such as methyl, preferably
hydrogen; and wherein
G is oriented at a position para to the point of attachment of the Z ring to
Y.
Most preferred compounds of the invention include compounds of formula I,
wherein
the heterocyclic ring "A" has the formula a) or b), as defined above; X is
pyridinyl, most
preferably wherein the pyridinyl together with the "A" ring and the group Y-Z-
G has the formula
a") or b") as defined above; Y is oxygen; Z is (Cs-C,o)aryl, preferably
phenyl; G is R'S-
(CR'sR")p ; wherein p is 0; R'S is selected from the group consisting of
hydrogen, -CN, halo
and oxadiazolyl; and wherein G is oriented at a position para to the point of
attachment of the
Z ring to Y.
Other most preferred compounds of the invention include compounds of formula
1,
wherein the heterocyclic ring "A" has the formula a) or b), as defined above;
X is pyridinyl,
most preferably wherein the pyridinyl together with the "A" ring and the group
Y-Z-G has the
formula a") or b") as defined above; Y is oxygen; Z is (Cs-C,o)aryl,
preferably phenyl; G is R'S-
(CR'sR")p ; wherein p is 1; R'S is R'9-(C=O)-(NRz')-; each of R's and R" is
independently
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hydrogen; R'9 is selected from the group consisting of (C,-C4)alkyl and (C3-
C$)cycloalkyl, such
as methyl, ethyl, propyl, butyl, or cyclobutyl; RZ' is selected from the group
consisting of
hydrogen or (C~-C4)alkyl; and wherein G is oriented at a position para to the
paint of
attachment of the Z ring to Y.
Other compounds of the invention are selected from the group consisting of:
1-[6-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,8,10-triaza-
spiro[5.5]undecane-
2,7,9,11-tetraone;
1-[6-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-
spiro(4.5]decane-
2,6,8,10-tetraone;
1-[6-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,3,8,10-tetraaza-
spiroj5.5]undecane-2,7,9,11-tetraone;
4-[6-(4-[1, 3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,1-dioxo-1 ~6-thia-
2,4,7,9-tetraaza-
spiro[4.5]decane-3,6,8,10-tetraone;
1-j6-(4-[1,3,4]Oxad iazol-2-yl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-
spiro[4.5]decane-
2,4,6,8,10-pentaone;
1-[6-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-2,2-dioxo-2A6-thia-1,7,9-
triaza-
spiro[4.5]decane-6,8,10-trione;
1-[6-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-2,2-dioxo-2T~6-thia-
1,8,10-triaza-
spiro[5.5]undecane-7,9,11-trione;
1-[6-(4-[ 1, 3,4] Oxad i azol-2-yl-ph epoxy)-pyrid in-3-yl]-1, 7, 9-triaza-s
piro[4.5]decane-
6,8,10-trione;
1-j6-(4-Cyclobutylmethoxymethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-
spiro[4.5]decane-
2,6,8,10-tetraone;
1-{6-[4-(2-Oxo-pyrrolidin-1-ylmethyl)-pher~oxy]-pyridin-3-yl}-1,7,9-triaza-
spiro[4.5Jdecane-2,6,8,10-tetraone;
1-[6-(1 H-Indazol-5-yloxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-
2,6,8,10-tetraone;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-methyl-1,7,9-triaza-spiro[4.5]decane-
2,6,8,10-
tetraone;
1-[6-(3-Fluoro-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-
tetraone;
4-[5-(2,7,9,11-Tetraoxo-1,8,10-triaza-spiro[5.5]undec-1-yl)-pyridin-2-yloxy]-
benzonitrile;
1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,8,10-triaza-spiro[5.5]undecane-2,7,9,11-
tetraone;
N-{4-[5-(2,7,9,11-Tetraoxo-1,8,10-triaza-spiro[5.5]undec-1-yl)-pyridin-2-
yloxy]-benzyl}-
acetamide;
Azetidine-1-carboxylic acid 4-[5-(2,7,9,11-tetraoxo-1,8,10-triaza-
spiro[5.5]undec-1-yl)-
pyridin-2-y)oxy]-benzylamide;
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1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,8,10-triaza-
spiro[5.5]undecane-
2,7,9,11-tetraone;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,8,10-triaza-spiro[5.5]undecane-
2,7,9,11-
tetraone;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-spiro[4.5]decane-
2,6,8,10-
tetraone;
1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-spiro[4.5]decane-
2,6,8,10-
tetraone;
4-[5-(2,6,8,10-Tetraoxo-1,3,7,9-tetraaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-
benzonitrile;
N-{4-[5-(2,6,8,10-Tetraoxo-1,3,7,9-tetraaza-spiro[4.5]dec-1-yl)-pyridin-2-
yloxy]-
benzyl}-acetamide;
Azetidine-1-carboxylic acid 4-[5-(2,6,8,10-tetraoxo-1,3,7,9-tetraaza-
spiro[4.5]dec-1-yl)-
pyridin-2-yloxy]-benzylamide;
1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-
spiro[4.5]decane-
2,6,8,10-tetraone;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,3,8,10-tetraaza-spiro[5.5]undecane-
2,7,9,11-
tetraone;
1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,3,8,10-tetraaza-spiro[5.5]undecane-
2,7,9,11-
tetraone;
4-[5-(2,7,9,11-Tetraoxo-1,3,8,10-tetraaza-spiro[5.5]undec-1-yl)-pyridin-2-
yloxy]-
benzonitrile;
N-{4-[5-(2,7,9,11-Tetraoxo-1,3,8,10-tetraaza-spiro[5.5]undec-1-yl)-pyridin-2-
yloxy]-
benzyl}-acetamide;
Azetidine-1-carboxylic acid 4-[5-(2,7,9,11-tetraoxo-1,3,8,10-tetraaza-
spiro[5.5]undec-
1-yl)-pyridin-2-yloxy]-benzylamide;
1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,3,8,10-tetraaza-
spiro[5.5]undecane-2,7,9,11-tetraone;
4-[6-(4-Fluoro-phenoxy)-pyrid in-3-yl]-1,1-dioxo-1 ~6-thia-2,4,7,9-tetraaza-
spiro[4.5]decane-3,6,8,10-tetraone;
4-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,1-dioxo-1 A6-thia-2,4,7,9-tetraaza-
spiro[4.5]decane-3,6,8,10-tetraone;
4-[5-( 1,1,3,6,8,10-Hexaoxo-1 ~s-thia-2,4,7,9-tetraaza-spiro[4.5]dec-4-yl)-
pyridin-2-
yloxy]-benzonitrile;
N-{4-[5-(1,1,3,6,8,10-Hexaoxo-1~6-thia-2,4,7,9-tetraaza-spiro[4.5]dec-4-yl)-
pyridin-2-
yloxy]-benzyl}-acetamide;
Azetidine-1-carboxylic acid 4-[5-(1,1,3,6,8,10-hexaoxo-1A6-this-2,4,7,9-
tetraaza-
spiro[4.5]dec-4-yl)-pyridin-2-yloxy]-benrylamide;
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1,1-Dioxo-4-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1 ~6-thia-2,4,7,9-
tetraaza-
spiro[4.5]decane-3,6,8,10-tetraone;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-spiro[4.5]decane-
2,4,6,8,10-
pentaone;
4-[5-(2,4,6,8,10-Pentaoxo-1,3,7,9-tetraaza-spiro[4.5]dec-1-yl)-pyridin-2-
yloxy]-
benzonitrile;
N-{4-[5-(2,4,6,8,10-Pentaoxo-1,3,7,9-tetraaza-spiro[4.5]dec-1-yl)-pyridin-2-
yloxy]-
benzyl}-acetamide;
Azetidine-1-carboxylic acid 4-[5-(2,4,6,8,10-pentaoxo-1,3,7,9-tetraaza-
spiro[4.5]dec-1-
yl)-pyridin-2-yloxy]-benzylamide;
1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-
spiro[4.5]decane-
2,4,6,8,10-pentaone;
1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,3,7,9-tetraaza-spiro[4.5]decane-
2,4,6,8,10-
pentaone;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-2,2-dioxo-2~6-thia-1,7,9-triaza-
spiro[4.5]decane-
6,8,10-trione;
1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-2,2-dioxo-2A6-this-1,7,9-triaza-
spiro[4.5]decane-
6,8, 9 0-trione;
4-[5-(2,2,6, 8,10-Pentaoxo-2~6-thia-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-
yloxy]-
benzonitrile;
N-{4-[5-(2,2,6, 8,10-Pentaoxo-2~6-thia-1,7,9-triaza-spiro[4.5]dec-1-yl)-
pyridin-2-yloxy]-
benzyl}-acetamide;
Azetidine-1-carboxylic acid 4-[5-(2,2,6,8,10-pentaoxo-2~6-thia-1,7,9-triaza-
spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzylamide;
2,2-Dioxo-1-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-2A6-this-1,7,9-
triaza-
spiro[4.5]decane-6,8,10-trione;
1-(6-(4-Fluoro-phenoxy)-pyridin-3-yl]-2,2-dioxo-2~6-thia-1,8,10-triaza-
spiro[5.5]undecane-7,9,11-trione;
1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-2,2-dioxo-2A6-thia-1,8,10-triaza-
spiro[5.5]undecane-7,9,11-trione;
4-[5-(2,2,7, 9,11-Pentaoxo-2A6-thia-1,8,10-triaza-spiro[5.5]undec-1-yl)-
pyridin-2-yloxy]-
benzonitrile;
N-{4-[5-(2,2,7, 9,11-Pentaoxo-27~6-thia-1,8,10-triaza-spiro[5.5]undec-1-yl)-
pyridin-2-
yloxy]-benzyl}-acetamide;
Azetidine-1-carboxylic acid 4-(5-(2,2,7,9,11-pentaoxo-2A6-thin-1,8,10-triaza-
spiro[5.5]undec-1-yl)-pyridin-2-yloxy]-benzylamide;
2,2-Dioxo-1-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-2A6-thia-9 ,8,10-
triaza-
spiro[5.5]undecane-7,9,11-trione;
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1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-6,8,10-
trione;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-6,8,10-
trione;
4-[5-(6,8,10-Trioxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-
benzonitrile;
N-{4-[5-(6,8,10-Trioxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-
benzyl}-
acetamide;
Azetidine-1-carboxylic acid 4-[5-(6,8,10-trioxo-1,7,9-triaza-spiro[4.5]dec-1-
yl)-pyridin-
2-yloxy]-benzylamide;
1-[6-(4-Pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-
spiro[4.5]decane-6,8,10-
trione;
1-[6-(3-Fluoro-4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,8,10-triaza-
spiro[5.5]undecane-2,7,9,11-tetraone;
1-[6-(2-Fluoro-4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,8,10-triaza-
spiro[5.5]undecane-2,7,9,11-tetraone;
1-[6-(3-Methyl-4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,8,10-triaza-
spiro[5.5]undecane-2,7,9,11-tetraone;
1-[4-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-phenyl]-1,8,10-triaza-
spiro[5.5]undecane-
2,7,9,11-tetraone;
1-[6-(Pyridin-4-yloxy)-pyridin-3-yl]-1,8,10-triaza-spiro[5.5]undecane-2,7,9,11-
tetraone;
1-[5-(Pyridin-4-yloxy)-pyridin-2-yl]-1,8,10-triaza-spiro[5.5]undecane-2,7,9,11-
tetraone;
1-[4-(Pyridin-4-yloxy)-phenyl]-1,8,10-triaza-spiro[5.5]undecane-2,7,9,11-
tetraone;
1-[4-(Pyridin-4-yloxy)-phenyl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-
tetraone;
Azetidine-1-carboxylic acid 4-[5-(2,6,8,10-tetraoxo-1,7,9-triaza-spiro[4.5]dec-
1-yl)-
pyridin-2-yloxy]-benzylamide; and
the pharmaceutically acceptable salts thereof.
Specific preferred compounds of formula I are selected from the group
consisting of:
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-
tetraone;
1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-1,8,10-triaza-spiro[5.5]undecane-
2,7,9,11-
tetraone;
4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-
benzonitrile;
1-[6-(4-(1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-
spiro[4.5]decane-
2,6,8,10-tetraone;
1-[6-(4-Ethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro(4.5]decane-2,6,8,10-
tetraone;
N-{4-(5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-
benzyl}-
acetamide;
N-{4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-
benzyl}-
propionamide;
N-{4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-
benzyl}-
butyramide;
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Pentanoic acid 4-[5-(2,6,8,10-tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-
pyridin-2-yloxy]-
benzylamide;
Cyclobutanecarboxylic acid 4-[5-(2,6,8,10-tetraoxo-1,7,9-triaza-spiro[4.5]dec-
1-yl)-
pyridin-2-yloxy]-benzylamide;
1-[6-(4-Bromo-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-
tetraone;
1-[6-(4-pyrazol-1-ylmethyl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-
spiro[4.5]decane-
2,6,8,10-tetraone;
and the pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition for the
treatment of
a condition selected from the group consisting of connective tissue disorders,
inflammatory
disorders, immunology/allergy disorders, infectious diseases, respiratory
diseases,
cardiovascular diseases, eye diseases, metabolic diseases, central nervous
system (CNS)
disorders, liver/kidney diseases, reproductive health disorders, gastric
disorders, skin
disorders and cancers and other diseases characterized by metalloproteinase
activity in a
mammal, including a human, comprising an amount of a compound of formula I or
a
pharmaceutically acceptable salt thereof effective in such treatments and a
pharmaceutically
acceptable carrier.
The present invention also relates to a pharmaceutical composition for the
inhibition of
matrix metalloproteinases or other metalloproteinases involved in matrix
degradation, in a
mammal, including a human, comprising an effective amount of a compound of
formula I or a
pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating a condition
selected from the
group consisting of connective tissue disorders, inflammatory disorders,
immunology/allergy
disorders, infectious diseases, respiratory diseases, cardiovascular diseases,
eye diseases,
metabolic diseases, central nervous system (CNS) disorders, liver/kidney
diseases,
reproductive health disorders, gastric disorders, skin disorders and cancers
and other
diseases characterized by matrix metalloproteinase activity in a mammal,
including a human,
comprising administering to said mammal an amount of a compound of formula 1
or a
pharmaceutically acceptable salt thereof effective in treating such a
condition.
The present invention also relates to a method for the inhibition of matrix
metalloproteinases or other metalloproteinases involved in matrix degradation,
in a mammal,
including a human, comprising administering to said mammal an effective amount
of a
compound of formula I or a pharmaceutically acceptable salt thereof.
The present inventors have also discovered that it is possible to identify
inhibitors of
formula I with differential metalloprotease activity (preferably MMP-13
inhibitory activity). One
group of preferred inhibitors of formula 1 the inventors have been able to
identify include those
which selectively inhibit MMP-13 preferentially over MMP-1. The compounds of
the invention
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also possess selectivity over a related group of enrymes known as reprolysins,
such as TACE
and aggrecanase. Another group of preferred inhibitors of formula I the
inventors have been
able to identify include those which selectively inhibit MMP-13 preferentially
over MMP-1 and
MMP-14. Another group of preferred inhibitors of formula I the inventors havF,
been able to
identify include those which selectively inhibit P,~MP-13 preferentially over
MMP-1 and 12.
Another group of preferred inhibitors of formula I the inventors have been
able to identify include
those which selectively inhibit MMP-13 preferentially over MMP-1, 12 and 14.
Another group of
preferred inhibitors of formula I the inventors have been able to identify
include those which
selectively inhibit MMP-13 preferentially over MMP-1, 2, 3, 7, 9 and 14. Most
preferred
compounds of the invention selectively inhibit MMP-13 preferentially over MMP-
1, 2, 3, 7, 9, 12
and 14 and mammalian reprolysins.
The term "treating", as used herein, refers to reversing, alleviating,
inhibiting the
progress of, or preventing the disorder or condition to which such term
applies, or one or more
symptoms of such disorder or condition. The term "treatment", as used herein,
refers to the act
of treating, as "treating" is defined immediately above.
"Connective tissue disorders" as used herein refers to disorders such as
degenerative
cartilage loss following traumatic joint injury, osteoarthritis, osteoporosis,
Paget's disease,
loosening of artificial joint implants, periodontal disease and gingivitis.
"Destruction of articular cartilage" as used herein refers to connective
tissue disorders
resulting in articular cartilage destruction, preferably joint injury,
reactive arthritis, acute
pyrophosphate arthritis (pseudogout), psoriatic arthritis, or juvenile
rheumatoid arthritis, more
preferably osteoarthritis.
"Inflammatory disorders" as used herein refers to disorders such as rheumatoid
arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis,
chondrocalcinosis, gout,
inflammatory bowel disease, ulcerative colitis, Crohn's disease and cachexia.
"Immunology/allergy disorders" as used herein refers to disorders such as
organ
transplant toxicity, allergic reactions, allergic contact hypersensitivity,
autoimmune disorders
such as those disorders associated with granulomatous inflammation/tissue
remodeling (such
as asthma), immunosuppression and sarcoid.
"Infectious diseases," including those mediated by viruses, bacteria, fungi or
mycobacterial infection, as used herein refers to disorders such as septic
arthritis, AIDS,
fever; Prion diseases, myasthenia gravis, Malaria, sepsis, hemodynamic shock
and septic
shock.
"Respiratory diseases" as used herein refers to disorders such as chronic
obstructive
pulmonary disease (including emphysema), acute respiratory distress syndrome,
asthma,
hyperoxic alveolar injury and idiopathic pulmonary fibrosis and other fibrotic
lung diseases.
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"Cardiovascular diseases" as used herein refers to disorders such as
atherosclerosis
including atherosclerotic plaque rupture; aortic aneurysm including abdominal
aortic aneurysm
and brain aortic aneurysm; congestive heart failure; myocardial and cerebral
infarction; stroke;
cerebral ischemia; coagulation and acute phase response; left ventricular
dilation; post
ischemic reperfusion injury; angiofibromas; hemangiomas; and restenosis.
"Eye diseases" as used herein refers to disorders such as aberrant
angiogenesis,
ocular angiogenesis, ocular inflammation, keratoconus, Sjogren's syndrome,
myopia, ocular
tumors, corneal graft rejection, corneal injury, neovascular glaucoma, corneal
ulceration,
corneal scarring, macular degeneration (including "Age Related Macular
Degeneration
(ARMD) including both wet and dry forms), proliferative vitreoretinopathy and
retinopathy of
prematurity.
"Metabolic diseases" as used herein refers to disorders such as diabetes
(including
non-insulin dependent diabetes mellitus, diabetic retinopathy, insulin
resistance, diabetic
ulceration).
"Central Nervous System" (CNS) disorders as used herein refers to disorders
such as
head trauma, spinal cord injury, Inflammatory diseases of the central nervous
system, neuro
degenerative disorders (acute and chronic), Alzheimer's disease, demyelinating
diseases of
the nervous system, Huntington's disease, Parkinson's disease, peripheral
neuropathy, pain,
cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic
lateral
sclerosis, multiple sclerosis, migraine, depression and anorexia.
"Liver/Kidney diseases" as used herein refers to disorders such as nephrotic
syndromes such as glomerulonephritis and glomerular disease of the kidney,
proteinuria,
cirrhosis of the liver and interstitial nephritis.
"Reproductive Health disorders" as used herein refers to disorders such as
endometriosis, contraception (male/female), dysmenorrhea, dysfunctional
uterine bleeding,
premature rupture of fetal membranes and abortifactant.
"Gastric disorders" as used herein refers to disorders such as colonic
anastomosis
and gastric ulcers.
"Skin disorders" as used herein refers to disorders such as skin aging,
pressure
sores, psoriasis, eczema, dermatitis, radiation damage, tissue ulceration,
decubital ulcers,
epidermolysis bullosa, abnormal wound healing (topical and oral formulations),
burns and
scleritis.
"Cancers" as used herein refers to disorders such as solid tumor cancer
including
colon cancer, breast cancer, lung cancer and prostrate cancer, tumor invasion,
tumor growth
tumor metastasis, cancers of the oral cavity and pharynx (lip, tongue, mouth,
pharynx),
esophagus, stomach, small intestine, large intestine, rectum, liver and
biliary passages,
pancreas, larynx, lung, bone, connective tissue, skin, cervix uteri, corpus
endometrium, ovary,
testis, bladder, kidney and other urinary tissues, eye brain and central
nervous system, thyroid
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and other endocrine gland, Hodgkin's disease, non-Hodgkin's lymphomas,
multiple myeloma
and hematopoietic malignancies including leukemias and lymphomas including
lymphocytic,
granulocytic and monocytic.
The subject invention also includes isotopically-labelled compounds, which are
identical to those recited in Formula 1, but for the fact that one or more
atoms are replaced by
an atom having an atomic mass or mass number different from the atomic mass or
mass
number usually found in nature. Examples of isotopes that can be incorporated
into
compounds of the invention include isotopes of hydrogen, carbon, nitrogen,
oxygen,
phosphorous, fluorine and chlorine, such as ZH, 3H, '3C, '4C, '5N, '80, "O,
3'P, 32P, ssS, '8F
and 36C/, respectively. Compounds of the present invention, prodrugs thereof
and
pharmaceutically acceptable salts of said compounds or of said prodrugs which
contain the
aforementioned isotopes and/or other isotopes of other atoms are within the
scope of this
invention. Certain isotopically-labelled compounds of the present invention,
for example those
into which radioactive isotopes such as 3H and '4C are incorporated, are
useful in drug and/or
substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e.,
'4C, isotopes are
particularly preferred for their ease of preparation and detectability.
Further, substitution with
heavier isotopes such as deuterium, i.e., zH, can afford certain therapeutic
advantages
resulting from greater metabolic stability, for example increased in vivo half-
life or reduced
dosage requirements and, hence, may be preferred in some circumstances.
Isotopically-
labelled compounds of Formula I of this invention and prodrugs thereof can
generally be
prepared by carrying out the procedures disclosed in the Schemes and/or in the
Examples
and Preparations below, by substituting a readily available isotopically-
labelled reagent for a
non-isotopically-labelled reagent.
This invention also encompasses pharmaceutical compositions containing
prodrugs of
compounds of the formula I. This invention also encompasses methods of
treating or preventing
disorders that can be treated or prevented by the inhibition of matrix
metalloproteinases or the
inhibition of mammalian reprolysin comprising administering prodrugs of
compounds of the
formula I. Compounds of formula I having free amino, amido, hydroxy,
sulfonamide or carboxylic
groups can be converted into prodrugs. Prodrugs include compounds wherein an
amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or four)
amino acid residues
which are covalently joined through peptide bonds to free amido, amino,
hydroxy or carboxylic
acid groups of compounds of formula I. The amino acid residues include the 20
naturally
occurring amino acids commonly designated by three letter symbols and also
include, 4-
hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine,
norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and
methionine
sulfone. Prodrugs also include compounds wherein carbonates, carbamates,
amides and alkyl
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esters, which are covalently, bonded to the above substituents of formula I
through the carbonyl
carbon prodrug sidechain. Prodrugs also include dimers of compounds of formula
I.
One of ordinary skill in the art will appreciate that the compounds of the
invention are
useful in treating a diverse array of diseases. One of ordinary skill in the
art will also
appreciate that when using the compounds of the invention in the treatment of
a specific
disease that the compounds of the invention may be combined with various
existing
therapeutic agents used for that disease.
For the treatment of rheumatoid arthritis, the compounds of the invention may
be
combined with agents such as TNF-a inhibitors such as anti-TNF monoclonal
antibodies
(such as infliximab, D2E7 and CDP-870) and TNF receptor immunoglobulin
molecules (such
as etanercept), ICE inhibitors, MEKK1 inhibitors, COX-2 inhibitors such as
celecoxib,
rofecoxib, valdecoxib and etoricoxib; low dose methotrexate, lefunimide,
steroids,
glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process
and release
inhibitors, IL-1 receptor antagonists such as Kineret~, CCR-1 antagonists,
hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.
The compounds of the invention can also be used in combination with existing
therapeutic agents for the treatment of osteoarthritis. Suitable agents to be
used in
combination include standard non-steroidal anti-inflammatory agents
(hereinafter NSAID's)
such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen,
fenoprofen,
ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin,
sulindac,
apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-
2 inhibitors
such as celecoxib, valdecoxib, paracoxib, etoricoxib and rofecoxib,
analgesics, steroids,
glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process
and release
inhibitors, CCR-1 antagonists, LTD-4, LTB-4 and 5-LO inhibitors, p38 kinase
inhibitors and
intraarticular therapies such as corticosteroids and hyaluronic acids such as
hyalgan and
synvisc.
The compounds of the present invention may also be used in combination with
anticancer agents such as endostatin and angiostatin or cytotoxic drugs such
as adriamycin,
daunomycin, cis-platinum, etoposide, paclitaxel, docetaxel and alkaloids, such
as vincristine
and antimetabolites such as methotrexate.
The compounds of the present invention may also be used in combination with
cardiovascular agents such as calcium channel blockers (such as amlodipine and
nifedipine),
lipid lowering agents such as statins (such as lovastatin, atorvastatin,
pravastatin and
simvastatin), adrenergics such as doxazosin and terazosin; fibrates, beta-
blockers, Ace
inhibitors (such as captopril, lisinopril, fosinopril, enalapril and
quinaprill), Angiotensin-2
receptor antagonists such as losartan and irbesartan; nitrates, CCB's,
diure:ics such as
digitalis and platelet aggregation inhibitors. The compounds of the present
invention may also
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be used in combination with plaque rupture preventitive agents such as
statins, zithromax,
NSAIDs including aspirin, heparin, urarfarin, abciximab, TPA and platelet
Inhibitors. The
compounds of the present invention may also be used in combination with stroke
treatment
agents such as NIF, NHEI's and CCRIR antagonists.
The compounds of the present invention may also be used in combination with
CNS
agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs
(such as
deprenyl, carbadopa, L-dopa, dopamine receptor agonists such as ropinirole,
pergolide and
pramipexole; MAOB inhibitors such as selegiline and rasagiline, catechol-O-
methyltrasferase
inhibitors such as tolcapone, A-2 inhibitors, dopamine reuptake inhibitors,
NMDA antagonists,
Nicotine agonists, NK-1 inhibitors, dopamine agonists and inhibitors of
neuror~t~l nitric oxide
synthase) and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2
inhibitors,
propentofylline or metryfonate.
The compounds of the present invention may also be used in combination with
osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax
and
immunosuppressant agents such as FK-506 and rapamycin.
The compounds of the present invention may also be used in combination with
agents
for the treatment of respiratory diseases such as PDE-IV inhibitors,
steroidals such as
fluticasone, triamcinolone, budesonide, budesonide and beclomethasone,
anticholinergics
such as ipratropium, sympathomimetics such as salmeterol, albuterol and
Xopenex,
decongestants such as fexofenadine, loratadine and cetirizine; leukotriene
antagonists such
as zafirlukast and motelukast; and mast cell stabilizers such as zileuton.
The compounds of the present invention may also be used in combination with
agents
for the treatment of skin disorders such as tretinoin, isotretinoin, steroids
such as cortisone
and mometasone, antibiotics such as tetracycline, antifungals such as
clotrimazole,
miconazole and fluconazole and PDE-IV inhibitors.
The compounds of the present invention may also be used in combination with
agents
for the treatment of diabetes such as insulin, including human or humanized
insulin and
inhaled insulin, aldose reductase inhibitors, sorbitol dehydrogenase
inhibitors, antidiabetic
agents such as biguanides such as metformin; glitazones, glycosidase
inhibitors such as
acarbose, sulfonylureas such as glimepiride and glipizide; and
thiazolidinediones such as
pioglitazone, rosiglitazone and trogliazone. Preferred combinations are useful
for treating the
side effects of diabetes such as retinopathy, nephropathy and neuropathy,
preferably
retinopathy.
Detailed Description of the Invention
The following reaction Schemes illustrate the preparation of the compounds of
the
present invention. Unless otherwise indicated each of X, Y, Z, G, R', R2, R3,
R4, R5, R6, R',
R8, R9, R'°, R", R'Z, R'3, R'°, R'S, R's, R", R'8, R'9,
Rz°, RZ' and RZZ in the reaction Schemes
and the discussion that follows is defined as above.
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SCHEME 1
HEN -X-Y-Z-G
O i-Y-Z-G
NH
Lz ~ H
O VI
O X-Y-Z-G
N
Lz
H
O L
IV
O X-Y-Z-G
L~
~2 A
0
O X-Y-Z-G
N
O
N A
H O
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SCHEME 2
HZN -X-Y-Z-G
' O i-Y-Z-G
NH
Lz ~H
O VI
X-Y-Z-G
L, N ,.
H
Lz H ~R, z
O IVo
L3 O
X-Y-Z-G
O RR,o
N
H
z R, z
L
O O
Illo
O X-Y-Z-G
N
O
N A
H O
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SCHEME 3
NOz X-L' X
N02 X-Y-Z-G
HzN X-Y-Z-G
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Scheme 1 refers to the preparation of compounds of the formula I. Referring to
Scheme
1, compounds of formula I, wherein the heterocyclic ring "A" has the formulae
a-n (i.e., a
compound of the formulae la-In, respectively):
X-Y-Z-G X-Y-Z-G
X-Y-Z-G I O a
H O ~ O a H O I O 4 H O N R~ R3
N N R N N R ~N ,~ Re
R3 O~ , Ra O R~
' s N
H ~
N OR' R~ la ~ H O~R ~ H R~ Rz Rs Rs Ic
R Ib ,
X-Y-Z-G X-Y-Z-G
X-Y-Z-G
H OI 1/O H OI '0I s O I O Rs
N N~ s N N~NiR N N~N R"
O~ N-R O~ R"
N " N O°C R,o
H O R'° R Id ; H O , Rz R'o N s
R 1e ; H R, R~R If ;
-Y-Z-G X-Y-Z-G X-Y-Z-G
4
H O .SO H O N-SOa Ra H O N-SOz
N N a 4 N , 3 N ,
O~ R O~ / R O~ ~~ Rs
N R3 H ~Rs N ~/~~R~
H OR, RZ Ig. R, RZ IRs Ih ' H R' 1R~ IRS\Rs Ii ;
X-Y-Z-G X-Y-Z-G
X-Y-Z-G I R R, ° , a
H O ( R Rio R"R,o H O N
N Rs H O ~ RB N ~ R Re
O~N Rs O~N ,~ R'
H O ~ i RZ N ~ s OI ~R RSR
H O ,RzRs R Ik ; R ' II ;
R
X-Y-Z-G X-Y-Z-G
H OI O H O ~ O
~N N ~ N N
O ,N-Rs and O~ ~ -Rs
N ~SOZ
H O Im O O In
can be prepared by reacting a compound of the formulae Illa-Illn,
respectively:
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X-Y-Z-G X-Y-Z-G X-Y-Z-G
O ~ O ( O ~ O R4 Ra
L' N R~ L' O N R4 L' O N ~ a
z R3 ~' R3 ', R
L L2 Rs Lz R
s
OR' Rz Illa ; O R\Rz R5 Illb ; R' Rz R5 R Illc
X-Y-Z-G X-Y-Z-G
X-Y-Z-G
OI O OI O s O s
N--~/ , N~ ,R I R
L N-Rs L N R~~ L' O N~N R'~
Lz " z ~;~ ,o
O Rio R Illd ; L O R~ Rz Rio llle . Lz \ ~~Rs
R' Rz RS Illf ;
I_Y_Z_G X_Y_Z_G X_Y-Z_G
4
O N_SO a O N_SOz R s
L~ ON.Spz R4 L~ z RR3 L1 R
'~ Ra
Lz R3 Lz O~Rs Lz \ ~~~R~
ORS Rz Illg ; R' R R5 Illh ~ ' z Rs R
R R s Illi ;
X-Y-Z-G
X_Y_Z_G X-Y-Z_G ~ R,> >o
0 R" ~ R" ,o O R Ria
~0 0 R L~ N
R'z
L' N Rs L~ N Ra
R7 Lz ~ R7 Ra
Lz Rs z ,'
O ~ z . L z Rs O ~RZRS Rs
R R III , p RJR Rs Illk ~ R IIII ;
X-Y-Z-G X-Y-Z-G
OI O OI O
L, N~ and L, N
z iN-Rs ~ -Rs
-SO
L 0 z Illm L O ~ Illn
wherein L' and Lz are leaving groups such as alkoxy, preferably methoxy,
ethoxy or benryloxy,
more preferably methoxy or ethoxy, with a urea of formula fl (i.e., HZN-(CO)-
NHz) in the
presence of a suitable base in a polar solvent. Suitable bases include
alkoxide bases, such as
sodium methoxide, sodium ethoxide, or potassium ferf-butoxide, preferably
sodium ethoxide.
Suitable solvents include tetrahydrofuran, dimethylformamide, or alcohols
(such as ethanol),
preferably tetrahydrofuran or dimethylformamide. The aforesaid reaction is
conducted at a
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temperature of about 20°C to about 90°C, preferably about
50°C to about 8(J°~:., for a time
period of about 5 minutes to about 8 hours.
A compound of formulae Illa-IIII, respectively, can be prepared by reacting a
compound of formulae IVa-IVI, respectively:
X-Y-Z-G
X-Y-Z-G X-Y-Z-G O R4 s
O
ON OR4 O ~ O 4 L~ N
N R H ' R~
Lz H ~' Rz L H . R3 Lz , a
R z a O RS R
O L3 R' IVa ; L O L3 RS L3 ~ Rz IVc ;
R~ Rz IVb ; R
X-Y-Z-G X-Y-Z-G X-Y-Z-G
O ~ O s
ON N-Rs L' ON~N~Rs L' O N~N RR~~
Lz H ~ R" H /- R" z H R' ° 6
O Ls R,o IVd ; Lz O ~po L O zRSR IVf ;
L3 Ri Rz IVe ~ L3 R~ R
X-Y-Z-G X-Y-Z-G
X-Y-Z-G O ~ -SO Ra
O ~ .SOz 4 ' O N_SOz R4 L~ N z R s
R L R
Lz H , R3 z H R3 Lz H ~' 6 R~
z L a L3
O L3' RJR IVg ; O Ls . RS R . O ~ R25 R IVi ;
R' ~Rz IVh , R
X-Y-Z-G
X-Y-Z-G OI R,~R~oR~s
X-Y-Z-G
R4 Rs O RnR~e Li RtR2e
z RS L~ N RR' Lz H ; 1 R~
L \Fi 'Rz Lz H ' R6 and O Rs R6
O Ls R~ IVj . p I R z IVk L3 Ri Rz IVI ;
' Ls ~R
R
wherein L' and Lz are leaving groups such as alkoxy, preferably methoxy,
ethoxy or benryloxy,
more preferably methoxy or ethoxy and wherein L3 is a suitable leaving group,
such as halo,
para-tolylsulfonyloxy (OTs), or methylsulfonyloxy (OMs), preferably halo, such
as bromo or
iodo, with a suitable base in a polar solvent. Suitable bases include tertiary
amines, ,such as
triethylamine. Other suitable bases include a strongly basic macro-reticular
resin or gel type
resin, such as Amberlyst 400~ resin (hydroxide form). Suitable solvents
include alcoholic
solvents, preferably ethanol. The aforesaid reaction can be conducted at a
temperature of
about -10 °C to about 50 °C, preferably about 20 °C, for
a period of about 6 to about 36 hours.
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A compound of formulae Illm-Illn, respectively, can be prepared by reacting a
compound of formulae IVm-IVn, respectively:
X-Y-Z-G ~-Y-Z-G
OI ~O O ~/O
L' N''t s L~ N N,Rs
N R z H
z L
L O H SOz and O L3 O
IVm IVn
wherein L3 is a suitable leaving group, with a suitable base in a polar
solvent according to
methods analogous to the preparation of the compounds of formulae Illa-Itfi in
the foregoing
paragraph. Suitable leaving groups of the formula L3 include halo, para-
tolylsulfonyloxy (OTs),
or methylsulfonyloxy (OMs). Preferably L3 is halo, such as chloro. The
aforesaid reaction can
be conducted at a temperature of about 0°C to about 50°C,
preferably about 20 °C, for a
period of about 1 hour to about 4 hours. Suitable solvents include
tetrahydrofuran,
dimethylformamide and alcohol.
A compound of formulae IVa-IVi, respectively, can be prepared by reacting a
compound of formula VI with a compound of general formula
(V)
(i.e., a compound of formulae Va-Vi, respectively):
a 0 a 0 a La 0 Ra Rs
L Ra L R ,, s
z R L3 ,
s Rs Ls ~ R~
R
R' Va ; R' z RR Vb ; R~ Rz /Rs Rs Vc ,
R
O Rs
O L4~ Rs L4~N R~~
L~ ,Rs N- L3 Rio
~ Ls~R" R~ z Rs Rs
R~~Ro Vd . R~'/'~ z IR~o Ve ; R Vf ;
R
Ra
4
L4 SO L4 SOz R4 L SOz 1 R3
z Ra
Rs i Ra
Ls Ra L3 ~~ s and Ls ~R~
s
R~ Rz Vg ~ R~ Rz R5 R Vh R R ~ ~ s R Vi
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wherein each of L3 and L4 is a suitable leaving group, such as halo, para-
tolylsulfonyloxy
(OTs), or methylsulfonyloxy (OMs). Preferably L3 is halo, such as bromo,
chloro or iodo.
Preferably L4 is chloro or fluoro. Optionally, the aforementioned reaction may
be conducted in
the presence of a tertiary amine base, such as N,N-dimethylaniiine or
pyridine, in the presence
of a suitable solvent, such as a hydrocarbon solvent (benzene or toluene),
tetrahydrofuran or
methylene chloride. The aforementioned reaction is conducted at a temperature
of about 20°C
to about 90°C, preferably about 50°C to about 80°C, for a
time period of about 30 minutes to
about 6 hours.
Preferably, the aforementioned reaction is conducted in an aromatic
hydrocarbon
solvent, such as benzene or toluene, in the absence of the aforementioned
base.
A compound of formulae IVj-IVI, respectively, can be prepared by reacting a
compound of formula VI with a compound of formula:
Ls_( A. )-La (V)
(i.e., a compound of formulae Vj-VI, respectively):
R» R» ~o R» Rio
,o R ,s
L4 Rs L4 Ra L4 R~z
Rs , R~ ~~ Ra
LR~ Rz ; L3 Rs and L3 R~
Vj R~ Rz Rs Vk R~ Rz Rs R VI
wherein each of L3 and L4 is a suitable leaving group, such as halo, para-
tolylsulfonyloxy (OTs)
or methylsulfonyloxy (OMs), according to the methods analogous to those
described in the
preparation of the compounds of formulae IVa-IVi in the foregoing paragraph.
Preferably L3 is
chloro, bromo, or iodo. Preferably L4 is chloro, bromo, or iodo. The aforesaid
reaction can be
conducted at a temperature of about 0°C to about 50°C,
preferably about 20°C, for a time
period of about 30 minutes to about 12 hours.
' Compounds of formulae IVm-IVn, respectively, can be prepared by reacting a
compound of formula VI with a compound of formula
L3-( A' )-L4 (V)
(i.e., a compound of formulas Vm-Vn, respectively):
//O ~/O
L4~N,Rs L4 N,Rs
and Ls
L-SOz Vm ~ Vn
wherein each of L3 and L4 is a suitable leaving group, such as halo, para-
tolylsulfonyloxy (OTs)
or methylsulfonyloxy (OMs), according to the methods analogous to those
described in the
preparation of the compounds of formulae IVa-IVi in the foregoing paragraph.
Preferably L3 is
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halo, such as chloro. Preferably L4 is halo, such as chloro. The aforesaid
reaction can be
conducted at a temperature of about 0°C to about 80°C,
preferably about 0°C to about 40°C,
for a time period of about 30 minutes to about 8 hours.
Alternatively, compounds of formulae IVd, IVe and IVf, respectively, can be
prepared by
reacting a compound of formula VI with a compound of formula
( A~)_Ls (V)
(i.e., a compound of formulae Vd', Ve' and Vf, respectively):
N=C=O N=C=O
N=C=O ~ "
--~ L3y~R" and Ls RR
R'~~ Vd' R' Z R,o Ve, R~ 2 5 R6 Vf
R R R
wherein L3 is preferably halo, most preferably chloro, bromo, or iodo.
Optionally, the
aforementioned reaction can be conducted in the presence of a tertiary amine
base in a
suitable solvent. Suitable bases include N,N-dimethylaniline or pyridine.
Suitable solvents
include hydrocarbon solvent (benzene or toluene), tetrahydrofuran, or
methylene chloride,
preferably aromatic hydrocarbon solvent, such as benzene or toluene. The
aforementioned
reaction is conducted at a temperature of about 20°C to about
90°C, preferably about 50°C to
about 80°C, for a time period of about 30 minutes to about 6 hours.
Preferably, the
aforementioned reaction is conducted in the absence of any aforementioned
base.
Alternatively, compounds of formulae IVm and IVn, respectively, can be
prepared by
reacting a compound of formula VI with a compound of formula
( A~ )_Ls (V)
(i.e., a compound of formulae Vm' and Vn', respectively):
O
L3 SOz N=C=O and 3~-~-N=C=O
Vm' L Vn'
wherein L3 is preferably halo, most preferably chloro. The aforementioned
reaction can be
conducted optionally in the presence of a tertiary amine base in a suitable
solvent. Suitable
bases include N,N-dimethylaniline or pyridine. Suitable solvents include a
hydrocarbon solvent
(benzene or toluene), tetrahydrofuran or methylene chloride, preferably
aromatic hydrocarbon
solvent, such as benzene or toluene. The aforesaid reaction can be conducted
at a
temperature of about -10°C to about 50°C, preferably about
0°C to about 30°C, for a time
period of about 30 minutes to about 12 hours. Preferably, the aforementioned
reaction is
conducted in the absence of any aforementioned base.
A compound of formula VI can be prepared by reacting a compound of formula HZN-
X-Y-Z-G with a compound of the formula VII:
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O
ii
/\5
C_~z
VII
wherein L' and Lz are leaving groups, such as methoxy, ethoxy, or benzyloxy;
preferably
ethoxy; and L5 is a leaving group, such as halo, para-tolylsulfonyloxy (OTs)
or
methylsulfonyloxy (OMs); preferably halo; most preferably chloro or bromo. The
aforesaid
reaction can be performed either neat or in the presence of a suitable
solvent, preferably neat,
in the presence of a suitable base. Suitable solvents include tetrahydrofuran
or
dimethylformamide. Suitable bases include a weak tertiary amine base,
preferably tertiary
aniline bases, most preferably N,N-dimethylaniline. Preferably, the
aforementioned reaction is
conducted at a temperature of about 23°C to about 100°C,
preferably about 50°C to about
90°C, for a time period of about 30 minutes to about 24 hours.
In the aforesaid reactions, each of the compounds of formulae IVj-IVI may be
isolated,
but are preferably carried on to the next step without isolation. Thus, in
Scheme 1, the
compound of formulae Illj-IIII is preferably prepared in a one pot preparation
from a compound
of the formula VI.
If the compounds of the formulae IVj-IVI are not isolated, the suitable
solvent for the
one-pot preparation is dimethylformamide, tetrahydrofuran, or alcohols,
preferably alcohols,
such as ethanol. Preferably, the one-pot preparation is conducted in the
presence of an
alkoxide base, preferably sodium methoxide or sodium ethoxide. The aforesaid
one pot
preparation is conducted at a temperature of about 40°C to about
90°C, preferably about 60°C
to about 80°C, for a time period of about 15 minutes to about 12 hours.
The compounds of formula H2N-X-Y-Z-G are commercially available or can be made
by methods well known to those skilled in the art. Alternatively, the
compounds of formula
HZN-X-Y-Z-G can be prepared as described in Scheme 3.
A compound of the formula VII can be made by methods well known in the art
such as
those described in PCT Patent Publication WO 98/58925 or reviewed in The
Orctanic
Chemistry of Drua Synthesis, D. Lednicer and L. A. Mitscher, Volume 1, pages
187 to 277 and
references therein. Each of the above referenced publications and applications
is hereby
incorporated by reference in its entirety.
Compounds of the formula II are commercially available or can be made by
methods
well known to those skilled in the art.
Scheme 2 refers to the preparation of a compound of the formula I, wherein the
heterocyclic ring "A" has the formula o, i.e., a compound of formula lo.
Referring to Scheme 2,
a compound of formula lo:
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X-Y-Z-G
O RR,o
~N N R,s
O R,z
N
p O
to .
can be prepared by reacting a compound of the formula Illo, wherein L' and Lz
are leaving
groups, with a urea of formula II (i.e., HzN-(CO)-NHz) in the presence of a
suitable base in a
polar solvent. Suitable leaving groups include methoxy, ethoxy, or benzyloxy,
preferably
ethoxy. Suitable bases include alkoxide bases, such as sodium methoxide,
sodium ethoxide
and potassium tent-butoxide, preferably sodium ethoxide. Suitable solvents
include
tetrahydrofuran, dimethylformamide, or alcohols (such as ethanol), preferably
tetrahydrofuran
or dimethylformamide. The aforesaid reaction is conducted at a temperature of
about 20°C to
about 90°C, preferably about 50°C to about 80°C, for a
time period of about 5 minutes to
about 8 hours.
A compound of formula Illo can be prepared by reacting a compound of formula
IVo,
wherein L3 is a leaving group, with a suitable base in a polar solvent.
Suitable leaving groups
include alkoxy (such as methoxy, ethoxy, or benzyioxy) or halo; preferably
methoxy or ethoxy.
Suitable bases include alkoxide bases, preferably sodium methoxide or sodium
ethoxide.
Suitable solvents include alcohols, preferably ethanol. The aforesaid reaction
can be
conducted at a temperature of about 0 °C to about 90 °C,
preferably of about 60 °C to about
90 °C, for a period of about 1 hour to about 36 hours.
A compound of formula IVo can be prepared by reacting a compound of formula VI
with the compound of formula Vo:
R,o
R"
~ R,z
O Vo
wherein Ls is a suitable leaving group, in a suitable solvent. Suitable Ls
includes alkoxy or
halo, such as chloro; preferably alkoxy; more preferably methoxy or ethoxy.
Optionally, the
aforesaid reaction may be conducted in the presence of a suitable tertiary
amine base, such
as triethylamine, N,N-dimethylaniline, or pyridine. Suitable solvents, include
hydrocarbon
solvents (benzene or toluene), tetrahydrofuran, or methylene chloride,
preferably
tetrahydrofuran. Preferably, the aforementioned reaction is conducted in
tetrahydrofuran or
dimethylformamide, in the presence of the aforementioned suitable tertiary
amine base. The
aforesaid reaction may be conducted at a temperature of about 20°C to
about 90°C,
preferably about 50°C to about 80°C, for a time period of about
30 minutes to about 6 hours.
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In the aforesaid reactions, a compound of formula IVo may be isolated, but is
preferably carried on to the next step without isolation. Thus, in Scheme 1, a
compound of
formula Illo is preferably prepared in a one-pot preparation from a compound
of the formula
VI.
If the compounds of the formulae IVo are not isolated, the suitable solvent
for the one-
pot preparation is dimethylformamide, tetrahydrofuran, or alcohols, preferably
alcohol, such as
ethanol. The aforesaid one pot preparation is suitably conducted at a
temperature of about
'0°C to about 70°C, preferably about 23°C to about
60°C, for a time period of about 30 minutes
to about 24 hours.
A compound of formula VI can prepared by reacting a compound of formula HZN-X-
Y-
Z-G with a compound of the formula VIl as described Scheme 1.
Scheme 3 refers to the prepay ation of compounds of the formula HzN-X-Y-Z-G,
which
are intermediates useful in the preparation of compounds of formula I in
Schemes 1 and 2.
Referring to Scheme 3, compounds of formula HZN-X-Y-Z-G can be prepared by
reacting a
compound of formula VIII with a reducing agent, such as tin 1l chloride, in
the presence of a
suitable acid, such as hydrochloric acid, in a polar erotic solvent. Suitable
solvents include an
alcoholic solvent, water, or mixtures thereof, preferably a mixture of ethanol
anc water. The
aforesaid reaction can be conducted at a temperature of about 40°C to
about 100°C for a
period of about 1 to about 12 hours.
Alternatively, the compounds of formula HZN-X-Y-Z-G can be prepared by
reacting a
compound of formula VIII with hydrogen gas, at a pressure between atmospheric
pressure
and 50 psi, in the presence of a catalyst and a polar solvent. Suitable
catalysts include a
palladium or platinum catalyst, preferably Adams catalyst (i.e., platinum
oxide), or palladium
adsorbed on charcoal. Suitable solvents include an alcoholic solvent,
preferably methanol.
The aforesaid reaction can be conducted at a temperature of about 20°C
to about 50°C,
preferably about 23°C, for a period of about 30 minutes to about 6
hours.
A compound of the formula VIII, wherein Y is oxygen, sulfur, -CHZS-, -CHZO-,
>NR'4,
-CHI[N(R'4)]- or -SOZ[N(R'4)]-, can be prepared by reacting a compound of
formula X, wherein
the group L' is fluoro or chloro, with a compound of the formula:
G-Z-Y-H (IX)
wherein Y is oxygen, sulfur, -CHZS-, -CH20-, >NR'4, -CHI[N(R'4)]- or -
SOZ[N(R'~)]-, in the
presence of a base in a polar aprotic solvent. Suitable bases include an
alkali metal hydride
base; preferably sodium hydride. Suitable solvents include dimethylformamide,
tetrahydrofuran or 1,2-dimethoxyethane; preferably dimethylformamide. The
aforesaid
reaction can be conducted at a temperature of about 40°C to about
140°C, preferably about
80°C to about 120°C, for about 1 hour to about 24 hours.
Alternatively, the aforesaid compound of formula VIII, wherein Y is oxygen,
sulfur,
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-CHzS-, -CH20-, >NR'4, -CHZ[N(R'4)]- or -SOZ[N(R'4)]-, can be prepared in
presence of an
alkali metal hydroxide base, preferably potassium hydroxide, optionally in the
presence of a
phase transfer catalyst, such as a quaternary ammonium or phosphonium salt,
preferably
tetrabutylammonium bromide, in an aromatic hydrocarbon solvent. Preferably the
solvent is
benzene or toluene. The aforesaid reaction can be conducted at a temperature
of about 0°C
to about 120°C, preferably at about 23°C, for about 1 hour to
about 12 hours.
Alternatively, the aforesaid compound of formula VIII, wherein Y is oxygen,
sulfur,
-CHZS-, -CH20-, >NR'4, -CHI[N(R'4)]- or -SOZ[N(R'4)]-, can be prepared under
so called
"Ulman coupling" conditions. Under such conditions, the aforesaid compound of
formula VIII
can be prepared by reacting a compound of formula X, wherein the group L' is
bromo or
chloro, with a compound of the formula:
G-Z-Y-H (IX)
wherein Y is oxygen, sulfur, -CHZS-, -CH20-, >NR'4, -CHZ[N(R'4)]- or -
S02[N(R")]-, in the
presence of a base and a catalyst in a polar aprotic solvent. Suitable bases
include an alkali
metal carbonate or hydroxide base, preferably potassium carbonate. Suitable
catalysts include
a copper (0) catalyst, preferably finely powdered copper bronze. Suitable
solvents include
dimethylformamide or 1-methyl-2-pyrrolidinone. The aforesaid reaction can be
conducted at a
temperature of about 80 °C to about 140 °C, for about 6 hours to
about 24 hours.
A compound of formula VIII, wherein the group Y is in an oxidized state, i.e.,
>S02,
>S=0, -CHZSO-, -CHZSOZ-, SO(CHZ)~ or -SOz(CHZ)~ , can be prepared by reacting
a
corresponding compound of formula VIII, wherein the group Y is in a
corresponding lower
oxidation state, with a suitable oxidizing agent in a solvent. The
corresponding lower oxidation
state for each compound of formula VIII, wherein the group Y is >S02 and >S=0
is a
compound of formula VIII, wherein the group Y is S. The corresponding lower
oxidation state
for each compound of formuia VIII, wherein the group Y is -CHZS02- and -CHZSO-
is a
compound of formula VIII, wherein the group Y is -CHZS-. The corresponding
lower oxidation
state for each compound of formula VI11, wherein the group Y is -SO~(CHZ)~ and
-SO(CHZ)"
is a compound of formula VIII, wherein the group Y is -S-(CH~)~ , Suitable
oxidizing agents
include a peroxy acid, preferably peracetic acid, or an organic peroxide,
preferably m-
chloroperoxybenzoic acid or tert-butyl hydroperoxide. Suitable solvents
include methylene
chloride or alcohol, such as ethanol. The aforesaid reaction can be conducted
at a
temperature of about -10°C to about 30°C, for about 1 hour to
about 8 hours.
A compound of the formula VIII, wherein Y is -O(CHZ)~ , -S(CHZ)~ or -
NR'4(CHZ)",
respectively, can be prepared by reacting a compound of the formula X, wherein
the group L'
is L8-(CHZ)~ and wherein the group L8 is halo, such as chloro, bromo, iodo,
mesyloxy (Ms0),
or tosyloxy (Ts0), with a compound of formula:
G-Z-W-H (IX)
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wherein the group W is oxygen, sulfur, or -NR'4, respectively, in the presence
of a base in a
polar aprotic solvent. Suitabie bases inciude an aikafi metal carbonate base,
preferably
potassium carbonate or cesium carbonate. Suitable solvents include
dimethylformamide or
tetrahydrofuran. The aforesaid reaction can be conducted at a temperature of
about 23°C to
about 80°C, preferably about 20°C to about 50°C, for
about 1 to about 24 hours.
A compound of the formula VIII, wherein Y is >C=0, -CH=CH- or - C_--C-, can be
prepared by reacting a compound of formula X, wherein the group L' is
dihydroxyborane; zinc
halide, such as zinc chloride; or trialkyl tin, such as tributyl tin, with a
compound of the formula:
G-Z-Y-L9 (IX)
wherein Y is >C=0, -CH=CH- or - C--__C-; and wherein the group L9 is halo;
preferably chloro,
bromo or iodo; in the presence of a catalyst in a solvent. Suitable catalysts
include a
palladium or nickel catalyst, preferably tetrakis triphenyl phosphine
palludium (0) (Pd(PPh3)4).
Suitable solvents include toluene, tetrahydrofuran, dimethylformamide, or
dimethylsulfoxide.
The aforesaid reaction can be conducted at a temperature of about 23°C
to about 110°C, for a
period of about 1 hour to about 24 hours. Such reactions can be facilitated by
the presence of
a copper salt, such as cuprous iodide or cuprous bromide.
Alternatively, a compound of the formula VIII, wherein Y is -C--__C-, can be
prepared by
reacting a compound of formula X, wherein L' is halo or triflate, preferably
bromo or iodo, with
a compound of the formula:
G-Z-Y-H (IX)
in the presence of a base, such as a trialkylamine base, preferably
triethylamine and a
palladium catalyst, preferably Pd(PPh3)4 in a solvent. Suitable solvents
include
tetrahydrofuran or dimethylformamide. The aforesaid reaction can be conducted
at a
temperature of about 23°C to about 60°C for a period of about 1
to about 24 hours.
A compound of the formula VIII, wherein Y is -CHZ(CHZ)ri , can be prepared by
reacting the aforementioned compound of the formula VIII, wherein Y is -CH=CH-
or -C--__C-,
with hydrogen gas, at ambient pressure to about 50 psi, in the presence of a
palladium
catalyst in a solvent. Preferably the palladium catalyst is palladium adsorbed
on charcoal.
Suitable solvents include methanol or ethyl acetate. The aforesaid reaction
can be conducted
at a temperature of about 20°C to about 50°C, for about 1 hour
to about 24 hours.
Compounds of the formulae X and IX (i.e., compounds of the formulae G-Z-Y-H, G-
Z-
W-H, or G-Z-Y-L9) are either commercially available or are well known and can
be prepared
by methods known to those skilled in the art.
The compounds of the formula I, which are basic in nature, are capable of
forming a
wide variety of different salts with various inorganic and organic acids.
Although such salts
must be pharmaceutically acceptable for administration to animals, it is often
desirable in
practice to initially isolate a compound of the formula I from the reaction
mixture as a
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pharmaceutically unacceptable salt and then simply convert the latter back to
the free base
compound by treatment with an alkaline reagent and subsequently convert the
free base to a
pharmaceutically acceptable acid addition salt. The acid addition salts of the
base
compounds of this invention are readily prepared by treating the base compound
with a
substantially equivalent amount of the chosen mineral or organic acid in an
aqueous solvent
medium or in a suitable organic solvent such as methanol or ethanol. Upon
careful
evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid
addition
salts of the base compounds of this invention are those which form non-toxic
acid addition
salts, i.e., salts containing pharmacologically acceptable anions, such as
hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid
phosphate, acetate,
lactate, citrate or acid citrate, tartrate, or bitartrate, succinate, maleate,
fumarate, gluconate,
saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-
(2-hydroxy-3-
naphthoafe)] salts.
Those compounds of the formula I which are also acidic in nature, are capable
of
forming base salts with various pharmacologically acceptable cations. Examples
of such salts
include the alkali metal or alkaline-earth metal salts and particularly, the
sodium and
potassium salts. These salts are all prepared by conventional techniques. The
chemical
bases which are used as reagents to prepare the pharmaceutically acceptable
base salts of
this invention are those which form non-toxic base salts with the herein
described acidic
compounds of formula I. These non-toxic base salts include those derived from
such
pharmacologically acceptable cations as sodium, potassium, calcium and
magnesium, etc.
These salts can easily be prepared by treating the corresponding acidic
compounds with an
aqueous solution containing the desired pharmacologically acceptable cations
and then
evaporating the resulting solution to dryness, preferably under reduced
pressure.
Alternatively, these salts may also be prepared by mixing lower alkanolic
solutions of
the acidic compounds and the desired alkali metal alkoxide together and then
evaporating the
resulting solution to dryness in the same manner as before. In either case,
stoichiometric
quantities of reagents are preferably employed in order to ensure completeness
of reaction
and maximum product yields.
BIOLOGICAL ASSAYS
The ability of the compounds of formula I or their pharmaceutically acceptable
salts
(hereinafter also referred to as the compounds of the present invention) to
inhibit
metalloproteinases or mammalian reprolysins and, consequently, demonstrate
their
effectiveness for treating diseases characterized by metalloproteinase
activity is shown by the
following in vifro and in vivo assay tests.
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MMP Assays
MMP-13 selective inhibitors can be identified by screening the inhibitors of
the present
invention through the MMP fluorescence assays described below and selecting
those agents
with MMP-13/MMP-X inhibition ICS ratios of 100 or greater and potency of less
than 100 nM,
where MMP-X refers to one or more other MMP's.
Non-selective collagenase inhibitors as used herein, unless otherwise
mentioned, refer
to agents which exhibit less than a 100 fold selectivity for the inhibition of
MMP-13 enzyme
activity over MMP-X enzyme activity or a potency of more than 100nM as defined
by the ICso
results from the MMP-13/MMP-X fluorescence assays described below.
The ability of collagenase inhibitors to inhibit collagenase activity is well
known in the art.
The degree of inhibition of a particular MMP for several compounds has been
well documented
in the art and those skilled in the art will know how to normalize different
assay results to those
assays reported herein. The following assays may be used to identify matrix
metalloproteinase
inhibitors.
Inhibition of Human Collaaenase (MMP-1)
Human recombinant collagenase is activated with trypsin. The amount of trypsin
is
optimized for each lot of collagenase-1 but a typical reaction uses the
following ratio: 5 pg trypsin
per 100 pg of collagenase. The trypsin and collagenase are incubated at room
temperature for
10 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean trypsin
inhibitor is added.
Stock solutions (10 mM) of inhibitors are made up in dimethylsulfoxide and
then diluted
using the following scheme:
10 mM -~---> 120 ~M ------> 12 pM ------> 1.2 pM ------> 0.12 pM
Twenty-five microliters of each concentration is then added in triplicate to
appropriate wells of
a 96 well microfluor plate. The final concentration of inhibitor will be a 1:4
dilution after
addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are
set up in wells
D7-D12 and negative controls (no enzyme, no inhibitors) are set in wells D1-
D6.
Collagenase-1 is diluted to 240 ng/ml and 25 ~I is then added to appropriate
wells of the
microfluor plate. Final concentration of collagenase in the assay is 60 ng/ml.
Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is made as a 5 mM
stock in dimethylsulfoxide and then diluted to 20 pM in assay buffer. The
assay is initiated by the
addition of 50 ~I substrate per well of the microfluor plate to give a final
concentration of 10 pM.
Fluorescence readings (360 nM excitation, 460 nm emission) are taken at time 0
and
then at 20 minute intervals. The assay is conducted at room temperature with a
typical assay
time of 3 hours
Fluorescence versus time is then plotted for both the blank and collagenase
containing
samples (data from triplicate determinations is averaged). A time point that
provides a good
signal (at least five fold over the blank) and that is on a linear part of the
curve (usually around
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120 minutes) is chosen to determine ICS values. The zero time is used as a
blank for each
compound at each concentration and these values are subtracted from the 120
minute data.
Data is plotted as inhibitor concentration versus % control (inhibitor
fluorescence divided by
fluorescence of collagenase alone x 100). ICS s are determined from the
concentration of
inhibitor that gives a signal that is 50% of the control.
If ICS s are reported to be less than 0.03 pM then the inhibitors are assayed
at
concentrations of 0.3 pM, 0.03 pM and 0.003 ~M.
Inhibition of Gelatinase (MMP-2)
Human recombinant 72 kD gelatinase (MMP-2, gelatinase A) is activated for 16-
18
hours with 1 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM
stock in
0.2 N NaOH) at 4°C, rocking gently.
10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in
assay
buffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaClz, 20 pM ZnClz and 0.02%
BRIJ-35
(vol./vol.)) using the following scheme:
10 mM--~ 120 IuM----> 12 pM----~ 1.2 pM---~ 0.12 ~M
Further dilutions are made as necessary following this same scheme. A minimum
of four
inhibitor concentrations for each compound are performed in each assay. 25 pL
of each
concentration is then added to triplicate wells of a black 96 well U-bottomed
microfluor plate.
As the final assay volume is 100 pL, final concentrations of inhibitor are the
result of a further
1:4 dilution (i.e. 30 pM ----> 3 uM -----~ 0.3 pM ----~ 0.03 pM, etc.). A
blank (no enzyme, no
inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also
prepared in
triplicate.
Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 ~L per well is
added to
appropriate wells of the microplate. Final enzyme concentration in the assay
is 25 ng/mL
(0.34 nM).
A five mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-
Dpa-
Ala-Arg-NHa) is diluted in assay buffer to 20 ~M. The assay is initiated by
addition of 50 ~L of
diluted substrate yielding a final assay concentration of 10 pM substrate. At
time zero,
fluorescence reading (320 excitation; 390 emission) is immediately taken any'
subsequent
readings are taken every fifteen minutes at room temperature with a PerSeptive
Biosystems
CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus
time.
An early time point on the linear part of this curve is chosen for ICSO
determinations. The zero
time point for each compound at each dilution is subtracted from the latter
time point and the
data then expressed as percent of enzyme control (inhibitor fluorescence
divided by
fluorescence of positive enzyme control x 100). Data is plotted as inhibitor
concentration
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versus percent of enzyme control. ICSO s are defined as the concentration of
inhibitor that
gives a signal that is 50% of the positive enzyme control.
Inhibition of Stromelvsin Activity (MMP-3)
Human recombinant stromelysin (MMP-3, stromelysin-1 ) is activated for 20-22
hours
with 2 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock
in 0.2 N
NaOH) at 37°C.
mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in
assay
buffer (50 mM TRIS, pH 7.5, 150 mM NaCI, 10 mM CaClz and 0.05% BRIJ-35
(vol./vol.))
using the following scheme:
10 10 mM---~ 120 uM---~ 12 pM---~ 1.2 ~M----a 0.12 ~M
Further dilutions are made as necessary following this same scheme. A minimum
of four
inhibitor concentrations for each compound are performed in each assay. 25 pL
of each
concentration is then added to triplicate wells of a black 96 well U-bottomed
microfluor plate.
As the final assay volume is 100 qL, final concentrations of inhibitor are the
result of a further
1:4 dilution (i.e. 30 pM ----> 3 pM ----~ 0.3 ~M ---~ 0.03 pM, etc.). A blank
(no enzyme, no
inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also
prepared in
triplicate.
Activated enzyme is diluted to 200 ng/mL in assay buffer, 25 pL per well is
added to
appropriate wells of the microplate. Final enzyme concentration in the assay
is 50 ng/mL
(0.875 nM).
A ten mM dimethylsulfoxide stock solution of substrate (Mca-Arg-Pro-Lys-Pro-
Val-
Glu-Nva-Trp-Arg-Lys(Dnp)-NHZ) is diluted in assay buffer to 6 ~M. The assay is
initiated by
addition of 50 pL of diluted substrate yielding a final assay concentration of
3 ~M substrate. At
time zero, fluorescence reading (320 excitation; 390 emission) is immediately
taken and
subsequent readings are taken every fifteen minutes at room temperature with a
PerSeptive
Biosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus
time.
An early time point on the linear part of this curve is chosen for ICso
determinations. The zero
time point for each compound at each dilution is subtracted from the latter
time point and the
data then expressed as percent of enzyme control (inhibitor fluorescence
divided by
fluorescence of positive enzyme control x 100). Data is plotted as inhibitor
concentration
versus percent of enzyme control. ICSO's are defined as the concentration of
inhibitor that
gives a signal that is 50% of the positive enzyme control.
Inhibition of Human 92 kD Gelatinase (MMP-9)
Inhibition of 92 kD gelatinase (MMP-9) activity is assayed using the Mca-Pro-
Leu-Gly-
Leu-Dpa-Ala-Arg-NHZ substrate (10 pM) under similar conditions as described
above for the
inhibition of human collagenase (MMP-1 ).
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Human recombinant 92 kD gelatinase (MMP-9, gelatinase B) is activated for 2
hours
with 1mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock
in 0.2 N
NaOH) at 37 C.
mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in
assay
5 buffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaClz, 20 ~M ZnClz, 0.02% BRIJ-
35
(vol./vol.)) using the following scheme:
10 mM--~ 120 pM----~ 12 ~M----~ 1.2 ~M----~ 0.12 pM
Further dilutions are made as necessary following this same scheme. A minimum
of
four inhibitor concentrations for each compound are performed in each assay.
25 pL of each
10 concentration is then added to triplicate wells of a black 96 well U-
bottomed microfluor plate.
As the final assay volume is 100 ~L, final concentrations of inhibitor are the
result of a further
1:4 dilution (i.e. 30 ~M -----~ 3 ~M -----~ 0.3 ~M ----> 0.03 ~M, etc.). A
blank (no enzyme, no
inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also
prepared in
triplicate.
Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 pL per well is
added to
appropriate wells of the microplate. Final enzyme concentration in the assay
is 25 ng/mL
(0.27 nM).
A five mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-
Dpa
Ala-Arg-NHz) is diluted in assay buffer to 20 ~M. The assay is initiated by
addition of 50 pL of
diluted substrate yielding a final assay concentration of 10 pM substrate. A 0
time
fluorescence reading (320 excitation; 390 emission) is immediately taken and
subsequent
readings are taken every fifteen minutes at room temperature with a PerSeptive
Biosystems
CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus
time.
An early time point on the linear part of this curve is chosen for ICso
determinations. The 0
time point for each compound at each dilution is subtracted from the latter
time point and the
data then expressed as percent of enzyme control (inhibitor fluorescence
divided by
fluorescence of positive enzyme control x 100). Data is plotted as inhibitor
concentration
versus percent of enzyme control. ICso's are defined as the concentration of
inhibitor that
gives a signal that is 50% of the positive enzyme control.
Inhibition of MMP-13
Human recombinant MMP-13 is activated with 2 mM APMA (p-aminophenyl mercuric
acetate) for 1.5 hours, at 37°C and is diluted to 400 mg/ml in assay
buffer (50 mM Tris, pH 7.5,
200 mM sodium chloride, 5 mM calcium chloride, 20 pM zinc chloride, 0.02%
brij). Twenty-five
microliters of diluted enzyme is added per well of a 96 well microfluor plate.
The enzyme is then
diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate
to give a final
concentration in the assay of 100 mg/ml.
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mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then
diluted in
assay buffer as per the inhibitor dilution scheme for inhibition of human
collagenase (MMP-1 ):
Twenty-five microliters of each concentration is added in triplicate to the
microfluor plate. The
final concentrations in the assay are 30 ~M, 3 pM, 0.3 pM and 0.03 pM.
5 Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NHz) is prepared as for
inhibition of human collagenase (MMP-1 ) and 50 p1 is added to each well to
give a final assay
concentration of 10 pM. Fluorescence readings (360 nM excitation; 450
emission) are taken at
time 0 and every 5 minutes for 1 hour.
Positive controls consist of enzyme and substrate with no inhibitor and blanks
consist of
10 substrate only.
ICSO s are determined as per inhibition of human collagenase (MMP-1 ). If ICS
s are
reported to be less than 0.03 ~M, inhibitors are then assayed at final
concentrations of 0.3 pM,
0.03 pM, 0.003 pM and 0.0003 ~M.
Collagen film MMP-13 Assay
Rat type I collagen is radiolabeled with '4C acetic anhydride (T.E. Cawston
and A.J.
Barrett, Anal. Biochem., 99, 340-345 (1979)) and used to prepare 96 well
plates containing
radiolabeled. collagen films (Barbara Johnson-Wint, Anal. Biochem., 104, 175-
181 (1980)).
When a solution containing collagenase is added to the well, the enzyme
cleaves the insoluble
collagen which unwinds and is thus solubilized. Collagenase activity is
directly proportional to
the amount of collagen solubilized, determined by the proportion of
radioactivity released into
the supernatant as measured in a standard scintillation counter. Collagenase
inhibitors are,
therefore, compounds which reduce the radioactive counts released with respect
to the
controls with no inhibitor present. One specific embodiment of this assay is
described in detail
below.
For determining the selectivity of compounds for MMP-13 versus MMP-1 using
collagen as a substrate, the following procedure is used. Recombinant human
proMMP-13 or
proMMP-1 is activated according to the procedures outlined above. The
activated MMP-13 or
MMP-1 is diluted to 0.6 ug/ml with buffer ( 50 mM Tris pH 7.5, 150 mM NaCI, 10
mM CaCl2 , 1
uM ZnCh, 0.05% Brij-35, 0.02% sodium azide).
Stock solutions of test compound (10mM) in dimethylsulfoxide are prepared.
Dilutions
of the test compounds in the Tris buffer, above, are made to 0.2, 2.0, 20,
200, 2000 and
20000 nM.
100 ~I of appropriate drug dilution and 100 p1 of diluted enzyme are pipetted
into wells
of a 96 well plate containing collagen films labeled with '4C-collagen. The
final enzyme
concentration is 0.3 ~g/ml while the final drug concentration is 0.1, 1.0, 10,
100, 1000 nM.
Each drug concentration and control is analyzed in triplicate. Triplicate
controls are also run
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for the conditions in which no enzyme is present and for enzyme in the absence
of any
compound.
The plates are incubated at 37°C for a time period such that around 30 -
50% of the
available collagen is solubilized - determined by counting additiorial control
wells at various
time points. In most cases around 9 hours of incubation are required. When the
assay has
progressed sufficiently, the supernatant from each well is removed and counted
in a
scintillation counter. The background counts (determined by the counts in the
wells with no
enzyme) are subtracted from each sample and the % release calculated in
relation to the wells
with enzyme only and no inhibitor. The triplicate values for each point are
averaged and the
data graphed as percent release versus drug concentration. ICSO's are
determined from the
point at which 50% inhibition of release of radiolabeled collagen is obtained.
To determine the identity of the active collagenases in cartilage conditioned
medium,
assays were conducted using collagen as a substrate, cartilage conditioned
medium
containing collagenase activity and inhibitors of varying selectivity. The
cartilage conditioned
medium was collected during the time at which collagen degradation was
occurring and thus
is representative of the collagenases responsible for the collagen breakdown.
Assays were
conducted as outlined above except that instead of using recombinant MMP-13 or
recombinant MMP-1, cartilage conditioned medium was the enzyme source.
1I_-1 Induced Cartilage Collagen Degradation From Bovine Nasal Cartilage
This assay uses bovine nasal cartilage explants which are commonly used to
test the
efficacy of various compounds to inhibit either IL-1 induced proteoglycan
degradation or IL-1
induced collagen degradation. Bovine nasal cartilage is a tissue that is very
similar to articular
cartilage, i.e. chondrocytes surrounded by a matrix that is primarily type II
collagen and
aggrecan. The tissue is used because it: (1 ) is very similar to articular
cartilage, (2) is readily
available, (3) is relatively homogeneous and (4) degrades with predictable
kinetics after IL-1
stimulation.
Two variations of this assay have been used to assay compounds. Both
variations
give similar data. The two variations are described below:
Variation 1
Three plugs of bovine nasal cartilage (approximately 2 mm diameter x 1.5 mm
long)
are placed into each well of a 24 well tissue culture plate. One ml of
serumless medium is
then added to each well. Compounds are prepared as 10 mM stock solutions in
DMSO and
then diluted appropriately in serumless medium to final concentrations, e~c..
., 50, 500 and 5000
nM. Each concentration is assayed in triplicate.
Human recombinant IL-1 a (5ng/mL) (IL-1 ) is added to triplicate control wells
and to
each well containing drug. Triplicate control wells are also set up in which
neither drug nor IL-
1 are added. The medium is removed and fresh medium containing IL-1 and the
appropriate
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drug concentrations is added on days 6, 12, 18 and 24 or every 3 - 4 days if
necessary. The
media removed at each time point is stored at -20°C for later analysis.
When the cartilage in
the IL-1 alone wells has almost completely resorbed (about day 21 ), the
experiment is
terminated. The medium, is removed and stored. Aliquots (100 p1) from each
well at each
time point are pooled, digested with papain and then analyzed for
hydroxyproline content.
Background hydroxyproline (average of wells with no IL-1 and no drug) is
subtracted from
each data point and the average calculated for each triplicate. The data is
then expressed as
a percent of the IL-1 alone average value and plotted. The ICSO is determined
from this plot.
Variation 2
The experimental set-up is the same as outlined above in Variation 1, until
day 12.
On day 12, the conditioned medium from each well is removed and frozen. Then
one ml of
phosphate buffered saline (PBS) containing 0.5 pg/ml trypsin is added to each
well and
incubation continued for a further 48 hours at 37°C. After 48 hours
incubation in trypsin, the
PBS solution is removed. Aliquots (50 p1) of the PBS/trypsin solution and the
previous two
time points (days 6 and 12) are pooled, hydrolyzed and hydroxyproline content
determined.
Background hydroxyproline (average of wells with no IL-1 and no drug) is
subtracted from
each data point and the average calculated for each triplicate. The data is
then expressed as
a percent of the IL-1 alone average value and plotted. The ICSO is determined
from this plot.
In this variation, the time course of the experiment is shortened
considerably. The addition of
trypsin for 48 hours after 12 days of IL-1 stimulation likely releases any
type II collagen that
has been damaged by collagenase activity but not yet released from the
cartilage matrix. In
the absence of IL-1 stimulation, trypsin treatment produces only low
background levels of
collagen degradation in the cartilage explants.
Inhibition of TNF Production
The ability or inability of the compounds or the pharmaceutically acceptable
salts thereof
to inhibit the production of TNF is shown by the following in vitro assay:
Human Monocyte Assay
Human mononuclear cells were isolated from anti-coagulated human blood using a
one-
step Ficoll-hypaque separation technique. (2) The mononuclear cells were
washed three times
in Hanks balanced salt solution (HBSS) with divalent cations and resuspended
to a density of 2 x
106 /ml in HBSS containing 1 % BSA. Differential counts determined using the
Abbott Cell Dyn
3500 analyzer indicated that monocytes ranged from 17 to 24% of the total
cells in these
preparations.
180 ~I of the cell suspension was aliquoted into flat bottom 96 well plates
(Costar).
Additions of compounds and LPS (100 ng/ml final concentration) gave a final
volume of 200 ~I.
All conditions were performed in triplicate. After a four hour incubation at
37°C in an humidified
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C02 incubator, plates were removed and centrifuged (10 minutes at
approximately 250 x g) and
the supernatants removed and assayed for TNF a using the R&D ELISA Kit.
Aga~ecanase Assay
Primary porcine chondrocytes from articular joint cartilage are isolated by
sequential
trypsin and collagenase digestion followed by collagenase digestion overnight
and are plated
at 2 X 105 cells per well into 48 well plates with 5 pCi / ml 35S (1000
Ci/mmol) sulphur in type I
collagen coated plates. Cells are allowed to incorporate label into their
proteoglycan matrix
(approximately 1 week) at 37°C, under an atmosphere of 5% CO2.
The night before initiating the assay, chondrocyte monolayers are washed two
times
in DMEM/ 1 % PSFIG and then allowed to incubate in fresh DMEM /1 % FBS
overnight.
The following morning chondrocytes are washed once in DMEMl1 %PSF/G. The final
wash is allowed to sit on the plates in the incubator while making dilutions.
Media and dilutions can be made as described in the Table below.
Control Media DMEM alone (control media)
IL-1 Media DMEM + IL-1 (5 ng/ml) i
Drug Dilutions Make all compounds stocks at 10 mM in
DMSO.
Make a 100 pM stock of each compound in
DMEM in 96 well
plate. Store in freezer overnight.
The next day perform serial dilutions
in DMEM with IL-1 to 5 ~M, I
500 nM and 50 nM.
Aspirate final wash from wells and add
50 ~I of compound from
above dilutions to 450 p1 of IL-1 media
in appropriate wells of the
48 well plates.
Final compound concentrations equal 500
nM, 50 nM and 5 nM.
All samples completed in triplicate with
Control and IL-1 alone
samples on each plate.
Plates are labeled and only the interior 24 wells of the plate are used. On
one of the
plates, several columns are designated as IL-1 (no drug) and Control (no Il_-
1, no drug).
These control columns are periodically counted to monitor 35S-proteoglycan
release. Control
and IL-1 media are added to wells (450 p1) followed by compound (50 ~I) so as
to initiate the
assay. Plates are incubated at 37°C, with a 5% COz atmosphere.
At 40-50 % release (when CPM from IL-1 media is 4-5 times control media) as
assessed by liquid scintillation counting (LSC) of media samples, the assay is
terminated (9-
12 hours). Media is removed from all wells and placed in scintillation tubes.
Scintillate is
added and radioactive counts are acquired (LSC). To solubilize cell layers,
500 ~I of papain
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digestion buffer (0.2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DTT and 1 mg/m! papain)
is added to
each well. Plates with digestion solution are incubated at 60°C
overnight. The cell layer is
removed from the plates the next day and placed in scintillation tubes.
Scintillate is then
added and samples counted (LSC).
The percent of released counts from the Iota! present in each well is
determined.
Averages of the triplicates are made with control background subtracted from
each well. The
percent of compound inhibition is based on IL-1 samples as 0% inhibition (100%
of total
counts).
The compounds of the present invention that were tested all have ICso's in at
(east
one of the above assays of less than 100 uM preferably less than 100nM.
Certain preferred
groups of compounds possess differential selectivity toward the various MMP's
or ADAMs.
One group of preferred compounds possesses selective activity towards MMP-13
over MMP-
1. Another preferred group of compounds possesses selective activity towards
MMP-13 over
MMP-1, MMP-3 and MMP-7. Another preferred group of compounds possesses
selective
activity towards MMP-13 over MMP-1, MMP-3, MMP-7 and MMP-17. Another preferred
group
of compounds possesses selective activity towards MMP-13 over MMP-1, MMP-2,
MMP-3,
MMP-7, MMP-9 and MMP-14 Another preferred group of compounds possesses
selective
activity towards MMP-13 over MMP-12 and MMP-14.
For administration to mammals, including humans, for the inhibition of matrix
metalloproteinases, a variety of conventional routes may be used including
oral, parenteral (e.g.,
intravenous, intramuscular or subcutaneous), buccal, anal and topical. In
general, the
compounds of the invention (hereinafter also known as the active compounds)
will be
administered at dosages of about 0.1 and 25 mg/kg body weight of the subject
to be treated per
day, preferably from about 0.3 to 5 mg/kg. Preferably the active compound will
be administered
orally or parenterally. However, some variation in dosage will necessarily
occur depending on the
condition of the subject being treated. The person responsible for
administration will, in any
event, determine the appropriate dose for the individual subject.
The compounds of the present invention can be administered in a wide variety
of
different dosage forms, in general, the therapeutically effective compounds of
this invention are
present in such dosage forms at concentration levels ranging from about 5.0%
to about 70% by
weight.
For oral administration, tablets containing various excipients such as
microcrystalfine
cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine
may be employed
along with various disintegrants such as starch (and preferably corn, potato
or tapioca starch),
alginic acid and certain complex silicates, together with granulation binders
like
polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating
agents such as
magnesium stearate, sodium lauryl sulfate and talc are often very useful for
tabletting purposes.
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Solid compositions of a similar type may also be employed as fillers in
gelatin capsules; preferred
materials in this connection also include lactose or milk sugar as well as
high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are desired for
oral
administration, the active ingredient may be combined with various sweetening
or flavoring
agents, coloring matter or dyes and, if so desired, emulsifying and/or
suspending agents as well,
together with such diluents as water, ethanol, propylene glycol, glycerin and
various like
combinations thereof. In the case of animals, they are advantageously
contained in an animal
feed or drinking water in a concentration of 5-5000 ppm, preferably 25 to 500
ppm.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous
and
intravenous use) a sterile injectable solution of the active ingredient is
usually prepared.
Solutions of a therapeutic compound of the present invention in either sesame
or peanut oil or in
aqueous propylene glycol may be employed. The aqueous solutions should be
suitably adjusted
and buffered, preferably at a pH of greater than 8, if necessary and the
liquid diluent first
rendered isotonic. These aqueous solutions are suitable intravenous injection
purposes. The
oily solutions are suitable for intraarticular, intramuscular and subcutaneous
injection purposes.
The preparation of all these solutions under sterile conditions is readily
accomplished by
standard pharmaceutical techniques well known to those skilled in the art. In
the case of
animals, compounds can be administered intramuscularly or subcutaneously at
dosage levels of
about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a
single dose or up to 3
divided doses.
The active compounds of the invention may also be formulated in rectal
compositions
such as suppositories or retention enemas, e.g., containing conventional
suppository bases
such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active
compounds of
the invention are conveniently delivered in the form of a solution or
suspension from a pump
spray container that is squeezed or pumped by the patient or as an aerosol
spray presentation
from a pressurized container or a nebulizer, with the use of a suitable
propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
carbon dioxide or
other suitable gas. In the case of a pressurized aerosol, the dosage unit may
be determined
by providing a valve to deliver a metered amount. The pressurized container or
nebulizer may
contain a solution or suspension of the active compound. Capsules and
cartridges (made, for
example, from gelatin) for use in an inhaler or insufflator may be formulated
containing a
powder mix of a compound of the invention and a suitable powder base such as
lactose or
starch.
For topical ocular administration, direct application to the affected eye may
be employed
in the form of a formulation as eyedrops, aerosol, gels or ointments, or can
be incorporated into
collagen (such as poly-2-hydroxyethylmethacrylate and co-polymers thereof), or
a hydrophilic
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polymer shield. The materials can also be applied as a contact lens or via a
local reservoir or as
a subconjunctival formulation.
For intraorbital administration a sterile injectable solution of the active
ingredient is
usually prepared. Solutions of a therapeutic compound of the present invention
in an aqueous
solution or suspension (particle size less than 10 micron) may be employed.
The aqueous
solutions should be suitably adjusted and buffered, preferably at a pH between
5 and 8, if
necessary and the liquid diluent first rendered isotonic. Small amounts of
polymers can be
added to increase viscosity or for sustained release (such as cellulosic
polymers, Dextran,
polyethylene glycol, or alginic acid). These solutions are suitable for
intraorbital injection
purposes. The preparation of all these solutions under sterile conditions is
readily accomplished
by standard pharmaceutical techniques well known to those skilled in the art.
In the case of
animals, compounds can be administered intraorbitally at dosage levels of
about 0.1 to 50
mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to
3 divided doses.
As with the other routes of administration and corresponding dosage forms
described
herein, dosage forms intended for oral administration are also suitably
formulated to provide
controlled-, sustained- and/or delayed release of the active ingredient.
Typically, these would
include delayed-release oral tablets, capsules and multiparticulates, as well
as enteric-coated
tablets and capsules which prevent release and adsorption of the active
ingredient in the
stomach of the patient and facilitate enteric delivery distal to the stomach,
i.e., in the intestine.
Other typical oral dosage forms would include sustained-release oral t2blets,
capsules and
multiparticulates which provide systemic delivery of the active ingredient in
a controlled
manner over a prolonged period of time, e.g., a 24-hour period. Where rapid
delivery of the
active ingredient is required or desirable, a controlled-release oral dosage
form may be
prepared in the form of a fast-dissolving tablet, which would also preferably
include highly
soluble salt forms of the active ingredient.
The following Examples illustrate the preparation of the compounds of the
present
invention. Melting points are uncorrected. NMR data are reported in parts per
million (b) and
are referenced to the deuterium lock signal from the sample solvent
(deuteriochloroform
unless otherwise specified). Commercial reagents were utilized without further
purification.
Chromatography refers to column chromatography performed using 32-63 mm silica
gel and
executed under nitrogen pressure (flash chromatography) conditions. Room or
ambient
temperature refers to 20-25°C. All non-aqueous reactions were run under
a nitrogen
atmosphere for convenience and to maximize yields. Concentration at reduced
pressure or in
vacuo means that a rotary evaporator was used.
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General Experimentals
General Example:
Compounds of the formula I can be prepared by reacting the appropriate
compound
of formula III with a urea of the formula It (f.e., HZN(CO)-NHZ) in the
presence of a suitable
base, such as an alkoxide base, preferably sodium ethoxide, in a polar
solvent, such as an
alcoholic solvent, preferably ethanol, at a temperature of 20°C to the
boiling point of the
solvent, preferably 80°C for 15 minutes to 3 hours.
General Preparation:
A compound of formula 111 can be prepared by reacting an appropriate compound
of
formula IV with a suitable base, such as a tertiary amine base or a polymer
bound base,
preferably Amberlyst-400~ resin (hydroxide form), in .a polar solvent, such as
an alcoholic
solvent, preferably ethanol, at a temperature of about 0°C to about
50°C, preferably about
20°C, for a period of about 6 to about 36 hours.
The compound of formula IV can be prepared by reacting the appropriate
compound
of the formula VI with a compound of the formula V, which has a general
formula of L3-(A')-L4
or L3-(A'), in an aprotic solvent, preferably and aromatic hydrocarbon solvent
such as benzene
or toluene, at a temperature of about 40°C and the boiling point of the
solvent, preferably
about 80°C, for a period of about 1 to about 6 hours.
The compound of formula VI can be prepared by reacting the appropriate
compound
of the formula NHz-X-Y-Z-G with a compound of the formula VII, which is a 2-
halo malonate
ester, preferably 2-bromodiethyl malonate, in the presence of a suitable base,
such as a
tertiary amine base, preferably N,N-dimethylaniline, at a temperature of about
20°C to about
100°C, preferably about 80°C, for a period of about 4 to about
48 hours.
EXAMPLE 1:
1-f6-(4-BROMO-PHENOXY)-PYRIDIN-3-YLl-1.7,9-TRIAZA-SPIROf4.51DECANE-
2.6.8,10 TETRAONE:
Example Structure Molecular MS (APC1, mlz):
Number Weight [M+H]+
1 ~~/~ 445.238 445
N
O N O
'1
N
O
I '
8r
Sodium metal (29 mg, 1.26 mmof) was added to 1.3 mL of ethanol and stirred
until
homogeneous. of 1-[6-(4-Bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-
dicarboxylic acid diethyl
ester (0.20 g, 0.42 mmol) was added, followed by urea (75 mg, 1.26 mmol) and
the mixture
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was stirred for 5 minutes at 80 °C. The mixture was cooled to ambient
temperature, acidifiied
with 1 M hydrochloric acid and extracted 3x with ethyl acetate. The combined
organic phases
were dried over sodium sulphate, filtered and concentrated in vacuo. The
residue was purified
by silica gel chromatography (3:1 hexane-ethyl acetate), affording 28 mg of 1-
[6-(4-Bromo-
phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone as a
colorless solid.
HPLC Ref. Time: 2.201 min; MS (APCI, mlz): 436 [M-H]'; 438 [M+H]+.
Preparation 1:
2-(4-Bromo-phenoxy)-5-vitro-oyridine:
4-Bromophenol (5.5 g, 32 mmol) was added to 42 mL of 50% w/w aqueous sodium
hydroxide. After stirring for 30 min, 44 mL of toluene was added, followed by
2-chloro-5-
nitropyridine (5.0 g, 32 mmol) and tetrabutylammonium bromide (10 g, 32 mmol).
After
stirring for 1.5 hours at 23°C, the mixture was diluted with 200 mL of
water, neutralized with
12M aqueous hydrochloric acid and the mixture was extracted 3x with ether. The
combined
organic layers were dried aver MgS04, filtered and concentrated in vacuo,
affording 6 g of 2-
(4-bromo-phenoxy)-5-vitro-pyridine. 1 H NMR (CDCI3, 500 MHz): 9.05 (d, 1 H, J
= 3.5 Hz), 8.51
(dd, 1 H, J = 3.5, 9.5 Hz), 7.58 (d, 2H, J = 9.0 Hz), 7.08 (m, 3H) ppm. MS
(APCI, m/z): 295
[M+H]+.
6-(4-Bromo-phenoxy)-pyridin-3-ylamine:
A mixture of 2-(4-bromo-phenoxy)-5-vitro-pyridine (6.0 g, 22.7 mmol), 200 mL
of
methanol and 50 mg of Pt02 was shaken under 50 psi of HZ for 1 hour at 23
°C. The mixture
was filtered through a pad of celite~ and the filtrate was concentrated in
vacuo, affording 6 g of
6-(4-bromo-phenoxy)-pyridin-3-ylamine. 1 H NMR (CD30D, 500 MHz): 7.85 (d, 1 H,
J = 3.5 Hz),
7.48 (d, 2H, J = 8.5 Hz), 7.25 (dd, 1 H, J = 3.5, 9.0 Hz), 6.91 (d, 2H, J =
9.0 Hz), 6.80 (d, 1 H, J
= 9.0 Hz) ppm. MS (APCI, m/z): 265 [M+H]+.
Preparation 2:
1-f6-(4-Bromo-phenoxy)-pyridin-3-yll-pyrrolidine-2,2-dicarboxylic acid diethyl
ester:
A mixture of of 6-(4-bromo-phenoxy)-pyridin-3-ylamine (4.5 g, 16.9 mmol), 2-
bromodimethylmalonate (4.1 g, 17 mmol) and N,N-dimethylaniline (2.1 g, 17
mmol) was
stirred at 80 °C for 24 hours. The mixture was cooled to 23 °C,
diluted with 50 mL of benzene
and was treated with 7 mL of 2-bromopropionyl chloride. After stirring at
reflux for 3 h, the
mixture was cooled to 23 °C, concentrated in vacuo and was diluted with
750 mL of ethanol.
Amberlyst-400 (hydroxide form) resin (75 g) was added and the mixture was
stirred for 24
hours at 23 °C. The mixture was filtered and the resin was washed with
50 mL of methanol.
The filtrate was concentrated in vacuo and the residue was purified by silica
gel
chromatography (2:1 hexane-ethyl acetate), affording 6 g of 1-[6-(4-bromo-
phenoxy)-pyridin-3-
yf]-pyrrolidine-2,2-dicarboxylic acid diethyl ester. 1 H NMR (CDCI3, 500 MHz):
8.06 (d, 1 H, J =
2.5 Hz), 7.75 (dd, 1 H, J = 2.5, 8.0 Hz), 7.52 (d, 2H, J = 9.0 Hz), 7.04 (d,
2H, J = 8.5 Hz), 6.95
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(d, 1 H, J = 9.0 Hz), 4.22 (q, 4H, J = 7.0 Hz), 2.75 (m, 2H), 2.66 (m, 2H),
1.12 (t, 6H, J = 7.5
Hz) ppm. MS (APGI, mlz): 479 [M+H]+.
The following compounds were prepared according to methods analogous to that
of
Example 1, substituting where appropriate the correct pyridine and diester:
TABLE 1
Example Structure Molecular Weight MS (APCI, m/z):
Number [M+H]+
2 o~N a 384.327 385.1
HN~
I0I ,N 0
'\'N
0
F
3 0 398.354 399.1
o ~ _
N o
HN 0
i/ H
O
F
Example 4
4-f 5-(2,6,8,10-TETRAOXO-1.7.9-TRIAZA-SPI RO f 4.51 DEC-1-YL)-PYRIDIN-2-YLOXYI
BENZONITRILE:
Example Structure Molecular MS (APCI, m/z):
Number Weight [M+H]+
4 ~ 391.346 392.1
HN NH
O ~O
'N w ~ ~N
i o ~ /
0 N
Following the procedure for pyrimidinetrione formation outlined in Example 1,
reaction
of 1-[6-(4-Cyano-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid
diethyl ester (58 mg,
0.14 mmol) with urea (0.030 g, 0.5 mmol) in 0.5 mL of 1 M sodium ethoxide in
ethanol afforded
14.3 mg of 4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-
yloxy]-benzonitrile
as a colorless solid. 1 H NMR (CD30D, 500 MHz): 8.06 (d, 1 H, J = 3.5 Hz),
7.78 (m, 3H), 7.31
(d, 2H, J = 8.5 Hz), 7.13 (d, 1 H, J = 9.0 Hz), 2.75 (m, 2H), 2.68 (m, 2H)
ppm. MS (APCI, m/z):
390 [M-H]-; 392 [M+H]+.
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Preparation 1:
1- 6- 4-C ano- henox - ridin-3- I - rrolidine-2 2-dicarbox iic acid dieth I
ester:
A mixture of 1-j6-(4-bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxyVic
acid
diethyl ester (0.28 g, 0.53 mmoi), zinc cyanide (0.037 g, 0.32 mmol),
tetrakistriphenyiphosphine palladium (0) (0.024 g, 0.021 mmol) and 0.66 m!_ of
dimethylformamide was heated to 80 °C for 24 hours. An additional 37mg
of zinc cyanide and
24 mg of tetrakistriphenylphosphine palladium (0) was added and the mixture
was stirred at 80
°C for an additional 48 hours. After cooling to room temperature, the
mixture was diluted with
toluene and was washed with 2M ammonium hydroxide (twice), brine, dried over
sodium
sulphate, filtered and concentrated in vacuo. Purification by radial
chromatography {ethyl
acetate-hexanes, then methanol) afforded 58 mg of 1-j6-(4-Cyano-phenoxy}-
pyridin-3-yl]
pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1 H NMR
{CDCI3, 500 MHz):
8.07 (d, 1 H, J = 3.5 Hz), 7.80 (dd, 1 H, J = 2.5, 9.0 Hz}, 7.69 (d, 2H, J =
9.0 Hz}, 7.25 (d, 2H, J
= 9.0 Hz), 7.02 (d, 1 H, J = 9.0 Hz), 4.21 (q, 4H, J = 7.5 Hz), 2.74 (m, 2H),
2.66 (m, 2H), 1.19
(t, 6H, J = 7.0 Hz) ppm. MS (APCI, mlz): 424 jM~-H]+.
Example 5
1-ffi-(4-(1 3 410XAD1AZOL-2-YL-PHENOXY?-PYRIDIN-3-YL1-1.7.9-TRIAZA
SPIROj4.51DECANE-2.6,8,10-TETRAONE:
Example Structure Molecular MS (APCI, m/z):
Number Weight jM+H]+
5 O N 0 434.371 ~ 435.1
HN ~
N' '' O
0
'1
N
0
O
N
Following the procedure for pyrimidinetrione formation outlined in Example 1,
reaction
of 1-[6-{4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yI]-5-oxo-pyrrolidine-2,2-
dicarboxy(ic acid
diethyl ester (200 mg, 0.44 mmoi) with urea (0.080 g, 1.3 mmol) in 1.3 mL of 1
M sodium
ethoxide in ethanol afforded 25 mg of 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy}-
pyridin-3-yl]-1,7,9-
triaza-spiro[4.5]decane-2,6,8,10-tetraone as a colorless solid. 1H NMR (CD30D,
500 MHz):
9.02 (s, 1 H), 8.14 (d, 2H, J = 8.0 Nz), 8.06 (d, 1 H, J = 2.0 Hz}, 7.78 (dd,
1 H, J = 2.5, 9.0 Hz),
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7.35 (d, 2H, J = 9.0 Hz), 7.12 (d, 1 H, J = 9.0 Hz), 2.74 (m, 2H), 2.66 (m,
2H) ppm. MS (APCI,
m/z): 435 [M+H]+.
Preparation 1:
1-f6-(4-Carboxy-phenoxy)-pyridin-3-yll-5-oxo-pyrrolidine-2.2-dicarboxylic acid
diethyl
ester:
A mixture of 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-
dicarboxylic acid
diethyl ester (0.70 g, 1.64 mmol), sodium carbonate (0.26 g, 1.64 mmol) and
16.4 mL of 1:1
tent-butyl alcohol-water was treated with potassium permanganate (0.26 g, 1.64
mmol). After
stirring for 2 hours at room temperature, the mixture was quenched with sodium
sulfite,
acidified with 1 M hydrochloric acid and extracted 3x with ethyl acetate. The
combined organic
layers were dried over sodium sulphate, filtered and concentrated in vacuo,
affording 1-[6-(4-
Carboxy-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl
ester as a
colorless syrup (0.5 g). 1 H NMR (CDCI3, 500 MHz): 8.14 (d, 2H, J = 8.5 Hz),
8.10 (d, 1 H, J =
3.0 Hz), 7.80 (dd, 1 H, J = 2.5, 8.5 Hz), 7.24 (d, 2H, J = 8.0 Hz), 7.02 (d, 1
H, J = 9.0 Hz), 4.21
(q, 4H, J = 7.0 Hz), 2.74 (m, 2H), 2.66 (m, 2H), 1.21 (t, 6H, J = 7.5 Hz) ppm.
MS (APCI, m/z):
443 [M+H]+.
Preparation 2:
1-f6-(4-Hydrazinocarbonyl-phenoxy)-pyridin-3-yli-5-oxo-pyrrolidine-2.2-
dicarboxylic
acid diethyl ester:
A mixture of affording 1-[6-(4-Carboxy-phenoxy)-pyridin-3-yl]-5-oxo-
pyrrolidine-2,2-
dicarboxylic acid diethyl ester (0.4 g, 0.97 mmol), 1-hydroxybenzotriazole
hydrate (0.176 g, 1.3
mmol), 1,2-dichloroethane (0.25 g, 1.3 mmol) and 6 mL of methylene chloride
was stirred at
room temperature for 20 minutes. The mixture was treated with boc-hydrazide
(0.17 g, 1.3
mmol) and stirred at room temperature overnight. The mixture was diluted with
ethyl acetate,
washed with 1M hydrochloric acid, sodium bicarbonate solution, brine, dried
over sodium
sulphate, filtered and concentrated in vacuo. The residue was dissolved in 5
mL of 1:1 vlv
methylene chloride-trifluoroacetic acid, stirred for 1 hours at ambient
temperature and was
concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with
1 M sodium
hydroxide, brine, dried over sodium sulphate, filtered and concentrated,
affording 1-[6-(4-
Hydrazinocarbonyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic
acid diethyl ester
(0.20 g) as a colorless syrup. HPLC: 2.770 min.
Preparation 3:
1-f6-(4-f 1.3.41oxadiazol-2-yl-phenoxy)-pyridin-3-yll-5-oxo-pyrrolidine-2.2-
dicarboxylic
acid diethyl ester:
A mixture of affording 1-[6-(4-Hydrazinocarbonyl-phenoxy)-pyridin-3-yl]-5-oxo-
pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.44 mmol),
trimethylorthoformate (0.1
mL, 0.91 mmol) and 1 mL of xylenes was refluxed for 24 hours. The mixture was
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concentrated in vacuo, affording 1-[6-(4-[1,3,4joxadiazol-2-y!-phenoxy)-
pyridin-3-ylj-5-oxo-
pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g) as a colorless syrup.
'MS (APCI, m/z):
467.2 [M+Hj+.
Example 6
~6-(4-ETHYL-PHENOXY)-PYRIDIN-3-YLl-1.7.9-TRIAZA-SPIROt4.51DECANE-
2.6.8.10-TETRAONE:
Example Structure Molecular MS (APCI, mlz}:
Number Weight [M+H]+
6 ~ 394.39 395.3
NN ~~~~~
N O
0
r~
0
i
CHI
Following the procedure for pyrimidinetrione formation outlined in Example 1,
reaction
of 1-[6-(4-ethyl-phenoxy)-pyridin-3-ylj-5-oxa-pyrroiidine-2,2-dicarboxylic
acid diethyl ester (200
mg, 0.41 mmol) with urea (0.088 g, 1.4 mmol) in 1.4 mL of 1 M sodium ethoxide
in ethanol
afforded 25 mg of 1-[6-(4-[1,3,4joxadiazol-2-yl-phenoxy)-pyridln-3-yl]-1,7,9-
triaza
spiro[4.5jdecane-2,6,8,10-tetraone as a colorless solid. 1 H NMR (CDCI3, 500
MHz): 8.73 (bs,
2H), 7.97 (d, 1 H, J = 2.0 Hz}, 7.78 (d, 1 H, J = 8.5 Hz), 7.22 (d, 2H, J =
8.5 Hz}, 7.05 (d, 2H, J
= 9.0 Hz}, 6.91 (d, 1 H, J = 9.0 Hz), 2.81 (q, 2H, J = 7.5 Hz}, 2.74 (m, 2H},
2.64 (m, 2H}, 1.26
(t, 3H, J = 8.0 Hz} ppm.
Preparation 1:
1- 6~-{4-Ethyl-phenoxyl-pyridin-3- r~l -5-oxo-pKrrolidine-2 2-dicarboxylic
acid diethyl
ester:
A mixture of 1-[6-(4-vinyl-phenoxy)-pyridin-3-yfj-pyrroiidine-2,2-dicarboxyiic
acrd
diethyl ester (0.20 g}, 50 mg of 10% palladium on charcoal and 20 mL of ethyl
acetate was
shaken under 50 psi of hydrogen gas for 2 hours. 'ihe mixture was filtered and
concentrated
in vacuo, affording 0.20 g of 1-[6-(4-ethyl-phenoxy)-pyridin-3-ylj-5-oxo-
plrralidine-2,2-
dicarboxylic acid diethyl ester as a colorless syrup. 1 H NMR (CDGI3, 500
MHz): 8.08 {d, 1 H, J
= 2.5 Hz), 7.73 (dd, 1 H, J = 2.5, 8.5 Hz}, 7.24 (d, 2H, J = 7.5 Hz), 7.05 {d,
2H, J = 8.0 Hz),
6.89 (d, 1 H, J = 9.0 Hz}, 4.21 (q, 4H, J = 7.0 Hz), 2.74 (m, 2H}, 2.65 (m,
4H}, 1.27 {t, 3H, J =
8.0 Hz), 1.20 {t, 6H, J = 7.5 Hz) ppm.
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Example 7
N-d4-!5-(2 6,8 10-TETRAOXO-1 7 9-TRIAZA-SPIR0~4.51DEC-1-YL)-PYRIDIN-2-
YLOXYI-BENZYL~-ACETAMIDE:
ExampleStructure Molecular MS (APCI,
Number Weight m/z):
[M+H]+
7 o~r"~ 0 437.415 438.2
~%
HN~
~
N ~
'
1
\ N
0 \
I / N
CH
"
,
~
0
A mixture of 1-{6-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-pyridin-3-yl}-
pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.52 mmol) and 2 mL of a 1:1
v/v solution of
trifluoroacetic acid in methylene chloride was stirred for 1 hours at ambient
temperature and
was then concentrated in vacuo. The residue was dissolved in 2.6 mL of
methylene chloride
and was treated with MMP-resin (polymer bound N-methyl morpholine-type base,
0.86 g, 1.75
mmol) and was treated with acetyl chloride (0.055 g, 0.7 mmol). After shaking
for 24 h, the
mixture was filtered and the resin was washed with methylene chloride. The
combined
filtrates were concentrated in vacuo, dissolved in 1.5 mL of 1 M sodium
ethoxide in ethanol and
treated with 94 mg of urea. After stirring for 10 minutes at 80 "C, the
mixtures were treated
with 2 g of a polystyrene-bound sulfonic acid resin, filtered and the resin
was washed with 10
mL of 2M ammonia in methanol. The combined filtrates were concentrated in
vacuo and
purified by reverse-phase chromatography (acetonitrile-water-trifluoroacetic
acid eluent)
followed by radial chromatography (10% methanol-methylene chloride),
affording: N-{4-[5-
(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy]-benzyl}-
acetamide as a
colorless solid. HPLC Ret. time: 2.201 min; MS (APCI, m/z): 436 [M-H]-; 438
[M+H]+.
Preparation 1:
1-f6-l4-vinyl-ohenoxvl-ovridin-3-vll-ovrrolidine-2,2-dicarboxvlic acid diethyl
ester:
A mixture of 1-[6-(4-bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic
acid
diethyl ester (5.8 g, 12.2 mmol), vinyltributyltin (3.9 mL, 12.3 mmol),
tetrakistriphenylphosphine
palladium (0) (0.60 g, 0.52 mmol) and 24 mL of toluene was heated to reflux
for 1 hour. After
cooling to room temperature, the mixture was concentrated in vacuo and
purified by silica gel
chromatography (Flash 40, 20% - 50% ethyl acetate-hexanes), affording 4.8 g of
1-[6-(4-Vinyl-
phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a
colorless syrup.
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Preparation 2:
1-(6-(4-Formyl-phenoxyl-pyridin-3-yil-oyrrolidine-2 2-dicarboxylic acid
diethyl ester:
A mixture of 1-[6-(4-Vinyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic
acid
diethyl ester (4.8 g, 11.3 mmol), sodium metaperiodate (4.8 g, 22 mmol),
osmium tetroxide
(10 mg) and 2:1 dioxane-water (189 mL) was stirred for 6 hours at ambient
temperature. The
mixture was quenched with sodium sulfite, diluted with water and extracted 3x
with ethyl
acetate. The combined organic phases were dried over sodium sulphate, filtered
and
concentrated in vacuo,affording 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-
pyrrolidine-2,2-
dicarboxylic acid diethyl ester as a colorless syrup (4.6 g).
Preparation 3:
1 ~6-j4-(tert-Butoxycarbonylamino-methyl)-phenoxyl-pyridin-3-yi}-pyrrofid':~~e-
2.2-
dicarboxylic acid diethyl ester:
A mixture of 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-
dicarboxylic acid
diethyl ester (0.1 g, 0.24 mmol), tent-butoxycarbonylamide (0.083 g, 0.71
mmol), triethylsilane
(0.11 mL, 0.083 g, 0.71 mmol) and acetonitrile (1 mL) was treated with
trifluoroacetic acid
(0.035 mL, 0.46 mmol) and stirred for 48 at ambient temperature. The mixture
was diluted
with ethyl acetate, washed with saturated sodium bicarbonate solution, brine,
dried over
sodium sulphate, filtered and concentrated in vacuo, affording 1-{6-[4-(tert
Butoxycarbonylamino-methyl)-phenoxy]-pyridin-3-yl}-pyrrolidine-2,2-
dicarboxylic acid diethyl
ester as a colorless syrup.
The following compounds were prepared according to methods analogous to that
of
Example 7, submitting where appropriate the correct pyridine and diester:
TABLE 2
ExampleStructure Molecular MS (APCI,
Number Weight m/z):
[M+H]''
8 451.443 452.2
H
OvN O
'
~
~
N
N
~
~
0 N 0
~/
'\'N
T
O
I / N
~u,,
O
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ExampleStructure Molecular MS (APCf,
Weight m/z):
Number ~M+Hl+
9 o~r"~ 0 465.47 466.2
~
HN~
~
I0 N 0
\ N
O
NCH
I
,
/
''
0
o~r"~ 0 479.497 480.2
~
HN~
tt
O ~N~iO
\ N
0 \
/'\~
~I ~H
~N
~
~CH~
0
11 o~N.~o 477.481 478.4
~
HN~
~
O N 0
N
O
I H /~,
~N~
T
f
~ ~
0
Example 12
1-f6-(4-PYRAZOL-1-YLMETHYL-PHENOXY)-PYRIDIN-3-YLl-1,7,9-TRIAZA
SPIROf4.51DECANE-2.6.8,10-TETRAONE:
Example Structure Molecular Weight MS (APCI, m/z):
Number [M+H]+
12 H 446.43 447.2
OYN 0
HlN ~,
O N- ' O
i 1l
w N
O ~ N
NJ
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Following the procedure for pyrimidinetrione formation outlined in Example 1,
reaction
of 5-oxo-1-[6-(4-pyrazol-1-ylmethyl- phenoxy}-pyridin-3-yl]-pyrrolidine-2,2-
dicarboxylic acid
diethyl ester {0.2 g, 0.4 mmol} with urea (0.074 g, 1.2 mmol) in 1.2 ml of 1 M
sodium ethaxide
in ethanol afforded 6 mg of 1-[6-(4-Pyrazoi-1-ylmethyl-phenoxy)-pyridin-3-yl]-
1,7,9-triaza-
spiro[4.5]decane-2,6,8,10-tetraone as a colorless solid. 'H NMR (CD30D, 500
MHz): 7.99 (d,
1 H, J = 2.5 Hz}, 7.72 {m, 2H), 7.53 {d, 1 H, J = 2.5 Hz), 7.29 (d, 2H, J =
8.5 Hz}, 7.10 (d, 2H, J
= 8.5 Hz), 6.97 (d, 1 H, J = 8.5 Hz), 6.35 (t, 1 H, J = 2.0 Hz), 5.38 (s, ZH),
2.75 (m, 2H}, 2.65
{m, 2H} ppm. MS (APCI, mlz): 447.2 [M+H]+.
Preparation 9 ;
1-L6-~4-Hydroxymethyl-phenoxy)-pyridin-3-y!1-5-oxa-pyrroiidine-2 2-
dicarboxylic acid
diethyl ester:
1-[6-{4-Hydroxymethyi-phenoxy)-pyridin-3-yl]-5-oxo-pyrralidine-2,2-
dicarboxyiic acid
diethyl ester: To a solution of 1-[6-(4-formyl-phenoxy}-pyridin-3-yl]-
pyrolidine-2,2-dicarboxylic
acid diethyl ester (1.0 g, 2.3 mmol) in 30 ml of ethanol was added sodium
barohydride {0.090
g, 2.3 mmol) at 0 °C. After stirring for 3 hours, the mixture was
concentrated in vacuo, diluted
with ethyl acetate and water, and the aqueous Layer was cautiously acidified
with 1 M
hydrochloric acid, then neutralized with saturated aqueous sodium bicarbonate.
The mixture
was extracted three times with ethyl acetate, and the combined organic layers
were dried over
sodium sulfate, filtered and concentrated in vacuo, affording 0.80 g
(80°I°) of 1-[6-(4-
hydroxymethyi-phenoxy}-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid
diethyl ester as a
colorless syrup.'H NMR (CDCI3, 400 MHz): 8.04 (d, 1 H, J = 2.4 Hz), 7.72 (dd,
1 H, J = 2.4, 8.8
Hz), 7.40 (d, 2H, J = 8.8 Nz}, 7.12 (d, 2H, J = 8.4 Hz), 6.91 (d, 1 H, J = 8.8
Hz), 4.70 (s, 2H),
4.19 (q, 4H, J = 7.6 Hz}, 2.75 (m, 2H}, 2.65 {m, 2H}, 1.18 (t, 6H, J = 7.2 Hz)
ppm. MS {APC1,
m/z}: 429.1 [M+H]+.
Preparation 2:
1-I6-t4-Bromomethyl-phenoxy)-pyridin-3-yl]-5-oxo-pvrrolidine-2.2-dicarboxylic
acid diethyl ester:
To a solution of 1-[6-{4-hydroxymethyl-phenoxy)-pyridin-3-yf]-5-oxo-
pyrrofidine-2,2
dicarboxylic acid diethyl ester (0.80 g, 1.9 mmol} in 9.4 ml of methylene
chloride was added
triethyiamine (0.46 ml, 0.33 g, 3.3 ml). After cooling to -40 °C, the
mixture was treated with
methanesulfonyf chloride (0.20 ml, 0.30 g, 2.61 mmol). After stirring for 1
hour, an additional
0.10 ml of methanesulfonyl chloride and 0.4 ml of triethylamine were added,
and stirring was
continued for 1 hour. A solution of anhydrous lithium bromide {1.6 g, 19 mmol,
flame dried
under vacuum before use) in tetrahydrofuran (20 ml) was added via cannula, and
the mixture
was warmed to room temperature and stirred for 2 hours. The mixture was
diluted with ethyl
acetate, and the organic phase was washed with water, dried over sodium
sulfate, filtered and
concentrated in vacuo. The residue was filtered through a pad of silica gel
eluting with 1:1
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ethyl acetate-hexanes, affording 0.65 g of 1-[6-(4-bromomethyl-phenoxy}-
pyridin-3-yl]-5-oxo
pyrrolidine-2,2-dicarboxyiic acid diethyl ester as a colorless syrup.'H NMR
(CDCi3, 500 MHz):
8.07 {d, 1 H, J = 3.0 Hz), 7.76 (dd, 1 H, J = 2.5, 8.5 Hz), 7.44 (d, 2H, J =
8.5 Hz), 7.12 (d, 2H, J
= 8.0 Hz), fi.95 (d, 1 H, J = 9.0 Hz}, 4.53 {s, 2H), 4.22 {q, 4H, J = 7.0 Hz),
2.75 (m, 2H), 2.65
(m, 2H), 1.20 (t, 6H, J = 7.0 Hz) ppm.
Preparation 3:
5-Oxo-1-j6-(4-pyrazol-1-ylmethyi-phenoxy)-pyridin-3-Yf1-twrrolidine-2.2-
dicarbox rlic
acid diethyl ester;
To a solution of 1-[6-(4-bromomethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-
2,2
dicarboxylic acid diethyl ester (0.2 g, 0.4 mmoi} in 0.8 mL of
dimethylformamide was added
pyrazole (0.056 g, 0.82 mmoi) and potassium carbonate (0.11 g, 0.82 mmol).
After stirring for
24 hours at 50 °C, the mixture was diluted with wafer, extracted three
times with ethyl acetate,
and the combined organic phases were dried over sodium sulfate, filtered and
concentrated in
vacuo, affording the crude product as a colorless syrup that was used directly
in the next step.
MS (APCl, mIz): 479.2 [M+H]''.
While the invention has bean described and illustrated with reference to
certain
particular embodiments thereof, those skilled in the art will appreciate that
various
adaptations, changes, modifications, substitutions, deletions, or additions of
procedures and
protocols may be made without departing from the spirit and scope of the
invention. For
example, effective dosages other than the particular dosages as set forth
herein above may
be applicable as a consequence of variations in the responsiveness of the
mammal being
treated for any of the indications with the compounds of the invention
indicated above.
Likewise, the specific pharmacological responses observed may vary according
to and
depending upon the particular active compounds selected or whether there are
present
pharmaceutical carriers, as well as the type of formulation and mode of
administration
employed and such expected variations or differences in the results are
contemplated in
accordance with the objects and practices of the present invention. !t is
intended, therefore,
that the invention be defined by the scope of the claims which follow and that
such claims be
interpreted as broadly as is reasonable.
