Note: Descriptions are shown in the official language in which they were submitted.
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N-UREIDO-PIPERIDINES AS ANTAGONISTS VIII FOR CCR-3 RECEPTOR
This invention relates to piperidine derivatives that are CCR-3 receptor
antagonists,
pharmaceutical compositions containing them, their use, and methods for
preparing them.
Tissue eosinophilia is a feature of a number of pathological conditions such
as
asthma, rhinitis, eczema and parasitic infections (see Bousquet, J. et al., N.
Eng. J. Med.
323: 1033-1039 (1990) and Kay, A. B. and Corrigan, C. J., Br. Med. Bull. 48:51-
64 (1992)).
In asthma, eosinophil accumulation and activation are associated with damage
to
bronchial epithelium and hyperresponsiveness to constrictor mediators.
Chemokines such
as RANTES, eotaxin and MCP-3 are known to activate eosinophils (see
Baggiolini, M. and
1o Dahinden, C. A., Immunol. Today. 15:127-133 (1994), Rot, A. M. et al., J.
Exp. Med. 176,
1489-1495 (1992) and Ponath, P. D. et al., J. Clin. Invest., Vol. 97, #3, 604-
612 (1996)).
However, unlike RANTES and MCP-3 which also induce the migration of other
leukocyte
cell types, eotaxin is selectively chemotactic for eosinophils (see Griffith-
Johnson, D. A. et
al., Biochem. Biophy. Res. Commun. 197:1167 ( 1993) and Jose, P. J. et al.,
Biochem.
~5 Biophy. Res. Commun. 207, 788 ( 1994)). Specific eosinophil accumulation
was observed
at the site of administration of eotaxin whether by intradermal or
intraperitoneal injection
or aerosol inhalation (see Griffith-Johnson, D. A. et al., Biochem. Biophy.
Res. Commun.
197:1167 ( 1993); Jose, P. J. et al., J. Exp. Med. 179, 881-887 ( 1994);
Rothenberg, M. E. et
al., J. Exp. Med. 181, 1211 ( 1995) and Ponath, P. D., J. Clin. Invest., Vol.
97, #3, 604-612
20 (1996)).
Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone
have
been used for treating many eosinophil-related disorders, including bronchial
asthma (R.
P. Schleimer et al., Am. Rev. Respir. Dis., 141, 559 (1990)). The
glucocorticoids are
believed to inhibit IL-5 and IL-3 mediated eosinophil survival in these
diseases. However,
25 prolonged use of glucocorticoids can lead to side effects such as glaucoma,
osteoporosis
and growth retardation in the patients (see Hanania, N. A. et al., J. Allergy
and Clin.
Immunol., Vol. 96, 571-579 ( 1995) and Saha, M. T. et al., Acta Paediatrica,
Vol. 86, #2,
138-142 ( 1997)). It is therefore desirable to have an alternative means of
treating
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eosinophil related diseases without incurring these undesirable side effects.
Recently, the CCR-3 receptor was identified as a major chemokine receptor that
eosinophils use for their response to eotaxin, RANTES and MCP-3. When
transfected into
a murine pre-beta. lymphoma line, CCR-3 bound eotaxin, RANTES and MCP-3
conferred
chemotactic responses on these cells to eotaxin, RANTES and MCP-3 (see Ponath,
P. D. et
al., J. Exp. Med. 183, 2437-2448 (1996)). The CCR-3 receptor is expressed on
the surface
of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly
selective for
eotaxin. Studies have shown that pretreatment of eosinophils with an anti-CCR-
3 mAb
completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 (see
Heath, H.
et al., J. Clin. Invest., Vol. 99, #2, 178-184 (1997)). Applicants' issued
U.S. patents U.S.
Patent Nos. 6,140,344 and 6,166,015 and published EP application EP903349,
published
March 24, 1999 disclose CCR-3 antagonists that inhibit eosinophilic
recruitment by
chemokine such as eotaxin.
Therefore, blocking the ability of the CCR-3 receptor to bind RANTES, MCP-3
and
eotaxin and thereby preventing the recruitment of eosinophils should provide
for the
treatment of eosinophil-mediated inflammatory diseases.
The present invention concerns novel piperidine derivatives which are capable
of
inhibiting the binding of eotaxin to the CCR-3 receptor and thereby provide a
means of
combating eosinophil induced diseases, such as asthma.
In a first aspect, this invention provides a compound of Formula (I):
R3
i
N~~~X~Ra
N
R5
R1_R2
(I)
wherein:
Rl is (C,-CZ)alkylene;
RZ is optionally substituted phenyl;
R3 is hydrogen, alkyl, acyl, aryl, or arylalkyl;
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ring A is a cycloalkyl, heterocyclyl, or optionally substituted phenyl;
L is -C(=O)-, -C(=S)-, -SOZ-, -C(=O)N(Ra)-, -C(=S) N(Ra)-, -SOZ N(Ra)-,
-C(=O)O-, -C(=S)O-, -S(=O)ZO-;
where Ra is hydrogen, alkyl, acyl, aryl, arylalkyl, alkoxycarbonyl, or
benzyloxycarbonyl;
X is absent, -(CR'R")O-, -(CR'R")S-,-(CR'R")NRb- or alkylene;
where R' and R" are independently hydrogen or alkyl, and Rb is hydrogen or
alkyl;
R4 is aryl or heteroaryl; and
RS is hydrogen or alkyl;
provided that when Ri is -CIIZ-, RZ is phenyl, R3 is hydrogen, RS is hydrogen,
A is phenyl, L
is -C(=O)NH- and X is absent, then R4 is not 2,5-difluorophenyl; or
prodrugs, individual isomers, ramecic and non-racemic mixtures of isomers, and
pharmaceutically acceptable salts thereof.
Also, within the compounds as defined above [they will be referred to in the
following under (i)), preferred are the following compounds:
(ii) The compound of (i), which is a compound of Formula (II):
R3
i
A N~~~X~Ra
N
R5
R1_R2
(II)
2o wherein R1-R5, A, L, and X are as defined in (i).
(iii) The compound of (i), which is a compound of Formula (III):
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R3
N~~~X~Ra
IV
R5
Ri_R2
(III)
wherein Rl-R5, A, L, and X are as defined in (i).
(iv) The compound of any one of (i) to (iii) wherein Rl is methylene.
(v) The compound of any one of (i) to (iii) wherein RZ is 4-chlorophenyl or
3,4-
dichlorophenyl.
(vi) The compound of any one of (i) to (iii) wherein R3 is hydrogen.
(vii) The compound of any one of (i) to (iii) wherein L is -C(=O)-, -SOZ-,
-C(=O)N(R~,)-, -C(=S)N(Ra)-, or -C(=O)O-.
(viii) The compound of (vii) wherein L is -C(=O)-.
(ix) The compound of (i), which is a compound of Formula (IV):
Rs
N~~~X~Ra
N
/ CI
(IV)
wherein R3, R4, A, L, and X are as defined in (i).
(x) The compound of (i), which is a compound of Formula (VI):
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H
N II X.Ra
O
N
/ CI
(VI)
wherein X and R4 are as defined in (i).
(xi) The compound of (vii) wherein X is absent, methylene, 1,2-ethanediyl, 1,3-
propanediyl, or 1,4-butanediyl.
(xii) The compound of (xi) wherein R4 is 3,4-dichlorophenyl, 3,4,5-
trimethoxyphenyl,
4-methanesulfonylphenyl, 3-methanesulfonylphenyl, 4-methoxynaphthalen-2-yl, 5-
(3,4-
dimethoxyphenyl)pyrimidin-2-yl, phenyl, 3-fluorophenyl, 4-ethylphenyl, 3-
methoxyphenyl, 2,4-difluorophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-
to fluorophenyl, 2-fluorophenyl, 4-carbamoylphenyl, 3-carbamoylphenyl, 4-
acetylphenyl, 4-
nitrophenyl, 2-methylphenyl, 2-chloro-4-fluorophenyl, 3,4-dimethoxyphenyl, 2,5-
dimethoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-
chloro-3-
nitrophenyl, 2-nitrophenyl, 2-vitro-4-trifluoromethylphenyl, 4-chlorophenyl, 3-
chlorophenyl, 2-chlorophenyl, 3-methylphenyl, 2-trifluoromethylphenyl, 2-
methoxyphenyl, 3-bromophenyl, 4-trifluoromethylphenyl, 3-
trifluoromethy~lphenyl, 3,5-
bis-trifluoromethylphenyl, 4-tert-butylphenyl, 4-ethoxyphenyl, 3-cyanophenyl,
4-
cyanophenyl, 4-methoxyphenyl, 3-nitrophenyl, 3,5-dimethoxyphenyl, 4-
iodophenyl, 4-
isopropylphenyl, 3-methoxycarbonylphenyl, 3-acetylphenyl, 2-methylphenyl,
indol-2-yl,
5-methoxyindol-2-yl, 5-chloroindol-2-yl, 2-methoxycarbonylphenyl, 3,5-
dichlorophenyl,
1-naphthyl, 3-chloro-2-methylphenyl, 2,5-dimethylphenyl, 2-thienyl, 3-
ethoxyphenyl, 3-
isoquinolyl, 2-methylquinolin-6-yl, 3-methylaminophenyl, 3-quinolyl, 2-
quinolyl, 5-
hydroxynaphthalen-2-yl, 8-hydroxyquinolin-2-yl, 5,7-dimethyl- [ 1,8]
naphthyridin-2-yl, 6-
quinolyl, 3-(acetylamino)phenyl, or 2,3,4-trimethoxyphenyl.
(xiii) The compound of (xii) wherein R4 is 3,4,5-trimethoxyphenyl, 4-acetyl-
phenyl, 3-
carbamoylphenyl, 4-carbamoylphenyl, 3-methanesulfonylphenyl or 4-
methanesulfonyl-
phenyl.
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(xiv) The compound of (viii), wherein X is -CHZS- and R4 is 5-(3,4-
dimethoxyphenyl)-
pyrimidin-2-yl, 5-(3,4-methylenedioxyphenyl)-pyrimidin-2-yl or 5-(4-
methoxyphenyl)pyrimidin-2-yl, and a salt thereof.
(xv) The compound of (i), wherein ring A is cycloalkyl or heterocyclyl or
substituted
phenyl.
(xvi) The compound of (xv), wherein ring A is cycloalkyl or heterocyclyl.
(xvii) The compound of (i), wherein RZ is substituted phenyl.
In a second aspect, this invention provides pharmaceutical compositions
containing
a therapeutically effective amount of a compound of Formula (I) or a
pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides processes disclosed herein for
preparing
compounds of Formula (I).
In a forth aspect, this invention provides novel intermediates disclosed
herein that
are useful for preparing compounds of Formula (I).
In a fifth aspect, this invention provides a compound of Formula (I) or a
pharmaceutically acceptable salt thereof for use in medical therapy or
diagnosis (e.g. for
treating asthma).
In a sixth aspect, this invention provides the use of a compound of Formula
(I) or a
pharmaceutically acceptable salt thereof for the manufacture of a medicament
useful for
treating a disease in a mammal treatable by administration of a CCR-3 receptor
antagonist
(e.g. asthma).
Unless otherwise stated, the following terms used in the specification and
claims have
the meanings given below.
"Acyl" means a radical -C(O)R, where R is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl,
cycloalkylalkyl, and
phenylalkyl are as defined herein. Representative examples include, but are
not limited to
formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,
benzylcarbonyl.
"Acylalkyl" means a radical -alkylene-C(O)R where R is hydrogen, alkyl,
haloalkyl,
cycloalkyl, cycloalkyl-alkyl, optionally substituted phenyl, benzyl, hydroxy,
alkoxy, amino,
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monoalkylamino or dialkylamino. Representative examples include methylcarbonyl-
methyl, 2-(ethoxycarbonyl)ethyl, 2-(methoxycarbonyl)ethyl, 2-carboxyethyl.
"Acylamino" means a radical -NR'C(O)R, where R' is hydrogen or alkyl, and R is
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein
alkyl, cycloalkyl,
cydoalkylalkyl, and phenylalkyl are as defined herein. Representative examples
include,
but are not limited to formylamino, acetylamino, cylcohexylcarbonylamino,
cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino.
"Alkoxy " means a radical -OR where R is an alkyl as defined herein e.g.,
methoxy,
ethoxy, propoxy, butoxy.
"Alkoxycarbonyl" means a radical -C(O)-R where R is alkoxy as defined herein.
"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon
atoms
or a branched monovalent hydrocarbon radical of three to six carbon atoms,
containing at
least one double bond, e.g., ethenyl, propenyl.
"Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six
carbon atoms or a branched saturated monovalent hydrocarbon radical of three
to six
carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-
butyl, pentyl.
"Alkylamino" or "Monoalkylamino" means a radical -NHR where R represents an
alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein. Representative
examples
include, but are not limited to methylamino, ethylamino, isopropylamino,
2o cyclohexylamino.
"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six
carbon
atoms or a branched saturated divalent hydrocarbon radical of three to six
carbon atoms,
e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene,
butylene,
pentylene.
"Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon
atoms
or a branched monovalent hydrocarbon radical of three to six carbon atoms,
containing at
least one triple bond, e.g., ethynyl, propynyl.
"Alkylsulfonyl" means a radical -S(O)ZR where R is an alkyl, cycloalkyl or
cycloalkyl-
alkyl group as defined herein, e.g., methylsulfonyl, ethylsulfonyl,
propylsulfonyl,
3o butylsulfonyl, cyclohexylsulfonyl.
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_g_
"Alkylsulfinyl" means a radical -S(O)R where R is an alkyl, cycloalkyl or
cycloalkyl-
alkyl group as defined herein e.g., methylsulfinyl, ethylsulfinyl,
propylsulfinyl,
butylsulfinyl, cyclohexylsulfinyl.
"Alkylthio " means a radical -SR where R is an alkyl as defined above e.g.,
methylthio,
ethylthio, propylthio, butylthio.
"Aryl" means a monocyclic or bicyclic aromatic hydrocarbon radical of
preferably 6
to 10 ring atoms which is optionally substituted with one or more
substituents, preferably
one, two or three, substituents preferably selected from the group consisting
of alkyl,
haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino,
dialkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, -SOzNR'R" (where R' and R" are
independently
hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy,
halo, nitro,
cyano, mercapto, methylenedioxy or ethylenedioxy. More specifically the term
aryl
includes, but is not limited to, phenyl, chlorophenyl, fluorophenyl,
methoxyphenyl, 1-
naphthyl, 2-naphthyl, and the derivatives thereof.
"Arylene" means a divalent aryl group as defined above.
"Arylalkyl" refers to an alkyl radical as defined herein in which one of the
hydrogen
atoms of the alkyl group is replaced with an aryl group. Typical arylalkyl
groups include,
but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-
naphthylethan-1-yl,
naphthobenzyl, 2-naphthophenylethan-1-yl.
"Aryloxy" means a radical -O-R where R is an aryl group as defined herein.
"Carbamoyl" means the radical -C(=O)NH2.
"Cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon radical of
three to
seven ring carbons e.g., cyclopropyl, cyclobutyl, cyclohexyl, 4-
methylcyclohexyl.
"Cycloalkyl-alkyl" means a radical -RXRy where RX is an alkylene group and RY
is
cycloalkyl group as defined herein, e.g., cyclohexylmethyl.
"Dialkylamino" means a radical -NRR' where R and R' independently represent an
al yl, cycloalkyl, or cycloalkylalkyl group as defined herein. Representative
examples
include, but are not limited to dimethylamino, methylethylamino,
di(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino,
(cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino,
(cyclohexylmethyl)(ethyl)amino.
"Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
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"Haloalkyl" means alkyl substituted with one or more same or different halo
atoms,
e.g., -CHZCI, -CF3, -CHZCF3, -CHZCCl3.
"Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms
having at
least one aromatic ring containing one, two, or three ring heteroatoms
selected from N, O,
or S, the remaining ring atoms being C, with the understanding that the
attachment point
of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is
optionally
substituted independently with one or more substituents, preferably one or two
substituents, selected from alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl,
acylamino,
amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, -
SOZNR'R" (where
Io R' and R" are independently hydrogen or alkyl), alkoxy, haloalkoxy,
alkoxycarbonyl,
carbamoyl, hydroxy, halo, nitro, cyano, mercapto, methylenedioxy,
ethylenedioxy or
optionally substituted phenyl. More specifically the term heteroaryl includes,
but is not
limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl,
imidazolyl, isoxazolyl,
pyrrolyl, pyrazolyl, pyrimidinyl, 5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl, 5-(4-
methoxyphenyl)-pyrimidin-2-yl, 5-(3,4-methylenedioxyphenyl)-pyrimidin-2-yl,
benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,
benzoisothiazolyl,
benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl,
tetrahydroquinolinyl,
isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl and derivatives
thereof.
"Heteroarylene" means a divalent heteroaryl group as defined above.
"Heteroarylalkyl" means an alkyl radical as defined herein in which one of the
hydrogen atoms of the alkyl group is replaced with a heteroaryl group
"Heteroalkyl" means an alkyl radical as defined herein wherein one, two or
three
hydrogen atoms have been replaced with a substituent independently selected
from the
group consisting of -ORa, -NRbR', and -S(O)nRd (where n is an integer from 0
to 2), with
the understanding that the point of attachment of the heteroalkyl radical is
through a
carbon atom, wherein Ra is hydrogen, acyl, alkyl, cycloalkyl, or
cycloalkylalkyl; Rb and R'
are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or
cycloalkylalkyl; when n
is 0, Rd is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1
or 2, Rd is alkyl,
cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or
dialkylamino;.
3o Representative examples include, but are not limited to, 2-hydroxyethyl, 3-
hydroxypropyl,
2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-
hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-
aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,
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aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl,
methylaminosulfonylpropyl.
"Heterocyclyl" means a saturated or unsaturated non-aromatic cyclic radical of
3 to
8 ring atoms in which one or two ring atoms are heteroatoms selected from NR"
{wherein
s each R" is independently hydrogen, alkyl, acyl, alkylsulfonyl,
aminosulfonyl,
(alkylamino)sulfonyl, (dialkylamino)sulfonyl, carbamoyl, (alkylamino)carbonyl,
(dialkylamino)carbonyl, (carbamoyl)alkyl, (alkylamino)carbonylalkyl, or
dialkylaminocarbonylalkyl}, O, or S(O)n (where n is an integer from 0 to 2),
the remaining
ring atoms being C. The heterocyclyl ring may be optionally substituted
independently
1o with one, two, or three substituents selected from alkyl, haloalkyl,
heteroalkyl, halo, nitro,
cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, arylalkyl, -
(X)n-
C(O)R (where X is O or NR', n is 0 or l, R is hydrogen, alkyl, haloalkyl,
hydroxy, alkoxy,
amino, monoalkylamino, dialkylamino or optionally substituted phenyl, and R'
is
hydrogen or alkyl), -alkylene-C(O)R (where R is hydrogen, alkyl, haloalkyl,
hydroxy,
1s alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted
phenyl) or
-S(O)nRd (where n is an integer from 0 to 2, and Rd is hydrogen (provided that
n is 0),
alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monoalkylamino,
dialkylamino, or
hydroxyalkyl). More specifically the term heterocyclyl includes, but is not
limited to,
tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-
methylpyrrolidin-3-
20 yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide,
thiomorpholino-1,1-dioxide,tetrahydrothiophenyl-S,S-dioxide, pyrrolinyl,
imidazolinyl,
and the derivatives thereof.
"Hydroxyalkyl" means an alkyl radical as defined herein, substituted with one
or
more, preferably one, two or three hydroxy groups, provided that the same
carbon atom
25 does not carry more than one hydroxy group. Representative examples
include, but are
not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-
(hydroxymethyl)-2-
methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-
dihydroxypropyl, 2-
hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and
2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-
dihydroxypropyl and
30 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly, as used herein, the term
"hydroxyalkyl"
is used to define a subset of heteroalkyl groups.
"Leaving group" has the meaning conventionally associated with it in synthetic
organic chemistry, i.e., an atom or a group capable of being displaced by a
nucleophile and
includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy,
arenesulfonyloxy,
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alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,
trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O-
dimethylhydroxylamino.
"Optionally substituted phenyl" means a phenyl group which is optionally
substituted with one or more substituents, preferably one, two or three,
substituents
preferably selected from the group consisting of alkyl, haloalkyl,
hydroxyalkyl,
heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, alkylthio,
alkylsulfinyl,
alkylsulfonyl, -S02NR'R" (where R' and R" are independently hydrogen or
alkyl), alkoxy,
haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, mercapto,
to methylenedioxy or ethylenedioxy. More specifically the term includes, but
is not limited
to, phenyl, chlorophenyl, fluorophenyl, bromophenyl, methylphenyl,
ethylphenyl,
methoxyphenyl, cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-
chlorophenyl,
3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-
methylphenyl,
3-chloro-4-fluorophenyl or 3,4-dichlorophenyl and the derivatives thereof.
"Optional" or "optionally" means that the subsequently described event or
circumstance may but need not occur, and that the description includes
instances where
the event or circumstance occurs and instances in which it does not. For
example, "aryl
group optionally mono- or di-substituted with an alkyl group" means that the
alkyl may
2o but need not be present, and the description includes situations where the
aryl group is
mono- or disubstituted with an alkyl group and situations where the aryl group
is not
substituted with the alkyl group.
"Pharmaceutically acceptable excipient" means an excipient that is useful in
preparing a pharmaceutical composition that is generally safe, non-toxic and
neither
biologically nor otherwise undesirable, and includes excipient that is
acceptable for
veterinary use as well as human pharmaceutical use. A "pharmaceutically
acceptable
excipient" as used in the specification and claims includes both one and more
than one
such excipient.
"Pharmaceutically acceptable salt" of a compound means a salt that is
3o pharmaceutically acceptable and that possesses the desired pharmacological
activity of the
parent compound. Such salts include: ( 1) acid addition salts, formed with
inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid,
and the like; or formed with organic acids such as acetic acid, propionic
acid, hexanoic
acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,
malonic acid,
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succinic acid, malic acid, malefic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, 3-
(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid,
ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic
acid, 4-
toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-
carboxylic
acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic
acid, salicylic
acid, stearic acid, muconic acid, and the like; or (2) salts formed when an
acidic proton
present in the parent compound either is replaced by a metal ion, e.g., an
alkali metal ion,
an alkaline earth ion, or an aluminum ion; or coordinates with an organic base
such as
ethanolamine, diethanolamine, triethanolamine, tromethamine, N-
methylglucamine.
"Phenylalkyl" refers to an alkyl radical as defined herein in which one of the
hydrogen atoms of the alkyl radical has been replaced by an optionally
substituted phenyl.
"Protecting group" refers to a grouping of atoms that when attached to a
reactive
group in a molecule masks, reduces or prevents that reactivity. Examples of
protecting
groups can be found in T.W. Green and P.G. Futs, Protective Groups in Organic
Chemistry, (Whey, 2°d ed. 1991) and Harrison and Harrison et al.,
Compendium of
Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996).
Representative
amino protecting groups include, formyl, acetyl, trifluoroacetyl, benzyl,
benzyloxycarbonyl
(CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-
ethanesulfonyl
(SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-
fluorenylmethyloxycarbonyl
(FMOC), nitro-veratryloxycarbonyl (NVOC). Representative hydroxy protecting
groups
include those where the hydroxy group is either acylated or alkylated such as
benzyl, and
trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl
ethers and allyl
ethers.
"Treating" or "treatment" of a disease includes: ( 1 ) preventing the disease,
i.e.,
causing the clinical symptoms of the disease not to develop in a mammal that
may be
exposed to or predisposed to the disease but does not yet experience or
display symptoms
of the disease; (2) inhibiting the disease, i.e., arresting or reducing the
development of the
3o disease or its clinical symptoms; or (3) relieving the disease, i.e.,
causing regression of the
disease or its clinical symptoms.
"A therapeutically effective amount" means the amount of a compound that, when
administered to a mammal for treating a disease, is sufficient to effect such
treatment for
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the disease. The "therapeutically effective amount" will vary depending on the
compound,
the disease and its severity and the age, weight, etc., of the mammal to be
treated.
"Prodrugs" means any compound which releases an active parent drug according
to
Formula I in vivo when such a prodrug is administered to a mammalian subject.
Prodrugs
of a compound of Formula I are prepared by modifying functional groups present
in the
compound of Formula I in such a way that the modifications may be cleaved in
vivo to
release the parent compound. Prodrugs include compounds of Formula I wherein a
hydroxy, amino, or sulfhydryl group in a compound of Formula I is bonded to
any group
that may be cleaved in vivo to regenerate the free hydroxyl, amino, or
sulfhydryl group,
Io respectively. Examples of prodrugs include, but are not limited to esters
(e.g., acetate,
formate, and benzoate derivatives), carbamates (e.g., N,N-
dimethylaminocarbonyl) of
hydroxy functional groups in compounds of Formula I.
Compounds that have the same molecular Formula but differ in the nature or
sequence of bonding of their atoms or the arrangement of their atoms in space
are termed
"isomers." Isomers that differ in the arrangement of their atoms in space are
termed
"stereoisomers". Stereoisomers that are not mirror images of one another are
termed
"diastereomers" and those that are non-superimposable mirror images of each
other are
termed "enantiomers". When a compound has an asymmetric center, for example,
if a
carbon atom is bonded to four different groups, a pair of enantiomers is
possible. An
2o enantiomer can be characterized by the absolute configuration of its
asymmetric center
and is described by the R- and S-sequencing rules of Cahn and Prelog, or by
the manner in
which the molecule rotates the plane of polarized light and designated as
dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can
exist as either
individual enantiomer or as a mixture thereof. A mixture containing equal
proportions of
the enantiomers is called a "racemic mixture".
The compounds of this invention may possess one or more asymmetric centers;
such
compounds can therefore be produced as individual (R)- or (S)-stereoisomers or
as
mixtures thereof. Unless indicated otherwise, the description or naming of a
particular
compound in the specification and claims is intended to include both
individual
3o enantiomers and mixtures, racemic or otherwise, thereof. The methods for
the
determination of stereochemistry and the separation of stereoisomers are well-
known in
the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th
edition J.
March, John Wiley and Sons, New York, 1992). The nomenclature used in this
application
is generally based on the IUPAC recommendations. For example, a compound of
Formula
(I) wherein Rl is methylene; RZ is 4-chlorophenyl; L is C(=O)NH; X is absent;
A is
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cyclopentyl; R3 is hydrogen; and R4 is 2-quinolyl (Compound 1 in Table 1), is
named (~)-
trans-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl] cydopentyl}-3-quinolin-2-yl-
urea.
Representative compounds of Formula (I) are shown in the following table.
Table I
Compound Structure M.P. ("C)
1
O
N~ NH-'
NH N
CI
2
O
N~ NH~
NH \
CI ~ \ N
O~CH3
3
O
N~ NHI\
NH
CI
CI
CI
4
O
N~ NH-'
NH
S
CI
O
.:
N~ N
CI ~ \ N
CI
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Compound Structure M.P. ("C)
6 O
O
v w ~CH3
N H I /
CI
7
O O_CH3
N N O
~CH3
CI ~ ~ O
CH3
8 NO2
O _
N HN-S
ii
O
CI
9
O
N~ N H
O
CI
N02
S
O
N~ NH~NH ~ ~ \CH3
CI
While the broadest definition of this invention is described before, certain
compounds of Formula (I) are preferred.
A preferred compound of the invention is a compound of Formula (I) wherein Rl
is
5 methylene.
One aspect of the invention relates to compounds of Formula (I) where ring A
is
cycloalkyl, heterocyclyl or substituted phenyl. Another preferred compound of
the
invention are compounds of Formula (I) wherein ring A is cyclopentyl.
Compounds
where ring A is cyclopentyl are bind unexpectedly potently to the CCR-3
receptor. Other
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preferred compounds of the invention are compounds of Formula (I) wherein ring
A is
heterocyclyl (particularly tetrahydropyranyl, S,S-dioxo-tetrahydothiophenyl,
tetrahydrothiophenyl or pyrrolidinyl) or compounds of Formula (I) wherein ring
A is
substituted phenyl.
A preferred compound of the invention is a compound of Formula (I) wherein Rz
is
phenyl ring substituted with one, or two substituents selected from alkyl,
alkoxy, haloalkyl,
halo, cyano or nitro; preferably methyl, ethyl, methoxy, trifluoromethyl,
chloro, fluoro or
bromo; most preferably 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl,
3,4-
difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-
methylphenyl, 3-
to chloro-4-fluorophenyl or 3,4-dichlorophenyl. Particularly preferred are 4-
chlorophenyl or
3,4-dichlorophenyl.
A preferred compound of the invention is a compound of Formula (I) wherein R3
is
hydrogen or methyl, preferably hydrogen.
A preferred compound of the invention is a compound of Formula (I) wherein L
is -
~5 C(=O)-, -SOZ-, -C(=O)N(Ra)-, -C(=S)N(Ra)-, or -C(=O)O-. More preferred are
compounds where L is -C(=O)-, -C(=O)N(R~,)-, most preferably -C(=O)N(Ra)-. In
the
preceding Ra is preferably hydrogen or methyl, most preferably hydrogen.
A preferred compound of the invention is a compound of Formula (I) wherein X
is
absent, methylene, I,2-ethanediyl, 1,3-propanediyl, or 1,4-butanediyl.
zo A preferred compound of the invention is a compound of Formula (I) wherein
R4 is
optionally substituted phenyl, optionally substituted heteroaryl wherein the
heteroaryl ring
is indolyl, thienyl, quinolinyl, substituted pyrimidin-2-yl, e.g. (5-(3,4-
dimethoxyphenyl)pyrimidin-2-yl, 5-(3,4-methylenedioxy)-pyrimidin-2-yl or 5-(4-
methoxyphenyl)pyrimidin-2-yl) or 1,8-naphthyridinyl. Preferably R4 is selected
from 3,4-
25 dichlorophenyl, 3,4,5-trimethoxyphenyl, 4-methanesulfonyl-phenyl, 3-
methanesulfonylphenyl, 4-methoxynaphthalen-2-yl, 5-(3,4-
dimethoxyphenyl)pyrimidin-
2-yl, phenyl, 3-fluorophenyl, 4-ethylphenyl, 3-methoxyphenyl, 2,4-
difluorophenyl,
3-trifluoromethylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-
carboxamidophenyl, 4-acetylphenyl, 4-nitrophenyl, 2-methylphenyl, 2-chloro-4-
3o fluorophenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,3-dichlorophenyl,
2,4-dichlorophenyl, 4-bromophenyl, 4-chloro-3-nitrophenyl, 2-nitrophenyl, 2-
nitro-4-
trifluoromethylphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-
methylphenyl,
2-trifluoromethylphenyl, 2-methoxyphenyl, 3-bromophenyl, 4-
trifluoromethylphenyl, 3-
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trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 4-tert-butylphenyl, 4-
ethoxyphenyl,
3-cyanophenyl, 4-cyanophenyl, 4-methoxyphenyl, 3-nitrophenyl, 3,5-
dimethoxyphenyl, 4-
iodophenyl, 4-isopropylphenyl, 3-methoxycarbonylphenyl, 3-acetylphenyl, 2-
methylphenyl, indol-2-yl, 5-methoxyindol-2-yl, 5-chloroindol-2-yl, 2-
methoxycarbonylphenyl, 3,5-dichlorophenyl, 1-naphthyl, 3-chloro-2-
methylphenyl, 2,5
dimethylphenyl, 2-thienyl, 3-ethoxyphenyl, 3-isoquinolyl, 2-methylquinolin-6-
yl, 3
methylaminophenyl, 3-quinolyl, 2-quinolyl, 5-hydroxynaphthalen-2-yl, 8-
hydroxyquinolin-2-yl, 5,7-dimethyl-[1,8]naphthyridin-2-yl, 6-quinolyl, 3-
(acetylamino)phenyl, or 2,3,4-trimethoxyphenyl. Particularly preferred are R4
being
to trimethoxyphenyl, e.g 3,4,5-trimethoxyphenyl, 4-acetyl-phenyl, 4-
carboxamido-phenyl
and 4-methanesulfonyl-phenyl.
Also preferred are compounds where X is -CHZS-, -CHZO-, -CHzCH2- and R4 is
heteroaryl, preferably optionally substituted pyrimidinyl, pyrazolyl or
thienyl. Particularly
preferred are compounds where X is -CHZS- and R4 is 5-(3,4-dimethoxyphenyl)-
pyrimidin-2-yl, 5-(3,4-methylenedioxyphenyl)-pyrimidin-2-yl, 5-(4-
methoxyphenyl)pyrimidin-2-yl
A specific compound of Formula (I) is a compound of Formula (II):
R3
A N~~~X~Ra
N
R5
R'-R2 (II)
wherein R1-RS, A, L, and X have any of the values described herein.
zo A specific compound of Formula (I) is a compound of Formula (III):
R3
~N~~~X~Ra
N
R5
R'-R2 (III)
wherein R~-R5, A, L, and X have any of the values described herein.
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A specific compound of Formula (I) is a compound of formula (IV):
R3
i
N~~~X~Ra
N
~I (IV)
wherein R3, R4, A, L, and X have any of the values described herein.
A specific compound of Formula (I) is a compound of formula (V):
H
i
N II X.Ra
0
N
~ /
wherein X and R4 have any of the values defined herein.
A specific compound of Formula (I) is a compound of formula (VI):
H
i
N II X.Ra
0
N
/ CI
(VI)
wherein X and R4 have any of the values defined herein.
l0 A specific compound of Formula (I) is a compound of formula (VII):
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H
N II X.Ra
O
N
CI
(VII)
wherein X and Ra have any of the values defined herein.
A specific compound of Formula (I) is a compound of formula (VIII):
Rx\N N X~Ra
O
N
CI
(VIII)
wherein X and R4 have any of the values defined herein; and Rc is hydrogen,
alkyl, acyl,
alkylsulfonyl, aminosulfonyl, (alkylamino)sulfonyl, (dialkylamino)sulfonyl,
carbamoyl,
(alkylamino)carbonyl, (dialkylamino)carbonyl, (carbamoyl)alkyl,
(alkylamino)carbonylalkyl, or diallcylaminocarbonylalkyl.
A specific compound of Formula (I) is a compound of formula (IX):
O H
i
O%S N~X~Ra
I IO
N
CI
to (IX)
wherein X and R4 have any of the values defined herein.
A specific compound of Formula (I) is a compound of formula (X):
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H
O N~X~Ra
'IO
N
CI
(X)
wherein X and Ra have any of the values defined herein.
A particularly preferred compound of the invention is:
traps-1-{2-[4-(4-chlorobenzyl)-piperidin-1-yl]-cyclopentyl}-3-(3,4,5-
trimethoxy-
phenyl)urea hydrochloride;
traps-1-{4-[4-(4-chlorobenzyl)-piperidin-1-yl]-tetrahydro-furan-3-yl}-3-(3,4,5-
trimethoxy-phenyl)urea;
(~)-1-{(1R,2R,4S)-2-(4-(4-chlorobenzyl)piperidin-1-yl]-
4-hydroxy-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea;
(~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-hydroxymethyl-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea; and
(~)-1-{ ( 1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-methoxymethyl-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea
or prodrugs, individual isomers, racemic and non-racemic mixtures of isomers,
and
pharmaceutically acceptable salts thereof.
The compounds of the invention are CCR-3 receptor antagonists and inhibit
eosinophil recruitment by CCR-3 chemokines such as RANTES, eotaxin, MCP-2, MCP-
3
and MCP-.4. Compounds of this invention and compositions containing them are
useful
in the treatment of eosiniphil-induced diseases such as inflammatory or
allergic diseases
and including respiratory allergic diseases such as asthma, allergic rhinitis,
hypersensitivity
lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g.,
chronic
eosinophilic pneumonia); inflammatory bowel diseases (e.g., Crohn's disease
and
ulcerative colitis); and psoriasis and inflammatory dermatoses such as
dermatitis and
eczema.
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The CCR-3 antagonistic activity of the compounds of this invention can be
measured
by in vitro assays such as ligand binding and chemotaxis assays as described
in more detail
in Examples 45, 46, and 47. In vivo activity was assayed in the Ovalbumin
induced Asthma
in Balb/c Mice Model as described in more detail in Example 48.
In general, the compounds of this invention can be administered in a
therapeutically
effective amount by any of the accepted modes of administration for agents
that serve
similar utilities. The actual amount of the compound of this invention, i.e.,
the active
ingredient, will depend upon numerous factors such as the severity of the
disease to be
to treated, the age and relative health of the subject, the potency of the
compound used, the
route and form of administration, and other factors.
Therapeutically effective amounts of compounds of Formula (I) may range from
approximately 0.01-20 mg per kilogram body weight of the recipient per day;
preferably
about 0.1-10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage
range
15 would most preferably be about 7 mg to 0.7 g per day.
In general, compounds of this invention will be administered as pharmaceutical
compositions by any one of the following routes: oral, transdermal, inhalation
(e.g.,
intranasal or oral inhalation) or parenteral (e.g., intramuscular, intravenous
or
subcutaneous) administration. A preferred manner of administration is oral
using a
2o convenient daily dosage regimen which can be adjusted according to the
degree of
affliction. Compositions can take the form of tablets, pills, capsules,
semisolids, powders,
sustained release formulations, solutions, suspensions, liposomes, elixirs, or
any other
appropriate compositions. Another preferred manner for administering compounds
of
this invention is inhalation. This is an effective means for delivering a
therapeutic agent
25 directly to the respiratory tract for the treatment of diseases such as
asthma and other
similar or related respiratory tract disorders (see U.S. Pat. No. 5,607,915).
The choice of formulation depends on various factors such as the mode of drug
administration and the bioavailability of the drug substance. For delivery via
inhalation
the compound can be formulated as liquid solutions or suspensions, aerosol
propellants or
3o dry powder and loaded into a suitable dispenser for administration. There
are three types
of pharmaceutical inhalation devices--nebulizer inhalers, metered-dose
inhalers (MDI)
and dry powder inhalers (DPI). Nebulizer devices produce a stream of high
velocity air
that causes the therapeutic agents (which has been formulated in a liquid
form) to spray as
a mist which is carried into the patient's respiratory tract. MDI's typically
have the
35 formulation packaged with a compressed gas. Upon actuation, the device
discharges a
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measured amount of therapeutic agent by compressed gas, thus affording a
reliable method
of administering a set amount of agent. DPI's administer therapeutic agents in
the form of
a free flowing powder that can be dispersed in the patient's inspiratory air-
stream during
breathing by the device. In order to achieve a free flowing powder, the
therapeutic agent is
formulated with an excipient, such as lactose. A measured amount of the
therapeutic is
stored in a capsule form and is dispensed to the patient with each actuation.
Recently,
pharmaceutical formulations have been developed especially for drugs that show
poor
bioavailability based upon the principle that bioavailability can be increased
by increasing
the surface area i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes
l0 a pharmaceutical formulation having particles in the size range from 10 to
1,000 nm in
which the active material is supported on a crosslinked matrix of
macromolecules. U.S.
Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in
which the
drug substance is pulverized to nanoparticles (average particle size of 400
nm) in the
presence of a surface modifier and then dispersed in a liquid medium to give a
pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of Formula (I) in
combination with at least one pharmaceutically acceptable excipient.
Acceptable
excipients are non-toxic, aid administration, and do not adversely affect the
therapeutic
benefit of the compound of Formula (I). Such excipient may be any solid,
liquid, semi-
2o solid or, in the case of an aerosol composition, gaseous excipient that is
generally available
to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose,
lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate,
sodium stearate,
glycerol monostearate, sodium chloride, dried skim milk. Liquid and semisolid
excipients
may be selected from glycerol, propylene glycol, water, ethanol and various
oils, including
those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,
soybean oil,
mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for
injectable solutions,
include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in
aerosol
form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
For liposomal formulations of the drug for parenteral or oral delivery the
drug and
the lipids are dissolved in a suitable organic solvent e.g. tert-butanol,
cyclohexane (1%
ethanol). The solution is lyopholized and the lipid mixture is suspended in an
aqueous
buffer and allowed to form a liposome. If necessary, the liposome size can be
reduced by
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sonification. (see, Frank Szoka, Jr. and Demetrios Papahadjopoulos,
"Comparative
Properties and Methods of Preparation of Lipid Vesicles (Liposomes)", Ann.
Rev. Biophys.
Bioeng., 9:467-508 ( 1980), and D. D. Lasic, "Novel Applications of
Liposomes", Trends in
Biotech., 16:467-608, (1998)).
Other suitable pharmaceutical excipients and their formulations are described
in
Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing
Company,
18th ed., 1990).
The level of the compound in a formulation can vary within the full range
employed
by those skilled in the art. Typically, the formulation will contain, on a
weight percent (wt
%) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the
total
formulation, with the balance being one or more suitable pharmaceutical
excipients.
Preferably, the compound is present at a level of about 1-80 wt %.
Representative
pharmaceutical formulations containing a compound of Formula (I) are described
in
Example 44.
The compounds of the present invention can be prepared in a number of ways
known to one skilled in the art. Preferred methods include, but are not
limited to, the
general synthetic procedures described below.
The starting materials and reagents used in preparing these compounds are
either
2o available from commercial suppliers such as Aldrich Chemical Co.,
(Milwaukee, Wis.,
USA), Bachem (Torrance, Calif., USA), Enika Chemie, or Sigma (St. Louis, Mo.,
USA),
Maybridge (Dist: Ryan Scientific, P.O. Box 6496, Columbia, S.C. 92960), Bionet
Research
Ltd., (Cornwall PL32 9QZ, UK), Menai Organics Ltd., (Gwynedd, N. Wales, UK),
Butt
Park Ltd., (Dist. Interchim, Montlucon Cedex, France) or are prepared by
methods known
to those skilled in the art following procedures set forth in references such
as Fieser and
Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,
1991);
Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier
Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and
Sons, 1991),
March's Advanced Organic Chemistry, (John Wiley and Sons, 1992), and Larock's
Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These
schemes are
merely illustrative of some methods by which the compounds of this invention
can be
synthesized, and various modifications to these schemes can be made and will
be suggested
to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated
and
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purified if desired using conventional techniques, including but not limited
to filtration,
distillation, crystallization, chromatography. Such materials may be
characterized using
conventional means, including physical constants and spectral data.
Synthesis of Compounds of Formula (I)
Compounds of Formula (I) are generally prepared from the precursor amine of
Formula (Ia) as shown below.
Rs Rs
I
A NH A N,LiX.Ra
N N
Rs Rs
R > _RZ R t _R2
Ia I
1o Preparation of compounds of Formula (Ia) and their conversion to compounds
of
Formula I is illustrated in the following Schemes 1-8.
Schemes 1-5 show methods of preparing compounds of Formula Ia having different
rings A. Specific exemplification is provided for R'-RZ being 4-chlorobenzyl
in
Preparations 1-6. Preparation of analogous compounds where Rl and RZ vary
within the
full scope of this invention may be readily prepared by one of skill in the
art,in light of this
specification and incorporated references.
Scheme 1. Synthesis of Cyclobutylamines - Ring A = Phenyl.
BH3, THF, D HZN~NRZ H2N~,,~NR2
~-~-,+
TMSO- .OTMS RZNH X"NR2
MeONH2-HCI ~ X = ~pMe NaBH3(OZCCF3) HZN~,,~NRZ
RZN = 4-(4-Chlorobenryl)piperidine
HN / CI
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Scheme 2. Synthesis of Cis Diamines - Ring A = Cyclopentyl and Cyclohexyl.
N OH N3 ONs R NH N NR2 Ph3P, H20 H2N NR2
3 NsCI z
~ n n n
'M'n
n = ~ RzNH = 4-(4-Chlorobenzyl)piperidine
n=2 CI
HN
Scheme 3. Synthesis of Trans Diamines - Ring A = Cycloalkyl,
Tetrahydrofuranyl,
Pyrrolidinyl or Tetrahydrothiophenyl.
O R NH HO NR2 2) NFiCOH HzN NRZ
2 ) Q
X x x
X=CHz
3a x = (CHz)2
X = CHOTBS R2NH = 4-(4-Chlorobenzyl)piperidine
X = CHCHzOTBS CI
X=O HN I
X = NBOC \
to General Procedure A: (Amine Alkylation with Epoxides)
A 0.5-1.5 M solution of the amine, RZNH (1 equiv), and the specified epoxide,
3a
(1.1-10 equiv) in EtOH is stirred at 80-95 °C for 2-4.5 days, allowed
to cool to room
temperature, and concentrated. The crude amino alcohol is purified by
chromatography
or recrystallization.
General Procedure B: (Amine Formation Using Methanesulfonyl Chloride and
Ammonium Hydroxide)
A 0.2-0.3 M solution of the amino alcohol ( 1 equiv) in CHZCl2 at 0 °C
is treated
successively with Et3N (2 equiv) and MeSOZCI (2 equiv), stirred at 0 °C
for 1-2 hours, and
partitioned between CHzCIZ and 10-15% NH40H. The aqueous phase is extracted
with
2o CHZC12 and the extracts are dried and concentrated. A 0.13M solution of the
residue in
2.5:1 dioxane:28-30 wt % NH40H is stirred at 70-80 °C for 2.5-18 hours,
allowed to cool to
room temperature, and concentrated. The residue is partitioned bet'veen EtOAc
and 1 N
NaOH, the aqueous phase is extracted with EtOAc, and the extracts are washed
with brine,
dried and concentrated. The crude product is purified by chromatography or
used without
further purification.
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Scheme 4. Synthesis of Sulfone - Ring A = Sulfolane (IS THIS CORRECT??).
Et02CHN CI R2NH Et02CHN NRZ HBr H2N, .NR2
.S.
O~ ~O O~ ~O O~ ~O
RzNH = 4-(4-Chlorobenzyl)piperidine
HN / CI
Scheme S. Synthesis of Aniline - Ring A = Phenyl.
02N F 02N NR2 HZN NR2
RZNH SnCl2
pc062 pc063
RZNH = 4-(4-Chlorobenzyl)piperidine
Schemes 6 and 7 show preparation of compounds of Formula Ia where ring A is
l0 substituted. Scheme 6 shows preparation of compounds of Formula Ia with a
substituted
cyclopentyl ring A. Scheme 7 shows preparation of compounds of Formula Ia with
a
substituted pyrrolidine ring A by treatment of the unsubstituted pyrrolidine
7a (R=H) with
the appropriate reagent to produce the substituted pyrrolidine 7b.
Scheme 6. Synthesis of Cycloallcyl Derivatives.
R,4 Rs
~X- L-.N[ NRz
NRz = 4-(4-chlorobenzyl)piperidinyl
HN / CI
R'
R' = OTBS HCI R' = CHzOTBS
R' = OH R' = CHZOH
R' = OMe HZNz R' = CH20Me
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Scheme 7. Synthesis of Pyrrolidine Derivatives.
3
4 ~ R 13
~
X L N
N NRz Reagent NRZ
i
i R,
R,
NRZ = 4-(4-chlorobenryl)piperidinyl,
HN / CI Reagent R'
CHZCHSOZMe (CHZ)2S02Me
ICH2CONH2 CH2CONHz
R' = BOC Ac20 Ac
HCI ~ R. = H CICOCHZCOZMe;COCH2COZH
KOH
NaNCO CONHZ
CICONMe2 CONMe2
MsCI Ms
CISOzNHBOC; SOzNH2
HCI
CISOZNMe2 SOZNMeZ
Schemes 8 and 9 show methods of converting compounds of Formula (Ia) to
compounds of Formula (I) where L and A are varied.
Scheme 8. Conversion of Primary Amines to Ureas and Benzamides.
1o Compounds of Formula (I) where L is -C(=O)NRa and X is absent are made as
shown below in Scheme 8 (exemplified with R4 being 3,4,5-trimethoxyphenyl) and
General
Procedures C and D. Compounds of Formula (I) where L is -C(=O)- and X is
absent are
made as shown below in Scheme 8 (exemplified with R4 being 3,4,5-
trimethoxyphenyl) and
General Procedures E and F.
Me02S
Me0
Me0 ~ ~ N
OH Me0 S
Me0 ~~~ O
Me0 O
Me0 ~ ~ N H2N NRZ
Me0 ~N NRz ~ N NRx
O
X X
RzN = 4-(4-chlorobenzyl)piperidinyl
x= C, O, S(O)", NR" HNl\y1 / CI
where n=0-2 and /~~w I
R' is as defined in the
Heterocyclyl definition
General Procedure C: (Urea Formation Usin Ig socyanates)
A 0.1-0.6 M solution of the amine ( 1 equiv) in CHZCl2 or CHZCIz and DMF at
0-20 °C is treated with the specified isocyanate (1.1-2 equiv), stirred
for 0.5-1.5 hours, and
partitioned between CHZCIz and saturated NaHC03. The aqueous phase is
extracted with
20 CHZC12 and the extracts are dried and concentrated. The crude urea is
purified by column
chromatography or preparative TLC or used in the next step without further
purification.
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General Procedure D: (Urea Formation Usin Isoc~anates followed by salt
formation)
A 0.1-0.6 M solution of the amine (1 equiv) in CHZCIz or CHZCIz and DMF at
0-20 °C is treated with the specified isocyanate (l.l-2 equiv), stirred
for 0.5-1.5 hours, and
partitioned between CHZCIz and saturated NaHC03. The aqueous phase is
extracted with
CHZCIZ and the extracts are dried and concentrated. The crude urea is purified
by column
chromatography or preparative TLC or used in the next step without further
purification.
A solution of the free base in CHZCI2 is treated with 1 N HCl in Et20 and
concentrated to
give the hydrochloride salt.
General Procedure E: (Amide Formation Using 1-Hydroxybenzotriazole and
1-(3-Dimethylaminoprop~rl)-3-ethylcarbodiimide Hydrochloride)
A 0.1-0.4 M solution of the amine ( 1 equiv) and the specified carboxylic acid
( 1.2-1.5
equiv) in CHZC12 at 0 °C is treated successively with 1-
hydroxybenzotriazole hydrate
(HOBt) (0.2-0.5 equiv) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (DEC) ( 1.3-2 equiv), stirred at 0-20 °C for 2-72 hours,
and partitioned
between CHzCl2 and saturated NaHC03. The aqueous phase is extracted with
CHZC1Z and
the extracts are dried and concentrated. The crude amide is purified by column
chromatography and/or preparative TLC.
General Procedure F: (Amide Formation Using 1-H d~xybenzotriazole and
1-(3-Dimethylaminoprop~ -3-ethylcarbodiimide Hydrochloride followed by salt
formation)
A 0.1-0.4 M solution of the amine ( 1 equiv) and the specified carboxylic acid
( 1.2-1.5
equiv) in CHZC12 at 0 °C is treated successively with 1-
hydroxybenzotriazole hydrate
(HOBt) (0.2-0.5 equiv) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (DEC) ( 1.3-2 equiv), stirred at 0-20 C for 2-72 hours, and
partitioned
between CHZC12 and saturated NaHC03. The aqueous phase is extracted with
CHZCIz and
the extracts are dried and concentrated. The crude amide is purified by column
chromatography and/or preparative TLC. A solution of the free base in CHZC12
is treated
3o with 1 N HCl in Et20 and concentrated to provide the hydrochloride salt.
Scheme 9 and following procedures G-O describe the various methods used to
convert compounds of Formula Ia to compounds of Formula I where L is varied.
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CI
O~S- R4 Procedure G
O
O
I Procedure H
R4 ~CI
O
II Procedurel
R~OH
Compound of + ~ Compound of
Formula la ~~\ Formula I
N Procedure J, K
R4
H2N .
Procedure L,M
S~
Procedure N
N
Ra
O O
~ 0 ~ N Procedure O
0
General Procedure G (Parallel Synthesis of Sulfonamides)
A mixture of the requisite amine Ia ( 1 equiv), the appropriate sulfonyl
chloride ( 1.5
equiv), and Amberlite IRA67 (2 equiv) in CHzCl2 (2 ml) was rotated overnight.
The
mixture was treated with PS-trisamine ( 1.2 equiv) (Argonaut Technologies
Inc., San
Carlos, CA, USA) and rotated overnight. The solid was collected by filtration
and washed
with CHZCIz, MeOH, and CHZCIz. The filtrate was concentrated to give the
product.
General Procedure H (Parallel Synthesis of Amides from Acid Chlorides
A mixture of the requisite amine Ia ( 1 equiv), the appropriate acid chloride
( 1.5
equiv), and Amberlite IRA67 (2 equiv) in CHZCl2 (2 ml) was rotated overnight.
The
mixture was treated with PS-trisamine ( 1.2 equiv) and MP-carbonate (2 equiv)
(Argonaut
Technologies, San Carlos, CA) and rotated overnight. The solid was collected
by filtration
and washed with CHZCIz, MeOH, and CHZC12. The filtrate was concentrated to
give the
product.
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General Procedure I (Parallel Synthesis of Amides from Carboxylic Acids)
A mixture of the requisite amine Ia ( 1 equiv), the appropriate carboxylic
acid ( 1.5
equiv), and PS-carobodiimide (2 equiv) (Argonaut Technologies Inc., San
Carlos, CA,
USA) in CHZCl2 (2 ml) was rotated overnight. The mixture was treated with
MP-carbonate (2 equiv) and rotated overnight. The solid was collected by
filtration and
washed with CHzCIZ, MeOH, and CHZCIz. The filtrate was concentrated to give
the
product.
General Procedure 1 (Parallel Synthesis of Ureas from Isocyanates and
Purification
by Parallel Chromatography)
1o A mixture of the requisite amine Ia ( 1 equiv) and the appropriate
isocyanate
(1.2 equiv) in CHZC12 (2 ml) was stirred overnight. The mixture was
concentrated to give
the crude product, which was purified by parallel chromatography using a step
gradient
(2.5% MeOH/CHZC12, 10% MeOH/CHZCIz).
~s by Catch
A mixture of the requisite amine Ia ( 1 equiv) and the appropriate isocyanate
( 1.2 equiv) in CHZC12 (2 ml) was stirred overnight. The mixture was treated
with
MP-TsOH and rotated for 3 hours. The solid was collected by filtration and
washed with
CHZCIz, MeOH, and CHzCl2. The solid was rotated with 2 M NH3 in MeOH for 2
hours.
2o The solid was collected by filtration and washed with CHZC12, MeOH, and
CHzCl2. The
filtrate was concentrated to give the purified product.
General Procedure L (Parallel Synthesis of Ureas from Anilines using Phoxime
Resin
A mixture of the appropriate aniline (3 equiv) and Phoxime resin ( 1 equiv) in
z5 CHZC12 (2 ml) was rotated for 3 hours. If the aniline had not dissolved,
triethylamine (3.5
equiv) was added. The mixture was rotated overnight. The solid was collected
by filtration
and washed with CH2C12, MeOH, CHZCl2, MeOH, and CHZCh. A mixture of the solid
and
the requisite amine Ia ( 1.1 equiv) in CHzCIz (0.5 ml) and toluene ( 1.5 ml)
were heated at
80 °C with shaking overnight and allowed to cool to room temperature.
The solid was
3o collected by filtration and washed with CHZC12, MeOH, and CHZCIz. The
filtrate was
concentrated to give the product.
General Procedure M (Parallel SXnthesis of Ureas from Anilines usi~
Triphosgene)
A mixture of the appropriate aniline ( 1.2 equiv), triphosgene (0.4 equiv),
and
triethylamine ( 1.4 equiv) in CHZC12 was heated at 35 °C for 1 hour.
After cooling to room
35 temperature, the requisite amine Ia ( 1 equiv) was added. The mixture was
stirred
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overnight, washed with Hz0 and brine, passed through Na2S04, and concentrated
to give
crude product which was purified by parallel chromatography.
General Procedure N (Parallel Synthesis of Thioureas from Thioisocyanates)
A mixture of the requisite amine Ia ( 1 equiv) and the appropriate
thioisocyanate ( 1.2
equiv) in CHZC12 (2 ml) was stirred overnight. The mixture was treated with MP-
TsOH
and rotated for 3 hours. The solid was collected by filtration and washed with
CHZCIZ,
MeOH, and CHzCl2. The solid was rotated with 2 M NH3 in MeOH for 2 hours. The
solid
was collected by filtration and washed with CHZC12, MeOH, and CHZC12. The
filtrate was
concentrated to give the purified product.
Io General Procedure O (Parallel Synthesis of Carbamates)
A mixture of the requisite amine Ia ( 1 equiv) and the appropriate succinimide
( 1.5
equiv) in CHZC12 (2 ml) was stirred overnight. If the reaction was not
complete, it was
heated at 38 °C for 1 hour. The mixture was washed with Hz0 and brine,
passed through
NaZS04 and concentrated to give the crude product which was purified via
parallel
~5 purification (step gradient 5% MeOH/CHZC12, 10% MeOH/CHZCh).
EXPERIMENTAL SECTION
General
Unless otherwise noted, all non-aqueous reactions were run under a nitrogen
atmosphere and NazS04 was used to dry all organic layers. Purifications were
typically
20 carried out by flash chromatography on silica gel (230-400 mesh) or
preparative TLC on
Uniplate Silica Gel GF PLC Plates (20 x 20 cm, 1000 microns) from Analtech,
Inc., Newark,
DE. Alumina used was basic with 6 wt % Hz0 (Brockmann III). Melting points
taken in
capillary tubes are uncorrected. IR spectra were determined in KBr. NMR
spectra were
run in CDCl3, unless otherwise indicated. IH NMR spectra were recorded on 300
MHz
25 instruments and'3C NMR spectra were recorded at 75.5 MHz. Mass spectral
analyses were
accomplished using electrospray ionization. Analytical reverse-phase HPLC was
performed on Shimadzu system equipped with a diode array spectrometer (range
190-300
nm; Hewlett Packard). The stationary phase was a Zorbax SB-Phenyl Rapid
Resolution
column (4.6 mm x 50 mm; Hewlett Packard), mobile phase A was 0.1%
trifluoroacetic
3o acid, and mobile phase B was CH3CN. A flow rate of 2.5 ml/min with a linear
gradient of
20-55% B in 5 min and then 55-20% B in 5 min was employed. Other physical and
analytical data were obtained by the physical and analytical chemistry group
at Roche
Bioscience. All parallel synthesis reactions were run in sealed tubes that
were vented prior
to rotated overnight. Amberlite IRA67 (Aldrich Chemical Co., Milwaukee, Wis.,
USA) was
35 washed consecutively with CHZC12, MeOH, CHZCl2, MeOH, CHZC12 and then dried
under
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vacuum prior to use. All products derived from parallel synthesis reactions
were
characterized via HPLC-MS.
EXAMPLES
The following Preparations ( 1-6) are useful for preparing synthetic
intermediates
that can be used to prepare compounds of the invention, as described in the
following
Examples.
Preparation 1: Preparation of (~)-traps-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexylamine
~NHZ
(~T N
1 o CI
Step A: Preparation of (~)-traps-2- f 4-(4-chlorobenz~l)piperidin-1-,
cyclohexanol
~OH
H N [~I N
+ --
CI CI
Following Procedure A, 4-(4-chlorobenzyl)-piperidine (see Preparation 7) (52
mg,
0.25 mmol) was alkylated with 7-oxa-bicyclo[4.1.0]heptane (0.25 ml, 2.5 mmol)
in EtOH
(0.5 ml) at 80 °C for 3 days. Chromatography of the crude product with
90:9.5:0.5-80:19:1
CHzCI2:MeOH:NH40H gave the product (68 mg, 88%) as a tan oil which solidified
upon
standing as a cream solid: mp 100-101.3 °C; IR 3379, 2929 cm-1; 1H NMR
8 1.05-1.76 (m,
12H), 2.02 (dt, J= 2.4,11.6 Hz, 1H), 2.06-2.20 (m, 2H), 2.49 (d, J= 7.0 Hz,
2H), 2.51-2.64
(m, 2H), 2.79 (m, 1H), 3.34 (m, 1H), 4.05 (m, 1H), 7.06 (m, 2H), 7.24 (m, 2H);
MS m/z
308 (M + H)+. Anal. (C18Hz6C1N0) C, H, N.
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Step B: Preparation of (~)-trans-2-L4-(4-chlorobenzyl)piperidin-l~rl]_
~clohexXlamine
~ _OH ~NHi
IIr~~IIYN [~1 N
CI CI
A solution of (~)-trans-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclohexanol (390
mg,
1.27 mmol) in CHZC12 (6 ml) at 0 °C was treated successively with Et3N
(350 ~1, 2.53
mmol) and MeSO2C1 ( 194 Etl, 2.53 mmol), stirred at 0 °C for 2 hours,
and partitioned
between CHZCIz and 10% NH40H. The aqueous phase was extracted with CHzCIz and
the
extracts were washed with brine, dried and concentrated. A solution of the
residue in THF
(3 ml) and 28-30 wt % NH40H ( 1.2 ml) was stirred at 70 °C for 24
hours, allowed to cool
to room temperature, and partitioned between EtOAc and 1 N NaOH. The aqueous
phase
was extracted with EtOAc and the extracts were washed with brine, dried and
concentrated.
Chromatography of the residue on alumina with 1:3 EtOAc:MeOH to 100% MeOH and
a
subsequent chromatography on alumina with 20:1 hexanes:EtOAc to 100% EtOAc
followed by 3:1 EtOAc:MeOH to 100% MeOH gave the product (260 mg, 67%) as a
tan oil
which solidified upon standing: mp 69.1-70.4 °C; 1H NMR 8 1.03-1.34 (m,
6H), 1.37-1.52
(m, 1H), 1.57-1.77 (m, 5H), 1.92-2.05 (m, 3H), 2.48 (d, J= 7.0 Hz, 2H), 2.45-
2.64 (m, 3H),
2.73 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 307 (M + H)t.
Preparation 2: Preparation of (~)-traps-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentylamine
NHz
- N
CI
Step A: Preparation of (~)-traps-2-l4-(4-chlorobenzyl)piperidin-1-yll-
cyclopentanol
~OH
HN - N
\ I \ '
CI CI
Following General Procedure A, a solution of 4-(4-chlorobenzyl)-piperidine (
17.86 g,
85.05 mmol) and 6-oxa-bicyclo[3.1.0]hexane (50 g, 0.6 mol) in EtOH (170 ml)
was stirred
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at 95 °C for 40 hours, allowed to cool to room temperature, and
concentrated. The residue
was crystallized in hot CHZC12 (80 ml), the crystallization mixture was
concentrated to half
the volume, and kept at 0 °C overnight and filtered, and the
precipitate was rinsed with
cold hexanes to give the product ( 18.2 g, 73%) as a tan solid. The mother
liquors were
concentrated to half the volume, diluted with CHzCl2 and kept at -10 °C
for 1 hour, and
the precipitate was rinsed with cold CH2C12 and hexanes to give additional
product ( 1.8 g,
7%) as a tan solid: mp 104.1-105.5 °C; IR 3436, 2928 cm-1; 1H NMR 8
1.19-1.75 (m, 8H),
1.81-1.99 (m, 4H), 2.06 (dt, J= 2.5,11.7 Hz, 1H), 2.47 (m, 1H), 2.50 (d, J=
7.0 Hz, 2H),
2.90 (m, 1H), 3.07 (m, 1H), 4.10 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); 13C NMR
8 21.63,
27.35, 32.01, 32.15, 34.31, 37.87, 42.47, 50.47, 52.97, 75.15, 75.22, 128.27,
130.43, 131.55,
139.04; MS m/z 294 (M + H)+. Anal. (C1~H24C1N0~O.1H20) C, H, N.
-traps-2- f 4-(4-chlorobenzvl)tiideridin-1-vl l -
/~ OH (/~~ NHz
~N V'~. N
CI CI
Following General Procedure B, a solution of (~)-traps-2-[4-(4-chlorobenzyl)-
piperidin-1-yl]-cyclopentanol (205 mg, 0.697 mmol) in CHZC12 (2.8 ml) at 0
°C was
treated successively with Et3N ( 190 yl, 1.4 mmol) and MeSO2C1 ( 110 yl, 1.4
mmol), stirred
at 0 °C for 1 hour, and partitioned between CHZCIz and 10% NH40H. The
aqueous phase
2o was extracted with CHZCIz and the extracts were dried and concentrated to
give 220 mg of
an oil. A solution of the residue ( 110 mg) in dioxane (2 ml) and 28-30 wt %
NH40H (0.8
ml) was stirred at 70-80 °C overnight, allowed to cool to room
temperature, and
concentrated. The residue was partitioned between EtOAc and 1 N NaOH, the
aqueous
phase was extracted with EtOAc, and the extracts were washed with brine, dried
and
concentrated. Chromatography of the residue on alumina with 10:1 hexanes:EtOAc
to
100% EtOAc followed by 95:4.75:0.25-60:38:2 CHZCIz:MeOH:NH40H gave the product
(87 mg, 85%) as an oil: 1H NMR b 1.18-1.71 (m, 9H), 1.76-2.00 (m, 3H), 2.07
(dt, J=
2.4,11.5 Hz, 1H), 2.31 (m, 1H), 2.50 (d, J= 6.9 Hz, 2H), 2.86-2.99 (m, 2H),
3.19 (m, 1H),
7.06 (m, 2H), 7.23 (m, 2H); MS m/z 293.2 (M + H)+.
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Preparation 3: Preparation of (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentylamine
~NH,
(~T N
CI
Step A: Preyaration of (~)-traps-4-nitro-benzenesulfonic acid 2-azido-
cyclopent~
ester
, N~
~N_ O ~N.
O
N'N + CI'O\~
OH
I
° Np
O
A solution of (~)-traps-2-azido-cyclopentanol (1.27 g, 10.0 mmol) (Zhang, Z.
da;
Scheffold, R. Helv. Chim. Acta 1993, 76, 2602) in CHZC12 (14 ml) at 0
°C was treated
successively with pyridine (0.88 ml, 10.9 mmol) and 4-nitro-benzenesulfonyl
chloride
(2.22 g, 10.0 mmol) and allowed to warm to room temperature slowly. The
reaction was
stirred for 4 days, during which additional pyridine (0.9 ml, 11 mmol) and
4-nitro-benzenesulfonic acid (2.2 g, 10 mmol) was added, and partitioned
between CHzCIz
and 1 N HCI. The aqueous phase was extracted with CHZC12 and the extracts were
washed
with saturated NaHC03, dried and concentrated. Chromatography of the residue
with
~5 10:1-4:1 hexanes:EtOAc gave the product (2.63 g, 84%) as a yellow oil: 1H
NMR b
1.61-1.90 (m, 4H), 2.00-2.16 (m, 2H), 3.96 (m, 1H), 4.72 (m, 1H), 8.14 (m,
2H), 8.43 (m,
2H).
Step B: Preparation of (~)-cis-1-(2-azido-c,~pentyl)-4-(4-
chlorobenz,~piperidine
N
N;N
, N'~ FiN
N N
o.s
O ~ i N.D W
i _ CI
O
CI
A murky solution of (~)-traps-4-nitro-benzenesulfonic acid 2-azido-cyclopentyl
ester
(630 mg, 2.0 mmol), 4-(4-chlorobenzyl)-piperidine (420 mg, 2.0 mmol), and Et3N
(280 yl,
2.0 mmol) in CH3CN (4 ml) was stirred at room temperature for 10 days and 65
°C for 2
days, allowed to cool to room temperature, and concentrated. The residue was
partitioned
between CHzCl2 and 1 N NaOH, the aqueous phase was extracted with CH2Clz and
the
extracts were dried and concentrated. Chromatography of the residue with 20:1-
1:1
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hexanes:EtOAc followed by chromatography with 100% CHzCl2 to 95:4.75:0.25
CHZCI2:MeOH:NH40H gave the product (145 mg, 22%) as a tan oil: 1H NMR 8 1.32-
1.90
(m, 13H), 2.33 (m, 1H), 2.49 (d, J= 6.4 Hz, 2H), 2.96 (m, 1H), 3.06 (m, 1H),
4.04 (t, J=
4.0 Hz, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 319.2 (M - H)-.
-cis-2- f 4-(4-chlorobenzvl) tiiperidin-1-vl I -
N_
~N ~NHz
N N
\~ \
CI CI
A solution of (~)-cis-1-(2-azido-cyclopentyl)-4-(4-chlorobenzyl)-piperidine
(210
mg, 0.65 mmol) in THF (2.5 ml) was treated successively with PPh3 (514 mg,
1.96 mmol)
1o and Hz0 ( 141 ~1, 7.83 mmol), refluxed for 3.5 hours, allowed to cool to
room temperature,
and concentrated. Chromatography of the residue with 90:9.5:0.5-75:23.75:1.25
CHzCI2:MeOH:NH40H gave the product (183 mg, 95 %) as a colorless oil which
solidified
upon standing to a cream solid: mp 69.6-71.3 °C; 1H NMR 8 1.20-1.35 (m,
2H), 1.43-1.93
(m, 11H), 2.17 (m, 1H), 2.49 (d, J= 6.9 Hz, 2H), 2.89-3.02 (m, 2H), 3.34 (t,
J= 4.4 Hz,
15 1H), 7.06 (m, 2H), 7.23 (m, 2H); 13C NMR 8 20.72, 27.08, 32.48, 32.61,
38.32, 42.95, 52.14,
53.09, 53.61, 71.49, 128.63, 130.80, 131.88, 139.58; MS mlz 293.2 (M + H)+.
Preparation 4: Preparation of (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexylamine
~NH=
(~T N
/
CI
2o Step A~ Preparation of (~)-trnns-4-nitro-benzenesulfonic acid 2-azido-
cyclohexyl ester
.N
O N,
N:N CI~ 0 ~ O
i .O O. O
OH o_ I i N,.,p
O
A solution of (~)-traps-2-azidocyclohexan-1-of (11.3 g, 80.0 mmol) (Zhang, Z.
da;
Scheffold, R. Helv. Chim. Actn 1993, 76, 2602] in CHzCl2 ( 110 ml) at 0
°C was treated
25 successively with pyridine ( 14.2 ml, 176 mmol) and 4-nitro-benzenesulfonyl
chloride (35.6
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g, 160 mmol), allowed to warm to room temperature slowly, stirred for 4 days,
and
partitioned between CHZCIz and 1 N HCI. The aqueous phase was extracted with
CHZC12
and the extracts were washed with saturated NaHC03, dried and concentrated.
Chromatography of the residue with 10:1-1:1 hexanes:EtOAc gave the product (19
g, 72%)
as a cream solid: 1H NMR 8 1.19-1.39 (m, 3H), 1.53-1.82 (m, 3H), 2.00-2.10 (m,
1H), 2.26
(m, 1H), 3.36 (m, 1H), 4.35 (ddd, J= 4.7, 9.2, 10.8 Hz, 1H), 8.17 (m, 2H),
8.41 (m, 2H).
Step B: Preparation of (~)-cis-1-(2-azido-c clohexyl)-4-(4-
chlorobenz~piperidine
:N N_
.dd_ ~N
,N H (~TN
N N
~ O
~0.0 ~ \ + / I
W /
~N_ CI
O
CI
1o A murky solution of (~)-trc~ns-4-nitro-benzenesulfonic acid 2-azido-
cydohexyl ester
( 1.77 g, 5.41 mmol), 4-(4-chlorobenzyl)-piperidine ( 1.14 g, 5.43 mmol), and
Et3N (0.75
ml, 5.4 mmol) in CH3CN ( 11.2 ml) was stirred at room temperature for 17
hours, 65 °C
for 31 hours, and 80 °C for 5 days, allowed to cool to room
temperature, and concentrated.
The residue was partitioned between CHZC12 and 1 N NaOH, the aqueous phase was
extracted with CHzCIz and the extracts were dried and concentrated.
Chromatography of
the residue with 98:1.9:0.1-95:4.75:0.25 CHZCI2:MeOH:NH40H to 100 % MeOH and
subsequent chromatography with 10:1 hexanes:EtOAc to 100% EtOAc followed by
95:5
EtOAc:MeOH gave, in order of elution, starting (~)-traps-4-nitro-
benzenesulfonic acid
2-azidocyclohexyl ester (1.2 g, 68%), desired product (155 mg, 9%), and
starting
4-(4-chlorobenzyl)-piperidine (810 mg, 71%). Product: 1H NMR b 1.19-1.81 (m,
12H),
1.92-2.08 (m, 3H), 2.22 (m, 1H), 2.48 (d, J= 7.0 Hz, 2H), 3.02 (m, 2H), 4.05
(m, 1H), 7.06
(m, 2H), 7.23 (m, 2H); MS m/z 333.2 (M + H)t.
Step C: Preparation of (~)-cis-2-(4-(4-chlorobenzyl)piperidin-1-
l~l=cyclohexylamine
:N N_
N ~NH~
N l(~1T~ N
/
\I ~I
~I CI
A solution of (~)-cis-1-(2-azido-cyclohexyl)-4-(4-chlorobenzyl)-piperidine
(155 mg,
0.463 mmol) in THF ( 1.8 ml) was treated successively with PPh3 (364 mg, 1.39
mmol) and
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H20 ( 141 pl, 5.56 mmol), refluxed for 3 hours, allowed to cool to room
temperature, and
concentrated. Chromatography of the residue with 95:4.75:0.25-75:23.75:1.25
CHZCI2:MeOH:NH40H gave the product (121 mg, 85 %) as a cream solid: 1H NMR 8
1.14-1.93 (m, 15H), 1.96 (dt, J= 11.8, 3.5 Hz, 1H), 2.48 (d, J= 7.0 Hz, 2H),
3.03-3.13 (m,
2H), 3.30 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 307.2 (M + H)+.
Preparation 5: Preparation of (~)-traps-2-(4-(4-chlorobenzyl)piperidin-1-yl]-
cyclobutylamine
NHZ
~N
i
CI
1o Step A: Preparation of (~)-2-~4-(4-chlorobenz~piperidin-1-~]-cyclobutanone
TMSO_ OTMS I ' I ~ CI
+ ~ CI O"N
H VL-J(N
1,2-Bis(trimethylsilyloxy)cyclobutene (5.0 g, 22 mmol) at 0 °C under Ar
was treated
dropwise during 15 min with a solution of 4-(4-chlorobenzyl)-piperidine (4.56
g, 21.7
mmol) in MeOH ( 10.9 ml) and allowed to warm to room temperature. The reaction
was
stirred over a period of 5 hours, during which additional 1,2-
bis(trimethylsilyloxy)-
cyclobutene (0.99 g, 4.3 mmol) was added, and concentrated. Chromatography of
the
residue with 95:4.75:0.25 CHzCI2:MeOH:NH40H gave the product (4.8 g, 80 %) as
a
yellow oil: 1H NMR 8 1.20-1.35 (m, 2H), 1.43-1.64 (m, 3H), 1.93-2.18 (m, 4H),
2.49 (d, J=
6.9 Hz, 2H), 2.64-2.91 (m, 3H), 3.14 (m, 1H), 3.90 (m, 1H), 7.05 (m, 2H), 7.23
(m, 2H);
MS m/z 278.1 (M + H)+.
Step B: Preparation of (~)-2-~4-(4-chlorobenzyl)piperidin-1-~]-cyclobutanone
O-methyl-oxime
O N 1 / CI ~ MeON N I ~ CI
A solution of (~)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutanone (1.74 g,
6.26
mmol) and MeONH2~HCl (2.63 g, 31.3 mmol) in MeOH (20 ml) was stirred at 65
°C
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under Ar for 3 hours, allowed to cool to room temperature, and concentrated.
The residue
was partitioned between CHzCl2 and saturated NaHC03, the aqueous phase was
extracted
with CHzCl2, and the extracts were dried and concentrated. Chromatography of
the
residue with 95:4.75:0.25 CHZCI2:MeOH:NH40H gave the product ( 1.5 g, 78 %) as
a
brown oil and predominantly one stereoisomer: 1H NMR b 1.05-1.65 (m, 4.5H),
1.92-2.11
(m, 4H), 2.45-2.65 (m, 3H), 2.73-2.96 (m, 2H), 3.22 (m, 1H), 3.73 (m, 1H),
3.82 (m, 3H),
4.57 (m, 0.5H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 307.1 (M + H)+.
Step C: Preparation of (~)-trnns-2-~4-(4-chlorobenz~piperidin-1-yll-
c cly obutylamine
MeON N I / CI ~ HZN N I ~ CI
l0
A mixture of NaBH4 (604 mg, 16.0 mmol) in THF ( 13 ml) under Ar was treated
dropwise with trifluoroacetic acid ( 1.23 ml, 16.0 mmol), stirred for 5 min,
treated dropwise
with a solution of (~)-2-(4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutanone
O-methyl-oxime (985 mg, 3.21 mmol) in THF (35 ml), and stirred at room
temperature
for 5 hours. The mixture was treated carefully with 6 N HCl ( 1.5 ml) until
the pH ~ 2,
stirred for 10 min, basified with 8 N NaOH until the pH ~ 10, and partitioned
between
EtOAc and 1 N NaOH. The aqueous phase was extracted with EtOAc and the
extracts were
washed with brine, dried (Na2S04) and concentrated. A solution of the residue
in MeOH
(30 ml) and 1 N HCl (3 ml) was stirred at 50 °C for 1 hour and at 75
°C for 5 hours,
allowed to cool to room temperature, and concentrated. The residue was
partitioned
between CHZC12 and 1 N NaOH, the aqueous phase was extracted with CHZCIz and
the
extracts were dried and concentrated. Chromatography of the residue on alumina
with
10:1 hexanes:EtOAc to 100% EtOAc followed by 98:1.9:0.1-90:9.5:0.5
CHZCIz:MeOH:NH40H gave 400 mg of the product (80% pure by 1H NMR) as a yellow
oil
which was used without further purification: 1H NMR 8 1.19-1.90 (m, 9H), 2.11
(m, 1H),
2.28 (m, 1H), 2.44-2.59 (m, 3H), 2.80 (m, 1H), 3.05 (m, 1H), 3.22 (m, 1H),
7.06 (m, 2H),
7.23 (m, 2H); MS m/z 279.2 (M + H)+.
Preparation 6: Preparation of (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclobutylamine
MeON N I / CI ~ FI N N 1 ~ CI
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A solution of (~)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutanone
O-methyl-oxime (438 mg, 1.43 mmol) in THF ( 13 ml) under Ar was treated
dropwise with
1 M BH3~THF complex in THF (8.6 ml, 8.6 mmol) and stirred at room temperature
for 3
hours and at 75 °C for 20 hours. The reaction was cooled to 0 °C
and treated carefully with
6 N HCl ( 1 ml) until the pH ~ 2. The THF was evaporated and a solution of the
residue in
EtOH (9 ml) and 6 N HCl ( 1 ml) was stirred at 75 °C for 1 hour. It was
then allowed to
cool to room temperature, basified with 8 N NaOH (4 ml) until the pH ~ 10,
diluted with
H20 (5 ml) to dissolve the resulting white precipitate, and concentrated. The
residue was
partitioned between CHZCIz and 1 N NaOH, the aqueous phase was extracted with
CHZC12,
and the extracts were dried and concentrated. Chromatography of the residue
with
90:9.5:0.5-60:38:2 CHzCIz:MeOH:NH40H gave, in order of elution, 70 mg of the
desired
product (80% pure by'H NMR) as a colorless oil which was used without further
purification, 48 mg ( 12%) of pure desired product as a colorless oil, and 125
mg of a
mixture of desired product, stereoisomeric (~)-traps-2-[4-(4-
chlorobenzyl)piperidin-1-yl]-
cyclobutylamine, and an unidentified impurity. Product: 1H NMR 8 1.19-1.70 (m,
8H),
1.89-2.05 (m, 3H), 2.50(d, J= 6.9 Hz, 2H), 2.56 (m, 1H), 2.78 (m, 2H), 3.44
(m, 1H), 7.06
(m, 2H), 7.23 (m, 2H);'3C NMR 8 24.39, 25.56, 31.63, 31.76, 38.01, 42.61,
49.17, 49.63,
51.74, 62.51, 128.25, 130.42, 131.50, 139.16; MS m/z 279.2 (M + 1)+.
Preparation 7: Preparation of 4-(4-chlorobenzyl)-piperidine
HN
CI
Step A~ Preparation of 4-(4-Chloro-benzylidene)-piperidine-1-carboxylic acid
tert-bu ,1 ester
P(Ph)3+Br 1) KHMDS
o O N I ~ CI
O N
0
The phosphorium salt ( lOg) was taken up in THF and placed in an ice bath. The
KHMDS (42m1) was added slowly, the ice bath was removed, and the reaction was
stirred
for 45 minutes at room temperature. The reaction solution was then cooled to -
78°C and
the ketone (4.2g) was added slowly. The reaction was stirred for 30 minutes,
the cooling
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bath was removed, and the reaction was stirred overnight at room temperature.
The
reaction solution was poured into a saturated NH4C1 ( 100m1) solution, the
layers were
separated, the aqueous layer was washed twice with EtOAc, the organic layers
were
combined, dried (MgS04), and concentrated to ~ 40m1. The solution was diluted
with
hexane and filtered to remove the majority of the Ph3P0. Chromatography of the
crude
product with 20:1-10:1 hexane:EtOAc gave the product as a colorless oil (4.7g)
Step B: Preparation of 4-(4-Chloro-benz~piperidine-1-carboxylic acid tert-
but;il ester
I \ Pt02, HZ O N
O' /N J ~CI CI
O
1o The protected piperidine ( lOg) was dissolved in EtOAc ( 100m1), the Pt02
was added,
and the mixture was stirred rapidly under HZ for 3 hours. The mixture was
filtered
through celite and concentrated. The crude product was taken up in hot hexane,
filtered
and allowed to crystallize. The product was recrystallized with hot hexane to
yield the
clean product (8.Og). Additional product was isolated form the mother liquor.
Step C: Preparation of 4-(4Chlorobenz,~l)piperidine
\ Y \
MeOH HNJ
O N J ~CI HCI C.
HCI
O
Methanol (400m1) was placed in an ice bath and AcCI (60m1) was added. After
the
2o addition was completed the solution was stirred at room temperature for one
hour. The
protected piperidine (62.8g) was added and the solution was stirred at room
temperature
overnight. The reaction solution was concentrated to ~70m1 (when product first
started to
precipitate out), diluted with ether (500m1), and the product was collected by
filtration
(44.9g). An additional 3.1g of the product was collected from the mother
liquor.
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Example 1: Preparation of (~)-traps-1-{2-[4-(4-chlorobenzyl)piperidin-1-ylJ-
cyclohexyl}-3-(3,4,5-trimethoxyphenyl) urea.
H H
N~N \ O~
NHZ
O ~ ~., O / O
N w
~N \ O~ .,.N O, I
~O
\ I \ '
CI CI
Following General Procedure C, (~)-traps-2-(4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexylamine (56 mg, 0.18 mmol) and 5-isocyanato-1,2,3-trimethoxybenzene
(76 mg,
0.36 mmol) were coupled in CHZC12 ( 1 ml) and DMF ( 1 ml) at room temperature
for 1.5
hour. After the combined extracts were washed with H20, dried and
concentrated,
preparative TLC with 95:4.75:0.25 CHzCIz:MeOH:NH40H followed by 90:9.5:0.5
CHZCIZ:MeOH:NH40H and subsequent preparative TLC with 93:6.65:0.35
CHZCI2:MeOH:NH40H gave the product (52 mg, 55%) as a grey solid: mp 196.9-
200.0 °C;
IR 1670, 1606, 1545, 1505 cm-1; 1H NMR ((CD3)ZSO, 87 °C] b 1.00-1.25
(m, 6H), 1.38-1.63
(m, 4H), 1.70 (m, 1H), 1.78 (m, 1H), 2.06 (m, 1H), 2.13-2.27 (m, 2H), 2.43 (d,
J= 6.8 Hz,
15 2H), 2.44 (m, 1H), 2.59 (m, 1H), 2.74 (m, 1H), 3.39 (m, 1H), 3.63 (s, 3H),
3.73 (s, 6H),
5.69 (d, J= 5.3 Hz, 1H), 6.75 ( s, 2H), 7.12 (m, 2H), 7.24 (m, 2H), 8.28 (s,
1H); MS m/z
516 (M + H)+.
Example 2: Preparation of (~)-traps-N {2-(4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexyl}-4-methanesulfonyl-benzamide
NHZ
\/"~ N 0 H ~ O
/ \0 N
+ HO \ I \/''~.,, O
/ I 0 ~~~ N
w
CI /
\ I
2o CI
Following General Procedure E, (~)-trnns-2-(4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexylamine (92 mg, 0.30 mmol) and 4-methanesulfonyl-benzoic acid (72 mg,
0.36
mmol) were coupled in CHZC12 (2 ml) using HOBt (8 mg, 0.06 mmol) and DEC (86
mg,
0.45 mmol) at room temperature for 16 hours. Purification of the crude product
by
25 preparative TLC with 93:6.65:0.35 CHZCI2:MeOH:NH40H gave the product ( 105
mg,
72%) as a tan solid: mp 184.5-186.7 °C; IR 1637 cm~l; 1H NMR b 0.94
(ddd, J= 3.9, 11.7,
23.9 Hz, 1H), 1.09-1.93 (m, 12H), 2.05 (dt, J= 2.4, 11.5 Hz, 1H), 2.35-2.74
(m, 6H),
3.10(m, 3H), 3.55-3.66 (m, 1H), 7.04 (m, 2H), 7.16 (m, 1H), 7.23 (m, 2H), 7.95
(m, 2H),
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8.04 (m, 2H); MS m/z 489 (M + H)+. Anal. (Cz6H33C1N2O3S) H, N; C: calcd,
63.85; found,
60.83. HPLC purity: 99.4%.
Example 3: Preparation of (~)-traps-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexyl}-3-(3-methanesulfonyl-phenyl)urea hydrochloride
H H
NHZ ~N~N ~ S~
0~ g a.. O ~ . o
N
N I W Sw ,~~ N
+ ~O
HCI
CI CI
A solution of triphosgene (60 mg, 0.2 mmol) in CHZCIz (3 ml) was treated with
a
solution of 3-methanesulfonyl-phenylamine ( 120 mg, 0.7 mmol) and Et3N ( 125
~l, 0.90
1o mmol) in CHZCl2 (3 ml), stirred at 40 °C for 1.5 hours, allowed to
cool to room
temperature, and added in 2 portions during 30 min to a solution of
(~)-traps-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cydohexylamine (88 mg, 0.29
mmol) in
CHZC12 ( 1 ml). The reaction was stirred for 1 hour and partitioned between
CHzCIZ and
saturated NaHC03. The aqueous phase was extracted with CHZC12 and the extracts
were
15 dried and concentrated. Purification of the residue by preparative TLC with
95:4.75:0.25
CHZCIZ:MeOH:NH40H gave the free base ( 140 mg, 0.28 mmol) as a cream solid. A
solution of the free base in CHzCl2 was treated with 1 N HCl in Et20 (0.5 ml,
0.5 mmol)
and EtOAc, allowed to stand at room temperature for 3 days, at 0 °C
overnight and at -20
°C overnight, and filtered to give the product (80 mg, 50%) as a white
solid: mp
20 150.2-151.6 °C; MS m/z 504 (M + H)+.
Example 4: Preparation of (~)-traps-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride
H H
NH= NuN ~ O~
~ a.. IOI
0.
a..N ~N ~ O. .....N o_ q
+ ~,
~~
O_
HCI
CI CI
25 Following General Procedure D, (~)-traps-2-[4-(4-chlorobenzyl)piperidin-1-
yl]-
cyclopentylamine (250 mg, 0.85 mmol) and 5-isocyanato-1,2,3-trimethoxybenzene
(355
mg, 1.70 mmol) were coupled in CHZCIz (5 ml) at room temperature for 1 hour.
After the
combined extracts were dried (MgS04) and concentrated, chromatography of the
residue
with 95:4.75:0.25 CHZCI2:MeOH:Et3N and subsequent chromatography with
98:1.9:0.1
30 CHzCI2:MeOH:Et~N gave the free base (248 mg, 0.494 mmol) as a white foam. A
solution
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of the free base ( 100 mg, 0.2 mmol) in CHZC12 was treated with 1 N HCl in
Et20 (0.5 ml,
0.5 mmol) and concentrated to give the product (104 mg, 56%) as a tan powder:
mp
136.1-138.0 °C; IR 1690, 1607, 1555, 1507 cm-1; 1H NMR [(CD3)ZSO] 8
1.40-2.15 (m,
11H), 2.53 (m, 1.6H), 2.70 (m, 0.4H), 2.80-2.95 (m, 2H), 3.33-3.60 (m, 3H),
3.59 (s, 3H),
3.71 (s, 6H), 4.24-4.38 (m, 1H), 6.74 ( s, 1.6H), 6.77 ( s, 0.4H), 6.85 (d, J
= 8.2 Hz, 0.8H),
6.91 (m, 0.2H), 7.21 (m, 2H), 7.33 (m, 2H), 8.77 (s, 0.8H), 8.86 (s, 0.2H),
10.10-10.23 (m,
0.8H), 10.45 (m, 0.2H);13C NMR [(CD3)zS0] 8 21.82, 26.88, 29.06, 32.57, 34.82,
40.68,
50.73, 51.01, 51.82, 56.02, 60.52, 71.47, 96.26, 128.51, 131.07, 131.27,
132.61, 136.25,
138.62, 153.10, 155.10; MS m/z 502 (M + H)+.
Example 5: Preparation of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
tetrahydro-
furan-3-yl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride
H H
NHZ NuN ~ 0~
O~ O \ O~ IOI I /
V'~. N \N W Ow ,.,., N O~ R
/ ~O
O
HCI
CI CI
Following General Procedure D, (~)-traps-4-[4-(4-chlorobenzyl)piperidin-1-yl]-
tetrahydrofuran-3-ylamine (3.03 g, 10.3 mmol) and 5-isocyanato-1,2,3-
trimethoxybenzene
(2.37 g, 11.3 mol) were coupled in CHZCIZ (60 ml) at 0 °C for 1 hour.
Chromatography of
the crude product with 1:1 hexanes:EtOAc to 100% EtOAc followed by
50:0.95:0.05-10:0.95:0.05 CHZCI2:MeOH:NH40H gave the free base (4.62 g, 9.2
mmol) as a
2o white foam. A solution of the free base (3.62 g, 7.2 mmol) in CHzCl2 was
treated with 1 N
HCl in Et20 (10 ml, 10 mmol) and concentrated to give the product (3.61 g,
83%) as a
white solid: mp 229.2-230.9 °C; IR 3273 (br), 2937, 1690, 1606, 1554,
1507 cm-~; 1H NMR
[(CD3)ZSO] 8 1.54-1.74 (m, 7H), 2.52 (m, 2H), 2.97 (m, 2H), 3.49-3.71 (m,
11H), 4.06 (m,
3H), 4.59 (m, 1H), 6.74 (s, 2H), 7.00 (d, J= 7.6 Hz, 1H), 7.22 (m, 2H), 7.35
(m, 2H), 8.85
(s, 1H), 10.8 (br s, 1H); MS m/z 504 (M + H)+.
Step A~ Preparation of (~)-traps-4-(4-(4-chlorobenz~piperidin-1-yll-tetrahydro-
furan-3-of
OH
HN O - N
O~O +
CI CI
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Following General Procedure A, 4-(4-chlorobenzyl)-piperidine ( 10.1 g, 48
mmol)
was alkylated with 3,6-dioxa-bicyclo[3.1.0]hexane (24.7 g, 288 mol) (Barili,
P. L.; Berti, G.;
Mastrorilli, E.; Tetrahedron 1993, 49, 6263) in EtOH (75 ml) at 90-95
°C for 45 hours.
Chromatography of the crude product with CHZC12 followed by 99:0.95:0.05-
95:4.75:0.25
CHZCI2:MeOH:NH40H gave the product (10.7g, 76%) as a white solid: 1H NMR 81.21
(m, 2H), 1.51 (m, 1H), 1.62 (m, 2H), 2.03 (tt, J= 2.5, 11.6 Hz, 2H), 2.19 (br,
1H), 2.50 (d, J
= 6.9 Hz, 2H), 2.73 (m, 2H), 3.08 (m, 1H), 3.61 (dd, J= 6.9, 9.3 Hz, 1H) ,
3.70 (dd, J= 3.1,
10.0 Hz, 1H), 3.93 (dd, J= 5.7, 10.0 Hz, 1H), 4.05 (dd, J= 7.0, 9.3 Hz, 1H),
4.33 (dt, J=
l0 3.0, 5.7 Hz, 1H), 7.05 (m, 2H), 7.24 (m, 2H); MS m/z 296.2 (M + H)+.
Step B: Preparation of (~)-traps-4-(4-(4-chlorobenz~piperidin-1-yll-tetrahydro-
furan-3-ylamine
OH ~NHz
O~N OV'~. N
\~ \
CI CI
Following General Procedure B, (~)-traps-4-[4-(4-chlorobenzyl)piperidin-1-yl]-
tetrahydrofuran-3-of ( 10.65 g, 36 mmol) in CHZCIZ ( 150 ml) was treated with
Et3N ( 10.2
ml, 72 mmol) and MeSO2C1 (5.53 ml, 72 mol) for 1.25 hours and the resultant
product was
heated in dioxane (205 ml) and NH40H (83 ml) for 4 hours. Chromatography of
the
2o crude product with 100:1.9:0.1-100:19:1 CHZCI2:MeOH:NH40H gave the product
(9.58 g,
90%) as a yellow oil:'H NMR 8 1.21-1.68 (m, 7H), 2.01 (m, 2H), 2.50 (d, J =
6.9 Hz, 2H),
2.58 (dt, J= 3.4, 6.8 Hz, 2H), 2.72 (m, 1H), 3.06 (m, 1H), 3.50 (m, 2H), 3.64
(dd, J= 6.5,
9.3 Hz, 1H), 3.99 (m, 2H), 7.05 (m, 2H), 7.25 (m, 2H); MS m/z 295.2 (M + H)t.
Example 6: Preparation of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-
yl]-
4-hydroxy-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea.
/ / p N II N ~ \ O~ HON O N I ~ Ow
-Cf O ~Cq
,,/~N O~ ~ '"~N O
i
\ ~ \
CI CI
A solution of (~)-1-{(1R,2R,4S)-4-(tert-butyl-dimethylsilanyloxy)-
2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-(3,4,5-
trimethoxyphenyl)urea (605
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mg, 0.96 mmol) in 1% HCl/EtOH (80 ml) was stirred at room temperature
overnight. The
EtOH was evaporated and the residue was partitioned between CHzCl2 and
saturated
NaHC03. The aqueous phase was extracted with CHZC12 and the extracts were
washed
with brine, dried (MgS04) and concentrated. Chromatography of the residue with
95:4.75:0.25-90:9.5:0.5 CHZCI2:MeOH:NH40H gave the product (440 mg, 89%) as a
yellow
solid: mp 98.7-102.0 °C; MS m/z 518 (M + H)+.
Step A: Preparation of (~)-(1R,2R,4R)-4-(tert-but;rl-dimeth, Is~,1
2- f 4-(4-chlorobenz~piperidin-1-yll -c~pentanol
OH
%' ~.. ~~~
\/ HN O - N
~S
O +
CI CI
Following General Procedure A, 4-(4-chlorobenzyl)-piperidine (741 mg, 3.53
mmol) was alkylated with cis-tert-butyl-dimethyl-(6-oxa-bicyclo[3.1.0]hex-3-
yloxy)-silane
(1.51 g, 7.06 mmol) (Asami, M. Bull. Chem. Soc. Jpn. 1990, 63, 1402) in EtOH
(5 ml) at
90-95 °C for 82 hours. Chromatography of the crude product with CHZC12
followed by
99:0.95:0.05-95:4.75:0.25 CHzCIz:MeOH:NH40H gave the product ( 1.16 g, 78%) as
a
yellow foam:'H NMR 8 0.00 (s, 6H), 0.81 (s, 9H), 1.19-1.99 (m, 12H), 2.44 (m,
2H), 2.80
(m, 2H), 3.13 (m, 1H), 4.07 (m, 1H), 4.28 (m, 1H), 6.99 (m, 2H), 7.17 (m,
2H);'3C NMR
8 -4.55, -4.50, 18.3, 26.1, 32.1, 32.2, 38.1, 39.8, 42.3, 44.0, 52.1, 53.0,
74.0, 75.7, 75.8, 128.7,
130.8, 131.9, 139.2; MS m/z 424.2 (M + H)+. HPLC purity 98.5%.
Step B: Preparation of (~)-(1R,2R,4S)-4-(tert-butyl-dimeth ls~Ylox~
2-[4-(4-chlorobenz~piperidin-1-yll-c;rclopentylamine
i i
/~ OH ~; /~ NHZ
O V'~. N O v'~. N
CI CI
Following General Procedure B, (~)-(1R,2R,4R)-4-(tert-butyl-
dimethylsilanyloxy)-
2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentanol (1.14 g, 2.68 mmol) in
CHZC12 (10 ml)
was treated with Et3N (740 ~tl, 5.36 mmol) and MeSO2C1 (410 ~1, 5.36 mmol) for
2 hours
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and the resultant product was heated in dioxane ( 15.6 ml) and NH40H (6.2 ml)
for 6
hours. Chromatography of the crude product with 98:1.9:0.1-80:19:1
CHZCI2:MeOH:NH40H gave the product (620 mg, 55%) as a colorless oiL'H NMR b
0.00
(s, 6H), 0.83 (s, 9H), 1.15-1.32 (m, 2H), 1.40-2.11 (m, 11H), 2.45 (m, 2H),
2.60 (m, 1H),
2.80 (m, 1H), 3.02 (m, 1H), 3.14 (m, 1H), 4.20 (m, 1H), 7.02 (m, 2H), 7.19 (m,
2H); 13C
NMR 8 -4.85, -4.87, 17.9, 25.8, 32.0, 32.1, 37.8, 39.2, 42.4, 44.8, 51.0,
52.8, 54.8, 72.8, 75.8,
128.2, 130.4, 131.5, 139.0; MS m/z 423.2 (M + H)+. HPLC purity 99.2%.
Stet/ C: Preparation of (~)-1-((1R,2R,4S)-4-(tert-butyl-dimeth~silan,~xK)-
2-[4-(4-chlorobenzyl)piperidin-1-yll-c~lopent~l-3-(3,4,5-trimethoxyphen 1)~
urea
i
I NHz Si ~N N 0~
O ~ /
~' N N ~ Ow ,,,~~ N 0
+ I / O
/ O~ I /
w
CI CI
1
Following General Procedure C, (~)-(1R,2R,4S)-4-(tert-butyl-
dimethylsilanyloxy)-
2-[4-(4-chlorobenzyl)piperidin-1-yl}-cyclopentylamine (610 mg, 1.44 mmol) and
5-isocyanato-1,2,3-trimethoxybenzene (603 mg, 2.88 mmol) were coupled in
CHZCl2 (8.5
ml) at 0 °C for 1 hour. Chromatography of the crude product with l:l
hexanes:EtOAc to
100% EtOAc gave the product (665 mg, 73%) as a yellow solid: mp 81.0-84.0
°C; IR 3379
(br), 2929, 1653, 1608, 1555, 1507 cm-l; 1H NMR [(CD3)ZSO} 8 0.03 (d, 6H),
0.86 ( s, 9H),
1.12-1.69 (m, 8H), 1.95 (m, 2H), 2.18 (m, 1H), 2.46 (m, 2H), 2.79 (m, 3H),
3.58 (s, 3H),
3.71 (s, 6H), 3.93 (m, 1H), 4.16 (m, 1H), 5.94 (d, J= 7.9 Hz, 1H), 6.70 (s,
2H), 7.16 (m,
2H), 7.30 (m, 2H), 8.43 (s, 1H); MS m/z 632 (M + H)+.
Example 7: Preparation of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-
yl]-
4-hydroxycyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
HO N~N ~ \ O\ HO N II
O ~ ~ O I / O
,,,~~ N O~ ~ ~ N O~ I
HCI
/ I
w W
CI CI
A solution of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-yl}-
4-hydroxy-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea ( 102 mg, 0.20 mmol) in
CHZC12
was treated with 1 N HCl in Et20 (0.5 ml, 0.5 mmol) and concentrated to give
the product
(110 mg, 100%) as a yellow solid: mp 137.0-143.0 °C; IR 3405 (br),
2935, 1685, 1606, 1554,
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1507 cm l; 1H NMR [(CD3)ZSO] b 1.48-2.12 (m, 11H), 2.54 (m, 2H), 2.90 (m, 2H),
3.45
(m, 1H), 3.58 (s, 3H), 3.71 (s, 6H), 4.22 (m, 1H), 4.48 (m, 1H), 5.16 (br s,
1H), 6.42 (d, J=
9.4 Hz, 1H), 6.70 (s, 2H), 7.21 (m, 2H), 7.34 (m, 2H), 10.19 (br s, 1H); MS
m/z 518 (M +
H)+.
Example 8: Preparation of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-
yl]-
4-hydroxymethyl-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
H H
\Si O N N \ O~ HO NuN \ O~
O I / ~ IOI I / O
,,,,, N ~ ,"" N O ~ 1
O
HCI
/
\~ \
CI CI
A solution of (~)-1-{(1R,2R,4S)-4-(tert-butyl-dimethylsilanyloxymethyl)-
2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-(3,4,5-
trimethoxyphenyl)urea (1.13
g, 1.75 mmol) in 1% HCl/EtOH (120 ml) was stirred at room temperature for 1
hour. The
EtOH was evaporated and the residue was partitioned between CHzCl2 and
saturated
NaHC03. The aqueous phase was extracted with CHZC12 and the extracts were
washed
with brine, dried (MgS04) and concentrated. Chromatography of the residue with
~5 95:4.75:0.25-90:9.5:0.5 CHZCI2:MeOH:NH40H gave the free base
(~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-hydroxymethyl-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea (690 mg, 1.30
mmol) as a
yellow solid. A solution of the free base ( 105 mg, 0.20 mmol) in CHZCIz was
treated with 1
N HCl in Et20 (0.5 ml, 0.5 mmol) and concentrated to give the product (112 mg,
74%) as
2o a yellow solid: mp 138.0-143.0 °C; IR 3417 (br), 2936, 1687, 1606,
1554, 1507 cm-';'H
NMR [(CD3)ZSO] 8 1.28-2.12 (m, lOH), 2.54 (m, 2H), 2.91 (m, 2H), 3.26-3.59 (m,
8H),
3.71 (s, 6H), 4.34 (m, 1H), 4.70 (br s, 1H), 6.66 (d, J= 8.3 Hz, 1H), 6.73 (s,
2H), 7.21 (m,
2H), 7.32 (m, 2H), 8.78 (s, 1H), 10.13 (br s, 1H); MS m/z 532 (M + H)+.
z5 Step A: Preparation of (~)-(1R,2R,4R)-4-(tert-butyl-dimeth ls~yloxymethyl)-
~~4-(4-chlorobenzXl)piperidin-1- l~-c~pentanol.
~OH
HN ~Si-O " ' N
~ ~- (/~[~ O + --r
/ I /
\ \
CI CI
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Following General Procedure A, 4-(4-chlorobenzyl)-piperidine (946 mg, 4.50
mmol) was alkylated with cis-tent-butyl-dimethyl-(6-oxa-bicyclo[3.1.0]hex-
3-ylmethoxy)silane ( 1.13 g, 4.96 mmol) (Asami, M. Takahashi, J.; moue, S.
Tetrahedron
Asymmetry 1994, 5, 1649) in EtOH (4 ml) at 95 °C for 4.5 days.
Chromatography of the
crude product with CHZCIz followed by 99:0.95:0.05-95:4.75:0.25
CHZCI2:MeOH:NH40H
gave the product (1.38 g, 74%) as a brown oiL'H NMR 8 0.00 (s, 6H), 0.84 (s,
9H),
1.34-1.86 (m, 8H), 2.08-2.31 (m, 5H), 2.48 (m, 2H), 2.80 (m, 1H), 3.13 (m,
1H), 3.28 (m,
1H), 3.48 (m, 2H), 4.28 (m, 1H), 7.00 (m, 2H), 7.19 (m, 2H); MS m/z 438.2 (M +
H)+.
Step B: Preparation of (~)-(1R,2R,4S)-4-(tert-butyl-dimeth lsilanyloxymeth~
2-f4-(4-chlorobenz;rl)piperidin-1- 1,~-open lamine
OH NHZ
~-O~N ~Si-O~N
/
CI CI
Following General Procedure B, a solution of (~)-( 1R,2R,4R)-4-(tert-butyl
dimethylsilanyloxymethyl)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentanol
(1.36 g,
3.0 mmol) in CHzCIz ( 15 ml) was treated with Et3N (0.83 ml, 6.0 mmol) and
MeSOZCI
(0.46 ml, 6.0 mmol) for 1 hour and the resultant product was heated in dioxane
( 17.2 ml)
and NH40H (6.9 ml) for 2.5 hours. Chromatography of the crude product with
98:1.9:0.1-90:9.5:0.5 CHzCIz:MeOH:NH40H gave the product (780 mg, 57%) as a
yellow
oil: ~H NMR 8 0.00 (s, 6H), 0.85 (s, 9H), 0.92-1.70 (m, 11H), 1.96-2.21 (m,
3H), 2.44 (m,
3H), 2.83 (m, 2H), 3.12 (m, 1H), 3.43 (d, J= 5.8 Hz, 2H), 7.02 (m, 2H), 7.19
(m, 2H); MS
m/z 438.2 (M + H)+. HPLC purity: 96.4%
Step C' Preparation of (~)-1-((1R 2R 4S)-4-(tert-butyl-dimethylsilan~x~eth
2-[4-(4-chlorobenz,~piperidin-1-~]-cyclopentyl~-3-(3,4,5-trimethoxyphen 1)~
urea
' ,Si O NHS \Si O NuN \ 0~
O ~ ~ 'OI I /
..", N ~N \ Ow ,.,,. N O~ R
+ ~ / O ---r
O~ ~
CI CI
Following General Procedure C, (~)-(1R,2R,4S)-4-(tert-butyl-dimethylsilanyloxy-
methyl)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentylamine (770 mg, 1.76
mmol) and
5-isocyanato-1,2,3-trimethoxybenzene (442 mg, 2.11 mmol) were coupled in
CHZC12 (10
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ml) at 0 °C for 30 min to give 1.19 g of the product as a yellow solid
which was used
directly in the next step: MS m/z 646.2 (M + H)+.
Example 9: Preparation of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-ylJ-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea dihydrochloride.
H H ~
O N N II N ( \ Ow HN N It N I \ Ow
O ~~ O
O ~ N O~ ~ ,,~~~ N O
2 HCI i
\ I \ I
C~ C~
A solution of (~)-traps-3-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidine-1-carboxylic acid tent-butyl
ester (410
mg, 0.68 mmol) in 2% HCl/MeOH (70 ml) was stirred at room temperature
overnight.
1o The MeOH was evaporated and the residue was partitioned between CHZC12 and
saturated
NaHC03. The aqueous phase was extracted with CHZCIz and the extracts were
washed
with brine, dried (MgS04) and concentrated. Chromatography of the residue on
alumina
with CHzCIz followed by 50:0.95:0.05-5:0.95:0.05 CHZCI2:MeOH:NH40H gave the
free
base (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-pyrrolidin-3-yl}-
15 3-(3,4,5-trimethoxyphenyl)urea (225 mg, 0.45 mmol) as a white solid. A
solution of the
free base (25 mg, 0.05 mmol) in CHZCIz was treated with 1 N HCl in EtzO (0.15
ml, 0.15
mmol) and concentrated to give the product (27 mg, 68%) as a yellow solid: mp
157.0-170.0 °C; IR 3416 (br), 2935, 1686, 1606, 1554, 1507 cm-i; 1H NMR
[(CD3)zS0] b
1.50-1.81 (m, 5H), 2.60 (d, J= 6.6 Hz, 2H), 3.00-3.99 (m, 20H), 4.68 (m, 1H),
6.76 (s, 2H),
20 7.21 (m, 2H), 7.32 (m, 2H); MS m/z 504 (M + H)+.
Step A: Preparation of (~)-traps-3-[4-(4-chlorobenz;rl)piperidin-1-yl]-4-h
d~x~
pyrrolidine-1-carboxylic acid tert-butyl ester
p NOH
HN ~ N~N
O +
~I ~I
ci ci
Following General Procedure A, 4-(4-chlorobenzyl)-piperidine ( 1.72 g, 8.19
mmol)
was alkylated with 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-
butyl ester
(1.82 g, 9.82 mmol) [Okada, T.; Sato, H.; Tsuji, T.; Tsushima, T.; Nakai, H.;
Yoshida, T.;
Matsuura, S. Chem. Phnrm. Bull. Jpn. 1993, 41, 132] in EtOH (5.5 ml) at 95
°C for 60
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hours. Chromatography of the crude product with CHZC12 followed by
100:0.95:0.05-30:0.95:0.05 CHZCI2:MeOH:NH40H gave the product ( 1.85 g, 54%)
as a
yellow solid: mp 61.9-64.5 °C; IR 3421 (br) cm-1; 1H NMR b 1.26-1.69
(m, 14H), 1.94 (br s,
1H), 2.19 (m, 2H), 2.53 (d, J= 6.9 Hz, 2H), 2.89 (m, 2H), 3.05-3.33 (m, 3H),
3.60-3.79 (m,
2H), 4.33 (m, 1H), 7.08 (m, 2H), 7.28 (m, 2H); MS m/z 395.2 (M + H)+.
Step B~ Preparation of (~)-traps-3-amino-4-(4-(4-chlorobenz~piperidin-1-yll-
Ryrrolidine-1-carboxylic acid tert-butyl ester
OH Q ~NHx
/ O N~N / O N~N
CI CI
1o Following General Procedure B, a solution of (~)-traps-3-[4-(4-
chlorobenzyl)-
piperidin-1-y1J-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.80
g, 4.56
mmol) in CHZC12 (20 ml) was treated with Et3N ( 1.26 ml, 9.12 mmol) and
MeSO2Cl (0.70
ml, 9.12 mmol) for 1 hour and the resultant product was heated in dioxane
(26.0 ml) and
NH40H ( 10.5 ml) for 6 hours to give 1.91 g of the product (91% pure by HPLC)
as a
15 yellow oil which was used directly for the next step:'H NMR 8 1.21-1.65 (m,
17H), 2.17
(m, 2H), 2.49 (d, J= 7.0 Hz, 2H), 2.73-3.43 (m, 7H), 7.05 (m, 2H), 7.25 (m,
2H); MS m/z
394.2 (M + H)+.
Step C: Preparation of (~)-traps-3-l4-(4-chlorobenzyl)piperidin-1-yll-
4-[3-(3,4,5-trimethox~phenyl)ureidol-p~rrolidine-1-carboxylic acid tert-but l~
ester
H H
Q NH p N~N~O~
-N~~" o~ \ o N~ I0'
N ~N I \ O\ ,,~~~N O
O
i
O
CI CI
Following General Procedure C, (~)-traps-3-amino-4-[4-(4-
chlorobenzyl)piperidin-
1-ylJ-pyrrolidine-1-carboxylic acid tert-butyl ester (394 mg, ~ 0.9 mmol) and
5-isocyanato-1,2,3-trimethoxybenzene (250 mg, 1.2 mmol) were coupled in CHZCIz
(6.0
ml) at 0 °C for 1 hour. Chromatography of the crude product with 1:1
hexanes:EtOAc to
25 100% EtOAc gave the product (445 mg, 77% from (~)-traps-3-[4-(4-
chlorobenzyl)-
piperidin-1-ylJ-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester) as a
white solid:
mp 99.0-102.5 °C; IR 3371 (br), 2932, 1655, 1607, 1552, 1507 cm-1; 1H
NMR 8 1.17-1.80
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(m, 14H), 2.18 (m, 2H), 2.48 (d, J= 7.0 Hz, 2H), 2.95-3.51 (m, 8H), 3.81 (m,
9H), 4.32
(br, 1H), 5.30 (br, 1H), 6.61 (s, 2H), 7.02 (m, 2H), 7.20 (m, 2H); MS m/z
603.2 (M + H)t.
Example 10: Preparation of (~)-cis-1-{2-(4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-
3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
H H
NHz NuN \ O~
~ IO' I /
N °~N O ~N
+ /
0~ O
HCI
CI CI
Following General Procedure D, a solution of (~)-cis-2-[4-(4-chlorobenzyl)-
l0 piperidin-1-yl]-cyclopentylamine ( 110 mg, 0.38 mmol) in CHZC12 (2 ml) at 0
°C was
treated with 5-isocyanato-1,2,3-trimethoxybenzene (98 mg, 0.47 mmol), stirred
for 1 hour,
and partitioned between CHzCIz and saturated NaHC03. The aqueous phase was
extracted
with CHZC12 and the extracts were dried and concentrated. Chromatography of
the residue
with EtOAc followed by 90:9.5:0.5 CHzCIZ:MeOH:NH40H and a subsequent
chromatography with 1:3 hexanes:EtOAc to 100% EtOAc followed by 95:4.75:0.25
CHZCI2:MeOH:NH40H gave the free base ( 190 mg, 0.38 mmol) as a colorless oil.
A
solution of the free base in CHzCl2 (2 ml) was treated with 1 N HCl in Et20 (
1 ml, 1 mmol)
and concentrated to give the product (193 mg, 96%) as a white solid: mp 117.5-
122.5 °C;
IR 1692, 1606, 1557, 1507 cm-1;'H NMR ((CD3)ZSO] 8 1.33-2.15 (m, 11H), 2.51
(m, 2H),
2.64 (br d, J= 7.8 Hz, 0.5H), 2.80-2.95 (m, 1.5H), 3.15-3.90 (m, 12H), 4.41
(m, 1H), 6.74
(s, 2H), 7.08-7.24 (m, 3H), 7.34 (m, 2H), 9.01 (br s, 0.7H), 9.06 (br s,
0.3H), 9.25-9.47 (m,
1H); HRMS (FAB) calcd for CZ~H3~C1N30,~ 502.2473 (M + H)+, found 502.2471.
Example 11: Preparation of (~)-cis-N {2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-
z5 4-methanesulfonyl-benzamide hydrochloride.
NHZ O
N ; N \ ~ O
/ 0
+ HO \ I
/ N HCI
O
CI /
CI
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Following General Procedure F, (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentylamine (105 mg, 0.358 mmol) and 4-methanesulfonyl-benzoic acid (86
mg, 0.43
mmol) were coupled in CHZCIz (2 ml) using HOBt ( 10 mg, 0.07 mmol) and DEC (
138 mg,
0.719 mmol) at 0 °C for 2.5 hours. Chromatography of the crude product
with CHzCIz
followed by 98:1.9:0.1 CHZCIz:MeOH:NH40H gave the free base ( 176 mg, 0.36
mmol) as a
colorless oil. A solution of the free base in CHZC12 was treated with 1 N HCl
in EtzO (0.8
ml, 0.8 mmol) and concentrated to give the product ( 183 mg, 100%) as a cream
foam: mp
125.3-131.9 °C; IR 1660 cm-1; ~H NMR 8 1.63-2.23 (m, 11H), 2.56 (d, J=
6.4 Hz, 2H),
2.56-2.85 (m, 2H), 3.05 (s, 0.3H), 3.06 (s, 2.7H), 3.20-3.34 (m, 1H), 3.60 (br
d, J= 11.7 Hz,
1H), 3.78 (br d, J= 10.8 Hz, 1H), 4.93 (m, 1H), 7.00-7.11 (m, 2H), 7.25 (m,
2H), 8.03 (m,
2H), 8.50 (m, 2H), 8.95 (m, O.1H), 9.06 (br d, J= 8.3 Hz, 1H), 11.65-11.90 (m,
1H); 13C
NMR 8 21.06, 26.85, 29.18, 29.38, 33.31, 36.77, 41.57, 44.76, 50.69, 53.67,
54.39, 68.88,
127.87, 129.08, 129.85, 130.64, 132.72, 137.61, 138.20, 143.57, 166.50; HRMS
(FAB) calcd
for CZSH3iC1N203S 475.1822 (M + H)+, found 475.1823.
1s Example 12: Preparation of (~)-traps-1-{1-acetyl-4-[4-(4-
chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
/~ N N ~ O~ 0 NuN ~ O~
HN I O ~ / ~ ~N~ IOI I / O
~' ,I,'~N O~ N O
HCI v
i
CI CI
A solution of (~)-trnns-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (80 mg, 0.16 mmol) and Et3N
(26 X11, 0.19
mmol) in CHzCIz ( 1 ml) at 0 °C was treated dropwise with acetic
anhydride ( 15 ~tl, 0.16
mmol), stirred at 0 °C for 10 min, and partitioned between CHzCIz and
saturated NaHC03.
The aqueous phase was extracted with CHZC12 and the extracts were dried and
concentrated. Purification of the residue by preparative TLC with 10:0.95:0.05
CHZCIz:MeOH:NH40H gave the free base as a white solid. A solution of the free
base in
CHzCl2 was treated with 1 N HCl in Et20 (0.2 ml, 0.2 mmol) and concentrated to
give the
product (84 mg, 91%) as a tan solid: mp 155.0-161.0 °C; IR 3415 (br),
2936, 1691, 1608,
1554, 1508 cm-1; 1H NMR [(CD3)zS0] 8 1.56-1.97 (m, 8H), 2.50-3.94 (m, 20H),
4.70 (m,
1H), 6.76 (s, 2H), 6.98 (m, 1H), 7.21 (m, 2H), 7.32 (m, 2H), 8.81 (s, 1H),
10.72 (s, 1H); MS
m/z 545 (M + H)t.
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Example 13: Preparation of (~)-cis-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexyl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
aNH~
o,, o
N ~N O\ N
+ ~ /
~O
\ ~ O
HCI
CI CI
Following General Procedure D, (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexylamine (53 mg, 0.17 mmol) and 5-isocyanato-1,2,3-trimethoxybenzene
(40 mg,
0.19 mmol) were coupled in CHZCIz ( 1 ml) at 0 °C for 1 hour.
Purification of the crude
product by preparative TLC with 93:6.65:0.35 CHZCI2:MeOH:NH40H gave the free
base
(75 mg, 0.15 mmol) as a tan foam. A solution of the free base ( 100 mg, 0.2
mmol) in
1o CHZClzwas treated with 1 N HCl in EtzO (0.3 ml, 0.3 mmol) and concentrated
to give the
product (83 mg, 85%) as a tan foam: mp 120.1-137.3 °C; IR 1691, 1607,
1558, 1507 crri';
1H NMR (CD30D) 8 1.35-2.15 (m, 13H), 2.58 (d, J= 6.4 Hz, 1.8H), 2.72 (m,
0.2H),
2.87-2.98 (m, 2H), 3.22 (m, 1H), 3.59 (m, 1H), 3.70 (s, 0.3H), 3.73 (s, 2.7H),
3.78 (s,
0.6H), 3.82 (s, 5.4H), 3.92 (m, 1H), 4.55 (m, 1H), 6.76 ( s, 1.8H), 6.77 ( s,
0.2H), 7.17 (m,
2H), 7.27 (m, 2H); MS m/z 516 (M + H)+. Anal. (CZgH39C12N3O4~1.15HZO) C, H, N.
Example 14: Preparation of (~)-cis-N {2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexyl}-4-methanesulfonyl-benzamide hydrochloride.
NH, O
~ O i \' O
~N : H
O N
+ HO \ I ~O
I O N HCI
CI
\ I
CI
zo Following General Procedure F, (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclohexylamine (30 mg, 0.10 mmol) and 4-methanesulfonyl-benzoic acid (24 mg,
0.12
mmol) were coupled in CHZC12 (1 ml) using HOBt (3 mg, 0.02 mmol) and DEC (30
mg,
0.16 mmol) at 0 °C for 2 hours and at room temperature for 2 hours.
Purification of the
crude product by preparative TLC with 90:9.5:0.5 CHZCI2:MeOH:NH40H gave the
free
2s base (46 mg, 0.09 mmol) as a white solid. A solution of the free base in
CHzCIz was treated
with 1 N HCl in Et20 (0.2 ml, 0.2 mmol) and concentrated to give the product
(47 mg,
88%) as a cream solid: mp 123.7-149.4 °C; IR 1659 cm 1; 1H NMR (CD30D)
8 1.28-2.20
(m, 13H), 2.59 (d, J = 6.2 Hz, 2H), 2.90-3.03 (m, 1H), 3.17 (s, 3H), 3.35 (m,
1H), 3.61 (m,
1H), 3.89 (m, 1H), 4.47-4.91 (m, 2H), 7.17 (d, J= 8.3 Hz, 2H), 7.28 (m, 2H),
8.10 (m, 4H);
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MS m/z 489 (M + H)+. Anal. (C26H34C1zNzOsS); calcd: C, 59.42; H, 6.52; N,
5.33; found: C,
55.39; H, 5.94; N, 4.88. HPLC purity: 98.6%.
Example 15: Preparation of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
1-methanesulfonyl-pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea
hydrochloride.
H H H H
N N ~ O~ O N N ~ O~
HN~ O ~ / O js N~ p I /
''' N O_ ~ "' N O_
HCI
/ '
y CI
A solution of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (78 mg, 0.15 mmol) and
pyridine (13 pl,
0.15 mmol) in CHZC12 (2.5 ml) at 0 °C was treated dropwise with MeSO2Cl
( 12 p,l, 0.15
1o mmol) and allowed to warm to room temperature slowly. The reaction was
stirred for 1
hour, during which additional pyridine (3 pl, 0.04 mmol) and MeSO2C1 (3 ~l,
0.04 mmol)
was added, and partitioned between CHZCIz and 10% aqueous NaOH. The aqueous
phase
was extracted with CHZC12 and the extracts were washed with brine, dried and
concentrated. Purification of the residue by preparative TLC with 10:0.95:0.05
15 CHZCI2:MeOH:NH40H gave the free base as a yellow semi-solid. A solution of
the free
base in CHZC12 was treated with 1 N HCl in EtZO (0.3 ml, 0.3 mmol) and
concentrated to
give the product (87 mg, 91%) as a tan solid: mp 148.0-158.0 °C; IR
3405 (br), 2933, 1691,
1608, 1554, 1507 cm-';'H NMR [(CD3)ZSO] 8 1.51-1.78 (m, 5H), 2.50 (m, 2H),
3.05-3.71
(m, 21H), 4.66 (m, 1H), 6.74 (s, 2H), 6.91 (br d, 1H), 7.21 (m, 2H), 7.34 (m,
2H), 8.84 (s,
20 1H), 10.75 (s, 1H); MS m/z 581 (M + H)+. Anal. (C27H3gC12N4O6S ~1.35H20) C,
H, N.
Example 16: Preparation of (~)-traps-3-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidine-1-sulfonic acid
dimethylamide
hydrochloride.
~N N ~ O~ O, N N ~ O~
HN, I O ~ / OaS-N~ ~ I /
'' ~N~
'.,~' N O_ ~ ,",~ N O_
v
HCI
/ I
25 cl cl
A solution of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (80 mg, 0.16 mmol) and Et3N
(33 pl, 0.24
mmol) in CHZC12 (2 ml) was treated with dimethylsulfamoyl chloride (21 pl,
0.20 mmol),
3o stirred at room temperature for 20 hours, and partitioned between CHZCIz
and saturated
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NaHC03. The aqueous phase was extracted with CH2C12 and the extracts were
dried and
concentrated. Purification of the residue by preparative TLC with 10:0.95:0.05
CH2C12:MeOH:NH40H gave the free base as a white solid. A solution of the free
base in
CH2C12 was treated with 1 N HCl in Et20 (0.35 ml, 0.35 mmol) and concentrated
to give
the product (93 mg, 93%) as a white solid: mp 141.0-143.0 °C; IR 3378
(br), 2937, 1691,
1607, 1555, 1508 cm-1; 1H NMR ([(CD3)2S0], D20 added, 87 °C) 8 1.53 (m,
2H), 1.86 (m,
3H), 2.58 (d, J= 6.7 Hz, 2H), 2.84 (s, 6H), 3.07-3.86 (m, 18H), 4.60 (m, 1H),
6.74 (s, 2H),
7.22 (m, 2H), 7.34 (m, 2H); MS m/z 610 (M + H)t. Anal. (C28H41C12N506S~1H20)
C, H,
N.
Example 17: Preparation of (~)-trans-3-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidine-1-carboxylic acid
dimethylamide
hydrochloride.
H H
HN N~N ~ O~ O N NuN ' ~ O~
O I / -
\ 1
I ~~~ N O~ ~ II ,/~ N O
v
HCI
/
CI CI
A solution of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (90 mg, 0.18 mmol) and Et3N
(37 ~1, 0.27
mmol) in CH2Cl2 (2 ml) at 0 °C was treated with dimethylcarbamyl
chloride (20 ~1, 0.22
mmol), allowed to warm to room temperature slowly, stirred for 75 min, and
partitioned
between CH2C12 and saturated NaHC03. The aqueous phase was extracted with
CH2C12
2o and the extracts were dried and concentrated. Purification of the residue
by preparative
TLC with 6:0.95:0.05 CH2C12:MeOH:NH40H gave the free amine as a white solid. A
solution of the free base in CH2C12 was treated with 1 N HCl in Et20 (0.2 ml,
0.2 mmol)
and concentrated to give the product (70 mg, 69%) as a yellow solid: mp 142.0-
144.5 °C;
IR 3272 (br), 2936, 1685, 1608, 1555, 1507 cm-1; ~H NMR ( [(CD3)2S0], D20
added, 87 °C)
8 1.54 (m, 2H), 1.84 (m, 3H), 2.54 (m, 2H), 2.82 (s, 6H), 3.05-3.76 (m, 18H),
4.55 (m,
1H), 6.76 (s, 2H), 7.22 (m, 2H), 7.34 (m, 2H); MS m/z 574 (M + H)+. Anal.
(C29H41C12NSO5~1.1H2O) C, H, N.
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Example 18: Preparation of (~)-traps-3-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidine-1-carboxylic acid amide
hydrochloride.
H H
NuN ~ O~ O N NuN ' ~ O~
HN~ IO ~ / H ~ ~, 'OI /
z
I"~~ N O~ ~ ,,~~ N O.
HCI v
/
CI CI
A solution of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (120 mg, 0.24 mmol) and NaOCN
(36
mg, 0.55 mmol) in CH3CN (2 ml) was treated with trifluoroacetic acid (36 ~1,
0.48 mmol).
The reaction mixture was stirred at room temperature for 20 hours and
concentrated. The
residue was partitioned between CHZC12 and saturated NaHC03, the aqueous phase
was
extracted with CHzCl2, and the extracts were dried and concentrated.
Purification of the
residue by preparative TLC with 5:0.95:0.05 CHzCIz:MeOH:NH40H gave the free
base as a
white solid. A solution of the free base in CHZCIz was treated with 1 N HCl in
EtzO (0.2
ml, 0.2 mmol) and concentrated to give the product (70 mg, 54%) as a yellow
solid: mp
158.0-162.0 °C; IR 3390 (br), 2935, 1654, 1605, 1554, 1508 cm~'; 1H NMR
([(CD3)ZSO],
DZO added, 87 °C) 8 1.53-1.86 (m, 5H), 2.59 (d, J= 6.8 Hz, 2H), 3.07-
3.86 (m, 18H), 4.60
(m, 1H), 6.74 (s, 2H), 7.22 (m, 2H), 7.34 (m, 2H); MS m/z 546 (M + H)+. Anal.
(Ca~H3~C1zN50s~l.lHzO) C, H, N
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Example 19: Preparation of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-
yl]-
4-methoxymethyl-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
HO N N ~ O~ O NuN ~ O~
O~ ~ I,,~' N O
HCI
CI CI
A mixture of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-hydroxymethyl-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea ( 160 mg, 0.30
mmol) and
silica gel ( 1.5 g) in CHzCIz (3 ml) at 0 °C was treated slowly with a
fresh 0.5 N solution of
diazomethane in Et20 (60 ml, 30 mmol), allowed to warm to room temperature,
stirred for
4 hours, and filtered. The silica gel was washed with methanol and the
filtrate was
1o concentrated. Purification of the residue by preparative TLC with 100:19:1
CHZCIz:MeOH:NH40H followed by another preparative TLC with 100:9.5:0.5
CHZCI2:MeOH:NH40H gave the free base (50 mg, 0.09 mmol) as a white foam. A
solution
of the free base in CHZC12 was treated with 1 N HCl in EtzO (0.3 ml, 0.3 mmol)
and
concentrated to give the product (48 mg, 30%) as a white solid: mp 109.0-112.0
°C; IR
15 3420 (br), 2934, 1686, 1606, 1554, 1507 cm-1;'H NMR ((CD3)ZSO] 8 1.32-2.28
(m, lOH),
2.54 (m, 2H), 2.91 (m, 2H), 3.26-3.50 (m, 8H), 3.59 (s, 3H), 3.71 (s, 6H),
4.33 (m, 1H),
6.62 (d, J= 8.3 Hz, 1H), 6.77 (s, 2H), 7.20 (m, 2H), 7.34 (m, 2H), 8.75 (s,
1H), 10.14 (br s,
1H); MS m/z 546 (M + H)+. Anal. (Cz9H4iC1aN34s~0.9H20) C, H, N.
Example 20: Preparation of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-
yl]-
20 4-methoxy-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
N N ~ O~ \ N~N~O~
HO ~ ~ O~ I0'
o / g
' N O~ ~ ',"~ N O,
HCI /
/
CI CI
A mixture of (~)-1-{(1R,2R,4S)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-hydroxy-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea (105 mg, 0.20 mmol) and
silica
25 gel ( 1.0 g) in CHZC12 (2 ml) at 0 °C was treated slowly with a
fresh 0.5 N solution of
diazomethane in EtzO (45 ml, 22.5 mmol), allowed to warm to room temperature
slowly,
stirred for 4 hours, and filtered. The silica gel was washed with methanol and
the filtrate
was concentrated. Purification of the residue by preparative TLC with 100:19:1
CHZCIz:MeOH:NH40H gave the free base (43 mg, 0.08 mmol) as a yellow solid. A
3o solution of the free base in CHZC12 was treated with 1 N HCl in EtzO (0.3
ml, 0.3 mmol)
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and concentrated to give the product (46 mg, 40%) as a tan solid: mp 112.5-
119.5 °C; IR
3390 (br), 2935, 1686, 1607, 1555, 1506 cm-1; 1H NMR [(CD3)ZSO] 8 1.46-1.98
(m, 7H),
2.22 (m, 2H), 2.54 (m, 2H), 2.90 (m, 2H), 3.24 (s, 3H), 3.42 (m, 2H), 3.58 -
3.85 (m, 11H),
4.50 (m, 1H), 6.36 (d, J= 9.1 Hz, 1H), 6.70 (s, 2H), 7.21 (m, 2H), 7.35 (m,
2H), 10.10 (s,
1H); MS m/z 532 (M + H)+. Anal. (CZgH39C1zN3O5~O.7HzO) C, H, N.
Example 21: Preparation of (~)-traps-2-{3-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidin-1-yl}-acetamide
dihydrochloride.
H H N N O
HN I N ~ N ~ ~ O\ N~ ~ I \ w
HzN~ O ~ O
."~~ N O~ ~ O N
v
2HCI
i
CI CI
1o A solution of (~)-trnns-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (90 mg, 0.18 mmol) in
anhydrous DMF
(2.5 ml) was treated successively with i-Pr2NEt (47 ~1, 0.27 mmol) and 2-
iodoactamide (40
mg, 0.22 mmol), stirred at room temperature for 24 hours, and partitioned
between
CHZCIz and saturated NaHC03. The aqueous phase was extracted with CHZC12, and
the
15 extracts were washed with H20 and brine, dried and concentrated.
Purification of the
residue by preparative TLC with 10:0.95:0.05 CHzCI2:MeOH:NH40H gave the free
amine
as a yellow solid. A solution of the free base in CHZC12 was treated with 1 N
HCl in Et20
(0.3 ml, 0.3 mmol) and concentrated to give the product (54 mg, 50%) as a tan
solid: mp
160.0-165.0 °C; IR 3414 (br), 2933, 1691, 1607, 1557, 1507 cm-1; 1H NMR
[(CD3)ZSO] 8
20 1.55-1.77 (m, 5H), 2.49 (m, 2H), 3.00-3.71 (m, 20H), 4.72 (br s, 1H), 6.76
(s, 2H), 7.01 (br
d, 1H), 7.21 (m, 2H), 7.34 (m, 2H), 7.58 (br s, 1H), 7.83 (br s, 1H), 9.12 (br
s, 1H); MS m/z
560 (M + H)+. Anal. (CzgHøpC13N5O5~1.3H2O) C, H, N.
Example 22: Preparation of (~)-traps-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-3-(4-methoxy-naphthalen-2-yl)urea.
H H
NHZ NuN \ \
a... IoI ~ . .
N HxN I \ \ N Ow
\ ~ O~ \
25 cl cl
A solution of triphosgene (47 mg, 0.16 mmol) in CHzCl2 (2 ml) was treated
dropwise
with a solution of (~)-trnns-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentylamine (140
mg, 0.48mmo1) and N,N-diisopropylethylamine ( 180 p,l, 1.0 mmol) in CHZCIa ( 1
ml) and
3o added to a solution of 4-methoxy-naphthalen-2-ylamine (83 mg, 0.48 mmol)
and
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N,N-diisopropylethylamine ( 180 pl, 1.0 mmol) in CHZCIz ( 1 ml). The reaction
was stirred
for 4 hours, washed with 1 N KHS04, saturated NaHC03, and brine, dried, and
concentrated. Purification of the residue by preparative TLC with 100:9.5:0.5
CHZCI2:MeOH:NH40H gave the product (100 mg, 43%) as a yellow solid: mp 175-190
°C;
MS m/z 492 (M + H)+.
Example 23: Preparation of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
1-(2-methanesulfonyl-ethyl)-pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea
dihydrochloride.
N N O
HN~N 0 N ~ / O\ O~N~ O I /
'~~~ N O ~ ~ ",~~ N O _
v
2HCI
/
CI CI
1o A solution of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (100 mg, 0.20 mmol) in MeOH (1
ml)
was treated with methyl vinyl sulfone ( 18 pl, 0.21 mmol). The mixture was
stirred at room
temperature overnight and concentrated. Purification of the residue by
preparative TLC
with 7:0.95:0.05 CHZCI2:MeOH:NH40H gave the free amine as a white solid. A
solution of
15 the free base in CHZCl2 was treated with 1 N HCl in EtzO (0.5 ml, 0.5 mmol)
and
concentrated to give the product ( 110 mg, 83%) as a white solid: mp 210.2-
211.8 °C; IR
3422 (br), 2930, 1686, 1607, 1556, 1507 cm-1; 1H NMR [(CD3)ZSO] 8 1.54-1.77
(m, 5H),
2.51 (m, 2H), 3.05-3.71 (m, 25H), 4.71 (br s, 1H), 6.75 (s, 2H), 6.92 (br d,
1H), 7.21 (m,
2H), 7.34 (m, 2H), 9.01 (s, 1H); MS m/z 609 (M + H)+. Anal.
(C29H43C13N406S~1.15HzO)
2o C, H, N.
Example 24: Preparation of (~)-traps-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-3-[2-(3,4,5-trimethoxyphenyl)-ethyl]urea hydrochloride.
H H
NHz NuN ~ O~
N HEN ~ 'OI I
o. ..... N 0_ q
i/
o_
2HC1
CI CI
25 A solution of triphosgene (47 mg, 0.16 mmol) in CHZC12 (2 ml) was treated
dropwise
with a solution of (~)-trnns-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentylamine (140
mg, 0.48mmo1) and N,N-diisopropylethylamine ( 180 ~tl, 1.0 mmol) in CHzCl2 ( 1
ml) and
added to a solution of 2-(3,4,5-trimethoxyphenyl)-ethylamine ( 101 mg, 0.48
mmol) and
N,N-diisopropylethylamine (180 pl, 1.0 mmol) in CHZCl2 (1 ml). The reaction
was stirred
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overnight and washed with saturated NaHC03. The aqueous phase was extracted
with
CHzCl2 and the extracts were washed with brine, dried, and concentrated.
Purification of
the residue by preparative TLC with 10:1 CHZCIZ:MeOH gave the free base (83
mg, 0.16
mmol) as a yellow oil. A solution of the free base in CHZCIz was treated with
1 N HCl in
EtzO (0.3 ml, 0.3 mmol) and concentrated to give the product (86 mg, 32%) as a
yellow
solid: mp 90.3-95 °C; MS m/z 530 (M + H)+.
Example 25: Preparation of (~)-traps-3-[4-(4-chlorobenzyl)piperidin-1-yl]-
4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidine-1-sulfonic acid amide
hydrochloride.
O N N O
HN~N O N ~ ~ O\ FiZN S N~ °
.''' N O~ ~ ° ''"' N O
HCI
CI CI
1o A solution of chlorosulfonyl isocyanate (23 pl, 0.26 mmol) in CHZC12 ( 1
ml) was
treated with t-BuOH (21 ~1, 0.22 mmol), stirred at room temperature for 1
hour, and
treated with a solution of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (110 mg, 0.22 mmol) and
pyridine (19 p,l,
0.24 mmol) in CHzCl2 ( 1 ml). The reaction was stirred at room temperature for
2 days
during which additional chlorosulfonyl isocyanate (46 ~1, 0.52 mmol) and t-
BuOH (42 E.tl,
0.44 mmol) was added, and partitioned between CHZCIZ and saturated NaHC03. The
aqueous phase was extracted with CHZC12 and the extracts were dried and
concentrated.
Purification of the residue by preparative TLC with 10:0.95:0.05
CHZCI2:MeOH:NH40H
gave 55 mg of a yellow solid.
2o A solution of the solid in 10% HCl/MeOH (20 ml) was stirred at room
temperature
overnight. The MeOH was evaporated and the residue was partitioned between
CHzCIz
and saturated NaHC03. The aqueous phase was extracted with CHZCIz and the
extracts
were dried (MgS04) and concentrated. Purification of the residue by
preparative TLC with
5:0.95:0.05 CHzCIz:MeOH:NH40H gave the free base as a yellow solid. A solution
of the
z5 free base in CHzCIz was treated with 1 N HCl in Et20 (0.1 ml, 0.1 mmol) and
concentrated
to give the product (20 mg, 48%) as a tan solid: mp 155.7-160.0 °C; IR
3404 (br), 1686,
1607, 1554, 1507 cm-1; 1H NMR [(CD3)ZSO] 8 1.48-1.77 (m, 5H), 2.54 (m, 2H),
3.00-3.83
(m, 18H), 4.60 (m, 1H), 6.73 (s, 2H), 6.85 (m, 1H), 7.11 (br s, 2H), 7.21 (m,
2H), 7.35 (m,
2H), 8.76 (s, 1H), 10.41 (s, 1H); MS m/z 582 (M + H)+. Anal.
(CZ6H3~C12NSO6S~l.lHzO)
3o C, H, N.
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Example 26: Preparation of (~)-traps-N {2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclobutyl}-4-methanesulfonyl-benzamide hydrochloride.
NHZ O
/ S,
N ; N \ ~ O
O
+ HO \ I ~ O
I ~'~~N HCI
O
CI
\
CI
Following General Procedure F, a solution of (~)-traps-2-[4-(4-chlorobenzyl)-
piperidin-1-y1J-cyclobutylamine (130 mg, 80% pure, 0.38 mmol) and
4-methanesulfonyl-benzoic acid ( 115 mg, 0.575 mmol) in CHZC12 ( 1 ml) at 0
°C was
treated successively with 1-hydroxybenzotriazole hydrate (HOBt) ( 13 mg, 0.10
mmol) and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (DEC) (138 mg,
0.719
mmol), allowed to warm to room temperature slowly, stirred for 3 days, and
partitioned
1o between CHZC12 and saturated NaHC03. The aqueous phase was extracted with
CHZC12
and the extracts were dried and concentrated. Purification of the residue by
preparative
TLC with 90:9.5:0.5 CHZCIz:MeOH:NH40H gave the free base ( 118 mg, 0.26 mmol)
as a
white solid. A solution of the free base (93 mg, 0.20 mmol) in CHzCl2 was
treated with 1 N
HCl in Et20 (0.5 ml, 0.5 mmol) and concentrated to give the product (90 mg,
21% from
(~)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutanone O-methyl-oxime) as a
tan
powder: mp 173.2-184.1 °C; IR 1657 cm~l; 1H NMR [(CD3)ZSO] b 1.45-2.20
(m, 9H), 2.52
(m, 2H), 2.65-2.80 (m, 2H), 3.20-3.45 (m, 5H), 3.68-3.79 (m, 1H), 4.79-4.92
(m, 1H), 7.21
(m, 2H), 7.34 (m, 2H), 8.00-8.19 (m, 4H), 9.38 (d, J= 8.3 Hz, 1H), 11.04-11.30
(m, 1H);
'3C NMR [(CD3)ZSOJ 8 17.86, 21.23, 28.00, 34.70, 40.50, 43.21, 46.54,
48.69,49.15, 64.74,
126.90, 128.07, 128.34, 130.60, 130.78, 138.20, 138.35, 143.08, 164.24; MS m/z
461 (M +
H)+. Anal. (C24H3oC1zN203S~0.4 CHZCl2) C, H, N.
Example 27: Preparation of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
1.1-dioxo-
tetrahydro-1~,6-thiophen-3-yl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride
H H
O NHx '. ~N N 0~
~ O ~ O S'~T 0 I /
0SV'~.N \N \ Ow .,~~~N O~ R
O HCI
1 /
\ O
CI CI
Following General Procedure C, (~)-traps-4-[4-(4-chlorobenzyl)piperidin-1-y1J-
l.l-dioxo-tetrahydro-1~,6-thiophen-3-ylamine (60 mg, 0.18 mmol) and
5-isocyanato-1,2,3-trimethoxybenzene (44 mg, 0.21 mmol) were coupled in CHZC12
(1.5
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ml) at 0 °C for 1 hour. Purification of the crude product by
preparative TLC with
90:9.5:0.5 CHzCIz:MeOH:NH40H and a subsequent preparative TLC with EtOAc gave
the
free base (55 mg, 0.10 mmol) as yellow solid. A solution of the free base in
CHZCIz was
treated with 1 N HCl in Et20 (0.3 ml, 0.3 mmol) and concentrated to give the
product (59
mg, 57%) as a yellow solid: mp 162.0-166.0 °C; IR 3377 (br), 2935,
1690, 1606, 1556, 1506
cm-'; 1H NMR [(CD3)ZSO] 8 1.48 (m, 2H), 1.78 (m, 3H), 2.56 (d, J= 6.5 Hz, 2H),
2.89 (m,
2H), 3.21-3.60 (m, 6H), 3.64 (s, 3H), 3.74 (s, 6H), 3.99 (m, 1H), 4.78 (m,
1H), 6.74 (s, 2H),
7.19 (m, 2H), 7.31 (m, 2H); MS m/z 552 (M + H)+. Anal. (CZ~H3~C12N30~0.4H20)
C, H,
N.
1o Step A' Preparation of (~)-traps-~4-f 4-(4-chlorobenz~piperidin-1-yl]-1.1-
dioxo-
tetrahydro-176-thiophen-3-yl~-carbamic acid ethyl ester
\ ~ cl
EtO2CHN~ I N
CC ll\\ CI ~ EtO2CHN N
S. +
O O H S.
0 O
A solution of (4-chloro-1.1-dioxo-tetrahydro-176-thiophen-3-yl)-carbamic acid
ethyl ester (500 mg, 2.07 mmol) (Ohba, K.; Mori, K.; Kitahara, T.; Kitamura,
S.; Matsui, M.
Agr. Biol. Chem. 1974, 38, 1679) and 4-(4-chlorobenzyl)-piperidine (599 mg,
2.85 mg) in
EtOH (5 ml) was refluxed for 22 hours, allowed to cool to room temperature,
and
concentrated. Chromatography of the residue on silica gel with 95:4.75:0.25-
90:9.5:0.5
CHZCI2:MeOH:NH40H and a subsequent preparative TLC with 10:1 CHZCIz:MeOH gave
the product (171 mg, 20%) as a yellow solid: 1H NMR S 1.16-1.33 (m, 5H), 1.45-
1.68 (m,
3H), 2.03 (m, 1H), 2.26 (m, 1H), 2.50 (d, J= 7.0 Hz, 2H), 2.80 (m, 2H), 2.92-
3.08 (m,
2H), 3.19-3.36 (m, 2H), 3.78 (m, 1H), 4.14 (q, J= 7.1 Hz, 2H), 4.25 (m, 1H),
5.24 (br, 1H),
7.04 (m, 2H), 7.21 (m, 2H); MS m/z 415.2 (M + H)+.
Step B' Preparation of (~)-trnns-4-[4-(4-chlorobenz~piperidin-1-yl]-1.1-dioxo-
tetrahydro-1~,6-thio~hen-3-ylamine
\ ~ cl \ ~ cl
H=N N
EtO2CHN_ N
~~,S.
Z5 O ~O O O
A solution of (~)-trnns-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-1.1-dioxo
tetrahydro-176-thiophen-3-yl}-carbamic acid ethyl ester (170 mg, 0.41 mmol) in
48%
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aqueous HBr (3 ml) was refluxed for 16 hours, allowed to cool to room
temperature, and
poured onto a mixture of ice and granular Na2C03. The reaction mixture was
completely
neutralized and extracted with CHZCl2 and the extracts were washed with brine,
dried and
concentrated. Purification of the residue by preparative TLC with 100:9.5:0.5
CHZCI2:MeOH:NH40H gave the product (60 mg, 43%) as a yellow solid: 1H NMR 8
1.26
(m, 2H), 1.49 (m, 1H), 1.66 (m, 4H), 2.00 (m, 1H), 2.29 (m, 1H), 2.50 (d, J=
7.0 Hz, 2H),
2.77-2.91 (m, 3H), 3.00-3.22 (m, 3H), 3.44 (m, 1H), 3.65 (m, 1H), 7.05 (m,
2H), 7.26 (m,
2H); MS m/z 343.1 (M + H)t.
Example 28: Preparation of (~)-traps-3-{3-[4-(4-chlorobenzyl)piperidin-1-yl]-
l0 4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidin-1-yl}-3-oxo-propinoic
acid.
H H N N O
HN~N O N ~ / O\ O~N~ O I
'' ''' N HO ,,~~' N
O
/
CI CI
A solution of (~)-traps-1-{4-[4-(4-chlorobenzyl)piperidin-1-yl]-
pyrrolidin-3-yl}-3-(3,4,5-trimethoxyphenyl)urea (82 mg, 0.16 mmol) in CHZC12
(3 ml) at 0
°C was treated successively with Et3N (27 pl, 0.20 mmol) and methyl
malonyl chloride ( 19
15 ~1, 0.18 mmol) and allowed to warm to room temperature slowly. The reaction
was stirred
for 19 hours, during which additional Et3N (27 p,l, 0.20 mmol) and methyl
malonyl
chloride ( 19 ~1, 0.18 mmol) was added, and partitioned between CHZC12 and
saturated
NaHC03. The aqueous phase was extracted with CHZC12 and the extracts were
dried and
concentrated to give 87 mg of ester as a yellow solid which was used
directlylin the next
2o step: 1H NMR b 1.08-1.61 (m, 5H), 2.03-2.48 (m, 4H), 2.74-3.93 (m, 21H),
4.50 (m, 1H),
5.82 (m, 1H), 6.70 (s, 2H), 7.02 (m, 2H), 7.25 (m, 2H), 7.49 (br s, 1H); MS
m/z 603.2 (M +
H )+.
A solution of the ester in 5% KOH/MeOH (6 ml) was stirred at room temperature
overnight. The MeOH was evaporated, the residue was treated carefully with 1 N
HCl
25 until the pH ~ 7 and extracted with CHZCIz, and extracts were dried and
concentrated.
Purification of the residue by preparative TLC with 95:5 MeOH:NH40H and a
subsequent
preparative TLC with 4:0.95:0.05 CHzCI2:MeOH:NH40H gave the product (40 mg,
42%)
as a yellow solid: mp 184.0-184.9 °C; IR 3377, 2924, 1607, 1554, 1506
cm~l; 1H NMR
[(CD3)ZSO] 8 1.15-1.49 (m, 5H), 2.15 (m, 2H), 2.50 (m, 2H), 3.00-3.71 (m,
18H), 4.62 (m,
30 1H), 6.80 (s, 2H), 7.13 (m, 3H), 7.25 (m, 2H), 8.87 (m, 1H); MS m/z 589 (M
+ H)+.
Example 29: Preparation of (~)-traps-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclobutyl}-3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
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H H
NH2 NuN \ O~
Oy
N ~N \ O\ I,~~~~N O
+ I~
~O
I 0~ I
HCI \
CI CI
A solution of (~)-traps-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutylamine
(130
mg, 80% pure, 0.38 mmol) in CHZCIz (1 ml) at 0 °C was treated with
5-isocyanato-1,2,3-trimethoxybenzene (110 mg, 0.53 mmol). The reaction was
stirred at 0
°C for 2 hours, during which additional 5-isocyanato-1,2,3-
trimethoxybenzene (25 mg,
0.12 mmol) was added, and partitioned between CHZC12 and saturated NaHC03. The
aqueous phase was extracted with CHzCl2 and the extracts were dried and
concentrated.
Chromatography of the residue with l:l hexanes:EtOAc to 100% EtOAc followed by
95:4.75:0.25-50:47.5:2.5 CHZCI2:MeOH:NH40H gave the free base ( 138 mg, 0.28
mmol) as
a glassy solid. A solution of the free base (74 mg, 0.15 mmol) in CHZC12 was
treated with 1
N HCl in Et20 (0.5 ml, 0.5 mmol) and concentrated to give the product (76 mg,
25% from
(~)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutanone O-methyl-oxime) as a
yellow
powder: mp 127.4-128.2 °C; IR 1691, 1607, 1555, 1507 cm-1; 1H NMR
[(CD3)ZSO, 77 °C] 8
1.45-1.85 (m, 6H), 1.93-2.20 (m, 3H), 2.54 (d, J= 6.7 Hz, 2H), 2.65-2.80 (m,
2H), 3.07 (br
s, 0.5H), 3.28 (m, 1H), 3.47-3.62 (m, 1.5H), 3.62 (s, 3H), 3.72 (s, 6H), 4.45-
4.58 (m, 1H),
6.75 (m, 2H), 6.90-7.03 (m, 1H), 7.19 (m, 2H), 7.31 (m, 2H), 8.67 (br s,
0.8H), 8.76 (br s,
0.2H), 10.70-11.00 (m, 1H); MS m/z 488 (M + H)+. Anal. (CZ6H34C12N3O4~O.65HZO)
C,
H, N.
zo Example 30: Preparation of (~)-cis-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl~-
cyclobutyl}-4-methanesulfonyl-benzamide hydrochloride.
NHZ O
O ~ S' O
~N : H~ I
i O N II
+ HO \ I ~O
I 0 N HCI
CI
\ I
CI
Following General Procedure F, (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclobutylamine ( 100 mg, 90% pure, 0.33 mmol) and 4-methanesulfonyl-benzoic
acid
(88 mg, 0.44 mmol) were coupled in CHZCIz (3 ml) using HOBt (25 mg, 0.18 mmol)
and
DEC ( 106 mg, 0.55 mmol) at 0 °C for 3.5 hours. Purification of the
crude product by
preparative TLC with 10:0.95:0.05 CHzCI2:MeOH:NH40H gave the free base ( 102
mg, 0.22
mmol) as a colorless oil. A solution of the free base (82 mg, 0.18 mmol) in
CHzCl2 was
treated with 1 N HCl in Et20 (0.5 ml, 0.5 mmol) and concentrated to give the
product (83
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mg, 64%) as a white solid: mp 130.0-132.5 °C; IR 3438, 2924, 1662, 1541
cm-'; MS m/z 461
(M + H)+. Anal. (C24H30C12N203S~0.35HZO) C, H, N.
Example 31: Preparation of (~)-cis-1-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclobutyl}-
3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
H H
NHZ NuN \ O~
Oy
N ~N \ O\ N O
~O
O
\ \
HCI
CI CI
Following General Procedure D, (~)-cis-2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclobutylamine (40 mg, 0.15 mmol) and 5-isocyanato-1,2,3-trimethoxybenzene
(37 mg,
0.18 mmol) were coupled in CHZC12 ( 1 ml) at 0 °C for 1 hour.
Purification of the crude
to product by preparative TLC with 100:9.5:0.5 CHZCIz:MeOH:NH40H and a
subsequent
preparative TLC with EtOAc gave the free base as a yellow solid. A solution of
the free base
in CHzCl2 was treated with 1 N HCl in Et20 (0.1 ml, 0.1 mmol) and concentrated
to give
the product (26 mg, 34%) as a tan solid: mp 123.7-127.9 °C; IR 3423,
2925, 1690, 1607,
1556, 1507. Anal. (CZ6H35C12N304~0.7Hz0) C, H, N.
Example 32: The following compound was prepared using General Procedure C,
with the
appropriate amine and isocyanate.
(~)-traps-1-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3,4,5-trimethoxyphenyl)urea.
Example 33: The following compounds were prepared using General Procedure E,
with
the appropriate amine and carboxylic acid.
(~)-trnns-N-{2- [4-(4-Chlorobenzyl)piperidin-1-yl] cyclohexyl}-
2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]acetamide; and
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]cyclopentyl}-
2- [ 5-( 3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl] acetamide.
Example 34: The following compounds were prepared following General Procedure
F,
using the appropriate amine and carboxylic acid.
(~)-cis-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide hydrochloride;
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(~)-cis-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-
cyclohexyl}-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide
hydrochloride; and
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-
cyclobutyl}-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide
hydrochloride.
Example 35: The following compounds were prepared following General Procedure
G,
using the appropriate amine and sulfonyl chloride.
to (~)-traps-4-Chloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzenesulfonamide;
(~)-trnns-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-fluoro-benzenesulfonamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-ethyl-benzenesulfonamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cydopentyl }-
3-methoxy-benzenesulfonamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2,4-dilluoro-benzenesulfonamide;
(~)-trnns-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-trifluoromethyl-benzenesulfonamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-methyl-benzenesulfonamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl }-
4-fluoro-benzenesulfonamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl }-
2-fluoro-benzenesulfonamide;
(~)-trnns-2-Chloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzenesulfonamide;
(~)-traps-4-Acetyl-N-{2-(4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzenesulfonamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cydopentyl } -
4-nitro-benzenesulfonamide;
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(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-nitro-benzenesulfonamide;
(~)-traps-3-Chloro-N-{ 2- [4-(4-chlorobenzyl)piperidin-1-yl] -cyclopentyl }-
2-methyl-benzenesulfonamide;
(~)-traps-Naphthalene-1-sulfonic acid {2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-amide;
(~)-traps-2-Chloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-fluoro-benzenesulfonamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
l0 3,4-dimethoxy-benzenesulfonamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2,5-dimethoxy-benzenesulfonamide;
(~)-traps-2,3-Dichloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cydopentyl}-
benzenesulfonamide;
~5 (~)-traps-2,4-Dichloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzenesulfonamide;
(~)-traps-3,4-Dichloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzenesulfonamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
2o 4-methanesulfonyl-benzenesulfonamide;
(~)-traps-4-Bromo-N-{ 2- [4-(4-chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
benzenesulfonamide;
(~)-traps-4-Chloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-nitro-benzenesulfonamide;
25 (~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-nitro-benzenesulfonamide; and
(~)-trnns-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cydopentyl}-
2-nitro-4-trifluoromethyl-benzenesulfonamide.
3o Example 36: The following compounds were prepared following General
Procedure H,
using the appropriate amine and acid chloride.
(~)-traps-4-Chloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzamide;
(~)-trnns-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-benzamide;
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(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-fluoro-benzamide;
(~)-traps-2-Chloro-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzamide;
(~)-traps-3-Chloro-N-{ 2- [4-(4-chlorobenzyl)piperidin-1-yl J -cyclopentyl}-
benzamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
2-methyl-benzamide;
(~)-traps-N-{ 2- [4- (4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-methyl-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-methyl-benzamide;
(~)-traps-N-{ 2- [4- (4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-methoxy-benzamide;
1s (~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-trifluoromethyl-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-methoxy-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-fluoro-benzamide;
(~)-traps-3-Bromo-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
benzamide;
(~)-traps-2,4-Dichloro-N-{ 2- [4-(4-chlorobenzyl)piperidin-1-yl] -cyclopentyl
}-
benzamide;
zs (~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-trifluoromethyl-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-trifluoromethyl-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3,5-bis-trifluoromethyl-benzamide;
(~)-traps-4-tent-Butyl-N-{ 2- [4- (4-chlorobenzyl)piperidin-1-yl] -cyclopentyl
}-
benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-ethoxy-benzamide;
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(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-cyano-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-cyano-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-methoxy-benzamide;
(~)-traps-N-{ 2- [ 4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl } -
3-nitro-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-nitro-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3,5-dimethoxy-benzamide;
(~)-traps-3,4-Dichloro-N-{ 2- [4-(4-chlorobenzyl)piperidin-1-yl] -cyclopentyl}
-
benzamide;
(~)-traps-4-Bromo-N-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cydopentyl}-
benzamide; and
(~)-traps-N-{ 2- [ 4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
4-iodo-benzamide.
2o Example 37: The following compounds were prepared following General
Procedure I,
using the appropriate amine and carboxylic acid.
(~)-trnns-N-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
4-isopropyl-benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cydopentyl}-isophthalamic
acid methyl ester;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl }-
4-methanesulfonyl-benzamide;
(~)-traps-3-Acetyl-N-{2-[4-(4-chlorobenzyl)piperidin-I-yl]-cyclopentyl}-
benzamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-o-tolyl-acetamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-m-tolyl-acetamide;
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(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-p-tolyl-acetamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl} -
2-(4-fluoro-phenyl)-acetamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
2-( 3-methoxy-phenyl)-acetamide;
(~)-traps-N-{ 2- (4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl }-
2-(4-methoxy-phenyl)-acetamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-(3-chloro-phenyl)-acetamide;
(~)-traps-N-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl } -
2-(4-chloro-phenyl)-acetamide;
(~)-traps-5-Methyl-1H-indole-2-carboxylic acid {2-[4-(4-chlorobenzyl)piperidin-
1-yl]-cyclopentyl}-amide;
(~)-traps-5-Fluoro-1H-indole-2-carboxylic acid {2-[4-(4-chlorobenzyl)piperidin-
1-yl]-cyclopentyl}-amide;
(~)-traps-2-(3-Bromo-phenyl)-N-{2- [4-(4-chlorobenzyl)piperidin-1-yl] -
cyclopentyl}-acetamide;
(~)-traps-N-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
2-(3,4,5-trimethoxyphenyl)-acetamide;
(~)-traps-1H-Indole-2-carboxylic acid {2-[4-(4-chlorobenzyl)piperic~in-1-yl]-
cyclopentyl}-amide;
(~)-traps-5-Methoxy-1H-indole-2-carboxylic acid {2-[4-(4-chlorobenzyl)-
piperidin-1-yl]-cyclopentyl}-amide; and
(~)-traps-5-Chloro-1H-indole-2-carboxylic acid {2-[4-(4-chlorobenzyl)piperidin-
1-yl] -cyclopentyl}-amide.
Example 38: The following compounds were prepared following General Procedure
J,
using the appropriate amine and isocyanate.
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-chloro-phenyl) urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-fluoro-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-o-tolyl-urea;
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(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-chloro-phenyl)urea;
(~)-trnns-1-{ 2- (4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-(3-chloro-phenyl)urea;
(~)-trnns-1-(3-Bromo-phenyl)-3-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-urea;
(~)-trnns-1-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-p-tolyl-urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-m-tolyl-urea;
(~)-trnns-1-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-(4-methoxy--
1o phenyl)urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3-methoxy-phenyl)urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-methoxy-phenyl)urea;
15 (~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-cydohexyl-
urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-ylJ-cyclopentyl}-
3-(3-trifluoromethyl-phenyl)urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-trifluoromethyl-phenyl)urea;
20 (~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-ethoxy-phenyl)urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-isopropyl-phenyl)urea;
(~)-trnns-1-{ 2- ( 4-( 4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
25 3-(4-cyano-phenyl)urea;
(~)-trnns-1-(3-Acetyl-phenyl)-3-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-urea;
(~)-trnns-1-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-( 3-vitro-phenyl) urea;
30 (~)-trnns-1-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-vitro-phenyl)urea;
(~)-trnns-2-( 3- { 2- [4-(4-Chlorobenzyl) piperidin-1-yl] -cyclopentyl}-
ureido)-benzoic acid methyl ester;
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(~)-traps-1-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-(3,5-dimethoxy-phenyl)urea;
(~)-traps-1-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-(2,4-dichloro-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3,5-dichloro-phenyl)urea;
(~)-traps-1- { 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-(3,4-dichloro-phenyl)urea;
(~)-traps-1-(4-Bromo-phenyl)-3-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
l0 cyclopentyl}-urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-fluoro-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3-fluoro-phenyl)urea;
15 (~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2,4-difluoro-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-(2,3-dichloro-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
20 3-(4-ethyl-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-naphthalen-1-yl-urea;
(~)-traps-1-(3,5-Bis-trifluoromethyl-phenyl)-3-{2-[4-(4-chlorobenzyl)piperidin-
1-yl]-cyclopentyl}-urea;
25 (~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-nitro-phenyl)urea; and
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-iodo-phenyl) urea.
30 Example 39: The following compounds were prepared following General
Procedure K,
using the appropriate amine and isocyanate.
(~)-traps-1-(4-Acetyl-phenyl)-3-{2- [4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-urea;
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(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-phenyl-urea;
(~)-traps-1-Benzyl-3-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclopentyl}-urea;
(~)-traps-1-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-(3-chloro-2-methyl-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-phenethyl-
urea;
(~)-traps-1- { 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-3-phenethyl-
urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2,5-dimethyl-phenyl)urea;
(~)-traps-1-{ ( 1R,2R)-2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cydopentyl}-
3-((S)-1-phenyl-ethyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3,4-dimethoxy-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-trifluoromethoxy-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-trifluoromethoxy-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-trifluoromethyl-phenyl)urea;
(~)-traps-1-(4-tert-Butyl-phenyl)-3-{2-[4-(4-chlorobenzyl)piperidin-1-yl]-
cyclopentyl}-urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-thiophen-2-yl-ethyl)urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-methyl-benzyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-chloro-3-nitro-phenyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-fluoro-benzyl)urea;
(~)-traps-1- { 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl } -
3-(2-methyl-benzyl)urea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3-methyl-benzyl)urea;
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(~)-trans-1-( 2-Chlorobenzyl)-3-{2- [4-(4-chlorobenzyl)piperidin-1-ylJ -
cyclopentyl}-urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-methoxy-benzyl)urea; and
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3,4-dichlorobenzyl)urea.
Example 40: The following compounds were prepared following General Procedure
L,
using the appropriate aniline and Phoxime resin.
(~)-trc~ns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3-ethoxy-phenyl)urea;
(~)-trans-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-naphthalen-2-yl-urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-isoquinolin-3-yl-urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2-methylquinolin-6-yl)urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3-methylamino-phenyl)urea;
(~)-trnns-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-quinolin-3-yl-urea;
(~)-trnns-1-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl}-
3-quinolin-2-yl-urea;
(~)-trans-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(5-hydroxy-naphthalen-2-yl)urea;
(~)-trans-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(8-hydroxy-quinolin-2-yl)urea; and
(~)-traps-1-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(5,7-dimethyl-( 1,8]naphthyridin-2-yl)urea.
Example 41: The following compounds were prepared following General Procedure
M,
using the appropriate aniline.
(~)-trnns-1-{2-(4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-quinolin-6-yl-urea;
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(~)-traps-N-[3-(3-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
ureido)-phenyl] -acetamide;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(2,3,4-trimethoxyphenyl)urea; and
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3-methanesulfonyl-phenyl)urea.
Example 42: The following compounds were prepared following General Procedure
N,
using the appropriate thioisocyanate.
Io (~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-o-tolyl-
thiourea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cydopentyl}-
3-m-tolyl-thiourea;
1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(3-chloro-phenyl)-thiourea;
15 (~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-3-p-tolyl-
thiourea;
(~)-traps-1-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-
3-(4-fluoro-phenyl)-thiourea; and
(~)-traps-1-{ 2- [4-(4-Chlorobenzyl)piperidin-1-yl] -cyclopentyl }-
3-(4-methoxy-phenyl)-thiourea.
Example 43: The following compounds were prepared following General Procedure
O,
using the appropriate succinimide.
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
4-fluoro-benzyl ester;
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
3-chlorobenzyl ester;
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
4-chlorobenzyl ester;
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
2-chlorobenzyl ester;
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
3-nitro-benzyl ester;
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(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
3-trifluoromethyl-benzyl ester;
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
3,4-dichlorobenzyl ester;
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
3,5-dichlorobenzyl ester;
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid
benzyl
ester; and
(~)-traps-{2-[4-(4-Chlorobenzyl)piperidin-1-yl]-cyclopentyl}-carbamic acid 4-
to nitro-benzyl ester.
Example 44: Formulation Examples
The following are representative pharmaceutical Formulations containing a
compound of Formula (I).
Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored
tablets.
Quantity per
Ingredient tablet, mg
compound of this invention 400
2o cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5
Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell
gelatin
capsule.
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Quantity per
Ingredient capsule, mg
compound of this invention 200
lactose, spray-dried 148
magnesium stearate 2
Suspension Formulation
The following ingredients are mixed
to form a suspension for oral
administration.
Ingredient Amount
compound of this invention 1.0 g
1o fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
propyl paraben 0.05 g
granulated sugar 25.5 g
sorbit (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 ml
colorings 0.5 mg
distilled water q.s. to 100 ml
Injectable Formulation
The following ingredients are mixed to form an injectable Formulation.
Ingredient Amount
compound of this invention 0.2 g
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sodium acetate buffer solution, 0.4M 2.0 ml
HCl ( 1N) or NaOH ( 1N) q.s. to suitable pH
water (distilled, sterile) q.s. to 20 ml
Liposomal Formulation
The following ingredients are mixed to form a liposomal Formulation.
Ingredient Amount
compound of this invention 10 mg
L-.alpha.-phosphatidylcholine 150 mg
tert-butanol 4 ml
1o Freeze dry the sample and lyophilize overnight. Reconstitute the sample
with 1 ml 0.9%
saline solution. Liposome size can be reduced by sonication.
Example 45: CCR-3 Receptor Binding Assay--In Vitro
The CCR-3 antagonistic activity of the compounds of the invention was
determined
by their ability to inhibit the binding of'z5I eotaxin to CCR-3 L1.2
transfectant cells (see
Ponath, P. D. et al., J. Exp. Med., Vol. 183, 2437-2448, (1996)).
The assay was performed in Costar 96-well polypropylene round bottom plates.
Test
compounds were dissolved in DMSO and then diluted with binding buffer (50 mM
HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.5% bovine serum albumin (BSA), 0.02%
sodium azide, pH 7.24) such that the final DMSO concentration was 2%. 25 l,~l
of the test
solution or only buffer with DMSO (control samples) was added to each well,
followed by
the addition of 25 ~tl of'25I-eotaxin ( 100 pmol) (NEX314, New England
Nuclear, Boston,
Mass.) and 1.5 x 105 of the CCR-3 L1.2 transfected cells in 25 yl binding
buffer. The final
reaction volume was 75 ~tl.
After incubating the reaction mixture for 1 hour at room temperature, the
reaction
was terminated by filtering the reaction mixture through polyethylenimine
treated Packard
Unifilter GF/C filter plate (Packard, Chicago, Ill.). The filters were washed
four times with
ice cold wash buffer containing 10 mm HEPES and 0.5M sodium chloride (pH 7.2)
and
dried at 65°C. for approximately 10 minutes. 25 pl/well of Microscint-
20~ scintillation
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fluid (Packard) was added and the radioactivity retained on the filters was
determined by
using the Packard TopCount~.
Compounds of this invention were active in this assay.
Compound Number from Table IC50 (~M)
1
1 0.5574
2 0.0185
3 1.1438
4 0.8644
2.6906
6 1.8558
7 1.4841
8 6.0949
9 5.1191
0.5122
5 Example 46: Inhibition of Eotaxin Mediated Chemotaxis of CCR-3 L1.2
Transfectant
Cells--In Vitro Assay
The CCR-3 antagonistic activity of the compounds of this invention can be
determined by measuring the inhibition of eotaxin mediated chemotaxis of the
CCR-3 L1.2
transfectant cells, using a slight modification of the method described in
Ponath, P. D. et
1o al., J. Clin. Invest. 97: 604-612 (1996). The assay is performed in a 24-
well chemotaxis
plate (Costar Corp., Cambridge, Mass.). CCR-3 L1.2 transfectant cells are
grown in culture
medium containing RPMI 1640, 10% Hyclone~ fetal calf serum, 55 mM 2-
mercaptoethanol and Geneticin 418 (0.8 mg/ml). 18-24 hours before the assay,
the
transfected cells are treated with n-butyric acid at a final concentration of
5 mM/1x106
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cells/ml, isolated and resuspended at 1x10' cells/ml in assay medium
containing equal parts
of RPMI 1640 and Medium 199 (M 199) with 0.5% bovine serum albumin.
Human eotaxin suspended in phosphate buffered saline at 1 mg/ml is added to
bottom chamber in a final concentration of 100 nm. Transwell culture inserts
(Costar
Corp., Cambridge, Mass.) having 3 micron pore size are inserted into each well
and L1.2
cells ( 1x106) are added to the top chamber in a final volume of 100 p,l. Test
compounds in
DMSO are added both to the top and bottom chambers such that the final DMSO
volume
is 0.5%. The assay is performed against two sets of controls. The positive
control contained
cells with no test compound in the top chamber and only eotaxin in the lower
chamber.
1o The negative control contains cells with no test compound in the top
chamber and neither
eotaxin nor test compound in lower chamber. The plate is incubated at 37
°C. After 4
hours, the inserts are removed from the chambers and the cells that have
migrated to the
bottom chamber are counted by pipetting out 500 ~1 of the cell suspension from
the lower
chamber to 1.2 ml Cluster tubes (Costar) and counting them on a FACS for 30
seconds.
Example 47: Inhibition of Eotaxin Mediated Chemotaxis of Human Eosinophils--In
Vitro Assay
The ability of compounds of the invention to inhibit eotaxin mediated
chemotaxis of
human eosinophils can be assessed using a slight modification of procedure
described in
Carr, M. W. et al., Proc. Natl. Acad. Sci. USA, 91: 3652-3656 ( 1994).
Experiments are
2o performed using 24 well chemotaxis plates (Costar Corp., Cambridge, Mass.).
Eosinophils
are isolated from blood using the procedure described in PCT Application,
Publication No.
WO 96/22371. The endothelial cells used are the endothelial cell line ECV 304
obtained
from European Collection of Animal Cell Cultures (Porton Down, Salisbury,
U.K.).
Endothelial cells are cultured on 6.5 mm diameter Biocoat® Transwell
tissue culture
inserts (Costar Corp., Cambridge, Mass.) with a 3.0 ~M pore size. Culture
media for ECV
304 cells consists of M199, 10% Fetal Calf Serum, L-glutamine and antibiotics.
Assay
media consists of equal parts RPMI 1640 and M199, with 0.5% BSA. 24 hours
before the
assay 2x105 ECV 304 cells are plated on each insert of the 24-well chemotaxis
plate and
incubated at 37 °C. 20 nM of eotaxin diluted in assay medium is added
to the bottom
3o chamber. The final volume in bottom chamber is 600 ~1. The endothelial
coated tissue
culture inserts are inserted into each well. 106 eosinophil cells suspended in
100 ~l assay
buffer are added to the top chamber. Test compounds dissolved in DMSO are
added to
both top and bottom chambers such that the final DMSO volume in each well was
0.5%. T
he assay is performed against two sets of controls. The positive control
contains cells in the
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top chamber and eotaxin in the lower chamber. The negative control contains
cells in the
top chamber and only assay buffer in the lower chamber. The plates are
incubated at
37 °C. in 5% COz /95% air for 1-1.5 hours.
The cells that migrate to the bottom chamber are counted using flow cytometry.
500
yl of the cell suspension from the lower chamber are placed in a tube, and
relative cell
counts are obtained by acquiring events for a set time period of 30 seconds.
Example 48: Inhibition of Eosinophil Influx Into the Lungs of Ovalbumin
Sensitized
Balb/c Mice by CCR-3 Antagonist--In Vivo Assay
The ability of the compounds of the invention to inhibit leukocyte
infiltration into
to the lungs can be determined by measuring the inhibition of eosinophil
accumulation into
the bronchioalveolar lavage (BAL) fluid of Ovalbumin (OA)-sensitized balb/c
mice after
antigen challenge by aerosol. Briefly, male balb/c mice weighing 20-25g are
sensitized with
OA ( 10 ~g in 0.2 ml aluminum hydroxide solution) intraperitoneally on days 1
and 14.
After a week, the mice are divided into ten groups. Test compound or only
vehicle
(control group) or anti-eotaxin antibody (positive control group) is
administered either
intraperitoneally, subcutaneously or orally. After 1 hour, the mice are placed
in a Plexiglass
box and exposed to OA aerosol generated by a PARISTAR.TM. nebulizer (PARI,
Richmond, Va.) for 20 minutes. Mice which have not been sensitized or
challenged are
included as a negative control. After 24 or 72 hours, the mice are
anesthetized (urethane,
approx. 1 g/kg, i.p.), a tracheal cannula (PE 60 tubing) is inserted and the
lungs are lavaged
four times with 0.3 ml PBS. The BAL fluid is transferred into plastic tubes
and kept on ice.
Total leukocytes in a 20 ~1 aliquot of the BAL fluid is determined by Coulter
Counter.TM.
(Coulter, Miami, Fla.). Differential leukocyte counts are made on Cytospin.TM.
preparations which have been stained with a modified Wright's stain
(DiffQuick.TM.) by
light microscopy using standard morphological criteria.
The foregoing invention has been described in some detail by way of
illustration and
example, for purposes of clarity and understanding. It will be obvious to one
of skill in the
art that changes and modifications may be practiced within the scope of the
appended
claims. Therefore, it is to be understood that the above description is
intended to be
3o illustrative and not restrictive. The scope of the invention should,
therefore, be determined
not with reference to the above description, but should instead be determined
with
reference to the following appended claims, along with the full scope of
equivalents to
which such claims are entitled.
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All patents, patent applications and publications cited in this application
are hereby
incorporated by reference in their entirety for all purposes to the same
extent as if each
individual patent, patent application or publication were so individually
denoted.
