-1A-
The instant application is divided out of Indian Patent Application No.
2102/KOLNP/2005.
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Application No. 60/466,567, filed
April 30, 2003 and U.S. Application No._____________filed April 28, 2004, the
entire disclosures of both are incorporated herein by reference.
BACKGROUND
This invention relates to ligands for the estrogen receptor (ER), and
specifically relates to 2-cyanopropanoic acid amide and ester derivatives useful for
the treatment of the inflammatory component of diseases and are particularly useful
in treating atherosclerosis, myocardial infarction, congestive heart failure,
inflammatory bowel disease, arthritis, type II diabetes, and autoimmune diseases
such as multiple sclerosis and rheumatoid arthritis.
The ability of ligands for the estrogen receptor to inhibit inflammatory gene
expression causing a reduction of cytokines, chemokines, adhesion molecules and
inflammatory enzymes provides a means to treat the inflammatory component of
diseases such as atherosclerosis, myocardial infarction (Ml), congestive heart failure
(CHF), inflammatory bowel disease and arthritis. Other potential therapeutic
indications for these type of molecules include type II diabetes (Cefalu, J Womens
Health & Gender-based Med., 2001, 10, 241 & Yuan et al.f Science, 2001, .293,
1673), osteoarthritis (Pelletier et al., Arthr. & Rheum., 2001, 44:1237 and Felson et
a!., Curr Opinion Rheum, 1998, 10, 269) asthma (Chin-Chi Lin et.ai., Immunol. Lett.,
2000, 73, 57), Alzheimer's disease (Roth, A. et. al.,; J. Neurosci. Res., 1999, 57,
399) and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
A common component of these chronic inflammatory conditions is
polymorphonuclear leukocyte and monocyte infiltration into the site of damage
through increased expression of cytokines and adhesion molecules responsible for
their recruitment. Overproduction of the cytokine interleukin (lL-6) has been
associated with states of chronic inflammation (Bauer M. A., Herrmann F., Ann.
Hematol., 1991, 62, 203). Synthesis of the IL-6 gene is induced by the transcription
factor, nuclear factor KB (NF-KB). Interference at this step in the inflammatory
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process can effectively regulate the uncontrolled proliferative process that occurs in
these chronic conditions.
In endothelial cells, 17(3-estradiol (E2) inhibits IL-1P induced NF-KB reporter
activity and IL-6 expression in an ER dependent fashion (Kurebayashi S. et. al., J.
Steroid Biochem. Molec. Biol., iS97, 60, ii). This correlates with anti-inflammatory
action of E2 in vivo as confirmed in different animal models of inflammation. In
models of atherosclerosis, E2 was shown to protect endothelial cell integrity and
function and to reduce leukocyte adhesion and intimal accumulation (Adams, M. R.
et al., Arterio., 1990, 1051, Sullivan, T. R. et al. J. Clin. Invst, 1995, 96, 24S2,
Nathan, L. et. al., Circ. Res., 1999, 85, 377). Similar effects of estrogen on the
vascular wall have also been demonstrated in animal models of myocardial
infarction (Delyani, J. A. et al., J. Molec. Cell. Cardiol., 1996, 28, 1001) and
congestive heart failure. Clinically, estrogen replacement therapy (ERT) has been
demonstrated to reduce the risk of mortality in patients with both CHF (Reis et. al., J.
Am. Coll. Cardio., 2000, 36, 529) and Ml (Grodstein, F. et. al., Ann. Int. /Wed., 2000,
133, 933, Alexander et. al., J. Am. Coll. Cardio., 2001, 38, 1 and Grodstein F. et. al.,
Ann. Int. Med, 2001, 735,1). In ERT, clinical studies demonstrated an influence of
E2 on the decrease in the production of p-amyloid 1-42 (Ap42), a peptide central for
the formation of senile plaques in Alzheimer's disease (Schonknecht, P. et. al.,
Neurosci. Lett., 2001, 307, 122).
However, 17-β-estradiol also strongly stimulates creatine kinase expression.
Thus, in ERT some potential unwanted side effects, such as an increase risk of
cardiovascular events in the first year of use, have been demonstrated (Hulley, S. et.
al., J. Am. Med. Assoc, 1998, 280, 605) as well as proliferative effects on uterine
and breast tissue.
SUMMARY OF THE INVENTION
In one embodiment, the invention is directed to compounds of formula I:
WO 2004/099150 PCT/US2004/013360
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wherein
B and D are independently CH or N, provided that B and D are not both N;
R1 R1a, R2 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon
atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl,
alkylthio of 1-6 carbon atoms, CF3, -OCF3, -NR5R6, or hydroxy;
or R1 and R2 together with carbon atoms to which they are attached form a
fused benzene ring, the naphthalene ring so formed being optionally substituted by
halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano,
thioalkyl of 1-6 carbon atoms, aryl, alkylthio of 1-6 carbon atoms, CF3, -OCF3,
-NR5R6, or hydroxy;
R3 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms
in the alkyl moiety, alkenyl of 2-7 carbon atoms, cycloalkylmethyl of 3-8 carbon
atoms in the cycloalkyl moiety, arylalkoxyalkyl, alkoxyalkyl, dialkylaminoalkyl having
1-6 carbon atoms in the alkyl moieties, or Het-alkyl having 1-6 carbon atoms in the
alkyl moiety;
WO 2004/099150 PCT/US2004/013360
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or A, wherein any phenyl ring in R4 is optionally substituted with R7;
R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl,
arylalkyl having 1-6 carbon atoms in the alkyl moiety, Het-alkyl having 1-6 carbon
atoms in the alkyl moiety, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6
carbon atoms, or cycloalkyl of 3-8 carbon atoms;
R7 is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, nitro,
cyano, alkylthio of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, CF3, or-OCF3;
R5 is alkyl of 1 -6 carbon atoms;
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A is hydrogen, cycloalkyl of 3-8 carbon atoms, alkoxyalkyl having 1-6 carbon
atoms in the alkyl and alkoxy moieties, dialkylaminoalkyl having 1-6 carbon atoms in
the alkyl moieties, aryl, Het, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6
carbon atoms, Het-alkyl having 1-6 carbon atoms in the alkyl moiety, arylalkyl having
1-6 carbon atoms in the alkyl moiety, or

W is aryl, -Y-aryl, or Het or -Y-Het;
Y is -O- or -IMH-;
Z is O or S;
Het is a saturated, unsaturated, or partially unsaturated heterocyclic ring or
ring system having 4-12 ring atoms and 1-3 heteroatoms selected from N, O, or S,
that may be optionally substituted with 1-3 R7 groups;
aryl is an aromatic ring or ring system having 6-14 carbon atoms in the ring or
ring system, that may be optionally substituted with 1-3 R7 groups;
with the proviso that at least one of the R1 R1a, or R2 groups is not hydrogen;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention is directed to pharmaceutical
compositions, comprising:
a pharmaceutical carrier; and
a compound of formula I or a pharmaceutically acceptable salt thereof.
In further embodiments, the invention is directed to methods of treating the
inflammatory component of a disease, comprising the step of:
administering an effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
The disease include atherosclerosis, myocardial infarction, congestive heart failure,
inflammatory bowel disease, arthritis, type II diabetes, and autoimmune disease
(such as multiple sclerosis or rheumatoid arthritis).
In yet further embodiments, the invention is directed to processes for
preparing a compound of formula I.
In yet other embodiments, the invention is directed to process for preparing a
substantially pure enantiomer of a compound of formula I.
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DESCRiPTION OF THE INVENTION
The invention provides substituted 2-cyanopropanoic acid amide and ester
derivatives represented by formula I that are useful for the treatment of the
inflammatory component of diseases and are particularly useful in treating
atherosclerosis, myccardial infarction, congestive heart failure, inflammatory bowel
disease, arthritis, type II diabetes, and autoimmune diseases such as multiple
sclerosis and rheumatoid arthritis.
This invention provides compounds of formula I having the structure

wherein
B and D are independently CH or N, provided that B and D are not both N;
R1 R1a, R2 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon
atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl,
alkylthio of 1-6 carbon atoms, CF3, -OCF3, -NR5R6, or hydroxy;
or R1 and R2 together with carbon atoms to which they are attached form a
fused benzene ring, the naphthalene ring so formed being optionally substituted by
halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano,
thioalkyl of 1-6 carbon atoms, aryl, alkylthio of 1-6 carbon atoms, CF3, -OCF3,
-NR5R6, or hydroxy;
R3 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms
in the alkyl moiety, alkenyl of 2-7 carbon atoms, cycloalkylmethyl of 3-8 carbon
atoms in the cycloalkyl moiety, arylalkoxyalkyl, alkoxyalkyl, dialkylaminoalkyl having
1-6 carbon atoms in the alkyl moieties, or Het-alkyl having 1-6 carbon atoms in the
alkyl moiety;
WO 2004/099150 PCT/US2004/013360

or A, wherein any phenyl ring in R4 is optionally substituted with R7,
R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl,
arylalkyl having 1-6 carbon atoms in the alkyl moiety, Het-alkyl having 1-6 carbon
atoms in the alkyl moiety, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6
carbon atoms, or cycloalkyl of 3-8 carbon atoms;
R7 is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, nitro,
cyano, alkylthio of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, CF3, or-OCF3;
R8 is alkyl of 1-6 carbon atoms;
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A is hydrogen, cycloalkyl of 3-8 carbon atoms, alkoxyalkyl having 1-6 carbon
atoms in the alkyl and alkoxy moieties, dialkylaminoalky! having 1-6 carbon atoms in
the alkyl moieties, aryl, Het, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6
carbon atoms, Het-alkyl having 1-6 carbon atoms in the alkyl moiety, arylalkyl having
i-S carbon atoms in the alkyl moiety, or

W is aryl, -Y-aryl, or Het or -Y-Het;
Y is -O- or -NH-;
Z is O or S;
Het is a saturated, unsaturated, or partially unsaturated heterocyclic ring or
ring system having 4-12 ring atoms and 1-3 heteroatoms selected from N, 0, or S,
that may be optionally substituted with 1-3 R7 groups;
aryl is an aromatic ring or ring system having 6-14 carbon atoms in the ring or
ring system, that may be optionally substituted with 1-3 R7 groups;
with the proviso that at least one of the R1 R1a, or R2 groups is not hydrogen;
or a pharmaceutically acceptable salt thereof.
The term "alkyl", employed alone, is defined herein as, unless otherwise
stated, either a (C1-C8) straight chain or branched-chain monovalent saturated
hydrocarbon moiety. It is preferred that the alkyl moiety contains 1-6 carbon atoms.
Examples of saturated hydrocarbon alkyl moieties include, but are not limited to,
chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,
isobutyl, sec-butyl; higher homologs such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and
the like.
The term "cycloalkyl", employed alone or in combination with other terms, is
defined herein as, unless otherwise stated, a monocyclic, bicyclic, tricyclic, fused,
bridged, or spiro monovalent saturated hydrocarbon moiety of 3-8 carbon atoms.
Any suitable ring position of the cycloalkyl moiety may be covalently linked to the
defined chemical structure. Examples of cycloalkyl moieties include, but are not
limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl,
adamantyl, spiro[4.5]decanyl, and homologs, isomers, and the like.
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The terms "halo" or "halogen", employed alone or in combination with other
terms, is defined herein as, unless otherwise stated, a fluorine, chlorine, bromine, or
iodine atom.
The term "an/I", employed alone or in combination with other terms, is defined
herein as, unless otherwise stated, an aromatic carbocyclic moiety of up to 14
carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up
to three rings) fused together or linked covalently. Any suitable ring position of the
aryl moiety may be covalently linked to the defined chemical structure. Examples of
an/I moieties include, but are not limited to, chemical groups such as phenyl, 1-
naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl,
phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and
the like.
The term "arylalkyl", employed alone or in combination with other terms, is
defined herein as, unless otherwise stated, an aryl, as herein before defined,
suitably substituted on any open ring position with an alkyl moiety wherein the alkyl
chain is either a (C1-C6) saturated hydrocarbon moiety. Examples of arylalkyl
moieties include, but are not limited to, chemical groups such as benzyl, 1-
phenylethyl, 2-phenylethyl, diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl,
fluorenylmethyl, and homologs, isomers, and the like.
The term "Het", employed alone or in combination with other terms, is defined
herein as, unless otherwise stated, an heterocyclic ring system having 4-14 ring
atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three
rings) fused together or linked covalently. The rings may contain from one to four
hetero atoms selected from nitrogen (N), oxygen (O), and sulfur (S), wherein the
nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are
optionally quarternized. Any suitable ring position of the heteroaryl moiety may be
covalently linked to the defined chemical structure. Examples of unsaturated Het
moieties include, but are not limited to, heterocycles such as furan, thiophene,
pyrrole, N-methylpyrrole, pyrazole, N-methyipyrazole, imidazole, N-methylimidazole,
oxazole, isoxazole, thiazole, isothiazole, 1H-tetrazole, 1 -methyltetrazoie, 1,3,4-
oxadiazole, 1H-1,2,4-triazole, i-methy!-1,2,4-triazole 1,3,4-triazole, 1-methyl-1,3,4-
triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzoxazole, benzisoxazole,
benzothiazole, benzofuran, benzothiophene, thianthrene, dibenzo[b,d]furan,
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dibenzo[b,d]thiophene, benzimidazole, N-methylbenzimidazole, indole, indazole,
quinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, 9H-carbazole, p-
carboline, and the like.
Het, as defined herein, also includes saturated or partial saturated
heterocyclic rings of 4-14 ring atoms, and 1-4 heteroaioms selected from N, O, and
S. Examples of saturated or partially saturated heteroaryl moieties include, but are
not limited to, chemical groups such as azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,
piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl,
dihydrobenzoxazolyl, dihydrobenzoimidazolonyl, dihydrofuranyl, dihydroimidazolyl,
dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,
dihydrooxazolyl, dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl,
dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl,
dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl,
dihydroazetidinyl, dihydro-1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
The term "Het-alkyl", employed alone or in combination with other terms, is
defined herein as, unless otherwise stated, a heteroaryl, as herein before defined,
suitably substituted on any open ring position with an alkyl moiety, wherein the alkyl
chain is either a (C1-C6) straight or branched-chain saturated hydrocarbon moiety.
Examples of heteroarylalkyl moieties include, but are not limited to, chemical groups
such as furanylmethyl, thienylethyl, indolylmethyl, and the like.
The term "hydroxyalkyl", employed alone or in combination with other terms,
is defined herein as, unless otherwise stated, a (C1-C6) straight chain hydrocarbon,
terminally substituted with a hydroxyl group. Examples of hydroxyalkyl moieties
include chemical groups such as -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, and higher
homologs. Similarly, dihydroxyalkyl indicates an alkyl moiety that is substituted by
two hydroxyl groups.
The term "alkoxy", employed alone or in combination with other terms, is
defined herein as, unless otherwise stated, either a (C1-C6) straight chain or
branched-chain hydrocarbon covalently bonded to an oxygen atom. Examples of
alkoxy moieties include, but are not limited to, chemical groups such as methoxy,
ethoxy, isopropoxy, sec-butoxy, tert-butoxy, and homologs, isomers, and the like.
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The term "alkylthio", employed alone or in combination with other terms, is
defined herein as, unless otherwise stated, either a (C1-C6) straight or branched-
chain hydrocarbon covalently bonded to a sulfur atom. Examples of aikylthio
moieties include, but are not limited to, chemical groups such as methylthio,
eihylthio, isopropyllhio, sec-butylihio, tert-butylthio, and homologs. isomers, and the
like.
The term "thioalkyl", employed alone or in combination with other terms, is
defined herein as, unless otherwise stated, a sulfhydryl group covalently bonded to
either a (C1-C6) straight or branched-chain hydrocarbon. Examples of thioalkyl
moieties include, but are not limited to, chemical groups such as thiomethyl,
thioethyl, thioisopropyl, and homologs, isomers, and the like.
The term "alkoxyalkyl" is defined herein as, unless otherwise stated, an alkyl,
as herein before defined, substituted by an alkoxy group, as herein before defined.
An example of an alkoxyalkyl moiety is methoxyethyl.
The term "arylalkoxyalkyl" is defined herein as, unless otherwise stated, an
alkyl, as herein before defined, substituted by an alkoxy group, as herein before
defined, wherein the alkoxy is substituted by an aryl, as herein before defined. An
example of an arylalkyloxyalkyl moiety is phenylmethoxymethyl.
The term "dialkylaminoalkyl" is defined herein as, unless otherwise stated, an
alkyl as herein before defined, substituted by an amino group independently
disubstituted with alkyl, as herein before defined. An example of a dialkylaminoalkyl
group is dimethylaminoethyl.
Unless otherwise indicated, each of the above terms (e.g., alkyl, aryl, Het) are
meant to include unsubstituted, monosubstituted, and polysubstituted forms of the
indicated radical or moiety. As described above, the moiety R7 represents typical
substituents for the radicals or moieties.
The compounds of the present invention may contain an asymmetric atom,
and some of the compounds may contain one or more asymmetric atoms or centers,
which may thus give rise to optical isomers (enantiomers) and diastereomers. While
shown without respect to the stereochemistry in Formula (I), the present invention
includes such optical isomers (enantiomers) and diastereomers (geometric isomers);
as well as the racemic and resolved, enantiomerically pure R and S stereoisomers;
as well as other mixtures of the R and S stereoisomers and pharmaceutically
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acceptable salts thereof. Optical isomers may be obtained in pure form by standard
procedures known to those skilled in the art, and include, but are not limited to,
diasteromeric salt formation, kinetic resolution, and asymmetric synthesis. It is also
understood that this invention encompasses all possible regioisomers, and mixtures
thereof, which may be obtained in pure form by standard separation procedures
known to those skilled in the art, and include, but are not limited to, column
chromatography, thin-layer chromatography, and high-performance liquid
chromatography.
The compounds of the present invention may contain isotopes of atoms for
diagnostic, therapeutic, or metabolic purposes. Such isotopes may or may not be
radioactive.
The compounds of this invention include racemates, enantiomers, geometric
isomers, or pro-drugs of the compounds shown by formula I.
Pharmaceutically acceptable salts of the compounds of formula I with an
acidic moiety can be formed from organic and inorganic bases. Suitable salts with
bases are, for example, metal salts, such as alkali metal or alkaline earth metal
salts, for example sodium, potassium, or magnesium salts; or salts with ammonia or
an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a
mono-, di- or tri-lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-,
triethyl-, tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower
alkylamine, for example mono-, di- or triethanolamine. Internal salts may
furthermore be formed. Similarly, when a compound of the present invention
contains a basic moiety, salts can be formed from organic and inorganic acids. For
example salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic,
fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic,
phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known pharmaceutically acceptable
acids.
As used in accordance with this invention, the term "providing," with respect
to providing a compound or substance covered by this invention, means either
directly administering such a compound or substance, or administering a pro-drug,
derivative, or analog that will form the effective amount of the compound or
substance within the body. This invention also covers providing the compounds of
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this invention to treat the disease states disclosed herein that the compounds are
useful for treating.
Preferred compounds of this invention include those of formula I in which:

A is hydrogen, aryl, or Het; or
a pharmaceutically acceptable salt thereof.
More preferred compounds of this invention include those of formula I in
which:

A is hydrogen, aryl, or Het; or
a pharmaceutically acceptable salt thereof.
In certain preferred embodiments, B and D are both CH. In certain other
preferred embodiments, one of B or D is N. In yet other preferred embodiments, B
is N and D is CH. In yet further embodiments, B is CH and D is N.
Preferred compounds of formula I include:
ethyl 2-cyano-3-(2,6-dimethoxyphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(2,6-dichlorophenyl)-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-[4-(dimethylamino)phenyl]-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-(1-naphthyl)-3-[2 (trifluoromethyl) phenyl]propanoate;
ethyl 2-cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(2,4-dimethoxyphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(2,5-dimethoxyphenyl)-3-(1-naphthyl)propanoate;
tert-butyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethyl) phenyl] propanoate;
ethyl 2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate;
tert-butyl 2-cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate;
tert-butyl 2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate;
terf-butyl 2-cyano-3-(1 -naphthyl)-3-[2-(trifluoromethoxy)phenyl] propanoate;
ethyl 2-cyano-3-(1 -naphthyl)-3-(2-nitrophenyl)propanoate;
tert-butyl 2-cyano-3-(2,6-dimethylphenyl)-3-(1-naphthyl)propanoate;
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fert-butyl (RR,SS)-2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethy!)phenyl]
propanoate;
fert-butyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
(-) ethyl (S'S)-2-cyano-3-(2-m?lhoxypheny!)-2-rn5thyl-3-(i -
naphthyl)propanoate;
(+) ethyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
ethyl (R,R,SS)-2-cyano-2-[(2-meihoxyphenyl)(1 -naphthyl)methyl]-4-
pentenoate;
ethyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)
propanoate;
tert-butyl (RR,SS)-2-cyano-3-(2-isopropylphenyl)-2-methy!-3-(1-
naphthyl)propanoate;
fert-butyl (RS,SR)-2-cyano-2-methyl-3-(1 -naphthyl)-3-[2-
(trifluoromethyl)phenyl]propanoate;
fert-butyl (RS,SR)-2-cyano-3-(2,6-dimethylphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
fert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 -
naphthyl)propanoate;
fert-butyl (RR, SS)-2-(3-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1 -
naphthyl)propanoate;
fert-butyl (RR,SS)-2-(2-bromobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1-
naphthyl)propanoate;
fert-butyl (RR,SS)-2-(2-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1-
naphthyl)propanoate;
fert-butyl (RR,SS)-2-cyano-2-(2,6-dichlorobenzyl)-3-(2-methoxyphenyl)-3-(1-
naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-3-(2,4-dimethoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
fert-butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-
(trifluoromethoxy)phenyl]propanoate;
ethyl 2-cyano-3-(3-methoxyphenyl)-3-(1-naphthyl)propanoate;
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ethyl 2-cyano-3-(4-methylphenyl)-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-(2-methy!phenyl)-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-(1 -naphthyl)-3-(2-naphthyl)propanoate;
ethyl 2-cyano-3-(4-fluoro-1-naphthyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-[4-(methylthio)ph5nyl]-3-(1-naphthyl)propanoate;
ethyl 3-[1,1'-binhenyll-4-yl-2-cyano-3-(1-naphthyl)propanoate;
ethyl 3-[1,1'-biphenyl]-2-yl-2-cyano-3-(1-naphthyl)propanoate;
ethyl 3-(4-chlorophenyl)-2-cyano-3-(1-naphthyl)propanoate;
ethyl 2-cy£no-3-[2-(methylthio)phenyl]-3-(1-naphthyl)propanoate;
ethyl-(RR,SS)- 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-2-methyl-3-[2-(methylthio)phenyl]-3-(1 -
naphthyl)propanoate;
(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic
acid;
(RR,SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-naphthyl)propanoic
acid;
(RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-
(trifluoromethyl)phenyl]propanoic acid;
(RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoicacid;
fert-butyl (R,R)-2-cyano-3-(2-isopropylphenyl)-2-methyI-3-(1-
naphthyl)propanoate;
tert-butyl (S,S)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
tert-butyl (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -
naphthyl)propanoate;
fert-butyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -
naphthyl)propanoate;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(piperazin-1-
ylcarbonyl)propanenitrile;
RR.SS)(3-[4-(3-chloro-2-methylphenyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile);
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(RR,S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)piperazin-1-
yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)-1-
piperazinyl]carbonyl}-3-(1-naphthyl)propanenitrile;
(R,R)-3-(2-m6ihoxyph5nyl)-2-methyl-2-{[4-(2-methylphsnyl)piperazin-1-
yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazin-i-
yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(S)-3-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]-2-[(S)-(2-methoxypheny!)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitri!e;
(S)3-(4-indan-4-yl-piperazin-1-yl)-2-[(S)(2-methoxy-phenyl)-naphthalen-1-yl-
methyl]-2-methyl-3-oxo-propionitrile;
(S,S)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-{[4-(1-
naphthyl)piperazin-1-yl]carbonyl}propanenitrile;
(S)-3-[4-(3,4-dimethylphenyl)piperazin-1-y!]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methy!-3-oxopropanenitrile;
(RR,SS) 3-[4-(H-indol-4-yl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)rnethyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(3-chlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2,3-dimethylpheny!)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(4-chlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(1H-lndol-4-yl)-piperazin-1-yl]-2-[(S)-(2-methoxy-phenyl)-naphthalen-
1-yl-methyl]-2-methyl-3-oxo-propionitrile;
(S,S)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3-
(trifluoromethyl)phenyl] piperidin-1-yl}carbonyl)propanenitrile;
(S)-3-[4-(4-chloro-phenyI)-3,6-dihydro-2H-pyridin-1-yl]-2-[(S)-(2-methoxy-
phenyI)-naphthalen-1-yl-methyl]-2-methyl-3-oxo-propionitrile;
(S,S)-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-2-[4-(3-
trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-propionitrile;
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(SS)2-[4-(4-Chloro-phenyl)-piperidine-1-carbonyl]-3-(2-methoxy-phenyl)-2-
methyl-3-naphthalen-1-yl-propionitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3-
(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)propanenitrile;
(RR>SS)-3-(2-methoxyphenyl)-2-methyl-3-(i-naphthyl)-2-(piperidin-1-
ylcarbonyl)propanenitrile;
{RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanamide;
(RR,SS)-2-cyano-N-ethyl-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphlhyl)propanamide;
(RR,SS)-N-(tert-butyl)-2-cyano-3-(2-methoxyphenyl)-2-methy!-3-(1-
naphthyl)propanamide;
(RR,SS)-2-cyano-3-(2-methoxyphenyl)-N,N,2-trimethyl-3-(1-
naphthyl)propanamide;
(RR,SS)-2-cyano-N-methoxy-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1-
naphthyl)propanamide;
(RR,SS)-2-benzyl-3-[4-(3,5-dichloro-4-pyridinyl)-1-piperazinyl]-2-[(2-
methoxyphenyl)(1-naphthyl)methyl]-3-oxopropanenitrile;
(R,S)-3-[4-(2,3-dimethylphenyl)piperazin-1-yl]-2-[(R,S)-(2-methoxyphenyl)(1-
naphthyl)rnethyl]-2-methyl-3-oxopropanenitrile;
(R,S)-3-[4-(3-isopropylphenyl)piperazin-1-yl]-2-[(R,S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(2SS)-3-[4-(3-chloro-2-methylphenyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2-fluorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2-chlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S,S)-3-(2-methoxyphenyl)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]carbonyl}-2-
methyl-3-(1-naphthyl)propanenitrile;
(R,S)-3-[4-(3-chloropyridin-4-yl)piperazin-1-yl]-2-[(R,S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
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(S)-3-[4-(2,3-dichlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(2S)-3-[4-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]-2-
[(S)-(2-methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(2S)-3-{4-[4-chloro-3-(trifluoromslhyl)phenyl]piperidin-i-yl}-2-[(S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR/SS)-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-2-(4-oxy-4-o-tolyl-
piperazine-1-carbony!)-propionitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-m6thyl-3-(1-naphthyl)-2-({4-[3-
(trifluoromethoxy)phenyl]piperazin-1-yl}carbonyl)propanenitrile;
(R,S)-3-[4-(2,3-difluorophenyl)piperazin-1-yl]-2-[(R,S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(R,S)-3-[4-(3-fluorophenyl)piperazin-1-yl]-2-[(R,S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-[(4-pyridin-3-
ylpiperazin-1-yl)carbonyl]propanenitrile;
(RR,SS)-3-[4-(2,3-dichlorophenyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazin-1-
yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(pyrrolidin-1-
ylcarbonyl)propanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-(morpholin-4-ylcarbonyl)-3-(1-
naphthyl)propanenitrile;
(RR,SS)-3-[4-(2-hydroxyethyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitri!e;
(RR,SS)-3-(2,6-dimethylmorpholin-4-yl)-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-2-cyano-N,N-diethyl-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR,SS)-2-cyano-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-(2-methoxyphenyl)-
2-methyl-3-(1-naphthyl)propanamide;
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(RR,SS)-3-azetidin-1-yl-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-
oxopropanenitrile;
(RR,SS)-2-cyano-N,N-diisopropyl-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR,SS)-3-(2-rneihoxyphenyi)-2-methyl-3-(i-naphlhyl)-2-[(3.3.5-
trimethylazepan-1-yl)carbonyl]propanenitrils;
(RR,SS)-3-(2,3-dihydro-H-indol-1-yl)-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,S-S)-3-(2-m6thoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(thiomorpholin-4-
ylcarbonyl)propanenitri!e;
((RR,SS)-3-azepan-1-yl-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-
oxopropanenitrile;
(R,R,SS)-2-cyano-N-cyclohexyl-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1-
naphthyl)propanamide;
(R,RSS)-2-cyano-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1-
naphthyl)propanamide;
(RR,SS)-3-(4-benzylpiperazin-1-yl)-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-
2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(3,4-dihydroisoquinolin-2(H)-yl)-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(4-methylphenyl)piperazin-1-
yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(RR,SS)-N,N-dibenzyl-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR,SS)-3-azocan-1-yl-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-
oxopropanenitrile;
4-chlorophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxylate;
2-nitrophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxy1ate;
4-(methoxycarbonyl)phenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-
methyl-3-(1-naphthyl)propanoyl]piperazine-1-carboxylate;
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4-methylphenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxylate;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoyl]-
N-(2-methylphsnyl)piperazine-1-carboxamide;
4-[(R,R,SS)-2-cyano-3-(2-rnethoxyphenyl)-2-meihyl-3-(i-naphthyl)propanoyl]-
N-[2-(trifluoromethyl)phenyl]piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoyl]-
N-(3-methoxyphenyl)piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl}-2-methyl-3-(1-naphthyl)propanoyl]-
N-(4-ethoxyphenyl)piperazine-1-carboxamide;
N-(2-bromophenyl)-4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoyl]-
N-(4-methylphenyl)piperazine-1 -carboxamide;
4-fluorophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxylate;
phenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -
naphthyl)propanoyl]piperazine-1-carboxylate;
(RR,SS)-3-[4-(4-bromobenzoyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
N-(4-chlorophenyl)-4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-rnethyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxamide;
methyl (2E)-2-cyano-3-(quinolin-3-yl)prop-2-enoate; and
pharmaceutically acceptable salts thereof.
This invention also provides processes for preparing the compounds of
formula I as defined herein, which processes preferably comprise steps (a)-(d) or
(e). (f), or (g):
(a) reacting a compound of formula

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wherein R5 is as defined hereinabove excepting hydrogen and Ar is a group
of formula (A), (B), or (C):

where R1 ,R2 and R1a are as defined hereinabove;
with a compound of formula Ar1MX wherein M is a metal such as Mg, X is a
halogen such as Cl or Br, and Ar1 is a group of formula (A) or (B) providing Ar
and Ar1 are not both of formula (A) or (B) to give a compound of formula I
wherein R4 is OR6 where R6 is defined hereinabove excepting hydrogen and
R3 is hydrogen;
(b) alkylating a compound of formula:

wherein R6) Ar1 and Ar are as defined above providing R5 is other than
hydrogen, with an alkylating agent of formula R3L where L is a leaving group
and R3 is as defined in claim 1 excepting hydrogen to give a corresponding
compound of formula I as defined in claim 1;
(c) hydrolyzing an ester of formula

wherein Ar, Ar1, R3 and R6 are as defined hereinabove providing R6 is
other than hydrogen, to give a corresponding compound of formula I wherein
R4 is OR6 where R6 is hydrogen;
(d) reacting an activated acid compound of formula:

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wherein Ar, Ar1, and R3 are as defined hereinabove,
with an amine of formula HNR5R6,

or
(e) reacting a compound of formula

wherein R5 is as defined hereinabove excepting hydrogen, in the
presence of strong base with an halide of formula
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AnArCHX
where Ar and Ar1 are as defined herein and X is halogen to give a
corresponding compound of formula I wherein R3 is hydrogen,
or
(f) converting a compound of formula I as definsd hsreinabovs having a reactive
substituent group or site to give a different compound of formula I;
or
(g) converting a compound of formula I to a pharmaceutically acceptable salt
thereof.
The compounds of the present invention can be prepared from commercially
available starting materials, compounds known in the literature, or readily prepared
intermediates, by employing standard synthetic methods and procedures known to
those skilled in the art. Standard synthetic methods and procedures for the
preparation of organic molecules and functional group transformations and
manipulations can be readily obtained from the relevant scientific literature or from
standard textbooks in the field. Although not limited to any one or several sources,
classic texts such as Smith, M. B.; March, J. March's Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001;
and Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
John Wiley & Sons: New York, 1999 are useful and recognized reference textbooks
of organic synthesis known to those in the art. The following synthetic schemes are
designed to illustrate, but not limit, general procedures for the preparation of
compounds of formula I.
The compounds used in the present invention may be prepared by the
method described in Scheme 1.
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Scheme 1
Condensation of a malonic acid derivative with an optionally substituted
aromatic or heteroaromatic aldehyde or ketone in the presence of a catalyst
provides the intermediate (1). This reaction is known to one skilled in the art as the
Knoevenagel reaction. The catalyst can be an ammonium salt derived from an
amine and a carboxylic acid. (G. Jones, Organic Reactions (1967) 15, 204; Y.
Sumida, Polymer Journal (1981) 13, 521), Lewis acid such as titanium tetrachloride
in pyridine (W. Lehnert, Tetrahedron Lett. (1970), 54, 4723) or a amine immobilized
on a resin (J. Simpson, Tetrahedron Lett., (1999), 40, 7031). Michael addition of an
aryl Grignard or Gilman reagent (N. Laitif, Egypt J. Chem (1974) 17, 879; C.
Cativieia, Tetrahedron, (1994) 50, 9837) provides 2-cyano propionate (2). Alkylation
of the anion of (2) with an alkyl halide or sulfonate (AA Fadda, Ind. J. Chem (1990)
29B, 171) provides ester (3). Subsequent hydrolysis of the ester under either acidic
or basic conditions provides acid (4). Activation of the acid using reagents familiar to
one skilled in the art, such as thionyl or oxalyl chloride, cyanuric chloride, pivaloyl
chloride, diphenylphosphoryl azide, diethyl cyanophosphate, diethyl
azodicarboxylate/triphenylphosphine, dicyclohexylcarbodimide, hydroxbenzotriazole,
and subsequent reaction with an amine provides an amide.
In the case where the amine is piperazine an optionally substituted aryl or
optionally substituted heteroaryl group can be attached to the piperazine ring using a
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Pd or Ni catalyst, with or without a ligand, a base such as sodium t-butoxide in a
solvent and an aryl chloride, bromide, iodide sulfonate or siloxane (D. Baranano,
Current Org. Chem. (1997) 1, 287; B. H. Yang, J. Organomet. Chem. (1999), 376,
125; E. Brenner, Tetrahedron (1999) 55, 12829). Alternatively a Cu catalyst, a base
and an aryl chloride, bromide, iodide sulfonate, an aryl boronic acid or aryl siloxane
(P.Y.S. Lam, J. Am Chem. Soc (2000)122, 7600; D.J. Cundy, Tetrahedron Letters
(1998)39, 7979) can be used. The N-oxide of the substiruted piperazines can be
prepared by oxidation of the basic nitrogen with reagents known to one skilled in the
art (e.g., 3-ch!oro perbenzoic acid, trifluoroacetic peracid).
The amide can also be prepared directly from ester (3) by a modification of
the Bodroux reaction in which the ester is converted directly into an amide by
reaction with the magnesium salt of an amine (Dolling, Ulf H.; EP-A-599376) as
shown in Scheme 2

Another route to the substituted piperazines amides involves the synthesis of
the piperazine amide and using a metal catalyzed coupling with a Pd or Ni catalyst,
with or without a ligand, a base such as sodium t-butoxide in a solvent and an aryl
chloride, bromide, iodide sulfonate or siloxane (D. Baranano, Current Org. Chem.
(1997) 1, 287; B. H. Yang, J. Organomet Chem (1999), 376, 125; E. Brenner,
Tetrahedron (1999) 55, 12829). Alternatively a Cu catalyst, a base and an aryl
chloride, bromide, iodide sulfonate, an aryl boronic acid or aryl siloxane (P.Y.S. Lam,
J. Am Chem. Soc. (2000)122, 7600; D.J. Cundy, Tetrahedron Letters (1998)39,
7979)can be used.
In those cases where the amine used in the condensation reaction with acid,
4 , is an acylated piperazine, the piperazine, if not commercially available, was
prepared by monoacylation of an excess of piperazine with an acid chloride,
chloroformate or isocyanate in the presence of a base using methods known to one
skilled in the art. Alternatively, the piperazine amide can be prepared by
condensation of acid 4 with an excess of piperazine to generate a monoacyl
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piperazine. Subsequent reaction with activated (optionally substituted) (heterro) aryl
acid derivatives, isocyanates, isothiocyanates or (optionally substituted) (hetero) aryl
chloroformates under conditions familiar to one skilled in the art produces the
disubstituted amide. This route is illustrated in Scheme 3.
Scheme 3

An alternative synthesis of the 3-(1-naphthyl)-3-phenyl-2-cyanopropanoic acid
ester (intermediate 2), involves the synthesis of a naphthyl aryl methyl halide and its
use in a subsequent alkylation of a cyanoacetic acid derivative. This route, based
on the work of L. Voegtli (Helv. Chim Acta. 38 (1955) 46, is shown in Scheme 4.

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The alcohol could be converted into a leaving group familiar to one skilled in
the art using methods familiar to one skilled in the art (eg PhsP/CCl4, Ph3P/CBr4,
methyltriphenoxy- phosphonium iodide, TsCI/Pyr, MsCI/TEA, Ac2O/Pyr).
The substantially pure enantiomers of the compounds of formula I may be
resolved by forming a ephedrine, cinchonidine, or quinidine salt of a compound of
claim 1 or a pharmaceutically acceptable salt thereof; and extracting said ephedrine,
cinchonidine, or quinidine salt with solvent. As used herein, "substantially pure
enantiomer" means an enantiomer present it a mixture with other enantiomer at a
proportion of at least about 90%, by weight, based on the total weight of all
enantiomers of the compound, preferably at least about 95%, by weight, and, more
preferably at least about 99%, by weight.
The compounds of this invention are useful in the treatment of the
inflammatory component of diseases and are therefore particularly useful in treating
atherosclerosis, myocardial infarction, congestive heart failure, arthritis, inflammatory
bowel disease, type II diabetes, osteoarthritis, asthma and any other autoimmune
disease in humans or other mammals which comprises administering to a human or
other mammal an antiinflammatory effective amount of a compound of the present
invention.
Representative compounds of this invention were evaluated in the following
standard pharmacological test procedures that demonstrated the antiinflammatory
activity for the compounds of this invention. The test procedures used and the
results obtained are briefly described below.
Test procedures:
Cells
T-175 flasks of 100% confluent HAECT-1 cells (immortalized human aortic
endothelial cells) were washed with 8 mL of HBSS (HEPES buffered saline solution)
and infected for four hours with 6 mL of a 1:10 dilution of Ad5-wt-hERa virus (an
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adenovirus transfection vector that mediates CMV promoter driven expression of
human ERα) in phenol red free Endothelial Cell Basal medium (Clonetics, San
Diego CA, Catalog # CC-3129) containing 0.25% bovine serum albumin (EBM-BSA).
After four hours, cells were washed with EBM-BSA and incubated overnight in the
same medium. Following overnight incubation, cells were washed with EBivl-BSA
and infected for 2 hours with 6 mL of a 1:10 dilution of Ad5-3x(NFKB).Luc virus
(Adenovirus luciferase expression vector driven by 3 repeats of the MHC NFkb site
5' to the thymidine kinase promoter) in EBM-BSA. After two hours, cells were
washed and incubated at 34°C for i hour. Cells were then washed, trypsinized,
counted and resuspended in 95%FBS / 5% dimethylsuifoxide at a concentration of
4x106 cells/mL, frozen as 1 or 5 mL aliquots in cryo-vials and stored at -150 °C.
Control (no ER infection) cells were processed as above without Ad5-wt-hERa virus
infection.
A representative compound selected from the compounds of Examples 1-130
was evaluated in the test procedure described below.
IL-6 and Creatine Kinase (CK)Test Procedure
ERa infected HAECT-1 cells or control cells were thawed, diluted 42x in warm
EBM-BSA, plated into 96-well plates at 0.1 mL/well and incubated for 4 hours at 34
°C. Test compounds were added to the cells as 2x stocks in EBM-BSA containing 2
ng/mL IL-1(5 (R&D Systems) and the 96-well plates were returned to the incubator
(34 °C). After 15-20 hours, 100 μL aliquots of media were removed from the cells
and assayed for IL-6 content using a BioSource human IL-6 ELISA Kit. Cells were
subsequently washed with 300 μL of Dulbecco's phosphate buffered saline and
lysed in 50 μL of Cell Culture Lysis Reagent (Promega). Luciferase was determined
on a Wallac Victor Luminometer (Gaithersburg, MD) using 10 ΜL of lysate and
mixing with 100 μL of Promega Luciferase Assay reagent. Creatine kinase was
determined from the rate of increase in A340 following addition of 100 μL of CK assay
reagent (Sigma, cat. No 47-10) to the remainder of the cell lysate.
Data Analyses
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For IC50 and EC50 calculations, mean IL-6, luciferase or CK values versus
log10 of the compound concentration were fitted to a four parameter logistic
equation. The IC50/ EC50 value, 'Hill slope', upper and lower limits of the curve were
iterativelv estimated.
Ovariectomized C5/BL/6 mice (16-20 g) (Taconic) were separated into
groups of eight mice each. After 5-7 days of recuperation, the mice were fed a chow
diet or an atherogenic diet (15.75% fat, i .25% cholesterol and 0.5% sodium cholate)
(Purina diet #21539). EE or test compound was administered once daily by gavage
in a methylcellulose/tween vehicle (0.1 ml per mouse) for 5 weeks. At the end of the
experimental period, the liver was collected and uterine wet weight was recorded.
RNA Analysis
Liver total RNA was prepared by using Trizol reagent (BRL). Estrogen and
compound regulation of NF-KB target genes were verified by real time reverse
transcriptase-polymerase chain reaction (RT-PCR) using an ABI PRISM 7700
Sequence Detection System according to the manufacturer's protocol (Applied
Biosystems). The data was analyzed using the Sequence Detector v1.7 software
(Applied Biosystems) and normalized to GAPDH using the Applied Biosystems
primer set.
The following table summarizes the results obtained in the standard
pharmacological test procedures described above using a representative compound
of this invention.
Table 1:
Effects of tested compounds on ER/NF-KB, IL-6 and CK expression in Ad5-wt-
ERot infected HAECT-1 cells
Example ER/NFKB lnterleukin-6 Creatine Kinase
# IC50
(nM) Efficacy IC50
(nM) Efficacy
(%) EC50
(nM) Efficacy
(%)
67 43
101 90
92 35 45 222
173 41
58
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153 100 84 41
92 86
222 100
Efficacy values are relative to the maximal inhibition (ER/NF-KB or IL-6 test
procedure) or stimulation (CK test procedure) observed with E2.
E2 inhibits NF-KB and IL-6 expression in Ad5-wt-ER infected HAECT-1 cells
with an IC50 value around 1 nM and induces expression of creatine kinase in the
same cells with similar potency (5.8 nM) (Table 1). In contrast, compounds of the
present invention potently and efficaciously inhibit NF-KB and IL-6 expression in
Ad5-wt-ER infected HAECT-1 cells but do not induce CK expression (Table 1) in an
ER-dependent manner. The ability of compounds of the present invention to inhibit
NF-KB and IL-6 expression without inducing CK activity (as shown for a
representative compound in Table 1) is demonstrates anti-inflammatory activity in
the absence of classic estrogenic activity.
Representative compounds selected from the compounds of Examples 131-
230 were evaluated in the test procedure described below.
Test procedures:
Cells
T-175 flasks of 100% confluent HAECT-1 cells (immortalized human aortic
endothelial cells) were washed with 8 ml of HBSS (HEPES buffered saline solution)
and infected for fours hours with 6 ml of a 1:10 dilution of Ad5-wt-hERa virus (an
adenovirus transfection vector that mediates CMV promoter driven expression of
human ERα) in phenol red free Endothelial Cell Basal medium (Clonetics, San
Diego, CA, Catalog # CC-3129) containing 0.25% bovine serum albumin (EDM-
BSA). After four hours, cells were washed with EDM-BSA and incubated overnight
in the same medium. Following overnight incubation, cells were washed with EDM-
BSA and infected for 2 hours with 6 ml of a 1:10 dilution of Ad5-3x(NF/cB).Luc virus
(Adenovirus luciferase expression vector driven by three repeats of the MHC NF/kb
sites 5' to the thymidine kinase promoter) in EDM-BSA. After two hours, cells were
washed and incubated at 34 °C for one hour. Cells were then washed, trypsinized,
counted, and resuspended in 95% FBS/5% dimethylsulfoxide at a concentration of
4x108 cells/ml, frozen as 1 or 5 ml aliquots in cryo-vials and stored at -150°C.
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Control (no ER infection) cells were processed as above without Ad5-wt-hERa virus
infection.
IL-6 and Creatine Kinase Assays
ERα infected HAECT-1 cells or control cells were thawed, diluted 42x in warm
EBivi-BSA, plated into 9G-vvell plates at 0.1 ml/well and incubated for 4 hours at 34
°C. Test compounds were added to the cells at 2x stocks in EBM-BSA containing 2
ng/ml IL-1β Ad6-IL-6(1250bp).Luc virus and plates were returned to the incubator
(34 °C). After 15 to 10 hours, cells were lysed with 50 μl of Promega Cell Culture
Lysis reagenet for about 5 minutes at room temperature on a shaker. After lysing,
15 μl of lysate is transferred to luminometer plates for luciferase determination.
Luciferase activity is evaluated using a Perkin Elmer Victor2 1420 muitilabe! counter.
Creatine kinase was determined from the rate of increase in A340 following addition
of 100 μl of CK assay reagent (Sigma catalog no. 47-10) to the remainder of the cell
lysate.
Data Analyses
For IC50 and EC50 calculations, mean IL-6, luciferase or CK values versus
log10 of the compound concentration were fitted to a four parameter logistic
equation. The IC50/EC50 value, 'Hill slope,' upper and lower limits of the curve were
iteratively estimated.
Endothelial Cell ER/IL-6 Assay
IL6 luc IL6 luc CK CK
Example IC50 (nM) %Efficacy (%) EC50 (nM) %Efficacy (%)
131 15 119 212 48
132 122 92 298 57
133 206 81
134 612 85
135 65 119
136 63 142
137 33 163
138 15 131 34 49
139 113 98
140 324 125






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Endothelial Cell ER/lL-6 Assay
IL6 luc IL6 luc CK CK
Example IC50 (nM) %Efficacy (%) EC50 (nM) %Efficacy (%)
226 220 115 138 18
160 1255 82 -10
161 798 122 5
164 32 48
Based on the results obtained in the standard pharmacological test
procedures, the compounds of this invention are selective antiinflammatory
compounds described herein useful for the treatment and prevention of chronic
inflammatory diseases without stimulating uterine and breast cell proliferation as
found with classic estrogens.
Accordingly, the compounds of this invention are useful in treating or
inhibiting osteoporosis and in the inhibition of bone demineralization, which may
result from an imbalance in an individual's formation of new bone tissues and the
resorption of older tissues, leading to a net loss of bone. Such bone depletion
results in a range of individuals, particularly in post-menopausal women, women who
have undergone bilateral oophorectomy, those receiving or who have received
extended corticosteroid therapies, those experiencing gonadal dysgenesis, and
those suffering from Cushing's syndrome. Special needs for bone, including teeth
and oral bone, replacement can also be addressed using these compounds in
individuals with bone fractures, defective bone structures, and those receiving bone-
related surgeries and/or the implantation of prosthesis. In addition to those
conditions described above, these compounds can be used in treatment or
inhibition of osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease,
osteomalacia, osteohalisteresis, multiple myeloma and other forms of cancer having
deleterious effects on bone tissues.
The compounds of this invention are also active in the brain and are therefore
useful for inhibiting or treating Alzheimer's disease, cognitive decline, decreased
libido, senile dementia, neurodegenerative disorders, depression, anxiety, insomnia,
schizophrenia, and infertility. The compounds of this invention are also useful in
treating or inhibiting benign or malignant abnormal tissue growth including,
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glomerulosclerosis, prostatic hypertrophy, uterine leiomyomas, breast cancer,
scleroderma, fibromatosis, endometriosis, endometrial cancer, potycystic ovary
syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian
cancer, melanoma, prostate cancer, cancers of the colon, CNS cancers, such as
glioma or astioblastomia.
The compounds of this invention are cardioprotective and are antioxidants,
and are useful in lowering cholesterol, triglycerides, Lipoprotein (a) (Lp(a)), and low
density lipoprotein (LDL) levels; inhibiting or treating hypercholesteremia,
hyperlipidemia, cardiovascular disease, atherosclerosis, peripheral vascular disease,
restenosis, and vasospasm. and inhibiting vascular wall damage from cellular events
leading toward immune mediated vascular damage.
The compounds of this invention are also useful in treating disorders
associated with inflammation or autoimmune diseases, including inflammatory bowel
disease (Crohn's disease, ulcerative colitis, indeterminate colitis), arthritis
(rheumatoid arthritis, spondyloarthropathies, osteoarthritis), pleurisy,
ischemia/reperfusion injury (e.g. stroke, transplant rejection, myocardial infarction,
etc.), asthma, giant cell arteritis, prostatitis, uveitis, psoriasis, multiple sclerosis,
systemic lupus erythematosus and sepsis.
The compounds of this invention are also useful in treating or inhibiting ocular
disorders including cataracts, uveitis, and macular degeneration and in treating skin
conditions such as aging, alopecia, and acne.
The compounds of this invention are also useful in treating or inhibiting
metabolic disorders such as disorders of lipid metabolism, appetite (e.g. anorexia
nervosa and bulimia), or type-ll diabetes.
Compounds in this invention are also useful in treating or inhibiting bleeding
disorders such as hereditary hemorrhagic telangiectasia, dysfunctional uterine
bleeding, and combating hemorrhagic shock.
The compounds of this invention are useful in disease states where
amenorrhea is advantageous, such as leukemia, endometrial ablations, chronic
renal or hepatic disease or coagulation diseases or disorders.
It is understood that the effective dosage of the active compounds of this
invention may vary depending upon the particular compound utilized, the mode of
administration, the condition, and severity thereof, of the condition being treated, as
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well as the various physical factors related to the individual being treated. It is
projected that compounds of this invention will be administered at an oral daily
dosage of from about 0.05 mg to about 30 mg per kilogram of body weight,
preferably administered in divided doses two to six times per day, or in a sustained
release form. For most large mammals, the- total daily dosage is from about 3.5 mg.
to about 2100 mg, preferably from about 3.5 to about 5 mg. In the case of a 70 kg
human adult, the total daily dose will generally be from about 3.5 mg to about 2100
mg and may be adjusted to provide the optimal therapeutic result.
The compounds of this invention can be formulated neat or with a
pharmaceutical carrier for administration, the proportion of which is determined by
the solubility and chemical nature of the compound, chosen route of administration
and standard pharmacological practice. The pharmaceutical carrier may be solid or
liquid.
A solid carrier can include one or more substances that may also act as
flavoring agents, sweetening agents, lubricants, solubilizers, suspending agents,
fillers, glidants, compression aids, binders, or tablet-disintegrating agents; it can also
be an encapsulating material. In powders, the carrier is a finely divided solid that is
in admixture with the finely divided active ingredient.
Solid dosage unit forms or compositions such as tablets, troches, pills,
capsules, powders, and the like, may contain a solid carrier binder such as gum
tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such
as magnesium stearate; and a sweetening agent such as sucrose, lactose, or
saccharin. When a dosage unit form is a capsule, it may contain, in addition to
materials of the above type, a liquid carrier such as a fatty oil. Various other
materials may be present as coatings or to modify the physical form of the dosage
unit. For instance, tablets may be coated with shellac, sugar or both.
Liquid carriers are used in preparing liquid dosage forms such as solutions,
suspensions, dispersions, emulsions, syrups, elixirs and pressurized compositions.
The active ingredient can be dissolved or suspended in a pharmaceutically
acceptable liquid carrier such as water, an organic solvent, a mixture of both, or
pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives,
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sweeteners, flavoring agents, suspending agents, thickening agents, colors,
viscosity regulators, stabilizers, or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water (partially containing
additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl
cellulose solution); alcohols, including monohydric alcohols such as ethanol and
polyhydric alcohols such as glycols and their derivatives; lethicins, and oils such as
fractionated coconut oil and arachis oil. For parenteral administration, the liquid
carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile
liquid carriers are useful in sterile liquid form compositions for parenteral
administration. The liquid carrier for pressurized compositions can be a halogenated
hydrocarbon or other pharmaceutically acceptable propellant.
A liquid pharmaceutical composition such as a syrup or elixir may contain, in
addition to one or more liquid carriers and the active ingredients, a sweetening agent
such as sucrose, preservatives such as methyl and propyl parabens, a
pharmaceutically acceptable dye or coloring agent, or a flavoring agent such as
cherry or orange flavoring.
Liquid pharmaceutical compositions that are sterile solutions or suspensions
can be administered intraocularly or parenterally, for example, by intramuscular,
intraperitoneal or subcutaneous injection. Sterile solutions can also be administered
intravenously. The pharmaceutical forms suitable for injectable use include sterile
aqueous solutions or dispersions and sterile powders for the extemporaneous
preparation of sterile injectable solutions or dispersions. In all cases, the form must
be sterile and must be fluid to the extent that easy, injectability exists. It must be
stable under the conditions of manufacture and storage and must be preserved
against the contaminating action of microorganisms such as bacteria and fungi. The
carrier can be a solvent or dispersion medium containing a liquid carrier, for
example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), suitable mixtures thereof, and vegetable oils. The liquid carrier
may be suitably mixed with a surfactant such as hydroxypropylcellulose.
The compounds of the present invention may also be administered rectally or
vaginally in the form of a conventional suppository. For administration by intranasal
or intrabronchial inhalation or insufflation, the compounds of this invention may be
formulated into an aqueous or partially aqueous solution, which can then be utilized
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in the form of an aerosol. The compounds of this invention may be administered
topically, or also transdermally through the use of a transdermal patch containing the
active compound and a carrier that is inert to the active compound, which is non
toxic- to the skin, and allows delivery of the agent for systemic absorption into the
blood stream via the skin. The carrier may take any number of forms such as
creams and ointments, pastes, gels, and occlusive devices. The creams and
ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or
water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or
hydrophilic petroleum containing the active ingredient may also be suitable. A
variety of occlusive devices may be used to release the active ingredient into the
blood stream such as a semipermeabie membrane covering a reservoir containing
the active ingredient with or without a carrier, or a matrix containing the active
ingredient. Other occlusive devices are known in the literature.
The following describes the preparation of representative compounds of this
invention. Compounds described as homogeneous were determined to be 98% or
greater a single peak (exclusive of enantiomers) by analytical reverse phase
chromatographic analysis with 254 nM UV detection. Melting points are reported as
uncorrected in degrees centigrade. The infrared data is reported as wavenumbers
at maximum absorption, vmax, in reciprocal centimeters, cm"1. Mass spectral data is
reported as the mass-to-charge ratio, m/z; and for high resolution mass spectral
data, the calculated and experimentally found masses, [M+H]+, for the neutral
formulae M are reported. Nuclear magnetic resonance data is reported as 5 in parts
per million (ppm) downfield from the standard, tetramethylsiiane; along with the
solvent, nucleus, and field strength parameters. The spin-spin homonuclear coupling
constants are reported as J values in hertz; and the multiplicities are reported as a:
s, singlet; d, doublet; t, triplet; q, quartet; quintet; or br, broadened. Italicized
elements or groups are those responsible for the chemical shifts. 13C NMR chemical
shift assignments were made by reasonable comparison to a full chemical shift
assignment determination for Example 1, Step a. The yields given below are for
informational purposes and may vary according to experimental conditions or
individual techniques.
Example 1, Parti
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Ethyl (E)-2-cyano-3-(2,6-dimethoxyphenyl)prop-2-enoate
A solution of ethyl cyanoacetate (817mg,7.22mmol), 2,6-
(dimethoxy)benzaldehyde (1g, 6.0 mmol), piperidinium acetate (0.430 mg, 3.0 mmol)
in toluene (25mL) is refluxed for four hours under a Dean Stark trap. The reaction is
cooled, diluted with isopropyl acetate. (25mL) and washed with 1N HCI, saturated
bicarbonate solution, and brine. The sample was evaporated to a solid.
Recrystallization from ethanol provided the title compound as white crystals
mp 99-101°C;
1H NMR (DMSO-D6): δ 0.79 (t, J=7.0S Hz, 3 H), 3.S4 (s, 6H), 4.29 (q, J=7.08 Hz, 2
H), 6.77 (d, J=8.55 Hz, 2 H), 7.50 (t, J=8.55 Hz, 1 H), 8.28 (s,1H)
MS (APCI) m/z [M+H]+ (262);
Anal, calcd for C14H15NO4: C:64.36 H:5.79 N:5.36 Found: C:64.13 H.5.71 N:5.31.
Example 1 Part 2
Ethyl 2-cyano-3-(2,6-dimethoxyphenyl)-3-(1-naphthyl)propanoate
Ethyl (E)-2-cyano-3-(2,6-dimethoxyphenyl)prop-2-enoate (522 mg, 2 mmol)
was disolved in 20 mL dry tetrahydrofuran (THF) and stirred under argon at room
temperature while 0.25 M 1-naphthyl magnesium bromide (9.6 mL, 2.4 mmol) was
added dropwise. The reaction was stirred 2 hrs., quenched with 1 N HCI, taken up
in ethyl acetate, washed with NaHCO3, brine, dried with MgSO4, filtered, and
evaporated. The crude reaction mixture was recrystallized from ethyl
acetate/hexanes to yield 390 mg.
1H NMR (400 MHz, DMSO-D6) δ 0.79 (t, J=7.08 Hz, 1 H) 0.90 (t, J=7.08 Hz, 1 H)
3.79 (d, J=10.49 Hz, 4 H) 3.92 (m, 1 H) 5.18 (d, J=11.23 Hz, 1 H) 5.26 (d, J=11.23
Hz, 1 H) 5.84 (d, J=11.47 Hz, 1 H) 5.94 (d, J=11.23 Hz, 1 H) 6.60 (d, J=8.54 Hz, 1
H) 6.67 (d, J=8.30 Hz, 1 H) 7.17 (t, J=8.30 Hz, 1 H) 7.22 (t, J=8.42 Hz, 1 H) 7.49 (m,
2 H) 7.72 (d, J=6.59 Hz, 1 H) 7.80 (dd, J=17.33, 8.30 Hz, 1 H) 7.89 (m, 1 H) 8.30 (d,
J=8.79 Hz, 1 H)
MS (APCI) m/z 390 ([M+H]+);
MS (APCI) m/z 407 ([M+NH4J+);
Anal, calcd for C24H23NO4: C:74.02 H:5.95 N:3.60 Found: C:73.73 H.5.78 N:3.57.
Example 2
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Ethyl 2-cyano-3-(2,6-dichlorophenyl)-3-(1-naphthyl)propanoate
Ethyl (E)-2-cyano-3-(2,6-dichlorophenyl)prop-2-enoate (540 mg, 2 mmol) was
dissolved in 20 mL dry THF and stirred under argon at room temperature while 0.25
M 1-naphlhyl magnesium bromide (9.6 mL, 2.4 mmol) was added dropwise. The
reaction was stirred 2 hours quenched with 1 N HCl, taken up in ethyl acetate,
washed with NaHCO3, brine, dried with MgSO4, filtered, and evaporated. The crude
reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to yield 450
mg the title compound as a yellowish oil.
1H NMR (400 MHz, DMSO-D6) δ 0.97 (t, J=7.08 Hz, 1 H) 1.07 (t, J=7.08 Hz, 1 H)
4.04 (m, 1 H) 4.16 (dd, J=7.08, 4.15 Hz, 1 H) 5.41 (d, J=9.27 Hz, 1 H) 5.58 (d,
J=11.23 Hz, 1 H) 6.01 (d, J=9.03 Hz, 1 H) 6.10 (d, J=11.47 Hz, 1 H) 7.36 (m, 1 H)
7.47 (m, 2 H) 7.53 (d, J=7.81 Hz, 1 H) 7.59 (t, J=7.81 Hz, 1 H) 7.66 (d, J=8.30 Hz, 1
H) 7.74 (d, J=7.57 Hz, 1 H) 7.81 (m, 1 H) 7.90 (d, J=8.05 Hz, 1 H) 7.95 (m, 1 H)
MS (APCI) m/z 398 ([M+H]+);
MS (APCI) m/z 415 ([M+NH4]+);
Anal, calcd for C22H17Cl2NO2: C:66.34 H:4.30 N:3.52 Found: C:66.18 H:4.35 N:3.48.
Example 3
Ethyl 2-cyano-3-[4-(dimethylamino)phenyl]-3-(1-naphthyl)propanoate
Ethyl (E)-2-cyano-3-[4-(dimethylamino)phenyl)]prop-2-enoate (489 mg, 2
mmol) was disolved in 20 mL dry THF and stirred under argon at room temperature
while 0.25 M 1-naphthyl magnesium bromide (9.6 mL, 2.4 mmol) was added
dropwise. The reaction was stirred 2 hrs., quenched with 1 N HCI, taken up in ethyl
acetate, washed with NaHCO3, brine, dried with MgSO4, filtered, and evaporated.
The crude reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to
yield 125 mg the title compound as a yellowish oil which became a hard foam upon
high vaccum.
1H NMR (400 MHz, DMSO-D6) δ 0.92 (dt, J=12.93, 7.08 Hz, 3 H) 2.79 (s, 3H) 2.82
(s, 3H) 4.01 (m, 1 H) 5.19 (d, J=9.76 Hz, 0.5 H) 5.26 (d, J=9.27 Hz, 0.5 H) 5.38 (m,
1 H) 6.58 (d, J=8.79 Hz, 1 H) 6.62 (d, J=8.79 Hz, 1 H) 7.15 (d, J=8.79 Hz, 1 H) 7.29
(m, 1.33 H) 7.49 (m, 3 H) 7.58 (d, J=7.32 Hz, 0.5 H) 7.69 (d, J=7.08 Hz, 0.5 H) 7.88
(m, 3 H) 8.12 (m, 0.66 H) 8.23 (d, J=8.30 Hz, 0.5 H)
MS (APCI) m/z 373 ([M+H]+);
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Anal. calcd for C24H24N2O2: C:77.39 H:6.49 N:7.52 Found: C:77.31 H:5.90 N.6.90.
Example 4
Ethyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethyl)phenyl]propanoate
2-(trifluoromethyl)phenyl magnesium bromide (550 mg, 2 rnmol) taken up in
10 mL dry THF with magnesium (59 mg, 2 mmol) overnight. To this was added ethyl
(E)-2-cyano-3-(1-naphthyl)prop-2-enoate (502 mg, 2 mmol) in THF (10 mL). The
reaction mixture allowed to stir overnight. The reaction was stirred 2 hrs., quenched
with 1 N HCl, taken up in ethyl acetate, washed with NaHCO3, brine, dried with
MgSO4, filtered, and evapo'rated. The crude reaction mixture was purified on silica
gel (20% ethyl acetate/hexanes) to yield 692 mg of the title compound as a yellow
oil.
1H NMR (400 MHz, DMSO-D6) δ 0.76 (t, J=7.08 Hz, 1 H) 0.92 (t, J=7.08 Hz, 1 H)
3.87 (m, 1 H) 4.02 (q, J=7.08 Hz, 0.5 H) 4.07 (q, J=7.08 Hz, 0.5 H) 5.23 (d, J=7.32
Hz, 0.5 H) 5.36 (d, J=8.30 Hz, 0.5 H) 5.87 (d, J=7.32 Hz, 0.5 H) 5.94 (d, J=8.30 Hz,
0.5 H) 7.27 (d, J=6.59 Hz, 0.5 H) 7.59 (m, 5 H) 7.80 (m, 1.5 H) 7.94 (m, 3 H) 8.13
(d, J=8.79 Hz, 0.5 H) 8.18 (d, J=7.81 Hz, 0.5 H)
MS (APCI) m/z 398 ([M+H]+);
Anal, calcd for C23H18F3NO2: C:69.52 H:4.57 N:3.52 Found: C:68.50 H:4.09 N.3.22.
Example 5
Ethyl 2-cyano-3-(2-isopropylphenyl)-3-(1 -naphthyl)propanoate
2-(isopropyl)phenyl magnesium bromide (502mg, 2 mmol) taken up in 10 mL
dry THF with magnesium (59 mg, 2 mmol) overnight. To this was added ethyl (E)-2-
cyano-3-(1-naphthyl)prop-2-enoate (502 mg, 2 mmol) in THF (10 mL). The reaction
mixture allowed to stir overnight. The reaction was stirred 2 hours, quenched with 1
N HCI, taken up in ethyl acetate, washed with NaHCO3, brine, dried with MgSO4,
filtered, and evaporated. The crude reaction mixture was purified on silica gel (20%
ethyl acetate/hexanes) to yield 302 mg of the title compound as a yellow oil.
1H NMR (400 MHz, DMSO-D6) δ 0.66 (d, J=6.59 Hz, 1.66 H) 0.83 (t, J=7.08 Hz,
1.66 H) 0.93 (t, J=7.08 Hz, 0.33 H) 1.00 (d, J=6.59 Hz,0.33 H) 1.20 (d, J=6.83 Hz,
2.33 H) 1.26 (d, J=6.S3 Hz, 0.66 H) 1.34 (t, J=7.20 Hz, 0.66 H) 2.94 (dt, J=13.54,
6.89 Hz, 0.66 H) 3.93 (qd, J=7.12, 1.59 Hz, 1.33 H) 4.05 (q, J=7.08 Hz, 0.66 H) 4.37
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(q, J=7.08 Hz, 0.33 H) 5.14 (d, J=7.81 Hz, 0.33 H) 5.23 (d, J=8.05 Hz, 0.66 H) 5.82
(t, J=7.69 Hz, 1 H) 7.11 (t, J=8.18 Hz, 0.33 H) 7.29 (m, 4 H) 7.44 (t, J=7.81 Hz, 0.66
H) 7.55 (m, 2 H) 7.69 (m, 2.33 H) 7.87 (t, J=8.42 Hz, 1 H) 7.95 (d, J=8.30 Hz, 0.33
H) 7.99 (d, J=7.81 Hz, 1 H) 8.07 (d, J=7.81 Hz, 0.66 H) 8.14 (d, J=7.32 Hz, 0.33 H)
8.20 (m, 1H)
MS (APCI) m/z 370 ([M-H]-);
Anal, calcd for C25H25NO2: C:80.83 H:6.78 N:3.77 Found: C:79.13 H:6.07 N:3.94.
Example 6
Ethyl 2-cyano-3-(2,4-dimethoxyphenyl)-3-(1-naphthyl)propanoate
A solution of 2-cyano-3-(2,4-dimethoxy-phenyl)-acrylic acid ethyl ester (522
mg, 2 mmol) in THF (20mL) was treated dropwise with 1-naphthyl magnesium
bromide (9.6mL, 2.4mmol) at room temperature. The reaction was stirred for 3
hours, quenched with 1N HCl and diluted with ethyl acetate (40mL). The organic
layer was separated and was washed sequentially with saturated aqueous sodium
bicarbonate solution and brine. The organic layer was dried over Na2SO4, filtered
and was concentrated in vacuo. Chromatography over silica gel (20% ethyl
acetate/hexanes) yielded 421 mg of the title compound as an off white solid.
1H NMR (400 MHz, DMSO-D6) δ 0.90 (td, J=7.08, 1.71 Hz, 3 H) 3.68 (s, 1.5 H) 3.71
(s, 1.5 H) 3.84 (s, 1.5 H) 3.94 (s, 1.5 H) 4.00 (m, 2 H) 5.08 (d, J=8.30 Hz, 0.5 H) 5.20
(d, J=9.27 Hz, 0.5 H) 5.74 (d, J=8.54 Hz, 0.5 H) 5.78 (d, J=9.27 Hz, 0.5 H) 6.36 (dd,
J=8.54, 2.44 Hz, 0.5 H) 6.45 (dd, J=8.66, 2.32 Hz, 0.5 H) 6.60 (dd, J=8.18, 2.32 Hz,
1 H) 6.80 (d, J=8.54 Hz, 0.5 H) 7.20 (d, J=8.54 Hz, 0.5 H) 7.51 (m, 3 .5H) 7.64 (d,
J=6.83 Hz, 0.5 H) 7.88 (m, 3.5 H) 8.06 (d, J=8.54 Hz, 0.5 H)
MS (APCI) m/z 390 ([M+H]+);
Anal, calcd for C24H23NO4: C:74.02 H:5.95 N:3.60 Found: C:73.84 H:5.91 N:3.54.
Example 7
Ethyl 2-cyano-3-(2,5-dimethoxyphenyl)-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 6 using 2-cyano-3-
(2,5-dimethoxy-phenyl)-acrylic acid ethyl ester as the starting material. This
provided 309 mg of the title compound as a yellow powder.
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1H NMR (400 MHz, DMS0-D6) δ 0.87 (t, J=7.20 Hz, 1.5 H) 0.91 (t, J=7.20 Hz, 1.5
H) 3.54 (s, 1.5 H) 3.62 (s, 1.5 H) 3.79 (s, 1.5 H) 3.88 (s, 1.5 H) 3.99 (m, 2 H) 5.16 (d,
J=8.79 Hz, 0.5 H) 5,30 (d, J=9.52 Hz, 0.5 H) 5.81 (d, J=8.79 Hz, 0.5 H) 5.85 (d,
J=9.76 Hz, 0.5 H) 6.54 (d, J=2.93 Hz, 0.5 H) 6.79 (ddd, J=8.79, 5.13, 3.17 Hz, 1 H)
6.97 (m, 1.5 H) 7.54 (m, 3 H) 7.67 (d, J=6.33 Hz, 0.5 H) 7.90 (m, 3 H) S.io (d,
J=S.3O Hz, 0.5 H)
MS (APCl) m/z 390 ([M+H]+);
Anal, calcd for C24H23NO4: C:74.02 H:5.95 N:3.60 Found: C:73.79 H:6.09 N:3.35.
Example 8 -- Part 1
tert-Butyl (E)-2-cyano-3-[2-(trifluoromethyl)phenyl]-2-propenoate
A mixture of 2-trifluoromethyl benzaldehyde (13.19mL, 100mmol), t-
butylcyanoacetate and piperazine resin (350mg) in toluene was heated under a Dan
Stark trap for 2 hours. The reaction was cooled, diluted with ethyl acetate and
filtered. The solution was concentrated in vacuo to yield the title compound as a
clear oil.
1H NMR (500 MHz,DMSO-D6 δ 1.52 (s, 9H), 7.78 (t, J=7.63 Hz, 1H), 7.88 (t, J=
7.79Hz,1H), 7.92 (d, J=7.79Hz,1H), 8.05 (d, J=7.63Hz, 1H), 8.46 (d, J=1.36Hz,1H)
MS (ESI) m/z 315 ([M+NH4]+);
Anal, calcd for C15H14F3NO2: C:60.61 H:4.75 N:4.71 Found: C:60.59 H:4.68 N:4.72.
Example 8 - Part 2
tert-Butyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethyl)phenyl]propanoate
The title compound was prepared according to example 6 using
tert-butyl (E)-2-cyano-3-[2-(trifluoromethyl)pheny!]-2-propenoate prepared in part A
as the starting material. This provided the title compound as a white foam.
1H NMR (500 MHz, DMSO-D6) δ 1.08 (s, 4.5 H) 1.14 (s, 4.5 H) 5.09 (d, J=7.63 Hz,
0.5 H) 5.26 (d, J=7.94 Hz, 0.5 H) 5.84 (d, J=7.79 Hz, 0.5 H) 5.91 (d, J=7.94 Hz, 0.5
H) 7.23 (d, J=7.33 Hz, 0.5 H) 7.45 (m, 0.5 H) 7.54 (m, 1.5 H) 7.59 (m, 1.5 H) 7.67
(m, 1 H) 7.71 (td, J=7.71, 1.22 Hz, 0.5 H) 7.81 (m, 1.5 H) 7.94 (m, 3 H) 8.13 (d,
J=8.55 Hz, 0.5 H) 8.17 (d, J=7.94 Hz, 0.5 H)
MS (ESI) m/z 443 ([M+NH4]+);
Anal, calcd for C25H22F3NO2: C:70.58 H:5.21 N-.3.29 Found: C:70.64 H:5.35 N:3.19.
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Example 9 Part 1
tert-Butyl (E)-2-cyano-3-(1 -naphthyl)prop-2-enoate
1-naphthaldehyde (17.4 mL, 128.06 mmol), tert-butyl cyano acetate (21.8 mL,
153.67 rnmol), piperidinium acetate (64 mmol), tolusns (250 mL), and ethanol
(20mL) were combined in a. flask fitted with a Dean-Stark apparatus and refluxed
with removal of water for 4 hrs. The reaction was cooled, taken up in isopropyl
acetate, washed twice with 1 N HCl, once with saturated aqueous NaHCO3, brine,
dried with MgSO4, filtered, and evaporated. Reaction yielded 33g of the title
compound as an oil. The oil crystallized (thick needles) after standing for a
prolonged period (4 months) at room temperature,
mp 51-53 °C;
1H NMR (400 MHz, DMSO-D6) δ 1.55 (s, 9 H) 7.62 (m, 3 H) 8.00 (m, 2 H) 8.10 (s, 1
H)8.12(s, 1 H)8.95(s, 1 H)
MS (APCl) m/z 280 ([M+H]+);
Anal. calcd for C18H17NO2: C:77.40 H:6.13 N:5.01 Found: C:76.30 H:5.95 N:4.81.
Example 9 Part 2
tert-Butyl 2-cyano-3,3-di(1 -naphthyl)propanoate
Tert-butyl (E)-2-cyano-3-(1-naphthyl)prop-2-enoate (559 mg, 2 mmol) was
disolved in 15 mL dry THF and stirred under argon at room temperature while 0.25
M 1-naphthyl magnesium bromide (9.6 mL, 2.4 mmol) was added dropwise. The
reaction was stirred 2 hrs., quenched with 1 N HCl, taken up in ethyl acetate,
washed with NaHCO3, brine, dried with MgSO4, filtered, and evaporated. The crude
reaction mixture was purified via crystallization from ethanol to yield 480 mg of the
title compound as a crystalline solid,
mp 156-157 °C;
1H NMR (400 MHz, DMSO-D6) δ 1.06 (s, 9 H) 5.26 (d, J=8.06 Hz, 1 H) 6.27 (d,
J=8.06 Hz, 1 H) 7.31 (dd, J=7.32, 1.22 Hz, 1 H) 7.40 (m, 2 H) 7.47 (m, 1 H) 7.61 (m,
2 H) 7.71 (ddd, J=8.48, 6.90, 1.46 Hz, 1 H) 7.90 (m, 5 H) 8.00 (dd, J=8.18,1.10 Hz,
1 H) 8.39 (d, J=8.54 Hz, 1 H)
MS (APCl) m/z 406 ([M-H]-);
Anal, calcd for C28H25NO2: C:82.53 H:6.18 N:3.44 Found: C:81.44 H.5.93 N.3.39.
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Example 10
Ethyl 2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 6 using 2-cyano-3-
naphthalen-i-yl-acrylic acid ethyl estsr and 2-methoxyphenyl magnesium bromide
as starting materials. This provided the title compound as a low melting solid which
NMR shows to be a 50:50 mixture of diastereomers
1H NMR (400 MHz, DMSO-D6) δ 0.88 (m, 3 H) 3.84 (s, 1.5 H) 3.94 (s, 1.5 H) 3.99
(m, 2 H) 5.15 (d, J=8.30 Hz, 0.5 H) 5.25 (d, J=9.27 Hz, 0.5 H) 5.34 (d, J=8.30 Hz,
0.5 H) 5.88 (d, J=9.52 Hz, 0.5 H) 6.78 (td, J=7.44, 0.98 Hz, 0.5 H) 6.88 (td, J=7.38,
0.85 Hz, 0.5 H) 6.95 (dd, J=7.69, 1.59 Hz, 0.5 H) 7.05 (t, J=7.69 Hz, 1 H) 7.23 (ddd,
J=15.68, 7.99, 1.71 Hz, 1 H) 7.35 (dd, J=7.81, 1.71 Hz, 0.5 H) 7.52 (m, 3 H) 7.60 (d,
J=7.81 Hz, 0.5 H) 7.65 (d, J=7.08 Hz, 0.5 H) 7.83 (d, J=8.30 Hz, 0.5 H) 7.90 (m, 3 H)
8.11 (d, J=8.79 Hz, 0.5 H)
MS (El) m/z M+. (359);
Anal, calcd for C23H21NO3: C:76.86 H:5.89 N:3.90 Found: C:76.51 H:5.85 N:3.83.
Example 11
Ethyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate
Fractional crystallization of the solid from example 10 in ethyl
acetate/hexanes provided colorless needles of the title compound,
mp 123-126 °C;
1H NMR (500 MHz, DMSO-D6) δ 0.89 (t, J=7.10 Hz, 3 H) 3.94 (s, 3 H) 4.01 (ddd,
J=14.16, 7.06, 1.07 Hz, 2 H) 5.15 (d, J=8.40 Hz, 1 H) 5.85 (d, J=8.55 Hz, 1 H) 6.78
(td, J=7.52, 0.99 Hz, 1 H) 6.96 (dd, J=7.64, 1.68 Hz, 1 H) 7.06 (dd, J=8.25, 0.92 Hz,
1 H) 7.22 (ddd, J=7.33, 1.83, 0.61 Hz, 1 H) 7.48 (m, 2 H) 7.59 (dd, J=8.17, 7.41 Hz,
1 H) 7.91 (m, 4 H)
MS (ESI) m/z 377 ([M+NH4]+);
Anal, calcd for C23H21NO3 . 0.15 H2O: C:76.29 H:5.93 N:3.87 Found: C:76.33 H:5.82
N:3.70.
Example 12
tert-Butyl2-cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate
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A mixture of Cul (681 mg, 3.58mmol) in THF (10mL), cooled to 0°, was treated
with a cold, 0°, solution of 2-isopropyl lithium (from 1.43g of 1-bromo-2-isopropyl-
benzene and nBuLi (4.48mL, 1.6M in hexane) in THF (10mL). This mixture was
added to a cold solution of 2-cyano-3-naphthalen-1-yl-acrylic acid f erf-butyl ester in
THF (10mL). The reaction was stirred and allowed to warm to room temperature
over an hour. The reaction was quenched with ammonium chloride and diluted with
ether. The aqueous layer was washed twice with ether and the organic layers were
combined and washed with saturated ammonium chloride and brine. The sample
was dried over Na2SO4 and was filtered and evaporated to a solid. Trituration of the
solid with provided the title compound as a white powder.
1H NMR (500 MHz, DMSO-D6) δ 0.64 (d, J=6.72 Hz, 1.5 H) 1.00 (d, J=6.72 Hz, 1
H) 1.11 (s, 4.5 H) 1.18 (s, 4.5 H) 1.22 (d, J=6.72 Hz, 1.5 H) 1.27 (d, 7=6.57 Hz, 1 H)
2.96 (m, 0.5 H) 5.00 (d, J=8.25 Hz, 0.5 H) 5.11 (d, J=7.94 Hz, 0.5 H) 5.77 (d, J=7.94
Hz, 0.5 H) 5.78 (d, J=8.09 Hz, 0.5 H) 7.12 (t, J=8.09 Hz, 0.5 H) 7.31 (m, 3.5 H) 7.44
(t, J=7.71 Hz, 0.5 H) 7.52 (m, 1 H) 7.59 (t, J=7.41 Hz, 0.5 H) 7.70 (m, 0.5 H) 7.75
(m, 0.5 H) 7.87 (t, J=8.78 Hz, 1 H) 7.95 (d, J=7.94 Hz, 0.5 H) 8.01 (m, 1 H) 8.22 (d,
J=8.70 Hz, 0.5 H)
MS (ESI) m/z 417 ([M+NH4]+);
Anal, calcd for C27H29NO2: C:81.17 H:7.32 N:3.51 Found: C:81.05 H:7.34 N:3.49.
Example 13
tert-Butyl 2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate
Terf-butyl (E)-2-cyano-3-(1-naphthyl)prop-2-enoate (2.23g, 8 mmol) was
dissolved in 40 mL dry THF and stirred under argon at room temperature while 1 M
2-methoxyphenyl magnesium bromide (9.6 mL, 9.6 mmol) was added dropwise.
The reaction was stirred 2 hrs., quenched with 1 N HCl, taken up in ethyl acetate,
washed with NaHCO3, brine, dried with MgSO4, filtered, and evaporated. The crude
reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to yield a
yellowish oil which recrystallized from ethanol to yield 1.661 g product as a
crystalline polymorphic solid.
1H NMR (400 MHz, DMSO-D6) δ 1.04 (s, 4.5 H) 1.09 (s, 4.5 H) 3.83 (s, 1.5 H) 3.95
(s, 1.5 H) 5.06 (d, J=8.79 Hz, 0.5 H) 5.11 (d, J=10.49 Hz, 0.5 H) 5.81 (d, J=8.79 Hz,
0.5 H) 5.86 (d, J=10.74 Hz, 1.5H) 6.80 (t, J=7.08 Hz, 0.5 H) 6.92 (t, J=7.44 Hz, 0.5
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H) 7.03 (m, 1.5 H) 7.23 (m, 1 H) 7.50 (m, 2 H) 7.59 (m, 1 H) 7.65 (d, J=6.59 Hz. 0.5
H) 7.82 (d, J=8.05 Hz, 0.5 H) 7.92 (m, 3 H) 8.22 (d, J=8.54 Hz, 0.5 H)
MS (APCl) m/z 388 ([M+H]+);
Anal, calcd for C-25H25NO3: C:77.49 H:6.50 N:3.61 Found: C:77.40 H.6.25 N:3.57
Example 14
tert-Butyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethoxy)phenyl]propanoate
The title compound was prepared according to example 6 using 2-cyano-3-(2-
trifluoromethoxy-phenyl)-acrylic acid tert-butyl ester as the starting material. The
crude product was chromatographed on silica using 25% ethyl acetate/ hexanes.
Recrystallization from methylene chloride/ hexane provided the title compound as a
crystalline solid,
mp 115-118°C
1H NMR (500 MHz, DMSO-D6) δ 1.04 (s, 5 H) 1.16 (s, 3 H) 5.19 (d, J=9.32 Hz, 0.4
H) 5.25 (d, J=9.47 Hz, 0.6 H) 5.76 (d, J=9.16 Hz, 0.4 H) 5.80 (d, J=9.62 Hz, 0.6 H)
7.46 (m, 6.4 H) 7.65 (ddd, J=8.44, 6.99,1.22 Hz, 0.6 H) 7.82 (d, J=7.18 Hz, 0.4 H)
7.87 (dd, J=5.65, 3.66 Hz, 0.6 H) 7.91 (d, J=8.09 Hz, 0.4 H) 7.97 (d, J=7.94 Hz, 1 H)
7.99 (dd, J=7.56, 1.91 Hz, 0.6 H) 8.04 (d, J=8.40 Hz, 0.4 H) 8.19 (d, J=8.70 Hz, 0.6
H)
MS (ESI) m/z 440 ([M-H]-);
Anal, calcd for C25H22F3NO3: C:68.02 H:5.02 N:3.17 Found: C:67.88 H:5.04 N:3.11.
Example 15
Ethyl 2-cyano-3-(1-naphthyl)-3-phenylpropanoate
A solution of 2-cyano-3-naphthalen-1-yl-acrylic acid ethyl ester
(0.502mg,2mmol) in THF(15mL) was treated with phenyl magnesiun bromide
(1.2mL,2M in THF) dropwise with stirring under nitrogen. After one hour the reaction
was quenched with 1N HCl. The solution was diluted with isopfopyl acetate (15mL)
and the organic layer was isolated. The organic layer was washed with bicarbonate
solution and brine. Chromatography over silica gel (15% MTBE/hexane) provided
the title compound as an oil from which solidified on standing. NMR suggests a 6:1
ratio of diastereomers.
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1H NMR (400 MHz, DMS0-D6) δ 0.89 (dt, J=9.70, 7.11 Hz, 3 H) 4.00 (ddd,
J=14.28, 7.08, 1.10 Hz, 2 H) 5.33 (d, J=9.76 Hz, 0.8 H) 5.40 (d, J=9.76 Hz, 0.2 H)
5.51 (d, J=9.76 Hz, 0.8 H) 5.55 (d, J=9.76 Hz, 0.2 H) 7.25 (m, 3.2 H) 7.40 (d, J=7.08
Hz, i.o H) 7.52 (m, 2.6 H) 7.60 (t, J=7.81 Hz, 1 H) 7.72 (d, J=7.08 Hz, 0.2 H) 7.84
(d, J=8.79 Hz, 0.2 H) 7.90 (d, J=3.05 Hz, i H) 7.94 (m, i.o H) S.iS (rn, 0.S hi) 8.30
(d, J=7.57 Hz, 0.2 H)
MS (El) m/z M+. (329);
Anal, calcd for C22H19NO2: C:80.22 H:5.81 N:4.25 Found: C-:80.03 H:5.94 N:4.21.
Example 16
Ethyl 2-cyano-3,3-bis(2-methoxyphenyl)propanoate
A solution of 2-cyano-3-(2-methoxy-phenyl)-acrylic acid ethyl ester (2mmol) in
THF (10mL) is treated with 2-methoxyphenyl magnesium bromide (2.4mmol,1M
THF) at room temperature. The reaction is stirred for 3 hours, quenched with 1N HCl
and diluted with isopropyl acetate (15mL). The aqueous layer is removed and the
organic layer is washed with bicarbonate then brine and is dried over Na2SO4.
Evaporation of the sample yields an oil which is chromatographed on silica gel (25%
ethyl acetate hexane) to yield the title compound as a viscous oil.
1H NMR (DMSO-D6): δ 0.93 (t, J=7.20 Hz, 3 H), 3.71 (s, 3 H), 3.79 (s, 3H), 4.00
(ddd, J=14.15 Hz, 7.08 Hz, 1.22 Hz, 2H), 4.98 (d, J=8.79 Hz, 1H), 5.35 (d, J=8.79
Hz, 1H), 6.85 (td, J=7.44 Hz, 0.98 Hz, 1H), 6.97 (m, 3H), 7.07 (dd, J=7.57 Hz,
J=1.71 Hz, 1H), 7.24 (m, 2H), 7.45 (dd, J=7.57 Hz, 1.46 Hz, 1H)
MS (APCl) m/z [M+NH4]+ (357);
Anal, calcd for C20H21NO4: C:70.78 H.6.24 N:4.13 Found: C:70.64 H:6.07 N:4.03.
Example 17
Ethyl 2-cyano-3-(1 -naphthyl)-3-(2-nitrophenyl)propanoate
The title compound was prepared using 2-cyano-3-(2-nitro-phenyl)-acrylic
acid ethyl
ester according to example 6.The title compound was a sticky viscous oil
1H NMR (DMSO-D6): 0.92 (td, J=7.08 Hz, 3.66 Hz, 2.5 H), 1.05 (t, J=7.08 Hz, 0.5
H), 3.44 (m, 0.5H), 4.02 (m, 1.5H), 4.35 (t, J=5.13 Hz, 0.5H), 5.41 (d, J=2.20 Hz,
0.5H), 5.43 (d, J=2.93 Hz, 0.5H), 6.25 (t, J=8.18 Hz, 1H), 7.41 (m, 1.5H), 7.50 (m,
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2.5H), 7.61 (m, 1.5H), 7.82 (m, 0.5 H), 7.91 (d, J=8.05 Hz, 1.5H), 7.96 (m, 1.5 H),
8.01 (dd, J=8.05 Hz, 1.22 Hz, 0.5 H), 8.05 (d, J=8.30 Hz, 0.5H), 8.10 (dd. J=8.05 Hz,
1.22 Hz, 0.5H)
MS (APCI) m/z 375 ([M+H]+);
Anal, calcd for C22H18N2O4: C:70.58 H:4.85 N:7.4S Found: 0:69.19 H:4.S7 N:6.97.
Example 18
tert-Butyl 2-cyano-3-(2,6-dimethyiphenyl)-3-(1-naphthyl)propanoate
2,6 (Dimethyl)phenyl magnesium bromide (50mL , 1.0M in THF)
was added dropwise to a a stirred solution of 2-cyano-3-naphthalen-1-yl-acry!ic acid
tert-butyl ester (11.6g,41.5mmol) in THF (170mL) under N2 . The reaction was
stirred overnight during which time a precipitate formed. The reaction was then
treated with HCl (250ml, 1N) and diluted with ethyl acetate (500mL). The organic
layer was separated and the aqueous layer was extracted with ethyl acetate
((250mL). The organic layers were combined and were washed with saturated brine
(250mL), dried over Na2SO4 and concentrated in vacuo to yield 16.1 g of a solid.
Recrystallization of the crude product yielded 12.4 g of the title compound
mp 124-128 °C;
1H NMR (500 MHz, DMSO-D6) δ 1.23 (s, 9 H) 1.33 (s, 6 H) 5.10 (d, J=6.57 Hz, 1 H)
5.44 (d, J=11.76 Hz, 0.5 H) 5.58 (d, J=6.87 Hz, 1.5 H) 7.00 (s, 1 H) 7.07 (m, 1 H)
7.35 (m, 1 H) 7.44 (m, 1 H) 7.53 (m, 0.5 H) 7.59 (t, J=7.79 Hz, 1 H) 7.64 (d, J=7.48
Hz, 0.5 H) 7.87 (t, J=6.95 Hz, 1 H) 7.92 (dd, J=11.53, 8.17 Hz, 2 H)
MS (ESI) m/z 403 ([M+NH4]+); Anal, calcd for C26H27NO2: C:81.01 H:7.06 N:3.63
Found: C:80.67 H:7.08 N:3.55.
Example 19
tert-Butyl (RR,SS)-2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethyl)phenyl]propanoate
A solution of 2-(trifluoromethyl)phenyl magnesium bromide in THF was
prepared (J. Med. Chem. 33 (1990) 1452) this material was used in the procedure
described in example 18 to yield the title compound as a reddish solid.
Chromatography over SiO2 using 105 to 40% ethyl acetate/hexanes yielded the title
compound as a white solid.
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mp 120.5-125.0 X; 1H NMR (500 MHz, DMSO-D6) δ 1.08 (s, 5 H) 1.14 (s, 3 H)
5.09 (d, J=7.79 Hz, 0.4 H) 5.26 (d, J=7.94 Hz, 0.6 H) 5.85 (d, J=7.79 Hz, 0.4 H) 5.91
(d, J=7.79 Hz, 0.6 H) 7.23 (d, J=7.18 Hz, 0.5 H) 7.45 (t, J=7.64 Hz, 0.5 H) 7.56 (m, 3
H) 7.69 (m, -i.5 H) 7.81 (m, 1.5 H) 7.94 (m, 3 H) 8.15 (dd, J=16.49, 8.25 Hz, 1 HV,
MS (ESI) m/z 443 ([ivi+NH4]+); Anal, calcd for C25H22F3NO2: C:7Q.58 H:5.21 N:3.29
Found: C:70.62 H:5.14
Example 20
ten-Butyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoat6
A solution of 2-cyano-3-(2-methoxy-phenyl)-3-naphthalen-1-yl-propionic acid
tert-butyl ester in THF ( 25mL) was treated at room temperature with potassium
bistrimethylsilyl amide (3.64mL, 2.4mmol, 0.66M in toluene). The reaction was
stirred for two hours and then methyl iodide was added (0.5mL, 8mmol). The
reaction was stirred at room temperature for one hour and was quenched with 1N
HCI. The reaction was diluted with ethyl acetate and the organic layer was isolated.
The organic layer was washes with saturated sodium bicarbonate solution and brine.
The organic layer was dried over Na2SO4, filtered and was concentrated in vacuo.
Trituration of the resulting solid with ethanol provided 700mg of the title compound
as a white powder.
1H NMR (400 MHz, DMSO-D6) δ 1.02 (s, 9 H) 1.62 (s, 3 H) 4.04 (s, 3 H) 5.76 (s, 1
H) 6.83 (td, J=7.50, 1.10 Hz, 1 H) 7.21 (m, 3 H) 7.47 (m, 2 H) 7.60 (t, J=7.32 Hz, 1
H) 7.89 (m, 3 H) 8.06 (d, J=7.08 Hz, 1 H)
MS (APCl) m/z 402 ([M+H]+);
Anal, calcd for C26H27NO3: C:77.78 H:6.78 N:3.49 Found: C:77.41 H:6.84 N:3.67.
Example 21 Part 1
(-) Ethyl (SS)2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
A sample of ethyl (RR,SS)cyano-3-(2-methoxypheny!)-2-methyl-3-(1-
naphthyl)propanoate was dissolved in methanol and was resolved by
chromatography on a preparative HPLC system using a Chiralcel OD (25 x 5cm)
column and 8:2 methanol:water as the eluant. The title compound was the first peak
to elute. Recrystallization from ethanol provided the title compound as colorless
crystals.
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mp 134.5-135.5 °C;
[α]D25 = -297.79° (1%, CHCl3);
Example 21 Part 2
(+) Ethyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-nsphthyl)propanoate
The title compound was the second peak to elute in example 21 part 1.
Recrystallization from ethanol provided the title compound as colorless crystals,
mp 134.5-135.5 °C;
[α]D25 = +289.80° (1%,CHCl3);
Example 22
Ethyl (RR,SS)-2-cyano-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-4-pentenoate
The title compound was prepared according to example 20 using allyl
bromide. Recrystallization of the crude product from methanol provided the title
compound as an off white solid.
1H NMR (500 MHz, DMSO-D6) δ 0.73 (t, J=7.10 Hz, 3 H) 2.43 (dd, J=13.74, 6.72
Hz, 1 H) 2.94 (dd, J=13.90, 7.94 Hz, 1 H) 3.92 (m, 2 H) 4.06 (s. 3 H) 5.18 (dd,
J=11.07, 1.60 Hz, 1 H) 5.21 (d, J=3.05 Hz, 1 H) 5.71 (m, 1 H) 5.88 (s, 1 H) 6.84 (t,
J=7.02 Hz, 1 H) 7.16 (d, J=8.25 Hz, 1 H) 7.25 (m, 2 H) 7.47 (m, 2 H) 7.58 (m, 1 H)
7.85 (d, J=8.25 Hz, 1 H) 7.88 (m, 1 H) 7.93 (m, 1 H) 8.08 (d, J=7.02 Hz, 1 H)
MS (ESI) m/z417 ([M+NH4]+);
Anal, calcd for C26H25NO3: C:78.17 H:6.31 N:3.51 Found: C:78.53 H:6.31 N:3.48.
Example 23
Ethyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 20 using benzyl
bromide. Recrystallization of the crude product from methanol provided the title
compound as a white solid.
1H NMR (500 MHz, DMSO-D6) δ 0.58 (t, J=7.10 Hz, 3 H) 2.90 (d, J=13.44 Hz, 1 H)
3.57 (d, J=13.59 Hz, 1 H) 3.79 (m, 2 H) 4.09 (s, 3 H) 6.05 (s, 1 H) 6.89 (t, J=7.86 Hz,
1 H) 7.10 (m, 2 H) 7.19 (d, J=7.94 Hz, 1 H) 7.30 (m, 5 H) 7.49 (m, 2 H) 7.56 (m, 1 H)
7.84 (d, J=8.25 Hz, 1 H) 7.89 (d, J=9.47 Hz, 1 H) 8.00 (d, J=8.09 Hz, 1 H) 8.07 (d,
J=7.18Hz, 1 H)
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MS (ESI) m/z467 ([M+NH4]+);
Anal, calcd for C30H27NO3: C:80.15 H:6.05 N:3.12 Found: C:79.99 H:6.00 N:3.04.
Example 24
fen-Butyl (RR,SS;)-2-cyano-3-(2-isopropylph6nyl)-2-methyl-3-(1-napht1nyl)propanoate
The title compound was prepared according to example 20 using tert-butyl 2-
cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate as the starting material.
Recrystallization from MeOH provided the title compound.
1H NMR (500 MHz, DMSO-D6) δ 0.26 (d, J=6.72 Hz, 3 H) 1.19 (d, J=6.72 Hz, 2 H)
1.21 (s, 9 H) 1.54 (s, 3 H) 2.95 (m, 1 H) 5.62 (s, 1 H) 7.26 (m, 2 H) 7.33 (m, 1 H)
7.44 (m, 2 H) 7.58 (m, 1 H) 7.72 (t, J=7.18 Hz, 1 H) 7.88 (d, J=7.79 Hz, 1 H) 7.99
(dd, J=7.79,4.28 Hz, 2 H) 8.47 (d, J=8.70 Hz, 1 H)
MS (ESI) m/z 370 ([M+H]+);
Anal, calcd for C28H31NO2: C:81.32 H:7.56 N:3.39 Found: C:81.23 H:7.54 N:3.38
Example 25 Part 1
tert-Butyl(RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-(trifluoromethyl)
phenyl]propanoate
The title compound was prepared according to example 20 using tert-butyl 2-
cyano-3-(2- trifluoromethyl)phenyl)-3-(1-naphthyl)propanoate as the starting
material.
Fractional recrystallization of the solid from MeOH provided the title compound as a
white solid,
mp 159-161 °C;
1H NMR (500 MHz, DMSO-D6) δ 1.14 (s, 9 H) 1.57 (s, 3 H) 5.78 (s, 1 H) 7.48 (t,
7=7.71 Hz, 1 H) 7.54 (m, 1 H) 7.57 (t, J=7.56 Hz, 2 H) 7.70 (ddd, J=8.47, 6.95, 1.22
Hz, 1 H) 7.74 (d, J=7.79 Hz, 1 H) 7.91 (m, 2 H) 7.98 (d, J=7.48 Hz, 1 H) 8.30 (d,
J=8.70 Hz, 1 H) 8.40 (d, J=7.94 Hz, 1 H)
MS (ESI) m/z 457 ([M+NH4]+);
Anal, calcd for C26H24F3NO2: C:71.06 H:5.50 N:3.19 Found: C:71.08 H:5.42N:3.19.
Example 25 Part 2
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tert-Butyl(R,R/SS)2-cyano-2-methyl-3-(1-naphthyl)-3-[2-(trifluoromethyl)
phenyljpropanoate
The mother liquors from example 25 part 1 were separated on a Primesphere
C18 (25x5cm) column in 1:4 water:methanol. This provided the title compound as a
white solid,
mp 136-138 °C;
1H NMR (500 MHz, DMSO-D6) δ 0.94 (s, 9 H) 1.58 (s, 3 H) 5.81 (s, 1 H) 7.51 (t,
J=7.41 Hz, 1 H) 7.58 (m, 3 H) 7.79 (d, J=7.79 Hz, 1 H) 7.82 (d, J=7.63 Hz, 1 H) 7.93
(dd, J=10.69, S.55 Hz, 2 H) 8.0S (t, J=8.17 Hz, 2 H) 8.22 (d, J=7.94 Hz, 1 H)
MS (ESI) m/z457 ([M+NH4]+);
Anal, calcd for C26H24F3NO2: C:71.06 H:5.50 N:3.19 Found: C:71.10 H:5.48 N:3.03.
Example 26
tert-Butyl (RS,SR)-2-cyano-3-(2,6-dimethylphenyl)-2-methyl-3-(1-
naphthyl)propanoate
The title compound was prepared according to example 20 using
2-cyano-3-(2,6-dimethyl-phenyl)-3-naphthalen-1-yl-propionic acid tert-butyl ester
as the starting material. Recrystallization from MeOH provided the title compound as
a white solid,
mp 155-156 °C;
1H NMR (500 MHz, DMSO-D6) δ 1.28 (s, 9 H) 1.68 (s, 3 H) 1.74 (s, 3 H) 2.78 (s, 3
H) 5.52 (s, 1 H) 6.82 (d, J=7.48 Hz, 1 H) 7.11 (t, J=7.64 Hz, 1 H) 7.28 (d, J=7.33 Hz,
1 H) 7.34 (td, J=7.71, 1.07 Hz, 1 H) 7.44 (t, J=7.41 Hz, 1 H) 7.48 (d, J=8.70 Hz, 1 H)
7.61 (t, J=7.79 Hz, 1 H) 7.91 (dd, J=11.30, 8.09 Hz, 2 H) 8.01 (d, J=7.33 Hz, 1 H)
MS (APCl) m/z 400 ([M+H]+);
Anal, calcd for C27H29NO2: C:81.17 H:7.32 N:3.51 Found: C:81.03 H:7.27 N:3.46.
Example 27
tert-Butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 20 using benzyl
bromide. Trituration of the solid in methanol provided the title compound as a white
powder,
mp 208 °C;
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1H NMR (500 MHz, DMS0-D6) δ 0.85 (s, 9 H) 2.89 (d, J=13.44 Hz, 1 H) 3.53 (d,
J=13.59 Hz, 1 H) 4.09 (s, 3 H) 6.00 (s, 1 H) 6.90 (td, J=7.52, 0.99 Hz, 1 H) 7.17 (m,
3 H) 7.29 (m, 4 H) 7.36 (dd, J=7.79, 1.53 Hz, 1 H) 7.50 (m, 2 H) 7.59 (m, 1 H) 7.85
(d, J=S.25 Hz, 1H) 7.90 (dd, J=8.09, 1.07 Hz, 1 H) 8.03 (d, J=S.40 Hz, 1 H) 8.14 (d,
J=7.18Hz, 1H)
MS (ESI) m/z 495 ([M+NH4]+);
Anal, calcd for C32H31NO3: C:80.48 H:6.54 N:2.93 Found: C:80.48 H:6.42 N:2.93.
Example 28
tert-Butyl (RR, SS)-2-(3-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1-
naphthyl)propanoate
The title compound was prepared according to example 20using tert-butyl
(RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate and 3-
chloro-benzyl bromide as the starting materials. Trituration with methanol provided
the title compound as a white solid,
mp 175-179 °C;
1H NMR (500 MHz, DMSO-D6) δ 0.87 (s, 9 H) 2.91 (d, J=13.59 Hz, 1 H) 3.56 (d,
J=13.74 Hz, 1 H) 4.08 (s, 3 H) 5.99 (s, 1 H) 6.89 (t, J=7.56 Hz, 1 H) 7.15 (d, J=7.18
Hz, 1 H) 7.19 (m, 2 H) 7.29 (td, J=7.83, 1.30 Hz, 1 H) 7.36 (m, 3 H) 7.50 (m, 2 H)
7.59 (t, J=7.79 Hz, 1 H)7.86 (d, J=8.25 Hz, 1 H) 7.90 (dd, J=7.86, 1.15 Hz, 1 H) 8.01
(d, J=8.25 Hz, 1 H) 8.12 (d, J=7.18 Hz, 1 H)
MS (APCl) m/z 529 ([M+NH4]+);
Anal, calcd for C32H30CINO3: C:75.06 H:5.91 N:2.74 Found: C:74.84 H:5.81 N:2.72.
Example 29
tert-Butyl(RR,SS)-2-(2-bromobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1-
naphthyl)propanoate
The title compound was prepared according to example 20using tert-butyl
(RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate and 2-
bromo-benzyl bromide as the starting materials. Chromatography on silica gel with
25% ethyl acetate/hexanes as the eluant provided the title compound as a white
solid.
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1H NMR (500 MHz, DMS0-D6) 6 0.89 (s, 9 H) 3.36 (d, J=14.35 Hz, 1 H) 3.75 (d,
J=14.51 Hz, 1 H) 4.11 (s, 3 H) 6.01 (s, 1 H) 6.90 (t, J=7.33 Hz, 1 H) 7.32 (m, 6 H)
7.54 (m, 4 H) 7.86 (d, J=8.09 Hz, 1 H) 7.90 (d, J=7.79 Hz, 1 H) 8.06 (d, J=8.55 Hz, 1
H)8.17(d, J=7.02Hz, 1 H)
MS (ESI) m/z 575 ([M+NH4]+);
Anal, calcd for C32H30BrNO3: C:69.07 H:5.43 N:2.52 Found: C:69.16 H:5.42 N:2.50.
Example 30
tert-Butyl (RR, SS)-2-(2-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-('i-
naphthyl)propanoate
The title compound was prepared according to example 20using tert-butyl
(RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyi)propanoate and 2-
chlorobenzyl bromide as the starting materials. Trituration with methanol provided
the title compound as a white solid.
1H NMR (500 MHz, DMSO-D6) δ 0.89 (s, 9 H) 3.32 (d, J=13.29 Hz, 1 H) 3.71 (d,
J=14.35 Hz, 1 H) 4.10 (s, 3 H) 6.01 (s, 1 H) 6.90 (td, J=7.56, 1.07 Hz, 1 H) 7.20 (dd,
J=8.32, 0.84 Hz, 1 H) 7.30 (m, 4 H) 7.42 (m, 2 H) 7.51 (m, 2 H) 7.59 (m, 1 H) 7.86
(d, J=8.25 Hz, 1 H) 7.90 (dd, J=8.02, 1.30 Hz, 1 H) 8.06 (d, J=8.40 Hz, 1 H) 8.16 (d,
J=7.02 Hz, 1 H)
MS (ESI) m/z 529 ([M+NH4]+);
Anal, calcd for C32H30CINO3 . 0.15 H2O: O.74.67 H:5.93 N:2.72 Found: C:74.63
H:5.87 N:2.66.
Example 31
tert-Butyl (RR,SS)-2-cyano-2-(2,6-dichlorobenzyl)-3-(2-methoxyphenyl)-3-(1-
naphthyl)propanoate
The title compound was prepared according to example 20using tert-butyl
(RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate and 2,6-
dichlorobenzyl bromide as the starting materials. Trituration with methanol provided
the title compound as a white solid.
1H NMR (500 MHz, DMSO-D6) δ 0.80 (s, 9 H) 3.61 (d, J=14.35 Hz, 1 H) 3.83 (d,
J=14.35Hz, 1 H)4.11 (s, 3 H) 6.05 (s, 1 H) 6.89 (td, J=7.56, 1.07 Hz, 1 H)7.18(dd,
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J=8.40, 0.92 Hz, 1 H) 7.30 (m, 2 H) 7.42 (m, 2 H) 7.53 (m, 4 H) 7.86 (d, J=8.25 Hz, 1
H) 7.90 (dd, J=8.09, 1.07 Hz, 1 H) 8.17 (t, J=7.86 Hz, 2 H)
MS (ESI) m/z 562 ([M+NH4J+);
Anal, calcd for C32H29Cl2NO3 . 0.30 H2O: C:69.64 H:5.41 N:2.54 Found: C:69.57
H:5.44 N:2.44.
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Example 32
Ethyl (RR,SS)-2-cyano-3-(2,4-dimethoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
The title compound was prepared according to example 20 using ethyl 2-
cyano-3-(2,4-dimethoxyphenyl)-3-(1-naphthyl)propanoate. Chromatography on silica
gel using 25% ethyl acstate/hexanes as eluant prcvidsd the title compound as a
white powder.
1H NMR (500 MHz, DMSO-D6) δ 0.75 (t, J=7.02 Hz, 3 H) 1.64 (s, 3 H) 3.70 (s, 3 H)
3.97 (m, 2 H) 4.04 (s, 3 H) 5.68 (s, 1 H) 6.42 (dd, J=8.70, 2.44 Hz, 1 H) 6.69 (d,
J=2.44 Hz, 1 H) 7.03 (d, J=3.70 Hz, 1 H) 7.46 (dq, J=9.62, 0.92 Hz, 2 H) 7.56 (t,
J=7.48 Hz, 1 H) 7.83 (d, J=8.25 Hz, 1 H) 7.87 (m, 2 H) 8.00 (d, J=7.18 Hz, 1 H)
MS (ESI)m/z404([M+H]+);
Anal, calcd for C25H25NO4: C:74.42 H:6.25 N:3.47 Found: C:73.77 H.6.32 N:3.31.
Example 33
tert-Butyl (RS,SR)-2-cyano-2-methyl-3-(1 -naphthyl)-3-[2-
(trifluoromethoxy)phenyl]propanoate
The title compound was prepared according to example 20 using tert-butyl 2-
cyano-3-(1-naphthyl)-3-[2-(trifluoromethoxy)phenyl]propanoate as the starting
material. Recrystallization from ethanol provided the title compound as a crystalline
solid.
mp 150-153 °C;
1H NMR (500 MHz, DMSO-D6) δ 1.25 (s, 9 H) 1.48 (s, 3 H) 5.70 (s, 1 H) 7.29 (d,
J=8.40 Hz, 1 H) 7.46 (ddd, J=8.09, 7.33, 1.07 Hz, 1 H) 7.49 (m, 2 H) 7.58 (td,
J=7.25, 5.65 Hz, 2 H) 7.69 (t, .7=7.41 Hz, 1 H) 7.91 (dd, J=6.41, 2.90 Hz, 1 H) 7.99
(d, J=8.09 Hz, 1 H) 8.18 (dd, J=7.86, 0.99 Hz, 1 H) 8.36 (d, J=8.70 Hz, 1 H)
MSm/z 00-E1394P;
Anal, calcd for C26H24F3NO3: C:68.56 H:5.31 N:3.08 Found: C:68.36 H.5.24 N:2.96.
Example 34
Ethyl 2-cyano-2-methyl-3,3-di(1 -naphthyl)propanoate
A solution of 2-cyano-3,3-di-naphtha!en-1-yl-propionic acid ethyl ester was
dissolved in THF (3mL) and treated with sodium bis-trimethylsilyl amide (39μl, 1M in
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THF) at room temperature. After 5 minutes methyl iodide was added (9ul) and the
reaction was stirred for 4 hours. The reaction was quenched with 1N HCl (3ml) and
was diluted with isopropyl acetate (3mL). The organic layer was washed with
bicarbonate then brine; dried over Na2SO4, filtered and evaporated to yield the title
compound as a crystalline material.
mp 186-188°C;
1H NMR (400 MHz, DMSO-D6) δ 0.81 (t, J=7.08 Hz, 3 H) 1.66 (s, 3 H) 4.01 (m, 2 H)
6.19 (s, 1 H) 7.32 (td, J=7.69, 1.22 Hz, I H) 7.43 (q, J=7.57 Hz, 2 H) 7.57 (d, J=7.32
Hz, 1 H) 7.62 (td, J=7.69, 3.90 Hz, 2 H) 7.77 (td, J=7.69, 0.98 Hz, 1 H) 7.39 (m, 4 H)
8.01 (d, J=7.32 Hz, 1 H) 8.10 (d, J=7.08 Hz, 1 H) 8.76 (d, J=8.54 Hz, 1 H)
MS (El) m/z M+. (393);
Anal, calcd for C27H93NO2: C:82.42 H:5.89 N:3.56 Found: C:82.20 H:5.84 N:3.52.
Example 35
Ethyl 2-cyano-3-(3-methoxyphenyl)-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 15, using 3-methoxy-
phenyl magnesium bromide. The sample is a viscous oil.
1H NMR (400 MHz, DMSO-D6) δ 0.85 (t, J=7.08 Hz, 1.5 H) 0.90 (t, J=7.20 Hz, 1.5
H) 2.04 (s, 1 H) 3.66 (s, 1.5 H) 3.67 (s, 1.5 H) 3.97 (m, 2 H) 5.30 (d, J=9.52 Hz, 0.5
H) 5.38 (d, J=10.01 Hz, 0.5 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.50 (d, J=9.76 Hz, 0.5 H)
6.76 (m, 1 H) 6.89 (d, J=8.30 Hz, 0.5 H) 6.97 (t, J=1.95 Hz, 0.5 H) 7.10 (m, 1 H) 7.15
(t, J=7.93 Hz, 0.5 H) 7.20 (t, J=7.93 Hz, 0.5 H) 7.49 (m, 1.5 H) 7.57 (t, J=7.69 Hz,
0.5 H) 7.70 (d, J=7.08 Hz, 0.5 H) 7.81 (d, J=8.05 Hz, 0.5 H) 7.90 (m, 2 H) 8.16 (d,
J=9.52 Hz, 0.5 H) 8.30 (d, J=8.05 Hz, 0.5 H)
MS (El) m/z M+. (359);
Anal, calcd for C23H21NO3: C:76.86 H:5.89 N:3.90 Found: C:75.45 H:5.83 N.3.58
Example 36
Ethyl 2-cyano-3-(4-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4-methoxy-
phenyl magnesium bromide. The sample is a viscous oil
1H NMR (400 MHz, DMSO-D6) δ 0.91 (dt, J=13.97, 7.05 Hz, 3 H) 3.66 (s, 1.5 H)
3.69 (s, 1.5 H) 4.01 (m, 2 H) 5.26 (d, J=9.76 Hz, 0.5 H) 5.33 (d, J=9.52 Hz, 0.5 H)
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5.45 (d, J=9.76 Hz, 0.5 H) 5.49 (d, J=9.76 Hz, 0.5 H) 6.69 (m, 0.5 H) 6.84 (ddd,
J=14.52, 6.71, 1.95 Hz, 2 H) 7.30 (d, J=8.79 Hz, 1 H) 7.48 (m, 3 H) 7.58 (t, J=7.57
Hz, 0.5 H) 7.71 (d, J=7.57 Hz, 0.5 H) 7.83 (d, J=8.30 Hz, 0.5 H) 7.91 (m, 2 H) 8.14
(dd, J=5.74,4.03 Hz, 0.5 H) 8.26 (d, J=8.30 Hz, 0.5 H)
MS (El) m/z M+. (359);
Anal, calcd for C-23H21NO3: C:76.86 H:5.89 N:3.90 Found: C:75.32 H:5.89 N:3.53.
Example 37
Ethyl 2-cyano-3-(4-methylphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4-methyl-
phenyl magnesium bromide. The sample is a viscous oil.
1H NMR (400 MHz, DMSO-D6) δ 0.90 (dt, J=12.45, 7.08 Hz, 3 H) 2.06 (s, 3 H)2.19
(s, 1.5 H) 2.22 (s, 1.5 H) 4.00 (ddd, J=13.85, 7.02, 4.03 Hz, 2 H) 5.28 (d, J=9.52 Hz,
0.5 H) 5.35 (d, J=9.52 Hz, 0.5 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.50 (d, J=9.52 Hz, 0.5
H) 7.09 (dd, J=15.13, 7.81 Hz, 2 H) 7.26 (d, J=8.30 Hz, 1 H) 7.41 (d, J=8.30 Hz, 1 H)
7.52 (m, 2.5 H) 7.70 (d, J=6.59 Hz, 0.5 H) 7.83 (d, J=8.05 Hz, 0.5 H) 7.91 (m, 1 H)
8.14 (dd, J=5.13, 4.39 Hz, 0.5 H) 8.26 (d, J=8.54 Hz, 0.5 H)
MS (El) m/z M+. (343);
Anal, calcd for C23H21NO2: C:80.44 H:6.16 N:4.08 Found: C:78.76 H:6.32 N:3.81.
Example 38
Ethyl 2-cyano-3-(2-methylphenyl)-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 15, using 2-methyl-
phenyl magnesium bromide. The sample is a viscous oil.
1H NMR (400 MHz, DMSO-D6) δ 0.81 (t, J=7.08 Hz, 1.5 H) 0.92 (t, J=7.08 Hz, 1.5
H) 2.13 (s, 3 H) 3.88 (m, 1 H) 4.05 (q, J=7.08 Hz, 1 H) 5.22 (t, J=8.18 Hz, 1 H) 5.62
(d, J=7.57 Hz, 0.5 H) 5.67 (d, J=8.79 Hz, 0.5 H) 7.20 (m, 3.5 H) 7.48 (m, 1.5 H) 7.57
(m, 1 H) 7.65 (m, 1.5 H) 7.77 (d, J=6.83 Hz, 0.5 H) 7.89 (m, 2 H) 7.97 (dd, J=8.05,
0.98 Hz, 0.5 H) 8.22 (d, J=8.54 Hz, 0.5 H)
MS (APCl) m/z [M+H]+ (344);
Anal, calcd for C23H21NO2: C:80.44 H:6.16 N:4.08 Found: C:78.56 H:6.10 N:3.91.
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Example 39
Ethyl 2-cyano-3-(1-naphthyl)-3-(2-naphthyl)propanoate
The title compound was prepared according to example 15, using 2-naphthyl
magnesium bromide. The sample is a viscous oil.
1H NMR (400 MHz, DMSO-D6) δ 0.32 (t, J=7.08 Hz, i.5 H) 0.39 (1, J=7.08 Hz, 1.5
H) 3.99 (m, 2 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.51 (d, J=9.76 Hz, 0.5 H) 5.70 (d,
J=9.76 Hz, 0.5 H) 5.74 (d, J=9.76 Hz, 0.5 H) 7.51 (m, 5 H) 7.64 (m, 1 H) 7.83 (m, 4
H) 7.93 (m, 2 H) 8.02 (d, J=7.08 Hz, 0.5 H) 3.15 (d, J=1.46 Hz, 0.5 H) S.25 (m, 0.5
H) 8.3S (d, J=8.54 Hz, 0.5 H)
MS (APCl) m/z 380 ([M+H]+);
Anal, calcd for C26H21NO2: C:82.30 H:5.58 N:3.69 Found: C:81.94 H:5.55 N:3.43.
Example 40
Ethyl 2-cyano-3-(4-fluoro-1 -naphthyl)-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 15, using 4-fluoro-(1-
naphthyl) magnesium bromide. The sample is a white foam.
1H NMR (400 MHz, DMSO-D6) δ 0.83 (m, 3 H) 3.93 (m, J=17.51, 14.15,7.14,3.66
Hz, 2 H) 5.37 (d, J=2.20 Hz, 0.5 H) 5.39 (d, J=2.20 Hz, 0.5 H) 6.30 (d, J=7.81 Hz, 1
H) 7.25 (d, J=8.05 Hz, 1 H) 7.31 (dd, J=7.32, 0.98 Hz, 0.5 H) 7.41 (m, 1 H) 7.47 (m,
1 H) 7.53 (ddd, J=8.48, 6.89, 1.46 Hz, 0.5 H) 7.60 (m, 1.5 H) 7.67 (m, 0.5 H) 7.73
(d, J=7.32 Hz, 0.5 H) 7.83 (m, 2.5 H) 7.97 (m, 2 H) 8.09 (dd, J=8.30, 0.98 Hz, 0.5 H)
8.13 (dd, J=8.18, 1.10 Hz, 0.5 H) 8.35 (d, J=8.54 Hz, 0.5 H) 8.46 (d, J=8.79 Hz, 0.5
H)
MS (APCl) m/z 398 ([M+H]+);
Anal, calcd for C26H20FNO2: C:78.57 H:5.07 N:3.52 Found: C:77.65 H:4.97 N:3.43.
Example 41
Ethyl 2-cyano-3-[4-(methylthio)phenyl]-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4-
(thiomethyl)phenyl magnesium bromide. The sample is a white foam
1H NMR (400 MHz, DMSO-D6) δ 0.91 (dt, J=14.34, 7.11 Hz, 3 H) 2.39 (d, J=9.76
Hz, 3 H) 4.01 (m, 2 H) 5.31 (d, J=9.52 Hz, 0.5 H) 5.39 (d, J=9.52 Hz, 0.5 H) 5.49 (d,
J=9.52 Hz, 0.5 H) 5.52 (d, J=9.76 Hz, 0.5 H) 7.17 (m, 2 H) 7.33 (d, J=8.30 Hz, 1 H)
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7.50 (m, 3.5 H) 7.59 (dd, J=8.30, 7.32 Hz, 0.5 H) 7.72 (d, J=6.59 Hz, 0.5 H) 7.84 (d,
J=8.30 Hz, 0.5 H) 7.92 (m, 2 H) 8.15 (m, 0.5 H) 8.27 (d, J=8.54 Hz, 0.5 H)
MS (El) m/z M+. (375);
Anal, calcd for C23H21NO2S: C:73.57 H:5.64 N:3.73 Found: 0:73.45 H:5.44 N:3.71.
Example 42
Ethyl 3-[1,1'-biphenyl]-4-yl-2-cyano-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4-biphenyl
magnesium bromide. The sample is a white foam
1H NMR (400 MHz, DMSO-D6) δ 0.90 (q, J=7.08 Hz, 3 H) 4.01 (m, 2 H) 5.39 (d,
J=9.76 Hz, 0.5 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.58 (d, J=9.76 Hz, 0.5 H) 5.62 (d,
J=10.01 Hz, 0.5 H) 7.32 (m, 1 H) 7.42 (m, 2 H) 7.57 (m, 9 H) 7.78 (d, J=6.59 Hz, 0.5
H) 7.85 (d, J=8.30 Hz, 0.5 H) 7.94 (m, 2 H) 8.23 (m, 0.5 H) 8.35 (d, J=8.30 Hz, 0.5
H)
MS (APCl) m/z 404 ([M-H]-);
Anal, calcd for C28H23NO2: C:82.94 H:5.72 N:3.45 Found: C:82.84 H:5.71 N:3.38.
Example 43
Ethyl 3-[1,1'-biphenyl]-2-yl-2-cyano-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 2-biphenyl
magnesium bromide. The sample is a white foam
1H NMR (400 MHz, DMSO-D6) δ 0.73 (t, J=7.08 Hz, 1.5 H) 0.90 (t, J=7.08 Hz, 1.5
H) 3.82 (m, 1 H) 4.02 (q, J=7.08 Hz, 1 H) 5.23 (d, J=8.30 Hz, 0.5 H) 5.31 (d, J=9.52
Hz, 0.5 H) 5.55 (d, J=8.30 Hz, 0.5 H) 5.66 (d, J=9.52 Hz, 0.5 H) 7.03 (d, J=8.79 Hz,
1.5 H) 7.18 (m, 2.5 H) 7.40 (m, 7.5 H) 7.62 (m, 1 H) 7.82 (m, 2 H) 8.05 (d, J=7.57
Hz, 0.5 H)
MS (APCl) m/z 404 ([M-H]-);
Anal, calcd for C28H23NO2: C:82.94 H:5.72 N:3.45 Found: C:82.40 H:5.94 N.3.39.
Example 44
Ethyl 3-(4-chlorophenyl)-2-cyano-3-(1 -naphthyl)propanoate
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The title compound was prepared according to example 15, using 4-
chlorophenyl magnesium bromide. The sample is a sticky oil.
1H NMR (400 MHz, DMSO-D6) δ 0.89 (dt, ,7=16.60, 7.08 Hz, 3 H) 2.42 (s, 1.5 H)
2.63 (s, 15 H) 4.01 (m, 2 H) 5.12 (d, J=7.08 Hz, 0.5 H) 5.26 (d, J=S.7S Hz, 0.5 H)
5.83 (d, J=7.32 Hz, 0.5 H) 5.92 (d, J=8.79 Hz, 0.5 H) 7.02 (m, i H) 7.23 (m, i.5)
7.39 (t, J=S.3O Hz, 1 H) 7.56 (m, 3 H) 7.88 (m, 3 H) 8.24 (d, J=3.54 Hz, 0.5 H)
MS (APCl) m/z [M+H]+ (364);
Anal, calcd for C22H18CINO2: C:72.63 H:4.99 N:3.85 Found: C:71.56 H:4.95 N:3.65.
Example 45
Ethyl 2-cyano-3-[2-(methylthio)phenyl]-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15 using 2-
(thiomethyl)phenyl magnesium bromide. The sample is a sticky white foam
1H NMR (400 MHz, DMSO-D6) S 0.91 (dt, J=16.23, 7.14 Hz, 3 H) 4.01 (m, 2 H)
5.36 (d, J=9.52 Hz, 0.5 H) 5.43 (d, J=9.76 Hz, 0.5 H) 5.56 (d, J=9.52 Hz, 0.5 H) 5.60
(d, J=10.01 Hz, 0.5 H) 7.39 (m, 3 H) 7.55 (m, 4 H) 7.72 (d, J=6.83 Hz, 0.5 H) 7.85 (d,
J=8.30 Hz, 0.5 H) 7.92 (m, 2 H) 8.17 (m, 0.5 H) 8.29 (d, J=8.54 Hz, 0.5 H)
MS (APCl) m/z [M+H]+ (376);
Anal, calcd for C23H21NO2S: C:73.57 H:5.64 N:3.73 Found: C:73.58 H:5.88 N:3.58.
Example 46
Ethyl-(RR,SS)- 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
A solution of 2-cyano-3-(2-methoxy-phenyl)-3-naphthalen-1-yl-propionic acid
ethyl ester (205mg, 0.57mmol) in THF (10mL) is cooled in a dry ice ethanol bath. A
solution of KHMDS (1.04ml, 0.68mmol, 0.66M toluene) is added dropwise. The bath
is removed and the reaction is warmed to room temperature over an hour. To this is
added methyl iodide (162mg, 1.14mmol) and the reaction is stirred at room
temperature for 30 minutes. The reaction is quenched with 1NHCl and is diluted with
ethyl acetate. The organic layer is isolated and is washed with saturated bicarbonate
solution then brine. The organic layer is dried with Na2SO4 , is filtered and
evaporated to a solid. Chromatography over silica gel (20%ethyl acetate/hexane)
yields the title compound as a solid. Re-crystallization from MeOH yields the title
compound (80mg) as white crystals.
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mp 134.5-135.5 °C;
1H NMR (400 MHz, DMS0-D6) δ 0.75 (t, J=7.08 Hz, 3 H) 1.65 (s, 3 H) 3.98 (m,
J=17.79, 10.65, 7.08, 3.78 Hz, 2 H) 4.05 (s, 3 H) 5.81 (s, 1 H) 6.83 (td, J=7.50, 1.10
Hz, 1 H) 7.16 (dt, J=7.S7, 1.56 Hz, 1 H) 7.26 (td, J=7.31, 1.71 Hz, 1 H) 7.46 (m, 1 H)
7.58 (dd, J=3.i3, 7.44 Hz, 'i H) 7.85 (d, J=o.54 Hz, 'i H) 7.83 (m, i H) 3.03 (d,
J=7.08 Hz, 1 H)
MS (APCl) m/z [M+H]+ (374);
Anal, calcd for C24H23NO3: C:77.19 H:6.21 N:3.75 Found: C:77.05 H:6.24 N:3.74.
Example 47
Ethyl (RR,SS)-2-cyano-2-methyl-3-[2-(methylthio)phenyl]-3-(1-naphthyl)propanoate
The title compound is prepared from 2-cyano-3-(2-methylsuifanyl-phenyl)-3-
naphthalen-1-yl-propionic acid ethyl ester according to example 46. The title
compound is obtained as white crystals from MeOH.
mp 154-156 °C;
1H NMR (400 MHz, DMSO-D6) δ 0.75 (t, J=7.08 Hz, 3 H) 1.71 (s, 3 H) 2.70 (s, 3 H)
3.96 (m, 2 H) 5.81 (s, 1 H) 7.11 (td, J=7.69, 1.22 Hz, 1 H) 7.29 (td, J=7.57, 1.46 Hz,
1 H) 7.34 (dd, J=7.93, 1.34 Hz, 1 H) 7.48 (dt, J=6.53, 2.96 Hz, 2 H) 7.53 (dd, J=8.05,
0.98 Hz, 1 H) 7.60 (t, J=7.57 Hz, 1 H) 7.89 (m, 2 H) 8.05 (d, J=7.08 Hz, 1 H) 8.15 (d,
J=9.52 Hz, 1 H)
MS (APCl) m/z [M+H]+ (390);
Anal, calcd for C24H23NO2S: O.74.01 H:5.95 N:3.60 Found: C:73.97 H:5.91 N:3.55.
Example 48
(RR,SS)-2-Cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoicacid
Ethyl-(RR, SS)- 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate (12.42g, 33.33 mmol) was dissolved in 100 mL THF to which
was added 2.5 M NaOH (18 mL). Reaction mixture heated to reflux for 8 hrs,
allowed to cool and stir overnight. The reaction mixture was acidified with 1 N HCl,
taken up in ethyl acetate, washed with brine, dried with MgSO4, filtered, evaporated,
and recrystallized from ethanol to tyield 11.44 g the title compound as a crystalline
solid,
mp 229 °C (dec);
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1H NMR (400 MHz, DMS0-D6) 6 1.62 (s, 2 H) 4.05 (s, 2 H) 5.77 (s, 1 H) 6.80 (td,
J=7.50, 1.10 Hz, 1 H)7.11 (dd, J=7.69, 1.59 Hz, 1 H) 7.15 (dd, J=8.30, 0.98 Hz, 1 H)
7.23 (td, J=7.81, 1.71 Hz, 1 H) 7.44 (m, 1 H) 7.59 (m, 1 H) 7.84 (d, J=8.30 Hz, 1 H)
7.89 (m, 1 H) 8.10 (d, J=7.32 Hz, 1 H)
MS (APCl) m/z 344 ([ivi-H]-);
Anal, calcd for C-22H19NO3 0.35 H2O: C:75.13 H:5.65 N:3.98 Found: C:75.16
H:5.61 N:3.76.
Example 49
(RR,SS)-2-Cyano-3-(2-isopropylpheny!)-2-methyl-3-(1-naphthyl)propanoicacid
A sample of tert-butyl (RR,SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-
naphthyl)propanoate (3.9g, 9.4mmol) was dissolved in CH2Cl2 (40mL). The sample
was treated with trifluoroacetic acid (40mL) and was stirred for 2 hours. The mixture
was evaporated to a solid. Recrystallization from ethyl acetate/hexanes provided the
title compound as white powder,
mp 214 °C(dec);
1H NMR (500 MHz, DMSO-D6) δ 0.33 (d, J=6.72 Hz, 3 H) 1.17 (d, J=6.87 Hz, 3 H)
1.52 (s, 3 H) 2.97 (m, 1 H) 5.68 (s, 1 H) 7.25 (m, 2 H) 7.32 (td, J=7.22, 2.21 Hz, 1 H)
7.41 (dd, J=7.33, 1.22 Hz, 1 H) 7.47 (t, J=7.71 Hz, 1 H) 7.58 (m, 1 H) 7.70 (td,
J=7.71, 1.07 Hz, 1 H) 7.87 (d, J=7.79 Hz, 1 H) 7.99 (dd, J=8.17, 0.69 Hz, 1 H) 8.05
(d, J=7.63 Hz, 1 H) 8.46 (d, J=8.70 Hz, 1 H) 14.01 (bs, 1 H)
MS (ESI) m/z 375 ([M+NH4]+);
Anal, calcd for C94H23NO2: C.80.64 H:6.49 N:3.92 Found: C:80.75 H:6.54 N:3.87.
Example 50
(RS,SR)-2-Cyano-2-methyl-3-(1-naphthyl)-3-[2-(trifluoromethyl)phenyl]propanoic
acid
The title compound was prepared according to example 49 using tert-butyl
(RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-(trifluoromethyl) phenyl] propanoate
as the starting material. Recrystallization from ethyl acetate/hexane provided the title
compound as a white solid,
mp 220 °C (dec);
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1H NMR (500 MHz, DMS0-D6) δ 1.54 (s, 3 H) 5.83 (s, 1 H) 7.52 (m, 4 H) 7.69 (m, 2
H) 7.90 (m, 2 H) 7.97 (d, J=7.94 Hz, 1 H) 8.32 (d, J=8.70 Hz, 1 H) 8.48 (d, J=8.09
Hz, 1 H) 14.08 (bs, 1 H)
MS (ESI) m/z 401 ([M+NH4]+);
Anal, calcd for C22H16F3NO2: C:68.93 H:4.2i N:3.65 Found: C:68.93 H:4.20 N:3.6i.
Example 51
(RR,SS)-2-Benzyl-2-Gyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoicacid
The title compound was prepared according to example 49 using tert-butyl
(RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate as the
starting material. Trituration with heptane provided the title compound as a white
solid.
mp 230-233 °C;
1H NMR (500 MHz, DMSO-D6) δ 2.81 (d, J=13.29 Hz, 1 H) 3.55 (d, J=13.44 Hz, 1
H) 4.08 (s, 3 H) 6.01 (s, 1 H) 6.87 (td, J=7.52, 0.69 Hz, 1 H) 7.14 (dd, J=7.18, 2.29
Hz, 2 H) 7.18 (d, J=8.25 Hz, 1 H) 7.29 (m, 5 H) 7.47 (m, 2 H) 7.57 (m, 1 H) 7.84 (d,
J=8.25 Hz, 1 H) 7.88 (dd, J=7.18, 2.75 Hz, 1 H) 8.01 (dd, J=7.48, 1.68 Hz, 1 H) 8.18
(d, J=7.18Hz, 1 H)
MS(ESI) m/z 422([M+H]+);
Anal, calcd for C28H23NO3 . 0.30 H2O: C:78.78 H:5.57 N:3.28 Found: C:78.84 H:5.50
N:3.28.
Example 52 Part 1
tert-Butyl (R,R)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-naphthyl)propanoate
A sample of tert-butyl (RR,SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-
naphthyl)propanoate was dissolved in methanol and was resolved by
chromatography on a preparative HPLC system using a Chiralcel OD (25 x 5cm)
column and 8:2 methanol:water as the eluant. The title compound was the first peak
to elute. Recrystallization from ethanol provided the title compound as colorless
crystals
[α]D25 = -439.8° (1%, CHCl3);
Example 52 Part 2
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tert-butyl (S,S)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-naphthyl)propanoate
The title compound is the second peak to elute in example 51 part 1.
Recrystallization from methanol provided the title compound as colorless needles.
[α]D25 =+434.2° (1%,CHCl3);
Example 53 Fart 1
tert-butyl (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
A sample of tert-butyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate was dissolved in methanol and was resolved by
chromatography on a preparative HPLC system using a Chiralcel OD (25 x 5cm)
column and 8:2 methanol:water as the eluant. The title compound was the first peak
to elute. Recrystallization from ethanol provided the title compound as colorless
crystals
[α]D25 = -283.8° (0.5%, CHCl3);
1H NMR (500 MHz, DMSO-D6) δ 1.03 (s, 9 H) 1.63 (s, 3 H) 4.06 (s, 3 H) 5.78 (s, 1
H) 6.85 (td, J=7.48, 1.07 Hz, 1 H) 7.17 (d, J=8.25 Hz, 1 H) 7.22 (dd, J=7.71, 1.60 Hz,
1 H) 7.26 (ddd, J=8.63, 6.95, 1.68 Hz, 1 H) 7.48 (m, 2 H) 7.62 (t, J=7.48 Hz, 1 H)
7.87 (d, J=8.25 Hz, 1 H) 7.92 (m, 2 H) 8.08 (d, J=7.18 Hz, 1 H)
Anal, calcd for C26H27NO3: C:77.78 H:6.78 N:3.49 Found: C:76.93 H:6.86 N:3.47.
Example 53 Part 2
tert-butyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
The title compound is the second peak to elute in example 53 part 1.
Recrystallization from methanol provided the title compound as colorless needles.
[α]D25 = +272.0° (0. 5%, CHCl3);
1H NMR (500 MHz, DMSO-D6) δ 1.03 (s, 9 H) 1.63 (s, 3 H) 4.06 (s, 3 H) 5.78 (s, 1
H) 6.85 (td, J=7.48, 1.07 Hz, 1 H)7.17 (d, J=8.25 Hz, 1 H) 7.22 (dd, J=7.71,1.60 Hz,
1 H) 7.26 (ddd, J=8.63, 6.95, 1.68 Hz, 1 H) 7.48 (m, 2 H) 7.62 (t, J=7.48 Hz, 1 H)
7.87 (d, J=8.25 Hz, 1 H) 7.92 (m, 2 H) 8.08 (d, J=7.18 Hz, 1 H)
Anal, calcd for C26H27NO3: C:77.78 H:6.78 N:3.49 Found: C:77.31 H:6.86 N:3.48.
Example 54
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(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(piperazin-1-
ylcarbonyl)propanenitrile
(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic
acid(10 g, 28.95 mmo!) was dissolved in 250 mL THF. A catalytic amount of DMF
was added lo the reaction mixture. Oxalyl chloride (3.03 mL, 34.72 mmol) was
added slowly. The reaction mixture was stirred until no more evolution of gas was
observed. The reaction mixture was rapidly heated to reflux, then cooled and
evaporated. 50 mL toluene was added and the reaction mixture was evaporated to
dryness. The acid chloride was dissolved in 500 mL CH2C-I2 and placed under
nitrogen. In a separate flask piperazine (3g, 34.74 mmol) was dissolved in 200 mL
CH2Cl2 under nitrogen. To this stirred solution was added a catalytic amount of
DMAP, and triethylamine (14.12 mL, 101.33 mmol). The acid chloride solution was
added slowly to this stirred mixture and allowed to react overnight after which water
was added to the reaction mixture. The organic layer was separated and washed
with brine, dried over MgSO4, filtered, evaporated to dryness, and purified on silica
gel (5% methanol/methylene chloride + 0.5% Et3N) to yield 7.26 g of the title
compound as a white foam.
1H NMR 500 MHz (DMSO-D6): δ 7.95 (d, 1H, J=7.18 Hz), 7.85 (m, 2H), 7.78 (d, 1H,
J=8.25 Hz), 7.52 (t, 1H, J=7.48 Hz), 7.41 (m, 2H), 7.21 (td, 1H, J=7.71 Hz, 1.53 Hz),
7.12 (d, 1H, J=8.25 Hz), 7.08 (dd, 1H, J=7.79 Hz, 1.53 Hz), 6.77 (t, 1H, J=7.48 Hz),
5.99 (s, 1H), 4.00 (s, 3H), 3.44 (bs, 4H), 2.62 (bs, 2H), 2.55 (bs, 2H), 1.59 (s, 3H)
MS(ESI)m/z414([M+H]+);
Anal, calcd for C26H27N3O2 • 0.20 H2O: C:74.95 H:6.95 N:9.80 Found: C:74.73
H:6.72 N:9.68
Example 55
(RR.SS)(3-[4-(3-chloro-2-methylphenyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile)
A mixture of 2-[(2-methoxy-phenyl)-naphthalen-1-yl-methyl]-2-methyl-3-oxo-3-
piperazin-1-yl-propionitrile (442mg, 1.05mmol) , 1-chloro-3-iodo-2-methyl-benzene
(258mg, 1.02mmol), NaOtBu (140mg, 1,.45mmol), Pd2(dba)3 (27mg, 0.029mmol),
racemic BINAP (39mg, 0.06mmol) in toluene (5mL) in a Carius tube was degassed
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with argon. The tube was sealed and placed in a preheated oil bath (80°) for 21
hours. The sample was cooled, diluted with isopropyl acetate (50mL), washed with
brine then water, was dried over Na2SO4, filtered and concentrated to an oil.
Chromatography on silica gel using 15% isopropyl acetate /hexane provided a foam
which was recrystsllized from ethyl ac-state/hexans to provide 220mg of the title
compound as an amorphous white powder.
1H NMR 500MHz(DMSO-D6): δ 7.99 (d, 1H, J = 7.18Hz), 7.88 (m, 2H), 7.80 (d, iH,
J = 8.24H-), 7.55 (t, 1H, J = 7.63Hz), 7.42 (m,.2H), 7.23 (dt, 1H, J = 8.56, 1.53Hz),
&.14 (m, 4H), 7.12 (brs, IH), 6.80 (t, 1h, J = 7.48Hz), 4.01 (s, 3H). 2.26 (s,3H), 1.64,
(s,3H); MS (ESI) m/z 538 ([M+H]+); Anal, calcd for C33H32CIN3O2: C:73.66 H:5.99
N:7.81 Found: C:73.98 H:6.33 N:7.46.
Example 56 Part 1
(RR,S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)piperazin-1-
yl]carbonyl}-3-(1-naphthyl)propanenitrile
A solution of ('R,R/S,S)2-cyano-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-
1-yl-propionic acid (1.2g, 347mmol) in THF (40mL) is treated with DMF (2 drops).
Oxalyl chloride (0.4mL, 4.60mmol) is added dropwise in order to control gas
evolution; when the gas evolution stopped the solution is heated to reflux for 5
minutes. The solution is cooled, the THF is evaporated in vacuo and the solid is
dissolved in dry toluene (15mL) and evaporated to a solid. This procedure is
repeated twice. The acid chloride is dissolved in dichloromethane (60mL). 1-o-tolyl-
piperazine hydrochloride (830mg, 3.91 mmol) and a crystal of DMAP are added to
the solution of acid. This is followed by the dropwise addition of TEA (1.1 mL,
7.84mmol). The reaction is stirred overnight. The reaction mixture is diluted with
dichloromethane (50mL), washed with aqueous HCI (10mL 0.5N) then saturated
NaHCO3 (10mL) and brine (10mL). The sample is dried over NaSO4, filtered and
concentrated in vacuo. This provided 1.7g a tan solid.
MS (ESI) m/z 504 ([M+H]+);
Anal, calcd for C33H33N3O2: C:78.70 H:6.60 N:8.34 Found: C:78.51 H:6.85 N:7.91.
Example 56 Part 2
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(SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)-1-piperaziny!]carbonyl}-
3-(1-naphthyl)propanenitrile
Preparative chiral HPLC (Chiracel OD, 25x2cm) in 5%methano!/water of
(RR,S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)piperazin-1-
yl]carbonyl}-3-(i-naphthyl)propanenitrile, prepared in example 56 part i, provided
570 mg of title compound as the first peak to elute.Recrystallization from ethanol
/hexane provided off white crystals,
mp 175-177 °C;
[α]D25 = -'iSS.7°(1%, CHCl3);
1H NMR 500MHz(DMSO-D6): δ 7.99 (d, 1H, J = 7.17Hz), 87.89 (d, 1H, J = 9.78),
7.87 (d, 1H, J = 10.38HZ). 7.80 (d, 1H, J = 8.1 OHz), 7.55 (t, 1H, J = 7.48Hz), 7.42
(m,2H), 7.23 (t, 1H, J = 7.63Hz), 7.14 (m, 4H), 6.95 (t, 1H, J = 7.18Hz), 6.48 (brs,
1H), 6.79 (t,1H, J = 7.48Hz), 6.02 (s, 1H), 4.01 (s,3H), 3.86 (brs, 3H), 2.68 (brs,3H),
2.22 (s,3H), 1.65 (s,3H)
MS (ESI) m/z: 504 ([M+H]+)
Anal, calcd for C33H33N3O2: C:78.70 H:6.60 N:8.34 Found: C:78.33 H.6.63 N:8.28.
Example 56 Part 3
(R,R)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)piperazin-1-yl]carbonyl}-
3-(1-naphthyl)propanenitrile
The second peak from the preparative HPLC described in example 56 part 2
provided 510mg of the title compound. Recrystallization from ethanol/hexanes
yielded a white powder,
mp 173-176 °C;
[α]D25 = +184.1° (1%, CHCl3);
Anal, calcd for C33H33N3O2: C:78.70 H:6.60 N:8.34 Found: C:77.93 H:6.63 N:8.13.
Example 57
(S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-
3-(1 -naphthyl)propanenitrile
The title compound was prepared according to Example 2B using racemic
(RR,SS)(3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazin-1-
WO 2004/099150 PCT/US2004/013360
-71 -
yl]carbonyl}-3-(1-naphthyl)propanenitrile as the starting material. Recrystallization
from ethanol/ether yielded white crystals.
mp 104-105 °C;
[a]D25 = -175.00° (1%, CHCl3);
HRMS Calc'd for i .00 C33H33N3O2; Theory 503.644; Found: 503.257.277
Example 58
(S)-3-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]-2-[(S)-(2-methoxypheny!)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitril8
A solution of (S,S)2-cyano-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-
propionic acid (0.45g, 1.30 mmol) in THF (150mL) is treated with DMF (2 drops).
Oxalyl chloride (0.16mL, 1.84 mmol) is added dropwise in order to control gas
evolution; when the gas evolution stopped the solution is heated to reflux for 5
minutes. The solution is cooled, the THF is evaporated in vacua and the solid is
dissolved in dry toluene (15mL) and evaporated to a solid. This procedure is
repeated twice. The acid chloride is dissolved in dichloromethane (10mL) this is
added to a solution of 1-(3,5-dimethoxy-phenyl)-piperazine
WE CLAIM:
T. A compound of formula I having the structure

wherein
B and D are independently CH or N, provided that B and D are not
bothN;
R1, R1a, R2 are each, independently, hydrogen, halogen, alkyl of 1-6
carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6
carbon atoms, aryl, alkylthio of 1-6 carbon atoms, CF3, -OCF3, -NR5R6, or
hydroxy;
or R1 and R2 together with carbon atoms to which they are attached
form a fused benzene ring, the naphthalene ring so formed being optionally
substituted by halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon-
atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl, alkylthio of 1-6 carbon
atoms, CF3, -OCF3, -NR5R6, or hydroxy;
R3 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon
atoms in the alkyl moiety, alkenyl of 2-7 carbon atoms, cycloalkylmethyl of 3-8
carbon atoms in the cycloalkyl moiety, arylalkoxyalkyl, alkoxyalkyl,
dialkylaminoalkyl having 1-6 carbon atoms in the alkyl moieties, or Het-alkyl
having 1-6 carbon atoms in the alkyl moiety;
AMENDED PAGE
159

or A, wherein any phenyl ring in R4 is optionally substituted with R7;
R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon
atoms, aryl, arylalkyl having 1-6 carbon atoms in the alkyl moiety, Het-alkyl
having 1-6 carbon atoms in the alkyl moiety, hydroxyalkyl of 1-6 carbon
atoms, dihydroxyalkyl of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
AMENDED PAGE
160
R7 is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen,
nitro, cyano, alkylthio of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, CF3,
o
or -OCF3;
R8 is alkyl of 1-6 carbon atoms;
A is hydrogen, cycloalkyl of 3-8 carbon atoms, alkoxyalkyl having 1-6
carbon atoms in the alkyl and alkoxy moieties, dialkylaminoalkyl having 1-6
carbon atoms in the alkyl moieties, aryl, Het, hydroxyalkyl of 1-6 carbon
atoms, dihydroxyalkyl of 1-6 carbon atoms, Het-alkyl having 1-6 carbon atoms
in the alkyl moiety, arylalkyl having 1-6 carbon atoms in the alkyl moiety, or

W is aryl, -Y-aryl, or Het or -Y-Het;
Y is-O-or-NH-;
Z is O or S;
Het is a saturated, unsaturated, or partially unsaturated heterocyclic
ring or ring system having 4-12 ring atoms and 1-3 heteroatoms selected from
N, O, or S, that may be optionally substituted with 1-3 R7 groups;
aryl is an aromatic ring or ring system having 6-14 carbon atoms in the
ring or ring system, that may be optionally substituted with 1-3 R7 groups;
with the proviso that at least one of the R1, R1a, or R2 groups is not
hydrogen;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein

A is hydrogen, aryl, or Het; or
a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein
AMENDED PAGE
161

A is hydrogen, aryl, or Het; or
a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, wherein
B and D are CH.
5. The compound according to claim 1, which is
ethyl 2-cyano-3-(2,6-dimethoxyphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(2,6-dichlorophenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-[4-(dimethylamino)phenyl]-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(1-naphthyl)-3-[2 (trifluoromethyl) phenyl]propanoate;
ethyl 2-cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(2,4-dimethoxyphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(2,5-dimethoxyphenyl)-3-(1-naphthyl)propanoate;
tert-butyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethyl) phenyl]
propanoate;
ethyl 2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate;
tert-butyl2-cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate;
tert-butyl 2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate;
tert-butyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethoxy)phenyl]
propanoate;
ethyl 2-cyano-3-(1-naphthyl)-3-(2-nitrophenyl)propanoate;
tert-butyl 2-cyano-3-(2,6-dimethylphenyl)-3-(1-naphthyl)propanoate;
tert-butyl (RR,SS)-2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethyl)phenyl]
propanoate;
tert-butyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
(-) ethyl (SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
AMENDED PAGE
162
(+) ethyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-4-
pentenoate;
ethyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)
propanoate;
tert-butyl (RR,SS)-2-cyano-3-(2-isopropylphenyl)-2~methyl-3-(1-
naphthyl)propanoate;
tert-butyl (RS, SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-
(trifluoromethyl)phenyl]propanoate;
tert-butyl (RS, SR)-2-cyano-3-(2,6-dimethylphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
tert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 -
naphthyl)propanoate;
tert-butyl (RR, SS)-2-(3-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-
(1-naphthyl)propanoate;
tert-butyl (RR,SS)-2-(2-bromobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-
(1-naphthyl)propanoate;
tert-butyl (RR,SS)-2-(2-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-
(1 -naphthyl)propanoate;
tert-butyl (RR,SS)-2-cyano-2-(2,6-dichlorobenzyl)-3-(2-methoxyphenyl)-
3-(1-naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-3-(2,4-dimethoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
tert-butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-
(trifluoromethoxy)phenyl]propanoate;
ethyl 2-cyano-3-(3-methoxyphenyl)-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-(4-methylphenyl)-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-(2-methylphenyl)-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-(1-naphthyl)-3-(2-naphthyl)propanoate;
ethyl 2-cyano-3-(4-fluoro-1-naphthyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-[4-(methylthio)phenyl]-3-(1-naphthyI)propanoate;
AMENDED PAGE
163
ethyl 3-[1,1'-biphenyl]-4-yl-2-cyano-3-(1-naphthyl)propanoate;
ethyl 3-[1,1'-biphenyl]-2-yl-2-cyano-3-(1 -naphthyl)propanoate;
ethyl 3-(4-chlorophenyl)-2-cyano-3-(1 -naphthyl)propanoate;
ethyl 2-cyano-3-[2-(methylthio)phenyl]-3-(1-naphthyl)propanoate;
ethyl-(RR,SSy 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-2-methyl-3-[2-(methylthio)phenyl]-3-(1-
naphthyl)propanoate;
(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoic acid;
(RR,SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-
naphthyl)propanoic acid;
(RS,SR)-cyano-2-methyl-3-(1-naphthyl)-3-[2-
(trifluoromethyl)phenyl]propanoic acid;
(RR,SS)-2-benzyl-2-cyano-3-(2-meth6xyphenyl)-3-(1-
naphthyl)propanoic acid;
tert-butyl (R,R)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
tert-butyl (S,S)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
tert-butyl (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
tert-butyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoate;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(piperazin-1-
ylcarbonyl)propanenitrile;
RR,SS)(3-[4-(3-chloro-2-methylphenyl)piperazin-1-yl]-2-[(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile);
(RR,S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-
methylphenyl)piperazin-1-yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(SS)-3-(2-methoxyphenyI)-2-methyl-2-{[4-(2-methylphenyl)-1-
piperazinyl]carbonyl}-3-(1-naphthyl)propanenitrile;
AMENDED PAGE
164
(R,R)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)piperazin-1-
yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazin-1-
yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(S)-3-[4-(3,5-dimethoxyphenyl)piperazin-1 -yl]-2-[(S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)3-(4-indan-4-yl-piperazin-1-yl)-2-[(S)(2-methoxy-phenyl)-naphthalen-
1-yl-methyl]-2-methyl-3-oxo-propionitrile;
(S,S)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-{[4-(1-
naphthyl)piperazin-1-yl]carbonyl}propanenitrile;
(S)-3-[4-(3,4-dimethylphenyl)piperazin-1-yl]-2-[(S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-nnethyl-3-oxopropanenitrile;
(RR,SS) 3-[4-(H-indol-4-yl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(3-chlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2,3-dimethylphenyl)piperazin-1-yl]-2-[(S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(4-chlorophenyl)piperazin-1 -yl]-2-[(S)-(2-methoxyphenyl)(1 -
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(1H-lndol-4-yl)-piperazin-1-yl]-2-[(S)-(2-methoxy-phenyl)-
naphthalen-1-yl-methyl]-2-methyl-3-oxo-propionitrile;
(S)S)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3-
(trifluoromethyl)phenyl] piperidin-1 -yl}carbonyl)propanenitrile;
(S)-3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(S)-(2-
methoxy-phenyl)-naphthalen-1-yl-methyl]-2-methyl-3-oxo-propionitrile;
(S,S)-3-(2-methoxy-phenyl)-2-methyl-3-naphtha!en-1-yl-2-[4-(3-
trif!uoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-propionitrile;
(SS)2-[4-(4-chloro-phenyl)-piperidine-1-carbonyl]-3-(2-methoxy-
phenyl)-2-methyl-3-naphthalen-1-yl-propionitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3-
(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)propanenitrile;
AMENDED PAGE
165
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(piperidin-1-
ylcarbonyl)propanenitrile;
(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl~3-(1-
naphthyl)propanamide;
(RR,SS)-2-cyano-N-ethyl-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR,SS)-N-(tert-butyl)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR, SS)-2-cyano-3-(2-methoxyphenyl)-N, N ,2-trimethyl-3-( 1 -
naphthyl)propanamide;
(RR,SS)-2-cyano-N-methoxy-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1-
naphthyl)propanamide;
(RR,SS)-2-benzyl-3-[4-(3f5-dichlora-4-pyridinyl)-1-piperazinyl]-2-[(2-
methoxyphenyl)(1-naphthyl)methyl]-3-oxopropanenitrile;
(R,S)-3-[4-(2,3-dimethylphenyl)piperazin-1-yl]-2-[(f?,S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(R,S)-3-[4-(3-isopropylphenyl)piperazin-1-yl]-2-[(f?,S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl]-2-[(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(2SS)-3-[4-(3-chloro-2-methylphenyl)piperazin-1-yl]-2-[(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2-fluorophenyl)piperazin-1 -yl]-2-[(S)-(2-methoxyphenyl)(1 -
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2-chlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(S,S)-3-(2-methoxyphenyl)-2-{[4-(3-methoxyphenyl)piperazin-1-
yl]carbonyl}-2-methyl-3-(1-naphthyl)propanenitri!e;
(R,S)-3-[4-(3-ch!oropyridin-4-yl)piperazin-1-yl]-2-[(R,S)-(2-
methoxyphenyl)(1-naphthyl)methyI]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2,3-dichlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyi)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
AMENDED PAGE
166
(2S)-3-[4-[4-chioro-3-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-
y!]-2-[(S)-(2-methoxyphenyl)(1-naphthyl)methyl]-2-meihyl-3-oxopropanenitrile;
(2S)-3-{4-[4-chloro-3-(trifluoromethyl)phenyl]piperidin-1-yl}-2-[(S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR/SS)-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-2-(4-oxy-4-
o-tolyl-piperazine-1 -carbonyl)-propionitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3-
(trifluoromethoxy)phenyl]piperazin-1-yl}carbonyl)propanenitrile;
(R,S)-3-[4-(2,3-difluorophenyl)piperazin-1-yl]-2-[(R,S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(R,S)-3-[4-(3-fluoropheny!)piperazin-1-yl]-2-[(R,S)-(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-[(4-pyridin-3-
ylpiperazin-1 -yl)carbonyl]propanenitrile;
(RR,SS)-3-[4-(2,3-dichlorophenyl)piperazin-1-yl]-2-[(2-
methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-
methylphenyl)piperazin-1-yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(RR,SS)-3-(2-methoxyph.enyl)-2-methyl-3-(1-naphthyl)-2-(pyrrolidin-1-
ylcarbonyl)propanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-(morpholin-4-ylcarbonyl)-3-
(1-naphthyl)propanenitrile;
(RR,SS)-3-[4-(2-hydroxyethyl)piperazin-1-y!]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2,6-dimethylmorpholin-4-yl)-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-2-cyano-N,N-diethyl-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR,SS)-2-cyano-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-(2-
methoxyphenyl)-2-methyl-3-(1-naphthyl)propanamide;
(RR,SS)-3-azetidin-1-yl-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-2-
methyl-3-oxopropanenitri!e;
AMENDED PAGE
167
(RR,SS)-2-cyano-N,N-diisopropyl-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-[(3,3,5-
trimethylazepan-1-yl)carbonyl]propanenitrile;
(RR,SS)-3-(2,3-dihydro-H-indol-1 -yl)-2-[(2-methoxyphenyl)(1 -
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-
(thiomorpholin-4-ylcarbonyl)propanenitrile;
(RR,SS)-3-azepan-1-yl-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-2-
methyl-3-oxopropanenitrile;
(RR,SS)-2-cyano-N-cyclohexyl-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1-
naphthyl)propanamide;
(RR,SS)-2-cyano-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1 -
naphthyl)propanamide;
(RR,SS)-3-(4-benzylpiperazin-1-yl)-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(3,4-dihydroisoquinolin-2(H)-yl)-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(4-
methylphenyl)piperazin-1-yl]carbonyl}-3-(1-naphthyl)propanenitrile;
(RR,SS)-N,N-dibenzyl-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanamide;
(RR,SS)-3-azocan-1-yl-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-2-
methyl-3-oxopropanenitrile;
4-chlorophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-
(1 -naphthyl)propanoyl]piperazine-1 -carboxylate;
2-nitrophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1 -carboxylate;
4-(methoxycarbonyi)phenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-
2-methyl-3-(1-naphthyl)propanoyl]piperazine-1-carboxy!ate;
4-methyl phenyl 4-[(RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-
(1 -naphthyl)propanoyl]piperazine-1-carboxylate;
AMENDED PAGE

168
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]-N-(2-methylphenyl)piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]-N-[2-(trifluoromethyl)phenyl]piperazine-1 -carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]-N-(3-methoxyphenyl)piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
. naphthyl)propanoyl]-N-(4-ethoxyphenyl)piperazine-1-carboxamide;
N-(2-bromophenyl)-4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-
3-(1-naphthyl)propanoyl]piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -
naphthyl)propanoy!]-N-(4-methylphenyl)piperazine-1-carboxamide;
4-fluorophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxylate;
phenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-
naphthyl)propanoyl]piperazine-1-carboxylate;
(RR,SS)-3-[4-(4-bromobenzoyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1-
naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
N-(4-chlorophenyl)-4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-
3-(1-naphthyl)propanoyl]piperazine-1-carboxamide;
methyl (2E)-2-cyano-3-(quinolin-3-yl)prop-2-enoate; or
a pharmaceutically acceptable salt thereof.
6. . A compound selected from group consisting of:
methyl-(SS,RR)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(quinolin-3-
yl)propanoate;
3-(2-methoxyphenyl)-2-methyl-3-quinolin-3-yl-2-({4-[3-
(trifluoromethyl)phenyl] piperidin-1-yl}carbonyl)propanenitrile;
methyl (2S*,3R*)-2-cyano-2-(methoxymethyl)-3-(2-methoxyphenyl)-3-
quinolin-3-y!propanoate; and
pharmaceutically acceptable salts thereof.
AMENDED PAGE
169
7. A pharmaceutical composition, comprising:
a pharmaceutical carrier; and
a compound according to any one of claims 1 to 6 or a
pharmaceutically acceptable salt thereof.
8. Use of a compound according to any one of claims 1 to 6 or a
pharmaceutically acceptable salt thereof in the preparation of a medicament
for treating the inflammatory component of a disease.
9. Use according to claim 8, wherein said disease is selected from the group
consisting of atherosclerosis, myocardial infarction, congestive heart failure,
inflammatory bowel disease, arthritis, type II diabetes, and autoimmune
disease.
10. Use according to claim 9, wherein said autoimmune disease is multiple
sclerosis or rheumatoid arthritis.
11. A process for preparing a compound of formula I as claimed in claim 1 which
comprises steps (a)-(d) or (e), (f):
(a) reacting a compound of formula

wherein R6 is as defined in claim 1 excepting hydrogen and Ar is a
group of formula (A), (B), or (C):

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170
where R1, R2 and R1a are as defined in claim 1;
with a compound of formula Ar1MX wherein Ar1is a group of formula
(A) or (B) providing Ar and Ar1 are not both of formula (A) or (B) to give
a compound of formula I wherein R4 is OR6 where R6 is defined in
claim 1 excepting hydrogen and R3 is hydrogen;
(b) alkylating a compound of formula:

wherein R6, Ar, and Ar are as defined above providing R6 is
other than hydrogen, with an alkylating agent of formula R3L where L is
a leaving group and R3 is as defined in claim 1 excepting hydrogen to
give a corresponding compound of formula I as defined in claim 1;
(c) hydrolyzing an ester of formula

wherein Ar, Ar1, R3 and R6 are as defined hereinabove providing
R6 is other than hydrogen, to give a corresponding compound of
formula I wherein R4 is OR6 where R6 is hydrogen;
(d) reacting an activated acid compound of formula:

wherein Ar, Ar1, and R3 are as defined hereinabove,
with an amine of formula HNR5R6,
AMENDED PAGE
171

or
(e) reacting a compound of formula
wherein R6 is as defined hereinabove excepting hydrogen, in
the presence of strong base with an halide of formula
Ar1ArCHX
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172
where Ar and Ar1 are as defined herein and X is halogen to give
a corresponding compound of formula I wherein R3 is hydrogen,
or
(f) converting a compound of formula I as defined in claim 1 having a
reactive substituent group or site to give a different compound of
formula I;
or
(g) converting a compound of formula I to a pharmaceutically acceptable
salt thereof.
12. A process, comprising the steps of:
forming a ephedrine, cinchonidine, or quinidine salt of a compound of
claim 1 or 6 or a pharmaceutically acceptable salt thereof; and
extracting said ephedrine, cinchonidine, or quinidine salt with solvent;
to form a substantially pure enantiomer of a compound of claim 1 or 6.

This invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof that are useful for the treatment of the inflammatory component of diseases and are particularly useful in treating atherosclerosis, myocardial infarction, congestive heart failure, inflammatory bowel disease, arthritis, type II diabetes, and autoimmune diseases such as multiple sclerosis and rheumatiod arthritis.